U.S. patent application number 14/683910 was filed with the patent office on 2015-08-06 for anti-viral compounds.
This patent application is currently assigned to AbbVie Inc.. The applicant listed for this patent is AbbVie Inc.. Invention is credited to Mary E. Bellizzi, David A. Betebenner, Jean C. Califano, Daniel D. Caspi, David A. DeGoey, Pamela L. Donner, Charles A. Flentge, Yi Gao, Charles W. Hutchins, Douglas K. Hutchinson, Tammie K. Jinkerson, Warren M. Kati, Ryan G. Keddy, Allan C. Krueger, Wenke Li, Dachun Liu, Clarence J. Maring, Mark A. Matulenko, Christopher E. Motter, Lissa T. Nelson, Sachin V. Patel, John K. Pratt, John T. Randolph, Todd W. Rockway, Kathy Sarris, Michael D. Tufano, Seble H. Wagaw, Rolf Wagner, Kevin R. Woller.
Application Number | 20150218194 14/683910 |
Document ID | / |
Family ID | 43066241 |
Filed Date | 2015-08-06 |
United States Patent
Application |
20150218194 |
Kind Code |
A1 |
Bellizzi; Mary E. ; et
al. |
August 6, 2015 |
Anti-Viral Compounds
Abstract
Compounds effective in inhibiting replication of Hepatitis C
virus ("HCV") are described. This invention also relates to
processes of making such compounds, compositions comprising such
compounds, and methods of using such compounds to treat HCV
infection.
Inventors: |
Bellizzi; Mary E.;
(Missoula, MT) ; Betebenner; David A.; (Grayslake,
IL) ; Califano; Jean C.; (Whitefish Bay, WI) ;
Caspi; Daniel D.; (Evanston, IL) ; DeGoey; David
A.; (Salem, WI) ; Donner; Pamela L.;
(Mundelein, IL) ; Flentge; Charles A.;
(Pittsburgh, PA) ; Gao; Yi; (Vernon Hills, IL)
; Hutchins; Charles W.; (Green Oaks, IL) ;
Hutchinson; Douglas K.; (Newton, CT) ; Jinkerson;
Tammie K.; (Pleasant Prairie, WI) ; Kati; Warren
M.; (Gurnee, IL) ; Keddy; Ryan G.; (Beach
Park, CA) ; Krueger; Allan C.; (Gurnee, IL) ;
Li; Wenke; (Gurnee, CN) ; Liu; Dachun; (Vernon
Hills, CN) ; Maring; Clarence J.; (Palatine, IL)
; Matulenko; Mark A.; (Libertyville, IL) ; Motter;
Christopher E.; (Oak Creek, WI) ; Nelson; Lissa
T.; (Highland Park, IL) ; Patel; Sachin V.;
(Round Lake, IL) ; Pratt; John K.; (Kenosha,
WI) ; Randolph; John T.; (Libertyville, IL) ;
Rockway; Todd W.; (Grayslake, IL) ; Sarris;
Kathy; (Mundelein, IL) ; Tufano; Michael D.;
(Chicago, IL) ; Wagaw; Seble H.; (Lake Bluff,
IL) ; Wagner; Rolf; (Antioch, IL) ; Woller;
Kevin R.; (Antioch, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Inc. |
North Chicago |
IL |
US |
|
|
Assignee: |
AbbVie Inc.
North Chicago
IL
|
Family ID: |
43066241 |
Appl. No.: |
14/683910 |
Filed: |
April 10, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14180886 |
Feb 14, 2014 |
9006387 |
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14683910 |
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12813301 |
Jun 10, 2010 |
8691938 |
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14180886 |
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61186291 |
Jun 11, 2009 |
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61242836 |
Sep 16, 2009 |
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61243596 |
Sep 18, 2009 |
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Current U.S.
Class: |
540/603 ;
544/124; 544/139; 544/141; 544/58.2; 544/60; 546/118; 546/187;
546/19; 546/279.1; 548/112; 548/162; 548/232; 548/305.4; 548/313.1;
548/314.7; 548/518 |
Current CPC
Class: |
C07C 33/26 20130101;
A61P 43/00 20180101; A61P 31/18 20180101; C07K 5/06 20130101; C07D
405/14 20130101; C07C 201/06 20130101; C07D 413/14 20130101; C07D
401/14 20130101; C07D 453/00 20130101; C07F 9/65583 20130101; A61P
1/16 20180101; C07D 417/14 20130101; A61P 31/12 20180101; C07D
403/14 20130101; C07D 207/08 20130101; A61P 31/14 20180101; C07D
207/09 20130101; C07D 471/04 20130101; C07D 207/16 20130101; A61P
31/00 20180101; C07D 491/113 20130101; C07C 205/19 20130101 |
International
Class: |
C07F 9/6558 20060101
C07F009/6558; C07D 405/14 20060101 C07D405/14; C07D 403/14 20060101
C07D403/14; C07D 401/14 20060101 C07D401/14; C07D 207/09 20060101
C07D207/09; C07D 491/113 20060101 C07D491/113; C07D 413/14 20060101
C07D413/14; C07D 471/04 20060101 C07D471/04; C07C 201/06 20060101
C07C201/06; C07D 207/08 20060101 C07D207/08; C07D 207/16 20060101
C07D207/16; C07D 417/14 20060101 C07D417/14 |
Claims
1. A compound of Formula I, or a pharmaceutically acceptable salt
thereof, ##STR00898## wherein: X is C.sub.3-C.sub.12carbocycle or
3- to 12-membered heterocycle, and is optionally substituted with
one or more R.sub.A; L.sub.1 and L.sub.2 are each independently
selected from bond; or C.sub.1-C.sub.6alkylene,
C.sub.2-C.sub.6alkenylene or C.sub.2-C.sub.6alkynylene, each of
which is independently optionally substituted at each occurrence
with one or more R.sub.L; L.sub.3 is bond or -L.sub.S-K-L.sub.S'-,
wherein K is selected from bond, --O--, --S--, --N(R.sub.B)--,
--C(O)--, --S(O).sub.2--, --S(O)--, --OS(O)--, --OS(O).sub.2--,
--S(O).sub.2O--, --S(O)O--, --C(O)O--, --OC(O)--, --OC(O)O--,
--C(O)N(R.sub.B)--, --N(R.sub.B)C(O)--, --N(R.sub.B)C(O)O--,
--OC(O)N(R.sub.B)--, --N(R.sub.B)S(O)--, --N(R.sub.B)S(O).sub.2--,
--S(O)N(R.sub.B)--, --S(O).sub.2N(R.sub.B)--,
--C(O)N(R.sub.B)C(O)--, --N(R.sub.B)C(O)N(R.sub.B')--,
N(R.sub.B)SO.sub.2N(R.sub.B')--, or --N(R.sub.B)S(O)N(R.sub.B')--;
A and B are each independently C.sub.3-C.sub.12carbocycle or 3- to
12-membered heterocycle, and are each independently optionally
substituted with one or more R.sub.A; D is
C.sub.3-C.sub.12carbocycle or 3- to 12-membered heterocycle, and is
optionally substituted with one or more R.sub.A; Y is selected from
-T'-C(R.sub.1R.sub.2)N(R.sub.5)-T-R.sub.D or
-T'-C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)-T-R.sub.D; R.sub.1 and
R.sub.2 are each independently R.sub.C, and R.sub.5 is R.sub.B; or
R.sub.1 is R.sub.C, and R.sub.2 and R.sub.5, taken together with
the atoms to which they are attached, form a 3- to 12-membered
heterocycle which is optionally substituted with one or more
R.sub.A; R.sub.3, R.sub.4, R.sub.6, and R.sub.7 are each
independently R.sub.C; or R.sub.3 and R.sub.6 are each
independently R.sub.C, and R.sub.4 and R.sub.7, taken together with
the atoms to which they are attached, form a 3- to 12-membered
carbocycle or heterocycle which is optionally substituted with one
or more R.sub.A; Z is selected from
-T'-C(R.sub.8R.sub.9)N(R.sub.12)-T-R.sub.D or
-T'-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)-T-R.sub.D; R.sub.8 and
R.sub.9 are each independently R.sub.C, and R.sub.12 is R.sub.B; or
R.sub.8 is R.sub.C, and R.sub.9 and R.sub.12, taken together with
the atoms to which they are attached, form a 3- to 12-membered
heterocycle which is optionally substituted with one or more
R.sub.A; R.sub.10, R.sub.11, R.sub.13, and R.sub.14 are each
independently R.sub.C; or R.sub.10 and R.sub.13 are each
independently R.sub.C, and R.sub.11 and R.sub.14, taken together
with the atoms to which they are attached, form a 3- to 12-membered
carbocycle or heterocycle which is optionally substituted with one
or more R.sub.A; T and T' are each independently selected at each
occurrence from bond, -L.sub.S-, -L.sub.S-M-L.sub.S'-, or
-L.sub.S-M-L.sub.S'-M'-L.sub.S''-, wherein M and M' are each
independently selected at each occurrence from bond, --O--, --S--,
--N(R.sub.B)--, --C(O)--, --S(O).sub.2--, --S(O)--, --OS(O)--,
--OS(O).sub.2--, --S(O).sub.2O--, --S(O)O--, --C(O)O--, --OC(O)--,
--OC(O)O--, --C(O)N(R.sub.B)--, --N(R.sub.B)C(O)--,
--N(R.sub.B)C(O)O--, --OC(O)N(R.sub.B)--, --N(R.sub.B)S(O)--,
--N(R.sub.B)S(O).sub.2--, --S(O)N(R.sub.B)--,
--S(O).sub.2N(R.sub.B)--, --C(O)N(R.sub.B)C(O)--,
--N(R.sub.B)C(O)N(R.sub.B')--, --N(R.sub.B)SO.sub.2N(R.sub.B')--,
--N(R.sub.B)S(O)N(R.sub.B')--, C.sub.3-C.sub.12carbocycle or 3- to
12-membered heterocycle, and wherein said
C.sub.3-C.sub.12carbocycle and 3- to 12-membered heterocycle are
each independently optionally substituted at each occurrence with
one or more R.sub.A; R.sub.D is each independently selected at each
occurrence from hydrogen or R.sub.A; R.sub.A is independently
selected at each occurrence from halogen, nitro, oxo, phosphonoxy,
phosphono, thioxo, cyano, or -L.sub.S-R.sub.E, wherein two adjacent
R.sub.A, taken together with the atoms to which they are attached
and any atoms between the atoms to which they are attached, can
optionally form carbocycle or heterocycle; R.sub.B and R.sub.B' are
each independently selected at each occurrence from hydrogen; or
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to
6-membered carbocycle or heterocycle; or 3- to 6-membered
carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle
or heterocycle in R.sub.B or R.sub.B is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl or C.sub.2-C.sub.6haloalkynyl; R.sub.C
is independently selected at each occurrence from hydrogen,
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to
6-membered carbocycle or heterocycle; or 3- to 6-membered
carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle
or heterocycle in R.sub.C is independently optionally substituted
at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl or C.sub.2-C.sub.6haloalkynyl; R.sub.E
is independently selected at each occurrence from --O--R.sub.S,
--S--R.sub.S, --C(O)R.sub.S, --OC(O)R.sub.S, --C(O)OR.sub.S,
--N(R.sub.SR.sub.S'), --S(O)R.sub.S, --SO.sub.2R.sub.S,
--C(O)N(R.sub.SR.sub.S'), --N(R.sub.S)C(O)R.sub.S',
--N(R.sub.S)C(O)N(R.sub.S'R.sub.S''), --N(R.sub.S)SO.sub.2R.sub.S',
--SO.sub.2N(R.sub.SR.sub.S'),
--N(R.sub.S)SO.sub.2N(R.sub.S'R.sub.S''),
--N(R.sub.S)S(O)N(R.sub.S'R.sub.S''), --OS(O)--R.sub.S,
--OS(O).sub.2--R.sub.S, --S(O).sub.2OR.sub.S, --S(O)OR.sub.S,
--OC(O)OR.sub.S, --N(R.sub.S)C(O)OR.sub.S,
--OC(O)N(R.sub.SR.sub.S'), --N(R.sub.S)S(O)--R.sub.S',
--S(O)N(R.sub.SR.sub.S') or --C(O)N(R.sub.S)C(O)--R.sub.S'; or
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl; R.sub.L is independently selected at
each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono,
thioxo, cyano, --O--R.sub.S, --S--R.sub.S, --C(O)R.sub.S,
--OC(O)R.sub.S, --C(O)OR.sub.S, --N(R.sub.SR.sub.S'),
--S(O)R.sub.S, --SO.sub.2R.sub.S, C(O)N(R.sub.SR.sub.S') or
--N(R.sub.S)C(O)R.sub.S; or C.sub.3-C.sub.6carbocycle 3- to
6-membered heterocycle, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl or C.sub.2-C.sub.6haloalkynyl; L.sub.S,
L.sub.S' and L.sub.S'' are each independently selected at each
occurrence from bond; or C.sub.1-C.sub.6alkylene,
C.sub.2-C.sub.6alkenylene or C.sub.2-C.sub.6alkynylene, each of
which is independently optionally substituted at each occurrence
with one or more R.sub.L; and R.sub.S, R.sub.S' and R.sub.S'' are
each independently selected at each occurrence from hydrogen;
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to
6-membered carbocycle or heterocycle; or 3- to 6-membered
carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle
or heterocycle in R.sub.S, R.sub.S' or R.sub.S' is independently
optionally substituted at each occurrence with one or more
substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl or C.sub.2-C.sub.6haloalkynyl.
2. The compound or salt of claim 1, wherein: A is selected from
C.sub.5-C.sub.6carbocycle, 5- to 6-membered heterocycle,
##STR00899## and is optionally substituted with one or more
R.sub.A; B is selected from C.sub.5-C.sub.6carbocycle, 5- to
6-membered heterocycle, ##STR00900## and is optionally substituted
with one or more R.sub.A; D is selected from
C.sub.5-C.sub.6carbocycle or 5- to 6-membered heterocycle, and is
optionally substituted with one or more R.sub.A; or D is hydrogen
or R.sub.A; Z.sub.1 is independently selected at each occurrence
from O, S, NH or CH.sub.2; Z.sub.2 is independently selected at
each occurrence from N or CH; Z.sub.3 is independently selected at
each occurrence from N or CH; Z.sub.4 is independently selected at
each occurrence from O, S, NH or CH.sub.2; and W.sub.1, W.sub.2,
W.sub.3, W.sub.4, W.sub.5 and W.sub.6 are each independently
selected at each occurrence from CH or N.
3. The compound or salt of claim 1, wherein: A is selected from
C.sub.5-C.sub.6carbocycle, 5- to 6-membered heterocycle,
##STR00901## and is optionally substituted with one or more
R.sub.A; B is selected from C.sub.5-C.sub.6carbocycle, 5- to
6-membered heterocycle, ##STR00902## and is optionally substituted
with one or more R.sub.A; D is selected from
C.sub.5-C.sub.6carbocycle or 5- to 6-membered heterocycle, and is
optionally substituted with one or more R.sub.A; or D is hydrogen
or R.sub.A; Z.sub.1 is independently selected at each occurrence
from O, S, NH or CH.sub.2; Z.sub.2 is independently selected at
each occurrence from N or CH; and W.sub.1, W.sub.2, W.sub.3,
W.sub.4, W.sub.5 and W.sub.6 are each independently selected at
each occurrence from CH or N.
4. The compound or salt of claim 1, wherein: A and B are each
independently C.sub.5-C.sub.6carbocycle or 5- to 6-membered
heterocycle, and are each independently optionally substituted with
one or more R.sub.A; D is selected from C.sub.5-C.sub.6carbocycle
or 5- to 6-membered heterocycle, and is optionally substituted with
one or more R.sub.A; and X is ##STR00903## wherein X.sub.3 is N and
is directly linked to -L.sub.3-D, and X is optionally substituted
with one or more R.sub.A, and two adjacent R.sub.A on X, taken
together with the ring atoms to which they are attached, optionally
form a 5- to 6-membered carbocycle or heterocycle.
5. A compound of Formula I, or a pharmaceutically acceptable salt
thereof, ##STR00904## wherein: X is ##STR00905## wherein the
nitrogen ring atom is directly linked to -L.sub.3-D, and wherein X
is optionally substituted with one or more R.sub.A; L.sub.1,
L.sub.2 and L.sub.3 are bond; A and B are each independently
##STR00906## and are each independently optionally substituted with
one or more R.sub.A; D is C.sub.3-C.sub.12carbocycle or 3- to
12-membered heterocycle, and is optionally substituted with one or
more R.sub.A; Y is -G-C(R.sub.1R.sub.2)N(R.sub.5)-T-R.sub.D,
-G-C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)-T-R.sub.D,
--N(R.sub.B)C(O)C(R.sub.1R.sub.2)N(R.sub.5)-T-R.sub.D, or
--N(R.sub.B)C(O)C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)-T-R.sub.D; Z is
-G-C(R.sub.8R.sub.9)N(R.sub.12)-T-R.sub.D,
-G-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)-T-R.sub.D,
--N(R.sub.B)C(O)C(R.sub.8R.sub.9)N(R.sub.12)-T-R.sub.D, or
--N(R.sub.B)C(O)C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)-T-R.sub.D;
R.sub.1 is R.sub.C, and R.sub.2 and R.sub.5, taken together with
the atoms to which they are attached, form a 3- to 12-membered
heterocycle which is optionally substituted with one or more
R.sub.A; R.sub.3 and R.sub.6 are each independently R.sub.C, and
R.sub.4 and R.sub.7, taken together with the atoms to which they
are attached, form a 3- to 12-membered carbocycle or heterocycle
which is optionally substituted with one or more R.sub.A; R.sub.8
is R.sub.C, and R.sub.9 and R.sub.12, taken together with the atoms
to which they are attached, form a 3- to 12-membered heterocycle
which is optionally substituted with one or more R.sub.A; R.sub.10
and R.sub.13 are each independently R.sub.C, and R.sub.11 and
R.sub.14, taken together with the atoms to which they are attached,
form a 3- to 12-membered carbocycle or heterocycle which is
optionally substituted with one or more R.sub.A; G is each
independently C.sub.5-C.sub.6carbocycle or 5- to 6-membered
heterocycle, and is each independently optionally substituted with
one or more R.sub.A; T is each independently selected at each
occurrence from bond, -L.sub.S-, -L.sub.S-M-L.sub.S'-, or
-L.sub.S-M-L.sub.S'-M'-L.sub.S''-, wherein M and M' are each
independently selected at each occurrence from bond, --O--, --S--,
--N(R.sub.B)--, --C(O)--, --S(O).sub.2--, --S(O)--, --OS(O)--,
--OS(O).sub.2--, --S(O).sub.2O--, --S(O)O--, --C(O)O--, --OC(O)--,
--OC(O)O--, --C(O)N(R.sub.B)--, --N(R.sub.B)C(O)--,
--N(R.sub.B)C(O)O--, --OC(O)N(R.sub.B)--, --N(R.sub.B)S(O)--,
--N(R.sub.B)S(O).sub.2--, --S(O)N(R.sub.B)--, S(O).sub.2(O)N--,
(R.sub.B)C(O)--, --N(R.sub.B)C(O)N(R.sub.B')--,
--N(R.sub.B)SO.sub.2N(R.sub.B')--, N(R.sub.B)S(O)N(R.sub.B')--,
C.sub.3-C.sub.12carbocycle or 3- to 12-membered heterocycle, and
wherein said C.sub.3-C.sub.12carbocycle and 3- to 12-membered
heterocycle are each independently optionally substituted at each
occurrence with one or more R.sub.A; R.sub.D is each independently
selected at each occurrence from hydrogen or R.sub.A; R.sub.A is
independently selected at each occurrence from halogen, nitro, oxo,
phosphonoxy, phosphono, thioxo, cyano, or -L.sub.S-R.sub.E; R.sub.B
and R.sub.B' are each independently selected at each occurrence
from hydrogen; or C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to
6-membered carbocycle or heterocycle; or 3- to 6-membered
carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle
or heterocycle in R.sub.B or R.sub.B is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl or C.sub.2-C.sub.6haloalkynyl; R.sub.C
is independently selected at each occurrence from hydrogen,
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to
6-membered carbocycle or heterocycle; or 3- to 6-membered
carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle
or heterocycle in R.sub.C is independently optionally substituted
at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl or C.sub.2-C.sub.6haloalkynyl; R.sub.E
is independently selected at each occurrence from --O--R.sub.S,
--S--R.sub.S, --C(O)R.sub.S, --OC(O)R.sub.S, --C(O)OR.sub.S,
--N(R.sub.SR.sub.S'), --S(O)R.sub.S, --SO.sub.2R.sub.S,
--C(O)N(R.sub.SR.sub.S'), --N(R.sub.S)C(O)R.sub.S',
--N(R.sub.S)C(O)N(R.sub.S'R.sub.S''), --N(R.sub.S)SO.sub.2R.sub.S',
--SO.sub.2N(R.sub.SR.sub.S'),
--N(R.sub.S)SO.sub.2N(R.sub.S'R.sub.S''),
--N(R.sub.S)S(O)N(R.sub.S'R.sub.S''), --OS(O)--R.sub.S,
--OS(O).sub.2--R.sub.S, --S(O).sub.2OR.sub.S, --S(O)OR.sub.S,
--OC(O)OR.sub.S, --N(R.sub.S)C(O)OR.sub.S,
--OC(O)N(R.sub.SR.sub.S'), --N(R.sub.S)S(O)--R.sub.S',
--S(O)N(R.sub.SR.sub.S') or --C(O)N(R.sub.S)C(O)--R.sub.S'; or
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl; R.sub.L is independently selected at
each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono,
thioxo, cyano, --O--R.sub.S, --S--R.sub.S, --C(O)R.sub.S,
--OC(O)R.sub.S, --C(O)OR.sub.S, --N(R.sub.SR.sub.S'),
--S(O)R.sub.S, --SO.sub.2R.sub.S, C(O)N(R.sub.SR.sub.S') or
--N(R.sub.S)C(O)R.sub.S; or C.sub.3-C.sub.6carbocycle 3- to
6-membered heterocycle, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl or C.sub.2-C.sub.6haloalkynyl; L.sub.S,
L.sub.S' and L.sub.S'' are each independently selected at each
occurrence from bond; or C.sub.1-C.sub.6alkylene,
C.sub.2-C.sub.6alkenylene or C.sub.2-C.sub.6alkynylene, each of
which is independently optionally substituted at each occurrence
with one or more R.sub.L; and R.sub.S, R.sub.S' and R.sub.S'' are
each independently selected at each occurrence from hydrogen;
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to
6-membered carbocycle or heterocycle; or 3- to 6-membered
carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle
or heterocycle in R.sub.S, R.sub.S' or R.sub.S' is independently
optionally substituted at each occurrence with one or more
substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl or C.sub.2-C.sub.6haloalkynyl.
6. The compound or salt of claim 5, wherein: T is independently
selected at each occurrence from --C(O)-L.sub.S'-M'-L.sub.S''- or
--N(R.sub.B)C(O)-L.sub.S'-M'-L.sub.S''-; and L.sub.S' is each
independently C.sub.1-C.sub.6alkylene, and is independently
optionally substituted at each occurrence with one or more
R.sub.L.
7. The compound or salt of claim 5, wherein: Y is
--N(R.sub.B)C(O)C(R.sub.1R.sub.2)N(R.sub.5)-T-R.sub.D; Z is
--N(R.sub.B)C(O)C(R.sub.8R.sub.9)N(R.sub.12)-T-R.sub.D; T is
independently selected at each occurrence from
--C(O)-L.sub.S'-M'-L.sub.S''-; and D is C.sub.5-C.sub.6carbocycle,
5- to 6-membered heterocycle, or 6- to 10-membered bicycles, and is
substituted with one or more R.sub.A.
8. The compound or salt of claim 7, wherein T is independently
selected at each occurrence from
--C(O)-L.sub.S'--N(R.sub.B)C(O)-L.sub.S''- or
--C(O)-L.sub.S'--N(R.sub.B)C(O)O-L.sub.S''-; and R.sub.2 and
R.sub.5, taken together with the atoms to which they are attached,
form ##STR00907## which is optionally substituted with one or more
R.sub.A; and R.sub.9 and R.sub.12, taken together with the atoms to
which they are attached, form ##STR00908## which is optionally
substituted with one or more R.sub.A.
9. The compound or salt of claim 5, wherein: Y is
-G-C(R.sub.1R.sub.2)N(R.sub.5)-T-R.sub.D; Z is
-G-C(R.sub.8R.sub.9)N(R.sub.12)-T-R.sub.D; G is each independently
##STR00909## and is each independently optionally substituted with
one or more R.sub.A; T is independently selected at each occurrence
from --C(O)-L.sub.S'-M'-L.sub.S''-; and D is
C.sub.5-C.sub.6carbocycle, 5- to 6-membered heterocycle, or 6- to
10-membered bicycles, and is substituted with one or more
R.sub.A.
10. The compound or salt of claim 9, wherein T is independently
selected at each occurrence from
--C(O)-L.sub.S'--N(R.sub.B)C(O)-L.sub.S''- or
--C(O)-L.sub.S'--N(R.sub.B)C(O)O-L.sub.S''-; and R.sub.2 and
R.sub.5, taken together with the atoms to which they are attached,
form ##STR00910## which is optionally substituted with one or more
R.sub.A; and R.sub.9 and R.sub.12, taken together with the atoms to
which they are attached, form ##STR00911## which is optionally
substituted with one or more R.sub.A.
11. A process of making an HCV inhibitor according to a scheme
selected from Scheme I to Scheme XXV.
12. A process of making an HCV inhibitor according to the following
scheme as defined in the specification: ##STR00912## ##STR00913##
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/180,886, filed Feb. 14, 2014, which is a
divisional of Ser. No. 12/813,301, filed Jun. 10, 2010 and now U.S.
Pat. No. 8,691,938, which claims the benefit from U.S. Provisional
Application Ser. No. 61/186,291 filed Jun. 11, 2009, U.S.
Provisional Application Ser. No. 61/242,836 filed Sep. 16, 2009,
and U.S. Provisional Application Ser. No. 61/243,596 filed Sep. 18,
2009; all of these applications are incorporated herein by
reference in their entireties.
FIELD
[0002] The present invention relates to compounds effective in
inhibiting replication of Hepatitis C virus ("HCV"). The present
invention also relates to compositions comprising these compounds
and methods of using these compounds to treat HCV infection.
BACKGROUND
[0003] HCV is an RNA virus belonging to the Hepacivirus genus in
the Flaviviridae family. The enveloped HCV virion contains a
positive stranded RNA genome encoding all known virus-specific
proteins in a single, uninterrupted, open reading frame. The open
reading frame comprises approximately 9500 nucleotides and encodes
a single large polyprotein of about 3000 amino acids. The
polyprotein comprises a core protein, envelope proteins E1 and E2,
a membrane bound protein p7, and the non-structural proteins NS2,
NS3, NS4A, NS4B, NS5A and NS5B.
[0004] HCV infection is associated with progressive liver
pathology, including cirrhosis and hepatocellular carcinoma.
Chronic hepatitis C may be treated with peginterferon-alpha in
combination with ribavirin. Substantial limitations to efficacy and
tolerability remain as many users suffer from side effects, and
viral elimination from the body is often inadequate. Therefore,
there is a need for new drugs to treat HCV infection.
SUMMARY
[0005] The present invention features compounds of Formulae I,
I.sub.A, I.sub.B, I.sub.C and I.sub.D, and pharmaceutically
acceptable salts thereof. These compounds and salts can inhibit the
replication of HCV and therefore are useful for treating HCV
infection.
[0006] The present invention also features compositions comprising
the compounds or salts of the present invention. The compositions
can also include additional therapeutic agents, such as HCV
helicase inhibitors, HCV polymerase inhibitors, HCV protease
inhibitors, HCV NS5A inhibitors, CD81 inhibitors, cyclophilin
inhibitors, or internal ribosome entry site (IRES) inhibitors.
[0007] The present invention further features methods of using the
compounds or salts of the present invention to inhibit HCV
replication. The methods comprise contacting cells infected with
HCV virus with a compound or salt of the present invention, thereby
inhibiting the replication of HCV virus in the cells.
[0008] In addition, the present invention features methods of using
the compounds or salts of the present invention, or compositions
comprising the same, to treat HCV infection. The methods comprise
administering a compound or salt of the present invention, or a
pharmaceutical composition comprising the same, to a patient in
need thereof, thereby reducing the blood or tissue level of HCV
virus in the patient.
[0009] The present invention also features use of the compounds or
salts of the present invention for the manufacture of medicaments
for the treatment of HCV infection.
[0010] Furthermore, the present invention features processes of
making the compounds or salts of the invention.
[0011] Other features, objects, and advantages of the present
invention are apparent in the detailed description that follows. It
should be understood, however, that the detailed description, while
indicating preferred embodiments of the invention, are given by way
of illustration only, not limitation. Various changes and
modifications within the scope of the invention will become
apparent to those skilled in the art from the detailed
description.
DETAILED DESCRIPTION
[0012] The present invention features compounds having Formula I,
and pharmaceutically acceptable salts thereof,
##STR00001##
wherein: [0013] X is C.sub.3-C.sub.12carbocycle or 3- to
12-membered heterocycle, and is optionally substituted with one or
more R.sub.A; [0014] L.sub.1 and L.sub.2 are each independently
selected from bond; or C.sub.1-C.sub.6alkylene,
C.sub.2-C.sub.6alkenylene or C.sub.2-C.sub.6alkynylene, each of
which is independently optionally substituted at each occurrence
with one or more R.sub.L; [0015] L.sub.3 is bond or
-L.sub.S-K-L.sub.S'-, wherein K is selected from bond, --O--,
--S--, --N(R.sub.B)--, --C(O)--, --S(O).sub.2--, --S(O)--,
--OS(O)--, --OS(O).sub.2--, --S(O).sub.2O--, --S(O)O--, --C(O)O--,
--OC(O)--, --OC(O)O--, --C(O)N(R.sub.B)--, --N(R.sub.B)C(O)--,
--N(R.sub.B)C(O)O--, --OC(O)N(R.sub.B)--, --N(R.sub.B)S(O)--,
--N(R.sub.B)S(O).sub.2--, --S(O)N(R.sub.B)--,
--S(O).sub.2N(R.sub.B)--, --C(O)N(R.sub.B)C(O)--,
--N(R.sub.B)C(O)N(R.sub.B')--, --N(R.sub.B)SO.sub.2N(R.sub.B')--,
or --N(R.sub.B)S(O)N(R.sub.B')--; [0016] A and B are each
independently C.sub.3-C.sub.12carbocycle or 3- to 12-membered
heterocycle, and are each independently optionally substituted with
one or more R.sub.A; [0017] D is C.sub.3-C.sub.12carbocycle or 3-
to 12-membered heterocycle, and is optionally substituted with one
or more R.sub.A; or D is hydrogen or R.sub.A; [0018] Y is selected
from -T'-C(R.sub.1R.sub.2)N(R.sub.5)-T-R.sub.D,
-T'-C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)-T-R.sub.D,
-L.sub.K-T-R.sub.D, or -L.sub.K-E; [0019] R.sub.1 and R.sub.2 are
each independently R.sub.C, and R.sub.5 is R.sub.B; or R.sub.1 is
R.sub.C, and R.sub.2 and R.sub.5, taken together with the atoms to
which they are attached, form a 3- to 12-membered heterocycle which
is optionally substituted with one or more R.sub.A; [0020] R.sub.3,
R.sub.4, R.sub.6, and R.sub.7 are each independently R.sub.C; or
R.sub.3 and R.sub.6 are each independently R.sub.C, and R.sub.4 and
R.sub.7, taken together with the atoms to which they are attached,
form a 3- to 12-membered carbocycle or heterocycle which is
optionally substituted with one or more R.sub.A; [0021] Z is
selected from -T'-C(R.sub.8R.sub.9)N(R.sub.12)-T-R.sub.D,
-T'-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)-T-R.sub.D,
-L.sub.K-T-R.sub.D, or -L.sub.K-E; [0022] R.sub.8 and R.sub.9 are
each independently R.sub.C, and R.sub.12 is R.sub.B; or R.sub.8 is
R.sub.C, and R.sub.9 and R.sub.12, taken together with the atoms to
which they are attached, form a 3- to 12-membered heterocycle which
is optionally substituted with one or more R.sub.A; [0023]
R.sub.10, R.sub.11, R.sub.13, and R.sub.14 are each independently
R.sub.C; or R.sub.10 and R.sub.13 are each independently R.sub.C,
and R.sub.11 and R.sub.14, taken together with the atoms to which
they are attached, form a 3- to 12-membered carbocycle or
heterocycle which is optionally substituted with one or more
R.sub.A; [0024] T and T' are each independently selected at each
occurrence from bond, -L.sub.S-, -L.sub.S-M-L.sub.S'-, or
-L.sub.S-M-L.sub.S'-M'-L.sub.S''-, wherein M and M' are each
independently selected at each occurrence from bond, --O--, --S--,
--N(R.sub.B)--, --C(O)--, --S(O).sub.2--, --S(O)--, --OS(O)--,
--OS(O).sub.2--, --S(O).sub.2O--, --S(O)O--, --C(O)O--, --OC(O)--,
--OC(O)O--, --C(O)N(R.sub.B)--, --N(R.sub.B)C(O)--,
--N(R.sub.B)C(O)O--, --OC(O)N(R.sub.B)--, --N(R.sub.B)S(O)--,
--N(R.sub.B)S(O).sub.2--, --S(O)N(R.sub.B)--,
--S(O).sub.2N(R.sub.B)--, --C(O)N(R.sub.B)C(O)--,
--N(R.sub.B)C(O)N(R.sub.B')--, --N(R.sub.B)SO.sub.2N(R.sub.B')--,
--N(R.sub.B)S(O)N(R.sub.B')--, C.sub.3-C.sub.12carbocycle or 3- to
12-membered heterocycle, and wherein said
C.sub.3-C.sub.12carbocycle and 3- to 12-membered heterocycle are
each independently optionally substituted at each occurrence with
one or more R.sub.A; [0025] L.sub.K is independently selected at
each occurrence from bond, -L.sub.S-N(R.sub.B)C(O)-L.sub.S'- or
-L.sub.S-C(O)N(R.sub.B)-L.sub.S'-; or C.sub.1-C.sub.6alkylene,
C.sub.2-C.sub.6alkenylene or C.sub.2-C.sub.6alkynylene, each of
which is independently optionally substituted at each occurrence
with one or more R.sub.L; or C.sub.3-C.sub.12carbocycle or 3- to
12-membered heterocycle, each of which is independently optionally
substituted at each occurrence with one or more R.sub.A; [0026] E
is independently selected at each occurrence from
C.sub.3-C.sub.12carbocycle or 3- to 12-membered heterocycle, and is
independently optionally substituted at each occurrence with one or
more R.sub.A; [0027] R.sub.D is each independently selected at each
occurrence from hydrogen or R.sub.A; [0028] R.sub.A is
independently selected at each occurrence from halogen, nitro, oxo,
phosphonoxy, phosphono, thioxo, cyano, or -L.sub.S-R.sub.E, wherein
two adjacent R.sub.A, taken together with the atoms to which they
are attached and any atoms between the atoms to which they are
attached, can optionally form carbocycle or heterocycle; [0029]
R.sub.B and R.sub.B' are each independently selected at each
occurrence from hydrogen; or C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each of which is
independently optionally substituted at each occurrence with one or
more substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano
or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered
carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle
or heterocycle in R.sub.B or R.sub.B' is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl or C.sub.2-C.sub.6haloalkynyl; [0030]
R.sub.C is independently selected at each occurrence from hydrogen,
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to
6-membered carbocycle or heterocycle; or 3- to 6-membered
carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle
or heterocycle in R.sub.C is independently optionally substituted
at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl or C.sub.2-C.sub.6haloalkynyl; [0031]
R.sub.E is independently selected at each occurrence from
--O--R.sub.S, --S--R.sub.S, --C(O)R.sub.S, --OC(O)R.sub.S,
--C(O)OR.sub.S, --N(R.sub.SR.sub.S'), --S(O)R.sub.S,
--SO.sub.2R.sub.S, --C(O)N(R.sub.SR.sub.S'),
--N(R.sub.S)C(O)R.sub.S', --N(R.sub.S)C(O)N(R.sub.S'R.sub.S''),
--N(R.sub.S)SO.sub.2R.sub.S', --SO.sub.2N(R.sub.SR.sub.S'),
--N(R.sub.S)SO.sub.2N(R.sub.S'R.sub.S''),
--N(R.sub.S)S(O)N(R.sub.S'R.sub.S''), --OS(O)--R.sub.S,
--OS(O).sub.2--R.sub.S, --S(O).sub.2OR.sub.S, --S(O)OR.sub.S,
--OC(O)OR.sub.S, --N(R.sub.S)C(O)OR.sub.S',
--OC(O)N(R.sub.SR.sub.S'), --N(R.sub.S)S(O)--R.sub.S',
--S(O)N(R.sub.SR.sub.S') or --C(O)N(R.sub.S)C(O)--R.sub.S'; or
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl; [0032] R.sub.L is independently
selected at each occurrence from halogen, nitro, oxo, phosphonoxy,
phosphono, thioxo, cyano, --O--R.sub.S, --S--R.sub.S,
--C(O)R.sub.S, --OC(O)R.sub.S, --C(O)OR.sub.S,
--N(R.sub.SR.sub.S'), --S(O)R.sub.S, --SO.sub.2R.sub.S,
C(O)N(R.sub.SR.sub.S') or --N(R.sub.S)C(O)R.sub.S'; or
C.sub.3-C.sub.6carbocycle 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl; wherein two adjacent R.sub.L, taken
together with the atoms to which they are attached and any atoms
between the atoms to which they are attached, can optionally form
carbocycle or heterocycle; [0033] L.sub.S, L.sub.S' and L.sub.S''
are each independently selected at each occurrence from bond; or
C.sub.1-C.sub.6alkylene, C.sub.2-C.sub.6alkenylene or
C.sub.2-C.sub.6alkynylene, each of which is independently
optionally substituted at each occurrence with one or more R.sub.L;
and [0034] R.sub.S, R.sub.S' and R.sub.S'' are each independently
selected at each occurrence from hydrogen; C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each of which is
independently optionally substituted at each occurrence with one or
more substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano
or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered
carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle
or heterocycle in R.sub.S, R.sub.S' or R.sub.S' is independently
optionally substituted at each occurrence with one or more
substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl or C.sub.2-C.sub.6haloalkynyl.
[0035] A and B preferably are independently selected from
C.sub.5-C.sub.6carbocycle (e.g., phenyl), 5- to 6-membered
heterocycle (e.g., pyridinyl or thiazolyl), or 8- to 12-membered
bicycles such as
##STR00002##
where Z.sub.1 is independently selected at each occurrence from O,
S, NH or CH.sub.2, Z.sub.2 is independently selected at each
occurrence from N or CH, Z.sub.3 is independently selected at each
occurrence from N or CH, Z.sub.4 is independently selected at each
occurrence from O, S, NH or CH.sub.2, and W.sub.1, W.sub.2,
W.sub.3, W.sub.4, W.sub.5 and W.sub.6 are each independently
selected at each occurrence from CH or N. A and B are each
independently optionally substituted with one or more R.sub.A.
[0036] More preferably, A is selected from
C.sub.5-C.sub.6carbocycle, 5- to 6-membered heterocycle,
##STR00003##
and is optionally substituted with one or more R.sub.A; B is
selected from C.sub.5-C.sub.6carbocycle, 5- to 6-membered
heterocycle,
##STR00004##
and is optionally substituted with one or more R.sub.A; where
Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4, W.sub.1, W.sub.2, W.sub.3,
W.sub.4, W.sub.5, W.sub.6 are as defined above. Preferably, Z.sub.3
is N and Z.sub.4 is NH. For instance, A can be selected from phenyl
(e.g.,
##STR00005##
pyridinyl (e.g.,
##STR00006##
thiazolyl (e.g.,
##STR00007##
and is optionally substituted with one or more R.sub.A; and B can
be selected from phenyl (e.g.,
##STR00008##
pyridinyl (e.g.,
##STR00009##
thiazolyl (e.g.,
##STR00010##
and is optionally substituted with one or more R.sub.A. Highly
preferably, both A and B are phenyl (e.g., both A and B are
##STR00011##
Also highly preferably, A is
##STR00012##
and B is
##STR00013##
[0037] or A is
##STR00014##
[0038] and B is
##STR00015##
[0039] or A is
##STR00016##
[0040] and B is
##STR00017##
[0041] or A is
##STR00018##
[0042] and B is
##STR00019##
[0043] or A is
##STR00020##
[0044] and B is
##STR00021##
[0045] wherein each A and B is independently optionally substituted
with one or more R.sub.A.
[0046] D preferably is selected from C.sub.5-C.sub.6carbocycle, 5-
to 6-membered heterocycle, or 6- to 12-membered bicycles, and is
optionally substituted with one or more R.sub.A. D can also be
preferably selected from C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, and is optionally
substituted with one or more substituents selected from R.sub.L.
More preferably, D is C.sub.5-C.sub.6carbocycle (e.g., phenyl), 5-
to 6-membered heterocycle (e.g., pyridinyl, pyrimidinyl,
thiazolyl), or 6- to 12-membered bicycles (e.g., indanyl,
4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl,
benzo[d][1,3]dioxol-5-yl), and is substituted with one or more
R.sub.M, where R.sub.M is halogen, nitro, oxo, phosphonoxy,
phosphono, thioxo, cyano, or -L.sub.S-R.sub.E. Also preferably, D
is phenyl, and is optionally substituted with one or more R.sub.A.
More preferably, D is phenyl, and is substituted with one or more
R.sub.M, wherein R.sub.M is as defined above. Highly preferably, D
is
##STR00022##
wherein R.sub.M is as defined above, and each R.sub.N is
independently selected from R.sub.D and preferably is hydrogen. One
or more R.sub.N can also preferably be halo such as F.
[0047] D is also preferably pyridinyl, pyrimidinyl, or thiazolyl,
optionally substituted with one or more R.sub.A. More preferably D
is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with
one or more R.sub.M. Highly preferably, D is
##STR00023##
wherein R.sub.M is as defined above, and each R.sub.N is
independently selected from R.sub.D and preferably is hydrogen. One
or more R.sub.N can also preferably be halo such as F. D is also
preferably indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl,
benzo[d]thiazolyl, or indazolyl, and is optionally substituted with
one or more R.sub.A. More preferably D is indanyl,
4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl,
or benzo[d][1,3]dioxol-5-yl, and is substituted with one or more
R.sub.M. Highly preferably, D is
##STR00024##
and is optionally substituted with one or more R.sub.M.
[0048] Preferably, R.sub.M is halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl. More preferably, R.sub.M is halogen,
hydroxy, mercapto, amino, carboxy; or C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each of which is
independently optionally substituted at each occurrence with one or
more substituents selected from halogen, hydroxy, mercapto, amino
or carboxy. Highly preferably, R.sub.M is C.sub.1-C.sub.6alkyl
which is optionally substituted with one or more substituents
selected from halogen, hydroxy, mercapto, amino or carboxy.
[0049] Also preferably, R.sub.M is halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or
cyano; or R.sub.M is -L.sub.S-R.sub.E, wherein L.sub.S is a bond or
C.sub.1-C.sub.6alkylene, and R.sub.E is --N(R.sub.SR.sub.S'),
--O--R.sub.S, --C(O)R.sub.S, --C(O)OR.sub.S,
--C(O)N(R.sub.SR.sub.S'), --N(R.sub.S)C(O)R.sub.S',
--N(R.sub.S)C(O)OR.sub.S', --N(R.sub.S)SO.sub.2R.sub.S',
--SO.sub.2R.sub.S, --SR.sub.S, or --P(O)(OR.sub.S).sub.2, wherein
R.sub.S and R.sub.S' can be, for example, each independently
selected at each occurrence from (1) hydrogen or (2)
C.sub.1-C.sub.6alkyl optionally substituted at each occurrence with
one or more halogen, hydroxy, --O--C.sub.1-C.sub.6alkyl or 3- to
6-membered heterocycle; or R.sub.M is C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each of which is
independently optionally substituted at each occurrence with one or
more substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano; or R.sub.M is C.sub.3-C.sub.6carbocycle or 3- to 6-membered
heterocycle, each of which is independently optionally substituted
at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl, C.sub.2-C.sub.6haloalkynyl,
--C(O)OR.sub.S, or --N(R.sub.SR.sub.S'). More preferably, R.sub.M
is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto,
amino, carboxy, or C.sub.1-C.sub.6alkyl (e.g., methyl, isopropyl,
tert-butyl), C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each
of which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, cyano, or carboxy. For example R.sub.M is
CF.sub.3, --C(CF.sub.3).sub.2--OH, --C(CH.sub.3).sub.2--CN,
--C(CH.sub.3).sub.2--CH.sub.2OH, or
--C(CH.sub.3).sub.2--CH.sub.2NH.sub.2. Also preferably R.sub.M is
-L.sub.S-R.sub.E where L.sub.S is a bond and R.sub.E is
--N(R.sub.SR.sub.S'), --O--R.sub.S, --N(R.sub.S)C(O)OR.sub.S',
--N(R.sub.S)SO.sub.2R.sub.S', --SO.sub.2R.sub.S, or --SR.sub.S. For
example where L.sub.S is a bond, R.sub.E is
--N(C.sub.1-C.sub.6alkyl).sub.2 (e.g., --NMe.sub.2);
--N(C.sub.1-C.sub.6alkylene-O--C.sub.1-C.sub.6alkyl).sub.2 (e.g.
--N(CH.sub.2CH.sub.2OMe).sub.2);
--N(C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkylene-O--C.sub.1-C.sub.6alkyl-
) (e.g. --N(CH.sub.3)(CH.sub.2CH.sub.2OMe));
--O--C.sub.1-C.sub.6alkyl (e.g., --O-Me, --O-Et, --O-isopropyl,
--O-tert-butyl, --O-n-hexyl); --O--C.sub.1-C.sub.6haloalkyl
(e.g.,--OCF.sub.3, --OCH.sub.2CF.sub.3);
--O--C.sub.1-C.sub.6alkylene-piperidine (e.g.,
--O--CH.sub.2CH.sub.2-1-piperidyl);
--N(C.sub.1-C.sub.6alkyl)C(O)OC.sub.1-C.sub.6alkyl (e.g.,
--N(CH.sub.3)C(O)O--CH.sub.2CH(CH.sub.3).sub.2),
--N(C.sub.1-C.sub.6alkyl)SO.sub.2C.sub.1-C.sub.6alkyl (e.g.,
--N(CH.sub.3)SO.sub.2CH.sub.3); --SO.sub.2C.sub.1-C.sub.6alkyl
(e.g., --SO.sub.2Me); --SO.sub.2C.sub.1-C.sub.6haloalkyl (e.g.,
--SO.sub.2CF.sub.3); or --S--C.sub.1-C.sub.6haloalkyl (e.g.,
SCF.sub.3). Also preferably R.sub.M is -L.sub.S-R.sub.E where
L.sub.S is C.sub.1-C.sub.6alkylene (e.g., --CH.sub.2--,
--C(CH.sub.3).sub.2--, --C(CH.sub.3).sub.2--CH.sub.2--) and R.sub.E
is --O--R.sub.S, --C(O)OR.sub.S, --N(R.sub.S)C(O)OR.sub.S', or
--P(O)(OR.sub.S).sub.2. For example R.sub.M is
--C.sub.1-C.sub.6alkylene-O--R.sub.S (e.g.,
--C(CH.sub.3).sub.2--CH.sub.2--OMe);
--C.sub.1-C.sub.6alkylene-C(O)OR.sub.S (e.g.,
--C(CH.sub.3).sub.2--C(O)OMe);
--C.sub.1-C.sub.6alkylene-N(R.sub.S)C(O)OR.sub.S' (e.g.,
--C(CH.sub.3).sub.2--CH.sub.2--NHC(O)OCH.sub.3); or
--C.sub.1-C.sub.6alkylene-P(O)(OR.sub.S).sub.2 (e.g.,
--CH.sub.2--P(O)(OEt).sub.2). Also more preferably R.sub.M is
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl,
C.sub.2-C.sub.6haloalkynyl, --C(O)OR.sub.S, or
--N(R.sub.SR.sub.S'). For example R.sub.M is cycloalkyl (e.g.,
cyclopropyl, 2,2-dichloro-1-methylcycloprop-1-yl, cyclohexyl),
phenyl, heterocyclyl (e.g., morpholin-4-yl,
1,1-dioxidothiomorpholin-4-yl, 4-methylpiperazin-1-yl,
4-methoxycarbonylpiperazin-1-yl, pyrrolidin-1-yl, piperidin-1-yl,
4-methylpiperidin-1-yl, 3,5-dimethylpiperidin-1-yl,
4,4-difluoropiperidin-1-yl, tetrahydropyran-4-yl, pyridinyl,
pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably,
R.sub.M is C.sub.1-C.sub.6alkyl which is optionally substituted
with one or more substituents selected from halogen, hydroxy,
mercapto, amino or carboxy (e.g., tert-butyl, CF.sub.3).
[0050] X preferably is C.sub.5-C.sub.6carbocycle, 5- to 6-membered
heterocycle, or 6- to 12-membered bicycles, and is optionally
substituted with one or more R.sub.A. X can also be
C.sub.5-C.sub.6carbocycle or 5- to 6-membered heterocycle which is
optionally substituted with one or more R.sub.A, wherein two
adjacent R.sub.A on X, taken together with the ring atoms to which
they are attached, optionally form a 5- to 6-membered carbocycle or
heterocycle. Also preferably, X is
##STR00025##
wherein X.sub.3 is C(H) or preferably N and is directly appended to
-L.sub.3-D; X.sub.4 is C.sub.2-C.sub.4alkylene,
C.sub.2-C.sub.4alkenylene or C.sub.2-C.sub.4alkynylene, each of
which optionally contains one or two heteroatoms selected from O, S
or N; and X is optionally substituted with one or more R.sub.A, and
two adjacent R.sub.A on X, taken together with the ring atoms to
which they are attached, can optionally form a 5- to 6-membered
carbocycle or heterocycle. In addition, X can be
##STR00026##
wherein X.sub.3 is C and is directly linked to -L.sub.3-D, X.sub.4
is C.sub.2-C.sub.4alkylene, C.sub.2-C.sub.4alkenylene or
C.sub.2-C.sub.4alkynylene each of which optionally contains one or
two heteroatoms selected from O, S or N, and X is optionally
substituted with one or more R.sub.A, and two adjacent R.sub.A on
X, taken together with the ring atoms to which they are attached,
optionally form a 5- to 6-membered carbocycle or heterocycle.
[0051] For instance, X can be
##STR00027##
wherein X.sub.1 is independently selected at each occurrence from
CH.sub.2, O, S or NH, X.sub.2 is independently selected at each
occurrence from CH or N, X.sub.3 is N and is directly linked to
-L.sub.3-D, and X.sub.3' is C and is directly linked to -L.sub.3-D;
and X is optionally substituted with one or more R.sub.A, and two
adjacent R.sub.A on X, taken together with the ring atoms to which
they are attached, optionally form a 5- to 6-membered carbocycle or
heterocycle. For another example, X is
##STR00028##
wherein X.sub.1 is independently selected at each occurrence from
CH.sub.2, O, S or NH, X.sub.2 is independently selected at each
occurrence from CH or N, X.sub.3 is N and is directly linked to
-L.sub.3-D, and X.sub.3' is C and is directly linked to -L.sub.3-D;
and wherein X is optionally substituted with one or more R.sub.A,
and two adjacent R.sub.A on X, taken together with the ring atoms
to which they are attached, optionally form a 5- to 6-membered
carbocycle or heterocycle.
[0052] Highly preferably, X is
##STR00029##
wherein X.sub.3 is C(H) or N and is directly linked to -L.sub.3-D,
X.sub.3' is C and is directly linked to -L.sub.3-D, and wherein X
is optionally substituted with one or more R.sub.A, and two
adjacent R.sub.A on X, taken together with the ring atoms to which
they are attached, optionally form a 5- to 6-membered carbocycle or
heterocycle. More preferably, X.sub.3 is N.
[0053] Non-limiting examples of X include:
##STR00030## ##STR00031## ##STR00032##
wherein ".fwdarw." indicates the covalent attachment to -L.sub.3-D.
Each X can be optionally substituted with one or more R.sub.A, and
two adjacent R.sub.A on X, taken together with the ring atoms to
which they are attached, optionally form a 5- to 6-membered
carbocycle or heterocycle.
[0054] Non-limiting examples of preferred X include the following
pyrrolidine rings, each of which is optionally substituted with one
or more R.sub.A:
##STR00033##
As shown, the relative stereochemistry at the 2- and 5-positions of
the above pyrrolidine ring may be either cis or trans. The
stereochemistries of optional substituents R.sub.A at the 3- or
4-positions of the pyrrolidine may vary relative to any substituent
at any other position on the pyrrolidine ring. Depending on the
particular substituents attached to the pyrrolidine, the
stereochemistry at any carbon may be either (R) or (S).
[0055] Non-limiting examples of preferred X also include the
following pyrrole, triazole or thiomorpholine rings, each of which
is optionally substituted with one or more R.sub.A:
##STR00034##
As shown, the relative stereochemistry at the 3- and 5-positions of
the thiomorpholine ring may be either cis or trans. Depending on
the particular substituents attached to the thiomorpholine, the
stereochemistry at any carbon may be either (R) or (S).
[0056] L.sub.1 and L.sub.2 are preferably independently bond or
C.sub.1-C.sub.6alkylene, L.sub.3 is preferably selected from bond,
C.sub.1-C.sub.6alkylene or --C(O)--, and L.sub.1, L.sub.2, and
L.sub.3 are each independently optionally substituted with one or
more R.sub.L. More preferably, L.sub.1, L.sub.2 and L.sub.3 are
each independently bond or C.sub.1-C.sub.6alkylene (e.g.,
--CH.sub.2-- or --CH.sub.2CH.sub.2--), and are each independently
optionally substituted with one or more R.sub.L. Highly preferably,
L.sub.1, L.sub.2 and L.sub.3 are bond.
[0057] Y is preferably selected from
-L.sub.S-C(R.sub.1R.sub.2)N(R.sub.5)-T-R.sub.D,
-L.sub.S-C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)-T-R.sub.D,
-G-C(R.sub.1R.sub.2)N(R.sub.5)-T-R.sub.D,
-G-C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)-T-R.sub.D,
--N(R.sub.B)C(O)C(R.sub.1R.sub.2)N(R.sub.5)-T-R.sub.D,
--N(R.sub.B)C(O)C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)-T-R.sub.D,
--C(O)N(R.sub.B)C(R.sub.1R.sub.2)N(R.sub.5)-T-R.sub.D,
--C(O)N(R.sub.B)C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)-T-R.sub.D,
--N(R.sub.B)C(O)-L.sub.S-E, or --C(O)N(R.sub.B)-L.sub.S-E. G is
C.sub.5-C.sub.6carbocycle or 5- to 6-membered heterocycle, such
as
##STR00035##
and is optionally substituted with one or more R.sub.A (e.g., one
or more chloro or bromo). E preferably is a 7- to 12-membered
bicycle (such as
##STR00036##
wherein U is independently selected at each occurrence from
--(CH.sub.2)-- or --(NH)--; V and Z.sub.20 are each independently
selected from C.sub.1-C.sub.4alkylene, C.sub.2-C.sub.4alkenylene or
C.sub.2-C.sub.4alkynylene, in which at least one carbon atom can be
independently optionally replaced with O, S or N), and is
optionally substituted with one or more R.sub.A. More preferably,
R.sub.1 is R.sub.C, and R.sub.2 and R.sub.5, taken together with
the atoms to which they are attached, form a 5- to 6-membered
heterocycle or 6- to 12-membered bicycle (e.g., or
##STR00037##
which is optionally substituted with one or more R.sub.A (such as,
but not limited to hydroxy, halo (e.g., fluoro),
C.sub.1-C.sub.6alkyl (e.g., methyl), or C.sub.2-C.sub.6alkenyl
(e.g., allyl)); and R.sub.3 and R.sub.6 are each independently
R.sub.C, and R.sub.4 and R.sub.7, taken together with the atoms to
which they are attached, form a 5- to 6-membered
carbocycle/heterocycle or 6- to 12-membered bicycle (e.g.,
##STR00038##
which is optionally substituted with one or more R.sub.A (such as,
but not limited to hydroxy, halo (e.g., fluoro),
C.sub.1-C.sub.6alkyl (e.g., methyl), or C.sub.2-C.sub.6alkenyl
(e.g., allyl)).
[0058] Y can also be selected from
-M-C(R.sub.1R.sub.2)N(R.sub.5)--C(O)-L.sub.Y'-M'-R.sub.D,
-M-C(R.sub.1R.sub.2)N(R.sub.5)-L.sub.Y'-M'-R.sub.D,
-L.sub.S-C(R.sub.1R.sub.2)N(R.sub.5)--C(O)-L.sub.Y'-M'-R.sub.D,
-L.sub.S-C(R.sub.1R.sub.2)N(R.sub.5)-L.sub.Y'-M'-R.sub.D,
-M-C(R.sub.3R.sub.4)C(R.sub.6R)--C(O)-L.sub.Y'-M'-R.sub.D,
-M-C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)-L.sub.Y'-M'-R.sub.D,
-L.sub.S-C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)--C(O)-L.sub.Y'-M'-R.sub.D,
or -L.sub.S-C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)-L.sub.Y'-M'-R.sub.D,
wherein M preferably is bond, --C(O)N(R.sub.B)-- or
--N(R.sub.B)C(O)--, M' preferably is bond, --C(O)N(R.sub.B)--,
--N(R.sub.B)C(O)--, --N(R.sub.B)C(O)O--,
N(R.sub.B)C(O)N(R.sub.B')--, --N(R.sub.B)S(O)-- or
--N(R.sub.B)S(O).sub.2--, and L.sub.Y' preferably is
C.sub.1-C.sub.6alkylene which is optionally substituted with one or
more R.sub.L. L.sub.Y', for example, is a C.sub.1-C.sub.6alkylene
such as, but not limited to
##STR00039##
and the optional R.sub.L is a substituent such as, but not limited
to phenyl, -SMe, or methoxy. Any stereochemistry at a carbon within
the group L.sub.Y' can be either (R) or (S). More preferably,
R.sub.1 is R.sub.C, and R.sub.2 and R.sub.5, taken together with
the atoms to which they are attached, form a 5- to 6-membered
heterocycle or 6- to 12-membered bicycle (e.g.,
##STR00040##
which is optionally substituted with one or more R.sub.A (e.g., one
or more hydroxy); and R.sub.3 and R.sub.6 are each independently
R.sub.C, and R.sub.4 and R.sub.7, taken together with the atoms to
which they are attached, form a 5- to 6-membered
carbocycle/heterocycle or 6- to 12-membered bicycle (e.g.,
##STR00041##
which is optionally substituted with one or more R.sub.A.
[0059] Also preferably, Y is selected from
--N(R.sub.B)CO--C(R.sub.1R.sub.2)N(R.sub.5)--C(O)-L.sub.Y'--N(R.sub.B)C(O-
)O--R.sub.D,
--N(R.sub.B)CO--C(R.sub.1R.sub.2)N(R.sub.5)--C(O)-L.sub.Y'--N(R.sub.B)C(O-
)--R.sub.D,
--N(R.sub.B)CO--C(R.sub.1R.sub.2)N(R.sub.5)--C(O)-L.sub.Y'-N(R.sub.B)S(O)-
.sub.2--R.sub.D,
--N(R.sub.B)CO--C(R.sub.1R.sub.2)N(R.sub.5)--C(O)-L.sub.Y'--N(R.sub.BR.su-
b.B')--R.sub.D,
--N(R.sub.B)CO--C(R.sub.1R.sub.2)N(R.sub.5)--C(O)-L.sub.Y'-O--R.sub.D,
--N(R.sub.B)CO--C(R.sub.1R.sub.2)N(R.sub.5)--C(O)-L.sub.Y'-R.sub.D,
--N(R.sub.B)CO--C(R.sub.1R.sub.2)N(R.sub.5)--R.sub.D,
-L.sub.S-C(R.sub.1R.sub.2)N(R.sub.5)--C(O)-L.sub.Y'--N(R.sub.B)C(O)O--R.s-
ub.D,
-L.sub.S-C(R.sub.1R.sub.2)N(R.sub.5)--C(O)-L.sub.Y'--N(R.sub.B)C(O)--
-R.sub.D,
-L.sub.S-C(R.sub.1R.sub.2)N(R.sub.5)--C(O)-L.sub.Y'--N(R.sub.B)S-
(O).sub.2--R.sub.D,
-L.sub.S-C(R.sub.1R.sub.2)N(R.sub.5)--C(O)-L.sub.Y'--N(R.sub.BR.sub.B')---
R.sub.D,
-L.sub.S-C(R.sub.1R.sub.2)N(R.sub.5)--C(O)-L.sub.Y'-O--R.sub.D,
-L.sub.S-C(R.sub.1R.sub.2)N(R.sub.5)--C(O)-L.sub.Y'-R.sub.D,
-L.sub.S-C(R.sub.1R.sub.2)N(R.sub.5)--R.sub.D,
--N(R.sub.B)CO--C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)--C(O)-L.sub.Y'--N(R.su-
b.B)C(O)O--R.sub.D,
--N(R.sub.B)CO--C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)--C(O)-L.sub.Y'-N(R.sub-
.B)C(O)--R.sub.D,
--N(R.sub.B)CO--C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)--C(O)-L.sub.Y'--N(R.su-
b.B)S(O).sub.2--R.sub.D,
--N(R.sub.B)CO--C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)--C(O)-L.sub.Y'--N(R.su-
b.BR.sub.B')--R.sub.D,
--N(R.sub.B)CO--C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)--C(O)-L.sub.Y'-O--R.su-
b.D,
--N(R.sub.B)CO--C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)--C(O)-L.sub.Y'-R.s-
ub.D, --N(R.sub.B)CO--C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)--R.sub.D,
-L.sub.S-C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)--C(O)-L.sub.Y'--N(R.sub.B)C(O-
)O--R.sub.D,
-L.sub.S-C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)--C(O)-L.sub.Y'--N(R.sub.B)C(O-
)--R.sub.D,
-L.sub.S-C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)--C(O)-L.sub.Y'--N(R.sub.B)S(O-
).sub.2--R.sub.D,
-L.sub.S-C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)--C(O)-L.sub.Y'--N(R.sub.BR.su-
b.B')--R.sub.D,
-L.sub.S-C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)--C(O)-L.sub.Y'-O--R.sub.D,
-L.sub.S-C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)--C(O)-L.sub.Y'-R.sub.D,
or -L.sub.S-C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)--R.sub.D, wherein
L.sub.Y' preferably is C.sub.1-C.sub.6alkylene which is optionally
substituted with one or more R.sub.L. R.sub.1 may be R.sub.C, and
R.sub.2 and R.sub.5, taken together with the atoms to which they
are attached, may form a 5- to 6-membered heterocycle or 6- to
12-membered bicycle (e.g.,
##STR00042##
which is optionally substituted with one or more R.sub.A; and
R.sub.3 and R.sub.6 may be each independently R.sub.C, and R.sub.4
and R.sub.7, taken together with the atoms to which they are
attached, may form a 5- to 6-membered carbocycle/heterocycle or 6-
to 12-membered bicycle (e.g.,
##STR00043##
which is optionally substituted with one or more R.sub.A.
[0060] Highly preferably, Y is selected from
--N(R.sub.B'')CO--C(R.sub.1R.sub.2)N(R.sub.5)--C(O)-L.sub.Y-N(R.sub.B'')C-
(O)-L.sub.S-R.sub.E or
--C(R.sub.1R.sub.2)N(R.sub.5)--C(O)-L.sub.Y-N(R.sub.B'')C(O)-L.sub.S-R.su-
b.E, or Y is
-G-C(R.sub.1R.sub.2)N(R.sub.5)--C(O)-L.sub.Y-N(R.sub.B'')C(O)-L.sub.S-R.s-
ub.E, wherein L.sub.Y is C.sub.1-C.sub.6alkylene optionally
substituted with one or more R.sub.L, and R.sub.B'' is each
independently R.sub.B. R.sub.B'' and R.sub.1 are each preferably
hydrogen or C.sub.1-C.sub.6alkyl, and R.sub.2 and R.sub.5, taken
together with the atoms to which they are attached, preferably form
a 5- to 6-membered heterocycle or 6- to 12-membered bicycle
(e.g.,
##STR00044##
which is optionally substituted with one or more R.sub.A (such as,
but not limited to hydroxy, halo (e.g., fluoro),
C.sub.1-C.sub.6alkyl (e.g., methyl), or C.sub.2-C.sub.6alkenyl
(e.g., allyl)). Preferably, L.sub.Y is C.sub.1-C.sub.6alkylene
substituted with one or more R.sub.L such as a
C.sub.3-C.sub.6carbocycle 3- to 6-membered heterocycle which is
optionally substituted with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl or C.sub.2-C.sub.6haloalkynyl. Highly
preferably, L.sub.Y is a C.sub.1-C.sub.6alkylene such as, but not
limited to,
##STR00045##
(stereochemistry at a carbon within the group L.sub.Y can be either
(R) or (S)), L.sub.Y is optionally substituted with one or more
R.sub.L (e.g., one or more phenyl or methoxy), G preferably is
##STR00046##
R.sub.B'' hydrogen; --C(R.sub.1R.sub.2)N(R.sub.5)-- is
##STR00047##
L.sub.S is a bond; and R.sub.E is methoxy.
[0061] Non-limiting examples of preferred Y include:
##STR00048## ##STR00049##
wherein T and R.sub.D are as defined herein. T, for example, can be
-L.sub.S-M-L.sub.S'-M'-L.sub.S''- where L.sub.S is a bond; M is
C(O); L.sub.S' is C.sub.1-C.sub.6alkylene such as, but not limited
to,
##STR00050##
where L.sub.S' is optionally substituted with one or more R.sub.L;
R.sub.L is a substituent such as, but not limited to phenyl or
methoxy; M' is --NHC(O)-- or --NMeC(O)--; and L.sub.S'' is a bond.
Any stereochemistry at a carbon within the group L.sub.S' can be
either (R) or (S). R.sub.D, for example is methoxy. T-R.sub.D
includes, but is not limited to:
##STR00051##
T-R.sub.D may also include certain stereochemical configurations;
thus T-R.sub.D includes, but is not limited
##STR00052##
[0062] Non-limiting example of preferred Y also include:
##STR00053## ##STR00054##
[0063] Z is preferably selected from
-L.sub.S-C(R.sub.8R.sub.9)N(R.sub.12)-T-R.sub.D,
-L.sub.S-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)-T-R.sub.D,
-G-C(R.sub.8R.sub.9)N(R.sub.12)-T-R.sub.D,
-G-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)-T-R.sub.D,
--N(R.sub.B)C(O)C(R.sub.8R.sub.9)N(R.sub.12)-T-R.sub.D,
--N(R.sub.B)C(O)C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)-T-R.sub.D,
--C(O)N(R.sub.B)C(R.sub.8R.sub.9)N(R.sub.12)-T-R.sub.D,
--C(O)N(R.sub.B)C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)-T-R.sub.D,
--N(R.sub.B)C(O)-L.sub.S-E, or --C(O)N(R.sub.B)-L.sub.S-E. G is
C.sub.5-C.sub.6carbocycle or 5- to 6-membered heterocycle, such
as
##STR00055##
and is optionally substituted with one or more R.sub.A (e.g., one
or more chloro or bromo). E preferably is a 8- to 12-membered
bicycle (such as
##STR00056##
wherein U is independently selected at each occurrence from
--(CH.sub.2)-- or --(NH)--; and V and Z.sub.20 are each
independently selected from C.sub.1-C.sub.4alkylene,
C.sub.2-C.sub.4alkenylene or C.sub.2-C.sub.4alkynylene, in which at
least one carbon atom is independently optionally replaced with O,
S or N), and is optionally substituted with one or more R.sub.A.
More preferably, R.sub.8 is R.sub.C, and R.sub.9 and R.sub.12,
taken together with the atoms to which they are attached, form a 5-
to 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,
##STR00057##
which is optionally substituted with one or more R.sub.A (such as,
but not limited to hydroxy, halo (e.g., fluoro),
C.sub.1-C.sub.6alkyl (e.g., methyl), or C.sub.2-C.sub.6alkenyl
(e.g., allyl)); and R.sub.10 and R.sub.13 are each independently
R.sub.C, and R.sub.11 and R.sub.14, taken together with the atoms
to which they are attached, form a 5- to 6-membered
carbocycle/heterocycle or 6- to 12-membered bicycle (e.g.,
##STR00058##
which is optionally substituted with one or more R.sub.A (such as,
but not limited to hydroxy, halo (e.g., fluoro),
C.sub.1-C.sub.6alkyl (e.g., methyl), or C.sub.2-C.sub.6alkenyl
(e.g., allyl)).
[0064] Z can also be selected from
-M-C(R.sub.8R.sub.9)N(R.sub.12)--C(O)-L.sub.Y'-M'-R.sub.D,
-M-C(R.sub.8R.sub.9)N(R.sub.12)-L.sub.Y'-M'-R.sub.D,
-L.sub.S-C(R.sub.8R.sub.9)N(R.sub.12)--C(O)-L.sub.Y'-M'-R.sub.D,
-L.sub.S-C(R.sub.8R.sub.9)N(R.sub.12)-L.sub.Y'-M'-R.sub.D,
-M-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)--C(O)-L.sub.Y'-M'-R.sub.D,
-M-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)-L.sub.Y'-M'-R.sub.D,
-L.sub.S-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)--C(O)-L.sub.Y'-M'-R.sub.D-
, or
-L.sub.S-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)-L.sub.Y'-M'-R.sub.D,
wherein M preferably is bond, --C(O)N(R.sub.B)-- or
--N(R.sub.B)C(O)--, M' preferably is bond, --C(O)N(R.sub.B)--,
--N(R.sub.B)C(O)--, --N(R.sub.B)C(O)O--,
N(R.sub.B)C(O)N(R.sub.B')--, --N(R.sub.B)S(O)-- or
--N(R.sub.B)S(O).sub.2--, and L.sub.Y' preferably is
C.sub.1-C.sub.6alkylene which is optionally substituted with one or
more R.sub.L. L.sub.Y', for example, is a C.sub.1-C.sub.6alkylene
such as, but not limited to,
##STR00059##
and the optional R.sub.L is a substituent such as, but not limited
to phenyl, --SMe, or methoxy. Any stereochemistry at a carbon
within the group L.sub.Y' can be either (R) or (S). More
preferably, R.sub.8 is R.sub.C, and R.sub.9 and R.sub.12, taken
together with the atoms to which they are attached, form a 5- to
6-membered heterocycle or 6- to 12-membered bicycle (e.g.,
##STR00060##
which is optionally substituted with one or more R.sub.A (e.g., one
or more hydroxy); and R.sub.10 and R.sub.13 are each independently
R.sub.C, and R.sub.11 and R.sub.14, taken together with the atoms
to which they are attached, form a 5- to 6-membered
carbocycle/heterocycle or 6- to 12-membered bicycle (e.g., or
##STR00061##
which is optionally substituted with one or more R.sub.A.
[0065] Also preferably, Z is selected from
--N(R.sub.B)CO--C(R.sub.8R.sub.9)N(R.sub.12)--C(O)-L.sub.Y'--N(R.sub.B)C(-
O)O--R.sub.D,
--N(R.sub.B)CO--C(R.sub.8R.sub.9)N(R.sub.12)--C(O)-L.sub.Y'--N(R.sub.B)C(-
O)--R.sub.D,
--N(R.sub.B)CO--C(R.sub.8R.sub.9)N(R.sub.12)--C(O)-L.sub.Y'-N(R.sub.B)S(O-
).sub.2--R.sub.D,
--N(R.sub.B)CO--C(R.sub.8R.sub.9)N(R.sub.12)--C(O)-L.sub.Y'--N(R.sub.BR.s-
ub.B')--R.sub.D,
--N(R.sub.B)CO--C(R.sub.8R.sub.9)N(R.sub.12)--C(O)-L.sub.Y'-O--R.sub.D,
--N(R.sub.B)CO--C(R.sub.8R.sub.9)N(R.sub.12)--C(O)-L.sub.Y'-R.sub.D,
--N(R.sub.B)CO--C(R.sub.8R.sub.9)N(R.sub.12)--R.sub.D,
-L.sub.S-C(R.sub.8R.sub.9)N(R.sub.12)--C(O)-L.sub.YN(R.sub.B)C(O)O--R.sub-
.D,
-L.sub.S-C(R.sub.8R.sub.9)N(R.sub.12)--C(O)-L.sub.Y'--N(R.sub.B)C(O)---
R.sub.D,
-L.sub.S-C(R.sub.8R.sub.9)N(R.sub.12)--C(O)-L.sub.Y'--N(R.sub.B)S-
(O).sub.2--R.sub.D,
-L.sub.S-C(R.sub.8R.sub.9)N(R.sub.12)--C(O)-L.sub.Y'--N(R.sub.BR.sub.B')--
-R.sub.D,
-L.sub.S-C(R.sub.8R.sub.9)N(R.sub.12)--C(O)-L.sub.Y'-O--R.sub.D,
-L.sub.S-C(R.sub.8R.sub.9)N(R.sub.12)--C(O)-L.sub.Y'-R.sub.D,
-L.sub.S-C(R.sub.8R.sub.9)N(R.sub.12)--R.sub.D,
--N(R.sub.B)CO--C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)--C(O)-L.sub.Y'--N(-
R.sub.B)C(O)O--R.sub.D,
--N(R.sub.B)CO--C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)--C(O)-L.sub.Y'--N(-
R.sub.B)C(O)--R.sub.D,
--N(R.sub.B)CO--C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)--C(O)-L.sub.Y'--N(-
R.sub.B)S(O).sub.2--R.sub.D,
--N(R.sub.B)CO--C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)--C(O)-L.sub.Y'--N(-
R.sub.BR.sub.B')--R.sub.D,
--N(R.sub.B)CO--C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)--C(O)-L.sub.Y'-O---
R.sub.D,
--N(R.sub.B)CO--C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)--C(O)-L.su-
b.Y'-R.sub.D,
--N(R.sub.B)CO--C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)--R.sub.D,
-L.sub.S-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)--C(O)-L.sub.Y'N(R.sub.B)C-
(O)O--R.sub.D,
-L.sub.S-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)--C(O)-L.sub.Y'--N(R.sub.B-
)C(O)--R.sub.D,
-L.sub.S-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)--C(O)-L.sub.Y'--N(R.sub.B-
)S(O).sub.2--R.sub.D,
-L.sub.S-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)--C(O)-L.sub.Y'--N(R.sub.B-
R.sub.B')--R.sub.D,
-L.sub.S-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)--C(O)-L.sub.Y'-O--R.sub.D-
,
-L.sub.S-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)--C(O)-L.sub.Y'-R.sub.D,
or -L.sub.S-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)--R.sub.D,
wherein L.sub.Y' preferably is C.sub.1-C.sub.6alkylene which is
optionally substituted with one or more R.sub.L. R.sub.8 may be
R.sub.C, and R.sub.9 and R.sub.12, taken together with the atoms to
which they are attached, may form a 5- to 6-membered heterocycle or
6- to 12-membered bicycle (e.g.,
##STR00062##
which is optionally substituted with one or more R.sub.A; and
R.sub.10 and R.sub.13 may be each independently R.sub.C, and
R.sub.11 and R.sub.14, taken together with the atoms to which they
are attached, may form a 5- to 6-membered carbocycle/heterocycle or
6- to 12-membered bicycle (e.g., or
##STR00063##
which is optionally substituted with one or more R.sub.A.
[0066] Highly preferably, Z is selected from
--N(R.sub.B'')CO--C(R.sub.8R.sub.9)N(R.sub.12)--C(O)-L.sub.Y-N(R.sub.B'')-
C(O)-L.sub.S-R.sub.E or
--C(R.sub.8R.sub.9)N(R.sub.12)--C(O)-L.sub.Y-N(R.sub.B'')C(O)-L.sub.S-R.s-
ub.E, or Z is
-G-C(R.sub.8R.sub.9)N(R.sub.12)--C(O)-L.sub.Y-N(R.sub.B'')C(O)-L.sub.S-R.-
sub.E, wherein L.sub.Y is C.sub.1-C.sub.6alkylene optionally
substituted with one or more R.sub.L, and R.sub.B'' is each
independently R.sub.B. R.sub.B'' and R.sub.8 are each preferably
hydrogen or C.sub.1-C.sub.6alkyl, and R.sub.9 and R.sub.12, taken
together with the atoms to which they are attached, preferably form
a 5- to 6-membered heterocycle or 6- to 12-membered bicycle
(e.g.,
##STR00064##
which is optionally substituted with one or more R.sub.A (such as,
but not limited to hydroxy, halo (e.g., fluoro),
C.sub.1-C.sub.6alkyl (e.g., methyl), or C.sub.2-C.sub.6alkenyl
(e.g., allyl)). Preferably, L.sub.Y is C.sub.1-C.sub.6alkylene
substituted with one or more R.sub.L such as a
C.sub.3-C.sub.6carbocycle 3- to 6-membered heterocycle which is
optionally substituted with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl or C.sub.2-C.sub.6haloalkynyl. Highly
preferably, L.sub.Y is a C.sub.1-C.sub.6alkylene such as, but not
limited to,
##STR00065##
(stereochemistry at a carbon within the group L.sub.Y can be either
(R) or (S)); L.sub.Y is optionally substituted with one or more
R.sub.L (e.g., one or more phenyl or methoxy); G preferably is
##STR00066##
R.sub.B'' is hydrogen; --C(R.sub.8R.sub.9)N(R.sub.12)-- is
##STR00067##
L.sub.S is a bond; and R.sub.E is methoxy.
[0067] Non-limiting examples of preferred Z include:
##STR00068## ##STR00069##
wherein T and R.sub.D are as defined herein. T, for example, can be
-L.sub.S-M-L.sub.S'-M'-L.sub.S''- where L.sub.S is a bond; M is
C(O); L.sub.S' is C.sub.1-C.sub.6alkylene such as, but not limited
to,
##STR00070##
where L.sub.S' is optionally substituted with one or more R.sub.L;
the optional R.sub.L is a substituent such as, but not limited to
phenyl or methoxy; M' is --NHC(O)-- or --NMeC(O)--; and L.sub.S''
is a bond. Any stereochemistry at a carbon within the group
L.sub.S' can be either (R) or (S). R.sub.D, for example is methoxy.
T-R.sub.D includes, but is not limited to:
##STR00071##
T-R.sub.D may also include certain stereochemical configurations;
thus T-R.sub.D includes, but is not limited
##STR00072##
[0068] Non-limiting examples of preferred Z also include:
##STR00073## ##STR00074##
[0069] T can be, without limitation, independently selected at each
occurrence from --C(O)-L.sub.S'-, --C(O)O-L.sub.S'-,
--C(O)-L.sub.S'--N(R.sub.B)C(O)-L.sub.S-,
C(O)-L.sub.S'--N(R.sub.B)C(O)O-L.sub.S''-,
--N(R.sub.B)C(O)-L.sub.S'-N(R.sub.B)C(O)-L.sub.S''-,
--N(R.sub.B)C(O)-L.sub.S'--N(R.sub.B)C(O)O-L.sub.S''-, or
--N(R.sub.B)C(O)-L.sub.S'--N(R.sub.B)-L.sub.S''-. Preferably, T is
independently selected at each occurrence from
--C(O)-L.sub.S'-M'-L.sub.S''- or
--N(R.sub.B)C(O)-L.sub.S'-M'-L.sub.S''-. More preferably, T is
independently selected at each occurrence from
--C(O)-L.sub.S'--N(R.sub.B)C(O)-L.sub.S''- or
--C(O)-L.sub.S'--N(R.sub.B)C(O)O-L.sub.S''-.
[0070] T can also be, for example,
-L.sub.S-M-L.sub.S'-M'-L.sub.S''- where L.sub.S is a bond; M is
C(O); L.sub.S' is C.sub.1-C.sub.6alkylene (e.g.,
##STR00075##
where L.sub.S' is optionally substituted with R.sub.T; the optional
R.sub.T is a substituent selected from --C.sub.1-C.sub.6alkyl,
--C.sub.2-C.sub.6alkenyl, --C.sub.1-C.sub.6alkyl-OH,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl, 3- to 6-membered
heterocycle (e.g., tetrahydrofuranyl), or
C.sub.3-C.sub.6carbocyclyl (e.g., phenyl, cyclohexyl); M' is
--NHC(O)--, --N(Et)C(O)-- or --N(Me)C(O)--; and L.sub.S'' is a
bond. R.sub.D preferably is hydrogen, --C.sub.1-C.sub.6alkyl (e.g.,
methyl), --O--C.sub.1-C.sub.6alkyl (e.g., methoxy, tert-butoxy),
methoxymethyl, or --N(C.sub.1-C.sub.6alkyl).sub.2 (e.g.,
--NMe.sub.2).
[0071] T-R can be, without limitation 0
##STR00076##
wherein the stereochemistry at a carbon within the group T-R.sub.D
can be either (R) or (S).
[0072] T can also be, without limitation, -L.sub.S-M-L.sub.S'-
where L.sub.S is a bond; M is C(O); L.sub.S' is
C.sub.1-C.sub.6alkylene (e.g.,
##STR00077##
where L.sub.S'' optionally substituted with R.sub.T; the optional
R.sub.T is a substituent selected from --C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-OH,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl, or a
C.sub.3-C.sub.6carbocyclyl (e.g., phenyl, cyclohexyl). R.sub.D, for
example is --OH; --OC(O)Me; --NH(C.sub.1-C.sub.6alkyl) (e.g.,
--NHMe, --NHEt); --N(C.sub.1-C.sub.6alkyl).sub.2 (e.g.,
--NMe.sub.2, --NEt.sub.2); a 3- to 10-membered heterocyclyl (e.g.,
pyrrolidinyl, imidazolidinyl, hexahydropyrimidinyl, morpholinyl,
piperidinyl) optionally substituted with one or more halogen, oxo;
C.sub.3-C.sub.10carbocycle (e.g., cyclopentyl) optionally
substituted with --OH; --C.sub.1-C.sub.6alkyl (e.g., isopropyl,
3-pentyl) optionally substituted with --OH; or NHR.sub.T where
R.sub.T is a 3- to 6-membered heterocyclyl (e.g., thiazolyl,
pyrimidinyl). T-R.sub.D includes, but is not limited to:
##STR00078## ##STR00079##
wherein the stereochemistry at a carbon within the group T-R.sub.D
can be either (R) or (S).
[0073] For each compound of Formula I, L.sub.K can also be
independently selected at each occurrence from a bond;
-L.sub.S'--N(R.sub.B)C(O)-L.sub.S-;
-L.sub.S'-C(O)N(R.sub.B)-L.sub.S-; or C.sub.1-C.sub.6alkylene,
C.sub.2-C.sub.6alkenylene, C.sub.2-C.sub.6alkynylene,
C.sub.3-C.sub.10carbocycle or 3- to 10-membered heterocycle, each
of which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, R.sub.T,
--O--R.sub.S, --S--R.sub.S, --N(R.sub.SR.sub.S'), --OC(O)R.sub.S,
--C(O)OR.sub.S, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl
or cyano, wherein L.sub.S and L.sub.S' are as defined above.
[0074] For Formula I as well as Formulae I.sub.A, I.sub.B, I.sub.C
and I.sub.D described below, including each and every embodiment
described thereunder, R.sub.A preferably is halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, cyano; or C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl; or -L.sub.A-O--R.sub.S,
-L.sub.A-S--R.sub.S, -L.sub.A-C(O)R.sub.S, -L.sub.A-OC(O)R.sub.S,
-L.sub.A-C(O)OR.sub.S, -L.sub.A-N(R.sub.SR.sub.S'),
-L.sub.A-S(O)R.sub.S, -L.sub.A-SO.sub.2R.sub.S,
-L.sub.A-C(O)N(R.sub.SR.sub.S'), -L.sub.A-N(R.sub.S)C(O)R.sub.S',
-L.sub.A-N(R.sub.S)C(O)N(R.sub.S'R.sub.S''),
-L.sub.A-N(R.sub.S)SO.sub.2R.sub.S',
-L.sub.A-SO.sub.2N(R.sub.SR.sub.S'),
-L.sub.A-N(R.sub.S)SO.sub.2N(R.sub.S'R.sub.S''),
-L.sub.A-N(R.sub.S)S(O)N(R.sub.S'R.sub.S''),
-L.sub.A-OS(O)--R.sub.S, -L.sub.A-OS(O).sub.2--R.sub.S,
-L.sub.A-S(O).sub.2OR.sub.S, -L.sub.A-S(O)OR.sub.S,
-L.sub.A-OC(O)OR.sub.S, -L.sub.A-N(R.sub.S)C(O)OR.sub.S',
-L.sub.A-OC(O)N(R.sub.SR.sub.S'),
-L.sub.A-N(R.sub.S)S(O)--R.sub.S', -L.sub.A-S(O)N(R.sub.SR.sub.S')
or -L.sub.A-C(O)N(R.sub.S)C(O)--R.sub.S', wherein L.sub.A is bond,
C.sub.1-C.sub.6alkylene, C.sub.2-C.sub.6alkenylene or
C.sub.2-C.sub.6alkynylene.
[0075] More preferably, R.sub.A is halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano;
or C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl.
[0076] Highly preferably, R.sub.A is halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano;
or C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.
[0077] L.sub.S, L.sub.S' and L.sub.S'' preferably are each
independently selected at each occurrence from bond; or
C.sub.1-C.sub.6alkylene, C.sub.2-C.sub.6alkenylene or
C.sub.2-C.sub.6alkynylene.
[0078] A and B can be the same or different. Likewise, L.sub.1 and
L.sub.2, or Y and Z, or Y-A- and Z--B--, or -A-L.sub.1- and
--B-L.sub.2-, can be the same or different. In some instances,
Y-A-L.sub.1- is identical to Z--B-L.sub.2-. In some other
instances, Y-A-L.sub.1- is different from Z--B-L.sub.2-.
[0079] In one embodiment, A and B are each independently 5- or
6-membered carbocycle or heterocycle (e.g., phenyl such as
##STR00080##
and are each independently optionally substituted with one or more
R.sub.A. X is 5- or 6-membered carbocycle or heterocycle or 6- to
12-membered bicycle (e.g.,
##STR00081##
wherein X.sub.3 is N and is directly linked to -L.sub.3-D) and is
optionally substituted with one or more R.sub.A. Specific examples
of X are described hereinabove. D is C.sub.5-C.sub.6carbocycle or
5- to 6-membered heterocycle (e.g., phenyl), and is optionally
substituted with one or more R.sub.A. Preferably, D is
##STR00082##
wherein R.sub.M and R.sub.N are as defined above. L.sub.1 and
L.sub.2 are each independently bond or C.sub.1-C.sub.6alkylene, and
L.sub.3 is bond, C.sub.1-C.sub.6alkylene or --C(O)--, and L.sub.1,
L.sub.2, and L.sub.3 are each independently optionally substituted
with one or more R.sub.L. Preferably, L.sub.1, L.sub.2, and L.sub.3
are bond. Y is
--N(R.sub.B)C(O)C(R.sub.1R.sub.2)N(R.sub.5)-T-R.sub.D, or
--N(R.sub.B)C(O)C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)-T-R.sub.D, and Z
is --N(R.sub.B)C(O)C(R.sub.8R.sub.9)N(R.sub.12)-T-R.sub.D, or
--N(R.sub.B)C(O)C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)-T-R.sub.D.
R.sub.1 is R.sub.C, and R.sub.2 and R.sub.5, taken together with
the atoms to which they are attached, form a 5- to 6-membered
heterocyclic ring (e.g.,
##STR00083##
which is optionally substituted with one or more R.sub.A; R.sub.3
and R.sub.6 are each independently R.sub.C, and R.sub.4 and
R.sub.7, taken together with the atoms to which they are attached,
form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g.,
##STR00084##
which is optionally substituted with one or more R.sub.A. R.sub.8
is R.sub.C, and R.sub.9 and R.sub.12, taken together with the atoms
to which they are attached, form a 5- to 6-membered heterocyclic
ring (e.g.,
##STR00085##
which is optionally substituted with one or more R.sub.A; and
R.sub.10 and R.sub.13 are each independently R.sub.C, and R.sub.11
and R.sub.14, taken together with the atoms to which they are
attached, form a 5- to 6-membered carbocyclic or heterocyclic ring
(e.g.,
##STR00086##
which is optionally substituted with one or more R.sub.A. T is
preferably independently selected at each occurrence from
--C(O)-L.sub.Y'--N(R.sub.B)C(O)-L.sub.S''- or
--C(O)-L.sub.Y'--N(R.sub.B)C(O)O-L.sub.S''-. L.sub.Y is each
independently L.sub.S' and, preferably, is each independently
C.sub.1-C.sub.6alkylene (e.g., --CH.sub.2--) and optionally
substituted with one or more substituents selected from R.sub.L. T
can also be, without limitation, selected from
--C(O)-L.sub.Y'-L.sub.S''-, --C(O)-L.sub.Y'-O-L.sub.S''-,
--C(O)-L.sub.Y'--N(R.sub.B)-L.sub.S'-, or
--C(O)-L.sub.Y'--N(R.sub.B)S(O).sub.2-L.sub.S'-. In some cases, at
least one of Y and Z is, or both Y and Z are independently,
##STR00087##
wherein non-limiting examples of R.sub.D include (1)
--O--C.sub.1-C.sub.6alkyl, --O--C.sub.2-C.sub.6alkenyl,
--O--C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each of which is
independently optionally substituted at each occurrence with one or
more substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle; or (2)
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl; and non-limiting examples of L.sub.Y'
include C.sub.1-C.sub.6alkylene optionally substituted with
halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy,
--O--C--C.sub.6alkyl, --O--C.sub.2-C.sub.6alkenyl,
--O--C.sub.2-C.sub.6alkynyl, or 3- to 6-membered carbocycle or
heterocycle, said 3- to 6-membered carbocycle or heterocycle being
optionally substituted with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl or C.sub.2-C.sub.6haloalkynyl.
[0080] In another embodiment, A is
##STR00088##
and is optionally substituted with one or more R.sub.A; B
##STR00089##
and is optionally substituted with one or more R.sub.A. Z.sub.1 is
independently selected at each occurrence from O, S, NH or
CH.sub.2; and Z.sub.2 is independently selected at each occurrence
from N or CH. X is 5- or 6-membered carbocycle or heterocycle or 6-
to 12-membered bicycle (e.g.,
##STR00090##
wherein X.sub.3 is N and is directly linked to -L.sub.3-D) and is
optionally substituted with one or more R.sub.A. Specific examples
of X are described hereinabove. D is C.sub.5-C.sub.6carbocycle or
5- to 6-membered heterocycle (e.g., phenyl), and is optionally
substituted with one or more R.sub.A. Preferably, D is
##STR00091##
wherein R.sub.M and R.sub.N are as defined above. L.sub.1 and
L.sub.2 are each independently bond or C.sub.1-C.sub.6alkylene, and
L.sub.3 is bond, C.sub.1-C.sub.6alkylene or --C(O)--, and L.sub.1,
L.sub.2, and L.sub.3 are each independently optionally substituted
with one or more R.sub.L. Preferably, L.sub.1, L.sub.2, and L.sub.3
are bond. Y is -L.sub.S-C(R.sub.1R.sub.2)N(R.sub.5)-T-R.sub.D or
-L.sub.S-C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)-T-R.sub.D, and Z is
-L.sub.S-C(R.sub.8R.sub.9)N(R.sub.12)-T-R.sub.D or
-L.sub.S-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)-T-R.sub.D. R.sub.1
is R.sub.C, and R.sub.2 and R.sub.5, taken together with the atoms
to which they are attached, form a 5- to 6-membered heterocyclic
ring (e.g.,
##STR00092##
which is optionally substituted with one or more R.sub.A; R.sub.3
and R.sub.6 are each independently R.sub.C, and R.sub.4 and
R.sub.7, taken together with the atoms to which they are attached,
form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g.,
##STR00093##
which is optionally substituted with one or more R.sub.A. R.sub.8
is R.sub.C, and R.sub.9 and R.sub.12, taken together with the atoms
to which they are attached, form a 5- to 6-membered heterocyclic
ring (e.g.,
##STR00094##
which is optionally substituted with one or more R.sub.A; and
R.sub.10 and R.sub.13 are each independently R.sub.C, and R.sub.11
and R.sub.14, taken together with the atoms to which they are
attached, form a 5- to 6-membered carbocyclic or heterocyclic ring
(e.g.,
##STR00095##
which is optionally substituted with one or more R.sub.A. T is
preferably independently selected at each occurrence from
--C(O)-L.sub.Y'-N(R.sub.B)C(O)-L.sub.S''- or
--C(O)-L.sub.Y'--N(R.sub.B)C(O)O-L.sub.S''-. L.sub.Y' is each
independently L.sub.S' and, preferably, is independently
C.sub.1-C.sub.6alkylene (e.g., --CH.sub.2--) and optionally
substituted with one or more substituents selected from R.sub.L. T
can also be, without limitation, selected from
--C(O)-L.sub.Y'-L.sub.S''-, C(O)-L.sub.Y'-O-L.sub.S''-,
--C(O)-L.sub.Y'--N(R.sub.B)-L.sub.S''-, or
--C(O)-L.sub.Y'--N(R.sub.B)S(O).sub.2-L.sub.S''-. In some cases, at
least one of Y and Z is, or both Y and Z are independently,
##STR00096##
wherein non-limiting examples of R.sub.D include (1)
--O--C.sub.1-C.sub.6alkyl, --O--C.sub.2-C.sub.6alkenyl,
--O--C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each of which is
independently optionally substituted at each occurrence with one or
more substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle; or (2)
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl; and non-limiting examples of L.sub.Y'
include C.sub.1-C.sub.6alkylene optionally substituted with
halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy,
--O--C.sub.1-C.sub.6alkyl, --O--C.sub.2-C.sub.6alkenyl,
--O--C.sub.2-C.sub.6alkynyl, or 3- to 6-membered carbocycle or
heterocycle, said 3- to 6-membered carbocycle or heterocycle being
optionally substituted with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl or C.sub.2-C.sub.6haloalkynyl.
[0081] In still yet another embodiment, A and B are each
independently 5- or 6-membered carbocycle or heterocycle (e.g., A
and B are each independently phenyl, such as
##STR00097##
and are each independently optionally substituted with one or more
R.sub.A. X is 5- or 6-membered carbocycle or heterocycle or 6- to
12-membered bicycle (e.g.,
##STR00098##
wherein X.sub.3 is N and is directly linked to -L.sub.3-D) and is
optionally substituted with one or more R.sub.A. Specific examples
of X are described hereinabove. D can be, for example,
C.sub.5-C.sub.6carbocycle or 5- to 6-membered heterocycle (e.g.,
phenyl), and is optionally substituted with one or more R.sub.A.
Preferably, D is
##STR00099##
wherein R.sub.M and R.sub.N are as defined above. L.sub.1 and
L.sub.2 are each independently bond or C.sub.1-C.sub.6alkylene, and
L.sub.3 is bond, C.sub.1-C.sub.6alkylene or --C(O)--, and L.sub.1,
L.sub.2, and L.sub.3 are each independently optionally substituted
with one or more R.sub.L. Preferably, L.sub.1, L.sub.2, and L.sub.3
are bond. Y is -G-C(R.sub.1R.sub.2)N(R.sub.5)-T-R.sub.D or
-G-C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)-T-R.sub.D, and Z is
-G-C(R.sub.8R.sub.9)N(R.sub.12)-T-R.sub.D or
-G-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)-T-R.sub.D. G is
independently C.sub.5-C.sub.6carbocycle or 5- to 6-membered
heterocycle, such as
##STR00100##
and is independently optionally substituted with one or more
R.sub.A. R.sub.1 is R.sub.C, and R.sub.2 and R.sub.5, taken
together with the atoms to which they are attached, form a 5- to
6-membered heterocyclic ring (e.g.,
##STR00101##
which is optionally substituted with one or more R.sub.A; R.sub.3
and R.sub.6 are each independently R.sub.C, and R.sub.4 and
R.sub.7, taken together with the atoms to which they are attached,
form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g.,
##STR00102##
which is optionally substituted with one or more R.sub.A. R.sub.8
is R.sub.C, and R.sub.9 and R.sub.12, taken together with the atoms
to which they are attached, form a 5- to 6-membered heterocyclic
ring (e.g.,
##STR00103##
which is optionally substituted with one or more R.sub.A; and
R.sub.10 and R.sub.13 are each independently R.sub.C, and R.sub.11
and R.sub.14, taken together with the atoms to which they are
attached, form a 5- to 6-membered carbocyclic or heterocyclic ring
(e.g.,
##STR00104##
which is optionally substituted with one or more R.sub.A. T is
preferably independently selected at each occurrence from
--C(O)-L.sub.Y'--N(R.sub.B)C(O)-L.sub.S''- or
--C(O)-L.sub.Y'--N(R.sub.B)C(O)O-L.sub.S''-. L.sub.Y' is each
independently L.sub.S' and, preferably, is each independently
C.sub.1-C.sub.6alkylene (e.g., --CH.sub.2--) and optionally
substituted with one or more substituents selected from R.sub.L. T
can also be, without limitation, selected from
--C(O)-L.sub.Y'-L.sub.S''-, --C(O)-L.sub.Y'-O-L.sub.S''-,
--C(O)-L.sub.Y'-N(R.sub.B)-L.sub.S''-, or
--C(O)-L.sub.Y'--N(R.sub.B)S(O).sub.2-L.sub.S''-. In some cases, at
least one of Y and Z is, or both Y and Z are independently,
##STR00105##
wherein non-limiting examples of R.sub.D include (1)
--O--C.sub.1-C.sub.6alkyl, --O--C.sub.2-C.sub.6alkenyl,
--O--C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each of which is
independently optionally substituted at each occurrence with one or
more substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle; or (2)
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl; and non-limiting examples of L.sub.Y'
include C.sub.1-C.sub.6alkylene optionally substituted with
halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy,
--O--C.sub.1-C.sub.6alkyl, --O--C.sub.2-C.sub.6alkenyl,
--O--C.sub.2-C.sub.6alkynyl, or 3- to 6-membered carbocycle or
heterocycle, said 3- to 6-membered carbocycle or heterocycle being
optionally substituted with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl or C.sub.2-C.sub.6haloalkynyl.
[0082] In yet another embodiment, A and B are each independently 5-
or 6-membered carbocycle or heterocycle (e.g., A and B are each
independently phenyl, such as
##STR00106##
and are each independently optionally substituted with one or more
R.sub.A. X is 5- or 6-membered carbocycle or heterocycle or 6- to
12-membered bicycle (e.g.,
##STR00107##
wherein X.sub.3 is N and is directly linked to -L.sub.3-D) and is
optionally substituted with one or more R.sub.A. Specific examples
of X are described hereinabove. D can be, for example,
C.sub.5-C.sub.6carbocycle or 5- to 6-membered heterocycle (e.g.,
phenyl), and is optionally substituted with one or more R.sub.A.
Preferably, D is
##STR00108##
wherein R.sub.M and R.sub.N are as defined above. L.sub.1 and
L.sub.2 are each independently bond or C.sub.1-C.sub.6alkylene, and
L.sub.3 is bond, C.sub.1-C.sub.6alkylene or --C(O)--, and L.sub.1,
L.sub.2, and L.sub.3 are each independently optionally substituted
with one or more R.sub.L. Preferably, L.sub.1, L.sub.2, and L.sub.3
are bond. Y is
--N(R.sub.B)C(O)C(R.sub.1R.sub.2)N(R.sub.5)-T-R.sub.D or
--N(R.sub.B)C(O)C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)-T-R.sub.D, and Z
is -G-C(R.sub.8R.sub.9)N(R.sub.12)-T-R.sub.D or
-G-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)-T-R.sub.D; or Y is
-G-C(R.sub.1R.sub.2)N(R.sub.5)-T-R.sub.D or
-G-C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)-T-R.sub.D, and Z is
--N(R.sub.B)C(O)C(R.sub.8R.sub.9)N(R.sub.12)-T-R.sub.D or
--N(R.sub.B)C(O)C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)-T-R.sub.D.
R.sub.1 is R.sub.C, and R.sub.2 and R.sub.5, taken together with
the atoms to which they are attached, form a 5- to 6-membered
heterocyclic ring (e.g.,
##STR00109##
which is optionally substituted with one or more R.sub.A; R.sub.3
and R.sub.6 are each independently R.sub.C, and R.sub.4 and
R.sub.7, taken together with the atoms to which they are attached,
form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g.,
##STR00110##
which is optionally substituted with one or more R.sub.A. R.sub.8
is R.sub.C, and R.sub.9 and R.sub.12, taken together with the atoms
to which they are attached, form a 5- to 6-membered heterocyclic
ring (e.g.,
##STR00111##
which is optionally substituted with one or more R.sub.A; and
R.sub.10 and R.sub.13 are each independently R.sub.C, and R.sub.11
and R.sub.14, taken together with the atoms to which they are
attached, form a 5- to 6-membered carbocyclic or heterocyclic ring
(e.g.,
##STR00112##
which is optionally substituted with one or more R.sub.A. G is
independently C.sub.5-C.sub.6carbocycle or 5- to 6-membered
heterocycle, such as
##STR00113##
and is independently optionally substituted with one or more
R.sub.A. T is preferably independently selected at each occurrence
from --C(O)-L.sub.Y'--N(R.sub.B)C(O)-L.sub.S''- or
--C(O)-L.sub.Y'--N(R.sub.B)C(O)O-L.sub.S''-. L.sub.Y' is each
independently L.sub.S' and, preferably, is each independently
C.sub.1-C.sub.6alkylene (e.g., --CH.sub.2--) and optionally
substituted with one or more substituents selected from R.sub.L. T
can also be, without limitation, selected from
--C(O)-L.sub.Y'-L.sub.S''-, C(O)-L.sub.Y'-O-L.sub.S''-,
--C(O)-L.sub.Y'--N(R.sub.B)-L.sub.S''-, or
--C(O)-L.sub.Y'--N(R.sub.B)S(O).sub.2-L.sub.S'-. In some cases, Y
is
##STR00114##
as described above, and Z is
##STR00115##
as described above. In some other cases, Y is
##STR00116##
or as described above, and Z is
##STR00117##
as described above.
[0083] In still another embodiment, A is 5- or 6-membered
carbocycle or heterocycle (e.g., phenyl such as
##STR00118##
and B is
##STR00119##
[0084] or A is
##STR00120##
[0085] and B is 5- or 6-membered carbocycle or heterocycle (e.g.,
phenyl such as
##STR00121##
A and B are each independently optionally substituted with one or
more R.sub.A. Z.sub.1 is independently selected at each occurrence
from O, S, NH or CH.sub.2; and Z.sub.2 is independently selected at
each occurrence from N or CH. X is 5- or 6-membered carbocycle or
heterocycle or 6- to 12-membered bicycle (e.g.,
##STR00122##
wherein X.sub.3 is N and is directly linked to -L.sub.3-D) and is
optionally substituted with one or more R.sub.A. Specific examples
of X are described hereinabove. D is C.sub.5-C.sub.6carbocycle or
5- to 6-membered heterocycle (e.g., phenyl), and is optionally
substituted with one or more R.sub.A. Preferably, D is or
##STR00123##
wherein R.sub.M and R.sub.N are as defined above. L.sub.1 and
L.sub.2 are each independently bond or C.sub.1-C.sub.6alkylene, and
L.sub.3 is bond, C.sub.1-C.sub.6alkylene or --C(O)--, and L.sub.1,
L.sub.2, and L.sub.3 are each independently optionally substituted
with one or more R.sub.L. Preferably, L.sub.1, L.sub.2, and L.sub.3
are bond. When A is 5- or 6-membered carbocycle or heterocycle
(e.g., phenyl such as
##STR00124##
Y is --N(R.sub.B)C(O)C(R.sub.1R.sub.2)N(R.sub.5)-T-R.sub.D,
--N(R.sub.B)C(O)C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)-T-R.sub.D,
-G-C(R.sub.1R.sub.2)N(R.sub.5)-T-R.sub.D or
-G-C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)-T-R.sub.D, and Z is
-L.sub.S-C(R.sub.8R.sub.9)N(R.sub.12)-T-R.sub.D or
-L.sub.S-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)-T-R.sub.D. When B
is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl such
as
##STR00125##
Y is -L.sub.S-C(R.sub.1R.sub.2)N(R.sub.5)-T-R.sub.D or
-L.sub.S-C(R.sub.3R.sub.4)C(R.sub.6R.sub.7)-T-R.sub.D, and Z is
--N(R.sub.B)C(O)C(R.sub.8R.sub.9)N(R.sub.12)-T-R.sub.D,
--N(R.sub.B)C(O)C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)-T-R.sub.D,
-G-C(R.sub.8R.sub.9)N(R.sub.12)-T-R.sub.D or
-G-C(R.sub.10R.sub.11)C(R.sub.13R.sub.14)-T-R.sub.D. R.sub.1 is
R.sub.C, and R.sub.2 and R.sub.5, taken together with the atoms to
which they are attached, form a 5- to 6-membered heterocyclic ring
(e.g.,
##STR00126##
which is optionally substituted with one or more R.sub.A; R.sub.3
and R.sub.6 are each independently R.sub.C, and R.sub.4 and
R.sub.7, taken together with the atoms to which they are attached,
form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g.,
##STR00127##
which is optionally substituted with one or more R.sub.A. R.sub.8
is R.sub.C, and R.sub.9 and R.sub.12, taken together with the atoms
to which they are attached, form a 5- to 6-membered heterocyclic
ring (e.g.,
##STR00128##
which is optionally substituted with one or more R.sub.A; and
R.sub.10 and R.sub.13 are each independently R.sub.C, and R.sub.11
and R.sub.14, taken together with the atoms to which they are
attached, form a 5- to 6-membered carbocyclic or heterocyclic ring
(e.g.,
##STR00129##
which is optionally substituted with one or more R.sub.A. G is
independently C.sub.5-C.sub.6carbocycle or 5- to 6-membered
heterocycle, such as
##STR00130##
and is independently optionally substituted with one or more
R.sub.A. T is preferably independently selected at each occurrence
from --C(O)-L.sub.Y'--N(R.sub.B)C(O)-L.sub.S''- or
--C(O)-L.sub.Y'--N(R.sub.B)C(O)O-L.sub.S''-. L.sub.Y' is each
independently L.sub.S' and, preferably, is each independently
C.sub.1-C.sub.6alkylene (e.g., --CH.sub.2--) and optionally
substituted with one or more substituents selected from R.sub.L. T
can also be, without limitation, selected from
--C(O)-L.sub.Y'-L.sub.S''-, --C(O)-L.sub.Y'-O-L.sub.S''-,
--C(O)-L.sub.Y'--N(R.sub.B)-L.sub.S'-, or
--C(O)-L.sub.Y'--N(R.sub.B)S(O).sub.2-L.sub.S''-. In some cases
when A is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl
such as
##STR00131##
Y is
##STR00132##
[0086] as described above, and Z is
##STR00133##
as described above. In some other cases when B is 5- or 6-membered
carbocycle or heterocycle (e.g., phenyl such as
##STR00134##
Y is
##STR00135##
[0087] as described above, and Z is
##STR00136##
as described above.
[0088] In another aspect, the present invention features compounds
of Formula I.sub.A and pharmaceutically acceptable salts
thereof.
##STR00137##
wherein: [0089] R.sub.NB is each independently selected from
R.sub.B; [0090] R.sub.C' is each independently selected from
R.sub.C; [0091] R.sub.D' is each independently selected from
R.sub.D; [0092] R.sub.2 and R.sub.5, taken together with the atoms
to which they are attached, form a 3- to 12-membered heterocycle
which is optionally substituted with one or more R.sub.A; [0093]
R.sub.9 and R.sub.12, taken together with the atoms to which they
are attached, form a 3- to 12-membered heterocycle which is
optionally substituted with one or more R.sub.A; [0094] A, B, D, X,
L.sub.1, L.sub.2, L.sub.3, T, R.sub.A, R.sub.B, R.sub.C, and
R.sub.D are as described above in Formula I.
[0095] In this aspect, A and B preferably are independently
selected from C.sub.5-C.sub.6carbocycle or 5- to 6-membered
heterocycle, and are each independently optionally substituted with
one or more R.sub.A. More preferably, at least one of A and B is
phenyl (e.g.,
##STR00138##
and is optionally substituted with one or more R.sub.A. Highly
preferably, both A and B are each independently phenyl (e.g.,
##STR00139##
and are each independently optionally substituted with one or more
R.sub.A.
[0096] D preferably is selected from C.sub.5-C.sub.6carbocycle, 5-
to 6-membered heterocycle, or 8- to 12-membered bicycles, and is
optionally substituted with one or more R.sub.A. D can also be
preferably selected from C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, and is optionally
substituted with one or more R.sub.L. More preferably, D is
C.sub.5-C.sub.6carbocycle, 5- to 6-membered heterocycle, or 6- to
12-membered bicycles, and is substituted with one or more R.sub.M,
where R.sub.M is halogen, nitro, oxo, phosphonoxy, phosphono,
thioxo, cyano, or -L.sub.S-R.sub.E. Also preferably, D is phenyl,
and is optionally substituted with one or more R.sub.A. More
preferably, D is phenyl, and is substituted with one or more
R.sub.M, wherein R.sub.M is as defined above. Highly preferably, D
is
##STR00140##
wherein R.sub.M is as defined above, and each R.sub.N is
independently selected from R.sub.D and preferably is hydrogen. One
or more R.sub.N can also preferably be halo such as F.
[0097] D is also preferably pyridinyl, pyrimidinyl, or thiazolyl,
optionally substituted with one or more R.sub.A. More preferably D
is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with
one or more R.sub.M. Highly preferably, D is
##STR00141##
wherein R.sub.M is as defined above, and each R.sub.N is
independently selected from R.sub.D and preferably is hydrogen. One
or more R.sub.N can also preferably be halo such as F. D is also
preferably indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl,
benzo[d]thiazolyl, or indazolyl, and is optionally substituted with
one or more R.sub.A. More preferably D is indanyl,
4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl,
or benzo[d][1,3]dioxol-5-yl, and is substituted with one or more
R.sub.M. Highly preferably, D is
##STR00142##
and is optionally substituted with one or more R.sub.M.
[0098] Preferably, R.sub.M is halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl. More preferably, R.sub.M is halogen,
hydroxy, mercapto, amino, carboxy; or C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each of which is
independently optionally substituted at each occurrence with one or
more substituents selected from halogen, hydroxy, mercapto, amino
or carboxy. Highly preferably, R.sub.M is C.sub.1-C.sub.6alkyl
which is optionally substituted with one or more substituents
selected from halogen, hydroxy, mercapto, amino or carboxy.
[0099] Also preferably, R.sub.M is halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or
cyano; or R.sub.M is -L.sub.S-R.sub.E, wherein L.sub.S is a bond or
C.sub.1-C.sub.6alkylene, and R.sub.E is --N(R.sub.SR.sub.S'),
--O--R.sub.S, --C(O)R.sub.S, --C(O)OR.sub.S,
--C(O)N(R.sub.SR.sub.S'), --N(R.sub.S)C(O)R.sub.S',
--N(R.sub.S)C(O)OR.sub.S', --N(R.sub.S)SO.sub.2R.sub.S',
--SO.sub.2R.sub.S, --SR.sub.S, or --P(O)(OR.sub.S).sub.2, wherein
R.sub.S and R.sub.S' can be, for example, each independently
selected at each occurrence from (1) hydrogen or (2)
C.sub.1-C.sub.6alkyl optionally substituted at each occurrence with
one or more halogen, hydroxy, --O--C.sub.1-C.sub.6alkyl or 3- to
6-membered heterocycle; or R.sub.M is C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each of which is
independently optionally substituted at each occurrence with one or
more substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano; or R.sub.M is C.sub.3-C.sub.6carbocycle or 3- to 6-membered
heterocycle, each of which is independently optionally substituted
at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl, C.sub.2-C.sub.6haloalkynyl,
--C(O)OR.sub.S, or --N(R.sub.SR.sub.S'). More preferably, R.sub.M
is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto,
amino, carboxy, or C.sub.1-C.sub.6alkyl (e.g., methyl, isopropyl,
tert-butyl), C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each
of which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, cyano, or carboxy. For example R.sub.M is
CF.sub.3, --C(CF.sub.3).sub.2--OH, --C(CH.sub.3).sub.2--CN,
--C(CH.sub.3).sub.2--CH.sub.2OH, or
--C(CH.sub.3).sub.2--CH.sub.2NH.sub.2. Also preferably R.sub.M is
-L.sub.S-R.sub.E where L.sub.S is a bond and R.sub.E is
--N(R.sub.SR.sub.S'), --O--R.sub.S, --N(R.sub.S)C(O)OR.sub.S',
--N(R.sub.S)SO.sub.2R.sub.S', --SO.sub.2R.sub.S, or --SR.sub.S. For
example where L.sub.S is a bond, R.sub.E is
--N(C.sub.1-C.sub.6alkyl).sub.2 (e.g., --NMe.sub.2);
--N(C.sub.1-C.sub.6alkylene-O--C.sub.1-C.sub.6alkyl).sub.2 (e.g.
--N(CH.sub.2CH.sub.2OMe).sub.2);
--N(C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkylene-O--C.sub.1-C.sub.6alkyl-
) (e.g. --N(CH.sub.3)(CH.sub.2CH.sub.2OMe));
--O--C.sub.1-C.sub.6alkyl (e.g., --O-Me, --O-Et, --O-isopropyl,
--O-tert-butyl, --O-n-hexyl); --O--C.sub.1-C.sub.6haloalkyl (e.g.,
--OCF.sub.3, --OCH.sub.2CF.sub.3);
--O--C.sub.1-C.sub.6alkylene-piperidine (e.g.,
--O--CH.sub.2CH.sub.2-1-piperidyl);
--N(C.sub.1-C.sub.6alkyl)C(O)OC.sub.1-C.sub.6alkyl (e.g.,
--N(CH.sub.3)C(O)O--CH.sub.2CH(CH.sub.3).sub.2),
--N(C.sub.1-C.sub.6alkyl)SO.sub.2C.sub.1-C.sub.6alkyl (e.g.,
--N(CH.sub.3)SO.sub.2CH.sub.3); --SO.sub.2C.sub.1-C.sub.6alkyl
(e.g., --SO.sub.2Me); --SO.sub.2C.sub.1-C.sub.6haloalkyl (e.g.,
--SO.sub.2CF.sub.3); or --S--C.sub.1-C.sub.6haloalkyl (e.g.,
SCF.sub.3). Also preferably R.sub.M is -L.sub.S-R.sub.E where
L.sub.S is C.sub.1-C.sub.6alkylene (e.g., --CH.sub.2--,
--C(CH.sub.3).sub.2--, --C(CH.sub.3).sub.2--CH.sub.2--) and R.sub.E
is --O--R.sub.S, --C(O)OR.sub.S, --N(R.sub.S)C(O)OR.sub.S', or
--P(O)(OR.sub.S).sub.2. For example R.sub.M is
--C.sub.1-C.sub.6alkylene-O--R.sub.S (e.g.,
--C(CH.sub.3).sub.2--CH.sub.2--OMe);
--C.sub.1-C.sub.6alkylene-C(O)OR.sub.S (e.g.,
--C(CH.sub.3).sub.2--C(O)OMe);
--C.sub.1-C.sub.6alkylene-N(R.sub.S)C(O)OR.sub.S' (e.g.,
--C(CH.sub.3).sub.2--CH.sub.2--NHC(O)OCH.sub.3); or
--C.sub.1-C.sub.6alkylene-P(O)(OR.sub.S).sub.2 (e.g.,
--CH.sub.2--P(O)(OEt).sub.2). Also more preferably R.sub.M is
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl,
C.sub.2-C.sub.6haloalkynyl, --C(O)OR.sub.S, or
--N(R.sub.SR.sub.S'). For example R.sub.M is cycloalkyl (e.g.,
cyclopropyl, 2,2-dichloro-1-methylcycloprop-1-yl, cyclohexyl),
phenyl, heterocyclyl (e.g., morpholin-4-yl,
1,1-dioxidothiomorpholin-4-yl, 4-methylpiperazin-1-yl,
4-methoxycarbonylpiperazin-1-yl, pyrrolidin-1-yl, piperidin-1-yl,
4-methylpiperidin-1-yl, 3,5-dimethylpiperidin-1-yl,
4,4-difluoropiperidin-1-yl, tetrahydropyran-4-yl, pyridinyl,
pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably,
R.sub.M is C.sub.1-C.sub.6alkyl which is optionally substituted
with one or more substituents selected from halogen, hydroxy,
mercapto, amino or carboxy (e.g., tert-butyl, CF.sub.3).
[0100] X preferably is C.sub.5-C.sub.6carbocycle, 5- to 6-membered
heterocycle, or 6- to 12-membered bicycles (e.g.,
##STR00143##
wherein X.sub.3 is N and is directly linked to -L.sub.3-D), and is
optionally substituted with one or more R.sub.A. Non-limiting
examples of X are described hereinabove.
[0101] L.sub.1 and L.sub.2 are preferably independently bond or
C.sub.1-C.sub.6alkylene, L.sub.3 is preferably selected from bond,
C.sub.1-C.sub.6alkylene or --C(O)--, and L.sub.1, L.sub.2, and
L.sub.3 are each independently optionally substituted with one or
more R.sub.L. More preferably, L.sub.1, L.sub.2 and L.sub.3 are
each independently bond or C.sub.1-C.sub.6alkylene (e.g.,
--CH.sub.2-- or --CH.sub.2CH.sub.2--), and are each independently
optionally substituted with one or more R.sub.L. Highly preferably,
L.sub.1, L.sub.2 and L.sub.3 are bond.
[0102] R.sub.2 and R.sub.5, taken together with the atoms to which
they are attached, preferably form a 5- to 6-membered heterocycle
or 6- to 12-membered bicycle (e.g.,
##STR00144##
which is optionally substituted with one or more R.sub.A.
[0103] R.sub.9 and R.sub.12, taken together with the atoms to which
they are attached, preferably form a 5- to 6-membered heterocycle
or 6- to 12-membered bicycle (e.g.,
##STR00145##
which is optionally substituted with one or more R.sub.A.
[0104] -T-R.sub.D' can be, without limitation, independently
selected at each occurrence from --C(O)-L.sub.Y'-,
--C(O)O-L.sub.Y'-R.sub.D',
--C(O)-L.sub.Y'--N(R.sub.B)C(O)-L.sub.S''-R.sub.D',
--C(O)-L.sub.Y'--N(R.sub.B)C(O)O-L.sub.S''-R.sub.D',
--N(R.sub.B)C(O)-L.sub.Y'--N(R.sub.B)C(O)-L.sub.S''-R.sub.D',
--N(R.sub.B)C(O)-L.sub.Y'--N(R.sub.B)C(O)O-L.sub.S''-R.sub.D', or
--N(R.sub.B)C(O)-L.sub.Y'--N(R.sub.B)-L.sub.S''-R.sub.D', wherein
L.sub.Y' is each independently L.sub.S' and, preferably, is each
independently C.sub.1-C.sub.6alkylene (e.g., --CH.sub.2--) and
optionally substituted with one or more substituents selected from
R.sub.L. Preferably, -T-R.sub.D' is independently selected at each
occurrence from --C(O)-L.sub.Y'-M'-L.sub.S''-R.sub.D' or
--N(R.sub.B)C(O)-L.sub.Y'-M'-L.sub.S''-R.sub.D'. More preferably,
-T-R.sub.D' is independently selected at each occurrence from
--C(O)-L.sub.Y'--N(R.sub.B)C(O)-L.sub.S''-R.sub.D' or
--C(O)-L.sub.Y'--N(R.sub.B)C(O)O-L.sub.S''-R.sub.D'. Highly
preferably, -T-R.sub.D' is independently selected at each
occurrence from --C(O)-L.sub.Y'--N(R.sub.B)C(O)--R.sub.D' or
--C(O)-L.sub.Y'--N(R.sub.B)C(O)O--R.sub.D', wherein L.sub.Y'
preferably is each independently C.sub.1-C.sub.6alkylene (e.g.,
--CH.sub.2--) and optionally substituted with one or more
substituents selected from R.sub.L.
[0105] R.sub.NB and R.sub.C' are preferably hydrogen, and R.sub.D'
preferably is independently selected at each occurrence from
R.sub.E. More preferably, R.sub.D' is independently selected at
each occurrence from C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl
or C.sub.2-C.sub.6alkynyl, each of which is independently
optionally substituted at each occurrence with one or more
substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl.
[0106] R.sub.A preferably is halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl; or -L.sub.A-O--R.sub.S,
-L.sub.A-S--R.sub.S, -L.sub.A-C(O)R.sub.S, -L.sub.A-OC(O)R.sub.S,
-L.sub.A-C(O)OR.sub.S, -L.sub.A-N(R.sub.SR.sub.S'),
-L.sub.A-S(O)R.sub.S, -L.sub.A-SO.sub.2R.sub.S,
-L.sub.A-C(O)N(R.sub.SR.sub.S'), -L.sub.A-N(R.sub.S)C(O)R.sub.S',
-L.sub.A-N(R.sub.S)C(O)N(R.sub.S'R.sub.S''),
-L.sub.A-N(R.sub.S)SO.sub.2R.sub.S',
-L.sub.A-SO.sub.2N(R.sub.SR.sub.S'),
-L.sub.A-N(R.sub.S)SO.sub.2N(R.sub.S'R.sub.S''),
-L.sub.A-N(R.sub.S)S(O)N(R.sub.S'R.sub.S''),
-L.sub.A-OS(O)--R.sub.S, -L.sub.A-OS(O).sub.2--R.sub.S,
-L.sub.A-S(O).sub.2OR.sub.S, -L.sub.A-S(O)OR.sub.S,
-L.sub.A-OC(O)OR.sub.S, -L.sub.A-N(R.sub.S)C(O)OR.sub.S',
-L.sub.A-OC(O)N(R.sub.SR.sub.S'),
-L.sub.A-N(R.sub.S)S(O)--R.sub.S', -L.sub.A-S(O)N(R.sub.SR.sub.S')
or -L.sub.A-C(O)N(R.sub.S)C(O)--R.sub.S', wherein L.sub.A is bond,
C.sub.1-C.sub.6alkylene, C.sub.2-C.sub.6alkenylene or
C.sub.2-C.sub.6alkynylene.
