U.S. patent application number 10/630278 was filed with the patent office on 2004-06-10 for composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives.
Invention is credited to Kadow, John F., Matiskella, John D., Meanwell, Nicholas A., Regueiro-Ren, Alicia, Ueda, Yasutsugu, Wang, Tao, Xue, Qiufen May, Yin, Zhiwei, Zhang, Zhongxing.
Application Number | 20040110785 10/630278 |
Document ID | / |
Family ID | 32475656 |
Filed Date | 2004-06-10 |
United States Patent
Application |
20040110785 |
Kind Code |
A1 |
Wang, Tao ; et al. |
June 10, 2004 |
Composition and antiviral activity of substituted
azaindoleoxoacetic piperazine derivatives
Abstract
This invention provides compounds having drug and bio-affecting
properties, their pharmaceutical compositions and method of use. In
particular, the invention is concerned with azaindoleoxoacetyl
piperazine derivatives. These compounds possess unique antiviral
activity, whether used alone or in combination with other
antivirals, antiinfectives, immunomodulators or HIV entry
inhibitors. More particularly, the present invention relates to the
treatment of HIV and AIDS.
Inventors: |
Wang, Tao; (Middletown,
CT) ; Zhang, Zhongxing; (Madison, CT) ;
Meanwell, Nicholas A.; (East Hampton, CT) ; Kadow,
John F.; (Wallingford, CT) ; Yin, Zhiwei;
(Meriden, CT) ; Xue, Qiufen May; (Thousand Oaks,
CA) ; Regueiro-Ren, Alicia; (Middletown, CT) ;
Matiskella, John D.; (Wallingtord, CT) ; Ueda,
Yasutsugu; (Clinton, CT) |
Correspondence
Address: |
STEPHEN B. DAVIS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
32475656 |
Appl. No.: |
10/630278 |
Filed: |
July 30, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10630278 |
Jul 30, 2003 |
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10214982 |
Aug 7, 2002 |
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10214982 |
Aug 7, 2002 |
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10038306 |
Jan 2, 2002 |
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60314406 |
Aug 23, 2001 |
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60266183 |
Feb 2, 2001 |
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Current U.S.
Class: |
514/300 ;
546/113 |
Current CPC
Class: |
C07D 471/04 20130101;
C07D 491/048 20130101; A61K 45/06 20130101; A61P 31/18 20180101;
A61P 31/12 20180101; A61K 31/496 20130101 |
Class at
Publication: |
514/300 ;
546/113 |
International
Class: |
C07D 471/02; A61K
031/4745 |
Claims
What is claimed is:
1. A compound of Formula I, including pharmaceutically acceptable
salts thereof, 2393wherein: Q is selected from the group consisting
of: 2394R.sup.1, R.sup.2, R.sup.3, and R.sup.4, are independently
selected from the group consisting of hydrogen, halogen, cyano,
nitro, COR.sup.56, XR.sup.57 C(O)R.sup.7, C(O)NR.sup.55R.sup.56, B,
D, and E with the proviso that at least one of R.sup.1-R.sup.4 is
selected from B or E; wherein--represents a carbon-carbon bond or
does not exist; m is 1 or 2; R.sup.5 is hydrogen or
(CH.sub.2).sub.nCH.sub.3, --C(O)(CH.sub.2).sub.nCH- .sub.3,
--C(O)O(CH.sub.2).sub.nCH.sub.3, --C(O) (CH.sub.2).sub.nN(CH.sub.3-
).sub.2 wherein n is 0-5; R.sup.6is O or does not exist; A is
selected from the group consisting of C.sub.1-6alkoxy, aryl and
heteroaryl; in which said aryl is phenyl or napthyl; said
heteroaryl is selected from the group consisting of pyridinyl,
pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl,
imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,
quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl,
benzoimidazolyl and benzothiazolyl; and said aryl or heteroaryl is
optionally substituted with one or two of the same or different
members selected from the group consisting of amino, nitro, cyano,
hydroxy, C.sub.1-6alkoxy, --C(O)NH.sub.2, C.sub.1-6alkyl,
--NHC(O)CH.sub.3, halogen and trifluoromethyl; 2395B is selected
from the group consisting of --C(=NR.sup.46)(R.sup.47),
C(O)NR.sup.40R.sup.41, aryl, heteroaryl, heteroalicyclic,
S(O).sub.2R.sup.8, C(O)R.sup.7, XR.sup.8a,
(C.sub.1-6)alkylNR.sup.40R.sup.41, (C.sub.1-6)alkylCOOR.sup.8b- ;
wherein said aryl, heteroaryl, and heteroalicyclic are optionally
substituted with one to three same or different halogens or from
one to three same or different substituents selected from the group
F; wherein aryl is napthyl or substituted phenyl; wherein
heteroaryl is a mono or bicyclic system which contains from 3 to 7
ring atoms for a mono cyclic system and up to 12 atoms in a fused
bicyclic system, including from 1 to 4 heteroatoms; wherein
heteroalicyclic is a 3 to 7 membered mono cyclic ring which may
contain from 1 to 2 heteroatoms in the ring skeleton and which may
be fused to a benzene or pyridine ring; q is 0, 1, or 2; D is
selected from the group consisting of (C.sub.1-6)alkyl and
(C.sub.2-6)alkenyl; wherein said (C.sub.1-6)alkyl and
(C.sub.2-6)alkenyl are optionally substituted with one to three
same or different halogens or from one to three same or different
substituents selected from the group consisting of
C(O)NR.sup.55R.sup.56, hydroxy, cyano and XR.sup.57; E is selected
from the group consisting of (C.sub.1-6)alkyl and
(C.sub.2-6)alkenyl; wherein said (C.sub.1-6)alkyl and
(C.sub.2-6)alkenyl are independently optionally substituted with a
member selected from the group consisting of phenyl, heteroaryl,
SMe, SPh, --C(O)NR.sub.56R.sub.57- , C(O)R.sub.57,
SO.sub.2(C.sub.1-6)alkyl and S0.sub.2Ph; wherein heteroaryl is a
monocyclic system which contains from 3 to 7 ring atoms, including
from 1 to 4 heteroatoms; F is selected from the group consisting of
(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl, aryl, heteroaryl,
heteroalicyclic, hydroxy, (C.sub.1-6)alkoxy, aryloxy,
(C.sub.1-6)thioalkoxy, cyano, halogen, nitro, --C(O)R.sup.57,
benzyl, --NR.sup.42C(O)--(C.sub.1-6)alkyl,
--NR.sup.42C(O)--(C.sub.3-6)cycloalkyl- , --NR.sup.42C(O)-aryl,
--NR.sup.42C(O)-heteroaryl, --NR.sup.42C(O)-heteroalicyclic, a 4,
5, or 6 membered ring cyclic N-lactam,
--NR.sup.42S(O).sub.2--(C.sub.1-6)alkyl,
--NR.sup.42S(O).sub.2--(C.sub.3-6cycloallkyl,
--NR.sup.42S(O)2-aryl, --NR.sup.42S(O).sub.2-heteroaryl,
--NR.sup.42S(O)2-heteroalicyclic, S(O).sub.2(C.sub.1-6)alkyl,
S(O).sub.2aryl, --S(O)2 NR.sup.42R.sup.43, NR.sup.42R.sup.43,
(C.sub.1-6)alkylC(O)NR.sup.42R.sup.43, C(O)NR.sup.42R.sup.43,
NHC(O)NR.sup.42R.sup.43, OC(O)NR.sup.42R.sup.43, NHC(O)OR.sup.54,
(C.sub.1-6)alkylNR.sup.42R.sup.43, COOR.sup.54 and
(C.sub.1-6)alkylCOOR.sup.54; wherein said (C.sub.1-6)alkyl,
(C.sub.3-7)cycloalkyl, aryl, heteroaryl, heteroalicyclic,
(C.sub.1-6)alkoxy, and aryloxy, are optionally substituted with one
to nine same or different halogens or from one to five same or
different substituents selected from the group G; wherein aryl is
phenyl; heteroaryl is a monocyclic system which contains from 3 to
7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic is
selected from the group consisting of aziridine, azetidine,
pyrrolidine, piperazine, piperidine, tetrahydrofuran,
tetrahydropyran, azepine, and morpholine; G is selected from the
group consisting of (C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl, aryl,
heteroaryl, heteroalicyclic, hydroxy, (C.sub.1-6)alkoxy, aryloxy,
cyano, halogen, nitro, --C(O)R.sup.57, benzyl,
--NR.sup.48C(O)--(C.sub.1-6)alkyl, --NR.sup.48C(O)--(C.sub.3-6)cy-
cloalkyl, --NR.sup.48C(O)-aryl, --NR.sup.48C(O)-heteroaryl,
--NR.sup.48C(O)-heteroalicyclic, a 4, 5, or 6 membered ring cyclic
N-lactam, --NR.sup.48S(O).sub.2--(C.sub.1-6)alkyl,
--NR.sup.48S(O).sub.2--(C.sub.3-6)cycloalkyl,
--NR.sup.48S(O)2-aryl, --NR.sup.48S(O).sub.2-heteroaryl,
--NR.sup.48S(O)2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide,
NR.sup.48R.sup.49, (C.sub.1-6)alkyl C(O)NR.sup.48R.sup.49,
C(O)NR.sup.48R.sup.49, NHC(O)NR.sup.48R.sup.49,
OC(O)NR.sup.48R.sup.49, NHC(O)OR.sup.54,
(C.sub.1-6)alkylNR.sup.48R.sup.4- 9, COOR.sup.54, and
(C.sub.1-6)alkylCOOR.sup.54; wherein aryl is phenyl; heteroaryl is
a monocyclic system which contains from 3 to 7 ring atoms,
including from 1 to 4 heteroatoms; heteroalicyclic is selected from
the group consisting of aziridine, azetidine, pyrrolidine,
piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine,
and morpholine; R.sup.7 is selected from the group consisting of
aryl, heteroaryl, and heteroalicyclic; wherein said aryl,
heteroaryl, and heteroalicyclic are optionally substituted with one
to three same or different halogens or with from one to three same
or different substituents selected from the group F; wherein for
R.sup.7, R.sup.8, R.sup.8a, R.sup.8b aryl is phenyl; heteroaryl is
a mono or bicyclic system which contains from 3 to 7 ring atoms for
mono cyclic systems and up to 10 atoms in a bicyclic system,
including from 1 to 4 heteroatoms; wherein heteroalicyclic is
selected from the group consisting of aziridine, azetidine,
pyrrolidine, piperazine, piperidine, tetrahydrofuran,
tetrahydropyran, azepine, and morpholine; R.sup.8 is selected from
the group consisting of hydrogen, (C.sub.1-6)alkyl,
(C.sub.3-7)cycloalkyl, (C.sub.2-6)alkenyl, (C.sub.3-7)cycloalkenyl,
(C.sub.2-6)alkynyl, aryl, heteroaryl, and heteroalicyclic; wherein
said (C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl, (C.sub.2-6)alkenyl,
(C.sub.3-7)cycloalkenyl, (C.sub.2-6)alkynyl, aryl, heteroaryl, and
heteroalicyclic are optionally substituted with one to six same or
different halogens or from one to five same or different
substituents selected from the group F; R.sup.8a is a member
selected from the group consisting of aryl, heteroaryl, and
heteroalicyclic; wherein each member is independently optionally
substituted with one to six same or different halogens or from one
to five same or different substituents selected from the group F;
R.sup.8b is selected from the group consisting of hydrogen,
(C.sub.1-6)alkyl and phenyl; R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16, are each independently
selected from the group consisting of hydrogen and
(C.sub.1-6)alkyl; wherein said (C.sub.1-6)alkyl is optionally
substituted with one to three same or different halogens; X is
selected from the group consisting of NH or NCH.sub.3, O, and S;
R.sup.40 and R.sup.41 are independently selected from the group
consisting of (a) hydrogen; (b) (C.sub.1-6)alkyl or
(C.sub.3-7)cycloalkyl substituted with one to three same or
different halogens or from one to two same or different
substituents selected from the group F; and (c) (C.sub.1-6)alkoxy,
aryl, heteroaryl or heteroalicyclic; or R.sup.40 and R.sup.41 taken
together with the nitrogen to which they are attached form a member
selected from the group consisting of aziridine, azetidine,
pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine, and
morpholine; and wherein said aryl, heteroaryl, and heteroalicyclic
are optionally substituted with one to three same or different
halogens or from one to two same or different substituents selected
from the group F; wherein for R.sup.40 and R.sup.41 aryl is phenyl;
heteroaryl is a monocyclic system which contains from 3 to 6 ring
atoms, including from 1 to 4 heteroatoms; heteroalicyclic is
selected from the group consisting of aziridine, azetidine,
pyrrolidine, piperazine, piperidine, tetrahydrofuran,
tetrahydropyran, azepine, and morpholine; provided when B is
C(O)NR.sup.40R.sup.41, at least one of R.sup.40 and R.sup.41 is not
selected from groups (a) or (b); R.sup.42 and R.sup.43 are
independently selected from the group consisting of hydrogen,
(C.sub.1-6)alkyl, allyl, (C.sub.1-6)alkoxy, (C.sub.3-7)cycloalkyl,
aryl, heteroaryl and heteroalicyclic; or R.sup.42 and R.sup.43
taken together with the nitrogen to which they are attached form a
member selected from the group consisting of aziridine, azetidine,
pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine, and
morpholine; and wherein said (C.sub.1-6)alkyl, (C.sub.1-6)alkoxy,
(C.sub.3-7)cycloalkyl, aryl, heteroaryl, and heteroalicyclic are
optionally substituted with one to three same or different halogens
or from one to two same or different substituents selected from the
group G; wherein for R.sup.42 and R.sup.43 aryl is phenyl;
heteroaryl is a monocyclic system which contains from 3 to 6 ring
atoms, including from 1 to 4 heteroatoms; heteroalicyclic is a
member selected from the group consisting of aziridine, azetidine,
pyrrolidine, piperazine, piperidine, tetrahydrofuran,
tetrahydropyran, azepine, and morpholine; R.sub.a and R.sub.b are
each independently H, (C.sub.1-6)alkyl or phenyl; R.sup.46 is
selected from the group consisting of H, OR.sup.57, and
NR.sup.55R.sup.56; R.sup.47 is selected from the group consisting
of H, amino, halogen, phenyl, and (C.sub.1-6)alkyl; R.sup.48 and
R.sup.49 are independently selected from the group consisting of
hydrogen, (C.sub.1-6)alkyl and phenyl; R.sup.50 is selected from
the group consisting of H, (C.sub.1-6)alkyl, (C.sub.3-6)cycloalkyl,
and benzyl; wherein each of said (C.sub.1-6)alkyl,
(C.sub.3-7)cycloalkyl and benzyl are optionally substituted with
one to three same or different halogen, amino, OH, CN or NO.sub.2;
R.sup.54 is selected from the group consisting of hydrogen and
(C.sub.1-6)alkyl; R.sup.54 is (C.sub.1-6)alkyl; R.sup.55 and
R.sup.56 are independently selected from the group consisting of
hydrogen and (C.sub.1-6)alkyl; and R.sup.57 is selected from the
group consisting of hydrogen, (C.sub.1-6)alkyl and phenyl.
