U.S. patent application number 13/944447 was filed with the patent office on 2013-11-14 for hcv protease inhibitors and uses thereof.
The applicant listed for this patent is AbbVie Inc.. Invention is credited to David D. Anderson, Todd D. Bosse, Hui-Ju Chen, Curt S. Cooper, Brian E. Green, Larry L. Klein, Allan C. Krueger, Daniel P. Larson, Dachun Liu, Keith F. McDaniel, Christopher E. Motter, John K. Pratt, Todd W. Rockway, Teresa A. Rosenberg, Jason P. Shanley, Ming C. Yeung.
Application Number | 20130303547 13/944447 |
Document ID | / |
Family ID | 39273111 |
Filed Date | 2013-11-14 |
United States Patent
Application |
20130303547 |
Kind Code |
A1 |
Green; Brian E. ; et
al. |
November 14, 2013 |
HCV Protease Inhibitors and Uses Thereof
Abstract
This invention relates to: (a) compounds of formula I and salts
thereof that, inter alia, are useful as hepatitis C virus (HCV)
inhibitors; (b) intermediates useful for the preparation of such
compounds and salts; (c) pharmaceutical compositions comprising
such compounds and salts; and (d) methods of use of such compounds,
salts, and compositions.
Inventors: |
Green; Brian E.; (Wonder
Lake, IL) ; Anderson; David D.; (Groton, CT) ;
Bosse; Todd D.; (Chicago, IL) ; Cooper; Curt S.;
(Vernon Hills, IL) ; Klein; Larry L.; (Lake
Forest, IL) ; Krueger; Allan C.; (Gurnee, IL)
; Larson; Daniel P.; (Oak Creek, WI) ; Liu;
Dachun; (Waukegan, IL) ; McDaniel; Keith F.;
(Wauconda, IL) ; Motter; Christopher E.; (Oak
Creek, WI) ; Pratt; John K.; (Kenosha, WI) ;
Rockway; Todd W.; (Grayslake, IL) ; Rosenberg; Teresa
A.; (Gurnee, IL) ; Yeung; Ming C.; (Grayslake,
IL) ; Chen; Hui-Ju; (Grayslake, IL) ; Shanley;
Jason P.; (Chicago, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Inc. |
North Chicago |
IL |
US |
|
|
Family ID: |
39273111 |
Appl. No.: |
13/944447 |
Filed: |
July 17, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12492518 |
Jun 26, 2009 |
8497275 |
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13944447 |
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PCT/US2007/088936 |
Dec 27, 2007 |
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12492518 |
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60877254 |
Dec 27, 2006 |
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Current U.S.
Class: |
514/255.05 ;
514/255.06; 514/423; 544/405; 544/407; 548/538 |
Current CPC
Class: |
C07D 207/16 20130101;
C07D 241/24 20130101; C07D 409/14 20130101; C07D 403/14 20130101;
C07K 7/02 20130101; A61P 31/00 20180101; C07D 403/12 20130101 |
Class at
Publication: |
514/255.05 ;
544/407; 548/538; 514/423; 514/255.06; 544/405 |
International
Class: |
C07D 403/12 20060101
C07D403/12; C07D 409/14 20060101 C07D409/14; C07D 403/14 20060101
C07D403/14; C07D 207/16 20060101 C07D207/16; C07D 241/24 20060101
C07D241/24 |
Claims
1. A compound or salt thereof, wherein: the compound corresponds in
structure to formula I: ##STR00133## A is a carbocyclyl optionally
substituted with one or more independently selected R.sup.A
substituents; each R.sup.A is independently selected from the group
consisting of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl,
alkenyloxycarbonyl, alkynyloxycarbonyl, alkyloxy, alkenyloxy,
alkynyloxy, carbocyclyloxy, heterocyclyloxy, aminocarbonyl,
carbocyclylcarbonyl, heterocyclylcarbonyl, carbocyclyloxycarbonyl,
heterocyclyloxycarbonyl, aminoalkylcarbonyl,
carbocyclylaminocarbonyl, heterocyclylaminocarbonyl,
carbocyclylalkylcarbonyl, heterocyclylalkylcarbonyl,
carbocyclylalkyloxycarbonyl, heterocyclylalkyoxycarbonyl,
alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl,
carbocyclylsulfonyl, heterocyclylsulfonyl,
alkylcarbocyclylsulfonyl, alkenylcarbocyclylsulfonyl,
alkynylcarbonylsulfonyl, alkylheterocyclylsulfonyl,
alkenylheterocyclylsulfonyl, alkynylheterocyclysulfonyl, amino,
alkylamino, carbocyclylamino, heterocyclylamino,
alkylcarbocyclylamino, and alkylheterocyclylamino, wherein: the
amino portion of the aminoalkylcarbonyl optionally is substituted
with one or two substituents independently selected from the group
consisting of alkyloxycarbonyl, carbocyclylalkyloxycarbonyl, and
heterocyclylalkyloxycarbonyl; R.sup.1 is selected from the group
consisting of optionally substituted carbocyclyl and optionally
substituted heterocyclyl; R.sup.2 is selected from the group
consisting of optionally substituted carbocyclyl and optionally
substituted heterocyclyl; R.sup.3 is selected from the group
consisting of hydrogen, alkyl, alkenyl, alkynyl, carbocyclylalkyl,
carbocyclylalkenyl, carbocyclyalkynyl, heterocyclylalkyl,
heterocyclylalkenyl, heterocyclylalkynyl, aminocarbonylalkyl,
aminocarbonylalkenyl, aminocarbonylalkynyl, carbocyclyl, and
heterocyclyl; R.sup.4 is selected from the group consisting
hydrogen, alkyl, alkenyl, and alkynyl; R.sup.5 is selected from the
group consisting of hydrogen, alkyl, alkenyl, alkynyl,
carbocyclylalkyl, carbocyclylalkenyl, carbocyclyalkynyl,
heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl,
aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl,
carbocyclyl, and heterocyclyl; R.sup.6 is selected from the group
consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl,
alkenylcarbonyl, alkynylcarbonyl, carbocyclyl, heterocyclyl, amino,
carbocyclylalkyl, and heterocyclylalkyl; R.sup.7 is selected from
the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carbocyclyl,
heterocyclyl, amino, carbocyclylalkyl, and heterocyclylalkyl;
R.sup.8 is aminocarbonyl optionally is substituted with one or two
substituents independently selected from the group consisting of
R.sup.B and R.sup.C; each R.sup.B is independently selected from
the group consisting of aminocarbonylalkyl, alkyloxy, alkenyloxy,
alkynyloxy, carbocyclyloxy, heterocyclyloxy, alkylcarbonyl,
alkenylcarbonyl, alkynylcarbonyl, carbocyclyl, and heterocyclyl,
wherein: the amino portion of the aminocarbonylalkyl optionally is
substituted with one or two substituents independently selected
from the group consisting of alkyl, alkenyl, and alkynyl, wherein:
the alkyl, alkenyl, and alkynyl optionally are substituted one or
more substituents independently selected from the group consisting
of hydroxy, alkyloxy, carbocyclyloxy, heterocyclyloxy, carbocyclyl,
heterocyclyl, and aminocarbonyl, wherein: the carbocyclyl and
heterocyclyl optionally are substituted with one or more
substituents independently selected from the group consisting of
halo, alkyl, alkenyl, alkenyl, alkynyl, hydroxy, alkyloxy,
alkenyloxy, and alkynyloxy, and the aminocarbonyl optionally is
substituted with one or two independently selected alkyl; and each
R.sup.C is independently selected from the group consisting of
alkyl, alkenyl, and alkynyl.
2. The compound or salt of claim 1, wherein the compound
corresponds in structure to formula selected from the group
consisting of: ##STR00134##
3. The compound or salt of claim 1, wherein each R.sup.A is
independently selected from the group consisting of carbocyclyl,
heterocyclyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,
alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,
carbocyclylcarbonyl, heterocyclylcarbonyl, carbocyclyloxycarbonyl,
heterocyclyloxycarbonyl, aminoalkylcarbonyl,
carbocyclylaminocarbonyl, heterocyclylaminocarbonyl,
carbocyclylalkyloxycarbonyl, heterocyclylalkyoxycarbonyl,
alkylcarbocyclylsulfonyl, and alkylheterocyclylsulfonyl, wherein:
the amino portion of the aminoalkylcarbonyl optionally is
substituted with one or two substituents independently selected
from the group consisting of alkyloxycarbonyl,
carbocyclylalkyloxycarbonyl, and heterocyclylalkyloxycarbonyl.
4. The compound or salt of claim 1, wherein each R.sup.A is
independently selected from the group consisting of carbocyclyl,
heterocyclyl, alkylcarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl,
carbocyclyloxycarbonyl, aminoalkylcarbonyl,
heterocyclylaminocarbonyl, carbocyclylalkyloxycarbonyl, and
alkylcarbocyclylsulfonyl, wherein: the amino portion of the
aminoalkylcarbonyl optionally is substituted with one or two
independently selected carbocyclylalkyloxycarbonyl.
5. The compound or salt of claim 1, wherein: R.sup.8 is
aminocarbonyl substituted with R.sup.B; and R.sup.B is selected
from the group consisting of aminocarbonylalkyl, carbocyclyl, and
heterocyclyl, wherein: the amino portion of the aminocarbonylalkyl
optionally is substituted with a substituent selected from the
group consisting of alkyl, alkenyl, and alkynyl, wherein: the
alkyl, alkenyl, and alkynyl optionally are substituted one or two
substituents independently selected from the group consisting of
hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and aminocarbonyl,
wherein: the carbocyclyl and heterocyclyl optionally are
substituted with one or more substituents independently selected
from the group consisting of halo, hydroxy, and alkyloxy, and the
aminocarbonyl optionally is substituted with one or two
independently selected alkyl.
6. The compound or salt of claim 1, wherein: R.sup.8 is
aminocarbonyl substituted with R.sup.B; and R.sup.B is selected
from the group consisting of aminocarbonylalkyl, carbocyclyl, and
heterocyclyl, wherein: the amino portion of the aminocarbonylalkyl
optionally is substituted with alkyl, wherein: the alkyl optionally
is substituted two substituents independently selected from the
group consisting of alkyloxy, carbocyclyl, heterocyclyl, and
aminocarbonyl, wherein: the carbocyclyl and heterocyclyl optionally
are substituted with one or more substituents independently
selected from the group consisting of halo, hydroxy, and alkyloxy,
and the aminocarbonyl optionally is substituted with two
independently selected alkyl.
7. The compound or salt of claim 1, wherein R.sup.1 is 6-membered
nitrogen-containing heterocyclyl.
8. The compound or salt of claim 1, wherein R.sup.2 is
C.sub.5-C.sub.6-cycloalkyl.
9. The compound or salt of claim 1, wherein R.sup.3 is alkyl.
10. The compound or salt of claim 1, wherein R.sup.4 is
hydrogen.
11. The compound or salt of claim 1, wherein R.sup.5 is alkyl.
12. The compound or salt of claim 1, wherein R.sup.6 is
hydrogen.
13. The compound or salt of claim 1, wherein R.sup.7 is
hydrogen.
14. The compound or salt of claim 1, wherein: A is selected from
the group consisting of C.sub.5-C.sub.7-carbocyclyl, wherein: the
carbocyclyl is optionally substituted with one, two, or three
independently selected R.sup.A substituents; each R.sup.A is
independently selected from the group consisting of carbocyclyl,
heterocyclyl, alkylcarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl,
carbocyclyloxycarbonyl, aminoalkylcarbonyl,
heterocyclylaminocarbonyl, carbocyclylalkyloxycarbonyl, and
alkylcarbocyclylsulfonyl, wherein: the amino portion of the
aminoalkylcarbonyl optionally is substituted with
carbocyclylalkyloxycarbonyl; R.sup.1 is 5-6-membered heterocyclyl;
R.sup.2 is C.sub.5-C.sub.6-carbocyclyl; R.sup.3 is selected from
the group consisting of hydrogen, alkyl, carbocyclylalkyl,
carbocyclyl, and aminocarbonylalkyl; R.sup.4 is selected from the
group consisting of hydrogen and alkyl; R.sup.5 is selected from
the group consisting of alkyl and carbocyclylalkyl; R.sup.6 is
selected from the group consisting of hydrogen and alkyl; R.sup.7
is selected from the group consisting of hydrogen and alkyl;
R.sup.8 is aminocarbonyl optionally substituted with R.sup.B; and
R.sup.B is independently selected from the group consisting of
aminocarbonylalkyl and carbocyclyl, wherein: the amino portion of
the aminocarbonylalkyl is substituted with alkyl, wherein: the
alkyl optionally is substituted with one or more substituents
independently selected from the group consisting of carbocyclyl and
aminocarbonyl, wherein: the carbocyclyl optionally is substituted
with one or more substituents selected from the group consisting of
halo and alkyloxy, and the aminocarbonyl optionally is substituted
with one or two independently selected alkyl.
15. The compound or salt of claim 1, wherein: A is selected from
the group consisting of C.sub.5-C.sub.6-single-ring carbocyclyl and
C.sub.7-bridged carbocyclyl, wherein: each such substituent
optionally is substituted with R.sup.A; R.sup.A is selected from
the group consisting of carbocyclyl, heterocyclyl, alkylcarbonyl,
alkyloxycarbonyl, carbocyclylcarbonyl, carbocyclyloxycarbonyl,
aminoalkylcarbonyl, heterocyclylaminocarbonyl,
carbocyclylalkyloxycarbonyl, and alkylcarbocyclylsulfonyl, wherein:
the amino portion of the aminoalkylcarbonyl optionally is
substituted with carbocyclylalkyloxycarbonyl; R.sup.1 is
5-6-membered nitrogen-containing heterocyclyl; R.sup.2 is
C.sub.5-C.sub.6-cycloalkyl; R.sup.3 is selected from the group
consisting of hydrogen, alkyl, aminocarbonylalkyl, cycloalkyl,
arylalkyl, and cycloalkylalkyl; R.sup.4 is hydrogen; R.sup.5 is
selected from the group consisting of alkyl and cycloalkylalkyl;
R.sup.6 is hydrogen; R.sup.7 is hydrogen; R.sup.8 is aminocarbonyl
substituted with R.sup.B; and R.sup.B is independently selected
from the group consisting of aminocarbonylalkyl and cycloalkyl,
wherein: the amino portion of the aminocarbonylalkyl optionally is
substituted with alkyl, wherein: the alkyl optionally is
substituted with aminocarbonyl, wherein: the aminocarbonyl
optionally is substituted with one or two independently selected
alkyl.
16. A pharmaceutical composition comprising one or more compounds
and/or salts recited in claim 1.
17. A method for treating hepatitis C in a mammal in need of such
treatment, wherein the method comprises administering to the mammal
one or more compounds and/or salts recited in claim 1.
Description
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
[0001] This patent application is a divisional of U.S. application
Ser. No. 12/492,518, filed Jun. 26, 2009, which is a continuation
of International Patent Application No. PCT/US2007/088936 (filed
Dec. 27, 2007), which, in turn, claims priority to U.S. Provisional
Patent Application No. 60/877,254 (filed Dec. 27, 2006). The entire
text of these patent applications is incorporated by reference into
this patent application.
FIELD OF THE INVENTION
[0002] This invention is directed to: (a) compounds and salts
thereof that, inter alia, are useful as hepatitis C virus (HCV)
inhibitors; (b) intermediates useful for the preparation of such
compounds and salts; (c) pharmaceutical compositions comprising
such compounds and salts; and (d) methods of use of such compounds,
salts, and compositions.
BACKGROUND OF THE INVENTION
[0003] Hepatitis C is a blood-borne, infectious, viral disease that
is caused by a hepatotropic virus called HCV. At least six
different HCV genotypes (with several subtypes within each
genotype) are known to date. In North America, HCV genotype 1a
predominates, followed by HCV genotypes 1b, 2a, 2b, and 3a. In the
United States, HCV genotypes 1, 2, and 3 are the most common, with
about 80% of the hepatitis C patients having HCV genotype 1. In
Europe, HCV genotype 1b is predominant, followed by HCV genotypes
2a, 2b, 2c, and 3a. HCV genotypes 4 and 5 are found almost
exclusively in Africa. As discussed below, the patient's HCV
genotype is clinically important in determining the patient's
potential response to therapy and the required duration of such
therapy.
[0004] An HCV infection can cause liver inflammation (hepatitis)
that is often asymptomatic, but ensuing chronic hepatitis can
result in cirrhosis of the liver (fibrotic scarring of the liver),
liver cancer, and/or liver failure. The World Health Organization
estimates that about 170 million persons worldwide are chronically
infected with HCV, and from about three to about four million
persons are newly infected globally each year. According to the
Centers for Disease Control and Prevention, about four million
people in the United States are infected with HCV. Co-infection
with the human immunodeficiency virus (HIV) is common, and rates of
HCV infection among HIV positive populations are higher.
[0005] There is a small chance of clearing the virus spontaneously,
but the majority of patients with chronic hepatitis C will not
clear it without treatment. Indications for treatment typically
include proven HCV infection and persistent abnormal liver function
tests. There are two treatment regimens that are primarily used to
treat hepatitis C: monotherapy (using an interferon agent--either a
"conventional" or longer-acting pegylated interferon) and
combination therapy (using an interferon agent and ribavirin).
Interferon, which is injected into the bloodstream, works by
bolstering the immune response to HCV; and ribavirin, which is
taken orally, is believed to work by preventing HCV replication.
Taken alone, ribavirin does not effectively suppress HCV levels,
but an interferon/ribavirin combination is more effective than
interferon alone. Typically, hepatitis C is treated with a
combination of pegylated interferon alpha and ribavirin for a
period of 24 or 48 weeks, depending on the HCV genotype.
[0006] The goal of treatment is sustained viral response--meaning
that HCV is not measurable in the blood after therapy is completed.
Following treatment with a combination of pegylated interferon
alpha and ribavirin, sustained cure rates (sustained viral
response) of about 75% or better occur in people with HCV genotypes
2 and 3 in 24 weeks of treatment, about 50% in those with HCV
genotype 1 with 48 weeks of treatment, and about 65% in those with
HCV genotype 4 in 48 weeks of treatment.
[0007] Treatment may be physically demanding, particularly for
those with prior history of drug or alcohol abuse, because both
interferon and ribavirin have numerous side effects. Common
interferon-associated side effects include flu-like symptoms,
extreme fatigue, nausea, loss of appetite, thyroid problems, high
blood sugar, hair loss, and skin reactions at the injection site.
Possible serious interferon-associated side effects include
psychoses (e.g., suicidal behavior), heart problems (e.g., heart
attack, low blood pressure), other internal organ damage, blood
problems (e.g., blood counts falling dangerously low), and new or
worsening autoimmune disease (e.g., rheumatoid arthritis).
Ribavirin-associated side effects include anemia, fatigue,
irritability, skin rash, nasal stuffiness, sinusitis, and cough.
Ribavirin can also cause birth defects, so pregnancy in female
patients and female partners of male patients must be avoided
during treatment and for six months afterward.
[0008] Some patients do not complete treatment because of the
serious side effects discussed above; other patients
(non-responders) continue to have measurable HCV levels despite
treatment; and yet other patients (relapsers) "clear" the virus
during therapy, but the virus returns sometime after completion of
the treatment regimen. Thus, there continues to be a need for
alternative compounds, compositions, and methods of treatment (used
either in combination with or in lieu of an interferon agent and/or
ribavirin) to alleviate the symptoms of hepatitis C, thereby
providing partial or complete relief. This invention provides
compounds (including salts thereof), compositions, and methods of
treatment that generally address such a need.
SUMMARY OF THE INVENTION
[0009] This invention is directed to compounds that correspond in
structure to formula I:
##STR00001##
[0010] In formula I:
[0011] A is selected from the group consisting of carbocyclyl and
heterocyclyl, wherein: [0012] the carbocyclyl and heterocyclyl
optionally are substituted with one or more independently selected
R.sup.A substituents;
[0013] each R.sup.A is independently selected from the group
consisting of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl,
alkenyloxycarbonyl, alkynyloxycarbonyl, alkyloxy, alkenyloxy,
alkynyloxy, carbocyclyloxy, heterocyclyloxy, aminocarbonyl,
carbocyclylcarbonyl, heterocyclylcarbonyl, carbocyclyloxycarbonyl,
heterocyclyloxycarbonyl, aminoalkylcarbonyl,
carbocyclylaminocarbonyl, heterocyclylaminocarbonyl,
carbocyclylalkylcarbonyl, heterocyclylalkylcarbonyl,
carbocyclylalkyloxycarbonyl, heterocyclylalkyoxycarbonyl,
alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl,
carbocyclylsulfonyl, heterocyclylsulfonyl,
alkylcarbocyclylsulfonyl, alkenylcarbocyclylsulfonyl,
alkynylcarbonylsulfonyl, alkylheterocyclylsulfonyl,
alkenylheterocyclylsulfonyl, alkynylheterocyclysulfonyl, amino,
alkylamino, carbocyclylamino, heterocyclylamino,
alkylcarbocyclylamino, and alkylheterocyclylamino, wherein: [0014]
the amino portion of the aminoalkylcarbonyl optionally is
substituted with one or two substituents independently selected
from the group consisting of alkyloxycarbonyl,
carbocyclylalkyloxycarbonyl, and heterocyclylalkyloxycarbonyl;
[0015] R.sup.1 is selected from the group consisting of optionally
substituted carbocyclyl and optionally substituted
heterocyclyl;
[0016] R.sup.2 is selected from the group consisting of optionally
substituted carbocyclyl and optionally substituted
heterocyclyl;
[0017] R.sup.3 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, carbocyclylalkyl, carbocyclylalkenyl,
carbocyclyalkynyl, heterocyclylalkyl, heterocyclylalkenyl,
heterocyclylalkynyl, aminocarbonylalkyl, aminocarbonylalkenyl,
aminocarbonylalkynyl, carbocyclyl, and heterocyclyl;
[0018] R.sup.4 is selected from the group consisting hydrogen,
alkyl, alkenyl, and alkynyl;
[0019] R.sup.5 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, carbocyclylalkyl, carbocyclylalkenyl,
carbocyclyalkynyl, heterocyclylalkyl, heterocyclylalkenyl,
heterocyclylalkynyl, aminocarbonylalkyl, aminocarbonylalkenyl,
aminocarbonylalkynyl, carbocyclyl, and heterocyclyl;
[0020] R.sup.6 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl,
alkynylcarbonyl, carbocyclyl, heterocyclyl, amino,
carbocyclylalkyl, and heterocyclylalkyl;
[0021] R.sup.7 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl,
alkynylcarbonyl, carbocyclyl, heterocyclyl, amino,
carbocyclylalkyl, and heterocyclylalkyl;
[0022] R.sup.8 is aminocarbonyl optionally is substituted with one
or two substituents independently selected from the group
consisting of R.sup.B and R.sup.C;
[0023] each R.sup.B is independently selected from the group
consisting of aminocarbonylalkyl, alkyloxy, alkenyloxy, alkynyloxy,
carbocyclyloxy, heterocyclyloxy, alkylcarbonyl, alkenylcarbonyl,
alkynylcarbonyl, carbocyclyl, and heterocyclyl, wherein: [0024] the
amino portion of the aminocarbonylalkyl optionally is substituted
with one or two substituents independently selected from the group
consisting of alkyl, alkenyl, and alkynyl, wherein: [0025] the
alkyl, alkenyl, and alkynyl optionally are substituted one or more
substituents independently selected from the group consisting of
hydroxy, alkyloxy, carbocyclyloxy, heterocyclyloxy, carbocyclyl,
heterocyclyl, and aminocarbonyl, wherein: [0026] the carbocyclyl
and heterocyclyl optionally are substituted with one or more
substituents independently selected from the group consisting of
halo, alkyl, alkenyl, alkenyl, alkynyl, hydroxy, alkyloxy,
alkenyloxy, and alkynyloxy, and [0027] the aminocarbonyl optionally
is substituted with one or two independently selected alkyl;
and
[0028] each R.sup.C is independently selected from the group
consisting of alkyl, alkenyl, and alkynyl.
[0029] This invention is also directed to the salts (including
pharmaceutically acceptable salts) of the compounds of the
invention.
[0030] This invention is also directed to pharmaceutical
compositions that comprise one or more compounds and/or salts of
the invention, and, optionally, one or more additional therapeutic
agents.
[0031] This invention is also directed to methods of use of the
compounds, salts, and/or compositions of the invention to, for
example, treat hepatitis C in a mammal in need of such
treatment.
[0032] This invention is also directed to a use of one or more
compounds and/or salts of the invention to prepare a medicament.
This medicament optionally can comprise one or more additional
therapeutic agents. In some embodiments, the medicament is useful
for treating hepatitis C in a mammal in need of such treatment.
[0033] Further benefits of Applicants' invention will be apparent
to one skilled in the art from reading this patent application.
DETAILED DESCRIPTION OF THE INVENTION
[0034] This detailed description is intended only to acquaint
others skilled in the art with Applicants' invention, its
principles, and its practical application so that others skilled in
the art may adapt and apply the invention in its numerous forms, as
they may be best suited to the requirements of a particular use.
This description and its specific examples are intended for
purposes of illustration only. This invention, therefore, is not
limited to the embodiments described in this patent application,
and may be variously modified.
A. Definitions
[0035] The term "alkyl" (alone or in combination with another
term(s)) means a straight-or branched-chain saturated hydrocarbyl
substituent typically containing from 1 to about 20 carbon atoms,
more typically from 1 to about 8 carbon atoms, and even more
typically from 1 to about 6 carbon atoms. Examples of such
substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, and hexyl. As in
this definition, throughout this detailed description Applicants
have provided illustrative examples. The provision of such
illustrative examples should not be interpreted as if the provided
illustrative examples are the only options available to one skilled
in the art.
[0036] The term "alkenyl" (alone or in combination with another
term(s)) means a straight- or branched-chain hydrocarbyl
substituent containing one or more double bonds and typically from
2 to about 20 carbon atoms, more typically from about 2 to about 8
carbon atoms, and even more typically from about 2 to about 6
carbon atoms. Examples of such substituents include ethenyl
(vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl,
1-butenyl, 2-butenyl, and 3-butenyl.
[0037] The term "alkynyl" (alone or in combination with another
term(s)) means a straight- or branched-chain hydrocarbyl
substituent containing one or more triple bonds and typically from
2 to about 20 carbon atoms, more typically from about 2 to about 8
carbon atoms, and even more typically from about 2 to about 6
carbon atoms. Examples of such substituents include ethynyl,
2-propynyl, 3-propynyl, 2-butynyl, and 3-butynyl.
[0038] The term "carbocyclyl" (alone or in combination with another
term(s)) means a saturated cyclic (i.e., "cycloalkyl"), partially
saturated cyclic (i.e., "cycloalkenyl"), or completely unsaturated
(i.e., "aryl") hydrocarbyl substituent containing from 3 to 14
carbon ring atoms ("ring atoms" are the atoms bound together to
form the ring or rings of a cyclic substituent). A carbocyclyl may
be a single-ring (monocyclic) or polycyclic ring structure.
[0039] A carbocyclyl may be a single ring structure, which
typically contains from 3 to 7 ring atoms, more typically from 3 to
6 ring atoms, and even more typically 5 to 6 ring atoms. Examples
of such single-ring carbocyclyls include cyclopropyl
(cyclopropanyl), cyclobutyl (cyclobutanyl), cyclopentyl
(cyclopentanyl), cyclopentenyl, cyclopentadienyl, cyclohexyl
(cyclohexanyl), cyclohexenyl, cyclohexadienyl, and phenyl. A
carbocyclyl may alternatively be polycyclic (i.e., may contain more
than one ring). Examples of polycyclic carbocyclyls include
bridged, fused, and spirocyclic carbocyclyls. In a spirocyclic
carbocyclyl, one atom is common to two different rings. An example
of a spirocyclic carbocyclyl is spiropentanyl. In a bridged
carbocyclyl, the rings share at least two common non-adjacent
atoms. Examples of bridged carbocyclyls include
bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, and adamantanyl.
In a fused-ring carbocyclyl system, two or more rings may be fused
together, such that two rings share one common bond. Examples of
two- or three-fused ring carbocyclyls include naphthalenyl,
tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl
(dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl.
[0040] The term "cycloalkyl" (alone or in combination with another
term(s)) means a saturated cyclic hydrocarbyl substituent
containing from 3 to 14 carbon ring atoms. A cycloalkyl may be a
single carbon ring, which typically contains from 3 to 7 carbon
ring atoms and more typically from 3 to 6 ring atoms. Examples of
single-ring cycloalkyls include cyclopropyl, cyclobutyl,
cyclopentyl, and cyclohexyl. A cycloalkyl may alternatively be
polycyclic or contain more than one ring. Examples of polycyclic
cycloalkyls include bridged, fused, and spirocyclic
carbocyclyls.
[0041] The term "aryl" (alone or in combination with another
term(s)) means an aromatic carbocyclyl containing from 6 to 14
carbon ring atoms. Examples of aryls include phenyl, naphthalenyl,
and indenyl.
[0042] In some instances, the number of carbon atoms in a
hydrocarbyl substituent (e.g., alkyl, alkenyl, alkynyl, or
cycloalkyl) is indicated by the prefix "C.sub.x-C.sub.y-", wherein
x is the minimum and y is the maximum number of carbon atoms in the
substituent. Thus, for example, "C.sub.1-C.sub.6-alkyl" refers to
an alkyl substituent containing from 1 to 6 carbon atoms.
Illustrating further, C.sub.3-C.sub.6-cycloalkyl means a saturated
hydrocarbyl ring containing from 3 to 6 carbon ring atoms.
[0043] The term "hydrogen" (alone or in combination with another
term(s)) means a hydrogen radical, and may be depicted as --H.
[0044] The term "hydroxy" (alone or in combination with another
term(s)) means --OH.
[0045] The term "carboxy" (alone or in combination with another
term(s)) means --C(O)--OH.
[0046] The term "amino" (alone or in combination with another
term(s)) means --NH.sub.2.
[0047] The term "halogen" or "halo" (alone or in combination with
another term(s)) means a fluorine radical (which may be depicted as
--F), chlorine radical (which may be depicted as --Cl), bromine
radical (which may be depicted as --Br), or iodine radical (which
may be depicted as --I).
[0048] A substituent is "substitutable" if it comprises at least
one carbon or nitrogen atom that is bonded to one or more hydrogen
atoms. Thus, for example, hydrogen, halogen, and cyano do not fall
within this definition. In addition, a sulfur atom in a
heterocyclyl containing such atom is substitutable with one or two
oxo substituents.
[0049] If a substituent is described as being "substituted", a
non-hydrogen radical is in the place of hydrogen radical on a
carbon or nitrogen of the substituent. Thus, for example, a
substituted alkyl substituent is an alkyl substituent in which at
least one non-hydrogen radical is in the place of a hydrogen
radical on the alkyl substituent. To illustrate, monofluoroalkyl is
alkyl substituted with a fluoro radical, and difluoroalkyl is alkyl
substituted with two fluoro radicals. It should be recognized that
if there are more than one substitution on a substituent, each
non-hydrogen radical may be identical or different (unless
otherwise stated).
[0050] If a substituent is described as being "optionally
substituted", the substituent may be either (1) not substituted or
(2) substituted. If a substituent is described as being optionally
substituted with up to a particular number of non-hydrogen
radicals, that substituent may be either (1) not substituted; or
(2) substituted by up to that particular number of non-hydrogen
radicals or by up to the maximum number of substitutable positions
on the substituent, whichever is less. Thus, for example, if a
substituent is described as a heteroaryl optionally substituted
with up to 3 non-hydrogen radicals, then any heteroaryl with less
than 3 substitutable positions would be optionally substituted by
up to only as many non-hydrogen radicals as the heteroaryl has
substitutable positions. To illustrate, tetrazolyl (which has only
one substitutable position) would be optionally substituted with up
to one non-hydrogen radical. To illustrate further, if an amino
nitrogen is described as being optionally substituted with up to 2
non-hydrogen radicals, then a primary amino nitrogen will be
optionally substituted with up to 2 non-hydrogen radicals, whereas
a secondary amino nitrogen will be optionally substituted with up
to only 1 non-hydrogen radical.
[0051] This patent application uses the terms "substituent" and
"radical" interchangeably.
[0052] The prefix "halo" indicates that the substituent to which
the prefix is attached is substituted with one or more
independently selected halogen radicals. For example, haloalkyl
means an alkyl substituent in which at least one hydrogen radical
is replaced with a halogen radical. Examples of haloalkyls include
chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl,
trifluoromethyl, and 1,1,1-trifluoroethyl. It should be recognized
that if a substituent is substituted by more than one halogen
radical, those halogen radicals may be identical or different
(unless otherwise stated).
[0053] The prefix "perhalo" indicates that every hydrogen radical
on the substituent to which the prefix is attached is replaced with
independently selected halogen radicals, i.e., each hydrogen
radical on the substituent is replaced with a halogen radical. If
all the halogen radicals are identical, the prefix typically will
identify the halogen radical. Thus, for example, the term
"perfluoro" means that every hydrogen radical on the substituent to
which the prefix is attached is substituted with a fluorine
radical. To illustrate, the term "perfluoroalkyl" means an alkyl
substituent wherein a fluorine radical is in the place of each
hydrogen radical.
[0054] The term "carbonyl" (alone or in combination with another
term(s)) means --C(O)--.
[0055] The term "aminocarbonyl" (alone or in combination with
another term(s)) means --C(O)--NH.sub.2.
[0056] The term "oxy" (alone or in combination with another
term(s)) means an ether substituent, and may be depicted as
--O--.
[0057] The term "alkyloxy" (alone or in combination with another
term(s)) means an alkylether substituent, i.e., --O-alkyl. Examples
of such a substituent include methoxy (--O--CH.sub.3), ethoxy,
n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and
tert-butoxy.
[0058] The term "alkylcarbonyl" (alone or in combination with
another term(s)) means --C(O)-alkyl.
[0059] The term "aminoalkylcarbonyl" (alone or in combination with
another term(s)) means --C(O)-alkyl-NH.sub.2.
[0060] The term "alkyloxycarbonyl" (alone or in combination with
another term(s)) means --C(O)--O-alkyl.
[0061] The term "carbocyclylcarbonyl" (alone or in combination with
another term(s)) means --C(O)-carbocyclyl.
[0062] Similarly, the term "heterocyclylcarbonyl" (alone or in
combination with another term(s)) means --C(O)-heterocyclyl.
[0063] The term "carbocyclylalkylcarbonyl" (alone or in combination
with another term(s)) means --C(O)-alkyl-carbocyclyl.
[0064] Similarly, the term "heterocyclylalkylcarbonyl" (alone or in
combination with another term(s)) means
--C(O)-alkyl-heterocyclyl.
[0065] The term "carbocyclyloxycarbonyl" (alone or in combination
with another term(s)) means --C(O)--O-carbocyclyl.
[0066] The term "carbocyclylalkyloxycarbonyl" (alone or in
combination with another term(s)) means
--C(O)--O-alkyl-carbocyclyl.
[0067] The term "thio" or "thia" (alone or in combination with
another term(s)) means a thiaether substituent, i.e., an ether
substituent wherein a divalent sulfur atom is in the place of the
ether oxygen atom. Such a substituent may be depicted as --S--.
This, for example, "alkyl-thio-alkyl" means alkyl-S-alkyl
(alkyl-sulfanyl-alkyl).
[0068] The term "thiol" or "sulfhydryl" (alone or in combination
with another term(s)) means a sulfhydryl substituent, and may be
depicted as --SH.
[0069] The term "(thiocarbonyl)" (alone or in combination with
another term(s)) means a carbonyl wherein the oxygen atom has been
replaced with a sulfur. Such a substituent may be depicted as
--C(S)--.
[0070] The term "sulfonyl" (alone or in combination with another
term(s)) means --S(O).sub.2--.
[0071] The term "aminosulfonyl" (alone or in combination with
another term(s)) means --S(O).sub.2--NH.sub.2.
[0072] The term "sulfinyl" or "sulfoxido" (alone or in combination
with another term(s)) means --S(O)--.
[0073] The term "heterocyclyl" (alone or in combination with
another term(s)) means a saturated (i.e., "heterocycloalkyl"),
partially saturated (i.e., "heterocycloalkenyl"), or completely
unsaturated (i.e., "heteroaryl") ring structure containing a total
of 3 to 14 ring atoms. At least one of the ring atoms is a
heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining
ring atoms being independently selected from the group consisting
of carbon, oxygen, nitrogen, and sulfur. A heterocyclyl may be a
single-ring (monocyclic) or polycyclic ring structure.
[0074] A heterocyclyl may be a single ring, which typically
contains from 3 to 7 ring atoms, more typically from 3 to 6 ring
atoms, and even more typically 5 to 6 ring atoms. Examples of
single-ring heterocyclyls include furanyl, dihydrofuranyl,
tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl,
tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl,
imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl,
pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl, oxazolidinyl,
isoxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl,
isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl,
oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl (furazanyl), or 1,3,4-oxadiazolyl), oxatriazolyl
(including 1,2,3,4-oxatriazolyl or 1,2,3,5-oxatriazolyl),
dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl,
1,3,2-dioxazolyl, or 1,3,4-dioxazolyl), oxathiazolyl, oxathiolyl,
oxathiolanyl, pyranyl, dihydropyranyl, thiopyranyl,
tetrahydrothiopyranyl, pyridinyl (azinyl), piperidinyl, diazinyl
(including pyridazinyl (1,2-diazinyl), pyrimidinyl (1,3-diazinyl),
or pyrazinyl (1,4-diazinyl)), piperazinyl, triazinyl (including
1,3,5-triazinyl, 1,2,4-triazinyl, and 1,2,3-triazinyl)), oxazinyl
(including 1,2-oxazinyl, 1,3-oxazinyl, or 1,4-oxazinyl)),
oxathiazinyl (including 1,2,3-oxathiazinyl, 1,2,4-oxathiazinyl,
1,2,5-oxathiazinyl, or 1,2,6-oxathiazinyl)), oxadiazinyl (including
1,2,3-oxadiazinyl, 1,2,4-oxadiazinyl, 1,4,2-oxadiazinyl, or
1,3,5-oxadiazinyl)), morpholinyl, azepinyl, oxepinyl, thiepinyl,
and diazepinyl.
[0075] A heterocyclyl may alternatively be polycyclic (i.e., may
contain more than one ring). Examples of polycyclic heterocyclyls
include bridged, fused, and spirocyclic heterocyclyls. In a
spirocyclic heterocyclyl, one atom is common to two different
rings. In a bridged heterocyclyl, the rings share at least two
common non-adjacent atoms. In a fused-ring heterocyclyl, two or
more rings may be fused together, such that two rings share one
common bond. Examples of fused ring heterocyclyls containing two or
three rings include indolizinyl, pyranopyrrolyl, 4H-quinolizinyl,
purinyl, naphthyridinyl, pyridopyridinyl (including
pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or
pyrido[4,3-b]-pyridinyl), and pteridinyl. Other examples of
fused-ring heterocyclyls include benzo-fused heterocyclyls, such as
indolyl, isoindolyl (isobenzazolyl, pseudoisoindolyl), indoleninyl
(pseudoindolyl), isoindazolyl (benzpyrazolyl), benzazinyl
(including quinolinyl (1-benzazinyl) or isoquinolinyl
(2-benzazinyl)), phthalazinyl, quinoxalinyl, quinazolinyl,
benzodiazinyl (including cinnolinyl (1,2-benzodiazinyl) or
quinazolinyl (1,3-benzodiazinyl)), benzopyranyl (including
chromanyl or isochromanyl), benzoxazinyl (including
1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl, or
3,1,4-benzoxazinyl), and benzisoxazinyl (including
1,2-benzisoxazinyl or 1,4-benzisoxazinyl).
