U.S. patent application number 15/272669 was filed with the patent office on 2017-01-12 for inhibitors of hepatitis c virus replication.
This patent application is currently assigned to Merck Sharp & Dohme Corp.. The applicant listed for this patent is Merck Sharp & Dohme Corp.. Invention is credited to Craig A. Coburn, Kun Liu, Steven W. Ludmerer, Richard Soll, Hao Wu, Bin Zhong, Jian Zhu.
Application Number | 20170008906 15/272669 |
Document ID | / |
Family ID | 42781502 |
Filed Date | 2017-01-12 |
United States Patent
Application |
20170008906 |
Kind Code |
A1 |
Coburn; Craig A. ; et
al. |
January 12, 2017 |
INHIBITORS OF HEPATITIS C VIRUS REPLICATION
Abstract
The present invention relates to compounds of formula (I) that
are useful as hepatitis C virus (HCV) NS5A inhibitors, the
synthesis of such compounds, and the use of such compounds for
inhibiting HCV NS5A activity, for treating or preventing HCV
infections and for inhibiting HCV viral replication and/or viral
production in a cell-based system. ##STR00001##
Inventors: |
Coburn; Craig A.; (Novato,
CA) ; Ludmerer; Steven W.; (North Wales, PA) ;
Liu; Kun; (Boston, MA) ; Wu; Hao; (Shanghai,
CN) ; Soll; Richard; (Shanghai, CN) ; Zhong;
Bin; (Shanghai, CN) ; Zhu; Jian; (Shanghai,
CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Merck Sharp & Dohme Corp. |
Rahway |
NJ |
US |
|
|
Assignee: |
Merck Sharp & Dohme
Corp.
Rahway
NJ
|
Family ID: |
42781502 |
Appl. No.: |
15/272669 |
Filed: |
September 22, 2016 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14711345 |
May 13, 2015 |
|
|
|
15272669 |
|
|
|
|
14473117 |
Aug 29, 2014 |
9090661 |
|
|
14711345 |
|
|
|
|
13260684 |
Dec 19, 2011 |
8871759 |
|
|
PCT/US2010/028653 |
Mar 25, 2010 |
|
|
|
14473117 |
|
|
|
|
61247318 |
Sep 30, 2009 |
|
|
|
61163958 |
Mar 27, 2009 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 498/10 20130101;
C07D 409/14 20130101; C07D 403/12 20130101; A61K 31/404 20130101;
A61P 31/14 20180101; C07K 5/06 20130101; A61K 31/423 20130101; A61K
31/4985 20130101; A61K 38/05 20130101; C07D 413/14 20130101; A61K
31/5365 20130101; A61K 31/506 20130101; A61K 31/5377 20130101; A61K
31/4178 20130101; A61P 31/00 20180101; C07D 405/14 20130101; A61K
31/4439 20130101; A61K 38/06 20130101; C07D 401/14 20130101; A61K
31/553 20130101; C07K 5/08 20130101; C07D 498/04 20130101; A61K
31/4184 20130101; A61K 31/5383 20130101; C07D 403/14 20130101; C07D
487/04 20130101; A61K 31/437 20130101; C07D 405/12 20130101; A61K
31/4025 20130101; A61P 1/16 20180101; A61P 31/12 20180101; C07D
471/04 20130101; A61K 45/06 20130101 |
International
Class: |
C07D 498/04 20060101
C07D498/04; A61K 31/4178 20060101 A61K031/4178; A61K 31/553
20060101 A61K031/553; A61K 45/06 20060101 A61K045/06; A61K 31/5365
20060101 A61K031/5365 |
Claims
1-39. (canceled)
40. A compound having the formula: ##STR00571## or a
pharmaceutically acceptable salt thereof, wherein: each occurrence
of R.sup.a is independently C.sub.1-6 alkyl or phenyl; Rb is H,
halogen or --CN; Rc is H or halogen; each occurrence of R.sup.d is
independently selected from H and C.sub.1-6 alkyl, or one
occurrence of R.sup.d is H and the other occurrence of R.sup.d is
phenyl, or both R.sup.d groups and the common carbon atom to which
they are attached combine to form a spirocyclic C.sub.3-8
cycloalkyl group; and p is 0, 1 or 2.
41. The compound of claim 40, wherein each occurrence of R.sup.a is
isopropyl; R.sup.b and R.sup.c are each H or F; and p is 0.
42. A pharmaceutical composition comprising an effective amount of
the compound of claim 40, or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier.
43. The pharmaceutical composition of claim 42, further comprising
a second therapeutic agent selected from the group consisting of
HCV antiviral agents, immunomodulators, and anti-infective
agents.
44. The pharmaceutical composition of claim 43, wherein the second
therapeutic agent is selected from the group consisting of HCV
protease inhibitors and HCV NS5B polymerase inhibitors.
45. A method of treating a patient infected with HCV comprising the
step of administering to the patient an amount of the compound of
claim 40, or a pharmaceutically acceptable salt thereof, effective
to prevent and/or treat infection by HCV in a subject in need
thereof.
46. A method of treating a patient infected with HCV comprising the
step of administering to the patient an amount of the compound of
claim 40, or a pharmaceutically acceptable salt thereof, effective
to inhibit HCV viral replication and/or viral production.
47. The method of claim 45, further comprising administering to the
patient a second therapeutic agent selected from the group
consisting of HCV antiviral agents, immunomodulators, and
anti-infective agents.
48. The method of claim 47, wherein the second therapeutic agent is
selected from the group consisting of HCV protease inhibitors and
HCV NS5B polymerase inhibitors.
49. The method of claim 45, wherein the patient is a human.
Description
FIELD OF THE INVENTION
[0001] The present disclosure relates to antiviral compounds that
are useful as inhibitors of hepatitis C virus (HCV) replication.
The compounds are expected to act on HCV NS5A (non-structural 5A)
protein. Compositions comprising such compounds, the use of such
compounds for treating HCV infection and/or reducing the likelihood
or severity of symptoms of HCV infection, methods for inhibiting
the function of the NS5A non-structural protein, and methods for
inhibiting HCV viral replication and/or viral production are also
provided.
BACKGROUND OF THE INVENTION
[0002] Hepatitis C virus (HCV) infection is a major health problem
that leads to chronic liver disease, such as cirrhosis and
hepatocellular carcinoma, in a substantial number of infected
individuals. Current treatments for HCV infection include
immunotherapy with recombinant interferon-.alpha. alone or in
combination with the nucleoside-analog ribavirin.
[0003] Several virally-encoded enzymes are putative targets for
therapeutic intervention, including a metalloprotease (NS2-3), a
serine protease (NS3, amino acid residues 1-180), a helicase (NS3,
full length), an NS3 protease cofactor (NS4A), a membrane protein
(NS4B), a zinc metalloprotein (NS5A) and an RNA-dependent RNA
polymerase (NS5B).
[0004] One identified target for therapeutic intervention is HCV
NS5A non-structural protein, which is described, for example, in
Seng-Lai Tan & Michael G. Katze, How Hepatitis C Virus
Counteracts the Interferon Response: The Jury Is Still Out on NS5A,
284 VIROLOGY 1-12 (2001); and in Kyu-Jin Park et al., Hepatitis C
Virus NS5A Protein Modulates c-Jun N-terminal Kinase through
Interaction with Tumor Necrosis Factor Receptor-associated Factor
2, 278(33) J. BIO. CHEM. 30711 (2003). A non-structural protein,
NS5A is an essential component for viral replication and assembly.
Mutations in NS5A at or near known sites of phosphorylation can
affect the ability for high-level replication in cell-culture
systems, suggesting an important role for NS5A phosphorylation in
viral replication efficiency. Inhibitors of the phosphorylation of
NS5A can lead to reduced viral RNA replication.
[0005] NS5A is a zinc metalloprotein organized into three discreet
domains. NS5A localizes to the membrane-associated site of RNA
synthesis via an N-terminal amphipathic .alpha.-helix anchor. The
crystal structure of domain I demonstrates that NS5A can exist as a
dimer, with a large putative RNA binding groove located at the
interface of the monomers. Timothy L. Tellinghuisen et al.,
Structure of the zinc-binding domain of an essential component of
the hepatitis C viral replicase, 435(7040) NATURE 374 (2005).
Robert A. Love et al., Crystal Structure of a Novel Dimeric Form of
NS5A Domain I Protein From Hepatitis C Virus, 89(3) J. VIROLOGY
4395-403 (2009). The interaction of NS5A with RNA is thought to be
critical for the function of this protein in RNA replication. No
structural information has yet been obtained for domains II or III.
Recent genetic mapping has shown that although some residues in
domain II are essential for RNA replication, many portions of
domain II and all of domain III are dispensable. Timothy L.
Tellinghuisen et al., Identification of Residues Required for RNA
Replication in Domains II and III of the Hepatitis C Virus NS5A
Protein, J. VIROLOGY 1073 (2008). Mutations constructed within
domain III result in virus that can maintain RNA replication but
that produces lower titers of infectious virus in cell culture,
demonstrating a second distinct role for NS5A after RNA replication
has occurred. Timothy L. Tellinghuisen et al., Regulation of
Hepatitis C Virion Production via Phosphorylation of the NS5A
Protein, 4(3) PLOS PATHOGENS e1000032 (2008); Nicole Appel et al.,
Mutational Analysis of Hepatitis C Virus Nonstructural Protein 5A:
Potential Role of Differential Phosphorylation in RNA Replication
and Identification of a Genetically Flexible Domain, 79(5) J.
VIROLOGY 3187 (2005). NS5A, unlike the other non-structural
proteins, can be trans-complemented, consistent with functions
outside of the viral replicase. The interaction of NS5A with
numerous host-signaling pathways has been described (Michael J.
Gale Jr. et al., Evidence That Hepatitis C Virus Resistance to
Interferon Is Mediated through Repression of the PKR Protein Kinase
by the Nonstructural 5A Protein, 230 VIROLOGY 217 (1997); Andrew
Macdonald & Mark Harris, Hepatitis C virus NS5A: tales of a
promiscuous protein, 85 J. GEN. VIROLOGY 2485 (2004).), suggesting
this protein may modify the host cell environment to a state
favorable for the virus, events that may require a form of NS5A
dissociated from the replication complex.
[0006] There is a clear and long-felt need to develop effective
therapeutics for treatment of HCV infection. Specifically, there is
a need to develop compounds that are useful for treating
HCV-infected patients and compounds that selectively inhibit HCV
viral replication.
SUMMARY OF THE INVENTION
[0007] The present disclosure relates to novel compounds of formula
(I) and/or pharmaceutically acceptable salts, hydrates, solvates,
prodrugs or isomers thereof. These compounds are useful, either as
compounds or their pharmaceutically acceptable salts (when
appropriate), in the inhibition of HCV (hepatitis C virus) NS5A
(non-structural 5A) protein, the prevention or treatment of one or
more of the symptoms of HCV infection, the inhibition of HCV viral
replication and/or HCV viral production, and/or as pharmaceutical
composition ingredients. As pharmaceutical composition ingredients,
these compounds, which includes reference to hydrates and solvates
of such compounds, and their salts may be the primary active
therapeutic agent, and, when appropriate, may be combined with
other therapeutic agents including but not limited to other HCV
antivirals, anti-infectives, immunomodulators, antibiotics or
vaccines.
[0008] More particularly, the present disclosure relates to a
compound of formula (I):
##STR00002##
and/or a pharmaceutically acceptable salt thereof, wherein:
##STR00003##
is chosen from the group consisting of 9-membered bicyclic aryl
ring systems that contain from 0 to 4 heteroatoms independently
chosen from the group consisting of N, O and S, and that are
substituted on C or N atoms by u substituents R.sup.1, [0009] each
R.sup.1 is independently chosen from the group consisting of
hydrogen, halogen, --OR.sup.3a, --CN,
--(CH.sub.2).sub.0-6C(O)R.sup.3, --CO.sub.2R.sup.3a,
--C(O)N(R.sup.3a).sub.2, --SR.sup.3a, --S(O)R.sup.3a,
--S(O.sub.2)R.sup.3a, --(CH.sub.2).sub.0-6N(R.sup.3a).sub.2,
--N(R.sup.3a)SO.sub.2R.sup.3a, --N(R.sup.3a)CO.sub.2R.sup.3a,
--N(R.sup.3a)C(O)R.sup.3, --N(R.sup.3a)COR.sup.3a,
--N(R.sup.3a)C(O)N(R.sup.3a), C.sub.1-6alkyl, C.sub.3-8carbocycle
containing from 0 to 3 heteroatoms chosen from N, O and S, and
phenyl, and the C.sub.1-6alkyl, C.sub.3-8carbocycle and phenyl are
substituted by from 0 to 3 substitutents independently chosen from
the group consisting of hydrogen, halogen, --OR.sup.3a, --CN,
--CO.sub.2R.sup.3a, --C(O)N(R.sup.3a).sub.2, --N(R.sup.3a).sub.2,
--N(R.sup.3a)CO.sub.2R.sup.3a, --SR.sup.3a, --S(O)R.sup.3a,
--S(O.sub.2)R.sup.3a, --N(R.sup.3a)SO.sub.2R.sup.3a,
--N(R.sup.3a)CO.sub.2R.sup.3a, --N(R.sup.3a)C(O)N(R.sup.3a),
C.sub.1-6alkyl, --O--C.sub.1-6alkyl, --S--C.sub.1-6alkyl, and
C.sub.3-8cycloalkyl, [0010] u is from 0 to 4, [0011] each R.sup.3
is independently chosen from the group consisting of hydrogen,
C.sub.1-6alkyl, --OH, --O--C.sub.1-6alkyl and C.sub.3-8cycloalkyl,
and [0012] each R.sup.3a is independently chosen from the group
consisting of hydrogen, C.sub.1-6alkyl and C.sub.3-8cycloalkyl;
##STR00004##
[0012] is a group chosen from the group consisting of [0013] (a)
--C.ident.C-- and [0014] (b) aryl ring systems B' chosen from the
group consisting of: [0015] (i) 5- to 7-membered monocyclic ring
systems and [0016] (ii) 8- to 10-membered bicyclic ring systems,
[0017] and the aryl ring systems B' containing from 0 to 4
heteroatoms independently chosen from the group consisting of N, O
and S, and substituted on C or N atoms by v substituents R.sup.2,
[0018] each R.sup.2 is independently chosen from the group
consisting of hydrogen, halogen, --OR.sup.4a, --CN,
--CO.sub.2R.sup.4a, --C(O)R.sup.4a, --C(O)N(R.sup.4a).sub.2,
--N(R.sup.4a).sub.2, --N(R.sup.4a)COR.sup.4,
--N(R.sup.4a)CO.sub.2R.sup.4a, --N(R.sup.4a)C(O)N(R.sup.4a),
--N(R.sup.4a)SO.sub.2R.sup.4a, --SR.sup.4a, --S(O)R.sup.4a,
--S(O.sub.2)R.sup.4a, C.sub.1-6alkyl substituted by from 0 to 4
R.sup.4 and C.sub.3-8cycloalkyl substituted by from 0 to 4 R.sup.4,
[0019] v is from 0 to 4, [0020] each R.sup.4 is independently
chosen from the group consisting of hydrogen, --OH, C.sub.1-6alkyl
and C.sub.3-8cycloalkyl; [0021] each R.sup.4a is independently
chosen from the group consisting of hydrogen, C.sub.1-6alkyl and
C.sub.3-8cycloalkyl;
[0022] R.sup.1 and R.sup.2 may be taken together with
##STR00005##
to form a 5- to 9-membered carbocyclic ring containing 1 or 2
heteroatoms independently chosen from the group consisting of N, O
and S;
[0023] each D is a group independently chosen from the group
consisting of: [0024] (a) a single bond, [0025] (b)
--C(O)N(R.sup.5)--, [0026] (c) --N(R.sup.5)C(O)--, and [0027] (d) a
5- or 6-membered aryl ring system D' containing from 0 to 4
heteroatoms independently chosen from the group consisting of N, O
and S, and substituted on C or N atoms by from 0 to 2 substituents
R.sup.5, [0028] each R.sup.5 is independently chosen from the group
consisting of hydrogen, halogen, --OR.sup.6, --CN,
--CO.sub.2R.sup.6, --C(O)N(R.sup.6).sub.2, --N(R.sup.6).sub.2,
--N(R.sup.6)COR.sup.6, --SR.sup.6, --S(O)R.sup.6,
--S(O.sub.2)R.sup.6, --N(R.sup.6)SO.sub.2R.sup.6,
--NCO.sub.2R.sup.6, --NC(O)N(R.sup.6).sub.2, C.sub.1-6alkyl
substituted by from 0 to 3 R.sup.6 and C.sub.3-8cycloalkyl
substituted by from 0 to 3 R.sup.6, and [0029] each R.sup.6 is
independently chosen from the group consisting of hydrogen,
C.sub.1-6alkyl and C.sub.3-8cycloalkyl;
[0030] each E is a group independently chosen from the group
consisting of: [0031] (a) a single bond, [0032] (b)
--(C(R.sup.7).sub.2).sub.0-2NR.sup.7C(O)O.sub.0-1--, and [0033] (c)
a pyrrolidinyl derivative chosen from the group consisting of:
[0033] ##STR00006## [0034] I is a bivalent group chosen from
--C(O)--, --CO.sub.2-- and --C(O)N(R.sup.7)--, [0035] J is a fused
ring system chosen from the group consisting of 3- to 7-membered
carbocycles and 5- or 6-membered aryl rings containing from 0 to 4
heteroatoms independently chosen from the group consisting of N, O
and S, and substituted on C or N atoms by substituents R.sup.9,
[0036] each R.sup.8a is independently chosen from the group
consisting of hydrogen, halogen, --OH, --OC.sub.1-6alkyl and
C.sub.1-6alkyl, or two R.sup.8a may be taken together to form oxo,
[0037] each R.sup.8b is independently chosen from the group
consisting of hydrogen, halogen, --OH, --OC.sub.1-6alkyl and
C.sub.1-6alkyl, or two R.sup.8b may be taken together to form oxo,
[0038] each R.sup.8c is independently chosen from the group
consisting of hydrogen and C.sub.1-6alkyl, [0039] or any two groups
selected from R.sup.8a, R.sup.8b and R.sup.8c may be taken together
to form a spiro-bicyclic or bridged bicyclic ring; [0040] each
R.sup.9 is independently chosen from the group consisting of
hydrogen, halogen, C.sub.1-6alkyl, --O--C.sub.1-6alkyl,
--S--C.sub.1-6alkyl, --NH--C.sub.1-6alkyl and
--NHC(O)--C.sub.1-6alkyl, [0041] each R.sup.7 is independently
chosen from the group consisting of hydrogen, C.sub.1-6alkyl and
phenyl, and the C.sub.1-6alkyl and phenyl are substituted by from 0
to 3 substitutents independently chosen from the group consisting
of hydrogen, halogen, C.sub.1-6alkyl, --O--C.sub.1-6alkyl and
--S--C.sub.1-6alkyl; and
[0042] each G is independently chosen from the group consisting of:
[0043] (a) hydrogen, [0044] (b) --OR.sup.10a, [0045] (c) --CN,
[0046] (d) --CO.sub.2R.sup.10a, [0047] (e) --C(O)N(R.sup.10).sub.2,
[0048] (f) --SR.sup.10a, [0049] (g) --S(O)R.sup.10a, [0050] (h)
--S(O.sub.2)R.sup.10a, [0051] (i) --N(R.sup.10).sub.2, [0052] (j)
--N(R.sup.10)SO.sub.2R.sup.10a, [0053] (k) --NCO.sub.2R.sup.10a,
[0054] (l) --NC(O)N(R.sup.10).sub.2, [0055] (m) C.sub.1-6alkyl
having 0 to 4 substituents R.sup.11, [0056] each R.sup.11 is
independently chosen from the group consisting of: [0057] (i) --OH,
[0058] (ii) --N(R.sup.10).sub.2, [0059] (iii)=NR.sup.10, [0060]
(iv) --O--C.sub.1-6alkyl, [0061] (v) --C(O)R.sup.10, [0062] (vi)
--S--C.sub.1-6alkyl, [0063] (vii) --SO.sub.2--C.sub.1-6alkyl,
[0064] (viii) 3- to 8-membered carbocycles containing from 0 to 3
heteroatoms independently chosen from the group consisting of N, O
and S, and having from 0 to 3 substitutents R.sup.12 on N or C
atoms, and each R.sup.12 is independently selected from the group
consisting of hydrogen, halogen, C.sub.1-6alkyl having from 0 to 3
substituents chosen from R.sup.10, --O--C.sub.1-6alkyl,
--S--C.sub.1-6alkyl, --OR.sup.10a, --CN, --C(O)R.sup.10,
--CO.sub.2R.sup.10a, --C(O)N(R.sup.10).sub.2, --SR.sup.10a,
--S(O)R.sup.10a, --S(O.sub.2)R.sup.10a,
--N(R.sup.10)SO.sub.2R.sup.10a, --NCO.sub.2R.sup.10a,
--NC(O)N(R.sup.10).sub.2 and --N(R.sup.10).sub.2, or two R.sup.12
are taken together to form oxo, and [0065] (ix) 5- or 6-membered
aryl containing from 0 to 3 heteroatoms independently chosen from
the group consisting of N, O and S, and having from 0 to 3
substitutents R.sup.13 on N or C atoms, and each R.sup.13 is
independently selected from the group consisting of hydrogen,
halogen, C.sub.1-6alkyl, --O--C.sub.1-6alkyl and 3- to 8-membered
carbocycles containing from 0 to 3 heteroatoms independently chosen
from the group consisting of N, O and S, [0066] (n) 3- to
8-membered carbocycles containing from 0 to 3 heteroatoms
independently chosen from the group consisting of N, O and S, and
having from 0 to 3 substitutents R.sup.10 on N or C atoms; and
[0067] (o) aryl ring systems G' chosen from the group consisting
of: [0068] (i) 5- to 7-membered monocyclic ring systems and [0069]
(ii) 8- to 10-membered bicyclic ring systems, [0070] and the aryl
ring systems G' containing from 0 to 4 heteroatoms independently
chosen from the group consisting of N, O and S, and substituted on
C or N atoms by 0 to 3 substitutents R.sup.10; [0071] each R.sup.10
is independently chosen from the group consisting of [0072] (i)
hydrogen, [0073] (ii) --CN, [0074] (iii) C.sub.1-6alkyl, [0075]
(iv) --O--C.sub.0-6alkyl, [0076] (v) --S--C.sub.0-6alkyl, [0077]
(vi) C.sub.1-6alkyl-O--R.sup.14, [0078] (vii) --C(O)R.sup.14,
[0079] (viii) --CO.sub.2R.sup.14, [0080] (ix) --SO.sub.2R.sup.14,
[0081] (x) --N(R.sup.14).sub.2, [0082] (xi)
--N(R.sup.14)SO.sub.2R.sup.14, [0083] (xii) --NCO.sub.2R.sup.14,
[0084] (xiii) --NC(O)N(R.sup.4).sub.2, and [0085] (xiv) 3- to
8-membered carbocycles containing from 0 to 3 heteroatoms
independently chosen from the group consisting of N, O and S,
[0086] or two R.sup.10 may be taken together to form oxo; [0087]
each R.sup.10a is independently chosen from the group consisting of
[0088] (i) hydrogen, [0089] (ii) --CN, [0090] (iii) C.sub.1-6alkyl,
[0091] (iv) C.sub.1-6alkyl-O--R.sup.14, [0092] (v) --C(O)R.sup.14
[0093] (vi) --CO.sub.2R.sup.14, [0094] (vii) --SO.sub.2R.sup.14,
[0095] (x) --N(R.sup.14).sub.2, [0096] (xi)
--N(R.sup.14)SO.sub.2R.sup.14, [0097] (xii) --NCO.sub.2R.sup.14,
[0098] (xiii) --NC(O)N(R.sup.14).sub.2, and [0099] (xiv) 3- to
8-membered carbocyclcs containing from 0 to 3 heteroatoms
independently chosen from the group consisting of N, O and S,
[0100] and two R.sup.10 or R.sup.10a groups can be taken together
with the N to which they are attached to form a ring, which may be
substituted by from 0 to 3 substituents R.sup.14, and [0101] each
R.sup.14 is independently chosen from the group consisting of
hydrogen, C.sub.1-6alkyl, C.sub.3-8cycloalkyl,
--(CH.sub.2).sub.0-3C.sub.3-8cycloalkyl and phenyl.
[0102] The present invention also includes pharmaceutical
compositions containing a compound of the present invention and
methods of preparing such pharmaceutical compositions. The present
invention further includes methods of treating or reducing the
likelihood or severity of HCV infection, methods for inhibiting the
function of the NS5A protein, and methods for inhibiting HCV viral
replication and/or viral production.
[0103] Other embodiments, aspects and features of the present
invention are either further described in or will be apparent from
the ensuing description, examples and appended claims.
DETAILED DESCRIPTION OF THE INVENTION
[0104] The present invention includes compounds of formula (I)
above, and pharmaceutically acceptable salts thereof. The compounds
of formula (I) are HCV NS5A inhibitors.
[0105] A first embodiment of the invention relates to compounds
having structural formula (I):
##STR00007##
and/or a pharmaceutically acceptable salt thereof, wherein:
##STR00008##
is chosen from the group consisting of 9-membered bicyclic aryl
ring systems that contain from 0 to 4 heteroatoms independently
chosen from the group consisting of N, O and S, and that are
substituted on C or N atoms by u substituents R.sup.1, [0106] each
R.sup.1 is independently chosen from the group consisting of
hydrogen, halogen, --OR.sup.3a, --CN, --C(O)R.sup.3,
--CO.sub.2R.sup.3a, --C(O)N(R.sup.3a).sub.2, --SR.sup.3a,
--S(O)R.sup.3a, --S(O.sub.2)R.sup.3a,
--(CH.sub.2).sub.0-6N(R.sup.3a).sub.2,
--N(R.sup.3a)SO.sub.2R.sup.3a, --N(R.sup.3a)CO.sub.2R.sup.3a,
--N(R.sup.3a)C(O)R.sup.3, --N(R.sup.3a)COR.sup.3a,
--N(R.sup.3a)C(O)N(R.sup.3a), C.sub.1-6alkyl, C.sub.3-8carbocycle
containing from 0 to 3 heteroatoms chosen from N, O and S, and
phenyl, and the C.sub.1-6alkyl, C.sub.3-8carbocycle and phenyl are
substituted by from 0 to 3 substitutents independently chosen from
the group consisting of hydrogen, halogen, --OR.sup.3a, --CN,
--CO.sub.2R.sup.3a, --C(O)N(R.sup.3a).sub.2, --N(R.sup.3a).sub.2,
--N(R.sup.3a)CO.sub.2R.sup.3a, --SR.sup.3a, --S(O)R.sup.3a,
--S(O.sub.2)R.sup.3a, --N(R.sup.3a)SO.sub.2R.sup.3a,
--N(R.sup.3a)CO.sub.2R.sup.3a, --N(R.sup.3a)C(O)N(R.sup.3a),
C.sub.1-6alkyl, --O--C.sub.1-6alkyl and --S--C.sub.1-6alkyl, [0107]
u is from 0 to 4, [0108] each R.sup.3 is independently chosen from
the group consisting of hydrogen, C.sub.1-6alkyl, --OH,
--O--C.sub.1-6alkyl and C.sub.3-8cycloalkyl, and [0109] each
R.sup.3a is independently chosen from the group consisting of
hydrogen, C.sub.1-6alkyl and C.sub.3-8cycloalkyl;
##STR00009##
[0109] is a group chosen from the group consisting of [0110] (a)
--C.ident.C-- and [0111] (b) aryl ring systems B' chosen from the
group consisting of: [0112] (i) 5- to 7-membered monocyclic ring
systems and [0113] (ii) 8- to 10-membered bicyclic ring systems,
[0114] and the aryl ring systems B' containing from 0 to 4
heteroatoms independently chosen from the group consisting of N, O
and S, and substituted on C or N atoms by v substituents R.sup.2,
[0115] each R.sup.2 is independently chosen from the group
consisting of hydrogen, halogen, --OR.sup.4a, --CN,
--CO.sub.2R.sup.4a, --C(O)N(R.sup.4a).sub.2, --N(R.sup.4a).sub.2,
--N(R.sup.4a)COR.sup.4, --N(R.sup.4a)CO.sub.2R.sup.4a,
--N(R.sup.4a)C(O)N(R.sup.4a), --N(R.sup.4a)SO.sub.2R.sup.4a,
--SR.sup.4a, --S(O)R.sup.4a, --S(O.sub.2)R.sup.4, C.sub.1-6alkyl
substituted by from 0 to 4 R.sup.4 and C.sub.3-8cycloalkyl
substituted by from 0 to 4 R.sup.4, [0116] v is from 0 to 4, [0117]
each R.sup.4 is independently chosen from the group consisting of
hydrogen, --OH, C.sub.1-6alkyl and C.sub.3-8cycloalkyl; [0118] each
R.sup.4a is independently chosen from the group consisting of
hydrogen, C.sub.1-6alkyl and C.sub.3-8cycloalkyl;
[0119] R.sup.1 and R.sup.2 may be taken together with
##STR00010##
to form a 5- to 9-membered carbocyclic ring containing 1 or 2
heteroatoms independently chosen from the group consisting of N, O
and S;
[0120] each D is a group independently chosen from the group
consisting of: [0121] (a) a single bond, [0122] (b)
--C(O)N(R.sup.5)--, [0123] (c) --N(R.sup.5)C(O)--, and [0124] (d) a
5- or 6-membered aryl ring system D' containing from 0 to 4
heteroatoms independently chosen from the group consisting of N, O
and S, and substituted on C or N atoms by from 0 to 2 substituents
R.sup.5, [0125] each R.sup.5 is independently chosen from the group
consisting of hydrogen, halogen, --OR.sup.6, --CN,
--CO.sub.2R.sup.6, --C(O)N(R.sup.6).sub.2, --N(R.sup.6).sub.2,
--N(R.sup.6)COR.sup.6, --SR.sup.6, --S(O)R.sup.6,
--S(O.sub.2)R.sup.6, --N(R.sup.6)SO.sub.2R.sup.6,
--NCO.sub.2R.sup.6, --NC(O)N(R.sup.6).sub.2, C.sub.1-6alkyl
substituted by from 0 to 3 R.sup.6 and C.sub.3-8cycloalkyl
substituted by from 0 to 3 R.sup.6, and [0126] each R.sup.6 is
independently chosen from the group consisting of hydrogen,
C.sub.1-6alkyl and C.sub.3-8cycloalkyl; [0127] each E is a group
independently chosen from the group consisting of: [0128] (a) a
single bond, [0129] (b)
--(C(R.sup.7).sub.2).sub.0-2NR.sup.7C(O)O.sub.0-1--, and [0130] (c)
a pyrrolidinyl derivative chosen from the group consisting of:
[0130] ##STR00011## [0131] I is a bivalent group chosen from
--C(O)--, --CO.sub.2-- and --C(O)N(R.sup.7)--, [0132] J is a fused
ring system chosen from the group consisting of 3- to 7-membered
carbocycles and 5- or 6-membered aryl rings containing from 0 to 4
heteroatoms independently chosen from the group consisting of N, O
and S, and substituted on C or N atoms by substituents R.sup.9,
[0133] each R.sup.8a is independently chosen from the group
consisting of hydrogen, halogen, --OH, --OC.sub.1-6alkyl and
C.sub.1-6alkyl, or two R.sup.8a may be taken together to form oxo,
[0134] each R.sup.8b is independently chosen from the group
consisting of hydrogen, halogen, --OH, --OC.sub.1-6alkyl and
C.sub.1-6alkyl, or two R.sup.8b may be taken together to form oxo,
[0135] each R.sup.8c is independently chosen from the group
consisting of hydrogen and C.sub.1-6alkyl, [0136] or any two groups
selected from R.sup.8a, R.sup.8b and R.sup.8c may be taken together
to form a spiro-bicyclic or bridged bicyclic ring; [0137] each
R.sup.9 is independently chosen from the group consisting of
hydrogen, halogen, C.sub.1-6alkyl, --O--C.sub.1-6alkyl,
--S--C.sub.1-6alkyl, --NH--C.sub.1-6alkyl and
--NHC(O)--C.sub.1-6alkyl, [0138] each R.sup.7 is independently
chosen from the group consisting of hydrogen, C.sub.1-6alkyl and
phenyl, and the C.sub.1-6alkyl and phenyl are substituted by from 0
to 3 substitutents independently chosen from the group consisting
of hydrogen, halogen, C.sub.1-6alkyl, --O--C.sub.1-6alkyl and
--S--C.sub.1-6alkyl; and
[0139] each G is independently chosen from the group consisting of:
[0140] (a) hydrogen, [0141] (b) --OR.sup.10a, [0142] (c) --CN,
[0143] (d) --CO.sub.2R.sup.10a, [0144] (e) --C(O)N(R.sup.10).sub.2,
[0145] (f) --SR.sup.10a, [0146] (g) --S(O)R.sup.10a, [0147] (h)
--S(O.sub.2)R.sup.10a, [0148] (i) --N(R.sup.10).sub.2, [0149] (j)
--N(R.sup.10)SO.sub.2R.sup.10a, [0150] (k) --NCO.sub.2R.sup.10a,
[0151] (l) --NC(O)N(R.sup.10).sub.2, [0152] (m) C.sub.1-6alkyl
having 0 to 4 substituents R.sup.11, [0153] each R.sup.11 is
independently chosen from the group consisting of: [0154] (i) --OH,
[0155] (ii) --N(R.sup.10).sub.2, [0156] (iii) .dbd.NR.sup.10,
[0157] (iv) --O--C.sub.1-6alkyl, [0158] (v) --C(O)R.sup.10, [0159]
(vi) --S--C.sub.1-6alkyl, [0160] (vii) --SO.sub.2--C.sub.1-6alkyl,
[0161] (viii) 3- to 8-membered carbocycles containing from 0 to 3
heteroatoms independently chosen from the group consisting of N, O
and S, and having from 0 to 3 substitutents R.sup.12 on N or C
atoms, and each R.sup.12 is independently selected from the group
consisting of hydrogen, halogen, C.sub.1-6alkyl having from 0 to 3
substituents chosen from R.sup.10, --O--C.sub.1-6alkyl,
--S--C.sub.1-6alkyl, --OR.sup.10a, --CN, --C(O)R.sup.10,
--CO.sub.2R.sup.10a, --C(O)N(R.sup.10).sub.2, --SR.sup.10a,
--S(O)R.sup.10a, --S(O.sub.2)R.sup.10a,
--N(R.sup.10)SO.sub.2R.sup.10a, --NCO.sub.2R.sup.10a,
--NC(O)N(R.sup.10).sub.2 and --N(R.sup.10).sub.2, or two R.sup.12
are taken together to form oxo, and [0162] (ix) 5- or 6-membered
aryl containing from 0 to 3 heteroatoms independently chosen from
the group consisting of N, O and S, and having from 0 to 3
substitutents R.sup.13 on N or C atoms, and each R.sup.13 is
independently selected from the group consisting of hydrogen,
halogen, C.sub.1-6alkyl, --O--C.sub.1-6alkyl and 3- to 8-membered
carbocycles containing from 0 to 3 heteroatoms independently chosen
from the group consisting of N, O and S, [0163] (n) 3- to
8-membered carbocycles containing from 0 to 3 heteroatoms
independently chosen from the group consisting of N, O and S, and
having from 0 to 3 substitutents R.sup.10 on N or C atoms; and
[0164] (o) aryl ring systems G' chosen from the group consisting
of: [0165] (i) 5- to 7-membered monocyclic ring systems and [0166]
(ii) 8- to 10-membered bicyclic ring systems, [0167] and the aryl
ring systems G' containing from 0 to 4 heteroatoms independently
chosen from the group consisting of N, O and S, and substituted on
C or N atoms by 0 to 3 substitutents R.sup.10; [0168] each R.sup.10
is independently chosen from the group consisting of [0169] (i)
hydrogen, [0170] (ii) --CN, [0171] (iii) C.sub.1-6alkyl, [0172]
(iv) --O--C.sub.0-6alkyl, [0173] (v) --S--C.sub.1-6alkyl, [0174]
(vi) C.sub.1-6alkyl-O--R.sup.14, [0175] (vii) --C(O)R.sup.14 [0176]
(viii) --CO.sub.2R.sup.14, [0177] (ix) --SO.sub.2R.sup.14, [0178]
(x) --N(R.sup.14).sub.2, [0179] (xi) --N(R.sup.14)SO.sub.2R.sup.14,
[0180] (xii) --NCO.sub.2R.sup.14, [0181] (xiii)
--NC(O)N(R.sup.14).sub.2, and [0182] (xiv) 3- to 8-membered
carbocycles containing from 0 to 3 heteroatoms independently chosen
from the group consisting of N, O and S, [0183] or two R.sup.10 may
be taken together to form oxo; [0184] each R.sup.10a is
independently chosen from the group consisting of [0185] (i)
hydrogen, [0186] (ii) --CN, [0187] (iii) C.sub.1-6alkyl, [0188]
(iv) C.sub.1-6alkyl-O--R.sup.14, [0189] (v) --C(O)R.sup.14, [0190]
(vi) --CO.sub.2R.sup.14, [0191] (vii) --SO.sub.2R.sup.14, [0192]
(x) --N(R.sup.14).sub.2, [0193] (xi) --N(R.sup.14)SO.sub.2R.sup.14,
[0194] (xii) --NCO.sub.2R.sup.14, [0195] (xiii)
--NC(O)N(R.sup.14).sub.2, and [0196] (xiv) 3- to 8-membered
carbocyclcs containing from 0 to 3 heteroatoms independently chosen
from the group consisting of N, O and S, [0197] and two R.sup.10 or
R.sup.10a groups can be taken together with the N to which they are
attached to form a ring, which may be substituted by from 0 to 3
substituents R.sup.14, and [0198] each R.sup.14 is independently
chosen from the group consisting of hydrogen, C.sub.1-6alkyl,
C.sub.3-8cycloalkyl, --(CH.sub.2).sub.0-3C.sub.3-8cycloalkyl and
phenyl. In this embodiment, all other groups are as provided in the
general formula above.
[0199] In a second embodiment of the invention,
##STR00012##
is chosen from the group consisting of
##STR00013##
where each X is independently chosen from the group consisting of
CR.sup.1 and N,
##STR00014##
Y is chosen from the group consisting of
##STR00015##
each R.sup.1 is independently chosen from the group consisting of
hydrogen, halogen, --OR.sup.3a, --CN, --C(O)R.sup.3,
--CO.sub.2R.sup.3a, --C(O)N(R.sup.3a).sub.2, --SR.sup.3a,
--S(O)R.sup.3a, --S(O.sub.2)R.sup.3a,
--(CH.sub.2).sub.0-6N(R.sup.3a).sub.2,
--N(R.sup.3a)SO.sub.2R.sup.3a, --N(R.sup.3a)CO.sub.2R.sup.3a,
--N(R.sup.3a)C(O)R.sup.3, --N(R.sup.3a)COR.sup.3a,
--N(R.sup.3a)C(O)N(R.sup.3a), C.sub.1-6alkyl, C.sub.3-8carbocycle
containing from 0 to 3 heteroatoms chosen from N, O and S, and
phenyl, and the C.sub.1-6alkyl, C.sub.3-8carbocycle and phenyl are
substituted by from 0 to 3 substitutents independently chosen from
the group consisting of hydrogen, halogen, --OR.sup.3a, --CN,
--CO.sub.2R.sup.3a, --C(O)N(R.sup.3a).sub.2, --N(R.sup.3a).sub.2,
--N(R.sup.3a)CO.sub.2R.sup.3a, --SR.sup.3a, --S(O)R.sup.3a,
--S(O.sub.2)R.sup.3a, --N(R.sup.3a)SO.sub.2R.sup.3a,
--N(R.sup.3a)CO.sub.2R.sup.3, --N(R.sup.3a)C(O)N(R.sup.3a),
C.sub.1-6alkyl, --O--C.sub.1-6alkyl and --S--C.sub.1-6alkyl, each
R.sup.3 is independently chosen from the group consisting of
hydrogen, C.sub.1-6alkyl, --OH, --O--C.sub.1-6alkyl and
C.sub.3-8cycloalkyl, and each R.sup.3a is independently chosen from
the group consisting of hydrogen, C.sub.1-6alkyl and
C.sub.3-8cycloalkyl. In all aspects of this embodiment, all other
groups are as provided in the general formula above or in the first
embodiment above.
[0200] In a first aspect of the second embodiment of the
invention,
##STR00016##
is chosen from the group consisting of
##STR00017##
where
##STR00018##
is substituted by from 0 to 3 additional R.sup.1, which are as
provided above.
[0201] In a second aspect of the second embodiment,
##STR00019##
is chosen from the group consisting of
##STR00020##
where
##STR00021##
is substituted by from 0 to 3 additional R.sup.1, which are as
provided above. In preferred instances of this aspect,
##STR00022##
is where
##STR00023##
is substituted by from 0 to 3 additional R.sup.1, which are as
provided above.
[0202] In a third aspect of the second embodiment,
##STR00024##
is chosen from the group consisting of
##STR00025##
where
##STR00026##
is substituted by from 0 to 3 additional R.sup.1, which are as
provided above. In preferred instances of this aspect,
##STR00027##
is
##STR00028##
where
##STR00029##
is substituted by from 0 to 3 additional R.sup.1, which are as
provided above.
[0203] In further aspects of the second embodiment, each R.sup.1 is
chosen from the group consisting of hydrogen, halogen, --CN and
C.sub.1-6alkyl. In particular, each R.sup.1 is chosen from the
group consisting of hydrogen, fluorine and --CN.
[0204] In a third embodiment of the invention,
##STR00030##
is chosen from the group consisting of --C.ident.C--, phenyl,
pyridinyl, pyrazinyl, pyrimidyl, 1,2,4-triazinyl, pyridazinyl,
thiazyl and 9-membered bicyclic ring systems that contain from 1 to
3 heteroatoms independently chosen from the group consisting of N,
O and S, v is from 0 to 4, each R.sup.2 is independently chosen
from the group consisting of hydrogen, halogen, --OR.sup.4a, --CN,
--CO.sub.2R.sup.4a, --C(O)N(R.sup.4a).sub.2, --N(R.sup.4a).sub.2,
--N(R.sup.4a)CO.sub.2R.sup.4a, --SR.sup.4a, --S(O)R.sup.4a,
--S(O.sub.2)R.sup.4a, --N(R.sup.4a)SO.sub.2R.sup.4a,
--N(R.sup.4a)CO.sub.2R.sup.4a, --N(R.sup.4a)C(O)N(R.sup.4a),
C.sub.1-6alkyl substituted by from 0 to 4 R.sup.4 and
C.sub.3-8cycloalkyl substituted by from 0 to 4 R.sup.4, each
R.sup.4 is independently chosen from the group consisting of
hydrogen, --OH, C.sub.1-6alkyl and C.sub.3-8cycloalkyl, and each
R.sup.4a is independently chosen from the group consisting of
hydrogen, C.sub.1-6alkyl and C.sub.3-8cycloalkyl. In particular
aspects of this embodiment,
##STR00031##
is phenyl, v is from 0 to 2, and each R.sup.2 is independently
chosen from the group consisting of fluorine, chlorine, --OH,
--CH.sub.3, --OCH.sub.3 and --CN. In all aspects of this
embodiment, all other groups are as provided in the general formula
above and/or in the first or second embodiments.
[0205] In a fourth embodiment of the invention,
##STR00032##
taken together with one substituent R.sup.1 and one substituent
R.sup.2, are represented by a group chosen from the group
consisting of:
##STR00033##
where W is chosen from the group consisting of
--(CH.sub.2).sub.1-3--, --(CH.sub.2).sub.0-2NH(CH.sub.2).sub.0-2--,
--(CH.sub.2).sub.0-2N(C.sub.1-6alkyl)(CH.sub.2).sub.0-2--,
--(CH.sub.2).sub.0-2O(CH.sub.2).sub.0-2- and
--(CH.sub.2).sub.0-2C(O)(CH.sub.2).sub.0-2--, where W is
substituted by from 0 to 4 R.sup.w, where each R.sup.w is
independently selected from C.sub.1-6alkyl and C.sub.3-8cycloalkyl;
and V is chosen from the group consisting of --C(O)-- and
--CH.sub.2--, and where V is --CH.sub.2--, V is substituted by from
0 to 2 R.sup.v, where each R.sup.v is independently selected from
the group consisting of C.sub.1-6alkyl and C.sub.3-8cycloalkyl. In
a first aspect of this embodiment,
##STR00034##
taken together with one substituent R.sup.1 and one substituent
R.sup.2, are represented by a group chosen from the group
consisting of
##STR00035##
In particular instances of this embodiment, and of the first aspect
of this embodiment, W is chosen from the group consisting of
--CH.sub.2--, --NH--, --N(C.sub.1-6alkyl)-, --C(O)--,
--CH.sub.2NH--, --CH.sub.2N(C.sub.1-6 alkyl)-,
--CH.sub.2CH.sub.2--, --C(O)CH.sub.2--, --CH.sub.2C(O)--,
--CH.sub.2O--, --CH.sub.2CH.sub.2CH.sub.2--,
--C(O)CH.sub.2CH.sub.2--, --CH.sub.2C(O)CH.sub.2--,
--CH.sub.2OCH.sub.2--, --CH.sub.2CH.sub.2C(O)--,
--CH.sub.2CH.sub.2O--, --CH.sub.2CH.sub.2NH--,
--CH.sub.2CH.sub.2N(C.sub.1-6alkyl)-, --CH.sub.2NHCH.sub.2--,
--CH.sub.2N(C.sub.1-6alkyl)CH.sub.2--, --NHCH.sub.2CH.sub.2--, and
--N(C.sub.1-6alkyl)CH.sub.2CH.sub.2--. In all aspects of this
embodiment, all other groups are as provided in the general formula
above.
[0206] In a fifth embodiment of the invention, each D is
independently chosen from the group consisting of a single bond,
--C(O)N(R.sup.5)--, --NR.sup.5C(O)--,
##STR00036##
where R.sup.5 is independently chosen from the group consisting of
hydrogen, halogen --OR.sup.6, --CN, --CO.sub.2R.sup.6,
--C(O)N(R.sup.6).sub.2, --N(R.sup.6).sub.2, --N(R.sup.6)COR.sup.6,
--SR.sup.6, --S(O)R.sup.6, --S(O.sub.2)R.sup.6,
--N(R.sup.6)SO.sub.2R.sup.6, --NCO.sub.2R.sup.6,
--NC(O)N(R.sup.6).sub.2, C.sub.1-6alkyl substituted by from 0 to 3
substituents R.sup.6 and C.sub.3-8cycloalkyl substituted by from 0
to 3 substituents R.sup.6, and each R.sup.6 is independently chosen
from the group consisting of hydrogen, C.sub.1-6alkyl and
C.sub.3-8cycloalkyl. In particular aspects of this embodiment, each
D is independently chosen from the group consisting of
##STR00037##
In this embodiment, all other groups are as provided in the general
formula above and/or in the first through fourth embodiments.