2. A compound of claim 1, including pharmaceutically acceptable
salts thereof wherein: R.sup.1 is hydrogen; Q is either:
2396wherein R.sup.2 is selected from the group consisting of
hydrogen, halogen, hydroxy, --O(C.sub.1-6)alkyl, cyano, nitro and
XR.sup.57; wherein R.sup.3 is selected from the group consisting of
hydrogen, halogen, hydroxy, --O(C.sub.1-6)alkyl, cyano,
--COOR.sup.56, nitro, XR.sup.57; phenyl optionally substituted with
one to three same or different halogens or one of methoxy, hydroxy
or XR.sup.57; furyl, oxazolyl, or pyrazolyl, independently
optionally substituted with halogen, methoxy, (C.sub.1-3)alkyl or
XR.sup.57; or (b) Q is: 2397wherein R.sup.2 and R.sub.3 are
independently selected from the group consisting of hydrogen,
halogen, hydroxy, --O(C.sub.1-6)alkyl, cyano, nitro, --COOR.sup.56,
XR.sup.57, --C(O) NR.sup.55R.sup.56; phenyl optionally substituted
with one to three same or different halogens or one of methoxy,
hydroxy or XR.sup.57; furyl, oxalzolyl or pyrazolyl, independently
optionally substituted with (C.sub.1-3)alkyl, halogen, methoxy or
XR.sup.57; and for both (a) and (b): m is 2; R.sup.5 is hydrogen;
R.sup.6 does not exist; A is selected from the group consisting of
C.sub.1-6alkoxy, aryl and heteroaryl; wherein said aryl is phenyl;
heteroaryl is selected from the group consisting of pyridinyl,
pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl,
imidazolyl, thiazolyl, oxazolyl and isoxazolyl; and said aryl or
heteroaryl is optionally substituted with one or two of the same or
different members selected from the group consisting of amino,
cyano, hydroxy C.sub.1-6alkoxy, C.sub.1-6alkyl, --NHC(O)CH.sub.3,
halogen and trifluoromethyl; represents a carbon-carbon bond; X is
NH or NCH.sub.3; R.sup.57 is H or (C.sub.1-3)alkyl; and R.sup.55
and R.sup.56 are independently H or (C.sub.1-6)alkyl.
3. A compound of claim 2, including pharmaceutically acceptable
salts thereof, wherein: A is selected from the group consisting of
phenyl and heteroaryl; wherein heteroaryl is pyridinyl, furanyl or
thienyl; and said phenyl or said heteroaryl is optionally
substituted with one to two of the same or different amino,
C.sub.1-6alkyl, hydroxy, or halogen; R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, and R.sup.16 are each
independently hydrogen or methyl with the proviso that only one is
methyl; Q is either: 2398and then R.sup.2 is selected from the
group consisting of hydrogen, halogen and methoxy; and R.sub.3 is
hydrogen; or (b) Q is: 2399and R.sup.2 is halogen or hydrogen and
R.sup.3 is hydrogen; and for both (a) and (b): R.sup.4 is selected
from the group consisting of B; B is selected from the group
consisting of --C(O)NR.sup.40R.sup.41, substituted phenyl,
heteroaryl, oxazoline, pyrazinone and methylene dioxy or ethylene
dioxy fused to a benzene or pyridine; wherein said heteroaryl or
phenyl is optionally substituted with one to three same or
different halogens or from one to two same or different
substituents selected from the group F.
4. A compound of claim 3, including pharmaceutically acceptable
salts thereof, wherein: B is selected from the group consisting of
--C(O)NR.sup.40R.sup.41, substituted phenyl and heteroaryl; wherein
said phenyl is substituted and heteroaryl is optionally substituted
with one to three same or different halogens or from one to two
same or different substituents selected from the group F; F is
selected from the group consisting of (C.sub.1-6)alkyl,
(C.sub.3-6)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,
(C.sub.1-6)alkoxy, (C.sub.1-6)thioalkoxy, cyano, halogen,
--C(O)R.sup.57, benzyl, --NR.sup.42C(O)--(C.sub.1-6)alkyl- ,
--NR.sup.42C(O)--(C.sub.3-6)cycloalkyl, --NR.sup.42C(O)-aryl,
--NR.sup.42C(O)-heteroaryl, --NR.sup.42C(O)-heteroalicyclic, 4, 5,
or 6 membered ring cyclic N-lactam, --NR
S(O).sub.2--(C.sub.1-6)alkyl, --NR.sup.42R.sup.43,
C(O)NR.sup.42R.sup.43 and COOR.sup.54; wherein said
(C.sub.1-6)alkyl, (C.sub.3-6)cycloalkyl, aryl, heteroaryl,
heteroalicyclic, (C.sub.1-6)alkoxy, are optionally substituted with
one to three same or different halogens or from one to two same or
different substituents selected from the group G; G is selected
from the group consisting of (C.sub.1-6)alkyl, hydroxy,
(C.sub.1-6)alkoxy, halogen, --NR.sup.48C(O)--(C.sub.1-6)alkyl,
--NR.sup.48C(O)--(C.sub.3)cycloalkyl, 4, 5, or 6 membered ring
cyclic N-lactam, --NR.sup.48S(O).sub.2--(C.sub.1- -6)alkyl,
NR.sup.48R.sup.49, (C.sub.1-6)alkyl C(O)NR.sup.48R.sup.49,
C(O)NR.sup.48R.sup.49 and (C.sub.1-6)alkylNR.sup.48R.sup.49;
R.sup.40 is hydrogen; and R.sup.41 is selected from the group
consisting of (C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl, phenyl and
heteroaryl; wherein said (C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl,
phenyl, or heteroaryl are substituted with one to three same or
different halogens or one to two same or different substituents
selected from the group consisting of methyl, (C.sub.1-3)alkoxy,
heteroaryl and aryl; wherein said aryl or heteroaryl are optionally
substituted with one to three same or different halogens or from
one to two same or different substituents selected from the group
consisting of (C.sub.1-6)alkyl, hydroxy, (C.sub.1-6)alkoxy,
--NR.sup.42C(O)--(C.sub.1-6)alkyl, NR.sup.42R.sup.43 and
C(O)NR.sup.42R.sup.43.
5. A compound of claim 4, including pharmaceutically acceptable
salts thereof, wherein: Q is 2400A is Phenyl, 2-pyridyl, or
3-pyridyl; B is selected from the group consisting of
--C(O)NR.sup.40R.sup.41 or heteroaryl; wherein said heteroaryl is
optionally substituted with one to three same or different halogens
or from one to two same or different substituents selected from the
group F.
6. A compound of claim 5, including pharmaceutically acceptable
salts thereof, wherein: B is heteroaryl, wherein said heteroaryl is
optionally substituted with one to three same or different halogens
or from one to two same or different substituents selected from the
group F.
7. A compound of claim 4, including pharmaceutically acceptable
salts thereof, wherein: Q is 2401R.sup.2 is selected from the group
consisting of hydrogen, halogen, and methoxy; R.sup.4 is B; B is
selected from the group consisting of --C(O)NR.sup.40R.sup.41 or
heteroaryl; wherein said heteroaryl is optionally substituted with
one to three same or different halogens or from one to two same or
different substituents selected from the group F;
8. A compound of claim 7, including pharmaceutically acceptable
salts thereof, wherein: A is phenyl, 2-pyridyl, or 3-pyridyl.
9. A compound of claim 8 including pharmaceutically acceptable
salts thereof, wherein: B is --C(O)NR.sup.40OR.sup.41.
10. A compound of claim 8 including pharmaceutically acceptable
salts thereof, wherein: B is heteroaryl, wherein said heteroaryl is
optionally substituted with one to three same or different halogens
or from one to two same or different substituents selected from the
group F.
11. A compound of claim 4 wherein: F is selected from the group
consisting of (C.sub.1-6)alkyl, (C.sub.3-6)cycloalkyl
(C.sub.1-6)alkoxy, hydroxy, heteroaryl, heteroalicyclic, methoxy,
--S(C.sub.1-3)alkyl, halogen, --C(O)R.sup.57,
C(O)NR.sup.42R.sup.43, --NR.sup.42C(O)--(C.sub.1-6)alkyl,
--NR.sup.42C(O)--(C.sub.3-6)cycloalkyl, --NR.sup.42C(O)-aryl,
--NR.sup.42C(O)-heteroaryl, --NR.sup.42C(O)-heteroalicyclic, 4, 5,
or 6 membered ring cyclic N-lactam,
--NR.sup.42S(O).sub.2--(C.sub.1-6)alkyl,
--NR.sup.42S(O).sub.2--(C.sub.3-6)cycloalkyl,
--NR.sup.42S(O)2-aryl, --NR.sup.42S(O).sub.2-heteroaryl,
--NR.sup.42S(O)2-heteroalicyclic, NR.sup.42R.sup.43,
NR.sup.55(C.sub.1-3)alkylNR.sup.55R.sup.56 and COOR.sup.54.