[0076] The term "heteroaryl" (alone or in combination with another
term(s)) means an aromatic heterocyclyl containing from 5 to 14
ring atoms. A heteroaryl may be a single ring or 2 or 3 fused
rings. Examples of heteroaryl substituents include 6-membered ring
substituents such as pyridyl, pyrazyl, pyrimidinyl, pyridazinyl,
and 1,3,5-, 1,2,4- or 1,2,3-triazinyl; 5-membered ring substituents
such as imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl,
isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl
and isothiazolyl; 6/5-membered fused ring substituents such as
benzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and
anthranilyl; and 6/6-membered fused rings such as benzopyranyl,
quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and
benzoxazinyl.
[0077] A prefix attached to a multi-component substituent only
applies to the first component. To illustrate, the term
"alkylcycloalkyl" contains two components: alkyl and cycloalkyl.
Thus, the C.sub.1-C.sub.6-prefix on C.sub.1-C.sub.6-alkylcycloalkyl
means that the alkyl component of the alkylcycloalkyl contains from
1 to 6 carbon atoms; the C.sub.1-C.sub.6-prefix does not describe
the cycloalkyl component. To illustrate further, the prefix "halo"
on haloalkyloxyalkyl indicates that only the alkyloxy component of
the alkyloxyalkyl substituent is substituted with one or more
halogen radicals. If halogen substitution may alternatively or
additionally occur on the alkyl component, the substituent would
instead be described as "halogen-substituted alkyloxyalkyl" rather
than "haloalkyloxyalkyl." And finally, if the halogen substitution
may only occur on the alkyl component, the substituent would
instead be described as "alkyloxyhaloalkyl."
[0078] If substituents are described as being "independently
selected" from a group, each substituent is selected independent of
the other. Each substituent therefore may be identical to or
different from the other substituent(s).
[0079] When words are used to describe a substituent, the
rightmost-described component of the substituent is the component
that has the free valence.
[0080] When a chemical formula is used to describe a substituent,
the dash on the left side of the formula indicates the portion of
the substituent that has the free valence.
[0081] When a chemical formula is used to describe a linking
element between two other elements of a depicted chemical
structure, the leftmost dash of the substituent indicates the
portion of the substituent that is bound to the left element in the
depicted structure. The rightmost dash, on the other hand,
indicates the portion of the substituent that is bound to the right
element in the depicted structure. To illustrate, if the depicted
chemical structure is X-L-Y and L is described as --C(O)--N(H)-,
then the chemical would be X--C(O)--N(H)-Y.
[0082] With reference to the use of the words "comprise" or
"comprises" or "comprising" in this patent application (including
the claims), Applicants note that unless the context requires
otherwise, those words are used on the basis and clear
understanding that they are to be interpreted inclusively, rather
than exclusively, and that Applicants intend each of those words to
be so interpreted in construing this patent application, including
the claims below.
B. Compounds
[0083] This invention is directed, in part, to compounds that
correspond in structure to formula I:
##STR00002##
[0084] In the compounds of formula I:
[0085] A is selected from the group consisting of carbocyclyl and
heterocyclyl, wherein:
[0086] the carbocyclyl and heterocyclyl optionally are substituted
with one or more independently selected R.sup.A substituents;
[0087] each R.sup.A is independently selected from the group
consisting of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl,
alkenyloxycarbonyl, alkynyloxycarbonyl, alkyloxy, alkenyloxy,
alkynyloxy, carbocyclyloxy, heterocyclyloxy, aminocarbonyl,
carbocyclylcarbonyl, heterocyclylcarbonyl, carbocyclyloxycarbonyl,
heterocyclyloxycarbonyl, aminoalkylcarbonyl,
carbocyclylaminocarbonyl, heterocyclylaminocarbonyl,
carbocyclylalkylcarbonyl, heterocyclylalkylcarbonyl,
carbocyclylalkyloxycarbonyl, heterocyclylalkyoxycarbonyl,
alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl,
carbocyclylsulfonyl, heterocyclylsulfonyl,
alkylcarbocyclylsulfonyl, alkenylcarbocyclylsulfonyl,
alkynylcarbonylsulfonyl, alkylheterocyclylsulfonyl,
alkenylheterocyclylsulfonyl, alkynylheterocyclysulfonyl, amino,
alkylamino, carbocyclylamino, heterocyclylamino,
alkylcarbocyclylamino, and alkylheterocyclylamino, wherein: [0088]
the amino portion of the aminoalkylcarbonyl optionally is
substituted with one or two substituents independently selected
from the group consisting of alkyloxycarbonyl,
carbocyclylalkyloxycarbonyl, and heterocyclylalkyloxycarbonyl;
[0089] R.sup.1 is selected from the group consisting of optionally
substituted carbocyclyl and optionally substituted
heterocyclyl;
[0090] R.sup.2 is selected from the group consisting of optionally
substituted carbocyclyl and optionally substituted
heterocyclyl;
[0091] as to R.sup.3, R.sup.4, and R.sup.5: [0092] R.sup.3 and
R.sup.5 are independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, carbocyclylalkyl,
carbocyclylalkenyl, carbocyclyalkynyl, heterocyclylalkyl,
heterocyclylalkenyl, heterocyclylalkynyl, aminocarbonylalkyl,
aminocarbonylalkenyl, aminocarbonylalkynyl, carbocyclyl, and
heterocyclyl, and R.sup.4 is selected from the group consisting
hydrogen, alkyl, alkenyl, and alkynyl, or [0093] one of R.sup.3 and
R.sup.4, together with R.sup.5, forms an optionally substituted
heterocyclyl, and the other one of R.sup.3 and R.sup.4 is as
defined above;
[0094] R.sup.6 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl,
alkynylcarbonyl, carbocyclyl, heterocyclyl, amino,
carbocyclylalkyl, and heterocyclylalkyl;
[0095] R.sup.7 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl,
alkynylcarbonyl, carbocyclyl, heterocyclyl, amino,
carbocyclylalkyl, and heterocyclylalkyl;
[0096] R.sup.8 is selected from the group consisting of
aminocarbonyl, hydroxy, alkoxy, and alkylsulfonylamino, wherein:
[0097] the aminocarbonyl optionally is substituted with one or two
substituents independently selected from the group consisting of
R.sup.B and R.sup.C;
[0098] each R.sup.B is independently selected from the group
consisting of aminocarbonylalkyl, alkyloxy, alkenyloxy, alkynyloxy,
carbocyclyloxy, heterocyclyloxy, alkylcarbonyl, alkenylcarbonyl,
alkynylcarbonyl, carbocyclyl, and heterocyclyl, wherein: [0099] the
amino portion of the aminocarbonylalkyl optionally is substituted
with one or two substituents independently selected from the group
consisting of alkyl, alkenyl, and alkynyl, wherein: [0100] the
alkyl, alkenyl, and alkynyl optionally are substituted one or more
substituents independently selected from the group consisting of
hydroxy, alkyloxy, carbocyclyloxy, heterocyclyloxy, carbocyclyl,
heterocyclyl, and aminocarbonyl, wherein: [0101] the carbocyclyl
and heterocyclyl optionally are substituted with one or more
substituents independently selected from the group consisting of
halo, alkyl, alkenyl, alkenyl, alkynyl, hydroxy, alkoxy,
alkenyloxy, and alkynyloxy, and [0102] the aminocarbonyl optionally
is substituted with one or two independently selected alkyl;
and
[0103] each R.sup.C is independently selected from the group
consisting of alkyl, alkenyl, and alkynyl.
[0104] The compounds of formula I are peptidomimetic ketoamide
compounds that differ from peptidomimetic ketoamide compounds known
to Applicants (e.g., US 2005/0249702 A1, U.S. Pat. No. 6,534,523)
by having a beta-amino acid residue rather than an alpha-amino acid
residue as the P2 residue. Applicants have discovered that such
compounds (and their salts) tend to inhibit HCV NS3 protease.
[0105] In some embodiments of the compounds of formula I:
[0106] R.sup.3 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, carbocyclylalkyl, carbocyclylalkenyl,
carbocyclyalkynyl, heterocyclylalkyl, heterocyclylalkenyl,
heterocyclylalkynyl, aminocarbonylalkyl, aminocarbonylalkenyl,
aminocarbonylalkynyl, carbocyclyl, and heterocyclyl;
[0107] R.sup.4 is selected from the group consisting hydrogen,
alkyl, alkenyl, and alkynyl;
[0108] R.sup.5 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, carbocyclylalkyl, carbocyclylalkenyl,
carbocyclyalkynyl, heterocyclylalkyl, heterocyclylalkenyl,
heterocyclylalkynyl, aminocarbonylalkyl, aminocarbonylalkenyl,
aminocarbonylalkynyl, carbocyclyl, and heterocyclyl;
[0109] R.sup.8 is aminocarbonyl optionally is substituted with one
or two substituents independently selected from the group
consisting of R.sup.B and R.sup.C;
[0110] each R.sup.B is independently selected from the group
consisting of aminocarbonylalkyl, alkyloxy, alkenyloxy, alkynyloxy,
carbocyclyloxy, heterocyclyloxy, alkylcarbonyl, alkenylcarbonyl,
alkynylcarbonyl, carbocyclyl, and heterocyclyl, wherein: [0111] the
amino portion of the aminocarbonylalkyl optionally is substituted
with one or two substituents independently selected from the group
consisting of alkyl, alkenyl, and alkynyl, wherein: [0112] the
alkyl, alkenyl, and alkynyl optionally are substituted one or more
substituents independently selected from the group consisting of
hydroxy, alkyloxy, carbocyclyloxy, heterocyclyloxy, carbocyclyl,
heterocyclyl, and aminocarbonyl, wherein: [0113] the carbocyclyl
and heterocyclyl optionally are substituted with one or more
substituents independently selected from the group consisting of
halo, alkyl, alkenyl, alkenyl, alkynyl, hydroxy, alkyloxy,
alkenyloxy, and alkynyloxy, and [0114] the aminocarbonyl optionally
is substituted with one or two independently selected alkyl;
and
[0115] each R.sup.C is independently selected from the group
consisting of alkyl, alkenyl, and alkynyl.
[0116] The compounds of formula I are discussed in more detail
below.
B1. Ring/Ring Structure A
[0117] As discussed above, A is selected from the group consisting
of carbocyclyl and heterocyclyl, wherein the carbocyclyl and
heterocyclyl optionally are substituted with one or more
independently selected R.sup.A substituents. In some embodiments,
the carbocyclyl and heterocyclyl are substituted with one, two, or
three independently selected R.sup.A substituents. In some such
embodiments, the carbocyclyl and heterocyclyl are substituted with
three independently selected R.sup.A substituents. In other such
embodiments, the carbocyclyl and heterocyclyl are substituted with
two independently selected R.sup.A substituents. In yet other such
embodiments, the carbocyclyl and heterocyclyl are substituted with
one R.sup.A substituent. In other embodiments, the carbocyclyl and
heterocyclyl are not substituted.
[0118] In some embodiments, A is selected from the group consisting
of C.sub.5-C.sub.7-carbocyclyl and 5-6-membered heterocyclyl,
wherein the C.sub.5-C.sub.7-carbocyclyl and 5-6-membered
heterocyclyl optionally are substituted with one, two, or three
independently selected R.sup.A substituents. In some such
embodiments, the C.sub.5-C.sub.7-carbocyclyl and 5-6-membered
heterocyclyl are substituted with three independently selected
R.sup.A substituents. In other such embodiments, the
C.sub.5-C.sub.7-carbocyclyl and 5-6-membered heterocyclyl are
substituted with two independently selected R.sup.A substituents.
In yet other such embodiments, the C.sub.5-C.sub.7-carbocyclyl and
5-6-membered heterocyclyl are substituted with one R.sup.A
substituent. In further such embodiments, the
C.sub.5-C.sub.7-carbocyclyl and 5-6-membered heterocyclyl are not
substituted.
[0119] In some embodiments, A is selected from the group consisting
of C.sub.5-C.sub.6-carbocyclyl, C.sub.7-bridged carbocyclyl, and
5-membered nitrogen-containing heterocyclyl, wherein each
substituent optionally is substituted with one, two, or three
independently selected R.sup.A substituents. In some such
embodiments, the C.sub.5-C.sub.6-carbocyclyl, C.sub.7-bridged
carbocyclyl, and 5-membered nitrogen-containing heterocyclyl are
substituted with three independently selected R.sup.A substituents.
In other such embodiments, the C.sub.5-C.sub.6-carbocyclyl,
C.sub.7-bridged carbocyclyl, and 5-membered nitrogen-containing
heterocyclyl are substituted with two independently selected
R.sup.A substituents. In yet other such embodiments, the
C.sub.5-C.sub.6-carbocyclyl, C.sub.7-bridged carbocyclyl, and
5-membered nitrogen-containing heterocyclyl are substituted with
one R.sup.A substituent. In further such embodiments, the
C.sub.5-C.sub.6-carbocyclyl, C.sub.7-bridged carbocyclyl, and
5-membered nitrogen-containing heterocyclyl are not
substituted.
[0120] In some embodiments, A is carbocyclyl optionally substituted
with one or more independently selected R.sup.A substituents. In
some such embodiments, the carbocyclyl is substituted with three
independently selected R.sup.A substituents. In other such
embodiments, the carbocyclyl is substituted with two independently
selected R.sup.A substituents. In yet other such embodiments, the
carbocyclyl is substituted with one R.sup.A substituent. In further
such embodiments, the carbocyclyl is not substituted.
[0121] In some embodiments, A is C.sub.5-C.sub.7-carbocyclyl
optionally substituted with one or more independently selected
R.sup.A substituents. In some such embodiments, the
C.sub.5-C.sub.7-carbocyclyl is substituted with three independently
selected R.sup.A substituents. In other such embodiments, the
C.sub.5-C.sub.7-carbocyclyl is substituted with two independently
selected R.sup.A substituents. In yet other such embodiments, the
C.sub.5-C.sub.7-carbocyclyl is substituted with one R.sup.A
substituent. In further such embodiments, the
C.sub.5-C.sub.7-carbocyclyl is not substituted. In some of latter
embodiments, the compounds of formula I are selected from the group
consisting of:
##STR00003##
[0122] In some embodiments, A is single-ring carbocyclyl optionally
substituted with one or more independently selected R.sup.A
substituents. In some such embodiments, the single-ring carbocyclyl
is substituted with three independently selected R.sup.A
substituents. In other such embodiments, the single-ring
carbocyclyl is substituted with two independently selected R.sup.A
substituents. In yet other such embodiments, the single-ring
carbocyclyl is substituted with one R.sup.A substituent. In further
such embodiments, the single-ring carbocyclyl is not
substituted.
[0123] In some embodiments, A is C.sub.5-C.sub.6-cycloalkyl
optionally substituted with one or more independently selected
R.sup.A substituents. In some such embodiments, the
C.sub.5-C.sub.6-cycloalkyl is substituted with three independently
selected R.sup.A substituents. In other such embodiments, the
C.sub.5-C.sub.6-cycloalkyl is substituted with two independently
selected R.sup.A substituents. In yet other such embodiments, the
C.sub.5-C.sub.6-cycloalkyl is substituted with one R.sup.A
substituent. In further such embodiments, the
C.sub.5-C.sub.6-cycloalkyl is not substituted.
[0124] In some embodiments, A is single-ring
C.sub.5-C.sub.6-carbocyclyl optionally substituted with one or more
R.sup.A substituents. In some such embodiments, the single-ring
C.sub.5-C.sub.6-carbocyclyl is substituted with three independently
selected R.sup.A substituents. In other such embodiments, the
single-ring C.sub.5-C.sub.6-carbocyclyl is substituted with two
independently selected R.sup.A substituents. In yet other such
embodiments, the single-ring C.sub.5-C.sub.6-carbocyclyl is
substituted with one R.sup.A substituent. In further such
embodiments, the single-ring C.sub.5-C.sub.6-carbocyclyl is not
substituted.
[0125] In some embodiments, A is C.sub.5-carbocyclyl optionally
substituted with one or more R.sup.A substituents. In some such
embodiments, the C.sub.5-carbocyclyl is substituted with three
independently selected R.sup.A substituents. In other such
embodiments, the C.sub.5-carbocyclyl is substituted with two
independently selected R.sup.A substituents. In yet other such
embodiments, the C.sub.5-carbocyclyl is substituted with one
R.sup.A substituent. In further such embodiments, the
C.sub.5-carbocyclyl is not substituted.
[0126] In some embodiments, A is cyclopentyl optionally substituted
with one or more independently selected R.sup.A substituents. In
some such embodiments, the cyclopentyl is substituted with three
independently selected R.sup.A substituents. In other such
embodiments, the cyclopentyl is substituted with two independently
selected R.sup.A substituents. In yet other such embodiments, the
cyclopentyl is substituted with one R.sup.A substituent. In further
such embodiments, the cyclopentyl is not substituted. In these
embodiments, the compounds of formula I correspond in structure to
formula I-1:
##STR00004##
[0127] In some embodiments, A is C.sub.6-carbocyclyl optionally
substituted with one or more independently selected R.sup.A
substituents. In some such embodiments, the C.sub.6-carbocyclyl is
substituted with three independently selected R.sup.A substituents.
In other such embodiments, the C.sub.6-carbocyclyl is substituted
with two independently selected R.sup.A substituents. In yet other
such embodiments, the C.sub.6-carbocyclyl is substituted with one
R.sup.A substituent. In further such embodiments, the
C.sub.6-carbocyclyl is not substituted.
[0128] In some embodiments, A is cyclohexyl optionally substituted
with one or more independently selected R.sup.A substituents. In
some such embodiments, the cyclohexyl is substituted with three
independently selected R.sup.A substituents. In other such
embodiments, the cyclohexyl is substituted with two independently
selected R.sup.A substituents. In yet other such embodiments, the
cyclohexyl is substituted with one R.sup.A substituent. In further
such embodiments, the cyclohexyl is not substituted. In these
embodiments, the compounds of formula I correspond in structure to
formula I-2:
##STR00005##
[0129] In some embodiments, A is polycyclic carbocyclyl optionally
substituted with one or more independently selected R.sup.A
substituents. In some such embodiments, the polycyclic carbocyclyl
is substituted with three independently selected R.sup.A
substituents. In other such embodiments, the polycyclic carbocyclyl
is substituted with two independently selected R.sup.A
substituents. In yet other such embodiments, the polycyclic
carbocyclyl is substituted with one R.sup.A substituent. In further
such embodiments, the polycyclic carbocyclyl is not
substituted.
[0130] In some embodiments, A is bridged carbocyclyl optionally
substituted with one or more independently selected R.sup.A
substituents. In some such embodiments, the bridged carbocyclyl is
substituted with three independently selected R.sup.A substituents.
In other such embodiments, the bridged carbocyclyl is substituted
with two independently selected R.sup.A substituents. In yet other
such embodiments, the bridged carbocyclyl is substituted with one
R.sup.A substituent. In further such embodiments, the bridged
carbocyclyl is not substituted.
[0131] In some embodiments, A is bicyclo[2.2.1]heptanyl optionally
substituted with one or more independently selected R.sup.A
substituents. In some such embodiments, the bicyclo[2.2.1]heptanyl
is substituted with three independently selected R.sup.A
substituents. In other such embodiments, the bicyclo[2.2.1]heptanyl
is substituted with two independently selected R.sup.A
substituents. In yet other such embodiments, the
bicyclo[2.2.1]heptanyl is substituted with one R.sup.A substituent.
In further such embodiments, the bicyclo[2.2.1]heptanyl in not
substituted. In the latter embodiments, the compounds of formula I
correspond in structure to formula I-3.
##STR00006##
[0132] In some embodiments, A is bicyclo[2.2.1]hept-2-enyl
optionally substituted with one or more independently selected
R.sup.A substituents. In some such embodiments, the
bicyclo[2.2.1]hept-2-enyl is substituted with three independently
selected R.sup.A substituents. In other such embodiments, the
bicyclo[2.2.1]hept-2-enyl is substituted with two independently
selected R.sup.A substituents. In yet other such embodiments, the
bicyclo[2.2.1]hept-2-enyl is substituted with one R.sup.A
substituent. In some such embodiments, the
bicyclo[2.2.1]hept-2-enyl in not substituted. In the latter
embodiments, the compounds of formula I correspond in structure to
formula I-4:
##STR00007##
[0133] In some embodiments, A is heterocyclyl optionally
substituted with one or more independently selected R.sup.A
substituents. In some such embodiments, the heterocyclyl is
substituted with three independently selected R.sup.A substituents.
In other such embodiments, the heterocyclyl is substituted with two
independently selected R.sup.A substituents. In yet other such
embodiments, the heterocyclyl is substituted with one R.sup.A
substituent. In further embodiments, the heterocyclyl is not
substituted.
[0134] In some embodiments, A is single-ring heterocyclyl
optionally substituted with one or more independently selected
R.sup.A substituents. In some such embodiments, the single-ring
heterocyclyl is substituted with three independently selected
R.sup.A substituents. In other such embodiments, the single-ring
heterocyclyl is substituted with two independently selected R.sup.A
substituents. In yet other such embodiments, the single-ring
heterocyclyl is substituted with one R.sup.A substituent. In
further such embodiments, the single-ring heterocyclyl is not
substituted.
[0135] In some embodiments, A is 5-6-membered heterocyclyl
optionally substituted with one or more independently selected
R.sup.A substituents. In some such embodiments, the 5-6-membered
heterocyclyl is substituted with three independently selected
R.sup.A substituents. In other such embodiments, the 5-6-membered
heterocyclyl is substituted with two independently selected R.sup.A
substituents. In yet other such embodiments, the 5-6-membered
heterocyclyl is substituted with one R.sup.A substituent. In
further such embodiments, the 5-6-membered heterocyclyl is not
substituted.
[0136] In some embodiments, A is 5-membered heterocyclyl optionally
substituted with one or more independently selected R.sup.A
substituents. In some such embodiments, the 5-membered heterocyclyl
is substituted with three independently selected R.sup.A
substituents. In other such embodiments, the 5-membered
heterocyclyl is substituted with two independently selected R.sup.A
substituents. In yet other such embodiments, the 5-membered
heterocyclyl is substituted with an R.sup.A substituent. In further
such embodiments, the 5-membered heterocyclyl is not
substituted.
[0137] In some embodiments, A is 5-membered nitrogen-containing
heterocyclyl optionally substituted with one or more independently
selected R.sup.A substituents. In some such embodiments, the
5-membered nitrogen-containing heterocyclyl is substituted with
three independently selected R.sup.A substituents. In other such
embodiments, the 5-membered nitrogen-containing heterocyclyl is
substituted with two independently selected R.sup.A substituents.
In yet other such embodiments, the 5-membered nitrogen-containing
heterocyclyl is substituted with one R.sup.A substituent. In
further such embodiments, the 5-membered nitrogen-containing
heterocyclyl is not substituted.
[0138] In some embodiments, A is pyrrolidinyl optionally
substituted with one or more independently selected R.sup.A
substituents. In some such embodiments, A is pyrrolidinyl
optionally substituted with three independently selected R.sup.A
substituents. In other such embodiments, A is pyrrolidinyl
optionally substituted with two independently selected R.sup.A
substituents. In yet other such embodiments, A is pyrrolidinyl
optionally substituted with one R.sup.A substituent. In these
embodiments, the compounds of formula I correspond in structure to
formula I-5:
##STR00008##
In further such embodiments, A is pyrrolidinyl, wherein the
pyrrolidinyl is not substituted. In these embodiments, the
compounds of formula I correspond in structure to formula I-6:
##STR00009##
[0139] In some embodiments, A is 6-membered heterocyclyl optionally
substituted with one or more independently selected R.sup.A
substituents. In some such embodiments, the 6-membered heterocyclyl
is substituted with three independently selected R.sup.A
substituents. In other such embodiments, the 6-membered
heterocyclyl is substituted with two independently selected R.sup.A
substituents. In yet other such embodiments, the 6-membered
heterocyclyl is substituted with an R.sup.A substituent. In further
such embodiments, the 6-membered heterocyclyl is not
substituted.
[0140] Suitable C.sub.5-C.sub.7-carbocyclyls for the embodiments
discussed above include cyclopentyl, cyclopentenyl,
cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl,
phenyl, cycloheptyl, cycloheptenyl, cycicoheptadienyl,
bicyclo[2.2.1]hept-2-eny, and bicyclo[2.2.1]heptanyl.
[0141] Suitable single-ring carbocyclyls for the embodiments
discussed above include cyclopropyl, cyclobutyl, cyclopentyl,
cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and
phenyl.
[0142] Suitable C.sub.5-C.sub.6-carbocyclyls for the embodiments
discussed above include cyclopentyl, cyclopentenyl,
cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and
phenyl.
[0143] Suitable C.sub.5-carbocyclyls for the embodiments discussed
above include cyclopentyl, cyclopentenyl, and cyclopentadienyl.
[0144] Suitable C.sub.6-carbocyclyls for the embodiments discussed
above include cyclohexyl, cyclohexenyl, cyclohexadienyl, and
phenyl.
[0145] Suitable polycyclic carbocyclyls for the embodiments
discussed above include spiropentanyl, bicyclo[2.2.1]heptanyl,
bicycle[2.2.1]hept-2-enyl, adamantanyl, naphthalenyl,
tetrahydronaphthalenyl, indenyl, indanyl, anthracenyl,
phenanthrenyl, and decalinyl.
[0146] Suitable bridged carbocyclyls for the embodiments discussed
above include bicyclo[2.2.1]heptanyl and
bicyclo[2.2.1]hept-2-enyl.
[0147] Suitable 5-6-membered heterocyclyls for the embodiments
discussed above furanyl, dihydrofuranyl, tetrahydrofuranyl,
thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl,
pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, dihydrooxazolyl,
isoxazolyl, dihydroisoxazolyl, oxazolidinyl, isoxazolidinyl,
thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl,
thiazolidinyl, isothiazolidinyl, imidazolyl, imidazolidinyl,
pyrazolyl, pyrazolinyl, pyrazolidinyl, oxathiolyl, oxathiolanyl,
triazolyl, oxadiazolyl, furazanyl, tetrazolyl, oxatriazolyl,
dioxazolyl, oxathiazolyl, oxathiazolidinyl, dihydrooxadiazolyl,
dioxazolidinyl, pyranyl, dihydropyranyl, tetrahydropyranyl,
pyridinyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl,
diazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, dihydropyrazinyl,
tetrahydropyrazinyl, piperazinyl, triazinyl, dihydrotriazinyl,
tetrahydrotriazinyl, triazinanyl, oxazinyl, dihydrooxazinyl,
morpholinyl, oxathiazinyl, dihydrooxathiazinyl, oxathiazinanyl,
oxadiazinyl, dihydrooxadiazinyl, oxadiazinanyl, thiopyranyl,
dihydrothiopyranyl, and tetrahydrothiopyranyl.
[0148] Suitable 6-membered heterocyclyls for the embodiments
discussed above include pyranyl, dihydropyranyl, tetrahydropyranyl,
pyridinyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl,
diazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, dihydropyrazinyl,
tetrahydropyrazinyl, piperazinyl, triazinyl, dihydrotriazinyl,
tetrahydrotriazinyl, triazinanyl, oxazinyl, dihydrooxazinyl,
morpholinyl, oxathiazinyl, dihydrooxathiazinyl, oxathiazinanyl,
oxadiazinyl, dihydrooxadiazinyl, oxadiazinanyl, thiopyranyl,
dihydrothiopyranyl, and tetrahydrothiopyranyl.
[0149] Suitable 5-membered heterocyclyls for the embodiments
discussed above include furanyl, dihydrofuranyl, tetrahydrofuranyl,
thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl,
pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, dihydrooxazolyl,
isoxazolyl, dihydroisoxazolyl, oxazolidinyl, isoxazolidinyl,
thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl,
thiazolidinyl, isothiazolidinyl, imidazolyl, imidazolidinyl,
pyrazolyl, pyrazolinyl, pyrazolidinyl, oxathiolyl, oxathiolanyl,
triazolyl, oxadiazolyl, furazanyl, tetrazolyl, oxatriazolyl,
dioxazolyl, oxathiazolyl, oxathiazolidinyl, dihydrooxadiazolyl, and
dioxazolidinyl.
[0150] Suitable 5-membered nitrogen-containing heterocyclyls for
the embodiments discussed above include pyrrolyl, pyrrolinyl,
pyrrolidinyl, oxazolyl, dihydrooxazolyl, isoxazolyl,
dihydroisoxazolyl, oxazolidinyl, isoxazolidinyl, thiazolyl,
isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl,
isothiazolidinyl, imidazolyl, imidazolidinyl, pyrazolyl,
pyrazolinyl, pyrazolidinyl, triazolyl, oxadiazolyl, furazanyl,
tetrazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl,
oxathiazolidinyl, dihydrooxadiazolyl, and dioxazolidinyl.
B2. Substituent R.sup.A
[0151] As discussed above, A is selected from the group consisting
of carbocyclyl and heterocyclyl, wherein the carbocyclyl and
heterocyclyl optionally are substituted with one or more
independently selected R.sup.A substituents. Each of these R.sup.A
substituents is independently selected as discussed below.
[0152] As discussed above, R.sup.A is selected from the group
consisting of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl,
alkenyloxycarbonyl, alkynyloxycarbonyl, alkyloxy, alkenyloxy,
alkynyloxy, carbocyclyloxy, heterocyclyloxy, aminocarbonyl,
carbocyclylcarbonyl, heterocyclylcarbonyl, carbocyclyloxycarbonyl,
heterocyclyloxycarbonyl, aminoalkylcarbonyl,
carbocyclylaminocarbonyl, heterocyclylaminocarbonyl,
carbocyclylalkylcarbonyl, heterocyclylalkylcarbonyl,
carbocyclylalkyloxycarbonyl, heterocyclylalkyoxycarbonyl,
alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl,
carbocyclylsulfonyl, heterocyclylsulfonyl,
alkylcarbocyclylsulfonyl, alkenylcarbocyclylsulfonyl,
alkynylcarbonylsulfonyl, alkylheterocyclylsulfonyl,
alkenylheterocyclylsulfonyl, alkynylheterocyclysulfonyl, amino,
alkylamino, carbocyclylamino, heterocyclylamino,
alkylcarbocyclylamino, and alkylheterocyclylamino, wherein: [0153]
the amino portion of the aminoalkylcarbonyl optionally is
substituted with one or two substituents independently selected
from the group consisting of alkyloxycarbonyl,
carbocyclylalkyloxycarbonyl, and heterocyclylalkyloxycarbonyl.
[0154] In some embodiments, R.sup.A is selected from the group
consisting of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl,
alkenyloxycarbonyl, alkynyloxycarbonyl, alkyloxy, alkenyloxy,
alkynyloxy, carbocyclyloxy, heterocyclyloxy, aminocarbonyl,
carbocyclylcarbonyl, heterocyclylcarbonyl, carbocyclyloxycarbonyl,
heterocyclyloxycarbonyl, aminoalkylcarbonyl,
carbocyclylaminocarbonyl, heterocyclylaminocarbonyl,
carbocyclylalkylcarbonyl, heterocyclylalkylcarbonyl,
carbocyclylalkyloxycarbonyl, heterocyclylalkyoxycarbonyl,
alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl,
carbocyclylsulfonyl, heterocyclylsulfonyl,
alkylcarbocyclylsulfonyl, alkenylcarbocyclylsulfonyl,
alkynylcarbonylsulfonyl, alkylheterocyclylsulfonyl,
alkenylheterocyclylsulfonyl, alkynylheterocyclysulfonyl, amino,
alkylamino, carbocyclylamino, heterocyclylamino,
alkylcarbocyclylamino, and alkylheterocyclylamino, wherein: [0155]
the amino portion of the aminoalkylcarbonyl optionally is
substituted with a substituent selected from the group consisting
of alkyloxycarbonyl, carbocyclylalkyloxycarbonyl, and
heterocyclylalkyloxycarbonyl.
[0156] In some embodiments, R.sup.A is selected from the group
consisting of carbocyclyl, heterocyclyl, alkylcarbonyl,
alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl,
alkenyloxycarbonyl, alkynyloxycarbonyl, carbocyclylcarbonyl,
heterocyclylcarbonyl, carbocyclyloxycarbonyl,
heterocyclyloxycarbonyl, aminoalkylcarbonyl,
carbocyclylaminocarbonyl, heterocyclylaminocarbonyl,
carbocyclylalkyloxycarbonyl, heterocyclylalkyoxycarbonyl,
alkylcarbocyclylsulfonyl, and alkylheterocyclylsulfonyl, wherein:
[0157] the amino portion of the aminoalkylcarbonyl optionally is
substituted with one or two substituents independently selected
from the group consisting of alkyloxycarbonyl,
carbocyclylalkyloxycarbonyl, and heterocyclylalkyloxycarbonyl.
[0158] In some embodiments, R.sup.A is selected from the group
consisting of carbocyclyl, heterocyclyl, alkylcarbonyl,
alkyloxycarbonyl, carbocyclylcarbonyl, carbocyclyloxycarbonyl,
aminoalkylcarbonyl, heterocyclylaminocarbonyl,
carbocyclylalkyloxycarbonyl, and alkylcarbocyclylsulfonyl, wherein:
[0159] the amino portion of the aminoalkylcarbonyl optionally is
substituted with one or two independently selected
carbocyclylalkyloxycarbonyl.
[0160] In some embodiments, each R.sup.A is independently selected
from the group consisting of carbocyclyl, heterocyclyl,
alkylcarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl,
carbocyclyloxycarbonyl, aminoalkylcarbonyl,
heterocyclylaminocarbonyl, carbocyclylalkyloxycarbonyl, and
alkylcarbocyclylsulfonyl, wherein: [0161] the amino portion of the
aminoalkylcarbonyl optionally is substituted with
carbocyclylalkyloxycarbonyl.
[0162] In some embodiments, R.sup.A is alkylcarbonyl. In some such
embodiments, R.sup.A is C.sub.1-C.sub.6-alkyl-carbonyl. In some
such embodiments, R.sup.A is methylcarbonyl.
[0163] In some embodiments, R.sup.A is carbocyclylcarbonyl. In some
such embodiments, R.sup.A is aryl-carbonyl. In some such
embodiments, R.sup.A is phenylcarbonyl.
[0164] In some embodiments, R.sup.A is alkyloxycarbonyl. In some
such embodiments, R.sup.A is C.sub.1-C.sub.6-alkyloxycarbonyl.
[0165] In some embodiments, R.sup.A is carbocyclylalkyloxycarbonyl.
In some such embodiments, R.sup.A is phenylalkyloxycarbonyl. In
other such embodiments, R.sup.A is naphthalenylalkyloxycarbonyl. In
further such embodiments, R.sup.A is fluorenylalkyloxycarbonyl.
[0166] In some embodiments, R.sup.A is carbocyclyloxycarbonyl. In
some such embodiments, R.sup.A is aryloxycarbonyl. In some such
embodiments, R.sup.A is phenoxycarbonyl. In other such embodiments,
R.sup.A is naphthalenoxycarbonyl.
[0167] In some embodiments, R.sup.A is carbocyclylaminocarbonyl. In
some such embodiments, R.sup.A is arylaminocarbonyl. In some such
embodiments, R.sup.A is phenylaminocarbonyl. In other such
embodiments, R.sup.A is naphthalenylaminocarbonyl.
[0168] In some embodiments, R.sup.A is aminoalkylcarbonyl, wherein
the amino portion of the aminoalkylcarbonyl is substituted with
carbocyclylalkyloxycarbonyl. In some such embodiments, R.sup.A is
aminoalkylcarbonyl, wherein the amino portion of the
aminoalkylcarbonyl is substituted with arylalkyloxycarbonyl. In
some such embodiments, R.sup.A is aminoalkylcarbonyl, wherein the
amino portion of the aminoalkylcarbonyl is substituted with
phenylalkyloxycarbonyl.
[0169] In some embodiments, R.sup.A is alkylcarbocyclylsulfonyl. In
some such embodiments, R.sup.A is alkylphenylsulfonyl.
B3. Substituent R.sup.8
[0170] As discussed above, R.sup.8 is selected from the group
consisting of aminocarbonyl, hydroxy, alkyloxy, and
alkylsulfonylamino, wherein the aminocarbonyl optionally is
substituted with one or two substituents independently selected
from the group consisting of R.sup.B and R.sup.C.
[0171] In some embodiments, R.sup.8 is aminocarbonyl optionally
substituted with one or two substituents independently selected
from the group consisting of R.sup.B and R.sup.C.
[0172] In some such embodiments, R.sup.8 is aminocarbonyl
optionally substituted with one or two independently selected
R.sup.B substituents. In some such embodiments, the aminocarbonyl
is substituted with two independently selected R.sup.B
substituents. In other such embodiments, the aminocarbonyl is
substituted with R.sup.B. In these embodiments, the compounds of
formula I correspond in structure to formula IA:
##STR00010##
[0173] In other such embodiments, R.sup.8 is aminocarbonyl
optionally substituted with one or two independently selected
R.sup.C substituents. In some such embodiments, the aminocarbonyl
is substituted with two independently selected R.sup.C
substituents. In other such embodiments, the aminocarbonyl is
substituted with R.sup.C. In these embodiments, the compounds of
formula I correspond in structure to formula IB:
##STR00011##
[0174] In further such embodiments, R.sup.8 is aminocarbonyl,
wherein the aminocarbonyl is not substituted.
B4. Substituent R.sup.B
[0175] As discussed above, R.sup.8 is selected from the group
consisting of aminocarbonyl, hydroxy, alkyloxy, and
alkylsulfonylamino, wherein the aminocarbonyl optionally is
substituted with one or two substituents independently selected
from the group consisting of R.sup.B and R.sup.C. Each of these
R.sup.B substituents is independently selected as discussed
below.
[0176] As discussed above, R.sup.B is selected from the group
consisting of aminocarbonylalkyl, alkyloxy, alkenyloxy, alkynyloxy,
carbocyclyloxy, heterocyclyloxy, alkylcarbonyl, alkenylcarbonyl,
alkynylcarbonyl, carbocyclyl, and heterocyclyl, wherein: [0177] the
amino portion of the aminocarbonylalkyl optionally is substituted
with one or two substituents independently selected from the group
consisting of alkyl, alkenyl, and alkynyl, wherein: [0178] the
alkyl, alkenyl, and alkynyl optionally are substituted one or more
substituents independently selected from the group consisting of
hydroxy, alkyloxy, carbocyclyloxy, heterocyclyloxy, carbocyclyl,
heterocyclyl, and aminocarbonyl, wherein: [0179] the carbocyclyl
and heterocyclyl optionally are substituted with one or more
substituents independently selected from the group consisting of
halo, alkyl, alkenyl, alkenyl, alkynyl, hydroxy, alkyloxy,
alkenyloxy, and alkynyloxy, and [0180] the aminocarbonyl optionally
is substituted with one or two independently selected alkyl.
[0181] In some embodiments, R.sup.B is selected from the group
consisting of aminocarbonylalkyl, carbocyclyl, and heterocyclyl,
wherein: [0182] the amino portion of the aminocarbonylalkyl
optionally is substituted with a substituent selected from the
group consisting of alkyl, alkenyl, and alkynyl, wherein: [0183]
the alkyl, alkenyl, and alkynyl optionally are substituted one or
two substituents independently selected from the group consisting
of hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and aminocarbonyl,
wherein: [0184] the carbocyclyl and heterocyclyl optionally are
substituted with one or more substituents independently selected
from the group consisting of halo, hydroxy, and alkyloxy, and
[0185] the aminocarbonyl optionally is substituted with one or two
independently selected alkyl.