[0107] More preferably, R.sub.A is halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano;
or C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl.
[0108] Highly preferably, R.sub.A is halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano;
or C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.
[0109] L.sub.S, L.sub.S' and L.sub.S'' preferably are each
independently selected at each occurrence from bond; or
C.sub.1-C.sub.6alkylene, C.sub.2-C.sub.6alkenylene or
C.sub.2-C.sub.6alkynylene.
[0110] A and B can be the same or different. Likewise, L.sub.1 and
L.sub.2 can be the same or different.
[0111] In one embodiment of this aspect, A, B, and D are each
independently phenyl, and are each independently optionally
substituted with one or more R.sub.A. Preferably, D is or
##STR00146##
wherein R.sub.M and R.sub.N are as defined above. L.sub.1 and
L.sub.2 are each independently bond or C.sub.1-C.sub.6alkylene, and
L.sub.3 is bond, C.sub.1-C.sub.6alkylene or --C(O)--, and L.sub.1,
L.sub.2, and L.sub.3 are each independently optionally substituted
with one or more R.sub.L. Preferably, L.sub.1, L.sub.2, and L.sub.3
are bond. -T-R.sub.D' is independently selected at each occurrence
from --C(O)-L.sub.Y'--N(R.sub.B)C(O)-L.sub.S''-R.sub.D' or
--C(O)-L.sub.Y'-N(R.sub.B)C(O)O-L.sub.S''-R.sub.D', wherein
L.sub.Y' is C.sub.1-C.sub.6alkylene (e.g., --CH.sub.2--) and
optionally substituted with one or more substituents selected from
R.sub.L, and L.sub.S'' preferably is bond. -T-R.sub.D' can also be,
without limitation, selected from
--C(O)-L.sub.Y'-L.sub.S''-R.sub.D',
C(O)-L.sub.Y'-O-L.sub.S''-R.sub.D',
--C(O)-L.sub.Y'--N(R.sub.B)-L.sub.S'-R.sub.D', or
--C(O)-L.sub.Y'--N(R.sub.B)S(O).sub.2-L.sub.S'-R.sub.D'.
[0112] In still another aspect, the present invention features
compounds of Formula I.sub.B and pharmaceutically acceptable salts
thereof:
##STR00147##
wherein: [0113] R.sub.C' is each independently selected from
R.sub.C; [0114] R.sub.D' is each independently selected from
R.sub.D; [0115] R.sub.2 and R.sub.5, taken together with the atoms
to which they are attached, form a 3- to 12-membered heterocycle
which is optionally substituted with one or more R.sub.A; [0116]
R.sub.9 and R.sub.12, taken together with the atoms to which they
are attached, form a 3- to 12-membered heterocycle which is
optionally substituted with one or more R.sub.A; [0117] A, B, D, X,
L.sub.1, L.sub.2, L.sub.3, T, R.sub.A, R.sub.C, and R.sub.D are as
described above in Formula I.
[0118] In this aspect, A and B preferably are independently
selected from 8- to 12-membered bicycles such as
##STR00148##
where Z.sub.1 is independently selected at each occurrence from O,
S, NH or CH.sub.2, Z.sub.2 is independently selected at each
occurrence from N or CH, Z.sub.3 is independently selected at each
occurrence from N or CH, Z.sub.4 is independently selected at each
occurrence from O, S, NH or CH.sub.2, and W.sub.1, W.sub.2,
W.sub.3, W.sub.4, W.sub.5 and W.sub.6 are each independently
selected at each occurrence from CH or N. A and B are each
independently optionally substituted with one or more R.sub.A.
[0119] More preferably, A is selected from
##STR00149##
and is optionally substituted with one or more R.sub.A; B is
selected from
##STR00150##
and is optionally substituted with one or more R.sub.A, where
Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4, W.sub.1, W.sub.2, W.sub.3,
W.sub.4, W.sub.5, W.sub.6 are as defined above. Preferably, Z.sub.3
is N and Z.sub.4 is NH. For instance, A can be selected from
##STR00151##
and is optionally substituted with one or more R.sub.A; and B can
be selected from
##STR00152##
and is optionally substituted with one or more R.sub.A.
[0120] Also preferably, A is
##STR00153##
and B is
##STR00154##
[0121] wherein A' and B' are independently selected from
C.sub.5-C.sub.6carbocycle or 5- to 6-membered heterocycle, and A
and B are independently optionally substituted with one or more
R.sub.A.
[0122] D preferably is selected from C.sub.5-C.sub.6carbocycle, 5-
to 6-membered heterocycle, or 6- to 12-membered bicycles, and is
optionally substituted with one or more R.sub.A. D can also be
preferably selected from C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, and is optionally
substituted with one or more substituents selected from R.sub.L.
More preferably, D is C.sub.5-C.sub.6carbocycle, 5- to 6-membered
heterocycle, or 6- to 12-membered bicycles, and is substituted with
one or more R.sub.M, where R.sub.M is halogen, nitro, oxo,
phosphonoxy, phosphono, thioxo, cyano, or -L.sub.S-R.sub.E. Also
preferably, D is phenyl, and is optionally substituted with one or
more R.sub.A. More preferably, D is phenyl, and is substituted with
one or more R.sub.M, wherein R.sub.M is as defined above. Highly
preferably, D is
##STR00155##
wherein R.sub.M is as defined above, and each R.sub.N is
independently selected from R.sub.D and preferably is hydrogen. One
or more R.sub.N can also preferably be halo such as F.
[0123] D is also preferably pyridinyl, pyrimidinyl, or thiazolyl,
optionally substituted with one or more R.sub.A. More preferably D
is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with
one or more R.sub.M. Highly preferably, D is
##STR00156##
wherein R.sub.M is as defined above, and each R.sub.N is
independently selected from R.sub.D and preferably is hydrogen. One
or more R.sub.N can also preferably be halo such as F. D is also
preferably indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl,
benzo[d]thiazolyl, or indazolyl, and is optionally substituted with
one or more R.sub.A. More preferably D is indanyl,
4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl,
or benzo[d][1,3]dioxol-5-yl, and is substituted with one or more
R.sub.M. Highly preferably, D is
##STR00157##
and is optionally substituted with one or more R.sub.M.
[0124] Preferably, R.sub.M is halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl. More preferably, R.sub.M is halogen,
hydroxy, mercapto, amino, carboxy; or C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each of which is
independently optionally substituted at each occurrence with one or
more substituents selected from halogen, hydroxy, mercapto, amino
or carboxy. Highly preferably, R.sub.M is C.sub.1-C.sub.6alkyl
which is optionally substituted with one or more substituents
selected from halogen, hydroxy, mercapto, amino or carboxy.
[0125] Also preferably, R.sub.M is halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or
cyano; or R.sub.M is -L.sub.S-R.sub.E, wherein L.sub.S is a bond or
C.sub.1-C.sub.6alkylene, and R.sub.E is --N(R.sub.SR.sub.S'),
--O--R.sub.S, --C(O)R.sub.S, --C(O)OR.sub.S,
--C(O)N(R.sub.SR.sub.S'), --N(R.sub.S)C(O)R.sub.S',
--N(R.sub.S)C(O)OR.sub.S', --N(R.sub.S)SO.sub.2R.sub.S',
--SO.sub.2R.sub.S, --SR.sub.S, or --P(O)(OR.sub.S).sub.2, wherein
R.sub.S and R.sub.S' can be, for example, each independently
selected at each occurrence from (1) hydrogen or (2)
C.sub.1-C.sub.6alkyl optionally substituted at each occurrence with
one or more halogen, hydroxy, --O--C.sub.1-C.sub.6alkyl or 3- to
6-membered heterocycle; or R.sub.M is C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each of which is
independently optionally substituted at each occurrence with one or
more substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano; or R.sub.M is C.sub.3-C.sub.6carbocycle or 3- to 6-membered
heterocycle, each of which is independently optionally substituted
at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl, C.sub.2-C.sub.6haloalkynyl,
--C(O)OR.sub.S, or --N(R.sub.SR.sub.S'). More preferably, R.sub.M
is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto,
amino, carboxy, or C.sub.1-C.sub.6alkyl (e.g., methyl, isopropyl,
tert-butyl), C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each
of which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, cyano, or carboxy. For example R.sub.M is
CF.sub.3, --C(CF.sub.3).sub.2--OH, --C(CH.sub.3).sub.2--CN,
--C(CH.sub.3).sub.2--CH.sub.2OH, or
--C(CH.sub.3).sub.2--CH.sub.2NH.sub.2. Also preferably R.sub.M is
-L.sub.S-R.sub.E where L.sub.S is a bond and R.sub.E is
--N(R.sub.SR.sub.S'), --O--R.sub.S, --N(R.sub.S)C(O)OR.sub.S',
--N(R.sub.S)SO.sub.2R.sub.S', --SO.sub.2R.sub.S, or --SR.sub.S. For
example where L.sub.S is a bond, R.sub.E is
--N(C.sub.1-C.sub.6alkyl).sub.2 (e.g., --NMe.sub.2);
--N(C.sub.1-C.sub.6alkylene-O--C.sub.1-C.sub.6alkyl).sub.2 (e.g.
--N(CH.sub.2CH.sub.2OMe).sub.2);
--N(C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkylene-O--C.sub.1-C.sub.6alkyl-
) (e.g. --N(CH.sub.3)(CH.sub.2CH.sub.2OMe));
--O--C.sub.1-C.sub.6alkyl (e.g., --O-Me, --O-Et, --O-isopropyl,
--O-tert-butyl, --O-n-hexyl); --O--C.sub.1-C.sub.6haloalkyl (e.g.,
--OCF.sub.3, --OCH.sub.2CF.sub.3);
--O--C.sub.1-C.sub.6alkylene-piperidine (e.g.,
--O--CH.sub.2CH.sub.2-1-piperidyl);
--N(C.sub.1-C.sub.6alkyl)C(O)OC.sub.1-C.sub.6alkyl (e.g.,
--N(CH.sub.3)C(O)O--CH.sub.2CH(CH.sub.3).sub.2),
--N(C.sub.1-C.sub.6alkyl)SO.sub.2C.sub.1-C.sub.6alkyl (e.g.,
--N(CH.sub.3)SO.sub.2CH.sub.3); --SO.sub.2C.sub.1-C.sub.6alkyl
(e.g., --SO.sub.2Me); --SO.sub.2C.sub.1-C.sub.6haloalkyl (e.g.,
--SO.sub.2CF.sub.3); or --S--C.sub.1-C.sub.6haloalkyl (e.g.,
SCF.sub.3). Also preferably R.sub.M is -L.sub.S-R.sub.E where
L.sub.S is C.sub.1-C.sub.6alkylene (e.g., --CH.sub.2--,
--C(CH.sub.3).sub.2--, --C(CH.sub.3).sub.2--CH.sub.2--) and R.sub.E
is --O--R.sub.S, --C(O)OR.sub.S, --N(R.sub.S)C(O)OR.sub.S, or
--P(O)(OR.sub.S).sub.2. For example R.sub.M is
--C.sub.1-C.sub.6alkylene-O--R.sub.S (e.g.,
--C(CH.sub.3).sub.2--CH.sub.2--OMe);
--C.sub.1-C.sub.6alkylene-C(O)OR.sub.S (e.g.,
--C(CH.sub.3).sub.2--C(O)OMe);
--C.sub.1-C.sub.6alkylene-N(R.sub.S)C(O)OR.sub.S' (e.g.,
--C(CH.sub.3).sub.2--CH.sub.2--NHC(O)OCH.sub.3); or
--C.sub.1-C.sub.6alkylene-P(O)(OR.sub.S).sub.2 (e.g.,
--CH.sub.2--P(O)(OEt).sub.2). Also more preferably R.sub.M is
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl,
C.sub.2-C.sub.6haloalkynyl, --C(O)OR.sub.S, or
--N(R.sub.SR.sub.S'). For example R.sub.M is cycloalkyl (e.g.,
cyclopropyl, 2,2-dichloro-1-methylcycloprop-1-yl, cyclohexyl),
phenyl, heterocyclyl (e.g., morpholin-4-yl,
1,1-dioxidothiomorpholin-4-yl, 4-methylpiperazin-1-yl,
4-methoxycarbonylpiperazin-1-yl, pyrrolidin-1-yl, piperidin-1-yl,
4-methylpiperidin-1-yl, 3,5-dimethylpiperidin-1-yl,
4,4-difluoropiperidin-1-yl, tetrahydropyran-4-yl, pyridinyl,
pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably,
R.sub.M is C.sub.1-C.sub.6alkyl which is optionally substituted
with one or more substituents selected from halogen, hydroxy,
mercapto, amino or carboxy (e.g., tert-butyl, CF.sub.3).
[0126] X preferably is C.sub.5-C.sub.6carbocycle, 5- to 6-membered
heterocycle, or 6- to 12-membered bicycles (e.g.,
##STR00158##
wherein X.sub.3 is N and is directly linked to -L.sub.3-D), and is
optionally substituted with one or more R.sub.A. Non-limiting
examples of X are described hereinabove.
[0127] L.sub.1 and L.sub.2 are preferably independently bond or
C.sub.1-C.sub.6alkylene, L.sub.3 is preferably selected from bond,
C.sub.1-C.sub.6alkylene or --C(O)--, and L.sub.1, L.sub.2, and
L.sub.3 are each independently optionally substituted with one or
more R.sub.L. More preferably, L.sub.1, L.sub.2 and L.sub.3 are
each independently bond or C.sub.1-C.sub.6alkylene (e.g.,
--CH.sub.2-- or --CH.sub.2CH.sub.2--), and are each independently
optionally substituted with one or more R.sub.L. Highly preferably,
L.sub.1, L.sub.2 and L.sub.3 are bond.
[0128] R.sub.2 and R.sub.5, taken together with the atoms to which
they are attached, preferably form a 5- to 6-membered heterocycle
or 6- to 12-membered bicycle (e.g.,
##STR00159##
which is optionally substituted with one or more R.sub.A. R.sub.9
and R.sub.12, taken together with the atoms to which they are
attached, preferably form a 5- to 6-membered heterocycle or 6- to
12-membered bicycle (e.g.,
##STR00160##
which is optionally substituted with one or more R.sub.A.
[0129] -T-R.sub.D' can be, without limitation, independently
selected at each occurrence from --C(O)-L.sub.Y'-R.sub.D',
--C(O)O-L.sub.Y'-R.sub.D',
--C(O)-L.sub.Y'--N(R.sub.B)C(O)-L.sub.S''-R.sub.D',
--C(O)-L.sub.Y'--N(R.sub.B)C(O)O-L.sub.S''-R.sub.D',
--N(R.sub.B)C(O)-L.sub.Y'--N(R.sub.B)C(O)-L.sub.S''-R.sub.D',
--N(R.sub.B)C(O)-L.sub.Y'--N(R.sub.B)C(O)O-L.sub.S''-R.sub.D', or
--N(R.sub.B)C(O)-L.sub.Y'--N(R.sub.B)-L.sub.S''-R.sub.D', wherein
L.sub.Y' is each independently L.sub.S' and, preferably, is each
independently C.sub.1-C.sub.6alkylene (e.g., --CH.sub.2--) and
optionally substituted with one or more substituents selected from
R.sub.L. Preferably, -T-R.sub.D' is independently selected at each
occurrence from --C(O)-L.sub.Y'-M'-L.sub.S''-R.sub.D' or
--N(R.sub.B)C(O)-L.sub.Y'-M'-L.sub.S''-R.sub.D'. More preferably,
-T-R.sub.D' is independently selected at each occurrence from
--C(O)-L.sub.Y'--N(R.sub.B)C(O)-L.sub.S''-R.sub.D' or
--C(O)-L.sub.Y'--N(R.sub.B)C(O)O-L.sub.S''-R.sub.D'. Highly
preferably, -T-R.sub.D' is independently selected at each
occurrence from --C(O)-L.sub.Y'--N(R.sub.B)C(O)--R.sub.D' or
--C(O)-L.sub.Y'-N(R.sub.B)C(O)O--R.sub.D', wherein L.sub.Y'
preferably is each independently C.sub.1-C.sub.6alkylene (e.g.,
--CH.sub.2--) and optionally substituted with one or more
substituents selected from R.sub.L.
[0130] R.sub.C' is preferably hydrogen, and R.sub.D' preferably is
independently selected at each occurrence from R.sub.E. More
preferably, R.sub.D' is independently selected at each occurrence
from C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl.
[0131] R.sub.A preferably is halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl; or -L.sub.A-O--R.sub.S,
-L.sub.A-S--R.sub.S, -L.sub.A-C(O)R.sub.S, -L.sub.A-OC(O)R.sub.S,
-L.sub.A-C(O)OR.sub.S, -L.sub.A-N(R.sub.SR.sub.S'),
-L.sub.A-S(O)R.sub.S, -L.sub.A-SO.sub.2R.sub.S,
-L.sub.A-C(O)N(R.sub.SR.sub.S'), -L.sub.A-N(R.sub.S)C(O)R.sub.S',
-L.sub.A-N(R.sub.S)C(O)N(R.sub.S'R.sub.S''),
-L.sub.A-N(R.sub.S)SO.sub.2R.sub.S',
-L.sub.A-SO.sub.2N(R.sub.SR.sub.S'),
-L.sub.A-N(R.sub.S)SO.sub.2N(R.sub.S'R.sub.S''),
-L.sub.AN(R.sub.S)S(O)N(R.sub.S'R.sub.S''),
-L.sub.A-OS(O)--R.sub.S, -L.sub.A-OS(O).sub.2--R.sub.S,
-L.sub.A-S(O).sub.2OR.sub.S, -L.sub.A-S(O)OR.sub.S,
-L.sub.A-OC(O)OR.sub.S, -L.sub.A-N(R.sub.S)C(O)OR.sub.S,
-L.sub.A-OC(O)N(R.sub.SR.sub.S'),
-L.sub.A-N(R.sub.S)S(O)--R.sub.S', -L.sub.A-S(O)N(R.sub.SR.sub.S')
or -L.sub.A-C(O)N(R.sub.S)C(O)--R.sub.S', wherein L.sub.A is bond,
C.sub.1-C.sub.6alkylene, C.sub.2-C.sub.6alkenylene or
C.sub.2-C.sub.6alkynylene.
[0132] More preferably, R.sub.A is halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano;
or C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl.
[0133] Highly preferably, R.sub.A is halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano;
or C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.
[0134] L.sub.S, L.sub.S' and L.sub.S'' preferably are each
independently selected at each occurrence from bond; or
C.sub.1-C.sub.6alkylene, C.sub.2-C.sub.6alkenylene or
C.sub.2-C.sub.6alkynylene.
[0135] A and B can be the same or different. Likewise, L.sub.1 and
L.sub.2 can be the same or different.
[0136] In one embodiment of this aspect, A is
##STR00161##
and is optionally substituted with one or more R.sub.A; B is
##STR00162##
and is optionally substituted with one or more R.sub.A; and D is
C.sub.5-C.sub.6carbocycle or 5- to 6-membered heterocycle (e.g.,
phenyl), and is optionally substituted with one or more R.sub.A.
Preferably, D is
##STR00163##
wherein R.sub.M and R.sub.N are as defined above. Z.sub.1 is
independently selected at each occurrence from O, S, NH or
CH.sub.2; and Z.sub.2 is independently selected at each occurrence
from N or CH. L.sub.1 and L.sub.2 are each independently bond or
C.sub.1-C.sub.6alkylene, and L.sub.3 is bond,
C.sub.1-C.sub.6alkylene or --C(O)--, and L.sub.1, L.sub.2, and
L.sub.3 are each independently optionally substituted with one or
more R.sub.L. Preferably, L.sub.1, L.sub.2, and L.sub.3 are bond.
-T-R.sub.D' is independently selected at each occurrence from
--C(O)-L.sub.Y'--N(R.sub.B)C(O)-L.sub.S''-R.sub.D' or
--C(O)-L.sub.Y'--N(R.sub.B)C(O)O-L.sub.S''-R.sub.D', wherein
L.sub.Y' is C.sub.1-C.sub.6alkylene (e.g., --CH.sub.2--) and
optionally substituted with one or more substituents selected from
R.sub.L, and L.sub.S'' preferably is bond. -T-R.sub.D' can also be,
without limitation, selected from
--C(O)-L.sub.Y'-L.sub.S''-R.sub.D,
--C(O)-L.sub.Y'-O-L.sub.S''-R.sub.D',
--C(O)-L.sub.Y'--N(R.sub.B)-L.sub.S''-R.sub.D', or
--C(O)-L.sub.Y'--N(R.sub.B)S(O).sub.2-L.sub.S''-R.sub.D'.
[0137] In yet another aspect, the present invention further
features compounds of Formula I.sub.C and pharmaceutically
acceptable salts thereof.
##STR00164##
wherein: [0138] R.sub.NB is R.sub.B; [0139] R.sub.C' is each
independently selected from R.sub.C; [0140] R.sub.D' is each
independently selected from R.sub.D; [0141] R.sub.2 and R.sub.5,
taken together with the atoms to which they are attached, form a 3-
to 12-membered heterocycle which is optionally substituted with one
or more R.sub.A; [0142] R.sub.9 and R.sub.12, taken together with
the atoms to which they are attached, form a 3- to 12-membered
heterocycle which is optionally substituted with one or more
R.sub.A; [0143] A, B, D, X, L.sub.1, L.sub.2, L.sub.3, T, R.sub.A,
R.sub.B, R.sub.C, and R.sub.D are as described above in Formula
I.
[0144] In this aspect, A preferably is C.sub.5-C.sub.6carbocycle or
5- to 6-membered heterocycle, and is optionally substituted with
one or more R.sub.A; and B preferably is 8- to 12-membered bicycle
(such as
##STR00165##
and is optionally substituted with one or more R.sub.A. Z.sub.1 is
O, S, NH or CH.sub.2; Z.sub.2 is N or CH; Z.sub.3 is N or CH;
Z.sub.4 is O, S, NH or CH.sub.2; and W.sub.1, W.sub.2, W.sub.3,
W.sub.4, W.sub.5 and W.sub.6 are each independently selected from
CH or N.
[0145] More preferably, A is phenyl (e.g.,
##STR00166##
and is optionally substituted with one or more R.sub.A; and B
is
##STR00167##
and is optionally substituted with one or more R.sub.A, where
Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4, W.sub.1, W.sub.2, W.sub.3,
W.sub.4, W.sub.5, W.sub.6 are as defined above. Preferably, Z.sub.3
is N and Z.sub.4 is NH. For instance, B can be
##STR00168##
and is optionally substituted with one or more R.sub.A.
[0146] Also preferably, A is C.sub.5-C.sub.6carbocycle (e.g.,
phenyl such as
##STR00169##
or 5- to 6-membered heterocycle; and B is
##STR00170##
wherein B' is selected from C.sub.5-C.sub.6carbocycle or 5- to
6-membered heterocycle. A and B are independently optionally
substituted with one or more R.sub.A.
[0147] D preferably is selected from C.sub.5-C.sub.6carbocycle, 5-
to 6-membered heterocycle, or 6- to 12-membered bicycles, and is
optionally substituted with one or more R.sub.A. D can also be
preferably selected from C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, and is optionally
substituted with one or more substituents selected from R.sub.L.
More preferably, D is C.sub.5-C.sub.6carbocycle, 5- to 6-membered
heterocycle, or 6- to 12-membered bicycles, and is substituted with
one or more R.sub.M, where R.sub.M is halogen, nitro, oxo,
phosphonoxy, phosphono, thioxo, cyano, or -L.sub.S-R.sub.E. Also
preferably, D is phenyl, and is optionally substituted with one or
more R.sub.A. More preferably, D is phenyl, and is substituted with
one or more R.sub.M, wherein R.sub.M is as defined above. Highly
preferably, D is
##STR00171##
wherein R.sub.M is as defined above, and each R.sub.N is
independently selected from R.sub.D and preferably is hydrogen. One
or more R.sub.N can also preferably be halo such as F.
[0148] D is also preferably pyridinyl, pyrimidinyl, or thiazolyl,
optionally substituted with one or more R.sub.A. More preferably D
is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with
one or more R.sub.M. Highly preferably, D is
##STR00172##
wherein R.sub.M is as defined above, and each R.sub.N is
independently selected from R.sub.D and preferably is hydrogen. One
or more R.sub.N can also preferably be halo such as F. D is also
preferably indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl,
benzo[d]thiazolyl, or indazolyl, and is optionally substituted with
one or more R.sub.A. More preferably D is indanyl,
4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl,
or benzo[d][1,3]dioxol-5-yl, and is substituted with one or more
R.sub.M. Highly preferably, D is
##STR00173##
and is optionally substituted with one or more R.sub.M.
[0149] Preferably, R.sub.M is halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl. More preferably, R.sub.M is halogen,
hydroxy, mercapto, amino, carboxy; or C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each of which is
independently optionally substituted at each occurrence with one or
more substituents selected from halogen, hydroxy, mercapto, amino
or carboxy. Highly preferably, R.sub.M is C.sub.1-C.sub.6alkyl
which is optionally substituted with one or more substituents
selected from halogen, hydroxy, mercapto, amino or carboxy.
[0150] Also preferably, R.sub.M is halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or
cyano; or R.sub.M is -L.sub.S-R.sub.E, wherein L.sub.S is a bond or
C.sub.1-C.sub.6alkylene, and R.sub.E is --N(R.sub.SR.sub.S'),
--O--R.sub.S, --C(O)R.sub.S, --C(O)OR.sub.S,
--C(O)N(R.sub.SR.sub.S'), --N(R.sub.S)C(O)R.sub.S',
--N(R.sub.S)C(O)OR.sub.S, --N(R.sub.S)SO.sub.2R.sub.S',
--SO.sub.2R.sub.S, --SR.sub.S, or --P(O)(OR.sub.S).sub.2, wherein
R.sub.S and R.sub.S' can be, for example, each independently
selected at each occurrence from (1) hydrogen or (2)
C.sub.1-C.sub.6alkyl optionally substituted at each occurrence with
one or more halogen, hydroxy, --O--C.sub.1-C.sub.6alkyl or 3- to
6-membered heterocycle; or R.sub.M is C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each of which is
independently optionally substituted at each occurrence with one or
more substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano; or R.sub.M is C.sub.3-C.sub.6carbocycle or 3- to 6-membered
heterocycle, each of which is independently optionally substituted
at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl, C.sub.2-C.sub.6haloalkynyl,
--C(O)OR.sub.S, or --N(R.sub.SR.sub.S'). More preferably, R.sub.M
is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto,
amino, carboxy, or C.sub.1-C.sub.6alkyl (e.g., methyl, isopropyl,
tert-butyl), C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each
of which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, cyano, or carboxy. For example R.sub.M is
CF.sub.3, --C(CF.sub.3).sub.2--OH, --C(CH.sub.3).sub.2--CN,
--C(CH.sub.3).sub.2--CH.sub.2OH, or
--C(CH.sub.3).sub.2--CH.sub.2NH.sub.2. Also preferably R.sub.M is
-L.sub.S-R.sub.E where L.sub.S is a bond and R.sub.E is
--N(R.sub.SR.sub.S'), --O--R.sub.S, --N(R.sub.S)C(O)OR.sub.S,
--N(R.sub.S)SO.sub.2R.sub.S', --SO.sub.2R.sub.S, or --SR.sub.S. For
example where L.sub.S is a bond, R.sub.E is
--N(C.sub.1-C.sub.6alkyl).sub.2 (e.g., --NMe.sub.2);
--N(C.sub.1-C.sub.6alkylene-O--C.sub.1-C.sub.6alkyl).sub.2 (e.g.
--N(CH.sub.2CH.sub.2OMe).sub.2);
--N(C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkylene-O--C.sub.1-C.sub.6alkyl-
) (e.g. --N(CH.sub.3)(CH.sub.2CH.sub.2OMe));
--O--C.sub.1-C.sub.6alkyl (e.g., --O-Me, --O-Et, --O-isopropyl,
--O-tert-butyl, --O-n-hexyl); --O--C.sub.1-C.sub.6haloalkyl (e.g.,
--OCF.sub.3, --OCH.sub.2CF.sub.3);
--O--C.sub.1-C.sub.6alkylene-piperidine (e.g.,
--O--CH.sub.2CH.sub.2-1-piperidyl);
--N(C.sub.1-C.sub.6alkyl)C(O)OC.sub.1-C.sub.6alkyl (e.g.,
--N(CH.sub.3)C(O)O--CH.sub.2CH(CH.sub.3).sub.2),
--N(C.sub.1-C.sub.6alkyl)SO.sub.2C.sub.1-C.sub.6alkyl (e.g.,
--N(CH.sub.3)SO.sub.2CH.sub.3); --SO.sub.2C.sub.1-C.sub.6alkyl
(e.g., --SO.sub.2Me); --SO.sub.2C.sub.1-C.sub.6haloalkyl (e.g.,
--SO.sub.2CF.sub.3); or --S--C.sub.1-C.sub.6haloalkyl (e.g.,
SCF.sub.3). Also preferably R.sub.M is -L.sub.S-R.sub.E where
L.sub.S is C.sub.1-C.sub.6alkylene (e.g., --CH.sub.2--,
--C(CH.sub.3).sub.2--, --C(CH.sub.3).sub.2--CH.sub.2--) and R.sub.E
is --O--R.sub.S, --C(O)OR.sub.S, --N(R.sub.S)C(O)OR.sub.S, or
--P(O)(OR.sub.S).sub.2. For example R.sub.M is
--C.sub.1-C.sub.6alkylene-O--R.sub.S (e.g.,
--C(CH.sub.3).sub.2--CH.sub.2--OMe);
--C.sub.1-C.sub.6alkylene-C(O)OR.sub.S (e.g.,
--C(CH.sub.3).sub.2--C(O)OMe);
--C.sub.1-C.sub.6alkylene-N(R.sub.S)C(O)OR.sub.S' (e.g.,
--C(CH.sub.3).sub.2--CH.sub.2--NHC(O)OCH.sub.3); or
--C.sub.1-C.sub.6alkylene-P(O)(OR.sub.S).sub.2 (e.g.,
--CH.sub.2--P(O)(OEt).sub.2). Also more preferably R.sub.M is
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl,
C.sub.2-C.sub.6haloalkynyl, --C(O)OR.sub.S, or
--N(R.sub.SR.sub.S'). For example R.sub.M is cycloalkyl (e.g.,
cyclopropyl, 2,2-dichloro-1-methylcycloprop-1-yl, cyclohexyl),
phenyl, heterocyclyl (e.g., morpholin-4-yl,
1,1-dioxidothiomorpholin-4-yl, 4-methylpiperazin-1-yl,
4-methoxycarbonylpiperazin-1-yl, pyrrolidin-1-yl, piperidin-1-yl,
4-methylpiperidin-1-yl, 3,5-dimethylpiperidin-1-yl,
4,4-difluoropiperidin-1-yl, tetrahydropyran-4-yl, pyridinyl,
pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably,
R.sub.M is C.sub.1-C.sub.6alkyl which is optionally substituted
with one or more substituents selected from halogen, hydroxy,
mercapto, amino or carboxy (e.g., tert-butyl, CF.sub.3).
[0151] X preferably is C.sub.5-C.sub.6carbocycle, 5- to 6-membered
heterocycle, or 6- to 12-membered bicycles (e.g.,
##STR00174##
wherein X.sub.3 is N and is directly linked to -L.sub.3-D), and is
optionally substituted with one or more R.sub.A. Non-limiting
examples of X are described hereinabove.
[0152] L.sub.1 and L.sub.2 are preferably independently bond or
C.sub.1-C.sub.6alkylene, L.sub.3 is preferably selected from bond,
C.sub.1-C.sub.6alkylene or --C(O)--, and L.sub.1, L.sub.2, and
L.sub.3 are each independently optionally substituted with one or
more R.sub.L. More preferably, L.sub.1, L.sub.2 and L.sub.3 are
each independently bond or C.sub.1-C.sub.6alkylene (e.g.,
--CH.sub.2-- or --CH.sub.2CH.sub.2--), and are each independently
optionally substituted with one or more R.sub.L. Highly preferably,
L.sub.1, L.sub.2 and L.sub.3 are bond. L.sub.1 and L.sub.2 can be
the same or different.
[0153] R.sub.2 and R.sub.5, taken together with the atoms to which
they are attached, preferably form a 5- to 6-membered heterocycle
or 6- to 12-membered bicycle (e.g.,
##STR00175##
which is optionally substituted with one or more R.sub.A. R.sub.9
and R.sub.12, taken together with the atoms to which they are
attached, preferably form a 5- to 6-membered heterocycle or 6- to
12-membered bicycle (e.g.,
##STR00176##
which is optionally substituted with one or more R.sub.A.
[0154] -T-R.sub.D' can be, without limitation, independently
selected at each occurrence from --C(O)-L.sub.Y'-R.sub.D',
--C(O)O-L.sub.Y'-R.sub.D',
--C(O)-L.sub.Y'--N(R.sub.B)C(O)-L.sub.S''-R.sub.D',
--C(O)-L.sub.Y'--N(R.sub.B)C(O)O-L.sub.S''-R.sub.D',
--N(R.sub.B)C(O)-L.sub.Y'--N(R.sub.B)C(O)-L.sub.S''-R.sub.D',
--N(R.sub.B)C(O)-L.sub.Y'--N(R.sub.B)C(O)O-L.sub.S''-R.sub.D', or
--N(R.sub.B)C(O)-L.sub.Y'--N(R.sub.B)-L.sub.S''-R.sub.D', wherein
L.sub.Y' is each independently L.sub.S' and, preferably, is each
independently C.sub.1-C.sub.6alkylene (e.g., --CH.sub.2--) and
optionally substituted with one or more substituents selected from
R.sub.L. Preferably, -T-R.sub.D' is independently selected at each
occurrence from --C(O)-L.sub.Y-M'-L.sub.S''-R.sub.D' or
--N(R.sub.B)C(O)-L.sub.Y'-M'-L.sub.S''-R.sub.D'. More preferably,
-T-R.sub.D' is independently selected at each occurrence from
--C(O)-L.sub.Y'--N(R.sub.B)C(O)-L.sub.S''-R.sub.D' or
--C(O)-L.sub.Y'--N(R.sub.B)C(O)O-L.sub.S''-R.sub.D'. Highly
preferably, -T-R.sub.D' is independently selected at each
occurrence from --C(O)-L.sub.Y'--N(R.sub.B)C(O)--R.sub.D' or
--C(O)-L.sub.Y'-N(R.sub.B)C(O)O--R.sub.D', wherein L.sub.Y'
preferably is each independently C.sub.1-C.sub.6alkylene (e.g.,
--CH.sub.2--) and optionally substituted with one or more
substituents selected from R.sub.L.
[0155] R.sub.NB and R.sub.C' are preferably hydrogen, and R.sub.D'
preferably is independently selected at each occurrence from
R.sub.E. More preferably, R.sub.D' is independently selected at
each occurrence from C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl
or C.sub.2-C.sub.6alkynyl, each of which is independently
optionally substituted at each occurrence with one or more
substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl.
[0156] R.sub.A preferably is halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl; or -L.sub.A-O--R.sub.S,
-L.sub.A-S--R.sub.S, -L.sub.A-C(O)R.sub.S, -L.sub.A-OC(O)R.sub.S,
-L.sub.A-C(O)OR.sub.S, -L.sub.A-N(R.sub.SR.sub.S'),
-L.sub.A-S(O)R.sub.S, -L.sub.A-SO.sub.2R.sub.S,
-L.sub.A-C(O)N(R.sub.SR.sub.S'), -L.sub.A-N(R.sub.S)C(O)R.sub.S',
-L.sub.A-N(R.sub.S)C(O)N(R.sub.S'R.sub.S''),
-L.sub.A-N(R.sub.S)SO.sub.2R.sub.S',
-L.sub.A-SO.sub.2N(R.sub.SR.sub.S'),
-L.sub.A-N(R.sub.S)SO.sub.2N(R.sub.S'R.sub.S''),
-L.sub.AN(R.sub.S)S(O)N(R.sub.S'R.sub.S''),
-L.sub.A-OS(O)--R.sub.S, -L.sub.A-OS(O).sub.2--R.sub.S,
-L.sub.A-S(O).sub.2OR.sub.S, -L.sub.A-S(O)OR.sub.S,
-L.sub.A-OC(O)OR.sub.S, -L.sub.A-N(R.sub.S)C(O)OR.sub.S,
-L.sub.A-OC(O)N(R.sub.SR.sub.S'),
-L.sub.A-N(R.sub.S)S(O)--R.sub.S', -L.sub.A-S(O)N(R.sub.SR.sub.S')
or -L.sub.A-C(O)N(R.sub.S)C(O)--R.sub.S', wherein L.sub.A is bond,
C.sub.1-C.sub.6alkylene, C.sub.2-C.sub.6alkenylene or
C.sub.2-C.sub.6alkynylene.
[0157] More preferably, R.sub.A is halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano;
or C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl.
[0158] Highly preferably, R.sub.A is halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano;
or C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.
[0159] L.sub.S, L.sub.S' and L.sub.S'' preferably are each
independently selected at each occurrence from bond; or
C.sub.1-C.sub.6alkylene, C.sub.2-C.sub.6alkenylene or
C.sub.2-C.sub.6alkynylene.
[0160] In one embodiment of this aspect, A is phenyl, and is
optionally substituted with one or more R.sub.A; and B
##STR00177##
and is optionally substituted with one or more R.sub.A, wherein
Z.sub.1 is O, S, NH or CH.sub.2; and Z.sub.2 is N or CH. D is
C.sub.5-C.sub.6carbocycle or 5- to 6-membered heterocycle (e.g.,
phenyl), and is optionally substituted with one or more R.sub.A.
Preferably, D is
##STR00178##
wherein R.sub.M and R.sub.N are as defined above. L.sub.1 and
L.sub.2 are each independently bond or C.sub.1-C.sub.6alkylene, and
L.sub.3 is bond, C.sub.1-C.sub.6alkylene or --C(O)--, and L.sub.1,
L.sub.2, and L.sub.3 are each independently optionally substituted
with one or more R.sub.L. Preferably, L.sub.1, L.sub.2, and L.sub.3
are bond. -T-R.sub.D' is independently selected at each occurrence
from --C(O)-L.sub.Y'--N(R.sub.B)C(O)-L.sub.S''-R.sub.D' or
--C(O)-L.sub.Y'--N(R.sub.B)C(O)O-L.sub.S''-R.sub.D', wherein
L.sub.Y' is C.sub.1-C.sub.6alkylene (e.g., --CH.sub.2--) and
optionally substituted with one or more substituents selected from
R.sub.L, and L.sub.S'' preferably is bond. -T-R.sub.D' can also be,
without limitation, selected from
--C(O)-L.sub.Y'-L.sub.S''-R.sub.D',
--C(O)-L.sub.Y'-O-L.sub.S''-R.sub.D',
C(O)-L.sub.Y'--N(R.sub.B)-L.sub.S''-R.sub.D', or
--C(O)-L.sub.Y'--N(R.sub.B)S(O).sub.2-L.sub.S''-R.sub.D'.
[0161] In yet another aspect, the present invention features
compounds of Formula I.sub.D and pharmaceutically acceptable salts
thereof.
##STR00179##
wherein: [0162] G.sub.1 and G.sub.2 are each independently selected
from C.sub.5-C.sub.6carbocycle or 5- to 6-membered heterocycle, and
are each independently optionally substituted with one or more
R.sub.A; [0163] R.sub.C' is each independently selected from
R.sub.C; [0164] R.sub.D' is each independently selected from
R.sub.D; [0165] R.sub.2 and R.sub.5, taken together with the atoms
to which they are attached, form a 3- to 12-membered heterocycle
which is optionally substituted with one or more R.sub.A; [0166]
R.sub.9 and R.sub.12, taken together with the atoms to which they
are attached, form a 3- to 12-membered heterocycle which is
optionally substituted with one or more R.sub.A; [0167] A, B, D, X,
L.sub.1, L.sub.2, L.sub.3, T, R.sub.A, R.sub.C, and R.sub.D are as
described above in Formula I.
[0168] In this aspect, A and B preferably are independently
selected from C.sub.5-C.sub.6carbocycle or 5- to 6-membered
heterocycle, and are each independently optionally substituted with
one or more R.sub.A. More preferably, at least one of A and B is
phenyl (e.g.,
##STR00180##
and is optionally substituted with one or more R.sub.A. Highly
preferably, both A and B are each independently phenyl (e.g.,
##STR00181##
and are each independently optionally substituted with one or more
R.sub.A.
[0169] D preferably is selected from C.sub.5-C.sub.6carbocycle, 5-
to 6-membered heterocycle, or 8- to 12-membered bicycles, and is
optionally substituted with one or more R.sub.A. D can also be
preferably selected from C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, and is optionally
substituted with one or more R.sub.L. More preferably, D is
C.sub.5-C.sub.6carbocycle, 5- to 6-membered heterocycle, or 6- to
12-membered bicycles, and is substituted with one or more R.sub.M,
where R.sub.M is halogen, nitro, oxo, phosphonoxy, phosphono,
thioxo, cyano, or -L.sub.S-R.sub.E. Also preferably, D is phenyl,
and is optionally substituted with one or more R.sub.A. More
preferably, D is phenyl, and is substituted with one or more
R.sub.M, wherein R.sub.M is as defined above. Highly preferably, D
is
##STR00182##
wherein R.sub.M is as defined above, and each R.sub.N is
independently selected from R.sub.D and preferably is hydrogen. One
or more R.sub.N can also preferably be halo such as F.
[0170] D is also preferably pyridinyl, pyrimidinyl, or thiazolyl,
optionally substituted with one or more R.sub.A. More preferably D
is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with
one or more R.sub.M. Highly preferably, D is
##STR00183##
wherein R.sub.M is as defined above, and each R.sub.N is
independently selected from R.sub.D and preferably is hydrogen. One
or more R.sub.N can also preferably be halo such as F. D is also
preferably indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl,
benzo[d]thiazolyl, or indazolyl, and is optionally substituted with
one or more R.sub.A. More preferably D is indanyl,
4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl,
or benzo[d][1,3]dioxol-5-yl, and is substituted with one or more
R.sub.M. Highly preferably, D is
##STR00184##
and is optionally substituted with one or more R.sub.M.
[0171] Preferably, R.sub.M is halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl. More preferably, R.sub.M is halogen,
hydroxy, mercapto, amino, carboxy; or C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each of which is
independently optionally substituted at each occurrence with one or
more substituents selected from halogen, hydroxy, mercapto, amino
or carboxy. Highly preferably, R.sub.M is C.sub.1-C.sub.6alkyl
which is optionally substituted with one or more substituents
selected from halogen, hydroxy, mercapto, amino or carboxy.
[0172] Also preferably, R.sub.M is halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or
cyano; or R.sub.M is -L.sub.S-R.sub.E, wherein L.sub.S is a bond or
C.sub.1-C.sub.6alkylene, and R.sub.E is --N(R.sub.SR.sub.S'),
--O--R.sub.S, --C(O)R.sub.S, --C(O)OR.sub.S,
--C(O)N(R.sub.SR.sub.S'), --N(R.sub.S)C(O)R.sub.S',
--N(R.sub.S)C(O)OR.sub.S, --N(R.sub.S)SO.sub.2R.sub.S',
--SO.sub.2R.sub.S, --SR.sub.S, or --P(O)(OR.sub.S).sub.2, wherein
R.sub.S and R.sub.S' can be, for example, each independently
selected at each occurrence from (1) hydrogen or (2)
C.sub.1-C.sub.6alkyl optionally substituted at each occurrence with
one or more halogen, hydroxy, --O--C.sub.1-C.sub.6alkyl or 3- to
6-membered heterocycle; or R.sub.M is C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each of which is
independently optionally substituted at each occurrence with one or
more substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano; or R.sub.M is C.sub.3-C.sub.6carbocycle or 3- to 6-membered
heterocycle, each of which is independently optionally substituted
at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl, C.sub.2-C.sub.6haloalkynyl,
--C(O)OR.sub.S, or --N(R.sub.SR.sub.S'). More preferably, R.sub.M
is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto,
amino, carboxy, or C.sub.1-C.sub.6alkyl (e.g., methyl, isopropyl,
tert-butyl), C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each
of which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, cyano, or carboxy. For example R.sub.M is
CF.sub.3, --C(CF.sub.3).sub.2--OH, --C(CH.sub.3).sub.2--CN,
--C(CH.sub.3).sub.2--CH.sub.2OH, or
--C(CH.sub.3).sub.2--CH.sub.2NH.sub.2. Also preferably R.sub.M is
-L.sub.S-R.sub.E where L.sub.S is a bond and R.sub.E is
--N(R.sub.SR.sub.S'), --O--R.sub.S, --N(R.sub.S)C(O)OR.sub.S,
--N(R.sub.S)SO.sub.2R.sub.S', --SO.sub.2R.sub.S, or --SR.sub.S. For
example where L.sub.S is a bond, R.sub.E is
--N(C.sub.1-C.sub.6alkyl).sub.2 (e.g., --NMe.sub.2);
--N(C.sub.1-C.sub.6alkylene-O--C.sub.1-C.sub.6alkyl).sub.2 (e.g.
--N(CH.sub.2CH.sub.2OMe).sub.2);
--N(C.sub.1-C.sub.6alkyl)(C.sub.1-C.sub.6alkylene-O--C.sub.1-C.sub.6alkyl-
) (e.g. --N(CH.sub.3)(CH.sub.2CH.sub.2OMe));
--O--C.sub.1-C.sub.6alkyl (e.g., --O-Me, --O-Et, --O-isopropyl,
--O-tert-butyl, --O-n-hexyl); --O--C.sub.1-C.sub.6haloalkyl (e.g.,
--OCF.sub.3, --OCH.sub.2CF.sub.3);
--O--C.sub.1-C.sub.6alkylene-piperidine (e.g.,
--O--CH.sub.2CH.sub.2-1-piperidyl);
--N(C.sub.1-C.sub.6alkyl)C(O)OC.sub.1-C.sub.6alkyl (e.g.,
--N(CH.sub.3)C(O)O--CH.sub.2CH(CH.sub.3).sub.2),
--N(C.sub.1-C.sub.6alkyl)SO.sub.2C.sub.1-C.sub.6alkyl (e.g.,
--N(CH.sub.3)SO.sub.2CH.sub.3); --SO.sub.2C.sub.1-C.sub.6alkyl
(e.g., --SO.sub.2Me); --SO.sub.2C.sub.1-C.sub.6haloalkyl (e.g.,
--SO.sub.2CF.sub.3); or --S--C.sub.1-C.sub.6haloalkyl (e.g.,
SCF.sub.3). Also preferably R.sub.M is -L.sub.S-R.sub.E where
L.sub.S is C.sub.1-C.sub.6alkylene (e.g., --CH.sub.2--,
--C(CH.sub.3).sub.2--, --C(CH.sub.3).sub.2--CH.sub.2--) and R.sub.E
is --O--R.sub.S, --C(O)OR.sub.S, --N(R.sub.S)C(O)OR.sub.S, or
--P(O)(OR.sub.S).sub.2. For example R.sub.M is
--C.sub.1-C.sub.6alkylene-O--R.sub.S (e.g.,
--C(CH.sub.3).sub.2--CH.sub.2--OMe);
--C.sub.1-C.sub.6alkylene-C(O)OR.sub.S (e.g.,
--C(CH.sub.3).sub.2--C(O)OMe);
--C.sub.1-C.sub.6alkylene-N(R.sub.S)C(O)OR.sub.S' (e.g.,
--C(CH.sub.3).sub.2--CH.sub.2--NHC(O)OCH.sub.3); or
--C.sub.1-C.sub.6alkylene-P(O)(OR.sub.S).sub.2 (e.g.,
--CH.sub.2--P(O)(OEt).sub.2). Also more preferably R.sub.M is
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl,
C.sub.2-C.sub.6haloalkynyl, --C(O)OR.sub.S, or
--N(R.sub.SR.sub.S'). For example R.sub.M is cycloalkyl (e.g.,
cyclopropyl, 2,2-dichloro-1-methylcycloprop-1-yl, cyclohexyl),
phenyl, heterocyclyl (e.g., morpholin-4-yl,
1,1-dioxidothiomorpholin-4-yl, 4-methylpiperazin-1-yl,
4-methoxycarbonylpiperazin-1-yl, pyrrolidin-1-yl, piperidin-1-yl,
4-methylpiperidin-1-yl, 3,5-dimethylpiperidin-1-yl,
4,4-difluoropiperidin-1-yl, tetrahydropyran-4-yl, pyridinyl,
pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably,
R.sub.M is C.sub.1-C.sub.6alkyl which is optionally substituted
with one or more substituents selected from halogen, hydroxy,
mercapto, amino or carboxy (e.g., tert-butyl, CF.sub.3).
[0173] X preferably is C.sub.5-C.sub.6carbocycle, 5- to 6-membered
heterocycle, or 6- to 12-membered bicycles (e.g.,
##STR00185##
wherein X.sub.3 is N and is directly linked to -L.sub.3-D), and is
optionally substituted with one or more R.sub.A. Non-limiting
examples of X are described hereinabove.
[0174] L.sub.1 and L.sub.2 are preferably independently bond or
C.sub.1-C.sub.6alkylene, L.sub.3 is preferably selected from bond,
C.sub.1-C.sub.6alkylene or --C(O)--, and L.sub.1, L.sub.2, and
L.sub.3 are each independently optionally substituted with one or
more R.sub.L. More preferably, L.sub.1, L.sub.2 and L.sub.3 are
each independently bond or C.sub.1-C.sub.6alkylene (e.g.,
--CH.sub.2-- or --CH.sub.2CH.sub.2--), and are each independently
optionally substituted with one or more R.sub.L. Highly preferably,
L.sub.1, L.sub.2 and L.sub.3 are bond.
[0175] R.sub.2 and R.sub.5, taken together with the atoms to which
they are attached, preferably form a 5- to 6-membered heterocycle
or 6- to 12-membered bicycle (e.g.,
##STR00186##
which is optionally substituted with one or more R.sub.A.
[0176] R.sub.9 and R.sub.12, taken together with the atoms to which
they are attached, preferably form a 5- to 6-membered heterocycle
or 6- to 12-membered bicycle (e.g.,
##STR00187##
which is optionally substituted with one or more R.sub.A. G.sub.1
and G.sub.2 preferably are each independently selected from
##STR00188##
and are each independently optionally substituted with one or more
R.sub.A (e.g., one or more chloro or bromo). More preferably,
G.sub.1 is
##STR00189##
(including any tautomer thereof), and G.sub.2 is
##STR00190##
(including any tautomer thereof), and each G.sub.1 and G.sub.2 is
independently optionally substituted with one or more R.sub.A
(e.g., one or more chloro or bromo).
[0177] -T-R.sub.D' can be, without limitation, independently
selected at each occurrence from --C(O)-L.sub.Y'-,
--C(O)O-L.sub.Y'-R.sub.D',
--C(O)-L.sub.Y'--N(R.sub.B)C(O)-L.sub.S''-R.sub.D',
--C(O)-L.sub.Y'--N(R.sub.B)C(O)O-L.sub.S'-R.sub.D',
--N(R.sub.B)C(O)-L.sub.Y'--N(R.sub.B)C(O)-L.sub.S''-R.sub.D',
--N(R.sub.B)C(O)-L.sub.Y'--N(R.sub.B)C(O)O-L.sub.S''-R.sub.D', or
--N(R.sub.B)C(O)-L.sub.Y'--N(R.sub.B)-L.sub.S''-R.sub.D', wherein
L.sub.Y' is each independently L.sub.S' and, preferably, is each
independently C.sub.1-C.sub.6alkylene (e.g., --CH.sub.2--) and
optionally substituted with one or more substituents selected from
R.sub.L. Preferably, -T-R.sub.D' is independently selected at each
occurrence from --C(O)-L.sub.Y-M'-L.sub.S''-R.sub.D' or
--N(R.sub.B)C(O)-L.sub.Y-M'-L.sub.S''-R.sub.D'. More preferably,
-T-R.sub.D' is independently selected at each occurrence from
--C(O)-L.sub.Y'--N(R.sub.B)C(O)-L.sub.S''-R.sub.D' or
--C(O)-L.sub.Y'--N(R.sub.B)C(O)O-L.sub.S''-R.sub.D'. Highly
preferably, -T-R.sub.D' is independently selected at each
occurrence from --C(O)-L.sub.Y'--N(R.sub.B)C(O)--R.sub.D' or
--C(O)-L.sub.Y'-N(R.sub.B)C(O)O--R.sub.D', wherein L.sub.Y'
preferably is each independently C.sub.1-C.sub.6alkylene (e.g.,
--CH.sub.2--) and optionally substituted with one or more
substituents selected from R.sub.L.
[0178] R.sub.C' is preferably hydrogen, and R.sub.D' preferably is
independently selected at each occurrence from R.sub.E. More
preferably, R.sub.D' is independently selected at each occurrence
from C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl.
[0179] R.sub.A preferably is halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl; or -L.sub.A-O--R.sub.S,
-L.sub.A-S--R.sub.S, -L.sub.A-C(O)R.sub.S, -L.sub.A-OC(O)R.sub.S,
-L.sub.A-C(O)OR.sub.S, -L.sub.A-N(R.sub.SR.sub.S'),
-L.sub.A-S(O)R.sub.S, -L.sub.A-SO.sub.2R.sub.S,
-L.sub.A-C(O)N(R.sub.SR.sub.S'), -L.sub.A-N(R.sub.S)C(O)R.sub.S',
-L.sub.A-N(R.sub.S)C(O)N(R.sub.S'R.sub.S''),
-L.sub.A-N(R.sub.S)SO.sub.2R.sub.S',
-L.sub.A-SO.sub.2N(R.sub.SR.sub.S'),
-L.sub.A-N(R.sub.S)SO.sub.2N(R.sub.S'R.sub.S''),
-L.sub.AN(R.sub.S)S(O)N(R.sub.S'R.sub.S''),
-L.sub.A-OS(O)--R.sub.S, -L.sub.A-OS(O).sub.2--R.sub.S,
-L.sub.A-S(O).sub.2OR.sub.S, -L.sub.A-S(O)OR.sub.S,
-L.sub.A-OC(O)OR.sub.S, -L.sub.A-N(R.sub.S)C(O)OR.sub.S,
-L.sub.A-OC(O)N(R.sub.SR.sub.S'),
-L.sub.A-N(R.sub.S)S(O)--R.sub.S', -L.sub.A-S(O)N(R.sub.SR.sub.S')
or -L.sub.A-C(O)N(R.sub.S)C(O)--R.sub.S', wherein L.sub.A is bond,
C.sub.1-C.sub.6alkylene, C.sub.2-C.sub.6alkenylene or
C.sub.2-C.sub.6alkynylene.
[0180] More preferably, R.sub.A is halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano;
or C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle, each of
which is independently optionally substituted at each occurrence
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl, cyano, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl or
C.sub.2-C.sub.6haloalkynyl.
[0181] Highly preferably, R.sub.A is halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano;
or C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.
[0182] L.sub.S, L.sub.S' and L.sub.S'' preferably are each
independently selected at each occurrence from bond; or
C.sub.1-C.sub.6alkylene, C.sub.2-C.sub.6alkenylene or
C.sub.2-C.sub.6alkynylene.
[0183] A and B can be the same or different. Likewise, L.sub.1 and
L.sub.2 can be the same or different.
[0184] In one embodiment of this aspect, A, B, and D are each
independently phenyl, and are each independently optionally
substituted with one or more R.sub.A; and G.sub.1 is
##STR00191##
and each G.sub.1 and G.sub.2 is independently optionally
substituted with one or more R.sub.A (e.g., one or more chloro or
bromo). Preferably, D is
##STR00192##
wherein R.sub.M and R.sub.N are as defined above. L.sub.1 and
L.sub.2 are each independently bond or C.sub.1-C.sub.6alkylene, and
L.sub.3 is bond, C.sub.1-C.sub.6alkylene or --C(O)--, and L.sub.1,
L.sub.2, and L.sub.3 are each independently optionally substituted
with one or more R.sub.L. Preferably, L.sub.1, L.sub.2, and L.sub.3
are bond. -T-R.sub.D' is independently selected at each occurrence
from --C(O)-L.sub.Y'--N(R.sub.B)C(O)-L.sub.S''-R.sub.D' or
--C(O)-L.sub.Y'--N(R.sub.B)C(O)O-L.sub.S''-R.sub.D', wherein
L.sub.Y is C.sub.1-C.sub.6alkylene (e.g., --CH.sub.2--) and
optionally substituted with one or more substituents selected from
R.sub.L, and L.sub.S'' preferably is bond. -T-R.sub.D' can also be,
without limitation, selected from
--C(O)-L.sub.Y'-L.sub.S''-R.sub.D',
--C(O)-L.sub.Y'-O-L.sub.S-R.sub.D,
--C(O)-L.sub.Y'--N(R.sub.B)-L.sub.S'-R.sub.D', or
--C(O)-L.sub.Y'--N(R.sub.B)S(O).sub.2-L.sub.S''-R.sub.D'.
[0185] The present invention also features the compounds of
Formulae I, I.sub.A, I.sub.B, I.sub.C and I.sub.D as described
herein (including each embodiment described herein) or salts
thereof, except that D is C.sub.3-C.sub.12carbocycle or 3- to
12-membered heterocycle which is substituted with J and optionally
substituted with one or more R.sub.A, where J is
C.sub.3-C.sub.12carbocycle or 3- to 12-membered heterocycle and is
optionally substituted with one or more R.sub.A, or J is
--SF.sub.5. Preferably, D is C.sub.5-C.sub.6carbocycle, 5- to
6-membered heterocycle or 6- to 12-membered bicycle and is
optionally substituted with one or more R.sub.A, and J is
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle and is
optionally substituted with one or more R.sub.A. More preferably, D
is C.sub.5-C.sub.6carbocycle or 5- to 6-membered heterocycle and is
optionally substituted with one or more R.sub.A, and J is
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle and is
optionally substituted with one or more R.sub.A. Highly preferably,
D is phenyl substituted with J and optionally substituted with one
or more R.sub.A, where J is C.sub.3-C.sub.6carbocycle or 3- to
6-membered heterocycle and is optionally substituted with one or
more R.sub.A. Preferred R.sub.AS are as described above. In one
embodiment, D is
##STR00193##
wherein each R.sub.N is independently selected from R.sub.D and
preferably is hydrogen, and J is as defined above and preferably is
C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle
optionally substituted with one or more R.sub.A. In another
embodiment, D is
##STR00194##
and J is C.sub.3-C.sub.6carbocycle or 3- to 6-membered heterocycle
and is optionally substituted with one or more R.sub.A.
[0186] Moreover, the present invention features the compounds of
Formulae I, I.sub.A, I.sub.B, I.sub.C and I.sub.D as described
herein (including each embodiment described herein, as well as
where D is C.sub.3-C.sub.12carbocycle or 3- to 12-membered
heterocycle substituted with J and optionally substituted with one
or more R.sub.A as described hereinabove) or salts thereof, except
that X is optionally substituted with one or more R.sub.A'.
Specific examples of X are as described above, such as or
##STR00195##
wherein X.sub.3 is N and is directly linked to -L.sub.3-D. Each
R.sub.A' is independently R.sub.A; or C.sub.1-C.sub.10alkyl,
C.sub.2-C.sub.10alkenyl or C.sub.2-C.sub.10alkynyl, each of which
contains 0, 1, 2, 3, 4 or 5 heteroatoms selected from O, S or N and
is optionally substituted with one or more R.sub.L. R.sub.A is as
defined above. In one embodiment, each R.sub.A' is independently
R.sub.A; or C.sub.1-C.sub.10alkyl, C.sub.2-C.sub.10alkenyl or
C.sub.2-C.sub.10alkynyl, each of which contains 0, 1, 2, 3, 4 or 5
heteroatoms selected from O, S or N and is optionally substituted
with one or more substituents selected from halogen, hydroxy,
mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,
thioxo, formyl or cyano. In another embodiments, each R.sub.A' is
independently selected from R.sub.A; or C.sub.1-C.sub.10alkyl,
C.sub.2-C.sub.10alkenyl or C.sub.2-C.sub.10alkynyl, each of which
contains 0, 1, 2, 3, 4 or 5 O and is optionally substituted with
one or more R.sub.L. In a further [0187] embodiment, each R.sub.A'
is independently selected from C.sub.1-C.sub.10alkyl,
C.sub.2-C.sub.10alkenyl or C.sub.2-C.sub.10alkynyl, each of which
contains 0, 1, 2 or 3 O and is optionally substituted with one or
more substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano.
[0188] In another aspect of the invention, each R.sub.A' is
independently R.sub.A or
--(R.sub.X--R.sub.Y)N--(R.sub.X--R.sub.Y'), wherein N is 0, 1, 2,
3, 4; each R.sub.X is independently O, S or N(R.sub.B); each
R.sub.Y is independently C.sub.1-C.sub.6alkylene,
C.sub.2-C.sub.6alkenylene or C.sub.2-C.sub.6alkynylene each of
which is optionally substituted with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; and R.sub.Y'
is independently C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl each of which is optionally substituted with
one or more substituents selected from halogen, hydroxy, mercapto,
amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl
or cyano. R.sub.A and R.sub.B are as defined above. In one
embodiment, each R.sub.X is O. For example, each R.sub.A' is
selected from
--(O--C.sub.1-C.sub.6alkylene).sub.N-(O--C.sub.1-C.sub.6alkyl),
wherein N preferably is 0, 1, 2 or 3.
[0189] In addition, the present invention features the compounds of
Formulae I, I.sub.A, I.sub.B, I.sub.C and I.sub.D as described
herein (including each embodiment described herein, as well as
where D is C.sub.3-C.sub.12carbocycle or 3- to 12-membered
heterocycle substituted with J and optionally substituted with one
or more R.sub.A as described hereinabove, or where X is optionally
substituted with one or more R.sub.A' as described herein above),
wherein: [0190] R.sub.E is independently selected at each
occurrence from --O--R.sub.S, --S--R.sub.S, --C(O)R.sub.S,
--OC(O)R.sub.S, --C(O)OR.sub.S, --N(R.sub.SR.sub.S'),
--S(O)R.sub.S, --SO.sub.2R.sub.S, --C(O)N(R.sub.SR.sub.S'),
--N(R.sub.S)C(O)R.sub.S', --N(R.sub.S)C(O)N(R.sub.S'R.sub.S''),
--N(R.sub.S)SO.sub.2R.sub.S', --SO.sub.2N(R.sub.SR.sub.S'),
--N(R.sub.S)SO.sub.2N(R.sub.S'R.sub.S''),
--N(R.sub.S)S(O)N(R.sub.S'R.sub.S''), --OS(O)--R.sub.S,
--OS(O).sub.2--R.sub.S, --S(O).sub.2OR.sub.S, --S(O)OR.sub.S,
--OC(O)OR.sub.S, --N(R.sub.S)C(O)OR.sub.S',
--OC(O)N(R.sub.SR.sub.S'), --N(R.sub.S)S(O)--R.sub.S',
--S(O)N(R.sub.SR.sub.S'), --P(O)(OR.sub.S).sub.2, or
--C(O)N(R.sub.S)C(O)--R.sub.S'; or C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl or C.sub.2-C.sub.6alkynyl, each of which is
independently optionally substituted at each occurrence with one or
more substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
cyano; or C.sub.3-C.sub.6carbocycle or 3- to 6-membered
heterocycle, each of which is independently optionally substituted
at each occurrence with one or more substituents selected from
halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl, C.sub.2-C.sub.6haloalkynyl,
C(O)OR.sub.S, or --N(R.sub.SR.sub.S'); and [0191] R.sub.S, R.sub.S'
and R.sub.S'' are each independently selected at each occurrence
from hydrogen; C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl or
C.sub.2-C.sub.6alkynyl, each of which is independently optionally
substituted at each occurrence with one or more substituents
selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,
--O--C.sub.1-C.sub.6alkyl,
--O--C.sub.1-C.sub.6alkylene-O--C.sub.1-C.sub.6alkyl, or 3- to
6-membered carbocycle or heterocycle; or 3- to 6-membered
carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle
or heterocycle in R.sub.S, R.sub.S' or R.sub.S' is independently
optionally substituted at each occurrence with one or more
substituents selected from halogen, hydroxy, mercapto, amino,
carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl or C.sub.2-C.sub.6haloalkynyl.
[0192] The compounds of the present invention can be used in the
form of salts. Depending on the particular compound, a salt of a
compound may be advantageous due to one or more of the salt's
physical properties, such as enhanced pharmaceutical stability
under certain conditions or desired solubility in water or oil. In
some instances, a salt of a compound may be useful for the
isolation or purification of the compound.
[0193] Where a salt is intended to be administered to a patient,
the salt preferably is pharmaceutically acceptable.
Pharmaceutically acceptable salts include, but are not limited to,
acid addition salts, base addition salts, and alkali metal
salts.
[0194] Pharmaceutically acceptable acid addition salts may be
prepared from inorganic or organic acids. Examples of suitable
inorganic acids include, but are not limited to, hydrochloric,
hydrobromic, hydroionic, nitric, carbonic, sulfuric, and phosphoric
acid. Examples of suitable organic acids include, but are not
limited to, aliphatic, cycloaliphatic, aromatic, araliphatic,
heterocyclyl, carboxylic, and sulfonic classes of organic acids.
Specific examples of suitable organic acids include acetate,
trifluoroacetate, formate, propionate, succinate, glycolate,
gluconate, digluconate, lactate, malate, tartaric acid, citrate,
ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate,
glutamate, benzoate, anthranilic acid, mesylate, stearate,
salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate
(pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate,
pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate,
sufanilate, cyclohexylaminosulfonate, algenic acid,
b-hydroxybutyric acid, galactarate, galacturonate, adipate,
alginate, bisulfate, butyrate, camphorate, camphorsulfonate,
cyclopentanepropionate, dodecylsulfate, glycoheptanoate,
glycerophosphate, hemisulfate, heptanoate, hexanoate, nicotinate,
2-naphthalesulfonate, oxalate, palmoate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and
undecanoate.
[0195] Pharmaceutically acceptable base addition salts include, but
are not limited to, metallic salts and organic salts. Non-limiting
examples of suitable metallic salts include alkali metal (group Ia)
salts, alkaline earth metal (group IIa) salts, and other
pharmaceutically acceptable metal salts. Such salts may be made,
without limitation, from aluminum, calcium, lithium, magnesium,
potassium, sodium, or zinc. Non-limiting examples of suitable
organic salts can be made from tertiary amines and quaternary
amine, such as tromethamine, diethylamine,
N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and
procaine. Basic nitrogen-containing groups can be quaternized with
agents such as alkyl halides (e.g., methyl, ethyl, propyl, butyl,
decyl, lauryl, myristyl, and stearyl chlorides/bromides/iodides),
dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl
sulfates), aralkyl halides (e.g., benzyl and phenethyl bromides),
and others.
[0196] The compounds or salts of the present invention may exist in
the form of solvates, such as with water (i.e., hydrates), or with
organic solvents (e.g., with methanol, ethanol or acetonitrile to
form, respectively, methanolate, ethanolate or acetonitrilate).
[0197] The compounds or salts of the present invention may also be
used in the form of prodrugs. Some prodrugs are aliphatic or
aromatic esters derived from acidic groups on the compounds of the
invention. Others are aliphatic or aromatic esters of hydroxyl or
amino groups on the compounds of the invention. Phosphate prodrugs
of hydroxyl groups are preferred prodrugs.
[0198] The compounds of the invention may comprise asymmetrically
substituted carbon atoms known as chiral centers. These compounds
may exist, without limitation, as single stereoisomers (e.g.,
single enantiomers or single diastereomer), mixtures of
stereoisomers (e.g. a mixture of enantiomers or diastereomers), or
racemic mixtures. Compounds identified herein as single
stereoisomers are meant to describe compounds that are present in a
form that is substantially free from other stereoisomers (e.g.,
substantially free from other enantiomers or diastereomers). By
"substantially free," it means that at least 80% of the compound in
a composition is the described stereoisomer; preferably, at least
90% of the compound in a composition is the described stereoisomer;
and more preferably, at least 95%, 96%, 97%, 98% or 99% of the
compound in a composition is the described stereoisomer. Where the
stereochemistry of a chiral carbon is not specified in the chemical
structure of a compound, the chemical structure is intended to
encompass compounds containing either stereoisomer of the chiral
center.
[0199] Individual stereoisomers of the compounds of this invention
can be prepared using a variety of methods known in the art. These
methods include, but are not limited to, stereospecific synthesis,
chromatographic separation of diastereomers, chromatographic
resolution of enantiomers, conversion of enantiomers in an
enantiomeric mixture to diastereomers followed by
chromatographically separation of the diastereomers and
regeneration of the individual enantiomers, and enzymatic
resolution.
[0200] Stereospecific synthesis typically involves the use of
appropriate optically pure (enantiomerically pure) or substantial
optically pure materials and synthetic reactions that do not cause
racemization or inversion of stereochemistry at the chiral centers.
Mixtures of stereoisomers of compounds, including racemic mixtures,
resulting from a synthetic reaction may be separated, for example,
by chromatographic techniques as appreciated by those of ordinary
skill in the art. Chromatographic resolution of enantiomers can be
accomplished by using chiral chromatography resins, many of which
are commercially available. In a non-limiting example, racemate is
placed in solution and loaded onto the column containing a chiral
stationary phase. Enantiomers can then be separated by HPLC.
[0201] Resolution of enantiomers can also be accomplished by
converting enantiomers in a mixture to diastereomers by reaction
with chiral auxiliaries. The resulting diastereomers can be
separated by column chromatography or
crystallization/re-crystallization. This technique is useful when
the compounds to be separated contain a carboxyl, amino or hydroxyl
group that will form a salt or covalent bond with the chiral
auxiliary. Non-limiting examples of suitable chiral auxiliaries
include chirally pure amino acids, organic carboxylic acids or
organosulfonic acids. Once the diastereomers are separated by
chromatography, the individual enantiomers can be regenerated.
Frequently, the chiral auxiliary can be recovered and used
again.
[0202] Enzymes, such as esterases, phosphatases or lipases, can be
useful for the resolution of derivatives of enantiomers in an
enantiomeric mixture. For example, an ester derivative of a
carboxyl group in the compounds to be separated can be treated with
an enzyme which selectively hydrolyzes only one of the enantiomers
in the mixture. The resulting enantiomerically pure acid can then
be separated from the unhydrolyzed ester.
[0203] Alternatively, salts of enantiomers in a mixture can be
prepared using any suitable method known in the art, including
treatment of the carboxylic acid with a suitable optically pure
base such as alkaloids or phenethylamine, followed by precipitation
or crystallization/re-crystallization of the enantiomerically pure
salts. Methods suitable for the resolution/separation of a mixture
of stereoisomers, including racemic mixtures, can be found in
ENANTIOMERS, RACEMATES, AND RESOLUTIONS (Jacques et al., 1981, John
Wiley and Sons, New York, N.Y.).
[0204] A compound of this invention may possess one or more
unsaturated carbon-carbon double bonds. All double bond isomers,
such as the cis (Z) and trans (E) isomers, and mixtures thereof are
intended to be encompassed within the scope of a recited compound
unless otherwise specified. In addition, where a compound exists in
various tautomeric forms, a recited compound is not limited to any
one specific tautomer, but rather is intended to encompass all
tautomeric forms.
[0205] Certain compounds of the invention may exist in different
stable conformational forms which may be separable. Torsional
asymmetry due to restricted rotations about an asymmetric single
bond, for example because of steric hindrance or ring strain, may
permit separation of different conformers. The invention
encompasses each conformational isomer of these compounds and
mixtures thereof.
[0206] Certain compounds of the invention may also exist in
zwitterionic form and the invention encompasses each zwitterionic
form of these compounds and mixtures thereof.
[0207] The compounds of the present invention are generally
described herein using standard nomenclature. For a recited
compound having asymmetric center(s), it should be understood that
all of the stereoisomers of the compound and mixtures thereof are
encompassed in the present invention unless otherwise specified.
Non-limiting examples of stereoisomers include enantiomers,
diastereomers, and cis-transisomers. Where a recited compound
exists in various tautomeric forms, the compound is intended to
encompass all tautomeric forms. Certain compounds are described
herein using general formulas that include variables (e.g., A, B,
D, X, L.sub.1, L.sub.2, L.sub.3, Y, Z, T, R.sub.A or R.sub.B,).
Unless otherwise specified, each variable within such a formula is
defined independently of any other variable, and any variable that
occurs more than one time in a formula is defined independently at
each occurrence. If moieties are described as being "independently"
selected from a group, each moiety is selected independently from
the other. Each moiety therefore can be identical to or different
from the other moiety or moieties.
[0208] The number of carbon atoms in a hydrocarbyl moiety can be
indicated by the prefix "C.sub.x-C.sub.y," where x is the minimum
and y is the maximum number of carbon atoms in the moiety. Thus,
for example, "C.sub.1-C.sub.6alkyl" refers to an alkyl substituent
containing from 1 to 6 carbon atoms. Illustrating further,
C.sub.3-C.sub.6cycloalkyl means a saturated hydrocarbyl ring
containing from 3 to 6 carbon ring atoms. A prefix attached to a
multiple-component substituent only applies to the first component
that immediately follows the prefix. To illustrate, the term
"carbocyclylalkyl" contains two components: carbocyclyl and alkyl.
Thus, for example, C.sub.3-C.sub.6carbocyclylC.sub.1-C.sub.6alkyl
refers to a C.sub.3-C.sub.6carbocyclyl appended to the parent
molecular moiety through a C.sub.1-C.sub.6alkyl group.
[0209] Unless otherwise specified, when a linking element links two
other elements in a depicted chemical structure, the
leftmost-described component of the linking element is bound to the
left element in the depicted structure, and the rightmost-described
component of the linking element is bound to the right element in
the depicted structure. To illustrate, if the chemical structure is
-L.sub.S-M-L.sub.S'- and M is --N(R.sub.B)S(O)--, then the chemical
structure is -L.sub.S-N(R.sub.B)S(O)-L.sub.S'-.
[0210] If a linking element in a depicted structure is a bond, then
the element left to the linking element is joined directly to the
element right to the linking element via a covalent bond. For
example, if a chemical structure is depicted as
-L.sub.S-M-L.sub.S'- and M is selected as bond, then the chemical
structure will be -L.sub.S-L.sub.S'-. If two or more adjacent
linking elements in a depicted structure are bonds, then the
element left to these linking elements is joined directly to the
element right to these linking elements via a covalent bond. For
instance, if a chemical structure is depicted as
-L.sub.S-M-L.sub.S'-M'-L.sub.S''-, and M and L.sub.S' are selected
as bonds, then the chemical structure will be
-L.sub.S-M'-L.sub.S''-. Likewise, if a chemical structure is
depicted as -L.sub.S-M-L.sub.S'-M'-L.sub.S''-, and M, L.sub.S`and
M` are bonds, then the chemical structure will be
-L.sub.S-L.sub.S''-.
[0211] When a chemical formula is used to describe a moiety, the
dash(s) indicates the portion of the moiety that has the free
valence(s).
[0212] If a moiety is described as being "optionally substituted",
the moiety may be either substituted or unsubstituted. If a moiety
is described as being optionally substituted with up to a
particular number of non-hydrogen radicals, that moiety may be
either unsubstituted, or substituted by up to that particular
number of non-hydrogen radicals or by up to the maximum number of
substitutable positions on the moiety, whichever is less. Thus, for
example, if a moiety is described as a heterocycle optionally
substituted with up to three non-hydrogen radicals, then any
heterocycle with less than three substitutable positions will be
optionally substituted by up to only as many non-hydrogen radicals
as the heterocycle has substitutable positions. To illustrate,
tetrazolyl (which has only one substitutable position) will be
optionally substituted with up to one non-hydrogen radical. To
illustrate further, if an amino nitrogen is described as being
optionally substituted with up to two non-hydrogen radicals, then a
primary amino nitrogen will be optionally substituted with up to
two non-hydrogen radicals, whereas a secondary amino nitrogen will
be optionally substituted with up to only one non-hydrogen
radical.
[0213] The term "alkenyl" means a straight or branched hydrocarbyl
chain containing one or more double bonds. Each carbon-carbon
double bond may have either cis or trans geometry within the
alkenyl moiety, relative to groups substituted on the double bond
carbons. Non-limiting examples of alkenyl groups include ethenyl
(vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl,
1-butenyl, 2-butenyl, and 3-butenyl.
[0214] The term "alkenylene" refers to a divalent unsaturated
hydrocarbyl chain which may be linear or branched and which has at
least one carbon-carbon double bond. Non-limiting examples of
alkenylene groups include --C(H).dbd.C(H)--,
--C(H).dbd.C(H)--CH.sub.2--, --C(H).dbd.C(H)--CH.sub.2--CH.sub.2--,
--CH.sub.2--C(H).dbd.C(H)--CH.sub.2--,
--C(H).dbd.C(H)--CH(CH.sub.3)--, and
--CH.sub.2--C(H).dbd.C(H)--CH(CH.sub.2CH.sub.3)--.
[0215] The term "alkyl" means a straight or branched saturated
hydrocarbyl chain. Non-limiting examples of alkyl groups include
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
t-butyl, pentyl, iso-amyl, and hexyl.
[0216] The term "alkylene" denotes a divalent saturated hydrocarbyl
chain which may be linear or branched. Representative examples of
alkylene include, but are not limited to, --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and
--CH.sub.2CH(CH.sub.3)CH.sub.2--.
[0217] The term "alkynyl" means a straight or branched hydrocarbyl
chain containing one or more triple bonds. Non-limiting examples of
alkynyl include ethynyl, 1-propynyl, 2-propynyl, 3-propynyl,
decynyl, 1-butynyl, 2-butynyl, and 3-butynyl.
[0218] The term "alkynylene" refers to a divalent unsaturated
hydrocarbon group which may be linear or branched and which has at
least one carbon-carbon triple bonds. Representative alkynylene
groups include, by way of example, --C.ident.C--,
--C.ident.C--CH.sub.2--, --C.ident.C--CH.sub.2--CH.sub.2--,
--CH.sub.2--C.ident.C--CH.sub.2--, --C.ident.C--CH(CH.sub.3)--, and
--CH.sub.2--C.ident.C--CH(CH.sub.2CH.sub.3)--.
[0219] The term "carbocycle" or "carbocyclic" or "carbocyclyl"
refers to a saturated (e.g., "cycloalkyl"), partially saturated
(e.g., "cycloalkenyl" or "cycloalkynyl") or completely unsaturated
(e.g., "aryl") ring system containing zero heteroatom ring atom.
"Ring atoms" or "ring members" are the atoms bound together to form
the ring or rings. A carbocyclyl may be, without limitation, a
single ring, two fused rings, or bridged or spiro rings. A
substituted carbocyclyl may have either cis or trans geometry.
Representative examples of carbocyclyl groups include, but are not
limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl,
cyclohexadienyl, adamantyl, decahydro-naphthalenyl,
octahydro-indenyl, cyclohexenyl, phenyl, naphthyl, indanyl,
1,2,3,4-tetrahydro-naphthyl, indenyl, isoindenyl, decalinyl, and
norpinanyl. A carbocycle group can be attached to the parent
molecular moiety through any substitutable carbon ring atom. Where
a carbocycle group is a divalent moiety linking two other elements
in a depicted chemical structure (such as A in Formula I), the
carbocycle group can be attached to the two other elements through
any two substitutable ring atoms. Likewise, where a carbocycle
group is a trivalent moiety linking three other elements in a
depicted chemical structure (such as X in Formula I), the
carbocycle group can be attached to the three other elements
through any three substitutable ring atoms, respectively.
[0220] The term "carbocyclylalkyl" refers to a carbocyclyl group
appended to the parent molecular moiety through an alkylene group.
For instance, C.sub.3-C.sub.6carbocyclylC.sub.1-C.sub.6alkyl refers
to a C.sub.3-C.sub.6carbocyclyl group appended to the parent
molecular moiety through C.sub.1-C.sub.6alkylene.
[0221] The term "cycloalkenyl" refers to a non-aromatic, partially
unsaturated carbocyclyl moiety having zero heteroatom ring member.
Representative examples of cycloalkenyl groups include, but are not
limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, and
octahydronaphthalenyl.
[0222] The term "cycloalkyl" refers to a saturated carbocyclyl
group containing zero heteroatom ring member. Non-limiting examples
of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, decalinyl and norpinanyl.
[0223] The prefix "halo" indicates that the substituent to which
the prefix is attached is substituted with one or more
independently selected halogen radicals. For example,
"C.sub.1-C.sub.6haloalkyl" means a C.sub.1-C.sub.6alkyl substituent
wherein one or more hydrogen atoms are replaced with independently
selected halogen radicals. Non-limiting examples of
C.sub.1-C.sub.6haloalkyl include chloromethyl, 1-bromoethyl,
fluoromethyl, difluoromethyl, trifluoromethyl, and
1,1,1-trifluoroethyl. It should be recognized that if a substituent
is substituted by more than one halogen radical, those halogen
radicals may be identical or different (unless otherwise
stated).
[0224] The term "heterocycle" or "heterocyclo" or "heterocyclyl"
refers to a saturated (e.g., "heterocycloalkyl"), partially
unsaturated (e.g., "heterocycloalkenyl" or "heterocycloalkynyl") or
completely unsaturated (e.g., "heteroaryl") ring system where at
least one of the ring atoms is a heteroatom (i.e., nitrogen, oxygen
or sulfur), with the remaining ring atoms being independently
selected from the group consisting of carbon, nitrogen, oxygen and
sulfur. A heterocycle may be, without limitation, a single ring,
two fused rings, or bridged or spiro rings. A heterocycle group can
be linked to the parent molecular moiety via any substitutable
carbon or nitrogen atom(s) in the group. Where a heterocycle group
is a divalent moiety that links two other elements in a depicted
chemical structure (such as A in Formula I), the heterocycle group
can be attached to the two other elements through any two
substitutable ring atoms. Likewise, where a heterocycle group is a
trivalent moiety that links three other elements in a depicted
chemical structure (such as X in Formula I), the heterocycle group
can be attached to the three other elements through any three
substitutable ring atoms, respectively.
[0225] A heterocyclyl may be, without limitation, a monocycle which
contains a single ring. Non-limiting examples of monocycles include
furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, isopyrrolyl,
pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl,
imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl,
tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl,
isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl
(including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl (also known as
"azoximyl"), 1,2,5-oxadiazolyl (also known as "furazanyl"), and
1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-oxatriazolyl
and 1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl,
1,2,4-dioxazolyl, 1,3,2-dioxazolyl, and 1,3,4-dioxazolyl),
oxathiolanyl, pyranyl (including 1,2-pyranyl and 1,4-pyranyl),
dihydropyranyl, pyridinyl, piperidinyl, diazinyl (including
pyridazinyl (also known as "1,2-diazinyl"), pyrimidinyl (also known
as "1,3-diazinyl"), and pyrazinyl (also known as "1,4-diazinyl")),
piperazinyl, triazinyl (including s-triazinyl (also known as
"1,3,5-triazinyl"), as-triazinyl (also known 1,2,4-triazinyl), and
v-triazinyl (also known as "1,2,3-triazinyl), oxazinyl (including
1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as
"pentoxazolyl"), 1,2,6-oxazinyl, and 1,4-oxazinyl), isoxazinyl
(including o-isoxazinyl and p-isoxazinyl), oxazolidinyl,
isoxazolidinyl, oxathiazinyl (including 1,2,5-oxathiazinyl or
1,2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazinyl and
1,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl,
thiomorpholinyl, and diazepinyl.
[0226] A heterocyclyl may also be, without limitation, a bicycle
containing two fused rings, such as, for example, naphthyridinyl
(including [1,8]naphthyridinyl, and [1,6]naphthyridinyl),
thiazolpyrimidinyl, thienopyrimidinyl, pyrimidopyrimidinyl,
pyridopyrimidinyl, pyrazolopyrimidinyl, indolizinyl, pyrindinyl,
pyranopyrrolyl, 4H-quinolizinyl, purinyl, pyridopyridinyl
(including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, and
pyrido[4,3-b]-pyridinyl), pyridopyrimidine, and pteridinyl. Other
non-limiting examples of fused-ring heterocycles include
benzo-fused heterocyclyls, such as indolyl, isoindolyl, indoleninyl
(also known as "pseudoindolyl"), isoindazolyl (also known as
"benzpyrazolyl" or indazolyl), benzazinyl (including quinolinyl
(also known as "1-benzazinyl") and isoquinolinyl (also known as
"2-benzazinyl")), benzimidazolyl, phthalazinyl, quinoxalinyl,
benzodiazinyl (including cinnolinyl (also known as
"1,2-benzodiazinyl") and quinazolinyl (also known as
"1,3-benzodiazinyl")), benzopyranyl (including "chromenyl" and
"isochromenyl"), benzothiopyranyl (also known as "thiochromenyl"),
benzoxazolyl, indoxazinyl (also known as "benzisoxazolyl"),
anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl,
benzofuranyl (also known as "coumaronyl"), isobenzofuranyl,
benzothienyl (also known as "benzothiophenyl", "thionaphthenyl",
and "benzothiofuranyl"), isobenzothienyl (also known as
"isobenzothiophenyl", "isothionaphthenyl", and
"isobenzothiofuranyl"), benzothiazolyl,
4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzothiadiazolyl,
benzimidazolyl, benzotriazolyl, benzoxazinyl (including
1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl, and
3,1,4-benzoxazinyl), benzisoxazinyl (including 1,2-benzisoxazinyl
and 1,4-benzisoxazinyl), and tetrahydroisoquinolinyl.
[0227] A heterocyclyl may also be, without limitation, a spiro ring
system, such as, for example, 1,4-dioxa-8-azaspiro[4.5]decanyl.
[0228] A heterocyclyl may comprise one or more sulfur atoms as ring
members; and in some cases, the sulfur atom(s) is oxidized to SO or
SO.sub.2. The nitrogen heteroatom(s) in a heterocyclyl may or may
not be quaternized, and may or may not be oxidized to N-oxide. In
addition, the nitrogen heteroatom(s) may or may not be
N-protected.
[0229] in a chemical formula refers to a single or double bond.
[0230] The term "pharmaceutically acceptable" is used adjectivally
to mean that the modified noun is appropriate for use as a
pharmaceutical product or as a part of a pharmaceutical
product.
[0231] The term "therapeutically effective amount" refers to the
total amount of each active substance that is sufficient to show a
meaningful patient benefit, e.g. a reduction in viral load.
[0232] The term "prodrug" refers to derivatives of the compounds of
the invention which have chemically or metabolically cleavable
groups and become, by solvolysis or under physiological conditions,
the compounds of the invention which are pharmaceutically active in
vivo. A prodrug of a compound may be formed in a conventional
manner by reaction of a functional group of the compound (such as
an amino, hydroxy or carboxy group). Prodrugs often offer
advantages of solubility, tissue compatibility, or delayed release
in mammals (see, Bungard, H., DESIGN OF PRODRUGS, pp. 7-9, 21-24,
Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well
known to practitioners of the art, such as, for example, esters
prepared by reaction of the parent acidic compound with a suitable
alcohol, or amides prepared by reaction of the parent acid compound
with a suitable amine. Examples of prodrugs include, but are not
limited to, acetate, formate, benzoate or other acylated
derivatives of alcohol or amine functional groups within the
compounds of the invention.
[0233] The term "solvate" refers to the physical association of a
compound of this invention with one or more solvent molecules,
whether organic or inorganic. This physical association often
includes hydrogen bonding. In certain instances the solvate will be
capable of isolation, for example when one or more solvent
molecules are incorporated in the crystal lattice of the
crystalline solid. "Solvate" encompasses both solution-phase and
isolable solvates. Exemplary solvates include, but are not limited
to, hydrates, ethanolates, and methanolates.
[0234] The term "N-protecting group" or "N-protected" refers to
those groups capable of protecting an amino group against
undesirable reactions. Commonly used N-protecting groups are
described in Greene and Wuts, PROTECTING GROUPS IN CHEMICAL
SYNTHESIS (3.sup.rd ed., John Wiley & Sons, NY (1999).
Non-limiting examples of N-protecting groups include acyl groups
such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl,
2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,
phthalyl, o-nitrophenoxyacetyl, benzoyl, 4-chlorobenzoyl,
4-bromobenzoyl, or 4-nitrobenzoyl; sulfonyl groups such as
benzenesulfonyl or p-toluenesulfonyl; sulfenyl groups such as
phenylsulfenyl (phenyl-S--) or triphenylmethylsulfenyl
(trityl-S--); sulfinyl groups such as p-methylphenylsulfinyl
(p-methylphenyl-S(O)--) or t-butylsulfinyl (t-Bu-S(O)--); carbamate
forming groups such as benzyloxycarbonyl,
p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl,
p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,
p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,
3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,
4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,
3,4,5-trimethoxybenzyloxycarbonyl,
1-(p-biphenylyl)-1-methylethoxycarbonyl,
dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,
t-butyloxycarbonyl, diisopropylmethoxycarbonyl,
isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl,
allyloxycarbonyl, 2,2,2-trichloro-ethoxy-carbonyl, phenoxycarbonyl,
4-nitro-phenoxycarbonyl, cyclopentyloxycarbonyl,
adamantyloxycarbonyl, cyclohexyloxycarbonyl, or phenylthiocarbonyl;
alkyl groups such as benzyl, p-methoxybenzyl, triphenylmethyl, or
benzyloxymethyl; p-methoxyphenyl; and silyl groups such as
trimethylsilyl. Preferred N-protecting groups include formyl,
acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl,
t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
[0235] The compounds of the present invention can be prepared using
a variety of methods. As a non-limiting example, the compounds of
the present invention can be prepared according to Scheme I
starting from compounds of Formula II (e.g., n=0 to 8), Formula V
(X.sub.4 can be, for example, O or NR.sub.A, where R.sub.A is as
described hereinabove and is preferably H or R.sub.E as defined
above such as C1-C6alkyl, 3- to 12-membered carbocycle or
heterocycle, --C(O)R.sub.S, --C(O)OR.sub.S,
--C(O)N(R.sub.SR.sub.S'), --SO.sub.2N(R.sub.SR.sub.S'),
--S(O).sub.2OR.sub.S, --S(O)OR.sub.S, --S(O)N(R.sub.SR.sub.S'), or
a suitable protecting group such as Boc or Fmoc), or Formula VIII
(E can be, for example, 3- to 7-membered carbocycle or heterocycle
and is optionally substituted with one or more R.sub.A), wherein A,
B, D, Y, Z and R.sub.A are as described above. The 1,4-diketones
II, V, and VIII can be reduced to the 1,4-diols using the methods
described below, and the resultant racemic, enantiomerically
enriched, or meso 1,4-diols may be converted to the dimesylates
III, VI, or IX, or alternatively to ditriflates, ditosylates, or
dihalides by the methods described below. The dimesylates III, VI,
and IX, ditriflates, ditosylates, or dihalides may be reacted with
an amine, including but not limited to, aniline,
3,5-difluoroaniline, 3,4-difluoroaniline, 4-fluoroaniline,
3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline,
heteroaryl amines, alkyl amines, cycloalkyl amines, substituted
benzylamines, or allylamine, under the conditions described below
to give the compounds of the invention. L.sub.1 and L.sub.2 can be
readily introduced to Formulae II, V and VIII, as appreciated by
those skilled in the art in light of the present invention.
Likewise, D-L.sub.3-NH.sub.2 can be used instead of D-NH.sub.2, as
appreciated by those skilled in the art.
##STR00196## ##STR00197##
[0236] As another non-limiting example, the compounds of the
present invention can be prepared starting from compounds of
Formula II and Formula III as shown in Scheme II. The 1,4-diketones
such as Formula IV may be prepared using known methods (see Nevar,
et al., Synthesis:1259-1262 (2000), such as the reaction of
a-bromoketones such as Formula II with methyl ketones such as
Formula III in the presence of a suitable Lewis acid such as
ZnCl.sub.2 or Ti(0iPr).sub.4. The 1,4-diketones IV may be reduced
to the 1,4-diols such as V by the action of NaBH.sub.4, LiAH.sub.4,
or DIBAL. Alternatively, enantioselective reduction of
1,4-diketones such as Formula IV can be accomplished by analogy
with reported methods (see Chong, et al., Tetrahedron: Asymmetry
6:409-418 (1995), Li, et al., Tetrahedron 63:8046-8053 (2007),
Aldous, et al., Tetrahedron: Asymmetry 11:2455-2462 (2000), Masui,
et al., Synlett:273-274 (1997), Jing, et al., Adv. Synth. Catal.
347:1193-1197 (2005), Sato, et al., Synthesis:1434-1438 (2004)),
such as reduction with (-) or (+)-diisopinocamheylchloroborane
(DIP-chloride), with borane and an oxazaborolidine catalyst, or
with asymmetric hydrogenation in the presence of a suitable
Ruthenium (II) catalyst, such as
[RuCl2{(R)-BNAP}{(R,R)-DPEN}](BINAP=2,2'-bis(diarylphosphino)-1,1'-binaph-
thyl; DPEN=1,2-diphenylethylenediamine). The resultant racemic,
enantiomerically enriched, or meso 1,4-diols V may be reacted with
methanesulfonyl chloride to provide the dimesylate Formula VI.
Alternatively Formula V may be converted to a ditriflate or
ditosylate by the action of p-toluenesulfonyl chloride or triflic
anhydride, or to a dihalide such as a dibromide or dichloride by
the action of PPh.sub.3 in the presence of CCl.sub.4 or CBr.sub.4,
or by the action of SOCl.sub.2, POCl.sub.3, or PBr.sub.3. The
dimesylate, ditriflate, ditosylate, or dihalide may be reacted with
an amine, such as 4-fluoroaniline (as shown for illustration in
Scheme II), with or without a co-solvent such as DMF at room
temperature to 100.degree. C., to give the pyrrolidines such as
Formula VII. In addition to 4-fluoroaniline, alternative amines may
be reacted with the dimesylate Formula VI, including but not
limited to aniline, 3,5-difluoroaniline, 3,4-difluoroaniline,
3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline,
heteroaryl amines, alkyl amines, cycloalkyl amines, substituted
benzylamines, or allylamine. The dinitro Formula VII may be reduced
to the diamino Formula VIII using Fe in the presence of NH.sub.4Cl,
HCl, or acetic acid, or by treatment with a hydride reducing agent,
such as sodium borohydride (with or without the addition of a
transition metal salt, such as BiCl.sub.3, SbCl.sub.3, NiCl.sub.2,
Cu.sub.2Cl.sub.2, or CoCl.sub.2) in a solvent such as ethanol or
THF. Alternatively, Formula VII can be reduced to the product
Formula VIII by hydrogenation in the presence of a suitable
catalyst, such as a palladium or platinum catalyst or Raney nickel.
The diamine Formula VIII may be reacted with a suitably protected
proline acid (Boc is shown, although Cbz, Troc, or Fmoc may be
substituted) in the presence of a peptide coupling reagent, such as
EDAC/HOBT, PyBOP, HATU, or DEBPT, in a solvent such as THF, DMF,
dichloromethane, or DMSO, with or without the addition of an amine
base such as Hunig's base, pyridine, 2,6-lutidine, or
triethylamine, to give Formula IX. Removal of the Boc protecting
groups to give X may be accomplished by treatment with an acid,
such as TFA, HCl, or formic acid. Compounds of the present
invention may be prepared by coupling of Formula X with an acid of
choice using the standard peptide coupling reagents and conditions
described above. Alternately, diamine VIII may be reacted with an
N-substituted proline in the presence of a peptide coupling reagent
such as EDAC/HOBT, PyBOP, HATU, T.sub.3P, or DEBPT, in a solvent
such as THF, DMF, dichloromethane, or DMSO, with or without the
addition of an amine base such as Hunig's base, pyridine,
2,6-lutidine, or triethylamine, to directly give compounds of the
present invention (Formula XI).
##STR00198##
in each Formula within Scheme II can be replaced with
##STR00199##
where D is defined above, and such compounds can be readily
prepared according to the process described in Scheme II (including
making compound XI directly from compound VIII).
##STR00200##
[0237] As yet another non-limiting example, the compounds of the
present invention can be prepared starting from compounds of
Formula II and Formula III as shown in Scheme III, where A, B, D,
Y, and Z are as described above, using conditions similar to those
described above for the preparation of IV in Scheme II. Similarly,
the resulting 1,4-diketone IV may be reduced to the 1,4-diols V
using the methods described above for Scheme II. The resultant
racemic, enantiomerically enriched, or meso 1,4-diols V may be
converted to the dimesylate VI or alternatively to a ditriflate,
ditosylate, or dihalide by the methods described above. The
dimesylate VI, ditriflate, ditosylate, or dihalide may be reacted
with an amine, including but not limited to, aniline,
3,5-difluoroaniline, 3,4-difluoroaniline, 4-fluoroaniline,
3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline,
heteroaryl amines, alkyl amines, cycloalkyl amines, substituted
benzylamines, or allylamine, under the conditions described above
the give the compounds of the invention. Alternatively, compounds
such as VIII, where R is a group such as allyl, 4-methoxybenzyl, or
2,4-dimethoxybenzyl, may be treated with reagents useful for the
removal of the R group (rhodium catalyst such as
Rh(Ph.sub.3P).sub.3Cl for R=allyl, treatment with an acid such as
TFA or HCl for R=4-methoxybenzyl or 2,4-dimethoxybenzyl,
hydrogenolysis with a Pd catalyst for R=substituted benzyl) to
generate compounds such as IX. Amine IX may be reacted with an aryl
halide or triflate such as X (iodide shown for illustration)
employing the Buchwald-Hartwig reaction in the presence of a
palladium catalyst (such as Pd(OAc).sub.2 or Pd.sub.2(dba).sub.3)
and a phosphine ligand (such as triphenylphosphine or XantPhos) and
a base (such as sodium bis(trimethylsilyl)amide, potassium
tert-butoxide, or K.sub.3PO.sub.4) to give the compounds of the
present invention. Alternatively, the compounds of the present
invention may be obtained by reaction of IX with an aldehyde or
ketone through reductive amination in the presence of a hydride
reducing agent, such as sodium borohydride or sodium
cyanoborohydride (with or without the addition of an acid, such as
acetic acid) in a solvent such as ethanol, toluene, THF, or
dichloromethane. Alternatively the reductive amination may be
conducted through the use of hydrogenation in the presence of a
suitable catalyst, such as a palladium or platinum catalyst or
Raney nickel. Alternatively, amine IX may react with electrophilic
reagents, such as alkyl halides, or with aryl electrophiles
(suitably electron deficient aryl and heteroaryl halides and
triflates) through nucleophilic aromatic substitution reactions to
give the compounds of the present invention.
##STR00201##
[0238] As a further non-limiting example, the compounds of the
present invention can be prepared starting from compounds of
Formula II and Formula III as shown in Scheme IV, where X.sub.5 in
Formula II and Formula III represents a halogen (e.g., Cl, Br, or
F) or a nitro group. The 1,4-diketones such as IV may be prepared
using known methods described above for the preparation of IV for
Scheme II. The 1,4-diketones IV may be reduced to the 1,4-diols
such as V by the action of NaBH.sub.4, LiAlH.sub.4, or DIBAL.
Alternatively, enantioselective reduction of 1,4-diketone such as
IV can be accomplished by the methods described above for the
preparation of V for Scheme II. The resultant racemic,
enantiomerically enriched, or meso 1,4-diols V may be reacted with
methansulfonyl chloride to provide the dimesylate VI. Alternatively
V may be converted to a ditriflate or ditosylate by the methods
described above for Scheme II. The dimesylate, ditriflate,
ditosylate, or dihalide may be reacted with an amine including but
not limited to aniline, 3,5-difluoroaniline, 3,4-difluoroaniline,
4-fluoroaniline, 3-fluoroaniline, 4-trifluoromethylaniline,
4-chloroaniline, heteroaryl amines, alkyl amines, cycloalkyl
amines, substituted benzylamines, or allylamine to give VII. When
X.sub.5 in Formula VII is nitro, the nitro groups may be reduced to
the tetraamino product IX using Fe in the presence of NH.sub.4Cl,
HCl, or acetic acid, or with a hydride reducing agent, such as
sodium borohydride (with or without the addition of a transition
metal salt, such as BiCl.sub.3, SbCl.sub.3, NiCl.sub.2,
Cu.sub.2Cl.sub.2, or CoCl.sub.2) in a solvent such as ethanol or
THF. Alternatively, VII (X.sub.5=nitro) can be reduced to the
product IX by hydrogenation in the presence of a suitable catalyst,
such as a palladium or platinum catalyst or Raney nickel.
Alternatively, compounds VII where X.sub.5=halogen may be reacted
with ammonia (R.dbd.H) or an amine bearing a suitable protecting
group (R=substituted benzyl such as 4-methoxybenzyl or 2,4
dimethoxybenzyl or R=allyl). The resulting products VIII may be
treated with a reagent useful for the removal of the R protecting
group (rhodium catalyst such as Rh(Ph.sub.3P).sub.3Cl for R=allyl,
treatment with an acid such as TFA or HCl for R=4-methoxybenzyl or
2,4-dimethoxybenzyl, hydrogenolysis with a Pd catalyst for
R=substituted benzyl) to give the product IX. Formula IX may be
reacted with a suitably protected proline acid (Boc is shown,
although Cbz, Troc, or Fmoc may be substituted) in the presence of
a peptide coupling reagent, such as EDAC/HOBT, PyBOP, HATU, or
DEBPT, in a solvent such as THF, DMF, dichloromethane, or DMSO,
with or without the addition of an amine base, such as Hunig's
base, pyridine, 2,6-lutidine, or triethylamine, to give X as a
mixture of the amide products. Conversion to the benzimidazole
compound XI may be accomplished by heating X in acetic acid
(50-100.degree. C.). Alternatively, XI may be prepared by reaction
of IX with an aldehyde, followed by treatment with an oxidant, such
as Cu(OAc).sub.2 or MnO.sub.2 (see Penning, et al., Bioorg. Med.
Chem. 16:6965-6975 (2008). After removal of the Boc protecting
groups from XI (accomplished by treatment with an acid, such as
TFA, HCl, or formic acid), the compounds of the present invention
may be prepared by coupling of the resulting diamine XII with an
acid of choice using the standard peptide coupling reagents and
conditions described above for Scheme II.
##STR00202##
in each Formula within Scheme IV can be replaced with
##STR00203##
where D is defined above, and such compounds can be readily
prepared according to the process described in Scheme IV.
##STR00204## ##STR00205##
[0239] Alternatively IX in Scheme IV may be prepared from a
compound of Formula II as shown in Scheme V. Compound VIII from
Scheme II may be treated with an acylating agent such as acetyl
chloride or acetic anhydride to give compound II (Scheme V).
Nitration of compound II to provide III may be accomplished using
known methods, such as treatment with nitric acid or potassium
nitrate in the presence of an acid such as sulfuric acid or
treatment with NO.sub.2BF.sub.4. Removal of the acetamide
protecting group may be accomplished by treatment with Boc
anhydride in the presence of DMAP to give IV, followed by
sequential treatment of IV with hydroxide (such as NaOH, KOH, or
LiOH) to remove the acetyl group and a strong acid such as TFA or
HCl to remove the Boc protecting group. The nitro groups in V may
be reduced to amino groups using the methods described above for
Scheme IV.
##STR00206##
in each Formula within Scheme V can be replaced with
##STR00207##
where D is defined above, and such compounds can be readily
prepared according to the process described in Scheme V.
##STR00208##
[0240] As still another non-limiting example, the compounds of the
present invention can be prepared starting from compounds of
Formula II as shown in Scheme VI, where A, B, D, Y, and Z are as
described above. A 1,4-diketone compound of Formula II (prepared as
described in Scheme III) may be reacted with an amine, including
but not limited to, aniline, 3,5-difluoroaniline,
3,4-difluoroaniline, 4-fluoroaniline, 3-fluoroaniline,
4-trifluoromethylaniline, 4-chloroaniline, heteroaryl amines, alkyl
amines, cycloalkyl amines, substituted benzylamines, or allylamine,
under acid catalyzed conditions, such as acetic acid, TFA, formic
acid or HCl, to give the compounds of the invention.
##STR00209##
[0241] As a further non-limiting example, the compounds of the
present invention can be prepared from a compound of Formula II as
shown in Scheme VII. A compound of Formula II, where R.sub.X is a
halogen, such as bromo, chloro, or iodo, or a triflate or a
nonaflate may be converted to a boronic acid or ester such as
Formula III, where R is hydrogen, methyl, ethyl, or a cyclic
pinacolate ester. For example a compound of Formula II can be
transformed to a compound of III by treatment with pinacol-borane
in the presence of a catalyst such as, for example,
tris(dibenzylidineacetone)palladium (0), and a ligand such as, for
example, tri-t-butylphosphine, in solvents such as, for example,
tetrahydrofuran, dioxane, or toluene at temperatures ranging from
ambient to about 130.degree. C. Alternatively, compound II can be
reacted with bis(pinacolato)diboron in the presence of a catalyst
such as, for example, Combiphos-Pd6 (CombiPhos Catalysts, Inc. (NJ,
USA), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct, or palladium acetate in the presence of a
ligand such as, for example,
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), and
a base such as, for example, potassium acetate in solvents such as,
for example, toluene, dioxane, tetrahydrofuran, dimethylformamide
or dimethyl sulfoxide at temperatures from about 60 to about
130.degree. C. to give compound III. Alternatively, a compound of
Formula II may be reacted with an organolithium reagent, such an
n-BuLi, sec-BuLi, or t-BuLi, followed by reaction with trimethyl
borate or triethyl borate, to give a compound of Formula III.
[0242] A compound of Formula III in Scheme VII can be coupled with
a compound of Formula IV, where R.sub.Y is a halogen, such as
bromo, chloro or iodo, under Suzuki reaction conditions to provide
a compound of Formula V. Such conditions include, for example, use
of a palladium catalyst such as, for example,
tris(dibenzylidineacetone)palladium (0), palladium acetate,
bis(triphenylphosphine)palladium (II) chloride,
tetrakis(triphenylphosphine)palladium, or
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct; base such as, for example, potassium
carbonate, potassium phosphate, potassium t-butoxide, sodium
carbonate, cesium carbonate, or cesium fluoride; and solvent such
as, for example, toluene, ethanol, water, or tetrahydrofuran, or
mixtures thereof heated in the temperature range from about 40 to
about 130.degree. C.
[0243] Removal of the Boc protecting groups from V may be
accomplished by treatment with an acid, such as TFA, HCl, or formic
acid. Compounds of the present invention such as VI may be prepared
by coupling the resulting amino compounds with an acid of choice
using the standard peptide coupling reagents, such as EDAC/HOBT,
PyBOP, HATU, or DEBPT, in a solvent such as THF, DMF,
dichloromethane, or DMSO, with or without the addition of an amine
base such as Hunig's base, pyridine, 2,6-lutidine, or
triethylamine. Each R.sub.Z is independently -L.sub.Y'-M'-R.sub.D
(e.g., -L.sub.Y-N(R.sub.B'')C(O)-L.sub.S-R.sub.E), and D, L.sub.3,
R.sub.1, R.sub.2, R.sub.5 , L.sub.Y, R.sub.B'', L.sub.S, R.sub.E ,
L.sub.Y', M' and R.sub.D are as defined above.
##STR00210##
[0244] As another non-limiting example, the compounds of the
present invention can be prepared according to Scheme VIII starting
from the compound of Formula II, initially cleaving the diol in
oxidative fashion followed by subsequent acid hydrolysis of the
acetonide. This dialdehyde intermediate is then treated with an
aryl boronate or aryl boronic acid (compound IV where A and Y are
as described previously, or compound VII) and aniline III (where W
is R.sub.M or J, and R.sub.M and J are as defined above) resulting
in the formation of Formula V or Formula VIII respectively. Formula
V can be derivatized by deprotonating the hydroxyl groups with a
strong base such as sodium hydride, butyl lithium, or potassium
hydride, followed by alkylation with R.sub.S-halogen. Alternatively
Formula VIII can be deprotonated with a strong base (e.g., sodium
hydride) and alkylated with R.sub.S-halogen as well, followed by
acid hydrolysis of the phenol protecting groups. The sulfonylation
of the phenols with nonafluorobutylsulfinyl fluoride in the
presence of a neutralizing agent such as potassium carbonate in a
polar aprotic solvent such as DMF, followed by heating provides a
compound of Formula IX. Boronate of Formula X is produced by
heating Formula IX with bis(pinacolato)diboron in the presence of
X-phos and a palladium catalyst, such as Pd2(dba)3 and a base such
as potassium acetate in an organic solvent such as dioxane. Formula
X is further derivatized to final product by heating a suitably
substituted heteroarylhalide in the presence of a palladium
catalyst such as PdCl2(dppf) in the presence of a base such as
sodium carbonate in a mixture of toluene and ethanol. R.sub.S is as
defined above.
##STR00211##
in each Formula within Scheme VIII can be replaced with
##STR00212##
where D is defined above, and such compounds can be readily
prepared according to the process described in Scheme VIII.
##STR00213##
[0245] As yet another non-limiting example, the compounds of the
present invention can be prepared according to Scheme IX starting
from the compounds of Formula II and Formula III. Formula III
carboxylic acid is activated towards coupling using reagents such
as isobutylchloroformate, DCC, EDAC, or HATU in the presence of an
organic base, such as diisopropylethylamine. Upon activation,
dianiline of Formula II is added to the reaction, with the
isolation of an intermediate amide, which is heated in acetic acid,
preferably at 60.degree. C., to yield the compound of Formula IV.
The benzimidazole of Formula IV is treated with SEM-Cl in the
presence of a base in an aprotic solvent such as THF, yielding two
protected benzimidazole regioisomers V. The boronate esters VI are
produced by heating Formula V with bis(pinacolato)diboron in the
presence of a palladium catalyst, such as PdCl2(dppf), X-Phos, and
a base such as potassium acetate in an organic solvent such as
dioxane. Heating yields both benzimidazole regioisomers VI. Diol
VII is cleaved in oxidative fashion followed by subsequent acid
hydrolysis of the acetonide. This dialdehyde intermediate is then
treated with an aryl boronate VI and aniline VIII (where W is
R.sub.M or J, and R.sub.M and J are as defined above) resulting in
the formation of the 3 benzimidazole regioisomers of Formula IX.
Formula X is produced by deprotonating the hydroxyl groups with a
strong base such as sodium hydride, butyl lithium, or potassium
hydride, followed by alkylation with R.sub.S-halogen, followed by
acid hydrolysis of the pyrollidine and benzimidazole protecting
groups, preferably by treatment with mineral acid, such as
hydrochloric acid in an alcoholic solvent such as methanol. The
carboxylic acid R.sub.Z--COOH is activated towards coupling using
reagents such as isobutylchloroformate, DCC, EDAC, or HATU in the
presence of an organic base, such as diisopropylethylamine. Upon
activation, Formula X is added to the reaction, with the isolation
of Formula XI.
##STR00214##
in each Formula within Scheme IX can be replaced with
##STR00215##
where D is defined above, and such compounds can be readily
prepared according to the process described in Scheme IX.
##STR00216##
[0246] Compounds of the invention of general formula (8), where
R.sub.20 is -L.sub.S'-M'-L.sub.S''-R.sub.D and D is as described
above, can be prepared according to the methods of Scheme X. The
bromoalkylketone (1) can be reacted with an arylalkylketone (2)
using the Lewis acid mediated conditions, described above in Scheme
II, to give the diaryldiketone (3). The diketone (3) can be
converted to the bisboronate (4) by reaction with
bis(pinacolato)diborane in the presence of a base such as potassium
acetate, a catalyst such as PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2, in a
solvent such as DMSO, dimethoxyethane or dioxane with heating to
between 60-100.degree. C. Bisboronate (4) can be converted to the
intermediate (5) by Suzuki reaction using, in analogous fashion,
the Suzuki conditions described in Scheme VII. The intermediate (5)
can be converted to (6) by reaction with an amine D-NH.sub.2 under
the analogous conditions described in Scheme VI. For example,
reaction of (5) with D-NH.sub.2 in the presence of an acid such as,
but not limited to, TFA, in a solvent such as, but not limited to,
toluene and with heating up to 110.degree. C. can provide
intermediates of general structure (6). Compounds (6) can be
converted to compounds of general formulas (7) and then (8) using,
in analogous fashion, the methods described in Scheme VII.
##STR00217##
[0247] The intermediates (6) can also be prepared using the route
depicted in Scheme XI. The intermediate (3) can be reacted with an
amine D-NH.sub.2 using, in analogous fashion, the conditions
described in Schemes VI and X to provide intermediates (9), which
can be converted to (10) using, analogously, conditions as
described above in Scheme X; and (10), in turn, can be converted to
compounds (6) using the Suzuki reaction conditions described in
Scheme VII.
##STR00218##
[0248] Compounds of the invention of general formula (15), where
R.sub.20 is -L.sub.S'-M'-L.sub.S''-R.sub.D and D is as described
above, can be prepared according to the methods of Scheme XII.
Compounds (11) can prepared according to the procedures to convert
(3) to (9), using general conditions as described in Scheme VI,
such as by reacting an appropriate nitrophenyldiketone with an
amine D-NH.sub.2 with heating in acetic acid to temperature of
about 70.degree. C. The compounds (11) can be converted to (12)
using the reduction conditions described in Scheme II. Compounds
(12) can be converted sequentially to compounds of general formulae
(13), (14) and (15) by using, in analogous fashion, the methods
described above in Scheme II.
##STR00219##
[0249] Compounds of general formula (19), where D is as described
above, can be prepared according to the methods of Scheme XIII.
Compounds of general formula (16) can be converted to compounds of
general formula (17) using a Buchwald reaction with
tert-butyl-2-carbamoylpyrrolidin-1-carboxylate. This Buchwald
reaction can be conducted in the presence of a base (e.g., cesium
carbonate), a palladium catalyst (e.g.,
tris(dibenzylideneacetone)dipalladium(0)), a phosphine ligand
(e.g., 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) in solvent
such as dioxane with heating to about 80-120.degree. C. The
intermediate (17) can be reduced to (18) and cyclized to (19)
using, in analogous fashion, the conditions described generally in
Scheme IV. Compounds (19) can be further reacted as illustrated in
Scheme IV to provide compounds of the invention.
##STR00220##
[0250] Compounds of the invention of general formula (23), where D
is as described above, can be prepared according to the methods of
Scheme XIV. Compounds (16) can be reacted with compound (20) using
a Buchwald reaction as described generally in Scheme XIII to
provide compounds (21). Compounds (21) can be reduced to compounds
(22) and cyclized to (23) using, in analogous fashion, the
conditions described generally in the foregoing Schemes.
##STR00221##
[0251] Compounds of the invention of general formula (29), where
R.sub.20 is -L.sub.S'-M'-L.sub.S-R.sub.D and D is as described
above, can be prepared according to the methods of Scheme XV.
Compounds of formula (24) can be converted to compounds of formula
(25) (Sonogashira reaction) by reaction with
trimethylsilylacetylene, a palladium catalyst (e.g.,
bis(triphenylphosphine)palladium(II)chloride), a copper catalyst
(e.g., copper(I)iodide), and a base (e.g., triethylamine) wherein
an amine base can also be used as solvent. The compounds (25) can
be desilylated to compounds (26) by reaction with a fluoride source
(e.g., tetrabutylammonium fluoride) in a solvent such as THF.
Compounds (26) can be converted to compounds (27) by formation of
the dianion of (26) with n-butyllithium and subsequent reaction
with a Weinreb amide (e.g.,
N-(tert-butoxycarbonyl)-L-proline-N'-methoxy-N'-methylamide). This
reaction can be conducted in an appropriate solvent such as THF or
dimethoxyethane. Compounds (27) can be converted to compounds (28)
by reaction with hydrazine in a solvent such as ethanol. The
compounds (28) can be converted to compounds (29) using the methods
described generally in the foregoing Schemes.
##STR00222##
[0252] Compounds of the invention of general formula (34), where
R.sub.20 is -L.sub.S'-M'-L.sub.S''-R.sub.D and D is as described
above, can be prepared according to the methods of Scheme XVI.
Compounds (24) can be converted to compounds (30) by reaction of
(24) with CO(g) under pressure (ca. 60 psi) in the presence of a
palladium catalyst (e.g., PdCl2(dppf)) in methanol as solvent and
with heating to around 100.degree. C. Compounds (30) can be
converted to compounds (31) by reaction with hydrazine in a solvent
such as methanol with heating to about 60-80.degree. C. Compounds
(31) can be converted to compounds (32) by reaction with
N-Boc-2-cyano-pyrrolidine in the presence of a base (e.g, potassium
carbonate) in a solvent such as butanol and with heating to around
150.degree. C. with irradiation in a microwave reactor. Compounds
(32) can be deprotected to compounds (33) and acylated to (34)
using, in analogous fashion, the conditions described generally in
the foregoing Schemes.
##STR00223##
[0253] Compounds of the invention of general formula (38), where
R.sub.20 is -L.sub.S'-M'-L.sub.S''-R.sub.D and D is as described
above, can be prepared according to the methods of Scheme XVII.
Compounds of formula (24) can be converted to compounds (35) by
reaction with CuCN in a solvent such as DMF and with heating to
about 160.degree. C. with microwave irradiation. Compounds (35) can
be converted to compounds (36) by reaction with HCl(g) in anhydrous
methanol at 0.degree. C. with warming to room temperature.
Compounds (36) can be converted to compounds (37) by reaction with
NH.sub.3(g) in anhydrous methanol at 0.degree. C. with warming to
room temperature. Compounds (37) can be converted to compounds (38)
by reaction with (41) in THF in the presence of a base (e.g.,
potassium carbonate).
##STR00224##
[0254] Compounds of formula (41), where R.sub.20 is
-L.sub.S'-M'-L.sub.S''-R.sub.D, can be prepared using the methods
of Scheme XVIII. Compounds (39) can be converted to compounds (40)
by sequential reaction of (39) with isobutylchloroformate in THF at
0.degree. C. followed by diazomethane. Compounds (40) can be
converted to compounds (41) by reaction with HBr in acetic
acid.
##STR00225##
[0255] Compounds of the invention of general formula (48), where
R.sub.20 is -L.sub.S'-M'-L.sub.S''-R.sub.D and D is as described
above, can be prepared according to the methods of Scheme XIX.
Compound (42) can be reacted with compound (43) using, in analogous
fashion, the Lewis acid mediated conditions described above in
Scheme II to provide compound (44). Compound (44) can be converted
sequentially to the diol (45), the mesylate (46) and the cyclic
intermediate (47) using, in analogous fashion, the conditions of
Scheme II. Compounds (47) can be converted to compounds (48) by
reaction with (20) under Buchwald conditions such as those referred
to Scheme XIV and described in Scheme XIII.
##STR00226##
[0256] Compounds of the invention of general formula (55), where
R.sub.20 is -L.sub.S'-M'-L.sub.S''-R.sub.D and D is as described
above, can be prepared according to the methods of Scheme XX.
Diethyl meso-2,5-dibromoadipate (49) can be reacted with an amine
D-NH.sub.2 in a solvent such as THF, dioxane, or dimethoxyethane
with heating from 50-100.degree. C. to give compounds (50).
Compounds (50) can be converted to (51) by alkaline hydrolysis with
a base (e.g., NaOH, KOH) in an alcohol (e.g., methanol, ethanol)
and water mixture for solvent. Compounds (51) can be converted to
(52) by reaction first with oxalylchloride, and treatment of the
intermediate acid chloride with diazomethane at 0.degree. C.
Compounds (52) can be converted to (53) by reaction with aqueous
HBr. Compounds (53) can be converted to compounds (54) by reaction
with thiourea in ethanol or like solvent. Compounds (54) can be
converted to compounds (55) using, in analogous fashion, the
conditions described above in Scheme II.
##STR00227##
[0257] Compounds of the invention of general formula (60), where
R.sub.20 is -L.sub.S'-M'-L.sub.S''-R.sub.D and D is as described
above, can be prepared according to the methods of Scheme XXI.
Compound (56) can be reacted with compound (57) in pyridine with
heating to about 135.degree. C. to form compound (58). Compound
(58) can be converted to compounds (59) by reaction of an amine
D-NH.sub.2 with POCl.sub.3 followed by addition of (58) and heating
at about 200.degree. C. in 1,2-dichlorobenzene. Compounds (59) can
be converted to compounds (60) using, in analogous fashion, the
conditions described above in Scheme VII.
##STR00228##
[0258] Compounds of the invention of general formula (66), where
R.sub.20 is -L.sub.S'-M'-L.sub.S''-R.sub.D and D are as described
above, can be prepared according to the methods of Scheme XXII.
Compounds of general formula (61) can be reacted with
borontribromide in dichloromethane at 0.degree. C. to give
compounds (62), which can be subjected to hydrogenation conditions
using platinum(II) oxide to give compounds (63). Coupling between
compounds (63) and proline derivatives (64) can be carried out
using standard coupling conditions described above to give
compounds (65), which can be converted to (66) by the action of
diethylazodicarboxylate and triphenylphosphine in THF.