12. A compound of claim 11 wherein: A is phenyl, 2-pyridyl, or
3-pyridyl.
13. A compound of claim 4, including pharmaceutically acceptable
salts thereof, wherein: Q is 2402R.sup.2 is selected from the group
consisting of hydrogen and methoxy; R.sup.3 is hydrogen; and B is
selected from the group consisting of --C(O)NR.sup.40R.sup.41 and
heteroaryl; wherein said heteroaryl is optionally substituted with
one to three same or different halogens or from one to two same or
different substituents selected from the group F.
14. A compound of claim 8 wherein R.sup.2 is fluoro.
15. A compound of claim 8 wherein R.sup.2 is methoxy.
16. A compound of claim 8 wherein: B is heteroaryl selected from
the group consisting of thiazole, pyridazine, pyrazine, pyrazole,
isoxazole, isothiazole, imidazole, furyl, thienyl, oxazole,
oxadiazole, thiadiazole, pyrimidine, pyrazole, triazine, triazole,
tetrazole, pyridyl, indole, azaindole, and diaza-indole; wherein
said heteroaryl is optionally substituted with one to three same or
different halogens or from one to two same or different
substituents selected from the group F.
17. A compound of claim 5 wherein: B is heteroaryl selected from
the group consisting of thiazole, pyridazine, pyrazine, pyrazole,
isoxazole, isothiazole, imidazole, furyl, thienyl, oxazole,
oxadiazole, thiadiazole, pyrimidine, pyrazole, triazine, triazole,
tetrazole, pyridyl, indole, azaindole, and diaza-indole; wherein
said heteroaryl is optionally substituted with one to three same or
different halogens or from one to two same or different
substituents selected from the group F.
18. A compound of claim 13 wherein: B is heteroaryl selected from
the group consisting of thiazole, pyridazine, pyrazine, pyrazole,
isoxazole, isothiazole, imidazole, furyl, thienyl, oxazole,
oxadiazole, thiadiazole, pyrimidine, pyrazole, triazine, triazole,
tetrazole, pyridyl, indole, azaindole, and diaza-indole; wherein
said heteroaryl is optionally substituted with one to three same or
different halogens or from one to two same or different
substituents selected from the group F.
19. A compound of claim 7 wherein: B is heteroaryl selected from
the group consisting of thiazole, pyridazine, pyrazine, pyrazole,
isoxazole, isothiazole, imidazole, furyl, thienyl, oxazole,
oxadiazole, thiadiazole, pyrimidine, pyrazole, triazine, triazole,
tetrazole, pyridyl, indole, azaindole, and diaza-indole; wherein
said heteroaryl is optionally substituted with one to three same or
different halogens or from one to two same or different
substituents selected from the group F.
20. A compound of claim 6 wherein: B is heteroaryl optionally
substituted with one to three same or different halogens or a
substituent selected from the group consisting of hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3
thioalkoxy, amino, --C(O)H, --COOH, --COOC.sub.1-C.sub.6 alkyl,
--NHC(O)--(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2--(C.sub.1-C.sub.6
alkyl), --C(O)--NH.sub.2, C(O)NHMe, C(O)NMe2, trifluoromethyl,
--NR.sup.55R.sup.56, NR.sup.55R.sup.56--(C.sub- .1-C.sub.6
alkyl)-NR.sup.55R.sup.56, -thiazole, pyrrole, piperazine,
pyrrolidine and N-pyrrolidone.
21. A compound of claim 7 wherein: B is --C(O)NH-heteroaryl wherein
said heteroaryl is optionally substituted with one to three same or
different halogens or a substituent selected from the group
consisting of (C.sub.1-C.sub.6 alkyl), amino,
--NHC(O)--(C.sub.1-C.sub.6 alkyl), -methoxy, --NHC(C.sub.1-C.sub.6
alkyl) and --N(C.sub.1-C.sub.6 alkyl).sub.2.
22. A compound of claim 10 wherein: B is heteroaryl optionally
substituted with one to three same or different halogens or a
substituent selected from the group consisting of (C.sub.1-C.sub.6
alkyl), amino, --NHC(O)--(C.sub.1-C.sub.6alkyl),
--NHS(O).sub.2--(C.sub.1-C.sub.6 alkyl), methoxy, --C(O)--NH.sub.2,
C(O)NHMe, C(O)NMe2, trifluoromethyl, --NHC(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl).sub.2, -heteroaryl and a 4, 5, or 6
membered cyclic N-lactam.
23. A compound of claim 9 wherein: B is --C(O)NH-heteroaryl wherein
said heteroaryl is optionally substituted with one to three same or
different halogens or a substituent selected from the group
consisting of (C.sub.1-C.sub.6 alkyl), amino,
--NHC(O)--(C.sub.1-C.sub.6 alkyl), -methoxy, --NHC(C.sub.1-C.sub.6
alkyl) and --N(C.sub.1-C.sub.6 alkyl).sub.2.
24. A compound of claim 16 wherein: B is heteroaryl optionally
substituted with one to three same or different halogens or a
substituent selected from the group consisting of hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3
thioalkoxy, amino, --C(O)H, --COOH, --COOC.sub.1-C.sub.6 alkyl,
--NHC(O)--(C.sub.1-C.sub.6alkyl), --NHS(O).sub.2--(C.sub.1-C.sub.6
alkyl), methoxy, --C(O)--NH.sub.2, C(O)NHMe, C(O)NMe2,
trifluoromethyl, --NR.sup.55R.sup.56,
NR.sup.55R.sup.56--(C.sub.1-C.sub.6 alkyl)-NR.sup.55R.sup.56,
-thiazole, pyrrole, piperazine, pyrrolidine and N-pyrrolidone.
25. A compound of claim 13 wherein: B is --C(O)NH-heteroaryl
wherein said heteroaryl is optionally substituted with one to three
same or different halogens or a substituent selected from the group
consisting of (C.sub.1-C.sub.6 alkyl), amino,
--NHC(O)--(C.sub.1-C.sub.6 alkyl), -methoxy, --NHC(C.sub.1-C.sub.6
alkyl) and --N(C.sub.1-C.sub.6 alkyl).sub.2.
26. A compound of claim 5 wherein: B is thienyl.
27. A compound of claim 24 wherein: B is thienyl optionally
substituted with one to three same or different halogens or a
substituent selected from the group consisting of hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3
thioalkoxy, amino, --C(O)H, --COOH, --COOC.sub.1-C.sub.6 alkyl,
--NHC(O)--(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2--(C.sub.1-C.sub.6
alkyl), --C(O)--NH.sub.2, C(O)NHMe, C(O)NMe2, trifluoromethyl,
--NR.sup.55R.sup.56, NR.sup.55R.sup.56--(C.sub- .1-C.sub.6
alkyl)-NR.sup.55R.sup.56, heteroaryl, piperazine, pyrrolidine,
N-pyrrolidone and trifluoromethyl.
28. A compound of claim 10 wherein: B is thienyl.
29. A compound of claim 27 wherein: B is thienyl optionally
substituted with one to three same or different halogens or a
substituent selected from the group consisting of hydroxy,
C.sub.1-C.sub.6 alkyl, amino, --NHC(O)--(C.sub.1-C.sub.6 alkyl),
--C(O)--NH.sub.2, C(O)NHMe, C(O)NMe.sub.2 and
--NR.sup.55R.sup.56.
30. A compound of claim 10 wherein: B is thienyl optionally
substituted with one to three same or different halogens or a
substituent selected from the group consisting of hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3
thioalkoxy, amino, --C(O)H, --COOH, --COOC.sub.1-C.sub.6 alkyl,
--NHC(O)--C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2--(C.sub.1-C.sub.6
alkyl), methoxy, --C(O)--NH.sub.2, C(O)NHMe, C(O)NMe2,
trifluoromethyl, --NR.sup.55R.sup.56,
NR.sup.55R.sup.56--(C.sub.1-C.sub.6 alkyl)-NR.sup.55R.sup.56,
heteroaryl, piperazine, pyrrolidine, N-pyrrolidone and
trifluoromethyl.
31. A compound of claim 16 wherein: B is heteroaryl selected from
the group consisting of thiazole, pyridazine, pyrazine, pyrazole,
isoxazole, isothiazole, imidazole, furyl, thienyl, oxazole,
oxadiazole, thiadiazole, pyrimidine, pyrazole, triazine, triazole,
tetrazole and pyridyl; wherein said heteroaryl is optionally
substituted with one to three same or different halogens or a
substituent selected from the group F consisting of hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3
thioalkoxy, amino, --C(O)H, --COOH, --COOC.sub.1-C.sub.6 alkyl,
--NHC(O)--(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2--(C.sub.1-C.sub.-
6 alkyl), methoxy, --C(O)--NH.sub.2, C(O)NHMe, C(O)NMe2,
trifluoromethyl, --NR.sup.55R.sup.56,
NR.sup.55R.sup.56--(C.sub.1-C.sub.6 alkyl)-NR.sup.55R.sup.56,
heteroaryl, piperazine, pyrrolidine, N-pyrrolidone and
trifluoromethyl.
32. A compound of claim 17 wherein: B is heteroaryl selected from
the group consisting of thiazole, pyridazine, pyrazine, pyrazole,
isoxazole, isothiazole, imidazole, furyl, thienyl, oxazole,
oxadiazole, thiadiazole, pyrimidine, pyrazole, triazine, triazole,
tetrazole and pyridyl; wherein said heteroaryl is optionally
substituted with one to three same or different halogens or a
substituent selected from the group F consisting of hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3
thioalkoxy, amino, --C(O)H, --COOH, --COOC.sub.1-C.sub.6 alkyl,
--NHC(O)--(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2--(C.sub.1-C.sub.-
6 alkyl), methoxy, --C(O)--NH.sub.2, C(O)NHMe, C(O)NMe2,
trifluoromethyl, --NR.sup.55R.sup.56,
NR.sup.55R.sup.56--(C.sub.1-C.sub.6 alkyl)-NR.sup.55R.sup.56,
heteroaryl, piperazine, pyrrolidine, N-pyrrolidone and
trifluoromethyl.
33. A compound of claim 18 wherein: B is heteroaryl selected from
the group consisting of thiazole, pyridazine, pyrazine, pyrazole,
isoxazole, isothiazole, imidazole, furyl, thienyl, oxazole,
oxadiazole, thiadiazole, pyrimidine, pyrazole, triazine, triazole,
tetrazole and pyridyl; wherein said heteroaryl is optionally
substituted with one to three same or different halogens or a
substituent selected from the group F consisting of hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3
thioalkoxy, amino, --C(O)H, --COOH, --COOC.sub.1-C.sub.6 alkyl,
--NHC(O)--(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2--(C.sub.1-C.sub.-
6 alkyl), methoxy, --C(O)--NH.sub.2, C(O)NHMe, C(O)NMe2,
trifluoromethyl, --NR.sup.55R.sup.56,
NR.sup.55R.sup.56--(C.sub.1-C.sub.6 alkyl)-NR.sup.55R.sup.56,
heteroaryl, piperazine, pyrrolidine, N-pyrrolidone and
trifluoromethyl.