[0186] In some embodiments, R.sup.B is selected from the group
consisting of aminocarbonylalkyl, carbocyclyl, and heterocyclyl,
wherein: [0187] the amino portion of the aminocarbonylalkyl
optionally is substituted with alkyl, wherein: [0188] the alkyl
optionally is substituted two substituents independently selected
from the group consisting of alkyloxy, carbocyclyl, heterocyclyl,
and aminocarbonyl, wherein: [0189] the carbocyclyl and heterocyclyl
optionally are substituted with one or more substituents
independently selected from the group consisting of halo, hydroxy,
and alkyloxy, and [0190] the aminocarbonyl optionally is
substituted with two independently selected alkyl.
[0191] In some embodiments, R.sup.B is selected from the group
consisting of aminocarbonylalkyl and carbocyclyl, wherein: [0192]
the amino portion of the aminocarbonylalkyl is substituted with
alkyl, wherein: [0193] the alkyl optionally is substituted with one
or more substituents independently selected from the group
consisting of carbocyclyl and aminocarbonyl, wherein: [0194] the
carbocyclyl optionally is substituted with one or more substituents
independently selected from the group consisting of halo and
alkyloxy, and [0195] the aminocarbonyl optionally is substituted
with one or two independently selected alkyl.
[0196] In some embodiments, R.sup.B is selected from the group
consisting of aminocarbonylalkyl and cycloalkyl, wherein: [0197]
the amino portion of the aminocarbonylalkyl optionally is
substituted with alkyl, wherein: [0198] the alkyl optionally is
substituted with aminocarbonyl, wherein: [0199] the aminocarbonyl
optionally is substituted with one or two independently selected
alkyl.
[0200] In some embodiments, R.sup.B is carbocyclyl. In some such
embodiments, R.sup.B is C.sub.3-C.sub.6-carbocyclyl.
[0201] In some embodiments, R.sup.B is cycloalkyl. In some such
embodiments, R.sup.B is C.sub.3-C.sub.6-cycloalkyl. In some such
embodiments, R.sup.B is cyclopropyl.
[0202] In some embodiments, R.sup.B is aminocarbonylalkyl, wherein
the amino portion of the aminocarbonylalkyl is substituted with
alkyl, alkenyl, and alkynyl, wherein: [0203] the alkyl, alkenyl,
and alkynyl optionally are substituted one or two substituents
independently selected from the group consisting of hydroxy,
alkyloxy, carbocyclyl, heterocyclyl, and aminocarbonyl, wherein:
[0204] the carbocyclyl and heterocyclyl optionally are substituted
with one or more substituents independently selected from the group
consisting of halo, hydroxy, and alkyloxy, and [0205] the
aminocarbonyl optionally is substituted with one or two
independently selected alkyl.
[0206] In some embodiments, R.sup.B is aminocarbonylalkyl, wherein
the amino portion of the aminocarbonylalkyl is substituted with
alkyl, alkenyl, and alkynyl, wherein: [0207] the alkyl, alkenyl,
and alkynyl are substituted with aminocarbonyl, wherein: [0208] the
aminocarbonyl optionally is substituted with one or two
independently selected alkyl.
[0209] In some embodiments, R.sup.B is aminocarbonylalkyl, wherein
the amino portion of the aminocarbonylalkyl is substituted with
alkyl, alkenyl, and alkynyl, wherein: [0210] the alkyl, alkenyl,
and alkynyl are substituted with aminocarbonyl, wherein: [0211] the
aminocarbonyl optionally is substituted with two
C.sub.1-C.sub.3-alkyl substituents.
[0212] In some embodiments, R.sup.B is aminocarbonylalkyl, wherein
the amino portion of the aminocarbonylalkyl is substituted with
alkyl, alkenyl, and alkynyl, wherein: [0213] the alkyl, alkenyl,
and alkynyl optionally are substituted one or two substituents
independently selected from the group consisting of alkyloxy and
carbocyclyl, wherein: [0214] the carbocyclyl optionally is
substituted with a substituent selected from the group consisting
of alkyloxy and halo.
[0215] In some embodiments, R.sup.B is aminocarbonylalkyl, wherein
the amino portion of the aminocarbonylalkyl is substituted with
alkyl, alkenyl, and alkynyl, wherein: [0216] the alkyl, alkenyl,
and alkynyl optionally are substituted with alkyloxy.
[0217] In some embodiments, R.sup.B is aminocarbonylalkyl, wherein
the amino portion of the aminocarbonylalkyl is substituted with
alkyl, alkenyl, and alkynyl, wherein: [0218] the alkyl, alkenyl,
and alkynyl optionally are substituted with cycloalkyl.
[0219] In some embodiments, R.sup.B is aminocarbonylalkyl, wherein
the amino portion of the aminocarbonylalkyl is substituted with
alkyl, alkenyl, and alkynyl, wherein: [0220] the alkyl, alkenyl,
and alkynyl optionally are substituted with phenyl, wherein: [0221]
the phenyl optionally is substituted with a substituent selected
from the group consisting of alkyloxy and halo.
B5. Substituent R.sup.C
[0222] As discussed above, R.sup.8 is selected from the group
consisting of aminocarbonyl, hydroxy, alkyloxy, and
alkylsulfonylamino, wherein the aminocarbonyl optionally is
substituted with one or two substituents independently selected
from the group consisting of R.sup.B and R.sup.C. Each of these
R.sup.C substituents is independently selected as discussed
below.
[0223] R.sup.C is selected from the group consisting of alkyl,
alkenyl, and alkynyl.
[0224] In some embodiments, R.sup.C is alkyl. In some such
embodiments, R.sup.C is C.sub.1-C.sub.6-alkyl.
B6. Substituent R.sup.1
[0225] As discussed above, R.sup.1 is selected from the group
consisting of optionally substituted carbocyclyl and optionally
substituted heterocyclyl. In some such embodiments, the carbocyclyl
and heterocyclyl are not substituted.
[0226] In some embodiments, R.sup.1 is selected from the group
consisting of C.sub.5-C.sub.6-carbocyclyl and 5-6-membered
heterocyclyl.
[0227] In some embodiments, R.sup.1 is carbocyclyl. In some such
embodiments, R.sup.1 is C.sub.5-C.sub.6-carbocyclyl.
[0228] In some embodiments, R.sup.1 is heterocyclyl. In some such
embodiments, R.sup.1 is 5-6-membered heterocyclyl.
[0229] In some embodiments, R.sup.1 is 6-membered heterocyclyl. In
some such embodiments, R.sup.1 is 6-membered nitrogen-containing
heterocyclyl.
[0230] In some embodiments, R.sup.1 is heteroaryl. In some such
embodiments, R.sup.1 is 6-membered heteroaryl.
[0231] In some embodiments, R.sup.1 is 6-membered
nitrogen-containing heteroaryl. In some such embodiments, R.sup.1
is pyrazinyl.
[0232] Suitable C.sub.5-C.sub.6-carbocyclyls for the embodiments
discussed above include cyclopentyl, cyclopentenyl,
cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and
phenyl.
[0233] Suitable 5-6-membered-heterocyclyls for the above
embodiments include furanyl, dihydrofuranyl, tetrahydrofuranyl,
thiophenyl (thiopyranyl), dihydrothiophenyl, tetrahydrothiophenyl,
pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, dihydrooxazolyl,
isoxazolyl, dihydroisoxazolyl, oxazolidinyl, isoxazolidinyl,
thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl,
thiazolidinyl, isothiazolidinyl, imidazolyl, imidazolidinyl,
pyrazolyl, pyrazolinyl, pyrazolidinyl, oxathiolyl, oxathiolanyl,
triazolyl, oxadiazolyl, furazanyl, tetrazolyl, oxatriazolyl,
dioxazolyl, oxathiazolyl, oxathiazolidinyl, dihydrooxadiazolyl,
dioxazolidinyl, pyranyl, dihydropyranyl, tetrahydropyranyl,
pyridinyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl,
diazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, dihydropyrazinyl,
tetrahydropyrazinyl, piperazinyl, triazinyl, dihydrotriazinyl,
tetrahydrotriazinyl, triazinanyl, oxazinyl, dihydrooxazinyl,
morpholinyl, oxathiazinyl, dihydrooxathiazinyl, oxathiazinanyl,
oxadiazinyl, dihydrooxadiazinyl, oxadiazinanyl, thiopyranyl,
dihydrothiopyranyl, and tetrahydrothiopyranyl.
[0234] Suitable 6-membered heterocyclyls for the embodiments
discussed above include pyranyl, dihydropyranyl, tetrahydropyranyl,
pyridinyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl,
diazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, dihydropyrazinyl,
tetrahydropyrazinyl, piperazinyl, triazinyl, dihydrotriazinyl,
tetrahydrotriazinyl, triazinanyl, oxazinyl, dihydrooxazinyl,
morpholinyl, oxathiazinyl, dihydrooxathiazinyl, oxathiazinanyl,
oxadiazinyl, dihydrooxadiazinyl, oxadiazinanyl, thiopyranyl,
dihydrothiopyranyl, and tetrahydrothiopyranyl.
[0235] Suitable 6-membered nitrogen-containing heterocyclyls for
the embodiments discussed above include pyridinyl,
dihydropyridinyl, tetrahydropyridinyl, piperidinyl, diazinyl,
pyrazinyl, pyridazinyl, pyrimidinyl, dihydropyrazinyl,
tetrahydropyrazinyl, piperazinyl, triazinyl, dihydrotriazinyl,
tetrahydrotriazinyl, triazinanyl, oxazinyl, dihydrooxazinyl,
morpholinyl, oxathiazinyl, dihydrooxathiazinyl, oxathiazinanyl,
oxadiazinyl, dihydrooxadiazinyl, and oxadiazinanyl.
[0236] Suitable 6-membered heteroaryls for the embodiments
discussed above include pyridyl, pyrazyl, pyrimidinyl, pyridazinyl,
and 1,3,5-, 1,2,4- or 1,2,3-triazinyl.
[0237] Suitable 6-membered nitrogen-containing heteroaryls for the
embodiments discussed above include pyridyl, pyrazyl, pyrimidinyl,
pyridazinyl, and 1,3,5-, 1,2,4- or 1,2,3-triazinyl.
B7. Substituent R.sup.2
[0238] As discussed above, R.sup.2 is selected from the group
consisting of optionally substituted carbocyclyl and optionally
substituted heterocyclyl. In some such embodiments, the carbocyclyl
and heterocyclyl are not substituted.
[0239] In some embodiments, R.sup.2 is selected from the group
consisting of C.sub.5-C.sub.6-carbocyclyl and 5-6-membered
heterocyclyl.
[0240] In some embodiments, R.sup.2 is carbocyclyl. In some such
embodiments, R.sup.2 is C.sub.5-C.sub.6-carbocyclyl.
[0241] In some embodiments, R.sup.2 is cycloalkyl. In some such
embodiments, R.sup.2 is C.sub.5-C.sub.6-cycloalkyl.
[0242] In some such embodiments, R.sup.2 is C.sub.5-carbocyclyl. In
some such embodiments, R.sup.2 is cyclopentyl.
[0243] In other such embodiments, R.sup.2 is C.sub.6-carbocyclyl.
In some such embodiments, R.sup.2 is cyclohexyl.
[0244] In some embodiments, R.sup.2 is heterocyclyl. In some such
embodiments, R.sup.2 is 5-6-membered heterocyclyl.
[0245] Suitable C.sub.5-C.sub.6-carbocyclyls for the embodiments
discussed above include cyclopentyl, cyclopentenyl,
cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and
phenyl.
[0246] Suitable C.sub.5-carbocyclyls for the embodiments discussed
above include cyclopentyl, cyclopentenyl, and cyclopentadienyl.
[0247] Suitable C.sub.6-carbocyclyls for the embodiments discussed
above include cyclohexyl, cyclohexenyl, cyclohexadienyl, and
phenyl.
[0248] Suitable 5-6-membered-heterocyclyls for the embodiments
discussed above include furanyl, dihydrofuranyl, tetrahydrofuranyl,
thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl,
pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, dihydrooxazolyl,
isoxazolyl, dihydroisoxazolyl, oxazolidinyl, isoxazolidinyl,
thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl,
thiazolidinyl, isothiazolidinyl, imidazolyl, imidazolidinyl,
pyrazolyl, pyrazolinyl, pyrazolidinyl, oxathiolyl, oxathiolanyl,
triazolyl, oxadiazolyl, furazanyl, tetrazolyl, oxatriazolyl,
dioxazolyl, oxathiazolyl, oxathiazolidinyl, dihydrooxadiazolyl,
dioxazolidinyl, pyranyl, dihydropyranyl, tetrahydropyranyl,
pyridinyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl,
diazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, dihydropyrazinyl,
tetrahydropyrazinyl, piperazinyl, triazinyl, dihydrotriazinyl,
tetrahydrotriazinyl, triazinanyl, oxazinyl, dihydrooxazinyl,
morpholinyl, oxathiazinyl, dihydrooxathiazinyl, oxathiazinanyl,
oxadiazinyl, dihydrooxadiazinyl, oxadiazinanyl, thiopyranyl,
dihydrothiopyranyl, and tetrahydrothiopyranyl.
B8. Substituent R.sup.3
[0249] As discussed above, in some embodiments, R.sup.3 is selected
from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
carbocyclylalkyl, carbocyclylalkenyl, carbocyclyalkynyl,
heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl,
aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl,
carbocyclyl, and heterocyclyl.
[0250] In some embodiments, R.sup.3 is selected from the group
consisting of hydrogen, alkyl, carbocyclylalkyl, heterocyclylalkyl,
aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl,
carbocyclyl, and heterocyclyl.
[0251] In some embodiments, R.sup.3 is selected from the group
consisting of hydrogen, alkyl, carbocyclylalkyl,
aminocarbonylalkyl, and carbocyclyl.
[0252] In some embodiments, R.sup.3 is alkyl. In some such
embodiments, R.sup.3 is C.sub.1-C.sub.6-alkyl. In some such
embodiments, R.sup.3 is selected from the group consisting of
ethyl, propyl, isopropyl, isobutyl, and tert-butyl.
[0253] In some embodiments, R.sup.3 is carbocyclylalkyl. In some
such embodiments, R.sup.3 is C.sub.5-C.sub.6-carbocyclylalkyl. In
other such embodiments, R.sup.3 is
carbocyclyl-C.sub.1-C.sub.6-alkyl. In yet other such embodiments,
R.sup.3 is C.sub.5-C.sub.6-carbocyclyl-C.sub.1-C.sub.6-alkyl.
[0254] In some embodiments, R.sup.3 is aminocarbonylalkyl. In some
such embodiments, R.sup.3 is
aminocarbonyl-C.sub.1-C.sub.6-alkyl.
[0255] In some embodiments, R.sup.3 is carbocyclyl. In some such
embodiments, R.sup.3 is C.sub.5-C.sub.6-carbocyclyl.
[0256] In some embodiments, R.sup.3 is cycloalkyl. In some such
embodiments, R.sup.3 is C.sub.5-C.sub.6-cycloalkyl.
B9. Substituent R.sup.4
[0257] As described above, in some embodiments, R.sup.4 is selected
from the group consisting hydrogen, alkyl, alkenyl, and
alkynyl.
[0258] In some embodiments, R.sup.4 is selected from the group
consisting of hydrogen and alkyl. In some such embodiments, R.sup.4
is selected from the group consisting of hydrogen and
C.sub.1-C.sub.6-alkyl. In some such embodiments, R.sup.4 is
selected from the group consisting of hydrogen and
C.sub.1-C.sub.3-alkyl. In some such embodiments, R.sup.4 is
selected from the group consisting of hydrogen and methyl.
[0259] In some embodiments, R.sup.4 is hydrogen.
[0260] In some embodiments, R.sup.4 is alkyl. In some such
embodiments, R.sup.4 is C.sub.1-C.sub.6-alkyl. In some such
embodiments, R.sup.4 is methyl.
B10. Substituent R.sup.5
[0261] As described above, in some embodiments, R.sup.5 is selected
from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
carbocyclylalkyl, carbocyclylalkenyl, carbocyclyalkynyl,
heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl,
aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl,
carbocyclyl, and heterocyclyl.
[0262] In some embodiments, R.sup.5 is selected from the group
consisting of hydrogen, alkyl, carbocyclylalkyl, heterocyclylalkyl,
aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl,
carbocyclyl, and heterocyclyl.
[0263] In some embodiments, R.sup.5 is selected from the group
consisting of hydrogen, alkyl, and carbocyclylalkyl.
[0264] In some embodiments, R.sup.5 is selected from the group
consisting of alkyl and carbocyclylalkyl. In some such embodiments,
R.sup.5 is selected from the group consisting of
C.sub.1-C.sub.6-alkyl and C.sub.5-C.sub.6-carbocyclylalkyl. In
other such embodiments, R.sup.5 is selected from the group
consisting of C.sub.1-C.sub.6-alkyl and
carbocyclyl-C.sub.1-C.sub.6-alkyl. In other such embodiments,
R.sup.5 is selected from the group consisting of
C.sub.1-C.sub.6-alkyl and
C.sub.5-C.sub.6-carbocyclyl-C.sub.1-C.sub.6-alkyl.
[0265] In some embodiments, R.sup.5 is alkyl. In some such
embodiments, R.sup.5 is C.sub.1-C.sub.6-alkyl.
[0266] In some embodiments, R.sup.5 is carbocyclylalkyl. In some
such embodiments, R.sup.5 is C.sub.5-C.sub.6-carbocyclylalkyl. In
other such embodiments, R.sup.5 is
carbocyclyl-C.sub.1-C.sub.6-alkyl. In further such embodiments,
R.sup.5 is C.sub.5-C.sub.6-carbocyclyl-C.sub.1-C.sub.6-alkyl.
[0267] In some embodiments, R.sup.5 is cycloalkylalkyl. In some
such embodiments, R.sup.5 is C.sub.3-C.sub.6-cycloalkylalkyl. In
some such embodiments, R.sup.5 is
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.6-- alkyl.
B11. Substituent R.sup.6
[0268] As discussed above, R.sup.6 is selected from the group
consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl,
alkenylcarbonyl, alkynylcarbonyl, carbocyclyl, heterocyclyl, amino,
carbocyclylalkyl, and heterocyclylalkyl.
[0269] In some embodiments, R.sup.6 is selected from the group
consisting of hydrogen, alkyl, alkenyl, and alkynyl.
[0270] In some embodiments, R.sup.6 is selected from the group
consisting of hydrogen and alkyl. In some such embodiments, R.sup.6
is selected from the group consisting of hydrogen and
C.sub.1-C.sub.6-alkyl.
[0271] In some embodiments, R.sup.6 is hydrogen.
[0272] In some embodiments, R.sup.6 is alkyl. In some such
embodiments, R.sup.6 is C.sub.1-C.sub.6-alkyl.
B12. Substituent R.sup.7
[0273] R.sup.7 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl,
alkynylcarbonyl, carbocyclyl, heterocyclyl, amino,
carbocyclylalkyl, and heterocyclylalkyl.
[0274] In some embodiments, R.sup.7 is selected from the group
consisting of hydrogen, alkyl, alkenyl, and alkynyl.
[0275] In some embodiments, R.sup.7 is selected from the group
consisting of hydrogen and alkyl. In some such embodiments, R.sup.7
is selected from the group consisting of hydrogen and
C.sub.1-C.sub.6-alkyl.
[0276] In some embodiments, R.sup.7 is hydrogen.
[0277] In some embodiments, R.sup.7 is alkyl. In some such
embodiments, R.sup.7 is C.sub.1-C.sub.6-alkyl.
C. Embodiments of Compounds of Formula I
[0278] Various embodiments of substituents R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.A,
R.sup.B, and R.sup.C have been discussed above. These substituent
embodiments can be combined to form various embodiments of
compounds of formula I. All embodiments of compounds of formula I
formed by combining the substituent embodiments discussed above are
within the scope of Applicants' invention. Illustrative examples
are provided below.
[0279] In some embodiments, A is cyclopentyl, and R.sup.8 is
aminocarbonyl substituted with R.sup.B. In these embodiments, the
compounds correspond in structure to the following formula
IA-1:
##STR00012##
[0280] In some embodiments, A is cyclohexyl, and R.sup.8 is
aminocarbonyl substituted with R.sup.B. In these embodiments, the
compounds correspond in structure to the following formula
IA-2:
##STR00013##
[0281] In some embodiments, A is bicyclo[2.2.1]heptanyl, and
R.sup.8 is aminocarbonyl substituted with R.sup.B. In these
embodiments, the compounds correspond in structure to the following
formula IA-3:
##STR00014##
[0282] In some embodiments, A is bicyclo[2.2.1]heptenyl, and
R.sup.8 is aminocarbonyl substituted with R.sup.B. In these
embodiments, the compounds correspond in structure to the following
formula IA-4:
##STR00015##
[0283] In some embodiments, A is pyrrolidinyl substituted with
R.sup.A, and R.sup.8 is aminocarbonyl substituted with R.sup.B. In
these embodiments, the compounds correspond in structure to the
following formula IA-5:
##STR00016##
[0284] In some embodiments, A is pyrrolidinyl, and R.sup.8 is
aminocarbonyl substituted with R.sup.B. In these embodiments, the
compounds correspond in structure to the following formula
IA-6:
##STR00017##
[0285] In some embodiments:
[0286] A is selected from the group consisting of
C.sub.5-C.sub.7-carbocyclyl and 5-6-membered heterocyclyl, wherein:
[0287] the carbocyclyl and heterocyclyl are optionally substituted
with one, two, or three independently selected R.sup.A
substituents;
[0288] each R.sup.A is independently selected from the group
consisting of carbocyclyl, heterocyclyl, alkylcarbonyl,
alkyloxycarbonyl, carbocyclylcarbonyl, carbocyclyloxycarbonyl,
aminoalkylcarbonyl, heterocyclylaminocarbonyl,
carbocyclylalkyloxycarbonyl, and alkylcarbocyclylsulfonyl, wherein:
[0289] the amino portion of the aminoalkylcarbonyl optionally is
substituted with carbocyclylalkyloxycarbonyl;
[0290] R.sup.1 is 5-6-membered heterocyclyl;
[0291] R.sup.2 is C.sub.5-C.sub.6-carbocyclyl;
[0292] R.sup.3 is selected from the group consisting of hydrogen,
alkyl, carbocyclylalkyl, carbocyclyl, and aminocarbonylalkyl;
[0293] R.sup.4 is selected from the group consisting of hydrogen
and alkyl;
[0294] R.sup.5 is selected from the group consisting of alkyl and
carbocyclylalkyl;
[0295] R.sup.6 is selected from the group consisting of hydrogen
and alkyl;
[0296] R.sup.7 is selected from the group consisting of hydrogen
and alkyl;
[0297] R.sup.8 is aminocarbonyl optionally substituted with
R.sup.B; and
[0298] R.sup.B is independently selected from the group consisting
of aminocarbonylalkyl and carbocyclyl, wherein: [0299] the amino
portion of the aminocarbonylalkyl is substituted with alkyl,
wherein: [0300] the alkyl optionally is substituted with one or
more substituents independently selected from the group consisting
of carbocyclyl and aminocarbonyl, wherein: [0301] the carbocyclyl
optionally is substituted with one or more substituents selected
from the group consisting of halo and alkyloxy, and [0302] the
aminocarbonyl optionally is substituted with one or two
independently selected alkyl.
[0303] In some embodiments:
[0304] A is selected from the group consisting of
C.sub.5-C.sub.6-single-ring carbocyclyl, C.sub.7-bridged
carbocyclyl, and 5-membered nitrogen-containing heterocyclyl,
wherein: [0305] each such substituent optionally is substituted
with R.sup.A;
[0306] R.sup.A is selected from the group consisting of
carbocyclyl, heterocyclyl, alkylcarbonyl, alkyloxycarbonyl,
carbocyclylcarbonyl, carbocyclyloxycarbonyl, aminoalkylcarbonyl,
heterocyclylaminocarbonyl, carbocyclylalkyloxycarbonyl, and
alkylcarbocyclylsulfonyl, wherein: [0307] the amino portion of the
aminoalkylcarbonyl optionally is substituted with
carbocyclylalkyloxycarbonyl;
[0308] R.sup.1 is 5-6-membered nitrogen-containing
heterocyclyl;
[0309] R.sup.2 is C.sub.5-C.sub.6-cycloalkyl;
[0310] R.sup.3 is selected from the group consisting of hydrogen,
alkyl, aminocarbonylalkyl, cycloalkyl, arylalkyl, and
cycloalkylalkyl.
[0311] R.sup.4 is hydrogen;
[0312] R.sup.5 is selected from the group consisting of alkyl and
cycloalkylalkyl;
[0313] R.sup.6 is hydrogen;
[0314] R.sup.7 is hydrogen;
[0315] R.sup.8 is aminocarbonyl substituted with R.sup.B; and
[0316] R.sup.B is independently selected from the group consisting
of aminocarbonylalkyl and cycloalkyl, wherein:
[0317] the amino portion of the aminocarbonylalkyl optionally is
substituted with alkyl, wherein: [0318] the alkyl optionally is
substituted with aminocarbonyl, wherein: [0319] the aminocarbonyl
optionally is substituted with one or two independently selected
alkyl.
D. Isomers
[0320] This invention also is directed, in part, to all isomers of
the compounds of formula I (and their salts) (i.e., structural and
stereoisomers). Structural isomers include chain and position
isomers. Stereoisomers include E/Z isomers (i.e., isomers with
regard to one or more double bonds), enantiomers (i.e.,
stereo-isomers that have opposite configurations at all stereogenic
centers), and diastereoisomers (i.e., stereo-isomers that have the
same configuration at one or more stereogenic centers, but differ
at other stereogenic centers).
E. Salts
[0321] This invention also is directed, in part, to all salts of
the compounds of formula I. A salt of a compound may be
advantageous due to one or more of the salt's properties, such as,
for example, enhanced pharmaceutical stability in differing
temperatures and humidities, or a desirable solubility in water or
other solvents. Where a salt is intended to be administered to a
patient (as opposed to, for example, being in use in an in vitro
context), the salt preferably is pharmaceutically acceptable and/or
physiologically compatible. The term "pharmaceutically acceptable"
is used adjectivally in this patent application to mean that the
modified noun is appropriate for use as a pharmaceutical product or
as a part of a pharmaceutical product. Pharmaceutically acceptable
salts include salts commonly used to form alkali metal salts and to
form addition salts of free acids or free bases. In general, these
salts typically may be prepared by conventional means by reacting,
for example, the appropriate acid or base with a compound of the
invention.
[0322] Pharmaceutically acceptable acid addition salts of the
compounds of formula I can be prepared from an inorganic or organic
acid. Examples of often-suitable inorganic acids include
hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric,
and phosphoric acid. Suitable organic acids generally include, for
example, aliphatic, cycloaliphatic, aromatic, araliphatic,
heterocyclic, carboxylic, and sulfonic classes of organic acids.
Specific examples of often suitable organic acids include acetate,
trifluoroacetate, formate, propionate, succinate, glycolate,
gluconate, digluconate, lactate, malate, tartaric acid, citrate,
ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate,
glutamate, benzoate, anthranilic acid, mesylate, stearate,
salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate
(pamoate), ethanesulfonate, benzenesulfonate, pantothenate,
2-hydroxyethanesulfonate, sulfanilate, cyclohexylaminosulfonate,
algenic acid, beta-hydroxybutyric acid, galactarate, galacturonate,
adipate, alginate, bisulfate, butyrate, camphorate,
camphorsulfonate, cyclopentanepropionate, dodecylsulfate,
glycoheptanoate, glycerophosphate, heptanoate, hexanoate,
nicotinate, oxalate, palmoate, pectinate, 2-naphthalesulfonate,
3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and
undecanoate.
[0323] Pharmaceutically acceptable base addition salts of the
compounds of formula I include, for example, metallic salts and
organic salts. Preferred metallic salts include alkali metal (group
Ia) salts, alkaline earth metal (group IIa) salts, and other
physiologically acceptable metal salts. Such salts may be made from
aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.
Preferred organic salts can be made from amines, such as
tromethamine, diethylamine, N,N'-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine
(N-methylglucamine), and procaine. Basic nitrogen-containing groups
can be quaternized with agents such as lower alkyl
(C.sub.1-C.sub.6) halides (e.g., methyl, ethyl, propyl, and butyl
chlorides, bromides, and iodides), dialkyl sulfates (e.g.,
dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain
halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides,
bromides, and iodides), arylalkyl halides (e.g., benzyl and
phenethyl bromides), and others.
F. Purity
[0324] Compounds of formula I (and salts thereof) with any level of
purity (including pure and substantially pure) are within the scope
of Applicants' invention. The term "substantially pure" in
reference to a compound/salt/isomer, means that the
preparation/composition containing the compound/salt/isomer
contains more than about 85% by weight of the compound/salt/isomer,
preferably more than about 90% by weight of the
compound/salt/isomer, preferably more than about 95% by weight of
the compound/salt/isomer, preferably more than about 97% by weight
of the compound/salt/isomer, and preferably more than about 99% by
weight of the compound/salt/isomer.
G. Methods for Preparation of the Compounds and Salts
[0325] The compounds of formula I (and their salts) can be prepared
as described in the general discussion and/or specific synthesis
examples below. In the discussion below, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.A, R.sup.B, and
R.sup.C have the meaning discussed above unless otherwise
stated.
##STR00018##
##STR00019##
##STR00020##
H. Compositions
[0326] This invention also is directed, in part, to compositions
comprising one or more compounds and/or salts of the in invention.
The compositions can be pharmaceutical compositions.
[0327] In some embodiments, the compositions further comprise one
or more additional therapeutic agents. Such therapeutic agents can
be, but need not be, additional HCV inhibitors.
[0328] The preferred composition depends on the method of
administration, and typically comprises one or more conventional
pharmaceutically acceptable carriers, adjuvants, and/or vehicles
(together referred to as "excipients"). Formulation of drugs is
generally discussed in, for example, Hoover, J., Remington's
Pharmaceutical Sciences (Mack Publishing Co., 1975) and Ansel's
Pharmaceutical Dosage Forms and Drug Delivery Systems (Lippincott
Williams & Wilkins, 2005).
[0329] Solid dosage forms for oral administration include, for
example, capsules, tablets, pills, powders, and granules. In such
solid dosage forms, the compounds or salts are ordinarily combined
with one or more excipients. If administered per os, the compounds
or salts can be mixed with, for example, lactose, sucrose, starch
powder, cellulose esters of alkanoic acids, cellulose alkyl esters,
talc, stearic acid, magnesium stearate, magnesium oxide, sodium and
calcium salts of phosphoric and sulfuric acids, gelatin, acacia
gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl
alcohol, and then tableted or encapsulated for convenient
administration. Such capsules or tablets can contain a
controlled-release formulation, as can be provided in, for example,
a dispersion of the compound or salt in hydroxypropylmethyl
cellulose. In the case of capsules, tablets, and pills, the dosage
forms also can comprise buffering agents, such as sodium citrate,
or magnesium or calcium carbonate or bicarbonate. Tablets and pills
additionally can be prepared with enteric coatings.
[0330] Liquid dosage forms for oral administration include, for
example, pharmaceutically acceptable emulsions (including both
oil-in-water and water-in-oil emulsions), solutions (including both
aqueous and non-aqueous solutions), suspensions (including both
aqueous and non-aqueous suspensions), syrups, and elixirs
containing inert diluents commonly used in the art (e.g., water).
Such compositions also can comprise, for example, wetting,
emulsifying, suspending, flavoring (e.g., sweetening), and/or
perfuming agents.
[0331] Parenteral administration includes subcutaneous injections,
intravenous injections, intramuscular injections, intrasternal
injections, and infusion. Injectable preparations (e.g., sterile
injectable aqueous or oleaginous suspensions) can be formulated
according to the known art using suitable dispersing, wetting
agents, and/or suspending agents. Acceptable vehicles and solvents
include, for example, water, 1,3-butanediol, Ringer's solution,
isotonic sodium chloride solution, bland fixed oils (e.g.,
synthetic mono- or diglycerides), fatty acids (e.g., oleic acid),
dimethyl acetamide, surfactants (e.g., ionic and non-ionic
detergents), and/or polyethylene glycols.
[0332] Formulations for parenteral administration may, for example,
be prepared from sterile powders or granules having one or more of
the excipients mentioned for use in the formulations for oral
administration. A compound or salt of the invention can be
dissolved in water, polyethylene glycol, propylene glycol, ethanol,
corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol,
sodium chloride, and/or various buffers. The pH may be adjusted, if
necessary, with a suitable acid, base, or buffer.
[0333] Suppositories for rectal administration can be prepared by,
for example, mixing a compound or salt of the invention with a
suitable nonirritating excipient that is solid at ordinary
temperatures, but liquid at the rectal temperature, and will
therefore melt in the rectum to release the drug. Suitable
excipients include, for example, cocoa butter; synthetic mono-,
di-, or triglycerides, fatty acids, and/or polyethylene
glycols.
[0334] Topical administration includes the use of transdermal
administration, such as transdermal patches or iontophoresis
devices.
[0335] Other excipients and modes of administration known in the
pharmaceutical art also may be used.
[0336] The preferred total daily dose of the compound or salt
(administered in single or divided doses) is typically from about
0.001 to about 100 mg/kg, more preferably from about 0.001 to about
30 mg/kg, and even more preferably from about 0.01 to about 10
mg/kg (i.e., mg of the compound or salt per kg body weight). Dosage
unit compositions can contain such amounts or submultiples thereof
to make up the daily dose. In many instances, the administration of
the compound or salt will be repeated a plurality of times.
Multiple doses per day typically may be used to increase the total
daily dose, if desired.
[0337] Factors affecting the preferred dosage regimen include the
type, age, weight, sex, diet, and condition of the patient; the
severity of the pathological condition; the severity of the
pathological condition; the route of administration;
pharmacological considerations, such as the activity, efficacy,
pharmacokinetic, and toxicology profiles of the particular compound
or salt used; whether a drug delivery system is utilized; and
whether the compound or salt is administered as part of a drug
combination. Thus, the dosage regimen actually employed can vary
widely, and therefore, can derive from the preferred dosage regimen
set forth above.
I. Kits
[0338] This invention also is directed, in part, to a kit
comprising one or more compounds and/or salts of the in invention.
The kit can optionally contain one or more additional therapeutic
agents and/or instructions for, for example, using the kit.
J. Methods of Use
[0339] This invention also is directed, in part, to a method for
inhibiting HCV serine protease. The method comprises exposing the
protease to one or more compounds and/or salts of this invention.
In some embodiments, the HCV serine protease is inhibited in vitro.
In other embodiments, the HCV serine protease is inhibited in
vivo.
[0340] The term "inhibiting" means reducing the level of HCV serine
protease activity either in vitro or in vivo. If a compound/salt of
the invention reduces the protease activity compared to the level
of protease activity before the virus was exposed to the
compound/salt, then the compound/salt inhibits protease activity.
In some embodiments, the compound/salt can inhibit protease
activity by at least about 10%, at least about 20%, at least about
30%, at least about 40%, at least about 50%, at least about 60%, at
least about 70%, at least about 80%, at least about 90%, or at
least about 95%.
[0341] This invention also is directed, in part, to a method for
treating a disease that can be treated by inhibiting HCV serine
protease. Thus, this invention also is directed, in part, to a
method for treating hepatitis C in an animal in need of such
treatment. These methods comprise administering to the animal one
or more compounds and/or salts of the invention, and, optionally,
one or more additional therapeutic agents. In some embodiments, a
therapeutically effective amount of the compound(s) and/or salt(s)
is administered to the animal "Treating" means ameliorating,
suppressing, eradicating, preventing, reducing the risk of, and/or
delaying the onset of the disease being treated. The methods of
treatment are particularly suitable for use with humans, but may be
used with other animals, particularly mammals. A
"therapeutically-effective amount" or "effective amount" is an
amount that will achieve the goal of treating the targeted
condition.
[0342] In some embodiments, the methods comprise combination
therapy, wherein the compound(s) and/or salt(s) of the invention
is/are co-administered with a second (or even a third, fourth,
etc.) compound, such as, for example, another therapeutic agent
used to treat hepatitis C (e.g., interferon or interferon/ribavirin
combination). In these embodiments, the compound(s) and/or salt(s)
of the invention and the second therapeutic agent may be
administered in a substantially simultaneous manner (e.g., within
about 5 minutes of each other), in a sequential manner, or both. It
is contemplated that such combination therapies may include
administering one therapeutic agent multiple times between the
administrations of the other. The time period between the
administration of each agent may range from a few seconds (or less)
to several hours or days, and will depend on, for example, the
properties of each composition and active ingredient (e.g.,
potency, solubility, bioavailability, half-life, and kinetic
profile), as well as the condition of the patient.
[0343] This invention also is directed, in part, to a use of one or
more compounds and/or salts of the invention, and, optionally one
or more additional therapeutic agents to prepare a medicament. In
some embodiments, the medicament is for co-administration with one
or more additional therapeutic agents.
[0344] In some embodiments, the medicament is for inhibiting the
HCV serine protease enzyme.
[0345] In some embodiments, the medicament is for treating
hepatitis C.
EXAMPLES
[0346] The following examples are merely illustrative, and not
limiting to this disclosure in any way.
Example 1
Preparation of
##STR00021##
[0347] Part A. Preparation of 4-oxo-pyrrolidine-1,3-dicarboxylic
acid 1-tert-butyl ester 3-ethyl ester
[0348] To a solution of BOC glycine methyl ester (J. Med. Chem.
2001, 44, 8, 1192-1201) (19.2 g, 101.5 mmol) in THF at 0.degree. C.
was added dropwise ethyl acrylate (11 mL, 101.5 mmol) over 10
minutes. The solution was stirred for 20 minutes, then KO.sup.tBu
(111.65 mL, 111.65 mmol) was added over 45 minutes. The solution
was allowed to warm to 25.degree. C. overnight. The resulting
solution concentrated in vacuo and portioned between ethyl acetate
and water containing 5 mL of acetic acid. The ethyl acetate layer
was removed and aqueous layer extracted with 2.times.200 mL of
ethyl acetate. The combined ethyl acetate layers were washed with
brine, dried over MgSO.sub.4, filtered and concentrated in vacuo to
afford an oil. MS (DCI/NH.sub.4) m/z=258 (M+H)+, 275
(M+NH.sub.4)+.
Part B. Preparation of
4-(1-phenyl-ethylamino)-2,5-dihydro-pyrrole-1,3-dicarboxylic acid
1-tert-butyl ester 3-ethyl ester
[0349] To a solution of the product from Part A (21 g, 81.6 mmol)
in ethanol (257) containing acetic acid (9.29 mL, 163.2 mmol) was
added d,l-alpha-methylbenzyl amine (20.77 mL, 163.20 mmol) in one
portion and the reaction mixture was stirred for 3 hours at room
temperature. The reaction mixture was poured over water and
extracted with ethyl acetate (3.times.300 mL), the combined organic
layers were dried over MgSO.sub.4, filtered and concentrated in
vacuo to afford an oil that was purified by flash chromatography on
SiO.sub.2 using ethyl acetate in hexanes as the mobile phase.