##STR00229##
[0259] Compounds of the invention of general formula (74), where
R.sub.20 is -L.sub.S'-M'-L.sub.S''-R.sub.D and D is as described
above, can be prepared according to the methods of Scheme XXIII.
Compound (67) can be converted to (68) by reduction of the nitro
group using tin(II) chloride in ethanol. Compound (69) can be made
from (68) by peptide coupling with Boc-proline, followed by heating
of the resulting amide in acetic acid at 80.degree. C. Compound
(69) can be reacted with SEM-Cl and diisopropylethylamine in
dichloromethane to give (70), which can be coupled with (71) using
a palladium catalyst such as PXPd using a base such as cesium
fluoride in a solvent such as N,N-dimethylformamide at 100.degree.
C. to give (72). Compound (72) can be converted to (73) by reaction
with Selectfluor.RTM. in a mixture of THF and water, followed by
hydrogenation using 3% Pt on carbon in ethylacetate and then
reduction using sodium borohydride in methanol. Compound (73) can
be reacted with methanesulfonyl chloride and triethylamine in
dichloromethane at -10.degree. C., followed by addition of an amine
(H.sub.2N-D) to give an intermediate that can be converted to (74)
by deprotection using 4N HCl in 1,4-dioxane and then coupling with
R.sub.20CO.sub.2H using peptide coupling procedures described
above.
##STR00230## ##STR00231##
[0260] Compounds of the invention of general formula (81), where
R.sub.20 is -L.sub.S'-M'-L.sub.S''-R.sub.D and D is as described
above, can be prepared according to the methods of Scheme XXIV.
Compound (75) can be converted to (76) using SnCl2 in ethanol.
Coupling of (76) with (64) using peptide coupling procedures
described above to give an amide that can be heated in acetic acid
at 100.degree. C. to give (77). Compound (77) can be reacted with
SEM-Cl and diisopropylethylamine in dichloromethane to give (78),
which can be reacted with (71) as described above to give (79).
Compound (79) can be converted to (80) using Selectfluor.RTM. in a
mixture of THF and water, followed by hydrogenation with Pt on
carbon in ethylacetate and reduction with sodium borohydride in
methanol. Compound (80) can be converted to compounds (81) by
mesylation with methanesulfonyl chloride and triethylamine at
temperatures less than 0.degree. C., followed by reaction with
primary amine H.sub.2N-D and deprotection using 4N HCl in
1,4-dioxane.
##STR00232## ##STR00233##
[0261] Certain amines, D-NH.sub.2, in the foregoing Schemes are
represented by formula (84), and may be prepared according to the
general method shown in Scheme XXV, wherein R.sub.N is as defined
above (e.g., halogen, alkyl, haloalkyl) and R.sub.M is
--N(R.sub.SR.sub.S') (e.g., --NEt.sub.2), heterocyclyl (e.g.,
pyrrolidin-1-yl, piperidin-1-yl, etc.), or --OR.sub.S (e.g.,
--O-t-butyl, --O-isopropyl, etc.). Fluoronitrobenzenes (82) can be
reacted with an appropriate amine in the presence of dibasic
potassium phosphate in a solvent such as DMSO optionally with
heating to give intermediates (83), wherein R.sub.M is
--N(R.sub.SR.sub.S') (e.g., --NEt.sub.2) or heterocyclyl (e.g.,
pyrrolidin-1-yl, piperidin-1-yl, etc.). Fluoronitrobenzenes (82)
can also be reacted with alkali metal alkoxides (e.g., potassium
tert-butoxide) to give intermediates (83), wherein R.sub.M is
--OR.sub.S (e.g., --O-t-butyl, --O-isopropyl, etc.). Intermediates
(83) may be converted to (84) using well-known nitro reduction
conditions. For example, (83) can be converted to (84) by catalytic
hydrogenation using palladium on carbon. Alternatively, (83) can be
converted to (84) by reaction with iron/ammonium chloride in
THF/methanol/water as solvent. Other conditions for effecting nitro
reduction include those described in the foregoing schemes and
those generally known to one skilled in the art.
##STR00234##
[0262] In the foregoing Schemes, compounds are shown wherein an
aromatic ring (e.g., phenyl) is substituted with groups in a
particular regiochemistry (e.g., para). A starting material or
intermediate with para-substitution provides a final product with
para-substitution in the foregoing Schemes. It is understood by one
of skill in the art that substitution in the foregoing Schemes of a
starting material or intermediate with a different regiochemistry
(e.g., meta) would provide a final product with a different
regiochemistry. For example, replacement of a para-substituted
starting material or intermediate in the foregoing Schemes with a
meta substituted starting material or intermediate would lead to a
meta-substituted product.
[0263] If a moiety described herein (e.g., --NH.sub.2 or --OH) is
not compatible with the synthetic methods, the moiety may be
protected with a suitable protecting group that is stable to the
reaction conditions used in the methods. The protecting group may
be removed at a suitable point in the reaction sequence to provide
a desired intermediate or target compound. Suitable protecting
groups and methods for protecting or deprotecting moieties are well
know in the art, examples of which can be found in Greene and Wuts,
supra. Optimum reaction conditions and reaction times for each
individual step may vary depending on the particular reactants
employed and substituents present in the reactants used. Solvents,
temperatures and other reaction conditions may be readily selected
by one of ordinary skill in the art based on the present
invention.
[0264] Other compounds of the invention can be similarly prepared
according to the above-described schemes as well as the procedures
described in following examples, as appreciated by those skilled in
the art. It should be understood that the above-described
embodiments and schemes and the following examples are given by way
of illustration, not limitation. Various changes and modifications
within the scope of the present invention will become apparent to
those skilled in the art from the present description.
[0265] Example compounds below were named using either ChemDraw
version 9.0 or ACD version 12 (ACD v12). Final compounds for
Examples 1-50 were named using ChemDraw unless otherwise indicated
as being named using ACD v12. Final compounds after Example 50 were
named using ACD v12. Intermediates were named using ChemDraw,
unless otherwise indicated as being named using ACD v12.
[0266] Certain compounds in the Examples below were purified using
reverse-phase HPLC. Purification was conducted using either a C18
or C8 reverse-phase column. Compounds were eluted using a gradient
of about 10-100% acetonitrile in 0.1% aqueous TFA; about 60-100%
methanol in 10 mM aqueous ammonium acetate; or about 10-95%
methanol in 10 mM aqueous ammonium acetate. For purifications
conducted with TFA, the product thus obtained may be in the form of
a TFA salt. Compounds may be characterized as the TFA salt or as
the free base following neutralization, extraction and
isolation.
[0267] Certain compounds in the Examples below were purified using
normal phase silica gel chromatography including traditional flash
chromatography or an automated purification system (e.g., Isco
Combi-Flash, Analogix Intelliflash) using pre-packed silica gel
columns (55 or 35 .mu.m silica gel, Isco gold columns) Typical
solvents for silica gel chromatography include: Ethyl acetate in
hexanes, Diethyl ether in hexanes, THF in hexanes, Ethyl acetate in
methylene chloride, Methanol in methylene chloride, Methanol in
methylene chloride with NH.sub.4OH, Acetone in hexanes, and
Methylene chloride in hexanes.
Example 1
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate
and
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00235##
[0268] Example 1A
1,4-Bis(4-nitrophenyl)butane-1,4-dione
[0269] Anhydrous zinc(II) chloride (2.73 g, 20.00 mmol) was stirred
in dry benzene (15 ml) while diethylamine (1.558 ml, 15.00 mmol)
and t-butanol (1.435 ml, 15.00 mmol) were added, and the resulting
mixture was stirred at room temperature for 90 min to give a cloudy
solution. To this mixture was added
2-bromo-1-(4-nitrophenyl)ethanone (2.44 g, 10.00 mmol) and
1-(4-nitrophenyl)ethanone (2.477 g, 15.00 mmol), and the resulting
mixture was stirred at room temperature overnight. The mixture was
poured into water (50 mL) and extracted with ethyl acetate
(3.times.50 ml). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated. The resulting residue
was triturated with dichloromethane to give an orange solid that
was collected by filtration and dried to give the title compound
(2.0 gm, 61% yield).
Example 1B
1,4-Bis(4-nitrophenyl)butane-1,4-diol
[0270] To a solution of the product from Example 1A (1.0 g, 3.05
mmol) in anhydrous THF (30 ml) at 0.degree. C. was added sodium
borohydride (0.357 g, 9.44 mmol). The resulting mixture was stirred
at 50.degree. C. overnight. The cooled mixture was poured into
water, extracted with ethyl acetate, dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The resulting solid was
triturated with dichloromethane to give a tan solid that was
collected by filtration and dried to give the title compound (0.82
gm, 81% yield).
Example 1C
1,4-Bis(4-nitrophenyl)butane-1,4-diyl dimethanesulfonate
[0271] To a solution of the product from Example 1B (0.80 g, 2.407
mmol) in dry CH.sub.2Cl.sub.2 (25 ml) at 0.degree. C. was added
triethylamine (1.007 ml, 7.22 mmol), followed by dropwise addition
of methanesulfonyl chloride (0.469 ml, 6.02 mmol). The resulting
mixture was stirred at 0.degree. C. for 30 min, during which time
the starting material slowly went into solution. After stirring an
additional 1 h at 0.degree. C., a precipitate began to form.
Saturated aq NH.sub.4Cl (4 ml) was added, and stirring was
continued at room temperature for 20 min. The mixture was washed
with water (2.times.10 ml), and the organic layer was treated with
hexanes (10 ml) to give an orange solid that was collected by
filtration to give the title compound (0.75 gm, 64% yield).
Example 1D
1-(4-Fluorophenyl)-2,5-bis(4-nitrophenyl)pyrrolidine
[0272] The product from Example 1C (0.6 gm, 1.228 mmol) and
4-fluoroaniline (2.0 ml, 20.82 mmol) were combined and stirred at
50.degree. C. overnight. The resulting mixture was partitioned
between 0.2 N HCl (50 ml) and ethyl acetate (3.times.50 ml), and
the combined organic layers were dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The crude product was purified
by chromatography on silica gel. using a solvent gradient of 0-40%
ethyl acetate in hexane to give the title compound as a mixture of
cis and trans isomers (0.5 gm, 100% yield).
Example 1E
4,4'-(1-(4-Fluorophenyl)pyrrolidine-2,5-diyl)dianiline
[0273] To a solution of the product from Example 1D (0.501 g, 1.23
mmol) in ethanol (5 ml) and THF (5.00 ml) was added iron powder
(0.412 g, 7.38 mmol) and a solution of ammonium chloride (0.197 g,
3.69 mmol) in water (1.0 ml). The resulting mixture was stirred at
80.degree. C. for 45 min. The mixture was cooled, filtered through
celite, washed with ethanol, and concentrated in vacuo. The crude
product was purified by chromatography on silica gel using a
solvent gradient of 0-100% ethyl acetate in hexanes to give the
title compound as a mixture of cis and trans isomers (0.135 gm,
32%).
Example 1F
(2S,2'S)-tert-Butyl
2,2'-(4,4'-(1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis-
(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate
[0274] To a mixture of the product from Example 1E (0.13 gm, 0.374
mmol), (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid
(0.201 gm, 0.935 mmol) and HATU (0.356 gm, 0.935 mmol) in DMSO (3
ml) was added Hunig's base (0.196 ml, 1.123 mmol), and reaction
mixture was stirred at room temperature for 90 min. The mixture was
poured into water and extracted by ethyl acetate. The organic
extract was dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo to give a crude product that was purified by column
chromatography on silica gel, eluting with a solvent gradient of
5-100% ethyl acetate in hexane to give title compound (0.28 gm,
100%).
Example 1G
(2S,2'S)--N,N'-(4,4'-(1-(4-Fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1-pheny-
lene))dipyrrolidine-2-carboxamide
[0275] To the product from Example 1F (0.28 gm, 0.377 mmol) in
CH.sub.2Cl.sub.2 (2.0 ml) was added TFA (2.0 ml). The reaction
mixture was stirred at room temperature for 45 min and concentrated
in vacuo. The residue was partitioned between into 3:1
CH.sub.2Cl.sub.2:2-PrOH and saturated aq. NaHCO.sub.3. The organic
layer was dried over Na.sub.2SO.sub.4, filtered and concentrated to
give the title compound (0.195 gm, 95% yield).
Example 1H
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate
and
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate
[0276] To a mixture of the product from Example 1G (0.03 gm, 0.055
mmol), (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid
(0.0262 gm, 0.138 mmol) and HATU (0.0526 gm, 0.138 mmol) in DMSO
(0.5 ml) was added Hunig's base (0.029 ml, 0.166 mmol), and the
resulting mixture was stirred at room temperature for 90 min. The
mixture was poured into water (2 ml) and extracted by ethyl acetate
(2.times.2 ml), and the combined organic layers were concentrated
and subjected to HPLC purification on a semi-prep C18
reverse-phased column using a gradient of 10-100% acetonitrile in
0.1% aq TFA. The trans-substituted pyrrolidine isomer was the first
of 2 stereoisomers to elute, providing the title compound as a 1:1
mixture of diastereomers (0.014 gm, 29% yield): 1H NMR (TFA salt)
(400 MHz, DMSO-D6) .delta. ppm 0.93-1.01 (m, J=4.99 Hz, 18H)
1.62-1.68 (m, 2H) 1.81-1.93 (m, 6H) 1.94-2.04 (m, 2H) 2.09-2.20 (m,
2H) 3.54 (s, 6H) 3.59-3.69 (m, 2H) 3.73-3.81 (m, 2H) 4.18-4.24 (m,
2H) 4.43 (dd, J=7.81, 5.42 Hz, 2H) 5.16 (d, 2H) 6.20 (dd, J=9.05,
4.39 Hz, 2H) 6.78 (t, J=8.89 Hz, 2H) 7.09 (d, J=8.89 Hz, 2H) 7.12
(d, 4H) 7.50 (d, J=8.02 Hz, 4H) 9.99 (s, 2H). The title compound
showed an EC.sub.50 value of less than about 0.1 nM in HCV 1b-Con1
replicon assays in the presence of 5% FBS. The 1b-Con1 replicon
assay is described below.
Example 2
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5R)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00236##
[0278] To a mixture of the product from Example 1G (0.03 gm, 0.055
mmol), (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid
(0.0262 gm, 0.138 mmol) and HATU (0.0526 gm, 0.138 mmol) in DMSO
(0.5 ml) was added Hunig's base (0.029 ml, 0.166 mmol), and the
resulting mixture was stirred at room temperature for 90 min. The
mixture was poured into water (2 ml) and extracted by ethyl acetate
(2.times.2 ml), and the combined organic layers were concentrated
and subjected to HPLC purification on a semi-prep C18
reverse-phased column using a gradient of 10-100% acetonitrile in
0.1% aq TFA. The cis-substituted pyrrolidine isomer was the second
of 2 stereoisomers to elute, providing the title compound (0.018
gm, 37% yield): 1H NMR (TFA salt) (400 MHz, DMSO-D6) .delta. ppm
0.93-1.01 (m, J=3.04 Hz, 18H) 1.75-1.94 (m, 6H) 1.94-2.05 (m, 2H)
2.11-2.22 (m, 2H) 2.31-2.35 (m, 1H) 3.54 (s, 6H) 3.61-3.70 (m, 2H)
3.74-3.83 (m, 2H) 4.22 (d, J=8.78 Hz, 2H) 4.46 (dd, J=8.02, 5.42
Hz, 2H) 4.65 (t, 2H) 6.34 (dd, 2H) 6.86 (t, J=8.89 Hz, 2H) 7.08 (d,
2H) 7.43 (d, J=7.81 Hz, 4H) 7.60 (d, J=8.57 Hz, 4H) 10.05 (s, 2H).
The title compound showed an EC.sub.50 value of less than about 0.1
nM in HCV 1b-Con1 replicon assays in the presence of 5% FBS.
Example 3
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00237##
[0280] The product from Example 1H was purified by chiral
chromatography on a Chiralpak AD-H semi-prep column eluting with a
1:1 mixture of hexanes:(2:1 IPA:EtOH). The title compound was the
first of 2 stereoisomers to elute. 1H NMR (400 MHz, DMSO-D6)
.delta. ppm 0.97 (s, 18H) 1.61-1.67 (m, J=5.64 Hz, 2H) 1.79-1.92
(m, 6H) 1.93-2.04 (m, J=5.86 Hz, 2H) 2.07-2.20 (m, J=6.51 Hz, 2H)
3.54 (s, 6H) 3.59-3.69 (m, 2H) 3.71-3.83 (m, 2H) 4.21 (d, J=8.89
Hz, 2H) 4.43 (dd, J=7.97, 5.37 Hz, 2H) 5.15 (d, J=6.51 Hz, 2H) 6.20
(dd, 2H) 6.78 (t, J=8.95 Hz, 2H) 7.13 (d, J=8.57 Hz, 4H) 7.50 (d,
J=8.57 Hz, 4H) 9.99 (s, 2H). The title compound showed an EC.sub.50
value of less than about 0.1 nM in HCV 1b-Con1 replicon assays in
the presence of 5% FBS.
Example 4
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00238##
[0282] The product from Example 1H was separated by chiral
chromatography on a Chiralpak AD-H semi-prep column eluting with a
1:1 mixture of hexanes:(2:1 IPA:EtOH). The title compound was the
second of 2 stereoisomers to elute. 1H NMR (400 MHz, DMSO-D6)
.delta. ppm 0.96 (s, 18H) 1.64 (d, J=5.53 Hz, 2H) 1.78-1.93 (m, 6H)
1.94-2.06 (m, 2H) 2.09-2.21 (m, 2H) 3.54 (s, 6H) 3.59-3.69 (m, 2H)
3.72-3.83 (m, 2H) 4.20 (d, J=8.89 Hz, 2H) 4.43 (dd, J=7.92, 5.42
Hz, 2H) 5.16 (d, J=6.29 Hz, 2H) 6.20 (dd, J=9.16, 4.39 Hz, 2H) 6.77
(t, J=8.95 Hz, 2H) 7.12 (d, J=8.57 Hz, 4H) 7.50 (d, J=8.57 Hz, 4H)
9.99 (s, 2H). The title compound showed an EC.sub.50 value of less
than about 0.1 nM in HCV 1b-Con1 replicon assays in the presence of
5% FBS.
Example 5
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(1-oxobutane-2,1-diyl)dicarbamate and
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(1-oxobutane-2,1-diyl)dicarbamate
##STR00239##
[0283] Example 5A
4,4'-((2S,5S)-1-(4-Fluorophenyl)pyrrolidine-2,5-diyl)dianiline and
4,4'-((2R,5R)-1-(4-Fluorophenyl)pyrrolidine-2,5-diyl)dianiline
[0284] The product from Example 1E was purified by column
chromatography on silica gel, eluting with a solvent gradient of
0-100% ethyl acetate in hexanes. The title compound eluted as the
first of 2 stereoisomers and was obtained as a racemic mixture of
trans diastereomers. 1H NMR (400 MHz, DMSO-D6) .delta. ppm 1.57 (d,
J=5.64 Hz, 2H) 2.36-2.42 (m, 2H) 4.86-4.91 (m, 4H) 4.96 (d, J=6.61
Hz, 2H) 6.17-6.25 (m, 2H) 6.47 (d, J=8.35 Hz, 4H) 6.74 (t, 2H) 6.82
(d, J=8.35 Hz, 4H).
Example 5B
(2S,2'S)-tert-Butyl
2,2'-(4,4'-((2S,5S)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1-phenyl-
ene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate and
(2S,2'S)-tert-Butyl
2,2'-(4,4'-((2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1-phenyl-
ene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate
[0285] The product from Example 5A (50 mg, 0.144 mmol) was
subjected to the conditions described in Example 1F to give the
title compound as a 1:1 mixture of diastereomers (105 mg, 98%): 1H
NMR (400 MHz, DMSO-D6) .delta. ppm 1.34 (d, 18H) 1.66 (d, J=5.10
Hz, 2H) 1.74-1.89 (m, 6H) 2.07-2.23 (m, 2H) 4.15-4.25 (m, 2H) 5.18
(d, J=3.47 Hz, 2H) 6.18-6.25 (m, 2H) 6.78 (t, J=8.95 Hz, 2H) 7.14
(d, J=8.24 Hz, 4H) 7.51 (t, J=8.29 Hz, 4H) 9.92 (d, 2H).
Example 5C
(2S,2'S)--N,N'-(4,4'-((2S,5S)-1-(4-Fluorophenyl)pyrrolidine-2,5-diyl)bis(4-
,1-phenylene))dipyrrolidine-2-carboxamide and
(2S,2'S)--N,N'-(4,4'-((2R,5R)-1-(4-Fluorophenyl)pyrrolidine-2,5-diyl)bis(-
4,1-phenylene))dipyrrolidine-2-carboxamide
[0286] The product from Example 5B was subjected to the conditions
described in Example 1G to give the title compound as a 1:1 mixture
of diastereomers.
Example 5D
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(1-oxobutane-2,1-diyl)dicarbamate and
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-fluorophenyl)pyrrolidine-
-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidin-
e-2,1-diyl))bis(1-oxobutane-2,1-diyl)dicarbamate
[0287] To a mixture of the product from Example 5C (0.102 g, 0.188
mmol), (S)-2-(methoxycarbonyl amino)butanoic acid (0.064 g, 0.395
mmol) and HATU (0.150 g, 0.395 mmol) in DMSO (2 ml) was added
Hunig's base (0.099 ml, 0.565 mmol), and the reaction was stirred
at room temperature for 45 min. The reaction mixture was
partitioned between water and ethyl acetate, and the organic layer
was dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The crude product was purified by column chromatography on
silica gel using a solvent gradient of 0-4% MeOH in dichloromethane
to give the title compound as a 1:1 mixture of stereoisomers (0.158
gm, 94% yield): 1H NMR (400 MHz, DMSO-D6) .delta. ppm 0.86-0.96 (m,
6H) 1.53 (d, J=4.34 Hz, 2H) 1.59-1.73 (m, 2H) 1.80-1.96 (m, J=6.29
Hz, 4H) 1.96-2.06 (m, 2H) 2.08-2.20 (m, 2H) 3.52 (s, 6H) 3.67-3.79
(m, 2H) 4.12-4.23 (m, 2H) 4.42 (dd, J=8.13, 4.66 Hz, 2H) 5.16 (d,
J=6.40 Hz, 2H) 6.20 (dd, J=9.22, 4.45 Hz, 2H) 6.77 (t, J=8.89 Hz,
2H) 7.12 (d, J=7.59 Hz, 4H) 7.30 (dd, J=7.59, 3.25 Hz, 2H) 7.50 (d,
J=8.24 Hz, 4H) 8.16 (s, 2H) 9.95 (s, 2H). The title compound showed
an EC.sub.50 value of from about 0.1 to about 1 nM in HCV 1b-Con1
replicon assays in the presence of 5% FBS.
Example 6
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(3-hydroxy-3-methyl-1-oxobutane-2,1-diyl)dicarbamat-
e and
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(3-hydroxy-3-methyl-1-oxobutane-2,1-diyl)dicarbamat-
e
##STR00240##
[0289] To a mixture of the product from Example 5C (0.1 g, 0.185
mmol), (S)-3-hydroxy-2-(methoxycarbonyl amino)-3-methylbutanoic
acid (0.074 g, 0.388 mmol) and HATU (0.147 g, 0.388 mmol) in DMSO
(2 ml) was added Hunig's base (0.097 ml, 0.554 mmol), and the
reaction mixture was stirred at room temperature for 45 min. The
reaction mixture was partitioned between water and ethyl acetate,
and the organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel using a solvent gradient of 0-4% MeOH
in dichloromethane to give the title compound as a 1:1 mixture of
stereoisomers (0.162 gm, 97% yield): 1H NMR (400 MHz, DMSO-D6)
.delta. ppm 1.15 (d, J=10.19 Hz, 12H) 1.64 (d, J=5.64 Hz, 2H)
1.87-1.98 (m, 6H) 2.09-2.22 (m, 2H) 3.55 (s, 6H) 3.58-3.66 (m, 2H)
3.66-3.74 (m, 2H) 3.83-3.92 (m, 2H) 4.37 (s, 2H) 4.44-4.50 (m, 2H)
5.07 (s, 2H) 5.11 (s, 2H) 5.17 (d, J=6.18 Hz, 2H) 6.15-6.28 (m, 2H)
6.78 (t, J=8.89 Hz, 2H) 7.13 (d, J=8.13 Hz, 4H) 7.51 (d, J=7.81 Hz,
4H) 8.11-8.23 (m, 2H) 9.67 (d, J=9.11 Hz, 2H). The title compound
showed an EC.sub.50 value of less than about 0.1 nM in HCV 1b-Con1
replicon assays in the presence of 5% FBS.
Example 7
Dimethyl
(2S,2'S,3R,3'R)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-fluorophe-
nyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene-
)bis(pyrrolidine-2,1-diyl))bis(3-methoxy-1-oxobutane-2,1-diyl)dicarbamate
and
Dimethyl
(2S,2'S,3R,3'R)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-fluorophe-
nyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene-
)bis(pyrrolidine-2,1-diyl))bis(3-methoxy-1-oxobutane-2,1-diyl)dicarbamate
##STR00241##
[0291] To a mixture of the product from Example 5C (0.025 gm, 0.046
mmol), (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid
(0.01941 gm, 0.102 mmol) and HATU (0.0439 gm, 0.115 mmol) in DMSO
(0.2 ml) was added Hunig's base (0.024 ml, 0.138 mmol). The mixture
was stirred at room temperature for 2 hr, and was then poured into
water and extracted with ethyl acetate. The organic phase was dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacu, and the
crude product was purified by chromatography on silica gel using a
solvent gradient of 0-5% MeOH in CH.sub.2Cl.sub.2 to give the title
compound (0.040 gm, 93% yield): 1H NMR (400 MHz, DMSO-D6) .delta.
ppm 1.09-1.31 (m, 6H) 1.64 (d, J=5.10 Hz, 2H) 1.83-1.93 (m,
J=12.42, 12.42 Hz, 4H) 1.93-2.03 (m, 2H) 2.11-2.19 (m, 2H)
3.10-3.18 (m, J=6.94 Hz, 2H) 3.24 (d, J=4.99 Hz, 6H) 3.42-3.49 (m,
J=10.84, 6.72 Hz, 2H) 3.53 (s, 6H) 3.58-3.70 (m, 2H) 3.79-3.89 (m,
2H) 4.26 (t, J=7.10 Hz, 2H) 4.41 (dd, J=7.97, 4.93 Hz, 2H) 5.16 (d,
J=6.29 Hz, 2H) 6.20 (dd, J=9.11, 4.34 Hz, 2H) 6.78 (t, J=8.95 Hz,
2H) 7.12 (d, 4H) 7.33 (dd, J=7.70, 3.47 Hz, 2H) 7.50 (d, J=8.13 Hz,
4H) 9.95 (s, 2H). The title compound showed an EC.sub.50 value of
from about 0.1 to about 1 nM in HCV 1b-Con1 replicon assays in the
presence of 5% FBS.
Example 8
dimethyl
(2S,2'S,3R,3'R)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-fluorophe-
nyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene-
)bis(pyrrolidine-2,1-diyl))bis(3-methoxy-1-oxobutane-2,1-diyl)dicarbamate
##STR00242##
[0293] The product from Example 7 was purified by chiral
chromatography on a Chiralpak AD-H semi-prep column eluting with a
1:3 mixture of hexanes:(1:1 IPA:EtOH). The title compound was the
first of 2 stereoisomers to elute. 1H NMR (400 MHz, DMSO-D6)
.delta. ppm 1.13 (d, J=6.18 Hz, 6H) 1.64 (d, J=5.64 Hz, 2H)
1.82-1.93 (m, 4H) 1.95-2.04 (m, 2H) 2.10-2.19 (m, 2H) 3.25 (s, 6H)
3.44-3.48 (m, 2H) 3.53 (s, 6H) 3.62-3.71 (m, 2H) 3.79-3.87 (m, 2H)
4.26 (t, J=7.75 Hz, 2H) 4.41 (dd, J=7.92, 4.99 Hz, 2H) 5.16 (d,
J=6.51 Hz, 2H) 6.20 (dd, J=9.16, 4.39 Hz, 2H) 6.78 (t, J=8.89 Hz,
2H) 7.13 (d, J=8.57 Hz, 4H) 7.34 (d, J=7.92 Hz, 2H) 7.50 (d, J=8.57
Hz, 4H) 9.95 (s, 2H). The title compound showed an EC.sub.50 value
of less than about 0.1 nM in HCV 1b-Con1 replicon assays in the
presence of 5% FBS.
Example 9
dimethyl
(2S,2'S,3R,3'R)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-fluorophe-
nyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene-
)bis(pyrrolidine-2,1-diyl))bis(3-methoxy-1-oxobutane-2,1-diyl)dicarbamate
##STR00243##
[0295] The product from Example 7 was purified by chiral
chromatography on a Chiralpak AD-H semi-prep column eluting with a
1:3 mixture of hexanes:(1:1 IPA:EtOH). The title compound was the
second of 2 stereoisomers to elute. 1H NMR (400 MHz, DMSO-D6)
.delta. ppm 1.12 (d, J=6.18 Hz, 6H) 1.64 (d, J=5.64 Hz, 2H)
1.82-1.93 (m, 4H) 1.95-2.06 (m, 2H) 2.10-2.21 (m, 2H) 3.24 (s, 6H)
3.42-3.48 (m, 2H) 3.53 (s, 6H) 3.61-3.73 (m, 2H) 3.78-3.88 (m, 2H)
4.26 (t, J=7.75 Hz, 2H) 4.41 (dd, J=7.92, 4.99 Hz, 2H) 5.16 (d,
J=6.18 Hz, 2H) 6.20 (dd, 2H) 6.78 (t, J=8.89 Hz, 2H) 7.13 (d,
J=8.46 Hz, 4H) 7.33 (d, J=7.81 Hz, 2H) 7.49 (d, J=8.46 Hz, 4H) 9.95
(s, 2H). The title compound showed an EC.sub.50 value of from about
0.1 to about 1 nM in HCV 1b-Con1 replicon assays in the presence of
5% FBS.
Example 10
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
and
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00244##
[0297] To a mixture of the product from Example 1G (0.030 g, 0.055
mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.024 g,
0.14 mmol) and HATU (0.052 g, 0.14 mmol) in DMSO (0.3 ml) was added
Hunig's base (0.024 ml, 0.166 mmol), and the resulting mixture was
stirred at room temperature for 90 min. The mixture was partitioned
between water and ethyl acetate, and the organic layer was
concentrated and subjected to HPLC purification on a semi-prep C18
reverse-phased column using a gradient of 10-100% acetonitrile in
0.1% aq TFA. The trans-substituted pyrrolidine isomer was the first
of 2 stereoisomers to elute, providing the title compound as a 1:1
mixture of diastereomers (9 mg, 16%): 1H NMR (TFA salt) (400 MHz,
DMSO-D6) .delta. ppm 0.85-0.96 (m, 12H) 1.64 (d, J=5.75 Hz, 2H)
1.82-1.92 (m, 6H) 1.95-2.06 (m, 2H) 2.08-2.20 (m, 2H) 3.52 (s, 6H)
3.57-3.68 (m, 2H) 3.74-3.86 (m, J=5.86 Hz, 2H) 4.02 (t, J=8.35 Hz,
2H) 4.42 (dd, J=7.92, 4.88 Hz, 2H) 5.16 (d, J=6.18 Hz, 2H) 6.20
(dd, J=9.16, 4.39 Hz, 2H) 6.77 (t, J=8.89 Hz, 2H) 7.12 (dd, J=8.51,
1.68 Hz, 4H) 7.31 (dd, J=8.24, 3.36 Hz, 2H) 7.50 (d, J=7.26 Hz, 4H)
9.99 (s, 2H). The title compound showed an EC.sub.50 value of less
than about 0.1 nM in HCV 1b-Con1 replicon assays in the presence of
5% FBS.
Example 11
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5R)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00245##
[0299] To a mixture of the product from Example 1G (0.030 g, 0.055
mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.024 g,
0.14 mmol) and HATU (0.052 g, 0.14 mmol) in DMSO (0.3 ml) was added
Hunig's base (0.024 ml, 0.166 mmol), and the resulting mixture was
stirred at room temperature for 90 min. The mixture was partitioned
between water and ethyl acetate, and the organic layer was
concentrated and subjected to HPLC purification on a semi-prep C18
reverse-phased column using a gradient of 10-100% acetonitrile in
0.1% aq TFA. The cis-substituted pyrrolidine isomer was the second
of 2 stereoisomers to elute, providing the title compound (11 mg,
20%): 1H NMR (TFA salt) (400 MHz, DMSO-D6) .delta. ppm 9.35 (s, 2H)
8.26 (s, 2H) 7.77-7.83 (m, 4H) 7.68-7.73 (m, 4H) 7.01 (t, J=8.95
Hz, 2H) 6.61-6.71 (m, 2H) 6.23 (d, J=8.35 Hz, 2H) 4.87-4.97 (m, 2H)
4.67-4.78 (m, 2H) 4.42-4.52 (m, 2H) 3.99-4.09 (m, 2H) 3.87-3.97 (m,
2H) 3.84 (s, 6H) 1.22 (dd, J=6.78, 2.11 Hz, 6H) 1.15 (dd, J=6.72,
2.06 Hz, 6H).
[0300] The title compound showed an EC.sub.50 value of less than
about 0.1 nM in HCV 1b-Con1 replicon assays in the presence of 5%
FBS.
Example 12
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00246##
[0302] The product from Example 10 was separated by chiral
chromatography on a Chiralpak AD-H semi-prep column eluting with a
1:1 mixture of hexanes:(2:1 2-PrOH:EtOH). The title compound eluted
as the first of 2 stereoisomers. 1H NMR (400 MHz, DMSO-D6) .delta.
ppm 0.84-0.97 (m, 12H) 1.64 (d, J=5.64 Hz, 2H) 1.88 (s, 6H)
1.95-2.05 (m, 2H) 2.08-2.19 (m, 2H) 3.52 (s, 6H) 3.58-3.66 (m, 2H)
3.76-3.85 (m, 2H) 4.02 (t, J=8.51 Hz, 2H) 4.42 (dd, J=8.02, 4.88
Hz, 2H) 5.15 (d, J=6.51 Hz, 2H) 6.20 (dd, J=9.16, 4.39 Hz, 2H) 6.78
(t, J=8.89 Hz, 2H) 7.13 (d, J=8.46 Hz, 4H) 7.31 (d, J=8.35 Hz, 2H)
7.50 (d, J=8.46 Hz, 4H) 9.99 (s, 2H). The title compound showed an
EC.sub.50 value of less than about 0.1 nM in HCV 1b-Con1 replicon
assays in the presence of 5% FBS.
Example 13
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00247##
[0304] The product from Example 10 was separated by chiral
chromatography on a Chiralpak AD-H semi-prep column eluting with a
1:1 mixture of hexanes:(2:1 2-PrOH:EtOH). The title compound eluted
as the second of 2 stereoisomers. 1H NMR (400 MHz, DMSO-D6) .delta.
ppm 0.82-0.97 (m, 12H) 1.65 (d, 2H) 1.80-2.05 (m, 8H) 2.08-2.20 (m,
2H) 3.52 (s, 6H) 3.57-3.68 (m, 2H) 3.76-3.87 (m, 2H) 4.01 (t, 2H)
4.42 (dd, 2H) 5.16 (d, J=6.40 Hz, 2H) 6.20 (dd, J=9.22, 4.45 Hz,
2H) 6.77 (t, J=8.95 Hz, 2H) 7.12 (d, J=8.57 Hz, 4H) 7.30 (d, J=8.35
Hz, 2H) 7.50 (d, J=8.46 Hz, 4H) 9.98 (s, 2H). The title compound
showed an EC.sub.50 value of less than about 0.1 nM in HCV 1b-Con1
replicon assays in the presence of 5% FBS.
Example 14
Dimethyl
(1S,1'S)-2,2'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(2-oxo-1-((R)-tetrahydrofuran-3-yl)ethane-2,1-diyl)-
dicarbamate and
Dimethyl
(1S,1'S)-2,2'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(2-oxo-1-((R)-tetrahydrofuran-3-yl)ethane-2,1-diyl)-
dicarbamate
##STR00248##
[0306] To a mixture of the product from Example 5C (0.013 g, 0.024
mmol), HATU (0.02275 gm, 0.060 mmol), and
(S)-2-(methoxycarbonylamino)-2-((R)-tetrahydrofuran-3-yl)acetic
acid (0.0107 gm, 0.053 mmol) in DMSO (0.200 ml) was added Hunig's
Base (0.013 ml, 0.072 mmol). The reaction was stirred at room
temperature for 2 hr, poured into water, and extracted with ethyl
acetate. The organic extract was dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo, and the crude material was
purified on a semi-prep C18 reverse-phased column using a gradient
of 10-100% acetonitrile in 0.1% aq TFA to give the title compound
(6.9 mg, 28% yield): 1H NMR (TFA salt) (400 MHz, DMSO-D6) .delta.
ppm 1.61-1.77 (m, 4H) 1.80-1.94 (m, 6H) 1.93-2.06 (m, 2H) 2.08-2.21
(m, 2H) 3.44 (dd, J=8.46, 6.29 Hz, 2H) 3.53 (s, 6H) 3.56-3.68 (m,
8H) 3.68-3.77 (m, 2H) 3.80-3.90 (m, 2H) 4.23 (t, J=8.84 Hz, 2H)
4.43 (dd, J=8.02, 4.77 Hz, 2H) 5.16 (d, J=6.29 Hz, 2H) 6.20 (dd,
J=9.11, 4.45 Hz, 2H) 6.77 (t, J=8.95 Hz, 2H) 7.13 (d, J=8.57 Hz,
4H) 7.50 (d, J=8.57 Hz, 4H) 7.60 (d, J=7.92 Hz, 2H) 9.98 (s, 2H).
The title compound showed an EC.sub.50 value of from about 0.1 to
about 1 nM in HCV 1b-Con1 replicon assays in the presence of 5%
FBS.
Example 15
Dimethyl
(1S,1'S)-2,2'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(2-oxo-1-((R)-tetrahydrofuran-3-yl)ethane-2,1-diyl)-
dicarbamate
##STR00249##
[0308] The product from Example 14 was separated by chiral
chromatography on a Chiralpak AD-H semi-prep column eluting with a
2:3 mixture of hexanes:(1:1 2-PrOH:EtOH). The title compound eluted
as the first of 2 stereoisomers. 1H NMR (400 MHz, DMSO-D6) .delta.
ppm 1.59-1.78 (m, 4H) 1.79-1.94 (m, 6H) 1.94-2.05 (m, 2H) 2.09-2.23
(m, J=5.10 Hz, 2H) 3.44 (dd, J=8.35, 6.40 Hz, 2H) 3.53 (s, 6H)
3.57-3.73 (m, 8H) 3.71-3.80 (m, 2H) 3.81-3.89 (m, 2H) 4.23 (t,
J=8.78 Hz, 2H) 4.43 (dd, J=7.97, 4.83 Hz, 2H) 5.16 (d, J=6.07 Hz,
2H) 6.16-6.24 (m, 2H) 6.78 (t, J=8.89 Hz, 2H) 7.13 (d, J=8.57 Hz,
4H) 7.50 (d, J=8.46 Hz, 4H) 7.60 (d, J=8.02 Hz, 2H) 9.98 (s, 2H).
The title compound showed an EC.sub.50 value of less than about 0.1
nM in HCV 1b-Con1 replicon assays in the presence of 5% FBS.
Example 16
Dimethyl
(1S,1'S)-2,2'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(2-oxo-1-((R)-tetrahydrofuran-3-yl)ethane-2,1-diyl)-
dicarbamate
##STR00250##
[0310] The product from Example 14 was separated by chiral
chromatography on a Chiralpak AD-H semi-prep column eluting with a
2:3 mixture of hexanes:(1:1 2-PrOH:EtOH). The title compound eluted
as the second of 2 stereoisomers. 1H NMR (400 MHz, DMSO-D6) .delta.
ppm 1.61-1.77 (m, 4H) 1.80-1.94 (m, 6H) 1.93-2.06 (m, 2H) 2.08-2.21
(m, 2H) 3.44 (dd, J=8.46, 6.29 Hz, 2H) 3.53 (s, 6H) 3.56-3.68 (m,
8H) 3.68-3.77 (m, 2H) 3.80-3.90 (m, 2H) 4.23 (t, J=8.84 Hz, 2H)
4.43 (dd, J=8.02, 4.77 Hz, 2H) 5.16 (d, J=6.29 Hz, 2H) 6.20 (dd,
J=9.11, 4.45 Hz, 2H) 6.77 (t, J=8.95 Hz, 2H) 7.13 (d, J=8.57 Hz,
4H) 7.50 (d, J=8.57 Hz, 4H) 7.60 (d, J=7.92 Hz, 2H) 9.98 (s, 2H).
The title compound showed an EC.sub.50 value of from about 0.1 to
about 1 nM in HCV 1b-Con1 replicon assays in the presence of 5%
FBS.
Example 17
(R,2S,2'S)--N,N'-(4,4'-((2S,5S)-1-(4-Fluorophenyl)pyrrolidine-2,5-diyl)bis-
(4,1-phenylene))bis(1-((R)-2-phenyl-2-(piperidin-1-yl)acetyl)pyrrolidine-2-
-carboxamide) and
(R,2S,2'S)--N,N'-(4,4'-((2R,5R)-1-(4-Fluorophenyl)pyrrolidine-2,5-diyl)bis-
(4,1-phenylene))bis(1-((R)-2-phenyl-2-(piperidin-1-yl)acetyl)pyrrolidine-2-
-carboxamide)
##STR00251##
[0312] To a mixture of (R)-2-phenyl-2-(piperidin-1-yl)acetic acid
TFA salt (0.0455 mg, 0.137 mmol), the product from Example 1G
(0.030 gm, 0.055 mmol), and HATU (0.0526 gm, 0.138 mmol) in DMSO
(0.300 ml) was added Hunig's base (0.029.0 ml, 0.166 mmol), and the
resulting mixture was stirred at rt for 2 hr. The mixture was
partitioned between water and ethyl acetate, the organic layer was
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
The crude product was subjected to HPLC purification on a semi-prep
C18 reverse-phased column using a gradient of 10-100% acetonitrile
in 0.1% aq TFA (8.3 mg, 11%): 1H NMR (TFA salt) (400 MHz, DMSO-D6)
.delta. ppm 1.20-1.42 (m, 4H) 1.61-2.02 (m, 16H) 2.62-2.81 (m, 4H)
3.01-3.23 (m, J=9.32 Hz, 4H) 3.87-3.98 (m, 2H) 4.40-4.47 (m, J=8.24
Hz, 2H) 5.14-5.24 (m, 2H) 5.50 (d, J=8.78 Hz, 2H) 6.23 (dd, J=8.89,
4.34 Hz, 2H) 6.75-6.84 (m, 2H) 7.16 (d, J=7.81 Hz, 4H) 7.48-7.59
(m, 12H) 7.62 (d, J=3.69 Hz, 4H) 9.89 (s, 2H) 10.17 (s, 2H). The
title compound showed an EC.sub.50 value of from about 0.1 to about
1 nM in HCV 1b-Con1 replicon assays in the presence of 5% FBS.
Example 18
(R,2S,2'S)--N,N'-(4,4'-((2S,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis-
(4,1-phenylene))bis(1-((R)-2-phenyl-2-(piperidin-1-yl)acetyl)pyrrolidine-2-
-carboxamide)
##STR00252##
[0314] To a mixture of (R)-2-phenyl-2-(piperidin-1-yl)acetic acid
TFA salt (0.0455 mg, 0.137 mmol), the product from Example 1G
(0.030 gm, 0.055 mmol), and HATU (0.0526 gm, 0.138 mmol) in DMSO
(0.300 ml) was added Hunig's base (0.029.0 ml, 0.166 mmol), and the
resulting mixture was stirred at rt for 2 hr. The mixture was
partitioned between water and ethyl acetate, the organic layer was
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
The crude product was subjected to HPLC purification on a semi-prep
C18 reverse-phased column using a gradient of 10-100% acetonitrile
in 0.1% aq TFA (8.7 mg, 12%): 1H NMR (TFA salt) (400 MHz, DMSO-D6)
.delta. ppm 1.22-1.43 (m, 4H) 1.62-2.03 (m, J=80.02 Hz, 16H)
2.08-2.18 (m, 2H) 2.62-2.85 (m, 4H) 3.04-3.24 (m, 4H) 3.88-3.99 (m,
2H) 4.41-4.52 (m, 2H) 4.64-4.72 (m, 2H) 5.52 (d, J=8.24 Hz, 2H)
6.36 (dd, J=9.05, 4.50 Hz, 2H) 6.88 (t, J=8.89 Hz, 2H) 7.41-7.68
(m, 18H) 9.89 (s, 2H) 10.23 (s, 2H). The title compound showed an
EC.sub.50 value of less than about 0.1 nM in HCV 1b-Con1 replicon
assays in the presence of 5% FBS.
Example 19
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(1-(4-fluorophenyl)-1H-pyrrole-
-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidin-
e-2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00253##
[0315] Example 19A
1-(4-Fluorophenyl)-2,5-bis(4-nitrophenyl)-1H-pyrrole
[0316] To a slurry of the product from Example 1A (1.5 g, 4.57
mmol) in acetic acid (22.85 mL) was added 4-fluoroaniline (4.33 ml,
45.7 mmol). The mixture was heated to 70.degree. C. for 24 h. After
cooling to rt the mixture was diluted with water and ether and
stirred vigorously, filtered and dried to provide 1.67 g (91%) of
the title compound.
Example 19B
4,4'-(1-(4-Fluorophenyl)-1H-pyrrole-2,5-diyl)dianiline
[0317] To a solution of example 19A (1.017 g, 2.496 mmol) in
ethanol (15 mL) and THF (15 mL) was added iron powder (0.836 g,
14.98 mmol) followed by ammonium chloride (0.401 g, 7.49 mmol) and
water (3.75 mL). Reaction mixture was refluxed for 45 minutes.
Slurry filtered through celite, washed with ethanol, combined
filtrate was concentrated and the residue purified by column
chromatography (gradient elution from 30% to 50% EtOAc:hexanes) to
provide 1.09 g (77%) of the title compound.
Example 19C
(2S,2'S)-tert-Butyl
2,2'-(4,4'-(1-(4-fluorophenyl)-1H-pyrrole-2,5-diyl)bis(4,1-phenylene))bis-
(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate
[0318] To a solution of Example 19B (1.09 g, 3.17 mmol) in DMF
(15.87 mL) at rt was added HATU (2.66 g, 6.98 mmol),
(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.503 g,
6.98 mmol), and Hunig's base (2.218 mL, 12.70 mmol). Stirring was
continued overnight. The mixture was partitioned between water and
EtOAc added. Organic phase washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated. Residue purified by column
chromatography (gradient elution from 20% to 50% EtOAc/hexanes). MS
(ESI; M+H) m/z=738.
Example 19D
(2S,2'S)--N,N'-(4,4'-(1-(4-Fluorophenyl)-1H-pyrrole-2,5-diyl)bis(4,1-pheny-
lene))dipyrrolidine-2-carboxamide
[0319] To the product from Example 19C (100 mg, 0.136 mmol) in
CH.sub.2Cl.sub.2 (2.0 mL) was added TFA (1.0 mL) and the reaction
was stirred 1 h. Mixture concentrated, the residue was partitioned
between water and 25% IPA-CHCl.sub.3 and neutralized with
NaHCO.sub.3. The organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated to give the title compound as a white
solid used without further purification. MS (DCI; M+H) m/z=538.
Example 19E
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(1-(4-fluorophenyl)-1H-pyrrole-
-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidin-
e-2, l-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate
[0320] To a mixture of the product from Example 19D (0.073 g, 0.136
mmol) in CH.sub.2Cl.sub.2 (10 mL) at rt was added Hunig's base
(0.070 mL, 0.407 mmol). To this was then added
(S)-2-methoxycarbonylamino-3,3-dimethyl-butyric acid (0.054 g,
0.285 mmol) followed by HATU (0.114 g, 0.299 mmol). Mixture stirred
for 2 hrs then washed with saturated NaHCO.sub.3 and the organic
phase concentrated and the residue purified by column
chromatography (1% gradient elution from 0% to 3%
MeOH--CH.sub.2Cl.sub.2) to provide the desired compound as a light
tan solid. MS (ESI; M+H) m/z=881; 1H NMR (400 MHz, DMSO-D6) .delta.
ppm 0.96 (s, 18H), 1.81-1.89 (m, 4H), 1.95-2.00 (m, 2H), 2.11-2.16
(m, 2H), 3.53 (s, 6H), 3.61-3.65 (m, 2H), 3.75-3.79 (m, 2H), 4.20
(d, J=8.85 Hz, 2H), 4.39-4.42 (m, 2H), 6.39 (s, 2H), 6.96 (d,
J=8.69 Hz, 4H), 7.07-7.10 (m, 4H), 7.17 (dd, J=8.70, 8.70 Hz, 2H),
7.41 (d, J=8.70 Hz, 4H), 10.01 (br s, 2H). The title compound
showed an EC.sub.50 value of less than about 0.1 nM in HCV 1b-Con1
replicon assays in the presence of 5% FBS.
Example 20
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-phenylpyrrolidine-2-
,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine--
2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate and
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-phenylpyrrolidine-2-
,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine--
2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00254##
[0321] Example 20A
2,5-Bis(4-nitrophenyl)-1-phenylpyrrolidine
[0322] A mixture of the product from Example 1C (50 mg, 0.102 mmol)
and aniline (0.2 ml, 2.19 mmol) were stirred at rt for 48 h. The
mixture was partitioned between IN aq. HCl and ethyl acetate, and
the organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel using a solvent gradient of 0-50%
ethyl acetate in hexanes. The title compound was obtained as a
yellow solid (19 mg, 48%).
Example 20B
(2S,2'S)-tert-Butyl
2,2'-(4,4'-(1-phenylpyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl-
)bis(oxomethylene)dipyrrolidine-1-carboxylate
[0323] The product from Example 20A (19 mg, 0.049 mmol) was
subjected to the conditions described in Example 1E. The crude
product was subjected to the conditions described in Example 1F to
give the title compound (33 mg, 93%).
Example 20C
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-phenylpyrrolidine-2-
,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine--
2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate and
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-phenylpyrrolidine-2-
,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine--
2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate
[0324] The product from Example 20B (30 mg, 0.041 mmol) was
subjected to the conditions described in Example 1G, and the crude
product was subjected to the conditions described in Example 1H.
The crude product was subjected to HPLC purification on a semi-prep
C18 reverse-phased column using a gradient of 10-100% acetonitrile
in 0.1% aq TFA. The trans-substituted pyrrolidine isomer was the
first of 2 stereoisomers to elute, providing the title compound as
a 1:1 mixture of diastereomers (7 mg, 19%): 1H NMR (TFA salt) (400
MHz, DMSO-D6) .delta. ppm 0.95 (d, J=5.31 Hz, 18H) 1.59-1.67 (m,
2H) 1.79-1.91 (m, 4H) 1.91-2.02 (m, 2H) 2.08-2.17 (m, 2H) 3.52 (s,
6H) 3.58-3.68 (m, 2H) 3.71-3.82 (m, 2H) 4.19 (d, J=9.00 Hz, 2H)
4.42 (dd, 2H) 5.17 (d, J=5.64 Hz, 2H) 6.24 (d, J=8.35 Hz, 2H) 6.39
(t, J=7.37 Hz, 2H) 6.90 (t, J=7.92 Hz, 2H) 7.07 (d, 2H) 7.11 (d,
4H) 7.48 (d, J=8.24 Hz, 4H) 9.98 (s, 2H). The title compound showed
an EC.sub.50 value of less than about 0.1 nM in HCV 1b-Con1
replicon assays in the presence of 5% FBS.
Example 21
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5R)-1-phenylpyrrolidine-2-
,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine--
2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00255##
[0326] The product from Example 20B (30 mg, 0.041 mmol) was
subjected to the conditions described in Example 1G, and the crude
product was subjected to the conditions described in Example 1H.
The crude product was subjected to HPLC purification on a semi-prep
C18 reverse-phased column using a gradient of 10-100% acetonitrile
in 0.1% aq TFA. The cis-substituted pyrrolidine isomer was the
second of 2 stereoisomers to elute, providing the title compound
(8.5 mg, 24%): 1H NMR (TFA salt) (400 MHz, DMSO-D6) .delta. ppm
0.96 (d, J=3.25 Hz, 18H) 1.74-1.91 (m, 6H) 1.93-2.03 (m, 2H)
2.10-2.20 (m, 2H) 3.53 (s, 6H) 3.58-3.69 (m, 2H) 3.72-3.83 (m, 2H)
4.20 (d, J=8.89 Hz, 2H) 4.45 (dd, J=7.97, 5.37 Hz, 2H) 4.68 (t,
J=5.20 Hz, 2H) 6.37 (d, J=8.24 Hz, 2H) 6.56 (t, J=7.26 Hz, 2H) 6.98
(t, J=7.92 Hz, 2H) 7.07 (d, 2H) 7.42 (d, J=8.02 Hz, 4H) 7.58 (d,
J=8.57 Hz, 4H) 10.03 (s, 2H). The title compound showed an
EC.sub.50 value of less than about 0.1 nM in HCV 1b-Con1 replicon
assays in the presence of 5% FBS.
Example 22
Dimethyl
(1R,1'R)-2,2'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl)dicarbamate
and
Dimethyl
(1R,1'R)-2,2'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl)dicarbamate
##STR00256##
[0328] The product from Example 5C (25 mg, 0.046 mmol) was
subjected to the conditions described in Example 5D, substituting
(R)-2-(methoxycarbonylamino)-2-phenylacetic acid for
(S)-2-(methoxycarbonyl amino)butanoic acid, to give the title
compound as a 1:1 mixture of diastereomers (42 mg, 48%): 1H NMR
(400 MHz, DMSO-D6) .delta. ppm 9.83 (s, 2H) 7.67 (d, J=7.81 Hz, 2H)
7.51-7.57 (m, 4H) 7.29-7.44 (m, 8H) 7.15 (d, J=8.46 Hz, 4H)
6.74-6.83 (m, 2H) 6.17-6.28 (m, J=9.00, 4.34 Hz, 2H) 5.48 (d,
J=7.81 Hz, 2H) 5.12-5.24 (m, 1H) 4.33-4.43 (m, J=8.13 Hz, 2H)
3.75-3.87 (m, 2H) 3.54 (s, 6H) 1.73-2.05 (m, 8H) 1.62-1.70 (m, 2H).
The title compound showed an EC.sub.50 value of less than about 0.1
nM in HCV 1b-Con1 replicon assays in the presence of 5% FBS.
Example 23
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-(trifluoromethyl-
)phenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethy-
lene)bis(pyrrolidine-2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicar-
bamate and
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-(trifluoromethyl-
)phenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethy-
lene)bis(pyrrolidine-2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicar-
bamate
##STR00257##
[0329] Example 23A
4,4'-((2S,5S)-1-(4-(Trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)dianiline
and
4,4'-((2R,5R)-1-(4-(Trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)diani-
line
[0330] The product from Example 1C (0.74 g, 1.5 mmol) was subjected
to the conditions described in Example 1D, substituting
4-(trifluoromethyl)aniline for 4-fluoroaniline. The product thus
obtained was subjected to the conditions described in Example 1E to
give the title compound as a racemic mixture of trans-substituted
pyrrolidine stereoisomers (0.10 g, 17%).
Example 23B
(2S,2'S)--N,N'-(4,4'-((2S,5S)-1-(4-(Trifluoromethyl)phenyl)pyrrolidine-2,5-
-diyl)bis(4,1-phenylene))dipyrrolidine-2-carboxamide and
(2S,2'S)--N,N'-(4,4'-((2R,5R)-1-(4-(Trifluoromethyl)phenyl)pyrrolidine-2,-
5-diyl)bis(4,1-phenylene))dipyrrolidine-2-carboxamide
[0331] The product from Example 23A (0.95 g, 0.24 mmol) was
subjected to the conditions described in Example 1F to give a solid
(0.166 g, 88%), which was dissolved in 4M HCl in 1,4-dioxane (2
ml), and the resulting mixture was stirred at rt for 30 min. The
resulting mixture was concentrated and dried in vacuo to give an
HCl salt of the title compound as a 1:1 mixture of
stereoisomers.
Example 23C
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-(trifluoromethyl-
)phenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethy-
lene)bis(pyrrolidine-2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicar-
bamate and
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-(trifluoromethyl-
)phenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethy-
lene)bis(pyrrolidine-2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicar-
bamate
[0332] The product from Example 23B (58 mg, 0.083 mmol) was
subjected to the conditions described in Example 1H to give the
title compound as a colorless solid (30 mg, 39%): 1H NMR (free
base) (400 MHz, DMSO-D6) .delta. ppm 10.03 (s, 2H) 7.52 (d, J=8.46
Hz, 4H) 7.25 (d, J=8.89 Hz, 2H) 7.14 (d, J=7.48 Hz, 4H) 7.06-7.11
(m, 2H) 6.36 (d, J=8.35 Hz, 2H) 5.23-5.33 (m, 2H) 4.39-4.48 (m, 2H)
4.21 (d, J=8.46 Hz, 2H) 3.71-3.82 (m, 2H) 3.58-3.69 (m, 2H) 3.54
(s, 6H) 2.08-2.21 (m, 2H) 1.93-2.06 (m, 2H) 1.76-1.94 (m, 4H)
1.61-1.73 (m, 2H) 0.96 (m, 18H). The title compound showed an
EC.sub.50 value of less than about 0.1 nM in HCV 1b-Con1 replicon
assays in the presence of 5% FBS.
Example 24
Dimethyl (2S,2'S,3
S,3'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-fluorophenyl)pyrrolidine-2-
,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine--
2,1-diyl))bis(3-methyl-1-oxopentane-2,1-diyl)dicarbamate and
Dimethyl
(2S,2'S,3S,3'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-fluorophe-
nyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene-
)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxopentane-2,1-diyl)dicarbamate
##STR00258##
[0334] The product from Example 1G (20 mg, 0.037 mmol) was
subjected to the conditions described in Example 1H, substituting
(2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid (15.4 mg,
0.081 mmol) for (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic
acid. The title compound was obtained as a 1:1 mixture of
diastereomers (13.5 mg, 41%) after silica gel chromatography (0-5%
MeOH/CH.sub.2Cl.sub.2): 1H NMR (free base) (400 MHz, DMSO-D6)
.delta. ppm 9.99 (s, 2H) 7.50 (dd, J=8.46, 1.52 Hz, 4H) 7.36 (dd,
J=8.35, 3.04 Hz, 2H) 7.13 (dd, J=8.62, 1.79 Hz, 4H) 6.78 (t, J=8.89
Hz, 2H) 6.20 (dd, J=9.16, 4.39 Hz, 2H) 5.16 (d, J=6.29 Hz, 2H) 4.43
(dd, J=7.92, 4.77 Hz, 2H) 4.02-4.13 (m, 2H) 3.77-3.89 (m, 2H)
3.57-3.67 (m, 2H) 3.52 (s, 6H) 2.08-2.21 (m, J=14.96 Hz, 2H)
1.94-2.05 (m, 2H) 1.81-1.93 (m, J=5.42 Hz, 4H) 1.60-1.79 (m, 4H)
1.42-1.57 (m, 2H) 1.04-1.18 (m, 2H) 0.89 (t, J=6.51 Hz, 6H)
0.76-0.85 (m, 6H). The title compound showed an EC.sub.50 value of
less than about 0.1 nM in HCV 1b-Con1 replicon assays in the
presence of 5% FBS.
Example 25
Dimethyl
(2S,2'S,3R,3'R)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-fluorophe-
nyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene-
)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxopentane-2,1-diyl)dicarbamate
and
Dimethyl
(2S,2'S,3R,3'R)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-fluorophe-
nyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene-
)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxopentane-2,1-diyl)dicarbamate
##STR00259##
[0336] The product from Example 1G (25 mg, 0.046 mmol) was
subjected to the conditions described in Example 1H, substituting
(2S,3R)-2-(methoxycarbonylamino)-3-methylpentanoic acid (19.2 mg,
0.102 mmol) for (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic
acid. The title compound was obtained as a 1:1 mixture of
diastereomers (20.5 mg, 50%) after silica gel chromatography (0-5%
MeOH/CH.sub.2Cl.sub.2): 1H NMR (free base) (400 MHz, DMSO-D6)
.delta. ppm 9.96 (s, 2H) 7.49 (d, J=8.35 Hz, 4H) 7.14 (t, J=7.43
Hz, 4H) 6.77 (t, J=8.89 Hz, 2H) 6.20 (dd, J=9.11, 4.45 Hz, 2H) 5.16
(d, J=6.40 Hz, 2H) 4.38-4.48 (m, 2H) 4.18-4.28 (m, 2H) 3.69-3.82
(m, 2H) 3.55-3.64 (m, 2H) 3.52 (s, 6H) 2.09-2.20 (m, 2H) 1.95-2.05
(m, 2H) 1.72-1.95 (m, 6H) 1.58-1.70 (m, J=5.64 Hz, 2H) 1.40-1.55
(m, 2H) 1.06-1.18 (m, 2H) 0.79-0.91 (m, 12H). The title compound
showed an EC.sub.50 value of less than about 0.1 nM in HCV 1b-Con1
replicon assays in the presence of 5% FBS.
Example 26
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-(1-(4-tert-butylphenyl)--
1H-pyrrole-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))bis(pyrr-
olidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00260##
[0337] Example 26A
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate
[0338] To an oven-dried 500-mL 3-neck flask purged with nitrogen
was added oxalyl chloride (5.32 mL, 60.8 mmol) and anhydrous
dichloromethane (125 mL), and the solution cooled to -78.degree. C.
A solution of anhydrous DMSO (7.30 mL, 103 mmol) in anhydrous
dichloromethane (25 mL) was added dropwise from a constant-pressure
addition funnel over 20-min period. A solution of (S)-tert-butyl
2-(hydroxymethyl)pyrrolidine-1-carboxylate (9.41 g, 46.8 mmol) in
anhydrous dichloromethane (50 mL) was added dropwise from a
constant-pressure addition funnel over 20-min period, then stirred
reaction mixture at -78.degree. C. for 30 min. Added triethylamine
(32.6 mL, 234 mmol) dropwise via syringe over a 5-min period and
stirred the thick white mixture in an ice-water bath for 30 min.
Quenched reaction with 10% (w/v) aq. citric acid (30 mL), poured
reaction into a separatory funnel with Et.sub.2O (550 mL) and 10%
(w/v) aq citric acid, separated layers, and washed organic phase
with water and brine. Dried the organic phase over anhydrous
Na.sub.2SO.sub.4, filtered, and concentrated to afford a yellow oil
(9.4 g), which was used directly in the next reaction.
Example 26B
(S)-tert-butyl 2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate
[0339] The product from Example 26A (20 g, 100 mmol) was dissolved
in methanol (50.2 mL) and ammonium hydroxide (50.2 mL) was added.
To this solution glyoxal (40% in water; 24.08 mL, 211 mmol) was
added, dropwise, over 10 min. The reaction was stirred at room
temperature overnight. Reaction was concentrated under reduced
pressure, diluted with 50 mL of water, and then extracted with
ethyl acetate. Washed organic layer with brine, dried
(Na.sub.2SO.sub.4) and concentrated to a tan solid. Solid was
treated with ether and concentrated. The solid was then triturated
with 2:1 diethyl ether:hexanes (150 mL) to afford 17 g of solid,
which was used directly in the next reaction.
Example 26C
(S)-tert-butyl
2-(4,5-dibromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate
[0340] N-bromosuccinimide (108 mmol) was added to a cold (0.degree.
C.) solution of the product from Example 26B (12.05 g, 50.8 mmol)
in dichloromethane (200 mL). Let stir in ice bath for 2 h and then
concentrated, dissolved in ethyl acetate (250 mL) washed with water
(3.times.150 mL), brine (1.times.100 mL), dried (MgSO.sub.4) and
concentrated to very dark residue, chased with
dichloromethane/hexanes (1:1) to get brown solid (.about.19 g).
Triturated solid with ether (.about.100 mL), filtered to isolate a
tan solid (13.23 g, 65% yield).
Example 26D
(S)-tert-butyl
2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate or
(S)-tert-butyl
2-(4-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate
[0341] Dissolved the product from Example 26C (6.25 g, 15.82 mmol)
in dioxane (200 mL) and water (200 mL) in a 1 L round bottom flask
equipped with a condenser and glass stopper, added a solution of
sodium sulfite (22.38 g, 174 mmol) in water (200 mL), and heated at
reflux with heating mantle for 16 h. Reaction was reddish-amber
homogeneous solution. Cooled reaction to room temperature, removed
dioxane and some water by rotary evaporation, extracted with
dichloromethane, washed the combined organic extracts with brine
(50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and
concentrated by rotary evaporation, co-evaporating with 2:1
hexanes/dichloromethane (100 mL) to give a beige foam (4.38 g).
Dissolved foam in dichloromethane (2 mL), added hexanes (2 mL),
applied solution to column, and purified by silica gel flash
chromatography eluting with 30% to 80% ethyl acetate/hexanes to
afford the title compound as a white solid (3.48 g).
Example 26E
1,4-bis(4-bromophenyl)butane-1,4-dione
[0342] To a solution of zinc(II) chloride (19.62 g, 144 mmol) in
benzene (108 mL) were added diethylamine (11.16 mL, 108 mmol) and
2-methylpropan-2-ol (10.32 mL, 108 mmol) and the mixture was
stirred at room temperature for 2 h.
2-bromo-1-(4-bromophenyl)ethanone (20.0 g, (72 mmol) and
1-(4-bromophenyl)ethanone (21.48 g, 108 mmol) were added in one
portion, and the mixture was stirred overnight (18 h). Quenched
with 5% H.sub.2SO.sub.4 (500 mL) and stirred vigorously to induce
precipitation of the product, which was collected by vacuum
filtration and washed with benzene, water, methanol, then
dichloromethane, successively. The product was dried under vacuum
to give the title compound as a white solid (11.15 g, 39.1%
yield).
Example 26F
2,5-bis(4-bromophenyl)-1-(4-tert-butylphenyl)-1H-pyrrole
[0343] To a solution of the product from Example 26E (4.00 g, 10.10
mmol) in toluene (40 mL) was added 4-tert-butylaniline (1.81 g,
12.12 mmol) followed by TFA (2.30 g, 20.20 mmol). Mixture heated to
110.degree. C. for 2 h. Mixture cooled to room temperature and
water and diethyl ether were added. Stirred for 15 min, filtered,
washed with water and diethyl ether and dried to provide the title
compound as a white solid (4.61 g; 90% yield).
Example 26G
1-(4-tert-butylphenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl)-1H-pyrrole
[0344] To a solution of the product from Example 26F (2.32 g, 4.56
mmol) in DMSO (26 mL) at room temperature were added
bis(pinacolato)diborane (2.54 g, 10.02 mmol), potassium acetate
(5.00 g, 36.4 mmol) and PdCl.sub.2(dppf) (744 mg, 0.91 mmol). The
mixture was degassed and heated to 85.degree. C. After 4 h, the
mixture was cooled to room temperature, diluted with
dichloromethane and washed with water followed by brine. The
organic phase was dried (Na.sub.2SO.sub.4) and concentrated. The
residue was taken up in 20% ethyl acetate:hexanes and filtered
through a short plug of silica gel (elution with 20% ethyl
acetate:hexanes) and concentrated to afford the title compound as a
light yellow solid (1.62 g; 59% yield).
Example 26H
(2S,2'S)-tert-butyl
2,2'-(4,4'-(4,4'-(1-(4-tert-butylphenyl)-1H-pyrrole-2,5-diyl)bis(4,1-phen-
ylene))bis(1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxylate
[0345] A mixture of the product from Example 26D (664 mg, 2.10
mmol), the product from Example 26G (1.48 g, 2.45 mmol), 2 M sodium
carbonate (1400 .mu.L, 2.80 mmol), and Pd(dppf)Cl2 (51.2 mg, 0.070
mmol) in DME (2800 .mu.L) was subjected to microwave irradiation at
140.degree. C. for 20 min. The mixture was diluted with ethyl
acetate, then washed with water and brine, and dried over
Na.sub.2SO.sub.4. The product was purified on silica gel eluted
with 30 to 70% ethyl acetate:hexanes to provide the title compound
(140 mg; 24% yield).
Example 261
(2S,2'S)-4,4'-(4,4'-(1-(4-tert-butylphenyl)-1H-pyrrole-2,5-diyl)bis(4,1-ph-
enylene))bis(2-(pyrrolidin-2-yl)-1H-imidazole)
[0346] To a solution of the product from Example 26H (135 mg, 0.164
mmol) in dichloromethane (2 mL) at room temperature was added TFA
(0.60 mL). After 3 h, the solvent was removed and the residue
partitioned between water and 25% isopropyl alcohol:CHCl.sub.3;
neutralized with NaHCO.sub.3. The organic phase was dried
(Na.sub.2SO.sub.4), filtered and concentrated. Residue used
directly in the next reaction (98 mg; 96% yield).
Example 26J
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-(1-(4-tert-butylphenyl)--
1H-pyrrole-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))bis(pyrr-
olidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
[0347] To a solution of the product from Example 261 (98 mg, 0.158
mmol) in DMF (2 mL) at room temperature was added
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (61 mg, 0.347
mmol), EDAC (66 mg, 0.347 mmol) and 1-hydroxybenzotriazole hydrate
(53 mg, 0.347 mmol). After 3 h, the mixture was transferred to a
separatory funnel with ethyl acetate and water. The organic phase
was concentrated and the residue purified by chromatography (1%
gradient elution from 0% to 4% methanol:dichloromethane) to provide
the desired material as a light yellow solid (70 mg; 30% yield).
.sup.1HNMR (MeOH-d4; 400 MHz): .delta. 7.55-7.30 (m, 6H), 7.25-6.96
(m, 8H), 6.45 (s, 2H), 5.12 (dd, J=5.43, 5.43 Hz, 2H), 4.20 (d,
J=7.26 Hz, 2H), 4.02-3.90 (m, 2H), 3.85-3.80 (m, 2H), 3.64 (s, 6H),
2.36-1.93 (m, 10H), 1.31 (s, 9H), 0.97-0.86 (m, 12H). The title
compound showed an EC.sub.50 value of less than about 0.1 nM in HCV
1b-Con1 replicon assays in the presence of 5% FBS.
Example 27
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,3R,4R,5S)-1-(4-fluo-
rophenyl)-3,4-dimethoxypyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1H-imid-
azole-4,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diy-
l)dicarbamate
##STR00261##
[0348] Example 27A
(2S,3R,4R,5S)-2,5-bis(4-bromophenyl)-1-(4-fluorophenyl)pyrrolidine-3,4-dio-
l
[0349] A solution of 3,4-O-isopropylidene-D-mannitol (2.24 g, 10.08
mmol) in 2:1 methanol-dichloromethane (45 mL) was treated with
iodobenzene diacetate (7.95 g, 24.19 mmol) followed by stirring at
room temperature for 5 h. The mixture was concentrated by rotary
evaporation and the residue was dissolved in 0.1M aq. sulfuric acid
solution (20.6 mL) followed by stirring at room temperature for 18
h. The mixture was adjusted to pH 6 by addition of solid sodium
bicarbonate. The mixture was then sequentially treated with
4-fluoroaniline (1.96 mL, 20.16 mmol), 4-bromophenylboronic acid
(3.64 g, 18.14 mmol), and absolute ethanol (40 mL). The mixture was
then heated in an oil bath (110.degree. C.) at reflux for 20 h. The
dark brown mixture was cooled to room temperature and concentrated
in vacuo. The residue was taken up in ethyl acetate (100 mL),
washed with water (50 mL), 0.33M aq. potassium phosphate tribasic
solution (2.times.50 mL), and brine (50 mL). The organic phase was
dried over anhydrous sodium sulfate, filtered, and the filtrate
concentrated by rotary evaporation to a dark reddish-brown oil.
Dissolved oil in dichloromethane-hexanes, concentrated in vacuo,
and dried in vacuo to give a dark brown foam. Purification by
silica gel flash chromatography eluting with a step gradient of 10%
to 15% ethyl acetate/dichloromethane afforded pure product as a
yellow solid (1.216 g, 24%).
Example 27B
(2S,3R,4R,5S)-2,5-bis(4-bromophenyl)-1-(4-fluorophenyl)-3,4-dimethoxypyrro-
lidine
[0350] Dissolved the product of Example 27A (237 mg, 0.467 mmol) in
a mixture of THF (3 mL) and DMF (1 mL) under a nitrogen atmosphere
and cooled to 0.degree. C. Added 60% sodium hydride dispersion in
mineral oil (56.1 mg, 1.402 mmol) in portions and stirred the
mixture at 0.degree. C. for 15 min. Then added neat iodomethane (65
.mu.L, 1.028 mmol), removed the cooling bath, and stirred the
reaction at room temperature for 14.5 h. Diluted the reaction in
ethyl acetate (50 mL), washed with saturated aq. ammonium chloride
solution (25 mL), water (2.times.25 mL), and brine (25 mL). Dried
the organic phase over anhydrous sodium sulfate, filtered, and
concentrated the filtrate by rotary evaporation. The yellow residue
was purified by silica gel flash chromatography eluting with 30%
hexanes/dichloromethane to afford the title compound as a white
foam (206 mg, 82%).
Example 27C
(2S,3R,4R,5S)-1-(4-fluorophenyl)-3,4-dimethoxy-2,5-bis(4-(4,4,5,5-tetramet-
hyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine
[0351] Charged a nitrogen-purged flask with the product of Example
27B (204 mg, 0.381 mmol), bis(pinacalato)diboron (242 mg, 0.953
mmol), potassium acetate (112 mg, 1.143 mmol), and anhydrous
dioxane (2 mL). Sparged the mixture with nitrogen for 30 min, added
1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloride
dichloromethane complex (31.1 mg, 0.038 mmol), sparged the mixture
again with nitrogen for 5 min, and heated in an oil bath at
85.degree. C. for 6 h. The reaction was vacuum filtered through a
small bed of celite 545, the collected solids were thoroughly
washed with 5% methanol/dichloromethane, and the filtrate
concentrated in vacuo, chasing the residue with
dichloromethane/hexanes to give a tan solid. Purification by silica
gel flash chromatography eluting with 5% ethyl
acetate/dichloromethane afforded the title compound as a
salmon-colored solid (238 mg, 99%).
Example 27D
(2S,2'S)-tert-butyl
2,2'-(4,4'-(4,4'-((2S,3R,4R,5S)-1-(4-fluorophenyl)-3,4-dimethoxypyrrolidi-
ne-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))dipyrrolidine-1--
carboxylate
[0352] A nitrogen-purged 5-mL microwave tube was charged with the
product of Example 27C (237 mg, 0.377 mmol), the product from
Example 26D (298 mg, 0.941 mmol), and a mixture of absolute ethanol
(1.5 mL) and toluene (1.5 mL). Sonicated to obtain a cloudy orange
mixture, added 1M aq sodium carbonate (0.941 mL, 0.941 mmol), and
sparged with nitrogen for 20 min. Added
1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloride
dichloromethane complex (30.8 mg, 0.038 mmol), sparged the mixture
again with nitrogen for 5 min, sealed the reaction tube with an
aluminum crimp cap, and heated in a microwave reactor with stirring
at 100.degree. C. for 1 h. Cooled reaction to room temperature,
diluted in ethyl acetate (75 mL), washed with water (2.times.25 mL)
and brine (25 mL), dried the organic phase over anhydrous magnesium
sulfate, filtered, and concentrated the filtrate by rotary
evaporation to a dark yellow solid. Purification by silica gel
flash chromatography eluting with 4% methanol/dichloromethane
afforded the title compound as a yellow solid (221 mg, 69%).
Example 27E
(S)-4,4'-(4,4'-((2S,3R,4R,5S)-1-(4-fluorophenyl)-3,4-dimethoxypyrrolidine--
2,5-diyl)bis(4,1-phenylene))bis(2-((S)-pyrrolidin-2-yl)-1H-imidazole)
[0353] A solution of the product of Example 27D (147.5 mg, 0.174
mmol) in anhydrous dichloromethane (2 mL) under nitrogen was
treated with TFA (1 mL) and stirred at room temperature for 30 min.
The solvent was removed in vacuo and chased with 1:10
dichloromethane-hexanes (3.times.50 mL) to afford a pale yellow
solid (193 mg). The solid TFA salt was dissolved in anhydrous
methanol (15 mL), treated with dry Amberlite IRA-400(OH) resin
(1.66 g, previously washed 10 g of wet resin (Supelco) with
deionized water (3.times.25 mL) and methanol (3.times.25 mL), then
dried in vacuo), and stirred for 2 h at room temperature. The
mixture was then vacuum filtered, the collected resin washed
thoroughly with methanol, the filtrate concentrated by rotary
evaporation, and the residue chased with 1:10
dichloromethane-hexanes to afford the title compound as a light
yellow solid (94 mg, 0.145 mmol, 83%).
Example 27F
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,3R,4R,5S)-1-(4-fluo-
rophenyl)-3,4-dimethoxypyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1H-imid-
azole-4,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diy-
l)dicarbamate
[0354] In an oven-dried round bottom flask, dissolved the product
of Example 27E (92 mg, 0.142 mmol) in a mixture of DMF (1 mL) and
DMSO (1 mL) under nitrogen and cooled the solution to 0.degree. C.
Added sequentially (S)-2-(methoxycarbonylamino)-3-methylbutanoic
acid (53.5 mg, 0.305 mmol), EDAC (61.1 mg, 0.312 mmol),
1-hydroxybenzotriazole hydrate (47.8 mg, 0.312 mmol), and
N-methylmorpholine (47 .mu.L, 0.426 mmol). Removed the cooling bath
and stirred at room temperature for 15 h. Diluted the reaction with
ethyl acetate (50 mL), washed with saturated aq. sodium bicarbonate
solution (25 mL), water (2.times.25 mL), and brine (25 mL). The
organic phase was dried over anhydrous magnesium sulfate, filtered,
and the filtrate concentrated by rotary evaporation. Purification
by silica gel flash chromatography eluting with 5%
methanol/dichloromethane afforded the title compound as a pale
yellow solid (78 mg, 56%). .sup.1H NMR (400 MHz, DMSO-d6) .delta.
ppm 0.86 (dd, J=17.67, 6.72 Hz, 12H), 0.97-1.37 (m, 3H), 1.41-2.29
(m, 11H), 3.53 (s, 6H), 3.69-3.86 (m, 4H), 4.04 (q, J=8.02 Hz, 2H),
4.12-4.23 (m, 2H), 5.07 (d, J=3.80 Hz, 2H), 5.35-5.48 (m, 2H), 6.31
(dd, J=9.16, 4.39 Hz, 2H), 6.74 (t, J=8.89 Hz, 2H), 7.12-7.71 (m,
12H), 11.53-12.31 (m, 2H); MS (ESI+) m/z 963 (M+H)+. The title
compound showed an EC.sub.50 value of less than about 0.1 nM in HCV
1b-Con1 replicon assays in the presence of 5% FBS.
Example 28
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-((2R,5R)-1-(4-tert-butylphenyl-
)pyrrolidine-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2-
,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate and dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-((2S,5S)-1-(4-tert-butylphenyl)pyrroli-
dine-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl)-
)bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00262##
[0355] Example 28A
1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-dione
[0356] Zinc chloride (27.4 g, 201 mmol), diethylamine (15.6 mL, 151
mmol) and t-butanol (14.4 mL, 151 mmol) were combined in benzene
(151 mL) at room temperature under a nitrogen atmosphere and
stirred for 2 h. 1-(4-chloro-3-nitrophenyl)ethanone (30.1 g, 151
mmol) and 2-bromo-1-(4-chloro-3-nitrophenyl)ethanone (28 g, 101
mmol) were added. The mixture was stirred vigorously for 20 h, and
the solid product was collected by filtration and rinsed with
benzene, water, methanol, and dichloromethane. The solid was dried
in a vacuum oven.
Example 28B
1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-diol
[0357] The product of Example 28A (5.75 g, 14.48 mmol) was
dissolved in ethanol (150 mL) at room temperature and treated with
sodium borohydride (1.21 g, 31.9 mmol) portionwise over 5 minutes.
The solution was heated at 70.degree. C. for 1 h and then cooled to
room temperature, quenched with water, extracted into ethyl
acetate, dried over sodium sulfate, and concentrated to dryness to
give 4.81 g (83%) of an off-white solid.
Example 28C
1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-diyl
dimethanesulfonate
[0358] The product of Example 28B (4.81 g, 11.99 mmol) and
triethylamine (5.85 mL, 42.0 mmol) were dissolved in
dichloromethane (80 mL) at room temperature and treated with
methanesulfonyl chloride (2.34 mL, 30.0 mmol) dropwise over 10
minutes. The resulting solution was stirred for 2 h then
concentrated to dryness and used directly in the next step.
Example 28D
1-(4-tert-butylphenyl)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine
[0359] The product from Example 28C (6.6 g, 11.84 mmol) was
slurried in DMF (30 mL) and 4-t-butyl aniline (18.7 mL, 118 mmol)
was added and the solution was heated at 55.degree. C. for 2 h then
cooled and poured into water and extracted into dichloromethane.
The organics were concentrated and the residue was purified by
chromatography on silica gel 120 g column, eluting with 0-5% ethyl
acetate/hexanes to give 4.41 g (72%) of a thick oil.
Example 28E
4,4'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(N-(4-methoxybenzyl)-2-
-nitroaniline)
[0360] The product from Example 28D (4.41 g, 8.57 mmol) was
combined, neat, with p-methoxy benzylamine (8.93 mL, 68.6 mmol) and
heated at 145.degree. C. for 1 h. The mixture was diluted with
dichloromethane and filtered. The filtrate was washed with 0.5 M
HCl, then NaHCO.sub.3 soln, then brine, concentrated and purified
by chromatography on silica gel with an 80 g column, eluting with
0-50% ethyl acetate/hexanes to give 4.13 g (67%) of an orange foamy
solid.
Example 28F
4,4'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(N1-(4-methoxybenzyl)b-
enzene-1,2-diamine)
[0361] The product from Example 28E (2 g, 2.79 mmol) was dissolved
in a mixture of THF (15 mL), ethanol (15 mL), and ethyl acetate (5
mL) then platinum oxide (0.254 g, 1.12 mmol) was added via THF
slurry. The flask was evacuated and purged with nitrogen twice,
then evacuated and opened to hydrogen balloon. The mixture was
stirred at room temperature for 20 h, then filtered through celite,
concentrated, and purified by chromatography on silica gel with an
80 g column, eluting with 0-40% ethyl acetate/dichloromethane to
give the first peak of trans product 0.508 g (28%).
Example 28G
(2S,2'S)-tert-butyl
2,2'-(5,5'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-(4-methoxybe-
nzylamino)-5,1-phenylene)bis(azanediyl)bis(oxomethylene))dipyrrolidine-1-c-
arboxylate
[0362] The product from Example 28F (0.422 g, 0.643 mmol) and
diisopropylethylamine (0.674 mL, 3.86 mmol) were dissolved in DMSO
(6 mL) at room temperature and treated with S-Boc-proline (0.319 g,
1.48 mmol) followed by HATU (0.514 g, 1.35 mmol). The solution was
stirred for 1 h at room temperature then diluted with water and the
solid product was filtered off and purified by chromatography on
silica gel with a 40 g column, eluting with 0-50% ethyl acetate in
dichloromethane to give 0.565 g (84%) of a yellow solid.
Example 28H
(2S,2'S)-tert-butyl
2,2'-(5,5'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-amino-5,1-ph-
enylene)bis(azanediyl)bis(oxomethylene))dipyrrolidine-1-carboxylate
[0363] The product from Example 28G (0.565 g, 0.538 mmol) was
dissolved in dichloromethane (5 mL) and water (0.25 mL) at room
temperature and treated with DDQ (0.244 g, 1.076 mmol) portionwise
over 2 minutes. The mixture was diluted with sodium bicarbonate
solution, extracted into dichloromethane, concentrated and purified
by chromatography on silica gel with a 40 g column, eluting with
0-15% methanol/dichloromethane to give 0.355 g (81%) of a yellow
solid.
Example 281
(2S,2'S)-tert-butyl
2,2'-(5,5'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(1H-benzo[d]imi-
dazole-5,2-diyl))dipyrrolidine-1-carboxylate
[0364] The product from Example 28H was dissolved in neat acetic
acid (3 mL) and heated at 72.degree. C. for 2 h. The solution was
concentrated and then poured into water and adjusted pH to -7-8
with sodium bicarbonate. The product was extracted into
dichloromethane, concentrated and purified by chromatography on
silica gel with a 40 g column, eluting with 0-5%
methanol/dichloromethane to give 0.185 g (55%) of a light yellow
solid.
Example 28J
(S)-5,5'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-
-2-yl)-1H-benzo[d]imidazole)
[0365] The product from Example 281 (0.204 g, 0.264 mmol) was
dissolved in THF (2 mL) at room temperature and treated with 4 M
hydrochloric acid in dioxane (2 mL). The mixture was concentrated
to dryness and used directly in the next step.
Example 28K
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-((2R,5R)-1-(4-tert-butylphenyl-
)pyrrolidine-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2-
,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate and dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-((2S,5S)-1-(4-tert-butylphenyl)pyrroli-
dine-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl)-
)bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
[0366] The product from Example 28J (0.150 g, 0.261 mmol) and
diisopropylethylamine (0.365 mL, 2.09 mmol) were dissolved in DMSO
(3 mL) at room temperature and treated with
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.105 g, 0.601
mmol) followed by HATU (0.204 g, 0.536 mmol). The solution was
stirred for 1 h at room temperature then diluted with water and the
solid product was filtered off and purified by chromatography on
silica gel with a 12 g column, eluting with 0-8% methanol in
dichloromethane to give 0.143 g (60%) of a yellow solid. .sup.1H
NMR (400 MHz, DMSO-D6) .delta. ppm 0.75-0.92 (m, 12H) 1.07 (s, 9H)
1.64-1.76 (m, 2H) 1.85-2.04 (m, 6H) 2.12-2.26 (m, 4H) 2.43 (dd,
J=7.75, 4.07 Hz, 2H) 3.53 (s, 6H) 3.76-3.87 (m, 4H) 4.04 (dd,
J=11.49, 6.51 Hz, 2H) 5.12 (t, J=7.59 Hz, 2H) 5.35 (d, J=3.25 Hz,
2H) 6.25 (d, J=8.46 Hz, 2H) 6.85-6.96 (m, 2H) 7.07 (t, J=7.97 Hz,
2H) 7.19 (s, 1H) 7.28 (d, J=8.35 Hz, 3H) 7.38 (dd, J=8.19, 1.90 Hz,
1H) 7.46 (d, J=8.13 Hz, 1H) 11.97-12.09 (m, 2H). The title compound
showed an EC.sub.50 value of less than about 0.1 nM in HCV 1b-Con1
replicon assays in the presence of 5% FBS.
Example 29
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-((2R,5R)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2,1-d-
iyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate and dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-((2S,5S)-1-(4-fluorophenyl)pyrrolidine-
-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis-
(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00263##
[0367] Example 29A
2,5-bis(4-chloro-3-nitrophenyl)-1-(4-fluorophenyl)pyrrolidine
[0368] The product from Example 28C (2.9 g, 5.2 mmol) and
4-fluoroaniline (5.0 mL, 52.0 mmol) were combined, neat, and heated
at 45.degree. C. for 20 h then cooled and poured into water and
extracted into dichloromethane. The organics were concentrated the
residue was purified by chromatography on silica gel with a 120 g
column, eluting with 0-5% ethyl acetate/hexanes to give 0.59 g
(24%) of a thick oil.
Example 29B
4,4'-(1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(N-(4-methoxybenzyl)-2-nit-
roaniline)
[0369] The product from Example 29A (0.88 g, 1.86 mmol) was
combined with 4-methoxy benzylamine (3.64 mL, 28.0 mmol) and heated
at 145.degree. C. for 1 h in a microwave reactor. The mixture was
diluted with dichloromethane and filtered. The filtrate was
concentrated and purified by chromatography on silica gel with a
330 g column, eluting with 0-60% ethyl acetate/hexanes to give 0.79
g (62%) of an orange foam solid.
Example 29C
4,4'-(1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-nitroaniline)
[0370] The product from Example 29B (0.78 g, 1.15 mmol) was
dissolved in dichloromethane (10 mL) at room temperature and
treated with TFA (1.8 mL, 23.0 mmol) for 3 h. The residue was
concentrated and partitioned between dichloromethane and sodium
bicarbonate solution. The organics were concentrated and purified
by chromatography on silica gel with a 40 g column, eluting with
dichloromethane to give 0.218 g (43%) of the trans isomer.
Example 29D
4,4'-(1-(4-fluorophenyl)pyrrolidine-2,5-diyl)dibenzene-1,2-diamine
[0371] The product from Example 29C (0.218 g, 0.50 mmol) was
dissolved in DMF (5 mL) then platinum oxide (0.226 g, 0.99 mmol)
was added via THF slurry. The flask was evacuated and purged with
nitrogen twice, then evacuated and opened to hydrogen balloon. The
mixture was stirred at room temperature for 20 h. The solution was
taken on to the next step without purification.
Example 29E
(2S,2'S)-tert-butyl
2,2'-(5,5'-(1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-amino-5,1-phenyl-
ene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate
[0372] The crude DMF solution of the product from Example 29D was
treated with diisopropylethylamine (0.296 mL, 1.70 mmol) and
S-Boc-proline (0.192 g, 0.89 mmol) followed by HATU (0.322 g, 0.85
mmol). The solution was stirred for 1.5 h at room temperature then
diluted with water and the solid product was filtered off and
purified by chromatography on silica gel with a 12 g column,
eluting with 0-3% methanol in dichloromethane to give 0.235 g (72%)
of a yellow solid.
Example 29F
(2S,2'S)-tert-butyl
2,2'-(5,5'-(1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(1H-benzo[d]imidazo-
le-5,2-diyl))dipyrrolidine-1-carboxylate
[0373] The product from Example 29E was dissolved in neat acetic
acid (2 mL) and heated at 60.degree. C. for 1 h. The solution was
concentrated then poured into water and adjusted pH to -7-8 with
sodium bicarbonate. The product was extracted into dichloromethane,
concentrated and purified by chromatography on silica gel with a 12
g column, eluting with 0-20% ethyl acetate in dichloromethane to
give 0.124 g (55%) of a light yellow solid.
Example 29G
(S)-5,5'-(1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-y-
l)-1H-benzo[d]imidazole)
[0374] The product from Example 29F (0.120 g, 0.163 mmol) was
dissolved in dichloromethane (2 mL) at room temperature and treated
with TFA (1 mL). The mixture was concentrated to dryness, dissolved
in 25% ISOPROPYL ALCOHOL/dichloromethane and washed with sodium
bicarbonate solution. The resulting solids were filtered off and
dried and the organics were concentrated and dried to give the
title compound (0.062 g 72% yield) of an off-white solid.
Example 29H
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-((2R,5R)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2,1-d-
iyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate and dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-((2S,5S)-1-(4-fluorophenyl)pyrrolidine-
-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis-
(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
[0375] The product from Example 29G (0.062 g, 0.116 mmol) and
diisopropylethylamine (0.101 mL, 0.58 mmol) were dissolved in DMSO
(2 mL) at room temperature and treated with
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.051 g, 0.289
mmol) followed by HATU (0.092 g, 0.243 mmol). The solution was
stirred for 1 h at room temperature then diluted with water and the
solid product was filtered off and purified by chromatography on
silica gel with a 12 g column, eluting with 0-7% methanol in
dichloromethane to give 0.021 g (21%) of a yellow solid. .sup.1H
NMR (400 MHz, DMSO-D6) .delta. ppm 0.78-0.90 (m, 12H) 1.70 (s, 2H)
1.87-2.03 (m, 6H) 2.13-2.26 (m, 4H) 2.54-2.62 (m, 2H) 3.54 (s, 6H)
3.82 (s, 4H) 4.03-4.11 (m, 2H) 5.09-5.18 (m, 2H) 5.32-5.42 (m, 2H)
6.28 (dd, J=8.89, 4.34 Hz, 2H) 6.70-6.80 (m, 2H) 7.01-7.10 (m, 2H)
7.20 (d, J=9.32 Hz, 1H) 7.27-7.34 (m, 3H) 7.38 (dd, J=8.13, 2.71
Hz, 1H) 7.45 (d, J=8.02 Hz, 1H) 12.03 (s, 2H). The title compound
showed an EC.sub.50 value of less than about 0.1 nM in HCV 1b-Con1
replicon assays in the presence of 5% FBS.
Example 30
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-((2S,5S)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2,1-d-
iyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00264##
[0377] The product from Example 29H was purified by chiral
chromatography on a Chirapak IA column eluting with a mixture of
hexane/EtOH/MeOH/1,2 Dichloroethane/diethylamine (25/25/25/25/0.1).
.sup.1H NMR (400 MHz, DMSO-D6) .delta. ppm 0.75-0.89 (m, 12H)
1.64-1.73 (m, 2H) 1.85-2.03 (m, 6H) 2.12-2.24 (m, 4H) 2.81-2.90 (m,
2H) 3.52 (s, 6H) 3.76-3.87 (m, 4H) 4.01-4.09 (m, 2H) 5.08-5.16 (m,
2H) 5.34 (q, J=6.65 Hz, 2H) 6.26 (dd, J=9.05, 4.50 Hz, 2H)
6.67-6.78 (m, 2H) 7.03 (t, J=8.02 Hz, 2H) 7.20 (s, 1H) 7.24-7.32
(m, 3H) 7.36 (d, J=8.13 Hz, 1H) 7.44 (d, J=7.92 Hz, 1H) 12.01-12.07
(m, 2H). The title compound showed an EC.sub.50 value of less than
about 0.1 nM in HCV 1b-Con1 replicon assays in the presence of 5%
FBS.
Example 31
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-((2R,5R)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))bis(pyrrolidine-2,1-d-
iyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00265##
[0379] The product from Example 29H was purified by chiral
chromatography on a Chirapak IA column eluting with a mixture of
hexane/EtOH/MeOH/1,2 Dichloroethane/diethylamine (25/25/25/25/0.1).
.sup.1H NMR (400 MHz, DMSO-D6) .delta. ppm 0.74-0.93 (m, 12H) 1.69
(t, J=9.65 Hz, 2H) 1.82-2.06 (m, 6H) 2.09-2.26 (m, 4H) 3.04-3.23
(m, 2H) 3.52 (s, 6H) 3.73-3.90 (m, 4H) 4.06 (t, J=8.46 Hz, 2H)
5.05-5.21 (m, 2H) 5.29-5.44 (m, 2H) 6.21-6.32 (m, 2H) 6.67-6.86 (m,
2H) 7.05 (t, J=8.78 Hz, 2H) 7.18 (s, 1H) 7.23-7.33 (m, 3H) 7.37 (d,
J=8.13 Hz, 1H) 7.45 (d, J=8.02 Hz, 1H) 12.04 (d, J=14.96 Hz, 2H).
The title compound showed an EC.sub.50 value of less than about 0.1
nM in HCV 1b-Con1 replicon assays in the presence of 5% FBS.
Example 32
(1R,4R)-1,4-bis(4-nitrophenyl)butane-1,4-diol
##STR00266##
[0381] To (S)-(-)-.alpha.,.alpha.-diphenyl-2-pyrrolidinemethanol
(2.71 g, 10.70 mmol) was added THF (80 mL) at 23.degree. C. The
very thin suspension was treated with trimethyl borate (1.44 g,
13.86 mmol) over 30 seconds, and the resulting solution was mixed
at 23.degree. C. for 1 h. The solution was cooled to 16-19.degree.
C., and N,N-diethylaniline borane (21.45 g, 132 mmol) was added
dropwise via syringe over 3-5 min (caution: vigorous H.sub.2
evolution), while the internal temperature was maintained at
16-19.degree. C. After 15 min, the H.sub.2 evolution had ceased. To
a separate vessel was added the product from Example 1A (22.04 g,
95 wt %, 63.8 mmol), followed by THF (80 mL), to form an orange
slurry. After cooling the slurry to 11.degree. C., the borane
solution was transferred via cannula into the dione slurry over 3-5
min. During this period, the internal temperature of the slurry
rose to 16.degree. C. After the addition was complete, the reaction
was maintained at 20-27.degree. C. for an additional 2.5 h. After
reaction completion, the mixture was cooled to 5.degree. C. and
methanol (16.7 g, 521 mmol) was added dropwise over 5-10 min,
maintaining an internal temperature <20.degree. C. (note:
vigorous H.sub.2 evolution). After the exotherm had ceased (ca. 10
min), the temperature was adjusted to 23.degree. C., and the
reaction was mixed until complete dissolution of the solids had
occurred. Ethyl acetate (300 mL) and 1 M HCl (120 mL) were added,
and the phases were partitioned. The organic phase was then washed
successively with 1 M HCl (2.times.120 mL), H.sub.2O (65 mL), and
10% aq. NaCl (65 mL). The organics were dried over MgSO.sub.4,
filtered, and concentrated in vacuo. Crystallization of the product
occurred during the concentration. The slurry was warmed to
50.degree. C., and heptane (250 mL) was added over 15 min. The
slurry was then allowed to mix at 23.degree. C. for 30 min and
filtered. The wet cake was washed with 3:1 heptane:ethyl acetate
(75 mL), and the orange, crystalline solids were dried at
45.degree. C. for 24 h to provide the title compound (15.35 g,
99.3% ee, 61% yield), which was contaminated with 11% of the meso
isomer (vs. dl isomer).
Example 33
(1S,4S)-1,4-bis(4-nitrophenyl)butane-1,4-diol
##STR00267##
[0383] The product from Example 1A (30 g, 95 wt %, 91.4 mmol) was
subjected to the conditions described in Example 32, substituting
(R)-(-)-.alpha.,.alpha.-diphenyl-2-pyrrolidinemethanol for
(S)-(-)-.alpha.,.alpha.-diphenyl-2-pyrrolidinemethanol, to give the
title compound (20.14 g, >99.55 ee, 61% yield) which was
contaminated with 9.7% of the meso isomer (vs. dl isomer).
Example 34
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-tert-butylphenyl-
)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bi-
s(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
and
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-tert-butylphenyl-
)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bi-
s(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00268##
[0384] Example 34A
1-(4-tert-butylphenyl)-2,5-bis(4-nitrophenyl)pyrrolidine
[0385] The product from Example 1C (3.67 g, 7.51 mmol) and
4-tert-butylaniline (11.86 ml, 75 mmol) in DMF (40 ml) was stirred
under nitrogen at 50.degree. C. for 4 h. The resulting mixture was
diluted into ethyl acetate, treated with 1M HCl, stirred for 10
minutes and filtered to remove solids. The filtrate organic layer
was washed twice with brine, dried with sodium sulfate, filtered
and evaporated. The residue was purified by chromatography on
silica gel eluting with ethyl acetate in hexane (5% to 30%) to give
a solid. The solid was triturated in a minimal volume of 1:9 ethyl
acetate/hexane to give a light yellow solid as a mixture of trans
and cis isomers (1.21 g, 36%).
Example 34B
4,4'-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dianiline
and
4,4'-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dianiline
[0386] To a solution of the product from Example 34A (1.1 g, 2.47
mmol) in ethanol (20 ml) and THF (20 ml) was added PtO.sub.2 (0.22
g, 0.97 mmol) in a 50 ml pressure bottle and stirred under 30 psi
hydrogen at room temperature for 1 h. The mixture was filtered
through a nylon membrane and evaporated. The residue was purified
by chromatography on silica gel eluting with ethyl acetate in
hexane (20% to 60%). The title compound eluted as the first of 2
stereoisomers (trans isomer, 0.51 g, 54%).
Example 34C
(2S,2'S)-tert-Butyl
2,2'-(4,4'-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-ph-
enylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate
and (2S,2'S)-tert-Butyl
2,2'-(4,4'-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-ph-
enylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate
[0387] To a mixture of the product from Example 34B (250 mg, 0.648
mmol), (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid
(307 mg, 1.427 mmol) and HATU (542 mg, 1.427 mmol) in DMSO (10 ml)
was added Hunig's base (0.453 ml, 2.59 mmol). The reaction mixture
was stirred at room temperature for 1 h. The mixture was
partitioned with ethyl acetate and water. The organic layer was
washed with brine, dried with sodium sulfate, filtered and
evaporated. The residue was purified by chromatography on silica
gel eluting with ethyl acetate in hexane (10% to 50%) to give the
title compound (500 mg, 99%).
Example 34D
(2S,2'S)--N,N'-(4,4-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bi-
s(4(4,1-phenylene))dipyrrolidine-2-carboxamide and
(2S,2'S)--N,N'-(4,4'-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)-
bis(4,1-phenylene))dipyrrolidine-2-carboxamide
[0388] To the product from Example 34C (498 mg, 0.638 mmol) in
dichloromethane (4 ml) was added TFA (6 ml). The reaction mixture
was stirred at room temperature for 1 h and concentrated in vacuo.
The residue was partitioned between 3:1 CHCl.sub.3:isopropyl
alcohol and saturated aq. NaHCO.sub.3. The aqueous layer was
extracted by 3:1 CHCl.sub.3:isopropyl alcohol again. The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered and
concentrated to give the title compound (345 mg, 93%).
Example 34E
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-tert-butylphenyl-
)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bi-
s(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
and
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-tert-butylphenyl-
)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bi-
s(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
[0389] The product from Example 34D (29.0 mg, 0.050 mmol),
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (19.27 mg, 0.110
mmol), EDAC (21.09 mg, 0.110 mmol), HOBT (16.85 mg, 0.110 mmol) and
N-methylmorpholine (0.027 ml, 0.250 mmol) were combined in DMF (2
ml). The reaction mixture was stirred at room temperature for 3 h.
The mixture was partitioned with ethyl acetate and water. The
organic layer was washed with brine twice, dried with sodium
sulfate, filtered and evaporated. The residue was purified by
chromatography on silica gel eluting with ethyl acetate in hexane
(50% to 80%) to give a solid. The solid was triturated with ethyl
acetate/hexane to give the title compound (13 mg, 29%). .sup.1H NMR
(400 MHz, DMSO-D6) .delta. ppm 0.85-0.95 (m, 12H) 1.11 (s, 9H)
1.59-1.65 (m, 2H) 1.79-2.04 (m, 8H) 2.10-2.18 (m, 2H) 2.41-2.46 (m,
2H) 3.52 (s, 6H) 3.57-3.67 (m, 2H) 3.76-3.86 (m, 2H) 4.00 (t,
J=7.56 Hz, 2H) 4.39-4.46 (m, 2H) 5.15 (d, J=7.00 Hz, 2H) 6.17 (d,
J=7.70 Hz, 2H) 6.94 (d, J=8.78 Hz, 2H) 7.13 (d, J=7.37 Hz, 4H) 7.30
(d, J=8.20 Hz, 2H) 7.50 (d, J=8.24 Hz, 4H) 9.98 (s, 2H); (ESI+) m/z
895 (M+H)+. The title compound showed an EC.sub.50 value of less
than about 0.1 nM in HCV 1b-Con1 replicon assays in the presence of
5% FBS.
Example 35
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-tert-butylphenyl-
)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bi-
s(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00269##
[0391] The product from Example 34E was purified by chiral
chromatography on a Chiralpak AD-H semi-prep column eluting with a
2:1 mixture of hexane:(2:1 isopropyl alcohol:EtOH). The title
compound was the first of the 2 diastereomers to elute. .sup.1H NMR
(400 MHz, DMSO-D6) .delta. ppm 0.88 (d, J=6.61 Hz, 6H) 0.93 (d,
J=6.72 Hz, 6H) 1.11 (s, 9H) 1.63 (d, J=5.42 Hz, 2H) 1.80-2.04 (m,
8H) 2.09-2.19 (m, 2H) 2.44-2.47 (m, 2H) 3.52 (s, 6H) 3.59-3.66 (m,
2H) 3.77-3.84 (m, 2H) 4.02 (t, J=8.40 Hz, 2H) 4.42 (dd, J=7.86,
4.83 Hz, 2H) 5.14 (d, J=6.18 Hz, 2H) 6.17 (d, J=8.67 Hz, 2H) 6.94
(d, J=8.78 Hz, 2H) 7.13 (d, J=8.46 Hz, 4H) 7.31 (d, J=8.35 Hz, 2H)
7.50 (d, J=8.35 Hz, 4H) 9.98 (s, 2H). The title compound showed an
EC.sub.50 value of less than about 0.1 nM in HCV 1b-Con1 replicon
assays in the presence of 5% FBS.
Example 36
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-tert-butylphenyl-
)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bi-
s(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00270##
[0393] The product from Example 34E was purified by chiral
chromatography on a Chiralpak AD-H semi-prep column eluting with a
2:1 mixture of hexane:(2:1 isopropyl alcohol:EtOH). The title
compound was the second of 2 diastereomers to elute. .sup.1H NMR
(400 MHz, DMSO-D6) .delta. ppm 0.87 (d, J=6.51 Hz, 6H) 0.92 (d,
J=6.72 Hz, 6H) 1.11 (s, 9H) 1.63 (d, J=5.53 Hz, 2H) 1.82-2.04 (m,
8H) 2.09-2.18 (m, 2H) 2.41-2.47 (m, 2H) 3.52 (s, 6H) 3.58-3.67 (m,
2H) 3.75-3.84 (m, 2H) 4.02 (t, J=7.26 Hz, 2H) 4.43 (dd, J=7.92,
4.88 Hz, 2H) 5.14 (d, J=6.18 Hz, 2H) 6.17 (d, J=8.78 Hz, 2H) 6.94
(d, J=8.67 Hz, 2H) 7.12 (d, J=8.46 Hz, 4H) 7.31 (d, J=8.35 Hz, 2H)
7.49 (d, J=8.46 Hz, 4H) 9.98 (s, 2H). The title compound showed an
EC.sub.50 value of less than about 0.1 nM in HCV 1b-Con1 replicon
assays in the presence of 5% FBS.
Example 37
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-tert-butylphenyl-
)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bi-
s(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00271##
[0394] Example 37A
(S)-2,5-dioxopyrrolidin-1-yl
2-(methoxycarbonylamino)-3-methylbutanoate
[0395] To a mixture of
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (19.66 g, 112
mmol) and N-hydroxysuccinimide (13.29 g, 116 mmol) was added ethyl
acetate (250 ml), and the mixture was cooled to 0-5.degree. C.
Diisopropylcarbodiimide (13.88 g, 110 mmol) was added and the
reaction mixture was stirred at 0-5.degree. C. for about 1 hour.
The reaction mixture was warmed to room temperature. The solids
(diisopropylurea by-product) were filtered and rinsed with ethyl
acetate. The filtrate was concentrated in vacuo to an oil.
Isopropyl alcohol (200 ml) was added to the oil and the mixture was
heated to about 50.degree. C. to obtain a homogeneous solution.
Upon cooling, crystalline solids formed. The solids were filtered
and washed with isopropyl alcohol (3.times.20 ml) and dried to give
the title compound as a white solid (23.2 g, 77% yield).
Example 37B
(S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxy-
lic acid
[0396] To a mixture of L-proline (4.44 g, 38.6 mmol), water (20
ml), acetonitrile (20 ml) and DIEA (9.5 g, 73.5 mmol) was added a
solution of the product from Example 37A (10 g, 36.7 mmol) in
acetonitrile (20 mL) over 10 minutes. The reaction mixture was
stirred overnight at room temperature. The solution was
concentrated under vacuum to remove the acetonitrile. To the
resulting clear water solution was added 6N HCl (9 ml) until
pH.about.2. The solution was transferred to a separatory funnel and
25% NaCl (10 ml) was added and the mixture was extracted with ethyl
acetate (75 ml), and then again with ethyl acetate (6.times.20 ml),
and the combined extracts were washed with 25% NaCl (2.times.10
ml). The solvent was evaporated to give a thick oil. Heptane was
added and the solvent was evaporated to give a foam, which was
dried under high vacuum. Diethyl ether was added and the solvent
was evaporated to give a foam, which was dried under high vacuum to
give the title compound (10.67 g) as a white solid.
[0397] The compound of Example 37B can also be prepreared according
to the following procedure:
[0398] To a flask was charged L-valine (35 g, 299 mmol), IN sodium
hydroxide solution (526 ml, 526 mmol) and sodium carbonate (17.42
g, 164 mmol). The mixture was stirred for 15 min to dissolve solids
and then cooled to 15.degree. C. Methyl chloroformate (29.6 g, 314
mmol) was added slowly to the reaction mixture. The mixture was
then stirred at rt for 30 min. The mixture was cooled to 15.degree.
C. and pH adjusted to -5.0 with concentrated HCl solution. 100 mL
of 2-methyltetrahydrofuran (2-MeTHF) was added and the adjustment
of pH continued until the pH reached .about.2.0. 150 mL of 2-MeTHF
was added and the mixture was stirred for 15 min. Layers were
separated and the aqueous layer extracted with 100 mL of 2-MeTHF.
The combined organic layer was dried over anhyd Na.sub.2SO.sub.4
and filtered, and Na.sub.2SO.sub.4 cake was washed with 50 mL of
2-MeTHF. The product solution was concentrated to .about.100 mL,
chased with 120 mL of IPAc twice. 250 mL of heptanes was charged
slowly and then the volume of the mixture was concentrated to 300
mL. The mixture was heated to 45.degree. C. and 160 mL of heptanes
charged. The mixture was cooled to rt in 2 h, stirred for 30 min,
filtered and washed with 2-MeTHF/heptanes mixture (1:7, 80 mL). The
wetcake was dried at 55.degree. C. for 24 h to give 47.1 g of
Moc-L-Val-OH product as a white solid (90%).
[0399] Moc-L-Val-OH (150 g, 856 mmol), HOBt hydrate (138 g, 899
mmol) and DMF (1500 ml) were charged to a flask. The mixture was
stirred for 15 min to give a clear solution. EDC hydrochloride (172
g, 899 mmol) was charged and mixed for 20 min. The mixture was
cooled to 13.degree. C. and (L)-proline benzyl ester hydrochloride
(207 g, 856 mmol) charged. Triethylamine (109 g, 1079 mmol) was
then charged in 30 min. The resulting suspension was mixed at rt
for 1.5 h. The reaction mixture was cooled to 15.degree. C. and
1500 mL of 6.7% NaHCO.sub.3 charged in 1.5 h, followed by the
addition of 1200 mL of water over 60 min. The mixture was stirred
at rt for 30 min, filtered and washed with water/DMF mixture (1:2,
250 mL) and then with water (1500 mL). The wetcake was dried at
55.degree. C. for 24 h to give 282 g of product as a white solid
(90%).
[0400] The resulting solids (40 g) and 5% Pd/Alumina were charged
to a Parr reactor followed by THF (160 mL). The reactor was sealed
and purged with nitrogen (6.times.20 psig) followed by a hydrogen
purge (6.times.30 psig). The reactor was pressurized to 30 psig
with hydrogen and agitated at room temperature for approximately 15
hours. The resulting slurry was filtered through a GF/F filter and
concentrated to approximately 135 g solution. Heptane was added
(120 mL), and the solution was stirred until solids formed. After
an addition 2-3 hours additional heptane was added drop-wise (240
mL), the slurry was stirred for approximately 1 hour, then
filtered. The solids were dried to afford the title compound.
Example 37C
(1R,4R)-1,4-bis(4-nitrophenyl)butane-1,4-diyl
dimethanesulfonate
[0401] The product from Example 32 (5.01 g, 13.39 mmol) was
combined with 2-methyltetrahydrofuran (70 mL) and cooled to
-5.degree. C., and N,N-diisopropylethylamine (6.81 g, 52.7 mmol)
was added over 30 seconds. Separately, a solution of
methanesulfonic anhydride (6.01 g, 34.5 mmol) in
2-methyltetrahydrofuran (30 mL) was prepared and added to the diol
slurry over 3 min., maintaining the internal temperature between
-15.degree. C. and -25.degree. C. After mixing for 5 min at
-15.degree. C., the cooling bath was removed and the reaction was
allowed to warm slowly to 23.degree. C. and mixed for 30 minutes.
After reaction completion, the crude slurry was carried immediately
into the next step.
Example 37D
(2S,5S)-1-(4-tert-butylphenyl)-2,5-bis(4-nitrophenyl)pyrrolidine
[0402] To the crude product solution from Example 37C (7.35 g,
13.39 mmol) was added 4-tert-butylaniline (13.4 g, 90 mmol) at
23.degree. C. over 1 minute. The reaction was heated to 65.degree.
C. for 2 h. After completion, the reaction mixture was cooled to
23.degree. C. and diluted with 2-methyltetrahydrofuran (100 mL) and
1 M HCl (150 mL). After partitioning the phases, the organic phase
was treated with 1 M HCl (140 mL), 2-methyltetrahydrofuran (50 mL),
and 25 wt % aq. NaCl (100 mL), and the phases were partitioned. The
organic phase was washed with 25 wt % aq. NaCl (50 mL), dried over
MgSO.sub.4, filtered, and concentrated in vacuo to approximately 20
mL. Heptane (30 mL) and additional 2-methyltetrahydrofuran were
added in order to induce crystallization. The slurry was
concentrated further, and additional heptane (40 mL) was slowly
added and the slurry was filtered, washing with
2-methyltetrahydrofuran:heptane (1:4, 20 mL). The solids were
suspended in MeOH (46 mL) for 3 h, filtered, and the wet solid was
washed with additional MeOH (18 mL). The solid was dried at
45.degree. C. in a vacuum oven for 16 h to provide the title
compound (3.08 g, 51% 2-step yield).
Example 37E
4,4'-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dianiline
[0403] To a 160 ml Parr stirrer hydrogenation vessel was added the
product from Example 37D (2 g, 4.49 mmol), followed by 60 ml of
THF, and Raney Nickel Grace 2800 (1 g, 50 wt % (dry basis)) under a
stream of nitrogen. The reactor was assembled and purged with
nitrogen (8.times.20 psig) followed by purging with hydrogen
(8.times.30 psig). The reactor was then pressurized to 30 psig with
hydrogen and agitation (700 rpm) began and continued for a total of
16 h at room temperature. The slurry was filtered by vacuum
filtration using a GF/F Whatman glass fiber filter. Evaporation of
the filtrate to afford a slurry followed by the addition heptane
and filtration gave the crude title compound, which was dried and
used directly in the next step.
Example 37F
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-tert-butylphenyl-
)pyrrolidine-2,5-diyl)bis(4,1-phenylene)bis(azanediyl)bis(oxomethylene))bi-
s(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
[0404] To a solution of the product from Example 37E (1.64 g, 4.25
mmol) in DMF (20 ml), the product from Example 37B (2.89 g, 10.63
mmol), and HATU (4.04 g, 10.63 mmol) in DMF (150 mL) was added
triethylamine (1.07 g, 10.63 mmol), and the solution was stirred at
room temperature for 90 min. To the reaction mixture was poured 20
mL of water, and the white precipitate obtained was filtered, and
the solid was washed with water (3.times.5 mL). The solid was blow
dried for 1 h. The crude material was loaded on a silica gel column
and eluted with a gradient starting with ethyl acetate/heptane
(3/7), and ending with pure ethyl acetate. The desired fractions
were combined and solvent distilled off to give a very light yellow
solid, which was dried at 45.degree. C. in a vacuum oven with
nitrogen purge for 15 h to give the title compound (2.3 g, 61%
yield). .sup.1H NMR (400 MHz, DMSO-D6) .delta. ppm 0.88 (d, J=6.61
Hz, 6H) 0.93 (d, J=6.72 Hz, 6H) 1.11 (s, 9H) 1.63 (d, J=5.42 Hz,
2H) 1.80-2.04 (m, 8H) 2.09-2.19 (m, 2H) 2.44-2.47 (m, 2H) 3.52 (s,
6H) 3.59-3.66 (m, 2H) 3.77-3.84 (m, 2H) 4.02 (t, J=8.40 Hz, 2H)
4.42 (dd, J=7.86, 4.83 Hz, 2H) 5.14 (d, J=6.18 Hz, 2H) 6.17 (d,
J=8.67 Hz, 2H) 6.94 (d, J=8.78 Hz, 2H) 7.13 (d, J=8.46 Hz, 4H) 7.31
(d, J=8.35 Hz, 2H) 7.50 (d, J=8.35 Hz, 4H) 9.98 (s, 2H).
[0405] Alternately, the product from example 37E (11.7 g, 85 wt %,
25.8 mmol) and the product from example 37B (15.45 g, 56.7 mmol)
are suspended in EtOAc (117 mL), diisopropylethylamine (18.67 g,
144 mmol) is added and the solution is cooled to 0.degree. C. In a
separate flask, 1-propanephosphonic acid cyclic anhydride
(T3P.RTM.) (46.0 g, 50 wt % in EtOAc, 72.2 mmol) was dissolved in
EtOAc (58.5 mL), and charged to an addition funnel. The T.sub.3P
solution is added to the reaction mixture drop-wise over 3-4 h and
stirred until the reaction is complete. The reaction is warmed to
room temperature, and washed with 1M HCl/7.5 wt % NaCl (100 mL),
then washed with 5% NaHCO.sub.3 (100 mL), then washed with 5% NaCl
solution (100 mL). The solution was concentrated to approximately
60 mL, EtOH (300 mL) was added, and the solution was concentrated
to 84 g solution.
[0406] A portion of the EtOH solution of product (29 g) was heated
to 40.degree. C., and added 134 g 40 w % EtOH in H.sub.2O. A slurry
of seeds in 58 wt/wt % EtOH/H.sub.2O was added, allowed to stir at
35-40.degree. C. (e.g, at 35 or 40.degree. C.) for several hours,
then cooled to 0.degree. C. The slurry was then filtered, and
washed with 58 wt/wt % EtOH/H.sub.2O. The product was dried at
40-60.degree. C. (e.g., 40.degree. C.) under vacuum, and then
rehydrated by placing a tray of water in the vacuum oven (or in a
tray dryer using 40.degree. C. and a humidified atmosphere) to give
the title compound in a hydrate crystalline form (Hydrate B).
[0407] The seeds described above was a EtOH--H.sub.2O solvate of
the title compound and was originally made according to the
following procedure. A solution was first prepared by slurrying the
amorphous, solid title compound in 37 weight % EtOH in heptane at
room temperature. The saturated solution (with respect to the
amorphous solid) was then filtered over to a new vial to give a
clear solution and seeded with partially crystalline solid obtained
from the same solvent system. Crystallization took place within a
few hours to produce the "Anhydrate A" form of the title compound.
Then a solution of 60 w % EtOH in H.sub.2Oat 5.degree. C. was
prepared using the amorphous title compound. To this clear solution
was added seeds of mainly Anhydrate A and desolvated EtOH solvate.
Conversion to the EtOH--H.sub.2O solvate took place within 2 days
to produce the original seeds, which can be used to make additional
seeds.
[0408] The title compound showed an EC.sub.50 value of less than
about 0.1 nM in HCV 1b-Con1 replicon assays in the presence of 5%
FBS.
Example 38
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00272##
[0409] Example 38A
(1S,4S)-1,4-bis(4-nitrophenyl)butane-1,4-diyl
dimethanesulfonate
[0410] The title compound was prepared using the methods from
Example 37C, substituting the product from Example 33 for the
product from Example 32.
Example 38B
(2R,5R)-1-(4-fluorophenyl)-2,5-bis(4-nitrophenyl)pyrrolidine
[0411] The title compound was prepared using the methods from
Example 37D, substituting 4-fluoroaniline for
4-tert-butylaniline.
Example 38C
4,4'-((2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)dianiline
[0412] To a solution of the product from Example 38B (2.34 g, 5.74
mmol) in 1:1 ethanol:THF (60 ml) in a 250 mL stainless steel
pressure bottle was added PtO.sub.2 (0.47 g, 2.06 mmol) and the
resulting mixture was placed under H.sub.2 pressure (30 psi) and
stirred at rt. for 90 min. The mixture was filtered through a nylon
membrane and the filtrate was concentrated in vacuo. The crude
product was purified by column chromatography on silica gel using a
solvent gradient of 0-65% ethyl acetate in hexanes to give the
title compound as a solid (0.736 g, 37%).
Example 38D
(2S,2'S)-tert-butyl
2,2'-(4,4'-((2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1-phenyl-
ene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate
[0413] To a solution of the product from Example 38C (3.54 g, 10.19
mmol), (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid
(5.48 g, 25.5 mmol), and HATU (9.69 g, 25.5 mmol) in anhydrous NMP
(50 mL) was added N,N-diisopropylethylamine (5.29 ml, 30.6 mmol),
and reaction mixture was stirred at room temperature for 30-45
minutes. The reaction mixture diluted with water (500 mL). The
precipitated product was filtered and washed with water
(3.times.100 mL), sodium bicarbonate solution (50 mL), and water
(50 mL). The product dried at 40.degree. C. for 15 h. This material
(8.5 g) was passed through a pad of silica gel and eluted with
ethyl acetate to afford the white solid product (7.9 g, 99%).
Example 38E
(2S,2'S)--N,N'-(4,4'-((2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4-
,1-phenylene))dipyrrolidine-2-carboxamide
[0414] To a solution of the product from Example 38D (7.9 g, 10.65
mmol) in dichloromethane (50 mL), was added 5M HCl solution in
isopropyl alcohol (50 mL) and the reaction mixture was stirred at
room temperature for 16 h. The solvent was evaporated by rotavap
under vacuum and crude material taken in dichloromethane containing
20% methanol (200 mL). The solution was washed with 5% ammonium
hydroxide solution (90 mL), brine (50 mL) and dried over
MgSO.sub.4. The solution was filtered and concentrated to give 6.5
g of crude product. This material was recrystallized from ethyl
acetate /heptane (8/2) to give the title compound (5.0 g, 87%
yield).