[0207] In a sixth embodiment of the invention, each E is
independently chosen from the group consisting of a single bond,
--CH.sub.2NHC(O)--, --CH.sub.2N(CH.sub.3)C(O)--,
--C(CH.sub.3)HNHC(O)--, --C(CH.sub.3)HN(CH.sub.3)C(O)--,
--C(CH.sub.3).sub.2NHC(O)--, --C(CH.sub.3).sub.2N(CH.sub.3)C(O)--,
--CH.sub.2NHC(O)O--, --CH.sub.2N(CH.sub.3)C(O)O--,
--C(CH.sub.3)HNHC(O)O--, --C(CH.sub.3)HN(CH.sub.3)C(O)O--,
--C(CH.sub.3).sub.2NHC(O)O--,
--C(CH.sub.3).sub.2N(CH.sub.3)C(O)O--,
##STR00038##
where one of R.sup.8a and R.sup.8b is --OH or fluorine. In a first
aspect of this embodiment, each E is independently chosen from the
group consisting of a single bond,
##STR00039##
where one of R.sup.8a and R.sup.8b is --OH or fluorine. In all
aspects of this embodiment, all other groups are as provided in the
general formula above and/or in the first through fifth
embodiments.
[0208] In some embodiments, adjacent D and E groups each may be
selected to be a single bond. In such embodiments, D and E are
combined to be one single bond, and all other groups are as
provided in the general formula above and/or in the first, second,
third and fourth embodiments. That is, where D is a single bond and
the adjacent E is a single bond,
##STR00040##
or
##STR00041##
is connected directly to G by one single bond.
[0209] In a seventh embodiment of the invention, each G is
independently chosen from the group consisting of: [0210] (a)
C.sub.1-6alkyl having 0 to 4 substituents R.sup.11, [0211] (b) 3-
to 8-membered carbocycles containing from 0 to 3 heteroatoms
independently chosen from the group consisting of N, O and S, and
having from 0 to 3 substitutents R.sup.10 on N or C atoms; and
[0212] (c) aryl ring systems G' chosen from the group consisting
of: [0213] (i) 5- to 7-membered monocyclic ring systems and [0214]
(ii) 8- to 10-membered bicyclic ring systems, [0215] and the aryl
ring systems G' containing from 0 to 4 heteroatoms independently
chosen from the group consisting of N, O and S, and substituted on
C or N atoms by 0 to 3 substitutents R.sup.10. In all aspects of
the seventh embodiment, G is chosen such that stable compounds
result. In all aspects of this seventh embodiment, all other groups
are as provided in the general formula above and/or in the first
through sixth embodiments.
[0216] In an eighth embodiment, each G is independently chosen from
the group consisting of:
[0217] (a) hydrogen,
[0218] (b) --CN,
[0219] (c) C.sub.1-5alkyl having 1 to 3 substituents R.sup.11,
[0220] each R.sup.11 is independently chosen from the group
consisting of --OH, --NH.sub.2, --NCH.sub.3H, --N(CH.sub.3).sub.2,
--N(CH.sub.2CH.sub.3).sub.2, .dbd.NH, .dbd.NCH.sub.3, --C(O)H,
--C(O)OH, --C(O)CH.sub.3, --C(O)OCH.sub.3, --NHC(O)H, --NHC(O)OH,
--NHC(O)CH.sub.3, --NHC(O)OCH.sub.3, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, pyranyl, pyrrolidinyl, piperidinyl,
oxacyclopentyl, and oxacyclohexyl, phenyl, pyridinyl, pyrimidinyl
and pyrrolyl, where [0221] the cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, pyranyl, pyrrolidinyl, piperidinyl,
oxacyclopentyl and oxacyclohexyl are substituted by from 0 to 2
substitutents R.sup.12 on N or C atoms, and each R.sup.12 is
independently selected from the group consisting of hydrogen,
halogen, carboxy, C.sub.1-6alkyl, --O--C.sub.1-6alkyl and
--S--C.sub.1-6alkyl; and [0222] the phenyl, pyridinyl, pyrimidinyl
and pyrrolyl are substituted by from 0 to 3 substitutents R.sup.13
on N or C atoms, and each R.sup.13 is independently selected from
the group consisting of hydrogen, halogen, C.sub.1-6alkyl and 3- to
8-membered cycloalkyl containing from 0 to 3 heteroatoms
independently chosen from the group consisting of N, O and S,
[0223] (d) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
pyranyl, pyrrolidinyl, piperidinyl, oxacyclopentyl and
oxacyclohexyl having from 0 to 3 substitutents R.sup.10 on N or C
atoms, the R.sup.10 independently selected from the group
consisting of hydrogen, halogen, carboxy, C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, --S--C.sub.1-6alkyl, phenyl and benzyl,
and
[0224] (e) aryl ring systems G' chosen from the group consisting
of: phenyl, pyridinyl and 9-membered bicyclic ring systems
containing from 0 to 2 heteroatoms independently chosen from the
group consisting of N and O.
[0225] In a first aspect of the eighth embodiment, G is
independently chosen from the group consisting of C.sub.1-4alkyl
having 1 to 2 substituents R.sup.11, wherein each R.sup.11 is
independently chosen from the group consisting of --OH, --NH.sub.2,
--NCH.sub.3H, --N(CH.sub.3).sub.2, --N(CH.sub.2CH.sub.3).sub.2,
--C(O)OCH.sub.3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
pyranyl, pyrrolidinyl, piperidinyl, oxacyclopentyl, oxacyclohexyl,
phenyl, pyridinyl, pyrimidinyl and pyrrolyl. In all aspects of the
eighth embodiment, G is chosen such that stable compounds result.
In all aspects of this eighth embodiment, all other groups are as
provided in the general formula above and/or in the first through
sixth embodiments.
[0226] In a ninth embodiment of the invention,
##STR00042##
is chosen from the group consisting of
##STR00043##
where
[0227] each X is independently chosen from the group consisting of
CR.sup.1 and N,
##STR00044##
is chosen from the group consisting of
##STR00045##
[0228] each R.sup.1 is independently chosen from the group
consisting of hydrogen, halogen, --OR.sup.3a, --CN, --C(O)R.sup.3,
--CO.sub.2R.sup.3a, --C(O)N(R.sup.3a).sub.2, --SR.sup.3a,
--S(O)R.sup.3a, --S(O.sub.2)R.sup.3a,
--(CH.sub.2).sub.0-6N(R.sup.3a).sub.2,
--N(R.sup.3a)SO.sub.2R.sup.3a, --N(R.sup.3a)CO.sub.2R.sup.3a,
--N(R.sup.3a)C(O)R.sup.3, --N(R.sup.3a)COR.sup.3a,
--N(R.sup.3a)C(O)N(R.sup.3a), C.sub.1-6alkyl, C.sub.3-8carbocycle
containing from 0 to 3 heteroatoms chosen from N, O and S, and
phenyl, and the C.sub.1-6alkyl, C.sub.3-8carbocycle and phenyl are
substituted by from 0 to 3 substitutents independently chosen from
the group consisting of hydrogen, halogen, --OR.sup.3a, --CN,
--CO.sub.2R.sup.3a, --C(O)N(R.sup.3a).sub.2, --N(R.sup.3a).sub.2,
--N(R.sup.3a)CO.sub.2R.sup.3a, --SR.sup.3a, --S(O)R.sup.3a,
--S(O.sub.2)R.sup.3a, --N(R.sup.3a)SO.sub.2R.sup.3a,
--N(R.sup.3a)CO.sub.2R.sup.3, --N(R.sup.3a)C(O)N(R.sup.3a),
C.sub.1-6alkyl, --O--C.sub.1-6alkyl and --S--C.sub.1-6alkyl,
[0229] each R.sup.3 is independently chosen from the group
consisting of hydrogen, C.sub.1-6alkyl, --OH, --O--C.sub.1-6alkyl
and C.sub.3-8cycloalkyl, and
[0230] each R.sup.3a is independently chosen from the group
consisting of hydrogen, C.sub.1-6alkyl and C.sub.3-8cycloalkyl;
##STR00046##
is chosen from the group consisting of --C.ident.C--, phenyl,
pyridinyl, pyrazinyl, pyrimidyl, 1,2,4-triazinyl, pyridazinyl,
thiazyl and 9-membered bicyclic ring systems that contain from 1 to
3 heteroatoms independently chosen from the group consisting of N,
O and S,
[0231] v is from 0 to 4,
[0232] each R.sup.2 is independently chosen from the group
consisting of hydrogen, halogen, --OR.sup.4a, --CN,
--CO.sub.2R.sup.4a, --C(O)N(R.sup.4a).sub.2, --N(R.sup.4a).sub.2,
--N(R.sup.4a)CO.sub.2R.sup.4a, --SR.sup.4a, --S(O)R.sup.4a,
--S(O.sub.2)R.sup.4a, --N(R.sup.4a)SO.sub.2R.sup.4a,
--N(R.sup.4a)CO.sub.2R.sup.4a, --N(R.sup.4a)C(O)N(R.sup.4a),
C.sub.1-6alkyl substituted by from 0 to 4 R.sup.4 and
C.sub.3-8cycloalkyl substituted by from 0 to 4 R.sup.4,
[0233] each R.sup.4 is independently chosen from the group
consisting of hydrogen, --OH, C.sub.1-6alkyl and
C.sub.3-8cycloalkyl, and
[0234] each R.sup.4a is independently chosen from the group
consisting of hydrogen, C.sub.1-6alkyl and C.sub.3-8cycloalkyl;
[0235] wherein each D is independently chosen from the group
consisting of a single bond, --C(O)N(R.sup.5)--,
--NR.sup.5C(O)--,
##STR00047##
where
[0236] R.sup.5 is independently chosen from the group consisting of
hydrogen, halogen --OR.sup.6, --CN, --CO.sub.2R.sup.6,
--C(O)N(R.sup.6).sub.2, --N(R.sup.6).sub.2, --N(R.sup.6)COR.sup.6,
--SR.sup.6, --S(O)R.sup.6, --S(O.sub.2)R.sup.6,
--N(R.sup.6)SO.sub.2R.sup.6, --NCO.sub.2R.sup.6,
--NC(O)N(R.sup.6).sub.2, C.sub.1-6 alkyl substituted by from 0 to 3
substituents R.sup.6 and C.sub.3-8cycloalkyl substituted by from 0
to 3 substituents R.sup.d, and
[0237] each R.sup.6 is independently chosen from the group
consisting of hydrogen, C.sub.1-6alkyl and C.sub.3-8cycloalkyl;
[0238] wherein each E is independently chosen from the group
consisting of a single bond, --CH.sub.2NHC(O)--,
--CH.sub.2N(CH.sub.3)C(O)--, --C(CH.sub.3)HNHC(O)--,
--C(CH.sub.3)HN(CH.sub.3)C(O)--, --C(CH.sub.3).sub.2NHC(O)--,
--C(CH.sub.3).sub.2N(CH.sub.3)C(O)--, --CH.sub.2NHC(O)O--,
--CH.sub.2N(CH.sub.3)C(O)O--, --C(CH.sub.3)HNHC(O)O--,
--C(CH.sub.3)HN(CH.sub.3)C(O)O--, --C(CH.sub.3).sub.2NHC(O)O--,
--C(CH.sub.3).sub.2N(CH.sub.3)C(O)O--,
##STR00048##
where one of R.sup.8a and R.sup.8b is --OH or fluorine;
[0239] wherein each G is independently chosen from the group
consisting of
[0240] (a) hydrogen,
[0241] (b) --CN,
[0242] (c) C.sub.1-5alkyl having 1 to 3 substituents R.sup.11,
[0243] each R.sup.11 is independently chosen from the group
consisting of --OH, --NH.sub.2, --NCH.sub.3H, --N(CH.sub.3).sub.2,
--N(CH.sub.2CH.sub.3).sub.2, .dbd.NH, .dbd.NCH.sub.3, --C(O)H,
--C(O)OH, --C(O)CH.sub.3, --C(O)OCH.sub.3, --NHC(O)H, --NHC(O)OH,
--NHC(O)CH.sub.3, --NHC(O)OCH.sub.3, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, pyranyl, pyrrolidinyl, piperidinyl,
oxacyclopentyl, and oxacyclohexyl, phenyl, pyridinyl, pyrimidinyl
and pyrrolyl, where [0244] the cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, pyranyl, pyrrolidinyl, piperidinyl,
oxacyclopentyl and oxacyclohcxyl are substituted by from 0 to 2
substitutents R.sup.12 on N or C atoms, and each R.sup.12 is
independently selected from the group consisting of hydrogen,
halogen, carboxy, C.sub.1-6alkyl, --O--C.sub.1-6alkyl and
--S--C.sub.1-6alkyl; and [0245] the phenyl, pyridinyl, pyrimidinyl
and pyrrolyl are substituted by from 0 to 3 substitutents R.sup.13
on N or C atoms, and each R.sup.13 is independently selected from
the group consisting of hydrogen, halogen, C.sub.1-6alkyl and 3- to
8-membered cycloalkyl containing from 0 to 3 heteroatoms
independently chosen from the group consisting of N, O and S,
[0246] (d) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
pyranyl, pyrrolidinyl, piperidinyl, oxacyclopentyl and
oxacyclohexyl having from 0 to 3 substitutents R.sup.10 on N or C
atoms, the R.sup.10 independently selected from the group
consisting of hydrogen, halogen, carboxy, C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, --S--C.sub.1-6alkyl, phenyl and benzyl,
and
[0247] (e) aryl ring systems G' chosen from the group consisting
of: phenyl, pyridinyl and 9-membered bicyclic ring systems
containing from 0 to 2 heteroatoms independently chosen from the
group consisting of N and O. In all aspects of this embodiment, all
other groups are as provided in the general formula above.
[0248] In a tenth embodiment of the invention,
##STR00049##
is chosen from the group consisting
##STR00050##
where
##STR00051##
is substituted by from 0 to 3 additional R.sup.1;
##STR00052##
is phenyl; v is from 0 to 2; each R.sup.2 is independently chosen
from the group consisting of fluorine, chlorine, --OH, --CH.sub.3,
--OCH.sub.3 and --CN; each D is independently chosen from the group
consisting of
##STR00053##
each E is independently chosen from the group consisting of a
single bond,
##STR00054##
where one of R.sup.8a and R.sup.8b is --OH or fluorine; and each G
is independently chosen from the group consisting of C.sub.1-4alkyl
having 1 to 2 substituents R.sup.11, wherein each R.sup.11 is
independently chosen from the group consisting of --OH, --NH.sub.2,
--NCH.sub.3H, --N(CH.sub.3).sub.2, --N(CH.sub.2CH.sub.3).sub.2,
--C(O)OCH.sub.3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
pyranyl, pyrrolidinyl, piperidinyl, oxacyclopentyl, oxacyclohexyl,
phenyl, pyridinyl, pyrimidinyl and pyrrolyl. In all aspects of this
embodiment, all other groups are as provided in the general formula
above or in the eighth embodiment.
[0249] In an eleventh embodiment of the invention, the compound
having structural formula (I) is a compound having structural
formula (Ia):
##STR00055##
or a pharmaceutically acceptable salt thereof, wherein
##STR00056##
is substituted by u substituents R.sup.1, and Y is selected from
the group consisting of O and NR.sup.1. In all aspects of this
embodiment, all other groups are as provided in the general formula
above or in any one of the first through tenth embodiments.
[0250] In a twelfth embodiment of the invention, the compound
having structural formula (Ia) is a compound having structural
formula (Ib):
##STR00057##
or a pharmaceutically acceptable salt thereof, wherein
##STR00058##
is substituted by u substituents R.sup.1, and Y is selected from
the group consisting of O and NR.sup.1. In particular aspects of
this embodiment,
##STR00059##
Y is substituted by u substituents R.sup.1, Y is O, and both
instances of G are
##STR00060##
In all aspects of this embodiment, all other groups are as provided
in the general formula above or in the eleventh embodiment.
[0251] In a thirteenth embodiment of the invention, the compound
having structural formula (Ia) is a compound having structural
formula (Ib):
##STR00061##
or a pharmaceutically acceptable salt thereof, wherein said
##STR00062##
is substituted by u substituents R.sup.1, and said
##STR00063##
and said
##STR00064##
taken together with one substituent R.sup.1 and one substituent
R.sup.2, are represented by a group chosen from the group
consisting of
##STR00065##
In particular aspects of this embodiment,
##STR00066##
and said
##STR00067##
taken together with one substituent R.sup.1 and one substituent
R.sup.2, are represented by
##STR00068##
wherein V is --CH.sub.2--, W is
--(CH.sub.2).sub.0-2O(CH.sub.2).sub.0-2--, R.sup.1 is fluorine, and
both instances of G are
##STR00069##
In all aspects of this embodiment, all other groups are as provided
in the general formula above or in the eleventh embodiment.
[0252] In a fourteenth embodiment of the invention,
##STR00070##
taken together with one substituent R.sup.1 and one substituent
R.sup.2, are represented by a group chosen from the group
consisting of:
##STR00071##
[0253] W is chosen from the group consisting of
--(CH.sub.2).sub.1-3--, --(CH.sub.2).sub.0-2NH(CH.sub.2).sub.0-2--,
--(CH.sub.2).sub.0-2N(C.sub.1-6alkyl)(CH.sub.2).sub.0-2--,
--(CH.sub.2).sub.0-2O(CH.sub.2).sub.0-2- and
--(CH.sub.2).sub.0-2C(O)(CH.sub.2).sub.0-2--, where W is
substituted by from 0 to 4 R.sup.w, where each R.sup.w is
independently selected from C.sub.1-6alkyl and C.sub.3-8cycloalkyl;
and
[0254] V is chosen from the group consisting of --C(O)-- and
--CH.sub.2--, and where V is --CH.sub.2--, V is substituted by from
0 to 2 R.sup.v, where each R.sup.v is independently selected from
the group consisting of C.sub.1-6alkyl and C.sub.3-8cycloalkyl;
[0255] each R.sup.1 is independently chosen from the group
consisting of hydrogen, halogen, --OR.sup.3, --CN, --C(O)R.sup.3,
--CO.sub.2R.sup.3, --C(O)N(R.sup.3a).sub.2, --SR.sup.3,
--S(O)R.sup.3, --S(O.sub.2)R.sup.3, --N(R.sup.3a).sub.2,
--(CH.sub.2).sub.0-6N(R.sup.3a).sub.2,
--N(R.sup.3a)SO.sub.2R.sup.3, --N(R.sup.3a)CO.sub.2R.sup.3,
--N(R.sup.3a)COR.sup.3, --N(R.sup.3a)C(O)N(R.sup.3a),
C.sub.1-6alkyl, C.sub.3-8carbocycle containing from 0 to 3
heteroatoms chosen from N, O and S, and phenyl, and the
C.sub.1-6alkyl, C.sub.3-8carbocycle and phenyl are substituted by
from 0 to 3 substitutents independently chosen from the group
consisting of hydrogen, halogen, --OR.sup.3a, --CN,
--CO.sub.2R.sup.3a, --C(O)N(R.sup.3a).sub.2, --N(R.sup.3a).sub.2,
--N(R.sup.3a)CO.sub.2R.sup.3a, --SR.sup.3a, --S(O)R.sup.3a,
--S(O.sub.2)R.sup.3a, --N(R.sup.3a)SO.sub.2R.sup.3a,
--N(R.sup.3a)CO.sub.2R.sup.3a, --N(R.sup.3a)C(O)N(R.sup.3a),
C.sub.1-6alkyl, --O--C.sub.1-6alkyl and --S--C.sub.1-6alkyl, [0256]
each R.sup.3 is independently chosen from the group consisting of
hydrogen, C.sub.1-6alkyl, --OH, --O--C.sub.1-6alkyl and
C.sub.3-8cycloalkyl, and [0257] each R.sup.3a is independently
chosen from the group consisting of hydrogen, C.sub.1-6alkyl and
C.sub.3-8cycloalkyl;
[0258] each R.sup.2 is independently chosen from the group
consisting of hydrogen, halogen, --OR.sup.4a, --CN,
--CO.sub.2R.sup.4a, --C(O)N(R.sup.4a).sub.2, --N(R.sup.4a).sub.2,
--N(R.sup.4a)CO.sub.2R.sup.4a, --SR.sup.4a, --S(O)R.sup.4a,
--S(O.sub.2)R.sup.4a, --N(R.sup.4a)SO.sub.2R.sup.4a,
--N(R.sup.4a)CO.sub.2R.sup.4a, --N(R.sup.4a)C(O)N(R.sup.4a),
C.sub.1-6alkyl substituted by from 0 to 4 R.sup.4 and
C.sub.3-8cycloalkyl substituted by from 0 to 4 R.sup.4, [0259] each
R.sup.4 is independently chosen from the group consisting of
hydrogen, --OH, C.sub.1-6alkyl and C.sub.3-8cycloalkyl, and [0260]
each R.sup.4a is independently chosen from the group consisting of
hydrogen, C.sub.1-6alkyl and C.sub.3-8cycloalkyl;
[0261] wherein each D is independently chosen from the group
consisting of a single bond, --C(O)N(R.sup.5)--,
--NR.sup.5C(O)--,
##STR00072##
where [0262] R.sup.5 is independently chosen from the group
consisting of hydrogen, halogen --OR.sup.6, --CN,
--CO.sub.2R.sup.6, --C(O)N(R.sup.6).sub.2, --N(R.sup.6).sub.2,
--N(R.sup.6)COR.sup.6, --SR.sup.6, --S(O)R.sup.6,
--S(O.sub.2)R.sup.6, --N(R.sup.6)SO.sub.2R.sup.6,
--NCO.sub.2R.sup.6, --NC(O)N(R.sup.6).sub.2, C.sub.1-6alkyl
substituted by from 0 to 3 substituents R.sup.6 and
C.sub.3-8cycloalkyl substituted by from 0 to 3 substituents
R.sup.6, and [0263] each R.sup.6 is independently chosen from the
group consisting of hydrogen, C.sub.1-6alkyl and
C.sub.3-8cycloalkyl;
[0264] wherein each E is independently chosen from the group
consisting of a single bond, --CH.sub.2NHC(O)--,
--CH.sub.2N(CH.sub.3)C(O)--, --C(CH.sub.3)HNHC(O)--,
--C(CH.sub.3)HN(CH.sub.3)C(O)--, --C(CH.sub.3).sub.2NHC(O)--,
--C(CH.sub.3).sub.2N(CH.sub.3)C(O)--, --CH.sub.2NHC(O)O--,
--CH.sub.2N(CH.sub.3)C(O)O--, --C(CH.sub.3)HNHC(O)O--,
--C(CH.sub.3)HN(CH.sub.3)C(O)O--, --C(CH.sub.3).sub.2NHC(O)O--,
--C(CH.sub.3).sub.2N(CH.sub.3)C(O)O--,
##STR00073##
where one of R.sup.8a and R.sup.8b is --OH or fluorine;
[0265] wherein each G is independently chosen from the group
consisting of
[0266] (a) hydrogen,
[0267] (b) --CN,
[0268] (c) C.sub.1-5alkyl having 1 to 3 substituents R.sup.11,
[0269] each R.sup.11 is independently chosen from the group
consisting of --OH, --NH.sub.2, --NCH.sub.3H, --N(CH.sub.3).sub.2,
--N(CH.sub.2CH.sub.3).sub.2, .dbd.NH, .dbd.NCH.sub.3, --C(O)H,
--C(O)OH, --C(O)CH.sub.3, --C(O)OCH.sub.3, --NHC(O)H, --NHC(O)OH,
--NHC(O)CH.sub.3, --NHC(O)OCH.sub.3, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, pyranyl, pyrrolidinyl, piperidinyl,
oxacyclopentyl, and oxacyclohexyl, phenyl, pyridinyl, pyrimidinyl
and pyrrolyl, where [0270] the cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, pyranyl, pyrrolidinyl, piperidinyl,
oxacyclopentyl and oxacyclohexyl are substituted by from 0 to 2
substitutents R.sup.12 on N or C atoms, and each R.sup.12 is
independently selected from the group consisting of hydrogen,
halogen, carboxy, C.sub.1-6alkyl, --O--C.sub.1-6alkyl and
--S--C.sub.1-6alkyl; and [0271] the phenyl, pyridinyl, pyrimidinyl
and pyrrolyl are substituted by from 0 to 3 substitutents R.sup.13
on N or C atoms, and each R.sup.13 is independently selected from
the group consisting of hydrogen, halogen, C.sub.1-6alkyl and 3- to
8-membered cycloalkyl containing from 0 to 3 heteroatoms
independently chosen from the group consisting of N, O and S,
[0272] (d) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
pyranyl, pyrrolidinyl, piperidinyl, oxacyclopentyl and
oxacyclohexyl having from 0 to 3 substitutents R.sup.10 on N or C
atoms, the R.sup.10 independently selected from the group
consisting of hydrogen, halogen, carboxy, C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, --S--C.sub.1-6alkyl, phenyl and benzyl,
and
[0273] (e) aryl ring systems G' chosen from the group consisting
of: phenyl, pyridinyl and 9-membered bicyclic ring systems
containing from 0 to 2 heteroatoms independently chosen from the
group consisting of N and O. In all aspects of this embodiment, all
other groups are as provided in the general formula above.
[0274] In another embodiment of the invention, the compound of the
invention is selected from the exemplary species depicted in
Examples 1 through 215 shown below, or pharmaceutically acceptable
salts thereof.
[0275] In another embodiment of the invention, for the compounds of
formula (I), variables
##STR00074##
D, E, G, R.sup.1, R.sup.2, u, v, R.sup.3, R.sup.3a, R.sup.4,
R.sup.4a, R.sup.5, R.sup.6, R.sup.7, I, J, R.sup.8a, R.sup.8b,
R.sup.8c, R.sup.9, R.sup.10, R.sup.10a, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, W, R.sup.w, V, and R.sup.v, are selected
independently from each other.
[0276] Other embodiments of the present invention include the
following:
[0277] (a) A pharmaceutical composition comprising an effective
amount of a compound of formula (I) and a pharmaceutically
acceptable carrier.
[0278] (b) The pharmaceutical composition of (a), further
comprising a second therapeutic agent selected from the group
consisting of HCV antiviral agents, immunomodulators, and
anti-infective agents.
[0279] (c) The pharmaceutical composition of (b), wherein the HCV
antiviral agent is an antiviral selected from the group consisting
of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
[0280] (d) A pharmaceutical combination that is (i) a compound of
formula (I) and (ii) a second therapeutic agent selected from the
group consisting of HCV antiviral agents, immunomodulators, and
anti-infective agents; wherein the compound of formula (I) and the
second therapeutic agent are each employed in an amount that
renders the combination effective for inhibiting HCV NS5A activity,
or for treating HCV infection and/or reducing the likelihood or
severity of symptoms of HCV infection, or for inhibiting HCV viral
replication and/or HCV viral production in a cell-based system.
[0281] (e) The combination of (d), wherein the HCV antiviral agent
is an antiviral selected from the group consisting of HCV protease
inhibitors and HCV NS5B polymerase inhibitors.
[0282] (f) A method of inhibiting HCV NS5A activity in a subject in
need thereof, which comprises administering to the subject an
effective amount of a compound of formula (I).
[0283] (g) A method of treating HCV infection and/or reducing the
likelihood or severity of symptoms of HCV infection in a subject in
need thereof, which comprises administering to the subject an
effective amount of a compound of formula (I).
[0284] (h) The method of (g), wherein the compound of formula (I)
is administered in combination with an effective amount of at least
one second therapeutic agent selected from the group consisting of
HCV antiviral agents, immunomodulators, and anti-infective
agents.
[0285] (i) The method of (h), wherein the HCV antiviral agent is an
antiviral selected from the group consisting of HCV protease
inhibitors and HCV NS5B polymerase inhibitors.
[0286] (j) A method of inhibiting HCV viral replication and/or HCV
viral production in a cell-based system, which comprises
administering to the subject an effective amount of a compound of
formula (I).
[0287] (k) The method of (j), wherein the compound of formula (I)
is administered in combination with an effective amount of at least
one second therapeutic agent selected from the group consisting of
HCV antiviral agents, immunomodulators, and anti-infective
agents.
[0288] (l) The method of (k), wherein the HCV antiviral agent is an
antiviral selected from the group consisting of HCV protease
inhibitors and HCV NS5B polymerase inhibitors.
[0289] (m) A method of inhibiting HCV NS5A activity in a subject in
need thereof, which comprises administering to the subject the
pharmaceutical composition of (a), (b), or (c) or the combination
of (d) or (e).
[0290] (n) A method of treating HCV infection and/or reducing the
likelihood or severity of symptoms of HCV infection in a subject in
need thereof, which comprises administering to the subject the
pharmaceutical composition of (a), (b), or (c) or the combination
of (d) or (e).
[0291] (o) A method of inhibiting HCV viral replication and/or HCV
viral production in a cell-based system, which comprises
administering to the subject the pharmaceutical composition of (a),
(b), or (c) or the combination of (d) or (c).
[0292] In the embodiments of the compounds and salts provided
above, it is to be understood that each embodiment may be combined
with one or more other embodiments, to the extent that such a
combination provides a stable compound or salt and is consistent
with the description of the embodiments. It is further to be
understood that the embodiments of compositions and methods
provided as (a) through (o) above are understood to include all
embodiments of the compounds and/or salts, including such
embodiments as result from combinations of embodiments.
[0293] The present invention also includes a compound of the
present invention for use (i) in, (ii) as a medicament for, or
(iii) in the preparation of a medicament for: (a) inhibiting HCV
NS5A activity, or (b) treating HCV infection and/or reducing the
likelihood or severity of symptoms of HCV infection, or (c)
inhibiting HCV viral replication and/or HCV viral production in a
cell-based system, or (d) use in medicine. In these uses, the
compounds of the present invention can optionally be employed in
combination with one or more second therapeutic agents selected
from HCV antiviral agents, anti-infective agents, and
immunomodulators.
[0294] Additional embodiments of the invention include the
pharmaceutical compositions, combinations and methods set forth in
(a)-(o) above and the uses set forth in the preceding paragraph,
wherein the compound of the present invention employed therein is a
compound of one of the embodiments, aspects, classes, sub-classes,
or features of the compounds described above. In all of these
embodiments, the compound may optionally be used in the form of a
pharmaceutically acceptable salt, or may be present in the form of
a solvate or hydrate as appropriate.
[0295] As used herein, all ranges are inclusive, and all sub-ranges
are included within such ranges, although not necessarily
explicitly set forth. In addition, the term "or," as used herein,
denotes alternatives that may, where appropriate, be combined; that
is, the term "or" includes each listed alternative separately as
well as their combination.
[0296] As used herein, the term "alkyl" refers to any linear or
branched chain alkyl group having a number of carbon atoms in the
specified range. Thus, for example, "C.sub.1-6 alkyl" (or
"C.sub.1-C.sub.6 alkyl") refers to all of the hexyl alkyl and
pentyl alkyl isomers as well as n-, iso-, sec- and tert-butyl, n-
and isopropyl, ethyl and methyl. As another example, "C.sub.1-4
alkyl" refers to n-, iso-, sec- and tert-butyl, n- and isopropyl,
ethyl and methyl. Where indicated, "C.sub.0" refers to hydrogen;
thus, for example, "C.sub.0-6 alkyl" (or "C.sub.0-C.sub.6 alkyl")
refers to all of the hexyl alkyl and pentyl alkyl isomers as well
as n-, iso-, sec- and tert-butyl, n- and isopropyl, ethyl, methyl
and hydrogen. Alkyl groups may be substituted as indicated.
[0297] The term "halogenated" refers to a group or molecule in
which a hydrogen atom has been replaced by a halogen. Similarly,
the term "haloalkyl" refers to a halogenated alkyl group. The term
"halogen" (or "halo") refers to atoms of fluorine, chlorine,
bromine and iodine (alternatively referred to as fluoro, chloro,
bromo, and iodo), preferably fluorine.
[0298] The term "alkoxy" refers to an "alkyl-O--" group, where
alkyl is as defined above. Alkoxy groups may be substituted as
indicated.
[0299] The term "cycloalkyl" refers to any cyclic ring of an alkane
or alkene having a number of carbon atoms in the specified range.
Thus, for example, "C.sub.3-8 cycloalkyl" (or "C.sub.3-C.sub.8
cycloalkyl") refers to cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl. The term "cycloalkoxy"
refers to a "cycloalkyl-O--" group, where cycloalkyl is as defined
above. Cycloalkyl groups may be substituted as indicated.
[0300] The term "aryl" (or "aryl ring system") refers to aromatic
mono- and poly-carbocyclic or heterocyclic ring systems wherein the
individual carbocyclic rings in the polyring systems are fused or
attached to each other via a single bond. As used herein, the term
aryl includes aromatic mono- and poly-carbocyclic ring systems that
include from 0 to 4 heteroatoms (non-carbon atoms) that are
independently chosen from N, O and S. Suitable aryl groups include
phenyl, naphthyl, biphenylenyl, pyridinyl, pyrimidinyl and
pyrrolyl, as well as those discussed below. Aryl groups may be
substituted as indicated. Aryl ring systems may include, where
appropriate, an indication of the variable to which a particular
ring atom is attached. Unless otherwise indicated, substituents to
the aryl ring systems can be attached to any ring atom, provided
that such attachment results in formation of a stable ring
system.
[0301] The term "carbocycle" (and variations thereof such as
"carbocyclic") as used herein, unless otherwise indicated, refers
to (i) a C.sub.5 to C.sub.7 monocyclic, saturated or unsaturated
ring, or (ii) a C.sub.8 to C.sub.10 bicyclic saturated or
unsaturated ring system. Each ring in (ii) is either independent
of, or fused to, the other ring, and each ring is saturated or
unsaturated. Carbocycle groups may be substituted as indicated.
When the carbocycles contain one or more heteroatoms independently
chosen from N, O and S, the carbocycles may also be referred to as
"heterocycles," as defined below. The carbocycle may be attached to
the rest of the molecule at any carbon or nitrogen atom that
results in a stable compound. The fused bicyclic carbocycles are a
subset of the carbocycles; i.e., the term "fused bicyclic
carbocycle" generally refers to a C.sub.8 to C.sub.10 bicyclic ring
system in which each ring is saturated or unsaturated and two
adjacent carbon atoms are shared by each of the rings in the ring
system. A fused bicyclic carbocycle in which both rings are
saturated is a saturated bicyclic ring system. Saturated
carbocyclic rings are also referred to as cycloalkyl rings, e.g.,
cyclopropyl, cyclobutyl, etc. A fused bicyclic carbocycle in which
one or both rings are unsaturated is an unsaturated bicyclic ring
system. Carbocycle ring systems may include, where appropriate, an
indication of the variable to which a particular ring atom is
attached. Unless otherwise indicated, substituents to the ring
systems can be attached to any ring atom, provided that such
attachment results in formation of a stable ring system.
[0302] Unless indicated otherwise, the term "heterocycle" (and
variations thereof such as "heterocyclic" or "heterocyclyl")
broadly refers to (i) a stable 5- to 7-membered, saturated or
unsaturated monocyclic ring, or (ii) a stable 8- to 10-membered
bicyclic ring system, wherein each ring in (ii) is independent of,
or fused to, the other ring or rings and each ring is saturated or
unsaturated, and the monocyclic ring or bicyclic ring system
contains one or more heteroatoms (e.g., from 1 to 6 heteroatoms, or
from 1 to 4 heteroatoms) independently selected from N, O and S and
a balance of carbon atoms (the monocyclic ring typically contains
at least one carbon atom and the bicyclic ring systems typically
contain at least two carbon atoms); and wherein any one or more of
the nitrogen and sulfur heteroatoms is optionally oxidized, and any
one or more of the nitrogen heteroatoms is optionally quaternized.
Unless otherwise specified, the heterocyclic ring may be attached
at any heteroatom or carbon atom, provided that attachment results
in the creation of a stable structure. Heterocycle groups may be
substituted as indicated, and unless otherwise specified, the
substituents may be attached to any atom in the ring, whether a
heteroatom or a carbon atom, provided that a stable chemical
structure results. Representative examples include pyranyl,
piperidinyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl,
imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,
thiomorpholinyl, thiazolidinyl, isothiazolidinyl, and
tetrahydrofuryl (or tetrahydrofuranyl). Unless expressly stated to
the contrary, the term "heteroaryl ring system" refers to aryl ring
systems, as defined above, that include from 1 to 4 heteroatoms
(non-carbon atoms) that are independently chosen from N, O and S.
In the case of substituted heteraromatic rings containing at least
one nitrogen atom (e.g., pyridine), such substitutions can be those
resulting in N-oxide formation. Representative examples of
heteroaromatic rings include pyridyl, pyrrolyl, pyrazinyl,
pyrimidinyl, pyridazinyl, thienyl (or thiophenyl), thiazolyl,
furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,
isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and
thiadiazolyl. Representative examples of bicyclic heterocycles
include benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl,
isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl,
isochromanyl, tetrahydroquinolinyl, quinolinyl,
tetrahydroisoquinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl,
2,3-dihydrobenzo-1,4-dioxinyl and benzo-1,3-dioxolyl.
[0303] Unless otherwise specifically noted as only "substituted",
alkyl, cycloalkyl, and aryl groups are not substituted. If
substituted, preferred substituents are selected from the group
that includes, but is not limited to, halo, C.sub.1-C.sub.20 alkyl,
--CF.sub.3, --NH.sub.2, --N(C.sub.1-C.sub.6 alkyl).sub.2,
--NO.sub.2, oxo, --CN, --N.sub.3, --OH, --O(C.sub.1-C.sub.6 alkyl),
C.sub.3-C.sub.10 cycloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, (C.sub.0-C.sub.6 alkyl) S(O).sub.0-2--,
aryl-S(O).sub.0-2--, (C.sub.0-C.sub.6
alkyl)S(O).sub.0-2(C.sub.0-C.sub.6 alkyl)-, (C.sub.0-C.sub.6
alkyl)C(O)NH--, H.sub.2N--C(NH)--, --O(C.sub.1-C.sub.6
alkyl)CF.sub.3, (C.sub.0-C.sub.6 alkyl)C(O)--, (C.sub.0-C.sub.6
alkyl)OC(O)--, (C.sub.0-C.sub.6alkyl)O(C.sub.1-C.sub.6 alkyl)-,
(C.sub.0-C.sub.6 alkyl)C(O).sub.1-2 (C.sub.0-C.sub.6 alkyl)-,
(C.sub.1-C.sub.6 alkyl)OC(O)NH--, aryl, aralkyl, heteroaryl,
heterocycloalkyl, halo-aryl, halo-aralkyl, halo-heterocycle and
halo-heterocycloalkyl.
[0304] Unless expressly stated to the contrary, all ranges cited
herein are inclusive. For example, a heteroaryl ring described as
containing from "0 to 3 heteroatoms" means the ring can contain 0,
1, 2, or 3 heteroatoms. It is also to be understood that any range
cited herein includes within its scope all of the sub-ranges within
that range. The oxidized forms of the heteroatoms N and S are also
included within the scope of the present invention.
[0305] When any variable (for example, R.sup.1 or R.sup.3) occurs
more than one time in any constituent or in formula (I) or in any
other formula depicting and describing compounds of the invention,
its definition on each occurrence is independent of its definition
at every other occurrence. Also, combinations of substituents
and/or variables are permissible only if such combinations result
in stable compounds.
[0306] Unless expressly stated to the contrary, substitution by a
named substituent is permitted on any atom provided such
substitution is chemically allowed and results in a stable
compound. A "stable" compound is a compound that can be prepared
and isolated and that has a structure and properties that remain or
can be caused to remain essentially unchanged for a period of time
sufficient to allow use of the compound for the purposes described
herein (e.g., therapeutic or prophylactic administration to a
subject).
[0307] As used herein, the term "compound" is intended to encompass
chemical agents described by generic formula (I) in all forms,
including hydrates and solvates of such chemical agents.
[0308] In the compounds of generic formula (I), the atoms may
exhibit their natural isotopic abundances, or one or more of the
atoms may be artificially enriched in a particular isotope having
the same atomic number, but an atomic mass or mass number different
from the atomic mass or mass number predominantly found in nature.
The present invention is meant to include all suitable isotopic
variations of the compounds of generic formula (I). For example,
different isotopic forms of hydrogen (H) include protium (.sup.1H)
and deuterium (.sup.2H or D). Protium is the predominant hydrogen
isotope found in nature. Enriching for deuterium may afford certain
therapeutic advantages, such as increasing in vivo half-life or
reducing dosage requirements, or may provide a compound useful as a
standard for characterization of biological samples.
Isotopically-enriched compounds within generic formula (I) can be
prepared without undue experimentation by conventional techniques
well known to those skilled in the art or by processes analogous to
those described in the Schemes and Examples herein using
appropriate isotopically-enriched reagents and/or
intermediates.
[0309] As a result of the selection of substituents and substituent
patterns, certain of the compounds of the present invention can
have asymmetric centers and can occur as mixtures of stereoisomers,
or as individual diastereomers, or enantiomers. All isomeric forms
of these compounds, whether isolated or in mixtures, are within the
scope of the present invention.
[0310] As would be recognized by one of ordinary skill in the art,
certain of the compounds of the present invention can exist as
tautomers. For the purposes of the present invention a reference to
a compound of formula (I) is a reference to the compound per se, or
to any one of its tautomers per se, or to mixtures of two or more
tautomers.
[0311] The compounds of the present invention may be administered
in the form of pharmaceutically acceptable salts. The term
"pharmaceutically acceptable salt" refers to a salt that possesses
the effectiveness of the parent compound and that is not
biologically or otherwise undesirable (e.g., is neither toxic nor
otherwise deleterious to the recipient thereof). Suitable salts
include acid addition salts that may, for example, be formed by
mixing a solution of the compound of the present invention with a
solution of a pharmaceutically acceptable acid such as hydrochloric
acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic
acid. Many of the compounds of the invention carry an acidic
moiety, in which case suitable pharmaceutically acceptable salts
thereof can include alkali metal salts (e.g., sodium or potassium
salts), alkaline earth metal salts (e.g., calcium or magnesium
salts), and salts formed with suitable organic ligands such as
quaternary ammonium salts. Also, in the case of an acid (--COOH) or
alcohol group being present, pharmaceutically acceptable esters can
be employed to modify the solubility or hydrolysis characteristics
of the compound.
[0312] The term "administration" and variants thereof (e.g.,
"administering" a compound) in reference to a compound of the
invention mean providing the compound or a prodrug of the compound
to the individual in need of treatment. When a compound of the
invention or a prodrug thereof is provided in combination with one
or more other active agents (e.g., antiviral agents useful for
treating HCV infection), "administration" and its variants are each
understood to include concurrent and sequential provision of the
compound or salt (or hydrate) and other agents.
[0313] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients, as well
as any product that results, directly or indirectly, from combining
the specified ingredients.
[0314] By "pharmaceutically acceptable" is meant that the
ingredients of the pharmaceutical composition must be compatible
with each other and not deleterious to the recipient thereof.
[0315] The terms "subject" (alternatively referred to herein as
"patient") as used herein, refer to an animal, preferably a mammal,
most preferably a human, who has been the object of treatment,
observation or experiment.
[0316] The term "effective amount" as used herein means that amount
of active compound or pharmaceutical agent that elicits the
biological or medicinal response in a tissue, system, animal or
human that is being sought by a researcher, veterinarian, medical
doctor or other clinician. In one embodiment, the effective amount
is a "therapeutically effective amount" for the alleviation of one
or more symptoms of the disease or condition being treated. In
another embodiment, the effective amount is a "prophylactically
effective amount" for reduction of the severity or likelihood of
one or more symptoms of the disease or condition. In another
embodiment, the effective amount is a "therapeutically effective
amount" for inhibition of HCV viral replication and/or HCV viral
production. The term also includes herein the amount of active
compound sufficient to inhibit HCV NS5A and thereby elicit the
response being sought (i.e., an "inhibition effective amount").
When the active compound (i.e., active ingredient) is administered
as the salt, references to the amount of active ingredient are to
the free acid or free base form of the compound.
[0317] It is understood that claimed compounds cause inhibition in
replicon assay testing. Thus, compounds described herein are useful
for inhibiting HCV replication, specifically the NS5A protein.
Compounds described herein have different uses, including the
prevention or treatment of one or more of the symptoms of HCV
infection, the inhibition of HCV viral replication and/or HCV viral
production, and/or as pharmaceutical composition ingredients.
[0318] The compounds of this invention are useful in the
preparation and execution of screening assays for antiviral
compounds. For example, the compounds of this invention are useful
for identifying resistant HCV replicon cell lines harboring
mutations within NS5A, which are excellent screening tools for more
powerful antiviral compounds. Furthermore, the compounds of this
invention are useful in establishing or determining the binding
site of other antivirals to the HCV replicase.
[0319] For the purposes of inhibiting HCV NS5A protein, treating
HCV infection and/or reducing the likelihood or severity of
symptoms of HCV infection and inhibiting HCV viral replication
and/or HCV viral production, the compounds of the present
invention, optionally in the form of a salt or a hydrate, can be
administered by any means that produces contact of the active agent
with the agent's site of action. They can be administered by one or
more conventional means available for use in conjunction with
pharmaceuticals, either as individual therapeutic agents or in a
combination of therapeutic agents. They can be administered alone,
but typically are administered with a pharmaceutical carrier
selected on the basis of the chosen route of administration and
standard pharmaceutical practice. The compounds of the invention
can, for example, be administered by one or more of the following:
orally, parenterally (including subcutaneous injections,
intravenous, intramuscular, intrasternal injection or infusion
techniques), by inhalation (such as in a spray form), or rectally,
in the form of a unit dosage of a pharmaceutical composition
containing an effective amount of the compound and conventional
non-toxic pharmaceutically-acceptable carriers, adjuvants and
vehicles. Liquid preparations suitable for oral administration
(e.g., suspensions, syrups, elixirs and the like) can be prepared
according to techniques known in the art and can employ any of the
usual media such as water, glycols, oils, alcohols and the like.
Solid preparations suitable for oral administration (e.g., powders,
pills, capsules and tablets) can be prepared according to
techniques known in the art and can employ such solid excipients as
starches, sugars, kaolin, lubricants, binders, disintegrating
agents and the like. Parenteral compositions can be prepared
according to techniques known in the art and typically employ
sterile water as a carrier and optionally other ingredients, such
as solubility aids. Injectable solutions can be prepared according
to methods known in the art wherein the carrier comprises a saline
solution, a glucose solution or a solution containing a mixture of
saline and glucose. Further description of methods suitable for use
in preparing pharmaceutical compositions of the present invention
and of ingredients suitable for use in said compositions is
provided in Remington's Pharmaceutical Sciences, 18.sup.th edition
(ed. A. R. Gennaro, Mack Publishing Co., 1990).