Part C. Preparation of
4-(1-phenyl-ethylamino)-pyrrolidine-1,3-dicarboxylic acid
1-tert-butyl ester 3-ethyl ester
[0350] A solution of Na(OAc).sub.3BH was prepared in acetic acid.
This solution was cooled in an ice bath and the imine product from
Part B (81.6 mmol) in 20 mL of acetic acid added in one portion.
The solution was warmed to 25.degree. C. and stirred for several
hours then quenched by pouring the solution over ice, diluting with
water and adjust the pH to 8 with NaOH followed by extracting the
product into diethyl ether (3.times.100 mL). The combined organic
layers were washed with brine and dried over MgSO.sub.4, filtered
and concentrated in vacuo to afford an oil that was purified by
flash chromatography on SiO.sub.2 using ethyl acetate in hexanes as
the mobile phase. MS (DCI/NH.sub.4) m/z=363 (M+H)+.
Part D. Preparation of 4-amino-pyrrolidine-1,3-dicarboxylic acid
1-tert-butyl ester 3-ethyl ester
[0351] A solution of the product from Part C (9.7 g, 26.8 mmol),
Pd(OH).sub.2/carbon (200 mg) in ethanol (200 mL) was treated with
H.sub.2 at 60 psi and room temperature. The solution was filtered
through celite and concentrated to a foam. MS (DCI/NH.sub.4)
m/z=259 (M+H)+.
Part E. Preparation of
cyclohexyl-[(pyrazine-2-carbonyl)-amino]acetic acid
[0352] To a solution containing 2-pyrazine carboxylic acid (10 g,
80.5 mmol) in dichloromethane (150 mL) was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDC
(18.5 g, 96.6 mmol) and 1-hydroxybenzotriazole HOBT (13.05 g, 96.6
mmol) and the resulting solution stirred at 25.degree. C. for 30
minutes. Then 1-cyclohexylglycine methyl ester (16.7 g, 80.5 mmol)
and Hunig's base (31.24 g, 241 mmol) was added and the reaction
mixture stirred for 2 hours. The reaction mixture was partitioned
between water and dichloromethane. The organic layer was removed
and dried over MgSO.sub.4, filtered and concentrated in vacuo and
purified via flash chromatography using ethyl acetate/hexane (20/80
to 30/70) to give a foam (13.3 g, 60%).
[0353] The product of the previous reaction (6.54 g, 24 mmol) was
dissolved in ethanol and treated with 1N sodium hydroxide (35.4 mL,
35.3 mmol) at 25.degree. C. for 4 hours. The mixture was
neutralized with 10% HCl to pH 4 and extracted with
dichloromethane. The organic layer was removed and dried over
MgSO.sub.4, filtered and concentrated in vacuo to afford a foam (5
g, 81%).
Part F. Preparation of
2-{2-cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimethyl-
-butyric acid tert-butyl ester
[0354] To a solution of the product from Part E (4.49 g, 17.1 mmol)
in methylene chloride (25 mL) was added EDC (3.93 g, 20.5 mmol) and
HOBT (2.76 g, 20.5 mmol). The resulting solution was stirred at
25.degree. C. for 20 minutes followed by the addition of Hunig's
base (6.55 mL, 37.6 mmol) and tert-leucine tert-butyl ester
hydrochloride (3.82 g, 17.1 mmol). After stirring for 2 hours, the
reaction mixture was partitioned between water and dichloromethane.
The organic layer was removed and dried over MgSO.sub.4, filtered
and concentrated in vacuo to afford a foam (7.24 g, 98% yield). MS
(DCI/NH.sub.4) m/z=433 (M+H)+.
Part G. Preparation of
2-{2-cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimethyl-
-butyric acid
[0355] The product from Part F (1.43 g, 3.3 mmol) was taken up in
methylene chloride (5 mL) and treated with TFA (5 mL) at 25.degree.
C. for 2 hours. The reaction mixture was concentrated in vacuo and
partitioned between water and methylene chloride. The organic layer
was removed and dried over MgSO.sub.4, filtered and concentrated in
vacuo to afford a foam (1.1 g, 88% yield). MS (ESI+) m/z=377
(M+H)+, 399 (M+Na)+; MS (ESI-) m/z=375 (M-H)-.
Part H. Preparation of
4-(2-{2-cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimet-
hyl-butyrylamino)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl
ester 3-ethyl ester
[0356] To a solution of the product from Part G (0.300 g, 0.694
mmol) in methylene chloride (10 mL) was added EDC (0.159 g, 0.832
mmol) and HOBT (0.112 g, 0.832 mmol) and the resulting solution
stirred at 25.degree. C. for 20 minutes. Then, Hunig's base (0.289
mL, 1.665 mmol) and 4-Amino-pyrrolidine-1,3-dicarboxylic acid
1-tert-butyl ester 3-ethyl ester (0.179 g, 0.694 mmol) was added
and the reaction continued for 18 hours at room temperature. The
reaction mixture was partitioned between water and dichloromethane.
The organic layer was removed and dried over MgSO.sub.4, filtered
and concentrated in vacuo to afford a foam (0.305 g, 71% yield).
Separation of diasteromers was accomplished with a Waters delta
prep C.sub.18 column with a water and acetonitrile gradient.
Part I. Preparation of
4-(2-{2-cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimet-
hyl-butyrylamino)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl
ester
[0357] To a solution of the product from Part H (0.150 g, 0.243
mmol) in ethanol (2 mL) was added 1 N NaOH (0.486 mL, 0.486 mmol)
for 4 hours. The solution was diluted with water and the pH
adjusted with 1N HCl. The product was extracted into methylene
chloride (3.times.30 mL), dried over MgSO.sub.4, filtered and
concentrated in vacuo to afford a foam (0.75 g, 52% yield). MS
(DCI/NH.sub.4) m/z=589 (M+H)+, 606 (M+NH.sub.4)+.
Part J. Preparation of
##STR00022##
[0359] To a solution of the product from Part I (75 mg, 0.127 mmol)
in 2 mL of dichloromethane was added EDC (29.3 mg, 0.153 mmol) and
HOBT (20.7 mg, 0.153 mmol). The resulting solution was stirred at
25.degree. C. for 20 minutes followed by the addition of Hunig's
base (50 uL, 0.280 mmol) and
3-amino-N-cyclopropyl-2-hydroxyhexanamide (as can be found in
WO2002018369-A2; Example 119, cpd xiii') (23.4 mg, 0.127 mmol) and
the reaction continued for 2 hours at room temperature. The
reaction mixture was partitioned between water and dichloromethane.
The organic layer was removed and dried over MgSO.sub.4, filtered
and concentrated in vacuo to afford a foam (0.856 g, 89% yield). MS
(DCI/NH.sub.4) m/z=757 (M+H)+, 744 (M+NH.sub.4)+.
Part K. Preparation of Title Product
[0360] To a solution of the product from Part J (40 mg, 0.053 mmol)
in dichloromethane (2 mL) was added Dess-Martin periodine (34 mg,
0.079 mmol) at 25.degree. C. and the reaction mixture stirred for 1
hour. The reaction was quenched with Na.sub.2S.sub.2O.sub.3 (sat.
aqueous) and the product was extracted into methylene chloride
(3.times.30 mL), dried over MgSO.sub.4, filtered and concentrated
in vacuo to afford a foam (0.75 g, 52% yield) that was purified by
prep TLC SiO.sub.2, (1.0 mm.times.20 mm.times.20 mm) using methanol
in dichloromethane as the mobile phase. The title product was
isolated as a white solid (30.9 mg, 78% yield). MS (ESI+) m/z=755
(M+H)+; MS (ESI-) m/z=753 (M-H)-
Example 2
Preparation of
##STR00023##
[0361] Part A. Preparation of
##STR00024##
[0363] To a solution of the product from Example 1, Part H (100 mg,
0.162 mmol) in 2 mL of dichloromethane was added 2 mL of TFA. The
reaction mixture was stirred for 45 minutes and then concentrated
in vacuo to afford a solid that was placed on high vacuum
overnight. MS (ESI+) m/z=517 (M+H)+; MS (ESI-) m/z=515 (M-H).
Part B. Preparation of
##STR00025##
[0365] To a solution of the product of Part A (132.6 mg, 0.257
mmol) in 2 mL of dichoromethane was added Hunig's base (0.89 mL,
0.513 mmol) and CBZ-NOS (70.4 mg, 0.282 mmol). The reaction was
stirred at 25.degree. C. for 40 minutes. Poured the reaction
mixture over 0.5N HCl and extracted with dichloromethane
(3.times.30 mL) The organic layer was removed and dried over
MgSO.sub.4, filtered and concentrated in vacuo to afford a foam
that was purified by reverse phase HPLC chromatography on C.sub.18
column using water/acetonitrile as the mobile phase to yield pure
diastereomers of the above compound. MS (ESI+) m/z=651 (M+H)+; MS
(ESI-) m/z=649 (M-H)-.
Part C. Preparation of
##STR00026##
[0367] The product from Part B (27 mg, 0.042 mmol) was taken up in
2 mL of ethanol containing 1N NaOH (0.46 mmol) and the resulting
solution stirred for 1 hour. The reaction mixture was poured over
0.5 N HCl and extracted with dichloromethane (3.times.30 mL). The
combined organic layers were dried over MgSO.sub.4, filtered and
concentrated in vacuo to afford a white foam (26 mg, 100% yield).
MS (DCI/NH.sub.4) m/z=623 (M+H)+, 640 (M+NH.sub.4)+.
Part D. Preparation of
##STR00027##
[0369] To a solution of the product from Part C (27 mg, 0.043 mmol)
in 1 mL of dichloromethane was added EDC (10 mg, 0.052 mmol) and
HOBT (7.0 mg, 0.052 mmol) and the resulting solution stirred at
25.degree. C. for 20 minutes. Then, Hunig's base (16 uL, 0.096
mmol) and 3-amino-N-cyclopropyl-2-hydroxyhexanamide
(WO2002018369-A2; Example 119, cpd xiii') (8.0 mg, 0.052 mmol) was
added and the reaction continued for 1 hour at room temperature.
The reaction mixture was partitioned between water and
dichloromethane. The organic layer was removed and dried over
MgSO.sub.4, filtered and concentrated in vacuo to afford a foam (14
mg, 41% yield). MS (ESI+) m/z=791 (M+H)+; MS (ESI-) m/z=789
(M-H)-.
Part E. Preparation of Title Product
[0370] To a solution of the product from Part D (14 mg, 0.018 mmol)
in 1 mL of dichloromethane was added Dess-Martin periodinane (11.3
mg, 0.027 mmol) for 1 hour. The reaction was quenched with Na2S2O3
(sat. aqueous) and the product was extracted into methylene
chloride (3.times.30 mL), dried over MgSO.sub.4, filtered and
concentrated in vacuo to afford a foam (0.75 g, 52% yield) that was
purified by prep TLC SiO.sub.2, (1.0 mm.times.20 mm.times.20 mm)
using methanol in dichloromethane as the mobile phase. The title
product was isolated as a white solid (6.8 mg, 49% yield). MS
(ESI+) m/z=789 (M+H)+; MS (ESI-) m/z=787 (M-H)-.
Example 3
Preparation of
##STR00028##
[0371] Part A. Preparation of
##STR00029##
[0373] To a solution of the Example 1G (358.9 mg, 0.953 mmol) in
methylene chloride (5 mL) was added EDC (219 mg, 1.144 mmol) and
HOBT (155 mg, 1.144 mmol) and the resulting solution stirred at
25.degree. C. for 20 minutes. Then, Hunig's base (0.36 mL, 2.097
mmol) and (3R,4R)-di-tert-butyl
4-aminopyrrolidine-1,3-dicarboxylate (Org. Biomol. Chem. 2004, 2,
2763-2776) (273 mg, 0.953 mmol) was added and the reaction
continued for 18 hours at room temperature. The reaction mixture
was partitioned between water and dichloromethane. The organic
layer was removed and dried over MgSO.sub.4, filtered and
concentrated in vacuo to afford a foam that was purified by flash
chromatography on SiO.sub.2 using methanol in dichloromethane as
the mobile phase. The title compound was isolated as a white foam
(542 mg, 88% yield). MS (ESI+) m/z=645 (M+H)+; MS (ESI-) m/z=643
(M-H)-.
Part B. Preparation of
##STR00030##
[0375] To a solution of the product from Part A (59.1 mg, 0.917
mmol) in ethyl acetate (4 mL) was added 4N HCl in dioxane (0.8 mL,
3.2 mmol) and the reaction mixture stirred for 5 hours at room
temperature. The resulting precipitate was filtered through a paper
disk, washed with ethyl acetate, and dried in vacuo yielding 28.1
mg of the title compound as a crystalline white solid, 56% yield.
MS (ESI+) m/z=545 (M+H)+; MS (ESI-) m/z=543 (M-H)-.
Part C. Preparation of
##STR00031##
[0377] To a solution of the amine product from Part B (84.0 mg,
0.155 mmol), Hunig's base (81 uL, 0.465 mmol) and 4 mL of
dichloromethane was added phenyl isocyanate (42 uL, 0.233 mmol) and
the reaction mixture stirred for 18 hours. The reaction mixture was
poured over 1N HCl and extracted with dichloromethane (3.times.30
mL). The combined organic layers were dried over MgSO.sub.4,
filtered and concentrated in vacuo to afford a foam.
[0378] The above compound was treated with 2 mL of dichloromethane
and 2 mL of TFA for 45 minutes. The solution was concentrated in
vacuo to afford an oil that was placed on high vacuum overnight. MS
(ESI+) m/z=608 (M+H)+; MS (ESI-) m/z=606 (M-H)-.
Part D. Preparation of
##STR00032##
[0380] The product of Part C (0.155 mmol) was taken up in 4 mL of
dichloromethane and treated with EDC (45 mg, 0.233 mmol) and HOBT
(34 mg, 0.233 mmol) for 20 minutes followed by the addition of
Hunig's base (60 uL, 0.341 mmol) and
3-amino-N-cyclopropyl-2-hydroxyhexanamide (WO2002018369-A2; Example
119, cpd xiii') (28.0 mg, 0.155 mmol). The reaction continued for
18 hours at room temperature. The reaction mixture was partitioned
between water and dichloromethane. The organic layer was removed
and dried over MgSO.sub.4, filtered and concentrated in vacuo to
afford a foam that was purified by flash chromatography on
SiO.sub.2 using methanol in dichloromethane as the mobile phase to
afford the title compound as a white solid. 23 mg, 20% yield.
Part E. Preparation of Title Product
[0381] To a solution of the product from Part D (23 mg, 0.030 mmol)
in 1 mL of dichloromethane was added Dess-Martin periodinane (19
mg, 0.045 mmol) for 1 hour. The reaction was quenched with
Na.sub.2S.sub.2O.sub.3 (sat. aqueous) and the product was extracted
into methylene chloride (3.times.30 mL), dried over MgSO.sub.4,
filtered and concentrated in vacuo to afford a white solid that was
purified by prep TLC SiO.sub.2, (1.0 mm.times.20 mm.times.20 mm)
using methanol in dichloromethane as the mobile phase. The title
product was isolated as a white solid (17 mg, 74% yield). MS (ESI+)
m/z=774 (M+H)+; MS (ESI-) m/z=772 (M-H)-.
Example 4
Preparation of
##STR00033##
[0382] Part A. Preparation of
##STR00034##
[0384] To a solution of the product from Example 3, Part B (136 mg,
0.278 mmol) in 3 mL of dichloromethane and 3 mL of 1N NaOH was
added benzoyl chloride (38 uL, 0.334 mmol) for 2 hours. The
reaction mixture was poured water and extracted with diethyl ether,
then the pH of the aqueous layer was adjusted to pH-2 with 1N HCl
and extract with ethyl acetate (3.times.30 mL). The combined
organic layers were dried over MgSO.sub.4, filtered and
concentrated in vacuo to afford a foam. MS (ESI+) m/z=593 (M+H)+;
MS (ESI-) m/z=591 (M-H)-.
Part B. Preparation of
##STR00035##
[0386] To a solution of the product from Part A (89 mg, 0.152 mmol)
in 2 mL of dichloromethane was added EDC (43 mg, 0.225 mmol) and
HOBT (30.0 mg, 0.225 mmol) and the resulting solution stirred at
25.degree. C. for 20 minutes. Then, Hunig's base (86 uL, 0.495
mmol) and 3-amino-N-cyclopropyl-2-hydroxyhexanamide
(WO2002018369-A2; Example 119, cpd xiii') (42 mg, 0.225 mmol) was
added and the reaction continued for 2 hours at room temperature.
The reaction mixture was partitioned between water and
dichloromethane. The organic layer was removed and dried over
MgSO.sub.4, filtered and concentrated in vacuo to afford a foam
that was purified by flash chromatography on SiO.sub.2 using
methanol in dichloromethane as the mobile phase to afford the title
compound as a white solid (44 mg, 38% yield) MS (ESI+) m/z=761
(M+H)+; MS (ESI-) m/z=759 (M-H)-.
Part C. Preparation of Title Product
[0387] To a solution of the product from Part B (44 mg, 0.058 mmol)
in 5 mL of dichloromethane was added Dess-Martin periodinane (37
mg, 0.087 mmol) for 1 hour. The reaction was quenched with
Na.sub.2S.sub.2O.sub.3 (sat. aqueous) and the product was extracted
into methylene chloride (3.times.30 mL), dried over MgSO.sub.4,
filtered and concentrated in vacuo to afford a white solid that was
purified by prep TLC SiO.sub.2, (1.0 mm.times.20 mm.times.20 mm)
using methanol in dichloromethane as the mobile phase. The title
product was isolated as a white solid (24 mg, 55% yield). MS (ESI+)
m/z=759 (M+H)+; MS (ESI-) m/z=757 (M-H)-.
Example 5
Preparation of
##STR00036##
[0388] Part A. Preparation of
##STR00037##
[0390] To a solution of the product from Example 3, Part B (140 mg,
0.257 mmol) in 4 mL of pyridine was added acetic anhydride (25 uL,
0.257 mmol) and the reaction continued at 25.degree. C. for 4
hours. The reaction mixture was partitioned between water and ethyl
acetate. The organic layer was removed and washed sequentially with
bicarbonate, brine, dried over MgSO4, filtered and concentrated in
vacuo to afford the title compound as a white solid (9.1 mg, 61%
yield). MS (ESI+) m/z=587 (M+H)+; MS (ESI-) m/z=585 (M-H)-.
Part B. Preparation of
##STR00038##
[0392] To a solution of the product from Part A (90 mg, 0.153 mmol)
in 4 mL of dichloromethane was added 2 mL of TFA. The reaction
mixture was stirred for 45 minutes and then concentrated in vacuo
to afford a solid that was placed on high vacuum overnight. MS
(ESI+) m/z=531 (M+H)+; MS (ESI-) m/z=529 (M-H)-.
Part C. Preparation of
##STR00039##
[0394] To a solution of the product from Part B (74 mg, 0.140 mmol)
in 2 mL of dichloromethane was added EDC (40 mg, 0.209 mmol) and
HOBT (28 mg, 0.209 mmol) and the resulting solution stirred at
25.degree. C. for 20 minutes. Then, Hunig's base (73 uL, 0.419
mmol) and 3-amino-N-cyclopropyl-2-hydroxyhexanamide
(WO2002018369-A2; Example 119, cpd xiii') (29 mg, 0.153 mmol) was
added and the reaction continued for 2 hours at room temperature.
The reaction mixture was partitioned between water and
dichloromethane. The organic layer was removed and dried over
MgSO.sub.4, filtered and concentrated in vacuo to afford a foam
that was purified by flash chromatography on SiO.sub.2 using
methanol in dichloromethane as the mobile phase to afford the title
compound as a white solid (30 mg, 31% yield). MS (ESI+) m/z=761
(M+H)+; MS (ESI-) m/z=759 (M-H)-.
Part D. Preparation of Title Product
[0395] To a solution of the product from Part C (30 mg, 0.043 mmol)
in 4 mL of dichloromethane was added Dess-Martin periodinane (27
mg, 0.064 mmol) for 1 hour. The reaction was quenched with
Na.sub.2S.sub.2O.sub.3 (sat. aqueous) and the product was extracted
into methylene chloride (3.times.30 mL), dried over MgSO.sub.4,
filtered and concentrated in vacuo to afford a white solid that was
purified by prep TLC SiO.sub.2, 1.0 mm.times.20 mm.times.20 mm
using methanol in dichloromethane as the mobile phase. The title
product was isolated as a white solid (17 mg, 56% yield). MS (ESI+)
m/z=697 (M+H)+; MS (ESI-) m/z=695 (M-H)-.
Example 6
Preparation of
##STR00040##
[0396] Part A. Preparation of
##STR00041##
[0398] To a solution of the product from Example 3, Part B (140 mg,
0.257 mmol) in 5 mL of dichloromethane was added EDC (74 mg, 0.386
mmol) and HOBT (52 mg, 0.386 mmol) and the resulting solution
stirred at 25.degree. C. for 20 minutes. Then, Hunig's base (134
uL, 0.771 mmol) and CBZ-Gly-OH (65 mg, 0.2084 mmol) was added and
the reaction continued for 2 hours at room temperature. The
reaction mixture was partitioned between water and dichloromethane.
The organic layer was removed and dried over MgSO.sub.4, filtered
and concentrated in vacuo to afford a foam that was purified by
flash chromatography on SiO.sub.2 using methanol in dichloromethane
as the mobile phase to afford the title compound as a white solid
(65 mg, 34% yield). MS (ESI+) m/z=736 (M+H)+; MS (ESI-) m/z=734
(M-H)-.
Part B. Preparation of
##STR00042##
[0400] To a solution of the product from Part A (53 mg, 0.072 mmol)
in 4 mL of dichloromethane was added 2 mL of TFA. The reaction
mixture was stirred for 45 minutes and then concentrated in vacuo
to afford a solid that was placed on high vacuum overnight. MS
(ESI+) m/z=680 (M+H)+; MS (ESI-) m/z=678 (M-H)-.
Part C. Preparation of
##STR00043##
[0402] To a solution of the product from Part B (60 mg, 0.088 mmol)
in 5 mL of dichloromethane was added EDC (25 mg, 0.133 mmol) and
HOBT (18 mg, 0.133 mmol) and the resulting solution stirred at
25.degree. C. for 20 minutes. Then, Hunig's base (46 uL, 0.265
mmol) and 3-amino-N-cyclopropyl-2-hydroxyhexanamide
(WO2002018369-A2; Example 119, cpd xiii') (20 mg, 0.106 mmol) was
added and the reaction continued for 2 hours at room temperature.
The reaction mixture was partitioned between water and
dichloromethane. The organic layer was removed and dried over
MgSO.sub.4, filtered and concentrated in vacuo to afford a foam
that was purified by flash chromatography on SiO.sub.2 using
methanol in dichloromethane as the mobile phase to afford the title
compound as a white solid (47 mg, 63% yield). MS (ESI+) m/z=680
(M+H)+; MS (ESI-) m/z=678 (M-H)-.
Part D. Preparation of Title Product
[0403] To a solution of the product from Part C (45 mg, 0.053 mmol)
in 4 mL of dichloromethane was added Dess-Martin periodinane (34
mg, 0.079 mmol) for 1 hour. The reaction was quenched with
Na.sub.2S.sub.2O.sub.3 (sat. aqueous) and the product was extracted
into methylene chloride (3.times.30 mL), dried over MgSO.sub.4,
filtered and concentrated in vacuo to afford a white solid that was
purified by prep TLC SiO.sub.2, 1.0 mm.times.20 mm.times.20 mm
using methanol in dichloromethane as the mobile phase. The title
product was isolated as a white solid (2.1 mg, 47% yield). MS
(ESI+) m/z=846 (M+H)+; MS (ESI-) m/z=844 (M-H)-.
Example 7
Preparation of
##STR00044##
[0404] Part A. Preparation of
##STR00045##
[0406] To a solution of the product from Example 6, Part B (60 mg,
0.088 mmol) in 5 mL of dichloromethane was added EDC (25 mg, 0.133
mmol) and HOBT (18 mg, 0.133 mmol) and the resulting solution
stirred at 25.degree. C. for 20 minutes. Then, Hunig's base (46 uL,
0.265 mmol) and hydroxyamide (WO2003062265-A2; Example 6, cpd 2.3)
(42 mg, 0.106 mmol) was added and the reaction continued for 2
hours at room temperature. The reaction mixture was partitioned
between water and dichloromethane. The organic layer was removed
and dried over MgSO.sub.4, filtered and concentrated in vacuo to
afford a foam that was purified by flash chromatography on
SiO.sub.2 using methanol in dichloromethane as the mobile phase to
afford the title compound as a white solid (49 mg, 54% yield). MS
(ESI+) m/z=1026 (M+H)+; MS (ESI-) m/z=1024 (M-H)-.
Part B. Preparation of Title Product
[0407] To a solution of the product from Part A (30 mg, 0.029 mmol)
in 2 mL of dichloromethane was added Dess-Martin periodinane (19
mg, 0.044 mmol) for 1 hour. The reaction was quenched with
Na.sub.2S.sub.2O.sub.3 (sat. aqueous) and the product was extracted
into methylene chloride (3.times.30 mL), dried over MgSO.sub.4,
filtered and concentrated in vacuo to afford a white solid that was
purified by prep TLC SiO.sub.2, (1.0 mm.times.20 mm.times.20 mm)
using methanol in dichloromethane as the mobile phase. The title
product was isolated as a white solid (25 mg, 83% yield). MS (ESI+)
m/z=1024 (M+H)+; MS (ESI-) m/z=1022 (M-H)-.
Example 8
Preparation of
##STR00046##
[0408] Part A. Preparation of
##STR00047##
[0410] To a solution of the product from Example 3, Part B (86 mg,
0.158 mmol) in 5 mL of dichloromethane was added Hunig's base (82
uL, 0.474 mmol) and methyl chloroformate (18 uL, 0.237 mmol). The
reaction was stirred at 25.degree. C. for 2 hours. The reaction
mixture was partitioned between water and dichloromethane. The
organic layer was removed and dried over MgSO.sub.4, filtered, and
concentrated in vacuo to afford a white solid (76 mg, 80% yield).
MS (ESI+) m/z=603 (M+H)+; MS (ESI-) m/z=601 (M-H)-.
Part B. Preparation of
##STR00048##
[0412] To a solution of the product from Part A (73 mg, 0.126 mmol)
in 4 mL of dichloromethane was added 4 mL of TFA. The reaction
mixture was stirred for 2 hours and then concentrated in vacuo to
afford a solid that was placed on high vacuum overnight. The
reaction mixture was partitioned between water and dichloromethane.
The organic layer was removed and dried over MgSO4, filtered and
concentrated in vacuo to afford a white solid. MS (ESI+) m/z=547
(M+H)+; MS (ESI-) m/z=545 (M-H)-.
Part C. Preparation of
##STR00049##
[0414] To a solution of the product from Part B (40 mg, 0.073 mmol)
in 5 mL of dichloromethane was added EDC (2.1 mg, 0.110 mmol) and
HOBT (16 mg, 0.110 mmol) and the resulting solution stirred at
25.degree. C. for 20 minutes. Then, Hunig's base (38 uL, 0.220
mmol) and 3-amino-N-cyclopropyl-2-hydroxyhexanamide
(WO2002018369-A2; Example 119, cpd xiii') (16 mg, 0.088 mmol) was
added and the reaction continued for 2 hours at room temperature.
The reaction mixture was partitioned between water and
dichloromethane. The organic layer was removed and dried over
MgSO.sub.4, filtered and concentrated in vacuo to afford a foam
that was purified by flash chromatography on SiO.sub.2 using
methanol in dichloromethane as the mobile phase to afford the title
compound as a white solid (28 mg, 55% yield). MS (ESI+) m/z=715
(M+H)+; MS (ESI-) m/z=713 (M-H)-.
Part D. Preparation of Title Product
[0415] To a solution of the product from Part C (52 mg, 0.073 mmol)
in 5 mL of dichloromethane was added Dess-Martin periodinane (46
mg, 0.1098 mmol) for 1 hour. The reaction was quenched with
Na.sub.2S.sub.2O.sub.3 (sat. aqueous) and the product was extracted
into methylene chloride (3.times.30 mL), dried over MgSO.sub.4,
filtered and concentrated in vacuo to afford a white solid that was
purified by prep TLC SiO.sub.2, (1.0 mm.times.20 mm.times.20 mm)
using methanol in dichloromethane as the mobile phase. The title
product was isolated as white solid (15 mg, 28% yield). MS (ESI+)
m/z=713 (M+H)+; MS (ESI-) m/z=711 (M-H)-.
Example 9
Preparation of
##STR00050##
[0416] Part A. Preparation of
##STR00051##
[0418] To a solution of the product from Example 3, Part B (50 mg,
0.092 mmol) in 4 mL of dichloromethane was added Hunig's base (48
uL, 0.274 mmol) and FMOC chloroformate (36 mg, 0.138 mmol). The
reaction was stirred at 25.degree. C. for 2 hours. The reaction
mixture was partitioned between water and dichloromethane. The
organic layer was removed and dried over MgSO.sub.4, filtered, and
concentrated in vacuo to afford a white solid (61 mg, 87% yield).
MS (ESI+) m/z=767 (M+H)+
Part B. Preparation of
##STR00052##
[0420] To a solution of the product from Part A (60 mg, 0.078 mmol)
in 5 mL of dichloromethane was added 5 mL of TFA. The reaction
mixture was stirred for 2 hours and then concentrated in vacuo to
afford a solid that was placed on high vacuum overnight. The
reaction mixture was partitioned between water and dichloromethane.
The organic layer was removed and dried over MgSO.sub.4, filtered
and concentrated in vacuo to afford a white solid (43 mg, 77%
yield). MS (ESI+) m/z=711 (M+H)+.
Part C. Preparation of
##STR00053##
[0422] To a solution of the product Part B (39 mg, 0.054 mmol) in 5
mL of dichloromethane was added EDC (16 mg, 0.081 mmol) and HOBT
(11 mg, 0.081 mmol) and the resulting solution stirred at
25.degree. C. for 20 minutes. Then, Hunig's base (85 uL, 0.488
mmol) and 3-amino-N-cyclopropyl-2-hydroxyhexanamide
(WO2002018369-A2; Example 119, cpd xiii') (12 mg, 0.065 mmol) was
added and the reaction continued for 2 hours at room temperature.
The reaction mixture was partitioned between water and
dichloromethane. The organic layer was removed and dried over
MgSO.sub.4, filtered and concentrated in vacuo to afford a foam
that was purified by flash chromatography on SiO.sub.2 using
methanol in dichloromethane as the mobile phase to afford the title
compound as a white solid (17 mg, 36% yield). MS (ESI+) m/z=880
(M+H)+.
Part D. Preparation of Title Product
[0423] To a solution of the product from Part C (15 mg, 0.017 mmol)
in 2 mL of dichloromethane was added Dess-Martin periodinane (1.1
mg, 0.026 mmol) for 1 hour. The reaction was quenched with
Na.sub.2S.sub.2O.sub.3 (sat. aqueous) and the product was extracted
into methylene chloride (3.times.30 mL), dried over MgSO.sub.4,
filtered and concentrated in vacuo to afford a white solid that was
purified by prep TLC SiO.sub.2, (1.0 mm.times.20 mm.times.20 mm)
using methanol in dichloromethane as the mobile phase. The title
product was isolated as white solid (15 mg, 93% yield). MS (ESI+)
m/z=877 (M+H)+; MS (ESI-) m/z=875 (M-H)-.
Example 10
Preparation of
##STR00054##
[0424] Part A. Preparation of
##STR00055##
[0426] To a solution of the product from Example 3, Part B (50 mg,
0.086 mmol) in 5 mL of dichloromethane was added Hunig's base (45
uL, 0.258 mmol) and phenyl chloroformate (16 uL, 0.129 mmol). The
reaction was stirred at 25.degree. C. for 2 hours. The reaction
mixture was partitioned between water and dichloromethane. The
organic layer was removed and dried over MgSO.sub.4, filtered, and
concentrated in vacuo to afford white solid. MS (ESI+) m/z=665
(M+H)+; MS (ESI-) m/z=663 (M-H)-.
Part B. Preparation of
##STR00056##
[0428] The product from Part A was taken up in 5 mL of
dichloromethane and 5 mL of TFA added. The reaction mixture was
stirred for 2 hours and then concentrated in vacuo to afford a
solid that was placed on high vacuum overnight. The reaction
mixture was partitioned between water and dichloromethane. The
organic layer was removed and dried over MgSO.sub.4, filtered and
concentrated in vacuo to afford a white solid. MS (ESI+) m/z=608
(M+H)+; MS (ESI-) m/z=607 (M-H)-.
Part C. Preparation of
##STR00057##
[0430] To a solution of the product from Part B (0.086 mmol) in 5
mL of dichloromethane was added EDC (21 mg, 0110 mmol) and HOBT (15
mg, 0.110 mmol) and the resulting solution stirred at 25.degree. C.
for 20 minutes. Then, Hunig's base (40 uL, 0.229 mmol) and
3-amino-N-cyclopropyl-2-hydroxyhexan amide (WO2002018369-A2;
Example 119, cpd xiii') (18 mg, 0.097 mmol) was added and the
reaction continued for 2 hours at room temperature. The reaction
mixture was partitioned between water and dichloromethane. The
organic layer was removed and dried over MgSO.sub.4, filtered and
concentrated in vacuo to afford a foam that was purified by flash
chromatography on SiO.sub.2 using methanol in dichloro methane as
the mobile phase to afford the title compound as a white solid (25
mg, 37% yield). MS (ESI+) m/z=777 (M+H)+; MS (ESI-) m/z=775
(M-H)-.
Part D. Preparation of Title Product
[0431] To a solution of the product from Part C (18 mg, 0.023 mmol)
in 2 mL of dichloromethane was added Dess-Martin periodinane (15
mg, 0.036 mmol) for 1 hour. The reaction was quenched with
Na.sub.2S.sub.2O.sub.3 (sat. aqueous) and the product was extracted
into methylene chloride (3.times.30 mL), dried over MgSO.sub.4,
filtered and concentrated in vacuo to afford a white solid that was
purified by prep TLC SiO.sub.2, (1.0 mm.times.20 mm.times.20 mm)
using methanol in dichloromethane as the mobile phase. The title
product was isolated as a white solid (14 mg, 78% yield). MS (ESI+)
m/z=775 (M+H)+; MS (ESI-) m/z=773 (M-H)-
Example 11
Preparation of
##STR00058##
[0432] Part A. Preparation of
##STR00059##
[0434] To a solution of the product from Example 3, Part B (50 mg,
0.086 mmol) in 5 mL of dichloromethane was added Hunig's base (45
uL, 0.258 mmol) and isobutyl chloroformate (17 uL, 0.129 mmol). The
reaction was stirred at 25.degree. C. for 2 hours. The reaction
mixture was partitioned between water and dichloromethane. The
organic layer was removed and dried over MgSO.sub.4, filtered, and
concentrated in vacuo to afford white solid. MS (ESI+) m/z=645
(M+H)+; MS (ESI-) m/z=643 (M-H)-.
Part B. Preparation of
##STR00060##
[0436] The product from Part A was taken up in 5 mL of
dichloromethane and 5 mL of TFA added. The reaction mixture was
stirred for 2 hours and then concentrated in vacuo to afford a
solid that was placed on high vacuum overnight. The reaction
mixture was partitioned between water and dichloromethane. The
organic layer was removed and dried over MgSO.sub.4, filtered and
concentrated in vacuo to afford a white solid. MS (ESI+) m/z=589
(M+H)+; MS (ESI-) m/z=587 (M-H)-.
Part C. Preparation of
##STR00061##
[0438] To a solution of the product from Part B (0.086 mmol) in 5
mL of dichloromethane was added EDC (21 mg, 0110 mmol) and HOBT (15
mg, 0.110 mmol) and the resulting solution stirred at 25.degree. C.
for 20 minutes. Then, Hunig's base (40 uL, 0.229 mmol) and
3-amino-N-cyclopropyl-2-hydroxyhexanamide (WO2002018369-A2; Example
119, cpd xiii') (18 mg, 0.097 mmol) was added and the reaction
continued for 2 hours at room temperature. The reaction mixture was
partitioned between water and dichloromethane. The organic layer
was removed and dried over MgSO.sub.4, filtered and concentrated in
vacuo to afford a foam that was purified by flash chromatography on
SiO.sub.2 using methanol in dichloromethane as the mobile phase to
afford the title compound as a white solid (39 mg, 61% yield). MS
(ESI+) m/z=757 (M+H)+; MS (ESI-) m/z=755 (M-H)-.
Part D. Preparation of Title Product
[0439] To a solution of the product of Part C (17 mg, 0.023 mmol)
in 2 mL of dichloromethane was added Dess-Martin periodinane (15
mg, 0.036 mmol) for 1 hour. The reaction was quenched with
Na.sub.2S.sub.2O.sub.3 (sat. aqueous) and the product was extracted
into methylene chloride (3.times.30 mL), dried over MgSO.sub.4,
filtered and concentrated in vacuo to afford a white solid that was
purified by prep TLC SiO.sub.2, 1.0 mm.times.20 mm.times.20 mm
using methanol in dichloromethane as the mobile phase. The title
product was isolated as a white solid (15 mg, 86% yield). MS (ESI+)
m/z=755 (M+H)+; MS (ESI-) m/z=753 (M-H)-.
Example 12
Preparation of
##STR00062##
[0440] Part A. Preparation of
##STR00063##
[0442] To a solution of the product from Example 3, Part B (50 mg,
0.086 mmol) in 5 mL of dichloromethane was added Hunig's base (45
uL, 0.258 mmol) and 2-naphthyl chloroformate (26 mg, 0.129 mmol).
The reaction was stirred at 25.degree. C. for 2 hours. The reaction
mixture was partitioned between water and dichloromethane. The
organic layer was removed and dried over MgSO.sub.4, filtered, and
concentrated in vacuo to afford white solid. MS (ESI+) m/z=715
(M+H)+; MS (ESI-) m/z=713 (M-H)-.
Part B. Preparation of
##STR00064##
[0444] The product from Part A was taken up in 5 mL of
dichloromethane and 5 mL of TFA added. The reaction mixture was
stirred for 2 hours and then concentrated in vacuo to afford a
solid that was placed on high vacuum overnight. The reaction
mixture was partitioned between water and dichloromethane. The
organic layer was removed and dried over MgSO.sub.4, filtered and
concentrated in vacuo to afford a white solid. MS (ESI+) m/z=659
(M+H)+; MS (ESI-) m/z=657 (M-H)-.
Part C. Preparation of
##STR00065##
[0446] To a solution of the product from Part B (0.086 mmol) in 5
mL of dichloromethane was added EDC (21 mg, 0110 mmol) and HOBT (15
mg, 0.110 mmol) and the resulting solution stirred at 25.degree. C.
for 20 minutes. Then, Hunig's base (40 uL, 0.229 mmol) and
3-amino-N-cyclopropyl-2-hydroxyhexanamide (WO2002018369-A2; Example
119, cpd xiii') (18 mg, 0.097 mmol) was added and the reaction
continued for 2 hours at room temperature. The reaction mixture was
partitioned between water and dichloromethane. The organic layer
was removed and dried over MgSO.sub.4, filtered and concentrated in
vacuo to afford a foam that was purified by flash chromatography on
SiO.sub.2 using methanol in dichloromethane as the mobile phase to
afford the title compound as a white solid (18 mg, 25% yield). MS
(ESI+) m/z=827 (M+H)+; MS (ESI-) m/z=825 (M-H)-.