34. A compound of claim 3 which is depicted in Table 2.
35. A compound of claim 3 which is depicted in Table 2-1.
36. A compound of claim 3 which is depicted in Table 3.
37. A compound of claim 3 which is depicted in Table 4.
38. A compound of claim 3 which is depicted in Table 5.
39. A compound of claim 1 wherein: A is selected from the group
consisting of phenyl and heteroaryl; wherein heteroaryl is
pyridinyl, furanyl or thienyl; wherein said phenyl or heteroaryl is
independently optionally substituted with one to two of the same or
different amino, C.sub.1-6alkyl, or halogen; represents a
carbon-carbon bond; R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, and R.sup.16 are each independently
hydrogen or methyl, with the proviso that only zero, one, or two is
methyl; Q is either: 2403R.sup.2 is selected from the group
consisting of hydrogen, halogen, and methoxy; and R.sub.3 is
hydrogen; or (b) Q is: 2404R.sub.2 and R.sup.3 are hydrogen; and
for both (a) and (b): R.sup.4 is selected from the group consisting
of B; B is heteroaryl selected from the group consisting of
triazole, pyrazole, oxazole, pyrazine, pyrimidine and oxadiazole;
wherein said heteroaryl is optionally substituted with one to three
same or different halogens or from one to two same or different
substituents selected from the group F; F is selected from the
group consisting of (C.sub.1-6)alkyl, heteroaryl,
--NR.sup.42C(O)--(C.sub.1-6)alkyl, --NR.sup.42R.sup.43 and
C(O)NR.sup.42R.sup.43; R.sup.5 is hydrogen; R.sub.6 does not exist;
and R.sup.42 and R.sup.43 are independently selected from the group
consisting of hydrogen and (C.sub.1-6)alkyl; or R.sup.42 and
R.sup.43 taken together with the nitrogen to which they are
attached form a heteroalicyclic selected from the group consisting
of aziridine, azetidine, pyrrolidine, piperazine, tetrahydrofuran,
tetrahydropyran, azepine and morpholine.
40. A compound of claim 39 wherein: R.sup.2 is H, Cl, F, or
methoxy; and R.sup.4 is selected from the group consisting of
2405
41. A compound of claim 40 wherein: R.sup.2 is methoxy or fluoro;
and one of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
R.sup.14, R.sup.15, or R.sup.16 is methyl and the others are
hydrogen.
42. A compound of claim 40 wherein: R.sup.2 is methoxy; and
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, and R.sup.16 are each hydrogen.
43. A compound of claim 41 wherein: one of R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, or R.sup.16 is
(R)-methyl and the others are hydrogen.
44. A compound of claim 41 wherein: one of R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, or R.sup.16 is
(S)-methyl and the others are hydrogen.
45. A compound of claim 39 wherein: R.sup.2 is methoxy, hydrogen,
chloro, or fluoro; and R.sup.4 is oxadiazole.
46. A compound of claim 54 wherein: R.sup.2 is methoxy, hydrogen,
chloro or fluoro; and R.sup.4 is oxadiazole substituted with a
single fluoro, chloro, amino or methyl group.
47. A compound of claim 2, including pharmaceutically acceptable
salts thereof, wherein: A is selected from the group consisting of
phenyl and heteroaryl; wherein said heteroaryl is pyridinyl,
furanyl or thienyl; and said phenyl or said heteroaryl is
optionally substituted with one to two of the same or different
amino, C.sub.1-6alkyl, hydroxy, or halogen; R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.15, and R.sup.16 are each hydrogen;
R.sup.13 and R.sup.14 are each independently hydrogen or methyl
with the proviso that only one is methyl; Q is either: 2406R.sup.2
is selected from the group consisting of hydrogen, halogen and
methoxy; and R.sub.3 is hydrogen; or (b) Q is: 2407and R.sup.2 is
halogen or hydrogen and R.sup.3 is hydrogen; and for both (a) and
(b): R.sup.4 is selected from the group consisting of B; and B is
selected from the group consisting of --C(O)NR.sup.40R.sup.41,
substituted phenyl, heteroaryl, oxazoline, pyrazinone, methylene
dioxy or ethylene dioxy fused to a benzene or pyridine; wherein
said heteroaryl or phenyl is optionally substituted with one to
three same or different halogens or from one to two same or
different substituents selected from the group F.
48. A compound of claim 47, including pharmaceutically acceptable
salts thereof, wherein: B is selected from the group consisting of
--C(O)NR.sup.40R.sup.41, substituted phenyl and heteroaryl; wherein
said phenyl is substituted and heteroaryl is optionally substituted
with one to three same or different halogens or from one to two
same or different substituents selected from the group F; F is
selected from the group consisting of (C.sub.1-6)alkyl,
(C.sub.3-6)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,
(C.sub.1-6)alkoxy, (C.sub.1-6)thioalkoxy, cyano, halogen,
--C(O)R.sup.57, benzyl, --NR.sup.42C(O)--(C.sub.1-6)alkyl- ,
--NR.sup.42C(O)--(C.sub.3-6)cycloalkyl, --NR.sup.42C(O)-aryl,
--NR.sup.42C(O)-heteroaryl, --NR.sup.42C(O)-heteroalicyclic, 4, 5,
or 6 membered ring cyclic N-lactam,
--NR.sup.42S(O).sub.2--(C.sub.1-6)alkyl, --NR.sup.42R.sup.43,
C(O)NR.sup.42R.sup.43 and COOR.sup.54; wherein said
(C.sub.1-6)alkyl, (C.sub.3-6)cycloalkyl, aryl, heteroaryl,
heteroalicyclic, (C.sub.1-6)alkoxy, are optionally substituted with
one to three same or different halogens or from one to two same or
different substituents selected from the group G; G is selected
from the group consisting of (C.sub.1-6)alkyl, hydroxy,
(C.sub.1-6)alkoxy, halogen, --NR.sup.48C(O)--(C.sub.1-6)alkyl,
--NR.sup.48C(O)--(C.sub.3)cycloalkyl, 4, 5, or 6 membered ring
cyclic N-lactam, --NR.sup.48S(O).sub.2--(C.sub.1- -6)alkyl,
NR.sup.48R.sup.49, (C.sub.1-6)alkyl C(O)NR.sup.48R.sup.49,
C(O)NR.sup.48R.sup.49 and (C.sub.1-6)alkylNR.sup.48R.sup.49;
R.sup.40 is hydrogen; R.sup.41 is (C.sub.1-6)alkyl,
(C.sub.3-7)cycloalkyl, phenyl, or heteroaryl; wherein said
(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl, phenyl, or heteroaryl are
substituted with one to three same or different halogens or one to
two same or different methyl, (C.sub.1-3)alkoxy, heteroaryl or
aryl; wherein said aryl or heteroaryl are optionally substituted
with one to three same or different halogens or from one to two
same or different substituents selected from the group consisting
of (C.sub.1-6)alkyl, hydroxy, (C.sub.1-6)alkoxy,
--NR.sup.42C(O)--(C.sub.1-6- )alkyl, NR.sup.42R.sup.43 and
C(O)NR.sup.42R.sup.43.
49. A compound of claim 2, including pharmaceutically acceptable
salts thereof, wherein: A is selected from the group consisting of
phenyl and heteroaryl; wherein heteroaryl is pyridinyl, furanyl or
thienyl; and said phenyl or said heteroaryl is optionally
substituted with one to two of the same or different amino,
C.sub.1-6alkyl, hydroxy, or halogen; R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, and R.sup.16 are each
independently hydrogen or methyl with the proviso that only one is
methyl; Q is either: 2408wherein R.sup.2 is selected from the group
consisting of hydrogen, halogen and methoxy; and R.sub.3 is
hydrogen; or (b) Q is: 2409wherein R.sup.2 is halogen or hydrogen;
and R.sup.3 is hydrogen; and for both (a) and (b): R.sup.4 is
selected from the group consisting of B; B is selected from the
group consisting of --C(O)NR.sup.40R.sup.41, substituted phenyl,
heteroaryl, oxazoline, pyrazinone, methylene dioxy or ethylene
dioxy fused to a benzene or pyridine; wherein said heteroaryl or
phenyl is optionally substituted with one to three same or
different halogens or from one to two same or different
substituents selected from the group F;
50. A compound of claim 49, including pharmaceutically acceptable
salts thereof, wherein: B is selected from the group consisting of
pyrazinone and methylene dioxy or ethylene dioxy fused to a benzene
ring; wherein said group is optionally substituted with one to
three same or different halogens or a substituent selected from the
group F consisting of (C.sub.1-C.sub.6 alkyl), amino,
--NHC(O)--(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2--(C.sub.1-C.sub.6
alkyl), methoxy, --C(O)--NH.sub.2, C(O)NHMe, C(O)NMe2,
trifluoromethyl, --NHC(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, -heteroaryl and a 4, 5, or 6 membered cyclic
N-lactam.
51. A compound of claim 49, including pharmaceutically acceptable
salts thereof, wherein: B is selected from the group consisting of
oxadiazole, triazole, pyrazole, pyrazine and pyrimidine; wherein
said group is optionally substituted with one to three same or
different halogens or a substituent selected from the group F
consisting of (C.sub.1-C.sub.6 alkyl), amino,
--NHC(O)--(C.sub.1-C.sub.6 alkyl), --NHS(O).sub.2--(C.sub.-
1-C.sub.6 alkyl), methoxy, --C(O)--NH.sub.2, C(O)NHMe, C(O)NMe2,
trifluoromethyl, --NHC(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, -heteroaryl, a 4, 5, or 6 membered cyclic N-lactam
and (C.sub.1-6)alkylNR.sup.48R.sup.49.
52. A compound of claim 49, including pharmaceutically acceptable
salts thereof, wherein: heteroaryl in B is selected from the group
consisting of pyrazine and pyrimidine.
53. A compound of claim 50, including pharmaceutically acceptable
salts thereof, wherein: heteroaryl in B is selected from the group
consisting of pyrazine and pyrimidine.
54. A compound of claim 1 wherein R.sup.9, R.sup.10, R.sup.15 and
R.sup.16 are each hydrogen; and R.sup.11, R.sup.12, R.sup.13, and
R.sup.14 are each independently hydrogen or methyl with the proviso
that up to one can be methyl.
55. A compound of claim 54, including pharmaceutically acceptable
salts thereof, wherein one of R.sup.11, R.sup.12, R.sup.13, and
R.sup.14 is methyl.
56. A compound of claim 55, wherein the carbon atom of the
piperazine ring to which the methyl group of R.sup.11, R.sup.12,
R.sup.13, and R.sup.14 is attached has an (R) configuration.
57. A compound of claim 1 wherein R.sup.11, R.sup.12, R.sup.13, and
R.sup.14 are each hydrogen; and R.sup.9, R.sup.10, R.sup.15 and
R.sup.16 are each independently hydrogen or methyl with the proviso
that up to one can be methyl.
58. A compound of claim 57, wherein one of R.sup.9, R.sup.10,
R.sup.15 and R.sup.16 is methyl.
59. A compound of claim 58, wherein the carbon atom of the
piperazine ring to which the methyl group of R.sup.9, R.sup.10,
R.sup.15 and R.sup.16 is attached has an (R) configuration.
60. A compound of claim 1, including pharmaceutically acceptable
salts thereof wherein: R.sup.1 is hydrogen; m is 2; R.sup.5 is
hydrogen; R.sup.6 does not exist; A is selected from the group
consisting of C.sub.1-6alkoxy, aryl and heteroaryl; wherein aryl is
phenyl; heteroaryl is selected from the group consisting of
pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl,
pyrrolyl, imidazolyl, thiazolyl, oxazolyl and isoxazolyl; and said
aryl or heteroaryl is optionally substituted with one or two of the
same or different amino, cyano, hydroxy C.sub.1-6alkoxy,
C.sub.1-6alkyl, --NHC(O)CH.sub.3, halogen and trifluoromethyl; and
represents a carbon-carbon bond.
61. A pharmaceutical formulation which comprises an antiviral
effective amount of a compound of Formula I, including
pharmaceutically acceptable salts thereof, as claimed in claim 1,
and a pharmaceutically acceptable carrier.