Example 38F
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-fluorophenyl)pyr-
rolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(py-
rrolidine-2,1-diyl))bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate
[0415] To a solution of the product from Example 38E (4.14 g, 7.64
mmol), (S)-2-methoxycarbonylamino-3,3-dimethyl-butyric acid (3.62
g, 19.11 mmol), and EDAC (3.66 g, 19.11 mmol) in anhydrous DMF (80
mL) was added N,N-diisopropylethylamine (2.96 g, 22.93 mmol) and
the solution was stirred at room temperature for 4 h. The reaction
mixture poured into 400 mL of water, and the white precipitate
obtained was filtered and washed with water (3.times.50 mL), sodium
bicarbonate (50 mL), water (50 ML), and dried at 45.degree. C. in a
vacuum oven with nitrogen purge for 15 h to give 7.0 g of the crude
product. The crude material was loaded on silica gel column (150 g
silica) and eluted with a gradient starting with ethyl
acetate/heptane (7/3), and ending with ethyl acetate. Desired
fractions were combined and solvent distilled off to give very
light yellow oil, which was triturated MTBE /heptane(1:9) for 1 h.
The white solid thus obtained was filtered and dried in a vacuum
oven with nitrogen purge to afford 6.1 g of product. The solid 5.5
g was dissolved in 16 mL of methanol and this solution was added
into water (220 mL) in a 500 mL flask. The slurry was stirred for
30 minutes, and the solid was collected by filtration, dried at
45.degree. C. with nitrogen purge for 15 h to give the title
compound (5.4 g). .sup.1H NMR (400 MHz, DMSO-D6) .delta. ppm 0.96
(s, 18H) 1.64 (d, J=5.53 Hz, 2H) 1.78-1.93 (m, 6H) 1.94-2.06 (m,
2H) 2.09-2.21 (m, 2H) 3.54 (s, 6H) 3.59-3.69 (m, 2H) 3.72-3.83 (m,
2H) 4.20 (d, J=8.89 Hz, 2H) 4.43 (dd, J=7.92, 5.42 Hz, 2H) 5.16 (d,
J=6.29 Hz, 2H) 6.20 (dd, J=9.16, 4.39 Hz, 2H) 6.77 (t, J=8.95 Hz,
2H) 7.12 (d, J=8.57 Hz, 4H) 7.50 (d, J=8.57 Hz, 4H) 9.99 (s, 2H).
The title compound showed an EC.sub.50 value of less than about 0.1
nM in HCV 1b-Con1 replicon assays in the presence of 5% FBS.
Example 39
N-(methoxycarbonyl)-L-valyl-N-(4-{(2S,5S)-1-(4-fluorophenyl)-5-[4-(2-{(2S)-
-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-4-yl)phenyl]p-
yrrolidin-2-yl}phenyl)-L-prolinamide (ACD v12) and
N-(methoxycarbonyl)-L-valyl-N-(4-{(2R,5R)-1-(4-fluorophenyl)-5-[4-(2-{(2S)-
-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-4-yl)phenyl]p-
yrrolidin-2-yl}phenyl)-L-prolinamide (ACD v12)
##STR00273##
[0416] Example 39A
1-(4-bromophenyl)-4-(4-nitrophenyl)butane-1,4-dione
[0417] Added benzene (108 mL) to anhydrous zinc(II) chloride (19.62
g, 144 mmol), followed by the addition of diethylamine (11.16 mL,
108 mmol) and 2-methylpropan-2-ol (10.32 mL, 108 mmol) and stirred
at room temperature for 2 h. Added
2-bromo-1-(4-bromophenyl)ethanone (20 g, 72.0 mmol) and
1-(4-nitrophenyl)ethanone (17.83 g, 108 mmol) together and stirred
mixture for 18 h. Added 5% aq. sulfuric acid (50 mL) and stirred
vigorously, then the product was collected by filtration, rinsed
with benzene, water, methanol, dichloromethane and dried under
vacuum to provide the product (15.0 g, 58% yield, colorless
powder).
Example 39B
1-(4-bromophenyl)-4-(4-nitrophenyl)butane-1,4-diol
[0418] Dissolved the product from Example 39A (3.64 g, 10.05 mmol)
in ethanol (67 mL) and added sodium borohydride (0.837 g, 22.11
mmol) portionwise. After stirring for 1 h at room temperature, the
mixture was filtered through celite and washed with methanol and
ethyl acetate and the filtrate concentrated to a solid. The solid
was dissolved in ethyl acetate (200 mL) and extracted with IN aq.
HCl (200 mL), then brine and the organic layer dried and
concentrated to a colorless oil (3.68 g, 100%) that was used
directly in the next reaction.
Example 39C
1-(4-bromophenyl)-4-(4-nitrophenyl)butane-1,4-diyl
dimethanesulfonate
[0419] Dissolved the product from Example 39B (3.68 g, 10.05 mmol)
in dichloromethane (167 mL) and cooled the solution in an ice bath
followed by the addition of triethylamine (4.20 mL, 30.1 mmol) and
methanesulfonyl chloride (1.96 mL, 25.1 mmol) dropwise. After
stirring for 15 min, the solution was concentrated to a solid (5.25
g, 100%) that was used directly in the next reaction.
Example 39D
2-(4-bromophenyl)-1-(4-fluorophenyl)-5-(4-nitrophenyl)pyrrolidine
[0420] Dissolved the product from Example 39C (5.25 g, 10.05 mmol)
in DMF (31 mL) and then added 4-fluoroaniline (9.65 mL, 101 mmol)
and heated solution at 50.degree. C. for 18 h. Solution was cooled
to room temperature and IN aq. HCl added (100 mL) then extracted
with ethyl acetate (2.times.200 mL), then combined organic extracts
washed with brine, dried and concentrated to an amber oil to which
methanol (10 mL) was added and after 3 h a yellow solid (1.05 g,
24%) resulted as the title compound as a 1/1 mixture of trans
pyrrolidine isomers.
Example 39E
1-(4-fluorophenyl)-2-(4-nitrophenyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)phenyl)pyrrolidine
[0421] Dissolved the product from Example 39D (1.05 g, 2.38 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.725
g, 2.86 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.194
g, 0.238 mmol), and potassium acetate (0.35 g, 3.57 mmol) in
dioxane (20 mL) and then bubbled nitrogen gas through the solution
for 10 min, then heated at 100.degree. C. for 1.5 h. Solution was
cooled to room temperature then filtered through celite and washed
with ethyl acetate (20 mL). The filtrate was dried, concentrated
and the residue purified by column chromatography on silica gel,
eluting with a solvent gradient of 10-50% ethyl acetate in hexane
to give the title compound (1.09 g, 94%) as a yellow solid and a
1/1 mixture of trans stereoisomers.
Example 39F
(2S)-tert-butyl
2-(4-(4-(1-(4-fluorophenyl)-5-(4-nitrophenyl)pyrrolidin-2-yl)phenyl)-1H-i-
midazol-2-yl)pyrrolidine-1-carboxylate
[0422] Dissolved the product from Example 39E (1.05 g, 2.15 mmol),
the product from Example 26D (0.748 g, 2.365 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.176
g, 0.215 mmol) in a mixture of toluene (10 mL), ethanol (10 mL) and
a IN aq. sodium bicarbonate solution (2.58 mL, 2.58 mmol) and
bubbled nitrogen gas through the solution for 10 min, then heated
at 90.degree. C. for 3 h. Solution was cooled to room temperature
and water (20 mL) added then extracted with dichloromethane (50
mL), then dried, concentrated and the residue purified by column
chromatography on silica gel, eluting with a solvent gradient of
0-100% ethyl acetate in hexane to give the title compound (0.28 g,
72%) as a yellow solid and a 1/1 mixture of trans
stereoisomers.
Example 39G
(2S)-tert-butyl
2-(4-(4-(5-(4-aminophenyl)-1-(4-fluorophenyl)pyrrolidin-2-yl)phenyl)-1H-i-
midazol-2-yl)pyrrolidine-1-carboxylate
[0423] Dissolved the product from Example 39F (300 mg, 0.502 mmol)
in ethanol (5 mL) and THF (5 mL) then added platinum(IV) oxide
(22.8 mg, 0.1 mmol) and a hydrogen balloon and stirred the solution
at room temperature for 2.5 h. Solution was filtered through celite
and washed with methanol (10 mL), then concentrated to give the
title compound (285 mg, 100%) as a colorless semi-solid and a 1/1
mixture of stereoisomers.
Example 39H
(2S)-tert-butyl
2-(4-(5-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-4--
yl)phenyl)-1-(4-fluorophenyl)pyrrolidin-2-yl)phenylcarbamoyl)pyrrolidine-1-
-carboxylate
[0424] Dissolved the product from Example 39G (285 mg, 0.502 mmol),
(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (162 mg,
0.753 mmol), HATU (305 mg, 0.803 mmol) and Hunig's base (0.263 mL,
1.506 mmol) in DMSO (5 mL) and stirred at room temperature for 1 h.
Dichloromethane (50 mL) was added followed by extraction with water
(2.times.50 mL), the organic extract dried, concentrated and the
residue dissolved in methanol (10 mL) followed by the addition of
potassium carbonate (400 mg, 2.89 mmol) and stirred the bright
yellow solution at room temperature for 30 min. The solution was
then filtered and the filtrate concentrated to an oil, which was
dissolved in a 95/5 dichloromethane/methanol mixture (50 mL) and
extracted with water (20 mL). The organic extract was dried and
concentrated to give the title product (350 mg, 91%) as a light
yellow solid and a 1/1 mixture of stereoisomers.
Example 391
(2S)--N-(4-(1-(4-fluorophenyl)-5-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-
-yl)phenyl)pyrrolidin-2-yl)phenyl)pyrrolidine-2-carboxamide
hydrochloride salt
[0425] Dissolved the product from Example 39H (350 mg, 0.458 mmol)
in 4M hydrochloric acid in dioxane solution (6 mL) and stirred the
solution at room temperature for 30 min then concentrated the
mixture under high vacuum to a solid (approx. 310 mg) as a
hydrochloride salt that was used directly in the next reaction.
Example 39J
N-(methoxycarbonyl)-L-valyl-N-(4-{(2S,5S)-1-(4-fluorophenyl)-5-[4-(2-{(2S)-
-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-4-yl)phenyl]p-
yrrolidin-2-yl}phenyl)-L-prolinamide (ACD v12) and
N-(methoxycarbonyl)-L-valyl-N-(4-{(2R,5R)-1-(4-fluorophenyl)-5-[4-(2-{(2S)-
-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-4-yl)phenyl]p-
yrrolidin-2-yl}phenyl)-L-prolinamide (ACD v12)
[0426] To a mixture of the product from Example 391 (300 mg, 0.45
mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (173 mg,
0.99 mmol), and HATU (428 mg, 1.125 mmol) in DMSO (5 ml) was added
Hunig's base (0.786 mL, 4.5 mmol), and the reaction was stirred at
room temperature for 1 h. Dichloromethane (50 mL) was added
followed by extraction with water (2.times.25 mL), the organic
extract dried, concentrated and the residue dissolved in methanol
(15 mL) followed by the addition of potassium carbonate (300 mg,
2.17 mmol) and stirred at room temperature for 20 min. The solution
was then filtered and the filtrate concentrated to an oil, which
was dissolved in a 95/5 dichloromethane/methanol mixture (50 mL)
and extracted with water (20 mL). The organic extract was dried and
concentrated, and the residue purified by column chromatography on
silica gel, eluting with a solvent gradient of 0-25% methanol in
dichloromethane to give the title compounds (0.13 g, 33%) as a
colorless solid and as a 1/1 mixture of diastereomers. .sup.1H NMR
(400 MHz, DMSO-D6) .delta. ppm 11.64 (s, 1H), 9.94 (s, 1H), 7.57
(d, J=8.1 Hz, 2H), 7.47 (m, 3H), 7.33 (d, J=1.7 Hz, 1H), 7.24 (m,
2H), 7.08 (m, 4H), 6.72 (m, 2H), 6.17 (m, 2H), 5.15 (m, 2H), 5.01
(m, 1H), 4.38 (m, 1H), 4.0 (m, 2H), 3.75 (m, 2H), 3.56 (m, 1H),
3.48 (s, 3H), 3.47 (s, 3H), 2.06 (m, 2H), 1.87 (m, 8H), 1.63 (m,
2H), 0.82 (in, 12H). The title compound showed an EC.sub.50 value
of less than about 0.1 nM in HCV 1b-Con1 replicon assays in the
presence of 5% FBS.
Example 40
N-(methoxycarbonyl)-L-valyl-N-(4-{(2S,5S)-1-(4-tert-butylphenyl)-5-[4-(2-{-
(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-4-yl)phen-
yl]pyrrolidin-2-yl}phenyl)-L-prolinamide (ACD v12) and
N-(methoxycarbonyl)-L-valyl-N-(4-{(2R,5R)-1-(4-tert-butylphenyl)-5-[4-(2-{-
(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-4-yl)phen-
yl]pyrrolidin-2-yl}phenyl)-L-prolinamide (ACD v12)
##STR00274##
[0427] Example 40A
2-(4-bromophenyl)-1-(4-tert-butylphenyl)-5-(4-nitrophenyl)pyrrolidine
[0428] The product from Example 39C (10.86 g, 20.79 mmol), DMF (65
mL) and 4-tert-butylaniline (26.5 mL, 166 mmol) was reacted
according to the procedure in Example 39D to provide the title
compound (5.0 g, 50%, yellow solid) as a mixture of cis and trans
pyrrolidine stereoisomers.
Example 40B
1-(4-tert-butylphenyl)-2-(4-nitrophenyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-d-
ioxaborolan-2-yl)phenyl)pyrrolidine
[0429] The product from Example 40A (2.0 g, 4.17 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.27
g, 5.01 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.681
g, 0.834 mmol), and potassium acetate (0.614 g, 6.26 mmol) in
dioxane (35 mL) was reacted according to the procedure in Example
39E to provide the title compound (1.5 g, 68%, yellow solid) as a
mixture of stereoisomers.
Example 40C
(2S)-tert-butyl
2-(4-(4-(1-(4-tert-butylphenyl)-5-(4-nitrophenyl)pyrrolidin-2-yl)phenyl)--
1H-imidazol-2-yl)pyrrolidine-1-carboxylate
[0430] The product from Example 40B (0.7 g, 1.33 mmol),
(S)-tert-butyl
2-(4-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.462 g,
1.463 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.109
g, 0.133 mmol) in a mixture of toluene (6 mL), ethanol (6 mL) and a
IN aq. sodium bicarbonate solution (1.6 mL, 1.6 mmol) was reacted
according to the procedure in Example 39F to provide the title
compound (0.66 g, 78%, yellow solid) as a mixture of
stereoisomers.
Example 40D
(2S)-tert-butyl
2-(4-(4-(5-(4-aminophenyl)-1-(4-tert-butylphenyl)pyrrolidin-2-yl)phenyl)--
1H-imidazol-2-yl)pyrrolidine-1-carboxylate
[0431] The product from example 40C (1.37 g, 2.153 mmol), in
ethanol (10 mL) and THF (10 mL) then added platinum(IV) oxide (196
mg, 0.862 mmol) and a hydrogen balloon and stirred the solution at
room temperature for 48 h. The reaction was then treated according
to the procedure in Example 39G to provide the title compound (1.3
g, 100%) as a mixture of stereoisomers.
Example 40E
(2R)-tert-butyl
2-(4-(5-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-4--
yl)phenyl)-1-(4-tert-butylphenyl)pyrrolidin-2-yl)phenylcarbamoyl)pyrrolidi-
ne-1-carboxylate
[0432] The product from Example 40D (1.3 g, 2.146 mmol),
(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.386 g,
6.44 mmol), HATU (1.305 g, 3.43 mmol) and Hunig's base (1.124 mL,
6.44 mmol) in DMSO (20 mL) was reacted according to the procedure
in Example 39H to provide the title compound (1.01 g, 59%) as a
mixture of stereoisomers.
Example 40F
(2R)--N-(4-(1-(4-tert-butylphenyl)-5-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidaz-
ol-4-yl)phenyl)pyrrolidin-2-yl)phenyl)pyrrolidine-2-carboxamide
hydrochloride salt
[0433] The product from Example 40E (610 mg, 0.76 mmol), in 2M
hydrochloric acid in dioxane solution (10 mL) was reacted according
to the procedure in Example 391 to provide the title compound (495
mg) as a hydrochloride salt and a mixture of stereoisomers.
Example 40G
N-(methoxycarbonyl)-L-valyl-N-(4-{(2S,5S)-1-(4-tert-butylphenyl)-5-[4-(2-{-
(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-4-yl)phen-
yl]pyrrolidin-2-yl}phenyl)-L-prolinamide (ACD v12) and
N-(methoxycarbonyl)-L-valyl-N-(4-{(2R,5R)-1-(4-tert-butylphenyl)-5-[4-(2-{-
(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-4-yl)phen-
yl]pyrrolidin-2-yl}phenyl)-L-prolinamide (ACD v12)
[0434] The product from Example 40F (372 mg, 0.617 mmol),
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (324 mg, 1.851
mmol), HATU (821 mg, 2.16 mmol) in DMSO (6 ml) and Hunig's base
(1.078 ml, 6.17 mmol) was reacted according to the procedure in
Example 39J then the reaction was diluted with acetonitrile and
water (0.1% TFA) and purified by reversed phase chromatography
(C18), eluting with 10-100% acetonitrile in water (0.1% TFA) to
give the title compounds (68 mg, 12% yield, white solid) as a 1/1
mixture of diastereomers. .sup.1H NMR (free base) (400 MHz,
DMSO-D6) .delta. ppm 0.80-0.96 (m, 12H), 1.10 (s, 9H), 1.65 (d,
J=6.07 Hz, 2H), 1.82-2.04 (m, 8H), 2.07-2.20 (m, 3H), 3.52 (s, 3H),
3.53 (s, 3H), 3.58-3.66 (m, 2H), 3.73-3.85 (m, 3H), 3.99-4.08 (m,
2H), 4.43 (dd, J=7.97, 4.93 Hz, 1H), 5.06 (dd, J=6.99, 2.87 Hz,
1H), 5.17 (d, J=6.40 Hz, 2H), 6.20 (d, J=8.89 Hz, 2H), 6.93 (d,
J=8.89 Hz, 2H), 7.14 (dd, J=8.51, 2.87 Hz, 4H), 7.30 (t, J=9.11 Hz,
2H), 7.37 (d, J=1.84 Hz, 1H), 7.50 (d, J=8.02 Hz, 2H), 7.61 (d,
J=8.13 Hz, 2H), 9.98 (s, 1H), 11.68 (s, 1H). The title compound
showed an EC.sub.50 value of less than about 0.1 nM in HCV 1b-Con1
replicon assays in the presence of 5% FBS.
Example 41
N-(methoxycarbonyl)-L-valyl-N-(4-{(2S,5R)-1-(4-tert-butylphenyl)-5-[4-(2-{-
(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-4-yl)phen-
yl]pyrrolidin-2-yl}phenyl)-L-prolinamide (ACD v12)
##STR00275##
[0436] To the product from Example 40F (493 mg, 0.818 mmol),
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (430 mg, 2.454
mmol), HATU (1088 mg, 2.86 mmol) in DMSO (8.2 mL) and Hunig's base
(1.5 mL, 8.59 mmol) was reacted according to the procedure in
Example 39J then the residue was diluted with acetonitrile and
water (0.1% TFA) and purified by reversed phase chromatography
(C18), eluting with 10-100% acetonitrile in water (0.1% TFA) to
give the title compound (80 mg, 11% yield, white solid). .sup.1H
NMR (free base) (400 MHz, DMSO-D6) .delta. ppm 0.89-1.04 (m, 12H),
1.20 (s, 9H), 1.86-2.12 (m, 10H), 2.15-2.27 (m, 3H), 2.43-2.49 (m,
2H), 3.60 (s, 3H), 3.61 (s, 3H), 3.66-3.74 (m, 1H), 3.81-3.93 (m,
2H), 4.06-4.15 (m, 2H), 4.52 (dd, J=7.86, 4.61 Hz, 1H), 4.74 (d,
J=5.20 Hz, 2H), 5.14 (dd, J=6.99, 3.31 Hz, 1H), 6.40 (d, J=8.78 Hz,
2H), 7.06-7.11 (m, 2H), 7.32-7.41 (m, 2H), 7.47 (d, J=1.73 Hz, 1H),
7.51 (d, J=7.81 Hz, 4H), 7.65 (d, J=8.46 Hz, 2H), 7.77 (d, J=8.24
Hz, 2H), 10.10 (s, 1H), 11.76 (s, 1H). The title compound showed an
EC.sub.50 value of less than about 0.1 nM in HCV 1b-Con1 replicon
assays in the presence of 5% FBS.
Example 42
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,5S)-1-(4-tert-butyl-
phenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))-
bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
and
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2R,5R)-1-(4-tert-butyl-
phenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))-
bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00276##
[0437] Example 42A
1,4-bis(4-bromophenyl)butane-1,4-diol
[0438] The product from Example 26E (3.42 g, 8.63 mmol) was
subjected to the conditions described in Example 39B to provide the
title product (3.45 g, 100% yield, colorless oil).
Example 42B
1,4-bis(4-bromophenyl)butane-1,4-diyl dimethanesulfonate
[0439] The product from Example 42A (3.45 g, 8.63 mmol) was
subjected to the conditions described in Example 39C to provide the
title product (4.8 g, 100%).
Example 42C
2,5-bis(4-bromophenyl)-1-(4-tert-butylphenyl)pyrrolidine
[0440] The product from Example 42B (5.2 g, 9.35 mmol) was
subjected to the conditions described in Example 39D, substituting
4-tert-butylaniline (11.91 mL, 74.8 mmol) for 4-fluoroaniline to
provide the title product (3.89 g, 81%) as a mixture of
isomers.
Example 42D
1-(4-tert-butylphenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl)pyrrolidine
[0441] Dissolved the product from Example 42C (3.88 g, 7.56 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (6.72
g, 26.5 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.617
g, 0.756 mmol), and potassium acetate (3.34 g, 34.0 mmol) in
dimethoxyethane (70 mL) and bubbled nitrogen gas through the
solution for 10 min, then heated at 85.degree. C. for 1 h. Solution
was cooled to room temperature then filtered through celite and
washed with ethyl acetate (20 mL), the filtrate dried, then
concentrated and the residue purified by column chromatography on
silica gel, eluting with a solvent gradient of 0-10% ethyl acetate
in hexane followed by trituration of the resultant solid with
diethyl ether to give the title compound (1.14 g, 25%) as a 1/1
mixture of trans stereoisomers.
Example 42E
(2S,2'S)-tert-butyl
2,2'-(4,4'-(4,4'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phen-
ylene))bis(1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxylate
[0442] Dissolved the products from Example 42D (0.915 g, 1.506
mmol), the product from Example 26D (1.429 g, 4.52 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.123
g, 0.151 mmol) in a mixture of toluene (7 mL), ethanol (7 mL) and a
2N aq. sodium bicarbonate solution (2.64 mL, 5.28 mmol) and bubbled
nitrogen gas through the solution for 10 min, then heated at
100.degree. C. for 3 h. Solution was cooled to room temperature and
water (20 mL) added then extracted with dichloromethane (50 mL),
then dried, concentrated and the residue purified by column
chromatography on silica gel, eluting with a solvent gradient of
0-80% ethyl acetate in hexane to give the title compound (0.93 g,
75%) as a 1/1 mixture of trans stereoisomers.
Example 42F
(S)-4,4'-(4,4'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phenyle-
ne))bis(2-((S)-pyrrolidin-2-yl)-1H-imidazole) hydrochloride
salt
[0443] To the product from Example 42E (1.11 g, 1.344 mmol), in 4M
hydrochloric acid in dioxane solution (5 mL) was reacted according
to the procedure in Example 391 to provide the title compound (1.12
g) as a hydrochloride salt and a mixture of stereoisomers.
Example 42G
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,5S)-1-(4-tert-butyl-
phenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))-
bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
and
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2R,5R)-1-(4-tert-butyl-
phenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))-
bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
[0444] To a mixture of the products from Example 42F (1.04 g, 1.662
mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.728 g,
4.15 mmol), and HATU (1.295 g, 3.41 mmol) in DMSO (20 mL) was added
Hunig's base (2.322 mL, 13.29 mmol), and the reaction was stirred
at room temperature for 1 h. Water (20 mL) was added to form a
solid that was dissolved in dichloromethane and purified by column
chromatography on silica gel, eluting with a solvent gradient of
0-5% methanol in dichloromethane to give a solid that was diluted
with acetonitrile and water (0.1% TFA) and further purified by
reversed phase chromatography (C18), eluting with 10-100%
acetonitrile in water (0.1% TFA) to give the title compound (92 mg,
6% yield, white solid) as a 1/1 mixture of diastereomers. .sup.1H
NMR (free base) (400 MHz, DMSO-D6) .delta. ppm 0.78-0.92 (m, 12H),
1.09 (s, 9H), 1.63-1.74 (m, 2H), 1.85-2.00 (m, 6H), 2.05-2.16 (m,
2H), 3.44-3.50 (m, 4H), 3.52 (s, 6H), 3.70-3.82 (m, 4H), 4.02-4.09
(m, 2H), 5.04 (dd, J=6.67, 3.20 Hz, 2H), 5.19 (t, J=6.18 Hz, 2H),
6.21 (d, J=8.57 Hz, 2H), 6.91 (dd, J=7.16, 1.63 Hz, 2H), 7.14 (dd,
J=8.19, 2.22 Hz, 4H), 7.20-7.30 (m, 2H), 7.36 (d, J=1.19 Hz, 2H),
7.61 (d, J=8.13 Hz, 4H), 11.67 (d, J=4.01 Hz, 2H). The title
compound showed an EC.sub.50 value of less than about 0.1 nM in HCV
1b-Con1 replicon assays in the presence of 5% FBS.
Example 43
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2R,5R)-1-(4-tert-butyl-
phenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))-
bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00277##
[0446] The product from Example 42G was purified by chiral
chromatography on a Chirapak IB column eluting with a mixture of
hexane/THF/MeOH (80/10/10). The title compound was the first of 2
diastereomers to elute. .sup.1H NMR (400 MHz, DMSO-D6) .delta. ppm
0.78-0.92 (m, 12H), 1.09 (s, 9H), 1.63-1.74 (m, 2H), 1.85-2.00 (m,
6H), 2.05-2.16 (m, 2H), 3.44-3.50 (m, 4H), 3.52 (s, 6H), 3.70-3.82
(m, 4H), 4.02-4.09 (m, 2H), 5.04 (dd, J=6.67, 3.20 Hz, 2H), 5.19
(t, J=6.18 Hz, 2H), 6.21 (d, J=8.57 Hz, 2H), 6.91 (dd, J=7.16, 1.63
Hz, 2H), 7.14 (dd, J=8.19, 2.22 Hz, 4H), 7.20-7.30 (m, 2H), 7.36
(d, J=1.19 Hz, 2H), 7.61 (d, J=8.13 Hz, 4H), 11.67 (d, J=4.01 Hz,
2H). The title compound showed an EC.sub.50 value of less than
about 0.1 nM in HCV 1b-Con1 replicon assays in the presence of 5%
FBS.
Example 44
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,5S)-1-(4-tert-butyl-
phenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))-
bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00278##
[0448] The product from Example 42G was purified by chiral
chromatography on a Chirapak IB column eluting with a mixture of
hexane/THF/MeOH (80/10/10). The title compound was the second of 2
diastereomers to elute. .sup.1H NMR (400 MHz, DMSO-D6) .delta. ppm
0.78-0.92 (m, 12H), 1.09 (s, 9H), 1.63-1.74 (m, 2H), 1.85-2.00 (m,
6H), 2.05-2.16 (m, 2H), 3.44-3.50 (m, 4H), 3.52 (s, 6H), 3.70-3.82
(m, 4H), 4.02-4.09 (m, 2H), 5.04 (dd, J=6.67, 3.20 Hz, 2H), 5.19
(t, J=6.18 Hz, 2H), 6.21 (d, J=8.57 Hz, 2H), 6.91 (dd, J=7.16, 1.63
Hz, 2H), 7.14 (dd, J=8.19, 2.22 Hz, 4H), 7.20-7.30 (m, 2H), 7.36
(d, J=1.19 Hz, 2H), 7.61 (d, J=8.13 Hz, 4H), 11.67 (d, J=4.01 Hz,
2H). The title compound showed an EC.sub.50 value of less than
about 0.1 nM in HCV 1b-Con1 replicon assays in the presence of 5%
FBS.
Example 45
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,5S)-1-(4-fluorophen-
yl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))bis(-
pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
and
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2R,5R)-1-(4-fluorophen-
yl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))bis(-
pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00279##
[0449] Example 45A
2,5-bis(4-bromophenyl)-1-(4-fluorophenyl)pyrrolidine
[0450] The product from Example 42B (5.2 g, 9.35 mmol) was
subjected to the conditions described in Example 39D to provide the
title product (6.41 g, 48%) as a mixture of cis and trans
isomers.
Example 45B
1-(4-fluorophenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl)pyrrolidine
[0451] The product from Example 45A (2.17 g, 4.57 mmol) was
subjected to the conditions described in Example 42D and purified
by column chromatography on silica gel, eluting with a solvent
gradient of 0-15% ethyl acetate in hexane to give the title
compound (1.65 g, 64%) as a mixture of cis and trans
stereoisomers.
Example 45C
(2S,2'S)-tert-butyl
2,2'-(4,4'-(4,4'-(1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylen-
e))bis(1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxylate
[0452] The product from Example 45B (1.0 g, 1.756 mmol) was
subjected to the conditions described in Example 42E to provide the
title product (1.0 g, 72%) as a mixture of cis and trans
isomers.
Example 45D
(S)-4,4'-(4,4'-(1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))-
bis(2-((S)-pyrrolidin-2-yl)-1H-imidazole)
[0453] Dissolved the product from Example 45C (150 mg, 0.19 mmol)
in dichloromethane (1 mL) and TFA (1 mL) and stirred the solution
at room temperature for 1 h then concentrated the mixture under
high vacuum to give a solid that was diluted with acetonitrile and
water (0.1% TFA) and purified by reversed phase chromatography
(C18), eluting with 10-100% acetonitrile in water (0.1% TFA) to
give the title compound (62 mg, 55% yield) as a 1/1 mixture of
trans diastereomers that eluted before the cis isomer.
Example 45E
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,5S)-1-(4-fluorophen-
yl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))bis(-
pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
and
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2R,5R)-1-(4-fluorophen-
yl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))bis(-
pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
[0454] To a mixture of the product from Example 45D (47 mg, 0.08
mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (29 mg,
0.168 mmol), and HATU (61 mg, 0.16 mmol) in DMSO (0.8 mL) was added
Hunig's base (0.035 mL, 0.2 mmol) was reacted according to the
procedure in Example 39J then the residue was diluted with
acetonitrile and water (0.1% TFA) and purified by reversed phase
chromatography (C18), eluting with 10-100% acetonitrile in water
(0.1% TFA) to give the title compound (54 mg, 75% yield, white
solid) as a 1/1 mixture of diastereomers. .sup.1H NMR (free base)
(400 MHz, DMSO-D6) .delta. ppm 11.62-12.13 (m, 2H), 7.59-7.71 (m,
J=8.13 Hz, 3H), 7.46-7.57 (m, J=8.24 Hz, 1H), 7.38 (d, J=1.84 Hz,
2H), 7.10-7.32 (m, 6H), 6.72-6.83 (m, 2H), 6.19-6.31 (m, 2H),
5.17-5.28 (m, 2H), 5.02-5.11 (m, J=6.72 Hz, 2H), 4.05 (t, J=8.40
Hz, 2H), 3.71-3.85 (m, 4H), 3.53 (s, 6H), 2.05-2.21 (m, 4H), 1.94
(s, 6H), 1.64-1.78 (m, 2H), 0.77-0.95 (m, 12H). The title compound
showed an EC.sub.50 value of less than about 0.1 nM in HCV 1b-Con1
replicon assays in the presence of 5% FBS.
Example 46
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2R,5R)-1-(4-fluorophen-
yl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))bis(-
pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00280##
[0456] The product from Example 45E was purified by chiral
chromatography on a Chirapak IB column eluting with a mixture of
hexane/THF/MeOH (85/7.5/7.5). .sup.1H NMR (400 MHz, DMSO-D6)
.delta. ppm 11.62-12.13 (m, 2H), 7.59-7.71 (m, J=8.13 Hz, 3H),
7.46-7.57 (m, J=8.24 Hz, 1H), 7.38 (d, J=1.84 Hz, 2H), 7.10-7.32
(m, 6H), 6.72-6.83 (m, 2H), 6.19-6.31 (m, 2H), 5.17-5.28 (m, 2H),
5.02-5.11 (m, J=6.72 Hz, 2H), 4.05 (t, J=8.40 Hz, 2H), 3.71-3.85
(m, 4H), 3.53 (s, 6H), 2.05-2.21 (m, 4H), 1.94 (s, 6H), 1.64-1.78
(m, 2H), 0.77-0.95 (m, 12H). The title compound showed an EC.sub.50
value of less than about 0.1 nM in HCV 1b-Con1 replicon assays in
the presence of 5% FBS.
Example 47
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,5S)-1-(4-fluorophen-
yl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))bis(-
pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00281##
[0458] The product from Example 45E was purified by chiral
chromatography on a Chirapak IB column eluting with a mixture of
hexane/THF/MeOH (85/7.5/7.5). .sup.1H NMR (400 MHz, DMSO-D6)
.delta. ppm 11.62-12.13 (m, 2H), 7.59-7.71 (m, J=8.13 Hz, 3H),
7.46-7.57 (m, J=8.24 Hz, 1H), 7.38 (d, J=1.84 Hz, 2H), 7.10-7.32
(m, 6H), 6.72-6.83 (m, 2H), 6.19-6.31 (m, 2H), 5.17-5.28 (m, 2H),
5.02-5.11 (m, J=6.72 Hz, 2H), 4.05 (t, J=8.40 Hz, 2H), 3.71-3.85
(m, 4H), 3.53 (s, 6H), 2.05-2.21 (m, 4H), 1.94 (s, 6H), 1.64-1.78
(m, 2H), 0.77-0.95 (m, 12H). The title compound showed an EC.sub.50
value of less than about 0.1 nM in HCV 1b-Con1 replicon assays in
the presence of 5% FBS.
Example 48
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,3R,4R,5S)-1-(4-tert-
-butylphenyl)-3,4-dimethoxypyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1H--
imidazole-4,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-
-diyl)dicarbamate
##STR00282##
[0459] Example 48A
(2S,3R,4R,5S)-2,5-bis(4-(benzyloxy)phenyl)-1-(4-tert-butylphenyl)pyrrolidi-
ne-3,4-diol
[0460] To a solution of
(1R,1'R)-1,1'-((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)diethane-1,2-d-
iol (200 mg, 0.90 mmol) in methanol (6 ml) and dichloromethane (3
ml) was added iodobenzene diacetate (696 mg, 2.16 mmol) and the
solution was stirred at room temperature for 5 h. Solution was
concentrated and to the residue was added 0.1M H.sub.2SO.sub.4 (4
ml) and stirring was continued at room temperature for 18 h. The pH
was adjusted to .about.6 with solid NaHCO.sub.3, and
4-tert-butylaniline (287 .mu.l, 1.80 mmol) was added followed by
4-benzyloxyphenylboronic acid (369 mg, 1.62 mmol) and
hexafluoroisopropyl alcohol (4 ml) and stirred at 60.degree. C. for
2 h. Solvent was concentrated and the residue dissolved in ethyl
acetate, washed with H.sub.20, 0.33 M K.sub.3PO.sub.4, brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated to give crude product
which was purified by chromatography on silica gel eluting with
0-20% ethyl acetate/dichloromethane to give title compound (249 mg,
46%).
Example 48B
(2S,3R,4R,5S)-2,5-bis(4-(benzyloxy)phenyl)-1-(4-tert-butylphenyl)-3,4-dime-
thoxypyrrolidine
[0461] To a solution of the product from Example 48A (200 mg, 0.33
mmol) in THF (2.1 ml) and DMF (0.7 ml) at 0.degree. C. was added,
in portions, sodium hydride, 60% in mineral oil (40.0 mg, 1.0 mmol)
and stirring continued at 0.degree. C. for 20 min. Iodomethane
(0.046 ml, 0.734 mmol) was added and stirring continued at room
temperature overnight. Diluted with ethyl acetate, washed with
saturated NH.sub.4Cl, H.sub.2O, brine, dried (Na.sub.2SO.sub.4),
filtered and concentrated to give crude product which was purified
by chromatography on silica gel eluting with 0-20% ethyl
acetate/dichloromethane to give title compound (170 mg, 80%).
Example 48C
4,4'-((2S,3R,4R,5S)-1-(4-tert-butylphenyl)-3,4-dimethoxypyrrolidine-2,5-di-
yl)diphenol
[0462] To a solution of the product from Example 48B (168 mg, 0.268
mmol) in ethyl acetate (3 ml) was added 10% palladium on carbon (17
mg) and the flask was evacuated and back-filled with H.sub.2 gas.
The solution was stirred under a balloon of H.sub.2 gas for 20 h,
filtered through Celite, and washed with ethyl acetate and
methanol. The filtrate was concentrated and the residue was
azeotroped with ether to give title compound (120 mg, 100%) as a
white solid.
Example 48D
4,4'-((2S,3R,4R,5S)-1-(4-tert-butylphenyl)-3,4-dimethoxypyrrolidine-2,5-di-
yl)bis(4,1-phenylene)
bis(1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate)
[0463] To a solution of the product from Example 48C (117 mg, 0.261
mmol) in DMF (1.3 ml) was added K.sub.2CO.sub.3 (81 mg, 0.588 mmol)
and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (0.101
ml, 0.575 mmol) and the solution was stirred at 100.degree. C. for
1 h. The cooled solution was diluted with ethyl acetate, washed
with H.sub.2O, brine, dried (Na.sub.2SO.sub.4), filtered and
concentrated to give an oil which was purified by chromatography on
silica gel eluting with 0-20% ethyl acetate/hexane to give title
compound (195 mg, 73.7% yield).
Example 48E
(2S,3R,4R,5S)-1-(4-tert-butylphenyl)-3,4-dimethoxy-2,5-bis(4-(4,4,5,5-tetr-
amethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine
[0464] To a pressure tube was added the product from Example 48D
(193 mg, 0.191 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (102
mg, 0.401 mmol),
dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (X-Phos)
(14.55 mg, 0.031 mmol), potassium acetate (112 mg, 1.145 mmol), and
dioxane (1.5 ml) and the solution was degassed with N.sub.2 gas for
30 min. Tris(dibenzylideneacetone)dipalladium(0) (6.99 mg, 7.63
mol) was added and degassing was continued another 10 min. The tube
was sealed and heated with stirring at 100.degree. C. overnight.
The cooled solution was diluted with ethyl acetate, washed with
H.sub.2O, brine, dried (Na.sub.2SO.sub.4), filtered and the
filtrate treated with 3-(mercaptopropyl) silica gel for 1 h. The
solution was filtered and solvent removed to give a yellow solid
which was purified by chromatography on silica gel eluting with
0-20% ethyl acetate/hexane to give title compound (99 mg, 78%
yield) as a white solid.
Example 48F
(2S,2'S)-tert-butyl
2,2'-(4,4'-(4,4'-((2S,3R,4R,5S)-1-(4-tert-butylphenyl)-3,4-dimethoxypyrro-
lidine-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))dipyrrolidin-
e-1-carboxylate
[0465] In a sealed tube was combined the product from Example 48E
(97 mg, 0.145 mmol), the product from Example 26D (115 mg, 0.363
mmol), 1 M Na.sub.2CO.sub.3 (0.363 ml, 0.363 mmol), EtOH (1.0 ml)
and toluene (1.0 ml) and the solution was degassed with N2 gas for
30 min. 1,1'-Bis(diphenylphosphino)ferrocenedichloro palladium(II)
dichloromethane complex (10.63 mg, 0.015 mmol) was added and
degassing was continued an additional 10 min. The tube was sealed
and heated at 100.degree. C. for 3 h. The cooled solution was
diluted with ethyl acetate, filtered through Celite and the residue
washed with ethyl acetate. The filtrate was concentrated in vacuo
and the resulting material was purified chromatography on silica
gel using a 12 g silica gel column eluting with 0-2%
methanol/dichloromethane to give title compound (85 mg, 66.1%
yield).
Example 48G
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-((2S,3R,4R,5S)-1-(4-tert-
-butylphenyl)-3,4-dimethoxypyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1H--
imidazole-4,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-
-diyl)dicarbamate
[0466] To a solution of the product from Example 48F (83 mg, 0.094
mmol) in dichloromethane (1.0 ml) was added TFA (1.0 ml, 12.98
mmol) and the solution was stirred at room temperature for 1 h.
Solvent was concentrated and the residue was azeotroped 2 times
with dichloromethane. The residue was placed under vacuum for 1 h
to remove final traces of TFA. To this residue (64.2 mg, 0.094
mmol) was added DMSO (500 .mu.l) followed by
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (41.1 mg, 0.234
mmol), HATU (89 mg, 0.234 mmol) and hunig's base (82 .mu.l, 0.469
mmol). pH was checked and additional Hunig's base was added to
adjust pH to .about.9. Stirring was continued at room temperature
for 1 h. The solution was diluted with ethyl acetate, washed with
H.sub.2O, brine, dried (Na.sub.2SO.sub.4), filtered and
concentrated to give crude residue. Purification was run by
chromatography on silica gel eluting with 0-4%
methanol/dichloromethane over 60 min to give title compound (7.5
mg, 8.01% yield). 1H NMR (400 MHz, CDCl3) .delta. ppm 0.86 (s, 12H)
1.13 (s, 9H) 1.86-2.02 (m, 2H) 2.02-2.12 (m, 2H) 2.12-2.25 (m, 2H)
2.25-2.41 (m, 1H) 2.90-3.17 (m, 2H) 3.43 (s, 6H) 3.53-3.65 (m, 2H)
3.70 (s, 6H) 3.74-3.89 (m, 2H) 4.16-4.26 (m, 2H) 4.26-4.37 (m, 1H)
5.18-5.26 (m, 2H) 5.26-5.32 (m, 2H) 5.33-5.41 (m, 2H) 6.28 (d,
J=8.78 Hz, 2H) 6.89-6.99 (m, 2H) 7.16 (s, 2H) 7.20 (s, 2H) 7.22 (s,
2H) 7.26 (s, 4H) 7.30-7.48 (br s, 1H) 7.58-7.82 (br s, 2H)
10.08-10.42 (br s, 1H). The title compound showed an EC.sub.50
value of less than about 0.1 nM in HCV 1b-Con1 replicon assays in
the presence of 5% FBS.
Example 49
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-((2S,3R,4R,5S)-1-(4-tert-butyl-
phenyl)-3,4-dimethoxypyrrolidine-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diy-
l))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00283##
[0467] Example 49A
(S)-tert-butyl
2-(2-amino-5-bromophenylcarbamoyl)pyrrolidine-1-carboxylate
[0468] A solution of the 2-amino-4-bromoaniline (6.0 g, 32.1 mmol),
Boc-Pro-OH (6.90 g, 32.1 mmol) and HATU (13.42 g, 35.3 mmol) in dry
DMSO (160 mL) was treated with diisopropylethylamine (14.0 mL, 10.4
g, 80 mmol) followed by stirring at room temperature for 18 h. The
mixture was diluted with ethyl acetate and extracted with water
(3.times.) and saturated sodium chloride solution. Drying
(Na.sub.2SO.sub.4) and concentration in vacuo afforded a brown
solid which was used directly in the next step.
Example 49B
(S)-tert-butyl
2-(5-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate
[0469] A solution of the compound of Example 49A in glatial acetic
acid (75 mL) was warmed at 60.degree. C. for 3 h. The mixture was
cooled and diluted with toluene and concentrated in vacuo. The
remainder of the acetic acid was removed by azeotroping with
toluene (2.times.) and the residue was chromatographed over a 360 g
silica gel cartridge, eluting with 25-75% ethyl acetate in
dichloromethane. These procedures afforded the product (10.0 g,
85%) as a light beige rigid foam.
Example 49C
(S)-tert-butyl
2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-
pyrrolidine-1-carboxylate
[0470] A solution of the compound of Example 49B (2.25 g, 6.14
mmol) in dry THF (25 mL) was treated with sodium hydride (295 mg of
60% in oil, 177 mg, 7.37 mmol) followed by stirring at room
temperature for 1 h. The solution was then treated with
SEM-Chloride (1.20 mL, 1.13 g, 6.76 mmol) followed by stirring at
room temperature for 18 h. The mixture was quenched by addition of
water and the mixture was diluted with ethyl acetate. The mixture
was extracted with water and saturated sodium chloride solution.
Drying (Na.sub.2SO.sub.4) and concentration in vacuo afforded an
oil, which was chromatographed over a 100 g silica gel cartridge,
eluting with 20-75% ethyl acetate in hexanes. These procedures
afforded the product (2.24 g, 73%) as a heavy oil, which solidified
after setting for several days. This mixture of both regioisomeric
SEM derivatives was not separated for use in the next step.
Example 49D
(S)-tert-butyl
2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)-
ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate
[0471] In a resealable pressure tube, a solution of the compound of
Example 49C (2.24 g, 4.51 mmol), bis(pinacolato)diboron (1.26 g,
4.96 mmol), and potassium acetate (1.33 g, 13.53 mmol) in dry
dioxane (23 mL) was degassed by nitrogen sparge for 30 min. The
solution was treated with 1,1'-bis(diphenylphosphino)ferrocene
palladium (II) chloride dichloromethane complex (111 mg, 0.14 mmol)
followed by degassing for another 5 min. The pressure tube was
sealed and warmed at 90.degree. C. for 4 h. The mixture was cooled
and diluted with ethyl acetate, followed by extraction with water
and saturated sodium chloride solution. The solution was dried
(Na.sub.2SO.sub.4) and stirred for 1 h with 3-mercaptopropyl)
silica gel. After filtration and concentration in vacuo the brown
oil was chromatographed over a 100 g silica gel cartridge, eluting
with 15-70% ethyl acetate in dichloromethane. These procedures
afforded the product (1.99 g, 81%) as a white rigid foam.
Example 49E
(S)-tert-butyl
2-(6-((2S,3R,4R,5S)-5-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1-(-
(2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-1-(4-tert-buty-
lphenyl)-3,4-dihydroxypyrrolidin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl-
)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate
[0472] A solution of 2,3-O-isopropylidene-D-mannitol (144 mg, 0.65
mmol) and iodobenzenediacetate (501 mg, 1.56 mmol) in 2:1
methanol-dichloromethane (3 mL) was stirred at room temperature for
5 h. The mixture was concentrated in vacuo to a white paste and
then suspended in 0.1 M sulfuric acid solution (1.0 mL) followed by
stirring at room temperature for 18 h. The solution was adjusted to
pH 6 by addition of solid sodium bicarbonate followed by addition
of 4-tert-butylaniline (206 .mu.L, 193 mg, 1.30 mmol) the product
from Example 49D (634 mg, 1.17 mmol) and hexafluoroisopropyl
alcohol (2.6 mL). The solution was then warmed at 70.degree. C. for
5 h. The solution was cooled and concentrated in vacuo. The residue
was dissolved in ethyl acetate and extracted with 0.33 M tribasic
potassium phosphate solution and saturated sodium chloride
solution. Drying (Na.sub.2SO.sub.4) and concentration in vacuo
afforded a brown oil, which was chromatographed over a 50 g silica
gel cartridge, eluting with 15-85% ethyl acetate in
dichloromethane. These procedures afforded the recovered boronate
(208 mg) as a viscous brown oil. The column was then re-eluted with
0-20% methanol in dichloromethane to afford the product (159 mg,
23%) as a brown solid.
Example 49F
(S)-tert-butyl
2-(6-((2S,3R,4R,5S)-5-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1-(-
(2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-1-(4-tert-buty-
lphenyl)-3,4-dimethoxypyrrolidin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl-
)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate
[0473] A solution of the product from Example 49E (154 mg, 0.14
mol) in dry THF was treated with sodium hydride (13 mg of 60% in
oil, 8 mg, 0.33 mmol) followed by stirring at room temperature for
30 min. The mixture was treated with methyl iodide (19 .mu.L, 43
mg, 0.30 mmol) followed by stirring at room temperature for 2 h.
The mixture was diluted with ethyl acetate and quenched by addition
of water. The mixture was extracted with water and saturated sodium
chloride solution. Drying (Na.sub.2SO.sub.4) and concentration in
vacuo afforded a brown oil, which was chromatographed over a 25 g
silica gel cartridge, eluting with 0-15% methanol in
dichloromethane. These procedures afforded the product (121 mg,
77%) as a beige foam.
Example 49G
(S)-5,5'-((2S,3R,4R,5S)-1-(4-tert-butylphenyl)-3,4-dimethoxypyrrolidine-2,-
5-diyl)bis(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole)
[0474] A solution of the compound of Example 49F (111 mg, 0.10
mmol) in ethanol (1 mL) was treated with 4 N hydrochloric acid
solution (2.0 mL) followed by warming at 60.degree. C. for 18 h.
The solution was cooled and concentrated in vacuo with
ethanol-toluene mixtures (2.times.) to afford the
tetrahydrochloride as a light yellow solid. This material was
dissolved in methanol (3 mL) and stirred with Amberlyte IRA 400
(OH-- form, 1.4 mequiv/g, 577 mg, 0.81 mequiv) for 1 h. The resin
was removed by filtration and the filtrate was concentrated in
vacuo to afford the product (29 mg, 45%) as a light amber
glass.
Example 49H
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(5,5'-((2S,3R,4R,5S)-1-(4-tert-butyl-
phenyl)-3,4-dimethoxypyrrolidine-2,5-diyl)bis(1H-benzo[d]imidazole-5,2-diy-
l))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
[0475] A solution of the compound of Example 49G (29 mg, 0.046
mmol), HOBt hydrate (18 mg, 0.114 mmol), EDAC (22 mg, 0.114 mmol)
and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (20 mg,
0.114 mmol) in dry DMF (0.5 mL) at 0.degree. C. was treated with
N-methylmorpholine (15 .mu.L, 14 mg, 0.137 mmol) followed by
stirring at 0.degree. C. for 30 min and warming to room temperature
for 2 h. The mixture was diluted with ethyl acetate and extracted
with water (3.times.) and saturated sodium chloride solution.
Drying (Na.sub.2SO.sub.4) and concentration in vacuo afforded an
oil which was dissolved in methanol and treated with a small amount
of potassium carbonate. After stirring 1 h, the mixture was
filtered and concentrated in vacuo to afford a yellow oil, which
was chromatographed over a 25 g silica gel cartridge, eluting with
0-15% methanol in dichloromethane to give the product (14 mg, 32%)
as a white solid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.39 (m,
4H), 7.30 (m, 4H), 7.07 (t, J=9.1 Hz, 2H), 6.87 (m, 2H), 6.31 (d,
J=8.9 Hz, 1H), 5.54 (m, 2H), 5.14 (dd, J=7.6, 4.6 Hz, 2H), 4.14 (m,
2H), 3.77 (m, 4H), 3.51 (m, 6H), 3.28 (m, 6H), 2.15 (m, 4H), 1.04
(s, 9H), 0.86 (m, 12H). The title compound showed an EC.sub.50
value of from about 0.1 to about 1 nM in HCV 1b-Con1 replicon
assays in the presence of 5% FBS.
Example 50
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-(1-(4-(pentafluorothio)p-
henyl)-1H-pyrrole-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))b-
is(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
##STR00284##
[0476] Example 50A
2,5-bis(4-bromophenyl)-1-(4-(pentafluorothio)phenyl)-1H-pyrrole
[0477] Title compound was prepared from the product from Example
26E using the methods from Example 26F substituting
4-aminophenylsulfur pentafluoride for 4-tert-butylaniline to
provide the desired compound.
Example 50B
1-(4-(pentafluorothio)phenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl)-1H-pyrrole
[0478] Title compound was prepared using the methods from Example
26G substituting the product from Example 50A for the product from
Example 26F to provide the desired compound.
Example 50C
tert-butyl
2,2'-(4,4'-(4,4'-(1-(4-(pentafluorothio)phenyl)-1H-pyrrole-2,5--
diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxy-
late
[0479] Title compound was prepared using the methods from Example
26H substituting the product from Example 50B for the product from
Example 26G to provide the desired compound.
Example 50D
4,4'-(4,4'-(1-(4-(pentafluorthio)phenyl)-1H-pyrrole-2,5-diyl)bis(4,1-pheny-
lene))bis(2-(pyrrolidin-2-yl)-1H-imidazole)
[0480] Title compound was prepared using the methods from Example
261 substituting the product from Example 50C for the product from
Example 26H to provide the desired compound.
Example 50E
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-(4,4'-(1-(4-(pentafluorothio)p-
henyl)-1H-pyrrole-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))b-
is(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
[0481] Title compound was prepared using the methods from Example
26J substituting the product from Example 50D for the product from
Example 261 to provide the desired compound. .sup.1HNMR (DMSO-d6;
400 MHz): .delta. 11.75 (br s, 2H), 7.88 (m, 2H), 7.56 (app d,
J=8.35 Hz, 4H), 7.45 (br s, 2H), 7.27 (m, 4H), 6.96 (app d, J=8.35
Hz, 4H), 6.50 (s, 2H), 5.04 (m, 2H), 4.03 (m, 2H), 3.78 (m, 4H),
3.53 (s, 6H), 2.11-1.85 (m, 10H), 0.86 (d, J=6.72 Hz, 6H), 0.82 (d,
J=6.72 Hz, 6H). The title compound showed an EC.sub.50 value of
less than about 0.1 nM in HCV 1b-Con1 replicon assays in the
presence of 5% FBS.
##STR00285##
Example 51
dimethyl
([1-(4-fluorophenyl)-1H-pyrrole-2,5-diyl]bis{benzene-4,1-diylcarb-
amoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarb-
amate
[0482] Example 19D (150 mg) and
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid were processed
using the method of Example 19E (substituting DMF as solvent) to
provide the title compound which was purified using gradient silica
gel chromatography (30-70% EtOAc in hexanes)(70 mg). .sup.1H NMR
(500 MHz, DMSO-D6) .delta. 9.76 (s, 2H), 7.16 (d, J=8.7, 4H), 7.06
(d, J=8.4, 2H), 6.92 (t, J=8.7, 2H), 6.83 (dd, J=5.0, 8.9, 2H),
6.71 (d, J=8.7, 4H), 6.14 (s, 2H), 4.15 (dd, J=5.1, 7.9, 2H), 3.77
(t, J=8.5, 2H), 3.59-3.50 (m, 2H), 3.40-3.31 (m, 2H), 3.27 (s, 6H),
1.95-1.82 (m, 2H), 1.79-1.52 (m, 8H), 0.67 (d, J=6.8, 6H), 0.62 (d,
J=6.7, 6H). MS (ESI; M+H) m/z=853.
##STR00286##
Example 52
dimethyl
([1-(4-fluoro-2-methylphenyl)-1H-pyrrole-2,5-diyl]bis{benzene-4,1-
-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimethyl-1-oxobutane-1,2-d-
iyl]})biscarbamate
[0483] Example 1A was processed using 4-fluoro-2-methylaniline and
the methods from Examples 19A, 19B, 19C, 19D, and 51
((S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid was used)
to provide the title compound. .sup.1H NMR (400 MHz, DMSO-D6)
.delta. 9.98 (s, 2H), 7.44-7.36 (m, 5H), 7.09-6.96 (m, 8H), 6.42
(s, 2H), 4.39 (dd, J=5.5, 8.1, 2H), 4.19 (d, J=8.7, 2H), 3.80-3.70
(m, 2H), 3.65-3.56 (m, 2H), 3.52 (s, 6H), 2.20-2.06 (m, 2H),
1.97-1.91 (m, 2H), 1.90-1.76 (m, 4H), 1.63 (s, 3H), 0.94 (s, 18H).
MS (ESI; M+H) m/z=895.
##STR00287##
Example 53
dimethyl
({(2S,5S)-1-[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl}bis{b-
enzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-
-1,2-diyl]})biscarbamate
Example 53A
dimethyl
({(2S,5S)-1-[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl}bis{b-
enzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-
-1,2-diyl]})biscarbamate and
dimethyl
({(2R,5R)-1-[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl}bis{b-
enzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-
-1,2-diyl]})biscarbamate
[0484] To a solution of the product from Example 23B (84 mg, 0.142
mmol) in DMSO (1.5 mL) was added
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (62.2 mg, 0.355
mmol), HATU (135 mg, 0.355 mmol), and Hunig'sBase (0.074 mL, 0.426
mmol), and the resulting mixture was stirred at rt for 90 min and
then partitioned between H.sub.2O (1 mL) and EtOAc (2.times.2 mL).
The combined organic layers were dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The drying agent was filtered
off, and the crude product was purified by column chromatography on
silica gel using a solvent gradient of 1-3% MeOH in
CH.sub.2Cl.sub.2 to give the title compounds as a 1:1 mixture.
Example 53B
dimethyl
({(2S,5S)-1-[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl}bis{b-
enzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-
-1,2-diyl]})biscarbamate
[0485] The product from Example 53A was separated on a Chiralpak
AD-H column using 1:1 hexanes:(1:1 EtOH:2-PrOH). The title compound
was the first component to elute. .sup.1H NMR (400 MHz, DMSO-D6)
.delta. ppm 0.88 (d, J=6.61 Hz, 6H), 0.93 (d, J=6.61 Hz, 6H),
1.63-1.72 (m, 2H), 1.78-2.06 (m, 8H), 2.06-2.20 (m, 2H), 3.52 (s,
6H), 3.56-3.67 (m, 2H), 3.73-3.86 (m, 2H), 4.03 (t, J=8.51 Hz, 2H),
4.42 (dd, J=7.92, 4.88 Hz, 2H), 5.27 (d, J=6.61 Hz, 2H), 6.36 (d,
J=8.67 Hz, 2H), 7.14 (d, J=8.57 Hz, 4H), 7.25 (d, J=8.89 Hz, 2H),
7.31 (d, J=8.35 Hz, 2H), 7.52 (d, J=8.57 Hz, 4H), 10.01 (s, 2H); MS
(ESI) m/z 906.3 (M+H).sup.+.
##STR00288##
Example 54
dimethyl
({(2R,5R)-1-[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl}bis{b-
enzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-
-1,2-diyl]})biscarbamate
[0486] The product from Example 53A was separated on a Chiralpak
AD-H column using 1:1 hexanes:(1:1 EtOH:2-PrOH). The title compound
was the second component to elute. .sup.1H NMR (400 MHz, DMSO-D6)
.delta. ppm 0.87 (d, J=6.61 Hz, 6H), 0.92 (d, J=6.72 Hz, 6H),
1.64-1.74 (m, 2H), 1.78-2.06 (m, 8H), 2.06-2.22 (m, 2H), 3.52 (s,
6H), 3.56-3.67 (m, 2H), 3.75-3.86 (m, 2H), 3.97-4.08 (m, 2H),
4.37-4.48 (m, 2H), 5.28 (d, J=6.51 Hz, 2H), 6.36 (d, J=8.78 Hz,
2H), 7.14 (d, J=8.57 Hz, 4H), 7.25 (d, J=8.89 Hz, 2H), 7.30 (d,
J=8.24 Hz, 2H), 7.52 (d, J=8.57 Hz, 4H), 10.01 (s, 2H); MS (ESI)
m/z 906.3 (M+H).sup.+.
##STR00289##
Example 55
dimethyl
([(2R,5S)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-3,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimethyl-1-oxobutane-1,2-di-
yl]})biscarbamate
Example 55A
1,4-bis(3-nitrophenyl)butane-1,4-dione
[0487] Anhydrous zinc(II) chloride (5.42 g, 39.7 mmol) was stirred
in dry benzene (50 mL) under nitrogen while diethylamine (3.10 mL,
29.8 mmol) and t-butanol (2.85 mL, 29.8 mmol) were added. The
resulting mixture was stirred at room temperature for 90 min to
give a cloudy solution. To this was added 1-(3-nitrophenyl)ethanone
(4.97 g, 29.8 mmol) followed by 2-bromo-1-(3-nitrophenyl)ethanone
(5.00 g, 19.87 mmol) and the resulting mixture allowed to stir at
room temperature overnight. A large portion of the benzene was
subsequently removed by decantation. The resulting mixture was then
treated with 5% sulfuric acid (25 mL) in a separatory funnel and
the aqueous phase drawn off. The organic phase was washed with
water (2.times.25 mL). A third washing resulted in an emulsion. The
contents of the funnel were emptied into a large volume of water
(750 mL) to which was added sodium chloride and the oil in water
mixture rapidly stirred. Methanol was added (75 mL) in portions to
try and disperse the oil and promote solidification of the product.
After nearly forty eight hours of stirring the product solidified
and was collected by vacuum filtration. The filter cake was water
washed, dried first in air and then a vacuum oven at 55.degree. C.
to provide the title compound (5.85 g, 90% yield) as a pale yellow
solid that was used directly in the next step.
Example 55B
1,4-bis(3-nitrophenyl)butane-1,4-diol
[0488] Sodium borohydride (0.6173 g, 17.74 mmol) was added to a
suspension of Example 55A (2.71 g, 8.26 mmol) in ethanol (150 mL)
and stirred at ambient temperature for 3 hours. The reaction was
quenched with water (.about.50 mL) and concentrated to a paste
which was taken up in 1:1 MeOH:THF. This suspension was filtered
through a celite plug and concentrated. The residue was taken up in
toluene and heated with stirring to form a white paste which was
then sonicated and scraped until a filterable solid formed. This
was filtered, rinsed with toluene and dried under vacuum to afford
2.84 g (100%) of the title compound as an off white solid. MS (DCI)
m/z 350 (M+NH.sub.4).
Example 55C
1,4-bis(3-nitrophenyl)butane-1,4-diyl dimethanesulfonate
[0489] Methanesulfonyl chloride (0.3 mL, 3.87 mmol) was added
dropwise to a cold (0.degree. C.) solution of Example 55B (0.5089
g, 1.531 mmol) and triethylamine (0.65 mL, 4.66 mmol) in THF (10
mL). The reaction was removed from the ice bath and stirred at
ambient temperature for 30 minutes. Solvent was removed under
vacuum to provide the title compound as a solid that was used
without purification.
Example 55D
1-(4-fluorophenyl)-2,5-bis(3-nitrophenyl)pyrrolidine
[0490] Example 55C (0.733 g, 1.5 mmol) was mixed with
4-fluoroaniline (1.5 mL, 15.63 mmol) and DMF (3 mL). The reaction
was stirred at 50.degree. C. for 24 hours. The reaction mixture was
partioned between EtOAc and water. The organic portion was washed
with water (2.times.), brine (1.times.), dried (MgSO.sub.4),
concentrated. Purification by flash chromatography (silica gel,
0-50% EtOAc/Hexanes). The material was dissolved in EtOAc and
washed with 1 M HCl (2.times.) to remove residual aniline, water
(1.times.), sat aqueous NaHCO3 (1.times.) and brine (1.times.)
dried (MgSO.sub.4) and concentrated to afford the title compound as
a mixture of trans and cis isomers (0.45 g, 73%).
Example 55E
3,3'-(1-(4-fluorophenyl)pyrrolidine-2,5-diyl)dianiline
[0491] A suspension of Pd/C (0.0527 g, 0.050 mmol) in THF (2 mL)
was added to a solution of Example 55D (0.45 g, 1.105 mmol) in THF
(7 mL)/EtOH (7 mL) under N.sub.2. The flask was flushed with
H.sub.2 and stirred under 1 atm H.sub.2 for 20 hours. The reaction
was filtered through a celite plug, rinsed with .about.100 mL (1:1
EtOH:THF) and solvent was removed under vacuum. The material was
used without purification. MS (DCI) m/z 348 (M+H).sup.+.
Example 55F
(2S,2'S)-tert-butyl
2,2'-(3,3'-((2S,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(3,1-phenyl-
ene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate
[0492] Diisopropylethylamine (0.8 mL, 4.58 mmol) was added to a
mixture of Example 55E (0.382 g, 1.1 mmol),
(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.5950 g,
2.76 mmol) and HATU (0.9196 g, 2.419 mmol) in dichloromethane (12
mL). The reaction was stirred at rt for 1 hr, diluted with
dichloromethane, washed with water (2.times.), brine (1.times.),
dried (MgSO.sub.4) and concentrated to give a brown residue. The
residue was taken up in ether, sonicated and filtered to afford the
title compound as a tan solid. The trans isomers remained in the
ether solution and are described further in Example 83. LC/MS Rt
2.27 m/z 742 (M+H).sup.+.
Example 55G
(2S,2'S)--N,N'-(3,3'-((2S,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(3-
,1-phenylene))dipyrrolidine-2-carboxamide
[0493] TFA (3 mL, 38.9 mmol) was added to a solution of Example 55F
(0.4033 g, 0.544 mmol) in dichloromethane (10 mL). After 90 minutes
the reaction was concentrated. The residue was sequentially
dissolved in and concentrated in vacuo from the following solvents:
dichloromethane (2.times.), methanol (2.times.), and ether
(1.times.). This semi-solid was taken up in dicholormethane and
washed with sat aq NaHCO.sub.3 (2.times.) water (1.times.) brine
(1.times.) dried (MgSO.sub.4) and filtered to provide the title
compound. LC/MS Rt 1.31 m/z 542 (M+H).sup.+.
Example 55H
dimethyl
([(2R,5S)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-3,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimethyl-1-oxobutane-1,2-di-
yl]})biscarbamate
[0494] Diisopropylethylamine (0.5 mL, 2.86 mmol) was added to a
mixture of Example 55G,
(S)-2-methoxycarbonylamino-3,3-dimethyl-butyric acid (0.2600 g,
1.374 mmol) and HATU (0.4527 g, 1.191 mmol) in dichloromethane(15
mL). The reaction was stirred at ambient temperature for 18 hours.
The reaction was diluted with dichloromethane, washed with water
(2.times.), brine (1.times.), dried (MgSO.sub.4), concentrated and
purified by flash chromatography (silica gel, 0-30%
EtOAc/dichloromethane) to afford 0.14 g (30%) of the title
compound. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 0.96 (s, 9H), 0.98
(s, 9H), 2.06-1.71 (m, 8H), 2.25-2.07 (m, 2H), 2.42 (t, J=7.1, 2H),
3.54 (d, J=3.2, 6H), 3.72-3.59 (m, 2H), 3.86-3.72 (m, 2H), 4.22 (d,
J=8.9, 2H), 4.51-4.37 (m, 2H), 4.69 (t, J=11.9, 2H), 6.42-6.28 (m,
2H), 6.96-6.83 (m, 2H), 7.08 (t, J=8.5, 2H), 7.39-7.18 (m, 4H),
7.76-7.54 (m, 4H), 10.03 (d, J=9.8, 2H). MS (ESI) m/z 884
(M+H).sup.+, 882 (M-H).sup.+.
##STR00290##
Example 56
dimethyl
([1-(4-chlorophenyl)-1H-pyrrole-2,5-diyl]bis{benzene-4,1-diylcarb-
amoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarb-
amate
[0495] Example 1A was processed using 4-chloroaniline and the
methods from Examples 19A, 19B, 19C, 19D, and 51 to provide the
title compound (72 mg). .sup.1H NMR (400 MHz, DMSO-d6) .delta.
10.00 (s, 2H), 7.45-7.36 (m, 6H), 7.31 (d, J=8.3, 2H), 7.04 (d,
J=8.4, 2H), 6.96 (d, J=8.6, 4H), 6.39 (s, 2H), 4.44-4.37 (m, 2H),
4.06-3.99 (m, 2H), 3.85-3.74 (m, 2H), 3.67-3.56 (m, 2H), 3.52 (s,
6H), 2.20-2.06 (m, 2H), 2.04-1.79 (m, 8H), 0.92 (d, J=6.7, 6H),
0.88 (d, J=6.7, 6H). MS (ESI; M+H) m/z=869.
##STR00291##
Example 57
dimethyl
([1-(4-fluorophenyl)-1H-pyrrole-2,5-diyl]bis{benzene-3,1-diylcarb-
amoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarb-
amate
[0496] Example 55A was processed using the methods of Example 19A,
19B, 19C, 19D, and 19E to provide the title compound. 1H NMR (400
MHz, DMSO-d6) .delta. 0.99-0.84 (m, 12H), 2.05-1.76 (m, 8H),
2.22-2.05 (m, 2H), 3.53 (s, 6H), 3.70-3.56 (m, 2H), 3.88-3.71 (m,
2H), 4.11-3.93 (m, 2H), 4.42 (dd, J=4.9, 7.9, 2H), 6.40 (s, 2H),
6.54 (d, J=7.9, 2H), 7.18-6.98 (m, 6H), 7.34 (dd, J=8.3, 15.4, 4H),
7.55 (s, 2H), 9.96 (d, J=11.2, 2H). MS (ESI) m/z 852
(M+H).sup.+.
##STR00292##
Example 58
dimethyl
({1-[4-(trifluoromethyl)phenyl]-1H-pyrrole-2,5-diyl}bis{benzene-4-
,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diy-
l]})biscarbamate
Example 58A
2,5-bis(4-nitrophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrrole
[0497] To a slurry of the product from Example 1A (1.00 g, 3.05
mmol) in acetic acid (30 mL) was added 4-(trifluoromethyl)aniline
(1.9 mL, 15 mmol). The mixture was heated to 170.degree. C. for 15
minutes under microwave irradiation. The cooled mixture was diluted
with water and diethyl ether and stirred vigorously for 15 minutes
and then filtered. The crude product was purified by chromatography
on silica gel eluting with a solvent gradient of 0-30% ethyl
acetate in hexane. Product containing fractions were combined and
concentrated under reduced pressure and then triturated with
diethyl ether to give the title compound (110 mg, 8% yield).
Example 58B
dimethyl
({1-[4-(trifluoromethyl)phenyl]-1H-pyrrole-2,5-diyl}bis{benzene-4-
,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diy-
l]})biscarbamate
[0498] Example 58A was processed using the methods of Examples 19B,
19C, 19D, and 51 to provide the title compound (44 mg). .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 10.01 (s, 2H), 7.71 (d, J=8.6, 2H), 7.42
(d, J=8.7, 4H), 7.31 (d, J=8.2, 2H), 7.22 (d, J=8.3, 2H), 6.95 (d,
J=8.6, 4H), 6.43 (s, 2H), 4.39 (dd, J=5.2, 8.1, 2H), 4.03 (d,
J=8.3, 2H), 3.85-3.75 (m, 2H), 3.66-3.56 (m, 2H), 3.52 (s, 6H),
2.18-2.08 (m, 2H), 2.01-1.79 (m, 8H), 0.92 (d, J=6.7, 6H), 0.87 (d,
J=6.6, 6H). MS (ESI; M+H) m/z=903.
##STR00293##
Example 59
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2R,5S)-5-(4-{2-[(2S)-1-({(2S)-2-[(methoxyca-
rbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1-
-phenylpyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl--
1-oxobutan-2-yl}carbamate
##STR00294##
[0499] Example 59A
(2S,2'S)-tert-butyl
2,2'-(4,4'-(4,4'-(1-phenylpyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(1H--
imidazole-4,2-diyl))dipyrrolidine-1-carboxylate
[0500] Example 42B and aniline were processed using the methods of
Examples 39D, 42D, and 42E to provide the title compound as a
mixture of stereoisomers. MS (ESI) m/z 770 (M+H)+.
Example 59B
4,4'-{[(2R,5S)-1-phenylpyrrolidine-2,5-diyl]dibenzene-4,1-diyl}bis{2-[(2S)-
-pyrrolidin-2-yl]-1H-imidazole}(ACD v12)
[0501] To the product of Example 59A (30 mg, 0.039 mmol) was added
dimethoxyethane (1.5 mL) and a solution of 4N hydrochloric acid in
dioxane (3 mL) and the resultant solution stirred at room
temperature for 1.5 hr. The solvent was then removed under vacuum
and the resultant residue was diluted with acetonitrile and water
(0.1% TFA) and purified by reversed phase chromatography (C18),
eluting with 10-100% acetonitrile in water (0.1% TFA) to afford 9.8
mg (44%) of the title compound and 8.5 mg of a mixture of the trans
diastereomers (MS (ESI) m/z 570 (M+H)+) that were processed further
as described in Example 89. For the title compound: MS (ESI) m/z
570 (M+H)+.
Example 59C
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2R,5S)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1--
phenylpyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-
-oxobutan-2-yl}carbamate
[0502] The product from Example 59B (9.8 mg, 0.012 mmol),
(S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid (5.4 mg,
0.031 mmol) and HATU (10.3 mg, 0.027 mmol) in DMSO (1 mL) was added
Hunig's base (0.017 mL, 0.098 mmol), and the reaction mixture was
stirred at room temperature for 1 hr. The reaction mixture was
partitioned between water and ethyl acetate, and the organic layer
was dried over MgSO.sub.4, filtered and concentrated in vacuo. The
crude product was purified by reversed phase chromatography (C18),
eluting with 10-100% acetonitrile in water (0.1% TFA) to afford 4.5
mg (41%) of the title compound. 1H NMR (TFA salt) (400 MHz,
DMSO-D6) .delta. ppm 14.50 (bs, 2H), 7.99 (s, 2H), 7.78 (m, 4H),
7.65 (m, 4H), 7.32 (m, 2H), 7.02 (t, J=8.0 Hz, 2H), 6.63 (t, J=7.4
Hz, 1H), 6.40 (d, J=8.2 Hz, 2H), 5.11 (t, J=6.9 Hz, 2H), 4.83 (m,
2H), 4.10 (t, J=7.7 Hz, 2H), 3.82 (m, 6H), 3.48 (s, 6H), 2.40 (m,
2H), 2.08 (m, 2H), 2.00 (m, 6H), 1.85 (m, 2H), 0.85 (m, 2H), 0.80
(m, 12H); MS (ESI) m/z 884 (M+H)+.
##STR00295##
Example 60
dimethyl
([(2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{benzene--
4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimethyl-1-oxobutane-1,-
2-diyl]})biscarbamate
Example 60A
dimethyl
([(2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{benzene--
4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimethyl-1-oxobutane-1,-
2-diyl]})biscarbamate and
dimethyl
([(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{benzene--
4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimethyl-1-oxobutane-1,-
2-diyl]})biscarbamate
[0503] The product from Example 34D (29.0 mg, 0.05 mmol),
(S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid (20.81 mg,
0.110 mmol), EDC (21.09 mg, 0.110 mmol), HOBT (16.85 mg, 0.110
mmol) and N-methylmorpholine (0.027 mL, 0.250 mmol) were combined
in DMF (2 mL). The mixture was stirred at room temperature for 3
hours. The reaction mixture was partitioned between ethyl acetate
and water. The organic layer was washed with brine twice, dried
with sodium sulfate, filtered and evaporated. The residue was
purified by chromatography on silica gel eluting with ethyl
acetate/hexane (50% to 80%) to give the title compound (32 mg, 69%)
as a mixture of trans diastereomers.
Example 60B
dimethyl
([(2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{benzene--
4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimethyl-1-oxobutane-1,-
2-diyl]})biscarbamate
[0504] The product from Example 60A was purified by chiral
chromatography on a Chiralpak AD-H semi-prep column eluting with a
3:1 mixture of hexane:(2:1 IPA:EtOH). The title compound was the
first of the 2 diastereomers to elute. .sup.1H NMR (400 MHz,
DMSO-D6) .delta. ppm 0.97 (s, 18H) 1.11 (s, 9H) 1.60-1.65 (m, 2H)
1.79-1.91 (m, 4H) 1.94-2.03 (m, 2H) 2.10-2.18 (m, 2H) 2.44-2.50 (m,
2H) 3.54 (s, 6H) 3.59-3.67 (m, 2H) 3.71-3.82 (m, 2H) 4.21 (d,
J=8.89 Hz, 2H) 4.43 (dd, J=7.92, 5.42 Hz, 2H) 5.14 (d, J=6.40 Hz,
2H) 6.18 (d, J=8.89 Hz, 2H) 6.94 (d, J=8.78 Hz, 2H) 7.08 (d, J=8.78
Hz, 2H) 7.13 (d, J=8.57 Hz, 4H) 7.50 (d, J=8.46 Hz, 4H) 9.99 (s,
2H); MS (ESI+) m/z 923 (M+H)+.
##STR00296##
Example 61
dimethyl
([(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{benzene--
4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimethyl-1-oxobutane-1,-
2-diyl]})biscarbamate
[0505] The product from Example 60A was purified by chiral
chromatography on a Chiralpak AD-H semi-prep column eluting with a
3:1 mixture of hexane:(2:1 IPA:EtOH). The title compound was the
second of the 2 diastereomers to elute. .sup.1H NMR (400 MHz,
DMSO-D6) .delta. ppm 0.96 (s, 18H) 1.11 (s, 9H) 1.60-1.66 (m, 2H)
1.78-1.92 (m, 4H) 1.94-2.04 (m, 2H) 2.08-2.19 (m, 2H) 2.42-2.50 (m,
2H) 3.54 (s, 6H) 3.59-3.67 (m, 2H) 3.74-3.81 (m, 2H) 4.20 (d,
J=8.89 Hz, 2H) 4.43 (dd, J=7.97, 5.37 Hz, 2H) 5.15 (d, J=6.29 Hz,
2H) 6.17 (d, J=8.89 Hz, 2H) 6.94 (d, J=8.89 Hz, 2H) 7.07 (d, J=8.89
Hz, 2H) 7.13 (d, J=8.46 Hz, 4H) 7.50 (d, J=8.57 Hz, 4H) 9.99 (s,
2H); MS (ESI+) m/z 923 (M+H)+.
##STR00297##
Example 62
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2R,5S)-1-(4-fluorophenyl)-5-(4-{2-[(2S)-1-{-
(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imida-
zol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]--
3-methyl-1-oxobutan-2-yl}carbamate
Example 62A
4,4'-{[(2R,5S)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl]dibenzene-4,1-diyl}b-
is{2-[(2S)-pyrrolidin-2-yl]-1H-imidazole}(ACD v12)
[0506] The product from Example 45C (0.15 g, 0.190 mmol) in
CH.sub.2Cl.sub.2 (1 mL) was treated with TFA (1 mL), and the
resulting mixture was stirred at rt for 1 h and then concentrated
in vacuo. The crude product was purified by column chromatography
on C18 silica using a solvent gradient of 10-100% CH.sub.3CN in
0.1% aq TFA. The desired cis-pyrrolidine isomer was the second of 2
components to elute. Fractions containing pure cis-isomer were
pooled and concentrated in vacuo. The residue was partitioned
between saturated aq. NaHCO.sub.3 and a 3:1 mixture of
CH.sub.2Cl.sub.2:2-PrOH (3x). The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
give the title compound (32 mg, 28%).
Example 62B
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2R,5S)-1-(4-fluorophenyl)-5-(4-{2-[(2S)-1-{-
(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imida-
zol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]--
3-methyl-1-oxobutan-2-yl}carbamate
[0507] The product from Example 62A (32 mg, 54 mmol) was subjected
to the method described in Example 5D, substituting
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid for
(S)-2-(methoxycarbonyl amino)butanoic acid, to give the title
compound (34 mg, 69%). .sup.1H NMR (400 MHz, DMSO-D6) .delta. ppm
0.78-0.93 (m, 12H), 1.78-2.24 (m, 12H), 2.37-2.46 (m, 2H), 3.54 (s,
6H), 3.68-3.87 (m, 4H), 4.66-4.79 (m, 2H), 5.02-5.13 (m, 2H), 6.39
(dd, J=9.16, 4.50 Hz, 2H), 6.81-6.92 (m, 2H), 7.23-7.34 (m, 2H),
7.39-7.80 (m, 12H), 11.67-12.12 (m, 2H); MS (ESI) m/z 902.7
(M+H).sup.+.
##STR00298##
Example 63
methyl
[(2S)-1-{(2S)-2-[4-(4-{(2R,5S)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1--
[4-(trifluoromethyl)phenyl]pyrrolidin-2-yl}phenyl)-1H-imidazol-2-yl]pyrrol-
idin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
Example 63A
(2R,5S)-2,5-bis(4-bromophenyl)-1-(4-(trifluoromethyl)phenyl)pyrrolidine
[0508] The product from Example 42B (11.13 g, 20.0 mmol) and
4-(trifluoromethyl)aniline (Aldrich, 32.2 g, 200 mmol) were
combined in DMF (50 mL), stirred at 50.degree. C. under nitrogen
for 16 hours, cooled and concentrated. The residue was diluted with
ethyl acetate, treated with 1M HCl, stirred for 10 minutes and
filtered to remove solids. The organic layer of the filtrate was
washed with brine, dried (Na.sub.2SO.sub.4), filtered and
concentrated. The residue was purified by flash chromatography
(silica gel, 0 to 1% ethyl acetate/hexane) to give the title
compound (1.0 g, 10%) as the second eluting stereoisomer. MS (ESI+)
m/z 526 (M+H).sup.+.
Example 63B
methyl
[(2S)-1-{(2S)-2-[4-(4-{(2R,5S)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1--
[4-(trifluoromethyl)phenyl]pyrrolidin-2-yl}phenyl)-1H-imidazol-2-yl]pyrrol-
idin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0509] The product from Example 63A (1.0 g, 1.90 mmol) was
processed using the methods described in Example 42D, 42E, 42F, and
42G to afford the title compound. .sup.1H NMR (free base) (400 MHz,
DMSO-d.sub.6) .delta. 0.80-0.95 (m, 12H) 1.83-2.18 (m, 14H) 3.54
(s, 6H) 3.79 (d, J=6.18 Hz, 3H) 3.97-4.15 (m, 3H) 4.87 (d, J=4.88
Hz, 2H) 5.02-5.14 (m, 2H) 6.54 (d, J=8.67 Hz, 2H) 7.15-7.80 (m,
14H) 11.56-12.30 (m, 2H); MS (ESI+) m/z 953 (M+H).sup.+.
##STR00299##
Example 64
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2R,5S)-1-(4-tert-butylphenyl)-5-(4-{2-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-i-
midazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1--
yl]-3-methyl-1-oxobutan-2-yl}carbamate
Example 64A
(2S,2'R)-2,2'-(4,4'-(4,4'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(-
4,1-phenylene))bis(1H-imidazole) bis trifluoroacetate salt
[0510] Example 42C was processed using the methods of Examples 42D,
42E, and 42F to provide a mixture of cis/trans pyrrolidine isomers.
The mixture of stereoisomers was dissolved in 10 ml of 80% (0.1%
TFA/water):20% CH.sub.3CN and applied to a 13 g C18 silica column.
The column was eluted with a gradient of 0.1% TFA(aq):CH3CN; 80/20
to 50:50 over 25 minutes, giving the cis stereoisomer of the title
compound as a light yellow solid trifluoroacetate salt, 88.6 mg,
58%.
Example 64B
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2R,5S)-1-(4-tert-butylphenyl)-5-(4-{2-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-i-
midazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1--
yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0511] The product from Example 64A was dissolved in 1 ml DMF and
added dropwise to a chilled (0-5.degree. C.) solution containing
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.41 g, 0.232
mmole), HOBt (0.036 g, 0.232 mmole), EDAC (0.045 g, 0.232 mmole)
and 4-methylmorpholine (0.138 g, 0.150 ml, 1.364 mmole) in 0.5 ml
DMF. The pH of the solution was measured and found to be 8. The
reaction was stirred a total of 3.5 hr in the ice bath. The
reaction mixture was diluted with 50 ml EtOAc and washed with 10%
NaHCO.sub.3, 10% NaCl, dried over anhydrous Na.sub.2SO.sub.4(s),
filtered and solvent removed in vacuo leaving a pinkish oil. The
oil was dissolved in 5 ml CH.sub.2Cl.sub.2 and applied to a 12 g
silica gel column. The column was eluted with a gradient of
CH.sub.2Cl.sub.2/MeOH, 99/1 to 94/6 over 25 minutes giving the
title compound as a white solid, 12.5 mg, 11%. 1H NMR (400 MHz,
DMSO-D6) d ppm 0.85 (s, 12H) 1.13 (s, 9H) 1.95 (s, 6H) 2.15 (s, 4H)
2.50 (s, 3H) 3.43 (s, 1H) 3.54 (s, 5H) 3.80 (s, 4H) 4.05 (s, 2H)
4.70 (s, 2H) 5.07 (s, 1H) 6.36 (d, J=8.78 Hz, 2H) 7.01 (s, 2H) 7.28
(s, 2H) 7.47 (s, 6H) 7.70 (s, 4H) 11.71 (s, 2H) 12.09 (s, 2H)
ESI+:940.8
##STR00300##
Example 65
methyl
{(2S)-1-[(2S)-2-(4-{4-[5-(4-{2-[(2S)-1-(2S)-1-{(2S)-2-[(methoxycarb-
onyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1-p-
henyl-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1--
oxobutan-2-yl}carbamate
Example 65A
(2S,2'R)-tert-butyl
2,2'-(4,4'-(4,4'-(1-phenyl-1H-pyrrole-2,5-diyl)bis(4,1-phenylene))bis(1H--
imidazole-4,2-diyl))dipyrrolidine-1-carboxylate
[0512] Example 26E and aniline were processed using the methods of
Examples 19A, 26G, and 26H to provide the title compound (150
mg).
Example 65B
(S)-4,4'-(4,4'-(1-phenyl-H-pyrrole-2,5-diyl)bis(4,1-phenylene))bis(2-((S)--
pyrrolidin-2-yl)-1H-imidazole)
[0513] To a suspension of the product from Example 65A (186 mg,
0.243 mmol) in dioxane (5 mL) was added HCl/dioxane (5 mL, 20
mmol). The mixture was stirred for 30 minutes and then concentrated
under reduced pressure to provide the title compound as a
hydrochloride salt.
Example 65C
methyl
{(2S)-1-[(2S)-2-(4-{4-[5-(4-{2-[(2S)-1-(2S)-1-{(2S)-2-[(methoxycarb-
onyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1-p-
henyl-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1--
oxobutan-2-yl}carbamate
[0514] A solution consisting of
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (90 mg, 0.47 mmol), 1H-benzo[d][1,2,3]triazol-1-ol
hydrate (72 mg, 0.47 mmol),
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (82 mg, 0.47
mmol) and 4-methylmorpholine (0.28 mL, 2.6 mmol) in DMF (1.6 mL)
was cooled in an icebath. To this mixture was added dropwise a
solution of the product from Example 65B (150 mg, 0.23 mmol) in DMF
(0.5 mL). Additional 4-methylmorpholine was added to the mixture
until the pH was adjusted to 8. The reaction was stirred for 3.5
hours and then the icebath was removed and the reaction was stirred
for an additional 16 hours. Water was then added to the reaction
mixture and the resulting precipitate was recovered by filtration.
The residue was washed with copious amounts of water followed by
diethyl ether. The crude product was purified by chromatography on
silica gel eluting with a solvent gradient of 0-5% methanol in
CH.sub.2Cl.sub.2 to provide the title compound. .sup.1H NMR (400
MHz, DMSO-d6) .delta. 12.12-11.64 (m, 2H), 7.57-7.45 (m, 4H),
7.42-7.36 (m, 2H), 7.36-7.29 (m, 3H), 7.29-7.05 (m, 4H), 7.04-6.91
(m, 4H), 6.54-6.43 (m, 2H), 5.06-4.96 (m, 2H), 4.06-3.96 (m, 2H),
3.84-3.67 (m, 4H), 3.52 (s, 6H), 2.17-1.80 (m, 10H), 0.91-0.76 (m,
12H). MS (ESI; M+H) m/z=881.
##STR00301##
Example 66
methyl
[(2S)-1-{(2S)-2-[4-(4-{(2S,5S)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1--
[4-(trifluoromethyl)phenyl]pyrrolidin-2-yl}phenyl)-1H-imidazol-2-yl]pyrrol-
idin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
Example 66A
(2R,5R)-2,5-bis(4-bromophenyl)-1-(4-(trifluoromethyl)phenyl)pyrrolidine
and
(2S,5S)-2,5-bis(4-bromophenyl)-1-(4-(trifluoromethyl)phenyl)pyrrolidine
[0515] The product from Example 42B (11.13 g, 20.0 mmol) and
4-(trifluoromethyl)aniline (32.2 g, 200 mmol) were combined in DMF
(50 mL). The mixture was stirred at 50.degree. C. under nitrogen
overnight. The reaction mixture was evaporated and the residue was
diluted with ethyl acetate, treated with 1M HCl, stirred for 10
minutes, and filtered to remove the solid. The organic layer of
filtrate was washed with brine, dried with sodium sulfate, filtered
and evaporated. The residue was purified by chromatography on
silica gel eluting with ethyl acetate/hexane (0 to 1%). The title
compounds (500 mg, 5%) were eluted as the first of 2 stereoisomers
and were obtained as a mixture of trans diastereomers.
Example 66B
(2R,5R)-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(-
4-(trifluoromethyl)phenyl)pyrrolidine and
(2S,5S)-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(-
4-(trifluoromethyl)phenyl)pyrrolidine
[0516] The products from Example 66A (500 mg, 0.952 mmol),
bis(pinacolato)diboron (725 mg, 2.86 mmol), potassium acetate (374
mg, 3.81 mmol) and bis(triphenylphosphine)palladium(II) chloride
(66.8 mg, 0.095 mmol) were combined in 1,2-dimethoxyethane (10 mL).
The mixture was purged with nitrogen for 15 minutes and stirred at
85.degree. C. for 2 hours. The reaction mixture was partitioned
between ethyl acetate and 1M HCl. The organic layer was washed with
saturated sodium bicarbonate, brine, dried with sodium sulfate,
filtered and evaporated. The residue was purified by chromatography
on silica gel eluting with hexane to ethyl acetate/hexane (10%) to
give a solid which was triturated with dichloromethane/hexane (1:3)
to give the title compounds (370 mg, 63%).
Example 66C
(2S,2'S)-tert-butyl
2,2'-(4,4'-(4,4'-((2R,5R)-1-(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-di-
yl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxyla-
te and
(2S,2'S)-tert-butyl
2,2'-(4,4'-(4,4'-((2S,5S)-1-(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-di-
yl)bis(4,1-phenylene))bis(1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxyla-
te
[0517] The products from Example 66B (257 mg, 0.415 mmol), the
product from Example 26D (341 mg, 1.079 mmol), potassium phosphate
tribasic (352 mg, 1.660 mmol) and
1,1'-bis(di-tert-butylphosphine)ferrocene palladium dichloride
(27.0 mg, 0.041 mmol) were combined in THF (4.5 mL)/water (1.5 mL).
The mixture was purged with nitrogen for 15 minutes and stirred at
70.degree. C. for 6 hours. The reaction mixture was partitioned
between ethyl acetate and saturated sodium bicarbonate. The organic
layer was washed with brine, dried with sodium sulfate, filtered
and evaporated. The residue was purified by chromatography on
silica gel eluting with methanol/dichloromethane (1% to 3%) to give
the title compounds (286 mg, 82%) as a solid.
Example 66D
(S)-4,4'-(4,4'-((2R,5R)-1-(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)-
bis(4,1-phenylene))bis(2-((S)-pyrrolidin-2-yl)-1H-imidazole)
and
(S)-4,4'-(4,4'-((2S,5S)-1-(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)-
bis(4,1-phenylene))bis(2-((S)-pyrrolidin-2-yl)-1H-imidazole)
[0518] To the products from Example 66C (385 mg, 0.459 mmol) in
dioxane (6 mL) was added 4M hydrochloric acid in dioxane (10 mL,
40.0 mmol) and the reaction stirred at room temperature for 1 hour.
The solvent was evaporated under high vacuum to give the title
compounds (approx. 360 mg) as hydrochloride salts.
Example 66E
methyl
[(2S)-1-{(2S)-2-[4-(4-{(2S,5S)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-H-imidazol-4-yl}phenyl)-1-[-
4-(trifluoromethyl)phenyl]pyrrolidin-2-yl}phenyl)-1H-imidazol-2-yl]pyrroli-
din-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate and
methyl
[(2S)-1-{(2S)-2-[4-(4-{(2R,5R)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1--
[4-(trifluoromethyl)phenyl]pyrrolidin-2-yl}phenyl)-1H-imidazol-2-yl]pyrrol-
idin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0519] The product from Example 66D (360 mg, 0.459 mmol),
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (161 mg, 0.919
mmol), 4-methylmorpholine (0.404 mL, 3.68 mmol),
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (194 mg, 1.011 mmol) and
1H-benzo[d][1,2,3]triazol-1-ol hydrate (155 mg, 1.011 mmol) were
combined in DMF (10 mL). The mixture was stirred at room
temperature for 20 hours. The reaction mixture was partitioned
between ethyl acetate and water. The organic layer was washed with
saturated sodium bicarbonate, brine twice, dried with sodium
sulfate, filtered and evaporated. The residue was purified by
chromatography on silica gel eluting with methanol/dichloromethane
(1% to 6%) to give the title compounds (223 mg, 51%) as a
solid.
Example 66F
methyl
[(2S)-1-{(2S)-2-[4-(4-{(2S,5S)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1--
[4-(trifluoromethyl)phenyl]pyrrolidin-2-yl}phenyl)-1H-imidazol-2-yl]pyrrol-
idin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0520] The product from Example 66E was purified by chiral
chromatography on a Chiralpak IB column eluting with a mixture of
hexane/THF/methanol (8/1/1). The title compound was the first of
the 2 diastereomers to elute. .sup.1H NMR (400 MHz, DMSO-D6)
.delta. ppm 0.78-0.90 (m, 12H) 1.71-1.77 (m, 2H) 1.86-2.02 (m, 6H)
2.09-2.18 (m, 4H) 2.51-2.54 (m, 2H) 3.53 (s, 6H) 3.74-3.84 (m, 4H)
4.04 (t, J=8.35 Hz, 2H) 5.06 (dd, J=6.83, 3.14 Hz, 2H) 5.28-5.41
(m, 2H) 6.41 (d, J=8.67 Hz, 2H) 7.12-7.33 (m, 8H) 7.36-7.72 (m, 6H)
11.62-12.13 (m, 2H); MS (ESI+) m/z 953 (M+H)+.
##STR00302##
Example 67
methyl
[(2S)-1-{(2S)-2-[4-(4-{(2R,5R)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1--
[4-(trifluoromethyl)phenyl]pyrrolidin-2-yl}phenyl)-1H-imidazol-2-yl]pyrrol-
idin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0521] The product from Example 66E was purified by chiral
chromatography on a Chiralpak IB column eluting with a mixture of
hexane/THF/methanol (8/1/1). The title compound was the second of
the 2 diastereomers to elute. .sup.1H NMR (400 MHz, DMSO-D6)
.delta. ppm 0.79-0.91 (m, 12H) 1.71-1.77 (m, 2H) 1.88-2.01 (m, 6H)
2.08-2.17 (m, 4H) 2.51-2.54 (m, 2H) 3.53 (s, 6H) 3.74-3.82 (m, 4H)
4.05 (t, J=8.40 Hz, 2H) 5.00-5.13 (m, 2H) 5.29-5.40 (m, 2H) 6.40
(d, J=8.57 Hz, 2H) 7.12-7.31 (m, 8H) 7.36-7.72 (m, 6H) 11.52-12.15
(m, 2H); MS (ESI+) m/z 953 (M+H)+.
##STR00303##
Example 68
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2R,5S)-1-(4-cyclopropylphenyl)-5-(4-{2-[(2S-
)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H--
imidazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-
-yl]-3-methyl-1-oxobutan-2-yl}carbamate
Example 68A
2,5-bis(4-bromophenyl)-1-(4-cyclopropylphenyl)pyrrolidine
[0522] The product from Example 42B (3.14 g, 5.64 mmol) and
4-cyclopropylaniline (6.01 g, 45.2 mmol) were combined in DMF (20
mL). The mixture was stirred at 50.degree. C. under nitrogen for 3
hours. The reaction mixture was partitioned between 1M HCl and
ethyl acetate. The organic layer was washed with brine three times,
dried with sodium sulfate, filtered and evaporated. The residue was
purified by chromatography on silica gel eluting with ethyl
acetate/hexane (0.5% to 1%) to give the title compound (2.12 g,
76%) as a mixture of stereoisomers as a sticky solid.
Example 68B
1-(4-cyclopropylphenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)phenyl)pyrrolidine
[0523] The product from Example 68A (2.12 g, 4.26 mmol),
bis(pinacolato)biboron (3.25 g, 12.79 mmol), potassium acetate
(1.674 g, 17.05 mmol) and bis(triphenylphosphine)palladium(II)
chloride (0.299 g, 0.426 mmol) were combined in 1,2-dimethoxyethane
(40 mL). The mixture was purged with nitrogen for 15 minutes and
stirred at 85.degree. C. for 2 hours. The reaction mixture was
partitioned between ethyl acetate and 1M HCl. The organic layer was
washed with saturated sodium bicarbonate, brine, dried with sodium
sulfate, filtered and evaporated. The residue was purified by
chromatography on silica gel eluting with hexane to ethyl
acetate/hexane (10%) to give a solid that was triturated with
diethyl ether/hexane (1/3) to give the title compound (1.05, 42%)
as a mixture of stereoisomers as a white solid.
Example 68C
(2S,2'S)-tert-butyl
2,2'-(4,4'-(4,4'-(1-(4-cyclopropylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phe-
nylene))bis(1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxylate
[0524] The product from Example 68B (1.04 g, 1.759 mmol), the
product from Example 26D (1.446 g, 4.57 mmol), PdCl.sub.2(dppf)
(0.129 g, 0.176 mmol) and 1.0 M sodium carbonate (4.57 mL, 4.57
mmol) were combined in the mixed solvent of ethanol (5 mL)/toluene
(5 mL). The mixture was purged with nitrogen for 15 minutes and
stirred at 80.degree. C. for 2 hours. The reaction mixture was
partitioned between ethyl acetate and saturated sodium bicarbonate,
brine, dried with sodium sulfate, filtered and evaporated. The
residue was purified by chromatography on silica gel eluting with
methanol/dichloromethane (1% to 3%) to give the title compound
(1.28 g, 90%) as a mixture of stereoisomers as a solid.
Example 68D
(S)-4,4'-(4,4'-((2R,5S)-1-(4-cyclopropylphenyl)pyrrolidine-2,5-diyl)bis(4,-
1-phenylene))bis(2-((S)-pyrrolidin-2-yl)-1H-imidazole)
[0525] The product from Example 68C (1.27 g, 1.568 mmol) was
dissolved in dichloromethane (12 mL). The mixture was cooled to
0.degree. C. and trifluoroacetic acid (8 mL, 104 mmol) was added
slowly. The mixture was warmed to room temperature and stirred for
1 h. The solvent was evaporated and the residue was purified by
chromatography on silica gel eluting with methanol/dichloromethane
(1% to 10%). The title compound (310 mg, 32%) eluted as the second
of 2 stereoisomers.
Example 68E
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2R,5S)-1-(4-cyclopropylphenyl)-5-(4-{2-[(2S-
)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H--
imidazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-
-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0526] The product of Example 68D (90 mg, 0.148 mmol),
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (51.7 mg, 0.295
mmol), 4-methylmorpholine (0.130 mL, 1.181 mmol),
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (62.2 mg, 0.325 mmol) and
1H-benzo[d][1,2,3]triazol-1-ol hydrate (49.7 mg, 0.325 mmol) were
combined in DMF (10 mL). The mixture was stirred at room
temperature for 2 hours. The reaction mixture was partitioned
between ethyl acetate and water. The organic layer was washed with
saturated sodium bicarbonate, brine twice, dried with sodium
sulfate, filtered and evaporated. The residue was purified by
chromatography on silica gel eluting with methanol/dichloromethane
(1% to 4%) to give the title compound (40 mg, 29%) as a solid.
.sup.1H NMR (400 MHz, DMSO-D6) .delta. ppm 0.39-0.47 (m, 2H)
0.71-0.78 (m, 2H) 0.82-0.92 (m, 12H) 1.65-1.72 (m, 1H) 1.82-2.03
(m, 8H) 2.09-2.17 (m, 4H) 2.40-2.45 (m, 2H) 3.54 (s, 6H) 3.75-3.83
(m, 4H) 4.02-4.09 (m, 2H) 4.64-4.75 (m, 2H) 5.03-5.11 (m, 2H) 6.32
(d, J=8.67 Hz, 2H) 6.73 (d, J=8.35 Hz, 2H) 7.29 (d, J=8.02 Hz, 2H)
7.37-7.81 (m, 10H) 11.47-12.17 (m, 2H); MS (ESI+) m/z 924.7
(M+H)+.
##STR00304##
Example 69
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2S,5S)-1-(4-tert-butylphenyl)-5-(4-{2-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}pyrrolidin-2-yl]--
1H-imidazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidi-
n-1-yl]-3,3-dimethyl-1-oxobutan-2-yl}carbamate
##STR00305##
[0527] Example 69A
(1R,4R)-1,4-bis(4-bromophenyl)butane-1,4-diol
[0528] To (S)-(-)-alpha, alpha-diphenyl-2-pyrrolidinemethanol (3.81
g, 15.04 mmol) was added THF (140 mL) at 23.degree. C. The thin
slurry was treated with trimethyl borate (2.189 mL, 19.63 mmol) to
form a clear solution. After stirring for 1.5 h, the solution was
cooled to 10-15.degree. C., and N,N-diethylaniline borane (33.1 mL,
186 mmol) was added over 5-10 min via a syringe. A slight exotherm
and H.sub.2 evolution were observed. To a separate vessel was
charged Example 26E (35.045 g, 88 mmol), followed by THF (140 mL),
to form a slurry. The slurry was cooled to 10.degree. C. The cooled
borane solution was transferred via cannula into the dione slurry
over approximately 5 minutes, maintaining the internal temperature
<25.degree. C. After the transfer was complete, the slurry was
held at 15.degree. C. for 5 min and then the temperature was
maintained at 23.degree. C. for 3 h. After reaction completion, the
solution was cooled to 5.degree. C., and methanol (31.6 mL, 780
mmol) was added slowly to maintain a temperature <20.degree. C.
(note: vigorous evolution of hydrogen). The hazy solution was mixed
for an additional 1 h in order to ensure complete quenching. The
hazy solution was diluted with EtOAc (500 mL) and 1 M HCl (220 mL).
The phases were partitioned, and the organic phase was washed
successively with 1 M HCl (2.times.220 mL), H.sub.2O (110 mL), and
25% aq. NaCl (110 mL). The organic layer was concentrated in vacuo,
then dissolved in EtOAc, filtered, concentrated and crystallized
from EtOAc/hexane to provide the title compound (16.92 g; 100% ee;
47% isolated yield).
Example 69B
(2S,5S)-2,5-bis(4-bromophenyl)-1-(4-tert-butylphenyl)pyrrolidine
[0529] To a mixture of the product from Example 69A (0.60 g, 1.500
mmol) in anhydrous CH.sub.2Cl.sub.2 (15 mL) at 0.degree. C. was
added Et.sub.3N (0.627 mL, 4.50 mmol), and the resulting mixture
was stirred at 0.degree. C. for 10 min until a homogenous solution
was obtained. To the cooled solution was added methanesulfonyl
chloride (0.292 mL, 3.75 mmol) dropwise, and the resulting mixture
was stirred at 0.degree. C. for 1.5 h until the reaction was
complete as determined by TLC (1:1 EtOAc:hexanes). Solvent was
removed in vacuo to give a solid, which was dried in vacuo. The
solid was dissolved in anhydrous DMF (5 mL), and
4-tert-butylaniline (2.39 mL, 15 mmol) was added. The resulting
mixture was stirred at 40.degree. C. for 4 h and then was
partitioned between IN aq. HCl (30 mL) and EtOAc (30 mL). The
organic layer was washed with H.sub.2O and dried over
Na.sub.2SO.sub.4. The drying agent was filtered off, the solvent
was removed in vacuo, and the crude product was purified by column
chromatography on silica gel using a solvent gradient of 0-20%
EtOAc in hexanes. The title compound was obtained as a colorless
solid (0.71 g, 92%). .sup.1H NMR indicated this material was a
87:13 mixture of trans:cis pyrrolidine isomers.
Example 69C
(2S,5S)-1-(4-tert-butylphenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxab-
orolan-2-yl)phenyl)pyrrolidine
[0530] The product from Example 69B (0.71 g, 1.38 mmol) was
subjected to the conditions described in Example 42D to give the
title compound as a colorless solid (0.56 g, 66%).
Example 69D
(2S,2'S)-tert-butyl
2,2'-(4,4'-(4,4'-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(-
4,1-phenylene))bis(1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxylate
[0531] The product from Example 69C (0.55 g, 0.91 mmol) was
subjected to the conditions described in Example 42E to give the
title compound (0.27 g, 36%).
Example 69E
(S)-4,4'-(4,4'-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-
-phenylene))bis(2-((S)-pyrrolidin-2-yl)-1H-imidazole)
[0532] A solution of the product from Example 69D (0.27 g, 0.33
mmol) in a 1:1 mixture of CH.sub.2Cl.sub.2:TFA (4 mL) was stirred
at rt for 40 min and then concentrated in vacuo. The residue was
partitioned between saturated aq NaHCO.sub.3 and a 3:1 mixture of
CH.sub.2Cl.sub.2:2-PrOH (2.times.), and the combined organic layers
were dried over Na.sub.2SO.sub.4. The drying agent was filtered
off, and the solvent was removed in vacuo to give the title
compound as an amorphous solid (0.18 g, 87%).
Example 69F
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2S,5S)-1-(4-tert-butylphenyl)-5-(4-{2-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}pyrrolidin-2-yl]--
1H-imidazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidi-
n-1-yl]-3,3-dimethyl-1-oxobutan-2-yl}carbamate
[0533] To a mixture of the product from Example 69E (0.10 g, 0.16
mmol) and (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid
(76 mg, 0.40 mmol) in anhydrous DMSO (1.6 mL) was added HATU (152
mg, 0.40 mmol) and Hunig's base (84 .mu.L, 0.48 mmol). The
resulting mixture was stirred at rt for 90 min, and was then
partitioned between H.sub.2O (5 mL) and EtOAc (2.times.5 mL). The
combined organic layers were concentrated in vacuo, and the residue
was dissolved in MeOH (1 mL). To the solution was added solid
K.sub.2CO.sub.3 (1-2 mg) and the resulting mixture was stirred at
rt for 30 min. The mixture was filter and concentrated in vacuo,
and the crude product was purified by column chromatography on
silica gel using a solvent gradient of 0-5% MeOH in
CH.sub.2Cl.sub.2 to give the title compound (0.12 g, 78%). .sup.1H
NMR (400 MHz, DMSO-D6) .delta. ppm 0.94 (s, 18H), 1.10 (s, 9H),
1.63-1.77 (m, 2H), 1.84-2.25 (m, 10H), 3.55 (s, 6H), 3.66-3.87 (m,
2H), 4.16-4.28 (m, 2H), 5.03-5.12 (m, 2H), 5.15-5.28 (m, 2H), 6.22
(d, J=8.46 Hz, 2H), 6.93 (d, J=8.67 Hz, 2H), 7.07 (d, 2H), 7.15 (d,
J=8.13 Hz, 4H), 7.23 (d, 1H), 7.38 (d, J=1.41 Hz, 2H), 7.52 (d,
1H), 7.62 (d, J=8.02 Hz, 4H), 11.66-12.10 (m, 2H). MS (ESI) m/z
969.1 (M+H).sup.+.
##STR00306##
Example 70
dimethyl
([(2S,3R,4R,5S)-1-(4-fluorophenyl)-3,4-dimethoxypyrrolidine-2,5-d-
iyl]bis{benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate
Example 70A
Tert-butyl
4,4'-((2S,3R,4R,5S)-1-(4-fluorophenyl)-3,4-dihydroxypyrrolidine-
-2,5-diyl)bis(4,1-phenylene)dicarbamate
[0534] A solution of 3.4-O-isopropylidene-D-mannitol (444 mg, 2.0
mmol) in 2:1 methanol-dichloromethane (8 mL) was treated with
iodobenzene diacetate (1.54 g, 4.79 mmol) followed by stirring at
RT for 5 h. The mixture was concentrated in vacuo to remove organic
solvents, and the residue was suspended in 0.1 M sulfuric acid
solution (4 mL) followed by stirring at RT for 18 h. The mixture
was adjusted to pH 6 by addition of solid sodium bicarbonate. The
mixture was then sequentially treated with 4-fluoroaniline (383
.mu.L, 444 mg, 4.00 mmol),
4-(tert-butoxycarbonylamino)phenylboronic acid (853 mg, 3.60 mmol)
and hexafluoroisopropyl alcohol (8 mL). The mixture was warmed at
50.degree. C. for 2 h. The solution was cooled and concentrated in
vacuo. The mixture was dissolved in ethyl acetate and extracted
with water, 0.33 M tribasic potassium phosphate solution, and
saturated sodium chloride solution. Drying (Na.sub.2SO.sub.4) and
concentration in vacuo afforded a brown solid, which was
chromatographed over a 100 g silica gel cartridge, eluting with
5-70% ethyl acetate in dichloromethane. These procedures afforded
the title compound (770 mg, 67%) as a nearly white solid. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.35 (d, J=8.3 Hz, 4H), 7.11 (d,
J=8.4 Hz, 4H), 6.67 (t, J=8.8 Hz, 2H), 6.51 (s, 2H), 6.22 (dd,
J=9.1, 4.3 Hz, 2H), 5.15 (d, J=6.3 Hz, 2H), 4.26 (d, J=5.7 Hz, 2H),
1.51 (s, 18H). MS+ESI m/z (rel abundance) 580 (100, M+H), 602 (15,
M+Na), 1159 (18, 2M+H).
Example 70B
(2S,3R,4R,5S)-2,5-bis(4-(tert-butoxycarbonylamino)phenyl)-1-(4-fluoropheny-
l)pyrrolidine-3,4-diyl diacetate
[0535] A solution of the compound of Example 70A (314 mg, 0.54
mmol), triethylamine (227 .mu.L, 164 mg, 1.65 mmol), and DMAP (13
mg, 0.11 mmol) in 1:1 ethyl acetate-tetrahydrofuran (2.8 mL) was
treated with acetic anhydride (128 .mu.L, 138 mg, 1.35 mmol)
followed by stirring at RT for 1 h. The mixture was treated with
water followed by stirring at RT for 30 min. The mixture was
diluted with ethyl acetate and extracted with water, saturated
sodium bicarbonate solution and saturated sodium chloride solution.
Drying (Na.sub.2SO.sub.4) and concentration in vacuo afforded the
title compound (330 mg, 92%) as a cream-colored solid, sufficiently
pure for further use. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.32 (d, J=8.4 Hz, 4H), 7.07 (d, J=8.5 Hz, 4H), 6.66 (t, J=8.8 Hz,
2H), 6.47 (s, 2H), 6.25 (dd, J=9.2, 4.3 Hz, 2H), 5.53 (dd, J=5.5,
1.9 Hz, 2H), 5.46 (d, J=7.2 Hz, 2H), 1.83 (s, 6H), 1.51 (s, 18H).
MS+ESI m/z (rel abundance) 664 (100, M+H).
Example 70C
(2S,3R,4R,5S)-2,5-bis(4-aminophenyl)-1-(4-fluorophenyl)pyrrolidine-3,4-diy-
l diacetate dihydrochloride
[0536] A solution of 4 N hydrogen chloride in dioxane (8 mL) was
treated with the compound of Example 70B (136 mg, 0.21 mmol)
followed by stirring at RT for 2 h. (During this time, the
mono-deprotection product started precipitating, and ca. 4 mL of
dichloromethane was added to speed the reaction by solublizing the
mono-hydrochloride) The mixture was added to excess ether and the
product collected by filtration and washed with ether. After drying
in a vacuum oven at 50.degree. C. for 18 h, these procedures
afforded the title compound (92 mg, 84%) as an off-white powder.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.28 (m, 8H), 6.81 (t,
J=8.9 Hz, 2H), 6.33 (m, 2H), 5.63 (m, 2H), 5.51 (dd, J=5.5, 1.9 Hz,
2H), 1.79 (s, 6H).
Example 70D
(2S,3R,4R,5S)-2,5-bis(4-aminophenyl)-1-(4-fluorophenyl)pyrrolidine-3,4-dio-
l
[0537] In a 25-mL round bottom flask, was dissolved Example 70C
(160.5 mg, 0.299 mmol) in MeOH (3 mL), added potassium carbonate
(165 mg, 1.197 mmol), and stirred at 25.degree. C. for 1.5 hr.
Filtered off the solids, washed with MeOH, and concentrated the
filtrate by rotary evaporation to dryness. Purified by flash
chromatography (silica gel, Alltech Extract-Clean 10 g column, 8%
MeOH/CH.sub.2Cl.sub.2) to afford the title compound as a yellow
solid (85 mg, 75%). .sup.1H NMR (400 MHz, DMSO-D6) .delta. ppm
4.10-4.19 (m, 2H), 4.73 (d, J=2.71 Hz, 2H), 4.80-4.88 (m, 2H), 4.84
(s, 4H), 6.21 (dd, J=9.22, 4.55 Hz, 2H), 6.45 (d, J=8.35 Hz, 4H),
6.72 (t, J=8.95 Hz, 2H), 6.77 (d, J=8.24 Hz, 4H); MS (DCI+) 380
(M+H).sup.+.
Example 70E
4,4'-((2S,3R,4R,5S)-1-(4-fluorophenyl)-3,4-dimethoxypyrrolidine-2,5-diyl)d-
ianiline
[0538] In an oven-dried 25-mL round bottom flask, dissolved the
product of Example 70D (83.6 mg, 0.220 mmol) in anhydrous THF (3
mL) under nitrogen, cooled to 0.degree. C. in an ice water bath,
added 60 wt % NaH dispersion in mineral oil (18.51 mg, 0.463 mmol),
and stirred at 0.degree. C. for 15 min. Then added iodomethane
(0.028 mL, 0.441 mmol) via microsyringe and stirred at 0.degree. C.
for 1 hr, then at 25.degree. C. for 3 hr. Removed the solvent by
rotary evaporation and dried the residue in vacuo. Purified by
flash chromatography (silica gel, Alltech Extract-Clean 10 g
column, gradient of 1% to 2% MeOH/CH.sub.2Cl.sub.2) to afford the
title compound as a yellow solid (59 mg, 66%). .sup.1H NMR (400
MHz, DMSO-D6) .delta. ppm 3.25 (s, 6H), 3.92-4.17 (m, 2H), 4.91 (s,
4H), 5.07-5.24 (m, 2H), 6.28 (dd, J=9.16, 4.50 Hz, 2H), 6.47 (d,
J=8.46 Hz, 4H), 6.73 (t, J=8.95 Hz, 2H), 6.86 (d, J=8.35 Hz, 4H);
MS (DCI+) m/z 408 (M+H).sup.+.
Example 70F
(2S,2'S)-tert-butyl
2,2'-(4,4'-((2S,3R,3R,5S)-1-(4-fluorophenyl)-3,4-dimethoxypyrrolidine-2,5-
-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-ca-
rboxylate
[0539] In a 10-mL round bottom flask, dissolved the product of
Example 70E (57 mg, 0.140 mmol) in anhydrous DMSO (1.2 mL) under
nitrogen, added (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic
acid (76 mg, 0.350 mmol), HATU (137 mg, 0.350 mmol), and
diisopropylethylamine (0.073 mL, 0.420 mmol), and stirred the
bright yellow solution at 25.degree. C. for 1 hr. Diluted the
reaction with EtOAc (50 mL), washed with H.sub.2O (3.times.25 mL)
and brine (15 mL), dried the organic phase over anhydrous
MgSO.sub.4, filtered, and concentrated by rotary evaporation to a
yellow residue. Purified by flash chromatography (silica gel,
Alltech Extract-Clean 10 g column, 3% MeOH/CH.sub.2Cl.sub.2) to
afford the title compound as a yellow solid (118 mg). .sup.1H NMR
(400 MHz, DMSO-D6) .delta. ppm 1.29 (s, 11H), 1.39 (s, 7H),
1.72-1.95 (m, 6H), 2.08-2.25 (m, 2H), 3.29 (s, 6H), 3.35-3.49 (m,
3H), 4.12 (d, J=0.87 Hz, 2H), 4.15-4.29 (m, 2H), 5.30-5.45 (m, 2H),
6.28 (dd, J=9.22, 4.45 Hz, 2H), 6.75 (t, J=8.89 Hz, 2H), 7.19 (d,
J=8.35 Hz, 4H), 7.50 (t, J=8.89 Hz, 4H), 9.70-10.14 (m, 2H); MS
(APCI+) m/z 802 (M+H).sup.+.
Example 70G
(2S,2'S)--N,N'-(4,4'-((2S,3R,4R,5)-1-(4-fluorophenyl)-3,4-dimethoxypyrroli-
dine-2,5-diyl)bis((4,1-phenylene))dipyrrolidine-2-carboxamide
[0540] Dissolved the product of Example 70F (112 mg, 0.140 mmol) in
anhydrous CH.sub.2Cl.sub.2 (1 mL) under nitrogen, added TFA (1 mL),
and stirred at 25.degree. C. for 30 min. Removed the solvent by
rotary evaporation, redissolved in 1:5 v/v
CH.sub.2Cl.sub.2/hexanes, and concentrated in vacuo. Took up the
residue in EtOAc (50 mL), washed with sat'd aq NaHCO.sub.3
(2.times.15 mL), dried the organic phase over anhydrous MgSO.sub.4,
filtered, and concentrated by rotary evaporation to afford the
title compound as a yellow solid (72 mg, 84%). .sup.1H NMR (400
MHz, DMSO-D6) .delta. ppm 1.57-1.69 (m, 4H), 1.70-1.85 (m, 2H),
1.96-2.10 (m, 2H), 2.82-2.95 (m, 4H), 3.28 (s, 6H), 3.66 (dd,
J=8.84, 5.58 Hz, 2H), 4.07-4.17 (m, 2H), 5.30-5.49 (m, 2H), 6.28
(dd, J=9.16, 4.39 Hz, 2H), 6.75 (t, J=8.89 Hz, 2H), 7.18 (d, J=8.57
Hz, 4H), 7.56 (d, J=8.57 Hz, 4H), 9.90 (s, 2H); MS (ESI+) m/z 602
(M+H).sup.+.
Example 70H
dimethyl
([(2S,3R,4R,5S)-1-(4-fluorophenyl)-3,4-dimethoxypyrrolidine-2,5-d-
iyl]bis{benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate
[0541] Dissolved the product of Example 70G (69.3 mg, 0.115 mmol)
in anhydrous DMF (1.2 mL) under nitrogen, cooled to 0.degree. C.,
then sequentially added
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (50.4 mg, 0.288
mmol), HOBT monohydrate (44.1 mg, 0.288 mmol), EDAC (56.3 mg, 0.288
mmol), and N-methylmorpholine (0.038 mL, 0.346 mmol). Removed the
cooling bath and stirred at 25.degree. C. for 13 hr. Diluted the
reaction with EtOAc (50 mL), washed with sat'd aq NaHCO.sub.3 (25
mL), H.sub.2O (2.times.25 mL), and brine (25 mL). Dried the organic
phase over anhydrous MgSO.sub.4, filtered, and concentrated by
rotary evaporation. Purified by flash chromatography (silica gel,
2.5 cm.times.15 cm, 6% MeOH/CH.sub.2Cl.sub.2) to afford the title
compound as a white solid (48 mg, 85%). .sup.1H NMR (400 MHz,
DMSO-D6) .delta. ppm 0.88 (d, J=6.61 Hz, 6H), 0.93 (d, J=6.72 Hz,
6H), 1.80-2.05 (m, 8H), 2.08-2.22 (m, 2H), 3.28 (s, 6H), 3.52 (s,
6H), 3.56-3.69 (m, 2H), 3.77-3.88 (m, 2H), 4.03 (t, J=8.51 Hz, 2H),
4.07-4.16 (m, 2H), 4.43 (dd, J=7.97, 4.83 Hz, 2H), 5.29-5.44 (m,
2H), 6.27 (dd, J=9.22, 4.45 Hz, 2H), 6.75 (t, J=8.89 Hz, 2H), 7.17
(d, J=8.46 Hz, 4H), 7.31 (d, J=8.46 Hz, 2H), 7.49 (d, J=8.57 Hz,
4H), 9.99 (s, 2H); MS (ESI+) m/z 408 (M+H).sup.+.
##STR00307##
Example 71
dimethyl
([(2S,3R,4R,5S)-1-(4-fluorophenyl)-3,4-dimethoxypyrrolidine-2,5-d-
iyl]bis{benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimethy-
l-1-oxobutane-1,2-diyl]})biscarbamate
[0542] Dissolved the product of Example 70D (58.5 mg, 0.097 mmol)
in anhydrous DMF (1 mL) under nitrogen, cooled to 0.degree. C.,
then sequentially added
(S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid (46.0 mg,
0.243 mmol), HOBt monohydrate (37.2 mg, 0.243 mmol), EDAC (47.5 mg,
0.243 mmol), and 4-methylmorpholine (0.032 mL, 0.292 mmol). Removed
the cooling bath and stirred overnight at 25.degree. C. for 16 hr.
Diluted the reaction with EtOAc (50 mL), washed with sat'd aq
NaHCO.sub.3 (25 mL), H.sub.2O (2.times.25 mL), and brine (25 mL).