Part D. Preparation of Title Product
[0447] To a solution of the product from Part C (19 mg, 0.023 mmol)
in 2 mL of dichloromethane was added Dess-Martin periodinane (15
mg, 0.036 mmol) for 1 hour. The reaction was quenched with
Na.sub.2S.sub.2O.sub.3 (sat. aqueous) and the product was extracted
into methylene chloride (3.times.30 mL), dried over MgSO.sub.4,
filtered and concentrated in vacuo to afford a white solid that was
purified by prep TLC SiO.sub.2, 1.0 mm.times.20 mm.times.20 mm
using methanol in dichloromethane as the mobile phase. The title
product was isolated as white solid (12 mg, 65% yield). MS (ESI+)
m/z=825 (M+H)+; MS (ESI-) m/z=823 (M-H)-.
Example 13
Preparation of
##STR00066##
[0448] Part A. Preparation of
##STR00067##
[0450] To a solution of the product from Example 3, Part B (50 mg,
0.086 mmol) in 5 mL of dichloromethane was added Hunig's base (45
uL, 0.258 mmol) and 1-naphthyl chloroformate (21 uL, 0.129 mmol).
The reaction was stirred at 25.degree. C. for 2 hours. The reaction
mixture was partitioned between water and dichloromethane. The
organic layer was removed and dried over MgSO.sub.4, filtered, and
concentrated in vacuo to afford white solid. MS (ESI+) m/z=715
(M+H)+; MS (ESI-) m/z=713 (M-H)-.
Part B. Preparation of
##STR00068##
[0452] The product from Part A was taken up in 5 mL of
dichloromethane and 5 mL of TFA added. The reaction mixture was
stirred for 2 hours and then concentrated in vacuo to afford a
solid that was placed on high vacuum overnight. The reaction
mixture was partitioned between water and dichloromethane. The
organic layer was removed and dried over MgSO.sub.4, filtered and
concentrated in vacuo to afford white solid (43 mg, 77% yield) MS
(ESI+) m/z=659 (M+H)+; MS (ESI-) m/z=657 (M-H)-
Part C. Preparation of
##STR00069##
[0454] To a solution of the product from Part B (0.086 mmol) in 5
mL of dichloromethane was added EDC (21 mg, 0110 mmol) and HOBT (15
mg, 0.110 mmol) and the resulting solution stirred at 25.degree. C.
for 20 minutes. Then, Hunig's base (40 uL, 0.229 mmol) and
3-amino-N-cyclopropyl-2-hydroxyhexanamide (WO2002018369-A2; Example
119, cpd xiii') (18 mg, 0.097 mmol) was added and the reaction
continued for 2 hours at room temperature. The reaction mixture was
partitioned between water and dichloromethane. The organic layer
was removed and dried over MgSO.sub.4, filtered and concentrated in
vacuo to afford a foam that was purified by flash chromatography on
SiO.sub.2 using methanol in dichloromethane as the mobile phase to
afford the title compound as a white solid (39 mg, 55% yield). MS
(ESI+) m/z=827 (M+H)+; MS (ESI-) m/z=825 (M-H)-.
Part D. Preparation of Title Product
[0455] To a solution of the product from Part C (19 mg, 0.023 mmol)
in 2 mL of dichloromethane was added Dess-Martin periodinane (15
mg, 0.036 mmol) for 1 hour. The reaction was quenched with
Na.sub.2S.sub.2O.sub.3 (sat. aqueous) and the product was extracted
into methylene chloride (3.times.30 mL), dried over MgSO.sub.4,
filtered and concentrated in vacuo to afford a white solid that was
purified by prep TLC SiO.sub.2, (1.0 mm.times.20 mm.times.20 mm)
using methanol in dichloromethane as the mobile phase. The title
product was isolated as white solid (14 mg, 75% yield). MS (ESI+)
m/z=825 (M+H)+; MS (ESI-) m/z=823 (M-H)-.
Example 14
Preparation of
##STR00070##
[0456] Part A. Preparation of
##STR00071##
[0458] To a solution of the (3R,4R)-di-tert-butyl
4-aminopyrrolidine-1,3-dicarboxylate (Org. Biomol. Chem. 2004, 2,
2763-2776) (200 mg, 0.698 mmol) in 5 mL of dichloromethane was
added phenyl isocyanate (75 uL, 0.698 mmol) and the reaction
mixture was stirred for 18 hours. The reaction mixture was
partitioned between water and dichloromethane. The organic layer
was removed and dried over MgSO.sub.4, filtered and concentrated in
vacuo to afford a white solid. MS (ESI+) m/z=406 (M+H)+; MS (ESI-)
m/z=404 (M-H)-.
Part B. Preparation of
##STR00072##
[0460] To a solution of the product from Part A (220 mg, 0.543
mmol) in 10 mL of ethyl acetate was added 4N HCl (1.36 mL, 5.42
mmol) and the reaction mixture was stirred for 18 hours. Then the
solution was concentrated in vacuo and triturated with
dichloromethane and hexanes resulting in off white solid. MS (ESI+)
m/z=306 (M+H)+.
Part C. Preparation of
##STR00073##
[0462] To a solution of the amine product from Part B (92 mg, 0.301
mmol), Hunig's base (157 uL, 0.904 mmol) and 4 mL of
dichloromethane was added phenyl isocyanate (32 uL, 0.301 mmol) and
the reaction mixture stirred for 18 hours. The reaction mixture was
poured over water and extracted with dichloromethane (3.times.30
mL). The combined organic layers were dried over MgSO.sub.4,
filtered and concentrated in vacuo to afford a foam that was
purified by flash chromatography on SiO.sub.2 using methanol in
dichloromethane as the mobile phase. The title compound was
isolated as a white solid (65 mg, 51% yield). MS (ESI+) m/z=425
(M+H)+; MS (ESI-) m/z=423 (M-H)-.
Part D. Preparation of
##STR00074##
[0464] The product from Part C (47 mg, 0.111 mmol) was taken up in
4 mL of dichloromethane and 4 mL of TFA added. The reaction mixture
was stirred for 2 hours and then concentrated in vacuo to afford a
solid that was placed on high vacuum overnight. The reaction
mixture was partitioned between water and dichloromethane. The
organic layer was removed and dried over MgSO.sub.4, filtered and
concentrated in vacuo to afford a white solid (36 mg, 88% yield).
MS (ESI+) m/z=368 (M+H)+.
Part E. Preparation of
##STR00075##
[0466] To a solution of the product from Part D (4.1 mg, 0.111
mmol) in 5 mL of dichloromethane was added EDC (32 mg, 0.166 mmol)
and HOBT (22 mg, 0.166 mmol) and the resulting solution stirred at
25.degree. C. for 20 minutes. Then, Hunig's base (58 uL, 0.332
mmol) and hydroxyamide (WO2003062265-A2; Example 6, cpd 2.3) (53
mg, 0.133 mmol) was added and the reaction continued for 2 hours at
room temperature. The reaction mixture was partitioned between
water and dichloromethane. The organic layer was removed and dried
over MgSO.sub.4, filtered and concentrated in vacuo to afford a
foam that was purified by flash chromatography on SiO.sub.2 using
methanol in dichloromethane as the mobile phase to afford the title
compound as a white solid (43 mg, 54% yield). MS (ESI+) m/z=715
(M+H)+; MS (ESI-) m/z=713 (M-H)-.
Part F. Preparation of Title Product
[0467] To a solution of the product from Part E (40 mg, 0.056 mmol)
in 4 mL of dichloromethane was added Dess-Martin periodinane (36
mg, 0.084 mmol) for 1 hour. The reaction was quenched with
Na.sub.2S.sub.2O.sub.3 (sat. aqueous) and the product was extracted
into methylene chloride (3.times.30 mL), dried over MgSO.sub.4,
filtered and concentrated in vacuo to afford a white solid that was
purified by prep TLC SiO.sub.2, (1.0 mm.times.20 mm.times.20 mm)
using methanol in dichloromethane as the mobile phase. The title
product was isolated as white solid (16 mg, 40% yield). MS (ESI+)
m/z=713 (M+H)+; MS (ESI-) m/z=711 (M-H)-.
Example 15
Preparation of
##STR00076##
[0468] Part A. Preparation of
##STR00077##
[0470] The product from Example 14, Part B (92 mg, 0.30 mmol) was
taken up in 5 mL of dichloromethane and treated with Hunig's base
(157 uL, 0.904 mmol) followed by the addition of CBZ-NOS (75 mg,
0.30 mmol) and the reaction mixture stirred for 18 hours. The
reaction mixture was partitioned between water and dichloromethane.
The organic layer was removed and dried over MgSO.sub.4, filtered
and concentrated in vacuo to afford a white solid (55 mg, 41%
yield). MS (ESI+) m/z=440 (M+H)+; MS (ESI-) m/z=438 (M-H)-.
Part B. Preparation of
##STR00078##
[0472] The product from Part A (50 mg, 0.114 mmol) was taken up in
2 mL of dichloromethane and 2 mL of TFA added. The reaction mixture
was stirred for 2 hours and then concentrated in vacuo to afford a
solid that was placed on high vacuum overnight. The reaction
mixture was partitioned between water and dichloromethane. The
organic layer was removed and dried over MgSO.sub.4, filtered and
concentrated in vacuo to afford white solid (38 mg, 88% yield). MS
(ESI+) m/z=384 (M+H)+; MS (ESI-) m/z=382 (M-H).
Part C. Preparation of
##STR00079##
[0474] To a solution of the product from Part B (43 mg, 0.114 mmol)
in 4 mL of dichloromethane was added EDC (33 mg, 0.171 mmol) and
HOBT (23 mg, 0.171 mmol) and the resulting solution stirred at
25.degree. C. for 20 minutes. Then, Hunig's base (60 uL, 0.341
mmol) and hydroxyamide (WO2003062265-A2; Example 6, cpd 2.3) (55
mg, 0.137 mmol) was added and the reaction continued for 2 hours at
room temperature. The reaction mixture was partitioned between
water and dichloromethane. The organic layer was removed and dried
over MgSO.sub.4, filtered and concentrated in vacuo to afford a
foam that was purified by flash chromatography on SiO.sub.2 using
methanol in dichloromethane as the mobile phase to afford the title
compound as a white solid (70 mg, 85% yield). MS (ESI+) m/z=715
(M+H)+; MS (ESI-) m/z=713 (M-H)-.
Part D. Preparation of Title Product
[0475] To a solution of the product from Part C (20 mg, 0.027 mmol)
in 4 mL of dichloromethane was added Dess-Martin periodinane (17
mg, 0.04 mmol) for 1 hour. The reaction was quenched with
Na.sub.2S.sub.2O.sub.3 (sat. aqueous) and the product was extracted
into methylene chloride (3.times.30 mL), dried over MgSO.sub.4,
filtered and concentrated in vacuo to afford a white solid that was
purified by prep TLC SiO.sub.2, (1.0 mm.times.20 mm.times.20 mm)
using methanol in dichloromethane as the mobile phase. The title
product was isolated as a white solid (16 mg, 80% yield). MS (ESI+)
m/z=728 (M+H)+; MS (ESI-) m/z=726 (M-H)-
Example 16
Preparation of
N--((S)-1-cyclohexyl-2-((S)-1-((1S,2R)-2-((S)-1-(cyclopropyl
amino)-1,2-dioxohexan-3-ylcarbamoyl)cyclopentylamino)-3,3-dimethyl-1-oxob-
utan-2-ylamino)-2-oxo ethyl)pyrazine-2-carboxamide
##STR00080##
[0476] Part A. Preparation of (1R,2S)-methyl
2-aminocyclopentanecarboxylate
[0477] To a solution of (1R,2S)-2-aminocyclopentanecarboxylic acid
(0.15 g, 0.9 mmol) in methanol (5 mL) was added 4N HCl in dioxane
(1 mL) and the reaction mixture was stirred at reflux overnight.
The reaction mixture was concentrated in vacuo to afford an oil
which was used directly for the next step.
Part B. Preparation of (1R,2S)-methyl
2-((S)-2-(S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimeth-
ylbutanamido)cyclopentanecarboxylate
[0478] To a solution of the product from Example 1, Part G (0.148
g, 0.394 mmol) in methylene chloride (5 mL) was added EDC (0.091 g,
0.474 mmol) and HOBT (0.064 g, 0.474 mmol) and the resulting
solution stirred at 25.degree. C. for 20 minutes. Then, Hunig's
base (0.151 mL, 0.87 mmol) and (1R,2S)-methyl
2-aminocyclopentanecarboxylate (0.071 g, 0.395 mmol) was added and
the reaction continued for 18 hours at room temperature. The
reaction mixture was partitioned between water and dichloromethane.
The organic layer was removed and dried over MgSO.sub.4, filtered
and concentrated in vacuo to afford a foam that was purified by
flash chromatography on SiO.sub.2 using 0-5% methanol in
dichloromethane as the mobile phase to afford the title compound as
a white solid (104 mg, 52% yield). MS (ESI+) m/z=502 (M+H)+.
Part C. Preparation of
(1R,2S)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)cyclopentanecarboxylic acid
[0479] A solution of the product from Part B (0.104 g, 0.207 mmol)
in ethanol (10 mL) was treated with sodium hydroxide (1N, 2 mL) for
2 h room temperature. The solution was neutralized with 1N HCl and
extracted with dichloromethane (3.times.30 mL), dried over
MgSO.sub.4, filtered and concentrated in vacuo to afford a white
solid (77 mg, 76%) which was used directly for the next step. MS
(DCI/NH.sub.4) m/z=488 (M+H)+; MS (DCI/NH.sub.4) m/z=505
(M+NH4)+.
Part D. Preparation of
N-((1S)-1-cyclohexyl-2-((2S)-1-((1S,2R)-2-(1-(cyclopropylamino)-2-hydroxy-
-1-oxohexan-3-ylcarbamoyl)cyclopentylamino)-3,3-dimethyl-1-oxobutan-2-ylam-
ino)-2-oxoethyl)pyrazine-2-carboxamide
[0480] To a solution containing the product from Part C (0.077 g,
0.158 mmol) in dichloromethane (5 mL) was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDC
(0.036 g, 0.189 mmol) and 1-hydroxybenzotriazole HOBT (25.6 mg,
0.189 mmol) and the resulting solution stirred at 25.degree. C. for
30 minutes. Then 3-amino-N-cyclopropyl-2-hydroxyhexanamide
(WO2002018369-A2; Example 119, cpd xiii') (29 mg, 0.158 mmol) and
Hunig's base (0.06 mL, 0.347 mmol) was added and the reaction
mixture stirred for 3 hours. The reaction mixture was partitioned
between 1N HCl and dichloromethane. The organic layer was removed
and dried over MgSO.sub.4, filtered and concentrated in vacuo to
afford a foam (97 mg, 93%). MS (ESI+) m/z=656 (M+H)+; MS (ESI-)
m/z=654 (M-H)-.
Part E. Preparation of Title Product
[0481] To a solution of the product from Part D (68 mg, 0.104 mmol)
in 5 mL of dichloromethane was added Dess-Martin periodinane (65
mg, 0.156 mmol) for 1 hour. The reaction was quenched with
Na.sub.2S.sub.2O.sub.3 (sat. aqueous) and the product was extracted
into methylene chloride (3.times.30 mL), dried over MgSO.sub.4,
filtered and concentrated in vacuo to afford a white solid that was
purified by prep TLC SiO.sub.2, (1.0 mm.times.20 mm.times.20 mm)
using methanol in dichloromethane as the mobile phase. The title
product was isolated as a white solid (44 mg, 65% yield). MS (ESI+)
m/z=654 (M+H)+; MS (ESI-) m/z=652 (M-H)-
Example 17
Preparation of
N-((1S)-1-cyclohexyl-2-((2S)-1-((1S,2R)-2-(1-(cyclopropyl
amino)-1,2-dioxohexan-3-ylcarbamoyl)cyclopentylamino)-3,3-dimethyl-1-oxob-
utan-2-ylamino)-2-oxoethyl)pyrazine-2-carboxamide
##STR00081##
[0482] Part A. Preparation of
##STR00082##
[0484] To a solution of the product from Example 16, Part C (43 mg,
0.087 mmol) in 5 mL of dichloromethane was added EDC (25 mg, 0.087
mmol) and HOBT (18 mg, 0.13 mmol) and the resulting solution
stirred at 25.degree. C. for 20 minutes. Then, Hunig's base (45 uL,
0.261 mmol) and hydroxyamide (WO2003062265-A2; Example 6, cpd 2.3)
(35 mg, 0.087 mmol) was added and the reaction continued for 2
hours at room temperature. The reaction mixture was partitioned
between water and dichloromethane. The organic layer was removed
and dried over MgSO.sub.4, filtered and concentrated in vacuo to
afford a foam that was purified by flash chromatography on
SiO.sub.2 using methanol in dichloromethane as the mobile phase to
afford the title compound as a white solid (40 mg, 55% yield). MS
(ESI+) m/z=(M+H)+; MS (ESI-) m/z=(M-H)-.
Part B. Preparation of Title Product
[0485] To a solution of the product from Part A (30 mg, 0.036 mmol)
in dichloromethane (mL) was added Dess-Martin periodine (23 mg,
0.054 mmol) at 25.degree. C. and the reaction mixture stirred for 1
hour. The reaction was quenched with Na.sub.2S.sub.2O.sub.3 (sat.
aqueous) and the product was extracted into methylene chloride
(3.times.30 mL), dried over MgSO.sub.4, filtered and concentrated
in vacuo to afford a foam that was purified by prep TLC SiO.sub.2,
(1.0 mm.times.20 mm.times.20 mm) using methanol in dichloromethane
as the mobile phase. The title product was isolated as a white
solid (mg, % yield). MS (ESI+) m/z=(M+H)+; MS (ESI-)
m/z=(M-H)-.
Example 18
Preparation of
N-((1S)-1-cyclohexyl-2-((2S)-1-((1S,2R)-2-(1-(cyclopropyl
amino)-1,2-dioxohexan-3-ylcarbamoyl)cyclohexylamino)-3,3-dimethyl-1-oxobu-
tan-2-ylamino)-2-oxoethyl)pyrazine-2-carboxamide
##STR00083##
[0486] Part A. Preparation of (1R,2S)-methyl
2-aminocyclohexanecarboxylate
[0487] To a solution of (1R,2S)-2-aminocyclohexanecarboxylic acid
(0.13 g, 0.91 mmol) in methanol (5 mL) was added 4N HCl in dioxane
(1 mL) and the reaction mixture was stirred at reflux overnight.
The reaction mixture was concentrated in vacuo to afford an oil
which was used directly for the next step.
Part B. Preparation of (1R,2S)-methyl
2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimet-
hylbutanamido)cyclohexanecarboxylate
[0488] To a solution of the product from Example 1, Part G (0.342
g, 0.9 mmol) in methylene chloride (10 mL) was added EDC (0.21 g,
1.09 mmol) and HOBT (0.147 g, 1.09 mmol) and the resulting solution
stirred at 25.degree. C. for 20 minutes. Then, Hunig's base (0.347
mL, 1.99 mmol) and -154 (crude from above) was added and the
reaction continued for 18 hours at room temperature. The reaction
mixture was partitioned between water and dichloromethane. The
organic layer was removed and dried over MgSO.sub.4, filtered and
concentrated in vacuo to afford a foam that was purified by flash
chromatography on SiO.sub.2 using 0-5% methanol in dichloromethane
as the mobile phase to afford the title compound as a white solid
(327 mg, 70% yield). MS (ESI+) m/z=516 (M+H)+.
Part C. Preparation of
(1R,2S)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)cyclohexanecarboxylic acid
[0489] A solution of the product from Part B (0.156 g, 0.302 mmol)
in ethanol (10 mL) was treated with sodium hydroxide (1N, 1 mL) for
2 h room temperature. The solution was neutralized with 1N HCl and
extracted with dichloromethane (3.times.30 mL), dried over
MgSO.sub.4, filtered and concentrated in vacuo to afford a white
solid (144 mg, 95%) which was used directly for the next step. MS
(ESI+) m/z=502 (M+H)+.
Part D. Preparation of
N-((1S)-1-cyclohexyl-2-((2S)-1-((1S,2R)-2-(1-(cyclopropylamino)-2-hydroxy-
-1-oxohexan-3-ylcarbamoyl)cyclohexylamino)-3,3-dimethyl-1-oxobutan-2-ylami-
no)-2-oxoethyl)pyrazine-2-carboxamide
[0490] To a solution containing the product from Part C (0.02 g,
0.04 mmol) in dichloromethane (2 mL) was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDC
(0.0.09 g, 0.048 mmol) and 1-hydroxybenzotriazole HOBT (6.5 mg,
0.048 mmol) and the resulting solution stirred at 25.degree. C. for
30 minutes. Then 3-amino-N-cyclopropyl-2-hydroxyhexanamide
(WO2002018369-A2; Example 119, cpd xiii') (7.4 mg, 0.04 mmol) and
Hunig's base (0.015 mL, 0.088 mmol) was added and the reaction
mixture stirred for 1 hours. The reaction mixture was partitioned
between 1N HCl and dichloromethane. The organic layer was removed
and dried over MgSO.sub.4, filtered and concentrated in vacuo to
afford a foam (97 mg, 93%) that was purified by preparative
thin-layer chromatography (1.0 mm.times.20.times.20 mm, SiO2) using
5% methanol in dichloromethane to give a solid (13.6 mg, 51%). MS
(ESI+) m/z=670 (M+H)+; MS (ESI-) m/z=668 (M-H)-.
Part E. Preparation of Title Product
[0491] To a solution of the product from Part D (13 mg, 0.019 mmol)
in dichloromethane (2 mL) was added Dess-Martin periodine (12.6 mg,
0.03 mmol) at 25.degree. C. and the reaction mixture stirred for 1
hour. The reaction was quenched with Na.sub.2S.sub.2O.sub.3 (sat.
aqueous) and the product was extracted into methylene chloride
(3.times.30 mL), dried over MgSO.sub.4, filtered and concentrated
in vacuo to afford a foam (g, % yield) that was purified by
preparative thin-layer chromatography (1.0 mm.times.20 mm.times.20
mm, SiO.sub.2) using 5% methanol in dichloromethane. The title
product was isolated as a white solid (10 mg, 77% yield). MS (ESI+)
m/z=668 (M+H)+; MS (ESI-) m/z=666 (M-H)-.
Example 19
Preparation of
N--((S)-1-cyclohexyl-2-((S)-1-((1S,2R)-2-((S)-1-((2-((S)-2-(dimethylamino-
)-2-oxo-1-phenylethylamino)-2-oxoethylamino)-1,2-dioxohexan-3-ylcarbamoyl)-
cyclohexylamino)-3,3-dimethyl-1-oxobutan-2-ylamino)-2-oxoethyl)pyrazine-2--
carboxamide
##STR00084##
[0492] Part A. Preparation of
N-((1S)-1-cyclohexyl-2-((2S)-1-((1S,2R)-2-((3S)-1-(2-((S)-2-(dimethylamin-
o)-2-oxo-1-phenylethylamino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-ylcar-
bamoyl)cyclohexylamino)-3,3-dimethyl-1-oxobutan-2-ylamino)-2-oxoethyl)pyra-
zine-2-carboxamide
[0493] To a solution of the product from Example 18, Part C (115
mg, 0.23 mmol) in 4 mL of dichloromethane was added EDC (66 mg,
0.344 mmol) and HOBT (46 mg, 0.344 mmol) and the resulting solution
stirred at 25.degree. C. for 20 minutes. Then, Hunig's base (120
uL, 0.688 mmol) and hydroxyamide (WO2003062265-A2; Example 6, cpd
2.3) (110 mg, 0.275 mmol) was added and the reaction continued for
2 hours at room temperature. The reaction mixture was partitioned
between water and dichloromethane. The organic layer was removed
and dried over MgSO.sub.4, filtered and concentrated in vacuo to
afford a foam that was purified by flash chromatography on
SiO.sub.2 using 0-10% methanol in dichloromethane as the mobile
phase to afford the title compound as a white solid (74.7 mg, 38%
yield) MS (ESI+) m/z=848 (M+H)+; MS (ESI-) m/z=846 (M-H)-.
Part B. Preparation of Title Product
[0494] To a solution of the product from Part A (74 mg, 0.087 mmol)
in dichloromethane (5 mL) was added Dess-Martin periodine (55.5 mg,
0.13 mmol) at 25.degree. C. and the reaction mixture stirred for 1
hour. The reaction was quenched with Na.sub.2S.sub.2O.sub.3 (sat.
aqueous) and the product was extracted into methylene chloride
(3.times.30 mL), dried over MgSO.sub.4, filtered and concentrated
in vacuo to afford a foam (82 mg) that was purified by preparative
thin-layer chromatography (1.0 mm.times.20 mm.times.20 mm,
SiO.sub.2) using 6% methanol in dichloromethane. The title product
was isolated as a white solid (49 mg, 66% yield). MS (ESI+) m/z=846
(M+H)+; MS (ESI-) m/z=844 (M-H)-.
Example 20
Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N3-((S)-1-(2-((S)-2-(dimethylamino)-2--
oxo-1-phenylethylamino)-2-oxoethylamino)-1,2-dioxohexan-3-yl)-N1-phenylpyr-
rolidine-1,3-dicarboxamide
##STR00085##
[0495] Part A. Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)pyrrolidine-3-carboxylic acid
[0496] A solution of the product from Example 3, Part A (0.2 g, 0.3
mmol) in dichloromethane (1 mL) was treated with trifluoroacetic
acid (4 mL) at 25.degree. C. for 2 h. The solvents were evaporated
and the residue was twice azeotroped with toluene. The crude
material was used directly for the next step.
Part B. Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-1-(phenylcarbamoyl)pyrrolidine-3-carbo-
xylic acid
[0497] To a suspension of the product from Part A and Hunig's base
(0.16 mL, 0.12 mmol) in dichloromethane (5 mL) was added phenyl
isocyanate (55 mg, 0.45 mmol) at 25.degree. C. After 30 minutes the
mixture was quenched with excess HCl (1N) and extracted (3.times.25
mL) with ethyl acetate. The organic layers were combined, dried
over sodium sulfate, and the solvents were evaporated. The crude
residue was purified via flash chromatography using 10% methanol in
dichloromethane to give a white solid (0.118 g, 62% for two steps).
MS (DCI/NH.sub.4) m/z=608 (M+H)+.
Part C. Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N3-((3S)-1-(2-((S)-2-(dimethylamino)-2-
-oxo-1-phenylethylamino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-yl)-N1-ph-
enylpyrrolidine-1,3-dicarboxamide
[0498] To a solution of the product from Part B (59 mg, 0.097 mmol)
in 4 mL of dimethylformamide was added EDC (28 mg, 0.146 mmol) and
HOBT (20 mg, 0.146 mmol) and the resulting solution stirred for 10
minutes. Hunig's base (69 uL, 0.388 mmol) and hydroxyamide
(WO2003062265-A2; Example 6, cpd 2.3) (39 mg, 0.097 mmol) was added
and the reaction was stirred for 2 hours at 25.degree. C. The
reaction mixture was concentrated, and partitioned between 5%
citric acid and dichloromethane. The organic layer was removed and
dried over sodium sulfate and concentrated in vacuo. to afford a
foam (74.7 mg, 38% yield). MS (DCI/NH.sub.4) m/z=954 (M+H)+.
Part D. Preparation of Title Product
[0499] To a solution of the product from Part C (33 mg, 0.035 mmol)
in dichloromethane (3 mL) was added Dess-Martin periodine (23 mg,
0.052 mmol) at 25.degree. C. and the reaction mixture stirred for 2
hour. The reaction was quenched with 10% Na.sub.2S.sub.2O.sub.3 and
the product was extracted into methylene chloride (3.times.10 mL),
dried over sodium sulfate and concentrated in vacuo. to afford a
foam that was purified by flash chromatography using 5% methanol in
dichloromethane. The title product was isolated as a white solid
(25 mg, 76% yield).
Example 21
Preparation of pyrazine-2-carboxylic acid
(cyclohexyl-{1-[3-(1-cyclopropyl
aminooxalyl-butylcarbamoyl)-bicyclo[2.2.1]hept-2-ylcarbamoyl]-2,2-dimethy-
l-propylcarbamoyl}-methyl)-amide
##STR00086##
[0500] Part A. Preparation of
3-exo-amino-bicyclo[2.2.1]heptane-2-exo-carboxylic acid methyl
ester
[0501] To 3-exo-amino-bicyclo[2.2.1]heptane-2-exo-carboxylic acid
(243.7 mg, 1.57 mmol) in methanol (15 ml) was added 4N HCl in
dioxane (1 mL). The solution was refluxed overnight then cooled and
concentrated in vacuo and the resulting clear oil dissolved in
minimal DCM. Ether and hexane were added and the product
crystallized. The crystals were collected and dried to give white
crystals (304 mg, 94% yield). MS (APCI) m/z 170 [M+H]+.
Part B. Preparation of
3-(2-{2-cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimet-
hyl-butyrylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid methyl
ester
[0502] To a solution of the product from Example 1, Part G (150 mg,
0.4 mmol) in DCM (4 ml) was added HOBT (64.6 mg, 0.48 mmol)
followed by EDAC (91.7 mg, 0.48 mmol). The mixture was stirred for
30 min then the ester product from Part A (122.9 mg, 0.60 mmol)
added followed by TEA (117 ul, 0.84 mmol). The mixture was stirred
overnight, the milky suspension diluted with DCM and the resulting
organic suspension washed with water, 1N HCl and brine. The organic
layer was dried and concentrated in vacuo to give a pale yellow
solid (207.1 mg, 98% yield). MS (APCI) m/z 528 [M+H]+.
Part C. Preparation of
1S,2R,3S,4R)-3-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetami-
do)-3,3-dimethylbutanamido)bicyclo[2.2.1]heptane-2-carboxylic
acid
[0503] To a solution of the peptide product from Part B (207 mg,
0.39 mmol) in methanol was added 1N NaOH (4 eq, 1.56 mmol, 1.56
mL). The mixture was stirred over a weekend. The methanol was
removed in vacuo and the aqueous solution acidified with 1N HCl
then extracted with ethyl acetate. The organic layer was washed
with brine, dried and concentrated in vacuo to give a white solid
(185 mg, 92% yield) as a mixture of diastereomers. The isomers were
separable by RP-HPLC (0.1% TFA in water/CH3CN gradient) giving 74.9
mg of the more polar isomer. MS (APCI) m/z 514 [M+H]+.
Part D. Preparation of pyrazine-2-carboxylic acid
[cyclohexyl-(1-{3-[1-(cyclopropyl
carbamoyl-hydroxy-methyl)-butylcarbamoyl]-bicyclo[2.2.1]hept-2-ylcarbamoy-
l}-2,2-dimethylpropyl carbamoyl)-methyl]-amide
[0504] To a solution of the product from Part C (74.9 mg, 0.15
mmol) and TEA (61 ul, 0.44 mmol) in DCM (1.5 ml) was added HOBT
(23.6 mg, 0.18 mmol) followed by EDAC (33.5 mg, 0.18 mmol). The
mixture was stirred for 30 min then
3-amino-N-cyclopropyl-2-hydroxyhexanamide (WO2002018369-A2; Example
119, cpd xiii') (51 mg, 0.29 mmol) added as a solid. The mixture
was stirred overnight then loaded on to a 10 g silica plug with
DCM. The plug was eluted with 2-5% methanol in dichloromethane.
Fractions were combined to give the desired product as a mixture of
diastereomers (23.7 mg, 24% yield). MS (APCI) m/z 682 [M+H]+.
Part E. Preparation of Title Product
[0505] To a solution of the product from Part D (23.7 mg, 0.03
mmol) in DCM (0.99 ml) was added Dess-Martin reagent (22.1 mg, 0.05
mmol) and the mixture stirred overnight. The cloudy suspension was
quenched with 10% aqueous Na.sub.2S.sub.2O.sub.3 and stirred for 30
min. The now clear layers were separated and the organic layer
dried and concentrated in vacuo to give the crude diketoamide. The
crude material was loaded onto silica with DCM then the column
eluted with hexane, 1:1 hexane/ethyl acetate, 1:2 hexane/ethyl
acetate then ethyl acetate. Fractions were combined and
concentrated to give the ketoamide (17.4 mg, 73.6% yield). MS (ESI)
m/z 702 [M+Na]+, m/z 680 [M+H]+, m/z 678 [M-H]-.
Example 22
Preparation of Pyrazine-2-carboxylic acid
(cyclohexyl-{1-[3-(1-cyclopropyl
aminooxalyl-butylcarbamoyl)-bicyclo[2.2.1]hept-5-en-2-ylcarbamoyl]-2,2-di-
methyl-propylcarbamoyl}-methyl)-amide
##STR00087##
[0506] Part A. Preparation of
3-exo-aminobicyclo[2.2.1]hept-5-ene-2-exo-carboxylic acid methyl
ester
[0507] To the aminoacid
3-exo-aminobicyclo[2.2.1]hept-5-ene-2-exo-carboxylic acid (232.4
mg, 1.5 mmol) in methanol (15 mL) was added 4N HCl in dioxane (1
ml). The solution was refluxed overnight. The solution was
concentrated in vacuo and the resulting clear oil dissolved in
minimal DCM. Ether was added and the product crystallized. The
crystals were collected and dried to give a white solid (266 mg,
86% yield).
Part B. Preparation of
3-(2-{2-Cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimet-
hyl-butyrylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl
ester
[0508] To a solution of the product from Example 1, Part G (150 mg,
0.4 mmol) in DCM (4 ml) was added HOBT (64.6 mg, 0.48 mmol)
followed by EDAC (91.7 mg, 0.48 mmol). The mixture was stirred for
30 min then the ester product from Part A added followed by TEA
(117 ul, 0.84 mmol). The mixture was stirred overnight, the milky
suspension diluted with DCM and the resulting organic suspension
washed with water, 1N HCl and brine. The organic layer was dried
and concentrated in vacuo to give a pale yellow solid (208.2 mg,
99% yield). MS (APCI) m/z 526 [M+H]+.
Part C. Preparation of
3-(2-{2-Cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimet-
hyl-butyrylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid
[0509] To a solution of the product from Part B (208 mg, 0.4 mmol)
in methanol was added 1N NaOH (1.6 mmol, 1.6 mL). The mixture was
stirred over a weekend. The methanol was removed in vacuo and the
aqueous solution acidified with 1N HCl then extracted with ethyl
acetate. The organic layer was washed with brine, dried and
concentrated in vacuo to give a white solid as a mixture of
diastereomers (174 mg, 85% yield). The isomers were separable by
RP-HPLC (0.1% TFA in water/CH3CN gradient) giving 55.5 mg of the
more polar compound. MS (APCI) m/z 512 [M+H]+.
Part D. Preparation of Pyrazine-2-carboxylic acid
[cyclohexyl-(1-{3-[1-(cyclopropyl
carbamoyl-hydroxy-methyl)-butylcarbamoyl]-bicyclo[2.2.1]hept-5-en-2-ylcar-
bamoyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-amide
[0510] To a solution of the product from Part C (55.5 mg, 0.11
mmol) and TEA (45 ul, 0.33 mmol) in DCM (1.1 ml) was added HOBT
(17.6 mg, 0.13 mmol) followed by EDAC (235 mg, 0.13 mmol). The
mixture was stirred for 30 min then
3-amino-N-cyclopropyl-2-hydroxyhexanamide (WO2002018369-A2; Example
119, cpd xiii') (40.4 mg, 0.22 mmol) added as a solid. The mixture
was stirred overnight then loaded on to a 10 g silica plug with
DCM. The plug was eluted with 2-5% methanol in dichloromethane.
Fractions were combined to give the product (36.7 mg, 50% yield) as
a mixture of isomers. MS (APCI) m/z 680 [M+H]+.
Part E. Preparation of Title Product
[0511] To a solution of the product from Part D (36.7 mg, 0.05
mmol) in DCM (1.5 ml) was added Dess-Martin reagent (34.3 mg, 0.08
mmol) and the mixture stirred overnight. The cloudy suspension was
quenched with 10% aqueous Na.sub.2S.sub.2O.sub.3 and stirred for 30
min. The now clear layers were separated and the organic layer
dried and concentrated in vacuo to give the crude diketoamide. The
crude material was loaded onto silica with DCM then the column
eluted with hexane, 1:1 hexane/ethyl acetate, 1:2 hexane/ethyl
acetate then ethyl acetate. Fractions were combined and
concentrated to give the ketoamide (30.5 mg, 83% yield). MS (ESI)
m/z 700 [M+Na]+, m/z 678 [M+H]+, m/z 676 [M-H]-.
Example 23
Preparation of
3-(2-{2-cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimet-
hyl-butyrylamino)-4-{1-[({[(dimethylcarbamoyl-phenyl-methyl)-carbamoyl]-me-
thyl}-carbamoyl)-hydroxy-methyl]-butylcarbamoyl}-pyrrolidine-1-carboxylic
acid benzyl ester
##STR00088##
[0512] Part A. Preparation of
4-(2-{2-cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimet-
hyl-butyrylamino)-pyrrolidine-1,3-dicarboxylic acid di-tert-butyl
ester
[0513] To a solution of the product from Example 1, Part G (310 mg,
0.82 mmol) in DCM (8.2 ml) was added HOBT (133.5 mg, 0.99 mmol)
followed by EDAC (189.4 mg, 0.99 mmol). The mixture was stirred for
30 min then and (3R,4R)-di-tert-butyl
4-aminopyrrolidine-1,3-dicarboxylate (Org. Biomol. Chem. 2004, 2,
2763-2776) (235.8 mg, 0.82 mmol) added. The mixture was stirred
overnight then the reaction mixture diluted with DCM and the
organic layer washed with water, 1N HCl, sat'd NaHCO3 and brine.
The organic layer was dried and concentrated in vacuo to give a
white solid which was purified on silica eluting with 0-100% ethyl
acetate in hexanes to give the title compound as a white solid (502
mg, 95% yield). MS (ESI) m/z 667 [M+Na]+, m/z 645 [M+H]+, m/z 643
[M-H]-.
Part B. Preparation of
4-(2-{2-cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimet-
hyl-butyrylamino)-pyrrolidine-3-carboxylic acid tert-butyl
ester
[0514] The product from Part A (470 mg, 0.73 mmol) was dissolved in
ethyl acetate (2.7 ml) and 4N HCl in dioxane (0.9 ml) added. The
solution was allowed to stand and a ppt formed after about 1 hour.
After 4 hours, the supernate was removed with a pipette and the
solid washed with ethyl acetate then dried to give the
hydrochloride salt (211.9 mg, 50% yield) as a white solid. MS
(APCI) m/z 545 [M+H]+.
Part C. Preparation of
4-(2-{2-cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimet-
hyl-butyrylamino)-pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester
3-tert-butyl ester
[0515] The product from Part B (100 mg, 0.17 mmol) was dissolved in
DCM (860 ul) then TEA (34.8 ul, 0.34 mmol) added followed by CBZ-Cl
(49 ul, 0.34 mmol). The reaction was stirred overnight. The
reaction mixture was loaded onto a silica plug then eluted with
ethyl acetate to give the title compound (107.2 mg, 92% yield). MS
(APCI) m/z 679 [M+H]+.
Part D. Preparation of
4-(2-{2-cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimet-
hyl-butyrylamino)-pyrrolidine-1,3-dicarboxylic acid 1-benzyl
ester
[0516] To the product from Part C (103 mg, 0.15 mmol) was added 4N
HCl/dioxane (5 ml) and the reaction stirred overnight at RT. The
solvent was removed in vacuo and the residue triturated with ether
to give the acid as a white solid (94.3 mg, 100% yield). MS (APCI)
m/z 623 [M+H]+.