62. The pharmaceutical formulation of claim 61, useful for treating
infection by HIV, which additionally comprises an antiviral
effective amount of an AIDS treatment agent selected from the group
consisting of: (a) an AIDS antiviral agent; (b) an anti-infective
agent; (c) an immunomodulator; and (d) HIV entry inhibitors.
63. A method for treating mammals infected with a virus, comprising
administering to said mammal an antiviral effective amount of a
compound of Formula I, including pharmaceutically acceptable salts
thereof, as claimed in claim 1.
64. The method of claim 63, comprising administering to said mammal
an antiviral effective amount of a compound of Formula I in
combination with an antiviral effective amount of an AIDS treatment
agent selected from the group consisting of: an AIDS antiviral
agent; an anti-infective agent; an immunomodulator; and HIV entry
inhibitors.
65. The method of claim 63 wherein the virus is HIV.
66. The method of claim 64 wherein the virus is HIV.
67. A compound of claim 1 having the Formula Ia, including
pharmaceutically acceptable salts thereof, 2410wherein: R.sup.2 is
methoxy, fluoro or chloro; R.sup.4 is selected from the group
consisting of a 1,2,3-triazolyl group having the formula 2411a
1,2,4-triazolyl group having the formula 2412D is hydrogen or
C.sub.1-C.sub.3 alkyl; E is selected from the group consisting of
hydrogen, (C.sub.1-C.sub.3)alkyl, O(C.sub.1-C.sub.3)alkyl and
CH.sub.2OCH.sub.3; and R.sup.11 is either hydrogen or methyl in
which the configuration to which the methyl is attached is (R);
with the proviso that when R.sup.4 is 2413then R.sup.11 is
hydrogen.
68. A compound of claim 67, including pharmaceutically acceptable
salts thereof, wherein: R.sup.2 is methoxy or fluorine; D is
hydrogen or methyl; and E is hydrogen, methyl or ethyl.
69. A compound of claim 68, including pharmaceutically acceptable
salts thereof, wherein: R.sup.2 is methoxy; D is hydrogen or
methyl; and E is hydrogen, methyl or ethyl.
70. A compound of claim 69, including pharmaceutically acceptable
salts thereof, wherein: R.sup.11 is hydrogen.
71. A compound of claim 70, including pharmaceutically acceptable
salts thereof, wherein: R.sup.4 is 2414and R.sup.11 is
hydrogen.
72. A compound of claim 71, including pharmaceutically acceptable
salts thereof, wherein: D is hydrogen.
73. A compound of claim 71, including pharmaceutically acceptable
salts thereof, wherein: D is methyl.
74. A compound of claim 70, including pharmaceutically acceptable
salts thereof, wherein: R.sup.4 is 2415
75. A compound of claim 74, including pharmaceutically acceptable
salts thereof, wherein: E is hydrogen.
76. A compound of claim 74, including pharmaceutically acceptable
salts thereof, wherein: E is methyl.
77. A compound of claim 74, including pharmaceutically acceptable
salts thereof, wherein: E is ethyl.
78. A compound of claim 68, including pharmaceutically acceptable
salts thereof, wherein: R.sup.2 is fluoro; D is hydrogen or methyl;
and E is hydrogen or methyl.
79. A compound of claim 78, including pharmaceutically acceptable
salts thereof, wherein: R.sup.4 is 2416and R.sup.11 is
hydrogen.
80. A compound of claim 79, including pharmaceutically acceptable
salts thereof, wherein: D is hydrogen.
81. A compound of claim 79, including pharmaceutically acceptable
salts thereof, wherein: D is methyl.
82. A compound of claim 78, including pharmaceutically acceptable
salts thereof, wherein: R.sup.4 is 2417
83. A compound of claim 82, including pharmaceutically acceptable
salts thereof, wherein: E is hydrogen.
84. A compound of claim 82, including pharmaceutically acceptable
salts thereof, wherein: E is methyl.
85. A compound of claim 68, including pharmaceutically acceptable
salts thereof, wherein: R.sup.2 is methoxy; D is hydrogen or
methyl; E is hydrogen, methyl or ethyl; and R.sup.11 is
(R)-methyl.
86. A compound of claim 85, including pharmaceutically acceptable
salts thereof, wherein: R.sup.4 is 2418
87. A compound of claim 86, including pharmaceutically acceptable
salts thereof, wherein: E is hydrogen.
88. A compound of claim 86, including pharmaceutically acceptable
salts thereof, wherein: E is methyl.
89. A compound of claim 86, including pharmaceutically acceptable
salts thereof, wherein: E is ethyl.
90. A pharmaceutical formulation which comprises an antiviral
effective amount of a compound of Formula Ia, including
pharmaceutically acceptable salts thereof, as claimed in claim 67,
and a pharmaceutically acceptable carrier.
91. The pharmaceutical formulation of claim 90, useful for treating
infection by HIV, which additionally comprises an antiviral
effective amount of an AIDS treatment agent selected from the group
consisting of: (a) an AIDS antiviral agent; (b) an anti-infective
agent; (c) an immunomodulator; and (d) HIV entry inhibitors.
92. A method for treating mammals infected with the HIV virus,
comprising administering to said mammal an antiviral effective
amount of a compound of Formula Ia, including pharmaceutically
acceptable salts thereof, as claimed in claim 67.
93. The method of claim 92, comprising administering to said mammal
an antiviral effective amount of a compound of Formula Ia in
combination with an antiviral effective amount of an AIDS treatment
agent selected from the group consisting of: an AIDS antiviral
agent; an anti-infective agent; an immunomodulator; and HIV entry
inhibitors.
Description
REFERENCE TO RELATED APPLICATIONS
[0001] This Continuation in Part application claims the benefit of
U.S. Ser. No. 10/214,982 filed Aug. 7, 2002 which claims the
benefit of U.S. Ser. No. 10/038,306 filed Jan. 2, 2002 and U.S.
Provisional Application Serial No. 60/314,406 filed Aug. 23, 2001
and Ser. No. 60/266,183 filed Feb. 2, 2001.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention provides compounds having drug and
bio-affecting properties, their pharmaceutical compositions and
method of use. In particular, the invention is concerned with
azaindole piperazine diamide derivatives that possess unique
antiviral activity. More particularly, the present invention
relates to compounds useful for the treatment of HIV and AIDS.
[0004] 2. Background Art
[0005] HIV-1 (human immunodeficiency virus-1) infection remains a
major medical problem, with an estimated 42 million people infected
worldwide at the end of 2002. The number of cases of HIV and AIDS
(acquired immunodeficiency syndrome) has risen rapidly. In 2002,
.about.5.0 million new infections were reported, and 3.1 million
people died from AIDS. Currently available drugs for the treatment
of HIV include nine nucleoside reverse transcriptase (RT)
inhibitors or approved single pill combinations(zidovudine or AZT
(or Retrovir.RTM.), didanosine (or Videx.RTM.), stavudine (or Zerit
.RTM.), lamivudine (or 3TC or Epivir.RTM.), zalcitabine (or DDC or
Hivid.RTM.), abacavir succinate (or Ziagen .RTM.), Tenofovir
disoproxil fumarate salt (or Viread.RTM.), Combivir.RTM.
(contains-3TC plus AZT), Trizivir.RTM. (contains abacavir,
lamivudine, and zidovudine); three non-nucleoside reverse
transcriptase inhibitors: nevirapine (or Viramune.RTM.),
delavirdine (or Rescriptor .RTM.) and efavirenz (or Sustiva .RTM.),
and eight peptidomimetic protease inhibitors or approved
formulations: saquinavir, indinavir, ritonavir, nelfinavir,
amprenavir, lopinavir, Kaletra .RTM. (lopinavir and Ritonavir), and
Atazanavir (Reyataz .RTM.). Each of these drugs can only
transiently restrain viral replication if used alone. However, when
used in combination, these drugs have a profound effect on viremia
and disease progression. In fact, significant reductions in death
rates among AIDS patients have been recently documented as a
consequence of the widespread application of combination therapy.
However, despite these impressive results, 30 to 50% of patients
ultimately fail combination drug therapies. Insufficient drug
potency, non-compliance, restricted tissue penetration and
drug-specific limitations within certain cell types (e.g. most
nucleoside analogs cannot be phosphorylated in resting cells) may
account for the incomplete suppression of sensitive viruses.
Furthermore, the high replication rate and rapid turnover of HIV-1
combined with the frequent incorporation of mutations, leads to the
appearance of drug-resistant variants and treatment failures when
sub-optimal drug concentrations are present (Larder and Kemp;
Gulick; Kuritzkes; Morris-Jones et al; Schinazi et al; Vacca and
Condra; Flexner; Berkhout and Ren et al; (Ref. 6-14)). Therefore,
novel anti-HIV agents exhibiting distinct resistance patterns, and
favorable pharmacokinetic as well as safety profiles are needed to
provide more treatment options.
[0006] Currently marketed HIV-1 drugs are dominated by either
nucleoside reverse transcriptase inhibitors or peptidomimetic
protease inhibitors. Non-nucleoside reverse transcriptase
inhibitors (NNRTIs) have recently gained an increasingly important
role in the therapy of HIV infections (Pedersen & Pedersen, Ref
15). At least 30 different classes of NNRTI have been described in
the literature (De Clercq, Ref. 16) and several NNRTIs have been
evaluated in clinical trials. Dipyridodiazepinone (nevirapine),
benzoxazinone (efavirenz) and bis(heteroaryl) piperazine
derivatives (delavirdine) have been approved for clinical use.
However, the major drawback to the development and application of
NNRTIs is the propensity for rapid emergence of drug resistant
strains, both in tissue cell culture and in treated individuals,
particularly those subject to monotherapy. As a consequence, there
is considerable interest in the identification of NNRTIs less prone
to the development of resistance (Pedersen & Pedersen, Ref
15).
[0007] Several indole derivatives including indole-3-sulfones,
piperazino indoles, pyrazino indoles, and
5H-indolo[3,2-b][1,5]benzothiazepine derivatives have been reported
as HIV-1 reverse transciptase inhibitors (Greenlee et al, Ref. 1;
Williams et al, Ref. 2; Romero et al, Ref. 3; Font et al, Ref. 17;
Romero et al, Ref. 18; Young et al, Ref. 19; Genin et al, Ref. 20;
Silvestri et al, Ref. 21). Indole 2-carboxamides have also been
described as inhibitors of cell adhesion and HIV infection
(Boschelli et al, U.S. Pat. No. 5,424,329, Ref. 4). Finally,
3-substituted indole natural products (Semicochliodinol A and B,
didemethylasterriquinone and isocochliodinol) were disclosed as
inhibitors of HIV-1 protease (Fredenhagen et al, Ref. 22). Other
indole derivatives exhibiting antiviral activity useful for
treating HIV are disclosed in PCT WO 00/76521 (Ref. 93). Also,
indole derivatives are disclosed in PCT WO 00/71535 (Ref. 94).
[0008] Structurally related aza-indole amide derivatives have been
disclosed previously (Kato et al, Ref. 23; Levacher et al, Ref. 24;
Dompe Spa, WO-09504742, Ref. 5(a); SmithKline Beecham PLC,
WO-09611929, Ref. 5(b); Schering Corp., U.S. Pat. No. 05,023,265,
Ref. 5(c)). However, these structures differ from those claimed
herein in that they are aza-indole mono-amide rather than
unsymmetrical aza-indole piperazine diamide derivatives, and there
is no mention of the use of these compounds for treating viral
infections, particularly HIV. Other azaindoles have been also
disclosed by Wang et al, Ref. 95. Indole and azaindole piperazine
containing derivatives have been disclosed in four different PCT
and issued U.S. patent applications (Reference 93-95, 106). Nothing
in these references can be construed to disclose or suggest the
novel compounds of this invention and their use to inhibit HIV
infection.
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SUMMARY DESCRIPTION OF THE INVENTION
[0116] The present invention comprises compounds of Formula I, or
pharmaceutically acceptable salts thereof, which are effective
antiviral agents, particularly as inhibitors of HIV.