[0320] The compounds of this invention can be administered orally
in a dosage range of 0.001 to 1000 mg/kg of mammal (e.g., human)
body weight per day in a single dose or in divided doses. One
dosage range is 0.01 to 500 mg/kg body weight per day orally in a
single dose or in divided doses. Another dosage range is 0.1 to 100
mg/kg body weight per day orally in single or divided doses. For
oral administration, the compositions can be provided in the form
of tablets or capsules containing 1.0 to 500 mg of the active
ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150,
200, 250, 300, 400, and 500 mg of the active ingredient for the
symptomatic adjustment of the dosage to the patient to be treated.
The specific dose level and frequency of dosage for any particular
patient may be varied and will depend upon a variety of factors
including the activity of the specific compound employed, the
metabolic stability and length of action of that compound, the age,
body weight, general health, sex, diet, mode and time of
administration, rate of excretion, drug combination, the severity
of the particular condition, and the host undergoing therapy.
[0321] As noted above, the present invention also relates to a
method of inhibiting HCV replicon activity, inhibiting HCV viral
replication and/or HCV viral production, treating HCV infection
and/or reducing the likelihood or severity of symptoms of HCV
infection with a compound of the present invention in combination
with one or more therapeutic agents and a pharmaceutical
composition comprising a compound of the present invention and one
or more therapeutic agents selected from the group consisting of a
HCV antiviral agent, an immunomodulator, and an anti-infective
agent. Such therapeutic agents active against HCV include, but are
not limited to, ribavirin, levovirin, viramidine, thymosin alpha-1,
R7025 (an enhanced interferon (Roche)), interferon-.beta.,
interferon-.alpha., pegylated interferon-.alpha.
(peginterferon-.alpha.), a combination of interferon-.alpha. and
ribavirin, a combination of peginterferon-.alpha. and ribavirin, a
combination of interferon-.alpha. and levovirin, and a combination
of peginterferon-.alpha. and levovirin. The combination of
peginterferon-.alpha. and ribaviron represents the current Standard
of Care for HCV treatment. The combination of one or more compounds
of the present invention with the Standard of Care for HCV
treatment, pegylated-interferon and ribaviron is specifically
contemplated as being encompassed by the present invention.
Interferon-.alpha. includes, but is not limited to, recombinant
interferon-.alpha.2a (such as ROFERON interferon), pegylated
interferon-.alpha.2a (PEGASYS), interferon-.alpha.2b (such as
INTRON-A interferon), pegylated interferon-.alpha.2b (PEGINTRON), a
recombinant consensus interferon (such as interferon alphacon-1),
albuferon (interferon-.alpha. bound to human serum albumin (Human
Genome Sciences)), and a purified interferon-.alpha. product.
Amgen's recombinant consensus interferon has the brand name
INFERGEN. Levovirin is the L-enantiomer of ribavirin which has
shown immunomodulatory activity similar to ribavirin. Viramidine
represents an analog of ribavirin disclosed in International Patent
Application Publication WO 01/60379. In accordance with the method
of the present invention, the individual components of the
combination can be administered separately at different times
during the course of therapy or concurrently in divided or single
combination forms.
[0322] Ribavirin, levovirin, and viramidine may exert their
anti-HCV effects by modulating intracellular pools of guanine
nucleotides via inhibition of the intracellular enzyme inosine
monophosphate dehydrogenase (IMPDH). IMPDH is the rate-limiting
enzyme on the biosynthetic route in de novo guanine nucleotide
biosynthesis. Ribavirin is readily phosphorylated intracellularly
and the monophosphate derivative is an inhibitor of IMPDH. Thus,
inhibition of IMPDH represents another useful target for the
discovery of inhibitors of HCV replication. Therefore, the
compounds of the present invention may also be administered in
combination with an inhibitor of IMPDH, such as those disclosed in
International Patent Application Publications WO 97/41211, WO
01/00622 and WO 00/25780; or mycophenolate mofetil. See Anthony C.
Allison and Elsie M. Eugui, Immunosuppressive and Other
Anti-Rheumetic Activities of Mychophenolate Mofetil, 44 (SUPPL.)
AGENTS ACTION 165 (1993).
[0323] For the treatment of HCV infection, the compounds of the
present invention may also be administered in combination with the
antiviral agent polymerase inhibitor R7128 (Roche).
[0324] The compounds of the present invention may also be combined
for the treatment of HCV infection with antiviral 2'-C-branched
ribonucleosides disclosed in Rogers E. Harry-O'Kuru et al., A
Short, Flexible Route to 2'-C-Branched Ribonucleosides, 62 J. ORG.
CHEM. 1754-59 (1997); Michael S. Wolfe and Rogers E. Harry-O'Kuru,
A Consise Synthesis of 2'-C-Methylribonucleosides, 36 TET. LETT.
7611-14 (1995); U.S. Pat. No. 3,480,613; and International Patent
Application Publications WO 01/90121, WO 01/92282, WO 02/32920, WO
04/002999, WO 04/003000 and WO 04/002422; the contents of each of
which are incorporated by reference in their entirety. Such
2'-C-branched ribonucleosides include, but are not limited to,
2'-C-methyl-cytidine, 2'-C-methyl-uridine, 2'-C-methyl-adenosine,
2'-C-methyl-guanosine, and
9-(2-C-methyl-.beta.-D-ribofuranosyl)-2,6-diaminopurine, and the
corresponding amino acid ester of the ribose C-2', C-3', and C-5'
hydroxyls and the corresponding optionally substituted cyclic
1,3-propanediol esters of the 5'-phosphate derivatives.
[0325] For the treatment of HCV infection, the compounds of the
present invention may also be administered in combination with an
agent that is an inhibitor of HCV NS3 serine protease. HCV NS3
serine protease is an essential viral enzyme and has been described
to be an excellent target for inhibition of HCV replication.
Exemplary substrate and non-substrate based inhibitors of HCV NS3
protease inhibitors are disclosed in International Patent
Application Publications WO 98/22496, WO 98/46630, WO 99/07733, WO
99/07734, WO 99/38888, WO 99/50230, WO 99/64442, WO 00/09543, WO
00/59929, WO 02/48116, WO 02/48172, WO 2008/057208 and WO
2008/057209, in British Patent No. GB 2 337 262, and in U.S. Pat.
Nos. 6,323,180, 7,470,664, and 7,012,066 and in Ashok Arasappan et
al., Discovery of Narlaprevir (SCH 900518): A Potent, Second
Generation HCV NS3 Serine Protease Inhibitor, ACS MED. CHEM. LETT.
DOI: 10.1021/ml9000276 (Feb. 15, 2010).
[0326] The compounds of the present invention may also be combined
for the treatment of HCV infection with nucleosides having anti-HCV
properties, such as those disclosed in International Patent
Application Publications WO 02/51425, WO 01/79246, WO 02/32920, WO
02/48165 and WO 2005/003147 (including R1656,
(2'R)-2'-deoxy-2'-fluoro-2'-C-methylcytidine, shown as compounds
3-6 on page 77); WO 01/68663; WO 99/43691; WO 02/18404 and WO
2006/021341, and U.S. Patent Application Publication US
2005/0038240, including 4'-azido nucleosides such as R1626,
4'-azidocytidine; U.S. Patent Application Publications US
2002/0019363, US 2003/0236216, US 2004/0006007, US 2004/0063658 and
US 2004/0110717; U.S. Pat. Nos. 7,105,499, 7,125,855, 7,202,224;
and International Patent Application Publications WO 02/100415, WO
03/026589, WO 03/026675, WO 03/093290, WO 04/011478, WO 04/013300
and WO 04/028481; the content of each is incorporated herein by
reference in its entirety.
[0327] For the treatment of HCV infection, the compounds of the
present invention may also be administered in combination with an
agent that is an inhibitor of HCV NS5B polymerase. Such HCV NS5B
polymerase inhibitors that may be used as combination therapy
include, but are not limited to, those disclosed in International
Patent Application Publications WO 02/057287, WO 02/057425, WO
03/068244, WO 2004/000858, WO 04/003138 and WO 2004/007512; U.S.
Pat. Nos. 6,777,392, 7,105,499, 7,125,855, 7,202,224 and U.S.
Patent Application Publications US 2004/0067901 and US
2004/0110717; the content of each is incorporated herein by
reference in its entirety. Other such HCV polymerase inhibitors
include, but are not limited to, valopicitabine (NM-283; Idenix)
and 2'-F-2'-beta-methylcytidine (see also WO 2005/003147).
[0328] In one embodiment, nucleoside HCV NS5B polymerase inhibitors
that are used in combination with the present HCV inhibitors are
selected from the following compounds:
4-amino-7-(2-C-methyl-.beta.-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimid-
ine;
4-amino-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimi-
dine;
4-methylamino-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d-
]pyrimidine;
4-dimethylamino-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]py-
rimidine;
4-cyclopropylamino-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrr-
olo[2,3-d]pyrimidine;
4-amino-7-(2-C-vinyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;
4-amino-7-(2-C-hydroxymethyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyr-
imidine;
4-amino-7-(2-C-fluoromethyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,-
3-d]pyrimidine;
4-amino-5-methyl-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]p-
yrimidine;
4-amino-7-(2-C-methyl-1-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrim-
idine-5-carboxylic acid;
4-amino-5-bromo-7-(2-C-methyl-(3-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimi-
dine;
4-amino-5-chloro-7-(2-C-methyl-3-D-ribofuranosyl)-7H-pyrrolo[2,3-d]p-
yrimidine;
4-amino-5-fluoro-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrro-
lo[2,3-d]pyrimidine;
2,4-diamino-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimi-
dine;
2-amino-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrim-
idine;
2-amino-4-cyclopropylamino-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-
-pyrrolo[2,3-d]pyrimidine;
2-amino-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin--
4(3H)-one;
4-amino-7-(2-C-ethyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]p-
yrimidine;
4-amino-7-(2-C,2-O-dimethyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[-
2,3-d]pyrimidine;
7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-on-
e; 2-amino-5-methyl-7-(2-C,
2-O-dimethyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one-
;
4-amino-7-(3-deoxy-2-C-methyl-3-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimi-
dine;
4-amino-7-(3-deoxy-2-C-methyl-.beta.-D-arabinofuranosyl)-7H-pyrrolo[-
2,3-d]pyrimidine;
4-amino-2-fluoro-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]p-
yrimidine;
4-amino-7-(3-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]-
pyrimidine;
4-amino-7-(3-C-methyl-1-D-xylofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;
4-amino-7-(2,4-di-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrim-
idine;
4-amino-7-(3-deoxy-3-fluoro-2-C-methyl-.beta.-D-ribofuranosyl)-7H-p-
yrrolo[2,3-d]pyrimidine; and the corresponding 5'-triphosphates; or
a pharmaceutically acceptable salt thereof.
[0329] The compounds of the present invention may also be combined
for the treatment of HCV infection with non-nucleoside inhibitors
of HCV polymerase such as those disclosed in U.S. Patent
Application Publications US 2006/0100262 and US 2009-0048239;
International Patent Application Publications WO 01/77091, WO
01/47883, WO 02/04425, WO 02/06246, WO 02/20497, WO 2005/016927 (in
particular JTK003), WO 2004/041201, WO 2006/066079, WO 2006/066080,
WO 2008/075103, WO 2009/010783 and WO 2009/010785; the content of
each is incorporated herein by reference in its entirety.
[0330] In one embodiment, non-nucleoside HCV NS5B polymerase
inhibitors that are used in combination with the present HCV NS5A
inhibitors are selected from the following compounds:
14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,
8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-6-(2-morpholin-4-ylethyl)-5,6,7,8-tetrahydroindolo[2,1-a][2-
,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-6-[2-(dimethylamino)ethyl]-3-methoxy-5,6,7,8-tetrahydroindo-
lo[2,1-a][2,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-3-methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benz-
odiazocine-11-carboxylic acid; methyl
({[(14-cyclohexyl-3-methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]-
benzodiazocin-11-yl)carbonyl]amino}sulfonyl)acetate;
({[(14-cyclohexyl-3-methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2,
1-a][2,5]benzodiazocin-11-yl)carbonyl]amino}sulfonyl)acetic acid;
14-cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-methyl-5,6,7,8-tetr-
ahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxamide;
3-chloro-14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydr-
oindolo[2,1-a][2,5]benzodiazocine 11-carboxylic acid;
N-(11-carboxy-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocin-
-7-yl)-N,N-dimethylethane-1,2-diaminium bis(trifluoroacetate);
14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxyli-
c acid;
14-cyclohexyl-6-methyl-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]b-
enzodiazocine-11-carboxylic acid;
14-cyclohexyl-3-methoxy-6-methyl-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,-
5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-6-[2-(dimethylamino)ethyl]-3-methoxy-7-oxo-5,6,7,8-tetrahyd-
roindolo[2,1-a][2,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-6-[3-(dimethylamino)propyl]-7-oxo-5,6,7,8-tetrahydroindolo[-
2,1-a][2,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-7-oxo-6-(2-piperidin-1-ylethyl)-5,6,7,8-tetrahydroindolo[2,-
1-a][2,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-6-(2-morpholin-4-ylethyl)-7-oxo-5,6,7,
8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-6-[2-(diethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[2,-
1-a][2,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-6-(1-methylpiperidin-4-yl)-7-oxo-5,6,7,8-tetrahydroindolo[2-
,1-a][2,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-N-[(dimethylamino)sulfonyl]-7-oxo-6-(2-piperidin-1-ylethyl)-
-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxamide;
14-cyclohexyl-6-[2-(dimethylamino)ethyl]-N-[(dimethylamino)sulfonyl]-7-ox-
o-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxamide;
14-cyclopentyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[-
2,1-a][2,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carbo-
xylic acid;
6-allyl-14-cyclohexyl-3-methoxy-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzo-
diazocine-11-carboxylic acid;
14-cyclopentyl-6-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydroindolo[2,1-a]-
[2,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-6-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydroindolo[2,1-a][-
2,5]benzodiazocine-11-carboxylic acid;
13-cyclohexyl-5-methyl-4,5,6,7-tetrahydrofuro[3',2':6,7][1,4]diazocino[1,-
8-a]indole-10-carboxylic acid;
15-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-6,7,8,9-tetrahydro-5H-indo-
lo[2,1-a][2,6]benzodiazonine-12-carboxylic acid;
15-cyclohexyl-8-oxo-6,7,8,9-tetrahydro-5H-indolo[2,1-a][2,5]benzodiazonin-
e-12-carboxylic acid;
13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-ca-
rboxylic acid; and pharmaceutically acceptable salts thereof.
[0331] The HCV replicons and NS5A inhibitory activity of the
present compounds may be tested using assays known in the art. HCV
inhibitors, such as those described in the Examples herein have
activities in genotype 1b, 2a and 1a replicon assays of from about
1 pM to about 1 .mu.M. The assay is performed by incubating a
replicon harboring cell-line in the presence of inhibitor for a set
period of time and measuring the effect of the inhibitor on HCV
replicon replication either directly by quantifying replicon RNA
level, or indirectly by measuring enzymatic activity of a
co-encoded reporter enzyme such as luciferase or .beta.-lactamase.
By performing a series of such measurements at different inhibitor
concentrations, the effective inhibitory concentration of the
inhibitor (EC.sub.50 or EC.sub.90) is determined. See Jan M.
Vrolijk et al., A replicons-based bioassay for the measurement of
interferons in patients with chronic hepatitis C, 110 J.
VIROLOGICAL METHODS 201 (2003). Such assays may also be run in an
automated format for high through-put screening. See Paul Zuck et
al., A cell-based .beta.-lactamase reporter gene assay for the
identification of inhibitors of hepatitis C virus replication, 334
ANALYTICAL BIOCHEMISTRY 344 (2004).
[0332] The present invention also includes processes for making
compounds of formula (I). The compounds of the present invention
can be readily prepared according to the following reaction schemes
and examples, or modifications thereof, using readily available
starting materials, reagents and conventional synthesis procedures.
In these reactions, it is also possible to make use of variants
which are themselves known to those of ordinary skill in this art,
but are not mentioned in greater detail. Furthermore, other methods
for preparing compounds of the invention will be readily apparent
to the person of ordinary skill in the art in light of the
following reaction schemes and examples. Unless otherwise
indicated, all variables are as defined above. The following
reaction schemes and examples serve only to illustrate the
invention and its practice.
GENERAL SCHEMES
##STR00075##
[0334] The synthesis of analogs containing the 4-azaindole core can
be accomplished starting from a suitably protected
2-amino-5-nitropyridine 2, which can then be reduced by catalytic
hydrogenation in order to convert the resulting free amino group to
its hydrazine by the action of NaNO.sub.2 and SnCl.sub.2. The
resulting pyridylhydrazine can be condensed with a ketone then
subjected to Fisher indole cyclization conditions to afford the
indole 6. Acidic deprotection of the acetyl groups can be
accomplished by using a strong acid to liberate the diamine, which
can be selectively coupled on the more reactive aniline nitrogen
using standard coupling agents, such as HATU. The aminopyridine
group can then be acylated with a reagent, such as acetyl chloride
or a carboxylic acid, in the presence of an amide bond-forming
reagent.
##STR00076##
[0335] 2-Bromo-3-aminopyridines can be coupled to a terminally
substituted alkyne using standard Sonagashira coupling procedures
to give intermediates 5, which can undergo TFAA-mediated
cyclization to provide the 4-azaindole compounds 6. Protecting
groups can be removed with a strong acid, such as aqueous HCl, and
the resulting amine can be acylated using an appropriately
substituted carboxylic acid and an amide bond forming reagent, such
as HATU.
##STR00077##
[0336] The synthesis of scaffolds B containing a 6-azaindole core
can be accomplished by the metallation of the 4-methylpyridine
analog 2 with a strong base, such as BuLi, and quenching the
resulting anion with the acylating agent, such as 3. Intermediate 4
can be globally deprotected by the action of a strong acid, such as
HBr, to give the diamino azaindole structure 5. Both amino groups
can be acylated using an appropriately substituted carboxylic acid
and an amide bond forming reagent, such as HATU. Compounds 6 can be
further functionalized at the C-3 indole position with
electrophiles, such as NCS.
##STR00078##
[0337] Iodo aminopyridines 2 can be coupled to a terminally
substituted alkyne using standard Sonagashira coupling procedures
to give intermediates 5, which can undergo a base-mediated
cyclization using a reagent, such as KOtBu, to provide the
7-azaindole compounds 4. Protecting groups can be removed with a
strong acid, such as aqueous HCl, and the resulting amine can be
acylated using an appropriately substituted carboxylic acid and an
amide bond forming reagent, such as HATU. Compounds 6 can then be
reduced using hydrogen and a catalyst then coupled a second time
with a carboxylic acid and HATU to provide 8. Treatment of 8 with
an electrophilic agent, such as NCS, provides the desired
compounds.
##STR00079## ##STR00080##
[0338] Compounds in the D series can be synthesized by reacting
dicarbonyl intermediate 2 with a 2-aminopyrimidine derivative in
the presence of a Lewis acid, such as boron trifluoride etherate.
The resulting heterocycle can be alkylated with a bromoketone
analog of an amino acid, such as proline, in the presence of a
tertiary amine base. The nitro group can be reduced, and the
resulting aniline can be acylated using an appropriately
substituted carboxylic acid and an amide bond forming reagent, such
as HATU, to give the final products.
##STR00081## ##STR00082##
[0339] Scaffold E-1 can be prepared by the condensing a benzoic
acid derivative, such as 1, with a phenylenediamine counterpart 2
in the presence of a dehydrating agent, such as polyphosphoric
acid. The resulting aniline can be acylated using an appropriately
substituted carboxylic acid, such as N-Boc-L-proline, and an amide
bond-forming reagent, such as HATU, and can then be subjected to
acidic conditions to remove the Boc group. Compounds 4 can be
coupled again with an appropriately substituted carboxylic acid and
an amide bond-forming reagent, such as HATU. The nitro group in 5
can be reduced under catalytic hydrogenating conditions, and the
resulting aniline can be further coupled with various amines to
give the target compounds.
##STR00083##
[0340] Scaffold E-2 can be prepared by the reacted with a benzoic
acid derivative with a phenylenediamine analog and an amide
bond-forming reagent, such as HATU, to give amides 3, which can be
cyclodehydrated by heating with a reagent, such as HOAc. The
resulting aniline can be acylated using an appropriately
substituted carboxylic acid and an amide bond-forming reagent, such
as HATU, to give intermediates 5. The nitro group can be reduced
under catalytic hydrogenating conditions, and the resulting aniline
can be sulfonylated with an appropriately substituted sulfonyl
chloride and a tertiary amine base to give the targets.
##STR00084##
[0341] Scaffold F can be prepared by the condensing a benzoic acid
derivative, such as 1, with an amino phenol counterpart 2 in the
presence of a dehydrating agent, such as polyphosphoric acid. The
resulting aniline can be acylated using an appropriately
substituted carboxylic acid, such as N-Boc-L-proline, and an amide
bond-forming reagent, such as HATU, and can then be subjected to
acidic conditions to remove the Boc group. Compounds 4 can be
coupled again with an appropriately substituted carboxylic acid and
an amide bond-forming reagent, such as HATU.
##STR00085##
[0342] Compounds having the benzofuran structure G can be prepared
by reacting an appropriately substituted salicylaldehyde with a
benzyl halide, such as 4-nitrobenzyl bromide, in the presence of a
tertiary amine base to give ethers 2. The benzylic ethers can be
treated with a base, such as DBU, and heated to elevated
temperatures to effect cyclization to the benzofurans 3. The nitro
groups in 3 can be reduced under catalytic hydrogenating
conditions, and the resulting anilines can be coupled with various
carboxylic acids to give the target compounds G-1.
##STR00086##
[0343] For differentially substituted compounds (R, R') having the
benzofuran structure G, the synthesis can be modified by reacting
an appropriately substituted bromo salicylaldehyde with a benzyl
halide, such as 4-nitrobenzyl bromide, in the presence of a
tertiary amine base to give ethers 2. The benzylic ethers can be
treated with a base, such as DBU, and heated to elevated
temperatures to effect cyclization to the benzofurans 3. The aryl
bromide can be converted to the aryl amine by reaction with LHMDS
and a palladium catalyst to provide 4, which can be coupled to an
appropriately substituted carboxylic acid to give 5. The nitro
group in 5 can be reduced under catalytic hydrogenating conditions,
and the resulting aniline can be coupled with a second carboxylic
acid analog to give the target compounds G-2.
##STR00087##
[0344] Appropriately substituted aminopyrimidines can be
cyclodehydrated after acylation with an appropriately substituted
ketone, such as 4'-nitro-2-bromobenzophenone, by 5 heating in a
solvent, such as MeOH, and an acid source, such as HBr. The
resulting heterocyclic nitro compound can be converted to the
aromatic amine by reduction with a reagent, such as SnCl.sub.2. The
final compounds H can be obtained by reacting 4 with an
appropriately substituted carboxylic acid and an amide bond-forming
reagent such as HATU.
##STR00088##
[0345] Compounds in scheme I can be prepared by reacting the
appropriately substituted aminopyridine with
4'-nitro-2-bromobenzophenone by heating in a solvent, such as
acetone, then effecting a cyclodehydration reaction using methanol
and an acid source, such as HBr. The resulting heterocyclic nitro
compound 3 can be converted to the aromatic amine by reduction with
a reagent such as SnCl.sub.2. The final compounds can be obtained
by reacting 4 with an appropriately substituted carboxylic acid and
an amide bond-forming reagent, such as HATU.
##STR00089##
[0346] Compounds in scheme J can be prepared by coupling indole
boronic acids with an appropriately substituted 2-bromoindole, such
as 2, under standard Suzuki conditions. The protecting groups can
be removed with HCl, and the nitro group in 4 can be reduced under
catalytic hydrogenation conditions. The penultimate diamine can be
coupled with an appropriately substituted carboxylic acid and an
amide bond-forming reagent, such as BOP, reagent to give compounds
with the targeted central scaffold.
##STR00090##
[0347] The synthesis of compounds with the indole core scaffold K
can be prepared using standard Fisher indole synthesis protocol
starting for an aryl hydrazine and a ketone such as 2. Conversion
of the aryl bromide to the aryl amine 4 could be effected by the
Pd-catalyzed reaction with LHMDS. The nitro group could be reduced
and the diamine can be coupled with an appropriately substituted
carboxylic acid and an amide bond-forming reagent, such as HATU, to
give compounds with the targeted scaffold.
##STR00091##
[0348] In an alternative procedure indoles K can be prepared
starting from a suitably protected and substituted aminoindole 3.
Lithiation and quenching with a boronate ester affords key
intermediate 4, which can be coupled to an appropriately
substituted aryl or heteroaryl halide to provide targets 5. The Boc
groups can be removed with acid, and the resulting aniline can be
coupled with an appropriately substituted carboxylic acid and an
amide bond-forming reagent, such as HATU. The nitro group in 7 can
be reduced and coupled in a second amide coupling reaction to give
the desired compounds.
##STR00092##
[0349] Tetracyclic indole scaffold L can be prepared as outline in
the scheme above. Cyclization of a carboxylic acid derivative 2
with PPA can provide the ketones 3, which can participate in a
Fischer indole reaction with an appropriately substituted
phenylhydrazine to give 4. The acetamide groups can be deprotected
under acidic conditions and the resulting aryl amines can be
coupled with an appropriately substituted carboxylic acid and an
amide bond-forming reagent, such as HATU, to give compounds with
the targeted scaffold.
##STR00093##
[0350] Scaffold M-1 compounds can be prepared by coupling proline 2
to amino ketone 1 using standard amide bond-forming procedures to
provide 3, which can be cyclized upon heating with ammonium acetate
at elevated temperatures. Intermediate 4 can be coupled to indole
boronic acids, such as using standard Suzuki-type conditions. The
Boc groups can be removed with acid, and the resulting aniline can
be coupled with an appropriately substituted carboxylic acid and an
amide bond-forming reagent, such as HATU. The pyrrolidine
protecting group can be removed under hydrogenating conditions, and
the resulting amine can coupled in a second amide coupling reaction
to give the desired compounds.
##STR00094##
[0351] Scaffold M-2 compounds can be prepared by reacting proline 1
with an anion of 4-ethynylbenzene to give intermediate ketone 2,
which can be cyclized with hydrazine. Intermediate 3 can be coupled
to indole boronic acids, such as using standard Suzuki-type
conditions. The Boc groups can be removed with acid and the
resulting aniline can be coupled with an appropriately substituted
carboxylic acid, and an amide bond-forming reagent such as HATU.
The pyrrolidine protecting group can be removed under hydrogenating
conditions, and the resulting amine can coupled in a second amide
coupling reaction to give the desired compounds.
##STR00095##
[0352] Thiazole analogs of scaffold M can be prepared from the
cyclocondensation reaction of Z-proline thioamide 2 with an
alpha-bromoacetophenone. Products 3 can be processed to the final
compounds using methodology similar to that described in scheme
M-2.
##STR00096##
[0353] Imidazole analogs of scaffold M can be prepared from the
cyclocondensation reaction of Z-proline bromomethyl ketone 1 with
an aromatic amidine derivative. Products 3 can be processed to the
final compounds using methodology similar to that described in
scheme M-2.
##STR00097## ##STR00098##
[0354] Isomeric imidazoles can be prepared starting from a
protected amino acid aldehyde, such as 1, and glyoxal in the
presence of ammonia. Halogenation of the resulting imidazole 2 with
NBS can be followed by a Pd-catalyzed cross coupling reaction with
a functionalized indole boronate ester, such as 4. Deprotection,
reduction and coupling with an appropriately substituted carboxylic
acid and an amide bond-forming reagent, such as HATU, can provide
intermediate compounds 8. A second deprotection/amide-coupling
procedure can provide the targeted M-5 scaffold.
##STR00099## ##STR00100##
[0355] Oxadiazole compounds can be prepared starting from indole
hydrazide 2 and coupling to an amino acid, such as Z-proline.
Cyclodehydration of intermediate 3 can be effected with a reagent,
such as TPP/iodine, to give the desired oxadiazole, which can be
protected on the indole nitrogen with Boc anhydride. Introduction
of the boronic acid functional group activates compound 6 for
coupling with a substituted aryl halide 7 to give intermediate 8.
Removal of the cbz and Boc groups afford the penultimate structure
10, which can be coupled with an appropriately substituted
carboxylic acid and an amide bond-forming reagent to give the
targets M-6.
##STR00101##
[0356] Oxadiazole analogs of scaffold M can be prepared by
cyclocondensation reactions of diarylhydrazine 2. Coupling to
heterocyclic boronic acids using methodology similar to that
described in scheme M-1 can provide the targeted compounds.
##STR00102## ##STR00103##
[0357] Double imidazole containing benzofuran compounds can be
prepared starting from a protected amino acid aldehyde, such as 2,
and glyoxal in the presence of ammonia. Halogenation of the
resulting imidazole 3 with NBS can ultimately provide intermediate
5, which can be coupled to a functionalized boronate ester, such as
11, to provide 12. Deprotection and coupling with an appropriately
substituted carboxylic acid and an amide bond-forming reagent, such
as HATU, can provide the targeted M-8 scaffold.
##STR00104##
[0358] An alternative synthesis of benzofurans can be realized
starting from benzofuran 1, which can be converted to boronate
ester 2, which can then coupled to an appropriately substituted
aryl halide to afford 5. Intermediate 5 can subsequently be
converted to a functionalized boronate ester and converted to the
final products in a manner similar to that described in Scheme
M-8.
##STR00105##
[0359] Benzoxazoles 3 can be prepared starting from a suitable
substituted benzoic acid and an aminophenol, such as 2, in the
presence of polyphosphoric acid. Such products can be converted to
the corresponding boronate esters using standard procedures.
Intermediates 4 can subsequently be coupled to a heterocyclic
halide in the presence of a Pd(II) catalyst to provide compounds 5.
Deprotection and coupling with an appropriately substituted
carboxylic acid and an amide bond-forming reagent, such as HATU,
can provide the targeted M-10 scaffold.
##STR00106##
[0360] The compounds in scheme N-1 can be prepared by heating
hydrazines 1 with ketones 2 in a microwave reactor in a polar
aprotic solvent, such as NMP. The indole acetamides 3 can be
deprotected with strong acid, such as HCl. The resulting aryl
amines can be coupled with an appropriately substituted carboxylic
acid, and an amide bond-forming reagent, such as HATU, to give
compounds of the targeted scaffold.
##STR00107##
[0361] Iodo anilines 1 can be coupled to a terminally substituted
alkyne using standard Sonagashira coupling procedures to give
intermediates 2, which can undergo cyclization using a reagent,
such as indium bromide, to provide the indole compounds 3.
Protecting groups can be removed with a strong acid, such as
aqueous HCl, and the resulting amine can be acylated using an
appropriately substituted carboxylic acid and an amide bond-forming
reagent, such as HATU. Compounds 5 can then be reduced using
hydrogen and a catalyst, then coupled a second time with a
carboxylic acid and HATU to provide the desired compounds.
##STR00108##
[0362] In a slight variation of scheme N-2, iodo anilines 1 can be
coupled to a terminally substituted alkyne using standard
Sonagashira coupling procedures to give intermediates 2, which can
undergo cyclization using a reagent such as palladium
chloride/ferric chloride to provide the indole compounds 3.
Compounds 3 can then be reduced using H.sub.2, and the protecting
group can be removed with a strong acid, such as aqueous HCl, and
the resulting amines can be acylated using an appropriately
substituted carboxylic acid and an amide bond-forming reagent, such
as HATU.
##STR00109##
[0363] Scaffold O can be prepared by reacting a protected proline
compound (such as Cbz) with a phenylenediamine analog and an amide
bond-forming reagent, such as HATU, to give amides 3, which can be
cyclodehydrated by heating with a reagent, such as HOAc. The
resulting benzimidazole can be coupled to an indole boronic acid
derivative using standard Suzuki conditions to provide 5. Removal
of the Boc groups with acid provides 7, which can be acylated using
an appropriately substituted carboxylic acid, such as
Boc-L-proline, and an amide bond-forming reagent, such as HATU, to
give intermediates 7. The Cbz group can be reduced under catalytic
hydrogenating conditions, and the Boc group can be deprotected with
acid to provide penultimate compounds 9. Amide bond formation
between 9 and carboxylic acids afford the targeted compounds.
##STR00110##
[0364] Heterocycles can be halogenated at C-3 by the action of
electrophilic agents, such as N-halosuccinimides, to provide
targets P-1.
##STR00111##
[0365] Heterocycles can be fluorinated at C-3 by the action of
electrophilic fluorinating agents, such as SELECTFLUOR, to provide
targets P-1.
##STR00112##
[0366] C-3 halogenated compounds can be converted to the
corresponding cyano analogs by cyanating agents, such as CuCN.
##STR00113##
[0367] The compounds in scheme P-4 can be functionalized by the
acylating indoles with Grignard reagents and zinc chloride.
##STR00114## ##STR00115##
[0368] The compounds in scheme P-5 can be functionalized by
deprotonating the indoles with a base such as ethylmagnesium
bromide and treating the resulting intermediate with chlorosulfonyl
isocyanate. Alternatively, the indoles 3 can be prepared using
Vilsmeier-Haack conditions, which can subsequently be protected and
coupled under Suzuki conditions to give intermediates 5. The
aldehydes can be oxidized using standard methodology for carboxylic
acid formation. Indole carboxylic acids 6 can be coupled to amines
using a reagent, such as HATU, to give 7, which can be further
functionalized by reduction of the nitro group, deprotection of the
Boc group and coupling of the anilines to an appropriately
substituted carboxylic acid and an amide bond-forming reagent, such
as HATU.
##STR00116##
[0369] C-3 halogenated compounds can be coupled to a variety of
alkyl and aryl boronic acids using standard Suzuki conditions.
##STR00117##
[0370] Compounds of scheme Q can be prepared starting from the
lactam 1. Reaction with ethyl chloroformate and treatment of the
product with a mild base, such as ammonium carbonate, provides
intermediate 3, which can be activated for coupling by conversion
to the corresponding vinyl triflate 4. Sonagashira coupling
provides compounds 5, which can be reduced with iron and ammonium
chloride to provide aniline 6. Deprotection of the indole and
coupling of the aniline to an appropriately substituted carboxylic
acid and an amide bond-forming reagent, such as HATU, provides the
desired targets.
##STR00118##
[0371] Amide coupling of the aniline from scheme K-1 with an
appropriately substituted carboxylic acid and a coupling agent can
provide intermediates 2, which can then be subjected to
Pd-catalyzed cross-coupling reactions to provide the final targets
R.
##STR00119##
[0372] Compounds in scheme S can be prepared by coupling indole
boronic acids with an appropriately substituted
2-bromobenzoxazoles, such as 5, under standard Suzuki conditions.
The nitro group in 6 can be reduced under catalytic hydrogenation
conditions and the protecting groups can be removed with HCl. The
penultimate diamine can be coupled with an appropriately
substituted carboxylic acid and an amide bond-forming reagent, such
as BOP, reagent to give compounds with the targeted central
scaffold.
##STR00120##
[0373] Compounds in scheme T can be prepared by starting from a
suitably substituted phenol 3 and a hydrazine reagent, such as 4,
using established Fisher indole conditions. The indole 3 position
can then be functionalized or the indole NH can be cyclized onto
the C-2 aromatic ring using standard conditions to give tetracycles
8, which can subsequently be converted to the corresponding
boronate esters using standard procedures. Intermediates 9 can then
be coupled to a heterocyclic halide in the presence of a Pd(II)
catalyst to provide compounds 10. Deprotection and coupling with an
appropriately substituted carboxylic acid and an amide bond-forming
reagent, such as HATU, can provide the targeted T scaffold.
[0374] The following examples serve only to illustrate the
invention and its practice. The examples are not to be construed as
limitations on the scope or spirit of the invention.
LIST OF ABBREVIATIONS
[0375] Ac.sub.2O Acetic anhydride [0376] B(OiPr).sub.3,
(iPrO).sub.3B Triisopropyl borate [0377] B(OMe).sub.3 Trimethyl
borate [0378] BF.sub.3 Boron trifluoride [0379] BOC, Boc, boc
tert-Butyloxycarbonyl [0380] BOP
Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate [0381] BrCN Cyanogen bromide [0382] BuLi,
n-BuLi Butyl lithium [0383] CBZ, Cbz, cbz Benzyloxycarbonyl [0384]
CDCl.sub.3 Deuterio-trichloromethane [0385] CH.sub.3CN, MeCN
Acetonitrile [0386] Cs.sub.2CO.sub.3 Cesium carbonate [0387]
CuBr.sub.2 Copper(II) bromide [0388] CuCN Copper(I) cyanide [0389]
CuI Copper iodide [0390] DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene
[0391] DCE Dichloroethane [0392] DCM, CH.sub.2Cl.sub.2
Dichloromethane [0393] DIPEA, DIEA Diisopropylethylamine [0394]
DMAP 4-Dimethylamino pyridine [0395] DMF Dimethylformamide [0396]
DMSO Dimethyl sulfoxide [0397] DPPF, Dppf, dppf
1,1'-bis(Diphenylphosphino)ferrocene [0398] EDC, EDCI
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide [0399] Et.sub.2O
Diethyl ether [0400] Et.sub.3N, TEA Triethylamine [0401] EtMgBr
Bromo(ethyl)magnesium or ethyl magnesium bromide [0402] EtOAc Ethyl
acetate [0403] EtOH Ethanol [0404] FeCl.sub.3 Ferric chloride or
Iron(III) chloride [0405] H.sub.2 Hydrogen or hydrogen atmosphere
[0406] H.sub.2O Water [0407] H.sub.2SO.sub.4 Sulfuric acid [0408]
HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0409] HBr Hydrobromic acid [0410] HCl
Hydrochloric acid [0411] HNO.sub.3 Nitric Acid [0412] HOAc, HAc
Acetic acid [0413] HOBT, HOBt 1-Hydroxy benzotriazole [0414] HPLC
High performance liquid chromatography [0415] InBr.sub.3 Indium
tribromide [0416] iPr.sub.2NH Diisopropylamine [0417]
K.sub.2CO.sub.3 Potassium carbonate [0418] KI Potassium iodide
[0419] KIO.sub.3 Potassium iodate [0420] KOAc, AcOK Potassium
acetate [0421] KOH Potassium hydroxide [0422] LDA Lithium
diisopropylamide [0423] LHMDS, LiHMDS Lithium hexamethyldisilamide
[0424] MeMgBr Bromo(methyl)magnesium or methyl magnesium bromide
[0425] MeOD Methan(.sup.2H)ol [0426] MeOH, CH.sub.3OH Methanol
[0427] MgSO.sub.4 Magnesium sulfate [0428] MOC, Moc Methoxy
carbonyl [0429] MS Mass spectroscopy [0430] N.sub.2 Nitrogen or
nitrogen atmosphere [0431] Na.sub.2CO.sub.3 Sodium carbonate [0432]
Na.sub.2SO.sub.4 Sodium sulfate (anhydrous) [0433] NaClO.sub.2
Sodium perchlorate [0434] NaH.sub.2PO.sub.4 Dihydrogen sodium
phosphate [0435] NaHCO.sub.3 Sodium hydrogen carbonate (sodium
bicarbonate) [0436] NaNO.sub.2 Sodium nitrite [0437] NaOH Sodium
hydroxide [0438] NBS N-bromosuccinimide [0439] NCS
N-chlorosuccinimide [0440] NH.sub.4OAc Ammonium acetate [0441] NMM
N-methylmorpholine [0442] NMR, .sup.1H-NMR Proton nuclear magnetic
resonance spectroscopy [0443] NXS N-halosuccinimide [0444]
P.sub.2O.sub.5, P.sub.4O.sub.10 Phosphorus pentoxide [0445] Pd
Palladium [0446] Pd(dppf)Cl.sub.2
Dichloro(1,1'-bis(Diphenylphosphino)ferrocene) palladium(II) [0447]
Pd(II) Palladium(II) [0448] Pd(PPh.sub.3).sub.2Cl.sub.2,
PdCl.sub.2(PPh.sub.3).sub.2
Dichlorobis(triphenylphosphine)palladium(II) [0449]
Pd(PPh.sub.3).sub.4 Tetrakis(triphenylphosphine)palladium(0) [0450]
Pd/C, Pd--C Palladium on carbon [0451] Pd.sub.2(dba).sub.3
Tris(dibenzylidene acetone)dipalladium(0) [0452] PdCl.sub.2
Palladium(II) chloride [0453] PE Petroleum ether [0454] Phg
Phenylglycine [0455] PhCH.sub.3, PhMe Toluene [0456] Piv Pivaloyl
[0457] PivCl Pivaloyl chloride [0458] POBr.sub.3 Phosphorus
oxybromide [0459] PPA Polyphosphoric acid [0460] PPH.sub.3, TPP
Triphenylphosphine [0461] Pro Proline [0462] Proc
iso-Propylcarbamate [0463] P.sup.tBu.sub.3 Tri-tert-butyl phosphine
[0464] Py Pyradine [0465] PyBOP
(Benzotriazole-1-yl-oxy)-tripyrrolidinophosphonium
hexafluorophosphate [0466] RPLC Reverse phase liquid chromatography
[0467] RT, rt, r.t. Room temperature, approximately 25.degree. C.
[0468] SiO.sub.2 Silica or silica gel [0469] SnCl.sub.2 Stannous
chloride or Tin(II) chloride [0470] SOCl.sub.2 Thionyl chloride
[0471] STP Standard temperature and pressure [0472] t-BuLi
tert-Butyl lithium [0473] t-BuNO.sub.2 tert-Butyl nitrate [0474]
t-BuOH tert-Butanol [0475] t-BuOK, KOt-Bu Potassium tert-butoxide
[0476] TFA Trifluoroacetic acid [0477] TFAA Trifluoroacetic
anhydride [0478] THF Tetrahydrofuran [0479] TLC Thin layer
chromatography [0480] ZnCl.sub.2 Zinc chloride
EXAMPLES
Example 1
N-{4-[5-(acetylamino)-1H-pyrrolo[3,2-b]pyridin-2-yl]phenyl}-1-(phenylacety-
l)-L-prolinamide
##STR00121##
[0481] Step 1
##STR00122##
[0483] To a suspension of 2-amino-5-nitropyridine (25.0 g, 0.18
mol) and 0.5 g of DMAP in 200 mL of pyridine, Ac.sub.2O (37 g, 0.36
mol) was added drop wise at 0.degree. C. The mixture was stirred at
RT for 5 hours. The volatile was removed in vacuo. The residue was
washed with EtOAc to yield an off-white solid (28 g, 86%). MS (ESI)
m/e (M+H.sup.+): 182.
Step 2
##STR00123##
[0485] A heterogeneous mixture of 2-acetamido-5-nitropyridine (28
g, 0.15 mol) and 10% Pd/C (2.8 g) in 300 mL of MeOH was stirred in
50 psi of H.sub.2 for 6 hours. The mixture was filtered through
CELITE, and concentrated in vacuo to yield a solid (20.5 g). MS
(EST) m/e (M+H.sup.+): 152.
Step 3
##STR00124##
[0487] NaNO.sub.2 (5.4 g, 78.2 mmol) was added slowly to a solution
of 2-acetamido-5-aminopyridine (9.0 g, 60 mmol) in 6 M aqueous HCl
(300 mL) at 0.degree. C. and was stirred for 45 minutes. A solution
of SnCl.sub.2 (40.5 g, 180 mmol) in 15 mL of 6 M aqueous HCl was
added, and the reaction mixture was allowed to warm to RT slowly
while stirring for 16 hours. The reaction mixture was basified with
40 percent aqueous KOH, extracted with EtOAc (3.times.), and the
organic layers are combined, dried over Na.sub.2SO.sub.4 and
concentrated in vacuo to give the desired compound (3.2 g). MS
(ESI) m/e (M+H.sup.+): 167.
Step 4
##STR00125##
[0489] A suspension of the product from step 3 (3.32 g, 20 mmol)
and N-(4-acetylphenyl)acetamide (3.54 g, 20 mmol) in 8 mL of EtOH
was diluted with TEA to adjust the pH to about 9.5. The resulting
reaction mixture was refluxed for 3 hours. The solvent was removed
in vacuo, and the resulting residue was treated with 5% aqueous
citric acid to form a precipitate. The precipitate was filtrated,
washed with water and dried in vacuo (3.2 g). MS (ESI) m/e
(M+H.sup.+): 326.
Step 5
##STR00126##
[0491] A mixture of the product from step 4 above (0.6 g, 1.8 mmol)
and PPA (5 mL) was heated to 90.degree. C. for 75 minutes under
N.sub.2. After cooling to RT, the reaction mixture was poured to an
ice water, neutralized with solid NaOH, while maintaining the
temperature of the mixture at or below RT. A solution of
iso-propanol and DCM (1:3) was added to exact the organic. The
combine organic phase was washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was
purified by preparative HPLC to yield a solid (280 mg). MS (ESI)
m/e (M+H.sup.+): 309.
Step 6
##STR00127##
[0493] A mixture of the 4-azaindole (280 mg, 0.9 mmol) in 10 mL of
3 N HCl was refluxed for 2 hours. The solvent was removed in vacuo.
The residue was purified by HPLC to yield a solid (120 mg). MS
(ESI) m/e (M+H.sup.+): 225.
Step 7
##STR00128##
[0495] To a suspension of the product from step 6 (23 mg, 0.1
mmol), acid (23 mg, 0.1 mmol) and DIPEA (20 mg, 0.15 mmol) in 1 mL
of CH.sub.3CN was added HATU (42 mg, 0.12 mmol). The resulting
mixture was stirred at RT overnight. After reaction completed, the
mixture was purified by pre-HPLC (10 mg). MS (ESI) m/e (M+H.sup.+):
440.
Step 8
##STR00129##
[0497] A mixture of product from step 7 (10 mg, 0.023 mmol) and TEA
(3 g, 0.03 mmol) in CH.sub.3CN (100 mL) was stirred at 0.degree. C.
Acetyl chloride (2 mg, 0.023 mmol) was added dropwise, and the
resulting mixture was stirred at RT for 0.5 hour. The solvent was
evaporated in vacuo, and the residue was purified by preparative
HPLC to afford the desired product (5 mg). MS (ESI) m/e
(M+H.sup.|): 482. .sup.1H NMR (MeOD): .delta. 8.25 (d, J=8.4 Hz,
1H), 7.74.about.7.89 (m, 4H), 7.26.about.7.32 (m, 5H),
7.00.about.7.02 (m, 2H), 4.63 4.64 (m, 1H), 3.72 3.84 (m, 4H), 2.18
2.33 (m, 2H), 2.07.about.2.10 (m, 5H).
Examples 2-3
[0498] The compounds of Examples 2 and 3 were prepared in a similar
manner starting from intermediate 7 in step 6.