Part E. Preparation of
3-(2-{2-cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimet-
hyl-butyrylamino)-4-{1-[({[(dimethylcarbamoyl-phenyl-methyl)-carbamoyl]-me-
thyl}-carbamoyl)-hydroxy-methyl]-butylcarbamoyl}-pyrrolidine-1-carboxylic
acid benzyl ester
[0517] To a solution of the product from Part D (94.3 mg, 0.15
mmol), hydroxyamide (WO2003062265-A2; Example 6, cpd 2.3) (53.5 mg,
0.15 mmol) and DIPEA (153.3 ul, 0.88 mmol) in THF (1.5 ml) was
added DEPBT (50.4 mg, 0.22 mmol). The mixture was stirred
overnight. The reaction mixture was partitioned between ethyl
acetate and sat'd Na.sub.2CO.sub.3. The organic layer was dried and
concentrated then loaded on to a 10 g silica plug with DCM. The
plug was eluted with 0-6% methanol in ethyl acetate to give the
title compound (73 mg, 51% yield) as a mixture of isomers. MS
(APCI) m/z 969 [M+H]+.
Part F. Preparation of Title Product
[0518] To a solution of the product from Part E (24 mg, 0.02 mmol)
in DCM (0.7 ml) was added Dess-Martin reagent (15.8 mg, 0.04 mmol)
and the mixture stirred overnight. The cloudy suspension was
quenched with 10% aqueous Na.sub.2S.sub.2O.sub.3 and stirred for 30
min. The now clear layers were separated and the organic layer
dried and concentrated in vacuo to give the crude diketoamide. The
crude material was loaded onto silica with DCM then the column
eluted with 0-6% methanol in ethyl acetate to give the title
compound (15.8 mg, 62.5% yield). MS (ESI) m/z 967 [M+H]+, m/z 965
[M-H]-.
Example 24
Preparation of pyrazine-2-carboxylic acid
(cyclohexyl-{1-[4-(1-cyclopropyl
aminooxalyl-butylcarbamoyl)-1-(toluene-4-sulfonyl)-pyrrolidin-3-ylcarbamo-
yl]-2,2-dimethylpropyl carbamoyl}-methyl)-amide
##STR00089##
[0519] Part A. Preparation of
4-(2-{2-cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimet-
hyl-butyrylamino)-1-(toluene-4-sulfonyl)-pyrrolidine-3-carboxylic
acid tert-butyl ester
[0520] The product from Example 23, Part B (100 mg, 0.17 mmol) was
dissolved in dichloromethane (1.7 ml). TEA (84 ul, 0.6 mmol) was
added followed by the sulfonyl chloride (65.6 mg, 0.34 mmol). The
reaction was stirred overnight then loaded onto a silica plug and
eluted with ethyl acetate to give the title compound as a white
solid (112 mg, 93% yield). MS (APCI) m/z 699 [M+H]+.
Part B. Preparation of
4-(2-{2-cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimet-
hyl-butyrylamino)-1-(toluene-4-sulfonyl)-pyrrolidine-3-carboxylic
acid
[0521] To the product from Part A (110 mg, 0.16 mmol) was added 4N
HCl/dioxane (5 ml) and the mixture stirred overnight. The reaction
mixture was concentrated in vacuo and the residue triturated with
ether to give (100.3 mg, 100% yield) of a white solid. MS (APCI)
m/z 643 [M+H]+.
Part C. Preparation of pyrazine-2-carboxylic acid
(cyclohexyl-{1-[4-[1-(cyclopropyl
carbamoyl-hydroxy-methyl)-butylcarbamoyl]-1-(toluene-4-sulfonyl)-pyrrolid-
in-3-ylcarbamoyl]-2,2-dimethyl-propylcarbamoyl}-methyl)-amide
[0522] To a solution of the product from Part B (50 mg, 0.08 mmol),
3-amino-N-cyclopropyl-2-hydroxyhexanamide (WO2002018369-A2; Example
119, cpd xiii') (14.5 mg, 0.08 mmol) and DIPEA (81.3 ul, 0147 mmol)
in THF (0.78 ml) was added DEPBT (26.7 mg, 0.12 mmol). The mixture
was stirred overnight then the reaction mixture partitioned between
ethyl acetate and sat'd Na.sub.2CO.sub.3. The organic layer was
dried and concentrated to give 50 mg crude product which was then
loaded on to a 10 g silica plug with DCM. The plug was eluted with
0-6% methanol in ethyl acetate to give the desired compound (42 mg,
67% yield). MS (APCI) m/z 811 [M+H]+.
Part D. Preparation of Title Product
[0523] To a solution of the product from Part C (42 mg, 0.05 mmol)
in DCM (1.5 ml) was added Dess-Martin reagent (32.9 mg, 0.08 mmol)
and the mixture stirred overnight. The cloudy suspension was
quenched with 10% aqueous Na.sub.2S.sub.2O.sub.3 and stirred for 30
min. The now clear layers were separated and the organic layer
dried and concentrated in vacuo to give the crude diketoamide. The
crude material was loaded onto silica with DCM then the column
eluted with 1:1 then 1:2 hexane/ethyl acetate followed by ethyl
acetate to give the product (31 mg, 74% yield) as a white solid. MS
(APCI) m/z 809 [M+H]+.
Example 25
Preparation of (3R,4R)-tert-butyl
3-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimet-
hylbutanamido)-4-((S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenylethylamino-
)-2-oxoethylamino)-1,2-dioxohexan-3-ylcarbamoyl)pyrrolidine-1-carboxylate
##STR00090##
[0524] Part A. Preparation of (3R,4R)-di-tert-butyl
4-(benzyloxycarbonylamino)pyrrolidine-1,3-dicarboxylate
[0525] To a solution of (3R,4R)-di-tert-butyl
4-aminopyrrolidine-1,3-dicarboxylate (Org. Biomol. Chem. 2004, 2,
2763-2776) (765 mg, 2.67 mmol) and Hunig's base (465 uL, 2.67 mmol)
in N,N-dimethylformamide (5 mL) was added Cbz succinimide (665 mg,
2.67 mmol). The mixture was stirred for 3 hours and partitioned
between EtOAc and water. The organic layer was washed repeatedly
with brine, dried (Na.sub.2SO.sub.4) and concentrated to a clear
oil (1.18 g, quantitative yield). MS (DCI/NH.sub.4) m/z=438
(M+NH.sub.4).sup.+.
Part B. Preparation of
(3R,4R)-4-(benzyloxycarbonylamino)pyrrolidine-3-carboxylic acid
compound with 2,2,2-trifluoroacetic acid (1:1)
[0526] To a solution of the product from Part A (1.18 g, 2.67 mmol)
in dichloromethane (5 mL) was added trifluoroacetic acid (25 mL) at
a fast drip. The light yellow solution was stirred at ambient temp
for 3 hours, concentrated and the residue was azeotroped several
times with mixtures of methanol and toluene to finally achieve a
sticky solid. MS (DCI/NH.sub.4) m/z=265 (M+H).sup.+.
Part C. Preparation of
(3R,4R)-4-(benzyloxycarbonylamino)-1-(tert-butoxycarbonyl)pyrrolidine-3-c-
arboxylic acid
[0527] A solution of the product from Part B (900 mg, 2.49 mmol) in
tetrahydrofuran/water (20 mL/5 mL) and 1 M NaOH (10 mL, 10 mmol)
was treated with di-tert-butyl dicarbonate (1.44 g, 6.2 mmol),
stirred for 16 hours and concentrated to remove the
tetrahydrofuran. The aqueous solution was washed 2.times.50 mL with
diethyl ether, acidified to pH 1 with 1M H.sub.3PO.sub.4 and
extracted 3.times.40 mL with EtOAc. The extracts were combined,
washed with 2 mL saturated brine, dried (Na.sub.2SO.sub.4) and
concentrated to give a white foam (860 mg, 95%). MS (DCI/NH.sub.4)
m/z=382 (M+NH.sub.4).sup.+.
Part D. Preparation of (3R,4R)-tert-butyl
3-(benzyloxycarbonylamino)-4-((3S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-ph-
enylethylamino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)pyrrol-
idine-1-carboxylate
[0528] A mixture of the product from Part C (72.8 mg, 0.2 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (58
mg, 0.3 mmol), 1-hydroxybenzotriazole (41 mg, 0.3 mmol), Hunig's
base (105 uL, 0.6 mmol) and
((3S)-3-amino-N-(2-((S)-2-(dimethylamino)-2-oxo-1-phenylethylamino)-2-oxo-
ethyl)-2-hydroxyhexanamide (WO2003062265-A2; Example 6, cpd 2.3)
(72.8 mg, 0.2 mmol)) in dichloromethane (8 mL) was stirred for 16
hours and diluted with 100 mL EtOAc, washed with 10 mL 1 M
H.sub.3PO.sub.4, 10 mL 10% NaHCO.sub.3, 3.times.20 mL with brine,
dried (Na.sub.2SO.sub.4), and concentrated to a white powder (120
mg, 84%). MS (ESI+) m/z=711 (M+H).sup.+.
Part E. Preparation of (3R,4R)-tert-butyl
3-amino-4-((3S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenylethylamino)-2-o-
xoethylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)pyrrolidine-1-carboxylate
[0529] The product from Part D (73 mg, 0.1 mmol) and 10% Pd/C (50
mg) were combined in MeOH (10 mL) and degassed under vacuum. The
mixture was placed under a balloon of H.sub.2, stirred for 16
hours, filtered through Celite to remove catalyst and the filtrate
was concentrated to a white powder (57 mg, 99%). MS (ESI+) m/z=577
(M+H).sup.+.
Part F. Preparation of (3R,4R)-tert-butyl
3-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimet-
hylbutanamido)-4-((3S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenylethylamin-
o)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)pyrrolidine-1-carbo-
xylate
[0530] A mixture of the product from Part E (57 mg, 0.1 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (29
mg, 0.15 mmol), 1-hydroxybenzotriazole (21 mg, 0.15 mmol), Hunig's
base (52 uL, 0.3 mmol) and the product from Example 1, Part G (38
mg, 0.1 mmol)) in dichloromethane (4 mL) was stirred for 6 hours,
diluted with 100 mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4,
10 mL 10% NaHCO.sub.3, 3.times.20 mL with brine, dried
(Na.sub.2SO.sub.4), and concentrated to a white powder (60 mg,
64%). MS (ESI+) m/z=936 (M+H).sup.+.
Part G. Preparation of Title Product
[0531] The product from Part F (60 mg, 0.064 mmol) in
dichloromethane (4 mL) was treated with Dess-Martin periodinane (33
mg, 0.077 mmol), stirred for 2 hours, treated with 10% aqueous
sodium sulfite (2 mL), stirred for 10 minutes and diluted with 50
mL EtOAc. The EtOAc layer was then washed with 10% aqueous sodium
bicarbonate, brine, dried (Na.sub.2SO.sub.4) and concentrated. The
crude product was flash chromatographed on an Alltech 2 g silica
cartridge eluting with dichloromethane.fwdarw.3% MeOH in
dichloromethane to give a white powder (20 mg, 33%). MS (ESI-)
m/z=932 (M-H).sup.+.
Example 26
Preparation of
N--((S)-1-cyclohexyl-2-((S)-1-((3R,4R)-4-((S)-1-(2-((S)-2-(dimethylamino)-
-2-oxo-1-phenylethylamino)-2-oxoethylamino)-1,2-dioxohexan-3-ylcarbamoyl)p-
yrrolidin-3-ylamino)-3,3-dimethyl-1-oxobutan-2-ylamino)-2-oxoethyl)pyrazin-
e-2-carboxamide 2,2,2-trifluoroacetate
##STR00091##
[0533] The product from Example 25, Part G (15 mg, 0.016 mmol) in
dichloromethane (1 mL) was treated with trifluoroacetic acid (1
mL), stirred for 1 hour and concentrated to give the title compound
as a white powder (13 mg, 95%). MS (ESI-) m/z=832 (M-H)+.
Example 27
Preparation of (3R,4R)-tert-butyl
3-(2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)acetamido)-4-(-
(S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenylethylamino)-2-oxoethyl
amino)-1,2-dioxohexan-3-ylcarbamoyl)pyrrolidine-1-carboxylate
##STR00092##
[0534] Part A. Preparation of (S)-tert-butyl
2-(2-cyclohexyl-2-(pyrazine-2-carboxamido) acetamido)acetate
[0535] A mixture of the product from Example 1, Part G (132 mg, 0.5
mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
(144 mg, 0.75 mmol), 1-hydroxybenzotriazole (102 mg, 0.75 mmol),
Hunig's base (260 uL, 1.5 mmol) and tert-butyl 2-aminoacetate (69
mg, 0.52 mmol)) in dichloromethane (15 mL) was stirred for 2 hours,
diluted with 100 mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4,
10 mL 10% NaHCO.sub.3, 3.times.20 mL with brine, dried
(Na.sub.2SO.sub.4), and concentrated. The crude material was
chromatographed on an Alltech 2 g silica cartridge eluting with 2:1
hexane/EtOAc to give a white foam (76 mg, 40%). MS (ESI-) m/z=375
(M-H).sup.+.
Part B. Preparation of
(S)-2-(2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)acetic
acid
[0536] The product from Part A (70 mg, 0.186 mmol) in
dichloromethane (0.5 mL) was treated with trifluoroacetic acid (2
mL), stirred for 3 hour and concentrated to give a sticky solid (70
mg, 87%).
Part C. Preparation of (3R,4R)-tert-butyl
3-(2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)acetamido)-4-(-
(3S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenylethylamino)-2-oxoethylamino-
)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)pyrrolidine-1-carboxylate
[0537] A mixture of the product from Part B (40 mg, 0.12 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (29
mg, 0.15 mmol), 1-hydroxybenzotriazole (21 mg, 0.15 mmol), Hunig's
base (70 uL, 0.4 mmol) and the product from Example 25, Part E (57
mg, 0.1 mmol)) in dichloromethane (4 mL) was stirred for 3 hours,
diluted with 100 mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4,
10 mL 10% NaHCO.sub.3, 3.times.20 mL with brine, dried
(Na.sub.2SO.sub.4), and concentrated to a yellow glass (70 mg,
80%). MS (ESI-) m/z=878 (M-H).sup.+.
Part D. Preparation of Title Product
[0538] The product from Part C (70 mg, 0.08 mmol) in
dichloromethane (4 mL) was treated with Dess-Martin periodinane (41
mg, 0.096 mmol), stirred for 2 hours, treated with 10% aqueous
sodium sulfite (2 mL), stirred for 10 minutes and diluted with 50
mL EtOAc. The EtOAc layer was then washed with 10% aqueous sodium
bicarbonate, brine, dried (Na.sub.2SO.sub.4) and concentrated. The
crude product was flash chromatographed on an Alltech 2 g silica
cartridge eluting with dichloromethane.fwdarw.5% MeOH in
dichloromethane to give a white powder (28 mg, 32%). MS (ESI-)
m/z=876 (M-H).sup.+.
Example 28
Preparation of (3R,4R)-tert-butyl
3-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3-methylb-
utanamido)-4-((S)-1-((2-((S)-2-(dimethylamino)-2-oxo-1-phenyl
ethylamino)-2-oxoethylamino)-1,2-dioxohexan-3-ylcarbamoyl)pyrrolidine-1-c-
arboxylate
##STR00093##
[0539] Part A. Preparation of (S)-tert-butyl
2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3-methylbutanoate
[0540] A mixture of the product from Example 1, Part G (132 mg, 0.5
mmol), N-(3-dimethyl aminopropyl)-N'-ethylcarbodiimide
hydrochloride (144 mg, 0.75 mmol), 1-hydroxybenzotriazole (102 mg,
0.75 mmol), Hunig's base (350 uL, 2.0 mmol) and (S)-tert-butyl
2-amino-3-methylbutanoate hydrochloride (109 mg, 0.52 mmol)) in
dichloromethane (15 mL) was stirred for 2 hours, diluted with 100
mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4, 10 mL 10%
NaHCO.sub.3, 3.times.20 mL with brine, dried (Na.sub.2SO.sub.4),
and concentrated to give a yellow foam (195 mg, 93%). MS (ESI-)
m/z=417 (M-H).sup.+.
Part B. Preparation of
(S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3-methylbuta-
noic acid
[0541] The product from Part A (50 mg, 0.12 mmol) in
dichloromethane (0.5 mL) was treated with trifluoroacetic acid (2
mL), stirred for 3 hour and concentrated to give a sticky solid. MS
(ESI+) m/z=363 (M+H).sup.+.
Part C. Preparation of (3R,4R)-tert-butyl
3-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3-methylb-
utanamido)-4-((3S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenyl
ethylamino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)pyrrolidi-
ne-1-carboxylate
[0542] A mixture of the product from Part B (40 mg, 0.12 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (29
mg, 0.15 mmol), 1-hydroxybenzotriazole (21 mg, 0.15 mmol), Hunig's
base (70 uL, 0.4 mmol) and the product from Example 25, Part E (57
mg, 0.1 mmol)) in dichloromethane (4 mL) was stirred for 3 hours,
diluted with 100 mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4,
10 mL 10% NaHCO.sub.3, 3.times.20 mL with brine, dried
(Na.sub.2SO.sub.4), and concentrated (51 mg, 55%). MS (ESI-)
m/z=920 (M-H).sup.+.
Part D. Preparation of Title Product
[0543] The product from Part C (50 mg, 0.054 mmol) in
dichloromethane (4 mL) was treated with Dess-Martin periodinane (28
mg, 0.065 mmol), stirred for 2 hours, treated with 10% aqueous
sodium sulfite (2 mL), stirred for 10 minutes and diluted with 50
mL EtOAc. The EtOAc layer was then washed with 10% aqueous sodium
bicarbonate, brine, dried (Na.sub.2SO.sub.4) and concentrated. The
crude product was flash chromatographed on an Alltech 2 g silica
cartridge eluting with dichloromethane.fwdarw.4% MeOH in
dichloromethane to give a white powder (20 mg, 40%). MS (ESI-)
m/z=918 (M-H).sup.+.
Example 29
Preparation of
N--((S)-1-cyclohexyl-2-((S)-1-((3R,4R)-4-((S)-1-(2-((S)-2-(dimethylamino)-
-2-oxo-1-phenylethylamino)-2-oxoethylamino)-1,2-dioxohexan-3-ylcarbamoyl)p-
yrrolidin-3-ylamino)-3-methyl-1-oxobutan-2-ylamino)-2-oxoethyl)pyrazine-2--
carboxamide 2,2,2-trifluoroacetate
##STR00094##
[0545] The product from Example 28, Part D (15 mg, 0.016 mmol) in
dichloromethane (1 mL) was treated with trifluoroacetic acid (1
mL), stirred for 1 hour and concentrated to give the title compound
as a tan powder (12 mg, 80%). MS (ESI) m/x=818 (M-H).sup.+.
Example 30
Preparation of (3R,4R)-tert-butyl
3-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3-phenylp-
ropanamido)-4-((S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenyl
ethylamino)-2-oxoethylamino)-1,2-dioxohexan-3-ylcarbamoyl)pyrrolidine-1-c-
arboxylate
##STR00095##
[0546] Part A. Preparation of (S)-tert-butyl
2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3-phenylpropanoate
[0547] A mixture of the product from Example 1, Part G (132 mg, 0.5
mmol), N-(3-dimethyl aminopropyl)-N'-ethylcarbodiimide
hydrochloride (144 mg, 0.75 mmol), 1-hydroxybenzotriazole (102 mg,
0.75 mmol), Hunig's base (350 uL, 2.0 mmol) and (S)-tert-butyl
2-amino-3-phenylpropanoate hydrochloride (134 mg, 0.52 mmol)) in
dichloromethane (15 mL) was stirred for 2 hours, diluted with 100
mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4, 10 mL 10%
NaHCO.sub.3, 3.times.20 mL with brine, dried (Na.sub.2SO.sub.4),
and concentrated to give a yellow wax (190 mg, 82%). MS (ESI-)
m/z=465 (M-H).sup.+.
Part B. Preparation of
(S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3-phenylprop-
anoic acid
[0548] The product from Part A (56 mg, 0.12 mmol) in
dichloromethane (0.5 mL) was treated with trifluoroacetic acid (2
mL), stirred for 3 hour and concentrated to give a sticky solid. MS
(ESI+) m/z=411 (M+H).sup.+.
Part C. Preparation of (3R,4R)-tert-butyl
3-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3-phenylp-
ropanamido)-4-((3S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenyl
ethylamino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)pyrrolidi-
ne-1-carboxylate
[0549] A mixture of the product from Part B (40 mg, 0.12 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (29
mg, 0.15 mmol), 1-hydroxybenzotriazole (21 mg, 0.15 mmol), Hunig's
base (70 uL, 0.4 mmol) and the product from Example 25, Part E (57
mg, 0.1 mmol)) in dichloromethane (4 mL) was stirred for 3 hours,
diluted with 100 mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4,
10 mL 10% NaHCO.sub.3, 3.times.20 mL with brine, dried
(Na.sub.2SO.sub.4), and concentrated (85 mg, 88%). MS (ESI-)
m/z=968 (M-H).sup.+.
Part D. Preparation of Title Product
[0550] The product from Part C (85 mg, 0.088 mmol) in
dichloromethane (4 mL) was treated with Dess-Martin periodinane (50
mg, 1.14 mmol), stirred for 2 hours, treated with 10% aqueous
sodium sulfite (2 mL), stirred for 10 minutes and diluted with 50
mL EtOAc. The EtOAc layer was then washed with 10% aqueous sodium
bicarbonate, brine, dried (Na.sub.2SO.sub.4) and concentrated. The
crude product was flash chromatographed on an Alltech 5 g silica
cartridge eluting with dichloromethane.fwdarw.4% MeOH in
dichloromethane to give a white powder (28 mg, 33%). MS (ESI-)
m/z=966 (M-H).
Example 31
Preparation of
N--((S)-1-cyclohexyl-2-((S)-1-((3R,4R)-4-((S)-1-(2-((S)-2-(dimethylamino)-
-2-oxo-1-phenylethylamino)-2-oxoethylamino)-1,2-dioxohexan-3-ylcarbamoyl)p-
yrrolidin-3-ylamino)-1-oxo-3-phenylpropan-2-ylamino)-2-oxoethyl)pyrazine-2-
-carboxamide 2,2,2-trifluoroacetate
##STR00096##
[0552] The product from Example 30, Part D (28 mg, 0.029 mmol) in
dichloromethane (1 mL) was treated with trifluoroacetic acid (1
mL), stirred for 1 hour and concentrated to give the title compound
as a tan powder (27.5 mg, 97%). MS (ESI-) m/z=866 (M-H).sup.+
Example 32
Preparation of (3R,4R)-tert-butyl
3-((S)-3-cyclohexyl-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetami-
do)propanamido)-4-((S)-1-((2-((S)-2-(dimethylamino)-2-oxo-1-phenyl
ethylamino)-2-oxoethylamino)-1,2-dioxohexan-3-ylcarbamoyl)pyrrolidine-1-c-
arboxylate
##STR00097##
[0553] Part A. Preparation of (S)-methyl
3-cyclohexyl-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)prop-
anoate
[0554] A mixture of the product from Example 1, Part G (132 mg, 0.5
mmol), N-(3-dimethylamino propyl)-N'-ethylcarbodiimide
hydrochloride (144 mg, 0.75 mmol), 1-hydroxybenzotriazole (102 mg,
0.75 mmol), Hunig's base (350 uL, 2.0 mmol) and (S)-methyl
2-amino-3-cyclohexylpropanoate hydrochloride (115 mg, 0.52 mmol))
in dichloromethane (15 mL) was stirred for 2 h, diluted with 100 mL
EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4, 10 mL 10%
NaHCO.sub.3, 3.times.20 mL with brine, dried (Na.sub.2SO.sub.4),
and concentrated (190 mg, 83%). The crude product was flash
chromatographed on Alltech 5 g silica cartridge eluting with 2:1
hexane/EtOAc to give white powder (130 mg, 60%). MS (ESI-) m/z=429
(M-H).sup.+.
Part B. Preparation of
(S)-3-cyclohexyl-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)propanoic acid
[0555] The product from Part A (130 mg, 0.3 mmol) in a solvent
mixture of THF/water/methanol (1.5:1.5:0.5 ml) was treated with
LiOH (63 mg, 1.5 mmol) and stirred for 3 hours. The mixture was
diluted with 50 mL EtOAc and acidified with 10% H.sub.3PO.sub.4.
The EtOAc layer was washed with brine, dried (Na.sub.2SO.sub.4),
and concentrated to a white powder (119 mg, 95%). MS (ESI+) m/z=417
(M+H).sup.+.
Part C. Preparation of (3R,4R)-tert-butyl
3-((S)-3-cyclohexyl-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetami-
do)propanamido)-4-((3S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenyl
ethylamino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)pyrrolidi-
ne-1-carboxylate
[0556] A mixture of the product from Part B (50 mg, 0.12 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (29
mg, 0.15 mmol), 1-hydroxybenzotriazole (21 mg, 0.15 mmol), Hunig's
base (70 uL, 0.4 mmol) and the product from Example 25, Part E (57
mg, 0.1 mmol)) in dichloromethane (4 mL) was stirred for 3 hours,
diluted with 100 mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4,
10 mL 10% NaHCO.sub.3, 3.times.20 mL with brine, dried
(Na.sub.2SO.sub.4), and concentrated. The crude product was flash
chromatographed on an Alltech 1 g silica cartridge eluting with
DCM.fwdarw.10% MeOH in DCM to give a white powder (42 mg, 43%). MS
(ESI-) m/z=974 (M-H).sup.+.
Part D. Preparation of Title Product
[0557] The product from Part C (40 mg, 0.040 mmol) in
dichloromethane (4 mL) was treated with Dess-Martin periodinane (21
mg, 0.049 mmol), stirred for 2 hours, treated with 10% aqueous
sodium sulfite (2 mL), stirred for 10 minutes and diluted with 50
mL EtOAc. The EtOAc layer was then washed with 10% aqueous sodium
bicarbonate, brine, dried (Na.sub.2SO.sub.4) and concentrated. The
crude product was flash chromatographed on an Alltech 2 g silica
cartridge eluting with dichloromethane.fwdarw.3% MeOH in
dichloromethane to give a white powder (20 mg, 50%). MS (ESI-)
m/z=972 (M-H).sup.+.
Example 33
Preparation of
N--((S)-1-cyclohexyl-2-((S)-3-cyclohexyl-1-((3R,4R)-4-((S)-1-(2-((S)-2-(d-
imethylamino)-2-oxo-1-phenylethylamino)-2-oxoethylamino)-1,2-dioxohexan-3--
ylcarbamoyl)pyrrolidin-3-ylamino)-1-oxopropan-2-ylamino)-2-oxoethyl)pyrazi-
ne-2-carboxamide
##STR00098##
[0559] The product from Example 32, Part D (15 mg, 0.0154 mmol) in
dichloromethane (0.3 mL) was treated with trifluoroacetic acid (2
mL), stirred for 1 hour and concentrated to give the title compound
as a tan powder (16 mg, 99%). MS (ESI-) m/z=872 (M-H).sup.+.
Example 34
Preparation of (3R,4R)-tert-butyl
3-((S)-1-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetyl)pyrrolidine-2-
-carboxamido)-4-((S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenyl
ethylamino)-2-oxoethylamino)-1,2-dioxohexan-3-ylcarbamoyl)pyrrolidine-1-c-
arboxylate
##STR00099##
[0560] Part A. Preparation of (S)-methyl
1-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetyl)pyrrolidine-2-carbox-
ylate
[0561] A mixture of the product from Example 1, Part G (132 mg, 0.5
mmol), N-(3-dimethylamino propyl)-N'-ethylcarbodiimide
hydrochloride (144 mg, 0.75 mmol), 1-hydroxybenzotriazole (102 mg,
0.75 mmol), Hunig's base (350 uL, 2.0 mmol) and
(S)-methylpyrrolidine-2-carboxylate hydrochloride (86 mg, 0.52
mmol)) in dichloromethane (15 mL) was stirred for 2 hours, diluted
with 100 mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4, 10 mL 10%
NaHCO.sub.3, 3.times.20 mL with brine, dried (Na.sub.2SO.sub.4),
and concentrated to give a yellow oil (190 mg, 99%). MS (ESI+)
m/z=375 (M+H).sup.+.
Part B. Preparation of
(S)-1-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetyl)pyrrolidine-2-ca-
rboxylic acid
[0562] The product from Part A (190 mg, 0.51 mmol) in a solvent
mixture of THF/water/methanol (3:3:1 ml) was treated with LiOH (105
mg, 2.5 mmol) and stirred for 3 hours. The mixture was diluted with
50 mL EtOAc and acidified with 10% H.sub.3PO.sub.4. The EtOAc layer
was washed with brine, dried (Na.sub.2SO.sub.4), and concentrated
to an off-white powder (175 mg, 95%). MS (ESI+) m/z=361
(M+H).sup.+.
Part C. Preparation of (3R,4R)-tert-butyl
3-((S)-1-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetyl)pyrrolidine-2-
-carboxamido)-4-((3S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenyl
ethylamino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)pyrrolidi-
ne-1-carboxylate
[0563] A mixture of the product from Part B (43 mg, 0.12 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (29
mg, 0.15 mmol), 1-hydroxybenzotriazole (21 mg, 0.15 mmol), Hunig's
base (70 uL, 0.4 mmol) and the product from Example 25, Part E (57
mg, 0.1 mmol)) in dichloromethane (4 mL) was stirred for 3 hours,
diluted with 100 mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4,
10 mL 10% NaHCO.sub.3, 3.times.20 mL with brine, dried
(Na.sub.2SO.sub.4), and concentrated. The crude product was flash
chromatographed on an Alltech 1 g silica cartridge eluting with DCM
4.6% MeOH in DCM to give a white powder (50 mg, 54%). MS (ESI-)
m/z=918 (M-H).sup.+.
Part D. Preparation of Title Product
[0564] The product from Part C (50 mg, 0.054 mmol) in
dichloromethane (4 mL) was treated with Dess-Martin periodinane (69
mg, 0.162 mmol), stirred for 2 hours, treated with 10% aqueous
sodium sulfite (2 mL), stirred for 10 minutes and diluted with 50
mL EtOAc. The EtOAc layer was then washed with 10% aqueous sodium
bicarbonate, brine, dried (Na.sub.2SO.sub.4) and concentrated. The
crude product was flash chromatographed on an Alltech 2 g silica
cartridge eluting with dichloromethane.fwdarw.3% MeOH in
dichloromethane to give a white powder (21 mg, 42%). MS (ESI-)
m/z=916 (M-H).sup.+.
Example 35
Preparation of (3R,4R)-tert-butyl
3-((S)-5-amino-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-5-
-oxopentanamido)-4-((S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenylethylami-
no)-2-oxoethylamino)-1,2-dioxohexan-3-ylcarbamoyl)pyrrolidine-1-carboxylat-
e
##STR00100##
[0565] Part A. Preparation of (S)-tert-butyl
5-amino-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-5-oxopen-
tanoate
[0566] A mixture of the product from Example 1, Part G (79 mg, 0.3
mmol), N-(3-dimethylamino propyl)-N'-ethylcarbodiimide
hydrochloride (86 mg, 0.45 mmol), 1-hydroxybenzotriazole (61 mg,
0.45 mmol), Hunig's base (210 uL, 1.2 mmol) and (S)-tert-butyl
2,5-diamino-5-oxopentanoate hydrochloride (72 mg, 0.3 mmol)) in
dichloromethane (8 mL) was stirred for 2 hours, diluted with 100 mL
EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4, 10 mL 10%
NaHCO.sub.3, 3.times.20 mL with brine, dried (Na.sub.2SO.sub.4),
and concentrated to give a yellow foam (117 mg, 87%). MS (ESI+)
m/z=448 (M+H).sup.+.
Part B. Preparation of
(S)-5-amino-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-5-oxopentanoic acid
[0567] The product from Part A (117 mg, 0.26 mmol) in
dichloromethane (3 mL) was treated with trifluoroacetic acid (3
mL), stirred for 2 hours and concentrated to give an orange foam
(130 mg, 99%). MS (ESI+) m/z=392 (M+H).sup.+.
Part C. Preparation of
##STR00101##
[0569] A mixture of the product from Part B (61 mg, 0.12 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (29
mg, 0.15 mmol), 1-hydroxybenzotriazole (21 mg, 0.15 mmol), Hunig's
base (70 uL, 0.4 mmol) and the product from Example 25, Part E (57
mg, 0.1 mmol)) in dichloromethane (4 mL) was stirred for 3 hours,
diluted with 100 mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4,
10 mL 10% NaHCO.sub.3, 3.times.20 mL with brine, dried
(Na.sub.2SO.sub.4), and concentrated. The crude product was flash
chromatographed on an Alltech 1 g silica cartridge eluting with
DCM.fwdarw.6% MeOH in DCM to give a white powder (35 mg, 37%). MS
(ESI-) m/z=949 (M-H).sup.+.
Part D. Preparation of Title Product
[0570] The product from Part C (35 mg, 0.037 mmol) in
dichloromethane (4 mL) was treated with Dess-Martin periodinane (47
mg, 0.11 mmol), stirred for 2 hours, treated with 10% aqueous
sodium sulfite (2 mL), stirred for 10 minutes and diluted with 50
mL EtOAc. The EtOAc layer was then washed with 10% aqueous sodium
bicarbonate, brine, dried (Na.sub.2SO.sub.4) and concentrated. The
crude product was flash chromatographed on an Alltech 1 g silica
cartridge eluting with dichloromethane.fwdarw.6% MeOH in
dichloromethane to give a white powder (28 mg, 80%). MS (ESI-)
m/z=947 (M-H).sup.+.
Example 36
Preparation of (3R,4R)-tert-butyl
3-((R)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimet-
hylbutanamido)-4-((S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenylethylamino-
)-2-oxoethylamino)-1,2-dioxohexan-3-ylcarbamoyl)pyrrolidine-1-carboxylate
##STR00102##
[0571] Part A. Preparation of (R)-methyl
2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanoate
[0572] A mixture of the product from Example 1, Part G (79 mg, 0.3
mmol), N-(3-dimethylamino propyl)-N'-ethylcarbodiimide
hydrochloride (86 mg, 0.45 mmol), 1-hydroxybenzotriazole (61 mg,
0.45 mmol), Hunig's base (210 uL, 1.2 mmol) and (R)-methyl
2-amino-3-methylbutanoate 2,2,2-trifluoroacetate (78 mg, 0.3 mmol))
in dichloromethane (8 mL) was stirred for 2 hours, diluted with 100
mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4, 10 mL 10%
NaHCO.sub.3, 3.times.20 mL with brine, dried (Na.sub.2SO.sub.4),
and The crude product was concentrated and the residue was flash
chromatographed on an Alltech 1 g silica cartridge eluting with
dichloromethane.fwdarw.2% MeOH in dichloromethane to give a white
foam (58 mg, 50%). MS (ESI+) m/z=391 (M+H).sup.+
Part B. Preparation of
(R)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl-
butanoic acid
[0573] The product from Part A (58 mg, 0.15 mmol) in a solvent
mixture of THF/water/methanol (2:2:0.7 ml) was treated with LiOH
(32 mg, 0.75 mmol) and stirred for 3 hours. The mixture was diluted
with 50 mL EtOAc and acidified with 10% H.sub.3PO.sub.4. The EtOAc
layer was washed with brine, dried (Na.sub.2SO.sub.4), and
concentrated to a clear glass (60 mg, 99%). MS (ESI+) m/z=377
(M+H).sup.+.
Part C. Preparation of (3R,4R)-tert-butyl
3-((R)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimet-
hylbutanamido)-4-((3S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenyl
ethylamino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)pyrrolidi-
ne-1-carboxylate
[0574] A mixture of the product from Part B (45 mg, 0.12 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (29
mg, 0.15 mmol), 1-hydroxybenzotriazole (21 mg, 0.15 mmol), Hunig's
base (70 uL, 0.4 mmol) and the product from Example 25, Part E (57
mg, 0.1 mmol)) in dichloromethane (4 mL) was stirred for 3 hours,
diluted with 100 mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4,
10 mL 10% NaHCO.sub.3, 3.times.20 mL with brine, dried
(Na.sub.2SO.sub.4), and concentrated. The crude product was flash
chromatographed on an Alltech 1 g silica cartridge eluting with DCM
4.4% MeOH in DCM to give a white powder (18 mg, 19%). MS (ESI-)
m/z=934 (M-H).sup.+.
Part D. Preparation of Title Product
[0575] The product from Part C (18 mg, 0.019 mmol) in
dichloromethane (2 mL) was treated with Dess-Martin periodinane (24
mg, 0.056 mmol), stirred for 2 hours, treated with 10% aqueous
sodium sulfite (2 mL), stirred for 10 minutes and diluted with 50
mL EtOAc. The EtOAc layer was then washed with 10% aqueous sodium
bicarbonate, brine, dried (Na.sub.2SO.sub.4) and concentrated. The
crude product was flash chromatographed on an Alltech 1 g silica
cartridge eluting with dichloromethane.fwdarw.4% MeOH in
dichloromethane to give a white powder (14 mg, 79%). MS (ESI-)
m/z=932 (M-H).sup.+.
Example 37
Preparation of (3R,4R)-tert-butyl
3-((S)-2-cyclohexyl-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetami-
do)acetamido)-4-((S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenyl
ethylamino)-2-oxoethylamino)-1,2-dioxohexan-3-ylcarbamoyl)pyrrolidine-1-c-
arboxylate
##STR00103##
[0576] Part A. Preparation of (S)-tert-butyl
2-cyclohexyl-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)acet-
ate
[0577] A mixture of the product from Example 1, Part E (132 mg, 0.5
mmol), N-(3-dimethylamino propyl)-N'-ethylcarbodiimide
hydrochloride (144 mg, 0.75 mmol), 1-hydroxybenzotriazole (102 mg,
0.75 mmol), Hunig's base (350 uL, 2.0 mmol) and (S)-tert-butyl
2-amino-2-cyclohexylacetate hydrochloride (130 mg, 0.52 mmol)) in
dichloromethane (15 mL) was stirred for 2 hours, diluted with 100
mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4, 10 mL 10%
NaHCO.sub.3, 3.times.20 mL with brine, dried (Na.sub.2SO.sub.4),
and concentrated to give a white foam (190 mg, 83%). MS (ESI-)
m/z=457 (M-H).sup.+.
Part B. Preparation of
(S)-2-cyclohexyl-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)acetic acid
[0578] The product from Part A (55 mg, 0.12 mmol) in
dichloromethane (0.5 mL) was treated with trifluoroacetic acid (2
mL), stirred for 3 hour and concentrated to give a sticky yellow
foam. MS (ESI+) m/z=403 (M+H).sup.+.
Part C. Preparation of (3R,4R)-tert-butyl
3-((S)-2-cyclohexyl-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetami-
do)acetamido)-4-((3S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenyl
ethylamino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)pyrrolidi-
ne-1-carboxylate
[0579] A mixture of the product from Part B (48 mg, 0.12 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (29
mg, 0.15 mmol), 1-hydroxybenzotriazole (21 mg, 0.15 mmol), Hunig's
base (70 uL, 0.4 mmol) and the product from Example 25, Part E (58
mg, 0.1 mmol)) in dichloromethane (3 mL) was stirred for 1 hour,
diluted with 100 mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4,
10 mL 10% NaHCO.sub.3, 20 mL with brine, dried (MgSO.sub.4), and
concentrated to give the title compound (70 mg, 72%). MS (ESI+)
m/z=961.6 (M+H).sup.+.