[0117] A first embodiment of a first aspect of the invention are
compounds of Formula I, including pharmaceutically acceptable salts
thereof, 1
[0118] wherein:
[0119] Q is selected from the group consisting of: 2
[0120] R.sup.1, R.sup.2, R.sup.3, and R.sup.4, are independently
selected from the group consisting of hydrogen, halogen, cyano,
nitro, COOR.sup.56, XR.sup.57, C(O)R.sup.7, C(O)NR.sup.55R.sup.56,
B, D, and E with the proviso that at least one of R.sup.1-R.sup.4
is selected from B or E;
[0121] wherein--represents a carbon-carbon bond or does not
exist;
[0122] m is 1 or 2;
[0123] R.sup.5 is hydrogen or (CH.sub.2).sub.nCH.sub.3,
--C(O)(CH.sub.2).sub.nCH.sub.3, --C(O)O(CH.sub.2).sub.nCH.sub.3,
--C(O) (CH.sub.2).sub.nN(CH.sub.3).sub.2 wherein n is 0-5;
[0124] R.sup.6 is O or does not exist;
[0125] A is selected from the group consisting of C.sub.1-6alkoxy,
aryl and heteroaryl; in which said aryl is phenyl or napthyl; said
heteroaryl is selected from the group consisting of pyridinyl,
pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl,
imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,
quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl,
benzoimidazolyl and benzothiazolyl; and said aryl or heteroaryl is
optionally substituted with one or two of the same or different
members selected from the group consisting of amino, nitro, cyano,
hydroxy, C.sub.1-6alkoxy, --C(O)NH.sub.2, C.sub.1-6alkyl,
--NHC(O)CH.sub.3, halogen and trifluoromethyl;
[0126] --W-- is 3
[0127] B is selected from the group consisting of
--C(.dbd.NR.sup.46)(R.su- p.47), C(O)NR.sup.40R.sup.41, aryl,
heteroaryl, heteroalicyclic, S(O).sub.2R.sup.8, C(O)R.sup.7,
XR.sup.8a, (C.sub.1-6)alkylNR.sup.40R.sup- .41,
(C.sub.1-6)alkylCOOR.sup.8b; wherein said aryl, heteroaryl, and
heteroalicyclic are optionally substituted with one to three same
or different halogens or from one to three same or different
substituents selected from the group F; wherein aryl is napthyl or
substituted phenyl; wherein heteroaryl is a mono or bicyclic system
which contains from 3 to 7 ring atoms for a mono cyclic system and
up to 12 atoms in a fused bicyclic system, including from 1 to 4
heteroatoms; wherein heteroalicyclic is a 3 to 7 membered mono
cyclic ring which may contain from 1 to 2 heteroatoms in the ring
skeleton and which may be fused to a benzene or pyridine ring;
[0128] q is 0, 1, or 2;
[0129] D is selected from the group consisting of (C.sub.1-6)alkyl
and (C.sub.2-6)alkenyl; wherein said (C.sub.1-6)alkyl and
(C.sub.2-6)alkenyl are optionally substituted with one to three
same or different halogens or from one to three same or different
substituents selected from the group consisting of
C(O)NR.sup.55R.sup.56, hydroxy, cyano and XR.sup.57;
[0130] E is selected from the group consisting of (C.sub.1-6)alkyl
and (C.sub.2-6)alkenyl; wherein said (C.sub.1-6)alkyl and
(C.sub.2-6)alkenyl are independently optionally substituted with a
member selected from the group consisting of phenyl, heteroaryl,
SMe, SPh, --C(O)NR.sub.56R.sub.57- , C(O)R.sub.57,
SO.sub.2(C.sub.1-6)alkyl and SO.sub.2Ph; wherein heteroaryl is a
monocyclic system which contains from 3 to 7 ring atoms, including
from 1 to 4 heteroatoms;
[0131] F is selected from the group consisting of (C.sub.1-6)alkyl,
(C.sub.3-7)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,
(C.sub.1-6)alkoxy, aryloxy, (C.sub.1-6)thioalkoxy, cyano, halogen,
nitro, --C(O)R.sup.57, benzyl, --NR.sup.42C(O)--(C.sub.1-6)alkyl,
--NR.sup.42C(O)--(C.sub.3-6)cycloalkyl, --NR.sup.42C(O)-aryl,
--NR.sup.42C(O)-heteroaryl, --NR.sup.42C(O)-heteroalicyclic, a 4,
5, or 6 membered ring cyclic N-lactam,
--NR.sup.42S(O).sub.2--(C.sub.1-6)alkyl,
--NR.sup.42S(O).sub.2--(C.sub.3-6)cycloalkyl,
--NR.sup.42S(O)2-aryl, --NR.sup.42S(O).sub.2-heteroaryl,
--NR.sup.42S(O)2-heteroalicyclic, S(O).sub.2(C.sub.1-6)alkyl,
S(O).sub.2aryl, --S(O)2 NR.sup.42R.sup.43, NR.sup.42R.sup.43,
(C.sub.1-6)alkylC(O)NR.sup.42R.sup.43, C(O)NR.sup.42R.sup.43,
NHC(O)NR.sup.42R.sup.43, OC(O)NR.sup.42R.sup.43, NHC(O)OR.sup.54,
(C.sub.1-6)alkylNR.sup.42R.sup.43, COOR.sup.54, and
(C.sub.1-6)alkylCOOR.sup.54; wherein said (C.sub.1-6)alkyl,
(C.sub.3-7)cycloalkyl, aryl, heteroaryl, heteroalicyclic,
(C.sub.1-6)alkoxy, and aryloxy, are optionally substituted with one
to nine same or different halogens or from one to five same or
different substituents selected from the group G; wherein aryl is
phenyl; heteroaryl is a monocyclic system which contains from 3 to
7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic is
selected from the group consisting of aziridine, azetidine,
pyrrolidine, piperazine, piperidine, tetrahydrofuran,
tetrahydropyran, azepine, and morpholine;
[0132] G is selected from the group consisting of (C.sub.1-6)alkyl,
(C.sub.3-7)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,
(C.sub.1-6)alkoxy, aryloxy, cyano, halogen, nitro, --C(O)R.sup.57,
benzyl, --NR.sup.48C(O)--(C.sub.1-6)alkyl,
--NR.sup.48C(O)--(C.sub.3-6)cy- cloalkyl, --NR.sup.48C(O)-aryl,
--NR.sup.48C(O)-heteroaryl, --NR.sup.48C(O)-heteroalicyclic, a 4,
5, or 6 membered ring cyclic N-lactam,
--NR.sup.48S(O).sub.2--(C.sub.1-6)alkyl,
--NR.sup.48S(O).sub.2--(C.sub.3-6)cycloalkyl,
--NR.sup.48S(O)2-aryl, --NR.sup.48S(O).sub.2-heteroaryl,
--NR.sup.48S(O)2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide,
NR.sup.48R.sup.49, (C.sub.1-6)alkyl C(O)NR.sup.48R.sup.49,
C(O)NR.sup.48R.sup.49, NHC(O)NR.sup.48R.sup.49,
OC(O)NR.sup.48R.sup.49, NHC(O)OR.sup.54',
(C.sub.1-6)alkylNR.sup.48R.sup.- 49, COOR.sup.54, and
(C.sub.1-6)alkylCOOR.sup.54; wherein aryl is phenyl; heteroaryl is
a monocyclic system which contains from 3 to 7 ring atoms,
including from 1 to 4 heteroatoms; heteroalicyclic is selected from
the group consisting of aziridine, azetidine, pyrrolidine,
piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine,
and morpholine;
[0133] R.sup.7 is selected from the group consisting of aryl,
heteroaryl, and heteroalicyclic; wherein said aryl, heteroaryl, and
heteroalicyclic are optionally substituted with one to three same
or different halogens or with from one to three same or different
substituents selected from the group F;
[0134] wherein for R.sup.7, R.sup.8, R.sup.8a, R.sup.8b aryl is
phenyl; heteroaryl is a mono or bicyclic system which contains from
3 to 7 ring atoms for mono cyclic systems and up to 10 atoms in a
bicyclic system, including from 1 to 4 heteroatoms; wherein
heteroalicyclic is selected from the group consisting of aziridine,
azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran,
tetrahydropyran, azepine, and morpholine;
[0135] R.sup.8 is selected from the group consisting of hydrogen,
(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl, (C.sub.2-6)alkenyl,
(C.sub.3-7)cycloalkenyl, (C.sub.2-6)alkynyl, aryl, heteroaryl, and
heteroalicyclic; wherein said (C.sub.1-6)alkyl,
(C.sub.3-7)cycloalkyl, (C.sub.2-6)alkenyl, (C.sub.3-7)cycloalkenyl,
(C.sub.2-6)alkynyl, aryl, heteroaryl, and heteroalicyclic are
optionally substituted with one to six same or different halogens
or from one to five same or different substituents selected from
the group F;
[0136] R.sup.8a is a member selected from the group consisting of
aryl, heteroaryl, and heteroalicyclic; wherein each member is
independently optionally substituted with one to six same or
different halogens or from one to five same or different
substituents selected from the group F;
[0137] R.sup.8b is selected from the group consisting of hydrogen,
(C.sub.1-6)alkyl and phenyl;
[0138] R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, R.sup.16, are each independently selected from the group
consisting of hydrogen and (C.sub.1-6)alkyl; wherein said
(C.sub.1-6)alkyl is optionally substituted with one to three same
or different halogens;
[0139] X is selected from the group consisting of NH or NCH.sub.3,
O, and S;
[0140] R.sup.40 and R.sup.41 are independently selected from the
group consisting of (a) hydrogen; (b) (C.sub.1-6)alkyl or
(C.sub.3-7)cycloalkyl substituted with one to three same or
different halogens or from one to two same or different
substituents selected from the group F; and (c) (C.sub.1-6)alkoxy,
aryl, heteroaryl or heteroalicyclic; or R.sup.40 and R.sup.41 taken
together with the nitrogen to which they are attached form a member
selected from the group consisting of aziridine, azetidine,
pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine, and
morpholine; and wherein said aryl, heteroaryl, and heteroalicyclic
are optionally substituted with one to three same or different
halogens or from one to two same or different substituents selected
from the group F; wherein for R.sup.40 and R.sup.41 aryl is phenyl;
heteroaryl is a monocyclic system which contains from 3 to 6 ring
atoms, including from 1 to 4 heteroatoms; heteroalicyclic is
selected from the group consisting of aziridine, azetidine,
pyrrolidine, piperazine, piperidine, tetrahydrofuran,
tetrahydropyran, azepine, and morpholine; provided when B is
C(O)NR.sup.40R.sup.41, at least one of R.sup.40 and R.sup.41 is not
selected from groups (a) or (b);
[0141] R.sup.42 and R.sup.43 are independently selected from the
group consisting of hydrogen, (C.sub.1-6)alkyl, allyl,
(C.sub.1-6)alkoxy, (C.sub.3-7)cycloalkyl, aryl, heteroaryl and
heteroalicyclic; or R.sup.42 and R.sup.43 taken together with the
nitrogen to which they are attached form a member selected from the
group consisting of aziridine, azetidine, pyrrolidine, piperazine,
4-NMe piperazine, piperidine, azepine, and morpholine; and wherein
said (C.sub.1-6)alkyl, (C.sub.1-6)alkoxy, (C.sub.3-7)cycloalkyl,
aryl, heteroaryl, and heteroalicyclic are optionally substituted
with one to three same or different halogens or from one to two
same or different substituents selected from the group G; wherein
for R.sup.42 and R.sup.43 aryl is phenyl; heteroaryl is a
monocyclic system which contains from 3 to 6 ring atoms, including
from 1 to 4 heteroatoms; heteroalicyclic is a member selected from
the group consisting of aziridine, azetidine, pyrrolidine,
piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine,
and morpholine;
[0142] R.sub.a and R.sub.b are each independently H,
(C.sub.1-6)alkyl or phenyl;
[0143] R.sup.46 is selected from the group consisting of H,
OR.sup.57, and NR.sup.55R.sup.56,
[0144] R.sup.47 is selected from the group consisting of H, amino,
halogen, phenyl, and (C.sub.1-6)alkyl;
[0145] R.sup.48 and R.sup.49 are independently selected from the
group consisting of hydrogen, (C.sub.1-6)alkyl and phenyl;
[0146] R.sup.50 is selected from the group consisting of H,
(C.sub.1-6)alkyl, (C.sub.3-6)cycloalkyl, and benzyl; wherein each
of said (C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl and benzyl are
optionally substituted with one to three same or different halogen,
amino, OH, CN or NO.sub.2;
[0147] R.sup.54 is selected from the group consisting of hydrogen
and (C.sub.1-6)alkyl;
[0148] R.sup.54 is (C.sub.1-6)alkyl;
[0149] R.sup.55 and R.sup.56 are independently selected from the
group consisting of hydrogen and (C.sub.1-6)alkyl; and
[0150] R.sup.57 is selected from the group consisting of hydrogen,
(C.sub.1-6)alkyl and phenyl.