TABLE-US-00001 Ex- am- ple Structure MW Name 2 ##STR00130## 654.776
(2S)-1- (phenyl- acetyl)- N-{2-[4- ({[(2S)- 1-(phenyl- acetyl)
pyrrolidin-2- yl]carbonyl} amino) phenyl]- 1H-pyrrolo [3,2-b]pyri-
din-5-yl} pyrrolidine- 2- carboxamide 3 ##STR00131## 686.774 benzyl
(2S)- 2-[(2- {4-[({2S)-1- [(benzyloxy) carbonyl] pyrrolidin-2-
yl}carbonyl) amino] phenyl}-1H- pyrrolo [3,2-b] pyridin-5-yl)
carbamoyl] pyrrolidine- 1- carboxylate
Example 4
tert-butyl
{(1S)-2-[(2S)-2-{[4-(5-bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)phen-
yl]carbamoyl}pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate
##STR00132##
[0499] Step 1
##STR00133##
[0501] NBS (14.9 g, 84 mmol) was added portion wise to a solution
of compound 3-aminopyridine (14.9 g, 84 mmol) in DMSO (80 mL) and
water (20 mL) at 0.degree. C., and the reaction was stirred at RT
for 3 hours. The mixture was poured into ice-water (250 mL) and
stirred for 30 minutes. The precipitate was collected and dried to
yield a solid (7.0 g). MS (ESI) m/e (M+H.sup.+): 250. .sup.1H NMR
(DMSO): .delta. 7.28 (d, J=7.6 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H),
5.69 (s, 2H).
Step 2
##STR00134##
[0503] 4-Ethynylacetanilide was prepared using the similar method
shown in Example 1, step 1. MS (ESI) m/e (M+H.sup.+): 160.
Step 3
##STR00135##
[0505] To a solution of 3-amino-2,6-dibromopyridine (9.41 g, 37.5
mmol), 4-ethynylacetanilide (4.77 g, 30 mmol) and
Pd(PPh.sub.3).sub.2Cl.sub.2 (1.31 g, 1.9 mmol) in a mixture of 150
mL of Et.sub.3N and 50 mL of DMF was added CuI (0.71 g, 0.4 mmol)
under N.sub.2. The resulting mixture was stirred at RT overnight.
The solvent was removed, and the residue was purified by
chromatography (8.5 g). MS (ESI) m/e (M+H.sup.+): 331. .sup.1HNMR
(DMSO): .delta. 7.59 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H),
7.21 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 2.12 (s, 3H).
Step 4
##STR00136##
[0507] To a 0.degree. C. solution of the product from step 3 (8.5
g, 25.7 mmol) and pyridine (4.0 g, 51.4 mmol) in 50 mL of
1,4-dioxane was added TFAA (10.8 g, 51.4 mmol). The resulting
mixture was then heated to 100.degree. C. overnight. The mixture
was cooled and poured into 200 mL of water, and the precipitate was
filtered and washed by water then dried to give a solid (1.3 g). MS
(ESI) m/c (M+H.sup.+): 331.
Step 5
##STR00137##
[0509] The reaction was conducted similar to that describe in
Example 1, step 6. MS (ESI) m/e (M+H+): 288.
Step 6
##STR00138##
[0511] To a suspension of the product from step 5 (0.1 mmol),
N-Boc-L-Phg-L-Pro-OH (0.1 mmol) and DIPEA (20 mg, 0.15 mmol) in 1
mL of CH.sub.3CN was added HATU (42 mg, 0.12 mmol). The resulting
mixture was stirred at RT overnight, concentrated and purified by
RPLC to give the desired compound. MS (ESI) m/e (M+H.sup.+): 619.
.sup.1H NMR (MeOD 400) .delta.: 7.85.about.7.77 (m, 5H),
7.43.about.7.36 (m, 6H), 6.89 (s, 1H), 5.50 (s, 1H), 4.54 (d, J=8.0
Hz 1H), 3.93 (t, 1H), 2.10.about.1.87 (m, 4H) 1.41 (s, 9H).
Example 5
(2S)--N-{3-chloro-2-[4-({[(2S)-1-(phenylacetyl)pyrrolidin-2-yl]carbonyl}am-
ino)
phenyl]-1H-pyrrolo[2,3-c]pyridin-5-yl}-1-(phenylacetyl)pyrrolidine-2--
carboxamide
##STR00139##
[0512] Step 1
##STR00140##
[0514] A heterogeneous mixture of 2-amino-4-methyl-5-nitropyridine
(4.15 g, 27 mmol) and 10% Pd/C (0.4 g) in 50 mL of THF was stirred
in 50 psi of H.sub.2 for 3 hours. The mixture was filtered through
CELITE and concentrated to yield a yellow solid (3.20 g). MS (ESI)
m/e (M+H.sup.+): 124. .sup.1H NMR (DMSO): .delta. 7.38 (s, 1H),
6.16 (s, 1H), 4.84 (s, 2H), 4.06 (s, 2H), 1.96 (s, 3H).
Step 2
##STR00141##
[0516] A mixture of diamine from step 1 (3.20 g, 26 mmol), TEA
(5.25 g, 52 mmol) and a catalytic amount of DMAP in THF (100 mL)
was stirred at 5-10.degree. C., then treated with pivaloyl chloride
(3.74 g, 31 mmol). The resulting mixture was stirred at RT for 5
hours, diluted with a 5% solution of citric acid, and extracted
with EtOAc. The combined organic extracts were sequentially washed
with water and brine, dried, filtered, and the filtrate was
concentrated in vacuo to yield a residue. The residue was purified
by column chromatography on silica gel to afford 7.4 g of the
desired compound. MS (ESI) m/e (M+H.sup.+): 292. .sup.1H NMR
(CDCl.sub.3): .delta. 8.77 (s, 1H), 8.47 (s, 1H), 8.20 (s, 1H),
7.15 (s, 1H), 2.24 (s, 3H), 1.30.about.1.32 (m, 18H).
Step 3
##STR00142##
[0518] To a cooled solution of 4-nitrobenzoic acid (12 g, 72 mmol)
in 50 mL of PhMe was added 20 mL of SOCl.sub.2 drop wise. After the
addition, the suspension was heated to reflux for 4 hours. The
solvent was removed, and the residue was azeotroped with 50 mL of
PhMe to afford 14.5 g of crude acid chloride. To a solution of TEA
(101 g, 100 mmol), a catalytic amount of DMAP and N,
O-dimethylhydroxylamine (5.3 g, 87 mmol) in 100 mL of DCM was added
drop wise 14.5 g of the freshly prepared acid chloride in 100 mL of
DCM. The resulting mixture was stirred at RT for 5 hours, then
diluted with a 5% solution of citric acid, and extracted with DCM.
The combined organic extracts were sequentially washed with water
and brine, dried and filtered, and the filtrate was concentrated to
yield a residue. The residue was purified by column chromatography
on silica gel to afford 7.0 g of the Weinreb amide. MS (ESI) m/e
(M+H.sup.+): 211. .sup.1H NMR (CDCl.sub.3): .delta. 8.25 (d, J=8.8
Hz, 2H), 7.82 (d, J=9.6 Hz, 2H), 3.52 (s, 3H), 3.82 (s, 3H).
Step 4
##STR00143##
[0520] A heterogeneous mixture of the nitro compound above and 10%
Pd/C in THF was stirred at STP with a balloon of H.sub.2 for 3
hours. The mixture was filtered through CELITE, and concentrated to
yield a yellow solid MS (ESI) m/e (M+H.sup.+): 181.
Step 5
##STR00144##
[0522] The product from step 4 was pivaloylated using conditions
described in step 2. MS (ESI) m/e (M+H.sup.+): 265. .sup.1H NMR
(CDCl.sub.3): .delta. 7.66 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.8 Hz,
2H), 3.51 (s, 3H), 3.32 (s, 3H).
Step 6
##STR00145##
[0524] A solution of compound isolated from step 2 above (2.2 g,
7.5 mmol) in 15 mL of THF was cooled to below -40.degree. C. t-BuLi
in hexane (15 mL, 2.5 M, 37.5 mmol) was added dropwise, and the
resulting solution was stirred at -40.degree. C. for 1 hour. A
solution of compound from step 5 (2.2 g, 8.25 mmol) in 10 mL of THF
was added drop wise, and the resulting solution was continued to
stir at this temperature for 30 minutes before being warmed to RT
and stirred for 30 minutes again. An aqueous 5% citric acid
solution was added to quench the reaction, which was extracted with
DCM (.times.3), and the combined organic layers were washed with
water and brine, dried over Na.sub.2SO.sub.4 and concentrated in
vacuo. The residue was purified by preparative HPLC to yield a
solid (0.4 g). MS (ESI) m/e (M+H.sup.+): 495. .sup.1H NMR
(CDCl.sub.3): .delta. 8.85 (s, 1H), 8.68 (s, 1H), 8.26 (s, 1H),
8.03.about.8.05 (m, 3H), 7.21 (d, J=8.8 Hz, 2H), 7.53 (s, 1H), 4.20
(s, 2H), 1.33.about.1.29 (m, 27H).
Step 7
##STR00146##
[0526] A solution of the product from step 6 (400 mg, 0.8 mmol) in
33% aqueous HBr (15 mL) was refluxed overnight. After cooling, the
mixture was concentrated in vacuo. The residue was purified by
preparative HPLC to give a solid (120 mg). MS (ESI) m/e
(M+H.sup.+): 225. .sup.1H NMR (MeOD): .delta. 8.04 (s, 1H), 7.78
(d, 2H), 7.04 (d, 2H), 6.86 (s, 1H), 6.71 (s, 1H).
Step 8
##STR00147##
[0528] The product from step 7 was coupled to 2 equivalents of
N-phenylacetyl-L-proline using 2 equivalents of HATU and DIEA in a
manner similar to that shown in Example 1. MS (ESI) m/e
(M+H.sup.+): 687. .sup.1H NMR (MeOD): .delta. 8.49.about.8.57 (m,
1H), 7.38.about.7.45 (m, 2H), 7.72.about.7.80 (m, 2H),
5.15.about.5.20 (m, 4H), 4.42.about.4.50 (m, 2H), 3.57.about.2.59
(m, 4H), 2.31.about.2.42 (m, 4H), 1.89.about.2.15 (m, 6H).
Step 9
##STR00148##
[0530] To a solution of product from step 8 (15 mg, 0.02 mmol) in 2
mL of dry THF was added NCS (2 mg, 0.015 mmol). The resulting
mixture was stirred at RT for 30 minutes. The solvent was
evaporated, and the residue was purified by prep HPLC to give 5 mg
of the desired product. MS (ESI) m/e (M+H.sup.+): 689. .sup.1H NMR
(MeOD): .delta. 8.53 (s, 1H), 7.91 (d, J=9.2 Hz, 2H), 7.77 (d,
J=8.8 Hz, 2H), 7.49 (s, 1H), 7.20.about.7.23 (m, 10H),
4.53.about.4.59 (m, 2H), 3.64.about.3.79 (m, 8H), 1.98.about.2.25
(m, 8H).
Example 6
(2S)--N-{3-chloro-2-[4-({[(2S)-1-(phenylacetyl)pyrrolidin-2-yl]carbonyl}am-
ino)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-1-(phenylacetyl)pyrrolidine-2-c-
arboxamide
##STR00149##
[0531] Step 1
##STR00150##
[0533] 2-Amino-5-nitropyridine (7.00 g, 50.0 mmol) was dissolved in
H.sub.2SO.sub.4 (2 M, 100 mL). Potassium iodate (4.28 g, 20 mmol)
was added portion at RT with stirring. The solution was heated to
100.degree. C. under reflux. Potassium iodide (8.00 g, 48.2 mmol)
was added drop wise over 1 hour as a solution in water (20 mL). A
brown solution resulted, with solid iodine collecting in the reflux
condenser. Heating at reflux was continued for 30 minutes, and the
mixture was cooled to RT. The mixture was adjusted to pH 7 with the
careful addition of solid NaHCO.sub.3. The mixture was diluted with
water (200 mL) and CH.sub.2Cl.sub.2 (250 mL) was added. Solid
sodium thiosulfate was added with vigorous stirring until the
iodine coloration had been disappeared. A significant amount of
yellowish solid remained out of solution, which was collected by
filtration, washed with water and dried to give a yellow solid
(10.5 g). The CH.sub.2Cl.sub.2 fraction was filtered through a
silicone-treated filter paper and evaporated to give a yellow solid
(2.4 g). The solids were combined to give the desired iodopyridine
(12.7 g). MS (ESI) m/e (M+H.sup.+): 266. .sup.1H NMR (DMSO):
.delta. 8.89 (s, 1H), 8.62 (s, 1H), 7.75 (bs, 1H).
Step 2
##STR00151##
[0535] A solution of the iodide (1.05 g, 4.8 mmol),
4-ethynylacetanilide (636 mg, 4.0 mmol) and
Pd(PPh.sub.3).sub.2Cl.sub.2 (76 mg, 0.4 mmol) in 10 mL of Et.sub.3N
and 5 mL of DMF was stirred at RT over 17 hours under N.sub.2. The
solvent was removed, and the residue was purified by column
chromatography to give the product (0.9 g). MS (ESI) m/e
(M+H.sup.+): 297. .sup.1H NMR (DMSO): .delta. 10.11 (s, 1H), 8.80
(s, 1H), 8.22 (s, 1H), 7.59 (s, 1H), 2.01 (s, 3H).
Step 3
##STR00152##
[0537] To a solution of the product from step 2 (730 mg, 2.5 mmol)
in 3 mL of THF and 6 mL of DMF was added t-BuOK (580 mg, 5.25
mmol). The resulting mixture was heated to 70.degree. C. for 6
hours. The solvent was removed and 10 mL of DCM, 5 mL of water was
added, and the resulting precipitate was filtered to give the
desired product as a yellow solid (680 mg). MS (ESI) m/e
(M+H.sup.+): 297. .sup.1H NMR (DMSO): .delta. 10.11 (s, 1H), 8.96
(s, 1H), 8.65 (s, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.8 Hz,
2H), 6.98 (s, 1H), 2.02 (s, 3H).
Step 4
##STR00153##
[0539] The synthetic method for the removal of the acetyl group was
the same as used in Example 1, step 6. MS (ESI) m/e (M+H.sup.+):
285.
Step 5
##STR00154##
[0541] The synthetic method used for the coupling of the proline
analog to the aniline prepared in step 4 was the same as used in
Example 1, step 7. MS (ESI) m/e (M+H.sup.+): 470.
Step 6
##STR00155##
[0543] A heterogeneous mixture of product from step 6 (20 mg, 0.04
mmol) and 10% Pd/C in 5 mL of MeOH was stirred in 10 psi of H.sub.2
for 3 hours. The mixture was filtered through CELITE, and
concentrated in vacuo to yield a yellow solid (17 g). MS (ESI) m/e
(M+H.sup.+): 440.
Step 7
##STR00156##
[0545] The product from step 6 was coupled to 1 equivalent of
N-phenylacetyl-L-proline using 1 equivalent of HATU and DIEA in a
manner similar to that shown in Example 1. MS (ESI) m/e
(M+H.sup.+): 655. .sup.1H NMR (MeOD): .delta. 8.26 (s, 1H), 8.19
(s, 1H), 7.30.about.7.51 (m, 3H), 7.18.about.7.27 (m, 1H), 6.65 (s,
1H), 4.51.about.4.56 (m, 2H), 3.61.about.3.76 (m, 8H),
1.95.about.2.15 (m, 8H).
Step 8
##STR00157##
[0547] To a solution of product from step 7 (30 mg, 0.04 mmol) in 4
mL of dry THF was added NCS (4 mg, 0.03 mmol). The resulting
mixture was stirred at RT for 30 minutes. The solvent was
evaporated, and the residue was purified by prep HPLC to give the
desired product. MS (ESI) m/e (M+H.sup.+): 690. .sup.1H NMR (MeOD):
.delta. 8.29 (s, 1H), 8.20 (s, 1H), 7.81.about.7.84 (m, 2H),
7.66.about.7.69 (m, 2H), 7.18.about.7.29 (m, 10H), 4.52.about.4.55
(m, 2H), 3.62.about.3.78 (m, 8H), 1.90.about.2.29 (m, 8H).
Example 7
N-[4-(3-oxo-7-{2-oxo-2-[(2S)-1-(phenylacetyl)pyrrolidin-2-yl]ethyl}-3,7-di-
hydroimidazo[1,2-a]pyrazin-2-yl)phenyl]-1-(phenylacetyl)-L-prolinamide
Step 1
##STR00158##
##STR00159##
[0549] To a stirred solution of 4-nitroacetophenone (20 g, 121
mmol) in 100 ml of DMSO was added slowly 42 m of 48 aqueous HBr
(363 mmol). The solution was stirred in an open flask at 55.degree.
C. and the reaction was followed by TLC. When the starting material
was consumed, the solution was poured into ice. The solid products
were filtered, washed with water, and dried under vacuum at RT over
P.sub.2O.sub.5.
Step 2
##STR00160##
[0551] Arylglyoxal hydrate (5 g, 27.8 mmol) was added in one
portion over a slurry of the heterocyclic amine (2.773 g, 29.2
mmol) in methylene chloride (10 ml). The resulting suspension was
treated with 1 drop of freshly distilled BF.sub.3.Et.sub.2O and
stirred until most of the amine was consumed. The reaction products
were isolated as hydrates by filtration of the thick, intensely
colored reaction mixture. The residue obtained by concentration is
allowed to cool, filtered with suction, washed twice with diethyl
ether and dried under reduced pressure to give the desired product
(4 g). MS (ESI) m/e (M+H.sup.+): 256.
Step 3
##STR00161##
[0553] The N-protected proline (10 g, 42.8 mmol) in dry ether (60
ml) and THF (60 ml) was stirred under argon at -25.degree. C. TEA
(42.8 mol, 4.08 ml) and ethyl chloroformate (42.8 mmol, 2.6 4.14
ml) were added to this solution. The solution was stirred for
further 30 minutes, the temperature then allowed to reach
-10.degree. C., and the diazomethane solution in ether (2-3
equivalents) was added drop wise. The suspension was stirred for an
additional 3 hours and allowed to reach ambient temperature. The
triethylamine hydrochloride was then filtered off, and the filtrate
was evaporated to half of its original volume. The resulting
solution was washed with saturated aqueous NaHCO.sub.3 (50 ml) and
brine (50 ml). The organic layer was dried and evaporated to give a
crude product, which was used without further purification. MS
(ESI) m/e (M+H.sup.+): 258.
Step 4
##STR00162##
[0555] To a solution of a-diazoketone (2 g, 7.78 mmol) in glacial
HOAc (25 ml) was treated with 48% HBr (2.8 ml) drop wise with
stirring. After stirring for 1 hour, the reaction mixture was
extracted with DCM and washed with water. Evaporation of the
solvent and crystallization from ether-pet ether gave the pure
product. MS (ESI) m/e (M+H.sup.+): 310.
Step 5
##STR00163##
[0557] The product from step 4 (420 mg, 1.35 mmol) and the
heterocycle from step 2 (347 mg, 1.35 mmol) in THF (2 ml) were
stirred at RT overnight with Et.sub.3N (0.3 mL). When the reaction
was completed, the mixture was concentrated, and the residue was
purified by RPLC to give the product (300 mg). MS (ESI) m/e
(M+H.sup.+): 486.
Step 6
##STR00164##
[0559] A solution of the product from step 5 (180 mg, 0.371 mmol)
in absolute EtOH (3 ml) was added to stannous chloride dihydrate
(418.6 mg, 1.85 mmol), and the mixture was stirred at 70.degree. C.
for 2 hours. The reaction mixture was cooled to RT and poured into
ice/water (50 ml), and the pH was made strongly alkaline by the
addition of saturated NaOH (100 ml) before being extracted with
EtOAc (2.times.). The organic phase was combined and washed with
brine, dried by MgSO.sub.4, filtered, and concentrated to yield the
crude product (150 mg). MS (ESI) m/z: (M+H.sup.+) 456.
Step 7
##STR00165##
[0561] The mixture of the product from step 6 (30 mg, 0.066 mmol),
N-phenylacetyl-L-proline (46.08 mg, 0.197 mmol), DIPEA (50.1 mg,
0.197 mmol) in CH.sub.3CN (2 mL) was stirred at RT for 5 minutes,
then HATU (74.86 mg, 0.197 mmol) was added into the mixture. The
mixture was stirred at RT overnight, concentrated, and the residue
was purified by RPLC to give the desired compound (20 mg). .sup.1H
NMR (DMSO) .delta.: 9.26 (s, 1H), 8.84-8.86 (m, 2H), 7.79-8.03 (m,
4H), 7.11-7.31 (m, 12H), 4.41.about.4.63 (m, 2H), 3.52.about.3.80
(m, 12H), 2.26.about.2.12 (m, 2H), 1.87.about.1.75 (m, 6H).
Example 8
(2S)-1-(cyclobutylcarbonyl)-N-{2-[4-({[(2S)-1-(pyridin-3-ylcarbonyl)pyrrol-
idin-2-yl]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}pyrrolidine-2-carbox-
amide
##STR00166##
[0562] Step 1
##STR00167##
[0564] p-Aminobenzoic acid (0.200 g, 1.45 mmol) and nitrophenylene
diamine (0.221 g, 1.45 mmol) were added into PPA (30 mL). The
mixture was stirred at 210.degree. C. for 20 minutes. Then, it was
poured into ice water and extracted with DCM. The organic layer was
washed with brine, dried (NaSO.sub.4), filtered and concentrated to
afford 200 mg of the desired compound. MS m/z: 255 (M+1).
Step 2
##STR00168##
[0566] Compound from step 1 above (1.2 g, 4.7 mmol), N-Boc-proline
(1.52 g, 7.07 mmol), EDCI (1.8 g, 9.44 mmol), HOBT (1.27 g, 9.44
mmol) and DIPEA (2.4 g, 18.8 mmol) were taken in DMF (30 mL) and
stirred for overnight at RT. DMF was removed under reduced
pressure, and the residue was extracted with DCM/water. The organic
layer was washed with brine, dried (NaSO.sub.4), concentrated and
purified by column (DCM: MeOH/100:1) to afford 1.2 g of the desired
compound. .sup.1H NMR (MeOD) .delta. 8.49 (s, 1H), 8.28-8.19 (m,
3H), 7.79-7.76 (d, J=4.4 Hz, 2H), 7.72-7.65 (m, 1H), 4.41-4.29 (t,
J=8.8 Hz, 1H), 3.59-3.51 (m, 2H), 2.18-1.95 (m, 4H), 1.49 (s,
9H).
Step 3
##STR00169##
[0568] Compound from step 2 (0.600 g, 1.06 mmol) was stirred in
MeOH/HCl (10 mL) for 1 hour at RT, and solvent was removed under
reduced pressure. The resulting compound was dried at high vacuum
to afford 370 mg of desired compound.
Step 4
##STR00170##
[0570] The product from step 3 (0.370 g, 1.052 mmol),
pyridine-3-carboxylic acid (0.157 g, 1.27 mmol), HATU (1.2 g, 3.18
mmol) and DIPEA (0.814 g, 6.36 mmol) were taken in DMF (10 mL) and
stirred for overnight at RT. DMF was removed under reduced
pressure, and the residue was extracted with DCM/water. The organic
layer was washed with brine, dried (NaSO.sub.4), concentrated and
purified by column (DCM: MeOH/100:1) to afford 300 mg of desired
compound. .sup.1H NMR (MeOD) .delta. ppm: 0.883 (s, 1H), 0.87-0.85
(d, J=4.4 Hz, 1H), 8.49 (s, 1H), 8.21-8.18 (m, 1H), 8.17-8.10 (m,
3H), 7.98-7.95 (d, J=8.8 Hz, 2H), 7.73-7.68 (m, 1H), 7.60-7.51 (m,
1H), 4.79-4.76 (t, J=6 Hz, 1H), 3.77-3.73 (m, 2H), 3.27-3.19 (m,
2H), 2.19-2.12 (m, 2H).
Step 5
##STR00171##
[0572] The product from step 4 (0.300 g, 0.657 mmol) was taken in
MeOH (10 mL) and Pd/C (0.07 g) was added under N.sub.2. The
reaction was stirred for overnight at RT under H.sub.2. The Pd/C
was filtered through CELITE, and the filtrate was concentrated
under reduced pressure to afford 234 mg of desired compound.
Step 6
##STR00172##
[0574] The product from step 5 (0.370 g, crude), N-Boc-proline
(0.157 g, 1.27 mmol), HATU (1.2 g, 3.18 mmol) and DIPEA (0.814 g,
6.36 mmol) were taken in DMF (10 mL) and stirred for overnight at
RT. DMF was removed under reduced pressure, and the residue was
extracted with DCM/water. The organic layer was washed with brine,
dried (NaSO.sub.4), concentrated and purified by column (DCM:
MeOH/100:1) to afford 300 mg of targeted compound.
Step 7
##STR00173##
[0576] The product from step 6 (0.600 g, 1.06 mmol) was stirred in
MeOH/HCl (15 mL) for 1 hour at RT, and the solvent was removed
under reduced pressure. The compound was dried at high vacuum to
afford 370 mg of desired compound. .sup.1H NMR (MeOD) .delta.: 9.39
(s, 1H), 9.18-8.82 (m, 2H), 8.39-8.38 (m, 1H), 8.32-8.22 (m, 1H),
8.21-8.10 (m, 2H), 8.09-7.98 (m, 2H), 7.86-7.72 (m, 1H), 7.71-7.65
(m, 1H), 4.87-4.84 (t, J=8.8 Hz, 2H), 3.51-3.34 (m, 8H), 2.49-2.38
(m, 4H).
Step 8
##STR00174##
[0578] The product from step 7 (0.100 g, 0.191 mmol),
cyclobutanecarboxylic acid (0.018 mg, 0.183 mmol), HATU (0.116 g,
0.305 mmol) and DIPEA (0.059 g, 0.416 mmol) were taken in DMF (5
mL) and stirred for overnight at RT. DMF was removed under reduced
pressure, and the residue was extracted with DCM/water. The organic
layer was washed with brine, dried (NaSO.sub.4) and concentrated.
The residue was purified by HPLC purification to afford 12 mg of
the final product. .sup.1H NMR (MeOD) .delta.: 8.91 (s, 1H), 8.75
(s, 1H), 8.41 (s, 1H), 8.25 (s, 1H), 7.96-7.95 (d, J=5.2 Hz, 4H),
7.73-7.67 (d, J=3.2 Hz, 2H), 7.52-7.51 (d, J=3.2 Hz, 1H), 4.54-4.82
(t, J=3.6 Hz, 2H), 3.63-3.46 (m, 4H), 2.48-2.46 (t, J=2 Hz, 1H),
2.34-2.29 (m, 6H), 2.18-2.10 (m, 4H), 2.08-2.02 (m, 4H).
Examples 9-15
[0579] Compounds of Examples 9-15 were prepared in a similar manner
to Example 8.
TABLE-US-00002 Ex- am- ple Structure MW Name 9 ##STR00175## 626.721
(2S)-1- (phenyl- carbonyl)-N- {4- [5-({[(2S)-1- (phenyl- carbonyl)
pyrrolidin-2- yl]carbonyl} amino)-1H- benzi- midazol- 2-yl]phenyl}
pyrrolidine- 2-car- boxamide 10 ##STR00176## 682.83 (2S)-1-
[(4Z,5Z)-4- ethyl- idenehept-5- enoyl]-N-{2- [4-({[(2S)-1-
(3-phenyl- propanoyl) pyrrolidin-2- yl]carbonyl} amino) phenyl]-
1H-benzimi- dazol-5-yl} pyrrolidine- 2- carboxamide 11 ##STR00177##
682.83 (2S)-1- [(4Z,5Z)-4- ethyl- idenehept- 5-enoyl]-N- {2-[3-
({[(2S)-1-(3- phenyl- propanoyl) pyrrolidin-2- yl]carbonyl} amino)
phenyl]- 1H-benzi- midazol- 5-yl} pyrrolidine- 2- carboxamide 12
##STR00178## 686.774 (2S)-1- [(2R)-2- hydroxy-2- phenyl-
acetyl]-N-(4- {5-[({(2S)- 1-[(2R)-2- hydroxy- 2-phenyl- acetyl]
pyrrolidin- 2-yl} carbonyl) amino]- 1H-benzi- midazol- 2-yl}phenyl)
pyrrolidine- 2- carboxamide 13 ##STR00179## 654.776 (2S)-1-
(phenyl- acetyl)- N-{4-[5- ({[(2S)-1- (phenyl- acetyl)
pyrrolidin-2- yl]carbonyl} amino)- 1H-benzi- midazol- 2-yl]phenyl}
pyrrolidine- 2-carbox- amide 14 ##STR00180## 885.041 tert-butyl
{(1S)-2- [(2S)-2- ({4-[5- ({[(2S)-1- {(2S)-2- [(tert- butoxy-
carbonyl) amino]-2- phenyl- acetyl} pyrrolidin- 2-yl] carbonyl}
amino)- 1H-benzi- midazol- 2-yl]phenyl} carbamoyl) pyrrolidin-1-
yl]-2-oxo-1- phenylethyl} carbamate 15 ##STR00181## 885.041
tert-butyl {(1R)-2- [(2S)-2-({4- [5-({[(2S)-1- {(2R)-2- [(tert-
butoxy- carbonyl) amino]-2- phenyl- acetyl} pyrrolidin- 2-yl]
carbonyl} amino)- 1H-benzi- midazol- 2-yl]phenyl} carbamoyl)
pyrrolidin- 1-yl]-2- oxo-1- phenyl- ethyl} carbamate
Example 16
Benzyl
(2S)-2-{[4-(4-{[4-methylphenyl)sulfonyl]amino}-1H-benzimidazol-2-yl-
)phenyl]carbamoyl}pyrrolidine-1-carboxylate
##STR00182##
[0580] Step 1
##STR00183##
[0582] To a solution of N-Boc-p-aminobenzoic acid (1.86 g, 7.84
mmol) in DMF, 3-nitrophenylenediamine (1.0 g, 6.536 mmol), HOBt
(0.875 g, 6.536 mmol) and EDCI (2.5 g, 9.804 mmol) were added, and
reaction was stirred for overnight at RT. The excess of solvent was
removed under reduced pressure, and the residue was diluted with
DCM. The organic layer was washed with brine, dried (NaSO.sub.4),
filtered, concentrated and purified by column to obtain 400 mg of
compound. MS m/z: 273 (M+1).
Step 2
##STR00184##
[0584] The compound from step 1 above (0.600 g, 1.611 mmol) and
KOAc (0.158 g, 1.609 mmol) were taken in HOAc (9.3 mL). The
reaction was stirred at 120.degree. C. for overnight, cooled to RT
and poured into ice-water. The aqueous layer was extracted with
DCM. The organic layer was washed with brine, dried (NaSO.sub.4),
filtered and concentrated to obtain 120 mg of the desired compound.
MS m/z: 255 (M+1). .sup.1H NMR (DMSO) .delta.: 11.44 (s, 1H),
8.95-9.01 (m, 2H), 8.81-8.83 (d, J=8.0 Hz, 2H), 8.22-8.27 (m, 1H),
8.22-8.27 (m, 2H), 4.97 (s, 2H).
Step 3
##STR00185##
[0586] To a solution of the aniline (0.200 g, 0.787 mmol) in DMF,
N-Boc-proline (0.186 g, 0.865 mmol), DIPEA (0.302 g, 2.361 mmol)
and HATU (0.329 g, 0.865 mmol) were added. The reaction was stirred
for overnight. The excess of solvent was removed under reduced
pressure, and the residue was diluted with DCM. The organic layer
was washed with brine, dried (NaSO.sub.4), filtered, concentrated
and purified by column to obtain 150 mg of the desired. MS m/z: 452
(M+1). .sup.1H NMR (MeOD) .delta.: 8.70-8.73 (m, 2H), 8.40-8.42 (d,
J=8 Hz, 2H), 7.87-7.89 (d, J=8 Hz, 1H), 7.50-7.53 (m, 2H),
6.78-6.80 (d, J=8 Hz, 1H), 3.83 (s, 1H), 3.69-3.76 (m, 2H),
3.56-3.60 (m, 4H), 1.37-1.43 (m, 9H).
Step 4
##STR00186##
[0588] To a solution of compound from step 3 above (0.200 g, 0.443
mmol), Pd/C (10 mg) was added under argon, and the reaction was
stirred for 2 hours in H.sub.2. The Pd/C was filtered and washed
with MeOH for several times. The solvent was evaporated to obtain
180 mg of desired compound. MS m/z: 422 (M+1). .sup.1H NMR (MeOD)
.delta.: 9.51 (s, 1H), 7.95-8.20 (m, 1H), 7.58-7.60 (m, 1H),
7.19-7.48 (m, 2H), 6.78-6.87 (m, 2H), 6.38 (s, 1H), 4.25-4.42 (m,
1H), 3.34-3.67 (m, 2H), 1.79-2.20 (m, 4H), 1.17-1.41 (m, 9H).
Step 5
##STR00187##
[0590] To a solution of the compound from step 4 above (0.196 g,
0.465 mmol) in THF, TEA (0.070 g, 0.693 mmol) and
4-methylbenzene-1-sulfonyl chloride (0.088 g, 0.461 mmol) were
added drop wise at 0.degree. C. The reaction was stirred for
overnight, and the solvent was removed under reduced pressure. The
residue was diluted with DCM and washed with brine.
[0591] The organic layer was dried (NaSO.sub.4), filtered and
concentrated. The residue was purified by preparative TLC to afford
110 mg of desired compound. MS m/z: 576 (M+1). .sup.1H NMR (MeOD)
.delta.: 7.98-8.00 (d, J=8.0 Hz, 2H), 7.78-7.80 (d, J=8.0 Hz, 2H),
7.66-7.68 (d, J=8.0 Hz, 2H), 7.26-7.28 (m, 11H), 7.19-7.21 (d,
J=8.0 Hz, 2H), 7.07-7.09 (m, 2H), 4.36-4.38 (m, 1H), 3.55-3.58 (m,
2H), 2.32-2.35 (m, 4H), 1.89-2.11 (m, 3H), 1.50 (s, 9H).
Step 6
##STR00188##
[0593] The product from step 5 above (0.180 g, 0.312 mmol) was
stirred in MeOH/HCl (5.0 mL) for 1 hour at RT. The solvent was
removed under reduced pressure and dried at high vacuum. It was
used directly without any further purification. The residue was
taken in DMF, benzoic acid (0.042 g, 0.344 mmol), DIPEA (0.320 g,
2.504 mmol) and HATU (0.143 g, 0.375 mmol) were added. The reaction
was stirred for overnight at RT. The excess of solvent was removed
under reduced pressure, and the residue was diluted with DCM. The
organic layer was washed with brine, dried (NaSO.sub.4), filtered,
concentrated and purified by column to afford 40 mg of the final
compound. MS m/z: 580 (M+1). .sup.1H NMR (MeOD) .delta.: 7.92-7.94
(d, J=8.8 Hz, 2H), 7.23-7.68 (m, 14H), 6.81-6.83 (d, J=10 Hz, 1H),
5.21 (s, 2H), 4.65-4.79 (m, 1H), 3.52-3.89 (m, 2H), 2.47-2.58 (m,
1H), 2.43 (s, 3H), 1.93-2.23 (m, 3H).
Example 17
(2S)-1-(3-phenylpropanoyl)-N-{4-[5-({[(2S)-1-(3-phenylpropanoyl)pyrrolidin-
-2-yl]carbonyl}amino)-1,3-benzoxazol-2-yl]phenyl}pyrrolidine-2-carboxamide
##STR00189##
[0594] Step 1
##STR00190##
[0596] p-Aminobenzoic acid (1.37 g, 10 mmol) and 2,4-diaminophenol
(1.24 g, 10 mmol) were combined under argon and treated with 12 mL
of PPA. The resulting solution was heated at 200.degree. C. for 30
minutes. The black solution was poured onto ice, and the resulting
yellow solid was collected (1.12 g). .sup.1H-NMR (DMSO) .delta.:
10.2-10.5 (s, 2H), 8.10-8.20 (m, 4H), 7.10-7.80 (m, 3H). MS m/z:
226 (M+1).
Step 2
##STR00191##
[0598] The product from step 1 above (0.100 g, 0.236 mmol),
N-Boc-proline (0.098 g, 0.355 mmol), HATU (0.135 g, 0.355 mmol),
TEA (0.100 g, 0.944 mmol) were taken in DCM (10 mL) and stirred
overnight at RT. The reaction was diluted with DCM, and the organic
layer was washed with water, brine, dried (NaSO.sub.4),
concentrated and purified by preparative TLC to afford 100 mg of
desired compound. MS m/z: 620 (M+1).
Step 3
##STR00192##
[0600] The product from step 2 above (0.100 g, 0.161 mmol) was
stirred in MeOH/HCl (3.0 mL) for 1 hour at RT, and the solvent was
removed under reduced pressure. The compound was dried at high
vacuum to afford 80 mg of the desired compound. MS m/z: 420
(M+1).
Step 4
##STR00193##
[0602] Compound from step 3 (0.080 g, 0.191 mmol),
3-phenylpropanoic acid (0.086 g, 0.574 mmol), HATU (0.218 g, 0.574
mmol), DIPEA (0.146 g, 1.146 mmol) were taken in DMF (3 mL) and
stirred for overnight at RT. DMF was removed under reduced
pressure, and the residue was extracted with DCM/water. The organic
layer was washed with brine, dried (NaSO.sub.4) and concentrated.
The residue was purified by HPLC purification to afford 108 mg of
target. .sup.1H NMR (DMSO) .delta.: 10.2-10.5 (s, 2H), 8.10-8.20
(m, 3H), 7.10-7.80 (m, 14H), 4.37-4.55 (m, 2H), 3.32-3.58 (m, 4H),
2.67-2.85 (m, 7H), 1.80-2.4 (m, 9H).
Example 18
(2S)-1-(3-phenylpropanoyl)-N-{4-[5-({[(2S)-1-(3-phenylpropanoyl)pyrrolidin-
-2-yl]carbonyl}amino)-1-benzofuran-2-yl]phenyl}pyrrolidine-2-carboxamide
##STR00194##
[0603] Step 1
##STR00195##
[0605] To a solution of 5-nitrosalicylaldehyde (1.0 g, 5.90 mmol)
in 1,4-dioxane (10 mL), p-nitrobenzyl bromide (1.33 g, 6.15 mmol)
and DIPEA (1.25 g, 9.70 mmol) were added, and the reaction was
refluxed at 100.degree. C. for 2 hours. The reaction was cooled,
and the solids were filtered, washed with EtOH and dried with high
vacuum to afford the desired compound. MS m/z: 303 (M+1).
Step 2
##STR00196##
[0607] To a solution of the target compound from step 1 (1.5 g,
4.96 mmol) in 1, 4-dioxane (5 mL), DBU (0.9 g, 6.45 mmol) was
added. The reaction was heated to 100.degree. C. for 3 hours, then
cooled to RT, and the resulting solid was filtered off and
sufficiently washed with EtOH to afford 927 mg of the desired
compound. .sup.1H NMR (MeOD) .delta.: 8.66 (s, 1H), 8.37-8.39 (d,
J=8.0 Hz, 2H), 8.30-8.32 (d, J=8.0 Hz, 1H), 8.18-8.21 (d, J=12 Hz,
2H), 7.78-7.80 (d, J=8.0 Hz, 1H), 7.70 (s, 1H).
Step 3
##STR00197##
[0609] To a solution of the product from step 2 above (0.050 g,
0.176 mmol) in 1,4-dioxane (1.8 mL), water (1.8 mL), Fe (0.054 g)
and HCl (1.1 .mu.L) were added. The reaction was heated to
110.degree. C. for 3 hours. Then, the solid was filtered, and the
organic layer was concentrated to afford 40 mg of the desired
compound. .sup.1H NMR (MeOD) .delta.: 8.01-8.05 (m, 2H), 7.90-7.96
(m, 1H), 7.79 (s, 1H), 7.46-7.51 (m, 1H), 7.34 (s, 1H), 7.17-7.21
(m, 2H). MS m/z: 225 (M+1).
Step 4
##STR00198##
[0611] To a solution of the product from step 3 above (0.020 g,
0.089 mmol) in DCM (10 mL) N-Boc-proline (0.042 g, 0.196 mmol) and
DIPEA (0.035 g, 0.267 mmol) were added. The reaction was stirred at
RT for 5 minutes and then HATU (0.101 g, 0.267 mmol) was added. The
reaction was stirred overnight and poured into brine and extracted
with EtOAc. The organic layer was dried (Na.sub.2SO.sub.4),
filtered and concentrated to afford 30 mg of the desired compound.
MS m/z: 619 (M+1).
Step 5
##STR00199##
[0613] The product from step 4 (0.70 g, 1.13 mmol) was stirred in
MeOH/HCl (20 mL) for 1 hour. The solvent was removed at high vacuum
to afford the desired proline compound, which was used directly to
the next step without further purification. 3-Phenylpropanoic acid
(0.428 g, 2.85 mmol) were taken in DCM (30 mL) was reacted with the
proline compound (0.500 g, 0.96 mmol) and DIPEA (0.9 g, 7.1 mmol).
The reaction was stirred at RT for 5 minutes, and then HATU (1.0 g,
2.85 mmol) was added. The reaction was stirred overnight and poured
into brine and extracted with EtOAc. The organic layer was dried
(Na.sub.2SO.sub.4), concentrated and purified by HPLC to afford 30
mg of the desired compound. .sup.1H NMR (CDCl.sub.3) .delta.:
9.85-9.87 (d, J=8.0 Hz, 2H), 7.86 (s, 1H), 7.42-7.44 (d, J=8.8 Hz,
2H), 7.46-7.48 (d, J=8.8 Hz, 2H), 7.03-7.31 (m, 9H), 6.90-6.99 (d,
J=3.6 Hz, 1H), 6.58 (s, 1H), 4.71-4.82 (m, 2H), 3.62-3.71 (m, 2H),
3.43-3.50 (m, 2H), 2.95-3.05 (m, 4H), 2.63-2.88 (m, 4H), 2.21-2.43
(m, 4H), 1.87-2.14 (m, 4H). MS m/z: 683 (M+1).
Example 19
N-{2-[4-(acetylamino)phenyl]-1-benzofuran-5-yl}-1-{(2R)-2-[(tert-butoxycar-
bonyl)amino]-2-phenylacetyl}-L-prolinamide
##STR00200##
[0614] Step 1
##STR00201##
[0616] K.sub.2CO.sub.3 (68 g, 0.497 mol) was added to a solution of
bromosalicylaldehyde (50 g, 0.248 mol) in DMF (300 ml). The
resulting solution was stirred at RT for 1 hour, then to it was
added compound 4-nitrobenzyl bromide (54 g, 0.25 mol). The reaction
mixture was stirred for 30 minutes, filtered, and the filtrate was
poured into water and extracted with EtOAc (3.times.). The combined
organic layers were dried and concentrated. The product was
recrystallized from dioxane to afford a white solid (50 g). .sup.1H
NMR (CDCl.sub.3) .delta.: 10.43 (s, 1H), 8.24 (d, J=4H), 7.51-7.58
(m, 2H), 7.37-7.42 (m, 4H), 7.31-7.36 (m, 6H), 5.52 (s, 1H), 4.57
(s, 2H), 3.90 (s, 2H), 3.34 (s, 2H), 2.06-2.15 (m, 6H), 1.86-1.88
(m, 1H), 1.41 (d, 18H).
Step 2
##STR00202##
[0618] DBU (9 ml, 61.58 mmol) was added to a solution of the
product from step 1 (10 g, 29.85 mmol) in dioxane (70 ml). The
resulting solution was heated to reflux for 1 hour, cooled and
filtered. The filter cake was washed with EtOAc and dried in air to
afford a yellow solid (6.5 g).
Step 3
##STR00203##
[0620] P.sup.tBu.sub.3 (1.93 ml, 0.32 mmol) was added to a solution
of the product from step 2 (2 g, 6.3 mmol) and Pd.sub.2(dba).sub.3
(0.29 g, 0.32 mmol) in THF (100 ml) under N.sub.2. Then a solution
of LiHMDS (18.9 ml, 18.9 mmol) was added dropwise. The resulting
solution was heated to reflux for 3 hours and then cooled to RT.
The reaction mixture was adjusted to pH=1 using 1M HCl, then
stirred for 0.5 hour. The reaction mixture was basified to
pH=8.about.9 using aq. saturated NaHCO.sub.3, and extracted with
EtOAc (3.times.). The combined organic layers were dried and
concentrated. The residue was recrystallized from MeOH to afford
the product as brown solid.
Step 4
##STR00204##
[0622] The mixture of the product from step 3 (500 mg, 2 mmol),
R-Boc-Phg-L-Pro-OH (660 mg, 2.16 mmol), NMM (400 mg, 4 mmol) and
DMF (30 ml) was stirred at RT for 30 minutes, then to it was added
HATU (1.13 g, 3 mmol). The resulting mixture was stirred at RT
overnight. The reaction mixture was diluted with water and
filtered. The cake was washed with water and dried; the solid was
used next step without purification.
Step 5
##STR00205##
[0624] The product from step 4 (0.4 g, 1.3 mmol) in THF (10 ml) was
hydrogenated using Raney Ni (0.2 mg) as the catalyst. After being
stirred under H.sub.2 atmosphere at RT overnight, the reaction
slurry was filtered through CELITE, and the filtrate was
concentrated under reduced pressure to afford 0.33 g of the desired
compound.
Step 6
##STR00206##
[0626] Ac.sub.2O (18 mg, 0.18 mmol) was added to a solution of the
aniline from step 5 (50 mg, 0.09 mmol) in THF (2 ml) at RT. The
resulting solution was stirred at RT overnight, concentrated, and
the residue was purified by RPLC to afford the desired product.
.sup.1H NMR (acetone-d6) .delta.: 7.95 (s, 1H, NH), 7.65-7.74 (m,
7H, ArH), 7.40-7.43 (m, 3H, ArH), 7.30-7.34 (m, 2H, ArH), 7.01 (s,
1H, ArH), 5.64 (s, 1H, CH), 4.56-4.59 (m, 1H, CH), 3.93-3.99 (m,
1H, CH.sub.2), 3.27-3.42 (m, 2H, CH.sub.2), 3.02-3.17 (m, 3H,
CH.sub.2), 1.98 (s, 3H, CH.sub.3), 1.98-1.95 (m, 4H, CH.sub.2),
1.22 (t, J=7.2 Hz, 6H, CH.sub.3).
Examples 20-36
[0627] Compounds of Examples 20-36 were prepared in a similar
manner as described in either Example 18 or Example 19.