Part D. Preparation of Title Product
[0580] The product from Part C (67 mg, 0.07 mmol) in
dichloromethane (2 mL) was treated with Dess-Martin periodinane (59
mg, 0.14 mmol), stirred for 2 hours, treated with 10% aqueous
sodium sulfite (2 mL), stirred for 10 minutes and diluted with 50
mL EtOAc. The EtOAc layer was then washed with 10% aqueous sodium
bicarbonate, brine, dried (MgSO.sub.4) and concentrated. The crude
product was flash chromatographed on an Alltech 5 g silica
cartridge eluting with ethyl acetate/methanol (98/2) to give the
title compound (24 mg, 36%). MS (ESI+) m/z=959.6 (M+H).sup.+.
Example 38
Preparation of
N--((S)-1-cyclohexyl-2-((S)-1-cyclohexyl-2-((3R,4R)-4-((S)-1-(2-((S)-2-(d-
imethylamino)-2-oxo-1-phenylethylamino)-2-oxoethylamino)-1,2-dioxohexan-3--
yl
carbamoyl)pyrrolidin-3-ylamino)-2-oxoethylamino)-2-oxoethyl)pyrazine-2--
carboxamide 2,2,2-trifluoroacetate
##STR00104##
[0582] The product from Example 37, Part D (17 mg, 0.018 mmol) in
dichloromethane (0.5 mL) was treated with trifluoroacetic acid (1
mL), stirred for 1 hour and concentrated to give the title compound
in quantitative yield. MS (ESI-) m/z=857.6 (M-H).sup.+.
Example 39
Preparation of (3R,4R)-tert-butyl
3-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)pentanamid-
o)-4-((S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenylethylamino)-2-oxoethyl-
amino)-1,2-dioxohexan-3-ylcarbamoyl)pyrrolidine-1-carboxylate
##STR00105##
[0583] Part A. Preparation of (S)-tert-butyl
2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)pentanoate
[0584] A mixture of the product from Example 1, Part E (132 mg, 0.5
mmol), N-(3-dimethylamino propyl)-N'-ethylcarbodiimide
hydrochloride (144 mg, 0.75 mmol), 1-hydroxybenzotriazole (102 mg,
0.75 mmol), Hunig's base (350 uL, 2.0 mmol) and (S)-tert-butyl
2-aminopentanoate hydrochloride (109 mg, 0.52 mmol)) in
dichloromethane (15 mL) was stirred for 2 hours, diluted with 100
mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4, 10 mL 10%
NaHCO.sub.3, 3.times.20 mL with brine, dried (Na.sub.2SO.sub.4),
and concentrated to give a white waxy solid (176 mg, 84%). MS
(ESI-) m/z=417 (M-H).sup.+.
Part B. Preparation of
(S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)pentanoic
acid
[0585] The product from Part A (50 mg, 0.12 mmol) in
dichloromethane (0.5 mL) was treated with trifluoroacetic acid (2.5
mL), stirred for 1 hour and concentrated to give a sticky
solid.
Part C. Preparation of (3R,4R)-tert-butyl
3-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)pentanamid-
o)-4-((3S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenylethylamino)-2-oxoethy-
lamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)pyrrolidine-1-carboxylate
[0586] A mixture of the product from Part B (43 mg, 0.12 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (29
mg, 0.15 mmol), 1-hydroxybenzotriazole (21 mg, 0.15 mmol), Hunig's
base (70 uL, 0.4 mmol) and the product from Example 25, Part E (58
mg, 0.1 mmol)) in dichloromethane (3 mL) was stirred for 1 hour,
diluted with 100 mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4,
10 mL 10% NaHCO.sub.3, 20 mL with brine, dried (MgSO.sub.4), and
concentrated to give the title compound (75 mg, 81%). MS (ESI+)
m/z=921.6 (M+H).sup.+.
Part D. Preparation of Title Product
[0587] The product from Part C (74 mg, 0.08 mmol) in
dichloromethane (2 mL) was treated with Dess-Martin periodinane (68
mg, 0.16 mmol), stirred for 1 hour, treated with 10% aqueous sodium
sulfite (2 mL), stirred for 10 minutes and diluted with 50 mL
EtOAc. The EtOAc layer was then washed with 10% aqueous sodium
bicarbonate, brine, dried (MgSO.sub.4) and concentrated. The crude
product was flash chromatographed on an Alltech 5 g silica
cartridge eluting with ethyl acetate/methanol (98/2) to give the
title compound (20 mg, 27%). MS (ESI+) m/z=919.6 (M+H).sup.+.
Example 40
Preparation of
N-((1S)-1-cyclohexyl-2-((2S)-1-((3R,4R)-4-((3S)-1-(2-((S)-2-(dimethylamin-
o)-2-oxo-1-phenylethylamino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-yl
carbamoyl)pyrrolidin-3-ylamino)-1-oxopentan-2-ylamino)-2-oxoethyl)pyrazin-
e-2-carboxamide 2,2,2-trifluoroacetate
##STR00106##
[0589] The product from Example 39, Part D (13 mg, 0.014 mmol) in
dichloromethane (0.5 mL) was treated with trifluoroacetic acid (1
mL), stirred for 1 hour and concentrated to give the title compound
in quantitative yield. MS (ESI+) m/z=819.6 (M+H).sup.+.
Example 41
Preparation of (3R,4R)-tert-butyl
3-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-4-methylp-
entanamido)-4-((S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenylethylamino)-2-
-oxoethylamino)-1,2-dioxohexan-3-ylcarbamoyl)pyrrolidine-1-carboxylate
##STR00107##
[0590] Part A. Preparation of (S)-tert-butyl
2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-4-methylpentanoate
[0591] A mixture of product from Example 1, Part E (132 mg, 0.5
mmol), N-(3-dimethylamino propyl)-N'-ethylcarbodiimide
hydrochloride (144 mg, 0.75 mmol), 1-hydroxybenzotriazole (102 mg,
0.75 mmol), Hunig's base (350 uL, 2.0 mmol) and (S)-tert-butyl
2-amino-4-methylpentanoate HCl (116 mg, 0.52 mmol)) in
dichloromethane (15 mL) was stirred for 2 h, diluted with 100 mL
EtOAc, washed with 10 mL 1M H.sub.3PO.sub.4, 10 mL 10% NaHCO.sub.3,
3.times.20 mL brine, dried (Na.sub.2SO.sub.4), and concentrated to
give white waxy solid (182 mg, 84%). MS (ESI-) m/z=431 (M-H).
Part B. Preparation of
(S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-4-methylpent-
anoic acid
[0592] The product from Part A (52 mg, 0.12 mmol) in
dichloromethane (0.5 mL) was treated with trifluoroacetic acid (2
mL), stirred for 3 h and concentrated to give a sticky solid.
Part C. Preparation of (3R,4R)-tert-butyl
3-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-4-methylp-
entanamido)-4-((3S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenylethyl
amino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)pyrrolidine-1--
carboxylate
[0593] A mixture of the product from Part B (45 mg, 0.12 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (29
mg, 0.15 mmol), 1-hydroxybenzotriazole (21 mg, 0.15 mmol), Hunig's
base (70 uL, 0.4 mmol) and the product from Example 25, Part E (58
mg, 0.1 mmol)) in dichloromethane (3 mL) was stirred for 1 hour,
diluted with 100 mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4,
10 mL 10% NaHCO.sub.3, 20 mL with brine, dried (MgSO.sub.4), and
concentrated to give the title compound (70 mg, 74%). MS (ESI+)
m/z=935.6 (M+H).sup.+
Part D. Preparation of Title Product
[0594] The product from Part C (66 mg, 0.07 mmol) in
dichloromethane (2 mL) was treated with Dess-Martin periodinane (59
mg, 0.14 mmol), stirred for 2 hours, treated with 10% aqueous
sodium sulfite (2 mL), stirred for 10 minutes and diluted with 50
mL EtOAc. The EtOAc layer was then washed with 10% aqueous sodium
bicarbonate, brine, dried (MgSO.sub.4) and concentrated. The crude
product was flash chromatographed on an Alltech 5 g silica
cartridge eluting with ethyl acetate/methanol (98/2) to give the
title compound (19 mg, 29%). MS (ESI-) m/z=931.7 (M-H).sup.+.
Example 42
Preparation of
N--((S)-1-cyclohexyl-2-((S)-1-((3R,4R)-4-((S)-1-(2-((S)-2-(dimethylamino)-
-2-oxo-1-phenylethylamino)-2-oxoethylamino)-1,2-dioxohexan-3-ylcarbamoyl)p-
yrrolidin-3-ylamino)-4-methyl-1-oxopentan-2-ylamino)-2-oxoethyl)pyrazine-2-
-carboxamide 2,2,2-trifluoroacetate
##STR00108##
[0596] The product from Example 41, Part D (12 mg, 0.013 mmol) in
dichloromethane (0.5 mL) was treated with trifluoroacetic acid (1
mL), stirred for 1 hour and concentrated to give the title compound
in quantitative yield. MS (ESI-) m/z=831.7 (M-H).sup.+
Example 43
Preparation of (3R,4R)-tert-butyl
3-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)butanamido-
)-4-((S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenylethylamino)-2-oxoethyla-
mino)-1,2-dioxohexan-3-ylcarbamoyl)pyrrolidine-1-carboxylate
##STR00109##
[0597] Part A. Preparation of (S)-tert-butyl
2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)butanoate
[0598] A mixture of the product from Example 1, Part E (132 mg, 0.5
mmol), N-(3-dimethylamino propyl)-N'-ethylcarbodiimide
hydrochloride (144 mg, 0.75 mmol), 1-hydroxybenzotriazole (102 mg,
0.75 mmol), Hunig's base (350 uL, 2.0 mmol) and (S)-tert-butyl
2-aminobutanoate hydrochloride (102 mg, 0.52 mmol)) in
dichloromethane (15 mL) was stirred for 2 hours, diluted with 100
mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4, 10 mL 10%
NaHCO.sub.3, 3.times.20 mL with brine, dried (Na.sub.2SO.sub.4),
and concentrated to give a white foam (182 mg, 90%). MS (ESI-)
m/z=403 (M-H).sup.-.
Part B. Preparation of
(S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)
butanoic acid
[0599] The product from Part A (49 mg, 0.12 mmol) in
dichloromethane (0.5 mL) was treated with trifluoroacetic acid (2.5
mL), stirred for 1 hour and concentrated to give a sticky
solid.
Part C. Preparation of (3R,4R)-tert-butyl
3-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)butanamido-
)-4-((3S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenylethylamino)-2-oxoethyl-
amino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)pyrrolidine-1-carboxylate
[0600] A mixture of product from Part B (42 mg, 0.12 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (29
mg, 0.15 mmol), 1-hydroxybenzotriazole (21 mg, 0.15 mmol), Hunig's
base (70 uL, 0.4 mmol) and the product from Example 25, Part E (58
mg, 0.1 mmol)) in dichloromethane (3 mL) was stirred for 1 h,
diluted with 100 mL EtOAc, washed with 10 mL 1M H.sub.3PO.sub.4, 10
mL 10% NaHCO.sub.3, 20 mL brine, dried (MgSO.sub.4), and
concentrated to title compound (54 mg, 59%). MS (ESI+) m/z=907.6
(M+H).sup.+.
Part D. Preparation of Title Product
[0601] The product from Part C (50 mg, 0.055 mmol) in
dichloromethane (2 mL) was treated with Dess-Martin periodinane (47
mg, 0.1 mmol), stirred for 2 h, treated with 10% aqueous sodium
sulfite (2 mL), stirred for 10 min and diluted with 50 mL EtOAc.
EtOAc layer was washed with 10% aqueous sodium bicarbonate, brine,
dried (MgSO.sub.4) and concentrated. Crude product was flash
chromatographed on an Alltech 5 g silica cartridge eluting with
ethyl acetate/methanol (98/2) to give title compound (16 mg, 32%).
MS (ESI+) m/z=905.6 (M+H).sup.+.
Example 44
Preparation of
N--((S)-1-cyclohexyl-2-((S)-1-((3R,4R)-4-((S)-1-(2-((S)-2-(dimethylamino)-
-2-oxo-1-phenylethylamino)-2-oxoethylamino)-1,2-dioxohexan-3-ylcarbamoyl)p-
yrrolidin-3-ylamino)-1-oxobutan-2-ylamino)-2-oxoethyl)pyrazine-2-carboxami-
de 2,2,2-trifluoroacetate
##STR00110##
[0603] The product from Example 43, Part D (9 mg, 0.01 mmol) in
dichloromethane (0.5 mL) was treated with trifluoroacetic acid (1
mL), stirred for 1 hour and concentrated to give the title compound
in quantitative yield. MS (ESI-) m/z=803.6 (M-H).sup.+.
Example 45
Preparation of (3R,4R)-tert-butyl
3-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-N,3,3-tri-
methylbutanamido)-4-((S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenylethylam-
ino)-2-oxoethylamino)-1,2-dioxohexan-3-ylcarbamoyl)pyrrolidine-1-carboxyla-
te
##STR00111##
[0604] Part A. Preparation of (3R,4R)-di-tert-butyl
4-(benzyl(methyl)amino)pyrrolidine-1,3-dicarboxylate
[0605] To a solution of (3R,4R)-di-tert-butyl
4-aminopyrrolidine-1,3-dicarboxylate (Org. Biomol. Chem. 2004, 2,
2763-2776) (430 mg, 1.5 mmol) in dichloromethane/methanol (18 mL/2
mL) was added benzaldehyde (153 uL, 1.5 mmol) and sodium
triacetoxyborohydride (1.89 g, 9.0 mmol). The mixture was stirred
overnight and partitioned between ethyl acetate and water. The
organic layer was washed with brine, dried with magnesium sulfate,
filtered and evaporated. The residue was purified on silica gel
eluting with ethyl acetate/hexane (1:3) to give the title compound
(495 mg, 88%). MS (ESI+) m/z=377 (M+H).sup.+.
Part B. Preparation of (3R,4R)-di-tert-butyl
4-(benzyl(methyl)amino)pyrrolidine-1,3-dicarboxylate
[0606] To a solution of the product from Part A (490 mg, 1.3 mmol)
in dichloromethane/methanol (18 mL/2 mL) was added formaldehyde
(104 uL, 37 wt. %, 1.4 mmol) and sodium triacetoxyborohydride (2.20
g, 10.4 mmol). The mixture was stirred overnight and partitioned
between ethyl acetate and water. The organic layer was washed with
brine, dried with magnesium sulfate, filtered and evaporated. The
residue was purified on silica gel eluting with ethyl
acetate/hexane (1:3) to give the title compound (369 mg, 73%). MS
(ESI+) m/z=391 (M+H).sup.+.
Part C. Preparation of (3R,4R)-di-tert-butyl
4-(methylamino)pyrrolidine-1,3-dicarboxylate
[0607] The product from Part B (360 mg, 0.92 mmol) was hydrogenated
using 10% Pd/C (50 mg) in ethyl acetate (20 mL). The reaction
mixture was stirred overnight under 1 atmosphere of H.sub.2,
filtered through celite and the filtrate was evaporated to give the
title compound (275 mg, 99%). MS (ESI+) m/z=301 (M+H).sup.+.
Part D. Preparation of (3R,4R)-di-tert-butyl
4-((S)-2-(benzyloxycarbonylamino)-N,3,3-trimethylbutanamido)pyrrolidine-1-
,3-dicarboxylate
[0608] A mixture of the product from Part C (270 mg, 0.9 mmol),
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (380 mg, 1.0 mmol), Hunig's base (470 uL, 2.7
mmol) and (S)-2-(benzyloxycarbonylamino)-3,3-dimethylbutanoic acid
(239 mg, 0.9 mmol)) in dichloromethane (5 mL) was stirred for 24
hours, diluted with 100 mL EtOAc, washed with 10 mL 1 M
H.sub.3PO.sub.4, 10 mL 10% NaHCO.sub.3, 20 mL with brine, dried
(MgSO.sub.4), and evaporated. The residue was purified on silica
gel eluting with ethyl acetate/hexane (1:3) to give the title
compound (402 mg, 82%). MS (ESI+) m/z=548 (M+H).sup.+.
Part E. Preparation of (3R,4R)-di-tert-butyl
4-((S)-2-amino-N,3,3-trimethylbutanamido)
pyrrolidine-1,3-dicarboxylate
[0609] The product from Part D (400 mg, 0.73 mmol) was hydrogenated
using 10% Pd/C (50 mg) in methanol (20 mL). The reaction mixture
was stirred overnight under 1 atmosphere of H.sub.2, filtered
through celite and evaporated to give the title compound (293 mg,
97%). MS (ESI+) m/z=414 (M+H).sup.+.
Part F. Preparation of (3R,4R)-di-tert-butyl
4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-N,3,3-tri-
methylbutanamido)pyrrolidine-1,3-dicarboxylate
[0610] A mixture of the product from Part E (290 mg, 0.70 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (148
mg, 0.77 mmol), 1-hydroxybenzotriazole (104 mg, 0.77 mmol), Hunig's
base (366 uL, 2.1 mmol) and the product from Example 1, Part E (184
mg, 0.7 mmol)) in dichloromethane (10 mL) was stirred for 3 hour,
diluted with 100 mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4,
10 mL 10% NaHCO.sub.3, 20 mL with brine, dried (MgSO.sub.4), and
concentrated to give the title compound (410 mg, 89%). MS (ESI+)
m/z=660 (M+H).sup.+.
Part G. Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-N,3,3-trimethylbutanamido)pyrrolidine-3-carboxylic
acid
[0611] The product from Part F (409 mg, 0.62 mmol) in
dichloromethane (2 mL) was treated with trifluoroacetic acid (5
mL), stirred for 4 hour and concentrated to give the title compound
in quantitative yield. MS (ESI+) m/z=503 (M+H).sup.+.
Part H. Preparation of
(3R,4R)-1-(tert-butoxycarbonyl)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2--
carboxamido)acetamido)-N,3,3-trimethylbutanamido)pyrrolidine-3-carboxylic
acid
[0612] The product from Part G (191 mg, 0.31 mmol) in THF/1M NaOH
(5 mL/1.5 mL) was treated with di-tert-butyl dicarbonate (100 mg,
0.46 mmol) and stirred for 2 hours. The mixture was concentrated to
remove THF, then added water and ethyl acetate, adjusted pH to 3 by
adding 1M HCl. The aqueous layer was extracted by ethyl acetate
again. The combined organic layers were dried with magnesium
sulfate, filtered and evaporated to give the title compound (182
mg, 97%). MS (ESI-) m/z=601.5 (M-H).sup.+.
Part I. Preparation of (3R,4R)-tert-butyl
3-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-N,3,3-tri-
methylbutanamido)-4-((3S)-1-(2-((S)-2-(dimethylamino)-2-oxo-1-phenylethyla-
mino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)pyrrolidine-1-ca-
rboxylate
[0613] A mixture from Part H (48 mg, 0.08 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (17
mg, 0.09 mmol), 1-hydroxybenzotriazole (12 mg, 0.09 mmol), Hunig's
base (42 uL, 0.24 mmol) and
((3S)-3-amino-N-(2-((S)-2-(dimethylamino)-2-oxo-1-phenylethylamino)-2-oxo-
ethyl)-2-hydroxyhexanamide (WO2003062265-A2; Example 6, cpd 2.3)
(29 mg, 0.08 mmol)) in dichloromethane (5 mL) was stirred for 3
hours and diluted with 100 mL EtOAc, washed with 10 mL 1 M
H.sub.3PO.sub.4, 10 mL 10% NaHCO.sub.3, 20 mL with brine, dried
(MgSO.sub.4), and concentrated to give the title compound (56 mg,
74%). MS (ESI-) m/z=947.7 (M-H).sup.+.
Part J. Preparation of Title Product
[0614] The product from Part I (47 mg, 0.05 mmol) in
dichloromethane (2 mL) was treated with Dess-Martin periodinane (42
mg, 0.10 mmol), stirred for 4 hours, treated with 10% aqueous
sodium sulfite (2 mL), stirred for 10 minutes and diluted with 50
mL EtOAc. The EtOAc layer was then washed with 10% aqueous sodium
bicarbonate, brine, dried (MgSO.sub.4) and concentrated. The crude
product was flash chromatographed on an Alltech 5 g silica
cartridge eluting with ethyl acetate/methanol (98/2) to give the
title compound (11 mg, 23%). MS (ESI-) m/z=945.7 (M-H).sup.+.
Example 46
Preparation of
N--((S)-1-cyclohexyl-2-((S)-1-(((3R,4R)-4-((S)-1-(2-((S)-2-(dimethylamino-
)-2-oxo-1-phenylethylamino)-2-oxoethylamino)-1,2-dioxohexan-3-ylcarbamoyl)-
pyrrolidin-3-yl)(methyl)amino)-3,3-dimethyl-1-oxobutan-2-ylamino)-2-oxoeth-
yl)pyrazine-2-carboxamide 2,2,2-trifluoroacetate
##STR00112##
[0616] The product from Example 45, Part J (6 mg, 0.006 mmol) in
dichloromethane (0.5 mL) was treated with trifluoroacetic acid (1
mL), stirred for 1 hour and concentrated to give the title compound
in quantitative yield. MS (ESI+) m/z=847.6 (M+H).sup.+.
Example 47
Preparation of (3R,4R)-tert-butyl
3-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-N,3,3-tri-
methylbutanamido)-4-((S)-1-(cyclopropylamino)-1,2-dioxohexan-3-ylcarbamoyl-
)pyrrolidine-1-carboxylate
##STR00113##
[0617] Part A. Preparation of (3R,4R)-tert-butyl
3-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-N,3,3-tri-
methylbutanamido)-4-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylca-
rbamoyl)pyrrolidine-1-carboxylate
[0618] A mixture the product from Example 45, Part H (48 mg, 0.08
mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
(17 mg, 0.09 mmol), 1-hydroxybenzotriazole (12 mg, 0.09 mmol),
Hunig's base (42 uL, 0.24 mmol) and
3-amino-N-cyclopropyl-2-hydroxyhexanamide (WO2002018369-A2; Example
119, cpd xiii') (15 mg, 0.08 mmol)) in dichloromethane (5 mL) was
stirred for 3 hours and diluted with 100 mL EtOAc, washed with 10
mL 1 M H.sub.3PO.sub.4, 10 mL 10% NaHCO.sub.3, 20 mL with brine,
dried (MgSO.sub.4), and concentrated to give the title compound (54
mg, 88%). MS (ESI+) m/z=771.6 (M+H).sup.+.
Part B. Preparation of Title Product
[0619] The product from Part A (52 mg, 0.067 mmol) in
dichloromethane (2 mL) was treated with Dess-Martin periodinane (59
mg, 0.14 mmol), stirred for 4 hours, treated with 10% aqueous
sodium sulfite (2 mL), stirred for 10 minutes and diluted with 50
mL EtOAc. The EtOAc layer was then washed with 10% aqueous sodium
bicarbonate, brine, dried (MgSO.sub.4) and concentrated. The crude
product was flash chromatographed on an Alltech 5 g silica
cartridge eluting with ethyl acetate to give the title compound (27
mg, 52%). MS (ESI-) m/z=767.7 (M-H).sup.+.
Example 48
Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-N,3,3-trimethylbutanamido)-N3-((S)-1-(2-((S)-2-(dimethylamino)-
-2-oxo-1-phenylethyl
amino)-2-oxoethylamino)-1,2-dioxohexan-3-yl)-N1-phenylpyrrolidine-1,3-dic-
arboxamide
##STR00114##
[0620] Part A. Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-N,3,3-trimethylbutanamido)-1-(phenylcarbamoyl)pyrrolidine-3-ca-
rboxylic acid
[0621] The product from Example 45, Part G (191 mg, 0.31 mmol),
phenyl isocyanate (37 uL, 0.34 mmol) and Hunig's base (162 uL, 0.93
mmol) in tetrahydrofuran (5 mL) was stirred for 2 hours. The
mixture was diluted with water and ethyl acetate and the pH was
adjusted to 3 by adding 1M HCl. The aqueous layer was extracted
with ethyl acetate again. The combined organic layers were dried
with magnesium sulfate, filtered and evaporated to give the title
compound in quantitative yield. MS (ESI+) m/z=622.5
(M+H).sup.+.
Part B. Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-N,3,3-trimethylbutanamido)-N3-((3S)-1-(2-((S)-2-(dimethylamino-
)-2-oxo-1-phenylethyl
amino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-yl)-N1-phenylpyrrolidine-1-
,3-dicarboxamide
[0622] A mixture the product from Part A (50 mg, 0.08 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (17
mg, 0.09 mmol), 1-hydroxybenzotriazole (12 mg, 0.09 mmol), Hunig's
base (42 uL, 0.24 mmol) and
((3S)-3-amino-N-(2-((S)-2-(dimethylamino)-2-oxo-1-phenylethylamino)-2-oxo-
ethyl)-2-hydroxyhexanamide (WO2003062265-A2; Example 6, cpd 2.3)
(29 mg, 0.08 mmol)) in dichloromethane (5 mL) was stirred for 3
hours and diluted with 100 mL EtOAc, washed with 10 mL 1 M
H.sub.3PO.sub.4, 10 mL 10% NaHCO.sub.3, 20 mL with brine, dried
(MgSO.sub.4), and concentrated to give the title compound (34 mg,
44%). MS (ESI+) m/z=968.6 (M+H).sup.+.
Part C. Preparation of Title Product
[0623] The product from Part B (29 mg, 0.03 mmol) in
dichloromethane (2 mL) was treated with Dess-Martin periodinane (26
mg, 0.06 mmol), stirred for 4 hours, treated with 10% aqueous
sodium sulfite (2 mL), stirred for 10 minutes and diluted with 50
mL EtOAc. The EtOAc layer was then washed with 10% aqueous sodium
bicarbonate, brine, dried (MgSO.sub.4) and concentrated. The crude
product was flash chromatographed on an Alltech 5 g silica
cartridge eluting with ethyl acetate to give the title compound (15
mg, 52%). MS (ESI+) m/z=966.6 (M+H).sup.+.
Example 49
Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-N,3,3-trimethylbutanamido)-N3-((S)-1-(cyclopropylamino)-1,2-di-
oxohexan-3-yl)-N1-phenyl pyrrolidine-1,3-dicarboxamide
##STR00115##
[0624] Part A. Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-N,3,3-trimethylbutanamido)-N3-((3S)-1-(cyclopropylamino)-2-hyd-
roxy-1-oxohexan-3-yl)-N1-phenylpyrrolidine-1,3-dicarboxamide
[0625] A mixture of the product from Example 48, Part A (50 mg,
0.08 mmol), N-(3-dimethyl aminopropyl)-N'-ethylcarbodiimide
hydrochloride (17 mg, 0.09 mmol), 1-hydroxybenzotriazole (12 mg,
0.09 mmol), Hunig's base (42 uL, 0.24 mmol) and
3-amino-N-cyclopropyl-2-hydroxyhexanamide (WO2002018369-A2; Example
119, cpd xiii') (15 mg, 0.08 mmol)) in dichloromethane (5 mL) was
stirred for 3 hours and diluted with 100 mL EtOAc, washed with 10
mL 1 M H.sub.3PO.sub.4, 10 mL 10% NaHCO.sub.3, 20 mL with brine,
dried (MgSO.sub.4), and concentrated to give the title compound (31
mg, 49%). MS (ESI+) m/z=790.7 (M+H).sup.+.
Part B. Preparation of Title Product
[0626] The product from Part A (24 mg, 0.03 mmol) in
dichloromethane (2 mL) was treated with Dess-Martin periodinane (26
mg, 0.06 mmol), stirred for 4 hours, treated with 10% aqueous
sodium sulfite (2 mL), stirred for 10 minutes and diluted with 50
mL EtOAc. The EtOAc layer was then washed with 10% aqueous sodium
bicarbonate, brine, dried (MgSO.sub.4) and concentrated. The crude
product was flash chromatographed on an Alltech 5 g silica
cartridge eluting with ethyl acetate to give the title compound (13
mg, 54%). MS (ESI+) m/z=788.7 (M+H).sup.+.
Example 50
Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3--((S)-1-(2-((R)-2-(dimethylami-
no)-2-oxo-1-(thiophen-2-yl)ethyl
amino)-2-oxoethylamino)-1,2-dioxohexan-3-yl)-N.sup.1-phenylpyrrolidine-1,-
3-dicarboxamide
##STR00116##
[0627] Part A. Preparation of (R)-tert-butyl
2-(dimethylamino)-2-oxo-1-(thiophen-2-yl)ethyl carbamate
[0628] To a solution of
(R)-2-(tert-butoxycarbonylamino)-2-(thiophen-2-yl)acetic acid (250
mg, 0.9716 mmol) in DMF (5 mL) and methylene chloride (5 mL) was
added dimethylamine hydrochloride (87 mg, 1.069 mmol), HOBt (158
mg, 1.166 mmol), and Hunig's Base (0.508 mL, 2.915 mmol) and the
resulting solution stirred at 0.degree. C. for 10 minutes. EDCI
(248 mg, 1.166 mmol) was added and the reaction stirred at
25.degree. C. for 18 hours. The mixture was concentrated in vacuo,
the resulting residue was diluted with ethyl acetate (45 mL), brine
(10 mL), and 5% H.sub.3PO.sub.4 aqueous solution (10 mL), and the
layers were separated. The organic layer was washed with 5%
H.sub.3PO.sub.4 aqueous solution (10 mL), twice with saturated
aqueous sodium bicarbonate solution (15 mL), water (15 mL), and
brine (15 mL). The organic layer was dried over sodium sulfate,
filtered, and concentrated in vacuo to afford the title compound as
a light colored solid. The crude material was taken on directly to
the next step.
Part B. Preparation of
(R)-2-amino-N,N-dimethyl-2-(thiophen-2-yl)acetamide
hydrochloride
[0629] To a solution of the product from Part A (276 mg, 0.9716
mmol) in methylene chloride (2 mL) was added 4N HCl in dioxane (2
mL) and the resulting solution stirred at 25.degree. C. for 18
hours. The solution was concentrated in vacuo, triturated in
diethyl ether, filtered, and dried under vacuum to afford the title
compound as a light colored solid (152 mg, 71% yield for two
steps). MS (DCI/NH.sub.4.sup.+) m/z=185 (M+H).sup.+.
Part C. Preparation of tert-butyl
(3S)-1-(2-((R)-2-(dimethylamino)-2-oxo-1-(thiophen-2-yl)ethylamino)-2-oxo-
ethylamino)-2-hydroxy-1-oxohexan-3-ylcarbamate
[0630] To a solution of
2-((3S)-3-(tert-butoxycarbonylamino)-2-hydroxyhexanamido)acetic
acid (WO2003062265-A2; Preparative Example 1, compound 1.1) (200
mg, 0.6572 mmol) in DMF (5 mL) and methylene chloride (5 mL) was
added the product from Part B (152 mg, 0.6900 mmol), HOBt (107 mg,
0.7886 mmol), and Hunig's Base (0.343 mL, 1.971 mmol) and the
resulting solution stirred at 0.degree. C. for 10 minutes. EDCI
(168 mg, 0.7886 mmol) was added and the reaction stirred at
25.degree. C. for 18 hours. The mixture was concentrated in vacuo,
the resulting residue was diluted with ethyl acetate (45 mL), brine
(10 mL), and 5% H.sub.3PO.sub.4 aqueous solution (10 mL), and the
layers were separated. The organic layer was washed with 5%
H.sub.3PO.sub.4 aqueous solution (10 mL), twice with saturated
aqueous sodium bicarbonate solution (15 mL), water (15 mL), and
brine (15 mL). The organic layer was dried over sodium sulfate,
filtered, and concentrated in vacuo to afford the title compound as
a light colored solid. (172 mg, 56% yield) MS (ESI.sup.+) m/z=471
(M+H).sup.+.
Part D. Preparation of
(3S)-3-amino-N-(2-((R)-2-(dimethylamino)-2-oxo-1-(thiophen-2-yl)ethylamin-
o)-2-oxoethyl)-2-hydroxyhexanamide hydrochloride
[0631] To a solution of the product from Part C (172 mg, 0.3655
mmol) in methylene chloride (2 mL) was added 4N HCl in dioxane (2
mL) and the resulting solution stirred at 25.degree. C. for 18
hours. The solution was concentrated in vacuo, triturated in
diethyl ether, filtered, and dried under vacuum to afford the title
compound as a light colored solid (147 mg, 99% yield). MS
(ESI.sup.+) m/z=371 (M+H).sup.+.
Part E. Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3-((3S)-1-(2-((R)-2-(dimethylami-
no)-2-oxo-1-(thiophen-2-yl)ethylamino)-2-oxoethylamino)-2-hydroxy-1-oxohex-
an-3-yl)-N.sup.1-phenylpyrrolidine-1,3-dicarboxamide
[0632] To a solution of the product from Example 3, Part B (100 mg,
0.1646 mmol) in DMF (2 mL) was added the product from Part D (74
mg, 0.1810 mmol), HOBt (27 mg, 0.1975 mmol), and Hunig's Base
(0.086 mL, 0.4937 mmol) and the resulting solution stirred at
0.degree. C. for 10 minutes. EDCI (42 mg, 0.1975 mmol) was added
and the reaction stirred at 25.degree. C. for 18 hours. The mixture
was concentrated in vacuo, the resulting residue was diluted with
ethyl acetate (45 mL), brine (10 mL), and 5% H.sub.3PO.sub.4
aqueous solution (10 mL), and the layers were separated. The
organic layer was washed with 5% H.sub.3PO.sub.4 aqueous solution
(10 mL), twice with saturated aqueous sodium bicarbonate solution
(15 mL), water (15 mL), and brine (15 mL). The organic layer was
dried over sodium sulfate, filtered, and concentrated in vacuo to
afford the title compound as a light colored solid. (103 mg, 65%
yield) MS (ESI.sup.+) m/z=961 (M+H).sup.+.
Part F. Preparation of Title Product
[0633] To a solution of the product from Part E (103 mg, 0.1073
mmol) in methylene chloride (1.5 mL) was added Dess-Martin
Periodinane (68 mg, 0.1609 mmol) and the reaction mixture stirred
at 25.degree. C. for 18 hours. The solution was filtered and the
filtrate was concentrated in vacuo and the residue was purified by
reverse phase HPLC to afford the title compound as a white solid.
(56 mg, 54% yield). MS (ESI.sup.+) m/z=959 (M+H).sup.+.
Example 51
Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3--((S)-1-(2-((S)-1-(dimethylami-
no)-3-methoxy-1-oxopropan-2-ylamino)-2-oxoethylamino)-1,2-dioxohexan-3-yl)-
-N.sup.1-phenylpyrrolidine-1,3-dicarboxamide
##STR00117##
[0634] Part A. Preparation of (S)-tert-butyl
1-(dimethylamino)-3-methoxy-1-oxopropan-2-yl carbamate
[0635] Same procedure described for Example 50, Part A was used,
starting with (S)-2-(tert-butoxycarbonylamino)-3-methoxypropanoic
acid. The crude product was taken onto the next step.
Part B. Preparation of
(S)-2-amino-3-methoxy-N,N-dimethylpropanamide hydrochloride
[0636] Same procedure described for Example 50, Part B was used,
starting with the product from Part A (126 mg, 38% yield) MS
(DCI/NH.sub.4.sup.+) m/z=147 (M+H).sup.+
Part C. Preparation of tert-butyl
(3S)-1-(2-((S)-1-(dimethylamino)-3-methoxy-1-oxopropan-2-ylamino)-2-oxoet-
hylamino)-2-hydroxy-1-oxohexan-3-ylcarbamate
[0637] Same procedure described for Example 50, Part C was used,
starting with the product from Part B. (80 mg, 28% yield) MS
(ESI.sup.+) m/z=433 (M+H).sup.+
Part D. Preparation of
(3S)-3-amino-N-(2-((S)-1-(dimethylamino)-3-methoxy-1-oxopropan-2-ylamino)-
-2-oxoethyl)-2-hydroxyhexanamide hydrochloride
[0638] Same procedure described for Example 50, Part D was used,
starting with the product from Part C. (53 mg, 78% yield) MS
(ESI.sup.+) m/z=333 (M+H).sup.+.
Part E. Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3--((S)-1-(2-((S)-1-(dimethylami-
no)-3-methoxy-1-oxopropan-2-ylamino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-
-3-yl)-N.sup.1-phenylpyrrolidine-1,3-dicarboxamide
[0639] Same procedure described for Example 50, Part E was used,
starting with the product from Part D. (65 mg, 49% yield) MS
(ESI.sup.+) m/z=923 (M+H).sup.+.
Part F. Preparation of Title Product
[0640] Same procedure described for Example 50, Part F was used,
starting with the product from Part E. (32 mg, 49% yield) MS
(ESI.sup.+) m/z=921 (M+H).sup.+.
Example 52
Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3--((S)-1,2-dioxo-1-(2-oxo-2-((R-
)-1-phenylethylamino)
ethylamino)hexan-3-yl)-N.sup.1-phenylpyrrolidine-1,3-dicarboxamide
##STR00118##
[0641] Part A. Preparation of tert-butyl
(3S)-2-hydroxy-1-oxo-1-(2-oxo-2-((R)-1-phenylethyl
amino)ethylamino)hexan-3-ylcarbamate
[0642] Same procedure described for Example 50, Part C was used,
starting with (R)-1-phenyl ethanamine (238 mg, 89% yield) MS
(ESI.sup.+) m/z=408 (M+H).sup.+.
Part B. Preparation of
(3S)-3-amino-2-hydroxy-N-(2-oxo-2-((R)-1-phenylethylamino)ethyl)hexanamid-
e hydrochloride
[0643] Same procedure described for Example 50, Part D was used,
starting with the product from Part A. (185 mg, 92% yield) MS
(ESI.sup.+) m/z=308 (M+H).sup.+.
Part C. Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3-((3S)-2-hydroxy-1-oxo-1-(2-oxo-
-2-((R)-1-phenylethylamino)
ethylamino)hexan-3-yl)-N.sup.1-phenylpyrrolidine-1,3-dicarboxamide
[0644] Same procedure described for Example 50, Part E was used,
starting with the product from Part B. (106 mg, 72% yield) MS
(ESI.sup.+) m/z=898 (M+H).sup.+.
Part D. Preparation of Title Product
[0645] Same procedure described for Example 50, Part F was used,
starting with the product from Part C. (65 mg, 61% yield) MS
(ESI.sup.+) m/z=896 (M+H).sup.+.
Example 53
Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3--((S)-1-(2-((S)-1-(dimethylami-
no)-3-methyl-1-oxobutan-2-yl
amino)-2-oxoethylamino)-1,2-dioxohexan-3-yl)-N.sup.1-phenylpyrrolidine-1,-
3-dicarboxamide
##STR00119##
[0646] Part A. Preparation of (S)-tert-butyl
1-(dimethylamino)-3-methyl-1-oxobutan-2-ylcarbamate
[0647] Same procedure described for Example 50, Part A was used,
starting with (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic
acid. The crude material was taken on directly to the next step. MS
(ESI.sup.+) m/z=245 (M+H).sup.+.
Part B. Preparation of (S)-2-amino-N,N,3-trimethylbutanamide
hydrochloride
[0648] Same procedure described for Example 50, Part B was used,
starting with the product from Part A. (286 mg, 86% yield) MS
(DCI/NH.sub.4.sup.+) m/z=145
(M+H).sup.+(S)-2-amino-N,N,3-trimethylbutanamide hydrochloride.