[0151] A preferred embodiment are compounds of Formula I, including
pharmaceutically acceptable salts thereof,
[0152] wherein:
[0153] R.sup.1 is hydrogen;
[0154] Q is either: 4
[0155] wherein R.sup.2 is selected from the group consisting of
hydrogen, halogen, hydroxy, --O(C.sub.1-6)alkyl, cyano, nitro and
XR.sup.57;
[0156] wherein R.sup.3 is selected from the group consisting of
hydrogen, halogen, hydroxy, --O(C.sub.1-6)alkyl, cyano,
--COOR.sup.56, nitro, XR.sup.57; phenyl optionally substituted with
one to three same or different halogens or one of methoxy, hydroxy
or XR.sup.57; furyl, oxazolyl, or pyrazolyl, independently
optionally substituted with halogen, methoxy, (C.sub.1-3)alkyl or
XR.sup.57; or
[0157] (b) Q is: 5
[0158] wherein R.sup.2 and R.sup.3 are independently selected from
the group consisting of hydrogen, halogen, hydroxy,
--O(C.sub.1-6)alkyl, cyano, nitro, --COOR.sup.56, XR.sup.57, --C(O)
NR.sup.55R.sup.56; phenyl optionally substituted with one to three
same or different halogens or one of methoxy, hydroxy or XR.sup.57;
furyl, oxalzolyl or pyrazolyl, independently optionally substituted
with (C.sub.1-3)alkyl, halogen, methoxy or XR.sup.57;
[0159] and for both (a) and (b):
[0160] m is 2;
[0161] R.sup.5 is hydrogen;
[0162] R.sup.6 does not exist;
[0163] A is selected from the group consisting of C.sub.1-6alkoxy,
aryl and heteroaryl; wherein said aryl is phenyl; heteroaryl is
selected from the group consisting of pyridinyl, pyrimidinyl,
pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl, imidazolyl,
thiazolyl, oxazolyl and isoxazolyl; and said aryl or heteroaryl is
optionally substituted with one or two of the same or different
members selected from the group consisting of amino, cyano, hydroxy
C.sub.1-6alkoxy, C.sub.1-6alkyl, --NHC(O)CH.sub.3, halogen and
trifluoromethyl;
[0164] represents a carbon-carbon bond;
[0165] X is NH or NCH.sub.3;
[0166] R.sup.57 is H or (C.sub.1-3)alkyl; and
[0167] R.sup.55 and R.sup.56 are independently H or
(C.sub.1-6)alkyl.
[0168] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0169] wherein:
[0170] A is selected from the group consisting of phenyl and
heteroaryl; wherein heteroaryl is pyridinyl, furanyl or thienyl;
and said phenyl or said heteroaryl is optionally substituted with
one to two of the same or different amino, C.sub.1-6alkyl, hydroxy,
or halogen;
[0171] R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, and R.sup.16 are each independently hydrogen or methyl
with the proviso that only one is methyl;
[0172] Q is either: 6
[0173] and then R.sup.2 is selected from the group consisting of
hydrogen, halogen and methoxy; and
[0174] R.sub.3 is hydrogen; or
[0175] (b) Q is: 7
[0176] and R.sup.2 is halogen or hydrogen and R.sup.3 is
hydrogen;
[0177] and for both (a) and (b):
[0178] R.sup.4 is selected from the group consisting of B;
[0179] B is selected from the group consisting of
--C(O)NR.sup.40R.sup.41, substituted phenyl, heteroaryl, oxazoline,
pyrazinone and methylene dioxy or ethylene dioxy fused to a benzene
or pyridine; wherein said heteroaryl or phenyl is optionally
substituted with one to three same or different halogens or from
one to two same or different substituents selected from the group
F.
[0180] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0181] wherein:
[0182] B is selected from the group consisting of
--C(O)NR.sup.40R.sup.41, substituted phenyl and heteroaryl; wherein
said phenyl is substituted and heteroaryl is optionally substituted
with one to three same or different halogens or from one to two
same or different substituents selected from the group F;
[0183] F is selected from the group consisting of (C.sub.1-6)alkyl,
(C.sub.3-6)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,
(C.sub.1-6)alkoxy, (C.sub.1-6)thioalkoxy, cyano, halogen,
--C(O)R.sup.57, benzyl, --NR.sup.42C(O)--(C.sub.1 6)alkyl,
--NR.sup.42C(O)--(C.sub.3-6)cy- cloalkyl, --NR.sup.42C(O)-aryl,
--NR.sup.42C(O)-heteroaryl, --NR.sup.42C(O)-heteroalicyclic, 4, 5,
or 6 membered ring cyclic N-lactam,
--NR.sup.42S(O).sub.2--(C.sub.1-6)alkyl, --NR.sup.42R.sup.43,
C(O)NR.sup.42R.sup.43 and COOR.sup.54; wherein said
(C.sub.1-6)alkyl, (C.sub.3-6)cycloalkyl, aryl, heteroaryl,
heteroalicyclic, (C.sub.1-6)alkoxy, are optionally substituted with
one to three same or different halogens or from one to two same or
different substituents selected from the group G;
[0184] G is selected from the group consisting of (C.sub.1-6)alkyl,
hydroxy, (C.sub.1-6)alkoxy, halogen,
--NR.sup.48C(O)--(C.sub.1-6)alkyl,
--NR.sup.48C(O)--(C.sub.3)cycloalkyl, 4, 5, or 6 membered ring
cyclic N-lactam, --NR.sup.48S(O).sub.2--(C.sub.1-6)alkyl,
NR.sup.48R.sup.49, (C.sub.1-6)alkyl C(O)NR.sup.48R.sup.49,
C(O)NR.sup.48R.sup.49 and (C.sub.1-6)alkylNR.sup.48R.sup.49;
[0185] R.sup.40 is hydrogen; and
[0186] R.sup.41 is selected from the group consisting of
(C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl, phenyl and heteroaryl;
wherein said (C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl, phenyl, or
heteroaryl are substituted with one to three same or different
halogens or one to two same or different substituents selected from
the group consisting of methyl, (C.sub.1-3)alkoxy, heteroaryl and
aryl; wherein said aryl or heteroaryl are optionally substituted
with one to three same or different halogens or from one to two
same or different substituents selected from the group consisting
of (C.sub.1-6)alkyl, hydroxy, (C.sub.1-6)alkoxy,
--NR.sup.42C(O)--(C.sub.1-6)alkyl, NR.sup.42R.sup.43 and
C(O)NR.sup.42 R.sup.43.
[0187] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0188] wherein:
[0189] Q is 8
[0190] A is Phenyl, 2-pyridyl, or 3-pyridyl;
[0191] B is selected from the group consisting of
--C(O)NR.sup.40R.sup.41 or heteroaryl; wherein said heteroaryl is
optionally substituted with one to three same or different halogens
or from one to two same or different substituents selected from the
group F.
[0192] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0193] wherein:
[0194] B is heteroaryl, wherein said heteroaryl is optionally
substituted with one to three same or different halogens or from
one to two same or different substituents selected from the group
F.
[0195] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0196] wherein:
[0197] Q is 9
[0198] R.sup.2 is selected from the group consisting of hydrogen,
halogen, and methoxy;
[0199] R.sup.4 is B;
[0200] B is selected from the group consisting of
--C(O)NR.sup.40R.sup.41 or heteroaryl; wherein said heteroaryl is
optionally substituted with one to three same or different halogens
or from one to two same or different substituents selected from the
group F.
[0201] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0202] wherein:
[0203] A is phenyl, 2-pyridyl, or 3-pyridyl.
[0204] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0205] wherein:
[0206] B is --C(O)NR.sup.40R.sup.41.
[0207] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0208] wherein:
[0209] B is heteroaryl, wherein said heteroaryl is optionally
substituted with one to three same or different halogens or from
one to two same or different substituents selected from the group
F.
[0210] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0211] wherein:
[0212] F is selected from the group consisting of (C.sub.1-6)alkyl,
(C.sub.3-6)cycloalkyl (C.sub.1-6)alkoxy, hydroxy, heteroaryl,
heteroalicyclic, methoxy, --S(C.sub.1-3)alkyl, halogen,
--C(O)R.sup.57, C(O)NR.sup.42R.sup.43,
--NR.sup.42C(O)--(C.sub.1-6)alkyl,
--NR.sup.42C(O)--(C.sub.3-6)cycloalkyl, --NR.sup.42C(O)-aryl,
--NR.sup.42C(O)-heteroaryl, --NR.sup.42C(O)-heteroalicyclic, 4, 5,
or 6 membered ring cyclic N-lactam,
--NR.sup.42S(O).sub.2--(C.sub.1-6)alkyl,
--NR.sup.42S(O).sub.2--C.sub.3-6)cycloalkyl, --NR.sup.42S(O)2-aryl,
--NR.sup.42S(O).sub.2-heteroaryl, --NR.sup.42S(O)2-heteroalicyclic,
NR.sup.42R.sup.43, NR.sup.55(C.sub.1-3)alkylNR.sup.55R.sup.56 and
COOR.sup.54.
[0213] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0214] wherein:
[0215] A is phenyl, 2-pyridyl, or 3-pyridyl.
[0216] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0217] wherein:
[0218] Q is 10
[0219] R.sup.2 is selected from the group consisting of hydrogen
and methoxy;
[0220] R.sup.3 is hydrogen; and
[0221] B is selected from the group consisting of
--C(O)NR.sup.40R.sup.41a- nd heteroaryl; wherein said heteroaryl is
optionally substituted with one to three same or different halogens
or from one to two same or different substituents selected from the
group F.
[0222] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0223] wherein:
[0224] R.sup.2 is fluoro.
[0225] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0226] wherein:
[0227] R.sup.2 is methoxy.
[0228] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0229] wherein:
[0230] B is heteroaryl selected from the group consisting of
thiazole, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole,
imidazole, furyl, thienyl, oxazole, oxadiazole, thiadiazole,
pyrimidine, pyrazole, triazine, triazole, tetrazole, pyridyl,
indole, azaindole, and diaza-indole; wherein said heteroaryl is
optionally substituted with one to three same or different halogens
or from one to two same or different substituents selected from the
group F.
[0231] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0232] wherein:
[0233] B is heteroaryl selected from the group consisting of
thiazole, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole,
imidazole, furyl, thienyl, oxazole, oxadiazole, thiadiazole,
pyrimidine, pyrazole, triazine, triazole, tetrazole, pyridyl,
indole, azaindole, and diaza-indole; wherein said heteroaryl is
optionally substituted with one to three same or different halogens
or from one to two same or different substituents selected from the
group F.