Dried the organic phase over anhydrous MgSO.sub.4, filtered, and
concentrated by rotary evaporation. Purified by flash
chromatography (silica gel, 2.5 cm.times.15 cm, 4%
MeOH/CH.sub.2Cl.sub.2) to afford the title compound as a
cream-colored solid (66 mg, 72%). .sup.1H NMR (400 MHz, DMSO-D6)
.delta. ppm 0.96 (s, 18H), 1.79-1.94 (m, 4H), 1.94-2.06 (m, 2H),
2.10-2.22 (m, 2H), 3.28 (s, 6H), 3.54 (s, 6H), 3.58-3.70 (m, 2H),
3.71-3.86 (m, 2H), 4.06-4.15 (m, 2H), 4.21 (d, J=8.89 Hz, 2H), 4.44
(dd, J=7.92, 5.31 Hz, 2H), 5.31-5.39 (m, 2H), 6.27 (dd, J=9.22,
4.45 Hz, 2H), 6.75 (t, J=8.89 Hz, 2H), 7.08 (d, J=8.78 Hz, 2H),
7.17 (d, J=8.57 Hz, 4H), 7.49 (d, J=8.57 Hz, 4H), 9.99 (s, 2H); MS
(ESI+) m/z 945 (M+H).sup.+.
##STR00308##
Example 72
dimethyl
([1-(4-tert-butylphenyl)-1H-pyrrole-2,5-diyl]bis{benzene-4,1-diyl-
carbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})bis-
carbamate
Example 72A
4,4'-(1-(4-tert-butylphenyl)-1H-pyrrole-2,5-diyl)dianiline
[0543] Example 1A was processed using the methods described
generally in Examples 26F and 19B to provide the title compound. MS
(ESI; M+H) m/z=382.
Example 72B
(2S,2'S)-tert-butyl
2,2'-(4,4'-(1-(4-tert-butylphenyl)-1H-pyrrole-2,5-diyl)bis(4,1-phenylene)-
bis(azanediyl)bis(oxomethylene))dipyrrolidine-1-carboxylate
[0544] To a solution of the product from Example 72A (0.310 g,
0.813 mmol) in DMF (5 mL) was added
(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.385 g,
1.79 mmol) 1-hydroxybenzotriazole hydrate (0.274 g; 1.79 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.343
g, 1.79 mmol) and the mixture stirred overnight. The mixture was
poured into water and extracted CH.sub.2Cl.sub.2. The organic
extract was dried (Na.sub.2SO.sub.4), filtered and concentrated to
give a crude product that was purified by trituration with ether to
give 325 mg (51%) of the title compound. .sup.1H NMR (400 MHz,
DMSO-D6) .delta. 1.25 (s, 24H) 1.83 (s, 6H) 2.15 (s, 2H) 3.45 (m,
4H) 4.18 (s, 2H) 6.40 (s, 2H) 6.98 (s, 6H) 7.37 (s, 6H) 9.98 (s,
2H).
Example 72C
(2S,2'S)--N,N'-(4,4'-(1-(4-tert-butylphenyl)-1H-pyrrole-2,5-diyl)bis(4,1-p-
henylene))dipyrrolidine-2-carboxamide
[0545] To a solution of the product from Example 72B (0.325 g,
0.419 mmol) in CH.sub.2Cl.sub.2 (5 mL) at rt was added TFA (1.0 mL)
and stirring continued for 5 h. The reaction was concentrated and
the residue partitioned between water and 25% isopropyl
alcohol-CHCl.sub.3. The organic phase was dried (Na.sub.2SO.sub.4),
filtered and concentrated to provide the title compound used
directly in the next reaction. MS (DCI; M+H) m/z=576.
Example 72D
dimethyl
([1-(4-tert-butylphenyl)-1H-pyrrole-2,5-diyl]bis{benzene-4,1-diyl-
carbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate
[0546] The product from Example 72C and the product from
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid were processed
using the method described in Example 72B. The crude residue was
purified by silica gel chromatography (1% gradient elution from 0%
to 4% MeOH:CH.sub.2Cl.sub.2) to provide 129 mg (35%) of the title
compound. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 0.89 (s, 12H) 1.25
(s, 9H) 1.89 (s, 6H) 1.98 (s, 2H) 2.13 (s, 2H) 3.52 (s, 6H) 3.61
(s, 2H) 3.80 (s, 2H) 4.00 (s, 2H) 4.39 (s, 2H) 6.38 (s, 2H) 6.95
(s, 6H) 7.34 (s, 8H) 9.96 (s, 2H).
##STR00309##
Example 73
methyl
[(2S)-1-{(2S)-2-[4-(4-{5-(4-{2-[1-{(2S)-1-(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1-[4-(me-
thylsulfonyl)phenyl]-1H-pyrrol-2-yl}phenyl)-1H-imidazol-2-yl]pyrrolidin-1--
yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0547] Example 26E and 4-(methylsulfonyl)aniline were processed
using the methods of Examples 26F, 26G, 26H, 65B, and 65C to
provide the title compound (78 mg). .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 12.17-11.67 (m, 2H), 7.92-7.82 (m, 2H), 7.62-7.49 (m, 4H),
7.48-7.40 (m, 2H), 7.39-7.15 (m, 4H), 7.08-6.92 (m, 4H), 6.59-6.47
(m, 2H), 5.08-4.99 (m, 2H), 4.08-3.98 (m, 2H), 3.84-3.69 (m, 4H),
3.53 (s, 6H), 3.24 (d, J=1.9, 3H), 2.20-1.81 (m, 10H), 0.91-0.77
(m, 12H). MS (ESI; M+H) m/z=959.
##STR00310##
Example 74
methyl
{(2S)-1-[(2S)-2-(5-{4-[1-(4-cyclohexylphenyl)-5-(4-{2-[(2S)-1-{(2S)-
-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol--
5-yl}phenyl)-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-me-
thyl-1-oxobutan-2-yl}carbamate
Example 74A
2,5-bis(4-bromophenyl)-1-(4-cyclohexylphenyl)-1H-pyrrole
[0548] The product from Example 26E and 4-cyclohexylaniline (Alfa)
were processed using the method described in Example 26F to provide
1.23 g (91%) of the title compound. .sup.1H NMR (400 MHz,
benzene-D6) .delta. 1.09 (s, 5H) 1.60 (s, 5H) 2.14 (s, 1H) 6.52 (s,
2H) 6.67 (s, 4H) 6.84 (s, 4H) 7.11 (s, 4H).
Example 74B
1-(4-cyclohexylphenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl)-1H-pyrrole
[0549] The product from Example 74A was processed using the method
described in Example 26G to provide 1.58 g (60%) of the title
compound. MS (ESI; M+H) m/z=630.
Example 74C
(2S,2'S)-tert-butyl
2,2'-(5,5'-(4,4'-(1-(4-cyclohexylphenyl)-1H-pyrrole-2,5-diyl)bis(4,1-phen-
ylene))bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate
[0550] A solution of the product from Example 74B (0.400 g, 0.635
mmol) and the product from Example 26D (0.442 g, 1.40 mmol) in
toluene (3 mL) and ethanol (3 mL) was treated with 1 M sodium
carbonate (2 mL) followed by
1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (0.052 g, 0.064 mmol), the mixture degassed
(3.times. vacuum/purge N.sub.2) and then heated to 90.degree. C.
for 4 h. The reaction was concentrated and the residue partitioned
between 25% isopropyl alcohol-CHCl.sub.3. The organic phase was
dried (Na.sub.2SO.sub.4) concentrated and the residue taken up in
ether, sonicated, filtered and dried to provide 499 mg (93%) of the
title compound. MS (ESI; M+H) m/z=848.
Example 74D
(S)-5,5'-(4,4'-(1-(4-cyclohexylphenyl)-1H-pyrrole-2,5-diyl)bis(4,1-phenyle-
ne))bis(2-((S)-pyrrolidin-2-yl)-1H-imidazole)
[0551] The product from Example 74C was processed using the method
described in Example 19D to provide the title compound. MS (ESI;
M+H) m/z=648.
Example 74E
methyl
{(2S)-1-[(2S)-2-(5-{4-[1-(4-cyclohexylphenyl)-5-(4-{2-[(2S)-1-{(2S)-
-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol--
5-yl}phenyl)-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-me-
thyl-1-oxobutan-2-yl}carbamate
[0552] To a solution of the product from Example 74D (0.190 g,
0.293 mmol) in DMF (5 mL) was added
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.113 g, 0.645
mmol), 1-hydroxybenzotriazole hydrate (0.099 g; 0.645 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.124
g, 0.645 mmol) and the mixture stirred for 3 h. The mixture was
poured into water and extracted CH.sub.2Cl.sub.2. The organic layer
was concentrated and the residue purified by chromatography
(gradient elution from 0% to 4% MeOH--CH.sub.2Cl.sub.2) to provide
100 mg (35%) of the title compound. .sup.1H NMR (400 MHz, DMSO-D6)
.delta. 0.84 (d, J=6.62 Hz, 6H) 0.87 (d, J=6.72 Hz, 6H) 1.20 (m,
2H) 1.35 (m, 4H) 1.78 (m, 4H) 1.92 (m, 6H) 2.10 (m, 4H) 3.52 (s,
6H) 3.76 (m, 4H) 4.02 (m, 2H) 5.03 (m, 2H) 6.47 (m, 2H) 6.99 (m,
6H) 7.18 (m, 3H) 7.27 (m, 2H) 7.41 (m, 2H) 7.51 (m, 4H) 11.74 (s,
2H).
##STR00311##
Example 75
methyl
{(2S)-1-[(2S)-2-(5-{4-[1-(4-cyclohexylphenyl)-5-(4-{2-[(2S)-1-{(2S)-
-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}pyrrolidin-2-yl]-1H-imida-
zol-5-yl}phenyl)-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]--
3,3-dimethyl-1-oxobutan-2-yl}carbamate
[0553] The product from Example 74D and
(S)-2-methoxycarbonylamino-3,3-dimethyl-butyric acid (Org. Process
Res. Develop. 2008, 12, 69) was processed using the method
described in Example 74E to provide 165 mg (57%) of the title
compound. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 0.86-0.96 (m, 18H)
1.23 (m, 2H) 1.36 (m, 4H) 1.78 (m, 4H) 1.88-2.00 (m, 4H) 2.10 (m,
4H) 3.54 (s, 6H) 3.77 (m, 4H) 4.21 (m, 2H) 5.05 (m, 2H) 6.46 (s,
2H) 6.96-7.03 (m, 6H) 7.19 (m, 2H) 7.38-7.55 (m, 7H) 7.70 (d,
J=8.35 Hz, 1H) 7.97 (d, J=8.46 Hz, 1H) 11.76 (s, 2H).
##STR00312##
Example 76
N-(methoxycarbonyl)-L-valyl-N-(4-{1-(4-tert-butylphenyl)-5-[4-(2-{(2S)-1-[-
N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)phenyl]-1H-p-
yrrol-2-yl}phenyl)-L-prolinamide
Example 76A
2-(4-bromophenyl)-1-(4-tert-butylphenyl)-5-(4-nitrophenyl)-1H-pyrrole
[0554] TFA (0.6 mL, 7.79 mmol) was added to a mixture of the
product from Example 39A (1.2335 g, 3.41 mmol) and
4-tert-butylaniline (0.8 mL, 5.07 mmol) in toluene (30 mL) and
heated at 110.degree. C. for 17 hours. The cooled reaction mixture
was poured into ether/water and stirred until nice solid formed.
The mixture was filtered to afford the title compound. .sup.1H NMR
(400 MHz, BENZENE-D6) .delta. 1.02 (s, 9H), 6.48 (d, J=3.8, 1H),
6.52 (d, J=3.8, 1H), 6.63 (d, J=8.5, 2H), 6.80 (d, J=8.5, 2H), 6.84
(d, J=8.9, 2H), 6.89 (d, J=8.5, 2H), 7.10 (d, J=8.5, 2H), 7.70 (d,
J=8.9, 2H).
Example 76B
N-(methoxycarbonyl)-L-valyl-N-(4-{1-(4-tert-butylphenyl)-5-[4-(2-{(2S)-1-[-
N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)phenyl]-1H-p-
yrrol-2-yl}phenyl)-L-prolinamide
[0555] Example 76A was processed using sequentially the methods of
Examples 19B, 55F, 39E (reaction temperature=85.degree. C.), 39F,
55G, and 26J (reaction solvent=dichloromethane) to provide the
title compound (0.14 g). .sup.1H NMR (400 MHz, METHANOL-D4) .delta.
0.94 (ddd, J=21.1, 19.5, 6.7, 12H), 1.30 (s, 10H), 2.36-1.92 (m,
10H), 3.63 (s, 6H), 3.76-3.67 (m, 1H), 3.89-3.78 (m, 1H), 4.02-3.89
(m, 2H), 4.19 (d, J=7.9, 2H), 4.50 (dd, J=8.1, 5.3, 1H), 5.11 (dd,
J=7.6, 5.5, 1H), 6.39 (d, J=3.7, 1H), 6.43 (d, J=3.6, 1H), 7.01
(dt, J=28.2, 8.3, 6H), 7.20 (s, 1H), 7.40 (ddd, J=19.1, 11.9, 5.7,
6H). MS (ESI) m/z 913 (M+H).sup.+.
##STR00313##
Example 77
N-(methoxycarbonyl)-L-valyl-N-(4-{5-[4-(2-{(2S)-1-[N-(methoxycarbonyl)-L-v-
alyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)phenyl]-1-[4-(pentafluoro-lambda.ab-
out.6.about.1-sulfanyl)phenyl]-1H-pyrrol-2-yl}phenyl)-L-prolinamide
[0556] Example 39A and 4-aminophenylsulfurpentafluoridewere
processed using sequentially the methods of Examples 76A, 19B, 55F,
39E (reaction temperature=85.degree. C.), 39F, 55G, and 26J
(reaction solvent=DMF) to provide the title compound (0.36 g).
.sup.1H NMR (400 MHz, DMSO-D6) .delta. 0.86 (ddd, J=6.9, 15.8,
21.6, 12H), 2.04-1.76 (m, 7H), 2.24-2.04 (m, 3H), 3.53 (d, J=3.0,
6H), 3.61 (dd, J=6.7, 16.0, 1H), 3.88-3.67 (m, 3H), 4.03 (dd,
J=8.3, 14.1, 2H), 4.40 (dd, J=5.0, 8.0, 1H), 5.12-4.92 (m, 1H),
6.49 (ddd, J=3.6, 14.2, 18.1, 2H), 7.09-6.84 (m, 4H), 7.38-7.12 (m,
4H), 7.50-7.38 (m, 3H), 7.58 (dd, J=8.3, 16.7, 2H), 7.89 (t, J=8.7,
2H), 10.01 (d, J=20.9, 1H), 12.16-11.66 (m, 1H). MS (ESI) m/z 983
(M+H).sup.+, 981 (M-H).sup.+.
##STR00314##
Example 78
methyl
{(2S)-1-[(2S)-2-(5-{3-[1-(4-tert-butylphenyl)-5-(4-{2-[(2S)-1-{(2S)-
-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol--
5-yl}phenyl)-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-me-
thyl-1-oxobutan-2-yl}carbamate
[0557] 2,4'-Dibromoacetophenone and 3'-bromoacetophenone were
processed using sequentially the methods of Examples 26E, 26F, 26G,
74C, 19D, and 74E to provide the title compound (232 mg). .sup.1H
NMR (400 MHz, DMSO-D6) .delta. 0.81-0.91 (m, 12H) 1.25 (s, 9H) 1.93
(m, 4H) 2.11 (m, 4H) 3.53 (s, 6H) 3.78 (m, 4H) 4.04 (m, 2H) 5.03
(m, 2H) 6.49 (m, 2H) 6.90-7.08 (m, 5H) 7.11-7.21 (m, 1H) 7.27-7.55
(m, 9H) 7.71 (d, J=8.35 Hz, 1H) 7.94-8.01 (m, 2H) 11.72 (br s,
2H).
##STR00315##
Example 79
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2R,3S,4S,5R)-1-(4-tert-butylphenyl)-3,4-dim-
ethoxy-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}p-
yrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazo-
l-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
Example 79A
1,2:3,4:5,6-Tri-O-isopropylidene-L-mannitol
[0558] A solution of L-mannonic acid y-lactone (9.87 g, 55.4 mmol)
in methanol (150 mL) at 0.degree. C. was treated with lithium
borohydride (2.1 g, 97 mmol) over 30 min. After addition was
complete, the mixture was warmed to RT for 30 min. The mixture was
then cautiously treated with a solution of hydrogen chloride in
dioxane (4 N, 2 mL). The solution was then concentrated in vacuo,
first on the rotary evaporator and then under high vacuum (0.3 mm
Hg) while warming with a heat gun to remove the last traces of
methanol. The solid obtained was then suspended in acetone (50 mL)
and treated with 2,2-dimethoxypropane (41 mL, 34.6 g, 332 mmol) and
a solution of hydrogen chloride in dioxane (4 N, 42 mL, 166 mmol)
followed by stirring at RT for 18 h. The mixture was concentrated
in vacuo to ca. 20% of original volume, and the inhomogeneous
mixture was added to saturated sodium bicarbonate solution (200 mL)
followed by stirring for 48 h. The precipitate was collected by
filtration and washed with water and air dried. The white solid was
dissolved in ethanol (200 proof, 175 mL) and filtered through
celite to remove particulate matter. The solution was cooled to
-78.degree. C. to effect crystallization. The solid was collected
by filtration, and the mother liquors concentrated to ca. half
volume, and re-cooled to -78.degree. C. The second crop of crystals
was collected by filtration and washed with ethanol. After drying
in a vacuum oven at 50.degree. C. for 3 h, these procedures
afforded the title compound (9.88 g, 59%) as a fluffy white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.19 (dt, J=6.0, 3.0 Hz,
2H), 4.08 (dd, J=8.3, 6.4 Hz, 2H), 3.99 (m, 2H), 3.95 (m, 2H), 1.43
(s, 6H), 1.39 (s, 6H), 1.36 (s, 6H). MS (+ESI) m/z (rel abundance)
303 (100, M+H), 320 (43, M+NH4).
Example 79B
3,4-O-Isopropylidene-L-mannitol
[0559] The compound of Example 79A (9.88 g, 32.7 mmol) was
suspended in 60% (v/v) acetic acid in water (150 mL) in a 1 L
roundbottom and the flask placed on the rotory evaporator and
rotated in the heating bath at 45.degree. C. for 1.5 h. The heating
bath was reduced in temperature to 40.degree. C. and a line to the
vacuum pump was attached to the rotory evaporator. The mixture was
concentrated under ca. 1 mm Hg pressure to a wet solid. This
material was diluted with dichloromethane (100 mL) and stirred at
RT for 10 min. The solution was filtered through celite, and the
filtrate concentrated in vacuo. The residue was dissolved in
toluene and concentrated in vacuo (2.times.) to remove residual
acetic acid. The white solid was then triturated with ether (60 mL)
and collected by filtration. After drying in a vacuum oven for 18
h, these procedures afforded the title compound (2.46 g, 34%) as a
white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 5.07 (d,
J=4.5 Hz, 2H), 4.45 (t, J=5.7 Hz, 2H), 3.86 (dd, J=4.9, 1.5 Hz,
2H), 3.54 (ddd, J=10.9, 5.5, 3.1 Hz, 2H), 3.48 (d, J=4.6 Hz, 2H),
3.37 (m, 2H), 1.28 (s, 6H).
Example 79C
(2R,3
S,4S,5R)-1-(4-tert-butylphenyl)-2,5-bis(4-(4-methoxybenzyloxy)phenyl-
)-pyrrolidine-3,4-diol
[0560] To a solution of Example 79B (1.0 g, 4.5 mmol) in CH.sub.3OH
(12.0 mL) and CH.sub.2Cl.sub.2 (6.0 mL) was added iodobenzene
diacetate (3.48 g, 10.8 mmol) and the solution was stirred at room
temperature for 5 h. Solvent was removed in vacuo and to the
residue was added 0.1 M H.sub.2SO.sub.4 (4 mL) and the solution was
stirred at room temperature for 18 h. The pH was adjusted to -6
with solid NaHCO.sub.3, and 4-tert-butylaniline (1.43 mL, 9.0 mmol)
was added followed by 4-(4-methoxybenzyloxy)phenylboronic acid
(2.09 g, 8.1 mmol) and hexafluoroisopropyl alcohol (8 mL). The
solution was heated at 50.degree. C. for 2 h, cooled and solvent
removed in vacuo leaving the aqueous layer which contained quite a
bit of solid material. The mixture was diluted with H.sub.2O and
0.33 M K.sub.3PO.sub.4 was added and the mixture was stirred
vigorously. The resulting white solid was collected by filtration
and dried in a vacuum oven to give title compound (1.49 g, 2.26
mmol, 50%). .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.10 (s, 9H)
3.75 (s, 6H) 4.21 (s, 2H) 4.95 (s, 2H) 5.02 (d, J=6.9 Hz, 2H) 5.75
(s, 2H) 6.20 (d, J=8.9 Hz, 2H) 6.85-6.97 (m, 10H) 7.05 (d, J=8.6
Hz, 4H) 7.37 (d, J=8.7 Hz, 4H).
Example 79D
(2R,3
S,4S,5R)-1-(4-tert-butylphenyl)-3,4-dimethoxy-2,5-bis-(4-(4-methoxyb-
enzyloxy)phenyl)pyrrolidine
[0561] To a solution of Example 79C (1.49 g, 2.26 mmol) in THF (17
mL) and DMF (5.7 mL) at 0.degree. C. was added, in portions, NaH,
60% in mineral oil (0.27 g, 6.77 mmol) and the mixture was stirred
at 0.degree. C. for 20 min. Iodomethane (0.31 mL, 4.97 mmol) was
added and the reaction mixture was stirred at room temperature for
18 h, diluted with EtOAc, washed with saturated NH.sub.4Cl,
H.sub.2O, and brine, dried (Na.sub.2SO.sub.4), filtered and solvent
removed in vacuo to give an oily product. The oil was diluted with
minimal ether and the oil began to solidify and the title compound
was isolated as a colorless solid (1.55 g, 2.25 mmol, 100%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.16 (s, 6H) 3.44 (s,
6H) 3.82 (s, 6H) 4.12-4.17 (m, 2H) 4.94 (s, 4H) 5.22 (dd, J=5.2,
1.63 Hz, 2H) 6.29 (d, J=8.9 Hz, 2H) 6.88-7.00 (m, 10H) 7.12 (d,
J=8.6 Hz, 4H) 7.34 (d, J=8.6 Hz, 4H). MS (ESI) m/z 688
(M+H).sup.+.
Example 79E
4,4'-((2R,3
S,4S,5R)-1-(4-tert-butylphenyl)-3,4-dimethoxypyrrolidine-2,5-diyl)dipheno-
l
[0562] To a solution of Example 79D (1.55 g, 2.25 mmol) in
CH.sub.2Cl.sub.2 (9 mL) was added trifluoroacetic acid (9 mL, 117
mmol) and stirring was continued at room temperature for 1 h.
Solvent was removed and the crude residue was dissolved in 1:1
EtOAc/saturated NaHCO.sub.3. The organic layer was separated,
washed with brine, dried (Na.sub.2SO.sub.4), filtered and solvent
removed in vacuo to give title compound (1.0 g, 2.23 mmol, 99%). MS
(ESI) m/z 448 (M+H).sup.+.
Example 79F
4,4'-((2R,3
S,4S,5R)-1-(4-tert-butylphenyl)-3,4-dimethoxypyrrolidine-2,5-diyl)bis(4,1-
-phenylene)bis(1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate)
[0563] To a solution of Example 79E (1.0 g, 2.23 mmol) in DMF (12
mL) was added K.sub.2CO.sub.3 (0.695 g, 5.0 mmol) and
1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (0.86 mL,
4.9 mmol) and the solution was stirred at 100.degree. C. for 1 h.
The cooled solution was diluted with EtOAc, washed with H.sub.2O,
brine, dried (Na.sub.2SO.sub.4), filtered and solvent removed in
vacuo to give crude product which was purified by flash
chromatography on silica gel eluting with 0-20% EtOAc/hexane to
give the title compound (1.63 g, 1.61 mmol, 72%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 1.17 (s, 9H) 3.42 (s, 6H) 4.10 (dd,
J=5.3, 1.90 Hz, 2H) 5.30 (dd, J=5.2, 1.9 Hz, 2H) 6.19 (d, J=8.8 Hz,
2H) 6.99-7.03 (m, 2H) 7.21-7.29 (m, 8H). MS (ESI) m/z 1012
(M+H).sup.+.
Example 79G
(2R,3
S,4S,5R)-1-(4-tert-butylphenyl)-3,4-dimethoxy-2,5-bis(4-(4,4,5,5-tet-
ramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine
[0564] To a pressure tube was combined Example 79F (216 mg, 0.21
mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane)
(114 mg, 0.45 mmol),
dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (16.3 mg,
0.034 mmol), potassium acetate (126 mg, 1.28 mmol) and dioxane (2
mL) and the mixture was de-gassed with N.sub.2 gas for 30 min.
Tris(dibenzylideneacetone)dipalladium(0) (7.8 mg, 8.54 mmol) was
added and de-gassing was continued for 10 min. The tube was sealed
and heated at 100.degree. C. for 30 min. The cooled solution was
diluted with EtOAc, washed with H.sub.2O, brine, dried
(Na.sub.2SO.sub.4), filtered and the filtrate treated with
3-mercaptopropyl functionalized silica gel for 1 h, filtered and
solvent removed in vacuo to give the title compound (143 mg,
100%).
Example 79H
(2S,2'S)-tert-butyl
2,2'-(4,4'-(4,4'-((2R,3S,4S,5R)-1-(4-tert-butylphenyl)-3,4-dimethoxypyrro-
lidine-2,5-diyl)bis(4,1-phenylene)bis(1H-imidazole-4,2-diyl))dipyrrolidine-
-1-carboxylate
[0565] To a pressure tube was combined Example 79G (140 mg, 0.21
mmol),
(S)-tert-butyl-2-(4-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate
(Example 26D) (166 mg, 0.524 mmol), 1 M Na.sub.2CO.sub.3 (0.524 mL,
0.524 mmol), EtOH (1 mL), and toluene (1 mL) and the mixture was
de-gassed with N.sub.2 gas for 30 min.
1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II)
dichloromethane complex (15.3 mg, 0.021 mmol) was added and
de-gassing was continued for 10 min. The tube was sealed and heated
at 100.degree. C. for 3 h, then stirred at room temperature for 16
h. The solution was diluted with EtOAc, filtered through Celite and
the filtrate washed with brine, dried (Na.sub.2SO.sub.4), filtered
and solvent removed in vacuo. Purified by flash chromatography on
silica gel eluting with 0-100% EtOAc/hexane to give title compound
(119 mg, 0.135 mmol, 64%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 1.13 (s, 9H) 1.49 (s, 18H) 1.88-2.02 (m, 2H) 2.06-2.22
(m, 4H) 2.99 (s, 2H) 3.33-3.48 (m, 4H) 3.43 (s, 6H) 4.23 (s, 2H)
4.96 (d, J=5.3 Hz, 2H) 5.29 (d, J=6.9 Hz, 2H) 6.29 (d, J=8.9 Hz,
2H) 6.94 (d, J=8.4 Hz, 2H) 7.13-7.29 (m, 8H). MS (ESI) m/z 886
(M+H).sup.+.
Example 791
methyl {(2S)-1-[(2S)-2-(4-{4-[(2R,3
S,4S,5R)-1-(4-tert-butylphenyl)-3,4-dimethoxy-5-(4-{2-[(2)-1-{(2S)-2-[(me-
thoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}ph-
enyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1--
oxobutan-2-yl}carbamate
[0566] To a solution of Example 79H (30 mg, 0.034 mmol) in
CH.sub.2Cl.sub.2 (1 mL) was added trifluoroacetic acid (1 mL) and
the solution was stirred at room temperature for 1 h. Solvent was
removed in vacuo and then dissolved in DMSO (0.5 mL).
N,N-diisopropylethylamine was added until pH 9-10, then
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (14.8 mg, 0.085
mmol) was added followed by HATU (32 mg, 0.085 mmol) and the
solution was stirred at room temperature for 1 h. The solution was
diluted with EtOAc, washed with H.sub.2O, brine, dried
(Na.sub.2SO.sub.4), filtered and solvent removed in vacuo.
Dissolved the residue in CH.sub.3OH (2 mL), added solid
K.sub.2CO.sub.3 and stirred at room temperature for 30 min. Solid
was filtered off and the filtrate was concentrated in vacuo and the
residue purified by flash chromatography on silica gel eluting with
0-5% CH.sub.3OH/CH.sub.2Cl.sub.2 to give title compound (21.6 mg,
0.022 mmol, 63%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
0.85 (s, 12H) 1.13 (s, 9H) 1.82-2.03 (m, 2H) 2.02-2.24 (m, 4H) 2.32
(br s, 2H) 3.04 (br s, 2H) 3.43 (s, 6H) 3.53-3.65 (m, 2H) 3.70 (s,
6H) 3.75-3.90 (m, 2H) 4.22 (s, 2H) 4.31 (d, J=15.7 Hz, 2H)
5.16-5.33 (m, 4H) 5.37 (d, J=9.1 Hz, 2H) 6.29 (d, J=8.9 Hz, 2H)
6.94 (s, 2H) 7.16 (s, 2H) 7.22 (d, J=8.0 Hz, 4H) 7.31-7.52 (m, 2H)
7.60-7.87 (m, 2H) 10.26 (s, 1H) 10.64 (s, 1H). MS (ESI) m/z 1000
(M+H).sup.+.
##STR00316##
Example 80
methyl
[(2S)-1-{(2S)-2-[5-(4-{1-[4-(dimethylamino)phenyl]-5-(4-{2-[(2S)-1--
{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imid-
azol-5-yl}phenyl)-1H-pyrrol-2-yl}phenyl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-
-3-methyl-1-oxobutan-2-yl]carbamate
[0567] Example 26E and N,N-dimethyl-p-phenylenediamine were
processed using sequentially the methods of Examples 76A, 39E, 39F,
55G (25% isopropylalcohol/chloroform used for extraction), and 26J
(reaction solvent=dichloromethane) to provide the title compound
(5.6 mg). 1H NMR (400 MHz, DMSO-d6) .delta. 0.94-0.75 (m, 12H),
2.04-1.78 (m, 6H), 2.21-2.03 (m, 4H), 2.89 (s, 6H), 3.38 (s, 1H),
3.53 (s, 6H), 3.84-3.68 (m, 3H), 4.10-3.96 (m, 2H), 5.04 (dd,
J=2.9, 6.7, 2H), 6.53-6.37 (m, 2H), 6.70-6.54 (m, 2H), 7.12-6.85
(m, 6H), 7.33-7.12 (m, 2H), 7.46-7.34 (m, 2H), 7.60-7.46 (m, 4H),
12.11-11.64 (m, 2H). MS (ESI) m/z 923 (M+H).sup.+.
##STR00317##
Example 81
dimethyl
([(2S,5S)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1--
diylcarbamoyl[(2S,4S)-4-hydroxypyrrolidine-2,1-diyl][(2S)-3,3-dimethyl-1-o-
xobutane-1,2-diyl]})biscarbamate and
dimethyl
([(2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1--
diylcarbamoyl[(2S,4S)-4-hydroxypyrrolidine-2,1-diyl][(2S)-3,3-dimethyl-1-o-
xobutane-1,2-diyl]})biscarbamate
Example 81A
(2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic
acid
[0568] To a solution of (2S,4S)-4-hydroxypyrrolidine-2-carboxylic
acid (3.9 g, 29.7 mmol) in THF (26.7 mL) and water (13.3 mL) was
added di-tert-butyl dicarbonate (7.14 g, 32.7 mmol) and sodium
hydroxide (2.0 N, 22.9 mL, 45.8 mmol) and the mixture stirred at
room temperature overnight. The mixture then had 10% citric acid
(50 mL) added followed by EtOAc and extraction with water and
brine. The organic extract was dried, filtered and concentrated to
afford 5.31 g (77%) of the title compound. MS (ESI) m/z 232
(M+H)+.
Example 81B
(2S,4S)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine--
2-carboxylic acid
[0569] To a solution of Example 81A (5.31, 22.96 mmol) and
imidazole (7.82 g, 115 mmol) in dichloromethane (106 mL) and DMF
(21.3 mL) was added tert-butyldimethylsilyl chloride (7.61 g, 50.5
mmol) and the mixture stirred at room temperature overnight. The
mixture then had water (425 mL) added and the solution was
extracted with EtOAc and the organic extract concentrated to a
residue that was dissolved in 25% EtOAc and 75% hexanes then
extracted with brine and the organic extract concentrated to a
solid. The resultant solid was dissolved in methanol (65 mL) and
water (85 mL) then lithium hydroxide monohydrate (1.93 g, 46 mmol)
added and the solution stirred at room temperature for 2 h.
Afterwards water (106 mL) and a solution of IN aqueous hydrochloric
acid was added until a pH of 2 was reached. The mixture was then
extracted with a mixture of 25% EtOAc and 75% hexanes, the organic
extract dried, filtered and concentrated to a colorless solid. MS
(ESI) m/z 346 (M+H)+.
Example 81C
(3 S,3'S,5 S,5'S)-tert-butyl
5,5'-(4,4'-((2S,5S)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1-phenyl-
ene))bis(azanediyl)bis(oxomethylene)bis(3-(tert-butyldimethylsilyloxy)pyrr-
olidine-1-carboxylate) and
(3S,3'S,5 S,5'S)-tert-butyl
5,5'-(4,4'-((2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(4,1-phenyl-
ene))bis(azanediyl)bis(oxomethylene)bis(3-(tert-butyldimethylsilyloxy)pyrr-
olidine-1-carboxylate)
[0570] The product of Example 81B (149 mg, 0.432 mmol) and the
product from Example 5A (50 mg, 0.144 mmol) were processed using
the method described in Example 1F to afford 74 mg (51%) of the
title compound as a 1:1 mixture of diastereomers. MS (ESI) m/z 1002
(M+H)+.
Example 81D
(2S,2'S,4S,4'S)--N,N'-(4,4'-((2S,5S)-1-(4-fluorophenyl)pyrrolidine-2,5-diy-
l)bis(4,1-phenylene))bis(4-hydroxypyrrolidine-2-carboxamide)
and
(2S,2'S,4S,4'S)--N,N'-(4,4'-((2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diy-
l)bis(4,1-phenylene))bis(4-hydroxypyrrolidine-2-carboxamide)
[0571] The product of Example 81C (74 mg, 0.074 mmol) was dissolved
in trifluoroacetic acid (4 mL), water (0.2 mL) and dichloromethane
(0.2 mL) and the mixture stirred at room temperature for 3 hours.
Afterwards the mixture was concentrated to an oil which was
dissolved in 75% CHCl.sub.3 and 25% isopropyl alcohol then
extracted with a saturated aqueous sodium bicarbonate solution, the
organic extract separated, dried, filtered and concentrated to a
colorless solid. MS (ESI) m/z 574 (M+H)+.
Example 81E
dimethyl
([(2S,5S)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1--
diylcarbamoyl[(2S,4S)-4-hydroxypyrrolidine-2,1-diyl][(2S)-3,3-dimethyl-1-o-
xobutane-1,2-diyl]})biscarbamate and
dimethyl
([(2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1--
diylcarbamoyl[(2S,4S)-4-hydroxypyrrolidine-2,1-diyl][(2S)-3,3-dimethyl-1-o-
xobutane-1,2-diyl]})biscarbamate
[0572] To the product from Example 81D (40 mg, 0.072 mmol),
(S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid (34.1 mg,
0.18 mmol) and HATU (60.2 mg, 0.158 mmol) in DMSO (3 mL) was added
Hunig's base (0.063 mL, 0.36 mmol), and the reaction mixture was
stirred at room temperature for 1 hr. The reaction mixture was
partitioned between water and ethyl acetate, and the organic layer
was dried over MgSO.sub.4, filtered and concentrated in vacuo. The
crude product was purified by column chromatography on silica gel
using a solvent gradient of 0-10% MeOH in dichloromethane to give
the title compound as a 1:1 mixture of stereoisomers (21 mg, 32%
yield): .sup.1H NMR (400 MHz, DMSO-D6) .delta. ppm 9.94 (s, 2H),
7.44 (d, J=8.4 Hz, 4H), 7.07 (m, 6H) 6.74 (t, J=8.9 Hz, 2H), 6.15
(dd, J=9.1, 4.4 Hz, 2H), 5.26 (dd, J=6.1, 3.3 Hz, 2H), 5.11 (d,
J=5.5 Hz, 2H), 4.33 (t, J=7.8 Hz, 2H), 4.19 (m, 2H), 4.07 (m, 2H),
3.93 (m, 2H), 3.48 (s, 6H), 2.34 (m, 2H), 1.66 (m, 2H), 1.59 (m,
2H), 1.20 (m, 2H), 0.91 (m, 18H).
##STR00318##
Example 82
dimethyl
([(2S,5S)-1-(3-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimethyl-1-oxobutane-1,2-di-
yl]})biscarbamate and
dimethyl
([(2R,5R)-1-(3-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimethyl-1-oxobutane-1,2-di-
yl]})biscarbamate
[0573] Example 1C and 3-fluoroaniline were processed using
sequentially the methods of Examples 1D, 1E, 1F, 1G, and 1H to
provide the title compounds. The trans diastereomers were separated
from the cis diastereomer at the stage of
4,4'-(1-(3-fluorophenyl)pyrrolidine-2,5-diyl)dianiline. Data for
the title compounds. .sup.1H NMR (free base) (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.96 (d, J=2.17 Hz, 18H), 1.75-1.92 (m,
7H), 1.93-2.05 (m, 2H), 2.10-2.21 (m, 2H), 2.31-2.44 (m, 2H),
3.43-3.51 (m, 4H), 3.53 (s, 6H), 3.59-3.73 (m, 6H), 3.73-3.82 (m,
2H), 4.21 (d, J=8.89 Hz, 2H), 4.46 (dd, J=7.92, 5.31 Hz, 2H), 4.70
(t, J=4.66 Hz, 2H), 6.07 (d, J=12.90 Hz, 1H), 6.19 (dd, J=8.35,
1.63 Hz, 1H), 6.37 (dt, J=8.35, 2.06 Hz, 1H), 6.97-7.05 (m, 2H),
7.08 (d, J=8.67 Hz, 2H), 7.41 (d, J=7.26 Hz, 4H), 7.60 (d, J=8.57
Hz, 4H), 10.07 (s, 2H). MS (ESI) m/z 885 (M+H).sup.+.
##STR00319##
Example 83
dimethyl
([(2S,5S)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-3,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimethyl-1-oxobutane-1,2-di-
yl]})biscarbamate and
dimethyl
([(2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-3,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimethyl-1-oxobutane-1,2-di-
yl]})biscarbamate
Example 83A
(2S,2'S)-tert-butyl
2,2'-(3,3'-((2S,5S)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(3,1-phenyl-
ene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate
and
(2S,2'S)-tert-butyl
2,2'-(3,3'-((2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(3,1-phenyl-
ene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate
[0574] The ether fraction from the work up of Example 55F was
purified using flash chromatography (silica gel, 0-30%
EtOAc/dichloromethane) to afford the title compound as a mixture of
trans diastereomers. MS (ESI) m/z 742 (M+H).sup.+.
Example 83B
dimethyl
([(2S,5S)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-3,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimethyl-1-oxobutane-1,2-di-
yl]})biscarbamate and
dimethyl
([(2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-3,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimethyl-1-oxobutane-1,2-di-
yl]})biscarbamate
[0575] The product from Example 83A was processed using the methods
described in Examples 55G and 55H to afford the title compound
(0.18 g, 27%). .sup.1H NMR (400 MHz, DMSO-D6) .delta. 0.97 (d,
J=4.5, 18H), 1.73-1.60 (m, 2H), 1.92-1.75 (m, 5H), 2.05-1.92 (m,
3H), 2.23-2.05 (m, 2H), 3.54 (d, J=1.5, 6H), 3.71-3.59 (m, 2H),
3.85-3.71 (m, 2H), 4.21 (d, J=8.9, 2H), 4.50-4.37 (m, 2H), 5.14 (d,
J=5.7, 2H), 6.30-6.19 (m, 2H), 6.85-6.75 (m, 2H), 6.88 (d, J=7.7,
2H), 7.09 (d, J=8.7, 2H), 7.23 (t, J=7.9, 2H), 7.40-7.30 (m, 2H),
7.58 (d, J=8.1, 2H), 10.07-9.96 (m, 2H). MS (ESI) m/z 884
(M+H).sup.+, 882 (M-H).sup.+.
##STR00320##
Example 84
dimethyl
([(2S,5S)-1-(4-methylphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate and
dimethyl
([(2R,5R)-1-(4-methylphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate
[0576] The title compound was prepared using the procedures
described for the synthesis of Examples 34A, 34B, 34C, 34D, and
34E, substituting 4-methylaniline for 4-tert-butylaniline. 1H NMR
(500 MHz, DMSO-D6) .delta. ppm 0.85-0.90 (m, 6H), 0.90-0.95 (m,
6H), 1.61-1.65 (m, 2H), 1.82-2.01 (m, 8H), 2.03 (s, 3H), 2.09-2.16
(m, 2H), 3.52 (s, 6H), 3.58-3.66 (m, 2H), 3.77-3.84 (m, 2H), 4.02
(t, 2H), 4.40-4.45 (m, 2H), 5.14 (d, J=6.6 Hz, 2H), 6.13-6.18 (m,
2H), 6.72 (d, J=8.4 Hz, 2H), 7.08-7.14 (m, 4H), 7.29-7.34 (m, 2H),
7.46-7.51 (m, 4H), 9.98 (s, 2H); MS m/z 852.3 (M+H).sup.+.
##STR00321##
Example 85
dimethyl
([(2S,5S)-1-(4-chlorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate and
dimethyl
([(2R,5R)-1-(4-chlorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate
Example 85A
1-(4-chlorophenyl)-2,5-bis(4-nitrophenyl)pyrrolidine
[0577] The product of Example 1B (0.50 g, 1.51 mmol) was suspended
in CH.sub.2Cl.sub.2 (15 mL). Triethylamine (0.626 mL, 4.51 mmol)
was added at 0.degree. C., the resulting mixture was stirred for 30
min, and methanesulfonyl chloride (0.293 mL, 3.76 mmol) was added.
The mixture was stirred at rt for 1 hr and then concentrated in
vacuo to give a light yellow solid. The solid was dissolved in DMF
(6 mL), 4-chloroaniline (1.92 g, 15.05 mmol) was added, and the
resulting mixture was stirred at 50.degree. C. overnight. The
mixture was partitioned between EtOAc and 1N aq HCl, and the
organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel using a solvent gradient of 0-12%
EtOAc in hexane to give the title compound (0.226 g, 35%).
Example 85B
4,4'-(trans-1-(4-chlorophenyl)pyrrolidine-2,5-diyl)dianiline
[0578] To a solution of the product of example 85A (0.214 g, 0.505
mmol) in EtOH (2.52 mL) and THF (2.52 mL) was added platinum(IV)
oxide (0.115 g, 0.505 mmol), and the resulting mixture was stirred
at rt under 1 atm H.sub.2 overnight. The mixture was filtered
through celite, and the filtrate was concentrated in vacuo. The
crude product was purified by column chromatography on silica gel
using a solvent gradient of 0-12% EtOAc in hexane to give a-mixture
of the title compound and some dichlorinated product
(4,4'-(trans-1-phenylpyrrolidine-2,5-diyl)dianiline).
Example 85C
dimethyl
([(2S,5S)-1-(4-chlorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]}-
)biscarbamate and
dimethyl
([(2R,5R)-1-(4-chlorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate
[0579] A mixture of the product from Example 85B was subjected to
the procedures described in Examples 34C, 34D, and 34E to give the
title compounds free of dichlorinated product. 1H NMR (TFA salt)
(400 MHz, DMSO-D6) .delta. ppm 0.84-0.89 (m, 6H), 0.89-0.94 (m,
6H), 1.61-1.66 (m, 2H), 1.80-2.03 (m, 8H), 2.06-2.18 (m, 2H), 3.51
(s, 6H), 3.56-3.65 (m, 2H), 3.74-3.84 (m, 2H), 4.01 (t, J=8.4 Hz,
2H), 4.36-4.44 (m, 2H), 5.16 (d, J=6.3 Hz, 2H), 6.21 (d, J=8.9 Hz,
2H), 6.93 (d, J=9.0 Hz, 2H), 7.08-7.13 (m, 4H), 7.26-7.31 (m, 2H),
7.46-7.51 (m, 4H), 9.99 (s, 2H). MS m/z 872.3 (M+H).sup.+.
##STR00322##
Example 86
dimethyl
([(2S,5S)-1-(4-bromophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1-d-
iylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})-
biscarbamate and
dimethyl
([(2R,5R)-1-(4-bromophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1-d-
iylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})-
biscarbamate
Example 86A
1-(4-bromophenyl)-2,5-bis(4-nitrophenyl)pyrrolidine
[0580] The product from Example 1C (0.7 g, 1.433 mmol) and
4-bromoaniline (2.54 g, 14.33 mmol) were suspended in DMF (6 mL)
and stirred at 50.degree. C. overnight. The resulting mixture was
partitioned between ethyl acetate (100 mL) and water (50 mL). The
organic phase was washed with IN HCl (2.times.50 mL) followed by a
brine wash then dried over MgSO.sub.4 filtered and concentrated.
The crude product was purified by chromatography on silica gel.
using a solvent gradient of 2-50% ethyl acetate in hexane to give
the title compound as a mixture of stereoisomers (74.4 mg, 11%
yield).
Example 86B
(2S,2'S)--N,N'-(4,4'-(1-(4-bromophenyl)pyrrolidine-2,5-diyl)bis(4,1-phenyl-
ene))dipyrrolidine-2-carboxamide
[0581] Example 86A was processed using the methods of Examples 1E,
1F, and 1G to provide the title compound as a mixture of
stereoisomers.
Example 86C
dimethyl
([1-(4-bromophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1-diylcarba-
moyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarba-
mate
[0582] The product from Example 86B (78.0 mg, 0.129 mmole) was
combined with EDAC (67.0 mg, 0.347 mmol), 1-hydroxybenzotriazole
hydrate (49.0 mg, 0.323 mmole) and
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (61.0 mg, 0.346
mmole) in dimethylformamide (1.4 mL) at room temperature under a
nitrogen atmosphere. To this solution was added
diisopropylethylamine (0.113 mL, 0.645 mmol). The mixture was
allowed to stir overnight at room temperature followed by partition
between ethyl acetate (20 mL) and water (5 mL). The organic phase
was washed with water (3.times.5 mL) then dried over MgSO.sub.4,
filtered and evaporated to dryness. The crude product was
chromatographed by reverse phase (C.sub.18) HPLC providing the
title compound as a 1:1 mixture of (trans) diastereomers (0.045 g,
38% yield) as an off white solid. 1H NMR (free base) (400 MHz,
DMSO-D6) .delta. ppm 0.72-1.03 (m, 12H) 1.65 (s, 2H) 1.79-2.19 (m,
11H) 3.52 (s, 6H) 3.58-3.67 (m, 2H) 3.75-3.86 (m, 2H) 3.95-4.09 (m,
2H) 4.43 (dd, J=7.92, 4.88 Hz, 2H) 5.08-5.25 (m, 2H) 6.19 (d,
J=8.89 Hz, 2H) 7.06 (d, J=8.89 Hz, 2H) 7.12 (d, J=7.16 Hz, 4H) 7.31
(dd, J=8.29, 3.96 Hz, 2H) 7.51 (dd, J=8.46, 1.52 Hz, 4H) 10.00 (s,
2H). MS ESI(+) m/z@ 916.6 (M+H)+.
##STR00323##
Example 87
methyl
{(2S)-1-[(2S)-2-{5-[(2S,5S)-1-(4-fluorophenyl)-5-{2-[(2S)-1-{(2S)-2-
-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}pyrrolidin-2-yl]-H-benzimid-
azol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3,3-dimet-
hyl-1-oxobutan-2-yl}carbamate and
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(4-fluorophenyl)-5-{2-[(2S)-1-{(2S)-2-
-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}pyrrolidin-2-yl]-H-benzimid-
azol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3,3-dimet-
hyl-1-oxobutan-2-yl}carbamate
[0583] The product from Example 29G (0.045 g, 0.084 mmol),
(S)-2-methoxycarbonylamino-3,3-dimethyl-butyric acid (0.037 g,
0.193 mmol), 4-methylmorpholine (0.037 mL, 0.336 mmol),
1H-benzo[d][1,2,3]triazol-1-ol hydrate (0.028 g, 0.185 mmol) and
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (0.035 g, 0.185 mmol) were combined in 2 mL DMF and
stirred for 2 hours. The reaction mixture was partitioned between
EtOAc and water. The organic layer was washed 3.times.20 mL with
brine, dried (Na.sub.2SO.sub.4), filtered and concentrated. The
crude material was flash chromatographed on a 4 g Isco Gold silica
cartridge eluting with 1.5-8% MeOH in methylene chloride. A second
reverse phase C-18 preparative chromatography eluting with 9:1
water/acetonitrile.fwdarw.100% acetonitrile afforded the title
compounds (29 mg, 28%; mix of trans diastereomers) as a light tan
powder. .sup.1H NMR (TFA salt) (400 MHz, DMSO-d.sub.6) .delta.
0.84-0.95 (m, 18H) 1.21-1.46 (m, 4H) 1.75-2.27 (m, 8H) 3.56 (s, 6H)
3.86 (t, J=5.26 Hz, 4H) 4.22 (dd, J=8.57, 4.45 Hz, 2H) 5.15-5.24
(m, 2H) 5.53 (d, J=4.88 Hz, 2H) 6.30 (dd, J=9.11, 4.34 Hz, 2H)
6.75-6.83 (m, 2H) 7.29 (d, J=8.57 Hz, 2H) 7.35 (d, J=8.46 Hz, 2H)
7.48 (d, J=7.92 Hz, 2H) 7.69 (d, J=7.37 Hz, 2H). MS (ESI+) m/z 879
(M+H).sup.+.
##STR00324##
Example 88
dimethyl
([(2S,5S)-1-(4-methoxyphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1-
-diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate and
dimethyl
([(2R,5R)-1-(4-methoxyphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1-
-diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate
[0584] The title compound was prepared using the procedures
described for the synthesis of Examples 34A, 34B, 34C, 34D, and
34E, substituting 4-methoxyaniline for 4-tert-butylaniline. 1H NMR
(TFA salt) (400 MHz, DMSO-D6) .delta. ppm 0.85-0.90 (m, 6H),
0.90-0.95 (m, 6H), 1.60-1.66 (m, 2H), 1.81-2.04 (m, 8H), 2.08-2.19
(m, 2H), 3.52 (s, 9H), 3.57-3.66 (m, 2H), 3.77-3.85 (m, 2H), 4.02
(t, 2H), 4.39-4.46 (m, 2H), 5.12 (d, J=6.3 Hz, 2H), 6.18 (d, J=9.0
Hz, 2H), 6.56 (d, J=9.0 Hz, 2H), 7.09-7.15 (m, 4H), 7.28-7.34 (m,
2H), 7.46-7.52 (m, 4H), 9.97 (s, 2H); MS m/z 868.5 (M+H).
##STR00325##
Example 89
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2S,5S)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1--
phenylpyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-
-oxobutan-2-yl}carbamate and
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2R,5R)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1--
phenylpyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-
-oxobutan-2-yl}carbamate
[0585] The trans diastereomers obtained in Example 59B (8.5 mg,
0.0107 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid
(4.67 mg, 0.027 mmol) and HATU (8.9 mg, 0.023 mmol) in DMSO (1 mL)
was added Hunig's base (0.015 mL, 0.085 mmol), and the reaction
mixture was stirred at room temperature for 1 hr. The reaction
mixture was partitioned between water and ethyl acetate, and the
organic layer was dried over MgSO.sub.4, filtered and concentrated
in vacuo. The crude product was purified by reversed phase
chromatography (C18), eluting with 10-100% acetonitrile in water
(0.1% TFA) to afford 5.0 mg (53%) of the title compound as a
mixture of trans diastereomers. 1H NMR (TFA salt) (400 MHz,
DMSO-D6) .delta. ppm 14.45 (bs, 2H), 7.97 (s, 2H), 7.66 (m, 4H),
7.38 (m, 4H), 7.31 (d, J=7.4 Hz, 2H), 6.92 (t, J=7.6 Hz, 2H), 6.43
(m, 1H), 6.28 (d, J=8.1 Hz, 2H), 5.37 (m, 2H), 5.09 (t, J=6.7 Hz,
2H), 4.09 (t, J=7.7 Hz, 2H), 3.81 (m, 6H), 3.53 (s, 6H), 2.40 (m,
2H), 2.08 (m, 2H), 2.02 (m, 6H), 1.85 (m, 2H), 0.85 (m, 2H), 0.80
(m, 12H); MS (ESI) m/z 884 (M+H)+.
##STR00326##
Example 90
dimethyl
([(2S,5S)-1-(biphenyl-4-yl)pyrrolidine-2,5-diyl]bis{benzene-4,1-d-
iylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})-
biscarbamate and
dimethyl
([(2R,5R)-1-(biphenyl-4-yl)pyrrolidine-2,5-diyl]bis{benzene-4,1-d-
iylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})-
biscarbamate
[0586] The product from Example 86C (24.9 mg, 0.027 mmole)
dissolved in a THF (1 mL) and water (0.3 mL) solution was combined
in a microwave tube with phenylboronic acid (6.90 mg, 0.054 mmole),
tribasic potassium phosphate (13.37 mg, 0.063 mmole) and
1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride
(1.42 mg, 2.17 mole). The tube was sealed and nitrogen bubbled
through at room temperature for five minutes. All gas lines were
subsequently removed and the reaction vessel immersed in a
50.degree. C. oil bath and heated for two and one half hours. The
contents of the tube were partitioned between ethylacetate (5 mL)
and brine (1 mL). The organic phase was washed with brine
(2.times.1 mL) then dried over MgSO.sub.4, filtered and
concentrated. The crude product was purified by silica gel
chromatography eluting with 5% EtOAc--hexane and progressing to
(75% EtOAc-hexane )+3% methanol to provide as a 1:1 mixture of
(trans) diastereomers the title compound (18.6 mg, 75% yield) as a
cream colored solid. 1H NMR (400 MHz, DMSO-D6) .delta. ppm
0.76-0.99 (m, 12H) 1.67 (s, 2H) 1.77-2.19 (m, 11H) 3.52 (s, 6H)
3.58-3.65 (m, 2H) 3.74-3.86 (m, 2H) 3.96-4.08 (m, 2H) 4.44 (d,
J=4.99 Hz, 2H) 5.25 (s, 2H) 6.35 (d, J=8.02 Hz, 2H) 7.17 (d, J=7.26
Hz, 5H) 7.24-7.34 (m, 6H) 7.45 (d, J=7.92 Hz, 2H) 7.52 (d, J=7.81
Hz, 4H) 10.00 (s, 2H). MS ESI(+) m/z@ 915.1 (M+H)+, m/z@ 972.3
(M+CH.sub.3CN+NH.sub.4)+.
##STR00327##
Example 91
methyl
{(2S)-1-[(2S)-2-(5-{(2S,5S)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[4-(trifl-
uoromethyl)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-yl]-3-
-methyl-1-oxobutan-2-yl}carbamate and
methyl
{(2S)-1-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-H-benzimidazol-5-yl}-1-[4-(triflu-
oromethyl)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-yl]-3--
methyl-1-oxobutan-2-yl}carbamate
Example 91A
(2S,2'S)-2,2'(6,6'-(1-(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)bis(-
1H-benzo[d]imidazole-6,2-diyl))dipyrrolidinium chloride
[0587] Example 28C and 4-trifluoromethylaniline were processed
using the methods of Examples 28D-28J to provide the title compound
as a mixture of cis and trans stereoisomers.
Example 91B
methyl
{(2S)-1-[(2S)-2-(5-{(2S,5S)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[4-(trifl-
uoromethyl)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-yl]-3-
-methyl-1-oxobutan-2-yl}carbamate and
methyl
{(2S)-1-[(2S)-2-(5-{(2R,5R)-5-{2-[2S)-(2-[(2)-{(2S)-2-(methoxycarbo-
nyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-H-benzimidazol-5-yl}-1-[4-(tr-
ifluoromethyl)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-yl-
]-3-methyl-1-oxobutan-2-yl}carbamate
[0588] The product from Example 91A (1:1 mixture of cis and trans
isomers), 0.018 g, 0.027 mmole), HOBt (0.013 g, 0.082 mmole), EDAC
(0.016 g, 0.082 mmole) and
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.014 g, 0.082
mmole) were combined in a 20 ml round bottom flask and dissolved in
1 ml DMF at room temperature, added 4-methylmorpholine (0.015 ml,
0.137 mmole) and the resulting clear slightly brown solution was
stirred at room temperature for 2 hr. The reaction mixture was
analyzed by LC-MS and determined to be complete. The reaction
mixture was diluted with 50 ml EtOAc, washed with 10% NaHCO.sub.3
and 10% NaCl, dried over anhydrous Na.sub.2SO.sub.4(s), filtered
and solvent removed in vacuo leaving the title compound as a light
brown solid. The material was purified by preparative HPLC on a
Phenomenex Luna C8(2) 5 um 100A AXIA column (30 mm.times.75 mm). A
gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water
(B) was used, at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-7.0
min linear gradient 10-95% A, 7.0-10.0 min 95% A, 10.0-12.0 min
linear gradient 95-10% A). The product fractions were collected and
evaporated to dryness in vacuo leaving the title compound as a tan
solid, (11 mg, 44%) and a mixture of diastereomeric trans isomers.
1H NMR (TFA salt) (400 MHz, DMSO-D6) d ppm 0.67-0.94 (m, 12H) 1.95
(m, 18H) 3.79-3.89 (m, 6H) 4.10 (s, 2H) 5.19 (s, 1H) 5.64 (s, 2H)
6.45 (s, 2H) 7.28 (s, 4H) 7.47 (s, 4H) 7.69 (s, 4H), 12.1 (b, 2H)
ESI+(m/z):900.6, ESI-(m/z):898.8.
##STR00328##
Example 92
dimethyl
([(2S,5S)-1-(4-hydroxyphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1-
-diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate and
dimethyl
([(2R,5R)-1-(4-hydroxyphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1-
-diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate
[0589] To a solution of the product from Example 88 (0.050 g, 0.058
mmol) in CH.sub.2Cl.sub.2 (1 mL) at -78.degree. C. was added a 1.0
M solution of borontribromide in CH.sub.2Cl.sub.2 (0.29 mL, 0.29
mmol). The resulting dark red color solution was stirred at
-78.degree. C. for 4 h, and then warmed to rt and washed with
water. The organic layer was dried over sodium sulphate, filtered,
and concentrated in vacuo. The crude product was purified by column
chromatography on silica gel using a solvent gradient of 0-7.5%
MeOH in CH.sub.2Cl.sub.2 to give the title compound (5.5 mg, 12%)
as a mixture of trans diastereomers. 1H NMR (400 MHz, DMSO-D6)
.delta. ppm 0.86-0.90 (m, 6H), 0.90-0.95 (m, 6H), 1.58-1.63 (m,
2H), 1.82-2.04 (m, 8H), 2.08-2.19 (m, 2H), 3.52 (s, 6H), 3.58-3.66
(m, 2H), 3.77-3.84 (m, 2H), 4.02 (t, J=8.5 Hz, 2H), 4.40-4.46 (m,
2H), 5.08 (d, J=6.3 Hz, 2H), 6.08 (d, J=8.8 Hz, 2H), 6.38 (d, J=8.8
Hz, 2H), 7.08-7.13 (m, 4H), 7.29-7.34 (m, 2H), 7.45-7.51 (m, 4H),
8.27 (d, J=1.2 Hz, 1H), 9.96 (s, 2H); MS m/z 854.4 (M+H).sup.+.
##STR00329##
Example 93
dimethyl
({(2S,5S)-1-[4-(propan-2-yl)phenyl]pyrrolidine-2,5-diyl}bis{benze-
ne-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate and
dimethyl
({(2R,5R)-1-[4-(propan-2-yl)phenyl]pyrrolidine-2,5-diyl}bis{benze-
ne-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-
-diyl]})biscarbamate
[0590] The title compound was prepared as a mixture of trans
diastereomers using the procedures described for the synthesis of
Examples 34A, 34B, 34C, 34D, and 34E, substituting
4-isopropylaniline for 4-tert-butylaniline. 1H NMR (TFA salt) (400
MHz, DMSO-D6) .delta. ppm 0.85-0.90 (m, J=5.8, 5.8 Hz, 6H),
0.90-0.96 (m, 6H), 1.02-1.06 (m, 6H), 1.60-1.65 (m, 2H), 1.81-2.04
(m, 8H), 2.08-2.19 (m, 2H), 2.56-2.65 (m, 1H), 3.52 (s, 6H),
3.58-3.66 (m, 2H), 3.76-3.85 (m, 2H), 4.02 (t, J=8.3 Hz, 2H),
4.40-4.45 (m, 2H), 5.14 (d, J=6.5 Hz, 2H), 6.15-6.20 (m, 2H), 6.79
(d, J=8.7 Hz, 2H), 7.09-7.16 (m, 4H), 7.29-7.34 (m, 2H), 7.47-7.52
(m, 4H), 9.97 (s, 2H); MS m/z 880.5 (M+H).sup.+.
##STR00330##
Example 94
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2S,5S)-1-(4-fluorophenyl)-5-(4-{2-[(2S)-1-{-
(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}pyrrolidin-2-yl]-1H-i-
midazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1--
yl]-3,3-dimethyl-1-oxobutan-2-yl}carbamate and
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2R,5R)-1-(4-fluorophenyl)-5-(4-{2-[(2S)-1-{-
(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}pyrrolidin-2-yl]-1H-i-
midazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1--
yl]-3,3-dimethyl-1-oxobutan-2-yl}carbamate
[0591] The product from Example 45D (28 mg, 0.048 mmol) was
subjected to the conditions described in example 45E, substituting
(S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid for
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid, to give the
title compound (18 mg, 41%) as a mixture of diastereomers. 1H NMR
(TFA salt) (400 MHz, DMSO-D6) .delta. ppm 0.86 (s, 9H), 0.87 (s,
9H), 1.70-1.81 (m, 2H), 1.94-2.25 (m, 6H), 2.34-2.44 (m, 2H), 3.55
(s, 6H), 3.72-3.95 (m, 4H), 4.19 (d, J=8.7 Hz, 2H), 5.09 (t, J=7.2
Hz, 2H), 5.35 (d, J=6.1 Hz, 2H), 6.26 (dd, J=9.1, 4.4 Hz, 2H), 6.81
(t, J=8.9 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 7.37 (d, J=7.2 Hz, 4H),
7.68 (dd, J=7.8, 5.4 Hz, 4H), 7.97 (s, 2H), 14.46 (br s, 2H); MS
m/z 930.8 (M+H).sup.+.
##STR00331##
Example 95
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2S,5S)-1-(4-cyclopropylphenyl)-5-(4-{2-[(2S-
)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H--
imidazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-
-yl]-3-methyl-1-oxobutan-2-yl}carbamate and
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2R,5R)-1-(4-cyclopropylphenyl)-5-(4-{2-[(2S-
)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H--
imidazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-
-yl]-3-methyl-1-oxobutan-2-yl}carbamate
Example 95A
(S)-4,4'-(4,4'-((2R,5R)-1-(4-cyclopropylphenyl)pyrrolidine-2,5-diyl)bis(4,-
1-phenylene))bis(2-((S)-pyrrolidin-2-yl)-1H-imidazole) and
(S)-4,4'-(4,4'-((2S,5S)-1-(4-cyclopropylphenyl)pyrrolidine-2,5-diyl)bis(4,-
1-phenylene))bis(2-((S)-pyrrolidin-2-yl)-1H-imidazole)
[0592] The product from Example 68C (1.27 g, 1.568 mmol) was
dissolved in dichloromethane (12 mL). The mixture was cooled to
0.degree. C. and trifluroacetic acid (8 mL, 104 mmol) was added
slowly. The mixture was warmed to room temperature and stirred for
1h. The solvent was evaporated and the residue was purified by
chromatography on silica gel eluting with methanol/dichloromethane
(1% to 10%). The title compound was eluted as the first of 2
stereoisomers and was obtained as a mixture of trans diastereomers
(510 mg, 53%).
Example 95B
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2S,5S)-1-(4-cyclopropylphenyl)-5-(4-{2-[(2S-
)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H--
imidazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-
-yl]-3-methyl-1-oxobutan-2-yl}carbamate and
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2R,5R)-1-(4-cyclopropylphenyl)-5-(4-{2-[(2S-
)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H--
imidazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-
-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0593] The product from Example 95A (150 mg, 0.246 mmol),
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (86 mg, 0.492
mmol), 4-methylmorpholine (0.216 mL, 1.968 mmol),
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (104 mg, 0.541 mmol) and
1H-benzo[d][1,2,3]triazol-1-ol hydrate (83 mg, 0.541 mmol) were
combined in DMF (10 mL). The mixture was stirred at room
temperature for 2 hours. The reaction mixture was partitioned
between ethyl acetate and water. The organic layer was washed with
saturated sodium bicarbonate, brine twice, dried with sodium
sulfate, filtered and evaporated. The residue was purified by
chromatography on silica gel eluting with methanol/dichloromethane
(1% to 4%) to give the title compound (78 mg, 34%) as a solid. 1H
NMR (400 MHz, DMSO-D6) .delta. ppm 0.35-0.41 (m, 2H) 0.65-0.72 (m,
2H) 0.81-0.92 (m, 12H) 1.58-1.64 (m, 1H) 1.66-1.72 (m, 2H)
1.86-2.03 (m, 6H) 2.07-2.17 (m, 4H) 2.24-2.30 (m, 2H) 3.53 (s, 6H)
3.74-3.82 (m, 4H) 4.04 (t, J=7.86 Hz, 2H) 5.06 (dd, J=6.72, 2.93
Hz, 2H) 5.14-5.26 (m, 2H) 6.19 (d, J=8.67 Hz, 2H) 6.64 (d, J=8.24
Hz, 2H) 7.10-7.30 (m, 6H) 7.34-7.69 (m, 6H) 11.64-12.11 (m, 2H); MS
(ESI+) m/z 924.8 (M+H)+.
##STR00332##
Example 96
dimethyl
([(2R,5R)-1-(4-cyclopropylphenyl)pyrrolidine-2,5-diyl]bis{benzene-
-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate
[0594] Example 38A and 4-cyclopropylaniline were processed using
sequentially the methods of Examples 34A, 34B, 34C, 66D, and 66E to
provide the title compound (62 mg). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 0.36-0.46 (m, 2H) 0.63-0.77 (m, 2H) 0.87 (d,
J=6.61 Hz, 6H) 0.92 (d, J=6.72 Hz, 6H) 1.52-2.46 (m, 15H) 3.52 (s,
6H) 3.57-3.66 (m, 2H) 3.75-3.85 (m, 2H) 4.02 (t, J=8.46 Hz, 2H)
4.42 (dd, J=8.02, 4.88 Hz, 2H) 5.14 (d, J=6.40 Hz, 2H) 6.14 (d,
J=8.78 Hz, 2H) 6.65 (d, J=8.67 Hz, 2H) 7.10 (d, J=8.57 Hz, 4H) 7.30
(d, J=8.35 Hz, 2H) 7.48 (d, J=8.57 Hz, 4H) 9.97 (s, 2H). MS (APCI)
m/z 878 (M+H).sup.+.
##STR00333##
Example 97
methyl
{(2S)-1-[(2S,4S)-2-{5-[(2S,5S)-1-(4-fluorophenyl)-5-{2-[(2S,4S)-4-h-
ydroxy-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl-
]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}-4-hydroxypyr-
rolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate and
methyl
{(2S)-1-[(2S,4S)-2-{5-[(2R,5R)-1-(4-fluorophenyl)-5-{2-[(2S,4S)-4-h-
ydroxy-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl-
]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}-4-hydroxypyr-
rolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
##STR00334##
[0595] Example 97A
(2S,4S)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine--
2-carboxylic acid
[0596]
(2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic
acid (5.31 g, 22.96 mmol) and imidazole (7.82 g, 115 mmol) were
combined in dichloromethane (106 mL) and dimethylformamide (22 mL)
at ambient temperature and treated with portionwise addition of
tert-butylchlorodimethylsilane (7.61 g, 50.5 mmol). The mixture was
stirred for 18 hours then diluted with water and extracted into
ethyl acetate and concentrated to provide the title compound.
Example 97B
[0597] The product from Example 29D (0.906 g, 2.62 mmol) was
processed as in Examples 29E, 29F, 29G, and 29H, substituting
Example 97A for S-Boc-proline in step 29E to give the title
compounds (0.012 g, 13%). 1H NMR (400 MHz, DMSO-D6) .delta. ppm
0.69-0.85 (m, 12H) 1.27-1.39 (m, 1H) 1.53 (dt, J=21.31, 6.64 Hz,
1H) 1.71 (s, 4H) 1.80-1.90 (m, 2H) 2.02 (d, J=7.70 Hz, 2H)
2.54-2.62 (m, 2H) 3.53 (s, 6H) 3.68 (t, J=10.63 Hz, 2H) 3.93-4.00
(m, 2H) 4.39 (s, 2H) 5.13 (s, 2H) 5.38 (s, 2H) 6.19-6.38 (m, 4H)
6.74 (d, J=2.60 Hz, 2H) 7.08 (s, 2H) 7.21-7.36 (m, 4H) 7.40-7.51
(m, 2H) 12.21-12.38 (m, 2H); MS TFA+ m/z 882.5 (M+H)+.
##STR00335##
Example 98
dimethyl
({(2R,5R)-1-[4-(morpholin-4-yl)phenyl]pyrrolidine-2,5-diyl}bis{be-
nzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimethyl-1-oxobut-
ane-1,2-diyl]})biscarbamate
Example 98A
4-(4-((2R,5R)-2,5-bis(4-nitrophenyl)pyrrolidin-1-yl)phenyl)morpholine
[0598] The product from Example 38A and 4-morpholinoaniline were
processed using the method described in Example 1D using NMP for
the solvent to afford the title compound. MS (ESI) m/z 475
(M+H).sup.+.
Example 98B
4,4'-((2R,5R)-1-(4-morpholinophenyl)pyrrolidine-2,5-diyl)dianiline
[0599] The product from Example 98A in tetrahydrofuran (20 mL) was
added to Ra--Ni (water wet, A-7000, 0.8 g, 12.63 mmol) in a 50 mL
pressure bottle and stirred for 2 hours at ambient temperature
under 30 psi of hydrogen. The mixture was filtered through a nylon
membrane and concentrated to afford the title compound (0.31 g,
44%). MS (DCI) m/z 415 (M+H).sup.+.
Example 98C
(2S,2'S)-tert-butyl
2,2'-(4,4'-((2R,5R)-1-(4-morpholinophenyl)pyrrolidine-2,5-diyl)bis(4,1-ph-
enylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate
[0600] The product from Example 98B was processed using
sequentially the methods of Examples 55F, 55G, and 26J (with
(S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid) to afford
the title compound (0.13 g). .sup.1H NMR (400 MHz, DMSO-D6) .delta.
0.93 (d, J=20.5, 17H), 1.92-1.79 (m, 4H), 2.05-1.93 (m, 3H),
2.21-2.08 (m, 2H), 2.43 (t, J=6.1, 3H), 2.84-2.75 (m, 4H), 3.54 (s,
6H), 3.68-3.58 (m, 6H), 3.83-3.70 (m, 2H), 4.20 (d, J=8.9, 2H),
4.43 (dd, J=7.9, 5.3, 2H), 5.12 (d, J=6.3, 2H), 6.17 (d, J=9.1,
2H), 6.60 (d, J=9.1, 2H), 7.07 (d, J=8.8, 2H), 7.11 (d, J=8.5, 4H),
7.48 (d, J=8.5, 4H), 9.98 (s, 2H). Impurity .sup.1H NMR (400 MHz,
DMSO-D6) .delta. 1.63 (d, J=5.6, 2H), 3.17 (d, J=5.3, 3H), 4.09 (q,
J=5.3, 1H). MS (ESI) m/z 952 (M+H.sup.+).
##STR00336##
Example 99
dimethyl
([(2S,5S)-1-{4-[6-(dimethylamino)pyridin-3-yl]phenyl}pyrrolidine--
2,5-diyl]bis{benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-meth-
yl-1-oxobutane-1,2-diyl]})biscarbamate and
dimethyl
([(2R,5R)-1-{4-[6-(dimethylamino)pyridin-3-yl]phenyl}pyrrolidine--
2,5-diyl]bis{benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-meth-
yl-1-oxobutane-1,2-diyl]})biscarbamate
Example 99A
5-(4-(2,5-bis(4-nitrophenyl)pyrrolidin-1-yl)phenyl)-N,N-dimethylpyridin-2--
amine
[0601] The product from Example 86A (25.7 mg, 0.055 mmole) was
combined in a microwave tube with
6-(dimethylamino)pyridine-3-ylboronic acid (17.49 mg, 0.105 mmole),
tribasic potassium phosphate (24.70 mg, 0.116 mole) and
1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride
(2.504 mg, 3.84 .mu.mole). The tube was sealed and a solvent
mixture of THF (2 mL) and water (0.6 mL) added via syringe. The
reaction mixture was sparged with nitrogen at room temperature for
three minutes during which time the solution turned black in color.
Chromatographic analysis indicated that the reaction was complete.
The contents of the microwave tube were partitioned between brine
(3 mL) and ethyl acetate (3 mL). The water was drawn off and the
organic phase dried over MgSO.sub.4, filtered and concentrated. The
crude product was purified by chromatography on silica gel from 2
up to 20% ethyl acetate in hexane to provide the title compound
(26.8 mg, 96% yield) as an orange solid as a mixture of
stereoisomers. MS ESI(+) m/z @ 510.4 (M+H)+.
Example 99B
4,4'-(1-(4-(6-(dimethylamino)pyridin-3-yl)phenyl)pyrrolidine-2,5-diyl)dian-
iline
[0602] The product from Example 99A (26.8 mg, 0.053 mmole) was
dissolved in THF (526 .mu.L) in a round bottom flask to which was
subsequently added ethanol (526 .mu.L) resulting in a yellow
precipitate. To this suspension was added platinum (IV) oxide (3.16
mg, 0.014 mmole). The flask was capped with a septum and the
contents vacuum degassed three times. Hydrogen was introduced via a
balloon and the mixture allowed to stir at room temperature for two
and one half hours. The reaction mixture was vacuum filtered
through a sand and celite plug, which was rinsed with THF and
methanol until the filtrate was u.v.(-). The filtrate was
concentrated in vacuo to provide the title compound in quantitative
yield as a white solid as a mixture of stereoisomers. MS ESI(+),
m/z @ 450.7 (M+H)+.
Example 99C
(2S,2'S)-tert-butyl
2,2'-(4,4'-(1-(4-(6-(dimethylamino)pyridin-3-yl)phenyl)pyrrolidine-2,5-di-
yl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carbo-
xylate
[0603] The product from Example 99B (23.83 mg, 0.053 mmole) was
reacted with (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic
acid (27.8 mg, 0.129 mmole) as described in Example 1F with minor
modification. The crude product was recovered by partition of the
reaction mixture between ethyl acetate (10 mL) and water (3 mL).
The organic phase was washed with water (3.times.3 mL), dried over
MgSO.sub.4, filtered and concentrated. Chromatography on silica gel
using a solvent gradient of 2-100% ethyl acetate in hexane provided
the title compound (32.6 mg, 73% yield) as a cream colored solid as
a mixture of stereoisomers.
Example 99D
(2S,2'S)--N,N'-(4,4'-(1-(4-(6-(dimethylamino)pyridin-3-yl)phenyl)pyrrolidi-
ne-2,5-diyl)bis(4,1-phenylene))dipyrrolidine-2-carboxamide
[0604] The product from Example 99C (32.6 mg, 0.039 mmole) was
reacted with trifluoroacetic acid (0.071 mL, 0.927 mmole) as
described in Example 1G to provide the title compound (22.5 mg, 90%
yield) as a cream colored solid as a mixture of stereoisomers.
Example 99E
dimethyl
([(2S,5S)-1-{4-[6-(dimethylamino)pyridin-3-yl]phenyl}pyrrolidine--
2,5-diyl]bis{benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-meth-
yl-1-oxobutane-1,2-diyl]})biscarbamate and
dimethyl
([(2R,5R)-1-{4-[6-(dimethylamino)pyridin-3-yl]phenyl}pyrrolidine--
2,5-diyl]bis{benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-meth-
yl-1-oxobutane-1,2-diyl]})biscarbamate
[0605] The product from Example 99D (22.5 mg, 0.035 mmole) was
reacted with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid
(19.41 mg, 0.111 mmole) as described in Example 86C. Chromatography
on silica gel (10% ethyl acetate/90% hexane to 100% ethyl
acetate/4% methanol) provided the title compound (14.5 mg, 43.3%
yield), an orange yellow solid that darkened somewhat on standing,
as a 1:1 mixture of trans diastereomers. 1H NMR (400 MHz, DMSO-D6)
.delta. ppm 0.77-0.99 (m, 12H) 1.67 (s, 2H) 1.76-2.24 (m, 11H) 2.98
(s, 6H) 3.52 (s, 6H) 3.58-3.65 (m, 2H) 3.76-3.90 (m, J=9.54 Hz, 2H)
3.95-4.11 (m, 2H) 4.36-4.47 (m, 2H) 5.19-5.27 (m, 2H) 6.30 (s, 2H)
6.58 (d, J=9.00 Hz, 1H) 7.17 (t, J=8.08 Hz, 4H) 7.30 (d, J=8.02 Hz,
3H) 7.52 (d, J=7.37 Hz, 4H) 7.57-7.63 (m, 1H) 7.63-7.68 (m, 1H)
7.91 (s, 1H) 8.18-8.22 (m, 1H) 10.00 (s, 2H). MS ESI(+) m/z @ 959.4
(M+H)+.
##STR00337##
Example 100
dimethyl
({(2R,5R)-1-[4-(methylsulfonyl)phenyl]pyrrolidine-2,5-diyl}bis{be-
nzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimethyl-1-oxobut-
ane-1,2-diyl]})biscarbamate
[0606] Example 38A and 4-(methylsulfonyl)aniline were processed
using sequentially the methods of Examples 98A, 98B, 55F, 55G, and
26J (with (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid;
reaction solvent=dichloromethane) to provide the title compound (55
mg). .sup.1H NMR (400 MHz, DMSO-D6) .delta. 0.96 (d, J=5.1, 18H),
1.24 (s, 1H), 1.69 (d, J=5.7, 2H), 2.04-1.74 (m, 7H), 2.22-2.07 (m,
2H), 2.98 (s, 3H), 3.54 (s, 6H), 3.70-3.58 (m, 2H), 3.83-3.70 (m,
2H), 4.20 (d, J=8.9, 2H), 4.43 (dd, J=7.8, 5.4, 2H), 5.32 (d,
J=6.1, 2H), 6.39 (d, J=9.0, 2H), 7.08 (d, J=8.8, 2H), 7.15 (d,
J=8.6, 4H), 7.43 (d, J=9.0, 2H), 7.53 (d, J=8.6, 4H), 10.03 (s,
2H). MS (ESI) m/z 966 (M+Na).sup.+, 943 (M-H).sup.+.
##STR00338##
Example 101
dimethyl
([(2S,5S)-1-{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidine-
-2,5-diyl]bis{benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate and
dimethyl
([(2R,5R)-1-{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidine-
-2,5-diyl]bis{benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-met-
hyl-1-oxobutane-1,2-diyl]})biscarbamate
[0607] Example 86A and
4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine
were processed using sequentially the methods of Examples 99A, 99B,
1F, 1G, and 86C to provide the title compound as a 1:1 mixture of
trans diastereomers. 1H NMR (free base) (400 MHz, DMSO-D6) .delta.
ppm 0.78-1.00 (m, 12H) 1.67 (s, 2H) 1.75-2.20 (m, 11H) 3.36-3.41
(m, 4H) 3.52 (s, 6H) 3.57-3.65 (m, 2H) 3.65-3.72 (m, 4H) 3.79 (s,
2H) 4.02 (s, 2H) 4.36-4.48 (m, 2H) 5.24 (s, 2H) 6.32 (d, J=7.70 Hz,
2H) 6.78 (d, J=9.00 Hz, 1H) 7.12-7.18 (m, 4H) 7.21 (d, J=8.78 Hz,
2H) 7.31 (d, J=8.35 Hz, 2H) 7.52 (d, J=7.48 Hz, 4H) 7.63-7.69 (m,
1H) 8.22-8.27 (m, 1H) 10.00 (s, 2H). MS ESI(+) m/z @ 1000.6
(M+H)+.
##STR00339##
Example 102
dimethyl
({(2S,5S)-1-[4-(pyridin-3-yl)phenyl]pyrrolidine-2,5-diyl}bis{benz-
ene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate and
dimethyl
({(2R,5R)-1-[4-(pyridin-3-yl)phenyl]pyrrolidine-2,5-diyl}bis{benz-
ene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,-
2-diyl]})biscarbamate
[0608] Example 86A and pyridin-3-ylboronic acid were processed
using sequentially the methods of Examples 99A, 99B, 1F, 1G, and
86C to provide the title compound as a 1:1 mixture of trans
diastereomers (35.8 mg). 1H NMR (free base) (400 MHz, DMSO-D6)
.delta. ppm 0.71-1.05 (m, 11H) 1.68 (s, 2H) 1.87 (s, 8H) 2.06-2.21
(m, 2H) 3.52 (s, 6H) 3.56-3.67 (m, 2H) 3.80 (s, 2H) 4.02 (d, J=1.73
Hz, 2H) 4.43 (dd, J=7.97, 4.93 Hz, 2H) 5.26 (d, J=6.29 Hz, 2H) 6.37
(d, J=7.92 Hz, 2H) 7.17 (dd, J=8.57, 1.95 Hz, 4H) 7.28-7.36 (m, 5H)
7.52 (d, J=7.81 Hz, 4H) 7.82-7.87 (m, 1H) 8.36 (dd, J=4.72, 1.36
Hz, 1H) 8.69 (s, 1H) 10.00 (s, 2H). MS ESI(+) m/z @ 915.6
(M+H)+
##STR00340##
Example 103
methyl
[(2S,3S)-1-{(2S)-2-[5-(4-{(2S,5S)-1-(4-tert-butylphenyl)-5-[4-(2-{(-
2S)-1-[N-(methoxycarbonyl)-O-methyl-D-threonyl]pyrrolidin-2-yl}-1H-imidazo-
l-5-yl)phenyl]pyrrolidin-2-yl}phenyl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3--
methoxy-1-oxobutan-2-yl]carbamate and
methyl
[(2S,3S)-1-{(2S)-2-[5-(4-{(2R,5R)-1-(4-tert-butylphenyl)-5-[4-(2-{(-
2S)-1-[N-(methoxycarbonyl)-O-methyl-D-threonyl]pyrrolidin-2-yl}-1H-imidazo-
l-5-yl)phenyl]pyrrolidin-2-yl}phenyl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3--
methoxy-1-oxobutan-2-yl]carbamate
[0609] The product from Example 201A (0.122 g, 0.639 mmol), and
HOBt (0.098 g, 0.639 mmole) were combined and dissolved in 2 ml DMF
then cooled in an ice bath between 0-5.degree. C. To this solution
was added EDAC (0.123 g, 0.639 mmol) followed by 4-methylmorpholine
(0.211 ml, 1.917 mmole) and the mixture was stirred 5 minutes, then
added dropwise the mixture of the products from Example 42F (0.2 g,
0.320 mmol), in DMF (2 ml) with a DMF wash (1 ml). The pH of the
solution was adjusted with additional 4-methylmorpholine (0.1 ml,
0.96 mmole) and the mixture was stirred a total of 90 minutes in
the ice bath. The reaction mixture was analyzed by LC-MS at 90 min
and determined the reaction to be complete. The reaction mixture
was diluted with 100 ml EtOAc and washed with 25 ml water. The
layers were separated and the aqueous layer was extracted with
another 100 ml EtOAc. The combined organic extracts were washed
with 10% NaHCO.sub.3 and 10% NaCl, dried over anhydrous
Na.sub.2SO.sub.4(s), filtered and solvent removed in vacuo leaving
a purple oil. The oil was dissolved in 10 ml CH.sub.2Cl.sub.2 and
applied to a 12 g silica gel column. The column was eluted with a
gradient of CH.sub.2Cl.sub.2/MeOH, 99/1 to 95/5 over 25 minutes.
The title compounds were isolated as a light yellow solid, 60 mg,
19%. 1H NMR (400 MHz, DMSO-D6) d ppm 0.86 (m, 2H) 1.00-1.18 (m,
15H) 1.27 (m, 2H) 1.70 (m, s H) 1.99 (m, 2H) 2.15 (m, 4H) 3.18 (d,
J=10.08 Hz, 6H) 3.54 (s, 6H) 3.81 (m, 4H) 4.27 (m, 2H) 5.06 (m, 2H)
5.21 (d, 2H) 6.21 (d, 2H) 6.94 (d, 2H) 7.17 (d, 2H) 7.29 (d, 2H)
7.38 (d, J=1.73 Hz, 2H) 7.51 (d, 2H) 7.62 (d, J=8.02 Hz, 2H) 11.68
(s, 2H), 12.01 (m, 2H); ESI+:972.6
##STR00341##
Example 105
methyl
{(2S)-1-[(2S)-2-(3-{4-[(2S,5S)-1-(4-tert-butylphenyl)-5-(4-{5-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-p-
yrazol-3-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-pyrazol-5-yl)pyrrolidin-1-yl-
]-3-methyl-1-oxobutan-2-yl}carbamate and
methyl
{(2S)-1-[(2S)-2-(3-{4-[(2R,5R)-1-(4-tert-butylphenyl)-5-(4-{5-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-p-
yrazol-3-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-pyrazol-5-yl)pyrrolidin-1-yl-
]-3-methyl-1-oxobutan-2-yl}carbamate
Example 105A
1-(4-tert-butylphenyl)-2,5-bis(4-((trimethylsilyl)ethynyl)phenyl)pyrrolidi-
ne
[0610] To an oven-dried microwave tube (Size M, 5 mL) purged with
nitrogen, added the product of Example 42C (340 mg, 0.662 mmol),
bis(triphenylphosphine)palladium(II) dichloride (18.60 mg, 0.026
mmol), THF (2 mL), and triethylamine (2 mL). Stirred at room
temperature for 5 min, then added copper(I) iodide (2.52 mg, 0.013
mmol), stirred the yellow mixture for 2 min, then nitrogen bubbled
through for 15 min. Added trimethylsilylacetylene (0.374 mL, 2.65
mmol), sealed the tube with an aluminum crimp cap, and heated in an
oil bath at 70.degree. C. for 20 hr. Cooled the reaction to room
temperature, added fresh bis(triphenylphosphine)palladium(II)
dichloride (18.60 mg, 0.026 mmol) and copper(I) iodide (2.52 mg,
0.013 mmol), added additional trimethylsilylacetylene (0.374 mL,
2.65 mmol), and continued heating at 80.degree. C. for 24 hr.
Cooled the reaction to room temperature, diluted with Et.sub.2O (50
mL), washed with H.sub.2O (2.times.25 mL) and brine (25 mL), dried
the organic phase over anhydrous MgSO.sub.4, filtered, and
concentrated by rotary evaporation to a light tan foam (470 mg).
Purified by flash chromatography (silica gel, 2.5 cm.times.10 cm,
2% Et.sub.2O/hexanes) to afford the title product as a yellow foam
(324 mg, 89%) as a mixture of stereoisomers. MS (ESI+) m/z 548
(M+H).sup.+.
Example 105B
1-(4-tert-butylphenyl)-2,5-bis(4-ethynylphenyl)pyrrolidine
[0611] Dissolved the product of Example 105A (322 mg, 0.588 mmol)
in anhydrous THF (5 mL) under nitrogen, added 1M TBAF in THF (1.322
mL, 1.322 mmol), and stirred at 25.degree. C. for 30 min. The
reaction darkened immediately upon addition and remained a brown
color throughout the reaction. Removed solvent by rotary
evaporation, dissolved the residue in Et.sub.2O (50 mL), washed
with H.sub.2O (2.times.25 mL) and brine (25 mL), dried the organic
phase over anhydrous MgSO.sub.4, filtered, and concentrated by
rotary evaporation to a light tan foam (289 mg). Purified by flash
chromatography (silica gel, 3.8 cm.times.14 cm, 20%
CH.sub.2Cl.sub.2/hexanes) to the title compound as a light yellow
foam (176 mg, 74%) as a mixture of stereoisomers. MS (ESI+) m/z 404
(M+H).sup.+.
Example 105C
(S)-3,3'-(4,4'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(1-(4,1-phen-
ylene))bis(1-(N-Boc-(S)-pyrrolidin-2-yl)prop-2-yn-1-one
[0612] In a flame-dried 10-mL round bottom flask, dissolved the
product of Example 105B (94.3 mg, 0.234 mmol) in anhydrous THF (2
mL) under nitrogen and cooled to -78.degree. C., added 1.6 M n-BuLi
in hexanes (0.365 mL, 0.584 mmol) slowly in a dropwise manner via
gas-tight syringe, and stirred the greenish-yellow solution for 1
hr at -78.degree. C. In a separate flame-dried 10-mL round bottom
flask purged with nitrogen, was prepared a solution of
N-(tert-butoxycarbonyl)-L-proline N'-methoxy-N'-methylamide (166
mg, 0.631 mmol) in anhydrous THF (1 mL), and cooled to -78.degree.
C. Added the dianion mixture dropwise via a gas-tight syringe
fitted with a 16G needle to the Weinreb amide solution and stirred
at -78.degree. C. for 30 min, replaced the dry ice-acetone bath
with an ice-water bath, and stirred at 0.degree. C. for 1 hr.
Removed the cooling bath and stirred at room temperature for 1 hr,
the cloudy yellow mixture became a dark yellow solution. Quenched
the reaction with sat'd aq NH.sub.4Cl (10 mL), extracted with
Et.sub.2O (2.times.25 mL), washed the combined ethereal extracts
with H.sub.2O (2.times.25 mL) and brine (25 mL), dried the organic
phase over anhydrous MgSO.sub.4, filtered, and concentrated by
rotary evaporation to a yellow oil (214 mg). Purified by flash
chromatography (silica gel, Alltech Extract-Clean 10 g column,
gradient of 5% to 7% EtOAc/CH.sub.2Cl.sub.2) to afford the title
compound as a yellow solid (77 mg, 41%) as a mixture of
stereoisomers. MS (ESI+) m/z 798 (M+H).sup.+, 1595
(2M+H).sup.+.
Example 105D
(2S,2'S)-tert-butyl
2,2'-(3,3'-(4,4'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phen-
ylene))bis(1H-pyrazole-5,3-diyl))dipyrrolidine-1-carboxylate
[0613] Dissolved the product of Example 105C (75 mg, 0.094 mmol) in
anhydrous absolute EtOH (1 mL) under nitrogen, added hydrazine
hydrate (0.023 mL, 0.235 mmol), and stirred the yellow solution at
room temperature for 1 hr. Removed the solvent by rotary
evaporation, azeotroped the yellow oil with toluene (2.times.5 mL),
redissolved in 1:5 v/v CH.sub.2Cl.sub.2/hexanes, concentrated, and
dried the light yellow solid in vacuo. Purified by flash
chromatography (silica gel, 2.5 cm.times.15 cm, 4%
MeOH/CH.sub.2Cl.sub.2) to afford the title compound as a white
solid (59 mg, 76%) as a mixture of stereoisomers. MS (ESI+) m/z 826
(M+H)+, 848 (M+Na).sup.+.
Example 105E
(S)-3,3'-(4,4'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phenyle-
ne))bis(5-((S)-pyrrolidin-2-yl)-1H-pyrazole
[0614] Dissolved the product of Example 105D (57.5 mg, 0.070 mmol)
in anhydrous CH.sub.2Cl.sub.2 (2 mL) under nitrogen, added TFA (1
mL, 12.98 mmol), and stirred at 25.degree. C. for 30 min. Removed
the solvent by rotary evaporation, took up the residue in 1:5 v/v
CH.sub.2Cl.sub.2/hexanes, concentrated to a yellow residue, and
dried in vacuo (83 mg). The TFA salt was dissolved in anhydrous
MeOH (7 mL) under nitrogen, treated with pre-washed (H.sub.2O and
MeOH) and dried Amberlite IRA-400(OH) resin (750 mg, .about.15
equivs of OH.sup.- based on .about.1.4 mequiv/g dry resin) and
stirred at 25.degree. C. for 2 hr. Vacuum filtered in a Buchner
funnel and washed the resin thoroughly with MeOH. The filtrate was
concentrated by rotary evaporation, the residue taken up in 1:5 v/v
CH.sub.2Cl.sub.2/hexanes, and concentrated in vacuo to give the
title compound as a light yellow solid (41 mg, 94%) as a mixture of
stereoisomers. MS (ESI+) m/z 626 (M+H).sup.+, 1251
(2M+H).sup.+.
Example 105F
methyl
{(2S)-1-[(2S)-2-(3-{4-[(2S,5S)-1-(4-tert-butylphenyl)-5-(4-{5-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-p-
yrazol-3-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-pyrazol-5-yl)pyrrolidin-1-yl-
]-3-methyl-1-oxobutan-2-yl}carbamate and
methyl
{(2S)-1-[(2S)-2-(3-{4-[(2R,5R)-1-(4-tert-butylphenyl)-5-(4-{5-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-p-
yrazol-3-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-pyrazol-5-yl)pyrrolidin-1-yl-
]-3-methyl-1-oxobutan-2-yl}carbamate
[0615] In an oven-dried 10-mL round bottom flask purged with
nitrogen, dissolved the product of Example 105E (39.7 mg, 0.063
mmol) in anhydrous DMF (1 mL) and cooled to 0.degree. C. Added
sequentially (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid
(23.89 mg, 0.136 mmol), HOBt hydrate (21.37 mg, 0.140 mmol), EDAC
(27.3 mg, 0.140 mmol), and N-methylmorpholine (0.021 mL, 0.190
mmol). Removed the cooling bath and stirred the dark yellow
solution at 25.degree. C. for 1 hr. Diluted the reaction with EtOAc
(50 mL), washed with H.sub.2O (3.times.25 mL) and brine (25 mL),
dried the organic phase over anhydrous MgSO.sub.4, filtered, and
concentrated by rotary evaporation to a light peach solid (63 mg).
Dissolved the crude material in CH.sub.2Cl.sub.2 and purified by
flash chromatography (silica gel, 2.5 cm.times.10 cm, 5%
MeOH/CH.sub.2Cl.sub.2) to afford a 1:1.25 trans:cis product mixture
(34 mg, 94% purity). Dissolved the residue in 1:1 v/v DMSO/MeOH (2
mL) and purified by RP-C.sub.18 HPLC (Waters Prep LC, 40 mm Module
with Nova Pak HR C.sub.18 6 .mu.m 40.times.100 mm Prep Pak
cartridge) eluting with a 30 min gradient of 90:10 0.1% TFA in
H.sub.2O/AcCN to 100% AcCN at 20 mL/min. Fractions containing a
mixture of the trans diastereomers were concentrated by rotary
evaporation, the residue taken up in 1:5 v/v
CH.sub.2Cl.sub.2/hexanes and evaporated (5 times), and dried in
vacuo to afford the title compounds as a cream-colored solid (12
mg, 16%). .sup.1H NMR (TFA salt) (400 MHz, DMSO-D6) .delta. ppm
0.76-0.94 (m, 12H), 1.10 (s, 9H), 1.13-1.31 (m, 3H), 1.71 (d,
J=5.42 Hz, 2H), 1.82-2.17 (m, 9H), 3.53 (s, 6H), 3.70-3.85 (m, 4H),
4.05 (t, J=8.08 Hz, 2H), 5.09-5.19 (m, 2H), 5.26 (d, J=5.96 Hz,
2H), 6.22 (d, J=8.78 Hz, 2H), 6.39 (d, J=1.30 Hz, 2H), 6.94 (d,
J=8.67 Hz, 2H), 7.20-7.31 (m, 6H), 7.62 (d, J=7.92 Hz, 4H); MS
(ESI+) m/z 940 (M+H).sup.+.
##STR00342##
Example 106
methyl
{(2S)-1-[(2S)-2-(3-{4-[(2R,5S)-1-(4-tert-butylphenyl)-5-(4-{5-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-p-
yrazol-3-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-pyrazol-5-yl)pyrrolidin-1-yl-
]-3-methyl-1-oxobutan-2-yl}carbamate
[0616] From the preparative HPLC separation of Example 105F was
obtained the title compound (cis) as a yellow solid (16 mg, 21%).
.sup.1H NMR (TFA salt) (400 MHz, DMSO-D6) .delta. ppm 0.77-0.93 (m,
12H), 1.14 (s, 9H), 1.17-1.31 (m, 2H), 1.80-2.18 (m, 11H), 3.35 (d,
J=8.02 Hz, 1H), 3.54 (s, 6H), 3.72-3.85 (m, 4H), 4.06 (t, J=8.29
Hz, 2H), 4.71-4.79 (m, 2H), 5.13-5.20 (m, 2H), 6.35 (d, J=8.78 Hz,
2H), 6.43 (s, 2H), 7.03 (d, J=8.78 Hz, 2H), 7.28 (d, J=8.35 Hz,
2H), 7.55 (d, J=8.24 Hz, 4H), 7.71 (d, J=7.59 Hz, 4H); MS (ESI+)
m/z 940 (M+H).sup.+.
##STR00343##
Example 107
methyl
{(2S)-1-[(2S)-2-(3-{4-[1-(4-tert-butylphenyl)-5-(4-{5-[(2S)-1-{(2S)-
-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-pyrazol-3-
-yl}phenyl)-1H-pyrrol-2-yl]phenyl}-1H-pyrazol-5-yl)pyrrolidin-1-yl]-3-meth-
yl-1-oxobutan-2-yl}carbamate
[0617] In an oven-dried 5-mL round bottom flask purged with
nitrogen, dissolved the product of Example 105E (5.1 mg, 8.15 mol)
in anhydrous DMF (400 .mu.L) and cooled to 0.degree. C. Added
sequentially (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid
(3.07 mg, 0.018 mmol), HOBt hydrate (2.75 mg, 0.018 mmol), EDAC
(3.51 mg, 0.018 mmol), and N-methylmorpholine (2.69 .mu.L, 0.024
mmol). Removed the cooling bath and stirred the dark yellow
solution at 25.degree. C. for 18 hr. Diluted the reaction in EtOAc
(50 mL), washed with H.sub.2O (2.times.10 mL) and brine (10 mL),
dried the organic over anhydrous MgSO.sub.4, filtered, and
concentrated by rotary evaporation to a yellow solid (9.6 mg).
Dissolved in 1:1 v/v MeOH/DMSO (1.5 mL) and purified by RP-C.sub.18
HPLC (Waters Prep LC, 40 mm Module with Nova Pak HR C.sub.18 6 in
40.times.100 mm Prep Pak cartridge) eluting with a 30 min gradient
of 90:10 0.1% TFA in H.sub.2O/AcCN to 100% AcCN at 20 mL/min. Pure
fractions were concentrated by rotary evaporation, azeotroped with
toluene (25 mL), the residue was taken up in 1:5 v/v
CH.sub.2Cl.sub.2/hexanes and evaporated (3 times), then dried in
vacuo to afford the title compound as an off-white solid (2.5 mg,
25%). .sup.1H NMR (TFA salt) (400 MHz, DMSO-D6) .delta. ppm
0.76-0.92 (m, 12H), 1.27 (s, 9H), 1.80-2.15 (m, 10H), 3.53 (s, 6H),
3.69-3.84 (m, 4H), 4.05 (t, J=8.24 Hz, 2H), 5.08-5.16 (m, 2H), 6.39
(s, 2H), 6.53 (s, 2H), 7.06 (dd, J=8.29, 2.87 Hz, 6H), 7.26 (d,
J=8.35 Hz, 2H), 7.37 (d, J=8.46 Hz, 2H), 7.44-7.55 (m, 4H), 12.92
(s, 2H); MS (ESI+) m/z 936 (M+H).sup.+.
##STR00344##
Example 108
N-(methoxycarbonyl)-L-valyl-N-{4-[(2S,5R)-5-(4-{[N-(methoxycarbonyl)-L-val-
yl]amino}phenyl)-1-{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2--
yl]phenyl}-L-prolinamide and
N-(methoxycarbonyl)-L-valyl-N-{4-[(2R,5S)-5-(4-{[N-(methoxycarbonyl)-L-val-
yl]amino}phenyl)-1-{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2--
yl]phenyl}-L-prolinamide
Example 108A
4-(5-(4-(2,5-bis(4-nitrophenyl)pyrrolidin-1-yl)phenyl)pyridin-2-yl)morphol-
ine
[0618] In a microwave tube (size L, 20 mL) purged with nitrogen and
sealed with a rubber septum, dissolved the product of Example 86A
(160 mg, 0.342 mmol) and
4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]-
morpholine (153 mg, 0.512 mmol) in THF (6 mL), added a solution of
potassium phosphate (176 mg, 0.803 mmol) in water (2 mL), and
sparged the reaction solution with nitrogen for 5 min. Added
1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride
(12.02 mg, 0.018 mmol) and stirred at 25.degree. C. for 15 min.
During this process, the reaction darkened quickly to a brown
color. Diluted the reaction with EtOAc (50 mL), washed with brine
(10 mL), dried the organic phase over anhydrous MgSO.sub.4,
filtered, and concentrated by rotary evaporation. Dissolved the
residue in CH.sub.2Cl.sub.2 and purified by flash chromatography
(silica gel, Alltech Extract-Clean 10 g column, 20%
EtOAc/CH.sub.2Cl.sub.2) to afford the title compound as a solid
(176 mg, 93%) as a mixture of stereoisomers. .sup.1H NMR (400 MHz,
DMSO-D6) .delta. ppm 1.82-1.94 (m, 2H), 2.53-2.62 (m, 2H),
3.37-3.47 (m, 4H), 3.64-3.74 (m, 4H), 5.03 (t, J=5.37 Hz, 2H), 6.40
(d, J=8.89 Hz, 2H), 6.82 (d, J=9.00 Hz, 1H), 7.34 (d, J=8.78 Hz,
2H), 7.69 (dd, J=8.84, 2.55 Hz, 1H), 7.83 (d, J=8.78 Hz, 4H), 8.28
(d, J=8.78 Hz, 4H), 8.29-8.31 (m, 1H); MS (ESI+) m/z 552
(M+H).sup.+.
Example 108B
4,4'-(1-(4-(6-morpholinopyridin-3-yl)phenyl)pyrrolidine-2,5-diyl)dianiline
[0619] Charged a 100-mL round bottom flask with the product of
Example 108A (174.7 mg, 0.317 mmol), partially dissolved in THF
(12.50 mL) and absolute EtOH (2.50 mL), evacuated on house vacuum
and filled flask with nitrogen, then added platinum (IV) oxide
(14.38 mg, 0.063 mmol), evacuated flask on house vacuum and filled
with hydrogen from a balloon, repeated evacuation/filling cycle 3
times, and stirred heterogeneous reaction mixture vigorously under
hydrogen (1 atm). After 2 hr, charged reaction with additional
platinum (IV) oxide (14.38 mg, 0.063 mmol) and continued to
vigorously stir under hydrogen at 25.degree. C. After 5 hr, added
additional platinum (IV) oxide (14.38 mg, 0.063 mmol). The reaction
mixture was then vacuum filtered through a bed of Celite 545 in a
Buchner funnel, the filter pad was washed with CHCl.sub.3 (100 mL)
and hot CHCl.sub.3 (2.times.50 mL), and the filtrate concentrated
by rotary evaporation to give the title compound as a yellow solid
(101 mg, 65%) as a mixture of stereoisomers. .sup.1H NMR (400 MHz,
DMSO-D6) .delta. ppm 1.71-1.87 (m, 2H), 2.24-2.31 (m, 1H),
3.37-3.45 (m, 4H), 3.64-3.74 (m, 4H), 4.57 (t, J=4.99 Hz, 2H), 4.95
(s, 4H), 6.42-6.53 (m, 3H), 6.57 (d, J=8.35 Hz, 4H), 6.76-6.89 (m,
2H), 7.15 (d, J=8.35 Hz, 4H), 7.26 (d, J=8.78 Hz, 2H), 7.68 (dd,
J=8.84, 2.44 Hz, 1H), 8.29 (d, J=2.39 Hz, 1H); MS (ESI+) m/z 492
(M+H).sup.+.
##STR00345##
Example 108C
methyl
(2S)-1-(4-(5-(4-aminophenyl)-1-(4-(6-morpholinopyridin-3-yl)phenyl)-
pyrrolidin-2-yl)phenylamino)-3-methyl-1-oxobutan-2-ylcarbamate
[0620] In an oven-dried 5-mL round bottom flask purged with
nitrogen, dissolved the product of Example 108B (70 mg, 0.142 mmol)
and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (26.2 mg,
0.150 mmol) in anhydrous DMSO (1.5 mL), added HATU (58.6 mg, 0.150
mmol) and diisopropylethylamine (0.050 mL, 0.285 mmol), and stirred
dark yellow solution at 25.degree. C. for 15 min. Diluted the
reaction with MeOH (1.5 mL) and purified by RP-C.sub.18 HPLC
(Waters Prep LC, 40 mm Module with Nova Pak HR C.sub.18 6 .mu.m
40.times.100 mm Prep Pak cartridge) eluting with a 30 min gradient
of 95:5 0.1% TFA in H.sub.2O/AcCN to 25:75 0.1% TFA in
H.sub.2O/AcCN, then 10 min to 100% AcCN at 20 mL/min. Pure
fractions were concentrated by rotary evaporation (water bath
35.degree.) to a small volume, partitioned between 20%
iPrOH/CHCl.sub.3 (50 mL), and sat'd aq NaHCO.sub.3 (15 mL),
separated layers, dried organic extract over anhydrous MgSO.sub.4,
filtered, and concentrated by rotary evaporation to afford the
title compound as a light yellow solid (48 mg, 52%). 1H NMR showed
the material to be .about.3:1 trans:cis mixture; MS (ESI+) m/z 649
(M+H).sup.+, 1297 (2M+H).sup.+.
Example 108D
N-(methoxycarbonyl)-L-valyl-N-{4-[(2S,5R)-5-(4-{[N-(methoxycarbonyl)-L-val-
yl]amino}phenyl)-1-{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2--
yl]phenyl}-L-prolinamide-ACD v12 and
N-(methoxycarbonyl)-L-valyl-N-{4-[(2R,5S)-5-(4-{[N-(methoxycarbonyl)-L-val-
yl]amino}phenyl)-1-{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2--
yl]phenyl}-L-prolinamide ACD v12
[0621] In an oven-dried 5-mL round bottom flask purged with
nitrogen, dissolved 3:1 trans/cis mixture of Example 108C (44 mg,
0.068 mmol) and the product of Example 37B (20.31 mg, 0.075 mmol)
in anhydrous DMSO (1 mL), added HATU (29.2 mg, 0.075 mmol) and
diisopropylethylamine (0.024 mL, 0.136 mmol), and stirred yellow
solution at 25.degree. C. for 30 min. Diluted the reaction with
MeOH (1 mL) and purified by RP-C.sub.18 HPLC (Waters Prep LC, 40 mm
Module with Nova Pak HR C.sub.18 6 .mu.m 40.times.100 mm Prep Pak
cartridge) eluting with a 30 min gradient of 95:5 0.1% TFA in
H.sub.2O/AcCN to 25:75 0.1% TFA in H.sub.2O/AcCN, then 10 min to
100% AcCN at 20 mL/min. The earlier eluting compound (18.8 mg, 31%)
was determined by .sup.1H NMR to be the trans diastereomers. The
fractions of the later eluting peak were concentrated by rotary
evaporation (water bath 35.degree. C.) to small volume, partitioned
between 20% iPrOH/CHCl.sub.3 (50 mL) and sat'd aq NaHCO.sub.3 (15
mL), separated layers, dried the organic phase over anhydrous
MgSO.sub.4, filtered, and concentrated by rotary evaporation to
afford a 2:3 trans:cis mixture as an off-white solid (10 mg). The
mixture was dissolved in 1:1 v/v MeOH/DMSO (1.5 mL) and purified by
RP-C.sub.18 HPLC (Phenomenex Luna C.sub.8(2) 5 m 100A AXIA column
(30 mm.times.75 mm)) eluting with a gradient of 90:10 10 mM
NH.sub.4OAc:MeOH to 100% MeOH to afford the title cis compounds as
a light beige solid (2 mg, 3%). .sup.1H NMR (400 MHz, DMSO-D6)
.delta. ppm 0.85-0.98 (m, 12H), 1.77-2.06 (m, 7H), 2.09-2.21 (m,
1H), 2.36-2.45 (m, 1H), 3.37-3.42 (m, 4H), 3.51 (s, 3H), 3.53 (s,
3H), 3.59-3.70 (m, 6H), 3.75-3.86 (m, 1H), 3.95 (t, J=8.13 Hz, 1H),
4.02 (t, J=8.57 Hz, 1H), 4.44 (dd, J=8.19, 4.72 Hz, 1H), 4.73 (s,
2H), 6.43 (d, J=8.89 Hz, 2H), 6.80 (d, J=8.89 Hz, 1H), 7.27 (d,
J=8.78 Hz, 2H), 7.29-7.38 (m, 2H), 7.44 (dd, J=8.57, 2.71 Hz, 4H),
7.54-7.64 (m, 4H), 7.67 (dd, J=8.89, 2.49 Hz, 1H), 8.27 (d, J=2.49
Hz, 1H), 10.04 (s, 2H); MS (ESI+) m/z 903 (M+H).sup.+, 920
(M+NH4).sup.+, 961 (M+AcCN+NH4).sup.+.
##STR00346##
Example 109
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(4-tert-butylphenyl)-5-{2-[(2S)-1-{(2-
S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimi-
dazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-
-1-oxobutan-2-yl}carbamate
Example 109A
2-bromo-1-(4-chloro-3-nitrophenyl)ethanone
Method A:
[0622] To a flask equipped with a magnetic stir bar and under an
atmosphere of N.sub.2 was added 4'-chloro-3'-nitroacetophenone
(10.0 g, 50.1 mmol) and THF (100 mL). To this stirring mixture was
added portion-wise phenyltrimethylammonium tribromide (19.78 g,
52.6 mmol) over a 15 minutes time period. The resultant mixture was
then stirred with monitoring every hour via LCMS. After 3 hr the
mixture was then filtered and resulting solids washed with EtOAc.
The organic solution was then concentrated, H.sub.2O and 10% aq.
NaHCO.sub.3 added and washed with EtOAc (2.times.300 mL). The
combined organic layers were then washed with Brine, dried
(MgSO.sub.4), filtered and concentrated. The residue material was
then subjected to purification via crystallization (dissolved
material in 100 mL EtOAc and slowly added hexanes until cloudy--let
stand for a few hours) to yield 9.81 g (70%) of
2-bromo-1-(4-chloro-3-nitrophenyl)ethanone as an off white colored
solid product. 1H NMR (500 MHz, DMSO-D6) .delta. ppm 5.00 (s, 2H)
7.98 (d, J=8.54 Hz, 1H) 8.24 (dd, J=8.54, 2.14 Hz, 1H) 8.61 (d,
J=1.98 Hz, 1H).
Method B:
[0623] In a 500 mL round-bottomed flask was added
1-(4-chloro-3-nitrophenyl)ethanone (11.98 g, 60 mmol) in benzene
(75 ml) to give a white suspension. Bromine (9.59 g, 60.0 mmol) was
added dropwise over 5 minutes to give a deep red solution. Stirred
for 1 hour to give a yellow solution that was concentrated in vacuo
to a yellow solid. Recrystallized from 9:1 hexane/ethyl acetate to
give 2-bromo-1-(4-chloro-3-nitrophenyl)ethanone as yellow
needles.
Example 109B
1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-dione
[0624] Zinc (II) chloride (14.68 g, 108 mmol) was added to toluene
(81 mL), then diethylamine (8.35 mL, 81 mmol) and tert-butanol
(7.73 mL, 81 mmol) were added and the resultant heterogenous
solution stirred at rt for approx. 2 h. Afterwards Example 109A
(15.0 g, 53.9 mmol) and 4'-chloro-3'-nitroacetophenone (16.13 g, 81
mmol) were added to the solution in one portion, and the resultant
mixture stirred at rt for 42 h). The reaction was then quenched
with 5% aqueous sulfuric acid (500 mL) and stirred vigorously to
induce solid formation. The resultant solid was vacuum filtered,
then washed with toluene, water, and methanol successively. Then
the solid was added to a solution of hot ethyl acetate and
resulting heterogeneous solution was stirred for 30 minutes and
then the solid was collected and dried overnight in a vacuum oven
to provide 16.6 g (78%) of the title compound. .sup.1H NMR (400
MHz, DMSO-d6) .delta. 8.61 (d, J=1.9 Hz, 2H), 8.27 (dd, J=8.4, 1.9
Hz, 2H), 7.96 (d, J=8.3 Hz, 2H), 3.48 (s, 4H).
Example 109C
(1S,4S)-1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-diol
[0625] (R)-(+)-alpha,alpha-diphenyl-2-pyrrolidinemethanol (1.08 g,
4.28 mmol) was dissolved in 70 mL of THF at ambient temperature in
a dry flask under nitrogen and the timethyl borate (650 uL, 5.54
mmol) was added dropwise. The resulting solution was stirred for 1
hr. The solution was cooled in a cold bath to .about.10.degree. C.
and the N,N-diethylaniline borane (9.18 mL, 51.6 mmol) was added
dropwise with some bubbling. After 15 min, this solution was
transferred to an addition funnel and added dropwise to
1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-dione (Example 109B)
(10.0 g, 25.2 mmol) suspended in 200 mL of THF and cooled
to.about.10.degree. C. Bubbling was observed. After the addition,
mixture was stirred at ambient temperature for 4 hours. The mixture
was cooled in an ice bath and 30 mL MeOH was added dropwise till
bubbling stopped, then the mixture was let stir at ambient
temperature for 30 min. The mixture was filtered to get rid of a
trace of insoluble unreacted SM. The filtrate was concentrated,
poured into 1 M HCl and extracted into ethyl acetate, dried over
sodium sulfate; concentrated to give the title compound (9.9 g,
99%) as a yellow waxy solid. Chiral HPLC e.e. >99.9% (RR diol
was undetectable). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.94 (d,
J=1.9 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 7.60 (dd, J=8.4, 1.9 Hz,
2H), 4.65 (m, 2H), 1.62 (m, 4H).
Example 109D
[0626] The product of Example 109C was processed as in Example
113A, 113B, 113C, and 113D, substituting 4-t-butylaniline for
4-cyclohexylaniline in the step 113A procedure to give 0.212 g
(22%) of the title compound. 1H NMR (400 MHz, DMSO-D6) .delta. ppm
0.74-0.92 (m, 12H) 1.07 (s, 9H) 1.69 (d, J=4.01 Hz, 2H) 1.86-2.05
(m, 6H) 2.13-2.24 (m, 4H) 2.54 (d, J=2.60 Hz, 2H) 3.51-3.56 (m, 6H)
3.81 (s, 4H) 4.05 (t, J=8.13 Hz, 2H) 5.09-5.18 (m, 2H) 5.35 (d,
J=3.47 Hz, 2H) 6.25 (d, J=8.78 Hz, 2H) 6.86-6.96 (m, 2H) 7.07 (t,
J=7.81 Hz, 2H) 7.20 (s, 1H) 7.26-7.32 (m, 3H) 7.38 (d, J=8.24 Hz,
1H) 7.46 (d, J=8.24 Hz, 1H) 11.98-12.08 (m, 2H); MS TFA+ m/z
889.
##STR00347##
Example 110
methyl
{(2S)-1-[(2S)-2-{5-[(2S,5S)-1-(4-tert-butylphenyl)-5-{2-[(2S)-1-{(2-
S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimi-
dazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-
-1-oxobutan-2-yl}carbamate
[0627] The product from Example 28K was purified by chiral
chromatography on a Chirapak IA column eluting with a mixture of
hexane/methanol/tetrahydrofuran (3:1:1) to give the title compound.
1H NMR (400 MHz, DMSO-D6) .delta. ppm 0.78-0.91 (m, 12H) 1.07 (s,
9H) 1.64-1.73 (m, 2H) 1.89-2.00 (m, 6H) 2.12-2.23 (m, 4H) 3.14-3.24
(m, 2H) 3.52 (s, 6H) 3.76-3.85 (m, 4H) 4.05 (td, J=8.38, 2.33 Hz,
2H) 5.07-5.16 (m, 2H) 5.30-5.39 (m, 2H) 6.23 (d, J=8.78 Hz, 2H)
6.90 (ddd, J=8.95, 4.72, 4.55 Hz, 2H) 7.06 (t, J=9.22 Hz, 2H) 7.17
(s, 1H) 7.23-7.31 (m, 3H) 7.37 (d, J=8.13 Hz, 1H) 7.44 (d, J=8.24
Hz, 1H) 12.02 (d, J=23.42 Hz, 2H); MS ESI+m/z 888 (M+H)+.
##STR00348##
Example 111
dimethyl
([(2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{benzene--
4,1-diylcarbamoyl(3S)-2-azabicyclo[2.2.1]heptane-3,2-diyl[(2S)-3-methyl-1--
oxobutane-1,2-diyl]})biscarbamate
##STR00349##
[0628] Example 111A
(3S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]-
heptane-3-carboxylic acid
[0629] (3S)-ethyl 2-azabicyclo[2.2.1]heptane-3-carboxylate (1.25 g,
7.39 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid
(1.42 g, 8.13 mmol), diisopropylethylamine (6.45 mL, 36.9 mmol),
and HATU (2.95 g, 7.76 mmol) were combined in dimethylformamide (40
mL) at ambient temperature and stirred for 2 hours. The solution
was diluted with water and the product filtered and dried. The
dried ester (1.0 g, 3.06 mmol) was taken up in water (15 mL) and
ethanol (15 mL) and treated with sodium hydroxide (0.5 g, 12.5
mmol) at ambient temperature for 17 hours. The solution was washed
with ether then the aqueous was neutralized with concentrated HCl
to pH 7 and the product extracted into ethyl acetate, dried over
sodium sulfate, and concentrated to give the title compound as a
waxy solid.
Example 111B
dimethyl
([(2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{benzene--
4,1-diylcarbamoyl(3S)-2-azabicyclo[2.2.1]heptane-3,2-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate
[0630] The product from Example 37E (0.05 g, 0.13 mmol), the
product from example 111A (0.097 g, 0.324 mmol),
diisopropylethylamine (0.113 mL, 0.648 mmol), and HATU (0.104 g,
0.272 mmol) were combined in dimethylformamide (2 mL) at ambient
temperature and stirred for 3 hours. The solution was poured into
brine, extracted into ethyl acetate, concentrated, and purified by
combi-flash 12 g silica column, eluting with 0-6% methanol in
dichloromethane to give the title compound as a solid. 1H NMR (400
MHz, DMSO-D6) .delta. ppm 0.91 (d, J=6.72 Hz, 6H) 0.98 (d, J=6.72
Hz, 6H) 1.11 (s, 9H) 1.32 (d, J=8.89 Hz, 2H) 1.36-1.46 (m, 2H)
1.59-1.74 (m, 6H) 1.76-1.84 (m, 2H) 1.90 (td, J=13.88, 6.94 Hz, 2H)
2.01-2.09 (m, 2H) 2.40-2.47 (m, 2H) 2.60 (d, J=1.19 Hz, 2H) 3.52
(s, 6H) 3.94 (s, 2H) 4.04-4.15 (m, 2H) 4.46 (s, 2H) 5.15 (d, J=6.51
Hz, 2H) 6.17 (d, J=8.78 Hz, 2H) 6.94 (d, J=8.78 Hz, 2H) 7.13 (d,
J=8.57 Hz, 4H) 7.22 (d, J=8.46 Hz, 2H) 7.49 (d, J=8.57 Hz, 4H) 9.95
(s, 2H)
##STR00350##
Example 112
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2R,5R)-1-(4-tert-butylphenyl)-5-(4-{2-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)(methyl)amino]-3-methylbutanoyl}pyrrolidin-2--
yl]-1H-imidazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrro-
lidin-1-yl]-3-methyl-1-oxobutan-2-yl}methylcarbamate
[0631] The product from Example 126H was processed as in Example
42B-42G, substituting
(S)-2-(methoxycarbonyl(methyl)amino)-3-methylbutanoic acid for
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid in step 42G, to
give 0.07 g (40%) of the title compound as a white solid. 1H NMR
(free base) (400 MHz, DMSO-D6) .delta. ppm 0.76 (d, J=6.61 Hz, 6H)
0.83 (d, J=6.51 Hz, 6H) 1.09 (s, 9H) 1.63-1.75 (m, 2H) 1.86-2.00
(m, 4H) 2.03-2.21 (m, 6H) 2.77 (s, 6H) 3.10-3.22 (m, 4H) 3.63 (s,
6H) 3.74-3.84 (m, 2H) 4.98-5.07 (m, 2H) 5.16-5.23 (m, 2H) 6.21 (d,
J=8.78 Hz, 2H) 6.88-6.96 (m, 2H) 7.15 (d, J=8.24 Hz, 4H) 7.22 (d,
J=8.35 Hz, 1H) 7.36 (d, J=1.52 Hz, 2H) 7.51 (d, J=8.24 Hz, 1H) 7.61
(d, J=8.13 Hz, 4H) 11.70 (s, 2H); MS ESI+m/z 968.7 (M+H)+; MS
ESI+m/z 968.7 (M+H)+.