TABLE-US-00003 Example Structure MW Name 20 ##STR00207## 654.773
(2S)-1-(phenylacetyl)-N-{4-[5- ({[(2S)-1-(phenylacetyl)
pyrrolidin-2-yl]carbonyl}amino)- 1-benzofuran-2-yl]phenyl}
pyrrolidine-2-carboxamide 21 ##STR00208## 885.039 tert-butyl
{(1S)-2-[(2S)-2-({4-[5- ({[(2S)-1-{(2S)-2-[(tert-
butoxycarbonyl)amino]-2- phenylacetyl}pyrrolidin-2-
yl]carbonyl}amino)-1- benzofuran-2-yl]phenyl}
carbamoyl)pyrrolidin-1-yl]-2- oxo-1-phenylethyl}carbamate 22
##STR00209## 885.039 tert-butyl {(1R)-2-[(2S)-2-({4-[5-
({[(2S)-1-{(2R)-2-[(tert- butoxycarbonyl)amino]-2-
phenylacetyl}pyrrolidin-2-yl] carbonyl}amino)-1-benzofuran-
2-yl]phenyl}carbamoyl) pyrrolidin-1-yl]-2-oxo-1-
phenylethyl}carbamate 23 ##STR00210## 856.984 propan-2-yl
[(1R)-2-oxo-1- phenyl-2-{(2S)-2-[(4-{5-[({(2S)-
1-[(2R)-2-phenyl-2-{[(propan-2- yloxy)carbonyl]amino}acetyl]
pyrrolidin-2-yl}carbonyl)amino]- 1-benzofuran-2-yl}phenyl)
carbamoyl]pyrrolidin-1- yl}ethyl]carbamate 24 ##STR00211## 800.876
methyl {(1R)-2-[(2S)-2-({4-[5- ({[(2S)-1-{(2R)-2-
[(methoxycarbonyl)amino]-2- phenylacetyl}pyrrolidin-2-
yl]carbonyl}amino)-1- benzofuran-2-yl]phenyl}
carbamoyl)pyrrolidin-1-yl]-2- oxo-1-phenylethyl}carbamate 25
##STR00212## 740.91 (2S)-1-[(2R)-2-(dimethylamino)-
2-phenylacetyl]-N-(4-{5-[({(2S)- 1-[(2R)-2-(dimethylamino)-2-
phenylacetyl]pyrrolidin-2-yl} carbonyl)amino]-1-benzofuran-2-
yl}phenyl)pyrrolidine-2- carboxamide 26 ##STR00213## 797.019
(2S)-1-[(2R)-2-(diethylamino)-2- phenylacetyl]-N-(4-{5-[({(2S)-1-
[(2R)-2-(diethylamino)-2- phenylacetyl]pyrrolidin-2-yl}
carbonyl)amino]-1-benzofuran-2- yl}phenyl)pyrrolidine-2-
carboxamide 27 ##STR00214## 798.947 propan-2-yl
[(1R)-2-{(2S)-2-[(4- {5-[({(2S)-1-[(2R)-2- (dimethylamino)-2-
phenylacetyl]pyrrolidin-2-yl} carbonyl)amino]-1-benzofuran-2-
yl}phenyl)carbamoyl]pyrrolidin- 1-yl}-2-oxo-1-
phenylethyl]carbamate 28 ##STR00215## 482.587
N-[2-(4-aminophenyl)-1- benzofuran-5-yl]-1-[(2R)-2-
(dimethylamino)-2- phenylacetyl]-L-prolinamide 29 ##STR00216##
853.127 (2S)-1-{(2R)-2-[methyl(3- methylbutyl)amino]-2-
phenylacetyl}-N-{4-[5-({[(2S)-1- {(2R)-2-[methyl(3-
methylbutyl)amino]-2- phenylacetyl}pyrrolidin-2-
yl]carbonyl}amino)-1- benzofuran-2-yl]phenyl}
pyrrolidine-2-carboxamide 30 ##STR00217## 552.679
N-{2-[4-(acetylamino)phenyl]-1- benzofuran-5-yl}-1-[(2R)-2-
(diethylamino)-2-phenylacetyl]- L-prolinamide 31 ##STR00218##
649.797 (2S)-1-acetyl-N-(2-{4-[({(2S)-1- [(2R)-2-(diethylamino)-2-
phenylacetyl]pyrrolidin-2- yl}carbonyl)amino]phenyl}-1-
benzofuran-5-yl)pyrrolidine-2- carboxamide 32 ##STR00219## 693.807
tert-butyl {(1R)-2-[(2S)-2-({4-[5- ({[(2S)-1-acetylpyrrolidin-2-
yl]carbonyl}amino)-1- benzofuran-2-yl]phenyl}
carbamoyl)pyrrolidin-1-yl]-2- oxo-1-phenylethyl}carbamate 33
##STR00220## 621.743 (2S)-1-acetyl-N-(2-{4-[({(2S)-1-
[(2R)-2-(dimethylamino)-2- phenylacetyl]pyrrolidin-2-
yl}carbonyl)amino]phenyl}-1- benzofuran-5-yl)pyrrolidine-2-
carboxamide 34 ##STR00221## 596.689 N-{4-[5-(acetylamino)-1-
benzofuran-2-yl]phenyl}-1- {(2R)-2-[(tert- butoxycarbonyl)amino]-2-
phenylacetyl}-L-prolinamide 35 ##STR00222## 814.903 methyl
{(1R)-2-[(2S)-2-({4-[5- ({[(2S)-1-{(2R)-2-
[(methoxycarbonyl)amino]-2- phenylacetyl}pyrrolidin-2-
yl]carbonyl}amino)-7-methyl-1- benzofuran-2-yl]phenyl}
carbamoyl)pyrrolidin-1-yl]-2- oxo-1-phenylethyl}carbamate 36
##STR00223## 825.073 (2S)-1-{(2R)-2-[ethyl(propyl)
amino]-2-phenylacetyl}-N-{4-[5- ({[(2S)-1-{(2R)-2-[ethyl(propyl)
amino]-2-phenylacetyl} pyrrolidin-2-yl]carbonyl}amino)-
1-benzofuran-2-yl]phenyl} pyrrolidine-2-carboxamide
Example 37
(2S)-1-(phenylacetyl)-N-{4-[6-({[(2S)-1-(phenylacetyl)pyrrolidin-2-yl]carb-
onyl}amino)imidazo[1,2-a]pyrimidin-2-yl]phenyl}pyrrolidine-2-carboxamide
##STR00224##
[0628] Step 1
##STR00225##
[0630] A suspension of pyrimidine (280 mg, 2 mmol), Pd/C (15 mg,
0.1 mmol) in 40 mL EtOH was hydrogenated under 30 psi for 1 hour.
The mixture was then filtered, and the filtrate was then
concentrated to give the product (200 mg). The residue was
dissolved in 20 ml THF and CbzCl (375 mg, 2.19 mmol) and pyridine
(1 ml) were added. The mixture was stirred at RT for 1 hour, then
the mixture was concentrated in vacuo, and the residue was
extracted with EtOAc (2.times.), washed with H.sub.2O (30 mL) and
brine (30 mL), dried over anhydrous NaSO.sub.4, concentrated in
vacuo to give the desired compound as white powder (330 mg). MS
(ESI) m/e (M+H.sup.+): 245.
Step 2
##STR00226##
[0632] A solution of the product from step 1 above (244 mg, 1.00
mmol) and 2-bromo-1-(4-nitrophenyl)ethanone (244 mg, 1 mmol) in 40
mL of acetone was heated to reflux and stirred for 6 hours. Then,
the mixture was cooled to RT and filtered, and the filtrate was
then dissolved in 30 ml MeOH, and 0.5 ml HBr was added, the mixture
was heated to reflux for another 3 hours; after that, the mixture
was concentrated in vacuo to give the product as a pale yellow
powder (120 mg). MS (ESI) m/e (M+H.sup.+): 390.
Step 3
##STR00227##
[0634] To the product from step 2 above (50 mg, 0.128 mmol) was
dissolved in 10 mL CH.sub.3OH was added SnCl.sub.2 (144 mg, 0.64
mmol). The reaction mixture was stirred at RT for 30 minutes and
then heated to reflux for 3 hours. MeOH was removed in vacuo, and
the residue was purified (DCM/MeOH=50:1) to afford the desired
compound (35 mg). MS (ESI) m/e (M+H.sup.+): 360.
Step 4
##STR00228##
[0636] The compound from step 3 (35 mg, 0.1 mmol) was dissolved in
5 ml of HOAc, then HBr (1.5 ml) was added. The reaction mixture was
heated to reflux and stirred for 6 hours, cooled and concentrated.
The residue was extracted with EtOAc (2.times.), washed with aq.
NaHCO.sub.3 and water (30 mL) and brine (30 mL), dried over
anhydrous NaSo.sub.4. Concentration afforded the desired compound
as a brown solid (16 mg). MS (ESI) m/e (M+H.sup.+): 226.
Step 5
##STR00229##
[0638] A mixture of the diamine product from step 4 above (16 mg,
0.071 mmol), N-phenylacetyl-L-proline (40 mg, 0.170 mmol), DIPEA
(36.9 mg, 0.02 mmol) in CH.sub.3CN (5 mL) was stirred at RT for 10
minutes, then HATU (54 mg, 0.142 mmol) was added. The mixture was
stirred at RT overnight then the mixture was concentrated, and the
residue was purified to give compound (15 mg). MS (ESI) m/e
(M+H.sup.+): 657. .sup.1H NMR (MeOD) .delta.: 9.45 (s, 1H), 8.31
(s, 1H), 8.05 (s, 1H), 7.61.about.7.48 (m, 4H), 7.34.about.7.21 (m,
10H), 4.60.about.4.52 (m, 2H), 3.83.about.3.69 (m, 8H),
2.24.about.1.97 (m, 8H).
Example 38
(2S)-1-(phenylacetyl)-N-{4-[6-({[(2S)-1-(phenylacetyl)pyrrolidin-2-yl]carb-
onyl}amino)imidazo[1,2-a]pyridin-2-yl]phenyl}pyrrolidine-2-carboxamide
##STR00230##
[0639] Step 1
##STR00231##
[0641] The mixture containing 2-amino-5-nitropyridine (1.39 g, 10
mmol) and p-nitro-alpha-bromoacetophenone (2.42 g, 10 mmol) in 100
mL of acetone was heated at reflux for 12 hours. The solid was
collected by filtration and then dissolved in 20 mL of MeOH and
treated with a trace amount of HBr. The mixture was stirred at
reflux for 1 hour, cooled and the solid was collected by filtration
to give the desired (1.4 g). MS (m/z): 285 (M+H).sup.+.
Step 2
##STR00232##
[0643] To a suspension of the product from step 1 above (0.7 g, 2.5
mmol) in MeOH (50 mL) was added 0.1 g of Pd/C (20%), and the
suspension was stirred under 25 psi of H.sub.2 at RT. After
filtration, the filtrate was concentrated in vacuo to give the
desired compound. MS (m/z): 225 (M+H).sup.+.
Step 3
##STR00233##
[0645] The mixture of the diamine from step 2 above (225 mg, 1
mmol), N-phenylacetylproline (1 mmol), DIPEA (5 mmol) and HATU (380
mg, 1 mmol) in 10 mL of MeCN was stirred at RT for 1 hour. The
reaction mixture was concentrated, and the residue was purified by
column chromatography to give the desired compound. .sup.1H NMR
(MeOD) .delta.: 9.3 (s, 1H), 8.2 (s, 1H), 7.5-7.1 (m, 16H), 4.6 (m,
1H), 4.5 (m, 1H), 3.8 (m, 8H), 2.3-1.8 (m, 8H).
Example 39
(2S,2'S)--N,N'-1H,1.sup.1H-2,2'-biindole-5,5'-diylbis[1-(phenylacetyl)pyrr-
olidine-2-carboxamide]
##STR00234##
[0646] Step 1
##STR00235##
[0648] To a suspension of the lactam (10.0 g, 56 mmol) in 200 ml of
1,2-dichloroethane, was added POBr.sub.3 (15.3 g, 53.2 mmol) at RT.
The resulting mixture was heated at reflux temperature in a
90.degree. C. oil bath for 0.5 hour (the reaction formed a copious
amount of precipitate, and an oil bath was preferred over a heating
mantle, as it provided gentle heating and avoided a darkening of
the precipitate). The reaction was cooled just below reflux
temperature, and imidazole (4.57 g, 62 mmol) was added in one
portion. The resulting gummy suspension was heated at reflux
temperature in an oil bath for another 2 hours. The reaction was
cooled to RT, and 100 mL of ice-water was added. Solid NaHCO.sub.3
(ca. 50 g) was added to the mixture until no further gas was
evolved. The suspension was extracted with DCM (4.times.), and the
combined DCM extracts were washed with 300 mL of brine. The DCM
extracts were filtered through silica gel and concentrated to
dryness to afford a crude product. The crude product was
recrystallized from chloroform to give 5.41 g of the desired
compound as a white solid. The filtrate was concentrated to
dryness, and the residue was purified by flash column
chromatography (30% EtOAc/Hex) to give an additional 2.6 g of
desired product. MS (ESI) m/e (M+H.sup.+): 242.
Step 2
##STR00236##
[0650] The mixture of compound from step 1 above (602.6 mg, 2.5
mmol), the indole boronic acid (1.034 g, 2.75 mmol),
Pd(dppf)Cl.sub.2(183 mg, 0.25 mmol), Na.sub.2CO.sub.3 (530 mg, 5.0
mmol) in 5 mL dioxane-H.sub.2O (5:1) was heated to reflux under
N.sub.2 atmosphere overnight. When reaction was complete the
mixture was poured into water and extracted with DCM. The organic
phase was dried over Na.sub.2SO.sub.4, concentrated, and the
residue was purified to give compound the desired product. MS (ESI)
m/e (M+H.sup.+): 493.
Step 3
##STR00237##
[0652] The product from step 2 (600 mg, 1.3 mmol) was added into
HCl (30 ml, 3M in MeOH). Then the mixture stirred at RT for 2-3
hours. When reaction was complete, the mixture was concentrated to
give the crude product (400 mg). MS (ESI) m/e (M+H.sup.+): 293.
Step 4
##STR00238##
[0654] The product from step 3 (400 mg, 1.36 mmol) was dissolved in
EtOAc and treated with Pd/C (100 mg, 20%). Then the mixture was
stirred at RT overnight under H.sub.2 atmosphere. When the reaction
was complete, the Pd/C was filtered off, and the resulting solution
was concentrated to give the crude product (300 mg). MS (ESI) m/e
(M+H.sup.+): 263.
Step 5
##STR00239##
[0656] A solution containing (131 mg, 0.5 mmol) of the product from
step 4, RCOOH (256.608 mg, 1.1 mmol), DIPEA (390 mg, 1.5 mmol) in
CH.sub.3CN (2 mL) was stirred at RT for 5 minutes, then HATU (418
mg, 1.1 mmol) was added into the mixture. The mixture was stirred
at RT overnight. When reaction was complete, the mixture was
concentrated, and the residue was purified to give the desired
product. .sup.1H NMR (MeOD) .delta.: 7.15-7.75 (m, 18H), 4.51-4.59
(m, 2H), 3.56-3.80 (m, 10H), 2.37 (s, 3H), 1.97-2.30 (m, 8H). MS
(ESI) m/e (M+H.sup.+): 693.
Example 40
di-tert-butyl
(1H,1'H-2,2'-biindole-5,5'-diylbis{carbamoyl(2S)pyrrolidine-2,1-diyl[(1R)-
-2-oxo-1-phenylethane-2,1-diyl]})biscarbamate
##STR00240##
[0658] This compound was prepared using the similar method as
Example 39, step 5 using N-Boc-R-Phg-L-Pro-OH. .sup.1H NMR (MeOD)
.delta.: 6.78-7.78 (m, 18H), 5.49 (m, 2H), 4.55-4.58 (m, 2H),
3.94-3.97 (m, 3H), 2.37 (s, 3H), 1.87-2.14 (m, 8H), 1.40 (s, 18H).
MS (ESI) m/e (M+H.sup.+): 924.
Example 41
tert-butyl
{(1R)-2-oxo-1-phenyl-2-[(2S)-2-({2-[4-({[(2S)-1-(phenylacetyl)
pyrrolidin-2-yl]carbonyl}amino)phenyl]-1H-indol-5-yl}carbamoyl)pyrrolidin-
-1-yl]ethyl}carbamate
##STR00241##
[0659] Step 1
##STR00242##
[0661] To a solution of 4-bromophenylhydrazine (2.5 g, 13.4 mmol)
in acetic acid (19.5 mL) and EtOH (14.5 mL), 4-nitroacetophenone
(1.66 g, 10.0 mmol) was added. The reaction was refluxed for 5
hours, and water (35 mL) was added. The resulting mixture was
stirred for another 1 hour, and the resulting solid was filtered,
washed with water to afford 3.1 g of the desired compound. .sup.1H
NMR (MeOD) .delta.: 8.21-8.23 (d, J=8.0 Hz, 2H), 8.01-8.03 (d,
J=8.0 Hz, 2H), 7.34-7.36 (d, J=8.0 Hz, 2H), 7.20-7.22 (d, J=8.0 Hz,
2H), 2.03 (s, 3H).
Step 2
##STR00243##
[0663] The product from step 1 above (2.0 g, 6.0 mmol) was added
into PPA (20 mL), and the mixture was stirred at 80.degree. C. for
1 hour before it was cooled in ice-bath, diluted with water/EtOAc
(60/20 mL) and stirred for another 1 hour. The mixture was
extracted with EtOAc and washed to yield the target. .sup.1H NMR
(MeOD) .delta.: 8.28-8.30 (d, J=8.0 Hz, 2H), 7.97-7.99 (d, J=8.0
Hz, 2H), 7.72 (s, 1H), 7.33-7.35 (d, J=8.0 Hz, 1H), 7.24-7.26 (d,
J=8.0 Hz, 1H), 7.02 (s, 1H).
Step 3
##STR00244##
[0665] An oven-dried argon-cooled round-bottom flask was charged
with the indole from step 2 (2.0 g, 6.31 mmol) and 0.05 equivalents
of Pd.sub.2(dba).sub.3 in THF (100 mL). A solution of
tri-tert-butyl phosphine (10 wt %) in hexane (1.93 mL, 0.63 mmol)
was added followed by lithium hexamethyldisilazane (1.0 M in THF)
(18.9 mL, 18.9 mmol). The dark solution was heated to reflux
overnight then cooled to RT. This mixture was poured into ice-cold
aq 1.0 M HCl (70 mL) and stirred vigorously. Hexane was added, and
stirring was continued for 30 minutes. The precipitate was
filtered, washed with 20 mL of cold water and then 20 mL of
THF:Hexanes (5:95) solution. The precipitate was washed with 200 mL
of MeOH, and the filtrate was concentrated to give 1.5 g of the
desired compound. MS m/z: 254 (M+1).
Step 4
##STR00245##
[0667] To a solution of the product from step 3 above (1 g, 3.9
mmol) in acetonitrile (20 mL) was added R--N-Boc-Phg-S-Pro-OH (1.4
g, 3.9 mmol), HATU (3 g, 7.8 mmol) and DIPEA (1 g, 7.8 mmol). The
mixture was stirred at RT overnight. The solvent was distilled, and
the residue was dissolved in EtOAc and washed with water. The
organic layer was dried and concentrated in vacuo, and the residue
was purified by column chromatography to give the desired compound
(1.8 g). MS (ESI) m/e (M+H.sup.+): 584.
Step 5
##STR00246##
[0669] To a solution of compound from step 4 (300 mg, 0.51 mmol) in
MeOH (10 mL) was added Pd/C (50 mg, 0.28 mmol). The mixture was
stirred under H.sub.2 atmosphere at RT for 1 hour. The catalyst was
filtered off, and the filtrate was concentrated in vacuo to give
the desired compound (230 mg) as a yellow oil, which was used
directly in next step. MS (ESI) m/e (M+H).sup.+: 554.
Step 6
##STR00247##
[0671] To a solution of the compound from step 5 (100 mg, 0.18
mmol) in acetonitrile (3 mL) was added compound
N-phenylacetyl-L-proline (42 mg, 0.18 mmol), HATU (140 mg, 0.36
mmol) and DIPEA (46 mg, 0.36 mmol). The mixture was stirred at RT
overnight then concentrated, and the residue was purified by RPLC
to give (60 mg). .sup.1H NMR (CDCl.sub.3) .delta.: 9.62 (s, 1H),
9.08 (s, 1H), 7.84 (s, 1H), 7.45-7.09 (m, 15H), 6.52 (s, 1H), 5.67
(s, 1H), 5.49 (m, 1H), 4.72-4.51 (m, 2H), 3.82-3.48 (m, 5H), 3.20
(m, 1H), 2.15-1.72 (m, 8H), 1.43 (s, 9H). MS (ESI) m/e (M+H.sup.+):
769.
Example 42
(2S)-1-(phenylacetyl)-N-{2-[5-({[(2S)-1-(phenylacetyl)pyrrolidin-2-yl]carb-
onyl}amino)-1H-indol-2-yl]pyrimidin-5-yl}pyrrolidine-2-carboxamide
##STR00248##
[0672] Step 1
##STR00249##
[0674] A mixture of 5-nitroindole (5 g, 30.9 mmol), Fe (8.6 g, 154
mmol), NH.sub.4Cl (16.5 g, 309 mmol), EtOH (80 mL) and water (20
mL) was refluxed under N.sub.2 protection for 2 hours. The mixture
was cooled to RT and filtered. The filtrate was concentrated and
dissolved in water. The mixture was basified with Na.sub.2CO.sub.3
and extracted with CH.sub.2Cl.sub.2 two times. The combined organic
phases were combined, dried over Na.sub.2SO.sub.4 and filtered. The
filtrate was concentrated to yield the product (3.6 g). MS (ESI)
m/e (M+H.sup.+): 133. .sup.1H NMR (DMSO) .delta.:10.55 (s, 1H),
7.12-7.06 (m, 2H), 6.68 (d, J=2.0 Hz, 1H), 6.48 (dd, J=8.4 Hz, 2.0
Hz, 1H), 6.12 (t, J=2.0 Hz, 1H), 4.39 (s, 2H).
Step 2
##STR00250##
[0676] A mixture of 5-aminoindole (20 g, 76 mmol), DMAP (9.2 g, 38
mmol) THF (250 mL) and CH.sub.3CN (100 mL) was cooled to 0.degree.
C. Boc.sub.2O (132 g, 304 mmol) was slowly added to the mixture.
The reaction mixture was allowed to warm to RT and stirred over the
weekend. The mixture was poured into water and exacted with
CH.sub.2Cl.sub.2 three times. The organic phase was combined, dried
over Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated,
dissolved in CH.sub.2Cl.sub.2 and poured into PE and filtered. The
solid was purified by column chromatography (PE/EA=20/1) to yield
the product (23 g). .sup.1H NMR (CDCl.sub.3): .delta. 8.05 (d,
J=8.0 Hz, 1H), 7.56 (d, J=3.2 Hz, 1H), 7.28 (d, J=2.4 Hz, 1H), 7.03
(dd, J=8.8 Hz, 1.6 Hz, 1H), 1.63 (s, 9H), 1.36 (s, 18H).
Step 3
##STR00251##
[0678] A mixture of the product from step 2 above (5.0 g, 11.6
mmol), (iPrO).sub.3B (17.5 mL, 92.8 mmol) and dry THF (100 mL) was
cooled to 0.degree. C. LDA (prepared from nBuLi and iPr.sub.2NH in
THF, about 116 mmol) was slowly added to the mixture at 0.degree.
C. The mixture was allowed to warm to RT and stirred for 2 hours.
The mixture was quenched by the addition of 1N HCl to pH=3 and
extracted with CH.sub.2Cl.sub.2 three times. The combined organic
phases were combined, dried over Na.sub.2SO.sub.4 and filtered. The
filtrate was concentrated and purified by column chromatography
(PE/CH.sub.2Cl.sub.2=1/1 to pure CH.sub.2Cl.sub.2 to
CH.sub.2Cl.sub.2/acetone=10/1 to pure acetone) to afford the
product (2.8 g). .sup.1H NMR (DMSO) .delta.: 9.22 (s, 1H), 8.10 (s,
2H), 7.84 (d, J=9.2 Hz, 1H), 7.65 (s, 1H), 7.20 (dd, J=9.2 Hz, 2.0
Hz, 1H), 6.48 (d, 1H), 1.51 (s, 9H), 1.41 (s, 9H).
Step 4
##STR00252##
[0680] A mixture of the pyrimidine compound (0.3 g, 2 mmol), Fe
powder (560 mg, 10 mmol), NH.sub.4Cl (1.07 g, 20 mmol), EtOH (8 mL)
and water (2 mL) was refluxed under N.sub.2 overnight. The mixture
was cooled to RT and filtered. The filtrate was concentrated and
dissolved in water. The mixture was basified with Na.sub.2CO.sub.3
and extracted with CH.sub.2Cl.sub.2 two times. The combined organic
phases were dried over Na.sub.2SO.sub.4 and filtered. The filtrate
was concentrated to yield the product (120 mg). MS (ESI) m/e
(M+H.sup.+): 130. .sup.1H NMR (DMSO) .delta.: 7.99 (s, 2H), 5.73
(s, 2H).
Step 5
##STR00253##
[0682] A mixture of the pyrimidine from step 4 (100 mg, 0.77 mmol),
indole boronic acid from step 3 (290 mg, 0.77 mmol),
Pd(dppf)Cl.sub.2 (56 mg, 0.077 mmol), Na.sub.2CO.sub.3 (244 mg, 2.3
mmol), THF (20 mL) and H.sub.2O (2 mL) was refluxed under N.sub.2
overnight. The mixture was poured into water and extracted with
CH.sub.2Cl.sub.2. The organic phase was combined, dried over
Na.sub.2SO.sub.4 and filtered. The filtrate was purified by prep
TLC (CH.sub.2Cl.sub.2/MeOH=20/1) to afford the product. MS (ESI)
m/e (M+H.sup.+): 426.
Step 6
##STR00254##
[0684] A mixture of compound from step 5 above was added to a
solution HCl in MeOH (4M) cooled with ice bath. The mixture was
allowed to warm to RT and stirred overnight. The mixture was
concentrated, dissolved in water, washed by CH.sub.2Cl.sub.2 and
concentrated. The residue was directly used in the next step
without further purification. MS (ESI) m/e (M+H.sup.+): 226
Step 7
##STR00255##
[0686] The product of step 6 above (0.22 mmol),
N-phenylacetyl-L-proline (51 mg, 0.22 mmol), DIPEA (100 mg), and
DMF (3 mL) was added HATU (84 mg, 0.22 mmol), and the mixture was
stirred at RT overnight. The mixture was purified by RPLC to afford
the product. MS (ESI) m/e (M+H.sup.+): 656. .sup.1H NMR
(CDCl.sub.3) .delta.: 10.42 (s, 1H), 10.01 (s, 1H), 9.77 (s, 1H),
8.32 (s, 1H), 7.34-7.27 (m, 11H), 7.05-7.00 (m, 2H), 6.58 (d, J=8.0
Hz, 1H), 4.63-4.53 (m, 2H), 3.84-3.58 (m, 8H), 2.30-1.94 (m,
8H).
Examples 43-87
[0687] Compounds of Examples 43-87 were prepared in a similar
manner as described in either Example 41 or Example 42.
TABLE-US-00004 Example Structure MW Name 43 ##STR00256## 884.054
tert-butyl {(1R)-2-[(2S)-2-({4-[5- ({[(2S)-1-{(2R)-2-[(tert-
butoxycarbonyl)amino]-2- phenylacetyl}pyrrolidin-2-
yl]carbonyl}amino)-1H-indol-2- yl]phenyl}carbamoyl)pyrrolidin-
1-yl]-2-oxo-1- phenylethyl}carbamate 44 ##STR00257## 799.891 methyl
{(1R)-2-[(2S)-2-({4-[5- ({[(2S)-1-{(2R)-2-
[(methoxycarbonyl)amino]-2- phenylacetyl}pyrrolidin-2-
yl]carbonyl}amino)-1H-indol-2- yl]phenyl}carbamoyl)pyrrolidin-
1-yl]-2-oxo-1- phenylethyl]carbamate 45 ##STR00258## 792.002
(2S)-1-[(2R)-2-phenyl-2- (pyrrolidin-1-yl)acetyl]-N-(4-{5-
[({(2S)-1-[(2R)-2-phenyl-2- (pyrrolidin-1-yl)acetyl]
pyrrolidin-2-yl}carbonyl)amino]- 1H-indol-2-yl}phenyl)
pyrrolidine-2-carboxamide 46 ##STR00259## 848.023 (2S)-1-{(2R)-2-
[(cyclopropylacetyl)amino]-2- phenylacetyl}-N-{4-[5-({[(2S)-1-
{(2R)-2-[(cyclopropylacetyl) amino]-2-phenylacetyl}
pyrrolidin-2-yl]carbonyl}amino)- 1H-indol-2-yl]phenyl}
pyrrolidine-2-carboxamide 47 ##STR00260## 852.055
(2S)-1-{(2R)-2-[(3- methylbutanoyl)amino]-2-
phenylacetyl}-N-{4-[5-({[(2S)-1- {(2R)-2-[(3-methylbutanoyl)
amino]-2-phenylacetyl} pyrrolidin-2-yl]carbonyl}amino)-
1H-indol-2-yl]phenyl} pyrrolidine-2-carboxamide 48 ##STR00261##
824.001 (2S)-1-[(2R)-2-(morpholin-4-yl)-
2-phenylacetyl]-N-(4-{5-[({(2S)- 1-[(2R)-2-(morpholin-4-yl)-2-
phenylacetyl]pyrrolidin-2- yl}carbonyl)amino]-1H-indol-2-
yl}phenyl)pyrrolidine-2- carboxamide 49 ##STR00262## 834.04
(2S)-1-(2,3-diphenylpropanoyl)- N-{4-[5-({[(2S)-1-(2,3-
diphenylpropanoyl)pyrrolidin-2- yl]carbonyl}amino)-1H-indol-2-
yl]phenyl}pyrrolidine-2- carboxamide 50 ##STR00263## 992.195
(2S)-1-[(2R)-2-{[(4- methylphenyl)sulfonyl]amino}-2-
phenylacetyl]-N-(4-{5-[({(2S)-1- [(2R)-2-{[(4-methylphenyl)
sulfonyl]amino}-2-phenylacetyl] pyrrolidin-2-yl}carbonyl)amino]-
1H-indol-2-yl}phenyl) pyrrolidine-2-carboxamide 51 ##STR00264##
904.132 (2S)-1-{(2R)-2- [(cyclohexylcarbonyl)amino]-2-
phenylacetyl}-N-{4-[5-({[(2S)-1- {(2R)-2-[(cyclohexylcarbonyl)
amino]-2-phenylacetyl} pyrrolidin-2-yl]carbonyl}amino)-
1H-indol-2-yl]phenyl} pyrrolidine-2-carboxamide 52 ##STR00265##
553.623 methyl {(1R)-2-[(2S)-2-({2-[4-
(acetylamino)phenyl]-1H-indol- 5-yl}carbamoyl)pyrrolidin-1-yl]-
2-oxo-1-phenylethyl}carbamate 53 ##STR00266## 595.704 tert-butyl
{(1R)-2-[(2S)-2-({4-[5- (acetylamino)-1H-indol-2-
yl]phenyl}carbamoyl)pyrrolidin- 1-yl]-2-oxo-1-
phenylethyl}carbamate 54 ##STR00267## 565.678
N-{2-[4-(acetylamino)phenyl]- 1H-indol-5-yl}-1-[(2R)-2-
(morpholin-4-yl)-2- phenylacetyl]-L-prolinamide 55 ##STR00268##
581.677 propan-2-yl {(1R)-2-[(2S)-2-({2-
[4-(acetylamino)phenyl]-1H- indol-5-yl}carbamoyl)pyrrolidin-
1-yl]-2-oxo-1- phenylethyl}carbamate 56 ##STR00269## 817.953
(2S)-1-{(2R)-2- [(cyclopentylcarbamoyl)amino]-
2-phenylacetyl}-N-(4-{5-[({(2S)- 1-[(2R)-2-(dimethylamino)-2-
phenylacetyl]pyrrolidin-2- yl}carbonyl)amino]-1H-indol-2-
yl}phenyl)pyrrolidine-2- carboxamide 57 ##STR00270## 816.019
tert-butyl {(2R)-1-[(2S)-2-({4-[5- ({[(2S)-1-{(2R)-2-[(tert-
butoxycarbonyl)amino]-3- methylbutanoyl}pyrrolidin-2-
yl]carbonyl}amino)-1H-indol-2- yl]phenyl}carbamoyl)pyrrolidin-
1-yl]-3-methyl-1-oxobutan-2- yl}carbamate 58 ##STR00271## 549.679
N-{2-[4-(acetylamino)phenyl]- 1H-indol-5-yl}-1-[(2R)-2-phenyl-
2-(pyrrolidin-1-yl)acetyl]-L- prolinamide 59 ##STR00272## 699.945
(2S)-1-[(2R)-2-(dimethylamino)- 4-methylpentanoyl]-N-(4-{5-
[({(2S)-1-[(2R)-2- (dimethylamino)-4- methylpentanoyl]pyrrolidin-2-
yl}carbonyl)amino]-1H-indol-2- yl}phenyl)pyrrolidine-2- carboxamide
(non-preferred name) 60 ##STR00273## 820.056
(2S)-1-[(2R)-2-phenyl-2- (piperidin-1-yl)acetyl]-N-(4-{5-
[({(2S)-1-[(2R)-2-phenyl-2- (piperidin-1-yl)acetyl]pyrrolidin- 2
-yl}carbonyl)amino]-1H-indol- 2-yl}phenyl)pyrrolidine-2-
carboxamide 61 ##STR00274## 785.914 (2S)-1-[(2R)-2-(1H-imidazol-1-
yl)-2-phenylacetyl]-N-(4-{5- [({(2S)-1-[(2R)-2-(1H-imidazol-
1-yl)-2-phenylacetyl]pyrrolidin- 2 -yl}carbonyl)amino]-1H-indol-
2-yl}phenyl)pyrrolidine-2- carboxamide 62 ##STR00275## 796.034
(2S)-1-[(2R)-2-(diethyalmino)-2- phenylacetyl]-N-(4-{5-[({(2S)-1-
[(2R)-2-(diethylamino)-2- phenylacetyl]pyrrolidin-2-
yl}carbonyl)amino]-1H-indol-2- yl}phenyl)pyrrolidine-2- carboxamide
63 ##STR00276## 692.822 tert-butyl {(1S)-2-[(2S)-2-({4-[5-
({[(2S)-1-acetylpyrrolidin-2- yl]carbonyl}amino)-1H-indol-2-
yl]phenyl}carbamoyl)pyrrolidin- 1-yl]-2-oxo-1-
phenylethyl}carbamate 64 ##STR00277## 692.822 tert-butyl
{(1R)-2-[(2S)-2-({4-[5- ({[(2S)-1-acetylpyrrolidin-2-
yl]carbonyl}amino)-1H-indol-2- yl]phenyl}carbamoyl)pyrrolidin-
1-yl]-2-oxo-1- phenylethyl}carbamate 65 ##STR00278## 692.866
tert-butyl {(1R)-2-oxo-1-phenyl- 2-[(2S)-2-({2-[4-({[(2S)-1-
(propan-2-yl)pyrrolidin-2- yl]carbonyl}amino)phenyl]-1H-
indol-5-yl}carbamoyl)pyrrolidin- 1-yl]ethyl}carbamate 66
##STR00279## 523.64 N-{2-[4-(acetylamino)phenyl]-
1H-indol-5-yl}-1-[(2R)-2- (dimethylamino)-2-
phenylacetyl]-L-prolinamide 67 ##STR00280## 563.706
N-{2-[4-(acetylamino)phenyl]- 1H-indol-5-yl}-1-[(2R)-2-phenyl-
2-(piperidin-1-yl)acetyl]-L- prolinamide 68 ##STR00281## 811.99
tert-butyl [(1R)-2-{(2S)-2-[(2-{4- [({(2S)-1-[(2R)-2-
(dimethylamino)-2- phenylacetyl]pyrrolidin-2-
yl}carbonyl)amino]phenyl}-1H- indol-5-yl)carbamoyl]pyrrolidin-
1-yl}-2-oxo-1- phenylethyl]carbamate 69 ##STR00282## 811.99
tert-butyl [(1R)-2-{(2S)-2-[(4-{5- [({(2S)-1-[(2R)-2-
(dimethylamino)-2-phenylacetyl] pyrrolidin-2-yl}carbonyl)amino]-
1H-indol-2-yl}phenyl) carbamoyl]pyrrolidin-1-yl}-2-
oxo-1-phenylethyl]carbamate 70 ##STR00283## 810.017
(2S)-1-[(2R)-2-(dimethylamino)- 2-phenylacetyl]-N-{4-[5-({[(2S)-
1-{(2R)-2-[(3,3- dimethylbutanoyl)amino]-2-
phenylacetyl}pyrrolidin-2- yl]carbonyl}amino)-1H-indol-2-
yl]phenyl}pyrrolidine-2- carboxamide 71 ##STR00284## 660.823
(2S)-1-(cyclopropylacetyl)-N-(4- {5-[({(2S)-1-[(2R)-2-
(dimethylamino)-2- phenylacetyl]pyrrolidin-2-
yl}carbonyl)amino]-1H-indol-2- yl}phenyl)pyrrolidine-2- carboxamide
72 ##STR00285## 676.823 (2S)-1-[(2R)-2-(dimethylamino)-
2-phenylacetyl]-N-(2-{4-[({(2S)- 1-[(2R)-tetrahydrofuran-2-
ylcarbonyl]pyrrolidin-2- yl}carbonyl)amino]phenyl}-1H-
indol-5-yl)pyrrolidine-2- carboxamide 73 ##STR00286## 920.035
tert-butyl [(1R)-2-{(2S)-2-[(4-{5- [({(2S)-1-[(2R)-2-[(tert-
butoxycarbonyl)amino]-2-(4- fluorophenyl)acetyl]pyrrolidin-2-
yl}carbonyl)amino]-1H-indol-2- yl}phenyl)carbamoyl]pyrrolidin-
1-yl}-1-(4-fluorophenyl)-2- oxoethyl]carbamate 74 ##STR00287##
852.142 (2S)-1-{(2R)-2-[methyl(3- methylbutyl)amino]-2-
phenylacetyl}-N-{4-[5-({[(2S)-1- {(2R)-2-[methyl(3-methylbutyl)
amino]-2-phenylacetyl} pyrrolidin-2-yl]carbonyl}amino)-
1H-indol-2-yl]phenyl} pyrrolidine-2-carboxamide 75 ##STR00288##
613.72 (2S)-1-[(2S)-tetrahydrofuran-2-
ylcarbonyl]-N-(4-{5-{[({(2S)-1- [(2S)-tetrahydrofuran-2-
ylcarbonyl]pyrrolidin-2- yl}carbonyl)amino]-1H-indol-2-
yl}phenyl)pyrrolidine-2- carboxamide 76 ##STR00289## 777.972
N-(tert-butoxycarbonyl)-D-valyl- N-{4-[5-({1-[(2R)-2-
(dimethylamino)-2- phenylacetyl]-L-prolyl}amino)-
1H-indol-2-yl]phenyl}-L- prolinamide 77 ##STR00290## 673.778
(2S)-1-[(2R)-2-(dimethylamino)- 2-phenylacetyl]-N-{2-[4-({[(2S)-
1-(1,3-oxazol-2- ylcarbonyl)pyrrolidin-2-
yl]carbonyl}amino)pyenyl]-1H- indol-5-yl}pyrrolidine-2- carboxamide
78 ##STR00291## 860.032 tert-butyl [(1R)-2-{[(2S)-1-({4-
[5-({(2S)-2-[{(2R)-2-[(tert- butoxycarbonyl)amino]-2-
phenylacetyl}(methyl)amino]pro- pranoyl}amino)-1H-indol-2-
yl]phenyl}amino)-1-oxopropan- 2-yl](methyl)amino}-2-oxo-1-
phenylethyl]carbamate 79 ##STR00292## 567.694 tert-butyl
{(1R)-2-[(2S)-2-({2-[4- (methylamino)phenyl]-1H-indol-
5-yl}carbamoyl)pyrrolidin-1-yl]- 2-oxo-1-phenylethyl}carbamate 80
##STR00293## 696.857 (2S)-1-[(2R)-2-(dimethylamino)-
2-phenylacetyl]-N-(2-[4-({[(2S)- 1-(phenylacetyl)pyrrolidin-2-
yl]carbonyl}amino)phenyl]-1H- indol-5-yl}pyrrolidine-2- carboxamide
81 ##STR00294## 765.964 (2S)-1-{[(3R)-1-benzylpyrrolidin-
3-yl]carbonyl}-N-(4-{5-[({(2S)- 1-[(2R)-2-(dimethylamino)-2-
phenylacetyl]pyrrolidin-2- yl}carbonyl)amino]-1H-indol-2-
yl}phenyl)pyrrolidine-2- carboxamide 82 ##STR00295## 765.964
(2S)-1-{[(3S)-1-benzylpyrrolidin- 3-yl]carbonyl}-N-(4-{5-[({(2S)-
1-[(2R)-2-(dimethylamino)-2- phenylacetyl]pyrrolidin-2-
yl}carbonyl)amino]-1H-indol-2- yl}phenyl)pyrrolidine-2- carboxamide
83 ##STR00296## 719.935 N,N-dimethyl-D-leucyl-N-{4-[5-
({1-[(2R)-2-(dimethylamino)-2- phenylacetyl]-L-prolyl}amino)-
1H-indol-2-yl]phenyl}-L- prolinamide 84 ##STR00297## 577.733
N-(2-{4-[(cyclopentylcarbonyl) amino]phenyl}-1H-indol-5-yl)-1-
[(2R)-2-(dimethylamino)-2- phenylacetyl]-L-prolinamide 85
##STR00298## 652.8 tert-butyl [(2S)-1-({4-[5-({1-
[(2R)-2-(dimethylamino)-2- phenylacetyl]-L-prolyl}amino)-
1H-indol-2-yl]phenyl}amino)-1- oxopropan-2-yl]carbamate 86
##STR00299## 714.872 tert-butyl [(1S)-2-({4-[5-({1-
[(2R)-2-(dimethylamino)-2- phenylacetyl]-L-prolyl}amino)-
1H-indol-2-yl]phenyl}amino)-2- oxo-1-phenylethyl]carbamate 87
##STR00300## 680.855 tert-butyl [(2R)-1-({4-[5-({1-
[(2R)-2-(dimethylamino)-2- phenylacetyl]-L-prolyl}amino)-
1H-indol-2-yl]phenyl}amino)-3- methyl-1-oxobutan-2-
yl]carbamate
Example 88
(2S,2'S)--N,N'-5,6,7,12-tetrahydrobenzo[6,7]cyclohepta[1,2-b]indole-3,9-di-
ylbis[1-(phenylacetyl)pyrrolidine-2-carboxamide]
##STR00301##
[0688] Step 1
##STR00302##
[0690] To a mixture of HNO.sub.3 (4 mL) and H.sub.2SO.sub.4 (2 mL)
at 0.degree. C. was slowly added the above carboxylic acid (2 g,
10.4 mmol). The mixture was stirred under 0.degree. C. for 30
minutes. The resulting solution was poured into 20 mL of H.sub.2O
at 0.degree. C., and the precipitate was filtered to give compound
(2 g) as a yellow solid. MS (ESI) m/e (M+H.sup.+): 238.
Step 2
##STR00303##
[0692] To a mixture of HOAc (10 mL) and Ac.sub.2O (3 mL) was added
the nitro compound from step 1 (1 g, 4.3 mmol) and Pd/C (100 mg,
0.6 mmol). The mixture was stirred under H.sub.2 for 6 hours. The
catalyst was filtered, and the filtrate was concentrated in vacuo
to give the desired compound (1 g) as a brown solid. MS (ESI) m/e
(M+H.sup.+): 236.
Step 3
##STR00304##
[0694] The compound from step 2 above (150 mg, 0.64 mmol) was
slowly added to PPA (6 mL) at 100.degree. C. The mixture was
stirred for 3 hours. After cooling, the resulting solution was
poured into 40 mL mixture of water and ice and extracted with DCM.
The organic layer was concentrated to give the cyclic product (70
mg) as a brown solid. MS (ESI) m/e (M+H.sup.+): 218.
Step 4
##STR00305##
[0696] To a solution of the ketone from step 3 (140 mg, 0.65 mmol)
in 10% HOAc/EtOH (10 mL) was added 4-acetamidophenylhydrazine (144
mg, 0.72 mmol). The mixture was stirred at reflux for 4 hours.
After cooling, the resulting solution was concentrated in vacuo,
washed with water and extracted by EtOAc. The organic layer was
concentrated in vacuo to give the desired compound (200 mg) as a
brown solid. MS (ESI) m/e (M+H.sup.+): 348.
Step 5
##STR00306##
[0698] To a solution of the product from step 4 above (200 mg, 0.57
mmol) in EtOH (10 mL) was added 6N HCl (2 mL, 12 mmol). The mixture
was stirred at reflux overnight and cooled, and the resulting
solution was concentrated then purified by silica gel flash
chromatography (petroleum ether/ethyl acetate=5:1) to give the
desired compound (150 mg) as a brown solid. MS (ESI) m/e
(M+H.sup.+): 264.
Step 6
##STR00307##
[0700] To a solution of the aniline from step 5 (40 mg, 0.15 mmol)
in MeCN (5 mL) was added the proline analog (70 mg, 0.3 mol), HATU
(250 mg, 0.6 mmol) and DIPEA (80 mg, 0.6 mmol). The mixture was
stirred overnight. The resulting solution was purified by pre-HPLC
to give the desired compound (10 mg) as a brown solid. .sup.1H NMR
.delta.: 7.62-7.20 (m, 16H), 4.58-4.54 (m, 2H), 3.79-3.60 (m, 6H),
2.95 (m, 2H), 2.80 (m, 2H), 2.26-1.94 (m, 8H). MS (ESI) m/e
(M+H.sup.+): 694.
Examples 89-98
[0701] Compounds of Examples 89-98 were prepared in a similar
manner as described in Example 88.