Part C. Preparation of tert-butyl
(3S)-1-(2-((S)-1-(dimethylamino)-3-methyl-1-oxobutan-2-ylamino)-2-oxoethy-
lamino)-2-hydroxy-1-oxohexan-3-ylcarbamate
[0649] Same procedure described for Example 50, Part C was used,
starting with the product from Part B. (557 mg, 86% yield) MS
(ESI.sup.+) m/z=431 (M+H).sup.+.
Part D. Preparation of
(3S)-3-amino-N-(2-((S)-1-(dimethylamino)-3-methyl-1-oxobutan-2-ylamino)-2-
-oxoethyl)-2-hydroxyhexanamide hydrochloride
[0650] Same procedure described for Example 50, Part D was used,
starting with the product from Part C. (473 mg, 99% yield) MS
(ESI.sup.+) m/z=331 (M+H).sup.+.
Part E. Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3-((3S)-1-(2-((S)-1-(dimethylami-
no)-3-methyl-1-oxobutan-2-ylamino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-
-yl)-N.sup.1-phenylpyrrolidine-1,3-dicarboxamide
[0651] Same procedure described for Example 50, Part E was used,
starting with the product from Part D. (98 mg, 65% yield) MS
(ESI.sup.+) m/z=921 (M+H).sup.+.
Part F. Preparation of Title Product
[0652] Same procedure described for Example 50, Part F was used,
starting with the product from Part E. (55 mg, 56% yield) MS
(ESI.sup.+) m/z=919 (M+H).sup.+.
Example 54
Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3-((3S)-1-(2-((S)-1-(dimethylami-
no)-3,3-dimethyl-1-oxobutan-2-ylamino)-2-oxoethylamino)-2-hydroxy-1-oxohex-
an-3-yl)-N.sup.1-phenylpyrrolidine-1,3-dicarboxamide
##STR00120##
[0653] Part A. Preparation of (S)-tert-butyl
1-(dimethylamino)-3,3-dimethyl-1-oxobutan-2-yl carbamate
[0654] Same procedure described for Example 50, Part A was used,
starting with (S)-2-(tert-butoxy
carbonylamino)-3,3-dimethylbutanoic acid. The crude material was
taken on directly to the next step. MS (ESI.sup.+) m/z=259
(M+H).sup.+.
Part B. Preparation of (S)-2-amino-N,N,3,3-tetramethylbutanamide
hydrochloride
[0655] Same procedure described for Example 50, Part B was used,
starting with the product from Part A. (287 mg, 80% yield) MS
(DCI/NH.sub.4.sup.+) m/z=159 (M+H).sup.+.
Part C. Preparation of tert-butyl
(3S)-1-(2-((S)-1-(dimethylamino)-3,3-dimethyl-1-oxobutan-2-ylamino)-2-oxo-
ethylamino)-2-hydroxy-1-oxohexan-3-ylcarbamate
[0656] Same procedure described for Example 50, Part C was used,
starting with the product from Part B. (570 mg, 91% yield) MS
(ESI.sup.+) m/z=445 (M+H).sup.+.
Part D. Preparation of
(3S)-3-amino-N-(2-((S)-1-(dimethylamino)-3,3-dimethyl-1-oxobutan-2-ylamin-
o)-2-oxoethyl)-2-hydroxyhexanamide hydrochloride
[0657] Same procedure described for Example 50, Part D was used,
starting with the product from Part C. The crude material was taken
on directly to the next step. MS (ESI.sup.+) m/z=345
(M+H).sup.+.
Part E. Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3-((3S)-1-(2-((S)-1-(dimethylami-
no)-3,3-dimethyl-1-oxobutan-2-ylamino)-2-oxoethylamino)-2-hydroxy-1-oxohex-
an-3-yl)-N.sup.1-phenylpyrrolidine-1,3-dicarboxamide
[0658] Same procedure described for Example 50, Part E was used,
starting with the product from Part D. (88 mg, 57% yield) MS
(ESI.sup.+) m/z=935 (M+H).sup.+.
Part F. Preparation of Title Product
[0659] Same procedure described for Example 50, Part F was used,
starting with the product from Part E. (15 mg, 17% yield) MS
(ESI.sup.+) m/z=933 (M+H).sup.+.
Example 55
Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3--((S)-1-(2-((S)-1-(dimethylami-
no)-4-methyl-1-oxopentan-2-yl
amino)-2-oxoethylamino)-1,2-dioxohexan-3-yl)-N.sup.1-phenylpyrrolidine-1,-
3-dicarboxamide
##STR00121##
[0660] Part A. Preparation of (S)-tert-butyl
1-(dimethylamino)-4-methyl-1-oxopentan-2-yl carbamate
[0661] Same procedure described for Example 50, Part A was used,
starting with (S)-2-(tert-butoxycarbonylamino)-4-methylpentanoic
acid. The crude material was taken on directly to the next step.
(444 mg, 93% yield) MS (ESI.sup.+) m/z=259 (M+H).sup.+.
Part B. Preparation of (S)-2-amino-N,N,4-trimethylpentanamide
hydrochloride
[0662] Same procedure described for Example 50, Part B was used,
starting with the product from Part A. (283 mg, 84% yield) MS
(DCI/NH.sub.4.sup.+) m/z=159 (M+H).sup.+.
Part C. Preparation of tert-butyl
(3S)-1-(2-((S)-1-(dimethylamino)-4-methyl-1-oxopentan-2-ylamino)-2-oxoeth-
ylamino)-2-hydroxy-1-oxohexan-3-ylcarbamate
[0663] Same procedure described for Example 50, Part C was used,
starting with the product from Part B. (547 mg, 89% yield) MS
(ESI.sup.+) m/z=445 (M+H).sup.+.
Part D. Preparation of
(3S)-3-amino-N-(2-((S)-1-(dimethylamino)-4-methyl-1-oxopentan-2-ylamino)--
2-oxoethyl)-2-hydroxyhexanamide hydrochloride
[0664] Same procedure described for Example 50, Part D was used,
starting with the product from Part C. (426 mg, 91% yield) MS
(ESI.sup.+) m/z=345 (M+H).sup.+.
Part E. Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3-((3S)-1-(2-((S)-1-(dimethylami-
no)-4-methyl-1-oxopentan-2-ylamino)-2-oxoethylamino)-2-hydroxy-1-oxohexan--
3-yl)-N.sup.1-phenylpyrrolidine-1,3-dicarboxamide
[0665] Same procedure described for Example 50, Part E was used,
starting with the product form Part D. (105 mg, 68% yield) MS
(ESI.sup.+) m/z=935 (M+H).sup.+.
Part F. Preparation of Title Product
[0666] Same procedure described for Example 50, Part F was used,
starting with the product form Part E. (63 mg, 60% yield) MS
(ESI.sup.+) m/z=933 (M+H).sup.+.
Example 56
Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3--((S)-1-(2-((S)-1-cyclopentyl--
2-(dimethylamino)-2-oxoethyl
amino)-2-oxoethylamino)-1,2-dioxohexan-3-yl)-N.sup.1-phenylpyrrolidine-1,-
3-dicarboxamide
##STR00122##
[0667] Part A. Preparation of (S)-tert-butyl
1-cyclopentyl-2-(dimethylamino)-2-oxoethylcarbamate
[0668] Same procedure described for Example 50, Part A was used,
starting with (S)-2-(tert-butoxy carbonylamino)-2-cyclopentylacetic
acid. The crude material was taken on directly to the next step.
(146 mg, 29% yield) MS (ESI.sup.+) m/z=271 (M+H).sup.+.
Part B. Preparation of
(S)-2-amino-2-cyclopentyl-N,N-dimethylacetamide hydrochloride
[0669] Same procedure described for Example 50, Part B was used,
starting with the product from Part A. (95 mg, 82% yield) MS
(DCI/NH.sub.4.sup.+) m/z=171 (M+H).sup.+.
Part C. Preparation of tert-butyl
(3S)-1-(2-((S)-1-cyclopentyl-2-(dimethylamino)-2-oxoethyl
amino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-ylcarbamate
[0670] Same procedure described for Example 50, Part C was used,
starting with the product from Part B. (185 mg, 93% yield) MS
(ESI.sup.+) m/z=457 (M+H).sup.+.
Part D. Preparation of
(3S)-3-amino-N-(2-((S)-1-cyclopentyl-2-(dimethylamino)-2-oxoethyl
amino)-2-oxoethyl)-2-hydroxyhexanamide hydrochloride
[0671] Same procedure described for Example 50, Part D was used,
starting with the product from Part C. (150 mg, 94% yield) MS
(ESI.sup.+) m/z=357 (M+H).sup.+.
Part E. Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3-((3S)-1-(2-((S)-1-cyclopentyl--
2-(dimethylamino)-2-oxoethyl
amino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-yl)-N.sup.1-phenylpyrrolid-
ine-1,3-dicarboxamide
[0672] Same procedure described for Example 50, Part E was used,
starting with the product from Part D. (104 mg, 67% yield) MS
(ESI.sup.+) m/z=947 (M+H).sup.+.
Part F. Preparation of Title Product
[0673] Same procedure described for Example 50, Part F was used,
starting with the product from Part E. (59 mg, 57% yield) MS
(ESI.sup.+) m/z=945 (M+H).sup.+.
Example 57
Preparation of
(3R,4R)--N.sup.3--((S)-1-(2-((S)-1-cyclohexyl-2-(dimethylamino)-2-oxoethy-
lamino)-2-oxoethylamino)-1,2-dioxohexan-3-yl)-4-((S)-2-((S)-2-cyclohexyl-2-
-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanamido)-N.sup.1-phenyl-
pyrrolidine-1,3-dicarboxamide
##STR00123##
[0674] Part A. Preparation of (S)-tert-butyl
1-cyclohexyl-2-(dimethylamino)-2-oxoethylcarbamate
[0675] Same procedure described for Example 50, Part A was used,
starting with (S)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetic
acid. The crude material was taken on directly to the next step.
(500 mg, 95% yield) MS (ESI.sup.+) m/z=285 (M+H).sup.+
Part B. Preparation of
(S)-2-amino-2-cyclohexyl-N,N-dimethylacetamide hydrochloride
[0676] Same procedure described for Example 50, Part B was used,
starting with the product form Part A. (358 mg, 92% yield) MS
(DCI/NH.sub.4.sup.+) m/z=185 (M+H).sup.+.
Part C. Preparation of tert-butyl
(3S)-1-(2-((S)-1-cyclohexyl-2-(dimethylamino)-2-oxoethyl
amino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-ylcarbamate
[0677] Same procedure described for Example 50, Part C was used,
starting with the product from Part B. (618 mg, 85% yield) MS
(ESI.sup.+) m/z=471 (M+H).sup.+.
Part D. Preparation of
(3S)-3-amino-N-(2-((S)-1-cyclohexyl-2-(dimethylamino)-2-oxoethyl
amino)-2-oxoethyl)-2-hydroxyhexanamide hydrochloride
[0678] Same procedure described for Example 50, Part D was used,
starting with the product from Part C. (525 mg, 98% yield) MS
(ESI.sup.+) m/z=371 (M+H).sup.+.
Part E. Preparation of
(3R,4R)--N.sup.3-((3S)-1-(2-((S)-1-cyclohexyl-2-(dimethylamino)-2-oxoethy-
lamino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-yl)-4-((S)-2-((S)-2-cycloh-
exyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanamido)-N.sup.1--
phenylpyrrolidine-1,3-dicarboxamide
[0679] Same procedure described for Example 50, Part E was used,
starting with the product from Part D. (94 mg, 59% yield) MS
(ESI.sup.+) m/z=961 (M+H).sup.+.
Part F. Preparation of Title Product
[0680] Same procedure described for Example 50, Part F was used,
starting with the product from Part E. (49 mg, 52% yield) MS
(ESI.sup.+) m/z=959 (M+H).sup.+.
Example 58
Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3-((3S)-1-(2-(2-(dimethylamino)--
1-(4-fluorophenyl)-2-oxoethyl
amino)-2-oxoethylamino)-1,2-dioxohexan-3-yl)-N.sup.1-phenylpyrrolidine-1,-
3-dicarboxamide
##STR00124##
[0681] Part A. Preparation of tert-butyl
2-(dimethylamino)-1-(4-fluorophenyl)-2-oxoethyl carbamate
[0682] Same procedure described for Example 50, Part A was used,
starting with 2-(tert-butoxycarbonylamino)-2-(4-fluorophenyl)acetic
acid. The crude material was taken on directly to the next step. MS
(ESI.sup.+) m/z=297 (M+H).sup.+.
Part B. Preparation of
2-amino-2-(4-fluorophenyl)-N,N-dimethylacetamide hydrochloride
[0683] Same procedure described for Example 50, Part B was used,
starting with the product from Part A. (391 mg, 91% yield) MS
(DCI/NH.sub.4.sup.+) m/z=197 (M+H).sup.+.
Part C. Preparation of tert-butyl
(3S)-1-(2-(2-(dimethylamino)-1-(4-fluorophenyl)-2-oxoethylamino)-2-oxoeth-
ylamino)-2-hydroxy-1-oxohexan-3-ylcarbamate
[0684] Same procedure described for Example 50, Part C was used,
starting with the product from Part B. (340 mg, 66% yield). MS
(ESI.sup.+) m/z=483 (M+H).sup.+.
Part D. Preparation of
(3S)-3-amino-N-(2-(2-(dimethylamino)-1-(4-fluorophenyl)-2-oxo
ethylamino)-2-oxoethyl)-2-hydroxyhexanamide hydrochloride
[0685] Same procedure described for Example 50, Part D was used,
starting with the product from Part C. (276 mg, 94% yield) The
crude material was taken on directly to the next step.
Part E. Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3-((3S)-1-(2-(2-(dimethylamino)--
1-(4-fluorophenyl)-2-oxoethyl
amino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-yl)-N.sup.1-phenylpyrrolid-
ine-1,3-dicarboxamide
[0686] Same procedure described for Example 50, Pat E was used,
starting with the product from Part D. (98 mg, 61% yield) MS (ESL')
m/z=973 (M+H).sup.+.
Part F. Preparation of Title Product
[0687] Same procedure described for Example 50, Part F was used,
starting with the product from Part E. (55 mg, 56% yield) MS (ESL')
m/z=971 (M+H).sup.+.
Example 59
Preparation of
(S)-2-(tert-butoxycarbonylamino)-2-(4-hydroxyphenyl)acetic acid
##STR00125##
[0688] Part A. Preparation of
(S)-2-(tert-butoxycarbonylamino)-2-(4-hydroxyphenyl)acetic acid
[0689] To a solution of (S)-2-amino-2-(4-hydroxyphenyl)acetic acid
(2.00 g, 11.96 mmol) and Et.sub.3N (1.67 mL, 11.96 mmol) in THF (30
mL) and H.sub.2O (30 mL) at 0.degree. C. was added di-tert-butyl
dicarbonate (2.61 g. 11.96 mmol). The solution was stirred at
0.degree. C. for 18 hours and then concentrated in vacuo. The
residue was diluted with ethyl acetate and washed with 5%
H.sub.3PO.sub.4 aqueous solution. The organic layer was dried over
sodium sulfate, filtered, and concentrated in vacuo to afford the
title compound as a light colored solid. The crude material was
taken on directly to the next step. (2.85 g, 86% yield) MS (ESL')
m/z=290 (M+Na).sup.+.
Part B. Preparation of (S)-methyl
2-(tert-butoxycarbonylamino)-2-(4-methoxyphenyl)acetate
[0690] To a solution of the product from Part A (1.00 g, 3.62 mmol)
in DMF (15 mL) was added potassium carbonate (1.226 g, 8.87 mmol)
and methyl iodide (0.552 mL, 8.87 mmol). The solution was stirred
at 25.degree. C. for 18 hours and then diluted with ethyl acetate
and washed with 5% H.sub.3PO.sub.4 aqueous solution and saturated
aqueous sodium bicarbonate solution. The organic layer was dried
over sodium sulfate, filtered, and concentrated in vacuo to afford
the title compound as a light colored solid. The crude material was
taken on directly to the next step. (1.06 g, 99% yield) MS (ESL')
m/z=318 (M+Na).sup.+.
Part C. Preparation of
(S)-2-(tert-butoxycarbonylamino)-2-(4-methoxyphenyl)acetic acid
[0691] To a solution of the product from Part B (1.06 g, 3.59 mmol)
in H.sub.2O (2 mL) and THF (2 mL) was added lithium hydroxide (226
mg, 5.38 mmol) and the solution stirred for 18 hours and then
concentrated in vacuo. The residue was diluted with ethyl acetate
and washed with 5% H.sub.3PO.sub.4 aqueous solution. The organic
layer was dried over sodium sulfate, filtered, and concentrated in
vacuo to afford the title compound as a light colored solid. The
crude material was taken on directly to the next step. (1.00 g, 99%
yield) MS (ESI.sup.+) m/z=304 (M+Na).sup.+.
Part D. Preparation of (S)-tert-butyl
2-(dimethylamino)-1-(4-methoxyphenyl)-2-oxoethyl carbamate
[0692] Same procedure described for Example 50, Part A was used,
starting with the product from Part C. The resulting solid was
purified by flash chromatography on SiO.sub.2 using ethyl acetate
in hexanes as the mobile phase. (909 mg, 89% yield). MS (ESI.sup.+)
m/z=309 (M+H).sup.+.
Part E. Preparation of
(S)-2-amino-2-(4-methoxyphenyl)-N,N-dimethylacetamide
hydrochloride
[0693] Same procedure described for Example 50, Part B was used,
starting with the product from Part D. (718 mg, 99% yield) MS
(ESI.sup.+) m/z=209 (M+H).sup.+.
Part F. Preparation of tert-butyl
(3S)-1-(2-((S)-2-(dimethylamino)-1-(4-methoxyphenyl)-2-oxoethylamino)-2-o-
xoethylamino)-2-hydroxy-1-oxohexan-3-ylcarbamate
[0694] Same procedure described for Example 50, Part C was used,
starting with Part E. (1.30 g, 99% yield). MS (ESI.sup.+) m/z=495
(M+H).sup.+
Part G. Preparation of
(3S)-3-amino-N-(2-((S)-2-(dimethylamino)-1-(4-methoxyphenyl)-2-oxoethylam-
ino)-2-oxoethyl)-2-hydroxyhexanamide hydrochloride
[0695] Same procedure described for Example 50, Part D was used,
starting with the product from Part F. The crude material was taken
on directly to the next step. (1.02 g, 90% yield) MS (ESI.sup.+)
m/z=395 (M+H).sup.+.
Part H. Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3-((3S)-1-(2-((S)-2-(dimethylami-
no)-1-(4-methoxyphenyl)-2-oxo
ethylamino)-2-oxoethylamino)-2-hydroxy-1-oxohexan-3-yl)-N.sup.1-phenylpyr-
rolidine-1,3-dicarboxamide
[0696] Same procedure described for Example 50, Part E was used,
starting with the product from Part G. (140 mg, 86% yield) MS
(ESI.sup.+) m/z=985 (M+H).sup.+.
Part I. Preparation of Title Product
[0697] Same procedure described for Example 50, Part F was used,
starting with the product from Part H. (33 mg, 24% yield) MS
(ESI.sup.+) m/z=983 (M+H).sup.+
Example 60
Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3--((S)-1-(2-((S)-2-(methylamino-
)-2-oxo-1-phenylethylamino)-2-oxoethylamino)-1,2-dioxohexan-3-yl)-N.sup.1--
phenylpyrrolidine-1,3-dicarboxamide
##STR00126##
[0698] Part A. Preparation of (S)-tert-butyl
2-(methylamino)-2-oxo-1-phenylethylcarbamate
[0699] To a solution of
(S)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (1.00 g, 3.98
mmol) in DMF (5 mL) and methylene chloride (5 mL) was added
methylamine hydrochloride (403 mg, 5.97 mmol), HOBt (645 mg, 4.78
mmol), and Hunig's Base (1.73 mL, 9.95 mmol) and the resulting
solution stirred at 0.degree. C. for 10 minutes. EDCI (916 mg, 4.78
mmol) was added and the reaction stirred at 25.degree. C. for 18
hours. The mixture was concentrated in vacuo, the resulting residue
was diluted with ethyl acetate (45 mL), brine (10 mL), and 5%
H.sub.3PO.sub.4 aqueous solution (10 mL), and the layers were
separated. The organic layer was washed with 5% H.sub.3PO.sub.4
aqueous solution (10 mL), twice with saturated aqueous sodium
bicarbonate solution (15 mL), water (15 mL), and brine (15 mL). The
organic layer was dried over sodium sulfate, filtered, and
concentrated in vacuo to afford the title compound as a light
colored solid. The crude material was taken on directly to the next
step. (1.04 g, 99% yield) MS (ESI.sup.+) m/z=265 (M+H).sup.+.
Part B. Preparation of (S)-2-amino-N-methyl-2-phenylacetamide
hydrochloride
[0700] Same procedure described for Example 50, Part B was used,
starting with the product from Part A. (781 mg, 99% yield) MS
(DCI/NH.sub.4.sup.+) m/z=165 (M+H).sup.+.
Part C. Preparation of tert-butyl
(3S)-2-hydroxy-1-(2-((S)-2-(methylamino)-2-oxo-1-phenylethylamino)-2-oxoe-
thylamino)-1-oxohexan-3-ylcarbamate
[0701] Same procedure described for Example 50, Part C was used,
starting with the product from Part B. (370 mg, 99% yield). MS
(ESI.sup.+) m/z=451 (M+H).sup.+.
Part D. Preparation of
(3S)-3-amino-2-hydroxy-N-(2-((S)-2-(methylamino)-2-oxo-1-phenylethylamino-
)-2-oxoethyl)hexanamide hydrochloride
[0702] Same procedure described for Example 50, Part D was used,
starting with the product from Part C. The crude material was taken
on directly to the next step. MS (ESL') m/z=351 (M+H).sup.+
Part E. Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3-
,3-dimethylbutanamido)-N.sup.3-((3S)-2-hydroxy-1-(2-((S)-2-(methylamino)-2-
-oxo-1-phenylethylamino)-2-oxoethylamino)-1-oxohexan-3-yl)-N.sup.1-phenylp-
yrrolidine-1,3-dicarboxamide
[0703] Same procedure described for Example 50, Part E was used,
starting with the product from Part D. (107 mg, 69% yield) MS
(ESI.sup.+) m/z=941 (M+H).sup.+.
Part F. Preparation of Title Product
[0704] Same procedure described for Example 50, Part F was used,
starting with the product from Part E. (49 mg, 46% yield) MS (ESL')
m/z=939 (M+H).sup.+.
Example 61
Preparation of
(3R,4R)--N.sup.3--((S)-1-(2-((S)-2-amino-2-oxo-1-phenylethylamino)-2-oxoe-
thylamino)-1,2-dioxohexan-3-yl)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-c-
arboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.1-phenylpyrrolidine-1,3-dicarbox-
amide
##STR00127##
[0705] Part A. Preparation of (S)-tert-butyl
2-amino-2-oxo-1-phenylethylcarbamate
[0706] To a solution of
(S)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (1.00 g, 3.98
mmol) in DMF (5 mL) and was added ammonium hydroxide (2.0 mL,
excess), and HOBt (645 mg, 4.78 mmol) and the resulting solution
stirred at 0.degree. C. for 10 minutes. EDCI (916 mg, 4.78 mmol)
was added and the reaction stirred at 25.degree. C. for 18 hours.
The mixture was concentrated in vacuo, the resulting residue was
diluted with ethyl acetate (45 mL), brine (10 mL), and 5%
H.sub.3PO.sub.4 aqueous solution (10 mL), and the layers were
separated. The organic layer was washed with 5% H.sub.3PO.sub.4
aqueous solution (10 mL), twice with saturated aqueous sodium
bicarbonate solution (15 mL), water (15 mL), and brine (15 mL). The
organic layer was dried over sodium sulfate, filtered, and
concentrated in vacuo to afford the title compound as a light
colored solid. The crude material was taken on directly to the next
step. (0.990 g, 99% yield) MS (ESL') m/z=251 (M+H).sup.+.
Part B. Preparation of (S)-2-amino-2-phenylacetamide
hydrochloride
[0707] Same procedure described for Example 50, Part B was used,
starting with the product from Part A. (680 mg, 92% yield) MS
(DCI/NH.sub.4.sup.+) m/z=151 (M+H).sup.+.
Part C. Preparation of tert-butyl
(3S)-1-(2-((S)-2-amino-2-oxo-1-phenylethylamino)-2-oxoethylamino)-2-hydro-
xy-1-oxohexan-3-ylcarbamate
[0708] Same procedure described for Example 50, Part C was used,
starting with the product from Part B. (359 mg, 99% yield). MS
(ESI.sup.+) m/z=437 (M+H).sup.+.
Part D. Preparation of
(3S)-3-amino-N-(2-((S)-2-amino-2-oxo-1-phenylethylamino)-2-oxoethyl)-2-hy-
droxyhexanamide hydrochloride
[0709] Same procedure described for Example 50, Part D was used,
starting with the product from Part C. The crude material was taken
on directly to the next step. MS (ESI.sup.+) m/z=337
(M+H).sup.+.
Part E. Preparation of
(3R,4R)--N.sup.3-((3S)-1-(2-((S)-2-amino-2-oxo-1-phenylethylamino)-2-oxoe-
thylamino)-2-hydroxy-1-oxohexan-3-yl)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazi-
ne-2-carboxamido)acetamido)-3,3-dimethylbutanamido)-N.sup.1-phenylpyrrolid-
ine-1,3-dicarboxamide
[0710] Same procedure described for Example 50, Part E was used,
starting with the product from Part D. (117 mg, 77% yield) MS
(ESI.sup.+) m/z=927 (M+H).sup.+.
Part F. Preparation of Title Product
[0711] Same procedure described for Example 50, Part F was used,
starting with the product from Part E. (70 mg, 60% yield) MS
(ESI.sup.+) m/z=925 (M+H).sup.+.
Example 62
Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3-
,3-dimethylbutanamido)-N.sup.3--((S)-1-((S)-1-((S)-2-(dimethylamino)-2-oxo-
-1-phenylethylamino)-3-methyl-1-oxobutan-2-ylamino)-1,2-dioxohexan-3-yl)-N-
.sup.1-phenylpyrrolidine-1,3-dicarboxamide
##STR00128##
[0712] Part A. Preparation of (2S)-benzyl
2-((3S)-3-(tert-butoxycarbonylamino)-2-hydroxyhexan
amido)-3-methylbutanoate
[0713] To a solution of
(3S)-3-(tert-butoxycarbonylamino)-2-hydroxyhexanoic acid
(WO2003062265-A2; Preparative Example 1, compound 1.08) (250 mg,
1.01 mmol) in DMF (5 mL) and methylene chloride (5 mL) was added
(S)-benzyl 2-amino-3-methylbutanoate hydrochloride (271 mg, 1.11
mmol), HOBt (164 mg, 1.21 mmol), and Hunig's Base (0.440 mL, 2.53
mmol) and the resulting solution stirred at 0.degree. C. for 10
minutes. EDCI (233 mg, 1.21 mmol) was added and the reaction
stirred at 25.degree. C. for 18 hours. The mixture was concentrated
in vacuo, the resulting residue was diluted with ethyl acetate (45
mL), brine (10 mL), and 5% H.sub.3PO.sub.4 aqueous solution (10
mL), and the layers were separated. The organic layer was washed
with 5% H.sub.3PO.sub.4 aqueous solution (10 mL), twice with
saturated aqueous sodium bicarbonate solution (15 mL), water (15
mL), and brine (15 mL). The organic layer was dried over sodium
sulfate, filtered, and concentrated in vacuo to afford the title
compound as a light colored solid. The resulting solid was purified
by flash chromatography on SiO.sub.2 using ethyl acetate in hexanes
as the mobile phase. (263 mg, 60% yield). MS (ESI.sup.+) m/z=437
(M+H).sup.+.
Part B. Preparation of
(2S)-2-((3S)-3-(tert-butoxycarbonylamino)-2-hydroxyhexanamido)-3-methylbu-
tanoic acid
[0714] To a solution of the product from Part A in ethanol (10 mL)
was added palladium on carbon and the resulting suspension was
stirred under hydrogen for 18 hours. The reaction vessel was purged
with nitrogen gas and the suspension filtered through celite. The
filtrate was concentrated and dried under vacuum to give the title
compound as a colorless oil. (201 mg, 96% yield).
Part C. Preparation of tert-butyl
(3S)-1-((S)-1-((S)-2-(dimethylamino)-2-oxo-1-phenylethyl
amino)-3-methyl-1-oxobutan-2-ylamino)-2-hydroxy-1-oxohexan-3-ylcarbamate
[0715] To a solution of the product from Part B (201 mg, 0.580
mmol) in DMF (2 mL) and methylene chloride (2 mL) was added
(S)-2-amino-N,N-dimethyl-2-phenylacetamide hydrochloride
(WO2003062265-A2; Preparative Example 5, step B, compound 2.1) (137
mg, 0.640 mmol), HOBt (94 mg, 0.700 mmol), and Hunig's Base (0.253
mL, 1.45 mmol) and the resulting solution stirred at 0.degree. C.
for 10 minutes. EDCI (133 mg, 0.700 mmol) was added and the
reaction stirred at 25.degree. C. for 18 hours. The mixture was
concentrated in vacuo, the resulting residue was diluted with ethyl
acetate (45 mL), brine (10 mL), and 5% H.sub.3PO.sub.4 aqueous
solution (10 mL), and the layers were separated. The organic layer
was washed with 5% H.sub.3PO.sub.4 aqueous solution (10 mL), twice
with saturated aqueous sodium bicarbonate solution (15 mL), water
(15 mL), and brine (15 mL). The organic layer was dried over sodium
sulfate, filtered, and concentrated in vacuo to afford the title
compound as a light colored solid. (133 mg, 45% yield). MS
(ESI.sup.+) m/z=507 (M+H).sup.+.
Part D. Preparation of
(3S)-3-amino-N-((S)-1-((S)-2-(dimethylamino)-2-oxo-1-phenylethyl
amino)-3-methyl-1-oxobutan-2-yl)-2-hydroxyhexanamide
hydrochloride
[0716] Same procedure described for Example 50, Part D was used,
starting with the product from Part C. The crude material was taken
on directly to the next step. MS (ESI.sup.+) m/z=407
(M+H).sup.+.
Part E. Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3-((3S)-1-((S)-1-((S)-2-(dimethy-
lamino)-2-oxo-1-phenylethyl
amino)-3-methyl-1-oxobutan-2-ylamino)-2-hydroxy-1-oxohexan-3-yl)-N.sup.1--
phenylpyrrolidine-1,3-dicarboxamide
[0717] Same procedure described for Example 50, Part E was used,
starting with the product from Part D. (126 mg, 77% yield) MS
(ESI.sup.+) m/z=997 (M+H).sup.+.
Part F. Preparation of Title Product
[0718] Same procedure described for Example 50, Part F was used,
starting with the product from Part E. (21 mg, 17% yield) MS
(ESI.sup.+) m/z=995 (M+H).sup.+
Example 63
Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3--((S)-1-((S)-1-((S)-2-(dimethy-
lamino)-2-oxo-1-phenylethyl
amino)-1-oxopropan-2-ylamino)-1,2-dioxohexan-3-yl)-N.sup.1-phenylpyrrolid-
ine-1,3-dicarboxamide
##STR00129##
[0719] Part A. Preparation of (2S)-benzyl
2-((3S)-3-(tert-butoxycarbonylamino)-2-hydroxyhexan
amido)propanoate
[0720] Same procedure described for Example 62, Part A was used,
starting with (s)-benzyl 2-aminopropanoate hydrochloride. The crude
material was taken on directly to the next step. (200 mg, 48%
yield) MS (ESI.sup.+) m/z=409 (M+H).sup.+.
Part B. Preparation of
(2S)-2-((3S)-3-(tert-butoxycarbonylamino)-2-hydroxyhexanamido)
propanoic acid
[0721] Same procedure described for Example 62, Part B was used,
starting with the product from Part A. The crude material was taken
on directly to the next step. (156 mg, 99% yield).
Part C. Preparation of tert-butyl
(3S)-1-((S)-1-((S)-2-(dimethylamino)-2-oxo-1-phenylethyl
amino)-1-oxopropan-2-ylamino)-2-hydroxy-1-oxohexan-3-ylcarbamate
[0722] Same procedure described for Example 62, Part C was used,
starting with the product from Part B. (221 mg, 94% yield) MS
(ESI.sup.+) m/z=479 (M+H).sup.+
Part D. Preparation of
(3S)-3-amino-N-((S)-1-(S)-2-(dimethylamino)-2-oxo-1-phenylethyl
amino)-1-oxopropan-2-yl)-2-hydroxyhexanamide hydrochloride
[0723] Same procedure described for Example 50, Part D was used,
starting with the product from Part C. The crude material was taken
on directly to the next step. (170 mg, 90% yield) MS (ESI.sup.+)
m/z=379 (M+H).sup.+
Part E. Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-3,3-dimethylbutanamido)-N.sup.3-((3S)-1-((S)-1-((S)-2-(dimethy-
lamino)-2-oxo-1-phenylethyl
amino)-1-oxopropan-2-ylamino)-2-hydroxy-1-oxohexan-3-yl)-N.sup.1-phenylpy-
rrolidine-1,3-dicarboxamide
[0724] Same procedure described for Example 50, Part E was used,
starting with the product Part D. (114 mg, 72% yield) MS
(ESI.sup.+) m/z=969 (M+H).sup.+.
Part F. Preparation of Title Product
[0725] Same procedure described for Example 50, Part F was used,
starting with the product from Part E. (38 mg, 33% yield) MS
(ESI.sup.+) m/z=967 (M+H).sup.+.
Example 64
Preparation of
(3R,4R)--N3-((S)-4-amino-1-cyclobutyl-3,4-dioxobutan-2-yl)-4-((S)-2-((S)--
2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-N,3,3-trimethylbutanamid-
o)-N1-(naphthalen-2-yl)pyrrolidine-1,3-dicarboxamide
##STR00130##
[0726] Part A. Preparation of
(3R,4R)-4-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)
acetamido)-N,3,3-trimethylbutanamido)-1-(naphthalen-2-ylcarbamoyl)pyrroli-
dine-3-carboxylic acid
[0727] A solution of the product from Example 45, Part G (400 mg,
0.65 mmol) and Hunig's base (350 uL, 2.0 mmol) in tetrahydrofuran
(15 mL) was treated with 2-naphthyl isocyanate (115 mg, 0.68 mmol),
stirred for 2 hours and concentrated under vacuum. The residue was
partitioned between EtOAc and water and acidified to pH 1 with 1 M
HCl. The EtOAc layer was then washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated to a yellow foam. MS (ESI+)
m/z=672 (M+H).sup.+.
Part B. Preparation of
(3R,4R)--N3-((2S)-4-amino-1-cyclobutyl-3-hydroxy-4-oxobutan-2-yl)-4-((S)--
2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-N,3,3-trimethylbu-
tanamido)-N1-(naphthalen-2-yl)pyrrolidine-1,3-dicarboxamide
[0728] A mixture of the product from Part A (250 mg, 0.37 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (106
mg, 0.55 mmol), 1-hydroxybenzotriazole (75 mg, 0.55 mmol), Hunig's
base (260 uL, 1.5 mmol) and
(3S)-3-amino-4-cyclobutyl-2-hydroxybutanamide hydrochloride (104
mg, 0.5 mmol)) in dichloromethane (10 mL) was stirred for 16 hours,
diluted with 100 mL EtOAc, washed with 10 mL 1 M H.sub.3PO.sub.4,
10 mL 10% NaHCO.sub.3, 3.times.20 mL with brine, dried
(Na.sub.2SO.sub.4), and concentrated. The residue was
chromatographed on an ISCO 12 g silica cartridge eluting with 8%
MeOH in DCM to give the title compound as a white powder (180 mg,
59% yield). MS (ESI+) m/z=826.4 (M+H).sup.+.
Part C. Preparation of Title Product
[0729] The product from Part B (83 mg, 0.1 mmol) in dichloromethane
(2 mL) was treated with Dess-Martin periodinane (85 mg, 0.2 mmol),
stirred for 4 hours, treated with 10% aqueous sodium sulfite (2
mL), stirred for 10 minutes and diluted with 20 mL EtOAc. The EtOAc
layer was then washed with saturated aqueous sodium bicarbonate,
brine, dried (MgSO.sub.4) and concentrated. The crude product was
flash chromatographed on an 5 g silica cartridge eluting with ethyl
acetate 4 methanol/ethyl acetate (2/98) to give the title compound
(7 mg, 8%). MS: (ESI+) m/z=824.6 (M+H)+.
Example 65
[0730] The following compounds were prepared utilizing the general
method-of-preparation discussion and specific synthesis examples
provided above:
##STR00131## ##STR00132##
Example 66
Biochemical HCV Protease Assay
[0731] Furthermore compounds were assayed for biochemical activity
by performing HCV protease assays. The assay provides an indication
of how effective compounds of the present invention are in
inhibiting HCV proteolytic activity. The inhibitor potency
(IC.sub.50) were detected for each compound to determine the most
preferred compounds. The following assay procedure was
followed:
[0732] The assay was performed in a 96-well white polystyrene half
area-plate (Costar 3693; Corning Inc, Corning, N.Y.) or white
microfluor U-bottom plates from Dynex. The release of the
fluorescence product was measured in a Fluoroskan plate fluorimeter
or a SpectraMAX Gemini XPS operated at wavelengths excitation 355
nm and emission 485 nm EDANS DABCYL substrate. The same conditions
were used in the HPLC assay. In a typical experiment the assay
volume was 200 .mu.L or 100 .mu.L depending on the assay plate used
but the final concentrations of all reagents were the same. For the
scNS3NS4A the protease (typically 30 nM) was diluted in assay
buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 10% Glycerol and 5 mM
DTT) and the mixture was incubated for 30-60 minutes at RT.
Reaction was initiated with the addition of 20 .mu.L (or 10 .mu.L
for the half area plate) substrate diluted in the same buffer. The
final concentration of DMSO in the assay mix was 10%. Assay
progress was monitored by acquiring data points every 30 sec for 30
minutes. Initial reaction rates, expressed as fluorescence units
per minute, were calculated by least-squares analysis of data
points using the Software GraphPad Prism 4. Inhibitor potency
(IC.sub.50) were determined by fitting the initial rates to the
appropriate equations using least squares regression analysis
performed by GraphPad Prism 4.
[0733] The IC.sub.50 values for compounds were determined.
Typically, the IC.sub.50 value in the range of 0.0001 .mu.m to 50
.mu.m relative to the uninhibited control demonstrates desired
inhibition activity.
[0734] It is understood that the foregoing detailed description and
accompanying examples are merely illustrative and are not to be
taken as limitations upon the scope of the invention, which is
defined solely by the appended claims and their equivalents.
Various changes and modifications to the disclosed embodiments will
be apparent to those skilled in the art. Such changes and
modifications, including without limitation those relating to the
chemical structures, substituents, derivatives, intermediates,
syntheses, formulations and/or methods of use of the invention, can
be made without departing from the spirit and scope thereof.
[0735] All references (patent and non-patent) cited above are
incorporated by reference into this patent application. The
discussion of those references is intended merely to summarize the
assertions made by their authors. No admission is made that any
reference (or a portion of any reference) is relevant prior art (or
prior art at all). Applicants reserve the right to challenge the
accuracy and pertinence of the cited references.
* * * * *