##STR00351##
Example 113
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(4-cyclohexylphenyl)-5-{2-[(2S)-1-{(2-
S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimi-
dazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-
-1-oxobutan-2-yl}carbamate
Example 113A
(2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(4-cyclohexylphenyl)pyrrolidine
[0632] The product of Example 109C (2.0 g, 4.99 mmol) and
triethylamine (1.51 mL, 14.96 mmol) were dissolved in
dichloromethane (50 mL) and cooled in an ice bath. Methanesulfonyl
chloride (0.855 mL, 10.97 mmol) in dichloromethane (2 mL) was added
dropwise and the resulting mixture was stirred at ambient
temperature for 2 hours. The solution was concentrated to dryness
and dissolved in dimethylformamide (8 mL). 4-Cyclohexylaniline
(5.24 g, 29.9 mmol) was added and the solution was heated at
65.degree. C. for 2 hours then poured into 1 M HCl and extracted
into dichloromethane, concentrated, and purified by combi-flash 80
g silica column, eluting with 0-20% ethyl acetate in hexanes to
give 1.38 g (51%) of the title compound.
##STR00352##
Example 113B
(2S,2'S)-tert-butyl
2,2'-(4,4'-((2R,5R)-1-(4-cyclohexylphenyl)pyrrolidine-2,5-diyl)bis(2-nitr-
o-4,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylat-
e
[0633] The product from Example 113A (1.29 g, 2.39 mmol),
(S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate (1.53 g, 7.16
mmol), cesium carbonate (2.33 g, 7.16 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.33 g, 0.573
mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.328 g, 0.358
mmol) were combined in dioxane (18 mL) and nitrogen was bubbled
through the solution for 15 min, then the flask was capped with a
reflux condenser and the solution heated at 100.degree. C. for 8
hours. After filtering through celite and concentrating, the
residue was purified by combi-flash 80 g silica column, eluting
with 0-20% ethyl acetate in dichloromethane to give 1.71 g (80%) of
the title compound.
##STR00353##
Example 113C
(2S,2'S)-tert-butyl
2,2'-(4,4'-((2R,5R)-1-(4-cyclohexylphenyl)pyrrolidine-2,5-diyl)bis(2-amin-
o-4,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylat-
e
[0634] The product from Example 113B (1.71 g, 1.91 mmol) was
dissolved in tetrahydrofuran (10 mL) and ethanol (10 mL) at ambient
temperature and treated with Platinum (IV) oxide (0.11 g, 0.48
mmol). The flask was evacuated and opened to a hydrogen balloon and
stirred for 18 hours then filtered through celite and concentrated
to give the title compound.
Example 113D
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(4-cyclohexylphenyl)-5-{2-[(2S)-1-{(2-
S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimi-
dazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-
-1-oxobutan-2-yl}carbamate
[0635] Example 113C was processed using the methods of Examples
281, 28J, and 28K to provide the title compound. 1H NMR (400 MHz,
DMSO-D6) .delta. ppm 0.76-0.91 (m, 12H) 1.03-1.29 (m, 6H) 1.55-1.74
(m, 7H) 1.84-2.06 (m, 6H) 2.11-2.25 (m, 6H) 3.53 (s, 6H) 3.81 (s,
4H) 4.02-4.13 (m, 2H) 5.08-5.18 (m, 2H) 5.32-5.38 (m, 2H) 6.24 (d,
J=8.57 Hz, 2H) 6.68-6.77 (m, 2H) 7.06 (t, J=7.54 Hz, 2H) 7.19 (s,
1H) 7.26-7.32 (m, 3H) 7.37 (d, J=8.24 Hz, 1H) 7.45 (d, J=8.35 Hz,
1H) 11.98-12.05 (m, 2H); MS ESI+m/z 914.5.
##STR00354##
Example 114
methyl
{(2S)-1-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[4-(4-met-
hylpiperazin-1-yl)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin--
1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0636] The product of Example 109C (1.0 g, 2.49 mmol) was processed
as in Examples 113A-113D, substituting
4-(4-methylpiperazin-1-yl)aniline for 4-cyclohexylaniline in the
procedure of Example 113A and substituting Raney Nickel in
tetrahydrofuran for platinum(IV) oxide in tetrahydrofuran and
ethanol in the procedure of Example 113C to give 0.028 g (50%) of
the title compound as a solid. 1H NMR (400 MHz, DMSO-D6) .delta.
ppm 0.77-0.90 (m, 12H) 1.65-1.72 (m, 2H) 1.85-2.04 (m, 8H) 2.13 (s,
3H) 2.15-2.23 (m, 4H) 2.32 (s, 2H) 2.77 (s, 6H) 3.54 (s, 6H) 3.82
(d, J=4.66 Hz, 4H) 4.02-4.08 (m, 2H) 5.09-5.18 (m, 2H) 5.28-5.37
(m, 2H) 6.23 (d, J=8.78 Hz, 2H) 6.54 (ddd, J=9.00, 4.66, 4.55 Hz,
2H) 7.02-7.08 (m, 2H) 7.19 (s, 1H) 7.26-7.31 (m, 3H) 7.36 (d,
J=8.13 Hz, 1H) 7.44 (d, J=8.35 Hz, 1H) 12.01 (s, 2H); MS ESI+m/z
556 (M+H)+.
##STR00355##
Example 115
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-(1,3-benzothiazol-2-yl)-5-{2-[(2S)-1--
{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benz-
imidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-met-
hyl-1-oxobutan-2-yl}carbamate
Example 115A
(2R,5R)-1-allyl-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine
[0637] The product from Example 109C (5.0 g, 12.46 mmol) and
allylamine were processed as in Example 113A to give 1.5 g (39%) of
the title compound as a thick oil.
Example 115B
(2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine
[0638] The product from Example 115A (2.0 g, 4.74 mmol) was
dissolved in acetonitrile (40 mL) and water (4 mL) and treated with
Tris(triphenylphosphine)rhodium(I) chloride (0.219 g, 0.237 mmol).
The mixture was heated at 100.degree. C. and nitrogen was bubbled
through the solution for 3 hours. The mixture was partitioned
between 5% sodium bicarbonate solution and ethyl acetate, then the
organics were concentrated and the product purified by combiflash
80 g silica column eluting with dichloromethane to give 1.33 g
(74%) of the title compound.
Example 115C
2-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)benzo[d]thiazole
[0639] The product from Example 115B (0.335 g, 0.877 mmol),
2-bromobenzo[d]thiazole (0.281 g, 1.32 mmol),
tris(dibenzylideneacetone)dipalladium(0) 0.08 g (0.088 mmol), BINAP
(0.055 g, 0.088 mmol), and sodium tert-butoxide (0.126 g, 1.32
mmol) were combined in dioxane (8 mL) and nitrogen was bubbled
through the solution for 10 minuets. The tube was sealed and heated
at 100.degree. C. for 18 hours. The reaction mixture was
partitioned between brine and dichloromethane and the organics were
concentrated and purified by combi-flash 24 g silica column,
eluting with 1:1 hexanes: dichloromethane, followed by 100%
dichloromethane to give 0.165 g (37%) of the title compound.
Example 115D
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-(1,3-benzothiazol-2-yl)-5-{2-[(2S)-1--
{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benz-
imidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-met-
hyl-1-oxobutan-2-yl}carbamate
[0640] The product from Example 115C was processed as in Examples
113B, 113C, and 113D to give 0.040 g (38%) of the title compound.
1H NMR (400 MHz, DMSO-D6) .delta. ppm 0.74-0.88 (m, 12H) 1.76-1.84
(m, 2H) 1.85-1.94 (m, 3H) 1.95-2.07 (m, 4H) 2.14-2.26 (m, 4H)
2.61-2.71 (m, 2H) 3.53 (s, 6H) 3.76-3.85 (m, 4H) 4.05 (t, J=8.51
Hz, 2H) 5.10-5.18 (m, 2H) 6.90 (t, J=7.54 Hz, 2H) 7.07-7.16 (m, 3H)
7.22-7.35 (m, 4H) 7.40 (d, J=8.13 Hz, 2H) 7.47 (d, J=8.35 Hz, 1H)
7.52-7.59 (m, 1H) 12.07 (s, 2H); MS ESI+m/z 889.
##STR00356##
Example 116
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-(4,5,6,7--
tetrahydro-1,3-benzothiazol-2-yl)pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyr-
rolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
Example 116A
(S)-pyrrolidine-2-carboxamide hydrochloride salt
[0641] To (S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate (29.8
g, 139 mmol) was added a solution of 4N HCl in dioxane (209 mL, 836
mmol) and the resultant mixture stirred at room temperature for 18
hrs. The mixture was then concentrated and triturated with diethyl
ether then vacuum filtered and dried under vacuum to provide 21.6 g
(104%) of the title product as a colorless solid.
Example 116B
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid
[0642] To (S)-2-amino-3-methylbutanoic acid (57 g, 487 mmol)
dissolved in dioxane (277 mL) was added a 2N aqueous sodium
hydroxide solution (803 mL, 1606 mmol) followed by the dropwise
addition of methyl chloroformate (75 mL, 973 mmol) over 1 hr which
caused warming of the solution to occur. After the addition, the
mixture was heated at 60.degree. C. for 22 hrs, then cooled and
extracted with dichloromethane (400 mL). The resultant aqueous
layer was cooled in an ice bath then 12N hydrochloric acid was
added dropwise until the pH was 2. The resultant mixture was
stirred at 0.degree. C. for 2 hrs then the resultant solid was
vacuum filtered and dried in a vacuum oven to provide 80 g (94%) of
the title compound as a colorless solid. .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 12.50 (bs, 1H), 7.34 (d, J=8.6 Hz, 1H), 3.84 (dd,
J=8.6, 6.0 Hz, 1H), 3.54 (s, 3H), 2.03 (m, 1H), 0.86 (t, J=7.0 Hz,
6H).
##STR00357##
Example 116C
methyl
(S)-1-((S)-2-carbamoylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarb-
amate
[0643] To the product of Example 116A (21.6 g, 144 mmol), the
product of Example 116B (29.1 g, 166 mmol),
1H-benzo[d][1,2,3]triazol-1-ol hydrate (27.6 g, 180 mmol),
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (34.6 g, 180 mmol) and 4-methylmorpholine (63.5 mL,
578 mmol) was dissolved in dichloromethane (960 mL) and stirred at
room temperature for 18 hrs. The resultant solution was then
concentrated to a residue, water was then added and the solution
extracted with a 25% isopropanol in chloroform solution
(2.times.2000 mL) the organic layer washed with brine then the
organic extract dried over MgSO.sub.4, then concentrated to a
yellow oil which was purified by column chromatography eluting with
a gradient of 0-10% methanol in dichloromethane to provide 25 g
(64%) of the title compound as a colorless solid. .sup.1H NMR (400
MHz, DMSO-d6) .delta. 7.28 (m, 2H), 6.81 (s, 1H), 4.24 (dd, J=8.1,
4.4 Hz, 1H), 4.00 (t, J=8.4 Hz, 1H), 3.75 (m, 1H), 3.55 (m, 1H),
3.50 (s, 3H), 2.02 (m, 1H), 1.97 (m, 2H), 1.80 (m, 2H), 0.92 (d,
J=6.7 Hz, 3H), 0.86 (d, J=8.6 Hz, 3H).
##STR00358##
Example 116D
2-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-4,5,6,7-tetrahy-
drobenzo[d]thiazole
[0644] The product from Example 109C (0.80 g, 1.489 mmol) and
4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine were processed using the
method of Example 113A to give 0.375 g (50%) of the title
compound
##STR00359##
Example 116E
dimethyl
([(2R,5R)-1-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)pyrrolidine-
-2,5-diyl]bis{(2-nitrobenzene-4,1-diyl)carbamoyl(2S)pyrrolidine-2,1-diyl[(-
2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate (ACD v12))
[0645] The product from Example 116D (0.375 g, 0.722 mmol) was
processed as in Example 113B, substituting the product from Example
116C for (S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate to
give 0.59 g (83%) of the title compound.
##STR00360##
Example 116F
dimethyl
([(2R,5R)-1-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)pyrrolidine-
-2,5-diyl]bis{(2-aminobenzene-4,1-diyl)carbamoyl(2S)pyrrolidine-2,1-diyl[(-
2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate (ACD v12))
[0646] The product from Example 116E (0.59 g, 0.596 mmol) was
dissolved in tetrahydrofuran (15 mL) and treated with Raney Nickel
slurry in water (0.25 mL). The flask was evacuated and opened to a
hydrogen balloon and stirred at ambient temperature for 1 hour. The
solution was filtered through a silica plug and concentrated to
dryness to give the title compound.
Example 116G
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-(4,5,6,7--
tetrahydro-1,3-benzothiazol-2-yl)pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyr-
rolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0647] The product from Example 116F (0.55 g, 0.592 mmol) was
dissolved in toluene (6 mL) and treated with acetic acid (0.34 mL,
5.92 mmol) and heated to 65.degree. C. for 4 hours. The solution
was concentrated to dryness and purified by combi-flash 12 g silica
column, eluting with 0-6% methanol in dichloromethane to give 0.245
g (48%) of the title compound. 1H NMR (400 MHz, DMSO-D6) .delta.
ppm 0.78-0.92 (m, 12H) 1.53-1.61 (m, 4H) 1.67-1.75 (m, 2H)
1.88-2.07 (m, 6H) 2.15-2.27 (m, 6H) 2.41-2.47 (m, 2H) 2.59 (d,
J=1.63 Hz, 2H) 3.54 (s, 6H) 3.79-3.87 (m, 4H) 4.07 (t, J=8.57 Hz,
2H) 5.12-5.20 (m, 2H) 5.38-5.46 (m, 2H) 7.05 (dd, J=12.79, 9.00 Hz,
2H) 7.22-7.33 (m, 4H) 7.39 (d, J=8.46 Hz, 1H) 7.46 (d, J=8.46 Hz,
1H) 12.06 (d, J=6.83 Hz, 2H); MS ESI+m/z 893.5.
##STR00361##
Example 117
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2S,3R,4R,5S)-1-(4-tert-butylphenyl)-3,4-die-
thoxy-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}py-
rrolidin-2-yl]-1H-imidazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-
-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0648] 3.4-O-isopropylidene-D-mannitol was processed using the
methods of Examples 79C, 79D, 79E, 79F, 79G, 79H, and 791 to
provide the title compound, wherein iodoethane was used in the
O-alkylation step (method of Example 79D) instead of iodomethane.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.86 (t, J=7.4 Hz,
12H) 1.04 (t, J=7.0 Hz, 6H) 1.13 (s, 9H) 1.85-2.03 (m, 4H)
2.03-2.13 (m, 2H) 2.13-2.24 (m, 2H) 2.24-2.40 (m, 2H) 3.03 (m, 2H)
3.54-3.89 (m, 9H) 3.69 (d, J=1.7 Hz, 6H) 4.25 (d, J=5.3 Hz, 2H)
4.31 (br s, 2H) 5.19-5.29 (m, 4H) 5.36 (br s, 2H) 6.28 (d, J=8.8
Hz, 2H) 6.90-6.98 (m, 4H) 7.12-7.23 (m, 6H). MS (ESI) m/z 1029
(M+H).sup.+.
##STR00362##
Example 118
methyl
{(2S)-1-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[6-(pyrro-
lidin-1-yl)pyridin-3-yl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-
-yl]-3-methyl-1-oxobutan-2-yl}carbamate
Example 118A
5-nitro-2-(pyrrolidin-1-yl)pyridine
[0649] To a slurry of 2-chloro-5-nitropyridine (10 g, 63.1 mmol) in
EtOH (100 mL) at room temperature was added pyrrolidine (15.72 mL,
189 mmol) and the mixture was heated at 70.degree. C. for 18 h. The
cooled solution was concentrated in vacuo and the residue
partitioned between CH.sub.2Cl.sub.2 and 1M NaOH. The organic layer
was dried (Na.sub.2SO.sub.4), filtered and solvent removed in vacuo
to give title compound (9.52 g, 78%). MS (ESI) m/z 194
(M+H).sup.+.
Example 118B
6-(pyrrolidin-1-yl)pyridin-3-amine
[0650] Material from Example 118A (9.52 g, 49.3 mmol) was dissolved
in THF (50 mL) and DMF (40 mL) and added to a pressure bottle
containing Raney Nickel 2800, water slurry (45%) (9.52 g, 162 mmol)
stirred for 2 h at 30 psi under H.sub.2 gas. The solution was
filtered through a nylon membrane, washed with CH.sub.3OH and the
filtrate concentrated in vacuo to give the title compound (7.78 g,
97%). .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.81-1.91 (m, 4H)
3.17-3.29 (m, 4H) 4.30 (s, 2H) 6.25 (d, J=8.7, 1H), 6.90 (dd,
J=2.8, 8.7, 1H), 7.55 (d, J=2.6, 1H). MS (ESI) m/z 164
(M+H).sup.+.
Example 118C
(2S,2'S)-tert-butyl
2,2'-(5,5'-((2R,5R)-1-(6-(pyrrolidin-1-yl)pyridine-3-yl)pyrrolidine-2,5-d-
iyl)bis(1H-benzo[d]imidazole-5,2-diyl)dipyrrolidine-1-carboxylate
[0651] Example 118B and Example 109C were processed using
sequentially the methods of Examples 113A, 113B, 116F, and 28I to
provide the title compound.
Example 118D
methyl
{(2S)-1-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[6-(pyrro-
lidin-1-yl)pyridin-3-yl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-
-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0652] To a solution of Example 118C (741 mg, 0.94 mmol) in dioxane
(4 mL) was added 4 M HCl in dioxane (4.0 mL) and the solution was
stirred at room temperature for 30 min. Solvent is removed in vacuo
and the residue is dissolved in DMF (9.4 mL). Added
N,N-diisopropylethylamine (0.99 mL, 5.65 mmol) followed by
(S)-2-(methoxycarbonyl-amino)-3-methylbutanoic acid (379 mg, 2.16
mmol), HOBT (331 mg, 2.16 mmol), and EDC (415 mg, 2.16 mmol) and
stirred at room temperature for 18 h. Poured into EtOAc, washed
with H.sub.2O, brine, dried (Na.sub.2SO.sub.4), filtered and
removed solvent in vacuo to give crude product which was purified
by flash chromatography on silica gel eluting with 0-6%
CH.sub.3OH/CH.sub.2Cl.sub.2 to give the title compound (165 mg,
0.183 mmol, 19%). 1H NMR (400 MHz, DMSO-d6) .delta. 0.73-0.95 (m,
12H) 1.66-2.27 (m, 12H) 3.09 (br s, 5H) 3.53 (s, 6H) 3.81 (br s,
4H) 4.06 (t, J=8.4 Hz, 2H) 5.13 (br s, 2H) 5.33 (br s, 2H) 6.12 (br
s, 1H) 6.64 (br s, 1H) 7.00-7.47 (m, 10H) 12.02 (s, 2H). MS (ESI)
m/z 903 (M+H).sup.+.
##STR00363##
Example 119
methyl
4-{4-[(2R,5R)-2,5-bis(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrol-
idin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-1-yl]-2-fluorophenyl}piperazine-
-1-carboxylate
Example 119A
1-(2-fluoro-4-nitrophenyl)piperazine
[0653] To a warm solution of piperazine (7.78 g, 90 mmol) in DMSO
(40 mL) was added dropwise 1,2-difluoro-4-nitrobenzene (2.0 mL,
18.07 mmol). The solution was stirred at 70.degree. C. for 2 h,
cooled to room temperature, diluted with EtOAc, washed with
H.sub.2O, brine, dried (Na.sub.2SO.sub.4), filtered and solvent
removed in vacuo to give the title compound (4.05 g, 17.98 mmol,
100%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 3.03-3.09 (m,
4H) 3.26-3.29 (m, 4H) 6.91 (t, J=8.8 Hz, 1H) 7.91 (dd, J=13.1, 2.6
Hz, 1H) 7.96-8.01 (m, 1H). MS (ESI) m/z 226 (M+H).sup.+.
Example 119B
Methyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate
[0654] To a solution of Example 119A (4.0 g, 17.76 mmol) in dioxane
(40 mL) at 0.degree. C. was added 2 M NaOH (29.3 mL, 58.6 mmol)
followed by dropwise addition of methyl chloroformate (2.75 mL,
35.5 mmol). The solution was warmed to room temperature and stirred
for 2 h. Diluted with EtOAc and added 1 N HCl until all solid had
dissolved, separated the phases and washed the organic phase with 1
N HCl, H.sub.2O, brine, dried (Na.sub.2SO.sub.4), filtered and
removed solvent in vacuo to give the title compound (4.69 g, 16.56
mmol, 93%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 3.20-3.31
(m, 4H) 3.62-3.71 (m, 4H) 3.75 (s, 3H) 6.92 (t, J=8.8 Hz, 1H) 7.93
(dd, J=12.9, 2.6 Hz, 1H) 7.98-8.02 (m, 1H). MS (ESI) m/z 284
(M+H).sup.+.
Example 119C
Methyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate
[0655] To a solution of Example 119B (3.0 g, 10.59 mmol) in EtOAc
(40 mL) was added 10% palladium on carbon (300 mg) and the solution
was stirred under a balloon of H.sub.2 gas for 1.5 h. The solution
was filtered through Celite, the catalyst washed with EtOAc, and
the filtrate concentrated in vacuo to give the title compound (2.68
g, 10.59 mmol, 100%).
Example 119D
methyl
4-{4-[(2R,5R)-2,5-bis(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrol-
idin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-1-yl]-2-fluorophenyl}piperazine-
-1-carboxylate
[0656] Example 119C and Example 109C were processed using
sequentially the methods of Examples 113A-113C, 261, and 118D to
provide the title compound. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
ppm 0.75-0.93 (m, 12H) 1.69 (br s, 2H) 1.82-2.07 (m, 7H) 2.10-2.28
(m, 4H) 2.61-2.73 (m, 5H) 3.54 (s, 6H) 3.56 (s, 3H) 3.82 (br s, 4H)
3.99-4.11 (m, 2H) 5.09-5.19 (m, 2H) 5.29-5.41 (m, 2H) 6.01-6.13 (m,
2H) 6.61-6.72 (m, 1H) 7.06 (s, 2H) 7.20 (s, 1H) 7.29 (d, J=9.1 Hz,
3H) 7.38 (d, J=8.1 Hz, 1H) 7.46 (d, 1H) 12.04 (s, 2H). MS (ESI) m/z
993 (M+H).sup.+.
##STR00364##
Example 120
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3-fluoro-4-(morpholin-4-yl)phenyl]-5-
-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-
-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-
-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
Example 120A
4-(2-Fluoro-4-nitrophenyl)morpholine
[0657] A suspension of morpholine (4.72 mL, 4.72 g, 54.2 mmol) and
dibasic potassium phosphate (9.44 g, 54.2 mmol) in DMSO (27 mL) was
treated with 3,4-difluoronitrobenzene (3.0 mL, 4.31 g, 27.1 mmol)
was warmed at 60.degree. C. for 18 h. The solution was cooled and
diluted with ethyl acetate and extracted with water (3.times.) and
saturated sodium chloride solution. Drying (Na.sub.2SO.sub.4) and
concentration in vacuo afforded the title compound (6.32 g, ca.
100%) as a yellow solid. H NMR (400 MHz, CDCl.sub.3) .delta. 8.00
(ddd, J=9.0, 2.6, 0.9 Hz, 1H), 7.92 (dd, J=13.1, 2.6 Hz, 1H), 6.92
(t, J=8.8 Hz, 1H), 3.88 (m, 4H), 3.29 (dd, J=5.5, 4.0 Hz, 4H).
MS+DCI m/z (rel abundance) 227 (10, M+H), 244 (100, M+NH4).
Example 120B
3-Fluoro-4-morpholinoaniline
[0658] A solution of the compound of Example 120A (2.26 g, 10.00
mmol) in ethyl acetate (35 mL) was treated with 10% palladium on
carbon (300 mg) followed by hydrogenation under one atmosphere
pressure for 6 h. The mixture was filtered through celite and
concentrated in vacuo to afford the title compound as a white
solid.
Example 120C
4-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2-fluorophen-
yl)morpholine
[0659] A solution of the compound of Example 109C (2.00 g, 4.99
mmol) and triethylamine (4.17 mL, 3.03 g, 29.9 mmol) in dry
dichloromethane (25 mL) at 0.degree. C. was treated with
methanesulfonyl chloride (1.17 mL, 1.71 g, 14.96 mmol) followed by
stirring at 0.degree. C. for 30 min. The solution was warmed to RT
and then concentrated in vacuo. The residue was combined with the
compound of Example 120B and N,N-dimethylaniline (1.26 mL, 1.21 g,
9.98 mmol) and dissolved in dry DMF (14 mL) followed by warming at
50.degree. C. for 2 h. The solution was cooled and diluted with
ethyl acetate, followed by extraction with water (3.times.) and 1 N
hydrochloric acid solution (2.times.) and saturated sodium chloride
solution. Drying (Na.sub.2SO.sub.4) and concentration in vacuo
afforded an orange oil, which was chromatographed over a 340 g
silica gel cartridge, eluting with 10-80% ethyl acetate in hexanes.
These procedures afforded the title compound (1.39 g, 50%) as an
orange rigid foam. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.92
(m, 2H), 7.58 (m, 9H), 7.31 (dd, J=8.3, 2.1 Hz, 2H), 6.69 (s, 1H),
5.99 (m, 2H), 5.20 (d, J=7.1 Hz, 2H), 3.79 (m, 4H), 2.92 (m, 6H),
2.54 (m, 2H), 1.88 (m, 2H).
Example 120D
Dimethyl
(2R,2'R)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(3-fluoro-4-morphol-
inophenyl)pyrrolidin-2,5-diyl)bis(2-nitro-4,1-phenylene))bis(azanediyl)bis-
(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)-
dicarbamate
[0660] In a microwave tube, a suspension of the Example 120C (1.39
g, 2.48 mmoL), the compound of Example 116C (2.02 g, 7.43 mmol),
XantPhos (129 mg, 0.22 mmol) and cesium carbonate (2.42 g, 7.43
mmoL) in dioxane (14 mL) was degassed by nitrogen sparge for 30
min. The mixture was treated with
tris(dibenzylideneacetone)dipalladium (0) (68 mg, 0.074 mmol)
followed by degassing for another 5 min. The microwave tube was
sealed and the mixture was warmed at 100.degree. C. for 2 h. The
mixture was cooled and diluted with ethyl acetate and extracted
with water (3.times.) and saturated sodium chloride solution. The
solution was dried (Na.sub.2SO.sub.4) and stirred overnight with
3-(mercaptopropyl) silica gel. Filtration and concentration in
vacuo afforded a solid, which was chromatographed over a 340 g
silica gel cartridge, eluting with 0-10% methanol in
dichloromethane. These procedures afforded the title compound as an
orange solid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 0.80-0.90
(m, 12H) 1.74 (br s, 2H) 1.82-2.03 (m, 10H) 2.08-2.20 (m, 2H)
2.71-2.81 (m, 4H) 3.52 (s, 6H) 3.62 (m, 4H) 3.76 (s, 2H) 4.02 (m,
2H) 4.50 (d, J=4.4 Hz, 2H) 5.39 (s, 2H) 6.04-6.19 (m, 2H) 6.72-6.81
(m, 1H) 7.32 (d, J=8.4 Hz, 2H) 7.47-7.60 (m, 4H) 7.80 (d, J=1.5 Hz,
2H) 10.41 (s, 2H). MS (ESI) m/z 1031 (M+H).sup.+.
Example 120E
Dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(3-fluoro-4-morphol-
inophenyl)pyrrolidine-2,5-diyl)bis(2-amino-4,1-phenylene)bis(azanediyl)bis-
(oxomethylene)bis(pyrrolidine-2,1
diyl)bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
[0661] To a solution of Example 120D (640 mg, 0.621 mmol) in EtOH
(4 mL) and THF (4 mL) was added PtO.sub.2 (35 mg) and the solution
was stirred under a balloon of H.sub.2 gas for 16 h. The solution
was filtered through Celite and washed with EtOAc. The filtrate was
concentrated in vacuo to give the title compound (322 mg, 0.332
mmol, 53%).
Example 120F
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3-fluoro-4-(morpholin-4-yl)phenyl]-5-
-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-
-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-
-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0662] To a solution of Example 120E (320 mg, 0.33 mmol) in toluene
(1.5 mL) was added glacial acetic acid (0.057 mL, 0.99 mmol) and
the solution was stirred at 50.degree. C. for 3 h. The cooled
solution was concentrated in vacuo and azeotroped 2 times with
toluene. The crude product was purified by flash chromatography on
silica gel eluting with 0-4% CH.sub.3OH/CH.sub.2Cl.sub.2 to give
the title compound (100 mg, 0.107 mmol, 32%). .sup.1H NMR (400 MHz,
DMSO-d6) .delta. ppm 0.72-0.92 (m, 12H) 1.69 (br s, 2H) 1.81-2.10
(m, 8H) 2.11-2.28 (m, 4H) 2.64-2.78 (m, 4H) 3.54 (s, 6H) 3.59 (s,
4H) 3.73-3.92 (m, 4H) 4.06 (s, 2H) 5.02-5.21 (m, 2H) 5.36 (s, 2H)
6.03-6.14 (m, 2H) 6.60-6.73 (m, 1H) 7.00-7.15 (m, 2H) 7.15-7.37 (m,
4H) 7.36-7.61 (m, 2H) 12.06 (br s, 2H). MS (ESI) m/z 935
(M+H).sup.+.
##STR00365##
Example 121
methyl
[(2S)-1-{(2S)-2-[5-(4-{(2S,3R,4R,5S)-1-(4-tert-butylphenyl)-5-(4-{2-
-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl-
]-1H-imidazol-5-yl}phenyl)-3,4-bis[2-(2-methoxyethoxyl)ethoxy]pyrrolidin-2-
-yl}phenyl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]car-
bamate
[0663] 3.4-O-isopropylidene-D-mannitol was processed using
sequentially the methods of Examples 79C, 79D
(1-bromo-2-(2-methoxyethoxyl)ethane as the alkylating agent with
added sodium iodide), 79E-79G, 79H (18 hour reaction time), 66D,
and 66E to provide the title compound (46 mg) as a light yellow
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.60 (d, J=7.9
Hz, 4H), 7.50 (d, J=8.4 Hz, 2H), 7.38 (s, 2H), 7.29 (d, J=8.6 Hz,
2H), 7.19 (s, 4H), 6.90 (m, 2H), 6.27 (d, J=8.6 Hz, 2H), 5.37 (s,
2H), 5.07 (d, J=3.6 Hz, 2H), 4.32 (s, 2H), 4.06 (m, 2H), 3.78 (d,
J=6.0 Hz, 2H), 3.66 (d, J=4.2 Hz, 4H), 3.53 (s, 6H), 3.17 (s, 6H),
2.10 (m, 4H), 1.93 (m, 4H), 1.07 (s, 9H), 0.86 (m, 12H). MS (+ESI)
m/z (rel abundance) 1177 (100, M+H), 1199 (5, M+Na).
##STR00366##
Example 122
methyl
{(2S)-1-[(2S)-2-(5-{4-[(2S,3R,4R,5S)-1-(4-tert-butylphenyl)-5-(4-{2-
-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl-
]-1H-imidazol-5-yl}phenyl)-3,4-bis(3-methoxypropoxy)pyrrolidin-2-yl]phenyl-
}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0664] 3.4-O-isopropylidene-D-mannitol was processed using
sequentially the methods of Examples 79C, 79D
(1-bromo-3-methoxypropane as the alkylating agent with added sodium
iodide), 79E-79H, 66D, and 66E to provide the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.60 (s, 4H), 7.52 (m,
2H), 7.37 (m, 2H), 7.30 (m, 4H), 7.18 (d, J=7.1 Hz, 4H), 6.91 (m,
2H), 6.24 (m, 2H), 5.40 (m, 2H), 5.06 (m, 2H), 4.31 (m, 2H), 4.11
(m, 2H), 3.78 (s, 4H), 3.66 (m, 4H), 3.56 (m, 10H), 3.14 (m, 14H),
2.14 (m, 6H), 1.94 (d, J=3.5 Hz, 8H), 1.43 (m, 6H), 1.07 (s, 10H),
0.89 (d, J=6.1 Hz, 6H), 0.84 (d, J=5.9 Hz, 6H).
##STR00367##
Example 123
methyl
{(2S)-1-[(2S)-2-(5-{4-[(2S,3R,4R,5S)-1-(4-tert-butylphenyl)-5-(4-{2-
-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl-
]-1H-imidazol-5-yl}phenyl)-3,4-bis(2-methoxyethoxy)pyrrolidin-2-yl]phenyl}-
-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0665] 3.4-O-isopropylidene-D-mannitol was processed using
sequentially the methods of Examples 79C, 79D
(1-bromo-2-methoxyethane as the alkylating agent with added sodium
iodide), 79E, 79F, 79G, and 79H, wherein Example 126G replaced
(S)-tert-butyl-2-(4-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate
in applying the method of Example 79H, to provide the title
compound (43 mg) as a light beige solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.60 (d, J=8.0 Hz, 4H), 7.47 (m, 2H), 7.37
(m, 2H), 7.27 (m, 4H), 7.19 (s, 4H), 6.90 (d, J=8.6 Hz, 2H), 6.26
(d, J=8.7 Hz, 2H), 5.37 (s, 2H), 5.06 (d, J=3.7 Hz, 2H), 4.30 (s,
2H), 4.03 (m, 2H), 3.79 (s, 4H), 3.66 (m, 6H), 3.53 (s, 6H), 3.25
(m, 6H), 3.12 (s, 6H), 2.13 (m, 4H), 1.94 (m, 6H), 1.07 (s, 9H),
0.89 (d, J=6.6 Hz, 6H), 0.84 (d, J=6.6 Hz, 6H). MS+ESI m/z (rel
abundance) 1088 (100, M+H).
##STR00368##
Example 124
methyl
{(2S)-1-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}-1-[6-(morph-
olin-4-yl)pyridin-3-yl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1--
yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0666] Example 109C and Example 154B were processed using the
methods of Examples 113A, 113B, 116F, 281 (reaction conducted at
50.degree. C. for 4 h), 66D, and 66E to provide the title compound
(120 mg) as a light beige solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.03 (s, 1H), 7.46 (d, J=8.2 Hz, 1H), 7.45
(s, 1H), 7.31 (d, J=6.4 Hz, 3H), 7.21 (s, 1H), 7.06 (t, J=8.0 Hz,
2H), 6.64 (m, 1H), 6.49 (m, 1H), 5.36 (d, J=6.2 Hz, 2H), 5.13 (s,
2H), 4.04 (m, 2H), 3.77 (m, 3H), 3.55 (m, 9H), 3.04 (s, 4H), 2.19
(s, 3H), 1.95 (m, 5H), 1.73 (s, 3H), 0.82 (m, 12H). MS+ESI m/z (rel
abundance) 918 (100, M+H).
##STR00369##
Example 125
methyl
{(2S)-1-[(2S)-2-(5-{4-[1-(2,3-dihydro-1H-inden-5-yl)-5-(4-{2-[(2S)--
1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-im-
idazol-5-yl}phenyl)-1H-pyrrol-2-yl]phenyl}-H-imidazol-2-yl)pyrrolidin-1-yl-
]-3-methyl-1-oxobutan-2-yl}carbamate
[0667] Example 26E and 5-aminoindan were processed using the
methods of Examples 76A, 39E, 39F, 55G, and 26J (reaction
solvent=dichloromethane) to provide the title compound (0.1446 g).
.sup.1H NMR (400 MHz, DMSO-D6) .delta. 0.91-0.79 (m, 12H),
2.18-1.87 (m, 12H), 2.74 (t, J=6.7, 2H), 2.86 (t, J=6.8, 2H), 3.53
(s, 6H), 3.84-3.68 (m, 4H), 4.10-3.98 (m, 2H), 5.03 (dd, J=6.8,
2.9, 2H), 6.54-6.40 (m, 2H), 7.10-6.86 (m, 5H), 7.22-7.13 (m, 2H),
7.33-7.22 (m, 2H), 7.45-7.35 (m, 2H), 7.53 (dd, J=13.7, 8.5, 4H),
11.70 (s, 1H), 12.07-11.96 (m, 1H). MS (ESI) m/z 920 (M+H).sup.+,
918 (M-H).sup.+.
##STR00370##
Example 126
methyl
[(2S)-1-{(2S)-2-[5-(4-{(2R,5R)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)-1--
[4-(pentafluoro-lambda-6-1-sulfanyl)phenyl]pyrrolidin-2-yl}phenyl)-1H-imid-
azol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
Example 126A
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid
[0668] A mixture of (S)-2-amino-3-methylbutanoic acid (10.0 g, 85.0
mmol), NaOH (3.41 g, 85.0 mmol) and NaHCO.sub.3 (4.7 g, 44.4 mmol)
in H.sub.2O (85 mL) was cooled to 0.degree. C. A mixture of methyl
chloroformate (7.3 mL, 94.0 mmol) dissolved in Et.sub.2O (40 mL)
was slowly added to the aqueous mixture and stirred for 20 hours
coming to ambient temperature. Mixture was adjusted to pH 2.0 with
HCl (conc). The mixture was extracted with CH.sub.2Cl.sub.2
(3.times.100 mL) and then dried (MgSO.sub.4), filtered and
concentrated to afford 7.5 g (50%) of the title compound. MS (ESI)
m/z 176 (M+H).sup.+.
Example 126B
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate
[0669] A mixture of oxalyl chloride (14.1 mL, 161 mmol) in
CH.sub.2Cl.sub.2 (331 mL) was cooled to -75.degree. C.
Dimethylsulfoxide (19.4 mL, 273 mmol) in CH.sub.2Cl.sub.2 (70 mL)
was slowly added over 30 minutes followed by stirring at
-75.degree. C. for an additional 15 minutes. At -75.degree. C.
(S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (25.0 g,
124 mmol) in CH.sub.2Cl.sub.2 (132 mL) was added slowly over one
hour, followed by a further 15 minutes of stirring. Then, still at
-75.degree. C., Et.sub.3N (87 mL, 621 mmol) was added over 30
minutes followed by another 15 minutes of stirring. Mixture was
then allowed to stir at 0.degree. C. for 90 minutes. Mixture was
quenched with 10% aqueous Citric acid at 0.degree. C. The mixture
was diluted with 10% aqueous Citric acid and partitioned. Organic
was washed with H.sub.2O (5.times.150 mL) and Brine. The organic
was then dried (MgSO.sub.4), filtered and concentrated to afford
24.7 g (100%) of the title compound. MS (ESI) m/z 200
(M+H).sup.+.
Example 126C
(S)-tert-butyl 2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate
[0670] A mixture of Example 126B (24.7 g, 124.0 mmol) and
NH.sub.4OH (62.0 mL, 497 mmol) in methanol (62 mL) was stirred at
0.degree. C. followed by slow addition of glyoxal hydrate (29.9 mL,
262 mmol) over 10 minutes. Mixture was stirred for 16 hours at
ambient temperature. The mixture was concentrated, diluted with
H.sub.2O and extracted with EtOAc (3.times.200 mL). The organic was
then dried (MgSO.sub.4), filtered and concentrated. Purification by
trituration with tBuOMe afforded 15.5 g (53%) of the title
compound. MS (ESI) m/z 238 (M+H).sup.+.
Example 126D
(S)-tert-butyl
2-(4,5-dibromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate
[0671] A mixture of Example 126C (15.5 g, 65.4 mmol) in
CH.sub.2Cl.sub.2 (260 mL) was stirred at 0.degree. C. followed by
portion-wise addition of 1-bromopyrrolidine-2,5-dione (24.5, 137.0
mmol) over 10 minutes. Mixture was stirred 0.degree. C. for 90
minutes. Mixture was concentrated, diluted with EtOAc (600 mL) and
washed with H.sub.2O (3.times.200 mL) and brine. The organic was
then dried (MgSO.sub.4), filtered and concentrated. Purification by
trituration with Et.sub.2O afforded 24.9 g (96%) of the title
compound. MS (ESI) m/z 396 (M+H).sup.+.
Example 126E
(S)-tert-butyl
2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate
[0672] A mixture of Example 126D (12.5 g, 31.5 mmol) in dioxane
(400 mL) and H.sub.2O (400 mL) had a solution of Na.sub.2SO.sub.3
(43.7 g, 347 mmol) in H.sub.2O (400 mL) added and was heated to
reflux for 21 hours. The mixture was concentrated to half volume
and extracted with CH.sub.2Cl.sub.2 (3.times.200 mL). The organic
was then washed with brine, dried (MgSO.sub.4), filtered and
concentrated. Purification by trituration (CH.sub.2Cl.sub.2,
tBuOMe, and Hexanes) afforded 5.2 g (52%) of the title compound. MS
(ESI) m/z 317 (M+H).sup.+.
Example 126F
(S)-5-bromo-2-(pyrrolidin-2-yl)-1H-imidazole hydrochloride
[0673] A mixture of Example 126E (5.0 g, 15.8 mmol) in 4M
HCl/Dioxane (40 mL) was allowed to stir for one hour. The mixture
was concentrated to afford 3.99 g (100%) of the title compound. MS
(ESI) m/z 217 (M+H).sup.+.
Example 126G
methyl
(S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1--
oxobutan-2-ylcarbamate
[0674] A mixture of Example 126F (3.99 g, 15.8 mmol), Example 126A
(2.77 g, 15.8 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (3.63 g, 19.0 mmol), 1-Hydroxy-benzotriazole hydrate
(2.90 g, 19.0 mmol) and N-methylmorpholine (12.2 mL, 111.0 mmol) in
DMF (150 mL) were allowed to stir overnight. Mixture was diluted
with H.sub.2O and extracted with EtOAc (3.times.300 mL). The
organic was washed with H.sub.2O and Brine. The organic was then
dried (MgSO.sub.4), filtered and concentrated. Purification by
chromatography (silica gel, 75% EtOAc in Hexanes) afforded 5.2 g
(88%) of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 0.79 (dd, J=6.67, 3.63 Hz, 6H), 1.84-1.96 (m, 3H),
2.02-2.14 (m, 2H), 3.51 (s, 3H), 3.66-3.80 (m, 2H), 3.96-4.03 (m,
1H), 4.91-4.99 (m, 1H), 7.06 (d, J=1.52 Hz, 1H), 7.26 (d, J=8.46
Hz, 1H), 12.01 (s, 1H). MS (ESI) m/z 373 (M+H).sup.+.
Example 126H
(1S,4S)-1,4-bis(4-bromophenyl)butane-1,4-diol
[0675] (1S,4S)-1,4-bis(4-bromophenyl)butane-1,4-diol was prepared
using the method of Example 69A and (R)-alpha,
alpha-diphenyl-2-pyrrolidinemethanol).
##STR00371##
Example 126I
(2R,5R)-2,5-bis(4-bromophenyl)-1-(4-sulfur pentafluoride
phenyl)pyrrolidine
[0676] A solution of methanesulfonic anhydride (2.95 mL, 23.02
mmol) in 2-Me THF (15 mL) was cooled in ice/salt bath to
.about.0.degree. C. To this cold solution a solution of Example
126H (4.0524 g, 10.13 mmol) and N,N-diisopropylethylamine (5.5 mL,
31.8 mmol) in 2-Me THF (40 mL) was added dropwise over 40 minutes.
The reaction was slowly warmed to 20.degree. C. At this time
4-aminophenylsulfur pentafluoride (7.1238 g, 32.5 mmol) was added
and the mixture was warmed to 38.degree. C. for 17 hours. The
reaction was cooled and partioned between EtOAc and water. The
organic fraction was washed with water (2.times.) brine (1.times.)
and concentrated. Purification by flash chromatography (silica gel,
EtOAc/hexane) afforded the title compound (1.95 g, 33%). LC/MS Rt
2.38 m/z 584 (M+H).sup.+.
Example 126J
(2R,5R)-1-(4-sulfur pentafluoride
phenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyr-
rolidine
[0677] The product from Example 126I was processed using the method
described in Example 39E to afford the title compound (1.67 g,
74%). MS (ESI) m/z 678 (M+H).sup.+.
Example 126K
methyl
[(2S)-1-{(2S)-2-[5-(4-{(2R,5R)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)-1--
[4-(pentafluoro-lambda-6-1-sulfanyl)phenyl]pyrrolidin-2-yl}phenyl)-1H-imid-
azol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0678] The product from Example 126J and Example 126G were
processed using the method described in Example 39F to afford the
title compound (0.75 g, 30%). .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 0.85 (dd, J=6.7, 15.8, 12H), 2.26-1.66 (m, 14H), 3.53 (s,
6H), 3.87-3.63 (m, 4H), 4.14-3.91 (m, 2H), 5.06 (dd, J=3.0, 6.7,
2H), 5.34 (s, 2H), 6.34 (d, J=9.1, 2H), 7.17 (d, J=8.2, 4H), 7.26
(dd, J=8.4, 17.3, 2H), 7.75-7.34 (m, 8H), 12.22-11.46 (m, 2H). MS
(ESI) m/z 1010 (M+H).sup.+, 1008 (M-H).sup.+.
##STR00372##
Example 127
methyl
[(2S)-1-{(2S)-2-[5-(4-{1-[4-(azepan-1-yl)phenyl]-5-(4-{2-[(2S)-1-{(-
2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidaz-
ol-5-yl}phenyl)-1H-pyrrol-2-yl}phenyl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-
-methyl-1-oxobutan-2-yl]carbamate
[0679] Example 26E and 4-(1-azepanyl)aniline were processed using
the methods of Examples 76A, 39E, 39F, 55G, and 26J (reaction
solvent=dichloromethane) to provide the title compound (6.1 mg). MS
(ESI) m/z 977 (M+H).sup.+.
##STR00373##
Example 128
methyl
{(2S)-1-[(2S)-2-(5-{4-[(2R,5R)-1-(4-cyclohexylphenyl)-5-(4-{2-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-i-
midazol-5-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1--
yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0680] Example 126H and 4-cyclohexylaniline were processed using
the methods of Examples 126I, 126J, and 126K to provide the title
compound (0.14 g). .sup.1H NMR (400 MHz, DMSO-D6) .delta. 0.85 (dd,
J=16.6, 6.9, 12H), 1.32-1.06 (m, 8H), 1.65 (dd, J=19.1, 6.2, 7H),
2.27-1.82 (m, 13H), 3.53 (s, 6H), 3.78 (d, J=6.8, 2H), 4.10-3.95
(m, 2H), 5.06 (dd, J=6.9, 3.1, 2H), 5.19 (t, J=6.7, 2H), 6.21 (d,
J=8.7, 2H), 6.76 (dd, J=8.6, 3.7, 2H), 7.19-7.08 (m, 4H), 7.34-7.19
(m, 2H), 7.37 (d, J=1.8, 1H), 7.50 (t, J=11.3, 1H), 7.65-7.57 (m,
3H), 11.68 (s, 1H), 12.10-11.93 (m, 1H). MS (ESI) m/z 966
(M+H).sup.+.
##STR00374##
Example 129
methyl
{(2S)-1-[(2S)-2-(4-chloro-5-{4-[(2R,5R)-5-(4-{4-chloro-2-[(2S)-1-{(-
2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidaz-
ol-5-yl}phenyl)-1-(4-cyclohexylphenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol--
2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0681] N-Chlorosuccinimide (0.046 g, 0.342 mmol) was added to a
solution of the product from Example 128 (0.1435 g, 0.149 mmol) in
dichloromethane (7 mL) and stirred at ambient temperature for 17
hours. The reaction was diluted with dichloromethane and washed
with sat aq NaHCO3 (2.times.) and concentrated. The residue was
purified by flash chromatography (silica gel, MeOH/dichloromethane)
then by prep HPLC to afford the title compound (20.4 mg, 13%).
.sup.1H NMR (free base) (400 MHz, DMSO-D6) .delta. 0.94-0.73 (m,
12H), 1.39-0.99 (m, 8H), 1.75-1.41 (m, 6H), 2.27-1.77 (m, 12H),
3.53 (s, 6H), 3.86-3.66 (m, 3H), 4.08-3.96 (m, 2H), 5.11-4.89 (m,
2H), 5.30-5.12 (m, 1H), 5.55-5.33 (m, 1H), 6.21 (d, J=8.7, 1H),
6.88-6.67 (m, 2H), 6.94 (dd, J=4.3, 8.4, 1H), 7.42-7.02 (m, 6H),
7.56-7.42 (m, 3H), 7.61 (t, J=8.5, 1H), 11.68 (d, J=10.7, 1H),
12.49-12.26 (m, 1H). MS (ESI) m/z 1034 (M+H).sup.+.
##STR00375##
Example 130
methyl
[(2S)-1-{(2S)-2-[5-(4-{(2R,5R)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)-1--
[4-(morpholin-4-yl)phenyl]pyrrolidin-2-yl}phenyl)-1H-imidazol-2-yl]pyrroli-
din-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0682] Example 126H and 4-morpholinoaniline were processed using
sequentially the methods of Examples 126I, 39E, 39F, 391, and 26J
(reaction solvent=dichloromethane) to provide the title compound
(0.16 g). .sup.1H NMR (300 MHz, DMSO-D6) .delta. 0.86 (dd, J=12.2,
6.6, 12H), 1.77-1.55 (m, 2H), 2.03-1.77 (m, 6H), 2.21-2.03 (m, 4H),
2.45-2.39 (m, 1H), 2.58-2.54 (m, 1H), 2.82-2.74 (m, 4H), 3.53 (s,
6H), 3.67-3.57 (m, 4H), 3.77 (d, J=6.1, 3H), 4.04 (t, J=8.3, 2H),
5.06 (dd, J=6.7, 3.0, 2H), 5.18 (t, J=5.0, 2H), 6.22 (d, J=9.0,
2H), 6.58 (dd, J=9.0, 1.9, 2H), 7.14 (d, J=8.4, 4H), 7.32-7.17 (m,
3H), 7.37 (d, J=1.8, 2H), 7.55-7.41 (m, 1H), 7.63 (t, J=10.0, 4H),
11.68 (s, 1H), 12.15-11.90 (m, 1H). MS (ESI) m/z 969
(M+H).sup.+.
##STR00376##
Example 131
methyl
[(2S)-1-{(2S)-2-[4-chloro-5-(4-{(2R,5R)-5-(4-{4-chloro-2-[(2S)-1-{(-
2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-H-imidazo-
l-5-yl}phenyl)-1-[4-(pentafluoro-lambda-6-sulfanyl)phenyl]pyrrolidin-2-yl}-
phenyl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbama-
te
[0683] The product from Example 126K was processed using the method
described in Example 129. The mixture of mono and dichlorinated
products was purified via reverse phase HPLC to afford the title
compound (90.9 mg, 19%). .sup.1H NMR (free base) (500 MHz, DMSO-D6)
.delta. 0.84 (dd, J=6.8, 16.1, 12H), 2.23-1.70 (m, 13H), 3.53 (s,
6H), 3.85-3.66 (m, 4H), 4.02 (ddd, J=4.8, 10.8, 16.1, 3H),
5.05-4.91 (m, 2H), 5.43 (d, J=5.8, 2H), 6.36 (d, J=9.1, 2H), 7.28
(d, J=8.4, 2H), 7.34 (d, J=8.3, 4H), 7.46 (d, J=9.4, 2H), 7.72-7.58
(m, 4H), 12.43 (s, 2H). MS(ESI) m/z 1078 (M+H).sup.+.
##STR00377##
Example 132
methyl
[(2S)-1-{(2S)-2-[4-chloro-5-(4-{(2R,5R)-5-(4-{2-[(2S)-1-{(2S)-2-[(m-
ethoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}p-
henyl)-1-[4-(pentafluoro-lambda-6-1-sulfanyl)phenyl]pyrrolidin-2-yl}phenyl-
)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0684] The product from Example 126K was processed using the method
described in Example 129. The mixture of mono and dichlorinated
products was purified via reverse phase HPLC to afford the title
compound (33.3 mg, 7%). .sup.1H NMR (free base) (500 MHz, DMSO-D6)
.delta. 0.94-0.76 (m, 12H), 2.24-1.63 (m, 13H), 3.53 (d, J=1.2,
6H), 3.86-3.68 (m, 4H), 4.10-3.98 (m, 2H), 5.02-4.93 (m, 1H), 5.06
(dd, J=3.2, 7.1, 1H), 5.48-5.30 (m, 2H), 6.35 (d, J=9.1, 2H),
7.21-7.10 (m, 2H), 7.36-7.21 (m, 4H), 7.58-7.38 (m, 4H), 7.73-7.59
(m, 4H), 12.50-11.65 (m, 2H). MS (ESI) m/z 1044 (M+H).sup.+, 1042
(M-H).sup.+.
##STR00378##
Example 133
methyl
[(2S)-1-{(2S)-2-[5-(4-{(2R,5R)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)-1--
[6-(piperidin-1-yl)pyridin-3-yl]pyrrolidin-2-yl}phenyl)-1H-imidazol-2-yl]p-
yrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0685] Example 126H and 6-(piperidin-1-yl)pyridine-3-amine were
processed using sequentially the methods of Examples 126I, 39E,
39F, 391, and 26J (reaction solvent=dichloromethane) to provide the
title compound (91.4 mg). .sup.1H NMR (400 MHz, DMSO-D6) .delta.
0.85 (dt, J=7.1, 14.3, 12H), 1.24 (s, 2H), 1.44 (s, 6H), 1.70 (d,
J=5.2, 2H), 2.04-1.82 (m, 6H), 2.23-2.04 (m, 4H), 3.21-3.03 (m,
4H), 3.53 (s, 6H), 3.87-3.67 (m, 4H), 4.12-3.96 (m, 2H), 5.06 (dd,
J=3.2, 7.0, 2H), 5.20 (t, J=6.8, 2H), 6.49 (dd, J=3.1, 9.1, 1H),
6.60 (dd, J=2.9, 9.2, 1H), 7.20-7.10 (m, 4H), 7.33-7.20 (m, 3H),
7.38 (d, J=1.8, 2H), 7.51 (t, J=10.4, 1H), 7.64 (dd, J=8.1, 15.7,
3H), 11.69 (s, 1.4H), 12.06 (t, J=32.1, 0.6H).
##STR00379##
Example 134
methyl
{(2S)-1-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}-1-[6-(piper-
idin-1-yl)pyridin-3-yl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1--
yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0686] Example 109C and 6-(piperidin-1-yl)pyridine-3-amine were
processed using sequentially the methods of Examples 113A, 113B,
116F (Ra--Ni reduction conducted in an SS pressure bottle for 120
min at 30 psi at room temperature), 281 (reaction conducted at
50.degree. C. for 4 hours), 391, and 26J (reaction
solvent=dichloromethane) to provide the title compound (71 mg).
.sup.1H NMR (400 MHz, METHANOL-D4) 0.89 (ddd, J=6.5, 20.7, 26.0,
12H), 1.62-1.43 (m, 6H), 2.48-1.80 (m, 13H), 2.72-2.60 (m, 2H),
3.10-2.97 (m, 4H), 3.64 (s, 6H), 3.93-3.78 (m, 2H), 4.09-3.94 (m,
2H), 4.22 (d, J=7.3, 2H), 5.21 (dd, J=5.2, 7.6, 1H), 5.44-5.30 (m,
2H), 6.50 (d, J=9.1, 1H), 6.83-6.71 (m, 1H), 7.59-7.15 (m, 7H). MS
(ESI) m/z 916 (M+H).sup.+, 914 (M-H).sup.+.
##STR00380##
Example 135
methyl
[(2S)-1-{(2S)-2-[5-(4-{1-[6-(4,4-difluoropiperidin-1-yl)pyridin-3-y-
l]-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrro-
lidin-2-yl]-1H-imidazol-5-yl}phenyl)-1H-pyrrol-2-yl}phenyl)-1H-imidazol-2--
yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
Example 135A
2-(4,4-difluoropiperidin-1-yl)-5-nitropyridine
[0687] To a slurry of 2-chloro-5-nitropyridine (5 g, 31.5 mmol) and
4,4-difluoropiperidine hydrochloride (4.97 g) in ethanol (40 mL) at
ambient temperature was added N,N-diisopropylethylamine (12.00 mL,
69.4 mmol) and the mixture heated to 70.degree. C. for 18 hours.
The reaction was concentrated, partitioned between CH2Cl2 and 1M
NaOH. The organic phase concentrated and purified by chromatography
(elution with 2% MeOH--CH2Cl2 then 3% MeOH--CH2Cl2) to provide the
title compound as a yellow oil. MS (DCI) m/z 261
(M+NH.sub.4).sup.+.
Example 135B
6-(4,4-difluoropiperidin-1-yl)pyridin-3-amine
[0688] The product from Example 135A (4.56 g, 18.75 mmol) and
solvent THF (20 mL)/DMF were added to Ra--Ni 2800, water slurry
(4.56 g, 78 mmol) in a 250 mL SS pressure bottle and stirred for 2
hr at 30 psi and ambient temperature. The mixture was filtered
through a nylon membrane and washed with MeOH. The filtrate was
concentrated and dried under vacuum to afford the title compound
(3.40 g, 85%). .sup.1H NMR (400 MHz, DMSO-D6) .delta. 2.03-1.88 (m,
4H), 3.49-3.38 (m, 4H), 4.61 (s, 2H), 6.73 (d, J=8.8, 1H), 6.93
(dd, J=2.9, 8.8, 1H), 7.61 (d, J=2.6, 1H). MS (ESI) m/z 214
(M+H.sup.+).
Example 135C
5-(2,5-bis(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-pyrrol-1-
-yl)-2-(4,4-difluoropiperidin-1-yl)pyridine
[0689] TFA (0.046 mL, 0.596 mmol) was added to a mixture of the
product from Example 138B (0.2114 g, 0.298 mmol) and the product
from Example 135B (0.095 g, 0.447 mmol) in toluene (2.98 mL). The
mixture was heated at 110.degree. C. for 18 hours. The reaction was
cooled and additional TFA (0.023 mL, 0.298 mmol) was added and
stirred for another hour. The solvent was removed under reduced
pressure and azatroped with toluene to afford the title
compound.
Example 135D
methyl
[(2S)-1-{(2S)-2-[5-(4-{1-[6-(4,4-difluoropiperidin-1-yl)pyridin-3-y-
l]-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrro-
lidin-2-yl]-1H-imidazol-5-yl}phenyl)-1H-pyrrol-2-yl}phenyl)-1H-imidazol-2--
yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0690] The product from Example 135C was processed using the method
described in Example 26J to afford the title compound. .sup.1H NMR
(400 MHz, DMSO-D6) .delta. 0.94-0.73 (m, 12H), 2.03-1.82 (m, 10H),
2.20-2.04 (m, 4H), 3.53 (s, 6H), 3.64 (s, 4H), 3.86-3.69 (m, 4H),
4.04 (dd, 2H), 5.04 (dd, J=3.0, 7.0, 2H), 6.53-6.39 (m, 2H),
6.93-6.79 (m, 1H), 7.06 (d, J=8.4, 3H), 7.13 (dd, J=10.9, 19.3,
1H), 7.30-7.21 (m, 2H), 7.39-7.30 (m, 1H), 7.42 (d, J=1.7, 1H),
7.48-7.43 (m, 1H), 7.66-7.49 (m, 4H), 7.85 (dd, J=2.7, 9.7, 1H),
12.16-11.64 (m, 2H). MS (ESI) m/z 1000 (M+H).sup.+, 998
(M-H).sup.+.
##STR00381##
Example 136
methyl
{(2S)-1-[(2S)-2-(4-{4-[5-(4-{2-[1-{(2S)-2-[(methoxycarbonyl)amino]--
3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1-{4-[(trifluor-
omethyl)sulfonyl]phenyl}-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidi-
n-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
Example 136A
2,5-bis(4-bromophenyl)-1-(4-(trifluoromethylsulfonyl)phenyl)-1H-pyrrole
[0691] To a slurry of the product from Example 26E (0.60 g, 1.52
mmol) and 4-(trifluoromethylsulfonyl)aniline (0.51 g, 2.27 mmol) in
toluene (12 mL) was added a IN solution of titanium(IV) chloride
(1.6 mL, 1.6 mmol) in toluene. The mixture was stirred overnight at
room temperature and then heated to reflux for 3 hours. The cooled
mixture was filtered and the solid residue was suspended in a
mixture of water and diethyl ether. The solid was diluted with
water and ether and stirred vigorously for 15 minutes. The mixture
was filtered and then washed thoroughly with diethyl ether to give
the title compound as a crude mixture that was used in subsequent
reactions without further purification (0.60 g, 68% yield
crude).
Example 136B
methyl
{(2S)-1-[(2S)-2-(4-{4-[5-(4-{2-[1-{(2S)-2-[(methoxycarbonyl)amino]--
3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1-{4-[(trifluor-
omethyl)sulfonyl]phenyl}-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidi-
n-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0692] Example 136A was processed using sequentially the methods of
Examples 26G, 26H, 65B, and 65C to provide the title compound (90
mg). .sup.1H NMR (400 MHz, DMSO-D6) .delta. 12.20-11.68 (m, 2H),
8.17-8.04 (m, 2H), 7.63-7.42 (m, 8H), 7.31-7.15 (m, 2H), 7.02-6.90
(m, 4H), 6.64-6.53 (m, 2H), 5.08-4.97 (m, 2H), 4.05-3.97 (m, 2H),
3.83-3.69 (m, 4H), 3.53 (s, 6H), 2.18-1.79 (m, 10H), 0.90-0.78 (m,
12H). MS (ESI; M+H) m/z=1013.
##STR00382##
Example 137
methyl
[(2S)-1-{(2S)-2-[4-(4-{1-[4-(2-cyanopropan-2-yl)phenyl]-5-(4-{2-[(2-
S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-
-imidazol-4-yl}phenyl)-1H-pyrrol-2-yl}phenyl)-1H-imidazol-2-yl]pyrrolidin--
1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0693] Example 26E and 2-(4-aminophenyl)-2-methylpropanenitrile
were processed using sequentially the methods of Examples 26F, 26G,
26H, 65B, and 65C to provide the title compound (100 mg). .sup.1H
NMR (400 MHz, DMSO-D6) .delta. 12.15-11.68 (m, OH), 7.58-7.44 (m,
OH), 7.44-7.36 (m, OH), 7.30-7.12 (m, OH), 7.07-6.91 (m, OH),
6.55-6.42 (m, OH), 5.06-4.96 (m, OH), 4.02 (t, J=8.3, OH),
3.81-3.67 (m, OH), 3.52 (s, OH), 2.15-1.82 (m, OH), 1.65 (s, OH),
0.90-0.74 (m, 1H). MS (ESI; M+H) m/z=948.
##STR00383##
Example 138
methyl
{(2S)-1-[(2S)-2-(4-{4-[1-(3-tert-butylphenyl)-5-(4-{2-[(2S)-1-{(2S)-
-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol--
4-yl}phenyl)-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-me-
thyl-1-oxobutan-2-yl}carbamate
Example 138A
1,4-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butane-1,4-d-
ione
[0694] To a solution of the product from Example 26E (2.00 g, 5.05
mmol), bis(pinacolato)diborane (3.85 g, 15.15 mmol), potassium
acetate (1.982 g, 20.20 mmol) in dimethoxyethane (50 mL) at room
temperature was added PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct
(0.412 g, 0.505 mmol) and the mixture degassed (purge with
N.sub.2). The mixture was heated to reflux for 1 hour. The cooled
mixture was filtered through celite and washed with ethyl acetate.
The filtrate was washed with water, brine and dried
(Na.sub.2SO.sub.4). After filtration and removal of solvent, the
residue was purified by chromatography (80 g column; gradient
elution from 0% to 40% ethyl acetate-hexanes) to provide the title
compound (2.22 g; 90%) as a white solid. .sup.1HNMR (CDCl.sub.3;
400 MHz): .delta. 8.02 (AA'XX', J=8.24 Hz, 4H), 7.91 (AA'XX',
J=8.13 Hz, 4H), 3.47 (s, 4H), 1.36 (s, 24H).
##STR00384##
Example 138B
di-tert-butyl
(2S,2'S)-2,2'-[(1,4-dioxobutane-1,4-diyl)bis(benzene-4,1-diyl-1H-imidazol-
e-5,2-diyl)]dipyrrolidine-1-carboxylate
[0695] A solution of the product from Example 138A (2.22 g, 4.53
mmol), PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (0.37 g, 0.45
mmol), 1 M sodium carbonate (18 mL, 18 mmol) and the product from
Example 26D (4.30 g, 13.6 mmol) in ethanol (23 mL)/toluene (23 mL)
was degassed (purge N.sub.2) and heated in oil bath at 90.degree.
C. overnight. The cooled mixture was concentrated and the residue
partitioned between water and ethyl acetate. The organic phase was
concentrated and the residue was purified by chromatography
(gradient elution from 30% to 100% ethyl acetate-hexane) to provide
the title compound (1.90 g, 59%) as a light tan solid. .sup.1HNMR
(DMSO-d.sub.6; 400 MHz): .delta. 12.06 (m, 2H), 8.04-7.96 (m, 4H),
7.89-7.78 (m, 4H), 7.69 (m, 2H), 4.85-4.75 (m, 2H), 3.53 (m, 2H),
3.35 (m, 4H), 2.24-1.87 (m, 10H), 1.39 (br s, 8H), 1.14 (br s,
10H). MS (ESI; M+H) m/z=709.
Example 138C
(S)-4,4'-(4,4'-(1-(3-tert-butylphenyl)-1H-pyrrole-2,5-diyl)bis(4,1-phenyle-
ne))bis(2-((S)-pyrrolidin-2-yl)-1H-imidazole)
[0696] To a solution of the product from Example 138B (180 mg, 0.25
mmol) and 3-tert-butylaniline (57 mg, 0.38 mmol) in toluene (2.0
mL) was added trifluoroacetic acid (39 .mu.L 0.50 mmol). The
mixture was heated to 110.degree. C. overnight. To the cooled
mixture was added trifluoroacetic acid (0.4 mL) and the mixture was
stirred for 1 hour at room temperature. The mixture was
concentrated under reduced pressure. The residue was partitioned
between 25% isopropyl alcohol in CHCl.sub.3 and saturated sodium
bicarbonate solution. The organic layer was separated and dried
over Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure to provide the title compound.
Example 138D
methyl
{(2S)-1-[(2S)-2-(4-{4-[1-(3-tert-butylphenyl)-5-(4-{2-[(2S)-1-{(2S)-
-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol--
4-yl}phenyl)-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-me-
thyl-1-oxobutan-2-yl}carbamate
[0697] A solution consisting of
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (109 mg, 0.57 mmol), 1H-benzo[d][1,2,3]triazol-1-ol
hydrate (87 mg, 0.57 mmol),
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (100 mg, 0.57
mmol) and 4-methylmorpholine (0.14 mL, 1.0 mmol) in DMF (2.6 mL)
was cooled in an icebath. To this mixture was added the product
from Example 138C (161 mg, 0.26 mmol). Additional
4-methylmorpholine was added to the mixture until the pH was
adjusted to 8. The reaction was stirred for 3.5 hours and then the
icebath was removed and the reaction was stirred for an additional
16 hours. Water was then added to the reaction mixture and the
resulting precipitate was recovered by filtration. The residue was
washed with copious amounts of water followed by diethyl ether. The
crude product was purified by chromatography on silica gel eluted
with a solvent gradient of 0-5% methanol in CH.sub.2Cl.sub.2 to
provide the title compound (15 mg, 6% yield). .sup.1H NMR (400 MHz,
DMSO-D6) .delta. 12.04-11.65 (m, 2H), 7.57-7.45 (m, 4H), 7.43-7.35
(m, 2H), 7.33-7.08 (m, 5H), 7.05-6.91 (m, 4H), 6.79 (t, J=7.5, 1H),
6.53-6.40 (m, 2H), 5.05-4.99 (m, 2H), 4.02 (t, J=8.3, 2H),
3.82-3.68 (m, 4H), 3.56-3.47 (m, 6H), 2.18-1.79 (m, 10H), 1.09 (s,
9H), 0.89-0.75 (m, 12H). MS (ESI; M+H) m/z=937.
##STR00385##
Example 139
methyl
{(2S)-1-[(2S)-2-(4-{4-[1-(4-cyclopropylphenyl)-5-(4-{2-[(2S)-1-{(2S-
)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-
-4-yl}phenyl)-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-m-
ethyl-1-oxobutan-2-yl}carbamate
Example 139A
(S)-4,4'-(4,4'-(1-(4-cyclopropylphenyl)-1H-pyrrole-2,5-diyl)bis(4,1-phenyl-
ene))bis(2-((S)-pyrrolidin-2-yl)-1H-imidazole)
tetrakis(2,2,2-trifluoroacetate)
[0698] To a solution of the product from Example 138B (0.30 g 0.43
mmol) and 4-cyclopropylaniline (85 mg, 0.64 mmol) in toluene (3.4
mL) was added trifluoroacetic acid (65 .mu.L 0.85 mmol). The
mixture was heated to 110.degree. C. overnight. To the cooled
mixture was added trifluoroacetic acid (1.0 mL) and the mixture was
stirred for 1 hour at room temperature. The mixture was
concentrated under reduced pressure and then triturated with
diethyl ether to provide the title compound (0.42 g, 28%
yield).
Example 139B
methyl
{(2S)-1-[(2S)-2-(4-{4-[1-(4-cyclopropylphenyl)-5-(4-{2-[(2S)-1-{(2S-
)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-
-4-yl}phenyl)-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-m-
ethyl-1-oxobutan-2-yl}carbamate
[0699] The title compound was prepared using the methods from
Example 138D substituting the product from Example 139A for the
product from Example 138C to provide the title compound (150 mg,
40% yield). .sup.1H NMR (400 MHz, DMSO-D6) .delta. 12.09-11.63 (m,
2H), 7.56-7.46 (m, 4H), 7.44-7.35 (m, 2H), 7.30-7.11 (m, 2H),
7.07-6.88 (m, 8H), 6.54-6.39 (m, 2H), 5.07-4.97 (m, 2H), 4.03 (t,
J=8.3, 2H), 3.83-3.66 (m, 4H), 3.52 (s, 6H), 2.18-1.79 (m, 10H),
1.26-1.19 (m, 1H), 0.98-0.90 (m, 2H), 0.90-0.74 (m, 12H), 0.69-0.60
(m, 2H). MS (ESI; M+H) m/z=921.
##STR00386##
Example 140
methyl
[(2S)-1-{(2S)-2-[5-bromo-4-(4-{1-(4-cyclopropylphenyl)-5-[4-(2-{(2S-
)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-4-yl)phenyl]-
-1H-pyrrol-2-yl}phenyl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobu-
tan-2-yl]carbamate
[0700] To a suspension of the product from Example 139 (47 mg,
0.051 mmol) in CH.sub.2Cl.sub.2 (0.5 mL) was added a mixture of
1-bromopyrrolidine-2,5-dione (9.1 mg, 0.051 mmol) in
CH.sub.2Cl.sub.2 (0.5 mL). The mixture was stirred overnight at
room temperature then concentrated under reduced pressure and
triturated with diethyl ether to provide a mixture of brominated
compounds that was subjected to reverse phase HPLC purification
eluted with a gradient of 10-100% CH.sub.3CN in 0.1% aqueous
trifluoroacetic acid to afford the title compound (8 mg, 13%
yield). .sup.1H NMR (TFA salt) (400 MHz, DMSO-D6) .delta. 14.32 (s,
1H), 12.44 (s, 1H), 7.97 (s, 1H), 7.62-7.48 (m, 4H), 7.31 (d,
J=8.4, 1H), 7.24 (d, J=8.5, 1H), 7.18-7.08 (m, 4H), 7.09-7.00 (m,
4H), 6.61 (d, J=3.7, 1H), 6.57 (d, J=3.7, 1H), 5.07 (t, J=7.0, 1H),
4.98-4.91 (m, 1H), 4.08 (t, J=7.9, 1H), 4.02 (t, J=8.3, 1H),
3.90-3.67 (m, 4H), 3.52 (s, 3H), 3.51 (s, 3H), 2.18-1.83 (m, 10H),
1.22 (s, 1H), 1.01-0.93 (m, 2H), 0.89-0.72 (m, 12H), 0.70-0.62 (m,
2H). MS (ESI; M+H) m/z=1000.
##STR00387##
Example 141
methyl
{(2S)-1-[(2S)-2-(5-bromo-4-{4-[5-(4-{5-bromo-2-[(2S)-1-{(2S)-2-[(me-
thoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}ph-
enyl)-1-(4-cyclopropylphenyl)-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl)pyrr-
olidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0701] The title compound was formed as an additional product in
Example 140. The mixture of products was subjected to reverse phase
HPLC purification eluted with a gradient of 10-100% CH.sub.3CN in
0.1% aqueous trifluoroacetic acid to afford the title compound (15
mg, 23% yield). .sup.1H NMR (TFA salt) (400 MHz, DMSO-D6) .delta.
12.43 (s, 2H), 7.54 (dd, 4H), 7.25 (d, J=8.4, 2H), 7.15-7.08 (m,
4H), 7.08-7.00 (m, 4H), 6.55 (s, 2H), 4.99-4.89 (m, 2H), 4.02 (t,
J=8.3, 2H), 3.82-3.68 (m, 4H), 3.51 (s, 6H), 2.22-2.03 (m, 4H),
2.00-1.81 (m, 6H), 1.27-1.19 (m, 1H), 1.02-0.92 (m, 2H), 0.90-0.77
(m, 12H), 0.70-0.61 (m, 2H). MS (ESI; M+H) m/z=1078.
##STR00388##
Example 142
methyl
{(2S)-1-[(2S)-2-(4-{4-[5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)am-
ino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1-(4-trity-
lphenyl)-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-
-1-oxobutan-2-yl}carbamate
Example 142A
(S)-4,4'-(4,4'-(1-(4-tritylphenyl)-1H-pyrrole-2,5-diyl)bis(4,1-phenylene))-
bis(2-((S)-pyrrolidin-2-yl)-1H-imidazole)
tetrakis(2,2,2-trifluoroacetate)
[0702] The title compound was prepared using the methods from
Example 139A substituting 4-tritylaniline for 4-cyclopropylaniline
to provide the title compound.
Example 142B
methyl
{(2S)-1-[(2S)-2-(5-bromo-4-{4-[5-(4-{5-bromo-2-[(2S)-1-{(2S)-2-[(me-
thoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}ph-
enyl)-1-(4-cyclopropylphenyl)-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl)pyrr-
olidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0703] The title compound was prepared using the methods from
Example 138D substituting the product from Example 142A for the
product from Example 138C to provide the title compound (71 mg, 43%
yield). .sup.1H NMR (400 MHz, DMSO-D6) .delta. 12.15-11.69 (m, 2H),
7.61-7.48 (m, 4H), 7.46-7.37 (m, 2H), 7.35-7.15 (m, 11H), 7.10-6.91
(m, 14H), 6.55-6.44 (m, 2H), 5.11-5.00 (m, 2H), 4.03 (t, J=8.5,
2H), 3.86-3.70 (m, 4H), 3.52 (s, 6H), 2.21-1.83 (m, 10H), 0.92-0.76
(m, 12H). MS (ESI; M+H) m/z=1123.
##STR00389##
Example 143
methyl
{(2S)-1-[(2S)-2-(5-bromo-4-{4-[4-bromo-5-(4-{5-bromo-2-[(2S)-1-{(2S-
)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-
-4-yl}phenyl)-1-(4-cyclohexylphenyl)-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2--
yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0704] To a suspension of the product from Example 74 (100 mg, 0.10
mmol) in CH.sub.2Cl.sub.2 (1.0 mL) at -78.degree. C. was added a
mixture of 1-bromopyrrolidine-2,5-dione (59 mg, 0.33 mmol) in
CH.sub.2Cl.sub.2 (1.0 mL). The mixture was stirred for 3 hours,
warming to room temperature then concentrated under reduced
pressure and triturated with diethyl ether to provide the title
compound (103 mg, 83% yield). .sup.1H NMR (400 MHz, DMSO-D6)
.delta. 12.47 (s, 1H), 11.02 (s, 1H), 7.54 (d, J=26.1, 4H),
7.29-6.98 (m, 10H), 6.71 (s, 1H), 5.01-4.90 (m, 2H), 4.02 (t,
J=8.1, 2H), 3.86-3.67 (m, 4H), 3.52 (s, 6H), 2.18-1.58 (m, 16H),
1.35-1.20 (m, 5H), 0.90-0.76 (m, 12H). MS (ESI; M+H) m/z=1200.
##STR00390##
Example 144
methyl
[(2S)-1-{(2S)-2-[4-(4-{5-(4-{2-[1-{(2S)-2-[(methoxycarbonyl)amino]--
3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1-[6-(piperidin-
-1-yl)pyridin-3-yl]-1H-pyrrol-2-yl}phenyl)-1H-imidazol-2-yl]pyrrolidin-1-y-
l}-3-methyl-1-oxobutan-2-yl]carbamate
Example 144A
5-nitro-2-(piperidin-1-yl)pyridine
[0705] To a slurry of 2-chloro-5-nitropyridine (100 g, 632 mmol) in
ethanol (2000 mL) at room temperature was added piperidine (206 mL,
2.08 mol) and the mixture heated to 60.degree. C. for 30 minutes.
The cooled mixture was concentrated and the residue taken up in
CH.sub.2Cl.sub.2 then washed with saturated NaHCO.sub.3 and brine.
The mixture was dried (Na.sub.2SO.sub.4), filtered, and
concentrated to provide the title compound as a yellow solid (130.4
g, 99% yield). .sup.1H NMR (400 MHz, DMSO-D6) .delta. 8.94 (d,
J=2.9, 1H), 8.17 (dd, J=9.6, 2.9, 1H), 6.93 (d, J=9.6, 1H),
3.79-3.73 (m, 4H), 1.69-1.64 (m, 2H), 1.61-1.51 (m, 4H).
Example 144B
tert-butyl 6-(piperidin-1-yl)pyridin-3-ylcarbamate
[0706] To a solution of the product from Example 144A (130.4 g, 629
mmol) and di-tert-butyl dicarbonate (165 g, 755 mmol) in ethanol
(750 mL) was added PtO.sub.2 (5.4 g, 24 mmol). The mixture was
pressurized at 40 psi with H.sub.2 and stirred overnight at room
temperature. To ensure complete reaction additional PtO.sub.2 (3.2
g, 14 mmol) was added and the pressurized mixture was heated to
50.degree. C. for 1 hour. The mixture was then filtered,
concentrated under reduced pressure and absorbed onto silicagel and
placed on top of a 4 to 5'' plug of silica in a 3000 mL sintered
glass funnel. Material was eluted with 15% diethyl ether in
CH.sub.2Cl.sub.2 and the filtrate was concentrated under reduced
pressure and the residue triturated with boiling hexanes.
Additional product was recovered upon concentration of the
filtrate, which was then chromatographed on silica gel etuled with
10% diethyl ether in CH.sub.2Cl.sub.2. The appropriate fractions
were collected and concentrated then triturated with boiling
hexanes. The two lots of lavender solids were combined to provide
the title compound (100 g, 57% yield). .sup.1H NMR (400 MHz, DMSO)
.delta. 9.02 (bs, 1H), 8.11 (s, 1H), 7.63-7.54 (m, 1H), 6.74 (d,
J=9.1, 1H), 3.42-3.37 (m, 4H), 1.57-1.49 (m, 6H), 1.45 (9, 1H).
Example 144C
6-(piperidin-1-yl)pyridin-3-amine dihydrochloride
[0707] The product from Example 144B (1.00 g, 3.62 mmol) was added
slowly to 4 M hydrochloric acid (10 mL, 40 mmol) and stirred at
room temperature. After stirring overnight, ether was added and the
solid filtered. Dried in vacuum oven to a white solid (0.817 g;
84%). .sup.1H NMR (400 MHz, methanol-d4) .delta. 1.77 (s, 6H), 3.65
(s, 4H), 7.41 (d, J=9.8 Hz, 1H), 7.70 (d, J=2.6 Hz, 1H), 7.79 (dd,
J=2.7, 9.8 Hz, 1H).
Example 144D
5-(2,5-bis(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)-1H-pyrrol-1-
-yl)-2-(piperidin-1-yl)pyridine
[0708] To a solution of the product from Example 138B (0.20 g, 0.28
mmol) and the product from Example 144C (0.11 g, 0.42 mmol) in
toluene (2.8 mL) was added TFA (22 .mu.L, 0.28 mmol). The mixture
was stirred at 110.degree. C. for 3 hours. To the cooled mixture
was added TFA (0.5 mL) and the mixture was stirred for 1 h at rt.
The solvent was then removed under reduced pressure and triturated
with diethylether and dried to provide 0.31 g of the desired
compound as a TFA salt. .sup.1HNMR (DMSO-d.sub.6; 400 MHz): .delta.
9.78 (br s, 2H), 7.84 (d, J=2.71 Hz, 1H), 7.75 (s, 2H), 7.67
(AA'XX', J=8.34 Hz, 4H), 7.35 (dd, J=9.11, 2.71 Hz, 1H), 7.18
(AA'XX', J=8.46 Hz, 4H), 6.79 (d, J=9.11 Hz, 1H), 6.53 (s, 2H),
4.79 (app t, J=7.81 Hz, 2H), 3.4-3.2 (m, 4H), 2.44-2.36 (m, 2H),
2.25-1.98 (m, 6H), 1.65-1.45 (m, 6H).
Example 144E
methyl
[(2S)-1-{(2S)-2-[4-(4-{5-(4-{2-[1-(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1-[6-(pi-
peridin-1-yl)pyridin-3-yl]-1H-pyrrol-2-yl}phenyl)-1H-imidazol-2-yl]pyrroli-
din-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0709] To a solution of
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (0.17 g, 0.89 mmol), 1H-benzo[d][1,2,3]triazol-1-ol
hydrate (0.14 g, 0.89 mmol),
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.16 g, 0.89
mmol) in DMF (1.0 mL) was added 4-methylmorpholine (0.3 mL, 2.7
mmol). This mixture was stirred at room temperature for 15 minutes
and then added to a solution of the product from Example 144D (0.31
g, 0.25 mmol) and 4-methylmorpholine (0.2 mL, 1.8 mmol) in DMF (0.7
mL). After stirring 4 h, water was added to this mixture and the
solid collected by filtration then washed with water and
diethylether. The residue was purified on silica gel eluted with
60% THF/Hexanes to provide 100 mg of the title compound. .sup.1H
NMR (400 MHz, DMSO) .delta. 12.17-11.70 (m, 2H), 7.84-7.76 (m, 1H),
7.64-7.50 (m, 4H), 7.49-7.40 (m, 2H), 7.31-7.02 (m, 7H), 6.76-6.69
(m, 1H), 6.52-6.41 (m, 2H), 5.09-5.01 (m, 2H), 4.04 (t, J=8.3, 2H),
3.83-3.71 (m, 4H), 3.53 (s, 6H), 3.50-3.44 (m, 4H), 2.18-2.04 (m,
4H), 2.03-1.86 (m, 6H), 1.61-1.46 (m, 6H), 0.90-0.79 (m, 12H). MS
(ESI; M+H) m/z=965.
##STR00391##
Example 145
methyl
{(2S)-1-[(2S)-2-(4-{4-[5-(4-{2-[2)-1-{(2S)-2-[(methoxycarbonyl)amin-
o]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1-{4-[(trifl-
uoromethyl)sulfanyl]phenyl}-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl)pyrrol-
idin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0710] Example 138B and 4-(trifluoromethylthio)aniline were
processed using the methods of Examples 139A and 138D to provide
the title compound (19 mg). .sup.1H NMR (400 MHz, DMSO-D6) .delta.
12.18-11.65 (m, 2H), 7.73-7.63 (m, 2H), 7.60-7.48 (m, 4H),
7.45-7.39 (m, 2H), 7.31-7.15 (m, 4H), 7.06-6.92 (m, 4H), 6.58-6.46
(m, 2H), 5.08-5.00 (m, 2H), 4.03 (t, J=8.4, 2H), 3.85-3.69 (m, 4H),
3.53 (s, 6H), 2.23-1.79 (m, 10H), 0.93-0.77 (m, 12H). MS (ESI; M+H)
m/z=981.
##STR00392##
Example 146
methyl
{(2S)-1-[(2S)-2-(4-{4-[5-(4-{2-[2)-1-{(2S)-2-[(methoxycarbonyl)amin-
o]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1-(2-methyl--
1,3-benzothiazol-5-yl)-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin--
1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0711] Example 138B and 2-methylbenzo[d]thiazol-5-amine
dihydrochloride were processed using the methods of Examples 139A
and 138D to provide the title compound (19 mg). .sup.1H NMR (400
MHz, DMSO-D6) .delta. 12.04-11.63 (m, 2H), 8.02-6.85 (m, 15H),
6.58-6.45 (m, 2H), 5.07-4.96 (m, 2H), 4.02 (t, J=8.4, 2H),
3.86-3.67 (m, 4H), 3.53 (s, 6H), 2.75 (s, 3H), 2.21-1.78 (m, 10H),
0.93-0.76 (m, 12H). MS (ESI; M+H) m/z=952.
##STR00393##
Example 147
diethyl
(4-{2,5-bis[4-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-
-yl}-1H-imidazol-4-yl)phenyl]-1H-pyrrol-1-yl}benzyl)phosphonate
[0712] Example 138B and diethyl 4-aminobenzylphosphonate were
processed using the methods of Examples 139A and 138D to provide
the title compound. .sup.1H NMR (400 MHz, DMSO-D6) .delta.
12.19-11.63 (m, 2H), 7.56-7.44 (m, 4H), 7.42-7.34 (m, 2H),
7.32-7.10 (m, 4H), 7.10-6.91 (m, 6H), 6.53-6.40 (m, 2H), 5.10-4.98
(m, 2H), 4.03 (t, J=8.4, 2H), 3.91-3.67 (m, 8H), 3.53 (s, 6H), 3.23
(d, J=21.8, 2H), 2.22-1.80 (m, 10H), 1.15-1.04 (m, 6H), 0.92-0.77
(m, 12H). MS (ESI; M+H) m/z=1031.
##STR00394##
Example 148
methyl
{(2S)-1-[(2S)-2-(4-{4-[1-(1H-indazol-6-yl)-5-(4-{2-[(2S)-1-{(2S)-2--
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-y-
l}phenyl)-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methy-
l-1-oxobutan-2-yl}carbamate
[0713] Example 138B and 1H-indazol-6-amine were processed using the
methods of Examples 139A and 138D to provide the title compound (24
mg). .sup.1H NMR (400 MHz, DMSO-D6) .delta. 13.08-12.99 (m, 1H),
12.05-11.62 (m, 2H), 8.13-8.04 (m, 1H), 7.74-7.66 (m, 1H),
7.54-7.42 (m, 4H), 7.41-7.34 (m, 2H), 7.31-7.09 (m, 3H), 7.05-6.77
(m, 5H), 6.58-6.47 (m, 2H), 5.06-4.97 (m, 2H), 4.02 (t, J=8.4, 2H),
3.83-3.66 (m, 4H), 3.53 (s, 6H), 2.20-1.78 (m, 10H), 0.89-0.76 (m,
12H). MS (ESI; M+H) m/z=921.
##STR00395##
Example 149
methyl
[(2S)-1-{(2S)-2-[4-(4-{1-[3-fluoro-4-(piperidin-1-yl)phenyl]-5-(4-{-
2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-y-
l]-1H-imidazol-4-yl}phenyl)-1H-pyrrol-2-yl}phenyl)-1H-imidazol-2-yl]pyrrol-
idin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0714] Example 138B and 3-fluoro-4-(piperidin-1-yl)aniline were
processed using the methods of Examples 139A and 138D to provide
the title compound. .sup.1H NMR (400 MHz, DMSO-D6) .delta.
12.15-11.69 (m, 2H), 7.62-7.49 (m, 4H), 7.48-7.39 (m, 2H),
7.32-7.15 (m, 2H), 7.12-6.77 (m, 7H), 6.52-6.42 (m, 2H), 5.08-4.99
(m, 2H), 4.04 (t, J=8.4, 2H), 3.84-3.70 (m, 4H), 3.53 (s, 6H),
3.01-2.89 (m, 4H), 2.19-1.82 (m, 10H), 1.68-1.43 (m, 6H), 0.92-0.75
(m, 12H). MS (ESI; M+H) m/z=982.
##STR00396##
Example 150
methyl
[(2S)-1-{(2S)-2-[4-(4-{1-[4-(hexyloxy)phenyl]-5-(4-{2-[(2S)-1-{(2S)-
-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol--
4-yl}phenyl)-1H-pyrrol-2-yl}phenyl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-me-
thyl-1-oxobutan-2-yl]carbamate
[0715] Example 138B and 4-(hexyloxy)aniline were processed using
the methods of Examples 139A and 138D to provide the title compound
(15 mg). .sup.1H NMR (400 MHz, DMSO-D6) .delta. 12.12-11.67 (m,
2H), 7.59-7.48 (m, 4H), 7.45-7.39 (m, 2H), 7.30-7.13 (m, 2H),
7.08-6.96 (m, 6H), 6.90-6.83 (m, 2H), 6.52-6.42 (m, 2H), 5.07-5.01
(m, 2H), 4.04 (t, J=8.5, 2H), 3.92 (t, J=6.4, 2H), 3.83-3.70 (m,
4H), 3.53 (s, 6H), 2.19-1.83 (m, 10H), 1.73-1.63 (m, 2H), 1.45-1.21
(m, 6H), 0.92-0.77 (m, 15H). MS (ESI; M+H) m/z=981.
##STR00397##
Example 151
diethyl
(4-{3-tert-butyl-2,5-bis[4-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl-
]pyrrolidin-2-yl}-1H-imidazol-4-yl)phenyl]-1H-pyrrol-1-yl}benzyl)phosphona-
te
[0716] The title compound was formed as an additional product from
Example 147. The mixture of products was purified by chromatography
on silica gel eluted with a solvent gradient of 0-5% methanol in
CH.sub.2Cl.sub.2 to provide the title compound. .sup.1H NMR (400
MHz, DMSO-D6) .delta. 11.68 (d, J=13.5, 2H), 7.55-7.39 (m, 5H),
7.37-7.23 (m, 3H), 7.21-6.90 (m, 8H), 6.43 (s, 1H), 5.07-4.99 (m,
2H), 4.06-3.97 (m, 2H), 3.83-3.58 (m, 8H), 3.53 (s, 6H), 3.07 (d,
J=21.5, 2H), 2.20-1.81 (m, 10H), 1.15 (s, 9H), 0.98 (t, J=7.0, 6H),
0.90-0.78 (m, 12H). MS (ESI; M+H) m/z=1087.
##STR00398##
Example 152
methyl
[(2S)-1-{(2S)-2-[4-(4-{1-[4-(2,2-dichloro-1-methylcyclopropyl)pheny-
l]-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrro-
lidin-2-yl]-1H-imidazol-4-yl}phenyl)-1H-pyrrol-2-yl}phenyl)-1H-imidazol-2--
yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0717] Example 138B and 4-(2,2-dichloro-1-methylcyclopropyl)aniline
were processed using the methods of Examples 139A and 138D to
provide the title compound (36 mg). .sup.1H NMR (400 MHz, DMSO-D6)
.delta. 12.18-11.68 (m, 2H), 7.55-7.42 (m, 4H), 7.41-7.22 (m, 6H),
7.17-6.90 (m, 6H), 6.57-6.44 (m, 2H), 5.08-5.00 (m, 2H), 4.03 (t,
J=8.3, 2H), 3.86-3.69 (m, 4H), 3.53 (s, 6H), 2.22 (t, J=8.5, 1H),
2.18-1.81 (m, 10H), 1.79-1.72 (m, 1H), 1.65 (s, 3H), 0.92-0.77 (m,
12H). MS (ESI; M+H) m/z=1003.
##STR00399##
Example 153
methyl
[(2S)-1-{(2S)-2-[4-(4-{1-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-
-2-yl)phenyl]-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbut-
anoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1H-pyrrol-2-yl}phenyl)-1H--
imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0718] Example 138B and
2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol were processed
using the methods of Examples 139A and 138D to provide the title
compound (45 mg). .sup.1H NMR (400 MHz, DMSO-D6) .delta.
12.08-11.71 (m, 2H), 8.80 (s, 1H), 8.01-7.37 (m, 8H), 7.33-7.13 (m,
4H), 7.06-6.89 (m, 4H), 6.57-6.47 (m, 2H), 5.03 (d, J=6.8, 2H),
4.03 (t, J=8.4, 2H), 3.77 (d, J=6.2, 4H), 3.53 (s, 6H), 2.21-1.80
(m, 10H), 0.92-0.76 (m, 12H). MS (ESI; M+H) m/z=1047.
##STR00400##
Example 154
methyl
[(2S)-1-{(2S)-2-[4-(4-{5-(4-{2-[(2)-(2S)-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1-[6-(mo-
rpholin-4-yl)pyridin-3-yl]-1H-pyrrol-2-yl}phenyl)-1H-imidazol-2-yl]pyrroli-
din-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
Example 154A
4-(5-nitropyridin-2-yl)morpholine
[0719] The title compound was prepared using the methods from
Example 144A substituting morpholine for piperidine to provide the
title compound.
Example 154B
6-morpholinopyridin-3-amine
[0720] To a solution of the product from Example 154A (12.5, 59.5
mmol) in THF (150 mL) was added to Ra--Ni 2800, water slurry (12.5
g, 212 mmol) in a 500 mL SS pressure bottle. The mixture was
pressurized (H.sub.2, 30 psi) and stirred for 2 hours at room
temperature. The mixture was filtered and then concentrated under
reduced pressure to provide the title compound.
Example 154C
methyl
[(2S)-1-{(2S)-2-[4-(4-{5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)am-
ino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1-[6-(morp-
holin-4-yl)pyridin-3-yl]-1H-pyrrol-2-yl}phenyl)-1H-imidazol-2-yl]pyrrolidi-
n-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0721] Example 138B and Example 154B were processed using the
methods of Examples 139A and 138D to provide the title compound.
.sup.1H NMR (400 MHz, DMSO-D6) .delta. 12.16-11.69 (m, 2H),
7.89-7.80 (m, 1H), 7.63-7.50 (m, 4H), 7.50-7.40 (m, 2H), 7.39-7.02
(m, 7H), 6.80-6.71 (m, 1H), 6.52-6.41 (m, 2H), 5.10-5.00 (m, 2H),
4.04 (t, J=8.7, 2H), 3.85-3.72 (m, 4H), 3.69-3.59 (m, 4H), 3.53 (s,
6H), 3.45-3.37 (m, 4H), 2.20-1.82 (m, 10H), 0.94-0.77 (m, 12H). MS
(ESI; M+H) m/z=967.
##STR00401##
Example 155
methyl
{(2S)-1-[(2S)-2-(4-{4-[1-{6-[bis(2-methoxyethyl)amino]pyridin-3-yl}-
-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrroli-
din-2-yl]-1H-imidazol-4-yl}phenyl)-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl-
)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
Example 155A
N,N-bis(2-methoxyethyl)-5-nitropyridin-2-amine
[0722] The title compound was prepared using the methods from
Example 144A substituting bis(2-methoxyethyl)amine for piperidine
to provide the title compound.
Example 155B
N2,N2-bis(2-methoxyethyl)pyridine-2,5-diamine
[0723] Example 155A was processed using the methods of Example 154B
to provide the title compound.
Example 155C
methyl
{(2S)-1-[(2S)-2-(4-{4-[1-{6-[bis(2-methoxyethyl)amino]pyridin-3-yl}-
-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrroli-
din-2-yl]-1H-imidazol-4-yl}phenyl)-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl-
)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0724] Example 138B and Example 155B were processed using the
methods of Examples 139A and 138D to provide the title compound.
.sup.1H NMR (400 MHz, DMSO-D6) .delta. 12.17-11.67 (m, 2H),
7.86-7.77 (m, 1H), 7.63-7.49 (m, 4H), 7.49-7.38 (m, 2H), 7.34-7.20
(m, 3H), 7.20-7.03 (m, 4H), 6.64-6.56 (m, 1H), 6.52-6.40 (m, 2H),
5.09-5.00 (m, 2H), 4.04 (t, J=8.2, 2H), 3.84-3.69 (m, 4H),
3.65-3.57 (m, 4H), 3.53 (s, 6H), 3.47-3.40 (m, 4H), 3.21 (s, 6H),
2.20-1.84 (m, 10H), 0.84 (m, 12H). MS (ESI; M+H) m/z=1013.
##STR00402##
Example 156
methyl
{(2S)-1-[(2S)-2-(4-{4-[1-(2-tert-butylphenyl)-5-(4-{2-[(2S)-1-{(2S)-
-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol--
4-yl}phenyl)-1H-pyrrol-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-me-
thyl-1-oxobutan-2-yl}carbamate
[0725] Example 138B and 2-tert-butylaniline were processed using
the methods of Examples 139A and 138D to provide the title compound
(10 mg). .sup.1H NMR (400 MHz, DMSO-D6) .delta. 12.07-11.64 (m,
2H), 7.61-7.11 (m, 12H), 7.06-6.93 (m, 4H), 6.65-6.49 (m, 2H),
5.08-4.97 (m, 2H), 4.04 (t, J=7.2, 2H), 3.82-3.69 (m, 4H), 3.53 (s,
6H), 2.17-1.83 (m, 10H), 0.92-0.77 (m, 21H). MS (ESI; M+H)
m/z=937.
##STR00403##
Example 157
methyl
[(2S)-1-{(2S)-2-[4-(4-{1-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phen-
yl]-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrr-
olidin-2-yl]-1H-imidazol-4-yl}phenyl)-1H-pyrrol-2-yl}phenyl)-1H-imidazol-2-
-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0726] Example 138B and
4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)aniline were processed using
the methods of Examples 139A and 138D to provide the title compound
(156 mg). .sup.1H NMR (400 MHz, DMSO-D6) .delta. 12.06-11.65 (m,
2H), 7.59-7.46 (m, 4H), 7.44-7.36 (m, 2H), 7.30-7.13 (m, 2H),
7.09-6.96 (m, 4H), 6.90 (p, 4H), 6.53-6.39 (m, 2H), 5.08-4.98 (m,
2H), 4.04 (t, J=8.4, 2H), 3.90 (s, 4H), 3.86-3.71 (m, 4H), 3.53 (s,
6H), 3.29-3.20 (m, 4H), 2.19-1.83 (m, 10H), 1.73-1.64 (m, 4H),
0.93-0.77 (m, 12H). MS (ESI; M+H) m/z=1022.
##STR00404##
Example 158
dimethyl
([1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1-diyl-
methanediylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate
Example 158A
4,4'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dibenzonitrile
[0727] A solution of Example 42C (2.0 g, 3.9 mmol) and copper(I)
cyanide (1.047 g, 11.69 mmol) in DMF (19 mL) was heated in a
microwave for 7 hours at 160.degree. C. Afterwards the mixture was
poured in water (700 mL) and then concentrated ammonium hydroxide
(40 mL) was added and the solution extracted with EtOAc. The
organic extract was dried, filtered, concentrated and the residue
purified by flash chromatography (silica gel, EtOAc/hexanes) to
afford 1.23 g (78%) of the title compound. MS (ESI) m/z 406
(M+H)+.
Example 158B
4,4'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene)dimetha-
namine
[0728] To a solution of Example 158A (0.63 g, 1.554 mmol) in THF
(21 mL) was added lithium aluminum hydride (0.236 g, 6.21 mmol)
then stirred at room temperature for 20 minutes and at 70.degree.
C. for 1 hour. The mixture was then cooled in an ice bath and a
solution of saturated aqueous ammonium chloride was added followed
by extraction with EtOAc and the organic layer extracted with
Rochelle's solution. The organic solution was then dried, filtered
and concentrated to give the title compound. MS (ESI) m/z 414
(M+H)+.
Example 158C
dimethyl
([1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1-diyl-
methanediylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-
-diyl]})biscarbamate
[0729] The product from Example 158B (45 mg, 0.109 mmol), the
product from Example 37B (62.2 mg, 0.228 mmol) and HATU (91 mg,
0.239 mmol) in DMSO (3 mL) was added Hunig's base (0.095 mL, 0.544
mmol), and the reaction mixture was stirred at room temperature for
1 hr. The reaction mixture was partitioned between water and
dichloromethane, and the organic layer was dried over MgSO.sub.4,
filtered and concentrated. Purification by flash chromatography
(silica gel, 0-10% methanol/dichloromethane) afforded 55 mg (55%)
of the title compound as a mixture of stereoisomers. 1H NMR (400
MHz, DMSO-D6) .delta. ppm 8.11 (m, 2H), 7.08 (s, 2H), 6.95 (m, 8H),
6.74 (d, J=8.8 Hz, 2H), 5.97 (d, J=8.7 Hz, 2H), 5.01 (m, 2H), 4.15
(m, 4H), 4.05 (m, 4H), 3.80 (m, 2H), 3.31 (s, 6H), 2.40 (m, 2H),
1.90 (m, 2H), 1.85 (m, 4H), 1.80 (m, 4H), 0.95 (s, 9H), 0.70 (m,
2H), 0.65 (m, 12H); MS (ESI) m/z 923 (M+H)+.
##STR00405##
Example 159
methyl
{(2S)-1-[(2S)-2-(4-{4-[(3S,5R)-4-(4-tert-butylphenyl)-5-(4-{2-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-i-
midazol-4-yl}phenyl)thiomorpholin-3-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-
-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
Example 159A
2,2'-thiobis(1-(4-bromophenyl)ethanone)
[0730] A solution of 2-bromo-1-(4-bromophenyl)ethanone (27.8 g, 100
mmol) was dissolved in acetone, the solution was cooled in an ice
bath then sodium sulfide nonahydrate (12.01 g, 50 mmol) dissolved
in water (100 mL) was added dropwise over 45 minutes time. The
resultant solution was stirred an additional 2 hours at room
temperature, the solid formed in the reaction was collected and
then washed with water then ethanol and dried in a vacuum oven to
provide 18.5 g (43%) of the title compound.
Example 159B
2,2'-thiobis(1-(4-bromophenyl)ethanol)
[0731] To a solution of Example 159A (5.0 g, 11.68 mmol) in ethanol
(78 mL) was added sodium borohydride (0.972 g, 25.7 mmol)
portionwise and the mixture was stirred at room temperature for 20
minutes. Afterwards the solution was concentrated, then a solution
of 1N aqueous hydrochloric acid (100 mL) was added and extracted
with EtOAc. The organic extract was dried, filtered and
concentrated to 5.05 g (100%) of a colorless solid as the title
compound.
Example 159C
N,N'-(2,2'-thiobis(1-(4-bromophenyl)ethane-2,1-diyl))bis(4-tert-butylanili-
ne)
[0732] To a solution of Example 159B (5.05 g, 11.68 mmol) in THF
(145 mL) and dichloromethane (145 mL) was added triethylamine (4.86
mL, 35.1 mmol) and the mixture cooled in an ice bath. To this
solution was added methanesulfonyl chloride (2.276 mL, 29.2 mmol)
dropwise followed by stirring at 0.degree. C. for an additional 30
minutes followed by concentration at room temperature to a residue.
The resultant residue was dissolved in DMF (39 mL) followed by the
addition of 4-tert-butylaniline (18.62 mL, 117 mmol) and the
mixture heated at 50.degree. C. for 5 hours. Afterwards 1N aqueous
hydrochloric acid was added followed by extraction with EtOAc. The
organic extract was dried, filtered and concentrated. Purification
by flash chromatography (silica gel, 0-30% EtOAc/hexanes) afforded
2.67 g (42%) of the title compound.
Example 159D
3,5-bis(4-bromophenyl)-4-(4-tert-butylphenyl)thiomorpholine
[0733] To a solution of Example 159C (350 mg, 0.504 mmol) in
toluene (5 mL) was added silica gel (1.0 g) that had been
dehydrated by heating at 180.degree. C. in a vacuum oven for 3
hours, and trifluoromethanesulfonic acid (0.045 mL, 0.504 mmol) and
heated at 100.degree. C. for 3 hours. After cooling to ambient
temperature, dichloromethane was added and the silica gel was
removed by filtration and the solution extracted with
half-saturated aqueous sodium bicarbonate solution. The organic
extract was dried, filtered and concentrated to afford 220 mg (80%)
of the title compound as a mixture of isomers. MS (ESI) m/z 546
(M+H)+.
Example 159E
4-(4-tert-butylphenyl)-3,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl)thiomorpholine
[0734] The product of Example 159D (200 mg, 0.367 mmol) was
processed using the method described in Example 42D to provide 105
mg (45%) of the title compound as a mixture of isomers. MS (ESI)
m/z 640 (M+H)+.
Example 159F
(2S,2'S)-tert-butyl
2,2'-(4,4'-(4,4'-(4-(4-tert-butylphenyl)thiomorpholine-3,5-diyl)bis(4,1-p-
henylene))bis(1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxylate
[0735] The product of Example 159E (190 mg, 0.297 mmol) and the
product from Example 26D (282 mg, 0.891 mmol) were processed using
the method described in Example 42E to provide 110 mg (43%) of the
title compound as a mixture of isomers. MS (ESI) m/z 859
(M+H)+.
Example 159G
4-(4-tert-butylphenyl)-3,5-bis(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl-
)phenyl)thiomorpholine
[0736] To the product of Example 159F (110 mg, 0.128 mmol) was
added dimethoxyethane (5 mL) and a solution of 4N hydrochloric acid
in dioxane (5 mL) and the resultant solution stirred at room
temperature for 1 hr. The solvent was then removed under vacuum and
the resultant residue was diluted with acetonitrile and water (0.1%
TFA) and purified by reversed phase chromatography (C18), eluting
with 10-100% acetonitrile in water (0.1% TFA) to afford 12 mg (14%)
of the title compound as a mixture of stereoisomers. MS (ESI) m/z
658 (M+H)+.
Example 159H
methyl
{(2S)-1-[(2S)-2-(4-{4-[(3S,5R)-4-(4-tert-butylphenyl)-5-(4-{2-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-i-
midazol-4-yl}phenyl)thiomorpholin-3-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-
-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0737] The product from Example 159G (10 mg, 0.015 mmol),
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (5.86 mg, 0.033
mmol) and HATU (12.71 mg, 0.033 mmol) in DMSO (0.5 mL) was added
Hunig's base (0.013 mL, 0.076 mmol), and the reaction mixture was
stirred at room temperature for 1.5 hr. The reaction mixture was
partitioned between water and dichloromethane, and the organic
layer was dried over MgSO.sub.4, filtered and concentrated in
vacuo. The crude product was redissolved in methanol (5 mL) then
added potassium carbonate (50 mg) then stirred at room temperature
for 20 minutes, the solids removed by filtration, the filtrate
concentrated and purified by chromatography (silica gel, 0-10%
methanol/dichloromethane) to afford 7 mg (47%) of the title
compound. 1H NMR (400 MHz, DMSO-D6) .delta. ppm 11.65 (m, 2H), 7.47
(m, 2H), 7.32 (m, 4H), 7.23 (m, 4H), 6.85 (m, 4H), 5.02 (m, 2H),
4.38 (m, 2H), 4.02 (m, 2H), 3.75 (m, 4H), 3.52 (s, 6H), 3.10 (m,
2H), 2.66 (m, 2H), 2.08 (m, 4H), 1.91 (m, 4H), 0.97 (s, 9H), 0.82
(m, 12H); MS (ESI) m/z 973 (M+H)+.
##STR00406##
Example 160
methyl
{(2S)-1-[(2S)-2-(4-{4-[(3S,5S)-4-(4-tert-butylphenyl)-5-(4-{2-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-i-
midazol-4-yl}phenyl)thiomorpholin-3-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-
-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate and
methyl
{(2S)-1-[(2S)-2-(4-{4-[(3R,5R)-4-(4-tert-butylphenyl)-5-(4-{2-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-i-
midazol-4-yl}phenyl)thiomorpholin-3-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-
-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0738] The product from Example 159E (100 mg, 0.156 mmol), the
product from Example 126G (146 mg, 0.391 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
dichloromethane adduct (25.5 mg, 0.031 mmol) in a mixture of
toluene (3 mL), ethanol (3 mL) and a 1N aq. sodium bicarbonate
solution (0.469 mL, 4.69 mmol) and bubbled nitrogen gas through the
solution for 10 min, then heated at 80.degree. C. for 18 h.
Solution was cooled to room temperature and water (20 mL) added
then extracted with dichloromethane (50 mL), then dried,
concentrated and the residue purified by reversed phase
chromatography (C18), eluting with 10-100% acetonitrile in water
(0.1% TFA) to afford 8.5 mg (6%) of the title compound as a mixture
of stereoisomers. 1H NMR (free base) (400 MHz, DMSO-D6) .delta. ppm
11.70 (bs, 2H), 7.64 (m, 4H), 7.45 (m, 2H), 7.37 (m, 4H), 7.28 (m,
2H), 7.01 (m, 2H), 6.46 (d, J=8.7 Hz, 2H), 5.38 (m, 2H), 5.07 (m,
2H), 4.03 (m, 2H), 3.52 (s, 6H), 3.10 (m, 2H), 2.12 (m, 4H), 1.91
(m, 4H), 1.12 (s, 9H), 0.86 (m, 12H); MS (ESI) m/z 973 (M+H)+.
##STR00407##
Example 161
methyl
{(2S)-1-[(2S)-2-(4-{4-[4-(4-tert-butylphenyl)-5-(4-{2-[(2S)-1-{(2S)-
-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-H-imidazol-4-
-yl}phenyl)-1,1-H-imidazol-4-yl
dioxidothiomorpholin-3-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-met-
hyl-1-oxobutan-2-yl}carbamate
##STR00408##
[0739] Example 161A
3,5-bis(4-bromophenyl)-4-(4-tert-butylphenyl)thiomorpholine
1,1-dioxide (ACD v12)
[0740] A solution of Example 159D (850 mg, 1.56 mmol) in mixture of
acetone (15 mL), water (5 mL) and THF (5 mL) was added a solution
of osmium tetroxide (2.5% in tert-butanol, 0.587 mL, 0.047 mmol)
and the mixture was stirred at room temperature for 1.5 hr. The
solution was then diluted with water and extracted with EtOAc, the
organic extract dried, filtered and concentrated to afford 900 mg
(100%) of the title compound. MS (ESI) m/z 578 (M+H)+.
Example 161B
methyl
{(2S)-1-[(2S)-2-(4-{4-[4-(4-tert-butylphenyl)-5-(4-{2-[(2S)-1-{(2S)-
-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-H-imidazol-4-
-yl}phenyl)-1,1-dioxidothiomorpholin-3-yl]phenyl}-1H-imidazol-2-yl)pyrroli-
din-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0741] Example 161A was processed using sequentially the methods of
Examples 42D, 42E, 159G, and 159H to provide the title compound as
a mixture of trans stereoisomers. 1H NMR (400 MHz, DMSO-D6) .delta.
ppm 11.73 (bs, 2H), 7.64 (m, 4H), 7.55 (m, 2H), 7.44 (m, 4H), 7.24
(m, 2H), 7.04 (m, 2H), 6.60 (m, 2H), 5.48 (m, 2H), 5.06 (m, 2H),
4.04 (m, 2H), 3.78 (m, 6H), 3.52 (s, 6H), 2.11 (m, 4H), 1.92 (m,
6H), 1.13 (s, 9H), 0.92 (m, 12H); MS (ESI) m/z 1005 (M+H)+.
##STR00409##
Example 162
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2R,5R)-1-(4-cyclopropylphenyl)-5-(4-{2-[(2S-
)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H--
imidazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-
-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0742] The product from Example 95B was purified by chiral
chromatography on a Chiralpak IB column eluting with a mixture of
hexane/THF/methanol (85/10/5). The title compound was the first of
the 2 diastereomers to elute. 1H NMR (400 MHz, DMSO-D6) .delta. ppm
0.33-0.43 (m, 2H) 0.65-0.72 (m, 2H) 0.79-0.91 (m, 12H) 1.56-1.64
(m, 1H) 1.66-1.72 (m, 2H) 1.84-2.03 (m, 6H) 2.06-2.19 (m, 4H) 3.53
(s, 6H) 3.73-3.84 (m, 4H) 4.04 (t, J=8.35 Hz, 2H) 5.06 (dd, J=6.89,
3.09 Hz, 2H) 5.14-5.23 (m, 2H) 6.19 (d, J=8.67 Hz, 2H) 6.60-6.67
(m, 2H) 7.09-7.31 (m, 6H) 7.34-7.68 (m, 6H) 11.62-12.11 (m, 2H); MS
(ESI+) m/z 924.6 (M+H).
##STR00410##
Example 163
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(4-cyclopropylphenyl)-5-{2-[(2S)-1-{(-
2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzim-
idazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methy-
l-1-oxobutan-2-yl}carbamate
[0743] Example 109C and 4-cyclopropylaniline were processed using
sequentially the methods of Examples 113A (cyclization reaction
conducted at room temperature overnight), 113B, 113C, 281 (reaction
conducted at 50.degree. C. for 3 hours), 28J, and 66E to provide
the title compound (122 mg) as a solid. 1H NMR (400 MHz, DMSO-D6)
.delta. ppm 0.32-0.39 (m, 2H) 0.63-0.69 (m, 2H) 0.77-0.90 (m, 12H)
1.53-1.61 (m, 1H) 1.66-1.74 (m, 2H) 1.86-2.04 (m, 8H) 2.14-2.23 (m,
4H) 3.54 (s, 6H) 3.78-3.87 (m, 4H) 4.00-4.07 (m, 2H) 5.10-5.18 (m,
2H) 5.31-5.39 (m, 2H) 6.22 (d, J=8.67 Hz, 2H) 6.57-6.65 (m, 2H)
7.00-7.07 (m, 2H) 7.16-7.32 (m, 4H) 7.36 (d, J=8.13 Hz, 1H) 7.44
(d, J=8.24 Hz, 1H) 11.97-12.27 (m, 2H); MS (ESI+) m/z 872.5
(M+H)+.
##STR00411##
Example 164
methyl
{(2S)-1-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[4-(morph-
olin-4-yl)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-yl]-3--
methyl-1-oxobutan-2-yl}carbamate
[0744] Example 109C and 4-morpholinoaniline were processed using
sequentially the methods of Examples 113A (cyclization reaction
conducted at room temperature overnight), 113B, 113C, 281 (reaction
conducted at 50.degree. C. for 2 hours), 28J, and 28K to provide
the title compound (100 mg) as a solid. 1H NMR (400 MHz, DMSO-D6)
.delta. ppm 0.76-0.91 (m, 12H) 1.66-1.72 (m, 2H) 1.87-2.03 (m, 8H)
2.15-2.22 (m, 4H) 2.72-2.78 (m, 4H) 3.53 (s, 6H) 3.57-3.62 (m, 4H)
3.78-3.86 (m, 4H) 4.00-4.12 (m, 2H) 5.09-5.18 (m, 2H) 5.30-5.37 (m,
2H) 6.25 (d, J=8.78 Hz, 2H) 6.52-6.59 (m, 2H) 7.05 (t, J=7.54 Hz,
2H) 7.18-7.32 (m, 4H) 7.36 (d, J=8.13 Hz, 1H) 7.44 (d, J=8.24 Hz,
1H) 11.91-12.28 (m, 2H); MS (ESI+) m/z 917.5 (M+H)+.
##STR00412##
Example 165
dimethyl
([(2R,5R)-1-{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidine-
-2,5-diyl]bis{(2-aminobenzene-4,1-diyl)carbamoyl(2S)pyrrolidine-2,1-diyl[(-
2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate
Example 165A
(2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(4-iodophenyl)pyrrolidine
[0745] Example 109C (3.34 g, 6.0 mmol) and 4-iodoaniline (7.88 g,
36.0 mmol) were processed using the method of Example 113A with the
reaction allowed to proceed for 4 days at room temperature to
provide the title compound (2.01 g, 57%) as a yellow solid.
Example 165B
4-(5-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)phenyl)pyr-
idin-2-yl)morpholine
[0746] The product from 165A (1.869 g, 3.2 mmol),
4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine
(0.929 g, 3.20 mmol), potassium phosphate (1.359 g, 6.40 mmol),
tris(dibenzylideneacetone)dipalladium(0) (0.029 g, 0.032 mmol) and
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (0.028
g, 0.096 mmol) were combined in THF (18 mL)/water (6 mL). The
mixture was purged with nitrogen for 15 minutes and stirred at room
temperature for 24 hours. The reaction mixture was partitioned
between ethyl acetate and saturated sodium bicarbonate. The organic
layer was washed with brine, dried with sodium sulfate, filtered
and evaporated. The residue was purified by chromatography on
silica gel eluting with ethyl acetate/hexane (20% to 40%) to give
the title compound (1.01 g, 51%) as a solid.
Example 165C
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-(6-morpholinopyr-
idin-3-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-nitro-4,1-phenylene))bis(azane-
diyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2-
,1-diyl)dicarbamate
[0747] The product from Example 165B (683 mg, 1.10 mmol), the
product from Example 116C (895 mg, 3.30 mmol), cesium carbonate
(1004 mg, 3.08 mmol), tris(dibenzylideneacetone)dipalladium(0)
(60.4 mg, 0.066 mmol) and
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (115 mg,
0.198 mmol) were combined in dioxane (15 mL). The mixture was
purged with nitrogen for 15 minutes and stirred at 100.degree. C.
for 3 hours. The mixture was partitioned between ethyl acetate and
saturated sodium bicarbonate. The organic layer was washed with
brine, dried with sodium sulfate, filtered and evaporated. The
residue was purified by chromatography on silica gel eluting with
methanol/dichloromethane (1% to 3%) to give the title compound (631
mg, 53%) as a solid.
Example 165D
dimethyl
([(2R,5R)-1-{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidine-
-2,5-diyl]bis{(2-aminobenzene-4,1-diyl)carbamoyl(2S)pyrrolidine-2,1-diyl[(-
2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate
[0748] The product from Example 165C (628 mg, 0.576 mmol) and
Ra--Ni 2800 (628 mg) were combined in THF (40 mL). The mixture was
hydrogenated at 30 psi for 4 hours. The mixture was filtered and
the filtrate was evaporated. The residue was purified by
chromatography on silica gel eluting with methanol/dichloromethane
(2% to 5%) to give the title compound (590 g, 99%) as a solid. 1H
NMR (400 MHz, DMSO-D6) .delta. ppm 0.88 (d, J=6.61 Hz, 6H) 0.91 (d,
J=6.72 Hz, 6H) 1.62-1.69 (m, 2H) 1.82-2.04 (m, 8H) 2.10-2.20 (m,
2H) 2.52-2.56 (m, 2H) 3.37-3.41 (m, 4H) 3.52 (s, 6H) 3.56-3.62 (m,
2H) 3.65-3.70 (m, 4H) 3.78-3.85 (m, 2H) 3.98-4.07 (m, 2H) 4.36-4.44
(m, 2H) 4.87 (s, 4H) 5.06 (d, J=6.32 Hz, 2H) 6.36 (d, J=8.78 Hz,
2H) 6.42 (d, J=8.02 Hz, 2H) 6.57 (d, J=1.19 Hz, 2H) 6.78 (d, J=8.89
Hz, 1H) 6.96 (d, J=8.02 Hz, 2H) 7.23 (d, J=8.78 Hz, 2H) 7.36 (d,
J=8.24 Hz, 2H) 7.68 (dd, J=8.78, 2.49 Hz, 1H) 8.27 (d, J=2.49 Hz,
1H) 9.24 (s, 2H); MS (ESI+) m/z 1030.6 (M+H)+.
##STR00413##
Example 166
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-{4-[6-(mo-
rpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyr-
rolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0749] The product from Example 165D (520 g, 0.505 mmol) and acetic
acid (0.087 mL, 1.514 mmol) were combined in toluene (10 mL). The
mixture was stirred at 50.degree. C. for 4 hours. The solvent was
evaporated and the residue was purified by chromatography on silica
gel eluting with methanol/dichloromethane (2% to 5%) to give the
title compound (309 mg, 62%) as a solid. 1H NMR (400 MHz, DMSO-D6)
.delta. ppm 0.73-0.90 (m, 12H) 1.70-1.76 (m, 2H) 1.84-2.05 (m, 8H)
2.14-2.21 (m, 2H) 2.55-2.60 (m, 2H) 3.34-3.39 (m, 4H) 3.53 (s, 6H)
3.62-3.69 (m, 4H) 3.75-3.87 (m, 4H) 4.02-4.08 (m, 2H) 5.06-5.17 (m,
2H) 5.40-5.47 (m, 2H) 6.40 (d, J=8.67 Hz, 2H) 6.75 (d, J=8.89 Hz,
1H) 7.02-7.20 (m, 4H) 7.25 (s, 1H) 7.28 (d, J=8.46 Hz, 2H) 7.34 (s,
1H) 7.39 (d, J=8.13 Hz, 1H) 7.47 (d, J=8.24 Hz, 1H) 7.60 (d, J=8.60
Hz, 1H) 8.21 (s, 1H) 11.96-12.11 (m, 2H); MS (ESI+) m/z 994.5
(M+H)+.
##STR00414##
Example 167
methyl
[(2S)-1-{(2S)-2-[5-(4-{5-(4-{2-[1-(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)-1-[4-(pi-
peridin-1-yl)phenyl]-1H-pyrrol-2-yl}phenyl)-1H-imidazol-2-yl]pyrrolidin-1--
yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0750] Example 26E and 4-piperidinoaniline (Maybridge) were
processed using sequentially the methods of Examples 26F, 26G, 74C,
19D, and 74E to provide the title compound (106 mg). .sup.1H NMR
(400 MHz, DMSO-D6) .delta. 0.83 (d, J=6.73 Hz, 6H) 0.87 (d, J=6.73
Hz, 6H) 1.50-1.62 (m, 6H) 1.90-2.15 (m, 10H) 3.13 (m, 4H) 3.53 (s,
6H) 3.77 (m, 4H) 4.04 (m, 2H) 5.04 (m, 2H) 6.47 (m, 2H) 6.80-7.35
(m, 10H) 7.42 (m, 2H) 7.53 (m, 4H) 11.73 (s, 2H).