TABLE-US-00005 Exam- ple Structure MW Name 89 ##STR00308## 679.826
(2S,2'S)-N,N'6,11-dihydro-5H- benzo[a]carbazole-3,8-diylbis[1-
(phenylacetyl)pyrrolidine-2- carboxamide] 90 ##STR00309## 711.825
dibenzyl (2S,2'S)-2,2'(6,11- dihydro-5H-benzo[a]carbazole-
3,8-diyldicarbamoyl) dipyrrolidine-1-carboxylate 91 ##STR00310##
528.453 N-(8-bromo-6,11-dihydro-5H- benzo[a]carbazol-3-yl)-1-
(phenylacetyl)-L-prolinamide 92 ##STR00311## 910.092 di-tert-butyl
(6,11-dihydro-5H- benzo[a]carbazole-3,8-diylbis
{carbamoyl(2S)pyrrolidine-2,1- diyl[(1S)-2-oxo-1-phenylethane-
2,1-diyl]})biscarbamate 93 ##STR00312## 643.586 tert-butyl
[(1S)-2-{(2S)-2-[(8- bromo-6,11-dihydro-5H- benzo[a]carbazol-3-yl)
carbamoyl]pyrrolidin-1-yl}-2- oxo-1-phenylethyl]carbamate 94
##STR00313## 765.942 (2S,2'S,C)-N,N'6,11-dihydro-5H-
benzo[a]carbazole-3,8-diylbis{1- [(2R)-2-(dimethylamino)-2-
phenylacetyl]pyrrolidine-2- carboxamide} 95 ##STR00314## 779.968
(2S,2'S)-N,N'5,6,7,12- tetrahydrobenzo[6,7]cyclohepta
[1,2-b]indole-3,9-diylbis{1- [(2R)-2-(dirnethylamino)-2-
phenylacetyl]pyrrolidine-2- carboxamide} 96 ##STR00315## 562.718
N-(6,11-dihydro-5H- benzo[a]carbazol-3-yl)-1-{(2S)-
2-[(3,3-dimethylbutanoyl)amino]- 2-phenylacetyl}-L-prolinamide 97
##STR00316## 564.69 tert-butyl{(1R)-2-[(2S)-2-(6,11-
dihydro-5H-benzo[a]carbazol-3- ylcarbamoyl)pyrrolidin-1-yl]-2-
oxo-1-phenylethyl}carbamate 98 ##STR00317## 924.119 di-tert-butyl
(5,6,7,12- tetrahydrobenzo[6,7]cyclohepta [1,2-b]indole-3,9-diylbis
{carbamoyl(2S)pyrrolidine-2,1- diyl[(1R)-2-oxo-1-phenylethane-
2,1-diyl]})biscathamate
Example 99
tert-butyl {(1R)-2-[(2S)-2-(5-{4-[5-({[(2S)-1-{(2R)-2-[(tert-butoxy
carbonyl)amino]-2-phenylacetyl}pyrrolidin-2-yl]carbonyl}amino)-1H-indol-2-
-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamat-
e
##STR00318##
[0702] Step 1
##STR00319##
[0704] HATU (20 g, 52.3 mmol) was added to a heterogeneous mixture
of the amino ketone (12 g, 48.5 mmol) and L-Cbz-Pro (12.4 g, 50
mmol) in MeCN (156 mL). The mixture was cooled in an ice-water
bath, and immediately afterward DIPEA (27 mL, 155 mmol) was added
dropwise. After the addition of the base, the cooling bath was
removed, and the reaction mixture was stirred for an additional 50
minutes. The volatile component was removed, and water (125 mL) was
added to the resulting crude solid and stirred for about 1 hour.
The off-white solid was filtered and washed with copious water, and
dried in vacuo to provide the desired compound as a white solid
(20.68 g). MS (ESI) m/e (M+H.sup.+): 446.
Step 2
##STR00320##
[0706] A mixture of the product from step 1 above (12.8 g, 31.12
mmol) and NH.sub.4OAc (12.0 g, 155.7 mmol) in xylenes (155 mL) was
heated in a sealed tube at 160.degree. C. for 2 hours. The volatile
component was removed in vacuo, and the residue was partitioned
carefully between EtOAc and water, where by enough saturated
NaHCO.sub.3 solution was added so as to make the pH of the aqueous
phase slightly basic after the shaking of the biphasic system. The
layers were separated, and the aqueous layer was extracted with an
additional EtOAc. The combined organic phase was washed with brine,
dried, filtered, and concentrated in vacuo to yield a yellow solid.
MS (ESI) m/e (M+H.sup.+): 426. .sup.1H NMR (CDCl.sub.3) .delta.:
7.31.about.7.52 (m, 9H), 7.17 (s, 1H), 5.12.about.5.20 (m, 2H),
5.00.about.5.01 (m, 1H), 3.50 3.52 (m, 2H), 2.96 2.97 (m, 1H), 1.97
2.17 (m, 3H).
Step 3
##STR00321##
[0708] A mixture of the product from step 2 above (327 mg, 0.77
mmol), indole boronic acid from Example 42 (290 mg, 0.77 mmol),
Pd(dppf)Cl.sub.2 (56 mg, 0.077 mmol), Na.sub.2CO.sub.3 (244 mg, 2.3
mmol), THF (20 mL) and H.sub.2O (2 mL) was refluxed under N.sub.2
overnight. The mixture was poured into water and extracted with
CH.sub.2Cl.sub.2. The organic phase was combined, dried over
Na.sub.2SO.sub.4 and filtered to give the desired compound, which
was used directly in the next step. MS (ESI) m/e (M+H.sup.+):
678.
Step 4
##STR00322##
[0710] A solution of the product of step 3 in HCl/CH.sub.3OH (5 N)
was stirred for 3 hours. Concentration in vacuo afforded the crude
product. MS (ESI) m/e (M+H.sup.+): 478.
Step 5
##STR00323##
[0712] This reaction was carried out using the standard
HATU-mediated coupling procedure described in step 1 between
Boc-L-Pro-OH and the product from step 4 above. MS (ESI) m/e
(M+H.sup.|): 808. .sup.1H NMR (MeOD) .delta.: 8.95 (bs, 1H),
6.82.about.7.56 (m, 17H), 6.50.about.6.62 (m, 1H), 5.74 (bs, 1H),
5.38.about.5.39 (m, 1H), 4.91.about.5.08 (m, 2H), 4.66 (bs, 1H),
3.79 (bs, 1H), 3.40.about.3.54 (m, 2H), 3.19 (bs, 1H),
1.93.about.2.25 (m, 4H), 1.75.about.1.88 (m, 4H), 1.35.about.1.32
(m, 9H).
Step 6
##STR00324##
[0714] To a solution of the product from step 5 (220 mg, 0.3 mmol)
in 20 mL of AcOH was added 3 mL of 48% HBr. The solution was heated
to 80.degree. C. for 6 hours. The volatiles were removed in vacuo,
and the residue was dissolved in DCM/i-PrOH (3:1), washed with
saturated Na.sub.2CO.sub.3 and brine, dried and concentrated in
vacuo to give a solid, which was used in the next step directly. MS
(ESI) m/e (M+H.sup.+): 441.
Step 7
##STR00325##
[0716] A cooled solution containing HATU (0.6 mmol), the diamine
from step 6 above (132 mg, 0.3 mmol) and R-Boc-Pro (129 mg, 0.6
mmol) in MeCN (3 mL), was treated with DIPEA (2.4 mmol), added
dropwise over 13 minutes. After the addition of the base was
completed, the cooling bath was removed, and the reaction mixture
was stirred for an additional 30 minutes. The volatile component
was removed in vacuo; water was added to the resulting crude solid
and stirred for about 1 hour. The off-white solid was filtered,
washed with water, and dried in vacuo to provide the desired
compound as a white solid. MS (ESI) m/e (M+H.sup.+): 908. .sup.1H
NMR (MeOD) .delta.: 7.66.about.7.84 (m, 6H), 7.28.about.7.40 (m,
12H), 6.80 (s, 1H), 5.40.about.5.45 (m, 2H), 5.18 5.20 (m, 1H),
3.70 4.02 (m, 4H), 1.80 2.12 (m, 8H), 1.35.about.1.37 (m, 18H).
Examples 100-116
[0717] Compounds of Examples 100-116 were prepared in a similar
manner as described in Example 99.
TABLE-US-00006 Example Structure MW Name 100 ##STR00326## 807.958
benzyl (2S)-2-[5-(4-{5-[(1- {(2R)-2-[(tert-butoxycarbonyl)
amino]-2-phenylacetyl}-L- prolyl)amino]-1H-indol-2-
yl}phenyl)-1H-imidazol-2- yl]pyrrolidine-1-carboxylate 101
##STR00327## 762.963 1-[(2R)-2-(dimethylamino)-2-
phenylacetyl]-N-{2-[4-(2-{(2S)- 1-[(2R)-2-(dimethylamino)-2-
phenylacetyl]pyrrolidin-2-yl}- 1H-imidazol-5-yl)phenyl]-1H-
indol-5-yl}-L-prolinamide 102 ##STR00328## 604.715
tert-butyl{(1R)-2-[(2S)-2-({2- [4-(1H-imidazol-4-yl)phenyl]-
1H-indol-5-yl}carbamoyl) pyrrolidin-1-yl]-2-oxo-1-
phenylethyl}carbamate 103 ##STR00329## 762.963
1-[(2S)-2-(dimethylamino)-2- phenylacetyl]-N-{2-[4-(2-{(2S)-
1-[(2S)-2-(dimethylamino)-2- phenylacetyl]pyrrolidin-2-yl}-
1H-imidazol-5-yl)phenyl]-1H- indol-5-yl}-L-prolinamide 104
##STR00330## 791.958 tert-butyl{(1R)-2-oxo-1-phenyl-
2-[(2s)-2-{[2-(4-{2-[(2S)-1- (phenylacetyl)pyrrolidin-2-yl]-
1H-imidazol-5-yl}phenyl)-1H- indol-5-yl]carbamoyl}pyrrolidin-
1-yl]ethyl}carbamate 105 ##STR00331## 715.86
tert-butyl{(1R)-2-[(2S)-2-{[2-(4- {2-[(2S)-1-acetylpyrrolidin-2-
yl]-1H-imidazol-5-yl}phenyl)- 1H-indol-5-yl]carbamoyl}
pyrrolidin-1-yl]-2-oxo-1- phenylethyl}carbamate 106 ##STR00332##
793.931 benzyl (2S)-2-(5-{4-[5-({1- [(2R)-2-phenyl-2-{{(propan-2-
yloxy)carbonyl]amino{acetyl]-L- prolyl}amino)-1H-indol-2-
yl]phenyl}-1H-imidazol-2- yl)pyrrolidine-1-carboxylate 107
##STR00333## 835.027 tert-butyl{(1R)-2-[(2S)-2-({2-
[4-(2-{(2S)-1-[(2R)-2- (dimethylamino)-2-
phenylacetyl]pyrrolidin-2-yl}- 1H-imidazol-5-yl)phenyl]-1H-
indol-5-yl}carbamoyl)pyrrolidin- 1-yl]-2-oxo-1-
phenylethyl}carbamate 108 ##STR00334## 893.064 propan-2-yl
[(1R)-2-{(2S)-2-[1- methyl-4-(4-{5-[({(2S)-1-[(2R)-
2-phenyl-2-{[(propan-2- yloxy)carbonyl]amino{acetyl]
pyrrolidin-2-yl}carbonyl)amino]- 1H-indol-2-yl}phenyl)-1H-
imidazol-2-yl]pyrrolidin-1-yl}-2- oxo-1-phenylethyl]carbamate 109
##STR00335## 701.833 propan-2-yl{(1R)-2-[(2S)-2-{[2-
(4-{2-[(2S)-1-acetylpyrrolidin-2- yl]-1H-imidazol-5-yl}phenyl)-
1H-indol-5-yl]carbamoyl} pyrrolidin-1-yl]-2-oxo-1-
phenylethyl}carbamate 110 ##STR00336## 659.795
propan-2-yl{(1R)-2-oxo-1- phenyl-2-[(2S)-2-{[2-(4-{2-
[(2S)-pyrrlidin-2-yl]-1H- imidazol-5-yl}phenyl)-1H-indol-
5-yl]carbamoyl}pyrrolidin-1- yl]ethyl}carbamate 111 ##STR00337##
547.663 propan-2-yl{(lR)-2-[(2S)-2-{5-
[4-(1H-indol-2-yl)phenyl]-1H- imidazol-2-yl}pyrrolidin-1-yl]-2-
oxo-1-phenylethyl}carbamate 112 ##STR00338## 489.626
(2R)-2-(dimethylamino)-1-[(2S)- 2-{5-[4-(1H-indol-2-yl)phenyl]-
1H-imidazol-2-yl}pyrrolidin-1- yl]-2-phenylethanone 113
##STR00339## 879.037 propan-2-yl [(1R)-2-oxo-1-
phenyl-2-{(2S)-2-[5-(4-{5- [({(2S)-1-[(2R)-2-phenyl-2-
{[(propan-2-yloxy)carbonyl] amino}acetyl]pyrrolidin-2-
yl}carbonyl)amino]-1H-indol-2- yl}phenyl)-1H-imidazol-2-yl]
pyrrolidin-1-yl}ethyl]carbamate 114 ##STR00340## 821
propan-2-yl{(1R)-2-[(2S)-2-({2- [4-(2-{(2S)-1-[(2R)-2-
(dimethylamino)-2-phenylacetyl] pyrrolidin-2-yl}-1H-imidazol-5-
yl)phenyl]-1H-indol-5- yl}carbamoyl)pyrrolidin-1-yl]-2-
oxo-1-phenylethyl}carbamate 115 ##STR00341## 582.108
propan-2-yl{(1R)-2-[(2S)-2-{4- [4-(3-chloro-1H-indol-2-
yl)phenyl]-1H-imidazol-2- yl}pyrrolidin-1-yl]-2-oxo-1-
phenylethyl}carbamate 116 ##STR00342## 754.894
N-(methoxycarbonyl)-L-valyl-N- {2-[4-(2-{(2S)-1-[N-
(methoxycarbonyl)-L- valyl]pyrrolidin-2-yl}-1H-
imidazol-5-yl)phenyl]-1H-indol- 5-yl}-1-prolinamide
Example 117
Propan-2-yl
[(1R)-2-oxo-1-phenyl-2-{(2S)-2-[3-(4-{5-[({(2S)-1-[(2R)-2-phenyl-2-{[(pro-
pan-2-yloxy)carbonyl]amino}acetyl]pyrrolidin-2-yl}carbonyl)amino]-1H-indol-
-2-yl}phenyl)-1H-pyrazol-5-yl]pyrrolidin-1-yl}ethyl]carbamate
##STR00343##
[0718] Step 1
##STR00344##
[0720] A solution of 4-bromophenylacetylene (5.0 g, 27.6 mmol) in
THF (100 mL) at 0.degree. C. was treated a solution of EtMgBr (3M
in THF, 9.84 mL, 29.5 mmol). After 10 minutes, the cooling bath was
removed, and the mixture was allowed to stir at RT for 3 hours. The
reaction mixture was then cooled to 0.degree. C. and added to the
Weinreb amide of Z-proline (6.10 g, 20.9 mmol) in THF (50 mL). The
reaction mixture was warmed to RT for 48 hours. The reaction
mixture was quenched with saturated NH.sub.4Cl and diluted with
EtOAc/H.sub.2O. The aqueous phase was back-extracted with EtOAc
(2.times.), and the combined organic layers were washed (H.sub.2O,
brine), dried (Na.sub.2SO.sub.4), and filtered. The solvent was
removed, and the residue was purified by silica gel (PE:
EA=10:1-4:1) to give the product (7.0 g) as a cream-colored solid.
.sup.1H NMR (CDCl.sub.3) .delta.: 7.37.about.7.47 (m, 2H),
7.10.about.7.30 (m, 7H), 4.98.about.5.32 (m, 2H), 4.32 4.47 (m,
1H), 3.45 3.61 (m, 2H), 2.15.about.2.27 (m, 1H), 2.03.about.2.12
(m, 1H), 1.76.about.193 (m, 2H). MS (ESI) m/e (M+H.sup.+): 413.
Step 2
##STR00345##
[0722] A mixture of the product from step 1 (7.0 g, 17 mmol) and
hydrazine hydrate (85%, 1.6 mL) in EtOH (50 mL) was heated at
80.degree. C. for 16 hours. The reaction mixture was cooled and
concentrated to afford the desired product (6.7 g). MS (ESI) m/e
(M+H.sup.+): 426.
Step 3
##STR00346##
[0724] A mixture of the product from step 2 above (0.77 mmol),
indole boronic acid from Example 42 (290 mg, 0.77 mmol),
Pd(dppf)Cl.sub.2 (56 mg, 0.077 mmol), Na.sub.2CO.sub.3 (244 mg, 2.3
mmol), THF (20 mL) and H.sub.2O (2 mL) was refluxed under N.sub.2
overnight. The mixture was poured into water and extracted with
CH.sub.2Cl.sub.2, dried over Na.sub.2SO.sub.4 and filtered to give
the desired compound, which was used directly in the next step. MS
(ESI) m/e (M+H.sup.+): 678.
Step 4
##STR00347##
[0726] A solution of the product from step 3 above (339 mg, 0.5
mmol) was dissolved in 3 mL of DCM and cooled to 0.degree. C. After
the addition of 3 mL of TFA, the reaction mixture was warmed to RT
and stirred for 3 hours. Removal of the solvent left the desired
product as an oil, which was used directly in the next reaction. MS
(ESI) m/e (M+H.sup.+): 378.
Step 5
##STR00348##
[0728] A solution containing PyBOP (0.3 mmol), the amine from step
4 above (132 mg, 0.3 mmol) and N-Boc-L-Pro-OH (62 mg, 0.3 mmol) in
DMF (2 mL) was treated with N-methylmorpholine (1.2 mmol). The
reaction mixture was stirred for 3 hours, diluted with EtOAc and
washed with water (5.times.). The organic phase was dried and
concentrated then chromatographed by RPLC to afford the desired
compound. MS (ESI) m/e (M+H.sup.+): 675.
Step 6
##STR00349##
[0730] The product from step 5 (100 mg, 0.15 mmol) was dissolved in
MeOH and treated with 20 mg of 20% Pd(OH).sub.2 then hydrogenated
at 45 psi for 4 hours. The catalyst was removed by filtration
through CELITE, and the filtrate was evaporated to leave the
desired product. MS (ESI) m/e (M+H.sup.+): 541.
Step 7
##STR00350##
[0732] A solution of the product from step 6 above was dissolved in
2 mL of DCM and 2 mL of TFA. The reaction mixture was stirred for 3
hours before the solvent was evaporated to give the desired product
as an oil, which was used directly in the next reaction. MS (ESI)
m/e (M+H.sup.+): 441.
Step 8
##STR00351##
[0734] A solution containing PyBOP (0.6 mmol), the diamine from
step 7 above (132 mg, 0.3 mmol) and R-i-Proc-Phg-OH (125 mg, 0.6
mmol) in DMF (5 mL) was treated with N-methylmorpholine (2.4 mmol).
The reaction mixture was stirred for 3 hours, diluted with 20 mL of
EtOAc and washed with water (5.times.). The organic phase was dried
and concentrated then chromatographed by RPLC to afford the desired
compound. .sup.1H NMR (MeOD) .delta.: 7.70.about.7.80 (m, 4H),
7.05.about.7.55 (m, 14H), 6.80.about.7.00 (m, 1H), 5.10.about.5.50
(m, 3H), 4.40.about.4.65 (m, 2H), 3.25.about.4.00 (m, 4H),
1.70.about.2.40 (m, 9H), 1.05.about.1.20 (m, 12H). MS (ESI) m/e
(M+H.sup.+): 880.
Example 118
Propan-2-yl
[(1R)-2-oxo-1-phenyl-2-{(2S)-2-[5-(4-{5-[({(2S)-1-[(2R)-2-phenyl-2-{[(pro-
pan-2-yloxy)carbonyl]amino}acetyl]pyrrolidin-2-yl}carbonyl)amino]-1H-indol-
-2-yl}phenyl)-1,3-thiazol-2-yl]pyrrolidin-1-yl}ethyl]carbamate
##STR00352##
[0735] Step 1
##STR00353##
[0737] Ethyl chloroformate (12 mL, 125 mmol) in 180 mL of THF was
added drop-wise to a cooled solution (-5.degree. C.) of compound
Z-Pro-OH (13.8 g, 55.5 mmol), TEA (7.71 mL, 55.5 mmol). The
resulting slurry was stirred for 20 minutes at -5.degree. C. before
saturated NH.sub.4OH (15 mL) was added. The solution was stirred at
RT for 18 hours, volatiles were removed, and the residue was taken
up in EtOAc (180 mL). The undissoloved white precipitate was
filtered off and rinsed with EtOAc (100 mL). The organic layers
were dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give
the desired product (13.5 g) as off-white amorphous solid. MS (ESI)
m/e (M+H.sup.+): 249.
Step 2
##STR00354##
[0739] Lawesson's reagent (16.1 g, 39.9 mmol) was added to a
stirred slurry of the amide (18 g, 72.6 mmol) in PhMe (200 mL) at
RT. The reaction mixture was heated to 100.degree. C. for 3 hours
before the solvent was removed. The residue was purified by flash
SiO.sub.2 chromatography (DCM/MeOH-1:0-20:1) to afford the product
(18 g). MS (ESI) m/e (M+H.sup.+): 265.
Step 3
##STR00355##
[0741] A mixture of the thioamide from step 2 (10.0 g, 37.8 mmol)
and the bromoacetophenone (10.0 g, 35.9 mmol) in EtOH (100 mL) was
heated at 90.degree. C. for 150 minutes. The reaction mixture was
cooled and concentrated, and the residue was purified by SiO.sub.2
chromatography to afford the product (11 g). MS (ESI) m/e
(M+H.sup.+): 444.
Step 4
##STR00356##
[0743] The product from step 3 above can be converted to the final
compounds using the same procedure as described in Example 117,
steps 4-8. .sup.1H NMR (MeOD) .delta.: 7.00.about.8.10 (m, 19H),
5.40.about.5.60 (m, 3H), 4.50.about.4.70 (m, 1H), 3.45.about.4.10
(m, 4H), 3.35.about.3.40 (m, 1H), 1.80.about.2.6 (m, 9H),
1.05.about.1.30 (m, 12H). MS (ESI) m/e (M+H.sup.+): 897.
Example 119
propan-2-yl
[(1R)-2-oxo-1-phenyl-2-{(2S)-2-[2-(4-{5-[({(2S)-1-[(2R)-2-phenyl-2-{[(pro-
pan-2-yloxy)carbonyl]amino}acetyl]pyrrolidin-2-yl}carbonyl)amino]-1H-indol-
-2-yl}phenyl)-1H-imidazol-5-yl]pyrrolidin-1-yl}ethyl]carbamate
##STR00357##
[0744] Step 1
##STR00358##
[0746] To a solution of 4-bromobenzonitrile (1.82 g, 10 mmol) in
anhydrous THF (50 mL) was added LiHMDS (2N, 15 mmol) under N.sub.2
atmosphere at RT, and the mixture was stirred for 1 hour. After
quenching with 1N HCl, the reaction mixture was heated at reflux
for 5 minutes. The precipitate was collected by filtration and then
dried in vacuo to give the desired compound (1.9 g). .sup.1H NMR
(DMSO) .delta.: 7.74 (d, 2H, J=8.2 Hz), 7.62 (d, 2H, J=8.2 Hz) 6.43
(br, 3H).
Step 2
##STR00359##
[0748] To a solution of Cbz-Pro-OH (2.9986 g, 12.0 mmol) in THF
(100 mL) was added TEA (1.7 mL, 12.2 mmol). The solution was cooled
to -25.degree. C. and ethyl chloroformate (1.6 mL, 12.3 mmol) was
added. The resulting solution was stirred at RT for 1 hour. The
precipitate was removed by filtration, and the filtrate was used in
next step without purification. A solution of 0.5 M diazomethane
was added to the above reaction mixture. The sample was stirred at
-10.degree. C. for 1 hour. The reaction mixture was concentrated to
one half of its original volume and washed once with saturated
NaHCO.sub.3 (50 mL). The organic layer was dried over MgSO.sub.4
and filtered. The crude material was adsorbed onto silica gel and
purified by flash chromatography (40 g SiO.sub.2, 0-50% ethyl
acetate in hexanes) to give the diazoketone (2.29 g). .sup.1H NMR
(CDCl.sub.3) .delta.: 7.32 (m, 5H) 5.13 (m, 2H), 4.61 (m, 1H),
3.81, 4.03, 4.17 (s, AB quartet, 2H, J=4.0 Hz), 3.58 (m, 2H),
1.88-2.09, 2.17-2.38 (2, br m, 4H).
[0749] To a solution of the N-carbobenzyloxy-L-proline diazoketone
(1.0 g, 3.6 mmol) in anhydrous diethyl ether (10 mL) was added a
saturated solution of HBr in diethyl ether until N.sub.2 evolution
ceased. The solution was stirred for about 1 hour at about
25.degree. C., then washed with saturated NaHCO.sub.3, water and
brine. The crude material was purified by silica gel column
chromatography and eluted with 40% ethyl acetate in pentane to
obtain the bromoketone (0.49 g) as clear oil. .sup.1H NMR
(CDCl.sub.3; mixture of cis-trans amide rotamers) .delta.: 7.35 (m,
5H), 5.28 (t, 1H), 5.17 (m, 2H), 4.32 (m, 1H), 3.58 (m, 2H),
1.84-2.30 (br m, 4H).
Step 3
##STR00360##
[0751] To a mixture of bromoketone (3.25 g, 10 mmol) and the
amidine (1.97 g, 10 mol) in THF (100 mL) was added NaHCO.sub.3 (1.7
g, 20 mmol), and the suspension was stirred at reflux for 12 hours.
The reaction was cooled, concentrated and chromatographed to give
compound 7 (0.425 g). MS (ESI) m/e (M+H.sup.+): 426, 428.
Step 4
##STR00361##
[0753] The product from step 3 above can be converted to the final
compounds using the same procedure as described in Example 117,
steps 4-8. .sup.1H NMR (MeOD) .delta.: 7.7-8.0 (m, 5H), 7.3-7.5 (m,
10H), 6.9-7.1 (m, 3H), 6.8 (d, J=4.8 Hz, 10H), 5.4-5.6 (m, 2H),
5.2-5.3 (m, 1H), 4.8 (s, 2H), 4.5-4.7 (m, 10H), 4.0 (d, J=2.4 Hz,
1H), 3.7 (d, J=4.84 Hz, 1H), 3.1-3.3 (m, 1H), 2.3-2.5 (m, 1H),
1.8-2.2 (m, 1H), 1.1-1.4 (m, 12H). MS (ESI) m/e (M+H.sup.+):
880.
Example 120
1-[(2R)-2-phenyl-2-{[(propan-2-yloxy)carbonyl]amino}acetyl]-N-{4-[5-(2-{(2-
S)-1-[(2R)-2-phenyl-2-{[(propan-2-yloxy)carbonyl]amino}acetyl]pyrrolidin-2-
-yl}-1H-imidazol-5-yl)-1-benzofuran-2-yl]phenyl}-L-prolinamide
##STR00362##
[0754] Step 1
##STR00363##
[0756] Glyoxal (2.0 mL of 40% in water) was added dropwise to a
MeOH solution of NH.sub.4OH (32 mL) and (S)-Boc-prolinal (8.564 g,
42.98 mmol), then the whole was stirred at ambient temperature for
19 hours. The volatile component was removed in vacuo, and the
residue was purified by a flash chromatography (silica gel, ethyl
acetate) followed by a recrystallization (ethyl acetate) to provide
compound as a white fluffy solid (4.43 g). .sup.1H NMR (DMSO)
.delta.: 11.68/11.59 (br s, 1H), 6.94 (s, 1H), 6.76 (s, 1H), 4.76
(m, 1H), 3.48 (m, 1H), 3.35-3.29 (m, 1H), 2.23-1.73 (m, 4H),
1.39/1.15 (s, 9H).
Step 2
##STR00364##
[0758] NBS (838.4 mg, 4.71 mmol) was added in batches over 15
minutes to a cooled (ice/water) CH.sub.2Cl.sub.2 (20 mL) solution
of imidazole (1.06 g, 4.50 mmol). The reaction mixture was stirred
for 75 minutes and concentrated. The crude material was purified by
RPLC to separate the mono bromide from its dibromo analog and the
starting material. The HPLC elute was neutralized with excess
NH.sub.3/MeOH, and the volatile component was removed in vacuo. The
residue was partitioned between CH.sub.2Cl.sub.2 and water, and the
aqueous layer was extracted with water. The combined organic phase
was dried (MgSO.sub.4), filtered, and concentrated to provide
compound as a white solid (374 mg). .sup.1H NMR (DMSO) .delta.:
12.12 (br s, 1H), 7.10 (m, 1H), 4.70 (m, 1H), 3.31 (m, 1H;
overlapped with water signal), 2.25-1.73 (m, 4H), 1.39/1.17 (s,
3.8H+5.2H).
Step 3
##STR00365##
[0760] To a mixture of the benzofuran from Example 19, step 1 (15
g, 0.05 mol), bis(pinacolato)diboron (25.4 g, 0.1 mol),
Pd(dppf)Cl.sub.2 (1 g), KOAc (0.1 mol) in dioxane (500 mL) was
stirred at reflux under N.sub.2 atmosphere for 2 hours.
Concentration of the reaction mixture left a residue that was
chromatographed to give the desired compound (12 g). .sup.1H NMR
(DMSO) .delta.: 8.28 (d, J=8.8 Hz, 2H), 8.10 (s, 1H), 7.95 (d,
J=8.8 Hz, 2H), 7.72 (d, J=8.8 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.05
(s, 1H).
Step 4
##STR00366##
[0762] This reaction was conducted in a similar manner to that
described in Example 117. MS (ESI) m/c (M+H.sup.+): 475.
Step 5
##STR00367##
[0764] The product from step 4 (475 mg, 1.0 mmol) was dissolved in
EtOH and treated with 20 mg of 10% Pd/C then hydrogenated over 5
hours. The catalyst was removed by filtration through CELITE, and
the filtrate was evaporated to leave the desired product. MS (ESI)
m/e (M+H.sup.+): 445.
Step 6
##STR00368##
[0766] A solution containing HATU (1.0 mmol), the amine from step 5
above (445 mg, 1.0 mmol) and N-Boc-L-Pro-OH (215 mg, 1.0 mmol) in
MeCN (10 mL) was treated with DIPEA (1.2 mmol). The reaction
mixture was stirred for 3 hours, diluted with EtOAc and washed with
water (5.times.). The organic phase was dried and concentrated then
chromatographed by silica gel chromatography (EtOAc) to afford the
desired compound. MS (ESI) m/c (M+H.sup.+): 642.
Step 7
##STR00369##
[0768] A solution of the product from step 6 above was dissolved in
2 mL of DCM and 2 mL of TFA. The reaction mixture was stirred for 3
hours before the solvent was evaporated to give the desired product
as an oil, which was used directly in the next reaction. MS (ESI)
m/e (M+H.sup.+): 442.
Step 8
##STR00370##
[0770] A solution containing BOP reagent (222 mg, 0.5 mmol), the
diamine from step 7 above (112 mg, 0.25 mmol) and R-i-Proc-Phg-OH
(125 mg, 0.6 mmol) in DMF (5 mL) was treated with
N-methylmorpholine (2.4 mmol). The reaction mixture was stirred for
3 hours, diluted with 20 mL of EtOAc and washed with water
(5.times.). The organic phase was dried and concentrated, then
chromatographed by RPLC to afford the desired compound. .sup.1H NMR
(MeOD) .delta.: 6.8-7.9 (m, 19H), 5.1-5.5 (m, 3H), 4.5 (m, 1H),
3.5-4.04 (m, 2H), 1.6-2.5 (m, 9H), 0.9-1.3 (m, 12H). MS (ESI) m/e
(M+H.sup.+): 880.
Example 121
propan-2-yl
{(1R)-2-[(2S)-2-(5-{2-[4-(acetylamino)phenyl]-1H-indol-5-yl}-1,3,4-oxadia-
zol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate
##STR00371##
[0771] Step 1
##STR00372##
[0773] A mixture of 5-carboxyindole (32.2 g, 0.2 mol), NaHCO.sub.3
(53.36 g, 0.64 mol), methyl iodide (122.22 g, 0.86 mol) in 60 mL of
DMF were stirred at RT for 2 days. Water and EtOAc are added, and
the organic layer was washed with bicarbonate solution, dried and
concentrated to obtain 5-(methoxycarbonyl)indole. .sup.1H NMR
(DMSO) .delta.: 11.44 (s, 1H), 8.22 (s, 1H), 7.68 (d, J=8.4 Hz,
1H), 7.37.about.7.47 (m, 2H), 6.56 (d, J=2.0 Hz, 1H), 3.80 (s, 3H).
MS (ESI) m/e (M+H.sup.+): 176.
Step 2
##STR00373##
[0775] A mixture of the ester (28 g, 0.16 mmol) and
NH.sub.2NH.sub.2 (85%, 50 mL) in ethanol (200 mL) was heated at
reflux for 48 hours. The reaction mixture was concentrated, and the
residue was purified by column chromatography (5% MeOH/DCM) to give
compound (25 g). .sup.1H NMR (DMSO) .delta.: 11.27 (s, 1H), 9.54
(s, 1H), 8.06 (s, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.37 (d, J=8.8 Hz,
2H), 4.42 (s, 1H), 6.48 (s, 2H), 3.32 (s, 1H). MS (ESI) m/e
(M+H.sup.+): 176.
Step 3
##STR00374##
[0777] The product from step 3 above was coupled using a standard
HATU amide bond forming procedure. MS (ESI) m/e (M+H.sup.+):
407.
Step 4
##STR00375##
[0779] To a suspension of the product from step 3 above (100 g,
0.25 mol), PPh.sub.3 (98.4 g, 0.375 mol) and DIPEA (96.7 g, 0.75
mol) in CH.sub.3CN (500 mL) at RT was added C.sub.2Cl.sub.6 (82.8
g, 0.35 mol). The reaction was stirred at RT for 1.5 hours, and the
solvent was removed, and the residue was portioned with
EtOAc/H.sub.2O. The layers were separated, the aqueous phase was
re-extracted with EtOAc (2.times.), and the combined organic layers
were removed in vacuo, and the residue purified by column
chromatography (5% MeOH/DCM) to give compound 4 (55 g). MS (ESI)
m/e (M+H.sup.+): 389
Step 5
##STR00376##
[0781] Di-tert-butyl dicarbonate (30.7 g, 142 mmol) was added drop
wise to a solution of indole (55.0 g, 142 mmol), DMAP (2.0 g) and
DIPEA (18.3 g, 142 mmol) in 50 mL of DCM at 0.degree. C. The
reaction was allowed to stir to RT overnight before it was
concentrated, and the residue purified by prep TLC (PE/EA=2:1). MS
(ESI) m/e (M+H.sup.|): 489.
Step 6
##STR00377##
[0783] A mixture of compound indole from step 5 (977 mg, 2 mmol),
(iPrO).sub.3B (3.0 g, 16 mmol) and dry THF (100 mL) was cooled to
0.degree. C. LDA (prepared from n-BuLi and iPr.sub.2NH in THF,
about 8 mmol) was slowly added and the mixture was allowed to warm
to RT over 2 hours. The mixture was quenched by 1N HCl to pH=3 and
extracted with CH.sub.2Cl.sub.2 three times. The combined organic
phases were combined, dried over Na.sub.2SO.sub.4 and filtered. The
filtrate was concentrated and purified by column chromatography
(PE/DCM=1/1 to pure CH.sub.2Cl.sub.2 to
CH.sub.2Cl.sub.2/acetone=10/1 to pure acetone) to afford the
product 8 (0.5 g).
Step 7
##STR00378##
[0785] A mixture of the product from step 6 (0.38 mmol), indole
boronic acid from Example 42 (145 mg, 0.38 mmol), Pd(dppf)Cl.sub.2
(28 mg, 0.038 mmol), Na.sub.2CO.sub.3 (122 mg, 1.15 mmol), THF (10
mL) and H.sub.2O (1 mL) was refluxed under N.sub.2 overnight. The
mixture was poured into water and extracted with CH.sub.2Cl.sub.2.
The organic phase was combined, dried over Na.sub.2SO.sub.4 and
filtered to give the desired compound, which was used directly in
the next step. MS (ESI) m/e (M+H.sup.+): 622.
Step 8
##STR00379##
[0787] The product from step 7 (0.15 mmol) was dissolved in MeOH
and treated with 20 mg of 20% Pd(OH).sub.2 then hydrogenated at 45
psi for 4 hours. The catalyst was removed by filtration through
CELITE, and the filtrate was evaporated then dissolved in 1 mL of
DCM then treated with 1 mL of TFA. After stirring for 2 hours, the
mixture was evaporated and the residue was used directly in the
next reaction without further purification. MS (ESI) m/e
(M+H.sup.+): 488.
Step 9
##STR00380##
[0789] A solution containing PyBOP (44 mg, 0.1 mmol), the amine
from step 8 above (49 mg, 0.1 mmol) and R-i-Proc-Phg-OH (21 mg, 0.1
mmol) in DMF (1 mL) was treated with N-methylmorpholine (0.6 mmol).
The reaction mixture was stirred for 3 hours, diluted with EtOAc
and washed with water (five times). The organic phase was dried and
concentrated, then chromatographed by RPLC to afford the desired
compound. .sup.1H NMR (MeOD): .delta.7.90.about.8.35 (m, 1H),
7.70.about.7.85 (m, 2H), 7.60.about.7.70 (m, 2H), 7.20.about.7.52
(m, 7H), 6.55.about.7.20 (m, 1H), 5.50.about.5.60 (m, 1H),
5.30.about.5.50 (m, 1H), 4.75.about.4.85 (m, 1H), 3.70.about.4.10
(m, 1H), 3.35.about.3.50 (m, 1H), 1.95.about.2.50 (m, 7H),
1.10.about.1.30 (m, 6H). MS (ESI) m/e (M+H.sup.+): 607.
Example 122
(2S)-1-(phenylacetyl)-N-{3-[5-({[(2S)-1-(phenylacetyl)pyrrolidin-2-yl]carb-
onyl}amino)-1H-indol-2-yl]phenyl}pyrrolidine-2-carboxamide
##STR00381##
[0790] Step 1
##STR00382##
[0792] A solution of the hydrazine (1 g, 5 mmol) and
3-acetylacetanilide (0.88 g, 5 mmol) in NMP (5 ml) was heated at
150.degree. C. under microwave for 10 minutes. The solution was
poured into water and extracted with EtOAc three times. The organic
layer was washed with water, dried over sodium sulfate and then
concentrated in vacuo. The residue was purified by RPLC to give the
desired compound. MS (m/z): 308 (M+H).sup.+.
Step 2
##STR00383##
[0794] To aqueous HCl (4N, 5 mL) was added the product from step 1
above (300 mg, 1 mmol), and the mixture was heated at reflux for 1
hour. The reaction mixture was cooled and concentrated, and the
residue was purified by RPLC to give compound (200 mg). MS (m/z):
224 (M+H).sup.+.
Step 3
##STR00384##
[0796] To a solution of the compound from step 2 above (35 mg,
0.148 mmol) in MeCN (5 mL) were added N-phenylacetyl-L-proline (15
mg, 0.0673 mmol), DIPEA (26 mg, 0.202 mmol) and HATU (56 mg, 0.148
mmol). The reaction was stirred overnight and concentrated, and the
residue was purified by RPLC to give the desired product (15 mg).
MS (ESI) m/e (M+H.sup.+): 654. .sup.1H NMR (MeOD) .delta.: 8.0 (m,
1H), 7.7 (m, 1H), 7.6-7.1 (m, 14H), 6.7 (m, 1H), 4.6 (m, 2H),
3.9-3.5 (m, 9H), 2.4-1.7 (m, 8H).
Example 123
(2S)-1-(phenylacetyl)-N-{4-[6-({[(2S)-1-(phenylacetyl)pyrrolidin-2-yl]carb-
onyl}amino)-1H-indol-2-yl]phenyl}pyrrolidine-2-carboxamide
##STR00385##
[0797] Step 1
##STR00386##
[0799] To a stirred solution of 4-ethynylaniline (1 g, 8.5 mmol) in
DCM (60 ml) was added acetyl chloride (0.8 g, 10 mmol) and TEA (1.7
g, 17 mmol). The mixture was stirred for 3 hours. The resulting
solution was washed with water, 1 N HCl and brine. The organic
layer was concentrated in vacuo to give the desired product (900
mg), which was used in next step without purification. MS (ESI) m/e
(M+H.sup.+): 160.
Step 2
##STR00387##
[0801] To a stirred solution of 4-ethynylacetanilide (800 mg, 3.1
mmol) in anhydrous THF (6 ml) was added compound 2 (0.5 g, 3.1
mmol), PdCl.sub.2(PPh).sub.3 (33 mg, 0.05 mmol), CuI (10 mg, 0.05
mmol) and TEA (2 mL). The mixture was protected from light and
stirred at RT overnight. The resulting solution was concentrated in
vacuo, and the residue was washed with DCM to give the desired
compound (300 mg) as a yellow solid. MS (ESI) m/e (M+H.sup.+):
296.
Step 3
##STR00388##
[0803] To a stirred solution of compound from step 2 above (200 mg,
0.68 mmol) in toluene (2 ml) was added InBr.sub.3 (2 mg, 0.004
mmol). The mixture was stirred at reflux for 3 hours. The resulting
solution was washed with water and extracted with EtOAc. The
combined organic layers were dried over sodium sulfate,
concentrated in vacuo to give the desired indole (170 mg) as a
brown solid. MS (ESI) m/e (M+H.sup.+): 296.
Step 4
##STR00389##
[0805] To a stirred solution of the product from step 3 above (100
mg, 0.34 mmol) in EtOH (5 ml) was added 3N HCl (1 mg). The mixture
was stirred at reflux overnight. The resulting solution was
concentrated in vacuo to give the desired aniline (80 mg) as a
brown solid. MS (ESI) m/e (M+H.sup.+): 254.
Step 5
##STR00390##
[0807] To a solution of the aniline from step 4 (50 mg, 0.2 mmol)
in acetonitrile (5 mL) was added N-phenylacetyl-L-proline (56 mg,
0.2 mol), HATU (167 mg, 0.4 mmol) and DIPEA (100 mg, 0.8 mmol). The
mixture was stirred overnight. The resulting solution was purified
by RPLC to give the desired compound (40 mg) as a brown solid. MS
(ESI) m/e (M+H.sup.+): 469.
Step 6
##STR00391##
[0809] To a solution of the nitro compound (40 mg, 0.08 mmol) in
THF (2 mL) was added Pd/C (20 mg, 0.1 mmol). The mixture was
stirred under H.sub.2 atmosphere for 1 hour. After replacement of
H.sub.2 with N.sub.2, the Pd/C was filtered off, and the filtrate
was evaporated in vacuo to give the desired aminoindole (40 mg) as
a brown solid. MS (ESI) m/e (M+H.sup.+): 439.
Step 7
##STR00392##
[0811] To a solution of the product from step 6 above (40 mg, 0.1
mmol) in acetonitrile (5 mL) was added N-phenylacetyl-L-proline (23
mg, 0.1 mmol), HATU (70 mg, 0.2 mmol) and DIPEA (25 mg, 0.2 mmol).
The mixture was stirred overnight. The resulting solution was
purified by RPLC to give the desired compound (15 mg) as a brown
solid. .sup.1H NMR (MeOD) .delta.: 7.81 (m, 1H), 7.70 (d, J=8.6 Hz,
2H), 7.60 (d, J=8.4 Hz, 2H), 7.39 (m, 1H), 7.30-7.28 (m, 10H), 6.96
(m, 1H), 6.69 (s, 1H), 4.63-4.50 (m, 2H), 3.78-3.60 (m, 8H),
2.23-1.92 (m, 8H). MS (ESI) m/c (M+H.sup.+): 654.
Example 124
(2S)-1-(phenylacetyl)-N-{3-[6-({[(2S)-1-(phenylacetyl)pyrrolidin-2-yl]carb-
onyl}amino)-1H-indol-2-yl]phenyl}pyrrolidine-2-carboxamide
##STR00393##
[0812] Step 1
##STR00394##
[0814] To a solution of 3-ethynylaniline (1.17 g, 10 mmol) and 1.5
ml Et.sub.3N in 40 mL DCM was added dropwise acetyl chloride (1 g,
13 mmol). The reaction mixture was stirred at RT for 1 hour. After
that, the solvents were evaporated, and the residue was extracted
with EtOAc (100 mL), washed with water (50 mL) and brine (50 mL),
dried over anhydrous NaSO.sub.4, and concentrated in vacuo to
afford 3-ethynylacetanilide (1.5 g). MS (ESI) m/e (M+H.sup.+):
160.
Step 2
##STR00395##
[0816] 3-nitroaniline (6.9 g, 0.05 mmol) was dissolved in 150 ml
ethanol, iodine chloride (8.1 g, 0.05 mmol) added with dropwise.
The reaction mixture was stirred at RT for 4 hours. After that, the
solvents were evaporated, and the residue was extracted with EtOAc
(100 mL), washed with water (50 mL) and brine (50 mL), dried over
anhydrous NaSO.sub.4. After concentrated in vacuo, the residue was
purified by column chromatography (PE/EtOAc=40:1.fwdarw.20:1) to
afford the desired product (8.9 g). MS (ESI) m/e (M+H.sup.+):
265.
Step 3
##STR00396##
[0818] 3-Ethynylacetanilide (480 mg, 3 mmol) and
2-iodo-5-nitroaniline (800 mg, 3 mmol) were dissolved in anhydrous
THF (30 mL), PdCl.sub.2(PPh.sub.3).sub.2 (105 mg, 0.15 mmol) and
CuI (28.5 mg, 0.15 mmol) Et.sub.3N (1 ml) was added sequentially.
The reaction mixture was protected by N.sub.2 and stirred at RT for
overnight. After that, the solvents were evaporated, and the
residue was extracted with EtOAc (50.times.2 mL), washed with water
(40 mL) and brine (30 mL), dried over anhydrous NaSO.sub.4. After
concentrated in vacuo, the residue was purified by column
chromatography (DCM/MeOH=50:1.fwdarw.20:1) to afford the desired
product (620 mg). MS (ESI) m/e (M+H.sup.|): 296.
Step 4
##STR00397##
[0820] To a solution of the product from step 3 (295 mg, 1.0 mol)
in DCE (15 mL) was added PdCl.sub.2 (9 mg, 0.05 mmol) and
FeCl.sub.3 (8 mg, 0.05 mmol). The reaction mixture was heated at
80.degree. C. for 2 hours. The reaction was cooled, and the
solvents were evaporated, and the residue was extracted with EtOAc
(2.times.), washed with water (30 mL) and brine (30 mL), dried over
anhydrous Na.sub.2SO.sub.4. After concentrated in vacuo, the
residue was purified by Prep-TLC (DCM/MeOH=50:1) to afford the
desired product (240 mg). MS (ESI) m/e (M+H.sup.+): 296. .sup.1H
NMR (DMSO) .delta.: 0.12 (s, 1H), 8.25 (d, J=8.0 Hz, 2H), 7.45-7.94
(m, 6H), 7.03 (s, 1H), 2.10 (s, 3H).
Step 5
##STR00398##
[0822] A suspension of the product from step 4 (200 mg, 0.67 mmol),
Pd/C (10 mg, 0.034 mmol) in 40 mL EtOH was under H.sub.2 protection
and stirred for 1 hour. The mixture was then filtered, and the
filtrate was then concentrated to give the product (160 mg). The
residue was dissolved in 20 ml 3N HCl, the mixture was stirred at
80.degree. C. for 1 hour. It was cooled to RT, concentrated in
vacuo and the residue was purified to give desired compound (120
mg) as a brown solid. MS (m/z) (M+H.sup.+): 224
Step 6
##STR00399##
[0824] The mixture of compound 10 (50 mg, 0.224 mmol),
N-phenylacetyl-L-proline (110 mg, 0.45 mmol), DIPEA (88 mg, 0.7
mmol) in CH.sub.3CN (5 mL) was stirred at RT for 5 minutes, then
HATU (82 mg, 0.54 mmol) was added to it. The mixture was stirred at
RT overnight. When reaction completed, the mixture was concentrated
in vacuo, the residue was purified by chromatography on silica gel
to give the desired target (70 mg). MS (ESI) m/e (M+H.sup.+): 654
.sup.1H NMR (MeOD): .delta. 7.95 (d, J=8.0 Hz, 2H), 7.86.about.7.21
(m, 13H), 6.98 (d, J=8.0 Hz, 1H), 6.72 (s, 1H), 4.57 (m, 2H), 3.53
(m, 3H), 2.02.about.2.31 (m, 8H).
Example 125
tert-butyl
[(1R)-2-{(2S)-2-[(2-{2-[(2S)-1-{(2R)-2-[(tert-butoxycarbonyl)
amino]-2-phenylacetyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1H-indol-5-y-
l)carbamoyl]pyrrolidin-1-yl}-2-oxo-1-phenylethyl]carbamate
##STR00400##
[0825] Step 1
##STR00401##
[0827] The mixture of 4-bromo-1,2-phenylenediamine (3.1 g, 16
mmol), L-proline (4.3 g, 16 mmol), DIPEA (3 ml) in MeCN (100 mL)
was stirred at RT for 5 minutes, then HATU (6 g, 17 mmol) was
added. The mixture was stirred at RT overnight. When reaction
completed, the mixture was concentrated, the residue was washed
with water (100 mL) and extracted with EtOAc (three times), washed
with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4. The
residue purified by was purified by column chromatography
(DCM/MeOH=100:1.fwdarw.50:1) to afford the desired compound (5.0
g). MS (ESI) m/e (M+H.sup.+): (418,420).
Step 2
##STR00402##
[0829] The product from step 1 (5 g, 7.2 mmol) was dissolved in 50
mL acetic acid. The reaction mixture was stirred at 100.degree. C.
for 4 hours. The mixture was cooled, and the acetic acid was
removed in vacuo. The residue was purified by column chromatography
(DCM/MeOH=150:1.fwdarw.100:1) to afford the desired compound (3.8
g). MS (ESI) m/e (M+H.sup.+): (400,402).
Step 3
##STR00403##
[0831] A suspension of the product from step 3 (1.2 g, 3 mmol),
1,5-bis-Boc-5-aminoindole-2-boronic acid (1.2 g, 3 mmol),
Pd(PPh.sub.3).sub.4 (240 mg), Na.sub.2CO.sub.3 (1 g, 9 mmol) and
H.sub.2O (3 mL) in 30 mL of THF under N.sub.2 protection was
reacted with refluxed at 75.degree. C. overnight. The mixture was
filtered, and the filtrate was washed with 50 mL of water and
extracted with 100 ml EtOAc and dried over anhydrous
Na.sub.2SO.sub.4. Removal of the solvent and column chromatography
(CH.sub.2Cl.sub.2/MeOH=250:1.fwdarw.200:1) afforded the desired
compound (500 mg). MS (ESI) m/e (M+H+): 652
Step 4
##STR00404##
[0833] The product from step 3 (500 mg, 0.9 mmol) was stirred in
MeOH/HCl (20 mL) for 16 hours. The solvent was removed under
reduced pressure and the residue was dried at high vacuum. MS (ESI)
m/e (M+H.sup.+): 452.
Step 5
##STR00405##
[0835] The mixture of aniline from step 4 (450 mg, 1 mmol),
(S)--N-Boc proline (215 mg 1 mmol), DIPEA (0.4 mL) in CH.sub.3CN
(10 mL) was stirred at RT for 10 minutes, then HATU (400 mg, 1.1
mmol) was added. The mixture was stirred at RT overnight,
concentrated, and the residue was purified by column chromatography
(CH.sub.2Cl.sub.2/MeOH=250:1.fwdarw.200:1). MS (ESI) m/e
(M+H.sup.+): 649.
Step 6
##STR00406##
[0837] The product from step 5 (290 mg, 0.45 mmol) was dissolved in
5 mL of acetic acid and HBr (1 mL) was added. The reaction mixture
was heated to 70-80.degree. C. and stirred for 4 hours. The mixture
was cooled to RT and concentrated in vacuo. The residue was
extracted with EtOAc (2.times.), washed with aq NaHCO.sub.3 and
water (30 mL) and brine (30 mL), dried over anhydrous sodium
sulfate. Evaporation of the solvent afforded the desired compound
as brown solid (160 mg). MS (ESI) m/e (M+H.sup.+): 415.
Step 7
##STR00407##
[0839] A mixture of the product from step 6 (100 mg, 0.24 mmol),
(R)--N-Boc-Phg (120 mg, 0.48 mmol), DIPEA (0.4 mL) in CH.sub.3CN
(10 mL) was stirred at RT for 10 minutes, then HATU (200 mg, 0.5
mmol) was added. The mixture was stirred at RT overnight then
concentrated, and the residue was purified by RPLC to afford the
desired compound (54 mg). MS (ESI) m/e (M+H.sup.+): 882. .sup.1H
NMR (MeOD) .delta.: 7.96.about.7.69 (m, 4H), 7.49.about.6.84 (m,
13H), 5.50.about.5.40 (m, 2H), 4.06.about.3.94 (m, 2H),
2.27.about.1.88 (m, 8H), 1.37 (s, 18H).
Example 126
(2S)--N-{4-[3-bromo-5-({[(2S)-1-(phenylacetyl)pyrrolidin-2-yl]carbonyl}ami-
no)-1H-indol-2-yl]phenyl}-1-(phenylacetyl)pyrrolidine-2-carboxamide
##STR00408##
[0841] To a solution of the indole (1 equiv) in 5 mL of THF was
added NBS (278 mg, 1 mmol) at RT, and the mixture was stirred for 1
hour. Concentration of the solvent and purification of the residue
by RPLC afforded the targeted halogenated compounds. .sup.1H NMR
(MeOD) .delta.: 7.9-7.5 (m, 5H), 7.4-7.0 (m, 12H), 5.2-4.9 (m, 2H),
4.4 (m, 2H), 3.8-3.5 (m, 6H), 2.5-1.8 (m, 8H).
Example 127
tert-butyl
{(1S)-2-[(2S)-2-({2-[4-(acetylamino)phenyl]-3-fluoro-1H-indol-5-
-yl}carbamoyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate
##STR00409##
[0843] To a solution of the indole (1 equiv.) in acetonitrile/DMSO
(5 ml, 1:1) was added SELECTFLUORO (1 equiv.) at 0.degree. C. The
mixture was stirred at RT for 3 3 hours before it was concentrated,
and the residue purified with RPLC. .sup.1H NMR (MeOD) .delta.:
7.9-7.08 (m, 3H), 7.8-7.7 (m, 2H), 7.5-7.3 (m, 6H), 7.3 (m, 1H),
5.5 (s, 1H), 4.6-4.5 (m, 2H), 4.0-3.9 (m, 1H), 3.8 (m, 1H), 3.7 (m,
1H), 2.4-2.3 (m, 1H), 2.2-2.1 (m, 7H), 2.1-2.0 (m, 3H), 2.0-1.9 (m,
1H), 1.4 (m, 9H). MS (m/z): 711 (M+H).sup.+.
Examples 128-154
[0844] Compounds of Examples 128-154 can be prepared by direct
halogenation of the indole or benzofuran compounds in a similar
manner as described in either Example 126 or Example 127.
TABLE-US-00007 Ex- am- ple Structure MW Name 128 ##STR00410##
688.233 (2S)-N-{4-[3-chloro-5-({[(2S)-1-
(phenylacetyl)pyrrolidin-2- yl]carbonyl}amino)-1H-indol-2-
yl]phenyl}-1-(phenylacetyl) pyrrolidine-2-carboxamide 129
##STR00411## 671.778 (2S)-N-{4-[3-fluoro-5-({[(2S)-1-
(phenylacetyl)pyrrolidin-2- yl]carbonyl}amino)-1H-indol-2-
yl]phenyl}-1-(phenylacetyl) pyrrolidine-2-carboxamide 130
##STR00412## 902.044 tert-butyl{(1S)-2-[(2S)-2-({4-[5-
({[(2S)-1-{(2S)-2-[(tert- butoxycarbonyl)amino]-2-
phenylacetyl}pyrrolidin-2- yl]carbonyl}amino)-3-fluoro-1H-
indol-2-yl]phenyl}[carbamoyl) pyrrolidin-1-yl]-2-oxo-1-
phenylethyl}carbamate 131 ##STR00413## 630.15
tert-butyl{(1S)-2-[(2S)-2-({2-[4- (acetylamino)phenyl]-3-chloro-
1H-indol-5-yl}carbamoyl) pyrrolidin-1-yl]-2-oxo-1-
phenylethyl}carbamate 132 ##STR00414## 779.684
(2S)-N-{4-[3-iodo-5-({[(2S)-1- (phenylacetyl)pyrrolidin-2-yl]
carbonyl}amino)-1H-indol-2-yl] phenyl}-1-(phenylacetyl)
pyrrolidine-2-carboxamide 133 ##STR00415## 710.813
tert-butyl{(1S)-2-[(2S)-2-({2-[4- (1[(2S)-1-acetylpyrrolidin-2-
yl]carbonyl}amino)phenyl]-3- fluoro-1H-indol-5-
yl}carbamoyl)pyrrolidin-1-yl]-2- oxo-1-phenylethyl}carbamate 134
##STR00416## 898.1 (2S)-1-{(2S)-2-[(3,3- dimethylbutanoyl)amino]-2-
phenylacetyl}-N-{4-[5-({[(2S)-1- {(2S)-2-[(3,3-dimethylbutanoyl)
amino]-2-phenylacetyl} pyrrolidin-2-yl]carbonyl}amino)-
3-fluoro-1H-indol-2-yl]pheny} pyrrolidine-2-carboxamide 135
##STR00417## 902.044 tert-butyl{(1R)-2-[(2S)-2-({4-
[5-(1[(2S)-1-{(2R)-2-[(tert- butoxycarbonyl)amino]-2-
phenylacetyl}pyrrolidin-2- yl]carbonyl}amino)-3-fluoro-1H-
indol-2-yl]phenyl}carbamoyl) pyrrolidin-1-yl]-2-oxo-1-
phenylethyl}carbamate 136 ##STR00418## 613.695
tert-butyl{(1R)-2-[(2S)-2-({2- [4-(acetylamino)phenyl]-3-
fluoro-1H-indol-5- yl}carbamoyl)pyrrolidin-1-yl]-2-
oxo-1-phenylethyl}carbamate 137 ##STR00419## 710.813 tert-butyl
{(1R)-2-[(2S)-2-({2- [4-({[(2S)-1-acetylpyrrolidin-2-
yl]carbonyl}amino)phenyl]-3- fluoro-1H-indol-5-
yl}carbamoyl)pyrrolidin-1-yl]-2- oxo-1-phenylethyl}carbamate 138
##STR00420## 639.733 tert-butyl{(1R)-2-[(2S)-2-({3-
fluoro-2-[4-(2-oxopyrrolidin-1- yl)phenyl]-1H-indol-5-
yl}carbamoyl)pyrrolidin-1-yl]-2- oxo-1-phenylethyl}carbamate 139
##STR00421## 567.669 N-{2-[4-(acetylamino)phenyl]-3-
fluoro-1H-indol-5-yl}-1-[(2R)-2- phenyl-2-(pyrrolidin-1-
yl)acetyl]-1-prolinamide 140 ##STR00422## 551.623
N-(tert-butoxycarbonyl)-D- alanyl-N-{2-[4-
(acetylamino)phenyl]-3-fluoro- 1H-indol-5-yl}-L-prolinamide 141
##STR00423## 541.631 N-{2-[4-(acetylamino)phenyl]-3-
fluoro-1H-indol-5-yl}-1-[(2R)-2- (dimethylamino)-2-
phenylacetyl]-L-prolinamide 142 ##STR00424## 593.705
N-(tert-butoxycarbonyl)-D- leucyl-N-{2-[4-
(acetylamino)phenyl]-3-fluoro- 1H-indol-5-yl}-L-prolinamide 143
##STR00425## 815.953 propan-2-yl[(1R)-2-{(2S)-2-[(4-
{5-[({(2S)-1-[(2R)-2- (dimethylamino)-2-
phenylacetyl]pyrrolidin-2-yl} carbonyl)amino]-3-fluoro-1H-
indol-2-yl}phenyl)carbamoyl] pyrrolidin-1-yl}-2-oxo-1-
phenylethyl]carbamate) 144 ##STR00426## 754.866 tert-butyl
(2S)-2-[(3-fluoro-2-{4- [({(2S)-1-[(2R)-2-phenyl-2-
{[(propan-2-yloxy)carbonyl] amino}acetyl]pyrrolidin-2-
yl}carbonyl)amino]phenyl}-1H- indol-5-yl)carbamoyl]
pyrrolidine-1-carboxylate 145 ##STR00427## 935.88 propan-2-yl[
(1R)-2-{(2S)-2-[(4- {3-bromo-5-[({(2S)-1-[(2R)-2-
phenyl-2-{[(propan-2- yloxy)carbonyl]amino}acetyl]
pyrrolidin-2-yl}carbonyl)amino]- 1-benzofuran-2-yl}phenyl)
carbamoyl]pyrrolidin-1-yl}-2- oxo-1-phenylethyl]carbamate 146
##STR00428## 819.806 (2S)-N-(4-{3-bromo-5-[({(2S)-1-
[(2R)-2-(dimethylamino)-2- phenylacetyl]pyrrolidin-2-
yl}carbonyl)amino]-1- benzofuran-2-yl}phenyl)-1-
[(2R)-2-(dimethylamino)-2- phenylacetyl]pyrrolidine-2- carboxamide
147 ##STR00429## 879.772 methyl{(1R)-2-[{(2S)-2-({4-[3-
bromo-5-({[(2S)-1-{(2R)-2- [(methoxycarbonyl)amino]-2-
phenylacetyl}pyrrolidin-2- yl]carbonyl}amino)-1-
benzofuran-2-yl]phenyl} carbamoyl)pyrrolidin-1-yl]-2-
oxo-1-phenylethyl}carbamate 148 ##STR00430## 749.847
methyl{(2S)-1-[(2S)-2-({4-[3- fluoro-5-({[(2S)-1-{(2S)-2-
[(methoxycarbonyl)amino]-3- methylbutanoyl}pyrrolidin-2-
yl]carbonyl}amino)-1H-indol-2- yl]phenyl}carbamoyl)pyrrolidin-
1-yl]-3-methyl-1-oxobutan-2- yl}carbamate 149 ##STR00431## 603.521
N-{2-[4-(acetylamino)phenyl]-3- bromo-1-benzofuran-5-yl}-1-
[(2R)-2-(dimethylamino)-2- phenylacetyl]-L-prolinamide 150
##STR00432## 875.915 (2S)-N-(4-{3-bromo-5-[({(2S)-1-
[(2R)-2-(diethylamino)-2- phenylacetyl]pyrrolidin-2-yl}
carbonyl)amino]-1-benzofuran- 2-yl}phenyl)-1-[(2R)-2-
(dimethylamino)-2-phenylacetyl] pyrrolidine-2-carboxamide 151
##STR00433## 700.639 (2S)-1-acetyl-N-(4-{3-bromo-5-
[({(2S)-1-[(2R)-2- (dimethylamino)-2-phenylacetyl]
pyrrolidin-2-yl}carbonyl)amino]- 1-benzofuran-2-yl}phenyl)
pyrrolidine-2-carboxamide 152 ##STR00434## 963.935
tert-butyl{(1S)-2-[(2S)-2-({4-[3- bromo-5-(1[(2S)-1-{(2S)-2-
[(tert-butoxycarbonyl)amino]-2- phenylacetyl}pyrrolidin-2-
yl]carbonyl}amino)-1- benzofuran-2-yl]phenyl}
carbamoyl)pyrrolidin-1-yl]-2- oxo-1-phenylethyl}carbamate) 153
##STR00435## 733.669 (2S)-N-{4-[3-bromo-5-({[(2S)-1-
(phenylacetyl)pyrrolidin-2-yl] carbonyl}amino)-1-benzofuran-
2-yl]phenyl}-1-(phenylacetyl) pyrrolidine-2-carboxamide 154
##STR00436## 963.935 tert-butyl{(1R)-2-[(2S)-2-({4-
[3-bromo-5-({[(2S)-1-{(2R)-2- [(tert-butoxycarbonyl)amino]-2-
phenylacetyl}pyrrolidin-2- yl]carbonyl}amino)-1-
benzofuran-2-yl]phenyl} carbamoyl)pyrrolidin-1-yl]-2-
oxo-1-phenylethyl}carbamate
Example 155
(2S)--N-{4-[3-cyano-5-({[(2S)-1-(phenylacetyl)pyrrolidin-2-yl]carbonyl}ami-
no)-1H-indol-2-yl]phenyl}-1-(phenylacetyl)pyrrolidine-2-carboxamide
##STR00437##
[0846] A mixture of the bromo compound from Example 126 (150 mg,
0.2 mmol), CuCN (50 mg, 0.6 mmol) and DMF (3 mL) was refluxed under
N.sub.2 protection overnight. The mixture was purified by RPLC to
afford the product. MS (ESI) m/e (M+H.sup.+): 679. .sup.1H NMR
(CDCl.sub.3) .delta.: 7.73-7.70 (m, 4H), 7.38-7.29 (m, 4H),
7.21-7.04 (m, 6H), 4.63-4.60 (m, 1H), 4.49-4.47 (m, 1H), 3.81-3.59
(m, 4H), 2.48-1.97 (m, 8H).
Example 156
(2S)--N-{4-[3-(2,2-dimethylpropanoyl)-5-({[(2S)-1-(phenylacetyl)
pyrrolidin-2-yl]carbonyl}amino)-1H-indol-2-yl]phenyl}-1-(phenylacetyl)pyr-
rolidine-2-carboxamide
##STR00438##
[0848] To a stirred solution of the indole (50 mg, 0.076 mmol) in
CH.sub.2Cl.sub.2 (5 mL) was added anhydrous ZnCl.sub.2 (54 mg, 0.4
mmol) then MeMgBr (3.0 M in Et.sub.2O, 0.4 mL, 0.4 mmol). The
resulting suspension was stirred for 10 minutes at RT and then
cooled to 0.degree. C. at an ice bath. A solution of pivaloyl
chloride (14 mg) in CH.sub.2Cl.sub.2(0.2 mL) was added to the
mixture. The reaction mixture was allowed to warm to RT and stirred
overnight. The reaction mixture was quenched by saturated aqueous
NH.sub.4Cl and exacted with CH.sub.2Cl.sub.2 3 times. The organic
layers were combined, dried over anhydrous Na.sub.2SO.sub.4 and
filtered. The filtrate was concentrated and purified by RPLC to
yield the product. MS (ESI) m/e (M+H.sup.+): 738. .sup.1H NMR
(MeOD) .delta.: 7.69-7.63 (m, 3H), 7.44-7.41 (m, 2H), 7.31-7.21 (m,
12H), 4.55-4.52 (m, 2H), 3.76-3.59 (m, 8H), 2.26-1.94 (m, 8H).
Example 157
5-({[(2S)-1-(phenylacetyl)pyrrolidin-2-yl]carbonyl}amino)-2-[4-({[(2S)-1-(-
phenylacetyl)pyrrolidin-2-yl]carbonyl}amino)phenyl]-1H-indole-3-carboxamid-
e
##STR00439##
[0850] To a solution of the indole (653 mg, 1 mmol) in THF 10 (mL)
was added EtMgBr (2 mL, 6 mmol), and the mixture was stirred at RT
for 30 minutes. Thereto was added chlorosulfonyl isocyanate (140
mg, 1 mmol), and the mixture was stirred at RT for 20 minutes.
Then, DMF (146 mg, 2 mmol) was added to the above mixture, and the
stirring continued for 20 minutes. After adding aqueous NaOH (2N, 1
mL), the resulting solution was heated at reflux for 5 minutes.
Concentration in vacuo, the residue was purified with RPLC to give
(67 mg). .sup.1H NMR (MeOD) .delta.: 8.0 (s, 1H), 7.6 (m, 4H),
7.1-7.4 (m, 12H), 4.5 (m, 4H), 3.5-3.7 (m, 8H), 2.5-2.0 (m,
6H).
Example 158
tert-butyl
{(1R)-2-[(2S)-2-({4-[5-({[(2S)-1-{(2R)-2-[(tert-butoxycarbonyl)-
amino]-2-phenylacetyl}pyrrolidin-2-yl]carbonyl}amino)-3-(cyclopropylcarbam-
oyl)-1H-indol-2-yl]phenyl}carbamoyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}c-
arbamate
##STR00440##
[0851] Step 1
##STR00441##
[0853] To a solution of POBr.sub.3 (113.2 g, 0.4 mol) in DCE (1 L)
was added DMF (14.6 g, 0.2 mol) dropwise under ice bath, and the
mixture was stirred at RT for 30 minutes. Thereto was added nitro
compound (17.8 g, 0.1 mol), and the mixture was stirred at reflux
for 4 hours. The precipitate was collected by filtration and then
washed with water and MeOH. The solid was dried in vacuo to give
the desired compound (13.5 g). .sup.1H NMR (DMSO) .delta.: 13.6 (s,
1H), 9.8 (s, 1H), 8.8 (s, 1H), 8.1 (d, J=9.2 Hz, 1H), 7.6 (d, J=9.2
Hz, 1H).
Step 2
##STR00442##
[0855] To a solution of the aldehyde from step 1 (13.5 g, 0.05 mol)
in DCM (100 mL) was added DMAP (0.6 g, 0.005 mol), TEA (10.1 g, 0.1
mol) and (Boc).sub.2O (21.8 g, 0.1 mol), and the mixture was
stirred at RT overnight. The mixture was concentrated, and the
residue was purified by column chromatography to give the desired
compound (14.7 g). .sup.1H NMR (CDCl.sub.3) .delta.: 9.8 (s, 1H),
8.8 (s, 1H), 8.1 (d, J=9.2 Hz, 1H), 7.6 (d, J=9.2 Hz, 1H), 1.4 (s,
9H).
Step 3
##STR00443##
[0857] The Suzuki coupling procedure was the same as described in
Example 117, step 3. MS (m/z): 482 (M+H).sup.+.
Step 4
##STR00444##
[0859] To a solution of compound from step 3 (2.4 g, 5 mmol) in pH
3.5 phosphate buffer (24 mL) and t-BuOH (30 mL) was added
2-methyl-2-butene (10 mL) and sodium chlorate (0.89 g, 10 mmol).
The reaction was stirred at RT for 16 hours and then extracted with
DCM (3.times.). The combined organic extracts were washed with
brine, dried over anhydrous MgSO.sub.4, and concentrated in vacuo
to give the desired carboxylic acid (2.3 g). MS (m/z): 498
(M+H).sup.+.
Step 5
##STR00445##
[0861] The mixture of compound from step 4 (1 mmol), cyclopropyl
amine (1 mmol), HATU (1 mmol) and DIPEA (5 mmol) in DCM was stirred
at RT overnight. Concentration and purification of the residue by
RPLC gave the desired compound (0.8 mmol). MS (m/z): 538
(M+H).sup.+.
Step 6
##STR00446##
[0863] To a solution of the amide from step 5 (0.8 mmol) in MeOH
(10 mL) was added Pd/C (100 mg) and the mixture was stirred under
H.sub.2 at RT for 1 hour. The Pd/C was removed by filtration, and
the filtrate was concentrated to give the desired compound (0.7
mmol). MS (m/z): 507 (M+H).sup.+.
Step 7
##STR00447##
[0865] To a solution of compound from step 6 (0.7 mmol) in DCM (5
mL) was added TFA (2 mL), and the mixture was stirred at RT
overnight. The solution was concentrated, and the residue was used
in next step without purification. MS (m/z): 307 (M+H).sup.+.
Step 8
##STR00448##
[0867] The coupling procedure was the same as used in Example 72,
step 7. .sup.1H NMR (MeOD) .delta.: 6.9-7.9 (m, 17H), 5.2-5.5 (m,
2H), 4.4-4.5 (m, 2H), 3.5-3.9 (m, 3H), 2.7-2.8 (m, 1H), 1.7-2.2 (m,
8H), 1.4 (s, 18H), 1.2 (m, 1H), 0.4-0.8 (m, 4H). MS (m/z): 967
(M+H).sup.+.
Example 159
tert-butyl
{(1R)-2-[(2S)-2-({4-[5-({[(2S)-1-{(2R)-2-[(tert-butoxy-carbonyl-
)amino]-2-phenylacetyl}pyrrolidin-2-yl]carbonyl}amino)-3-(4-methoxyphenyl)-
-1H-indol-2-yl]phenyl}carbamoyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carba-
mate
##STR00449##
[0868] Step 1
##STR00450##
[0870] NBS (103 mg, 0.5769 mmol) was added in portions to the
solution of the indole (510 mg, 0.5769 mmol) in 20 mL of THF, the
mixture was stirred at RT for 1 hour, then concentrated. The
residue was purified by Prep-HPLC to afford the desired compound
(500 mg). MS (ESI) m/e (M+H.sup.+): 962.
Step 2
##STR00451##
[0872] The mixture of the product from step 1 above (100 mg, 0.104
mmol), 4-methoxy-phenylboronic acid (24 mg, 0.1558 mmol),
Pd(dppf)Cl.sub.2 (7.6 mg, 0.0104 mmol), Na.sub.2CO.sub.3 (3.3 mg,
0.0312 mmol) in 10 mL of dioxane and 2 mL of water was heated to
reflux under N.sub.2 atmosphere overnight. The mixture was cooled
and concentrated, then the residue was purified by RPLC to give the
desired product (30 mg). .sup.1H NMR (MeOD) .delta.:
7.71.about.7.54 (m, 3H), 7.42.about.7.26 (m, 16H), 6.96.about.6.92
(m, 3H), 5.45 (s, 2H), 4.53.about.4.50 (m, 2H), 3.92.about.3.81 (m,
5H), 2.08.about.1.84 (m, 8H), 1.42.about.1.32 (m, 18H). MS (ESI)
m/e (M+H.sup.+): 991.
Examples 160-177
[0873] Compounds of Examples 160-177 were prepared in a similar
manner as described in Examples 155-159.
TABLE-US-00008 Example Structure MW Name 160 ##STR00452## 729.887
(2S)-1-(phenylacetyl)-N-{4-[3- phenyl-5-({[(2S)-1-
(phenylacetyl)pyrrolidin-2- yl]carbonyl}amino)-1H-indol-2-
yl]phenyl}pyrrolidine-2- carboxamide 161 ##STR00453## 681.842
(2S)-N-{4-[3-ethyl-5-({[(2S)-1- (phenylacetyl)pyrrolidin-2-
yl]carbonyl}amino)-1H-indol-2- yl]phenyl}-1-(phenylacetyl)
pyrrolidine-2-carboxamide 162 ##STR00454## 695.826
(2S)-N-{4-[3-acetyl-5-({[(2S)-1- (phenylacetyl)pyrrolidin-2-
yl]carbonyl}amino)-1H-indol-2- yl]phenyl}-1-(phenylacetyl)
pyrrolidine-2-carboxamide 163 ##STR00455## 757.897
(2S)-1-(phenylacetyl)-N-{4-[5- ({[(2S)-1-(phenylacetyl)
pyrrolidin-2-yl]carbonyl}amino)- 3-(phenylcarbonyl)-1H-indol-2-
yl]phenyl}pyrrolidinc-2- carboxamide 164 ##STR00456## 730.874
(2S)-1-(phenylacetyl)-N-{2-[4- ({[(2S)-1-(phenylacetyl)
pyrrolidin-2-yl]carbonyl} amino)phenyl]-3-(pyridin-4-yl)-
1H-indol-5-yl}pyrrolidine-2- carboxamide 165 ##STR00457## 761.886
benzyl(2S)-2-[(4-{5-[({(2S)-1- [(benzyloxy)carbonyl]pyrrolidin-
2-yl}carbonyl)amino]-3-phenyl- 1H-indol-2-yl}phenyl)
carbamoyl]pyrrolidine-1- carboxylate 166 ##STR00458## 678.798
(2S)-N-{4-[3-cyano-5-({[(2S)-1- (phenylacetyl)pyrrolidin-2-
yl]carbonyl}amino)-1H-indol-2- yl]phenyl}-1-(phenylacetyl)
pyrrolidine-2-carboxamide 167 ##STR00459## 693.853
(2S)-N-{4-[3-cyclopropyl-5- ({[(2S)-1-(phenylacetyl)
pyrrolidin-2-yl]carbonyl}amino)- 1H-indol-2-yl]phenyl}-1-
(phenylacetyl)pyrrolidine-2- carboxamide 168 ##STR00460## 791.912
benzyl (2S)-2-[(4-{5-[({(2S)-1- [(benzyloxy)carbonyl]pyrrolidin-
2-yl}carbonyl)amino]-3-(3- methoxyphenyl)-1H-indol-2-
yl}phenyl)carbamoyl]pyrrolidine- 1-carboxylate 169 ##STR00461##
974.18 tert-butyl {(1R)-2-[(2S)-2-({4- 5-({[(2S)-1-{(2R)-2-[(tert-
butoxycarbonyl)amino]-2- phenylacetyl}pyrrolidin-2-
yl]carbonyl}amino)-3-(3- methylphenyl)-1H-indol-2-
yl]phenyl}carbamoyl)pyrrolidin- 1-yl]-2-oxo-1-
phenylethyl}carbamate 170 ##STR00462## 974.18 tert-butyl
{(1R)-2-[(2S)-2-({4- [5-({[(2S)-1-{(2R)-2-[(tert-
butoxycarbonyl)amino]-2- phenylacetyl}pyrrolidin-2-
yl]carbonyl}amino)-3-(2- methylphenyl)-1H-indol-2-
yl]phenyl}carbamoyl)pyrrolidin- 1-yl]-2-oxo-1-
phenylethyl}carbamate 171 ##STR00463## 961.14
tert-butyl{(1R)-2-[(2S)-2-({2- [4-({[(2S)-1-{(2R)-2-[(tert-
butoxycarbonyl)amino]-2- phenylacetyl}pyrrolidin-2-
yl]carbonyl}amino)phenyl]-3- (pyridin-4-yl)-1H-indol-5-
yl}carbamoyl)pyrrolidin-1-yl]-2- oxo-1-phenylethyl}carbamate 172
##STR00464## 909.064 tert-butyl{(1R)-2-[(2S)-2-({4-
[5-({(2S)-1-{(2R)-2-[(tert- butoxycarbonyl)amino]-2-
phenylacetyl}pyrrolidin-2- yl]carbonyl}amino)-3-cyano-1H-
indol-2-yl]phenyl}carbamoyl) pyrrolidin-1-yl]-2-oxo-1-
phenylethyl}carbamate 173 ##STR00465## 764.936
(2S)-N-(4-{3-cyano-5-[({(2S)-1- [(2R)-2-(dimethylamino)-2-
phenylacetyl]pyrrolidin-2- yl}carbonyl)amino]-1H-indol-2-
yl}phenyl)-1-[(2R)-2- (dimethylamino)-2-phenylacetyl]
pyrrolidine-2-carboxamide 174 ##STR00466## 620.714 tert-butyl
{(1R)-2-[(2S)-2-({2- [4-(acetylamino)phenyl]-3- cyano-1H-indol-5-
yl}carbamoyl)pyrrolidin-1-yl]-2- oxo-1-phenylethyl}carbamate 175
##STR00467## 955.133 tert-butyl{(1R)-2-[(2S)-2-({4-
[5-({[(2S)-1-{(2R)-2-[(tert- butoxycarbonyl)amino]-2-
phenylacetyl}pyrrolidin-2- yl]carbonyl}amino)-3-
(dimethylcarbamoyl)-1H-indol- 2-yl]phenyl}carbamoyl)
pyrrolidin-1-yl]-2-oxo-1- phenylethyl}carbamate 176 ##STR00468##
942.091 methyl 5-({[(2S)-1-{(2R)-2- [(tert-butoxycarbonyl)amino]-2-
phenylacetyl}pyrrolidin-2- yl]carbonyl}amino)-2-[4-({[(2S)-
1-{(2R)-2-[(tert- butoxycarbonyl)amino]-2-
phenylacetyllpyrrolidin-2- yl]carbonyl}amino)phenyl]-1H-
indole-3-carboxylate 177 ##STR00469## 928.064
5-({[(2S)-1-{(2R)-2-[(tert- butoxycarbonyl)amino]-2-
phenylacetyl}pyrrolidin-2- yl]carbonyl}amino)-2-[4-({[(2S)-
1-{(2R)-2-Rtert-butoxycarbonyl) amino]-2-phenylacetyl}
pyrrolidin-2-yl]carbonyl}amino) phenyl]-1H-indole-3-carboxylic
acid
Example 178
tert-butyl
{(1R)-2-[(2S)-2-({2-[3-(acetylamino)prop-1-yn-1-yl]-1H-indol-5--
yl}carbamoyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate
##STR00470##
[0874] Step 1
##STR00471##
[0876] Ethyl carbonochloridate (3 mL) was added to the nitro lactam
(2.0 g, 11.2 mmol), and the mixture was stirred for 3 hours before
being concentrated to give the crude product. MS (ESI) m/e (M+H+):
325. The crude product was dissolved in DMF (25 mL), then
(NH.sub.4).sub.2CO.sub.3 (1.5 g) was added, and the mixture was
stirred overnight. The mixture was evaporated and the residue was
poured into ice-water and extracted with DCM, and the organics were
dried. The solvent was removed, and the residue was purified by
chromatography on silica gel to give the desired compound as a
white solid. MS (ESI) m/e (M+H.sup.+): 251.
Step 2
##STR00472##
[0878] The mixture of the triflate (382 mg, 1.0 mmol),
N-(prop-2-ynyl)acetamide (97 mg, 1.0 mmol), Et.sub.3N (3 mL) in
CH.sub.3CN (3 mL) was stirred at RT for 3 hours. The mixture was
concentrated, and the residue was purified by chromatography on
silica gel to give compound target compound (254 mg). MS (ESI) m/e
(M+H.sup.+): 330.
Step 3
##STR00473##
[0880] A solution of the nitro compound from step 2 above (165 mg,
0.50 mmol) in absolute EtOH (3 mL) was added Fe power (280 mg, 2.5
mmol) and NH.sub.4Cl (535 mg, 5.0 mmol). The mixture was stirred at
70.degree. C. for 2 hours, cooled and poured into ice/water (50
ml). The mixture was extracted with EtOAc (200 ml), and the organic
phase was combined and washed with brine, dried and concentrated to
yield the crude product (150 mg). MS (ESI) m/z: (M+H) 300.
Step 4
##STR00474##
[0882] To a solution of the aniline from step 3 (150 mg, 0.50 mmol)
in absolute EtOH (3 mL) was added K.sub.2CO.sub.3 (138 mg, 1.0
mmol), and the mixture was stirred at RT for 12 hours. The reaction
mixture was poured into water (10 mL), extracted with EtOAc (20
mL), and the organic phases were combined and washed with brine,
dried over MgSO.sub.4 and concentrated to yield the crude product
(113 mg). MS (ESI) m/z: (M+H+) 228.
Step 5
##STR00475##
[0884] The mixture of the indole (113 mg, 0.5 mmol),
R-Boc-Phg-L-Pro-OH (175 mg, 0.5 mmol), DIPEA (115 mg, 1.0 mmol) in
MeCN (2 mL) was stirred at RT for 5 minutes, then HATU (190 mg, 0.5
mmol) was added into the mixture. The mixture was stirred at RT
overnight then concentrated. The residue was purified by RPLC to
give the desired compound (110 mg). .sup.1H NMR (MeOD) .delta.:
1.37 (s, 9H), 1.96.about.2.14 (m, 7H), 3.92.about.3.94 (m, 2H),
4.51.about.4.54 (m, 1H), 5.41 (s, 1H), 6.56 (s, 1H),
7.20.about.7.43 (m, 7H), 7.72 (s, 1H). MS (ESI) m/z: (M+H+)
576.
Example 179
N-{4-[5-(furan-3-yl)-1H-indol-2-yl]phenyl}-1-(phenylacetyl)-L-prolinamide
##STR00476##
[0885] Step 1
##STR00477##
[0887] The mixture of the indole from Example 41 (1.6 mg, 5.575
mmol), 1-phenylacetyl pyrrolidine-2-carboxylic acid (1.3 g, 5.575
mmol), DIPEA (1.45 g, 11.15 mmol) in DMF (50 mL) was stirred at RT
for 30 minutes, then HATU (2.54 g, 6.689 mmol) was added. The
mixture was stirred at RT overnight, concentrated in vacuo, and the
residue was purified by chromatography on silica gel to give the
desired product (2.3 g). MS (ESI) m/e (M+H.sup.+): 504.
Step 2
##STR00478##
[0889] A suspension of the product from step 1 above (18 mg,
0.03583 mmol), furan-2-boronic acid (6 mg, 0.05374 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (1.4 mg), Na.sub.2CO.sub.3 (7.6 mg,
0.07166 mmol) and H.sub.2O (0.15 mL) in 0.5 mL of acetonitrile
under N.sub.2 protection was heated at 150.degree. C. for 10
minutes in a microwave reactor. The mixture was cooled, filtered
and washed with 10 mL of DCM. The solvents were removed, and the
residue was purified by HPLC to give the desired product. .sup.1H
NMR (MeOD) .delta.: 7.79.about.7.74 (m, 3H), 7.67.about.7.62 (m,
3H), 7.50 (s, 1H), 7.37.about.7.22 (m, 6H), 6.78.about.6.75 (m,
2H), 4.57.about.4.55 (m, 1H), 3.78.about.3.61 (m, 4H),
2.24.about.1.99 (m, 4H).
Examples 180-189b
[0890] Compounds of Examples 180-189b were prepared in a similar
manner as described in Example 179.
TABLE-US-00009 Example Structure MW Name 180 ##STR00479## 557.701
N-(4-{5-[6-(dimethylamino)-4- methylpyridin-3-yl]-1H-indol-2-
yl}phenyl)-1-(phenylacetyl)-1- prolinamide 181 ##STR00480## 555.704
N-{4-[5-(1-benzothiophen-3-yl)- 1H-indol-2-yl]phenyl}-1-
(phenylacetyl)-1-prolinamide 182 ##STR00481## 579.708
N-{4-[5-(1-benzyl-1H-pyrazol-4- yl)-1H-indol-2-yl]phenyl}-1-
(phenylacetyl)-L-prolinamide 183 ##STR00482## 557.655
N-{4-[5-(2,3-dihydro-1,4- benzodioxin-6-yl)-1H-indol-2-
yl]phenyl}-1-(phenylacetyl)-L- prolinamide 184 ##STR00483## 550.666
1-(phenylacetyl)-N-{4-[5- (quinolin-8-yl)-1H-indol-2-
yl]phenyl}-L-prolinamide 185 ##STR00484## 505.644
1-(phenylacetyl)-N-{4-[5- (thiophen-3-yl)-1H-indol-2-
yl]phenyl}-L-prolinamide 186 ##STR00485## 563.662 tert-butyl
{(1S)-2-[(2S)-2-{[4-(5- cyano-1H-indol-2-yl)phcnyl]
carbamoyllpyrrolidin-1-yl]-2- oxo-1-phenylethyl}carbamate 187
##STR00486## 879.037 propan-2-yl [(1R)-2-oxo-1-
phenyl-2-{(2S)-2-[4-(2-{4- [({[(2S)-1-[(2R)-2-phenyl-2-
{[(propan-2-yloxy)carbonyl] amino}acetyl]pyrrolidin-2-
yl}carbonyl)amino]phenyl}-1H- indol-5-yl)-1H-imidazol-2-yl]
pyrrolidin-1-yl}ethyl]carbamate 188 ##STR00487## 606.687
propan-2-yl {(1R)-2-[(2S)-2-(5- {2-[4-(acetylamino)phenyl]-
1H-indol-5-yl}-1,3,4-oxadiazol-2- yl)pyrrolidin-1-yl]-2-oxo-1-
phenylethyl}carbamate 189 ##STR00488## 576.704
N-{4-[5-(5-{(2S)-1-[(2R)-2- (diethylamino)-2-
phenylacetyl]pyrrolidin-2-yl}- 1,3,4-oxadiazol-2-yl)-1H-indol-
2-yl]phenyl}acetamide 189a ##STR00489## 806.9 methyl
[(2S)-1-{(2S)-2-[5-(10- {2-[(2S)-1-{(2S)-2-
[(methoxycarbonyl)amino]-3- methylbutanoyl}pyrrolidin-2-yl]-
1H-imidazo1-5-yl}indolo[1,2-c] [1,3]benzoxazin-3-yl)-1H-
imidazol-2-yl]pyrrolidin-1-yl}-3- methyl-1-oxobutan-2- yl]carbamate
189b ##STR00490## 824.9 methyl [(2S)-1-{(2S)-2-[5-(12-
fluoro-10-{2-[(2S)-1-{(2S)-2- [(methoxycarbonyl)amino]-3-
methylbutanoyl}pyrrolidin-2-yl]- 1H-imidazol-5-yl}indolo[1,2-c]
[1,3]benzoxazin-3-yl)-1H- imidazol-2-yl]pyrrolidin-1-yl}-3-
methyl-1-oxobutan-2- yl]carbamate
Example 189b
Alternative Procedure: Methyl
[(2S)-1{(2S)-2-[5-(12-fluoro-10-{2-[(2S)-1-{(2s)-2-[(methoxycarbonyl)amin-
o]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}indolo[1,2-c][1,3]be-
nzoxazin-3-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]-
carbamate
##STR00491##
[0891] Step 1
##STR00492##
[0893] To a solution of compound 3-bromophenol (51 g, 0.3 mol) and
Et.sub.3N (36 g, 0.36 mol) in 500 mL of DCM was added dropwise
acetyl chloride (26 g, 0.33 mol) in an ice-water bath. The mixture
was stirred at RT for 30 minutes. The mixture was washed with 1 N
HCl, saturated Na.sub.2CO.sub.3 and brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo to give a oil (62
g).
Step 2
##STR00493##
[0895] AlCl.sub.3 (40 g, 0.3 mol) was slowly added to the product
from step 1 (21.5 g, 0.1 mol) in an ice-water bath. The mixture was
stirred at 140.degree. C. for 2 hours. After cooling to
60-70.degree. C., the mixture was slowly poured into an ice water.
The resulting solution was extracted with DCM. The combined organic
phases were washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated in vacuo. The residue was purified by column
chromatography to give the desired compound (14 g). MS (ESI) m/e
(M+H.sup.+): 214.
Step 3
##STR00494##
[0897] A mixture of the ketone obtained in step 2 (4.2 g, 20 mmol)
and 4-bromophenyl hydrazine hydrochloride (4.4 g, 20 mmol) in AcOH
and EtOH (1:10, 100 mL) was heated to reflux for 6 hours. The
solvent was removed in vacuo to give a solid, which was used in the
next step without further purification (9.2 g crude). MS (ESI) m/e
(M+H.sup.+): 383.
Step 4
##STR00495##
[0899] A mixture of product from step 3 (9.2 g) in PPA was heated
to 80.degree. C. for 2 hours. After cooling to RT, the mixture was
poured into ice water. The resulting solution was extracted with
DCM. The combined organic phases were washed with brine, dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was
purified by column chromatography to give the desired indole (4.8
g). MS (ESI) m/e (M+H.sup.+): 368.
Step 5
##STR00496##
[0901] To a mixture of the indole from step 4 (6 g, 16.3 mmol) in
DMSO/CH.sub.3CN (1:1, 24 mL) was added SELECTFLUOR.RTM. (5.8 g,
16.3 mmol) in portion at RT. The mixture was stirred for an
additional 1 hour at RT, and the mixture was purified by HPLC to
give a solid (1.0 g). MS (ESI) m/e (M+H.sup.+): 386.
Step 6
##STR00497##
[0903] A mixture of the compound from step 5 (650 mg, 1.63 mmol),
CH.sub.2Br.sub.2 (1.5 g, 8.62 mmol) and K.sub.2CO.sub.3 (1.2 g, 8.7
mmol) in DMF (32.5 mL) was stirred for 5 hours at 80.degree. C.
Then the mixture was evaporated in vacuo. The residue was diluted
with EA and water. The organic layer was separated, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo to give a solid, which
was directly used to next step without further purification (610
mg). MS (ESI) m/e (M+H.sup.+): 396.
Step 7
##STR00498##
[0905] To a solution of the product from step 6 (1 mmol) in
1,4-dioxane was added bis pinacol borate (1.1 mmol) and
Pd(dppf)Cl.sub.2 (0.02 mmol) and KOAc (2 mmol). The reaction
mixture was stirred under N.sub.2 and heated to 110.degree. C. for
3 hours. After that, the solvent was removed under vacuum, and the
residue was purified by column chromatography to afford the
product. MS (ESI) m/e (M+H.sup.+): 492.
Step 8
##STR00499##
[0907] A suspension of the boronate from above (2 mmol), tert-butyl
2-(2-bromo-1H-imidazol-5-yl) pyrrolidine-1-carboxylate (2.4 mmol),
Pd(dppf) Cl.sub.2 (200 mg), Na.sub.2CO.sub.3 (3 mmol) and in
THF/H.sub.2O (10:1, 33 mL) was refluxed at 75.degree. C. overnight
under N.sub.2 protection. The mixture was cooled and filtered, and
the filtrate was washed with water (50 mL) and extracted with EtOAc
(100 mL), washed with brine and dried over anhydrous sodium
sulfate. After concentrated in vacuo, the residue was purified by
column chromatography to afford the desired compound. MS (ESI) m/e
(M+H.sup.+): 710.
Step 9
##STR00500##
[0909] The protected proline from above (1.3 mmol) was added to
HCl/CH.sub.3OH (10 mL, 3M). The mixture was stirred at RT for 2-3
hours before the mixture was concentrated to give the crude
product, which was used in the next step without further
purification. MS (ESI) m/e (M+H.sup.+): 510
Step 10
##STR00501##
[0911] To a mixture of the crude product from step 9 (1.0 mmol),
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (2.0 mmol) and
DIPEA (8 mmol) in CH.sub.3CN (10 mL) was added BOP (2.2 mmol). The
resulting mixture was stirred at RT. After LCMS showed the starting
material to be consumed, the mixture was filtered, and the filtrate
was purified by HPLC to give the desired compound as a white solid.
MS (ESI) m/e (M+H.sup.+): 825. .sup.1H NMR (MeOD): .delta.