##STR00415##
Example 168
methyl
[(2S)-1-{(2S)-2-[5-(4-{5-(4-{2-[1-(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)-1-[4-(tr-
icyclo[3.3.1.1-3,7-]dec-1-yl)phenyl]-1H-pyrrol-2-yl}phenyl)-1H-imidazol-2--
yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0751] Example 26E and 4-(1-adamantanyl)aniline hydrochloride
(Enamine) were processed using sequentially the methods of Examples
26F, 26G, 74C, 19D, and 74E to provide the title compound (320 mg).
.sup.1H NMR (400 MHz, methanol-D4) .delta. 0.91 (m, 12H) 1.75-2.35
(m, 25H) 3.64 (s, 6H) 3.84 (m, 2H) 4.00 (m, 2H) 4.20 (m, 2H) 5.12
(m, 2H) 6.48 (s, 2H) 7.02 (m, 6H) 7.31 (m, 4H) 7.46 (m, 6H) 7.72
(d, J=8.13 Hz, 1H) 7.82 (d, J=8.24 Hz, 1H).
##STR00416##
Example 169
methyl
[(2S)-1-{(2S)-2-[5-(4-{5-(4-{2-[1-(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)-1-[4-(mo-
rpholin-4-yl)phenyl]-1H-pyrrol-2-yl}phenyl)-1H-imidazol-2-yl]pyrrolidin-1--
yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0752] Example 26E and 4-morpholinoaniline (Aldrich) were processed
using sequentially the methods of Examples 26F, 26G, 74C, 19D, and
74E to provide the title compound (133 mg). .sup.1H NMR (400 MHz,
DMSO-D6) .delta. 0.83 (d, J=6.83 Hz, 6H) 0.87 (d, J=6.61 Hz, 6H)
1.88-2.17 (m, 10H) 3.11 (m, 4H) 3.53 (s, 6H) 3.70-3.80 (m, 8H)
3.97-4.08 (m, 2H) 5.04 (m, 2H) 6.41-6.51 (m, 2H) 6.84-7.35 (m, 10H)
6.93-7.02 (m, 6H) 11.71-12.03 (m, 2H).
##STR00417##
Example 170
methyl
{(2S)-1-[(2S)-2-(5-bromo-4-{4-[(2S,5S)-5-(4-{5-bromo-2-[(2S)-1-{(2S-
)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-
-4-yl}phenyl)-1-(4-tert-butylphenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2--
yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0753] To a solution of Example 44 (0.100 g, 0.106 mmol) in
CH.sub.2Cl.sub.2 (5 mL) at rt was added N-bromosuccinimide (0.019
mL, 0.223 mmol). After 15 min, the reaction was washed with
saturated NaHCO.sub.3 and concentrated. Residue purified by
chromatography (1% gradient elution from 0% to 4%
MeOH--CH.sub.2Cl.sub.2; 12 g column) to provide 60 mg (51%) of the
title compound as a light yellow solid. .sup.1H NMR (400 MHz,
DMSO-D6) .delta. 0.8 (d, J=6.61 Hz, 6H) 0.87 (d, J=6.56 Hz, 6H)
1.11 (s, 9H) 1.72-1.75 (m, 2H) 1.87-1.98 (m, 7H) 2.10-2.15 (m, 5H)
3.53 (s, 6H) 3.70-3.75 (m, 4H) 4.00=4.06 (m, 2H) 4.96-5.00 (m, 2H)
5.27-5.35 (m, 2H) 6.24 (d, J=8.78 Hz, 2H) 6.97 (d, J=8.78 Hz, 2H)
7.24-7.35 (m, 6H) 7.60-7.65 (m, 4H) 12.41 (m, 2H).
##STR00418##
Example 171
methyl
{(2S)-1-[(2S)-2-(5-{4-[(2S,5S)-1-(4-tert-butylphenyl)-5-(4-{5-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-4H-1-
,2,4-triazol-3-yl}phenyl)pyrrolidin-2-yl]phenyl}-4H-1,2,4-triazol-3-yl)pyr-
rolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate and
methyl
{(2S)-1-[(2S)-2-(5-{4-[(2R,5R)-1-(4-tert-butylphenyl)-5-(4-{5-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-4H-1-
,2,4-triazol-3-yl}phenyl)pyrrolidin-2-yl]phenyl}-4H-1,2,4-triazol-3-yl)pyr-
rolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
Example 171A
Dimethyl
4,4'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dibenzoate
[0754] A mixture of Example 42C (0.5 g, 0.974 mmol), Et.sub.3N
(0.407 mL, 2.92 mmol) and
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (71.3
mg, 0.097 mmol) in methanol (20 mL) was subjected to an atmosphere
of carbon monoxide gas (60 psi) for 24 hours at 100.degree. C. The
mixture was filtered through celite and concentrated. Purification
by chromatography (silica gel, 25% EtOAc in hexanes) afforded 396
mg (86%) of the title compound. MS (ESI) m/z 472 (M+H).sup.+.
Example 171B
4,4'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dibenzohydrazide
[0755] A mixture of Example 171A (350 mg, 0.742 mmol) and Hydrazine
(0.140 .mu.L, 4.45 mmol) in methanol (10 mL) was refluxed for 72
hours. The mixture was concentrated to afford 350 mg of the title
compound as a mixture of stereoisomers. MS (ESI) m/z 472
(M+H).sup.+.
Example 171C
(2S,2'S)-tert-butyl
2,2'-(5,5'-(4,4'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phen-
ylene))bis(4H-1,2,4-triazole-5,3-diyl))dipyrrolidine-1-carboxylate
[0756] A mixture of Example 171B (105 mg, 0.223 mmol),
(S)-1-N-Boc-2-cyano-pyrrolidine (175 mg, 0.891 mmol), and
K.sub.2CO.sub.3 (9.23 mg, 0.067 mmol) in n-butanol (0.5 mL) was
heated to 150.degree. C. for 90 minutes in a microwave. The mixture
was diluted with EtOAc and then washed with H.sub.2O and Brine. The
organic was then dried (MgSO.sub.4), filtered and concentrated.
Purification by chromatography (silica gel, 90% EtOAc in Hexanes)
afforded 59 mg (32%) of the title compound as a mixture of
stereoisomers. MS (ESI) m/z 829 (M+H).sup.+.
Example 171D
(S)-5,5'-(4,4'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phenyle-
ne))bis(3-((S)-pyrrolidin-2-yl)-4H-1,2,4-triazole)
pentahydrochloride
[0757] A mixture of Example 171C (59 mg, 0.071 mmol) in 4M
HCl/Dioxane (2 mL) was allowed to stir for one hour. The mixture
was concentrated to afford 58 mg (100%) of the title compound as a
mixture of stereoisomers. MS (ESI) m/z 628 (M+H).sup.+.
Example 171E
methyl
{(2S)-1-[(2S)-2-(5-{4-[(2S,5S)-1-(4-tert-butylphenyl)-5-(4-{5-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-4H-1-
,2,4-triazol-3-yl}phenyl)pyrrolidin-2-yl]phenyl}-4H-1,2,4-triazol-3-yl)pyr-
rolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate and
methyl
{(2S)-1-[(2S)-2-(5-{4-[(2R,5R)-1-(4-tert-butylphenyl)-5-(4-{5-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-4H-1-
,2,4-triazol-3-yl}phenyl)pyrrolidin-2-yl]phenyl}-4H-1,2,4-triazol-3-yl)pyr-
rolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0758] A mixture of Example 171D (58 mg, 0.071 mmol),
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (25 mg, 0.142
mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
(30 mg, 0.157 mmol), 1-Hydroxy-benzotriazole hydrate (24 mg, 0.157
mmol) and N-methylmorpholine (78 .mu.L, 0.712 mmol) in DMF (1 mL)
were allowed to stir overnight. Mixture was diluted with EtOAc. The
organic was then washed with H.sub.2O and Brine. The organic was
then dried (MgSO.sub.4), filtered and concentrated. Compound
subjected to HPLC purification on a semi-prep C18 reverse-phased
column using a gradient of 10-100% acetonitrile in 0.1% aq. TFA to
afford both the title compounds of Example 171 (24 mg, 70%) which
eluted first (trans isomers) and title compound of Example 172
which eluted second (Cis isomer). .sup.1H NMR (free base) (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.27 (d, J=6.72 Hz, 2H), 0.71 (dd,
J=6.61, 2.49 Hz, 2H), 0.78-0.95 (m, 9H), 1.03 (d, J=6.07 Hz, 12H),
1.09 (s, 9H), 1.22 (s, 2H), 1.65-1.77 (m, 3H), 1.82-2.30 (m, 10H),
3.52 (s, 6H), 3.57-3.66 (m, 1H), 3.71-3.92 (m, 3H), 4.00-4.16 (m,
2H), 5.07-5.15 (m, 1H), 5.25-5.34 (m, 2H), 5.65 (d, J=4.88 Hz, 1H),
6.21 (dd, J=8.73, 3.20 Hz, 2H), 6.94 (dd, J=8.78, 2.82 Hz, 2H),
7.16-7.46 (m, 6H), 7.83-7.92 (m, 4H), 14.01 (s, 1H); MS (ESI) m/z
943 (M+H).sup.+.
##STR00419##
Example 172
methyl
{(2S)-1-[(2S)-2-(5-{4-[(2R,5S)-1-(4-tert-butylphenyl)-5-(4-{5-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-4H-1-
,2,4-triazol-3-yl}phenyl)pyrrolidin-2-yl]phenyl}-4H-1,2,4-triazol-3-yl)pyr-
rolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0759] The title compound, Example 172, was the second eluting
compound described in the procedures for Example 171E. The
procedure afforded 21 mg (61%) of the title compound (Cis isomer).
.sup.1H NMR (free base) (400 MHz, DMSO-d.sub.6) .delta. ppm 0.27
(d, J=6.29 Hz, 2H), 0.71 (d, J=6.61 Hz, 2H), 0.81-0.96 (m, 9H),
1.03 (d, J=6.07 Hz, 12H), 1.12 (s, 9H), 1.22 (s, 2H), 1.82-2.30 (m,
12H), 3.52 (s, 6H), 3.72-3.91 (m, 4H), 4.03-4.17 (m, 2H), 4.33 (d,
J=4.23 Hz, 1H), 4.73-4.83 (m, 2H), 5.09-5.18 (m, 2H), 6.33 (d,
J=8.78 Hz, 2H), 7.03 (dd, J=8.78, 3.04 Hz, 2H), 7.29 (d, J=7.70 Hz,
1H), 7.57-7.69 (m, 4H), 7.92-8.01 (m, 4H), 13.84 (s, 2H); MS (ESI)
m/z 943 (M+H).sup.+.
##STR00420##
Example 173
methyl
{(2S)-1-[(2S)-2-(2-{4-[(2S,5S)-1-(4-tert-butylphenyl)-5-(4-{4-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-i-
midazol-2-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-4-yl)pyrrolidin-1--
yl]-3-methyl-1-oxobutan-2-yl}carbamate and
methyl
{(2S)-1-[(2S)-2-(2-{4-[(2R,5R)-1-(4-tert-butylphenyl)-5-(4-{4-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-i-
midazol-2-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-4-yl)pyrrolidin-1--
yl]-3-methyl-1-oxobutan-2-yl}carbamate
Example 173A
4,4'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dibenzonitrile
[0760] A mixture of Example 42C (1.0 g, 1.948 mmol) and CuCN (523
mg, 5.84 mmol) in Dimethylformamide (9.5 mL) was heated to
160.degree. C. for 4.5 hours in a microwave. Mixture was poured
into a dimethylamine/H.sub.2O mixture (1/10) and extracted with
EtOAc (3.times.150 mL). The combined organics were washed with
H.sub.2O and Brine. The organic was then dried (MgSO.sub.4),
filtered and concentrated. Purification by chromatography (silica
gel, 20% EtOAc in Hexanes) afforded 395 mg (50%) of the title
compound. MS (ESI) m/z 406 (M+H).sup.+.
Example 173B
dimethyl
4,4'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dibenzimidate
[0761] A mixture of Example 173A (0.5 g, 1.233 mmol) in anhydrous
MeOH (12 mL) at 0.degree. C. was bubbled an excess amount of HCl
(g) for 45 minutes. Mixture was then stirred at ambient temperature
for 24 hours and then concentrated to afford the title
compound.
Example 173C
4,4'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dibenzimidamide
[0762] A mixture of Example 173B (0.579 g, 1.233 mmol) in anhydrous
MeOH (12 mL) at 0.degree. C. was bubbled an excess amount of
NH.sub.3 (g) for 45 minutes. Mixture was then stirred at ambient
temperature for 24 hours and then concentrated and subjected to
purification via chromatography (C18 reverse-phased column using a
gradient of 10-100% acetonitrile in 0.1% aq. TFA) to afford the
title compound as a mixture of trans isomers; Cis isomer was
discarded. MS (ESI) m/z 440 (M+H).sup.+.
Example 173D
methyl
(S)-1-((S)-2-(2-diazoacetyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2--
ylcarbamate
[0763] A mixture of Example 37B (100 mg, 0.367 mmol) and Et.sub.3N
(154 .mu.L, 1.102 mmol) in tetrahydrofuran (4 mL) at 0.degree. C.
was added Isobutyl chloroformate (50 .mu.L, 0.386 mmol). Mixture
was then stirred at 0.degree. C. for 30 minutes followed by
addition of excess diazomethane in Et.sub.2O. Mixture was allowed
to slowly come to ambient temperature over 3 hours. Mixture was
then concentrated and diluted with EtOAc. Organic was then washed
with saturated aqueous NaHCO.sub.3 and brine. Organic was dried
(MgSO.sub.4), filtered and concentrated. Purification by
chromatography (silica gel, 100% EtOAc) afforded 82 mg (75%) of the
title compound. MS (ESI) m/z 297 (M+H).sup.+.
Example 173E
methyl
(S)-1-((S)-2-(2-bromoacetyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2--
ylcarbamate
[0764] A mixture of Example 173D (70 mg, 0.236 mmol) in HOAc (0.6
mL) at ambient temperature was added 48% HBr (80 .mu.L, 0.709
mmol). Mixture was stirred at ambient temperature for 1 hour.
Mixture was poured into ice/H.sub.2O and extracted with
CH.sub.2Cl.sub.2 (3.times.75 mL). Organic was dried
(Na.sub.2SO.sub.4), filtered and concentrated afford 63 mg (76%) of
the title compound. MS (ESI) m/z 350 (M+H).sup.+.
Example 173F
methyl
{(2S)-1-[(2S)-2-(2-{4-[(2S,5S)-1-(4-tert-butylphenyl)-5-(4-{4-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-i-
midazol-2-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-4-yl)pyrrolidin-1--
yl]-3-methyl-1-oxobutan-2-yl}carbamate and
methyl
{(2S)-1-[(2S)-2-(2-{4-[(2R,5R)-1-(4-tert-butylphenyl)-5-(4-{4-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-i-
midazol-2-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-4-yl)pyrrolidin-1--
yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0765] A mixture of Example 173E (59.6 mg, 0.171 mmol), Example
173C (25 mg, 0.057 mmol) and K.sub.2CO.sub.3 (65 mg, 0.470 mmol) in
tetrahydrofuran (1 mL) was refluxed for 4 hours. Mixture was
diluted with CH.sub.2Cl.sub.2 and washed with H.sub.2O and Brine.
The organic was then dried (MgSO4), filtered and concentrated.
Compound subjected to HPLC purification on a semi-prep C18
reverse-phased column using a gradient of 10-100% acetonitrile in
0.1% aq. TFA to afford 4.5 mg (6.7%) the title compound Example 173
(Trans isomers). .sup.1H NMR (free base) (400 MHz, DMSO-d.sub.6)
.delta. ppm 0.78-0.89 (m, 12H), 1.09 (s, 9H), 1.68-1.74 (m, 4H),
1.88-2.04 (m, 8H), 3.52 (s, 6H), 3.70-3.78 (m, 4H), 4.04 (t, J=8.19
Hz, 2H), 5.07 (t, J=4.61 Hz, 2H), 5.26 (s, 2H), 6.21 (d, J=8.46 Hz,
2H), 6.82 (s, 2H), 6.93 (d, J=8.67 Hz, 2H), 7.22 (d, J=8.89 Hz,
2H), 7.26 (d, J=8.13 Hz, 4H), 7.78 (d, J=8.13 Hz, 4H), 7.82 (d,
J=7.70 Hz, 2H), 12.11-12.20 (m, 2H). MS (ESI) m/z 941
(M+H).sup.+.
##STR00421##
Example 174
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}-1-(6-methox-
ypyridin-3-yl)pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-met-
hyl-1-oxobutan-2-yl}carbamate
[0766] Example 109C and 6-methoxypyridin-3-amine were processed
using sequentially the methods of Examples 113A (dichloromethane
used as solvent and cyclization conducted at room temperature
overnight), 165C, 113C, and 166 to provide the title compound which
was purified by HPLC on a semi-prep C18 reverse-phased column using
a gradient of 10-100% acetonitrile in 0.1% aq. TFA to afford 27 mg
of the title compound. .sup.1H NMR (free base) (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.76-0.86 (m, 12H), 1.69-1.76 (m, 2H),
1.84-2.04 (m, 4H), 2.13-2.22 (m, 4H), 2.52-2.60 (m, 2H), 3.52 (s,
6H), 3.55 (s, 3H), 3.76-3.85 (m, 4H), 4.05 (t, J=8.40 Hz, 2H),
5.08-5.16 (m, 2H), 5.31-5.41 (m, 2H), 6.36-6.45 (m, 2H), 6.74 (dd,
J=9.00, 3.04 Hz, 2H), 7.05 (t, J=8.57 Hz, 2H), 7.15-7.24 (m,
J=17.02 Hz, 3H), 7.28 (d, J=8.46 Hz, 2H), 7.31 (s, 1H), 7.37 (d,
J=8.13 Hz, 1H), 7.45 (d, J=8.13 Hz, 1H), 12.03 (s, 2H); MS (ESI)
m/z 864 (M+H).sup.+.
##STR00422##
Example 175
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[6-(dimethylamino)pyridin-3-yl]-5-{2--
[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-
-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-y-
l]-3-methyl-1-oxobutan-2-yl}carbamate
Example 175A
N,N-dimethyl-5-nitropyridin-2-amine
[0767] A mixture of 2-chloro-5-nitropyridine (5.0 g, 31.5 mmol) and
40% solution of Dimethylamine (10.66 g, 95 mmol) in ethanol (40 mL)
was heated to 75.degree. C. for 1 hour. The mixture was cooled to
ambient temperature, diluted with CH.sub.2Cl.sub.2 and washed with
saturated aqueous NaHCO.sub.3 (3.times.100 mL) and brine. The
organic was dried (MgSO.sub.4), filtered and concentrated to afford
5.27 g (100%) of the title compound. MS (ESI) m/z 168
(M+H).sup.+.
Example 175B
N,N.sup.2-dimethylpyridine-2,5-diamine
[0768] A mixture of Example 175A (5.27 g, 31.5 mmol) and Raney
Nickel (5.27 g, 90 mmol) in tetrahydrofuran (60 mL) was subjected
to an atmosphere (30 psi) of hydrogen gas for 2 hours at ambient
temperature. Mixture was filtered and concentrated to afford 4.3 g
(100%) of the title compound. MS (ESI) m/z 138 (M+H).sup.+.
Example 175C
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[6-(dimethylamino)pyridin-3-yl]-5-{2--
[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-
-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-y-
l]-3-methyl-1-oxobutan-2-yl}carbamate
[0769] Example 175B was processed using the methods referred to or
described in Example 174 to provide the title compound (8.5 mg).
.sup.1H NMR (free base) (400 MHz, DMSO-d.sub.6) .delta. ppm
0.75-0.86 (m, 12H), 1.71 (d, J=4.99 Hz, 2H), 1.86-2.05 (m, 6H),
2.12-2.23 (m, 3H), 2.55 (s, 2H), 2.70 (s, 6H), 3.16 (s, 2H), 3.52
(s, 6H), 3.81 (s, 3H), 4.05 (t, J=8.35 Hz, 2H), 5.09-5.18 (m, 2H),
5.33 (d, J=5.53 Hz, 2H), 6.33 (d, J=9.00 Hz, 1H), 6.63 (dd, J=9.05,
2.98 Hz, 1H), 7.04 (d, J=7.70 Hz, 2H), 7.19-7.31 (m, 4H), 7.34-7.48
(m, 2H), 12.02 (s, 2H); MS (ESI) m/z 877 (M+H).sup.+.
##STR00423##
Example 176
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-(6-tert-butylpyridin-3-yl)-5-{2-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-b-
enzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3--
methyl-1-oxobutan-2-yl}carbamate
[0770] 6-tert-Butylpyridin-3-amine was processed using the methods
referred to or described in Example 174 to provide the title
compound (62.5 mg) of the title compound. H NMR (free base) (400
MHz, DMSO-d) .delta. ppm 0.74-0.88 (m, 12H), 1.08 (s, 9H),
1.68-1.77 (m, 2H), 1.83-2.04 (m, 7H), 2.12-2.23 (m, 4H), 2.53-2.61
(m, 2H), 3.16 (d, J=5.20 Hz, 2H), 3.52 (s, 6H), 3.76-3.85 (m, 4H),
4.00-4.11 (m, 3H), 5.08-5.16 (m, 2H), 5.37-5.46 (m, 2H), 6.54-6.61
(m, 1H), 6.88-6.96 (m, 2H), 7.08 (t, J=9.00 Hz, 2H), 7.20 (s, 1H),
7.25-7.31 (m, 3H), 7.39 (d, J=8.13 Hz, 1H), 7.47 (d, J=8.24 Hz,
1H), 7.60 (d, J=3.25 Hz, 1H), 12.04 (d, J=27.76 Hz, 2H); MS (ESI)
m/z 890 (M+H).sup.+.
##STR00424##
Example 177
methyl
{(2S)-1-[(2S)-2-(6-{(2S,5S)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}-1-[6-(piper-
idin-1-yl)pyridin-3-yl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1--
yl]-3-methyl-1-oxobutan-2-yl}carbamate
Example 177A
5-((2S,5S)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2-(piperidin-1--
yl)pyridine
[0771] (1R,4R)-1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-diol
(prepared using (S)-(+)-alpha,alpha-diphenyl-2-pyrrolidinemethanol
and the method of Example 109C) (0.60 g, 1.5 mmol) was processed
using the method described in Example 182A to give the title
compound (0.41 g, 50%).
Example 177B
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(6-(piperidin-1-yl)-
pyridin-3-yl)pyrrolidine-2,5-diyl)bis(2-nitro-4,1-phenylene))bis(azanediyl-
)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-d-
iyl)dicarbamate
[0772] The product from Example 177A (0.20 g, 0.369 mmol) was
combined with the product from Example 116C (0.30 g, 1.11 mmol),
cesium carbonate (0.336 g, 1.03 mmol), Xantphos (38 mg, 0.066 mmol)
and tris(dibenzylideneacetone)dipalladium (20.3 mg, 0.022 mmol).
Anhydrous 1,4-dioxane (3.7 mL) was added, and the mixture was
bubbled with N.sub.2 gas for 15 min. The resulting mixture was
stirred in a sealed tube at 100.degree. C. for 2 h. The mixture was
cooled to ambient temperature, diluted with water and extracted
with ethyl acetate. The organic extract was washed with brine,
dried (NaSO.sub.4), filtered and concentrated. Purification by
flash chromatography twice (silica gel, 0-10%
MeOH/CH.sub.2Cl.sub.2) afforded the title compound (235 mg,
60%).
Example 177C
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(6-(piperidin-1-yl)-
pyridin-3-yl)pyrrolidine-2,5-diyl)bis(2-amino-4,1-phenylene))bis(azanediyl-
)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-d-
iyl)dicarbamate
[0773] To a solution of the product from Example 177B (237 mg,
0.234 mmol) in ethanol (1.2 mL) and tetrahydrofuran (1.2 mL) was
added platinum(IV) oxide (13.29 mg, 0.059 mmol). The mixture was
placed under a hydrogen atmosphere for about 1 hour. The mixture
was filtered over celite, washing with methanol and concentrated.
Purification by flash chromatography (silica gel, 0-10%
MeOH/CH.sub.2Cl.sub.2) afforded the title compound (186 mg,
84%).
Example 177D
methyl
{(2S)-1-[(2S)-2-(6-{(2S,5S)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}-1-[6-(piper-
idin-1-yl)pyridin-3-yl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1--
yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0774] To a solution of the product from Example 177C (113 mg,
0.119 mmol) in toluene (1.2 mL) was added acetic acid (34 .mu.L,
0.593 mmol) and 3A molecular sieves. The mixture was heated to
60.degree. C. for 2 hours. The reaction was cooled to ambient
temperature and diluted with ethyl acetate. The organic phase was
washed with saturated aqueous NaHCO.sub.3, dried
(Na.sub.2SO.sub.4), filtered and concentrated. The crude product
was purified by reverse-phase HPLC (C18) using a solvent gradient
of 10-90% CH.sub.3CN in water (0.1% TFA). Fractions containing the
desired product were pooled and concentrated in vacuo, and the
residue was partitioned between saturated aq. NaHCO.sub.3, and
CH.sub.2Cl.sub.2. The organic layer was dried (Na.sub.2SO.sub.4),
filtered and concentrated to afford the title compound (9 mg, 8%).
1H NMR (400 MHz, DMSO-D6) .delta. ppm 0.78-0.85 (m, 7H), 0.87 (dd,
J=6.7, 3.0 Hz, 6H), 1.23 (s, 1H), 1.43 (s, 6H), 1.72 (s, 2H), 1.97
(s, 5H), 2.18 (s, 3H), 3.09 (s, 4H), 3.30 (s, 2H), 3.53 (d, J=1.5
Hz, 6H), 3.81 (s, 4H), 4.07 (s, 2H), 5.13 (s, 2H), 5.33 (s, 2H),
6.48 (d, J=4.4 Hz, 1H), 6.59-6.64 (m, 1H), 7.05 (s, 2H), 7.22 (s,
1H), 7.25-7.34 (m, 4H), 7.37 (s, 1H), 7.44 (s, 1H), 12.06 (s, 2H);
MS (ESI) m/z 916 (M+H).sup.+.
##STR00425##
Example 178
methyl
{(2S)-1-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-H-benzimidazol-6-yl}-1-[6-(triflu-
oromethyl)pyridin-3-yl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1--
yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0775] Example 109C and 5-amino-2-(trifluoromethyl)pyridine were
processed using sequentially the methods of Examples 182A, 177B,
177C, and 177D to provide the title compound. 1H NMR (400 MHz,
DMSO-D6) .delta. ppm 0.79-0.89 (m, 15H), 1.61 (s, 4H), 1.97 (s,
6H), 2.19 (s, 5H), 3.50-3.58 (m, 7H), 3.82 (s, 4H), 3.99-4.10 (m,
2H), 5.15 (s, 2H), 6.89-6.98 (m, 2H), 7.19 (s, 1H), 7.26-7.34 (m,
4H), 7.36 (d, J=8.2 Hz, 1H), 11.94 (d, J=12.9 Hz, 2H). MS m/z 901
(M+H).sup.+.
##STR00426##
Example 179
N-(methoxycarbonyl)-L-valyl-N-{4-[(2S,5S)
1-(4-tert-butylphenyl)-5-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolid-
in-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]phenyl}-L-prolinamide
and
N-(methoxycarbonyl)-L-valyl-N-{4-[(2R,5R)-1-(4-tert-butylphenyl)-5-(2-{(2S-
)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyr-
rolidin-2-yl]phenyl}-L-prolinamide
Example 179A
1-(4-chloro-3-nitrophenyl)-4-(4-nitrophenyl)butane-1,4-dione
[0776] To a mixture of zinc chloride (39.1 g, 287 mmol) in benzene
(215 mL) was added diethylamine (22.24 mL, 215 mmol) and
2-methylpropan-2-ol (20.57 mL, 215 mmol). The resulting mixture was
stirred at rt for 2h, and 2-bromo-1-(4-nitrophenyl)ethanone (35.0
g, 143 mmol) and 1-(4-chloro-3-nitrophenyl)ethanone (42.9 g, 215
mmol) were added in one portion. The resulting mixture was stirred
at rt overnight. Added 5% aq. H.sub.2SO.sub.4 (50 mL) and stirred
vigorously to induce precipitation. The resulting solid was
collected by filtration and washed successively with benzene,
water, methanol, and CH.sub.2Cl.sub.2. The solid was dried in vacuo
to give the title compound.
Example 179B
1-(4-chloro-3-nitrophenyl)-4-(4-nitrophenyl)butane-1,4-diol
[0777] To a solution of the product from Example 179A (10.0 g, 27.6
mmol) in EtOH (220 mL) was added sodium borohydride (2.190 g, 57.9
mmol) in several portions over 1 h. The resulting mixture was
stirred at rt for 1 h, filtered through celite, and concentrated in
vacuo. The residue was dissolved in EtOAc and washed by 1N aq. HCl.
The organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to give the title compound (9.29 g, 92%)
Example 179C
1-(4-tert-butylphenyl)-2-(4-chloro-3-nitrophenyl)-5-(4-nitrophenyl)pyrroli-
dine
[0778] To a solution of product from Example 179B (9.29 g, 25.3
mmol) in anhydrous CH.sub.2Cl.sub.2 (200 mL) at 0.degree. C. was
added triethylamine (10.53 mL, 76 mmol), followed by dropwise
addition of methanesulfonyl chloride (4.93 mL, 63.3 mmol). The
resulting mixture was stirred at 0.degree. C. for 2 h, and then
concentrated in vacuo. The resulting solid was dissolved in
anhydrous DMF (70 mL), 4-tert-butylaniline (40.4 mL, 253 mmol) was
added, and the resulting mixture was stirred at 50.degree. C. for 1
h. The resulting mixture was cooled to rt and poured into ice cold
IN aq. HCl (500 mL) to give a yellow precipitate. The precipitate
was collected by filtration and dried to give the title compound
(13.2 g).
Example 179D
4-(1-(4-tert-butylphenyl)-5-(4-nitrophenyl)pyrrolidin-2-yl)-N-(4-methoxybe-
nzyl)-2-nitroaniline
[0779] The product from Example 179C (13.2 g, 27.5 mmol) and
4-methoxybenzylamine (18 mL, 139 mmol) were combined and stirred at
145.degree. C. for 1.5 h. The mixture was cooled to rt, and
CH.sub.2Cl.sub.2 was added. The resulting precipitate was filtered
off, and the filtrate was washed successively with 1N aq. HCl and
saturated aq. NaHCO.sub.3. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel using a
solvent gradient of 0-25% EtOAc in hexane to give the title
compound (5.0 g, 31%).
Example 179E
4-(5-(4-aminophenyl)-1-(4-tert-butylphenyl)pyrrolidin-2-yl)-N1-(4-methoxyb-
enzyl)benzene-1,2-diamine
[0780] To a solution of the product from Example 179D (2.74 g, 4.72
mmol) in EtOH (25 mL) and THF (25 mL) was added platinum(IV) oxide
(0.5 g, 2.2 mmol). The resulting mixture was stirred at rt under 1
atm H.sub.2 overnight. The mixture was filtered through celite,
washed with methanol, and the filtrate was concentrated in vacuo.
The crude product was purified by column chromatography on silica
gel using a solvent gradient of 0-45% EtOAc in hexane to give the
title compound (1.74 g, 71%).
Example 179F
(2S)-tert-butyl
2-(4-(5-(3-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)-4-(4-me-
thoxybenzylamino)phenyl)-1-(4-tert-butylphenyl)pyrrolidin-2-yl)phenylcarba-
moyl)pyrrolidine-1-carboxylate
[0781] To a mixture of the product from Example 179E (1.74 g, 3.33
mmol), (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid
(1.793 g, 8.33 mmol) and HATU (3.17 g, 8.33 mmol) in DMSO (33 mL)
was added Hunig's base (1.746 mL, 10.00 mmol). The resulting
mixture was stirred at rt for 1 h and was partitioned between
H.sub.2O and CH.sub.2Cl.sub.2. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel using a
solvent gradient of 0-25% EtOAc in hexane to give the title
compound (2.1 g, 69%).
Example 179G
(2S)-tert-butyl
2-(4-(5-(4-amino-3-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)-
phenyl)-1-(4-tert-butylphenyl)pyrrolidin-2-yl)phenylcarbamoyl)pyrrolidine--
1-carboxylate
[0782] To a solution of the product from Example 179F (1.06 g, 1.16
mmol) in CH.sub.2Cl.sub.2 (40 mL) and H.sub.2O (2 mL) was added
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.316 g, 1.393
mmol) in several portions. The mixture was stirred at rt for 20 min
and was washed with saturated.aq. NaHCO.sub.3. The organic layer
was dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The crude product was purified by column chromatography on
silica gel using a solvent gradient of 0-25% EtOAc in hexane to
give the title compound (0.53 g, 57%).
Example 179H
(2S)-tert-butyl
2-(4-(5-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidaz-
ol-5-yl)-1-(4-tert-butylphenyl)pyrrolidin-2-yl)phenylcarbamoyl)pyrrolidine-
-1-carboxylate
[0783] A solution of product from Example 179G (0.526 g, 0.662
mmol) in acetic acid (4.73 mL, 83 mmol) was stirred at 65.degree.
C. for 1 h. The resulting mixture was partitioned between
CH.sub.2Cl.sub.2 and saturated aq. NaHCO.sub.3. The organic layer
was dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The crude product was purified by column chromatography on
silica gel using a solvent gradient of 0-2.5% MeOH in
CH.sub.2Cl.sub.2 to give the title compound (0.23 g, 45%).
Example 179I
(S)--N-(4-((2S,5S)-1-(4-tert-butylphenyl)-5-(2-((S)-pyrrolidin-2-yl)-1H-be-
nzo[d]imidazol-5-yl)pyrrolidin-2-yl)phenyl)pyrrolidine-2-carboxamide
and
(S)--N-(4-((2R,5R)-1-(4-tert-butylphenyl)-5-(2-((S)-pyrrolidin-2-yl)-1H-be-
nzo[d]imidazol-5-yl)pyrrolidin-2-yl)phenyl)pyrrolidine-2-carboxamide
[0784] To a solution of the product from Example 179H (0.302 g,
0.389 mmol) in CH.sub.2Cl.sub.2 (3 mL) was added TFA (2.5 mL), and
the resulting mixture was stirred at rt for 1.5 h. The mixture was
concentrated in vacuo, and the crude product was purified by
reversed-phase HPLC (C18) using a solvent gradient of 10-100%
acetonitrile in H.sub.2O (0.1% TFA). The trans-pyrrolidine isomer
eluted before the cis-pyrrolidine isomer. Fractions containing the
trans-isomer were concentrated in vacuo, and the residue was
partitioned between CH.sub.2Cl.sub.2 and saturated aq. NaHCO.sub.3.
The organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to give the title compound (83 mg, 37%).
Example 179J
N-(methoxycarbonyl)-L-valyl-N-{4-[(2S,5S)
1-(4-tert-butylphenyl)-5-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolid-
in-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]phenyl}-L-prolinamide
and
N-(methoxycarbonyl)-L-valyl-N-{4-[(2R,5R)-1-(4-tert-butylphenyl)-5-(2-{(2S-
)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyr-
rolidin-2-yl]phenyl}-L-prolinamide
[0785] To a mixture of the product from Example 1791 (83 mg, 0.144
mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (63 mg,
0.361 mmol), and HATU (0.137 g, 0.361 mmol) in DMSO (1.5 mL) was
added Hunig's base (0.101 mL, 0.578 mmol), and the resulting
mixture was stirred at rt for 1 h. The mixture was partitioned
between CH.sub.2Cl.sub.2 and H.sub.2O. The organic layer was dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
crude product was purified by column chromatography on silica gel
using a solvent gradient of 0-3.5% MeOH in CH.sub.2Cl.sub.2 to give
the title compounds (80 mg, 60%). 1H NMR (400 MHz, DMSO-D6) .delta.
ppm 0.74-0.99 (m, 12H), 1.09 (s, 9H), 1.59-1.73 (m, 2H), 1.81-2.05
(m, 6H), 2.07-2.24 (m, 2H), 3.50-3.56 (m, 6H), 3.58-3.67 (m, 1H),
3.76-3.85 (m, 2H), 3.99-4.10 (m, 2H), 4.43 (dd, J=8.0, 4.9 Hz, 1H),
5.08-5.16 (m, 1H), 5.16-5.25 (m, 1H), 5.26-5.37 (m, 1H), 6.21 (d,
J=8.8 Hz, 2H), 6.88-6.97 (m, 2.5H), 7.00-7.08 (m, 1H), 7.11-7.20
(m, J=5.7 Hz, 2.5H), 7.21-7.34 (m, 2H), 7.37 (dd, J=8.2, 2.0 Hz,
0.5H), 7.45 (d, J=8.3 Hz, 0.5H), 7.50 (d, J=8.3 Hz, 2H), 9.98 (s,
1H), 12.01 (m, 1H); MS m/z 891.6 (M+H).sup.+.
##STR00427##
Example 180
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2R,5R)-1-(4-tert-butylphenyl)-5-(4-{5-chlor-
o-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-
-yl]-1H-imidazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-5-chloro-1H-imidazol--
2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0786] To a solution of the product from Example 43 (114 mg, 0.121
mmol) in CH.sub.2Cl.sub.2 (1.2 mL) was added N-chlorosuccinimide
(54 mg, 0.41 mmol), and the resulting mixture was stirred at rt for
9 h. The mixture was diluted by CH.sub.2Cl.sub.2 and washed with
saturated aq NaHCO.sub.3. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude
product was subjected to reversed-phase HPLC (C18) using a solvent
gradient of 40%-100% acetonitrile in water (0.1% TFA). Fractions
containing the desired product were pooled and concentrated in
vacuo. The residue was purified on a preparative TLC plate, eluting
with 3% MeOH in CH.sub.2Cl.sub.2 to give the title compound (3.5
mg, 3%). 1H NMR (400 MHz, DMSO-D6) .delta. ppm 0.80-0.92 (m, 12H),
1.11 (s, 9H), 1.72 (d, J=5.0 Hz, 2H), 1.87-2.04 (m, 6H), 2.05-2.23
(m, 2H), 3.53 (s, 6H), 3.72-3.82 (m, 2H), 4.04 (t, J=8.4 Hz, 2H),
4.98 (dd, J=6.8, 3.5 Hz, 2H), 5.29 (dd, J=3.5, 2.5 Hz, 2H), 6.23
(d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 7.27 (d, J=8.6 Hz, 2H),
7.32 (d, J=8.2 Hz, 4H), 7.61 (d, J=8.1 Hz, 4H), 12.41 (s, 2H); MS
m/z 1009.1 (M+H).sup.+.
##STR00428##
Example 181
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2R,5R)-1-(4-tert-butyl-2-chlorophenyl)-5-(4-
-{5-chloro-2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyr-
rolidin-2-yl]-1H-imidazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-5-chloro-1H--
imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0787] The product from Example 43 (114 mg, 0.121 mmol) was
subjected to the procedure described in Example 180 to give the
title compound (4.7 mg, 4%). 1H NMR (TFA salt) (400 MHz, DMSO-D6)
.delta. ppm 0.78-0.89 (m, 12H), 1.05 (s, 9H), 1.85-1.97 (m, 10H),
2.04-2.18 (m, 4H), 3.52 (s, 6H), 3.69-3.81 (m, 4H), 4.03 (t, J=8.3
Hz, 2H), 4.95 (dd, J=7.0, 4.0 Hz, 2H), 5.53 (d, J=7.5 Hz, 2H),
6.91-6.95 (m, 1H), 6.96-7.02 (m, 2H), 7.26 (d, J=8.5 Hz, 2H),
7.30-7.41 (m, 4H), 7.49 (d, J=7.6 Hz, 4H), 12.34 (s, 2H); MS m/z
1045.1 (M+H).sup.+.
##STR00429##
Example 182
methyl
[(2S)-1-{(2S)-2-[4-(4-{(2S,5S)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1--
[6-(piperidin-1-yl)pyridin-3-yl]pyrrolidin-2-yl}phenyl)-1H-imidazol-2-yl]p-
yrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
Example 182A
5-((2S,5S)-2,5-bis(4-bromophenyl)pyrrolidin-1-yl)-2-(piperidin-1-yl)pyridi-
ne
[0788] To a suspension of the product of Example 69A (0.50 g, 1.25
mmol) in anhydrous CH.sub.2Cl.sub.2 (12 mL) at 0.degree. C. was
added Et.sub.3N (0.52 mL, 3.75 mmol), followed by methanesulfonyl
chloride (0.243 mL, 3.12 mmol). The resulting mixture was stirred
and 0.degree. C. for 90 min and then evaporated to dryness. The
solid was dissolved in anhydrous DMF (10 mL), and Example 144C
(1108 mg, 6.25 mmol) was added. The resulting mixture was stirred
at 40.degree. C. overnight, and was partitioned between 0.2 N aq
HCl and EtOAc. The organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The crude product was purified
by column chromatography on silica gel using a solvent gradient of
EtOAc and hexane to give the title compound (107 mg, 16%).
Example 182B
methyl
[(2S)-1-{(2S)-2-[4-(4-{(2S,5S)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1--
[6-(piperidin-1-yl)pyridin-3-yl]pyrrolidin-2-yl}phenyl)-1H-imidazol-2-yl]p-
yrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0789] The product from Example 182A was subjected to the
procedures described in Examples 42D, 42E, 42F, and 42G to give the
title compound. 1H NMR (free base) (400 MHz, DMSO-D6) .delta. ppm
0.80-0.94 (m, 12H), 1.24 (s, 4H), 1.44 (s, 6H), 1.89-2.04 (m, 6H),
2.07-2.20 (m, 4H), 3.12 (s, 4H), 3.53 (s, 6H), 3.77 (d, J=6.7 Hz,
2H), 4.05 (t, J=8.4 Hz, 2H), 5.06 (dd, J=6.7, 3.0 Hz, 2H), 5.19 (d,
J=6.4 Hz, 2H), 6.45-6.53 (m, 1H), 6.56-6.63 (m, 1H), 7.15 (d, J=8.2
Hz, 4H), 7.21-7.32 (m, 4H), 7.38 (d, J=1.8 Hz, 2H), 7.62 (d, J=8.0
Hz, 4H), 11.69 (s, 2H); MS m/z=968.8 (M+H).sup.+.
##STR00430##
Example 183
methyl
[(2S)-1-{(2S)-2-[4-(4-{(2S,5S)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1--
[6-(trifluoromethyl)pyridin-3-yl]pyrrolidin-2-yl}phenyl)-1H-imidazol-2-yl]-
pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
Example 183A
5-((2S,5S)-2,5-bis(4-bromophenyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrid-
ine
[0790] The product from Example 69A (1.0 g, 2.5 mmol) was subjected
to the procedure described in Example 182A, substituting
6-(trifluoromethyl)pyridin-3-amine for Example 144C, to give the
title compound (0.13 g, 10%).
Example 183B
methyl
[(2S)-1-{(2S)-2-[4-(4-{(2S,5S)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1--
[6-(trifluoromethyl)pyridin-3-yl]pyrrolidin-2-yl}phenyl)-1H-imidazol-2-yl]-
pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0791] The product from Example 183A was subjected to the
procedures described in Examples 42D, 42E, 42F, and 42G to give the
title compound. 1H NMR (TFA salt) (400 MHz, DMSO-D6) .delta. ppm
0.75-0.91 (m, 12H), 1.84 (d, J=5.6 Hz, 2H), 1.96-2.10 (m, 6H),
2.11-2.20 (m, J=10.8, 5.5 Hz, 2H), 3.54 (s, 6H), 3.76-3.91 (m, 4H),
4.10 (t, J=7.9 Hz, 2H), 5.11 (t, J=6.8 Hz, 2H), 5.56 (d, J=5.1 Hz,
2H), 6.74 (dd, J=8.8, 2.5 Hz, 1H), 7.32 (d, J=8.5 Hz, 2H), 7.41 (d,
J=7.8 Hz, 4H), 7.44-7.48 (m, J=8.8 Hz, 1H), 7.71 (d, J=8.2 Hz, 4H),
7.76 (d, J=2.5 Hz, 1H), 7.97 (s, 2H), 14.50 (s, 2H); MS m/z 953.6
(M+H).sup.+.
##STR00431##
Example 184
methyl
{(2S)-1-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}-1-[2-(piper-
idin-1-yl)pyrimidin-5-yl]pyrrolidin-2-yl}-1H-benzimdazol-2-yl)pyrrolidin-1-
-yl]-3-methyl-1-oxobutan-2-yl}carbamate
Example 184A
2-(piperidin-1-yl)pyrimidin-5-amine
[0792] To a suspension of 2-chloro-5-nitropyrimidine (1.5 g, 9.40
mmol) in EtOH (15 mL) was added piperidine (2.79 mL, 28.2 mmol),
and the resulting mixture was refluxed for 2 h. The cooled mixture
was concentrated in vacuo, and the residue was partitioned between
CH.sub.2Cl.sub.2 and saturated aq. NaHCO.sub.3. The organic layer
was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo
to give a solid (1.65 g, 84%). The solid was placed in a 250 mL
stainless steel pressure bottle and dissolved in THF (20 mL).
Raney-Ni 2800 in water slurry (1.650 g, 28.1 mmol) was added, and
the mixture was stirred at rt for 2 h under H.sub.2 gas at a
pressure of 30 psi. The mixture was filtered through a nylon
membrane and concentrated in vacuo to give the title compound (1.4
g, 99%).
Example 184B
5-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2-(piperidin-1--
yl)pyrimidine
[0793] The product from Example 109C (1.09 g, 2.72 mmol) was
subjected to the conditions described in Example 182A, substituting
Example 184A for Example 144C, to give the title compound (0.59 g,
40%).
Example 184C
methyl
{(2S)-1-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}-1-[2-(piper-
idin-1-yl)pyrimidin-5-yl]pyrrolidin-2-yl}-1H-benzimdazol-2-yl)pyrrolidin-1-
-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0794] The product from Example 184B was subjected to the
procedures described in Examples 177B, 177C, and 177D to give the
title compound. 1H NMR (TFA salt) (400 MHz, DMSO-D6) .delta. ppm
0.71-0.91 (m, 12H), 1.24 (s, 2H), 1.32-1.41 (m, 4H), 1.44-1.52 (m,
2H), 1.82 (d, J=5.1 Hz, 2H), 1.92-2.26 (m, 12H), 3.86 (s, 6H), 4.12
(t, J=8.0 Hz, 2H), 5.20 (dd, J=8.0, 5.2 Hz, 2H), 5.54 (d, J=6.2 Hz,
2H), 7.33 (d, J=8.3 Hz, 2H), 7.40 (d, J=7.8 Hz, 2H), 7.51 (s, 2H),
7.57-7.61 (m, 2H), 7.72 (d, J=8.3 Hz, 2H); MS m/z 917.5
(M+H).sup.+.
##STR00432##
Example 185
methyl
{(2S)-1-[(2S)-2-(5-{4-[(2S,5S)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)-1--
{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2-yl]phenyl}-1H-imida-
zol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
and
methyl
{(2S)-1-[(2S)-2-(5-{4-[(2R,5R)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)-1--
{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2-yl]phenyl}-1H-imida-
zol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
Example 185A
2,5-bis(4-bromophenyl)-1-(4-iodophenyl)pyrrolidine
[0795] The product from Example 42B (1.39 g, 2.499 mmol) in DMF
(6.25 mL) was treated with 4-iodoaniline (Aldrich, 4.38 g, 19.99
mmol), heated at 40-50.degree. C. for two hours, cooled and diluted
into EtOAc. The EtOAc layer was washed 3.times.50 mL with 1 M HCl,
with water, brine, dried (Na.sub.2SO.sub.4), filtered and
concentrated. Purification by flash chromatography on an ISCO 40 g
silica cartridge eluting with 0-20% EtOAc in hexane afforded the
title compound as a tan foam as a mixture of stereoisomers (0.96 g,
66%). MS (ESI) m/z 584 (M+H).sup.+.
Example 185B
4-(5-(4-(2,5-bis(4-bromophenyl)pyrrolidin-1-yl)phenyl)pyridin-2-yl)morphol-
ine
[0796] The product from Example 185A (0.1 g, 0.171 mmol),
4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine
(0.050 g, 0.171 mmol), potassium phosphate (0.028 mL, 0.343 mmol),
tris(dibenzylideneacetone)dipalladium(0) (1.570 mg, 1.715 mol) and
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (1.504
mg, 5.14 mol) were combined in THF (1.2 mL)/water (0.4 mL). The
mixture was sparged with nitrogen for 15 minutes diluted into
EtOAc, washed with 1M sodium bicarbonate, brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated. Purification by
flash chromatography on an Isco 12 g silica cartridge eluting with
20-70% EtOAc in hexane gave the title compound as a cream colored
powder (91 mg, 86%). %). MS (ESI) m/z 620 (M+H).sup.+.
Example 185C
methyl
{(2S)-1-[(2S)-2-(5-{4-[(2S,5S)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)-1--
{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2-yl]phenyl}-1H-imida-
zol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
and
methyl
{(2S)-1-[(2S)-2-(5-{4-[(2R,5R)-5-(4-{2-[(2S)-1-{(2S)-2-[(methoxycar-
bonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)-1--
{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2-yl]phenyl}-1H-imida-
zol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0797] The product from Example 185B was processed as described in
Example 42D, 42E, 42F, and 42G to afford the title compounds.
.sup.1H NMR (free base) (400 MHz, DMSO-d.sub.6) .delta. 0.77-0.94
(m, 12H) 1.71-2.47 (m, 16H) 3.36-3.42 (m, 4H) 3.53 (s, 6H)
3.63-3.71 (m, 4H) 3.74-3.84 (m, 3H) 4.00-4.08 (m, 1H) 4.79 (d,
J=4.23 Hz, 1H) 5.02-5.11 (m, 2H) 5.24-5.32 (m, 1H) 6.37 (d, J=8.89
Hz, 1H) 6.49 (d, J=8.78 Hz, 1H) 6.79 (dd, J=14.91, 8.95 Hz, 1H)
7.12-7.78 (m, 15H) 8.23-8.31 (m, 1H) 11.64-12.11 (m, 2H). MS (ESI)
m/z 1046 (M+H).sup.+.
##STR00433##
Example 186
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2S,5S)-1-(4-cyclopropylphenyl)-5-(4-{2-[(2S-
)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H--
imidazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-
-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0798] The product from Example 95B was purified by chiral
chromatography on a Chiralpak IB column eluting with a mixture of
hexane/THF/methanol (85/10/5). The title compound was the second of
the 2 diastereomers to elute. 1H NMR (400 MHz, DMSO-D6) .delta. ppm
0.35-0.42 (m, 2H) 0.65-0.73 (m, 2H) 0.80-0.92 (m, 12H) 1.58-1.65
(m, 1H) 1.67-1.71 (m, 2H) 1.87-2.02 (m, 6H) 2.07-2.17 (m, 4H) 3.53
(s, 6H) 3.70-3.85 (m, 4H) 4.05 (t, J=8.35 Hz, 2H) 5.06 (dd, J=6.72,
2.82 Hz, 2H) 5.16-5.25 (m, 2H) 6.19 (d, J=8.67 Hz, 2H) 6.64 (d,
J=8.57 Hz, 2H) 7.09-7.32 (m, 6H) 7.36-7.69 (m, 6H) 11.60-12.09 (m,
2H); MS (ESI+) m/z 924.6 (M+H).sup.+.
##STR00434##
Example 187
dimethyl
([(2R,5R)-1-{3-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidine-
-2,5-diyl]bis{(2-aminobenzene-4,1-diyl)carbamoyl(2S)pyrrolidine-2,1-diyl[(-
2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate
Example 187A
(2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-1-(3-iodophenyl)pyrrolidine
[0799] The mesylate of Example 109C (4.17 g, 7.48 mmol) in DMF (15
ml) was treated with 3-iodoaniline (Aldrich, 7.2 mL, 59.8 mmol),
stirred at ambient temperature for 48 hours and diluted into EtOAc.
The EtOAc layer was washed 3.times.50 mL with 1 M HCl, with water,
brine, dried (Na.sub.2SO.sub.4), filtered and concentrated.
Purification by flash chromatography on an Isco 300 g silica
cartridge eluting with 10-30% EtOAc in hexane afforded the title
compound as a bright yellow foam (2.6 g, 60 %). MS (ESI) m/z 584
(M+H).sup.+.
Example 187B
4-(5-(3-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)phenyl)pyr-
idin-2-yl)morpholine
[0800] The product from Example 187A (1.4 g, 2.396 mmol),
4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine
(0.695 g, 2.396 mmol), potassium phosphate (1.017 g, 4.79 mmol),
tris(dibenzylideneacetone)dipalladium(0) (0.022 g, 0.024 mmol) and
1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (0.021
g, 0.072 mmol) were combined in THF (18 mL)/water (6 mL). The
mixture was sparged with nitrogen for 15 minutes, stirred for 6
hours diluted into EtOAc, washed with 1M sodium bicarbonate, brine,
dried (Na.sub.2SO.sub.4), filtered and concentrated. Purification
by flash chromatography on an Isco 120 g silica cartridge eluting
with 20-60% EtOAc in hexane gave the title compound as a yellow
glass (1.1 g, 74%). MS (ESI) m/z 620 (M+H).sup.+.
Example 187C
dimethyl
([(2R,5R)-1-{3-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidine-
-2,5-diyl]bis{(2-aminobenzene-4,1-diyl)carbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate
[0801] The product from Example 187B (0.5 g, 0.806 mmol), was
processed using the methods in Examples 165C and 165D to afford the
title compound (400 mg, 45% two steps). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 0.89 (dd, J=11.82, 6.61 Hz, 12H) 1.35-2.22
(m, 14H) 3.36-3.46 (m, 8H) 3.52 (s, 6H) 3.56-3.86 (m, 4H) 3.97-4.43
(m, 4H) 4.85 (s, 4H) 5.09 (s, 2H) 6.25 (d, J=7.26 Hz, 1H) 6.42-6.51
(m, 3H) 6.58 (s, 2H) 6.66 (d, J=7.59 Hz, 1H) 6.81 (d, J=8.78 Hz,
1H) 6.95-7.02 (m, 3H) 7.36 (d, J=8.35 Hz, 2H) 7.51 (dd, J=8.73,
2.33 Hz, 1H) 8.12 (d, J=2.06 Hz, 1H) 9.23 (s, 2H). MS (ESI) m/z
1031 (M+H).sup.+.
##STR00435##
Example 188
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-{3-[6-(mo-
rpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyr-
rolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0802] The product from Example 187C (0.4 g, 0.388 mmol) was
treated with acetic acid (0.089 ml, 1.553 mmol) in toluene (7.77
ml) at 50.degree. C. for 4 hours, cooled and concentrated. The
residue was dissolved in EtOAc, washed with 10% sodium bicarbonate,
brine, dried (Na.sub.2SO.sub.4), filtered and concentrated.
Purification by flash chromatography on an Isco Gold 12 g silica
cartridge eluting with 1-6% MeOH in dichloromethane afforded the
title compound (183 mg, 45%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 0.71-0.90 (m, 12H) 1.62-2.28 (m, 14H) 3.37-3.43 (m, 4H)
3.53 (s, 6H) 3.64-3.68 (m, 4H) 3.80 (s, 4H) 4.05 (t, J=8.35 Hz, 2H)
5.08-5.19 (m, 2H) 5.48 (s, 2H) 6.29 (d, J=8.02 Hz, 1H) 6.54-6.64
(m, 2H) 6.76 (d, J=8.89 Hz, 1H) 6.93 (d, J=4.66 Hz, 1H) 7.11 (d,
J=8.13 Hz, 2H) 7.23-7.30 (m, 3H) 7.34-7.40 (m, 2H) 7.46 (s, 2H)
8.05 (s, 1H) 12.01 (s, 2H). MS (ESI) m/z 995 (M+H).sup.+.
##STR00436##
Example 189
methyl
[(2S,3R)-1-{(2S)-2-[(4-{(2S,5S)-1-(4-tert-butylphenyl)-5-[4-({[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]carbo-
nyl}amino)phenyl]pyrrolidin-2-yl}phenyl)carbamoyl]pyrrolidin-1-yl}-3-metho-
xy-1-oxobutan-2-yl]carbamate
Example 189A
(S)-tert-butyl
2-(4-((2S,5S)-1-(4-tert-butylphenyl)-5-(4-((S)-1-((S)-2-(methoxycarbonyla-
mino)-3-methylbutanoyl)pyrrolidine-2-carboxamido)phenyl)pyrrolidin-2-yl)ph-
enylcarbamoyl)pyrrolidine-1-carboxylate
[0803] To a solution of the product from Example 213 (33 mg, 0.052
mmol) in anhydrous DMSO (0.5 mL) was added
(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (13.3 mg,
0.062 mmol), HATU (23.5 mg, 0.062 mmol) and Hunig's base (18 .mu.L,
0.10 mmol). The resulting mixture was stirred at rt for 90 min and
then partitioned between H.sub.2O and EtOAc. The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo.
The crude product was purified by column chromatography on silica
gel using a solvent gradient of 0-10% MeOH in CH.sub.2Cl.sub.2 to
give the title compound (33 mg, 76%).
Example 189B
methyl
[(2S,3R)-1-{(2S)-2-[(4-{(2S,5S)-1-(4-tert-butylphenyl)-5-[4-({[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]carbo-
nyl}amino)phenyl]pyrrolidin-2-yl}phenyl)carbamoyl]pyrrolidin-1-yl}-3-metho-
xy-1-oxobutan-2-yl]carbamate
[0804] A solution of the product from Example 189A (30 mg, 0.036
mmol) in a 1:1 mixture of CH.sub.2Cl.sub.2:TFA (0.4 mL) was stirred
at rt for 45 min. The mixture was concentrated in vacuo, and the
residue was partitioned between saturated aq. NaHCO.sub.3 and EtOAc
(2.times.). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a
solid. The solid was subjected to the procedure described in
Example 189A (27 mg), substituting
(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid for
(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid, to give
the title compound (17 mg, 52%). 1H NMR (400 MHz, DMSO-D6) .delta.
ppm 0.85-0.97 (m, 6H), 1.08-1.19 (m, 12H), 1.60-1.66 (m, 2H),
1.80-2.05 (m, 8H), 2.08-2.20 (m, 2H), 3.25 (s, 3H), 3.42-3.50 (m,
2H), 3.52 (s, 3H), 3.53 (s, 3H), 3.58-3.72 (m, 2H), 3.76-3.87 (m,
2H), 3.98-4.06 (m, 1H), 4.26 (t, J=7.81 Hz, 1H), 4.38-4.46 (m, 2H),
5.15 (d, J=6.40 Hz, 2H), 6.17 (d, J=8.78 Hz, 2H), 6.94 (d, J=8.89
Hz, 2H), 7.13 (d, J=8.24 Hz, 4H), 7.32 (t, J=8.84 Hz, 2H), 7.49
(dd, J=8.57, 2.06 Hz, 4H), 9.96 (d, J=15.51 Hz, 2H). MS (ESI) m/z
910.6 (M+H).sup.+.
##STR00437##
Example 190
dimethyl
([1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1-diyl-
carbonylhydrazine-2,1-diylcarbonyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate)
[0805] To a solution of the product from Example 171B (50 mg, 0.106
mmol) and the product from Example 37B (72 mg, 0.27 mmol) in
anhydrous DMSO (1 mL) was added HATU (100 mg, 0.27 mmol) and
Hunig's base (56 .mu.L, 0.32 mmol). The resulting mixture was
stirred at rt for 90 min, and then partitioned between H.sub.2O and
EtOAc (2.times.). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel using a
solvent gradient of 0-10% MeOH in CH.sub.2Cl.sub.2 to give the
title compound (68 mg, 65%) as a mixture of cis and trans
stereoisomers. 1H NMR (400 MHz, DMSO-D6) .delta. ppm 0.81-0.98 (m,
12H), 1.08-1.17 (m, 9H), 1.64-1.77 (m, 2H), 1.78-2.06 (m, 8H),
2.07-2.22 (m, 2H), 3.50-3.55 (m, 6H), 3.58-3.69 (m, 2H), 3.70-3.83
(m, 2H), 3.96-4.08 (m, 2H), 4.38-4.49 (m, J=8.13 Hz, 2H), 4.76-4.87
(m, 0.7H), 5.28-5.40 (m, 1.3H), 6.14-6.33 (m, 2H), 6.92-7.08 (m,
2H), 7.27-7.38 (m, J=8.02 Hz, 5H), 7.62 (d, J=8.35 Hz, 1H),
7.79-7.96 (m, 4H), 9.87-9.98 (m, 2H), 10.31-10.44 (m, 2H); MS (ESI)
m/z 981.1 (M+H).sup.+.
##STR00438##
Example 191
methyl
{(2S)-1-[(2S)-2-(5-{4-[(2S,5S)-1-(4-tert-butylphenyl)-5-{2-[(2S)-1--
{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benz-
imidazol-6-yl}pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3--
methyl-1-oxobutan-2-yl}carbamate and
methyl
{(2S)-1-[(2S)-2-(5-{4-[(2R,5R)-1-(4-tert-butylphenyl)-5-{2-[(2S)-1--
{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benz-
imidazol-6-yl}pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3--
methyl-1-oxobutan-2-yl}carbamate
Example 191A
1-(4-bromophenyl)-4-(4-chloro-3-nitrophenyl)butane-1,4-dione
[0806] Zinc chloride (2.73 g, 20 mmole) was treated with anhydrous
benzene (10 mL) followed by diethylamine (1.55 mL, 15 mmole) and
tert-butanol (1.4 mL, 15 mmole) and the resulting slurry was
stirred at room temperature for 1.75 hr until all solids had
dissolved. To the cloudy suspension was added
4'-chloro-3'-nitroacetophenone followed by 2,4'-dibromoacetophenone
and the resulting light yellow slurry was stirred at room
temperature for 68 hours. The resulting thick white slurry was
treated with 25 mL 5% aqueous sulfuric acid with stirring and the
resulting slurry was filtered. The solid was washed with water (50
mL), MeOH (50 mL) and CH.sub.2Cl.sub.2 (50 mL), then dried in vacuo
at room temperature for 1 hr and at 55.degree. C. for 5 hr. giving
the title compound as a white solid, 3.4 g, 86%.
Example 191B
1-(4-bromophenyl)-4-(4-chloro-3-nitrophenyl)butane-1,4-diol
[0807] The product from Example 191A (4.62 g, 11.65 mmole) was
mixed with EtOH (100 mL) and the resulting slurry was treated in
portions over a five minute period with solid NaBH.sub.4 (0.97 g,
25.6 mmole). The resulting foaming slurry was stirred and heated at
reflux for 1 hr. The reaction was deemed complete by LC-MS. The
reaction mixture was cooled to room temperature and concentrated in
vacuo to an oily residue. The residue was dissolved in
CH.sub.2Cl.sub.2 and applied to an 80 g silica gel column. The
column was eluted with a gradient of hexane/acetone, 90/10 to 20/80
over 32 minutes. The fractions containing product were pooled and
concentrated in vacuo giving the title compound as a white solid,
3.14 g, 67%.
Example 191C
1-(4-bromophenyl)-4-(4-chloro-3-nitrophenyl)butane-1,4-diyl
dimethanesulfonate
[0808] The product from Example 191B (3.14 g, 7.84 mmole) was
dissolved in 70 mL CH.sub.2Cl.sub.2 and cooled in an ice-acetone
bath to -10.degree. C. Triethylamine (3.82 mL, 27.4 mmole) was
added dropwise to the cold solution, followed by dropwise addition
of methanesulfonyl chloride (1.53 mL, 19.59 mmole) in 20 mL
CH.sub.2Cl.sub.2 over 10 minutes. The resulting clear solution was
stirred in the cold for 90 min. The reaction was deemed complete by
LC-MS analysis and the solvent was removed in vacuo leaving a light
yellow solid as the title compound, (4.36 g, 100%), that was used
directly in the next reaction.
Example 191D
2-(4-bromophenyl)-1-(4-tert-butylphenyl)-5-(4-chloro-3-nitrophenyl)pyrroli-
dine
[0809] The light yellow solid, obtained in Example 191C (4.36 g,
7.84 mmole) was treated with DMF (15 mL) followed by dropwise
addition of 4-tert-butylaniline (12.47 mL, 78 mmole), then placed
in an oil bath at 52.degree. C. and stirred for a total of 12 hr.
The reaction mixture was concentrated in vacuo to an oily residue.
The mixture was diluted with 100 mL EtOAc and washed with 50 mL 0.5
M HCl. The aqueous layer was back extracted with 100 mL EtOAc. The
combined organic extracts were washed with 10% NaHCO.sub.3, 10%
NaCl, dried over anhydrous Na.sub.2SO.sub.4(s), filtered and
solvent removed in vacuo leaving a reddish oil. The oil was
dissolved in CH.sub.2Cl.sub.2 (10 mL) and applied to an 80 g silica
gel column. The column was eluted with a gradient of
hexane/Acetone, 90/10 to 30/70 over 32 minutes. The title compound
was isolated as a 1:1 mixture of cis and trans-pyrrolidine isomers,
3.13 g, 75%.
Example 191E
4-(5-(4-bromophenyl)-1-(4-tert-butylphenyl)pyrrolidin-2-yl)-N-(2,4-dimetho-
xybenzyl)-2-nitroaniline
[0810] The product from Example 191D (1.1 g, 2.14 mmole) was
treated with 2,4-dimethoxybenzylamine (3.22 mL, 21.41 mmole) and
the resulting slurry was heated at 140.degree. C. (oil bath) for 1
hr. The resulting homogeneous red reaction mixture was concentrated
in vacuo leaving a red oil. The oil was diluted with 30 mL
CH.sub.2Cl.sub.2, filtered solid and applied the filtrate to a 120
g silica gel column. The column was eluted with CH2Cl2 over a 25
min period. The fractions were pooled and concentrated in vacuo
giving the title compound as an orange foamy solid as a mixture of
stereoisomers (1.18 g).
Example 191F
4-(5-(4-bromophenyl)-1-(4-tert-butylphenyl)pyrrolidin-2-yl)-N1-(2,4-dimeth-
oxybenzyl)benzene-1,2-diamine
[0811] The product from example 191E (1.18 g, 1.831 mmole) was
dissolved in a mixture of THF(10 mL):EtOH(10 mL):EtOAc (10 mL),
treated with PtO.sub.2 (42 mg) and evacuated 10 minutes, followed
by introduction of H.sub.2 (g) via balloon. The reaction mixture
was stirred overnight at room temperature. The next day, the
reaction mixture was filtered and the solvent removed in vacuo
leaving a dark green foamy solid. The solid was dissolved in 10 mL
CH.sub.2Cl.sub.2 applied to a 40 g silica gel column and eluted
with a gradient of hexane/EtOAc; 90/10 to 30/70 over 20 minutes.
The title compound was isolated as a white foamy solid as a mixture
of isomers 0.54 g, 48%.
Example 191G
methyl
(2S)-1-((2S)-2-(5-(5-(4-bromophenyl)-1-(4-tert-butylphenyl)pyrrolid-
in-2-yl)-2-(2,4-dimethoxybenzylamino)phenylcarbamoyl)pyrrolidin-1-yl)-3-me-
thyl-1-oxobutan-2-ylcarbamate
[0812]
(S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2--
carboxylic acid (0.339 g, 1.245 mmole) and HOBt (0.191 g, 1.245
mmole) were dissolved in DMF (4 mL) cooled in an ice bath and
treated with EDAC (0.245 g, 1.245 mmole) and N-Methylmorpholine
(NMM) (0.55 mL, 4.98 mmole). The resulting solution was stirred 5
minutes in the ice bath, treated dropwise with the product from
Example 191F in DMF (4 mL) and the resulting dark mixture was
stirred in the ice bath for 1 hr then at room temperature for 18
hr. The next day, the reaction mixture was diluted with EtOAc (50
mL) and the organic layer was washed with 10% NaHCO.sub.3 and 10%
NaCl, dried over anhydrous Na.sub.2SO.sub.4(s), filtered and the
solvent was removed in vacuo leaving an oily residue as the title
compound as a mixture of isomers (0.65 g). ESI+(m/z): 868.2.
Example 191H
methyl
(2S)-1-((2S)-2-(2-amino-5-(5-(4-bromophenyl)-1-(4-tert-butylphenyl)-
pyrrolidin-2-yl)phenylcarbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylc-
arbamate
[0813] The product from example 191G (0.65 g, 0.748 mmole) was
dissolved in CH.sub.2Cl.sub.2 (10 mL) then added concentrated
trifluoroacetic acid (2 mL, 26 mmole)) and the reaction mixture was
stirred 10 minutes. The solvent was removed in vacuo and the
residue was re-evaporated twice from CH.sub.2C.sub.2 and once from
toluene. The residue was dissolved in EtOAc (100 mL) washed with
10% NaHCO.sub.3, dried over anhydrous Na.sub.2SO.sub.4(s), filtered
and solvent removed in vacuo leaving a brown foamy material as the
title compound as a mixture of isomers (0.5 g).
[0814] Example 1911 methyl
(2S)-1-((2S)-2-(6-(5-(4-bromophenyl)-1-(4-tert-butylphenyl)pyrrolidin-2-y-
l)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarba-
mate
[0815] The product from Example 191H (0.5 g, 0.696 mmole) was
treated with acetic acid (5 mL, 87 mmole) and heated in an oil bath
at 75.degree. C. for 70 min. The reaction mixture was cooled to
room temperature and concentrated in vacuo leaving an oily residue.
The residue was dissolved in EtOAc (100 mL) washed with 10%
NaHCO.sub.3 (20 mL) and 10% NaCl (20 mL), dried over anhydrous
Na.sub.2SO.sub.4(s), filtered and solvent removed in vacuo leaving
a brown foamy solid. The residue was dissolved in 10 mL
CH.sub.2Cl.sub.2 and applied to a 12 g silica gel column. The
column was eluted with a gradient of CH2Cl2/MeOH, 99/1 to 95/5 over
15 minutes and the product was isolated as a tan solid as a mixture
of isomers (0.31 g). ESI (m/z)+: 702.3.
Example 191J
methyl
(2S)-1-((2S)-2-(6-(1-(4-tert-butylphenyl)-5-(4-(4,4,5,5-tetramethyl-
-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-2-yl)-
pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate
[0816] The product from Example 1911 (0.31 g, 0.442 mmole),
bis(pinacolato)diboron (0.34 g, 1.327 mmole) and potassium acetate
(0.17 g, 1.77 mmole) were combined and dissolved in toluene (5 mL),
added 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II)
dichloromethane complex (32 mg, 0.044 mmole) and the reaction
mixture was bubbled with N.sub.2 for 5 minutes, sealed and placed
in an oil bath at 95.degree. C. for 2 hr. The mixture was cooled to
room temperature and diluted with EtOAc (100 mL) washed with water
(20 mL) and 10% NaCl (20 mL), dried over anhydrous
Na.sub.2SO.sub.4(s), filtered and solvent removed in vacuo leaving
a brown oil. The oil was dissolved in CH.sub.2Cl.sub.2 (10 mL),
applied to a 12 g silica gel column and the column was eluted with
a gradient of hexane:EtOAc, 50:50 to 0:100 over 18 minutes. The
title compound was isolated as a white solid as a mixture of
isomers (0.23 g).
Example 191K
(2S)-tert-butyl
2-(5-(4-(1-(4-tert-butylphenyl)-5-(2-((S)-1-((S)-2-(methoxycarbonylamino)-
-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)pyrrolidin-2-y-
l)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate
[0817] The product from example 191J (0.23 g, 0.308 mmole) and the
product from Example 26D (0.195 g, 0.615 mmole) were combined in a
20 mL microwave tube and dissolved in toluene (1.5 mL)/ethanol(1.5
mL). To this solution was added 1M aqueous sodium carbonate 0.92
mL, 0.92 mmole) followed by
1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II)
dichloromethane complex (23 mg, 0.036 mmole) and the resulting
mixture was bubbled with N.sub.2 for 10 minutes, sealed and heated
at 100.degree. C. for 2 hr. The reaction mixture was cooled to room
temperature and diluted with EtOAc (50 mL). The aqueous carbonate
layer was separated and the organic layer was washed with water (20
mL) and 10% NaCl (20 mL), dried over anhydrous Na.sub.2SO.sub.4(s),
filtered and solvent removed in vacuo leaving a foamy solid. The
solid was dissolved in 10 mL CH.sub.2Cl.sub.2 and applied to a 12 g
silica gel column. The column was eluted with a gradient of
CH2Cl2/MeOH, 99/1 to 95/5 over 20 minutes. The title compound was
obtained as a tan solid as a mixture of isomers (0.11 g).
Example 191L
(2S)-2-(5-(4-(1-(4-tert-butylphenyl)-5-(2-((S)-1-((S)-2-(methoxycarbonylam-
ino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)pyrrolidin-
-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidinium chloride
[0818] The product from example 191K (0.11 g, 0.28 mmole) was
dissolved in dioxane (2 mL), then added 4N HCl/dioxane (1 mL). The
resulting solid mass is stirred 30 minutes at room temperature. The
solvent is removed in vacuo leaving a tan solid as the title
compound as a mixture of isomers (0.092 g) which stored under
vacuum overnight.
Example 191M
methyl
{(2S)-1-[(2S)-2-(5-{4-[(2S,5S)-1-(4-tert-butylphenyl)-5-{2-[(2S)-1--
{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benz-
imidazol-6-yl}pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3--
methyl-1-oxobutan-2-yl}carbamate and
methyl
{(2S)-1-[(2S)-2-(5-{4-[(2R,5R)-1-(4-tert-butylphenyl)-5-{2-[(2S)-1--
{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benz-
imidazol-6-yl}pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3--
methyl-1-oxobutan-2-yl}carbamate
[0819] The product from example 191L (0.092 g, 0.116 mmole),
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.020 g, 0.116
mmole) and HOBt (000.018 g, 0.116 mmole) were combined in a 25 mL
RB flask and dissolved in DMF (1 mL). The reaction mixture was
placed in an ice bath and treated with EDAC (0.022 g, 0.116 mmole)
and N-methylmorpholine (0.12 mL, 1.091 mmole. The light yellow
reaction mixture was stirred in the ice bath for 1 hr, then stirred
at room temperature for 9 hr. The reaction mixture was diluted with
EtOAc (100 mL) washed with water (20 mL) and 10% NaCl (20 mL),
dried over anhydrous Na.sub.2SO.sub.4(s), filtered and solvent
removed in vacuo leaving an oily residue. The residue was dissolved
in 5 mL CH2Cl2 and applied to a 12 g silica gel column. The column
was eluted with a gradient of CH.sub.2Cl.sub.2/MeOH, 99/1 to 95/5
over 22 minutes. The title compound was isolated from the first
fraction eluted from the column as a white solid consisting of a
mixture of trans-pyrrolidine isomers, 21 mg, 19%. .sup.1H NMR (400
MHz, DMSO-d6) .delta. ppm 0.71-0.95 (m, 12H) 1.11 (s, 9H) 1.99 (m,
6H) 2.13 (m, 4H) 3.53 (s, 6H) 3.81 (m, 4H) 4.04 (m, 4H) 5.06 (m,
2H) 5.11-5.15 (m, 1H) 5.18-5.26 (m, 1H) 5.32 (m, 1H) 6.25 (m, 2H)
6.86-6.96 (m, 1H) 7.05 (m, 2H) 7.33 (m, 6H) 7.61 (m, 2H) 11.53 (s,
1H) 11.68 (s, 1H) 12.00 (m, 2H); ESI+: 914.5.
##STR00439##
Example 192
methyl
{(2S)-1-[(2S)-2-(5-{4-[(2R,5S)-1-(4-tert-butylphenyl)-5-{2-[(2S)-1--
{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benz-
imidazol-6-yl}pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3--
methyl-1-oxobutan-2-yl}carbamate and
methyl
{(2S)-1-[(2S)-2-(5-{4-[(2S,5R)-1-(4-tert-butylphenyl)-5-{2-[(2S)-1--
{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benz-
imidazol-6-yl}pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3--
methyl-1-oxobutan-2-yl}carbamate
[0820] The title compound was isolated from the late fraction
eluted from the column described in Example 191M as a white solid
as a mixture of cis pyrrolidine isomers, 18 mg, 17%. .sup.1H NMR
(free base) (400 MHz, DMSO-d.sub.6) .delta. ppm 0.71-0.95 (m, 12H)
1.11 (s, 9H) 1.99 (m, 6H) 2.13 (m, 4H) 3.53 (s, 6H) 3.81 (m, 4H)
4.04 (m, 4H) 4.72 (m, 1H), 4.83 (m, 1H) 5.11-5.15 (m, 1H) 5.18-5.26
(m, 1H) 5.32 (m, 1H) 6.25 (m, 2H) 6.86-6.96 (m, 1H) 7.05 (m, 2H)
7.33 (m, 6H) 7.61 (m, 2H) 11.53 (s, 1H) 11.68 (s, 1H) 12.00 (m,
2H); ESI+: 914.5.
##STR00440##
Example 193
dimethyl
([(2S,5S)-1-{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidine-
-2,5-diyl]bis{benzene-4,1-diylimino[(2S)-3-methyl-1-oxobutane-1,2-diyl]})b-
iscarbamate and
dimethyl
([(2R,5R)-1-{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidine-
-2,5-diyl]bis{benzene-4,1-diylimino[(2S)-3-methyl-1-oxobutane-1,2-diyl]})b-
iscarbamate
[0821] Example 86A and
4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine
were processed using sequentially the methods of Examples 99A, 99B,
and 1F (substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoic
acid (38.2 mg, 0.218 mmole) for
(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid). Reverse
phase (C.sub.18) HPLC provided the title compound, a white solid,
as a 1:1 mixture of trans diastereomers (40.4 mg, 50.6% yield). 1H
NMR (free base) (400 MHz, DMSO-D6) .delta. ppm 0.89 (d, J=6.72 Hz,
12H) 1.67 (d, J=5.64 Hz, 2H) 1.92-2.04 (m, 2H) 3.37-3.41 (m, 4H)
3.53 (d, J=2.06 Hz, 6H) 3.67 (d, J=5.10 Hz, 4H) 3.94 (t, J=8.08 Hz,
2H) 5.25 (s, 2H) 6.33 (d, J=8.67 Hz, 2H) 6.78 (d, J=8.89 Hz, 1H)
7.14-7.23 (m, 6H) 7.32 (d, J=8.67 Hz, 2H) 7.54 (d, J=7.92 Hz, 4H)
7.66 (dd, J=8.84, 2.55 Hz, 1H) 8.26 (d, J=2.49 Hz, 1H) 10.01 (s,
2H). MS ESI(+) m/z @ 806.5 (M+H)+.
##STR00441##
Example 194
dimethyl
({(2S,5S)-1-[4-(1-hydroxy-2-methylpropan-2-yl)phenyl]pyrrolidine--
2,5-diyl}bis{benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate)
Example 194A
ethyl 2-methyl-2-(4-nitrophenyl)propanoate
[0822] Into a 500 mL Morton flask equipped for mechanical stirring
was added at room temperature under nitrogen ethyl
2-(4-nitrophenyl)acetate (10.0 g, 55.2 mmole), anhydrous
dimethylformamide (200 mL) 18-crown-6 (2.189 g, 8.28 mmole) and
methyl iodide (23.13 mL, 370 mmole). The flask was cooled in an ice
bath and sodium hydride as a 60% mineral oil dispersion (7.73 g,
193 mmole) was added in portions so as to maintain the internal
temperature at or below +10.degree. C. The addition required fifty
three minutes. On completion of the addition the reaction mixture
was allowed to slowly warm to room temperature and stirred
overnight. Subsequent cooling in an ice bath was followed by the
drop wise addition of water (200 mL) with vigorous stirring. The
mixture was partitioned between water (1200 mL) and ethyl ether
(200 mL). The aqueous phase was extracted with ethyl ether
(3.times.200 mL each) and the combined organics water washed
(3.times.150 mL), dried over MgSO.sub.4, filtered and concentrated
to provide the title compound in nearly quantitative yield
sufficiently pure for use as isolated.
Example 194B
2-methyl-2-(4-nitrophenyl)propan-1-ol
[0823] To a solution of the product from Example 194A (12.32 g,
55.2 mmole) in anhydrous THF (300 mL) at room temperature under
nitrogen was added dropwise via cannulae 1M BH.sub.3 in THF (200
mL) over ten and one half minutes. On completion of the addition
the flask was equipped with a condenser and the mixture heated
under nitrogen to reflux in an oil bath for ten hours before
cooling to room temperature. The reaction was quenched by the
cautious drop wise addition of methanol (60 mL). The resulting
mixture was concentrated to an oil which was then dissolved in
ethyl acetate (150 mL) and treated with IN HCl and allowed to stir
at room temperature for one hour. The resulting organic phase was
washed with brine (4.times.50 mL), dried over MgSO.sub.4, filtered
and concentrated. The residue was taken up in toluene (25 mL) and
re-concentrated. The oily solid was suspended in hexane (50 mL) and
collected by vacuum filtration. The cake was washed with hexane (50
mL) then dried under vacuum to provide the title compound (9.55 g,
89% yield) as a light orange solid. MS (DCI+) m/z @ 213.1
(M+NH.sub.4)+.
Example 194C
2-(4-aminophenyl)-2-methylpropan-1-ol
[0824] The product from Example 194B (0.321 g, 1.644 mmole) was
dissolved in a mixture of THF (10 mL) and ethanol (2 mL). To this
was added platinum(IV)oxide (0.030 g, 0.131 mmole). The flask was
capped with a septum and the contents vacuum degassed three times.
Hydrogen was introduced via a balloon and the mixture stirred at
room temperature. An additional 38.2 mg (0.167 mmole) of catalyst
was added in two aliquots before chromatographic analysis indicated
that the starting material was consumed. After stirring overnight
under hydrogen the mixture was filtered through a sand/celite plug
followed by an ethyl acetate rinse. The filtrate was concentrated
to dryness and the residue purified by chromatography on amine
modified silica gel eluting with ethyl acetate-hexane beginning at
8% and advancing to 66% ethyl acetate to provide the title compound
(0.3645 g, 68% yield) as a clear oil. MS (DCI+) m/z @ 183.1
(M+NH.sub.4)+.
Example 194D
2-(4-((2S,5S)-2,5-bis(4-nitrophenyl)pyrrolidin-1-yl)phenyl)-2-methylpropan-
-1-ol
[0825] The product from Example 194C (0.595 g, 3.60 mmole) was
combined in DMF (3 mL) with
(1R,4R)-1,4-bis(4-nitrophenyl)butane-1,4-diyl dimethanesulfonate
(0.259 g, 0.530 mmole), prepared as described in Example 37C, then
heated overnight under nitrogen in an oil bath at 50.degree. C. The
reaction mixture was partitioned between ethyl acetate (50 mL) and
water (50 mL). The organic phase was water washed (3.times.25 mL),
dried over MgSO.sub.4, filtered and concentrated to an oil.
Chromatography on silica gel eluting with ethyl acetate-hexane
provided the title compound (0.0835 g, 34.1% yield) as an orange
semi-solid.
Example 194E
2-(4-((2S,5S)-2,5-bis(4-aminophenyl)pyrrolidin-1-yl)phenyl)-2-methylpropan-
-1-ol
[0826] The product from Example 194D (83.5 mg, 0.181 mmole) was
reacted as described in Example 99B to provide the title compound
in quantitative yield as a light yellow solid. MS (DCI+) m/z @
402.3 (M+H)+.
Example 194F
dimethyl
({(2S,5S)-1-[4-(1-hydroxy-2-methylpropan-2-yl)phenyl]pyrrolidine--
2,5-diyl}bis{benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-meth-
yl-1-oxobutane-1,2-diyl]})biscarbamate)
[0827] The product from Example 194E (73.0 mg, 0.181 mmole) was
reacted with the product from Example 37B (104.0 mg, 0.380 mmole)
as described in Example 37F. The title compound was isolated after
purification by reverse phase (C18) HPLC as an off white solid
(97.4 mg, 59% yield). 1H NMR (free base) (400 MHz, DMSO-D6) .delta.
ppm 0.79-0.96 (m, 12H) 1.03 (s, 6H) 1.61 (s, 2H) 1.76-2.04 (m, 8H)
2.04-2.17 (m, 2H) 3.20 (dd, J=5.42, 1.84 Hz, 2H) 3.51 (s, 6H) 3.60
(dd, 2H) 3.78 (s, 2H) 4.01 (t, J=8.46 Hz, 2H) 4.35-4.49 (m, 3H)
5.14 (s, 2H) 6.16 (d, J=8.78 Hz, 2H) 6.89 (d, J=8.78 Hz, 2H) 7.12
(d, J=8.57 Hz, 4H) 7.29 (d, J=8.35 Hz, 2H) 7.48 (d, J=8.46 Hz, 4H)
9.97 (s, 2H). MS ESI(+), m/z @ 910.7 (M+H)+.
##STR00442##
Example 195
methyl
[(1S,2R)-2-methoxy-1-({(2S)-2-[4-(4-{5-[4-(2-{(2S)-1-[N-(methoxycar-
bonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-imidazol-4-yl)phenyl]-1-(6--
piperidin-1-ylpyridin-3-yl)-1H-pyrrol-2-yl}phenyl)-1H-imidazol-2-yl]pyrrol-
idin-1-yl}carbonyl)propyl]carbamate
[0828] The title compound was prepared using the methods from
Example 144E substituting
(2S,3S)-3-methoxy-2-(methoxycarbonylamino)butanoic acid for
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid to provide the
title compound (280 mg, 37% yield). .sup.1H NMR (400 MHz, DMSO-D6)
.delta. 12.12-11.70 (m, 2H), 7.85-7.76 (m, 1H), 7.63-7.49 (m, 4H),
7.49-7.39 (m, 2H), 7.34-7.03 (m, 7H), 6.77-6.69 (m, 1H), 6.54-6.41
(m, 2H), 5.08-4.99 (m, 2H), 4.27 (t, J=7.6, 2H), 3.86-3.75 (m, 4H),
3.54 (s, 6H), 3.50-3.43 (m, 4H), 3.17 (s, 6H), 2.19-1.88 (m, 10H),
1.61-1.44 (m, 6H), 1.12-0.99 (m, 6H). MS (ESI; M+H) m/z=997.
##STR00443##
Example 196
N-(methoxycarbonyl)-L-valyl-N-{4-[(2S,5S)-5-(4-{[N-(methoxycarbonyl)-L-val-
yl]amino}phenyl)-1-{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2--
yl]phenyl}-L-prolinamide and
N-(methoxycarbonyl)-L-valyl-N-{4-[(2R,5R)-5-(4-{[N-(methoxycarbonyl)-L-val-
yl]amino}phenyl)-1-{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2--
yl]phenyl}-L-prolinamide
##STR00444##
[0829] Example 196A
methyl
(2S)-1-(4-(5-(4-aminophenyl)-1-(4-(6-morpholinopyridin-3-yl)phenyl)-
pyrrolidin-2-yl)phenylamino)-3-methyl-1-oxobutan-2-ylcarbamate
[0830] In an oven-dried 5-mL round bottom flask purged with
nitrogen, dissolved
4,4'-(1-(4-(6-morpholinopyridin-3-yl)phenyl)pyrrolidine-2,5-diy-
l)dianiline (30 mg, 0.061 mmol; prepared from Example 86A and
4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine
using the methods of Examples 99A and 99B), and
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (11.22 mg, 0.064
mmol) in anhydrous DMSO (1 mL), added HATU (26.3 mg, 0.067 mmol)
and diisopropylethylamine (0.021 mL, 0.122 mmol), and stirred
yellow solution at 25.degree. C. for 30 min. Diluted the reaction
with MeOH (1 mL) and purified by RP-C.sub.18 HPLC (Waters Prep LC,
40 mm Module with Nova Pak HR C.sub.18 6 .mu.m 40.times.100 mm Prep
Pak cartridge) eluting with a 30 min gradient of 95:5 0.1% TFA in
H.sub.2O/AcCN to 25:75 0.1% TFA in H.sub.2O/AcCN, then 10 min to
100% AcCN at 20 mL/min. Pure fractions were concentrated by rotary
evaporation (water bath 35.degree.) to a small volume, partitioned
between 20% iPrOH/CHCl.sub.3 (50 mL) and sat'd aq NaHCO.sub.3 (15
mL), separated layers, dried the organic extract over anhydrous
MgSO.sub.4, filtered, and concentrated by rotary evaporation to
afford the title compound as an off-white solid (14.6 mg, 37%) as a
mixture of stereoisomers. MS (ESI+) m/z 649 (M+H).sup.+, 707
(M+AcCN+NH.sub.4), 1297 (2M+H).sup.+.
Example 196B
N-(methoxycarbonyl)-L-valyl-N-{4-[(2S,5S)-5-(4-{[N-(methoxycarbonyl)-L-val-
yl]amino}phenyl)-1-{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2--
yl]phenyl}-L-prolinamide and
N-(methoxycarbonyl)-L-valyl-N-{4-[(2R,5R)-5-(4-{[N-(methoxycarbonyl)-L-val-
yl]amino}phenyl)-1-{4-[6-(morpholin-4-yl)pyridin-3-yl]phenyl}pyrrolidin-2--
yl]phenyl}-L-prolinamide
[0831] In a nitrogen-purged 5-mL round bottom flask, dissolved the
product of Example 196A (14 mg, 0.022 mmol) in anhydrous DMSO (1
mL), added the product of Example 37B (6.46 mg, 0.024 mmol), HATU
(9.30 mg, 0.024 mmol), and diisopropylethylamine (7.54 .mu.L, 0.043
mmol). Stirred at 25.degree. C. for 1 hr, diluted the reaction with
MeOH (1 mL) and purified by RP-C.sub.18 HPLC (Waters Prep LC, 40 mm
Module with Nova Pak HR C.sub.18 6 .mu.m 40.times.100 mm Prep Pak
cartridge) eluting with a 30 min gradient of 95:5 0.1% TFA in
H.sub.2O/AcCN to 25:75 0.1% TFA in H.sub.2O/AcCN, then 10 min to
100% AcCN at 20 mL/min. Pure fractions were concentrated by rotary
evaporation (water bath 35.degree. C.) to near-dryness, the residue
taken up in 1:5 v/v CH.sub.2Cl.sub.2/hexanes and evaporated (3
times), and the residue dried in vacuo to give a yellow solid (11
mg). The TFA salt was dissolved in 20% iPrOH/CHCl.sub.3 (30 mL),
washed thoroughly with sat'd aq NaHCO.sub.3 (5 mL), extracted the
aqueous phase with 20% iPrOH/CHCl.sub.3 (20 mL), dried the combined
organic extracts over anhydrous MgSO4, filtered, and concentrated
by rotary evaporation to afford the title compounds as a white
solid (7 mg, 35%). .sup.1H NMR (400 MHz, DMSO-D6) .delta. ppm
0.83-0.96 (m, 12H), 1.60-1.71 (m, 2H), 1.81-2.21 (m, 7H), 3.36-3.43
(m, 4H), 3.49-3.56 (m, 6H), 3.58-3.65 (m, 1H), 3.65-3.70 (m, 4H),
3.75-3.85 (m, 1H), 3.94 (t, J=8.08 Hz, 1H), 4.02 (t, J=8.19 Hz,
1H), 4.42 (dd, J=7.86, 4.93 Hz, 1H), 5.24 (d, J=5.31 Hz, 2H), 6.32
(d, J=8.35 Hz, 2H), 6.78 (d, J=9.00 Hz, 1H), 7.13-7.19 (m, 4H),
7.21 (d, J=8.78 Hz, 2H), 7.26-7.35 (m, 2H), 7.48-7.56 (m, 4H), 7.66
(dd, J=7.86, 1.14 Hz, 1H), 8.25 (d, J=2.17 Hz, 1H), 10.00 (d,
J=3.47 Hz, 2H); MS (ESI+) m/z 903 (M+H).sup.+.
##STR00445##
Example 197
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2S,5S)-1-(4-tert-butylphenyl)-5-(4-{2-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}pyrrolidin-2-yl]--
1H-imidazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidi-
n-1-yl]-3,3-dimethyl-1-oxobutan-2-yl}carbamate and
methyl
{(2S)-1-[(2S)-2-(4-{4-[(2R,5R)-1-(4-tert-butylphenyl)-5-(4-{2-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}pyrrolidin-2-yl]--
1H-imidazol-4-yl}phenyl)pyrrolidin-2-yl]phenyl}-1H-imidazol-2-yl)pyrrolidi-
n-1-yl]-3,3-dimethyl-1-oxobutan-2-yl}carbamate
[0832] The product from Example 42F (0.228 g, 0.364 mmol) was
processed as in Example 1H to give 0.035 g (10%) of the title
compound as a solid as a mixture of trans isomers. 1H NMR (free
base) (400 MHz, DMSO-D6) .delta. ppm 0.91 (d, J=7.59 Hz, 18H) 1.08
(s, 9H) 1.63-1.73 (m, 2H) 1.83-2.24 (m, 12H) 3.54 (s, 6H) 3.70-3.80
(m, 2H) 4.21 (d, J=7.92 Hz, 2H) 5.06 (dd, J=6.99, 3.52 Hz, 2H)
5.15-5.25 (m, 2H) 6.21 (d, J=8.67 Hz, 2H) 6.92 (dd, J=8.73, 2.44
Hz, 2H) 7.05 (d, J=8.78 Hz, 2H) 7.14 (dd, J=8.24, 3.47 Hz, 4H) 7.37
(s, 2H) 7.61 (d, J=8.02 Hz, 4H) 11.69 (s, 2H); MS ESI+ m/z 968.8
(M+H)+.
##STR00446##
Example 198
methyl
[(2S)-1-{(2S)-2-[(4-{(2R,5R)-5-{4-[({1-[(2S)-2-[(methoxycarbonyl)am-
ino]-4-(methylsulfanyl)butanoyl]pyrrolidin-2-yl}carbonyl)amino]phenyl}-1-[-
4-(trifluoromethyl)phenyl]pyrrolidin-2-yl}phenyl)carbamoyl]pyrrolidin-1-yl-
}-4-(methylsulfanyl)-1-oxobutan-2-yl]carbamate
Example 198A
(S)-2-(methoxycarbonylamino)-4-(methylthio)butanoic acid
[0833] To a solution of (S)-2-amino-4-(methylthio)butanoic acid
(1.0 g, 6.7 mmol) in dioxane at 0.degree. C. was added NaOH (11.06
g, 22.12 mmol) followed by dropwise addition of methyl
chloroformate (1.04 mL, 13.4 mmol) and the solution was warmed to
room temperature with stirring over 2 h. The solution was diluted
with EtOAc, washed with 1 N HCl, brine, dried (Na.sub.2SO.sub.4),
filtered and solvent removed in vacuo to give the title compound
(1.3 g, 6.27 mmol, 94%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 1.95-2.07 (m, 1H) 2.07-2.13 (m, 3H) 2.14-2.28 (m, 1H) 2.59 (t,
J=7.4 Hz, 2H) 3.71 (s, 3H) 4.52 (br s, 1H) 5.33 (br s, 1H).
Example 198B
(2S,2'S)--N,N'-(4,4'-((2R,5R)-1-(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-
-diyl)bis(4,1-phenylene)dipyrrolidine-2-carboxamide
[0834] Example 38A and 4-trifluoromethylaniline were processed
using the methods of Examples 34A, 34B, 34C, and 34D to provide the
title compound.
Example 198C
methyl
[(2S)-1-{(2S)-2-[(4-{(2R,5R)-5-{4-[({1-[(2S)-2-[(methoxycarbonyl)am-
ino]-4-(methylsulfanyl)butanoyl]pyrrolidin-2-yl}carbonyl)amino]phenyl}-1-[-
4-(trifluoromethyl)phenyl]pyrrolidin-2-yl}phenyl)carbamoyl]pyrrolidin-1-yl-
}-4-(methylsulfanyl)-1-oxobutan-2-yl]carbamate
[0835] Example 198B and Example 198A were processed using the
method of Example 1H to provide the title compound which was
purified by flash chromatography on silica gel eluting with 10-80%
EtOAc/CH.sub.2Cl.sub.2 (29 mg). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 1.78 (d, J=6.1 Hz, 2H) 1.83-2.00 (m, 6H) 2.02 (s, 6H)
2.04-2.26 (m, 4H) 2.43-2.61 (m, 8H) 3.47-3.83 (m, 4H) 3.69 (s, 6H)
4.75 (dd, J=8.0, 2.0 Hz, 4H) 5.15 (d, J=6.7 Hz, 2H) 5.43 (d, 2H)
6.32 (d, J=8.7 Hz, 2H) 7.09 (d, J=8.5 Hz, 4H) 7.18 (d, J=8.8 Hz,
2H) 7.42 (d, J=8.6 Hz, 4H) 9.05 (s, 2H). MS (ESI) m/z 971
(M+H).sup.+.
##STR00447##
Example 199
methyl
[(2S,3S)-1-{(2S)-2-[(4-{(2R,5R)-5-(4-{[(1-{(2S,3S)-2-[(methoxycarbo-
nyl)amino]-3-methylpentanoyl}pyrrolidin-2-yl)carbonyl]amino}phenyl)-1-[4-(-
trifluoromethyl)phenyl]pyrrolidin-2-yl}phenyl)carbamoyl]pyrrolidin-1-yl}-3-
-methyl-1-oxopentan-2-yl]carbamate
Example 199A
(2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid
[0836] To a solution of (2S,3S)-2-amino-3-methylpentanoic acid (1.0
g, 7.62 mmol) in dioxane (10 mL) at 0.degree. C. was added NaOH
(12.58 g, 25.2 mmol) followed by dropwise addition of methyl
chloroformate (1.18 mL, 15.25 mmol). The solution was warmed to
room temperature with stirring over 2 h, diluted with EtOAc, washed
with 1 N HCl, brine, dried (Na.sub.2SO.sub.4), filtered and solvent
removed in vacuo to give the title compound (1.4 g, 7.4 mmol, 97%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.27-1.39 (m, 1H)
1.38-1.53 (m, 2H) 1.58-1.72 (m, 3H) 1.82-1.94 (m, 2H) 2.04 (d,
J=3.8 Hz, 2H) 3.70 (s, 3H) 4.94 (br s, 1H).
Example 199B
methyl
[(2S,3S)-1-{(2S)-2-[(4-{(2R,5R)-5-(4-{[(1-{(2S,3S)-2-[(methoxycarbo-
nyl)amino]-3-methylpentanoyl}pyrrolidin-2-yl)carbonyl]amino}phenyl)-1-[4-(-
trifluoromethyl)phenyl]pyrrolidin-2-yl}phenyl)carbamoyl]pyrrolidin-1-yl}-3-
-methyl-1-oxopentan-2-yl]carbamate
[0837] To a solution of Example 198B (60 mg, 0.101 mmol) in DMSO
(0.5 mL) was added Example 199A (48 mg, 0.254 mmol), followed by
HATU (96 mg, 0.254 mmol) and N,N-diisopropylethylamine (0.089 mL,
0.507 mmol) and the solution was stirred at room temperature for 1
h. Diluted with EtOAc, washed with H.sub.2O, brine, dried
(Na.sub.2SO.sub.4), filtered and removed solvent in vacuo to give
crude product which was purified by flash chromatography on silica
gel eluting with 10-80% EtOAc/CH.sub.2Cl.sub.2 to give the title
compound (11 mg, 0.012 mmol, 12%). .sup.1H NMR (400 Hz, CDCl.sub.3)
.delta. ppm 0.78-1.00 (m, 12H) 1.69-1.81 (m, 4H) 1.81-1.94 (m, 2H)
1.99-2.10 (m, 2H) 2.09-2.24 (m, 2H) 2.50 (br s, 2H) 2.53-2.61 (m,
2H) 3.63 (br s, 2H) 3.68 (s, 6H) 3.75-3.87 (m, 2H) 4.34 (t, J=8.5
Hz, 2H) 4.79 (d, J=6.3 Hz, 2H) 5.14 (d, J=6.6 Hz, 2H) 5.28 (d,
J=9.3 Hz, 2H) 6.32 (d, J=8.7 Hz, 2H) 7.08 (d, J=8.4 Hz, 4H) 7.18
(d, J=8.8 Hz, 2H) 7.41 (d, J=8.5 Hz, 4H) 9.23 (s, 2H). MS (ESI) m/z
935 (M+H).sup.+.
##STR00448##
Example 200
methyl
[(2S,3R)-3-methoxy-1-{(2S)-2-[(4-{(2R,5R)-5-(4-{[(1-{(2S,3R)-3-meth-
oxy-2-[(methoxycarbonyl)amino]butanoyl}pyrrolidin-2-yl)carbonyl]amino}phen-
yl)-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-yl}phenyl)carbamoyl]pyrrolid-
in-1-yl}-1-oxobutan-2-yl]carbamate
Example 200A
(2S,3R)-3-Methoxy-2-(methoxycarbonylamino)butanoic acid
[0838] A solution of O-methyl-L-threonine (1.01 g, 7.59 mmol) in
saturated bicarbonate solution (93 mL) was treated dropwise with
methyl chloroformate (900 .mu.L, 1.10 g, 11.61 mmol), followed by
stirring at RT for 24 h. The mixture was extracted methyl t-butyl
ether and cooled to 0.degree. C. The mixture was adjusted to pH 1-2
by addition of concentrated hydrochloric acid solution. The mixture
was extracted with ethyl acetate (3.times.) and the combined
extracts were extracted with saturated sodium chloride solution and
dried (Na.sub.2SO.sub.4). The solution was concentrated in vacuo to
afford the title compound (1.31 g, 90%) as a white solid. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 5.44 (d, J=8.7 Hz, 1H), 4.39 (dd,
J=8.7, 2.3 Hz, 1H), 4.00 (dd, J=6.2, 2.4 Hz, 1H), 3.71 (s, 3H),
3.36 (s, 3H), 1.21 (t, J=7.2 Hz, 3H). MS (+ESI) m/z (rel abundance)
192 (60, M+H), 209 (100, M+NH4).
Example 200B
methyl
[(2S,3R)-3-methoxy-1-{(2S)-2-[(4-{(2R,5R)-5-(4-{[(1-{(2S,3R)-3-meth-
oxy-2-[(methoxycarbonyl)amino]butanoyl}pyrrolidin-2-yl)carbonyl]amino}phen-
yl)-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-yl}phenyl)carbamoyl]pyrrolid-
in-1-yl}-1-oxobutan-2-yl]carbamate
[0839] Example 198B (60 mg, 0.101 mmol) and Example 200A (48.5 mg,
0.254 mmol) were processed in the same manner as Example 199B to
give the title compound (10.5 mg, 0.011 mmol, 11%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 1.19 (s, 3H) 1.21 (s, 3H) 1.78
(d, J=6.1 Hz, 2H) 1.94-2.16 (m, 6H) 2.40-2.57 (m, 4H) 3.36 (s, 6H)
3.66-3.84 (m, 6H) 3.69 (s, 6H) 4.64-4.72 (m, 2H) 4.81 (d, J=8.1 Hz,
2H) 5.14 (d, J=6.7 Hz, 2H) 5.64 (d, J=7.9 Hz, 2H) 6.31 (d, J=8.8
Hz, 2H) 7.08 (d, J=8.6 Hz, 4H) 7.18 (d, J=8.8 Hz, 2H) 7.43 (d,
J=8.6 Hz, 4H) 8.85 (s, 2H). MS (ESI) m/z 939 (M+H).sup.+.
##STR00449##
Example 201
methyl
[(2S,3S)-3-methoxy-1-{(2S)-2-[(4-{(2R,5R)-5-(4-{[(1-{(2S,3S)-3-meth-
oxy-2-[(methoxycarbonyl)amino]butanoyl}pyrrolidin-2-yl)carbonyl]amino}phen-
yl)-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-yl}phenyl)carbamoyl]pyrrolid-
in-1-yl}-1-oxobutan-2-yl]carbamate
Example 201A
(2S,3S)-3-Methoxy-2-(methoxycarbonylamino)butanoic acid
[0840] A solution of allo-O-methyl-L-threonine (519 mg, 3.90 mmol)
in saturated sodium bicarbonate solution (47.6 mL) was treated
dropwise with methyl chloroformate (453 .mu.L, 553 mg, 5.85 mmol)
followed by stirring at RT for 18 h. The mixture was extracted with
ether and the aqueous phase was cooled to 0.degree. C. and
acidified to pH 2-3 by addition of concentrated hydrochloric acid
solution. The mixture was extracted with ethyl acetate (3.times.).
The combined organic layers were extracted with saturated sodium
chloride solution and dried (Na.sub.2SO.sub.4). Concentration in
vacuo afforded the title compound (640 mg, 86%) as a colorless oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.48 (d, J=7.8 Hz, 1H),
4.52 (d, J=4.7 Hz, 1H), 3.71 (s, 3H), 3.39 (s, 3H), 1.25 (t, J=7.6
Hz, 3H).
Example 201B
methyl
[(2S,3S)-3-methoxy-1-{(2S)-2-[(4-{(2R,5R)-5-(4-{[(1-{(2S,3S)-3-meth-
oxy-2-[(methoxycarbonyl)amino]butanoyl}pyrrolidin-2-yl)carbonyl]amino}phen-
yl)-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-yl}phenyl)carbamoyl]pyrrolid-
in-1-yl}-1-oxobutan-2-yl]carbamate
[0841] Example 198B (40 mg, 0.068 mmol) and Example 201A (32.3 mg,
0.169 mmol) were processed in the same manner as Example 199B to
give the title compound (22 mg, 0.023 mmol, 35%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 1.24 (s, 3H) 1.25 (s, 3H) 1.78 (d,
J=6.2 Hz, 2H) 1.87-1.99 (m, 2H) 1.99-2.16 (m, 4H) 2.45-2.58 (m, 4H)
3.20 (s, 6H) 3.46-3.56 (m, 2H) 3.65-3.83 (m, 6H) 3.69 (s, 6H)
4.51-4.59 (m, 2H) 4.78 (d, J=6.7 Hz, 2H) 5.14 (d, J=6.7 Hz, 2H)
5.39 (d, J=9.3 Hz, 2H) 6.30 (d, J=8.7 Hz, 2H) 7.08 (d, J=8.5 Hz,
4H) 7.16 (d, J=8.8 Hz, 2H) 7.40 (d, J=8.5 Hz, 4H) 8.94 (s, 2H). MS
(ESI) m/z 939 (M+H).sup.+.
##STR00450##
Example 202
methyl
[(1S)-2-{(2S)-2-[(4-{(2R,5R)-5-(4-{[(1-{(2S)-2-[(methoxycarbonyl)am-
ino]-2-phenylacetyl}pyrrolidin-2-yl)carbonyl]amino}phenyl)-1-[4-(trifluoro-
methyl)phenyl]pyrrolidin-2-yl}phenyl)carbamoyl]pyrrolidin-1-yl}-2-oxo-1-ph-
enylethyl]carbamate
Example 202A
(S)-2-(methoxycarbonylamino)-2-phenylacetic acid
[0842] To a solution of (S)-2-amino-2-phenylacetic acid (0.5 g,
3.31 mmol) in dioxane at 0.degree. C. was added NaOH (5.46 g, 10.92
mmol) followed by dropwise addition of methyl chloroformate (0.51
mL, 6.62 mmol) and the solution was warmed to room temperature with
stirring over 1 h. Diluted with EtOAc, washed with 1 N HCl, brine,
dried (Na.sub.2SO.sub.4), filtered and removed solvent in vacuo to
give the title compound (0.35 g, 1.673 mmol, 51%).
Example 202B
methyl
[(1S)-2-{(2S)-2-[(4-{(2R,5R)-5-(4-{[(1-{(2S)-2-[(methoxycarbonyl)am-
ino]-2-phenylacetyl}pyrrolidin-2-yl)carbonyl]amino}phenyl)-1-[4-(trifluoro-
methyl)phenyl]pyrrolidin-2-yl}phenyl)carbamoyl]pyrrolidin-1-yl}-2-oxo-1-ph-
enylethyl]carbamate
[0843] Example 198B (40 mg, 0.068 mmol) and Example 202A (35 mg,
0.169 mmol) were processed in the same manner as Example 199B to
give the title compound (7.5 mg, 7.7 mol, 11%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 1.76-2.05 (m, 8H) 2.43-2.58 (m, 4H)
3.18-3.29 (m, 2H) 3.57-3.65 (m, 2H) 3.67 (s, 6H) 4.82-4.86 (m, 2H)
5.18 (d, J=6.9 Hz, 2H) 5.48 (d, J=7.7 Hz, 2H) 5.99 (d, J=7.7 Hz,
2H) 6.35 (d, J=8.8 Hz, 2H) 7.11 (d, J=8.5 Hz, 4H) 7.21 (d, J=8.7
Hz, 2H) 7.27-7.32 (m, 4H) 7.32-7.43 (m, 10H) 8.92 (s, 2H). MS (ESI)
m/z 975 (M+H).sup.+.
##STR00451##
Example 203
methyl
[(2S)-3-methoxy-1-{(2S)-2-[(4-{(2R,5R)-5-(4-{[(1-{(2S)-3-methoxy-2--
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)carbonyl]amino}p-
henyl)-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-yl}phenyl)carbamoyl]pyrro-
lidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
Example 203A
(S)-(tert-butoxycarbonylamino)-3-hydroxy-3-methylbutanoic acid
[0844] A solution of the (S)-2-amino-3-hydroxy-3-methylbutanoic
acid (252 mg, 1.89 mmol) in saturated sodium bicarbonate solution
(6.3 mL) and tetrahydrofuran (6.3 mL) was treated with
di-tert-butyl-dicarbonate (764 mg, 3.50 mmol) followed by stirring
at RT for 24 h. The mixture was concentrated in vacuo to remove
tetrahydrofuran and the mixture was extracted with hexanes. The
aqueous phase was cooled to 0.degree. C. and was acidifed to pH 3
by addition of 1 M citric acid solution. The mixture was extracted
with ethyl acetate and the combined organic layers were dried
(Na.sub.2SO.sub.4). Concentration in vacuo afforded a gummy solid,
containing other impurities in addition to the desired product.
This material was dissolved in ethyl acetate and the mixture
filtered through a millipore filter to remove undissolved material.
The filtrate was concentrated in vacuo and after setting at RT for
a week, eventually solidified to give the title compound as a white
solid. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 4.08 (s,
1H), 1.45 (s, 9H), 1.29 (s, 3H), 1.25 (s, 3H). MS (-ESI) m/z (rel
abundance) 232 (100, M-H).
Example 203B
(S)-2-(tert-butoxycarbonylamino)-3-methoxy-3-methylbutanoic
acid
[0845] To a solution of Example 203A (363 mg, 1.56 mmol) in THF (7
mL) at 0.degree. C. was added NaH (373 mg, 9.34 mmol) and stirring
was continued for 15 min. Iodomethane (0.78 mL, 12.45 mmol) was
added and the solution was allowed to warm to room temperature and
stirred for 18 h. Solution was quenched with H.sub.2O, diluted with
EtOAc, washed with H.sub.2O, brine, dried (Na.sub.2SO.sub.4),
filtered and solvent removed to give the title compound (165 mg,
0.67 mmol, 43%). MS (ESI) m/z 248 (M+H).sup.+.
Example 203C
(S)-3-methoxy-2-(methoxycarbonylamino)-3-methylbutanoic acid
[0846] To a solution of Example 203B (163 mg, 0.66 mmol) in
CH.sub.2Cl.sub.2 (2 mL) was added trifluoroacetic acid (2 mL) and
the solution was stirred at room temperature for 1 h. Solvent was
removed in vacuo and the residue was suspended in saturated
NaHCO.sub.3, extracted with EtOAc, the organic extracts combined,
washed with brine, dried (Na.sub.2SO.sub.4), filtered and solvent
removed in vacuo. The residue was dissolved in dioxane (1 mL) and 1
M NaOH (1.1 mL, 2.175 mmol) was added followed by the dropwise
addition of methyl chloroformate (0.102 mL, 1.3 mmol). The solution
was stirred at room temperature for 16 h, diluted with EtOAc,
washed with 1 N HCl, brine, dried (Na.sub.2SO.sub.4), filtered and
solvent removed in vacuo to give the title compound (96 mg, 0.468
mmol, 71%).
Example 203D
methyl
[(2S)-3-methoxy-1-{(2S)-2-[(4-{(2R,5R)-5-(4-{[(1-{(2S)-3-methoxy-2--
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)carbonyl]amino}p-
henyl)-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-yl}phenyl)carbamoyl]pyrro-
lidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate
[0847] Example 198B (80.7 mg, 0.136 mmol) and Example 203C (70 mg,
0.341 mmol) were processed in the same manner as Example 199B to
give the title compound (62 mg, 0.064 mmol, 47%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 1.25 (s, 3H) 1.33 (s, 3H) 1.39 (s, 2H)
1.74-1.82 (m, 2H) 1.89 (s, 2H) 1.93-2.16 (m, 5H) 2.38-2.59 (m, 4H)
3.16-3.27 (m, 2H) 3.24 (s, 3H) 3.43-3.56 (m, 2H) 3.69 (s, 3H)
3.71-3.78 (m, 2H) 3.80 (s, 3H) 3.84-3.94 (m, 1H) 4.61 (s, 1H)
4.70-4.81 (m, 2H) 5.15 (d, J=6.3 Hz, 2H) 5.58 (s, 1H) 6.32 (d,
J=8.7 Hz, 2H) 7.05-7.13 (m, 4H) 7.19 (d, J=8.7 Hz, 2H) 7.33-7.50
(m, 4H) 8.71 (s, 1H) 8.92 (s, 1H). MS (ESI) m/z 967
(M+H).sup.+.
##STR00452##
Example 204
dimethyl
([(2S,5S)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-3,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]}-
)biscarbamate and
dimethyl
([(2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-3,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]}-
)biscarbamate
Example 204A
(2S,2'S)-tert-butyl
2,2'-(3,3'-((2S,5S)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(3,1-phenyl-
ene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate
and
(2S,2'S)-tert-butyl
2,2'-(3,3'-((2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(3,1-phenyl-
ene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate
[0848] The ether fraction from the work up of Example 55F was
concentrated and purified by flash chromatography (silica gel,
dichloromethane/EtOAc) to afford the title compound as a mixture of
trans diastereomers (0.20 g, 10%). MS (ESI) m/z 742
(M+H).sup.+.
Example 204B
dimethyl
([(2S,5S)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-3,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]}-
)biscarbamate and
dimethyl
([(2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-3,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]}-
)biscarbamate
[0849] The product from Example 204A was processed using the method
described in Examples 19D and 19E (used
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid) to afford the
title compounds (60.5 mg, 22%). .sup.1H NMR (free base) (400 MHz,
DMSO-D6) .delta. 0.99-0.81 (m, 12H), 1.67 (dd, J=3.4, 5.0, 3H),
2.06-1.79 (m, 8H), 2.20-2.06 (m, 5H), 3.52 (d, J=2.3, 6H), 3.63 (q,
J=7.1, 1H), 3.88-3.75 (m, 1H), 4.08-3.96 (m, 2H), 4.41 (dt, J=12.8,
25.2, 2H), 5.11 (d, J=28.1, 2H), 6.24 (dd, J=6.0, 10.9, 2H), 6.80
(td, J=4.2, 8.9, 2H), 6.88 (dd, J=5.5, 6.4, 2H), 7.22 (ddd, J=5.3,
10.4, 20.8, 2H), 7.32 (d, J=8.3, 2H), 7.43-7.34 (m, 2H), 7.57 (d,
J=7.8, 2H), 10.00 (d, J=7.8, 2H). MS (ESI) m/z 856 (M+H).sup.+.
##STR00453##
Example 205
dimethyl
({(2R,5R)-1-[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl}bis{b-
enzene-3,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-
-1,2-diyl]})biscarbamate
Example 205A
(1S,4S)-1,4-bis(3-nitrophenyl)butane-1,4-diol
[0850] The product from Example 55A was processed using the method
described in Example 33 to afford the title compound (1.74 g, 84%).
MS (DCI) m/z 350 (M+NH.sub.4).sup.+.
Example 205B
(2R,5R)-2,5-bis(3-nitrophenyl)-1-(4-(trifluoromethyl)phenyl)pyrrolidine
[0851] The product from Example 205A and 4-aminobenzotrifluoride
were processed using the method described in Examples 55C and 55D
to afford the title compound (0.27 g, 19%). MS (ESI) m/z 858
(M+H).sup.+.
Example 205C
3,3'-((2R,5R)-1-(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)dianiline
[0852] The product from Example 205B was processed using the method
described in Example 55E. The title compound was isolated by flash
chromatography (silica gel, methanol/dichloromethane). MS (ESI) m/z
398 (M+H).sup.+, 396 (M-H).sup.+.
Example 205D
(2S,2'S)-tert-butyl
2,2'-(3,3'-((2R,5R)-1-(4-(trifluoromethyl)phenyl)pyrrolidine-2,5-diyl)bis-
(3,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate
[0853] The product from Example 205C was processed using the method
described in Example 19C replacing DMF with dichloromethane to
afford the title compound (0.36 g, 77%). MS (ESI) m/z 792
(M+H.sup.+).
Example 205E
dimethyl
({(2R,5R)-1-[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl}bis{b-
enzene-3,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate
[0854] The product from Example 205D was processed using the method
described in Examples 19D and 19E (used
(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid and replacing
HATU with HOBt and EDC) to afford the title compound (13.5 mg, 3%).
.sup.1H NMR (TFA salt) (400 MHz, METHANOL-D4) .delta. 1.08-0.89 (m,
12H), 1.88-1.73 (m, 2H), 2.32-1.93 (m, 10H), 2.62 (t, J=6.9, 2H),
3.64 (s, 6H), 3.77-3.67 (m, 2H), 4.00-3.90 (m, 2H), 4.20 (d, J=8.0,
2H), 4.56-4.45 (m, 2H), 5.26 (d, J=6.5, 2H), 6.42 (d, J=8.8, 2H),
6.98 (d, J=7.6, 2H), 7.17 (d, J=7.4, 2H), 7.27 (t, J=7.8, 2H),
7.52-7.37 (m, 4H). MS (ESI) m/z 906 (M+H).sup.+, 904
(M-H).sup.+.
##STR00454##
Example 206
dimethyl
({(2R,5S)-1-[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl}bis{b-
enzene-3,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate
[0855] The product for Example 206 was isolated from the
purification of Example 205E (12.5 mg, 3%). .sup.1H NMR (TFA salt)
(400 MHz, DMSO-D6) .delta. 0.90 (dt, J=6.2, 10.3, 12H), 2.23-1.73
(m, 12H), 2.47-2.39 (m, 6H), 3.52 (d, J=3.3, 4H), 3.89-3.73 (m,
2H), 4.03 (t, J=8.4, 2H), 4.44 (dd, J=4.9, 7.8, 2H), 4.83 (t,
J=5.5, 2H), 6.50 (d, J=8.7, 2H), 7.36-7.15 (m, 6H), 7.39 (d, J=8.7,
2H), 7.73-7.57 (m, 4H), 10.04 (d, J=10.0, 2H). MS (ESI) m/z 906
(M+H).sup.+, 904 (M-H).sup.+.
##STR00455##
Example 207
dimethyl
([(2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{pyridine-
-5,2-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-d-
iyl]})biscarbamate and
dimethyl
([(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{pyridine-
-5,2-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-d-
iyl]})biscarbamate
Example 207A
1,4-bis(6-chloropyridin-3-yl)butane-1,4-dione
[0856] The zinc chloride (3.04 g, 22.82 mmol), tert-butyl alcohol
(1.576 mL, 16.71 mmol) and diethylamine (1.731 mL, 16.71 mmol) were
combined in benzene (12 mL). The resulting slurry was stirred at
room temperature for 2 hours until all solid dissolved. To this
slurry was added 1-(6-chloropyridin-3-yl)ethanone (2.60 g, 16.71
mmol; reference: Bioorganic & Medicinal Chemistry Letters,
1998, 8, 3087-3092), followed by
2-bromo-1-(6-chloropyridin-3-yl)ethanone (2.61 g, 11.14 mmol;
reference: Bioorganic & Medicinal Chemistry Letters, 1998, 8,
3087-3092). The resulting clear yellow solution was stirred at room
temperature for 88 hours. The thick reaction mixture was treated
with 5% H.sub.2SO.sub.4 (10 mL), stirred for 30 minutes, filtered
and dried to give the title compound (2.91 g, 85%) as a solid.
Example 207B
1,4-bis(6-chloropyridin-3-yl)butane-1,4-diol
[0857] The product from Example 207A (2.90 g, 9.38 mmol) and sodium
borohydride (0.745 g, 19.70 mmol) were combined in ethanol (94 mL)
at 0.degree. C. The mixture was warmed to room temperature and
stirred for 6 hours. The solvent was evaporated and the residue was
partitioned between ethyl acetate and 1M HCl. The organic layer was
washed with water, brine, dried with sodium sulfate, filtered and
evaporated to give the title compound (2.62 g, 89%).
Example 207C
1,4-bis(6-chloropyridin-3-yl)butane-1,4-diyl dimethanesulfonate
[0858] The product from Example 207B (2.23 g, 7.12 mmol) and
triethylamine (2.98 mL, 21.36 mmol) were combined in
dichloromethane (50 mL). The mixture was cooled to -20.degree. C.
and methanesulfonyl chloride (1.383 mL, 17.80 mmol) was added. The
mixture was stirred at room temperature for 1 hour. The solvent was
evaporated to give the title product (approx 3.34 g) which was
directly used for the next reaction.