7.83-7.85 (m, 3H), 7.72 (s, 1H), 7.53 (s, 2H), 7.46-7.48 (m, 1H),
7.42 (s, 1H), 5.92 (s, 2H), 5.20-5.22 (m, 2H), 4.20-4.23 (m, 2H),
4.06-4.09 (m, 2H), 3.86-3.88 (m, 2H), 3.61 (s, 6H), 2.50-2.52 (m,
2H), 1.96-2.20 (m, 8H), 0.90-0.98 (m, 12H).
Example 190
(2S)-1-[(2R)-2-(dimethylamino)-2-phenylacetyl]-N-(2-{5-[({(2S)-1-[(2R)-2-(-
dimethylamino)-2-phenylacetyl]pyrrolidin-2-yl}carbonyl)amino]-1,3-benzoxaz-
ol-2-yl}-1H-indol-5-yl)pyrrolidine-2-carboxamide
##STR00502##
[0912] Step 1
##STR00503##
[0914] To a solution of imidazole (13.6 g, 0.2 mol) in 1 L of DCM
was added BrCN (7.4 g, 66 mmol), and the mixture was heated at
reflux for 30 minutes. The mixture was cooled to RT, and the white
precipitate removed by filtration, and the filtrate concentrated to
100 mL then cooled to 0.degree. C. for 2 days. The crystallized
solid was filtered and washed with cold DCM, then dried in vacuo to
give the desired product (8.8 g) as a white solid.
Step 2
##STR00504##
[0916] A solution containing the product from step 1 (8.36 g, 54.2
mmol) and 2-amino-4-nitrophenol (8.74 g, 54.2 mmol) in anhydrous
THF (200 mL) was allowed to reflux under N.sub.2 for 14 hours. The
mixture was cooled to RT, filtered, and the precipitate was washed
with THF (cold) then dried in vacuo to afford the desired product
(9.0 g), as a yellow solid. MS (ESI) m/c (M+H.sup.|): 180. .sup.1H
NMR (DMSO) .delta.: 7.85.about.7.96 (m, 3H), 7.52 (d, J=8.8 Hz,
1H).
Step 3
##STR00505##
[0918] To a suspension of the product from step 2 (3.58 g, 20 mmol)
in acetonitrile (300 mL) was added CuBr.sub.2 (8.96 g, 40 mmol).
The solution became dark green and t-butyl nitrite (4.12 g, 40
mmol) was added RT over 5 minutes, whereupon the mixture heated at
45.degree. C. for 2 hours. The reaction mixture was poured into
water (800 mL) and DCM (800 mL), and the phases were separated. The
aqueous phase was extracted with DCM (3.times.800 mL), dried with
Na.sub.2SO.sub.4 and evaporated to afford the crude product.
Purification by column chromatography afforded the desired product.
MS (ESI) m/e (M+H.sup.+): 243/245. .sup.1H NMR (DMSO) .delta.: 8.71
(s, 1H), 8.42 (d, J=9.2 Hz, 1H), 8.10 (d, J=9.2 Hz, 1H).
Step 4
##STR00506##
[0920] The mixture of compound from step 3 above (603 mg, 2.5
mmol), the indole boronic acid from Example 42 (1.0 g, 2.75 mmol),
Pd(dppf)Cl.sub.2 (183 mg, 0.25 mmol), Na.sub.2CO.sub.3 (530 mg, 5.0
mmol) in 5 mL dioxane-H.sub.2O (5:1) was heated to reflux under
N.sub.2 atmosphere overnight. When reaction was complete, the
mixture was poured into water and extracted with DCM. The organic
phase was dried over Na.sub.2SO.sub.4 and concentrated, and the
residue was purified to give compound the desired product. MS (ESI)
m/e (M+H.sup.+): 596.
Step 5
##STR00507##
[0922] The product from step 4 (596 mg, 1.0 mmol) was dissolved in
EtOAc and treated with Pd/C (100 mg, 20%). Then, the mixture was
stirred at RT overnight under H.sub.2 atmosphere. When the reaction
was complete, the Pd/C was filtered off, and the resulting solution
was concentrated to give the crude product MS (ESI) m/e
(M+H.sup.+): 565. This material was covered with 5 mL of 3M HCl,
and the mixture was stirred at RT for 2 hours. Evaporation of the
solvent afforded the desired product, which was used directly
without further purification. MS (ESI) m/e (M+H.sup.+): 265.
Step 6
##STR00508##
[0924] The compound was coupled using the procedure similar to that
which was described in Example 40 starting from 265 mg (1.0 mmol)
of the product from step 5. .sup.1H NMR (MeOD) .delta.: 8.12 (s,
1H), 7.97 (d, J=2 Hz, 1H), 7.30.about.7.70 (m, 15H),
5.30.about.5.35 (m, 2H), 4.51.about.4.60 (m, 2H), 3.85.about.3.95
(m, 2H), 3.15.about.3.25 (m, 2H), 3.06 (s, 3H), 2.54 (s, 6H),
1.80.about.2.30 (m, 8H). MS (ESI) m/e (M+H.sup.+): 781.
Example 191
1-[(2R)-2-(diethylamino)-2-phenylacetyl]-N-{2-[4-(5-{(2S)-1-[(2R)-2-(dieth-
ylamino)-2-phenylacetyl]pyrrolidin-2-yl}-1,3,4-oxadiazol-2-yl)phenyl]-H-in-
dol-5-yl}-L-prolinamide
##STR00509##
[0925] Step 1
##STR00510##
[0927] To a solution of N-Cbz-L-Pro (14.9 g, 0.06 mol) and TEA
(8.08 g, 0.08 mol) in 100 mL of DCM added dropwise isopropyl
chloroformate (8.05 g, 0.066 mol) at 0.degree. C. After addition,
the solution was continued to stir for 1 hour before the hydrazide
(13.0 g, 0.05 mol) was added, and the mixture was continued to stir
for another 1 hour. The solvent was evaporated in vacuo, and the
residue was recrystallized from EtOH to give a white solid (22.1
g). .sup.1H NMR (DMSO) .delta.: 10.47 (s, 1H), 10.03 (s, 1H), 7.86
(d, J=8.0 Hz, 2H), 7.62 (d, J=8.0 Hz, 2H), 7.31.about.7.61 (m, 5H),
4.91.about.5.14 (m, 2H), 4.26 4.35 (m, 1H), 3.30.about.3.4 (m, 2H),
1.95.about.2.19 (s, 4H). MS (ESI) m/e (M+H.sup.+): 494.
Step 2
##STR00511##
[0929] To a solution of the product from step 1 (2.1 g, 4.26 mmol),
DIPEA (2.3 mL, 17.7 mmol) and PPh.sub.3 (1.71 g, 6.5 mmol) in 20 mL
of MeCN was added hexachloroethane (1.41 g, 5.97 mmol), and the
mixture was stirred at RT for 1.5 hours. The solvent was
evaporated, and the residue was purified by chromatography to give
a white solid (1.75 g). MS (ESI) m/e (M+H.sup.+): 494.
Step 3
##STR00512##
[0931] A mixture of the product from step 2 above (494 mg, 1.0
mmol), indole boronic acid from Example 42 (377 mg, 1.0 mmol),
Pd(dppf)Cl.sub.2 (73 mg, 0.10 mmol), Na.sub.2CO.sub.3 (318 mg, 3.0
mmol), THF (25 mL) and H.sub.2O (5 mL) was refluxed under N.sub.2
overnight. The mixture was poured into water and extracted with
CH.sub.2Cl.sub.2. The organic phase was combined, dried over
Na.sub.2SO.sub.4 and filtered to give the desired compound, which
was used directly in the next step. MS (ESI) m/e (M+H.sup.+):
680.
Step 4
##STR00513##
[0933] Following the procedure described in Example 99, steps 4-7,
the oxadiazole from step 3 above was converted to the desired
product. .sup.1H NMR (MeOD) .delta.: 8.09 (d, J=8.8 Hz, 2H), 7.99
(d, J=8.8 Hz, 2H), 7.83 (s, 1H), 7.66.about.7.68 (m, 4H),
7.55.about.7.58 (m, 6H), 7.38.about.7.40 (m, 1H), 7.22.about.7.24
(m, 1H), 6.98 (s, 1H), 5.39 (s, 1H), 5.37.about.5.39 (m, 2H),
4.52.about.4.54 (m, 1H), 4.12.about.4.14 (m, 1H), 3.94.about.3.96
(m, 1H), 3.10 3.41 (m, 8H), 2.72 2.76 (m, 2H), 1.84 2.24 (m, 8H),
1.34.about.1.41 (m, 6H), 1.16.about.1.19 (m, 6H). MS (ESI) m/e
(M+H.sup.+): 821.
Example 192
Methyl
{(2S)-1-[(2S)-2-{5-[4-(5-{2-[(2S)-1-{(2S)-2-[(methoxy-carbonyl)amin-
o]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}-1-benzofuran-2-yl)p-
henyl]-1H-imidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamat-
e
##STR00514##
[0934] Step 1
##STR00515##
[0936] A 2 L, 3-necked round bottomed flask equipped with an
overhead stir and a N.sub.2 inlet was charged with a solution of
oxalyl chloride (130 mL, 0.26 mol) in DCM (250 mL). The solution
was cooled to -78.degree. C., and a solution of DMSO (20 mL, 0.28
mol) in DCM (30 mL) was added dropwise. After 30 minutes, a
solution of (S)--N-Boc-prolinol (40 g, 0.20 mol) in DCM (200 mL)
was added dropwise. After 30 minutes, TEA (140 mL, 1.00 mol) was
added to the solution, and the flask was transferred to an
ice/water bath and stirred for another 30 minutes. The reaction
mixture was diluted with DCM (200 mL) and washed successively with
H.sub.2O, 1M HCl, saturated NaHCO.sub.3, and brine. The DCM layer
was dried over Na.sub.2SO.sub.4, filtered, and concentrated to
afford crude (S)-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl
ester (40 g) as an oil, which was used without further
purification.
Step 2
##STR00516##
[0938] Glyoxal (2.0 mL of 40% in water) was added dropwise over 11
minutes to a methanol solution of NH.sub.4OH (32 mL) and
(S)-Boc-prolinal (8.564 g, 42.98 mmol) and stirred at ambient
temperature for 19 hours. The volatile components were removed in
vacuo, and the residue was purified by a flash silica gel
chromatography (EtOAc) followed by a recrystallization (EtOAc) to
provide the desired compound as a white fluffy solid (4.43 g).
.sup.1H NMR (DMSO) .delta.: 11.68, 11.59 (br s, 1H), 6.94 (s, 1H),
6.76 (s, 1H), 4.76 (m, 1H), 3.48 (m, 1H), 3.35-3.29 (m, 1H),
2.23-1.73 (m, 4H), 1.39/1.15 (s, 9H). MS (ESI) m/e (M+H.sup.+):
238.
Step 3
##STR00517##
[0940] To a suspension of the compound from step 2 (140 g, 0.59
mol) in THF (2000 ml) was added NBS (200 g, 1.1 mol). The mixture
was stirred at RT under N.sub.2 protection overnight before the
solvent was removed, and the residue was purified by chromatography
on silica gel to give 230 g of the desired dibromo compound. MS
(ESI) m/e (M+H.sup.+): 396.
Step 4
##STR00518##
[0942] To a suspension of compound from step 3 (230 g, 0.58 mol) in
EtOH/H.sub.2O (3000 ml) was added Na.sub.2SO.sub.3 (733 g, 5.8
mol). The resulting mixture was stirred under reflux overnight.
After cooling to RT, the mixture was extracted by DCM and
concentrated under vacuum. The resulting residue was purified by
chromatography on silica gel to give the desired bromo imidazole
target. MS (ESI) m/e (M+H.sup.|): 317.
Step 5
##STR00519##
[0944] To a stirred solution of ethyl 4-bromophenylacetate (50 g,
205.8 mmol) in CCl.sub.4 (500 mL) was added NBS (38 g, 214.7 mmol),
then 48% aqueous HBr (4 drops). After the addition, the solution
was stirred overnight at 80.degree. C. under argon. Then the
reaction was cooled to RT, filtered, and concentrated. The
resulting oil was directly used the next step.
Step 6
##STR00520##
[0946] To a solution of the compound from step 5 (2 g, 6.2 mmol) in
DMF (20 mL) was added 5-bromosalicylaldehyde (1.21 g, 6.0 mmol) and
Cs.sub.2CO.sub.3 (2 g, 12.3 mmol) under N.sub.2 protection. The
resulting suspension was stirred for 5 hours at 160.degree. C.,
then cooled and treated with water. The resulting precipitate was
filtered, and the filtrate cake was dried in vacuo to give the
desired compound, which was used directly in next step.
Step 7
##STR00521##
[0948] A suspension of the product from step 6 above (4.43 g, 12.58
mmol), bis(pincolato)diboron (8.31 g, 32.72 mmol), AcOK (3.72 g,
37.7 mmol) and Pd(dppf)Cl.sub.2 (921 mg, 1.26 mmol) in dioxane (100
mL) was heated to reflux for 4 hours under N.sub.2. The mixture was
concentrated, the residue was partitioned between H.sub.2O and DCM,
and the aqueous phase was extracted with DCM. The combined organic
layers were washed with brine, dried over Na.sub.2SO.sub.4,
concentrated. The residue was purified by chromatography on silica
gel to afford the desired compound (5 g).
Step 8
##STR00522##
[0950] A suspension of the product from step 4 (5 mmol), the
boronate ester from step 7 (2 mmol), Pd(dppf)Cl.sub.2 (146 mg, 0.2
mmol), and Na.sub.2CO.sub.3 (636 mg, 6 mmol) were refluxed in
THF/H.sub.2O (10:1, 33 mL) overnight under N.sub.2 protection. The
mixture was cooled and filtered, and the filtrate was washed with
water (50 mL) then extracted with EtOAc (100 mL), washed with brine
and dried over anhydrous sodium sulfate. The solution was
concentrated and the resulting residue was purified by column
chromatography (PE/EA=8:1.fwdarw.5:1) to afford the desired
compound. MS (ESI) m/z (M+H).sup.+: 641).
Step 9
##STR00523##
[0952] The product from step 8 (1.3 mmol) was added into 3M
HCl/CH.sub.3OH (20 mL) and the mixture was stirred at RT for 2 to 3
hours. The mixture was concentrated, and the crude product was used
directly in the next step without further purification. MS (ESI)
m/z (M+H).sup.+: 441.
Step 10
##STR00524##
[0954] To a mixture of the product from step 9 (1 mmol),
N-Moc-L-valine (2.1 mmol) and DIPEA (0.4 mL) in DMF (3 mL) was
added BOP reagent (2.2 mmol). The resulting mixture was stirred at
RT for 16 hours. The solution was subjected directly to RPLC to
afford the desired compound. .sup.1H NMR (MeOD) .delta.: 7.7-8.1
(m, 10H), 7.4 (m, 1H), 5.3 (m, 2H), 4.3 (m, 2H), 4.1 (d, J=4.8 Hz,
2H), 3.9 (m, 2H), 3.7 (m, 6H), 2.6 (d, J=4.8 Hz, 2H), 2.0-2.4 (m,
8H), 1.3-1.4 (m, 2H), 0.9-1.0 (m, 12H). MS (ESI) m/z (M+H).sup.+:
780.
Examples 193-202
[0955] Compounds of Examples 193-202 were prepared in a similar
manner as described in Example 192.
TABLE-US-00010 Ex- am- M + ple Structure .sup.1H NMR 1 Name 193
##STR00525## (MeOD) .delta.: 7.2-8.1 (m, 20 H), 5.2-5.6 (m, 4 H),
3.9- 4.2 (m, 2 H), 3.1 (m, 2 H), 2.6 (m, 8 H), 1.9-2.5 (m, 8 H),
1.0-1.5 (m, 12 H). 844 (2R)-2-(diethylamino)-1-
[(2S)-2-(5-{4-[5-(2-{(2S)- 1-[(2R)-2-(diethylamino)-
2-phenylacetyl]pyrrolidin- 2-yl}-1H-imidazol-5-yl)-1-
benzofuran-2-yl]phenyl}- 1H-imidazol-2-yl) pyrrolidin-1-yl]-2-
phenylethanone 194 ##STR00526## (MeOD) .delta.: 8.0-8.1 (m, 3 H),
7.7-7.9 (m, 6 H), 7.4 (d, J = 2.4Hz, 1 H), 5.3 (d, J = 5.6 Hz, 2
H), 4.1 (m, 2 H), 3.9 (m, 4 H), 3.7 (m, 6 H), 2.5-2.6 (m, 2 H),
2.1- 2.3 (m, 6 H), 1.1-1.2 (m, 2 H), 0.4-0.6 (m, 9 H). 775 Methyl
{(1S)-1-cyclopropyl- 2-[(2S)-2-{5-[4-(5-{2-[(2S)-
1-{(2S)-2-cyclopropyl-2- [(methoxycarbonyl)amino]
acetyl}pyrrolidin-2-yl]-1H- imidazol-5-yl}-1-
benzofuran-2-yl)phenyl]- 1H-imidazol-2-yl} pyrrolidin-1-yl]-2-
oxoethyl}carbamate 195 ##STR00527## (MeOD) .delta.: 7.7-8.1 (m, 9
H), 7.4(m, 16 H), 5.3-5.4 (m, 2 H), 3.5-4.1 (m, 12 H), 2.6 (d, J =
4.8 Hz, 26 H), 2.2 (d, J = 4.8 Hz, 6 H), 1.1-1.2 (m, 2 H), 0.4- 0.7
(m, 8 H). 775 Methyl {(1R)-1- cyclopropyl-
2-[(2S)-2-{5-[4-(5-{2-[(2S)- 1-{(2R)-2-cyclopropyl-2-
[(methoxycarbonyl) amino]acetyl}pyrrolidin- 2-yl]-1H-imidazol-5-
yl}-1-benzofuran-2-yl) phenyl]-1H-imidazol-2-yl}
pyrrolidin-1-yl]-2- oxoethyl}carbamate 196 ##STR00528## (MeOD)
.delta.: 7.8-7.9 (m, 5 H), 7.1-7.6 (m, 5 H), 5.6- 5.7 (m, 1 H), 5.2
(d, J = 4.8 Hz, 1 H), 4.0-4.2 (m, 3 H), 3.6-3.8 (m, 8 H), 2.0-2.5
(m, 10 H), 1.6 (d, J = 4.8 Hz, 1 H), 1.3 (m, 1 H), 0.8-1.1 (m, 11
H), 0.4 (m, 26 H). 780 Methyl {(2R)-1-[(2S)-2-{5-
[2-(4-{2-[(2S)-1-{(2R)-2- [(methoxycarbonyl)amino]-
3-methylbutanoyl} pyrrolidin-2-yl]- 1H-imidazol-5-yl}phenyl)-
1-benzofuran-5-yl]-1H- imidazol-2-yl}pyrrolidin-1- yl]-3-methyl-1-
oxobutan-2-yl}carbamate 197 ##STR00529## (MeOD), .delta. 8.10(d, J
= 4 Hz, 2 H), 8.01(s, 1 H), 7.94(s, 1 H), 7.87(d, J = 2 Hz, 2 H),
7.84(m, 1 H), 7.73(d, J = 4 Hz, 1 H), 7.44(m, 1 H), 5.25(m, 2 H),
4.33(m, 2 H), 4.16(m, 2 H), 3.89(m, 2 H), 3.67(s, 6 H), 2.58(m, 2
H), 2.20(m, 6 H), 0.97(m, 18 H) 806 Methyl {(2S)-1-[(2S)-2-
{5-[4-(5-{2-[(2S)-1-{(2S)-2- [(methoxycarbonyl)amino]-
3,3-dimethylbutanoyl} pyrrolidin-2-yl]-1H- imidazol-5-yl}-1-
benzofuran-2-yl) phenyl]-1H-imidazol-2-yl} pyrrolidin-1-yl]-3,3-
dimethyl-1-oxobutan-2- yl}carbamate 198 ##STR00530## (MeOD)
.delta.: 7.6-8.1 (m, 9 H), 7.3-7.5 (m, 11 H), 7.2 (m, 1H), 5.4-5.5
(m, 2 H), 5.3 (m, 2 H), 4.1 (d, J = 4.8 Hz, 2 H), 3.7 (d, J = 2.4
Hz, 6 H), 1.9-2.4 (m, 8 H) 848 Methyl {(1R)-2-[(2S)-2-
{5-[4-(5-{2-[(2S)-1-{(2R)-2- [(methoxycarbonyl)amino]-
2-phenylacetyl}pyrrolidin- 2-yl]-1H-imidazol-4-yl}-1- benzofuran-2-
yl)phenyl]-1H-imidazol-2- yl}pyrrolidin-1-yl}-2-oxo-1-
phenylethyl}carbamate 199 ##STR00531## (MeOD) .delta. 8.08(d, J = 4
Hz, 2 H), 8.04(s, 1 H), 7.89(d, 3 H), 7.78(m, 1 H), 7.77 (m, 2 H),
7.42(m,1 H), 5.34(t, J = 4 Hz, 2 H), 4.42(d, J = 4Hz, 2 H), 4.10(s,
2 H), 3.82(m, 2 H), 3.79(m, 3 1 H), 3.64(s, 3 H), 2.57(m, 2 H),
2.20(m, 6 H), 1.88(m, 2 H), 1.48(m, 2 H), 1.32(m, 2 H), 0.97(m, 12
H). 806 Methyl {(2S,3R)-1-[(2S)-2- (5-{2-[4-(2-{(2S)-1-[N-
(mahoxycarbonyl)-L- alloisoleucyl]pyrrolidin-2-
yl}-1H-imidazol-5-yl) phenyl]-1-benzofuran-5- yl}-1H-imidazol-2-yl)
pyrrolidin-1-yl]-3-methyl-1- oxopentan-2-yl}carbamate 200
##STR00532## (MeOD) .delta.: 7.6-8.1 (m, 9 H), 7.4 (m, 6 H), 5.4
(m, 2 H), 4.6 (m, 2 H), 3.5-4.1 (m, 13 H), 2.5-2.7 (m, 6 H), 2.3
(m, 5 H). 755 Methyl {(2S)-3-hydroxy-1- [(2S)-2-{5-[4-(5-{2-[(2S)-
1-{({2S)-3-hydroxy-2- [(methoxycarbonyl)amino]
propanoyl}pyrrolidin-2- yl]-1H-imidazol-5-yl}-1-
benzofuran-2-yl)phenyl]- 1H-imidazol-2-yl} pyrrolidin-1-yl]-1-
oxopropan-2-yl}carbamate 201 ##STR00533## (MeOD), .delta. 8.04(d, J
= 4 Hz, 2 H), 7.97(s, 1H), 7.84(d, J = 2 Hz, 2H), 7.81(m, 1 H),
7.76(m, 1 H), 7.64(d, J = 4 Hz, 2 H), 7.38(m, 1 H), 5.29(m, 2 H),
4.49(m, 2 H), 4.15(m, 2 H), 3.97(m, 1 H), 3.92(m, 1 H), 3.66(m, 6
H), 2.63(m, 1 H), 2.60(m, 1 H), 2.54(m, 2 H), 2.16- 2.22(m, 6 H),
1.16 (d, J = 2 Hz, 6 H). 783 Methyl {(2S,3R)-3-
hydroxy-1-[(2S)-2-{5-[4- (5-{2-[(2S)-1-{(2S,3R)-
3-hydroxy-2-[(methoxy- carbonyl)amino] butanoyl}pyrrolidin-2-yl]-
1H-imidazol-5-yl}-1- benzofuran-2-yl)phenyl] 1H-imidazol-2-yl}
pyrrolidin-1-yl]-1- oxobutan-2-yl}carbamate 202 ##STR00534##
(MeOD), .delta. 8.05(d, J = 4 Hz, 2 H), 7.97(s, 1 H), 7.84(d, 1 H),
7.81(d, J = 2 Hz, 2 H), 7.76(m, 1 H), 7.64(d, J = 4Hz, 2 H),
7.39(m, 1 H), 5.25(m, 2 H), 4.45(m, 2 H), 4.03(m, 2 H), 3.84(m, 2
H), 3. 85(m, 2 H), 3.64(s, 6 H), 2.55(m, 2 H), 2.22(m, 6 H),
1.70(m, 2 H), 1.51(m, 4 H), 0.98(m, 12 806 Methyl {(2S)-1-[(2S)-2-
{5-[4-(5-{2-[(2S)-1-{(2S)-2- [(methoxycarbonyl)
amino]-4-methylpentanoyl} pyrrolidin-2-yl]-1H- imidazol-5-yl}-1-
benzofuran-2-yl) phenyl]-1H-imidazol-2- yl}pyrrolidin-1-yl]-4-
methyl-1-oxopentan- 2-yl}carbamate H)
Example 203
Methyl
{(2S)-1-[(2S)-2-{5-[3-fluoro-4-(5-{2-[(2S)-1-{(2S)-2-[(methoxycarbo-
nyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}-1-benzofura-
n-2-yl)phenyl]-1H-imidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-
carbamate
##STR00535##
[0956] Step 1
##STR00536##
[0958] To a solution of 5-bromobenzofuran (3.9 g, 20 mmol) in dry
THF (30 mL) cooled to -78.degree. C. under N.sub.2-protected LDA
(prepared from n-BuLi and iPr.sub.2NH in THF (.about.30 mmol)) was
slowly added. The mixture was stirred at the same temperature for
30 minutes, then triisopropylborate (5.64 g, 30 mmol) was added to
the mixture. The mixture was allowed to warm to RT and stirred for
2 hours. The mixture was then quenched with 1N HCl to pH=3 and
extracted with EtOAc. The combined organic phases were combined,
dried and filtered. The filtrate was concentrated to afford the
desired product (4.3 g). MS (ESI) m/e (M+H.sup.+): 241.
Step 2
##STR00537##
[0960] A suspension of the boronic acid from step 1 (1.44 mg, 6.0
mmol), 2-fluoro-4-iodobromobenzene (1.8 g, 6.0 mmol),
Pd(dppf)Cl.sub.2 (600 mg), Na.sub.2CO.sub.3 (954 mg, 9.0 mmol) and
in THF/H.sub.2O (9:1, 100 mL) was refluxed at 75.degree. C.
overnight under N.sub.2 protection. The mixture was cooled and
filtered. The filtrate was washed with water (150 mL) and extracted
with EtOAc (200 mL), washed with brine and dried over anhydrous
sodium sulfate. The solution was evaporated and the residue was
purified by column chromatography (PE/EA=8:1.fwdarw.5:1) to afford
the desired compound. MS (ESI) m/e (M+H.sup.+): 370.
Step 3
##STR00538##
[0962] To a solution of the product from step 2 (1.85 g, 5 mmol),
bis(pinacolato)diboron (2.54 g, 10 mmol) and Pd(dppf)Cl.sub.2 (80
mg) and KOAc (0.98 g, 10 mmol) were dissolved in 1,4-dioxane (30
mL), and the reaction mixture was heated at 110.degree. C. for 16
hours. The solvent was evaporated, and the residue was purified by
column chromatography with silica gel elution with PE to afford the
desired product as white solid (1.95 g). MS (ESI) m/e (M+H.sup.+):
465.
Step 4
##STR00539##
[0964] A suspension of the bromoimidazole from Example 192 (5
mmol), the boronate ester from step 3 (2 mmol), Pd(dppf)Cl.sub.2
(146 mg, 0.2 mmol) and Na.sub.2CO.sub.3 (636 mg, 6 mmol) was
refluxed in THF/H.sub.2O (10:1, 33 mL) overnight under N.sub.2
protection. The mixture was cooled and filtered, and the filtrate
was washed with water (50 mL) and extracted with EtOAc (100 mL),
washed with brine and dried over anhydrous sodium sulfate. The
solution was concentrated, and the resulting residue was purified
by column chromatography (PE/EtOAc=8:1) to afford the desired
compound. MS (ESI) m/e (M+H.sup.+): 683.
Step 5
##STR00540##
[0966] The product from step 4 (682 mg, 1.0 mmol) was treated with
3M HCl/CH.sub.3OH (10 mL) and the mixture was stirred at RT for 3
hours. The reaction mixture was concentrated, and the crude product
was used directly in the next step without further purification. MS
(ESI) m/e (M+H.sup.+): 483.
[0967] Step 6
##STR00541##
[0968] To a mixture of the product from step 5 (482 mg, 1.0 mmol),
N-Moc-L-valine (2.1 mmol) and DIPEA (0.4 mL) in DMF (3 mL) was
added BOP reagent (977 mg, 2.2 mmol). The resulting mixture was
stirred at RT for 16 hours. The solution was subjected directly to
RPLC to afford the desired compound as white solid (40 mg). .sup.1H
NMR (MeOD) .delta.: 7.99 (s, 1H), 7.89-7.80 (m, 5H), 7.72-7.67 (m,
2H), 7.47 (s, 1H), 5.27-5.22 (m, 2H), 4.22 (d, 2H), 4.09 (d, 2H),
3.89-3.84 (m, 2H), 3.64 (s, 6H), 2.55-2.02 (m, 10H), 0.92 (d, 6H),
0.88 (d, 6H). MS (ESI) m/e (M+H.sup.+): 797.
Examples 204-212
[0969] Compounds of Examples 204-212 were prepared in a similar
manner as described in Example 203.
TABLE-US-00011 Example Structure M + 1 Name 204 ##STR00542## 866
Methyl {(1R)-2-{(2S)-2-{5-{3-fluoro-4-(5-{2-
[(2S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-
phenylacetyl}pyrrolidin-2-yl]-1H-imidazol-5-
yl}-1-benzofuran-2-yl)phenyl]-1H-imidazol-
2-yl}pyrrolidin-1-yl]-2-oxo-1- phenylethyl}carbamate 205
##STR00543## 797 Methyl {2S)-1-[(2S)-2-{5-[3-fluoro-4-(5-{2-
[(2S)-1-{(2,9-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl}pyrrolidin-2-yl]-1H-
imidazol-5-yl}-1-benzofuran-2-yl)phenyl]-
1H-imidazol-2-yl}pyrrolidin-1-yl]-3-methyl-
1-oxobutan-2-yl}carbamate 206 ##STR00544## 816 Methyl
{(2,9-1-[(2S)-2-{5-[2-(2,6-difluoro-4-
{2-[(2S)-1-{(2,9-2-[(methoxycarbonyl)
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-
1H-imidazol-5-yl}phenyl)-1-benzofuran-5-
yl]-1H-imidazol-2-yl}pyrrolidin-1-yl]-3-
methyl-1-oxobutan-2-yl}carbamate 207 ##STR00545## 878 Methyl
{(1R)-2-[(2S)-2-{5-[3-methoxy-4-(5-
{2-[(2S)-1-{(2R)-2-[(methoxycarbonyl)
amino]-2-phenylacetyl}pyrrolidin-2-yl]-1H-
imidazol-5-yl}-1-benzofuran-2-yl)phenyl]-
1H-imidazol-2-yl}pyrrolidin-1-yl]-2-oxo-1- phenylethyl}carbamate
208 ##STR00546## 814 Methyl {(2S)-1-[(2S)-2-{5-[2-(2-chloro-4-{2-
[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl}pyrrolidin-2-yl]-1H-
imidazol-4-yl}phenyl)-1-benzofuran-5-yl]-
1H-imidazol-2-yl}pyrrolidin-1-yl] 209 ##STR00547## 873 Methyl
{(1R)-2-[(2S)-2-{4-[3-cyano-4-(5-{2-
[(2S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-
phenylacetyl}pyrrolidin-2-yl]-1H-imidazol-5-
yl}-1-benzofuran-2-yl)phenyl]-1H-imidazol-
2-yl}pyrrolidin-1-yl]-2-oxo-1- phenylethyl}carbamate 210
##STR00548## 794 Methyl {(2S)-1-[(2,5)-2-{5-[2-(4-{2-[(2S)-1-
{(2S)-2-[(methoxycarbonyl)amino]-3-
methylbutanoyl}pyrrolidin-2-yl]-1H-
imidazol-4-yl}-2-methylphenyl)-1- benzofuran-5-yl]-1H-imidazol-2-
yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2- yl}carbamate 211
##STR00549## Methyl [(1S)-2-[(2S)-2-(5-{3-fluoro-4-[5-(2-
{(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-2-
(tetrahydro-2H-pyran-4-yl)acetyl]pyrrolidin-
2-yl}-1H-imidazol-5-yl)-1-benzofuran-2-
yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-
2-oxo-1-(tetrahydro-2H-pyran-4- yl)ethyl]carbamate 212 ##STR00550##
832 Methyl {(2S)-1-[(2S)-2-{4-[3-fluoro-4-(5-{2-
[(2S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-
phenylacetyl}pyrrolidin-2-yl]-1H-imidazol-5-
yl}-1-benzofuran-2-yl)phenyl]-1H-imidazol-
2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2- yl}carbamate
Example 213
Methyl {(1R)-2-[(2S)-2-{5-[4-(5-{2-[(2S)-1-{(2R)-2
[(methoxy-carbonyl)amino]-2-phenylacetyl}pyrrolidin-2-yl]-1H-imidazol-5-y-
l}-1,3-benzoxazol-2-yl)phenyl]-1H-imidazol-2-yl}pyrrolidin-1-yl]-2-oxo-1-p-
henylethyl}carbamate
##STR00551##
[0970] Step 1
##STR00552##
[0972] 4-Bromobenzoic acid (20 g, 0.1 mol) and
2-amino-4-bromophenol (18.8 g, 0.1 mol) were added into
polyphosphoric acid (250 mL), and the mixture was stirred at
140.degree. C. for 90 minutes. After cooling in an ice-bath, the
reaction mixture was diluted with water (4000 mL) and neutralized
with NaOH. The resulting solid was filtered off and dried to afford
the desired benzoxazole. MS (ESI) m/e (M+H.sup.+): 354.
Step 2
##STR00553##
[0974] A suspension of the product from step 1 above (10.6 g, 30
mmol), bis(pinacolato)diboron (30.3 g, 120 mmol), KOAc (7.6 g, 78
mmol) and Pd(dppf)Cl.sub.2 (1.1 g, 1.5 mmol) in dioxane (300 ml)
was stirred at 100.degree. C. under N.sub.2 protection overnight.
The reaction mixture was cooled and concentrated, then
chromatographed on silica gel gave the product compound. MS (ESI)
m/e (M+H.sup.+): 366.
Step 3
##STR00554##
[0976] A suspension of the product from step 2 (1.2 g, 2.6 mmol),
bromoimidazole from Example 192 (2 g, 6.3 mmol), Na.sub.2CO.sub.3
(1.3 g, 12 mmol) and Pd(dppf)Cl.sub.2 (220 mg, 0.3 mmol) in
THF/H.sub.2O (36 ml) was stirred at 100.degree. C. under N.sub.2
protection overnight. The reaction mixture was concentrated and
purified by chromatography on silica gel to give the desired
compound. MS (ESI) m/e (M+H.sup.+): 666.
Step 4
##STR00555##
[0978] A solution of the product from step 3 (400 mg, 0.6 mmol) in
HCl/MeOH (20 ml) was stirred at ambient temperature for 3 hours,
then concentrated and dried under high vacuum to give to desired
product. MS (ESI) m/e (M+H.sup.+): 466.
Step 5
##STR00556##
[0980] To a mixture of the product from step 4 (233 mg, 0.5 mmol),
N-Moc-D-Phg (1.1 mmol) and DIPEA (0.2 mL) in DMF (3 mL) was added
BOP reagent (488 mg, 1.1 mmol). The resulting mixture was stirred
at RT for 16 hours before the solution was subjected directly to
RPLC to afford the desired compound. .sup.1H NMR (MeOD) .delta.:
8.4 (d, J=8.4 Hz, 2H), 8.2 (s, 1H), 8.0 (m, 3H), 7.9 (m, 3H),
7.5-7.4 (m, 10H), 5.5 (s, 2H), 5.3 (m, 2H), 4.1-4.0 (m, 2H), 3.6
(d, J=2.8 Hz, 6H), 3.3 (m, 1H), 3.3-3.1 (m, 1H), 2.5-2.3 (m, 2H),
2.2-2.1 (m, 4H), 2.0 (m, 2H). MS (ESI) m/e (M+H.sup.+): 780.
Examples 214-215
[0981] Compounds of Examples 214-215 were prepared in a similar
manner as described in Example 213.
TABLE-US-00012 Example Structure .sup.1H NMR M + 1 Name 214
##STR00557## (MeOD) .delta.: 8.4 (d, J = 8.4 Hz, 2 H), 8.1 (s, 1
H), 7.9 (m, 3 H), 7.8 (m, 2 H), 7.7 (m, 1 H), 5.3 (m, 2 H), 4.2 (m,
2 H), 4.1-4.0 (m, 2 H), 3.9-3.8 (m, 2 H), 3.6 (s, 2 H), 2.6 (m, 2
H), 2.3 (m, 2 H), 2.2 (m, 4 H), 2.0 (m, 2 H), 0.9 (m, 12 H). 848
Methyl {(2S)-1-[(2S)-2- {5-[2-(4-{2-[(2S)-1-{(2S)-
2-[(methoxycarbonyl) amino]-3- methylbutanoyl} pyrrolidin-2-yl]-1H-
imidazol-5-yl}phenyl)- 1,3-benzoxazol-5-yl]-1H-
imidazo1-2-yl}pyrrolidin- 1-yl]-3-methyl-1- oxobutan-2-yl}carbamate
215 ##STR00558## (MeOD) .delta.: 8.4 (d, J = 6.8 Hz, 2 H), 8.2-8.1
(s, 1 H), 8.0 (m, 3 H), 7.9-7.8 (m, 3 H), 5.3 (m, 2 H), 4.1-4.0 (m,
2 H), 4.0 (m, 2 H), 3.9-3.8 (m, 2 H), 3.7 (m, 6 H), 2.6 (m, 2 H),
2.4-2.1 (m, 6 H), 1.3- 1.1 (m, 2 H), 0.7-0.6 (m, 3 H), 0.6-0.5 (m,
3 H), 0.4 (m, 2 H). 776 Methyl {(1R)-1- cyclopropyl-2-[(2S)-2-{5-
[4-(5-{2-[(2S)-1-{(2R)-2- cyclopropyl-2- (methoxycarbonyl)
amino]acetyl}pyrrolidin- 2-yl]-1H-imidazol-5-yl}- 1,3-benzoxazol-2-
yl)phenyl]-1H-imidazol- 2-yl}pyrrolidin-1-yl]-2-
oxoethyl}carbamate
Examples 216-227
[0982] Compounds of Examples 216-227 were prepared in a similar
manner as described in Example 189b (Alternative Procedure).
TABLE-US-00013 Example Structure M + 1 Name 216 ##STR00559## 875
dimethyl (indolo[1,2- c][1,3]benzoxazine-3,10-diylbis{1H-
imidazole-5,2-diyl(2S)pyrrolidine-
2,1-diy[(1R)-2-oxo-1-phenylethane- 2,1-diyl]})biscarbamate 217
##STR00560## 821 methyl [(2S)-1-{(2S)-2-[5-(11-{2-
[(2S)-1-{(2S)-2-[(methoxycarbonyl)
amino]-3-methylbutanoyl}pyrrolidin- 2-yl]-1H-imidazol-5-yl}-6,7-
dihydroindolo[1,2-d][1,4] benzoxazepin-3-yl)-1H-imidazol-2-
yl]pyrrolidin-1-yl}-3-methyl-1- oxobutan-2-yl]carbamate 218
##STR00561## 835 methyl [(2S)-1-{(2S)-2-[5-(3-{2-
[(2S)-1-{(2S)-2-[(methoxycarbonyl)
amino]-3-methylbutanoyl}pyrrolidin- 2-yl]-1H-imidazol-5-yl}-6,6-
dimethylindolo[1,2-c][1,3] benzoxazin-10-yl)-1H-imidazol-2-
yl]pyrrolidin-1-yl}-3-methyl-1- oxobutan-2-yl]carbamate 219
##STR00562## 839 methyl [(2S)-1-{(2S)-2-[5-(12-fluoro-
10-{2-[(2S)-1-{(2S)-2- [(methoxycarbonyl)amino]-3-
methylbutanoyl}pyrrolidin-2-yl]-1H-
imidazol-5-yl}-6-methylindolo[1,2-
c][1,3]benzoxazin-3-yl)-1H-imidazol-
2-yl]pyrrolidin-1-yl}-3-methyl-1- oxobutan-2-yl]carbamate 220
##STR00563## 804 methyl [(2S)-1-{(2S)-2-[5-(3-{2-
[(2,9-1-{(2S)-2-[(methoxycarbonyl)
amino]-3-methylbutanoyl}pyrrolidin-
2-yl]-1H-imidazol-5-yl}indolo[1,2-
c]quinazolin-10-yl)-1H-imidazol-2- yl]pyrrolidin-1-yl}-3-methyl-1-
oxobutan-2-yl]carbamate 221 ##STR00564## 835 methyl
[(2S)-1-{(2S)-2-[5-(12-{2- R25)-1-{(2S)-2-[(methoxycarbonyl)
amino]-3-methylbutanoyl}pyrrolidin-
2-yl]-1H-imidazol-5-yl}-7,8-dihydro-
6H-indolo[1,2-e][1,5]benzoxazocin-
3-yl)-1H-imidazol-2-yl]pyrrolidin-1- yl}-3-methyl-1-oxobutan-2-
yl]carbamate 222 ##STR00565## 820 methyl [(2S)-1-{(2S)-2-[5-[3-{2-
[(2S)-1-{(2S)-2-[methoxycarbonyl)
amino]-3-methylbutanoyl}pyrrolidin-
2-yl]-1H-imidazol-5-yl}-6-oxo-5,6-
dihydroindolo[1,2-c]quinazolin-10-
yl)-1H-imidazol-2-yl]pyrrolidin-1- yl}-3-methyl-1-oxobutan-2-
yl]carbamate 223 ##STR00566## 883 methyl [(2S)-1-{(2S)-2-[5-(10-{2-
[(2,9-1-{(2S)-2-[(methoxycarbonyl)
amino]-3-methylbutanoyl}pyrrolidin- 2-yl]-1H-imidazol-5-yl}-6-
phenylindolo[1,2-c][1,3]benzoxazin-
3-yl)-1H-imidazol-2-yl]pyrrolidin-1- yl}-3-methyl-1-oxobutan-2-
yl]carbamate 224 ##STR00567## 818 methyl [(2S)-1-{(2S)-2-[5-(3-{2-
[(2S)-1-{(2S)-2-[(methoxycarbonyl)
amino]-3-methylbutanoyl}pyrrolidin- 2-yl]-1H-imidazol-5-yl}-6-
methylindolo[1,2-c]quinazolin-10-
yl)-1H-imidazol-2-yl]pyrrolidin-1-
yl}-3-methyl-1-oxobutan-2-yl]carbamate 225 ##STR00568## 875.1
methyl [(2S)-1-{(2S)-2-[5-(10'-{2-
[(2S)-1-{(2S)-2-[(methoxycarbonyl)
amino]-3-methylbutanoyl}pyrrolidin- 2-yl]-1H-imidazol-5-yl}spiro
[cyclohexane-1,6'-indolo[1,2- c][1,3]benzoxazin]-3'-yl)-1H-
imidazol-2-yl]pyrrolidin-1-yl}-3- methyl-1-oxobutan-2-yl]carbamate
226 ##STR00569## 842 methyl [(2S)-1-{(2S)-2-[5-(1,12-
difluoro-10-{2-[(2S)-1-{(2S)-2- [(methoxycarbonyl)amino]-3-
methylbutanoyl}pyrrolidin-2-yl]-1H- imidazol-5-yl}indolo[1,2-
c][1,3]benzoxazin-3-yl)-1H-imidazol-
2-yl]pyrrolidin-1-yl}-3-methyl-1- oxobutan-2-yl]carbamate 227
##STR00570## 832 methyl [(2S)-1-{(2S)-2-[5-(12-cyano-
10-{2-{(2S)-1-{(2S)-2- [(methoxycarbonyl)amino]-3-
methylbutanoyl}pyrrolidin-2-yl]-1H- imidazol-5-yl}indolo[1,2-
c][1,3]benzoxazin-3-yl)-1H-imidazol-
2-yl]pyrrolidin-1-yl}-3-methyl-1- oxobutan-2-yl]carbamate
Example 228
Measuring Compound Inhibitory Potency
[0983] Measurement of inhibition by compounds was performed using
the HCV replicon system. Several different replicons encoding
different HCV genotypes or mutations were used. In addition,
potency measurements were made using different formats of the
replicon assay, including different ways of measurements and
different plating formats. See Jan M. Vrolijk et al., A
replicons-based bioassay for the measurement of interferons in
patients with chronic hepatitis C, 110 J. VIROLOGICAL METHODS 201
(2003); Steven S. Carroll et al., Inhibition of Hepatitis C Virus
RNA Replication by 2'-Modified Nucleoside Analogs, 278(14) J.
BIOLOGICAL CHEMISTRY 11979 (2003). However, the underlying
principles are common to all of these determinations, and are
outlined below.
[0984] Stable neomycin phosphotransferase encoding
replicon-harboring cell lines were used, so all cell lines were
maintained under G418 selection prior to the assay. In some cases,
the cell lines encoded a luciferase:Neor fusion and could be
assayed either directly by determination of RNA copy number, or
indirectly through measurement of the luciferase activity.
[0985] To initiate an assay, replicon cells were plated in the
presence of a dilution series of test compound in the absence of
G418. Typically, the assays were performed in a 96-well plate
format for manual operation, or a 384-well plate in an automated
assay. Replicon cells and compound were incubated for 24 to 72
hours. At the end of the assay, cells are washed free of media and
compound and then lysed. Luciferase activity was measured using a
conventional luciferase assay. EC.sub.50 determinations were
calculated as a percent of a DMSO control by fitting the data to a
four parameter fit function.
[0986] The activity table below provides representative data
illustrating observed activity against genotype 1b.
TABLE-US-00014 Activity Table Example EC.sub.50 (nM) 2 9 6 200 14
10 15 0.045 19 25 26 0.063 30 26 39 0.24 40 0.026 41 0.05 42 14 45
0.02 49 0.072 58 0.97 60 0.13 62 0.067 72 0.17 94 0.006 95 0.01 96
0.015 99 0.038 100 0.031 101 0.5 102 8.3 103 5.7 105 0.08 107 0.04
116 0.065 119 0.013 125 0.016 129 0.7 130 0.05 131 17 137 0.009 138
8.5 144 0.036 155 0.9 158 0.5 159 0.002 169 0.004 178 317 186 0.015
189a 0.15 189b 0.001 190 0.067 191 0.02 192 0.002 193 0.05 203
0.004 213 0.009
[0987] It will be appreciated that various of the above-discussed
and other features and functions, or alternatives thereof, may be
desirably combined into many other different systems or
applications. It will also be appreciated that various presently
unforeseen or unanticipated alternatives, modifications, variations
or improvements therein, also intended to be encompassed by the
following claims, may be subsequently made by those skilled in the
art.
* * * * *