Example 207D
5,5'-(1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-chloropyridine)
[0859] The product from Example 207C (3.34 g, 7.12 mmol) and
4-tert-butylaniline (6.38 g, 42.7 mmol) were combined in DMF (20
mL). The mixture was stirred at room temperature for 24 hours. The
reaction mixture was partitioned between ethyl acetate and 1M HCl.
The organic layer was washed with brine twice, dried with sodium
sulfate, filtered and evaporated. The residue was purified by
chromatography on silica gel eluting with ethyl acetate/hexane (5%
to 30%) to give the title compound (2.95 g, 97%) as a yellow solid
as a mixture of stereoisomers.
Example 207E
dimethyl
([(2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{pyridine-
-5,2-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-d-
iyl]})biscarbamate and
dimethyl
([(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{pyridine-
-5,2-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-d-
iyl]})biscarbamate
[0860] The product from Example 207D (0.171 g, 0.40 mmol), the
product from Example 116C (0.326 g, 1.200 mmol), cesium carbonate
(0.365 g, 1.120 mmol), tris(dibenzylideneacetone)dipalladium(0)
(0.022 g, 0.024 mmol) and
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.042 g,
0.072 mmol) were combined in dioxane (4 mL). The mixture was purged
with nitrogen for 15 minutes and stirred at 100.degree. C. for 3
hours. The reaction mixture was partitioned between ethyl acetate
and saturated sodium bicarbonate. The organic layer was washed with
brine, dried with sodium sulfate, filtered and evaporated. The
residue was purified by chromatography on silica gel eluting with
methanol/dichloromethane (1% to 4%) to give the title compound (5
mg, 1%) as a mixture of trans diastereomers. 1H NMR (500 MHz,
DMSO-D6) .delta. ppm 0.88 (t, J=6.41 Hz, 6H) 0.92 (t, J=7.32 Hz,
6H) 1.12 (s, 9H) 1.68-1.75 (m, 2H) 1.81-1.99 (m, 8H) 2.07-2.18 (m,
2H) 2.50-2.53 (m, 2H) 3.52 (s, 6H) 3.57-3.64 (m, 2H) 3.78-3.86 (m,
2H) 3.98-4.03 (m, 2H) 4.55-4.63 (m, 2H) 5.27 (d, J=6.26 Hz, 2H)
6.18-6.27 (m, 2H) 6.99 (dd, J=8.77, 1.60 Hz, 2H) 7.28-7.37 (m, 2H)
7.59 (dd, J=8.62, 2.06 Hz, 2H) 7.96 (d, J=8.39 Hz, 2H) 8.12-8.20
(m, 2H) 10.53 (s, 2H); MS (ESI+) m/z 896.6 (M+H)+.
##STR00456##
Example 208
dimethyl
([(2S,5S)-1-phenylpyrrolidine-2,5-diyl]bis{benzene-4,1-diylcarbam-
oyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbam-
ate and
dimethyl
([(2R,5R)-1-phenylpyrrolidine-2,5-diyl]bis{benzene-4,1-diylcarbam-
oyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbam-
ate
[0861] The title compound was isolated from Example 85C as an
additional product. 1H NMR (TFA salt) (400 MHz, DMSO-D6) .delta.
ppm 0.83-0.88 (m, 6H), 0.88-0.94 (m, 6H), 1.60-1.65 (m, 2H),
1.79-2.02 (m, 8H), 2.06-2.18 (m, 2H), 3.51 (s, 6H), 3.55-3.64 (m,
2H), 3.75-3.83 (m, 2H), 4.01 (t, J=8.3 Hz, 2H), 4.38-4.43 (m, 2H),
5.16 (d, J=6.4 Hz, 2H), 6.23 (d, J=8.3 Hz, 2H), 6.39 (t, J=7.3 Hz,
1H), 6.90 (t, J=7.9 Hz, 2H), 7.09-7.14 (m, 4H), 7.25-7.31 (m, 2H),
7.45-7.50 (m, 4H), 9.97 (s, 2H); MS m/z 838.4 (M+H).sup.+.
##STR00457##
Example 209
dimethyl
({(2S,5S)-1-[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl}bis{b-
enzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimethyl-1-oxobu-
tane-1,2-diyl]})biscarbamate
[0862] The product from Example 23C was separated by chiral
chromatography on a Chiralpak AD-H semi-prep column eluting with
40% 2-PrOH:EtOH (1:1)/60% hexanes. The title compound was the first
of 2 components to elute. 1H NMR (400 MHz, DMSO-D6) .delta. ppm
0.97 (s, 18H), 1.61-1.73 (m, 2H), 1.75-1.93 (m, 4H), 1.94-2.06 (m,
2H), 2.08-2.21 (m, 2H), 3.54 (s, 6H), 3.57-3.70 (m, 2H), 3.70-3.83
(m, 2H), 4.21 (d, J=8.89 Hz, 2H), 4.38-4.48 (m, 2H), 5.27 (d,
J=6.51 Hz, 2H), 6.37 (d, J=8.78 Hz, 2H), 7.08 (d, J=8.89 Hz, 2H),
7.15 (d, J=8.57 Hz, 4H), 7.25 (d, J=8.89 Hz, 2H), 7.52 (d, J=8.57
Hz, 4H), 10.02 (s, 2H); MS (ESI) m/z 951.6 (M+H).sup.+.
##STR00458##
Example 210
dimethyl
({(2R,5R)-1-[4-(trifluoromethyl)phenyl]pyrrolidine-2,5-diyl}bis{b-
enzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3,3-dimethyl-1-oxobu-
tane-1,2-diyl]})biscarbamate
[0863] The product from Example 23C was separated by chiral
chromatography on a Chiralpak AD-H semi-prep column eluting with
40% 2-PrOH:EtOH (1:1)/60% hexanes. The title compound was the
second of 2 components to elute. 1H NMR (400 MHz, DMSO-D6) .delta.
ppm 0.96 (s, 18H), 1.64-1.75 (m, 2H), 1.76-1.93 (m, 4H), 1.94-2.06
(m, 2H), 2.07-2.21 (m, 2H), 3.54 (s, 6H), 3.58-3.70 (m, 2H),
3.70-3.86 (m, 2H), 4.20 (d, J=8.89 Hz, 2H), 4.38-4.47 (m, 2H), 5.28
(d, J=6.18 Hz, 2H), 6.36 (d, J=8.89 Hz, 2H), 7.07 (d, J=8.89 Hz,
2H), 7.14 (d, J=8.57 Hz, 4H), 7.25 (d, J=8.78 Hz, 2H), 7.52 (d,
J=8.57 Hz, 4H), 10.03 (s, 2H); MS (ESI) m/z 951.4 (M+H).sup.+.
##STR00459##
Example 211
dimethyl
([(2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S,3R)-3-methyl-1-oxopentane-1,2-di-
yl]})biscarbamate
[0864] The product from Example 25 was separated by chiral
chromatography on a Chiralpak AD-H semi-prep column eluting with
50% 2-PrOH:EtOH (1:1)/50% hexanes. The title compound was the
second of 2 components to elute. 1H NMR (400 MHz, DMSO-D6) .delta.
ppm 0.76-0.92 (m, 12H), 1.05-1.19 (m, 2H), 1.37-1.54 (m, 2H),
1.57-1.70 (m, 2H), 1.69-1.96 (m, 6H), 1.94-2.07 (m, 2H), 2.07-2.22
(m, 2H), 3.53 (s, 6H), 3.55-3.64 (m, 2H), 3.69-3.83 (m, 2H),
4.17-4.28 (m, 2H), 4.42 (dd, J=7.81, 5.20 Hz, 2H), 5.16 (d, J=6.29
Hz, 2H), 6.20 (dd, J=9.22, 4.45 Hz, 2H), 6.77 (t, J=8.95 Hz, 2H),
7.13 (d, J=8.46 Hz, 4H), 7.49 (d, J=8.46 Hz, 2H), 9.97 (s, 2H); MS
(ESI) m/z 884.4 (M+H).sup.+.
##STR00460##
Example 212
dimethyl
([(2R,5R)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S,3S)-3-methyl-1-oxopentane-1,2-diyl]})biscarbamate
[0865] The product from Example 24 was separated by chiral
chromatography on a Chiralpak AD-H semi-prep column eluting with
50% 2-PrOH:EtOH (1:1)/50% hexanes. The title compound was the
second of 2 components to elute. 1H NMR (400 MHz, DMSO-D6) .delta.
ppm 0.80 (t, J=7.37 Hz, 6H), 0.88 (d, J=6.72 Hz, 6H), 1.02-1.18 (m,
2H), 1.41-1.59 (m, 2H), 1.59-1.75 (m, 4H), 1.80-1.95 (m, 4H),
1.95-2.06 (m, 2H), 2.08-2.23 (m, 2H), 3.52 (s, 6H), 3.56-3.67 (m,
2H), 3.74-3.89 (m, 2H), 4.07 (t, J=8.95 Hz, 2H), 4.39-4.47 (m, 2H),
5.16 (d, J=6.18 Hz, 2H), 6.20 (dd, J=9.22, 4.45 Hz, 2H), 6.78 (t,
J=8.95 Hz, 2H), 7.13 (d, J=8.46 Hz, 4H), 7.35 (d, J=8.46 Hz, 2H),
7.50 (d, J=8.57 Hz, 4H), 9.99 (s, 2H); MS (ESI) m/z 884.4
(M+H).sup.+.
##STR00461##
Example 213
N-(methoxycarbonyl)-L-valyl-N-{4-[(2S,5S)-5-(4-aminophenyl)-1-(4-tert-buty-
lphenyl)pyrrolidin-2-yl]phenyl}-L-prolinamide
[0866] To a solution of the product from Example 37B (17.7 mg,
0.065 mmol) and the product from Example 37E (50 mg, 0.130 mmol) in
anhydrous DMSO (1.3 mL) was added HATU (27.1 mg, 0.071 mmol) and
Hunig'sBase (0.015 mL, 0.084 mmol). The resulting mixture was
stirred at rt for 30 min, and was then partitioned between H.sub.2O
(5 mL) and EtOAc (3.times.5 mL). The combined organic layers were
dried over Na.sub.2SO.sub.4. The drying agent was filtered off, and
solvent was removed in vacuo. The crude product was purified by
column chromatography on silica gel using a solvent gradient of
0-5% MeOH in CH.sub.2Cl.sub.2 to give the title compound (20 mg,
24%). 1H NMR (400 MHz, DMSO-D6) .delta. ppm 0.88 (d, J=6.72 Hz,
3H), 0.93 (d, J=6.72 Hz, 3H), 1.11 (s, 9H), 1.52-1.66 (m, 2H),
1.79-2.06 (m, 4H), 2.06-2.20 (m, 1H), 2.34-2.47 (m, 2H), 3.52 (s,
3H), 3.56-3.67 (m, 1H), 3.74-3.87 (m, 1H), 4.02 (t, J=8.51 Hz, 1H),
4.42 (dd, J=8.08, 4.83 Hz, 1H), 4.83-4.94 (m, 2H), 5.02 (d, J=7.16
Hz, 0.5H), 5.08 (d, J=7.59 Hz, 0.5H), 6.18 (d, J=8.78 Hz, 2H), 6.48
(d, J=8.35 Hz, 2H), 6.84 (d, J=8.35 Hz, 2H), 6.93 (d, J=8.89 Hz,
2H), 7.11 (d, J=8.57 Hz, 2H), 7.31 (d, J=8.35 Hz, 1H), 7.48 (d,
J=8.57 Hz, 2H), 9.97 (s, 1H); MS (ESI) m/z 640.3 (M+H).sup.+.
##STR00462##
Example 214
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-tert-butylphenyl-
)pyrrolidine-2,5-diyl)bis(thiazole-4,2-diyl)bis(azanediyl)bis(oxomethylene-
))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
and
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-tert-butylphenyl-
)pyrrolidine-2,5-diyl)bis(thiazole-4,2-diyl)bis(azanediyl)bis(oxomethylene-
))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
Example 214A
diethyl 1-(4-tert-butylphenyl)pyrrolidine-2,5-dicarboxylate
[0867] A solution of diethyl meso-2,5-dibromoadipate (2.0 g, 5.55
mmol) and 4-tert-butylaniline (3.32 g, 22.22 mmol) in
dimethoxyethane (12 mL) was stirred at reflux for 10 h. The cooled
mixture was partitioned between EtOAc (100 mL) and 1N aq HCl
(2.times.100 mL), and the organic layer was dried over
Na.sub.2SO.sub.4. The drying agent was filtered off, and the
solvent was removed in vacuo. The crude product was purified by
column chromatography on silica gel using a solvent gradient of
0-20% EtOAc in hexanes to give the title compound as an oil (1.95
g, quant.). 1H NMR indicated a 3:2 mixture of cis:trans pyrrolidine
isomers.
Example 214B
1-(4-tert-butylphenyl)pyrrolidine-2,5-dicarboxylic acid
[0868] To a solution of the product from Example 214A (1.95 g, 5.61
mmol) in MeOH (50 mL) was added a solution of NaOH (0.95 g, 23.8
mmol) in H.sub.2O (10 mL). The resulting mixture was stirred at rt
overnight. The mixture was concentrated in vacuo to ca. 10 mL and
was poured into 1N HCl (50 mL). The mixture was extracted with
CH.sub.2Cl.sub.2 (3.times.50 mL), and the combined organic layers
were dried over Na.sub.2SO.sub.4. The drying agent was filtered
off, and the solvent was removed in vacuo to give the title
compound as a light orange solid (1.42 g, 87%) as a mixture of
stereoisomers.
Example 214C
trans-1-(4-tert-butylphenyl)pyrrolidine-2,5-dicarboxylic acid
[0869] The product from Example 214B was subjected to column
chromatography on C18 silica gel using a solvent gradient of 10-60%
acetonitrile in H.sub.2O (0.1% TFA). The title compound was the
first of 2 major components to elute.
Example 214D
1,1'-(trans-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-diazoethanone-
)
[0870] To a solution of the product from Example 214C (0.963 g,
3.31 mmol) in dry CH.sub.2Cl.sub.2 (20 mL) at 0.degree. C. was
added oxalyl chloride (1.157 mL, 13.22 mmol), followed by 2-3 drops
of DMF, and the resulting mixture was stirred at rt for 30 min
until no further bubbling was observed. The cooled mixture was cone
by evaporation with dry N.sub.2, and the residue was dissolved in
dry CH.sub.2Cl.sub.2 (10 mL). To the 0.degree. C. solution was
added a solution of diazomethane in Et.sub.2O (.about.0.6 M, 20 mL)
and the resulting mixture was stirred at 0.degree. C. for 1 h. The
mixture was concentrated in vacuo, and the crude product was
purified by column chromatography on silica gel using a solvent
gradient of 0-100% EtOAc in hexanes to give the title compound
(0.54 g, 48%).
Example 214E
4,4'-(trans-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dithiazol-2-amine
[0871] A solution of the product from Example 214D (0.50 g, 1.47
mmol) in Et.sub.2O (10 mL) was treated dropwise with 48% aq.
hydrogen bromide (0.500 mL, 4.42 mmol). The resulting mixture was
stirred at rt for 30 min. Water (1 mL) was added, and the mixture
was extracted with Et.sub.2O (3.times.10 mL). The combined organic
layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated
in vacuo. The residue was dissolved in EtOH (15 mL). To the
resulting solution was added thiourea (0.45 g, 5.89 mmol), and the
resulting mixture was stirred at rt for 1 h and then concentrated
to ca. 1 mL. Water (10 mL) was added, and the pH was neutralized
using saturated aq. NaHCO.sub.3. The resulting solid was collected
by filtration and dried in vacuo to give the title compound (0.455
g, 77%).
Example 214F
(2S,2'S)-tert-butyl
2,2'-(4,4'-(trans-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(thiazole-
-4,2-diyl)bis(azanediyl)bis(oxomethylene))dipyrrolidine-1-carboxylate
[0872] A mixture of the product from Example 214E (0.2 g, 0.501
mmol), (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid
(0.431 g, 2.002 mmol), and
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (1.151 g, 6.01 mmol) in DMF (4 mL) and pyridine (4
mL) was stirred at rt overnight. The mixture was partitioned
between IN aq. HCl and EtOAc (3x), and the combined organic layers
were dried over Na.sub.2SO.sub.4. The drying agent was filtered
off, and the solvent was removed in vacuo. The crude product was
purified by column chromatography on silica gel using a solvent
gradient of 0-100% EtOAc in hexanes to give the title compound
(0.28 g, 71%) as a mixture of trans diastereomers.
Example 214G
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-1-(4-tert-butylphenyl-
)pyrrolidine-2,5-diyl)bis(thiazole-4,2-diyl)bis(azanediyl)bis(oxomethylene-
))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
and
dimethyl
(2S,2'S)-1,1'-((2S,2'S)-2,2'-(4,4'-((2S,5S)-1-(4-tert-butylphenyl-
)pyrrolidine-2,5-diyl)bis(thiazole-4,2-diyl)bis(azanediyl)bis(oxomethylene-
))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate
[0873] A solution of the product from Example 214F was stirred in
2N HCl in dioxane (0.4 mL) for 1 h and then concentrated in vacuo.
The residue was subjected to the procedure described in Example 10
to give the title compound as mixture of trans diastereomers. 1H
NMR (free base) (400 MHz, DMSO-D6) .delta. ppm 0.80-0.97 (m, 14H),
1.12-1.16 (m, 9H), 1.69-2.06 (m, 8H), 2.08-2.22 (m, 2H), 3.51-3.57
(m, 6H), 3.57-3.68 (m, 2H), 3.77-3.91 (m, 2H), 3.95-4.06 (m, 2H),
4.47-4.59 (m, J=7.16 Hz, 1H), 5.08-5.17 (m, 2H), 6.31 (t, J=8.24
Hz, 2H), 6.70 (d, J=21.04 Hz, 2H), 7.02 (dd, J=8.67, 6.40 Hz, 2H),
7.35 (d, J=8.35 Hz, 2H), 12.24 (s, 2H).
##STR00463##
Example 215
dimethyl
([3-bromo-1-(4-fluorophenyl)-1H-pyrrole-2,5-diyl]bis{benzene-4,1--
diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]}-
)biscarbamate
[0874] To a suspension of the product from Example 51 (455 mg,
0.534 mmol) in CH.sub.2Cl.sub.2 (2.7 mL) was added a mixture of
1-bromopyrrolidine-2,5-dione (95 mg, 0.534 mmol) in
CH.sub.2Cl.sub.2 (2.7 mL). The mixture was stirred overnight at
room temperature then concentrated under reduced pressure and
triturated with diethyl ether to provide a mixture of compounds
that was subjected to reverse phase HPLC purification eluted with a
gradient of 60-100% MeOH in 10 mM ammonium acetate to afford the
title compound (84 mg, 17% yield). .sup.1H NMR (free base) (400
MHz, DMSO-D6) .delta. 10.06 (s, 1H), 10.02 (s, 1H), 7.46 (d, J=8.7,
2H), 7.41 (d, J=8.7, 2H), 7.30 (d, J=7.7, 2H), 7.15-7.03 (m, 6H),
6.98 (d, J=8.7, 2H), 6.53 (s, 1H), 4.45-4.33 (m, 2H), 4.01 (t,
J=7.7, 2H), 3.85-3.73 (m, 2H), 3.66-3.54 (m, 2H), 3.51 (s, 6H),
2.20-2.05 (m, 2H), 2.03-1.77 (m, 8H), 0.97-0.79 (m, 12H). MS (ESI;
M+H) m/z=933.
##STR00464##
Example 216
dimethyl
([3,4-dibromo-1-(4-fluorophenyl)-1H-pyrrole-2,5-diyl]bis{benzene--
4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-di-
yl]})biscarbamate
[0875] The title compound was formed as an additional product in
Example 215. The mixture of products was subjected to reverse phase
HPLC purification eluted with a gradient of 60-100% MeOH in 10 mM
ammonium acetate to afford the title compound (125 mg, 23% yield).
.sup.1H NMR (free base) (400 MHz, DMSO-D6) .delta. 10.08 (bs, 2H),
7.47 (d, J=8.7, 4H), 7.33-7.27 (m, 2H), 7.13-7.01 (m, 8H),
4.43-4.35 (m, 2H), 4.01 (t, J=8.4, 2H), 3.84-3.74 (m, 2H),
3.65-3.55 (m, 2H), 3.51 (s, 6H), 2.21-2.05 (m, 2H), 2.05-1.78 (m,
8H), 0.91 (d, J=6.7, 6H), 0.86 (d, J=6.6, 6H). MS (ESI; M+H)
m/z=1011.
##STR00465##
Example 217
[0876] The title compound was formed as a by-product in Example
215. The mixture of products was subjected to reverse phase HPLC
purification eluted with a gradient of 60-100% MeOH in 10 mM
ammonium acetate to afford the title compound (61 mg, 12% yield).
.sup.1H NMR (free base) (400 MHz, DMSO-D6) .delta. 10.00 (s, 2H),
7.41 (d, J=8.7, 2H), 7.38 (d, J=8.9, 2H), 7.29 (d, J=6.6, 2H), 7.14
(d, J=7.3, 1H), 7.11-7.05 (m, 3H), 7.01-6.93 (m, 2H), 6.89 (t,
J=8.7, 2H), 4.37 (dd, J=4.9, 7.4, 2H), 4.00 (t, J=8.4, 2H),
3.84-3.74 (m, 2H), 3.64-3.55 (m, 2H), 3.51 (s, 6H), 2.19-2.05 (m,
2H), 2.03-1.78 (m, 8H), 1.23 (s, 9H), 0.91 (dd, J=2.1, 6.6, 6H),
0.86 (d, J=6.4, 6H). MS (ESI; M+H) m/z=989.
##STR00466##
Example 218
methyl
{(2S)-1-[(2S)-2-(4-{4-[4-(4-tert-butylphenyl)-5-(4-{2-[(2S)-1-{(2S)-
-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol--
4-yl}phenyl)-4H-1,2,4-triazol-3-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-y-
l]-3-methyl-1-oxobutan-2-yl}carbamate
Example 218A
4-bromo-N'-(4-bromobenzoyl)benzoylhydrazide
[0877] Dissolved equimolar amounts of 4-bromobenzohydrazide (1.097
g, 5 mmol) and 4-bromobenzoyl chloride (1.120 g, 5 mmol) in
anhydrous pyridine (25 mL) under nitrogen and heated at reflux (oil
bath 135.degree. C.) for 6 hr. Cooled reaction to room temperature,
poured the mixture into absolute EtOH (100 mL), and cooled in a
freezer overnight to give white crystals. Collected solids by
vacuum filtration, washed solids with absolute EtOH (2.times.5 mL),
and dried in vacuo to afford the title compound as a white solid
(953 mg, 48%). .sup.1H NMR (400 MHz, DMSO-D6) .delta. ppm 7.75 (d,
J=8.57 Hz, 4H), 7.86 (d, J=8.46 Hz, 4H), 10.63 (s, 2H); MS (ESI-)
m/z 395/397/399 (M-H).sup.- with two bromines.
Example 218B
3,5-bis(4-bromophenyl)-4-(4-tert-butylphenyl)-4H-1,2,4-triazole
[0878] In an oven-dried 10-mL round bottom flask, equipped with a
septum and purged with nitrogen, 4-tert-butylaniline (450 mg, 3.01
mmol) was dissolved in anhydrous 1,2-dichlorobenzene (1.5 mL) and
the solution cooled to 0.degree. C. A solution of phosphorus
oxychloride (0.047 mL, 0.502 mmol) in anhydrous 1,2-dichlorobenzene
(0.5 mL) was added slowly in dropwise manner from a gas-tight
syringe. Upon completion of addition, removed the cooling bath and
stirred at room temperature for 1 hr to form the phosphoryl
triamide in situ (reaction became progressively cloudy). Then added
the product of Example 218A (200 mg, 0.502 mmol), replaced septum
with a reflux condenser, and heated reaction in an oil bath at
200.degree. C. for 4 hr. Cooled light brown colored solution to
room temperature, then placed in a freezer for 3 days and collected
an off-white solid (20 mg, 4-bromo-N-(4-tert-butylphenyl)benzamide
by-product) by vacuum filtration. The filtrate was treated with
hexanes (.about.50 mL) and the cloudy solution cooled in a freezer
for 30 min. Collected an off-white solid (73 mg) by vacuum
filtration and concentrated the filtrate by rotary evaporation to a
solution of product in 1,2-dichlorobenzene. The latter was purified
by flash chromatography (silica gel, 3.8 cm.times.15 cm bed,
gradient of CH.sub.2Cl.sub.2, 20% EtOAc/CH.sub.2Cl.sub.2, and 30%
EtOAc/CH.sub.2Cl.sub.2) to afford the title compound as a fluffy
white solid (154 mg, 60%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 1.36 (s, 9H), 7.06 (d, J=8.46 Hz, 2H), 7.29 (d, J=8.57
Hz, 4H), 7.43 (d, J=8.57 Hz, 4H), 7.46 (d, J=8.57 Hz, 2H); MS
(ESI+) m/z 510/512/514 (M+H).sup.+ with two bromines.
Example 218C
4-(4-tert-butylphenyl)-3,5-bis((4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)phenyl)-4H-1,2,4-triazole
[0879] Charged an oven-dried 25-mL round bottom flask, purged with
nitrogen, with the product of Example 218B (144.2 mg, 0.282 mmol),
bis(pinacalato)diboron (215 mg, 0.846 mmol), potassium acetate (90
mg, 0.917 mmol), and anhydrous dioxane (1.5 mL). Sparged the
mixture with nitrogen for 30 min, added
1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (23.03 mg, 0.028 mmol), re-sparged with
nitrogen for 5 min, replaced rubber septum with a glass stopper,
and heated in an oil bath (85.degree. C.) for 2 hr. Cooled reaction
to room temperature, vacuum filtered through a small bed of Celite
545, washed catalyst thoroughly with CH.sub.2Cl.sub.2, and
concentrated the filtrate by rotary evaporation to a dark brown
oil. Purified by flash chromatography (silica gel, Alltech
Extract-Clean 10 g column, 1:1 EtOAc/CH.sub.2Cl.sub.2) to afford a
dark beige solid (230 mg). Repurified by flash chromatography
(silica gel, Alltech Extract-Clean 10 g column, 3%
MeOH/CH.sub.2Cl.sub.2) eluting with to afford the title compound as
a beige solid (171 mg, 100%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 1.27 (s, 9H), 1.33 (s, 24H), 7.06 (d, J=8.46 Hz, 2H),
7.38-7.47 (m, 6H), 7.71 (d, J=7.92 Hz, 4H); MS (ESI+) m/z 606
(M+H).sup.+, 1211 (2M+H).sup.+.
Example 218D
(2S,2'S)-tert-butyl
2,2'-(4,4'-(4,4'-(4-(4-tert-butylphenyl)-4H-1,2,4-triazole-3,5-diyl)bis(4-
,1-phenylene))bis(1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxylate
[0880] Charged a nitrogen-purged microwave tube (size M, 5 mL) with
the product of Example 218C (171 mg, 0.282 mmol), the product of
Example 26D (223 mg, 0.706 mmol), and a mixture of absolute EtOH
(1.5 mL) and toluene (1.5 mL), then added 1M aq sodium carbonate
(0.706 mL, 0.706 mmol) and sparged the mixture with nitrogen for 20
min. Added
1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (23.07 mg, 0.028 mmol), sparged again with
nitrogen for 5 min, sealed the tube with an aluminum crimp cap, and
heated in a microwave reactor (Personal Chemistry Emrys Creator)
with stirring at 100.degree. C. for 1 hr. Cooled the reaction to
room temperature, diluted reaction in EtOAc (75 mL), washed with
H.sub.2O (2.times.25 mL) and brine (25 mL), dried organic phase
over anhydrous MgSO.sub.4, filtered, and concentrated by rotary
evaporation to a yellow solid (330 mg). Purified by flash
chromatography (silica gel, 3.8 cm x 15 cm, gradient of 4%, 6%, 8%,
and 10% MeOH/CH.sub.2Cl.sub.2) to afford the title compound as a
light yellow solid (135 mg, 58%). MS (ESI+) m/z 824
(M+H).sup.+.
Example 218E
4-(4-tert-butylphenyl)-3,5-bis(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl-
)phenyl)-4H-1,2,4-triazole
[0881] Dissolved the product of Example 218D (131.5 mg, 0.160 mmol)
in anhydrous CH.sub.2Cl.sub.2 (2 mL) under nitrogen, added
trifluoroacetic acid (1 mL, 12.85 mmol), and stirred at 25.degree.
C. for 30 min. Removed the solvent by rotary evaporation, took up
the residue in 20% iPrOH/CHCl.sub.3 (50 mL), washed with sat'd aq
NaHCO.sub.3 (10 mL), extracted the aqueous phase with 20%
iPrOH/CHCl.sub.3 (2.times.25 mL), dried the combined organic
extracts over anhydrous MgSO.sub.4, filtered, and concentrated by
rotary evaporation. Took up residue in 1:5 v/v CH2Cl2/hexanes and
concentrated in vacuo to afford the title compound as a light tan
solid (114 mg). .sup.1H NMR (400 MHz, DMSO-D6) .delta. ppm 1.30 (s,
9H), 1.66-1.94 (m, 6H), 1.98-2.12 (m, 2H), 2.80-3.07 (m, 4H),
3.70-3.86 (m, 1H), 4.12-4.22 (m, 2H), 4.34 (d, J=4.01 Hz, 1H), 7.34
(t, J=8.08 Hz, 6H), 7.47-7.57 (m, 4H), 7.68 (d, J=8.35 Hz, 4H),
11.90 (s, 2H); MS (ESI+) 624 (M+H).sup.+; (ESI-) m/z 622
(M-H).sup.-.
Example 218F
(methyl
{(2S)-1-[(2S)-2-(4-{4-[4-(4-tert-butylphenyl)-5-(4-{2-[(2S)-1-{(2S-
)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-
-4-yl}phenyl)-4H-1,2,4-triazol-3-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1--
yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0882] In an oven-dried 5-mL round bottom flask purged with
nitrogen, dissolved the product of Example 218E (50 mg, 0.080 mmol)
in anhydrous DMF (1 mL), and cooled to 0.degree. C. Added
sequentially (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid
(29.5 mg, 0.168 mmol), HOBt hydrate (27.6 mg, 0.180 mmol), EDAC
(35.3 mg, 0.180 mmol), and N-methylmorpholine (0.035 mL, 0.321
mmol). Stirred the solution at 25.degree. C. for 15 hr. Diluted the
reaction in EtOAc (50 mL), washed with sat'd aq NaHCO.sub.3 (25
mL), H.sub.2O (3.times.25 mL), and brine (25 mL), dried the organic
phase over anhydrous MgSO.sub.4, filtered, and concentrated by
rotary evaporation to an off-white solid (72 mg). Purified by flash
chromatography (silica gel, Alltech Extract-Clean 10 g column,
gradient of 6% to 8% MeOH/CH.sub.2Cl.sub.2) to afford the title
compound as an off-white solid (49 mg, 65%). .sup.1H NMR (400 MHz,
DMSO-D6) .delta. ppm 0.82 (d, J=6.72 Hz, 6H), 0.86 (d, J=6.72 Hz,
6H), 1.29 (s, 9H), 1.79-2.01 (m, 5H), 2.03-2.22 (m, 4H), 3.53 (s,
6H), 3.70-3.86 (m, 4H), 4.04 (t, J=8.35 Hz, 2H), 5.04 (dd, J=6.67,
3.20 Hz, 2H), 7.23-7.43 (m, 8H), 7.48-7.60 (m, 4H), 7.61-7.73 (m,
4H), 11.77-12.21 (m, 2H); MS (ESI+) m/z 939 (M+H).sup.+.
##STR00467##
Example 219
methyl
{(2S)-1-[(2S)-2-(4-{4-[4-(4-cyclohexylphenyl)-5-(4-{2-[(2S)-1-{(2S)-
-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol--
4-yl}phenyl)-4H-1,2,4-triazol-3-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-y-
l]-3-methyl-1-oxobutan-2-yl}carbamate
Example 219A
3,5-bis(4-bromophenyl)-4-(4-cyclohexylphenyl)-4H-1,2,4-triazole
[0883] In an oven-dried 10-mL round bottom flask, equipped with a
septum and purged with nitrogen, 4-cyclohexylaniline (545 mg, 3.01
mmol) was dissolved in anhydrous 1,2-dichlorobenzene (1.5 mL) and
the solution cooled to 0.degree. C. A solution of phosphorus
oxychloride (78 mg, 0.502 mmol) in anhydrous 1,2-dichlorobenzene
(0.5 mL) was added slowly in a dropwise manner from a gas-tight
syringe. The reaction became an unstirrable solid gel; removed the
cooling bath, added additional 1,2-dichlorobenzene (0.5 mL),
sonicated the mixture, and stirred the thick suspension at room
temperature for 1 hr to form the phosphoryl triamide in situ. Added
the product of Example 218A (200 mg, 0.502 mmol), replaced the
septum with a reflux condenser, and heated the reaction in an oil
bath at 200.degree. C. for 4 hr under nitrogen. The reaction
quickly became a homogeneous gold colored solution upon refluxing.
Cooled the solution to room temperature and purified by flash
chromatography (silica gel, 3.8 cm.times.15 cm, gradient of
CH.sub.2Cl.sub.2 to 20% EtOAc/CH.sub.2Cl.sub.2 to 40%
EtOAc/CH.sub.2Cl.sub.2) to afford the title compound as a fluffy
white solid (201 mg, 74%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 1.19-1.33 (m, 1H) 1.35-1.50 (m, 4H) 1.78 (d, J=14.42
Hz, 1H) 1.84-1.98 (m, 4H) 2.51-2.65 (m, 1H) 7.04 (d, J=8.35 Hz, 2H)
7.28 (d, J=8.57 Hz, 6H) 7.43 (d, J=8.57 Hz, 4H); MS (ESI+) m/z
536/538540 (M+H).sup.+, 1072/1074/1076 (2M+H).sup.+ with two
bromines.
Example 219B
4-(4-cyclohexylphenyl)-3,5-bis(4(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2--
yl)phenyl)-4H-1,2,4-triazole
[0884] Charged an oven-dried 10-mL round bottom flask, purged with
nitrogen, with the product of Example 219A (100 mg, 0.186 mmol),
bis(pinacalato)diboron (142 mg, 0.558 mmol), potassium acetate
(59.4 mg, 0.605 mmol), and anhydrous dioxane (3 mL). Sparged the
thick white mixture with nitrogen for 30 min, added
1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (15.20 mg, 0.019 mmol), re-sparged with
nitrogen for 5 min, replaced rubber septum with a glass stopper,
and heated in an oil bath (85.degree. C.). Reaction became
homogeneous upon heating and darkened with time to a reddish-brown
color. TLC (SiO2, 50% EtOAc/CH.sub.2Cl.sub.2). After 2 hr, cooled
reaction to room temperature, added additional
bis(pinacalato)diboron (71 mg, .about.1.5 equiv) and potassium
acetate (30 mg, .about.1.75 equiv), and heated for 1 hr at
85.degree. C. Cooled the brown colored reaction to room
temperature, vacuum filtered through a small bed of Celite 545,
washed the collected solids thoroughly with CH.sub.2Cl.sub.2, and
concentrated the filtrate by rotary evaporation to a brown foam.
Purified by silica gel flash chromatography (Alltech Extract-Clean
column, 10 g bed) eluting with 30% EtOAc/CH.sub.2Cl.sub.2 to afford
the product as a light brown oil (190 mg). Repurified by silica gel
flash chromatography (Alltech Extract-Clean column, 10 g bed)
eluting with 3% MeOH/CH.sub.2Cl.sub.2 to afford the title compound
as a light beige foam (122 mg, 100%). MS (ESI+) m/z 632
(M+H).sup.+, 1263 (2M+H).sup.+.
Example 219C
methyl
{(2S)-1-[(2S)-2-(4-{4-[4-(4-cyclohexylphenyl)-5-(4-{2-[(2S)-1-{(2S)-
-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol--
4-yl}phenyl)-4H-1,2,4-triazol-3-yl]phenyl}-1H-imidazol-2-yl)pyrrolidin-1-y-
l]-3-methyl-1-oxobutan-2-yl}carbamate
[0885] Charged a nitrogen-purged microwave tube (size M, 5 mL) with
the product of Example 219B (118 mg, 0.187 mmol), the product of
Example 126G (174 mg, 0.467 mmol), and a mixture of absolute EtOH
(1 mL) and toluene (1 mL), then added 1M aq sodium carbonate (0.467
mL, 0.467 mmol) and sparged the mixture with nitrogen for 20 min.
Added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (15.26 mg, 0.019 mmol), sparged again with
nitrogen for 5 min, sealed the tube with an aluminum crimp cap, and
heated in a microwave reactor (Personal Chemistry Emrys Creator)
with stirring at 100.degree. C. for 1 hr. Cooled reaction to room
temperature, diluted reaction in EtOAc (50 mL), washed with
H.sub.2O (2.times.25 mL) and brine (25 mL), dried the organic phase
over anhydrous MgSO.sub.4, filtered, and concentrated by rotary
evaporation to a solid. Purified by flash chromatography (silica
gel, step gradient 5% to 8% to 10% MeOH/CH.sub.2Cl.sub.2) to afford
the product as a tan solid (72 mg) which was .about.85% pure (2
main impurities). Dissolved impure product in 1.5 mL 1:1 v/v
MeOH/DMSO and purified by RP-C18 HPLC (Waters Prep LC, 40 mm Module
with Nova Pak HR C.sub.18 6 .mu.m 40.times.100 mm Prep Pak
cartridge) eluting with a 30 min gradient of 95:5 0.1% TFA in
H2O/AcCN to 25:75 0.1% TFA in H.sub.2O/AcCN, then 10 min to 100%
AcCN at 20 mL/min. Pure fractions were concentrated by rotary
evaporation (water bath 35.degree. C.) to a small volume,
partitioned between 20% iPrOH/CHCl.sub.3 (50 mL) and sat'd aq
NaHCO.sub.3 (15 mL), separated layers, dried the organic extract
over anhydrous MgSO.sub.4, filtered, and concentrated by rotary
evaporation to afford the title compound as a white solid (34.5 mg,
19%). .sup.1H NMR (400 MHz, DMSO-D6) .delta. ppm 0.83 (d, J=6.72
Hz, 6H) 0.86 (d, J=6.72 Hz, 6H) 1.29-1.47 (m, 5H) 1.65-2.01 (m,
12H) 2.04-2.21 (m, 4H) 3.53 (s, 6H) 3.72-3.84 (m, 4H) 4.04 (t,
J=8.40 Hz, 2H) 5.04 (dd, J=6.89, 3.20 Hz, 2H) 7.23-7.40 (m, 10H)
7.51-7.72 (m, 6H) 11.84 (s, 2H); MS (ESI+) m/z 965 (M+H).sup.+.
[0886] Examples 220-308 were prepared in analogous fashion
according to the methods and conditions illustrated in the
foregoing schemes and examples.
##STR00468##
Example 220
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(4-tert-butylphenyl)-5-{2-[(2S)-1-{(2-
S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}pyrrolidin-2-yl]-1H-ben-
zimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3,3--
dimethyl-1-oxobutan-2-yl}carbamate
[0887] .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 0.88 (d, J=13.55
Hz, 18H), 1.07 (s, 9H), 1.62-1.78 (m, 2H), 1.91-2.09 (m, 4H),
2.10-2.26 (m, 4H), 2.54-2.62 (m, 2H), 3.55 (s, 6H), 3.74-3.90 (m,
4H), 4.23 (dd, J=8.78, 4.55 Hz, 2H), 5.09-5.23 (m, 2H), 5.31-5.43
(m, 2H), 6.26 (d, J=8.89 Hz, 2H), 6.84-6.97 (m, 2H), 7.06 (dd,
J=8.29, 2.55 Hz, 2H), 7.12 (t, J=9.43 Hz, 2H), 7.20 (s, 1H), 7.30
(s, 1H), 7.38 (d, J=8.24 Hz, 1H) 7.45 (d, J=8.24 Hz, 1H), 12.02 (s,
2H); MS (ESI+) m/z 916 (M+H).sup.+.
##STR00469##
Example 221
dimethyl
([(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{1H-benzi-
midazole-5,2-diyl(2S)pyrrolidine-2,1-diyl[(2R)-1-oxo-2-phenylpropane-1,2-d-
iyl]})biscarbamate
[0888] .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.03-1.10 (m,
9H), 1.49-1.58 (m, 2H), 1.67 (d, J=16.70 Hz, 6H), 1.70-1.95 (m,
4H), 2.04 (s, 3H), 2.35-2.43 (m, 1H), 2.97-3.11 (m, 2H), 3.22-3.29
(m, 1H), 3.50 (s, 6H), 3.61-3.91 (m, 1H), 5.08-5.22 (m, 2H),
5.29-5.49 (m, 2H), 6.21-6.39 (m, 2H), 6.84-6.99 (m, 2H), 7.07-7.50
(m, 17H), 7.53 (d, J=8.24 Hz, 1H), 7.61 (s, 2H), 12.10 (two s, 2H);
MS (ESI+) m/z 984 (M+H).sup.+.
##STR00470##
[0889] Example 222
(2R,2'R)-1,1'-{[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[1H--
benzimidazole-5,2-diyl(2S)pyrrolidine-2,1-diyl]}bis(2-amino-2-phenylpropan-
-1-one)
[0890] .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.10 (s, 9H),
1.55-1.66 (m, 3H), 1.68-1.82 (m, 4H), 1.83-2.02 (m, 5H), 1.93 (s,
6H), 2.12-2.31 (m, 3H), 2.57 (d, J=3.90 Hz, 2H), 5.26-5.36 (m, 2H),
5.41-5.57 (m, 2H), 6.30 (d, J=8.78 Hz, 2H), 6.93 (d, J=8.78 Hz,
2H), 7.17-7.31 (m, 2H), 7.38 (s, 2H), 7.47-7.66 (m, 13H), 8.43 (s,
6H); MS (ESI+) m/z 868 (M+H).sup.+.
##STR00471##
Example 223
methyl
{(2S,3R)-1-[(2S,4S)-2-{5-[(2R,5R)-1-(4-tert-butylphenyl)-5-(2-{(2S,-
4S)-4-hydroxy-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}--
1H-benzimidazol-5-yl)pyrrolidin-2-yl]-1H-benzimidazol-2-yl}-4-hydroxypyrro-
lidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate
[0891] .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 0.96 (d, J=5.96
Hz, 6H), 1.09 (s, 9H), 1.74 (d, J=5.64 Hz, 2H), 2.06-2.15 (m, 3H),
2.96-3.03 (m, 1H), 3.10 (s, 6H), 3.55 (s, 6H), 3.72 (dd, J=9.65,
2.39 Hz, 3H), 3.94 (dd, J=10.25, 4.72 Hz, 2H), 4.23-4.33 (m, 2H),
4.38 (t, J=7.10 Hz, 1H), 4.44-4.53 (m, 2H), 5.26 (dd, J=8.46, 4.23
Hz, 2H), 5.49 (d, J=5.53 Hz, 2H), 6.25 (d, J=8.78 Hz, 2H), 6.94 (d,
J=8.78 Hz, 2H), 7.22 (d, J=8.46 Hz, 2H), 7.37 (d, J=7.59 Hz, 2H),
7.46 (s, 2H), 7.69 (d, J=7.92 Hz, 2H); MS (ESI+) m/z 952
(M+H).sup.+.
##STR00472##
Example 224
methyl
{(2S)-1-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[4-(1-met-
hoxy-2-methylpropan-2-yl)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrr-
olidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0892] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 0.74-0.93 (m, 12H)
1.04 (s, 6H) 1.69 (d, J=4.34 Hz, 2H) 1.85-1.94 (m, 2H) 1.95-2.03
(m, 6H) 2.13-2.25 (m, 2H) 2.53-2.63 (m, 4H) 3.11 (s, 3H) 3.53 (s,
6H) 3.81 (s, 4H) 4.05-4.15 (m, 2H) 5.09-5.19 (m, 2H) 5.32-5.41 (m,
2H) 6.25 (d, J=8.78 Hz, 2H) 6.87 (ddd, J=8.89, 4.77, 4.55 Hz, 2H)
7.07 (t, J=7.37 Hz, 2H) 7.20 (s, 1H) 7.25-7.33 (m, 3H) 7.38 (d,
J=8.24 Hz, 1H) 7.46 (d, J=8.46 Hz, 1H) 12.00-12.09 (m, 2H); MS
ESI+918.
##STR00473##
Example 225
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[4-(1-hydroxy-2-methylpropan-2-yl)phe-
nyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrol-
idin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrr-
olidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0893] 1H NMR (400 MHz, DMSO-D6) d ppm 0.76-0.91 (m, 12H) 1.01 (d,
J=2.60 Hz, 6H) 1.64-1.72 (m, 2H) 1.91 (dd, J=14.42, 6.83 Hz, 2H)
1.95-2.05 (m, 4H) 2.14-2.23 (m, 4H) 2.54-2.60 (m, 2H) 3.53 (s, 6H)
3.76-3.87 (m, 4H) 4.11 (q, J=4.77 Hz, 4H) 4.42 (s, 1H) 5.09-5.17
(m, 2H) 5.31-5.40 (m, 2H) 6.25 (d, J=8.78 Hz, 2H) 6.83-6.92 (m, 2H)
7.07 (t, J=7.21 Hz, 2H) 7.20 (s, 1H) 7.26-7.32 (m, 3H) 7.38 (d,
J=8.13 Hz, 1H) 7.46 (d, J=8.35 Hz, 1H) 11.99-12.06 (m, 2H); MS
ESI+m/z 904.5 (M+H)+.
##STR00474##
Example 226
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-{2-[4-(tr-
ifluoromethyl)phenyl]-1,3-thiazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2--
yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0894] 1H NMR (400 MHz, DMSO-D6) d ppm 0.73-0.91 (m, 12H) 1.79-1.95
(m, 4H) 1.96-2.06 (m, 4H) 2.15-2.27 (m, 2H) 2.69-2.76 (m, 2H)
3.43-3.50 (m, 2H) 3.53 (s, 6H) 3.78-3.88 (m, 4H) 4.01-4.10 (m, 2H)
5.11-5.18 (m, 2H) 5.32-5.41 (m, 2H) 6.43 (s, 1H) 7.09-7.18 (m, 2H)
7.27 (dd, J=8.24, 2.39 Hz, 2H) 7.35 (s, 1H) 7.41-7.46 (m, 2H) 7.51
(d, J=8.35 Hz, 1H) 7.57-7.62 (m, 2H) 7.64-7.70 (m, 2H) 12.12 (s,
2H); MS ESI+m/z 983.4 (M+H)+.
##STR00475##
Example 227
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-(4-tert-butyl-2,6-dimethylphenyl)-5-{-
2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-y-
l]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-
-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0895] 1H NMR (400 MHz, DMSO-D6) d ppm 0.77-0.89 (m, 12H) 1.02 (s,
9H) 1.84-2.05 (m, 10H) 2.13-2.19 (m, 4H) 2.24-2.30 (m, 6H) 3.53 (s,
6H) 3.80 (s, 4H) 4.04 (t, J=8.08 Hz, 2H) 5.07-5.14 (m, 2H) 5.25 (s,
2H) 6.61 (dd, J=5.10, 2.71 Hz, 2H) 7.06 (dd, J=11.87, 8.51 Hz, 2H)
7.20-7.37 (m, 6H) 11.89 (s, 1H) 11.99 (s, 1H); MS ESI+m/z 916.6
(M+H)+.
##STR00476##
Example 228
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-(4-phenyl-
cyclohexyl)pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-
-1-oxobutan-2-yl}carbamate
[0896] 1H NMR (400 MHz, DMSO-D6) d ppm 0.78-0.93 (m, 12H) 1.15-1.44
(m, 4H) 1.46-1.59 (m, 2H) 1.67-1.78 (m, 2H) 1.84-1.96 (m, 4H)
1.98-2.10 (m, 4H) 2.14-2.27 (m, 4H) 2.67-2.75 (m, 2H) 3.07-3.21 (m,
1H) 3.45-3.52 (m, 1H) 3.54 (s, 6H) 3.78-3.91 (m, 4H) 4.03-4.13 (m,
2H) 4.64-4.73 (m, 2H) 5.17 (d, J=4.88 Hz, 2H) 7.00-7.06 (m, 2H)
7.09 (t, J=7.32 Hz, 2H) 7.14-7.24 (m, 3H) 7.30 (d, J=8.46 Hz, 2H)
7.38 (d, J=8.02 Hz, 1H) 7.43-7.50 (m, 3H) 12.00 (s, 2H); MS ESLD+
m/z 914.
##STR00477##
Example 229
methyl
{(2S)-1-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[4-(tetra-
hydro-2H-pyran-4-yl)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidi-
n-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0897] 1H NMR (400 MHz, DMSO-D6) d ppm 0.73-0.94 (m, 12H) 1.41-1.60
(m, 6H) 1.65-1.75 (m, 2H) 1.86-1.94 (m, 2H) 1.95-2.05 (m, 4H)
2.14-2.24 (m, 4H) 2.37-2.46 (m, 2H) 3.53 (s, 6H) 3.77-3.86 (m, 7H)
4.02-4.10 (m, 2H) 5.09-5.17 (m, 2H) 5.32-5.39 (m, 2H) 6.26 (d,
J=8.67 Hz, 2H) 6.72-6.81 (m, 2H) 7.06 (t, J=7.64 Hz, 2H) 7.20 (s,
1H) 7.26-7.31 (m, 3H) 7.37 (d, J=8.13 Hz, 1H) 7.45 (d, J=8.13 Hz,
1H) 12.00-12.05 (m, 2H); MS ESLD+m/z 917 (M+H)+.
##STR00478##
Example 230
methyl
{(2S)-1-[(2S,4S)-2-{6-[(2R,5R)-1-(4-tert-butylphenyl)-5-{2-[(2S,4S)-
-4-hydroxy-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin--
2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}-4-hydrox-
ypyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0898] 1H NMR (500 MHz, DMSO-D6) d ppm 0.67-0.91 (m, 12H) 1.07 (s,
9H) 1.69 (d, J=3.97 Hz, 2H) 1.78-1.89 (m, 2H) 2.01 (d, J=13.12 Hz,
2H) 2.37-2.44 (m, 2H) 3.53 (s, 6H) 3.67 (d, J=10.07 Hz, 2H)
3.95-4.07 (m, 4H) 4.38 (s, 2H) 5.12 (s, 2H) 5.37 (s, 2H) 6.25 (d,
J=8.54 Hz, 2H) 6.34 (s, 2H) 6.86-6.94 (m, 2H) 7.09 (d, J=7.93 Hz,
2H) 7.22-7.33 (m, 4H) 7.39-7.51 (m, 2H) 12.27 (d, J=21.05 Hz, 2H);
MS ESLD+m/z 920.
##STR00479##
Example 231
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-(1,3-benzodioxol-5-yl)-5-{2-[(2S)-1-{-
(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzi-
midazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-meth-
yl-1-oxobutan-2-yl}carbamate
[0899] 1H NMR (400 MHz, DMSO-D6) d ppm 0.78-0.91 (m, 12H) 1.64-1.72
(m, 2H) 1.86-2.04 (m, 6H) 2.14-2.24 (m, 4H) 3.29 (s, 2H) 3.54 (s,
6H) 3.82 (s, 4H) 4.05-4.11 (m, 2H) 5.10-5.18 (m, 2H) 5.29-5.36 (m,
2H) 5.66 (d, J=2.93 Hz, 1H) 5.70-5.75 (m, 2H) 5.99 (d, J=2.28 Hz,
1H) 6.45-6.51 (m, 1H) 7.02-7.09 (m, 2H) 7.21 (s, 1H) 7.28 (s, 1H)
7.31 (d, J=6.40 Hz, 2H) 7.37 (d, J=8.13 Hz, 1H) 7.45 (d, J=8.24 Hz,
1H) 12.03 (s, 2H); MS TFA+ m/z 876.8 (M+H)+.
##STR00480##
Example 232
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-(4-{[(4S)-
-2-oxo-1,3-oxazolidin-4-yl]methyl}phenyl)pyrrolidin-2-yl]-1H-benzimidazol--
2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0900] 1H NMR (400 MHz, DMSO-D6) d ppm 0.77-0.92 (m, 12H) 1.63-1.74
(m, 2H) 1.86-2.04 (m, 6H) 2.13-2.26 (m, 4H) 2.55-2.65 (m, 2H)
3.25-3.33 (m, 2H) 3.54 (s, 6H) 3.75-3.87 (m, 6H) 4.05-4.17 (m, 3H)
5.09-5.19 (m, 2H) 5.36 (d, J=5.10 Hz, 2H) 6.27 (d, J=8.57 Hz, 2H)
6.71-6.79 (m, 2H) 7.05 (t, J=9.60 Hz, 2H) 7.20 (s, 1H) 7.27-7.33
(m, 3H) 7.37 (d, J=8.24 Hz, 1H) 7.45 (d, J=8.13 Hz, 1H) 7.63 (s,
1H) 12.03 (s, 2H); MS ESI+m/z 931.5 (M+H)+.
##STR00481##
Example 233
methyl
{(2S)-1-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[4-(propa-
n-2-yloxy)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-yl]-3--
methyl-1-oxobutan-2-yl}carbamate
[0901] 1H NMR (400 MHz, DMSO-D6) d ppm 0.76-0.89 (m, 12H) 1.07 (t,
J=5.42 Hz, 6H) 1.68 (d, J=3.47 Hz, 2H) 1.85-2.05 (m, 6H) 2.14-2.25
(m, 4H) 2.58 (d, J=4.77 Hz, 2H) 3.53 (s, 6H) 3.81 (s, 4H) 4.05 (t,
J=8.40 Hz, 2H) 4.13-4.25 (m, 1H) 5.08-5.20 (m, 2H) 5.32 (d, J=5.31
Hz, 2H) 6.23 (d, J=9.00 Hz, 2H) 6.45-6.55 (m, 2H) 7.05 (t, J=8.19
Hz, 2H) 7.20 (s, 1H) 7.26-7.33 (m, 3H) 7.37 (d, J=8.24 Hz, 1H) 7.44
(d, J=8.35 Hz, 1H) 12.02 (d, J=4.55 Hz, 2H); MS ESI+m/z 890.4
(M+H)+.
##STR00482##
Example 234
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[2-(4-fluorophenyl)-1,3-thiazol-5-yl]-
-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-
-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolid-
in-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0902] 1H NMR (400 MHz, DMSO-D6) d ppm 0.75-0.85 (m, 12H) 1.77-1.83
(m, 2H) 1.87-1.93 (m, 2H) 1.95-2.06 (m, 4H) 2.14-2.25 (m, 6H) 3.53
(s, 6H) 3.77-3.86 (m, 4H) 4.03-4.10 (m, 2H) 5.12-5.18 (m, 2H)
5.28-5.35 (m, 2H) 7.06-7.16 (m, 5H) 7.28 (dd, J=8.29, 2.01 Hz, 2H)
7.33 (s, 1H) 7.40-7.45 (m, 2H) 7.47-7.55 (m, 3H) 12.10 (s, 2H); MS
ESI+m/z 933.4 (M+H)+.
##STR00483##
Example 235
methyl
{(2S)-1-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[4-(trifl-
uoromethoxy)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrolidin-1-yl]--
3-methyl-1-oxobutan-2-yl}carbamate
[0903] 1H NMR (400 MHz, DMSO-D6) d ppm 0.74-0.87 (m, 12H) 1.67-1.76
(m, 2H) 1.86-1.92 (m, 2H) 1.96-2.06 (m, 4H) 2.15-2.23 (m, 6H) 3.53
(s, 6H) 3.77-3.88 (m, 4H) 4.05 (t, J=8.84 Hz, 2H) 5.12 (t, J=7.05
Hz, 2H) 5.37-5.46 (m, 2H) 6.34 (d, J=9.11 Hz, 2H) 6.89 (q, J=7.30
Hz, 2H) 7.02-7.11 (m, 2H) 7.21 (s, 1H) 7.26-7.33 (m, 3H) 7.39 (d,
J=8.35 Hz, 1H) 7.47 (d, J=8.13 Hz, 1H) 12.06 (d, J=17.02 Hz, 2H);
MS ESI+m/z 916.4 (M+H)+.
##STR00484##
Example 236
methyl
{(2S)-1-[(2S,4S)-2-{5-[(2R,5R)-1-(4-tert-butylphenyl)-5-{2-[(2S,4S)-
-4-methoxy-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin--
2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}-4-methox-
ypyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0904] 1H NMR (400 MHz, DMSO-D6) d ppm 0.75-0.88 (m, 12H) 1.07 (s,
9H) 1.67-1.76 (m, 2H) 1.88-2.00 (m, 4H) 2.06-2.16 (m, 2H) 3.12-3.21
(m, 2H) 3.25 (d, J=4.23 Hz, 6H) 3.54 (s, 6H) 3.59-3.69 (m, 2H)
4.02-4.13 (m, 4H) 4.16-4.28 (m, 2H) 5.11 (td, J=9.38, 6.51 Hz, 2H)
5.35 (t, J=5.37 Hz, 2H) 6.23-6.28 (m, 2H) 6.90 (d, J=8.89 Hz, 2H)
7.06 (d, J=10.19 Hz, 2H) 7.22 (d, J=3.25 Hz, 1H) 7.25-7.32 (m, 3H)
7.38 (d, J=8.35 Hz, 1H) 7.45 (d, J=8.24 Hz, 1H) 11.79 (d, J=18.32
Hz, 2H); MS ESI+m/z 948.5 (M+H)+.
##STR00485##
Example 237
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[2,5-difluoro-4-(trifluoromethyl)phen-
yl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrroli-
din-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrro-
lidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0905] 1H NMR (400 MHz, DMSO-D6) d ppm 0.74-0.90 (m, 12H) 1.74-1.83
(m, 2H) 1.86-1.93 (m, 2H) 1.94-2.05 (m, 4H) 2.13-2.25 (m, 4H)
3.44-3.48 (m, 2H) 3.53 (s, 6H) 3.77-3.88 (m, 4H) 4.06 (t, J=4.23
Hz, 2H) 5.10-5.16 (m, 2H) 5.63-5.74 (m, 2H) 6.60-6.73 (m, 1H)
7.04-7.20 (m, 4H) 7.24-7.31 (m, 3H) 7.38 (d, J=8.46 Hz, 1H) 7.46
(d, J=8.13 Hz, 1H) 12.08 (d, J=27.11 Hz, 2H); MS ESI+m/z 936.4
(M+H)+.
##STR00486##
Example 238
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[3-fluoro-4-(trifluoromethyl)phenyl]--
5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin--
2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidi-
n-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0906] 1H NMR (400 MHz, DMSO-D6) d ppm 0.75-0.90 (m, 12H) 1.71-1.79
(m, 2H) 1.87-1.95 (m, 2H) 1.97-2.04 (m, 4H) 2.13-2.25 (m, 6H) 3.53
(s, 6H) 3.77-3.86 (m, 4H) 4.04-4.11 (m, 2H) 5.11-5.18 (m, 2H)
5.46-5.56 (m, 2H) 6.24 (dd, J=8.24, 2.39 Hz, 2H) 7.04-7.11 (m, 2H)
7.19-7.25 (m, 2H) 7.28 (dd, J=8.46, 3.69 Hz, 2H) 7.32 (s, 1H) 7.41
(d, J=8.13 Hz, 1H) 7.49 (d, J=8.24 Hz, 1H) 12.09 (dd, J=15.72, 2.17
Hz, 2H); MS ESI+m/z 918.4 (M+H)+.
##STR00487##
Example 239
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-(4-cyanophenyl)-5-{2-[(2S)-1-{(2S)-2--
[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-
-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-ox-
obutan-2-yl}carbamate
[0907] 1H NMR (400 MHz, DMSO-D6) d ppm 0.76-0.90 (m, 12H) 1.70-1.79
(m, 2H) 1.90 (dd, J=12.25, 6.40 Hz, 2H) 1.95-2.02 (m, 4H) 2.15-2.24
(m, 6H) 3.54 (s, 6H) 3.78-3.85 (m, 4H) 4.06 (t, J=8.29 Hz, 2H)
5.10-5.16 (m, 2H) 5.46-5.55 (m, 2H) 6.42 (d, J=8.67 Hz, 2H) 7.05
(dd, J=12.90, 8.57 Hz, 2H) 7.22 (s, 1H) 7.25-7.34 (m, 5H) 7.40 (d,
J=8.24 Hz, 1H) 7.47 (d, J=8.24 Hz, 1H) 12.09 (s, 2H); MS ESI+m/z
857.4 (M+H)+.
##STR00488##
Example 240
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[4-(2-cyanopropan-2-yl)phenyl]-5-{2-[-
(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]--
1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl-
]-3-methyl-1-oxobutan-2-yl}carbamate
[0908] 1H NMR (400 MHz, DMSO-D6) d ppm 0.75-0.91 (m, 12H) 1.47 (s,
6H) 1.67-1.76 (m, 2H) 1.85-1.95 (m, 2H) 1.96-2.03 (m, 4H) 2.15-2.24
(m, 6H) 3.53 (s, 6H) 3.77-3.85 (m, 4H) 4.05 (t, J=8.46 Hz, 2H)
5.10-5.17 (m, 2H) 5.37-5.45 (m, 2H) 6.34 (d, J=8.89 Hz, 2H)
6.97-7.04 (m, 2H) 7.07 (t, J=8.35 Hz, 2H) 7.21 (s, 1H) 7.28 (d,
J=10.52 Hz, 3H) 7.39 (d, J=8.13 Hz, 1H) 7.47 (d, J=8.24 Hz, 1H)
12.05 (d, J=13.01 Hz, 2H); MS ESI+m/z 899.4 (M+H)+.
##STR00489##
Example 241
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-(4-cyano-3-fluorophenyl)-5-{2-[(2S)-1-
-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-ben-
zimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-me-
thyl-1-oxobutan-2-yl}carbamate
[0909] 1H NMR (400 MHz, DMSO-D6) d ppm 0.74-0.92 (m, 12H) 1.74 (t,
J=9.00 Hz, 2H) 1.87-1.94 (m, 2H) 1.96-2.06 (m, 4H) 2.15-2.25 (m,
4H) 2.55-2.63 (m, 2H) 3.54 (s, 6H) 3.82 (s, 4H) 4.06 (t, J=8.40 Hz,
2H) 5.14 (d, J=2.28 Hz, 2H) 5.55 (dd, J=16.26, 6.07 Hz, 2H)
6.18-6.33 (m, 2H) 7.01-7.15 (m, 2H) 7.23 (s, 1H) 7.25-7.35 (m, 4H)
7.42 (d, J=7.70 Hz, 1H) 7.49 (d, J=8.46 Hz, 1H) 12.10 (s, 2H); MS
ESI+m/z 875.4 (M+H)+.
##STR00490##
Example 242
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-
-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-
-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-
-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0910] 1H NMR (400 MHz, DMSO-D6) d ppm 0.75-0.91 (m, 12H) 1.69-1.77
(m, 2H) 1.91 (dd, J=14.26, 6.67 Hz, 2H) 1.96-2.07 (m, 4H) 2.14-2.24
(m, 4H) 2.54-2.60 (m, 2H) 3.53 (s, 6H) 3.78-3.86 (m, 4H) 4.06 (t,
J=8.40 Hz, 2H) 5.10-5.17 (m, 2H) 5.36-5.44 (m, 2H) 6.05 (dd,
J=9.11, 2.17 Hz, 1H) 6.29 (d, J=2.60 Hz, 1H) 6.89-6.95 (m, 1H) 7.06
(t, J=8.51 Hz, 2H) 7.22 (s, 1H) 7.26-7.33 (m, 3H) 7.39 (d, J=8.35
Hz, 1H) 7.47 (d, J=7.59 Hz, 1H) 12.03-12.09 (m, 2H); MS ESI+m/z
912.8 (M+H)+.
##STR00491##
Example 243
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[4-(1-amino-2-methylpropan-2-yl)pheny-
l]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolid-
in-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrol-
idin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0911] 1H NMR (400 MHz, DMSO-D6) d ppm 0.74-0.92 (m, 12H) 1.01 (d,
J=5.20 Hz, 6H) 1.65-1.76 (m, 2H) 1.86-1.93 (m, 2H) 1.98 (d, J=4.01
Hz, 4H) 2.13-2.25 (m, 4H) 2.41 (s, 2H) 2.53-2.61 (m, 2H) 3.53 (s,
6H) 3.81 (s, 4H) 4.05 (t, J=8.35 Hz, 2H) 5.08-5.17 (m, 2H)
5.32-5.41 (m, 2H) 6.27 (d, J=8.89 Hz, 2H) 6.81-6.92 (m, 2H) 7.07
(t, J=7.97 Hz, 2H) 7.20 (s, 1H) 7.25-7.32 (m, 3H) 7.38 (d, J=8.13
Hz, 1H) 7.46 (d, J=8.13 Hz, 1H) 12.02 (d, J=19.63 Hz, 2H); MS
ESI+m/z 903.4 (M+H)+.
##STR00492##
Example 244
methyl
(2-{4-[(2R,5R)-2-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-meth-
ylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-5-{2-[(2S)-1-{(2S)-2-[(m-
ethoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6--
yl}pyrrolidin-1-yl]phenyl}-2-methylpropyl)carbamate
[0912] 1H NMR (400 MHz, DMSO-D6) d ppm 0.75-0.91 (m, 12H) 1.00 (d,
J=6.07 Hz, 6H) 1.64-1.75 (m, 2H) 1.83-1.94 (m, 2H) 1.96-2.05 (m,
4H) 2.14-2.23 (m, 4H) 2.89-3.00 (m, 2H) 3.17 (d, J=5.20 Hz, 2H)
3.42 (s, 3H) 3.53 (s, 6H) 3.77-3.87 (m, 4H) 3.99-4.07 (m, 2H)
5.08-5.20 (m, 2H) 5.32-5.42 (m, 2H) 6.27 (d, J=8.46 Hz, 2H)
6.72-6.80 (m, 1H) 6.83-6.93 (m, 2H) 7.07 (t, J=8.62 Hz, 2H) 7.20
(s, 1H) 7.26-7.33 (m, 3H) 7.38 (d, J=8.13 Hz, 1H) 7.45 (d, J=8.57
Hz, 1H) 12.03 (d, J=12.36 Hz, 2H)
[0913] MS ESI+m/z 961.4 (M+H)+
##STR00493##
Example 245
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3-fluoro-4-(piperidin-1-yl)phenyl]-5-
-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-
-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-
-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate MS (ESI) m/z 934
(M+H)+
##STR00494##
[0914] Example 246
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(1,1-dioxidothiomorpholin-4-yl)-3--
fluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutano-
yl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol--
2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate MS (ESI)
m/z 984 (M+H).sup.+
##STR00495##
[0915] Example 247
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3-fluoro-4-(4-methylpiperidin-1-yl)p-
henyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrr-
olidin-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}py-
rrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate MS (ESI) m/z 948
(M+H).sup.+
##STR00496##
[0916] Example 248
methyl
{(2S)-1-[(2S)-2-(6-{(5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)ami-
no]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[4-(tricyclo-
[3.3.1.1-3,7-]dec-1-yl)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl)pyrrol-
idin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate +ESI m/z (rel
abundance) 967 (100, M+H)
##STR00497##
[0917] Example 249
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[4-(azepan-1-yl)-3-fluorophenyl]-5-{2-
-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl-
]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1--
yl]-3-methyl-1-oxobutan-2-yl}carbamate +ESI m/z (rel abundance) 948
(100, M+H)
##STR00498##
[0918] Example 250
methyl
{(2S,3R)-1-[(2S)-2-{6-[(2R,5R)-1-(4-tert-butylphenyl)-5-(2-{(2S)-1--
[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol--
6-yl)pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-ox-
obutan-2-yl}carbamate MS (ESI) m/z 920 (M+H).sup.+
##STR00499##
[0919] Example 251
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-(4-cyclopropyl-2-fluorophenyl)-5-{2-[-
(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]--
1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl-
]-3-methyl-1-oxobutan-2-yl}carbamate MS (ESI) m/z 890
(M+H).sup.+
##STR00500##
[0920] Example 252
methyl
[(2S)-1-{(2S)-2-[4-(3-{5-(3-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)am-
ino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl}phenyl)-1-[6-(pipe-
ridin-1-yl)pyridin-3-yl]-1H-pyrrol-2-yl}phenyl)-1H-imidazol-2-yl]pyrrolidi-
n-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate MS (ESI; M+H)
m/z=964.5
##STR00501##
[0921] Example 253
methyl
{(2S)-1-[(2S)-2-{6-[(2S,5S)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}-1-{4-[(2-me-
thoxyethyl)(methyl)amino]phenyl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrr-
olidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate MS (ESI; M+H)
m/z=919.4
##STR00502##
[0922] Example 254
methyl
{(2S,3R)-1-[(2S)-2-{6-[(2S,5S)-1-(4-tert-butylphenyl)-5-(2-{(2S)-1--
[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol--
6-yl)pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-ox-
obutan-2-yl}carbamate MS (ESI; M+H) m/z=920.5
##STR00503##
[0923] Example 255
methyl
[(2S)-1-(2-{5-[(2R,5R)-5-[2-(1-{(2S)-2-[(methoxycarbonyl)amino]-3-m-
ethylbutanoyl}pyrrolidin-2-yl)-1H-benzimidazol-5-yl]-1-{4-[2-(piperidin-1--
yl)ethoxy]phenyl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl)-3--
methyl-1-oxobutan-2-yl]carbamate MS (ESI; M+H) m/z=959.6
##STR00504##
[0924] Example 256
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3-chloro-4-(piperidin-1-yl)phenyl]-5-
-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-
-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-
-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (ESI+) m/z 949.5
(M+H)+
##STR00505##
[0925] Example 257
methyl
{(2S)-1-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-5-yl}-1-[4-(piper-
idin-1-yl)-3-(trifluoromethyl)phenyl]pyrrolidin-2-yl}-1H-benzimidazol-2-yl-
)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (ESI+) m/z
983.5 (M+H)+
##STR00506##
[0926] Example 258
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3-cyano-4-(piperidin-1-yl)phenyl]-5--
{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2--
yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin--
1-yl]-3-methyl-1-oxobutan-2-yl}carbamate ESI+) m/z 940.4 (M+H)+
##STR00507##
[0927] Example 259
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-(6-ethoxypyridin-3-yl)-5-{2-[(2S)-1-{-
(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzi-
midazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-meth-
yl-1-oxobutan-2-yl}carbamate ESI+m/z 878 (M+H)+
##STR00508##
[0928] Example 260
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}-1-{6-[methy-
l(methylsulfonyl)amino]pyridin-3-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}-
pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate ESI+m/z 940
(M+H)+
##STR00509##
[0929] Example 261
2-methylpropyl
{5-[(2R,5R)-2,5-bis(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-y-
l}-1H-benzimidazol-6-yl)pyrrolidin-1-yl]pyridin-2-yl}methylcarbamate
ESI+m/z 963 (M+H)+
##STR00510##
[0930] Example 262
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[4-(3,5-dimethylpiperidin-1-yl)-3-flu-
orophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-
pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-y-
l}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate ESI+m/z 962
(M+H)+
##STR00511##
[0931] Example 263
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[4-(diethylamino)-3-fluorophenyl]-5-{-
2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-y-
l]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-
-yl]-3-methyl-1-oxobutan-2-yl}carbamate ESI+m/z 922 (M+H)+
##STR00512##
[0932] Example 264
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-(6-cyclohexylpyridin-3-yl)-5-{2-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-b-
enzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3--
methyl-1-oxobutan-2-yl}carbamate
[0933] LC/MS: m/z 916.4 TFA method
##STR00513##
Example 265
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[3-fluoro-4-(pyrrolidin-1-yl)phenyl]--
5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin--
2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidi-
n-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate ESI+(m/z): 919.4
(m+H)
##STR00514##
[0934] Example 266
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-(4-tert-butylphenyl)-5-{2-[(2S)-1-{(2-
S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-indol-6-
-yl}pyrrolidin-2-yl]-1H-indol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2--
yl}carbamate m/z=886.5 (LC/MS)
##STR00515##
[0935] Example 267
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-(4-tert-butoxy-3-fluorophenyl)-5-{2-[-
(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]--
1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl-
]-3-methyl-1-oxobutan-2-yl}carbamate (ESI; M+H) m/z=922.4
##STR00516##
[0936] Example 268
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[3-fluoro-4-(propan-2-yloxy)phenyl]-5-
-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-
-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-
-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (ESI; M+H) m/z=908.5
##STR00517##
[0937] Example 269
[0938] methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-(3-fluoro-4-hydroxyphenyl)-5-{2-[(2S)-1-{(2-
S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimi-
dazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-
-1-oxobutan-2-yl}carbamate (ESI; M+H) m/z=866.3
##STR00518##
Example 270
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-(3-fluoro-4-methoxyphenyl)-5-{2-[(2S)-
-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-b-
enzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3--
methyl-1-oxobutan-2-yl}carbamate (ESI; M+H) m/z=880
##STR00519##
[0939] Example 271
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)pheny-
l]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolid-
in-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrol-
idin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0940] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 0.73-0.90 (m, 12H)
1.32-2.28 (m, 20H) 2.76 (s, 4H) 3.54 (s, 6H) 3.82 (s, 4H) 3.99-4.12
(m, 2H) 5.10-5.20 (m, 2H) 5.36 (d, J=7.59 Hz, 2H) 5.83-5.95 (m, 2H)
7.01-7.14 (m, 2H) 7.20 (s, 1H) 7.26-7.33 (m, 3H) 7.41 (d, J=8.24
Hz, 1H) 7.49 (d, J=8.24 Hz, 1H) 12.01-12.31 (m, 2H); MS (ESI; M+H)
m/z=951.5.
##STR00520##
Example 272
dimethyl
([(2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{1,3-thia-
zole-4,2-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1-
,2-diyl]})biscarbamate ESI m/z 908.4 (M+H)
##STR00521##
[0941] Example 273
dimethyl
([(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{1,3-thia-
zole-4,2-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1-
,2-diyl]})biscarbamate ESI m/z 908.4 (M+H)
##STR00522##
[0942] Example 274
dimethyl
([(2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{1,3-thia-
zole-4,2-diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S)-3,3-dimethyl-1-oxobutane-1,2-diyl]})biscarbamate ESI m/z
936.5 (M+H)
##STR00523##
[0943] Example 275
dimethyl
([(2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{1,3-thia-
zole-4,2-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S,3R)-3-methoxy-1-oxobuta-
ne-1,2-diyl]})biscarbamate ESI m/z 940.5 (M+H)
##STR00524##
[0944] Example 276
dimethyl
([(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{1,3-thia-
zole-4,2-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S,3R)-3-methoxy-1-oxobuta-
ne-1,2-diyl]})biscarbamate ESI m/z 940.5 (M+H)
##STR00525##
[0945] Example 277
dimethyl
([(2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{1,3-thia-
zole-4,2-diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S,3S)-3-methyl-1-oxopentane-1,2-diyl]})biscarbamate ESI m/z
936.5 (M+H)
##STR00526##
[0946] Example 278
dimethyl
([(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{1,3-thia-
zole-4,2-diylcarbamoyl(2S)pyrrolidine-2,1-diyl
[(2S,3S)-3-methyl-1-oxopentane-1,2-diyl]})biscarbamate ESI m/z
936.5 (M+H)
##STR00527##
[0947] Example 279
methyl
{(2S)-1-[(2S)-2-{6-[1-(4-tert-butylphenyl)-5-{2-[(2S)-1-{(2S)-2-[(m-
ethoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-3H-imidazo[4,5-b]p-
yridin-6-yl}pyrrolidin-2-yl]-3H-imidazo[4,5-b]pyridin-2-yl}pyrrolidin-1-yl-
]-3-methyl-1-oxobutan-2-yl}carbamate LCMS m/z 890 (M+H)
##STR00528##
[0948] Example 280
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-(4-tert-butylphenyl)-5-{2-[(2S)-1-{(2-
S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1,3-benzox-
azol-6-yl}pyrrolidin-2-yl]-1,3-benzoxazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-
-oxobutan-2-yl}carbamate ESI+:(M+H): 890.5
##STR00529##
[0949] Example 281
N-(methoxycarbonyl)-L-valyl-N-{5-[1-(4-tert-butylphenyl)-5-(2-{(2S)-1-[N-(-
methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-benzimidazol-6-yl)pyrrolidin--
2-yl]-2-methoxyphenyl}-L-prolinamide ESI+:(M+H): 921.5
##STR00530##
[0950] Example 282
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-(4-tert-butyl-2-fluorophenyl)-5-{2-[(-
2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1-
H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-
-3-methyl-1-oxobutan-2-yl}carbamate ESI+:(M+H): 906.4
##STR00531##
[0951] Example 283
{[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[1H-benzimidazole--
6,2-diyl(2S)pyrrolidine-2,1-diyl]}bis[(1-hydroxycycloheptyl)methanone]MS
(ESI) positive ion 854 (M+H).sup.+
##STR00532##
[0952] Example 284
(1S,4R,1'S,4'R)-1,1'-{[(2R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis-
[1H-benzimidazole-6,2-diyl(2S)pyrrolidine-2,1-diylcarbonyl]}bis(7,7-dimeth-
ylbicyclo[2.2.1]heptan-2-one) MS (ESI) positive ion 902
(M+H).sup.+
##STR00533##
[0953] Example 285
1,1'-{[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[1H-benzimida-
zole-6,2-diyl(2S)pyrrolidine-2,1-diyl]}bis(2,2-diphenylpropan-1-one)
MS (ESI) positive ion (M+H).sup.+. Is not observed but MS (APCI)
positive ion 990 (M+H).sup.+ observed
##STR00534##
[0954] Example 286
(2S,2'S)-1,1'-{[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[1H--
benzimidazole-6,2-diyl(2S)pyrrolidine-2,1-diyl]}bis(3,3,3-trifluoro-2-meth-
oxy-2-phenylpropan-1-one) MS (ESI) positive ion 1006
(M+H).sup.+
##STR00535##
[0955] Example 287
{[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[1H-benzimidazole--
6,2-diyl(2S)pyrrolidine-2,1-diyl]}bis[(1-phenylcyclopentyl)methanone]MS
(ESI) positive ion 918.6 (M+H).sup.+
##STR00536##
[0956] Example 288
1,1'-{[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[1H-benzimida-
zole-6,2-diyl(2S)pyrrolidine-2,1-diyl]}bis(2-cyclopentyl-2-phenylethanone)
MS (ESI) positive ion 946 (M+H).sup.+
##STR00537##
[0957] Example 289
1,1'-{[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[1H-benzimida-
zole-6,2-diyl(2S)pyrrolidine-2,1-diyl]}bis(2-cyclohexyl-2-phenylethanone)
MS (ESI) positive ion 974 (M+H).sup.+
##STR00538##
[0958] Example 290
[0959]
(2R,2'R)-1,1'-{[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]-
bis[1H-benzimidazole-6,2-diyl(2S)pyrrolidine-2,1-diyl]}bis(3,3,3-trifluoro-
-2-methoxy-2-phenylpropan-1-one) MS (ESI) positive ion 1006
(M+H).sup.+.
##STR00539##
Example 291
{[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[1H-benzimidazole--
6,2-diyl(2S)pyrrolidine-2,1-diyl]}bis[(2,2,3,3-tetramethylcyclopropyl)meth-
anone]MS (ESI) positive ion 822 (M+H).sup.+
##STR00540##
[0960] Example 292
1,1'-{[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[1H-benzimida-
zole-6,2-diyl(2S)pyrrolidine-2,1-diyl]}bis(3-methyl-2-phenylbutan-1-one)
MS (ESI) positive ion 893 (M+NH.sub.4--H.sub.2O).sup.+
##STR00541##
[0961] Example 293
{[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[1H-benzimidazole--
6,2-diyl(2S)pyrrolidine-2,1-diyl]}bis{[(1R,3R)-2,2-dimethyl-3-(2-methylpro-
p-1-en-1-yl)cyclopropyl]methanone}MS (ESI) positive ion 874
(M+H).sup.+
##STR00542##
[0962] Example 294
{[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[1H-benzimidazole--
6,2-diyl(2S)pyrrolidine-2,1-diyl]}bis[(2,2-dichloro-1-methylcyclopropyl)me-
thanone]MS (ESI) positive ion 874 (M+H).sup.+
##STR00543##
[0963] Example 295
(2R,2'R)-1,1'-{[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[1H--
benzimidazole-6,2-diyl(2S)pyrrolidine-2,1-diyl]}bis(2-hydroxy-2-phenylbuta-
n-1-one) MS (ESI) positive ion (M+H).sup.+
##STR00544##
[0964] Example 296
{[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[1H-benzimidazole--
6,2-diyl(2S)pyrrolidine-2,1-diyl]}bis{[1-(trifluoromethyl)cyclopropyl]meth-
anone}MS (ESI) positive ion 846 (M+H).sup.+
##STR00545##
[0965] Example 297
{[(2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[1H-benzimidazole--
6,2-diyl(2S)pyrrolidine-2,1-diyl]}bis[(1-phenylcyclopropyl)methanone]MS
(ESI) positive ion 862.5 (M+H).sup.+
##STR00546##
[0966] Example 298
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(difluoromethoxy)phenyl]-5-{2-[(2S-
)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H--
benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-
-methyl-1-oxobutan-2-yl}carbamate (ESI+) m/z 898.4 (M+H)+
##STR00547##
[0967] Example 299
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(3,5-difluoro-4-methoxyphenyl)-5-{2-[-
(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]--
1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl-
]-3-methyl-1-oxobutan-2-yl}carbamate (ESI+) m/z 898.4 (M+H)+
##STR00548##
[0968] Example 300
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[4-(4,4-dimethylpiperidin-1-yl)-3-flu-
orophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-
pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-y-
l}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0969] MS+ESI m/z (rel abundance) 962 (100, M+H); .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 7.52 (d, J=8.2, 1 H), 7.44 (d, J=8.1,
1H), 7.35 (d, J=8.1, 3H), 7.26 (s, 1H), 7.14 (m, 2H), 6.75 (s, 1H),
6.12 (m, 2H), 5.40 (s, 2H), 5.19 (s, 2H), 4.12 (t, J=8.4, 2H), 3.88
(s, 4H), 3.60 (s, 6H), 2.70 (m, 5H), 2.24 (s, 4H), 1.99 (m, 7H),
1.75 (s, 2H), 1.46 (s, 3H), 1.39 (s, 8H), 0.89 (m, 20H).
##STR00549##
Example 301
methyl
{(2S)-1-[(2S)-2-{6-[1-(4-tert-butylphenyl)-5-{4-fluoro-2-[(2S)-1-{(-
2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzim-
idazol-6-yl}pyrrolidin-2-yl]-4-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl-
]-3-methyl-1-oxobutan-2-yl}carbamate MS (ESI) m/z 924 (M+H)
##STR00550##
[0970] Example 302
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-(4-cyclopropyl-3-fluorophenyl)-5-{2-[-
(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]--
1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl-
]-3-methyl-1-oxobutan-2-yl}carbamate MS (ESI) m/z 891
(M+H).sup.+
##STR00551##
[0971] Example 303
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)-
amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}-1-{4-[2-(2--
methoxyethoxyl)ethoxy]phenyl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrroli-
din-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate MS (ESI) m/z 950
(M+H).sup.+, 948 (M-H).sup.+
##STR00552##
[0972] Example 304
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[3-fluoro-4-(3-methylpyrrolidin-1-yl)-
phenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyr-
rolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}p-
yrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0973] 1H NMR (400 MHz, DMSO-D6) .delta. ppm 0.76-0.89 (m, 12H)
0.95 (d, J=6.72 Hz, 3H) 1.62-1.72 (m, 2H) 1.83-2.06 (m, 9H)
2.09-2.24 (m, 6H) 2.52-2.61 (m, 2H) 2.91-3.15 (m, 4H) 3.52 (s, 6H)
3.74-3.86 (m, 4H) 4.05 (t, J=8.35 Hz, 2H) 5.08-5.17 (m, 2H)
5.26-5.38 (m, 2H) 5.97-6.10 (m, 2H) 6.35-6.45 (m, 1H) 7.01-7.08 (m,
2H) 7.19 (s, 1H) 7.25-7.32 (m, 3H) 7.36 (d, J=8.24 Hz, 1H) 7.44 (d,
J=7.92 Hz, 1H) 12.01 (s, 2H).
##STR00553##
Example 305
methyl
{(2S)-1-[(2S)-2-{5-[(2R,5R)-1-[2,3-difluoro-4-(piperidin-1-yl)pheny-
l]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolid-
in-2-yl]-1H-benzimidazol-5-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrol-
idin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0974] ESI+(m/z): 951.5; 1H NMR (400 MHz, DMSO-D6) .delta. ppm
0.74-0.90 (m, 12H) 1.35-1.41 (m, 2H) 1.44-1.51 (m, 4H) 1.73-1.83
(m, 2H) 1.86-2.02 (m, 6H) 2.14-2.23 (m, 4H) 2.59-2.72 (m, 6H) 3.53
(s, 6H) 3.77-3.84 (m, 4H) 3.97-4.10 (m, 2H) 5.06-5.18 (m, 2H)
5.46-5.56 (m, 2H) 6.36-6.47 (m, 2H) 7.03-7.11 (m, 2H) 7.23-7.45 (m,
6H) 11.95-12.10 (m, 2H)
##STR00554##
Example 306
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-(4-ethoxy-3-fluorophenyl)-5-{2-[(2S)--
1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-be-
nzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-m-
ethyl-1-oxobutan-2-yl}carbamate ESI+(m/z): 894.4
##STR00555##
[0975] Example 307
methyl
{(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[4-(tert-butylamino)-3-fluorophenyl]--
5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin--
2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidi-
n-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
[0976] ESI+(m/z): 922; 1H NMR (400 MHz, DMSO-D6) .delta. ppm
0.75-0.90 (m, 12H) 0.97 (s, 9H) 1.61-1.71 (m, 2H) 1.83-2.04 (m, 6H)
2.12-2.23 (m, 4H) 3.52 (s, 6H) 3.76-3.86 (m, 4H) 4.01-4.08 (m, 2H)
5.09-5.17 (m, 2H) 5.27-5.37 (m, 2H) 5.98-6.07 (m, 2H) 6.56-6.66 (m,
1H) 7.06 (t, J=7.92 Hz, 2H) 7.19 (s, 1H) 7.27 (d, J=9.00 Hz, 3H)
7.38 (d, J=8.24 Hz, 1H) 7.46 (d, J=8.13 Hz, 1H) 12.00 (s, 1H) 12.08
(s, 1H)
##STR00556##
Example 308
ethyl
5-{(2R,5R)-1-(4-tert-butylphenyl)-5-[1-(ethoxycarbonyl)-2-{(2S)-1-[N-
-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl]pyrrolidi-
n-2-yl}-2-{1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-benzimidazol-
e-1-carboxylate and
ethyl
5-{(2R,5R)-1-(4-tert-butylphenyl)-5-[1-(ethoxycarbonyl)-2-{(2S)-1-[N-
-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-benzimidazol-6-yl]pyrrolidi-
n-2-yl}-2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-benzimi-
dazole-1-carboxylate
[0977] ESI+(m/z): 1032.5; 1H NMR (400 MHz, DMSO-D6) .delta. ppm
0.70-1.04 (m, 12H) 1.08 (s, 9H) 1.33-1.46 (m, 6H) 1.65-1.77 (m, 2H)
1.81-2.13 (m, 8H) 2.20-2.28 (m, 2H) 2.55-2.62 (m, 2H) 3.53 (d,
J=4.23 Hz, 6H) 3.80-3.92 (m, 4H) 4.04-4.13 (m, 2H) 4.41-4.59 (m,
4H) 5.38-5.49 (m, 2H) 5.66-5.76 (m, 2H) 6.17-6.33 (m, 2H) 6.82-7.00
(m, 3H) 7.18-7.56 (m, 5H) 7.75-7.91 (m, 2H)
[0978] The title compounds of Examples 52, 53, 54, 58, 59, 60, 61,
62, 63, 64, 65, 66, 67, 68, 69, 74, 75, 76, 77, 79, 80, 81, 82, 83,
84, 85, 86, 87, 88, 89, 90, 91, 93, 94, 95, 96, 97, 99, 101, 102,
103, 109, 110, 111, 112, 113, 117, 121, 122, 123, 125, 126, 127,
128, 129, 130, 131, 132, 135, 136, 137, 138, 139, 140, 141, 144,
145, 146, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 159,
160, 161, 162, 163, 166, 167, 168, 169, 170, 171, 173, 176, 178,
179, 180, 181, 183, 184, 185, 186, 188, 189, 191, 192, 194, 195,
197, 198, 199, 200, 201, 202, 203, 205, 207, 208, 209, 210, 211,
212, 214, 215, 216, 217, 218, 219, 220, 221, 224, 226, 227, 228,
229, 230, 231, 233, 234, 235, 236, 237, 238, 240, 241, 242, 245,
247, 248, 250, 251, 252, 254, 256, 257, 258, 262, 263, 264, 266,
267, 268, 270, 271, 272, 273, 274, 275, 276, 277, 278, 282, 294,
295, 296, 297, 298, 299, 300, 301, 302, 305, and 306 showed an
EC.sub.50 value of less than about 0.1 nM in HCV 1b-Con1 replicon
assays in the presence of 5% FBS. The title compounds of Examples
51, 55, 56, 57, 70, 71, 72, 73, 78, 98, 100, 108, 114, 115, 116,
119, 120, 133, 134, 142, 143, 147, 164, 172, 174, 182, 196, 204,
206, 222, 223, 225, 239, 244, 249, 253, 259, 261, 265, 281, 287,
288, 292, 303, 304, 307, and 308 showed an EC.sub.50 value of from
about 0.1 to about 1 nM in HCV 1b-Con1 replicon assays in the
presence of 5% FBS. The title compounds of Examples 92, 105, 106,
107, 118, 124, 158, 165, 175, 177, 187, 190, 193, 213, 232, 243,
246, 255, 260, 269, 279, 280, 283, 284, 285, 286, 289, 290, 291,
and 293 showed an EC.sub.50 value of from about 1 to about 100 nM
in HCV 1b-Con1 replicon assays in the presence of 5% FBS.
[0979] The present invention also contemplates pharmaceutically
acceptable salts of each compound in Examples 1-308, as well as
pharmaceutically acceptable salts of each compound described
hereinbelow.
[0980] The following compounds were similarly prepared according to
the procedures described above:
##STR00557## ##STR00558## ##STR00559## ##STR00560## ##STR00561##
##STR00562## ##STR00563##
[0981] When tested using HCV 1b-Con1 replicon assays in the
presence of 5% FBS, each of the above compounds showed an EC.sub.50
value of less than 1 nM.
[0982] In addition, the following mixtures of stereoisomers were
prepared according to procedures similar to those described above,
where each compound in each stereoisomer mixture can be readily
isolated using chiral chromatography or other suitable methods as
appreciated by those skilled in the art and, therefore, the present
invention also features each compound in these stereoisomer
mixtures:
##STR00564## ##STR00565## ##STR00566## ##STR00567## ##STR00568##
##STR00569## ##STR00570## ##STR00571## ##STR00572## ##STR00573##
##STR00574## ##STR00575## ##STR00576##
[0983] When tested using HCV 1b-Con1 replicon assays in the
presence of 5% FBS, each of the above mixtures (except mixture 12)
showed an EC.sub.50 value of less than 1 nM. Mixture 12 showed an
EC.sub.50 value of from about 1 to 10 nM in HCV 1b-Con1 replicon
assays in the presence of 5% FBS.
[0984] Likewise, the following compounds of Formula I or
pharmaceutically acceptable salts thereof can be similarly prepared
according to the schemes and procedures described above,
##STR00577##
wherein A is selected from Table 1a, B is selected from Table 1b, D
is selected from Table 2, Y and Z are each independently selected
from Table 3, and
##STR00578##
is selected from Table 4, and A, B, D and X are each independently
optionally substituted with one or more R.sub.A, and wherein
L.sub.1, L.sub.2, L.sub.3 and R.sub.A are as described above.
Preferably, L.sub.1, L.sub.2 and L.sub.3 are bond.
TABLE-US-00001 TABLE 1a A ##STR00579## ##STR00580## ##STR00581##
##STR00582## ##STR00583## ##STR00584## ##STR00585## ##STR00586##
##STR00587## ##STR00588## ##STR00589## ##STR00590## ##STR00591##
##STR00592## ##STR00593## ##STR00594## ##STR00595## ##STR00596##
##STR00597## ##STR00598## ##STR00599## ##STR00600## ##STR00601##
##STR00602## ##STR00603## ##STR00604## ##STR00605## ##STR00606##
##STR00607## ##STR00608## ##STR00609## ##STR00610## ##STR00611##
##STR00612## ##STR00613## ##STR00614## ##STR00615## ##STR00616##
##STR00617## ##STR00618## ##STR00619## ##STR00620## ##STR00621##
##STR00622## ##STR00623## ##STR00624## ##STR00625## ##STR00626##
##STR00627## ##STR00628## ##STR00629## ##STR00630## ##STR00631##
##STR00632## ##STR00633## ##STR00634## ##STR00635## ##STR00636##
##STR00637## ##STR00638## ##STR00639## ##STR00640## ##STR00641##
##STR00642## ##STR00643## ##STR00644## ##STR00645## ##STR00646##
##STR00647## ##STR00648##
TABLE-US-00002 TABLE 1b B ##STR00649## ##STR00650## ##STR00651##
##STR00652## ##STR00653## ##STR00654## ##STR00655## ##STR00656##
##STR00657## ##STR00658## ##STR00659## ##STR00660## ##STR00661##
##STR00662## ##STR00663## ##STR00664## ##STR00665## ##STR00666##
##STR00667## ##STR00668## ##STR00669## ##STR00670## ##STR00671##
##STR00672## ##STR00673## ##STR00674## ##STR00675## ##STR00676##
##STR00677## ##STR00678## ##STR00679## ##STR00680## ##STR00681##
##STR00682## ##STR00683## ##STR00684## ##STR00685## ##STR00686##
##STR00687## ##STR00688## ##STR00689## ##STR00690## ##STR00691##
##STR00692## ##STR00693## ##STR00694## ##STR00695## ##STR00696##
##STR00697## ##STR00698## ##STR00699## ##STR00700## ##STR00701##
##STR00702## ##STR00703## ##STR00704## ##STR00705## ##STR00706##
##STR00707## ##STR00708## ##STR00709## ##STR00710## ##STR00711##
##STR00712## ##STR00713## ##STR00714## ##STR00715## ##STR00716##
##STR00717## ##STR00718##
TABLE-US-00003 TABLE 2 D ##STR00719## ##STR00720## ##STR00721##
##STR00722## ##STR00723## ##STR00724## ##STR00725## ##STR00726##
##STR00727## ##STR00728## ##STR00729## ##STR00730## ##STR00731##
##STR00732## ##STR00733## ##STR00734## ##STR00735## ##STR00736##
##STR00737## ##STR00738## ##STR00739## ##STR00740## ##STR00741##
##STR00742## ##STR00743## ##STR00744## ##STR00745## ##STR00746##
##STR00747## ##STR00748## ##STR00749## ##STR00750## ##STR00751##
##STR00752## ##STR00753## ##STR00754## ##STR00755## ##STR00756##
##STR00757## ##STR00758## ##STR00759## ##STR00760## ##STR00761##
##STR00762## ##STR00763## ##STR00764## ##STR00765## ##STR00766##
##STR00767##
TABLE-US-00004 TABLE 3 Y and Z ##STR00768## ##STR00769##
##STR00770## ##STR00771## ##STR00772## ##STR00773## ##STR00774##
##STR00775## ##STR00776## ##STR00777## ##STR00778## ##STR00779##
##STR00780## ##STR00781## ##STR00782## ##STR00783## ##STR00784##
##STR00785## ##STR00786## ##STR00787## ##STR00788## ##STR00789##
##STR00790## ##STR00791## ##STR00792## ##STR00793## ##STR00794##
##STR00795## ##STR00796## ##STR00797## ##STR00798## ##STR00799##
##STR00800## ##STR00801## ##STR00802## ##STR00803## ##STR00804##
##STR00805## ##STR00806## ##STR00807## ##STR00808## ##STR00809##
##STR00810## ##STR00811## ##STR00812## ##STR00813## ##STR00814##
##STR00815## ##STR00816## ##STR00817## ##STR00818## ##STR00819##
##STR00820## ##STR00821## ##STR00822## ##STR00823## ##STR00824##
##STR00825## ##STR00826## ##STR00827## ##STR00828## ##STR00829##
##STR00830## ##STR00831## ##STR00832## ##STR00833##
TABLE-US-00005 TABLE 4 ##STR00834## ##STR00835## ##STR00836##
##STR00837## ##STR00838## ##STR00839## ##STR00840## ##STR00841##
##STR00842## ##STR00843## ##STR00844## ##STR00845## ##STR00846##
##STR00847## ##STR00848## ##STR00849## ##STR00850## ##STR00851##
##STR00852## ##STR00853## ##STR00854## ##STR00855## ##STR00856##
##STR00857## ##STR00858## ##STR00859## ##STR00860## ##STR00861##
##STR00862## ##STR00863## ##STR00864## ##STR00865## ##STR00866##
##STR00867## ##STR00868## ##STR00869## ##STR00870##
[0985] Other examples of the compounds of Formula I are provided in
Table 5.
TABLE-US-00006 TABLE 5 ##STR00871## ##STR00872## ##STR00873##
##STR00874## ##STR00875## ##STR00876## ##STR00877## ##STR00878##
##STR00879## ##STR00880## ##STR00881## ##STR00882## ##STR00883##
##STR00884## ##STR00885## ##STR00886## ##STR00887## ##STR00888##
##STR00889## ##STR00890## ##STR00891## ##STR00892## ##STR00893##
##STR00894## ##STR00895## ##STR00896## ##STR00897##
[0986] Each compound's anti-HCV activity can be determined by
measuring the activity of the luciferase reporter gene in the
replicon in the presence of 5% FBS. The luciferase reporter gene is
placed under the translational control of the poliovirus IRES
instead of the HCV IRES, and HuH-7 cells are used to support the
replication of the replicon.
[0987] The inhibitory activities of the compounds of the present
invention can be evaluated using a variety of assays known in the
art. For instance, two stable subgenomic replicon cell lines can be
used for compound characterization in cell culture: one derived
from genotype 1a-H77 and the other derived from genotype 1b-Con1,
obtained from University of Texas Medical Branch, Galveston, Tex.
or Apath, LLC, St. Louis, Mo., respectively. The replicon
constructs can be bicistronic subgenomic replicons. The genotype 1a
replicon construct contains NS3-NS5B coding region derived from the
H77 strain of HCV (1a-H77). The replicon also has a firefly
luciferase reporter and a neomycin phosphotransferase (Neo)
selectable marker. These two coding regions, separated by the FMDV
2a protease, comprise the first cistron of the bicistronic replicon
construct, with the second cistron containing the NS3-NS5B coding
region with addition of adaptive mutations E1202G, K1691R, K2040R
and S2204I. The 1b-Con1 replicon construct is identical to the
1a-H77 replicon, except that the HCV 5' UTR, 3' UTR, and NS3-NS5B
coding region are derived from the 1b-Con1 strain, and the adaptive
mutations are K1609E, K1846T and Y3005C. In addition, the 1b-Con1
replicon construct contains a poliovirus IRES between the HCV IRES
and the luciferase gene. Replicon cell lines can be maintained in
Dulbecco's modified Eagles medium (DMEM) containing 10% (v/v) fetal
bovine serum (FBS), 100 IU/ml penicillin, 100 mg/ml streptomycin
(Invitrogen), and 200 mg/ml G418 (Invitrogen).
[0988] The inhibitory effects of the compounds of the invention on
HCV replication can be determined by measuring activity of the
luciferase reporter gene. For example, replicon-containing cells
can be seeded into 96 well plates at a density of 5000 cells per
well in 100 .mu.l DMEM containing 5% FBS. The following day
compounds can be diluted in dimethyl sulfoxide (DMSO) to generate a
200.times. stock in a series of eight half-log dilutions. The
dilution series can then be further diluted 100-fold in the medium
containing 5% FBS. Medium with the inhibitor is added to the
overnight cell culture plates already containing 100 .mu.l of DMEM
with 5% FBS. In assays measuring inhibitory activity in the
presence of human plasma, the medium from the overnight cell
culture plates can be replaced with DMEM containing 40% human
plasma and 5% FBS. The cells can be incubated for three days in the
tissue culture incubators after which time 30 .mu.l of Passive
Lysis buffer (Promega) can be added to each well, and then the
plates are incubated for 15 minutes with rocking to lyse the cells.
Luciferin solution (100 .mu.l, Promega) can be added to each well,
and luciferase activity can be measured with a Victor II
luminometer (Perkin-Elmer). The percent inhibition of HCV RNA
replication can be calculated for each compound concentration and
the EC.sub.50 value can be calculated using nonlinear regression
curve fitting to the 4-parameter logistic equation and GraphPad
Prism 4 software. Using the above-described assays or similar
cell-based replicon assays, representative compounds of the present
invention showed significantly inhibitory activities against HCV
replication.
[0989] The present invention also features pharmaceutical
compositions comprising the compounds of the invention. A
pharmaceutical composition of the present invention can comprise
one or more compounds of the invention, each of which has Formula I
(or I.sub.A, I.sub.B, I.sub.C or I.sub.D).
[0990] In addition, the present invention features pharmaceutical
compositions comprising pharmaceutically acceptable salts,
solvates, or prodrugs of the compounds of the invention. Without
limitation, pharmaceutically acceptable salts can be zwitterions or
derived from pharmaceutically acceptable inorganic or organic acids
or bases. Preferably, a pharmaceutically acceptable salt retains
the biological effectiveness of the free acid or base of the
compound without undue toxicity, irritation, or allergic response,
has a reasonable benefit/risk ratio, is effective for the intended
use, and is not biologically or otherwise undesirable.
[0991] The present invention further features pharmaceutical
compositions comprising a compound of the invention (or a salt,
solvate or prodrug thereof) and another therapeutic agent. By way
of illustration not limitation, these other therapeutic agents can
be selected from antiviral agents (e.g., anti-HIV agents, anti-HBV
agents, or other anti-HCV agents such as HCV protease inhibitors,
HCV polymerase inhibitors, HCV helicase inhibitors, IRES inhibitors
or NS5A inhibitors), anti-bacterial agents, anti-fungal agents,
immunomodulators, anti-cancer or chemotherapeutic agents,
anti-inflammation agents, antisense RNA, siRNA, antibodies, or
agents for treating cirrhosis or inflammation of the liver.
Specific examples of these other therapeutic agents include, but
are not limited to, ribavirin, .alpha.-interferon,
.beta.-interferon, pegylated interferon-.alpha., pegylated
interferon-lambda, ribavirin, viramidine, R-5158, nitazoxanide,
amantadine, Debio-025, NIM-811, R7128, R1626, R4048, T-1106,
PSI-7851 (Pharmasset) (nucleoside polymerase inhibitor), PSI-938
(Pharmasset) (nucleoside polymerase inhibitor), PF-00868554,
ANA-598, IDX184 (nucleoside polymerase inhibitor), IDX102, IDX375
(non-nucleoside polymerase inhibitor), GS-9190 (non-nucleoside
polymerase inhibitor), VCH-759, VCH-916, MK-3281, BCX-4678,
MK-3281, VBY708, ANA598, GL59728, GL60667, BMS-790052 (NS5A
inhibitor), BMS-791325 (protease Inhibitor), BMS-650032,
BMS-824393, GS-9132, ACH-1095 (protease inhibitor), AP-H005, A-831
(Arrow Therapeutics) (NS5A inhibitor), A-689 (Arrow Therapeutics)
(NS5A inhibitor), INX08189 (Inhibitex) (polymerase inhibitor),
AZD2836, telaprevir (protease Inhibitor), boceprevir (protease
Inhibitor), ITMN-191 (Intermune/Roche), BI-201335 (protease
Inhibitor), VBY-376, VX-500 (Vertex) (protease Inhibitor), PHX-B,
ACH-1625, IDX136, IDX316, VX-813 (Vertex) (protease Inhibitor), SCH
900518 (Schering-Plough), TMC-435 (Tibotec) (protease Inhibitor),
ITMN-191 (Intermune, Roche) (protease Inhibitor), MK-7009 (Merck)
(protease Inhibitor), IDX-PI (Novartis), BI-201335 (Boehringer
Ingelheim), R7128 (Roche) (nucleoside polymerase inhibitor),
MK-3281 (Merck), MK-0608 (Merck) (nucleoside polymerase inhibitor),
PF-868554 (Pfizer) (non-nucleoside polymerase inhibitor),
PF-4878691 (Pfizer), IDX-184 (Novartis), IDX-375 (Pharmasset),
PPI-461 (Presidio) (NS5A inhibitor), BILB-1941 (Boehringer
Ingelheim), GS-9190 (Gilead), BMS-790052 (BMS), Albuferon
(Novartis), ABT-450 (Abbott/Enanta) (protease Inhibitor), ABT-333
(Abbott) (non-nucleoside polymerase inhibitor), ABT-072 (Abbott)
(non-nucleoside polymerase inhibitor), ritonavir, another
cytochrome P450 monooxygenase inhibitor, or any combination
thereof.
[0992] In one embodiment, a pharmaceutical composition of the
present invention comprises one or more compounds of the present
invention (or salts, solvates or prodrugs thereof), and one or more
other antiviral agents.
[0993] In another embodiment, a pharmaceutical composition of the
present invention comprises one or more compounds of the present
invention (or salts, solvates or prodrugs thereof), and one or more
other anti-HCV agents. For example, a pharmaceutical composition of
the present invention can comprise a compound(s) of the present
invention having Formula I, I.sub.A, I.sub.B, I.sub.C, or I.sub.D
(or a salt, solvate or prodrug thereof), and an agent selected from
HCV polymerase inhibitors (including nucleoside or non-nucleoside
type of polymerase inhibitors), HCV protease inhibitors, HCV
helicase inhibitors, CD81 inhibitors, cyclophilin inhibitors, IRES
inhibitors, or NS5A inhibitors.
[0994] In yet another embodiment, a pharmaceutical composition of
the present invention comprises one or more compounds of the
present invention (or salts, solvates or prodrugs thereof), and one
or more other antiviral agents, such as anti-HBV, anti-HIV agents,
or anti-hepatitis A, anti-hepatitis D, anti-hepatitis E or
anti-hepatitis G agents. Non-limiting examples of anti-HBV agents
include adefovir, lamivudine, and tenofovir. Non-limiting examples
of anti-HIV drugs include ritonavir, lopinavir, indinavir,
nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir,
TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine,
stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine,
delavirdine, TMC-125, L-870812, S-1360, enfuvirtide, T-1249, or
other HIV protease, reverse transcriptase, integrase or fusion
inhibitors. Any other desirable antiviral agents can also be
included in a pharmaceutical composition of the present invention,
as appreciated by those skilled in the art.
[0995] In a preferred embodiment, a pharmaceutical composition of
the invention comprises a compound of the invention (e.g., a
compound of Formula I, I.sub.A, I.sub.B, I.sub.C, or I.sub.D, or
preferably a compound selected from Examples 1-308, or a salt,
solvate or prodrug thereof), and a HCV protease inhibitor. In
another preferred embodiment, a pharmaceutical composition of the
invention comprises a compound of the invention (e.g., a compound
of Formula I, I.sub.A, I.sub.B, I.sub.C, or I.sub.D, or preferably
a compound selected from Examples 1-308, or a salt, solvate or
prodrug thereof), and a HCV polymerase inhibitor (e.g., a
non-nucleoside polymerase inhibitor, or preferably a nucleoside
polymerase inhibitor). In yet another preferred embodiment, a
pharmaceutical composition of the present invention comprises (1) a
compound of the invention (e.g., a compound of Formula I, I.sub.A,
I.sub.B, I.sub.C, or I.sub.D, or preferably a compound selected
from Examples 1-308, or a salt, solvate or prodrug thereof), (2) a
HCV protease inhibitor, and (3) a HCV polymerase inhibitor (e.g., a
non-nucleoside polymerase inhibitor, or preferably a nucleoside
polymerase inhibitor). Non-limiting examples of protease and
polymerase inhibitors are described above.
[0996] A pharmaceutical composition of the present invention
typically includes a pharmaceutically acceptable carrier or
excipient. Non-limiting examples of suitable pharmaceutically
acceptable carriers/excipients include sugars (e.g., lactose,
glucose or sucrose), starches (e.g., corn starch or potato starch),
cellulose or its derivatives (e.g., sodium carboxymethyl cellulose,
ethyl cellulose or cellulose acetate), oils (e.g., peanut oil,
cottonseed oil, safflower oil, sesame oil, olive oil, corn oil or
soybean oil), glycols (e.g., propylene glycol), buffering agents
(e.g., magnesium hydroxide or aluminum hydroxide), agar, alginic
acid, powdered tragacanth, malt, gelatin, talc, cocoa butter,
pyrogen-free water, isotonic saline, Ringer's solution, ethanol, or
phosphate buffer solutions. Lubricants, coloring agents, releasing
agents, coating agents, sweetening, flavoring or perfuming agents,
preservatives, or antioxidants can also be included in a
pharmaceutical composition of the present invention.
[0997] The pharmaceutical compositions of the present invention can
be formulated based on their routes of administration using methods
well known in the art. For example, a sterile injectable
preparation can be prepared as a sterile injectable aqueous or
oleagenous suspension using suitable dispersing or wetting agents
and suspending agents. Suppositories for rectal administration can
be prepared by mixing drugs with a suitable nonirritating excipient
such as cocoa butter or polyethylene glycols which are solid at
ordinary temperatures but liquid at the rectal temperature and will
therefore melt in the rectum and release the drugs. Solid dosage
forms for oral administration can be capsules, tablets, pills,
powders or granules. In such solid dosage forms, the active
compounds can be admixed with at least one inert diluent such as
sucrose lactose or starch. Solid dosage forms may also comprise
other substances in addition to inert diluents, such as lubricating
agents. In the case of capsules, tablets and pills, the dosage
forms may also comprise buffering agents. Tablets and pills can
additionally be prepared with enteric coatings. Liquid dosage forms
for oral administration can include pharmaceutically acceptable
emulsions, solutions, suspensions, syrups or elixirs containing
inert diluents commonly used in the art. Liquid dosage forms may
also comprise wetting, emulsifying, suspending, sweetening,
flavoring, or perfuming agents. The pharmaceutical compositions of
the present invention can also be administered in the form of
liposomes, as described in U.S. Pat. No. 6,703,403. Formulation of
drugs that are applicable to the present invention is generally
discussed in, for example, Hoover, John E., REMINGTON'S
PHARMACEUTICAL SCIENCES (Mack Publishing Co., Easton, Pa.: 1975),
and Lachman, L., eds., PHARMACEUTICAL DOSAGE FORMS (Marcel Decker,
New York, N.Y., 1980).
[0998] Any compound described herein, or a pharmaceutically
acceptable salt thereof, can be used to prepared pharmaceutical
compositions of the present invention.
[0999] In a preferred embodiment, a compound of the invention
(e.g., a compound of Formula I, I.sub.A, I.sub.B, I.sub.C, or
I.sub.D, or preferably a compound selected from Examples 1-308, or
a salt, solvate or prodrug thereof) is formulated in a solid
dispersion, where the compound of the invention can be molecularly
dispersed in an amorphous matrix which comprises a pharmaceutically
acceptable, hydrophilic polymer. The matrix may also contain a
pharmaceutically acceptable surfactant. Suitable solid dispersion
technology for formulating a compound of the invention includes,
but is not limited to, melt-extrusion, spray-drying,
co-precipitation, freeze drying, or other solvent evaporation
techniques, with melt-extrusion and spray-drying being preferred.
In one example, a compound of the invention is formulated in a
solid dispersion comprising copovidone and vitamin E TPGS. In
another example, a compound of the invention is formulated in a
solid dispersion comprising copovidone and Span 20.
[1000] A solid dispersion described herein may contain at least 30%
by weight of a pharmaceutically acceptable hydrophilic polymer or a
combination of such hydrophilic polymers. Preferably, the solid
dispersion contains at least 40% by weight of a pharmaceutically
acceptable hydrophilic polymer or a combination of such hydrophilic
polymers. More preferably, the solid dispersion contains at least
50% (including, e.g., at least 60%, 70%, 80% or 90%) by weight of a
pharmaceutically acceptable hydrophilic polymer or a combination of
such polymers. A solid dispersion described herein may also contain
at least 1% by weight of a pharmaceutically acceptable surfactant
or a combination of such surfactants. Preferably, the solid
dispersion contains at least 2% by weight of a pharmaceutically
acceptable surfactant or a combination of such surfactants. More
preferably, the solid dispersion contains from 4% to 20% by weight
of the surfactant(s), such as from 5% to 10% by weight of the
surfactant(s). In addition, a solid dispersion described herein may
contain at least 1% by weight of a compound of the invention,
preferably at least 5%, including, e.g., at least 10%. In one
example, the solid dispersion comprises 5% of a compound of the
invention (e.g., a compound of Formula I, I.sub.A, I.sub.B,
I.sub.C, or I.sub.D, or preferably a compound selected from
Examples 1-308, or a salt, solvate or prodrug thereof), which is
molecularly dispersed in a an amorphous matrix comprising 7%
Vitamin E-TPGS and 88% copovidone; the solid dispersion can also be
mixed with other excipients such as mannitol/aerosil (99:1), and
the weight ratio of the solid dispersion over the other excipients
can range from 5:1 to 1:5 with 1:1 being preferred. In another
example, the solid dispersion comprises 5% of a compound of the
invention (e.g., a compound of Formula I, I.sub.A, I.sub.B,
I.sub.C, or I.sub.D, or preferably a compound selected from
Examples 1-308, or a salt, solvate or prodrug thereof), which is
molecularly dispersed in a an amorphous matrix comprising 5% Span
20 and 90% copovidone; the solid dispersion can also be mixed with
other excipients such as mannitol/aerosil (99:1), the solid
dispersion can also be mixed with other excipients such as
mannitol/aerosil (99:1), and the weight ratio of the solid
dispersion over the other excipients can range from 5:1 to 1:5 with
1:1 being preferred.
[1001] Various additives can also be included in or mixed with the
solid dispersion. For instance, at least one additive selected from
flow regulators, binders, lubricants, fillers, disintegrants,
plasticizers, colorants, or stabilizers may be used in compressing
the solid dispersion to tablets. These additives can be mixed with
ground or milled solid dispersion before compacting. Disintegrants
promote a rapid disintegration of the compact in the stomach and
keeps the liberated granules separate from one another.
Non-limiting examples of suitable disintegrants are cross-linked
polymers such as cross-linked polyvinyl pyrrolidone, cross-linked
sodium carboxymethylcellulose or sodium croscarmellose.
Non-limiting examples of suitable fillers (also referred to as
bulking agents) are lactose monohydrate, calcium hydrogenphosphate,
microcrystalline cellulose (e.g., Avicell), silicates, in
particular silicium dioxide, magnesium oxide, talc, potato or corn
starch, isomalt, or polyvinyl alcohol. Non-limiting examples of
suitable flow regulators include highly dispersed silica (e.g.,
colloidal silica such as Aerosil), and animal or vegetable fats or
waxes. Non-limiting examples of suitable lubricants include
polyethylene glycol (e.g., having a molecular weight of from 1000
to 6000), magnesium and calcium stearates, sodium stearyl fumarate,
and the like. Non-limiting examples of stabilizers include
antioxidants, light stabilizers, radical scavengers, or stabilizers
against microbial attack.
[1002] The present invention further features methods of using the
compounds of the present invention (or salts, solvates or prodrugs
thereof) to inhibit HCV replication. The methods comprise
contacting cells infected with HCV virus with an effective amount
of a compound of the present invention (or a salt, solvate or
prodrug thereof), thereby inhibiting the replication of HCV virus
in the cells. As used herein, "inhibiting" means significantly
reducing, or abolishing, the activity being inhibited (e.g., viral
replication). In many cases, representative compounds of the
present invention can reduce the replication of HCV virus (e.g., in
an HCV replicon assay as described above) by at least 10%, 20%,
30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more.
[1003] The compounds of the present invention may inhibit one or
more HCV subtypes. Examples of HCV subtypes that are amenable to
the present invention include, but are not be limited to, HCV
genotypes 1, 2, 3, 4, 5 and 6, including HCV genotypes 1a, 1b, 2a,
2b, 2c, 3a or 4a. In one embodiment, a compound or compounds of the
present invention (or salts, solvates or prodrugs thereof) are used
to inhibit the replication of HCV genotype 1a. In another
embodiment, a compound or compounds of the present invention (or
salts, solvates or prodrugs thereof) are used to inhibit the
replication of HCV genotype 1b. In still another embodiment, a
compound or compounds of the present invention (or salts, solvates
or prodrugs thereof) are used to inhibit the replication of both
HCV genotypes 1a and 1b.
[1004] The present invention also features methods of using the
compounds of the present invention (or salts, solvates or prodrugs
thereof) to treat HCV infection. The methods typically comprise
administering a therapeutic effective amount of a compound of the
present invention (or a salt, solvate or prodrug thereof), or a
pharmaceutical composition comprising the same, to an HCV patient,
thereby reducing the HCV viral level in the blood or liver of the
patient. As used herein, the term "treating" refers to reversing,
alleviating, inhibiting the progress of, or preventing the disorder
or condition, or one or more symptoms of such disorder or condition
to which such term applies. The term "treatment" refers to the act
of treating. In one embodiment, the methods comprise administering
a therapeutic effective amount of two or more compounds of the
present invention (or salts, solvates or prodrugs thereof), or a
pharmaceutical composition comprising the same, to an HCV patient,
thereby reducing the HCV viral level in the blood or liver of the
patient.
[1005] A compound of the present invention (or a salt, solvate or
prodrug thereof) can be administered as the sole active
pharmaceutical agent, or in combination with another desired drug,
such as other anti-HCV agents, anti-HIV agents, anti-HBV agents,
anti-hepatitis A agents, anti-hepatitis D agents, anti-hepatitis E
agents, anti-hepatitis G agents, or other antiviral drugs. Any
compound described herein, or a pharmaceutically acceptable salt
thereof, can be employed in the methods of the present invention.
In one embodiment, the present invention features methods of
treating HCV infection, wherein said methods comprise administering
a compound of the invention (e.g., a compound of Formula I,
I.sub.A, I.sub.B, I.sub.C, or I.sub.D, or preferably a compound
selected from Examples 1-308, or a salt, solvate or prodrug
thereof), interferon and ribavirin to an HCV patient. The
interferon preferably is .alpha.-interferon, and more preferably,
pegylated interferon-.alpha. such as PEGASYS (peginterferon
alfa-2a).
[1006] A compound of the present invention (or a salt, solvent or
prodrug thereof) can be administered to a patient in a single dose
or divided doses. A typical daily dosage can range, without
limitation, from 0.1 to 200 mg/kg body weight, such as from 0.25 to
100 mg/kg body weight. Single dose compositions can contain these
amounts or submultiples thereof to make up the daily dose.
Preferably, each dosage contains a sufficient amount of a compound
of the present invention that is effective in reducing the HCV
viral load in the blood or liver of the patient. The amount of the
active ingredient, or the active ingredients that are combined, to
produce a single dosage form may vary depending upon the host
treated and the particular mode of administration. It will be
understood that the specific dose level for any particular patient
will depend upon a variety of factors including the activity of the
specific compound employed, the age, body weight, general health,
sex, diet, time of administration, route of administration, rate of
excretion, drug combination, and the severity of the particular
disease undergoing therapy.
[1007] The present invention further features methods of using the
pharmaceutical compositions of the present invention to treat HCV
infection. The methods typically comprise administering a
pharmaceutical composition of the present invention to an HCV
patient, thereby reducing the HCV viral level in the blood or liver
of the patient. Any pharmaceutical composition described herein can
be used in the methods of the present invention.
[1008] In addition, the present invention features use of the
compounds or salts of the present invention for the manufacture of
medicaments for the treatment of HCV infection. Any compound
described herein, or a pharmaceutically acceptable salt thereof,
can be used to make medicaments of the present invention.
[1009] The compounds of the present invention can also be
isotopically substituted. Preferred isotopic substitution include
substitutions with stable or nonradioactive isotopes such as
deuterium, .sup.13C, .sup.15N or .sup.18O. Incorporation of a heavy
atom, such as substitution of deuterium for hydrogen, can give rise
to an isotope effect that could alter the pharmacokinetics of the
drug. In one example, at least 5 mol % (e.g., at least 10 mol %) of
hydrogen in a compound of the present invention is substituted with
deuterium. In another example, at least 25 mole % of hydrogen in a
compound of the present invention is substituted with deuterium. In
a further example, at least 50, 60,70, 80 or 90 mole % of hydrogen
in a compound of the present invention is substituted with
deuterium. The natural abundance of deuterium is about 0.015%.
Deuterium substitution or enrichment can be achieved, without
limitation, by either exchanging protons with deuterium or by
synthesizing the molecule with enriched or substituted starting
materials. Other methods known in the art can also be used for
isotopic substitutions.
[1010] The foregoing description of the present invention provides
illustration and description, but is not intended to be exhaustive
or to limit the invention to the precise one disclosed.
Modifications and variations are possible in light of the above
teachings or may be acquired from practice of the invention. Thus,
it is noted that the scope of the invention is defined by the
claims and their equivalents.
* * * * *