[0234] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0235] wherein:
[0236] B is heteroaryl selected from the group consisting of
thiazole, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole,
imidazole, furyl, thienyl, oxazole, oxadiazole, thiadiazole,
pyrimidine, pyrazole, triazine, triazole, tetrazole, pyridyl,
indole, azaindole, and diaza-indole; wherein said heteroaryl is
optionally substituted with one to three same or different halogens
or from one to two same or different substituents selected from the
group F.
[0237] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0238] wherein:
[0239] B is heteroaryl selected from the group consisting of
thiazole, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole,
imidazole, furyl, thienyl, oxazole, oxadiazole, thiadiazole,
pyrimidine, pyrazole, triazine, triazole, tetrazole, pyridyl,
indole, azaindole, and diaza-indole; wherein said heteroaryl is
optionally substituted with one to three same or different halogens
or from one to two same or different substituents selected from the
group F.
[0240] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0241] wherein:
[0242] B is heteroaryl optionally substituted with one to three
same or different halogens or a substituent selected from the group
consisting of hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3 thioalkoxy, amino, --C(O)H, --COOH,
--COOC.sub.1--C.sub.6 alkyl, --NHC(O)--(C.sub.1--C.sub.6 alkyl),
--NHS(O).sub.2--(C.sub.1-C.sub.6 alkyl), --C(O)--NH.sub.2,
C(O)NHMe, C(O)NMe2, trifluoromethyl, --NR.sup.55R.sup.56,
NR.sup.55R.sup.56--(C.sub.1--C.sub.6 alkyl)--NR.sup.55R.sup.56,
-thiazole, pyrrole, piperazine, pyrrolidine and N-pyrrolidone.
[0243] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0244] wherein:
[0245] B is --C(O)NH-heteroaryl wherein said heteroaryl is
optionally substituted with one to three same or different halogens
or a substituent selected from the group consisting of
(C.sub.1-C.sub.6 alkyl), amino, --NHC(O)--(C.sub.1-C.sub.6 alkyl),
-methoxy, --NHC(C.sub.1-C.sub.6 alkyl) and --N(C.sub.1-C.sub.6
alkyl).sub.2.
[0246] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0247] wherein:
[0248] B is heteroaryl optionally substituted with one to three
same or different halogens or a substituent selected from the group
consisting of (C.sub.1-C.sub.6 alkyl), amino,
--NHC(O)--(C.sub.1--C.sub.6 alkyl),
--NHS(O).sub.2--(C.sub.1-C.sub.6 alkyl), methoxy, --C(O)--NH.sub.2,
C(O)NHMe, C(O)NMe2, trifluoromethyl, --NHC(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl).sub.2, -heteroaryl and a 4, 5, or 6
membered cyclic N-lactam.
[0249] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0250] wherein:
[0251] B is --C(O)NH-heteroaryl wherein said heteroaryl is
optionally substituted with one to three same or different halogens
or a substituent selected from the group consisting of
(C.sub.1-C.sub.6 alkyl), amino, --NHC(O)--(C.sub.1-C.sub.6 alkyl),
-methoxy, --NHC(C.sub.1-C.sub.6 alkyl) and --N(C.sub.1-C.sub.6
alkyl).sub.2.
[0252] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0253] wherein:
[0254] B is heteroaryl optionally substituted with one to three
same or different halogens or a substituent selected from the group
consisting of hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3 thioalkoxy, amino, --C(O)H, --COOH,
--COOC.sub.1-C.sub.6 alkyl, --NHC(O)--(C.sub.1-6alkyl),
--NHS(O).sub.2--(C.sub.1-C.sub.6 alkyl), methoxy, --C(O)--NH.sub.2,
C(O)NHMe, C(O)NMe2, trifluoromethyl, --NR.sup.55R.sup.56,
NR.sup.55R.sup.56--(C.sub.1-C.sub.6 alkyl)--NR.sup.55R.sup.56,
-thiazole, pyrrole, piperazine, pyrrolidine and N-pyrrolidone.
[0255] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0256] wherein:
[0257] B is --C(O)NH-heteroaryl wherein said heteroaryl is
optionally substituted with one to three same or different halogens
or a substituent selected from the group consisting of
(C.sub.1-C.sub.6 alkyl), amino, --NHC(O)--(C.sub.1-C.sub.6 alkyl),
-methoxy, --NHC(C.sub.1-C.sub.6 alkyl) and --N(C.sub.1-C.sub.6
alkyl).sub.2.
[0258] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0259] wherein:
[0260] B is thienyl.
[0261] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0262] wherein:
[0263] B is thienyl optionally substituted with one to three same
or different halogens or a substituent selected from the group
consisting of hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3 thioalkoxy, amino, --C(O)H, --COOH,
--COOC.sub.1-C.sub.6 alkyl, --NHC(O)--(C.sub.1-C.sub.6 alkyl),
--NHS(O).sub.2--(C.sub.1-C.sub.6 alkyl), --C(O)--NH.sub.2,
C(O)NHMe, C(O)NMe2, trifluoromethyl, --NR.sup.55R.sup.56,
NR.sup.55R.sup.56--(C.sub.1-C.sub.6 alkyl)--NR.sup.55R.sup.56,
heteroaryl, piperazine, pyrrolidine, N-pyrrolidone and
trifluoromethyl.
[0264] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0265] wherein:
[0266] B is thienyl.
[0267] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0268] wherein:
[0269] B is thienyl optionally substituted with one to three same
or different halogens or a substituent selected from the group
consisting of hydroxy, C.sub.1-C.sub.6 alkyl, amino,
--NHC(O)--(C.sub.1-C.sub.6 alkyl), --C(O)--NH.sub.2, C(O)NHMe,
C(O)NMe.sub.2 and --NR.sup.55R.sup.56.
[0270] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0271] wherein:
[0272] B is thienyl optionally substituted with one to three same
or different halogens or a substituent selected from the group
consisting of hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3 thioalkoxy, amino, --C(O)H, --COOH,
--COOC.sub.1-C.sub.6 alkyl, --NHC(O)--(C.sub.1-C.sub.6 alkyl),
--NHS(O).sub.2--(C.sub.1-C.sub.6 alkyl), methoxy, --C(O)--NH.sub.2,
C(O)NHMe, C(O)NMe2, trifluoromethyl, --NR.sup.55R.sup.56,
NR.sup.55R.sup.56--(C.sub.1-C.sub.6 alkyl)--NR.sup.55R.sup.56,
heteroaryl, piperazine, pyrrolidine, N-pyrrolidone and
trifluoromethyl.
[0273] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0274] wherein:
[0275] B is heteroaryl selected from the group consisting of
thiazole, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole,
imidazole, furyl, thienyl, oxazole, oxadiazole, thiadiazole,
pyrimidine, pyrazole, triazine, triazole, tetrazole and pyridyl;
wherein said heteroaryl is optionally substituted with one to three
same or different halogens or a substituent selected from the group
F consisting of hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3 thioalkoxy, amino, --C(O)H, --COOH,
--COOCl--C.sub.6 alkyl, --NHC(O)--(C.sub.1-C.sub.6 alkyl),
--NHS(O).sub.2--(C.sub.1-C.sub.6 alkyl), methoxy, --C(O)--NH.sub.2,
C(O)NHMe, C(O)NMe2, trifluoromethyl, --NR.sup.55R.sup.56,
NR.sup.55R.sup.56--(C.sub.1-C.sub.6 alkyl)--NR.sup.55R.sup.56,
heteroaryl, piperazine, pyrrolidine, N-pyrrolidone and
trifluoromethyl.
[0276] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0277] wherein:
[0278] B is heteroaryl selected from the group consisting of
thiazole, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole,
imidazole, furyl, thienyl, oxazole, oxadiazole, thiadiazole,
pyrimidine, pyrazole, triazine, triazole, tetrazole and pyridyl;
wherein said heteroaryl is optionally substituted with one to three
same or different halogens or a substituent selected from the group
F consisting of hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3 thioalkoxy, amino, --C(O)H, --COOH,
--COOC.sub.1-C.sub.6 alkyl, --NHC(O)--(C.sub.1-C.sub.6 alkyl),
--NHS(O).sub.2--(C.sub.1-C.sub.6 alkyl), methoxy, --C(O)--NH.sub.2,
C(O)NHMe, C(O)NMe2, trifluoromethyl, --NR.sup.55R.sup.56,
NR.sup.55R.sup.56--(C.sub.1-C.sub.6 alkyl)--NR.sup.55R.sup.6,
heteroaryl, piperazine, pyrrolidine, N-pyrrolidone and
trifluoromethyl.
[0279] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0280] wherein:
[0281] B is heteroaryl selected from the group consisting of
thiazole, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole,
imidazole, furyl, thienyl, oxazole, oxadiazole, thiadiazole,
pyrimidine, pyrazole, triazine, triazole, tetrazole and pyridyl;
wherein said heteroaryl is optionally substituted with one to three
same or different halogens or a substituent selected from the group
F consisting of hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.3 thioalkoxy, amino, --C(O)H, --COOH,
--COOC.sub.1-C.sub.6 alkyl, --NHC(O)--(C.sub.1-C.sub.6 alkyl),
--NHS(o).sub.2--(C.sub.1-C.sub.6 alkyl), methoxy, --C(O)--NH.sub.2,
C(O)NHMe, C(O)NMe2, trifluoromethyl, --NR.sup.55R.sup.56,
NR.sup.55R.sup.56--(C.sub.1-C.sub.6 alkyl)--NR.sup.55R.sup.56,
heteroaryl, piperazine, pyrrolidine, N-pyrrolidone and
trifluoromethyl.
[0282] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0283] wherein:
[0284] A compound of claim 3 is depicted in Table 2.
[0285] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0286] wherein:
[0287] A compound of claim 3 is depicted in Table 2-1.
[0288] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0289] wherein:
[0290] A compound of claim 3 is depicted in Table 3.
[0291] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0292] wherein:
[0293] A compound of claim 3 is depicted in Table 4.
[0294] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0295] wherein:
[0296] A compound of claim 3 is depicted in Table 5.
[0297] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0298] wherein:
[0299] A is selected from the group consisting of phenyl and
heteroaryl; wherein heteroaryl is pyridinyl, furanyl or thienyl;
wherein said phenyl or heteroaryl is independently optionally
substituted with one to two of the same or different amino,
C.sub.1-6alkyl, or halogen;
[0300] represents a carbon-carbon bond;
[0301] R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, and R.sup.16 are each independently hydrogen or methyl,
with the proviso that only zero, one, or two is methyl;
[0302] Q is either: 11
[0303] R.sup.2 is selected from the group consisting of hydrogen,
halogen, and methoxy; and
[0304] R.sub.3 is hydrogen; or
[0305] (b) Q is: 12
[0306] R.sup.2 and R.sup.3 are hydrogen;
[0307] and for both (a) and (b):
[0308] R.sup.4 is selected from the group consisting of B;
[0309] B is heteroaryl selected from the group consisting of
triazole, pyrazole, oxazole, pyrazine, pyrimidine and oxadiazole;
wherein said heteroaryl is optionally substituted with one to three
same or different halogens or from one to two same or different
substituents selected from the group F;
[0310] F is selected from the group consisting of (C.sub.1-6)alkyl,
heteroaryl, --NR.sup.42C(O)--(C.sub.1-6)alkyl, --NR.sup.42R.sup.43
and C(O)NR.sup.42R.sup.43;
[0311] R.sup.5 is hydrogen;
[0312] R.sup.6 does not exist; and
[0313] R.sup.42 and R.sup.43 are independently selected from the
group consisting of hydrogen and (C.sup.1-6)alkyl; or R.sup.42 and
R.sup.43 taken together with the nitrogen to which they are
attached form a heteroalicyclic selected from the group consisting
of aziridine, azetidine, pyrrolidine, piperazine, tetrahydrofuran,
tetrahydropyran, azepine and morpholine.
[0314] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0315] wherein:
[0316] R.sup.2 is H, Cl, F, or methoxy; and
[0317] R.sup.4 is selected from the group consisting of 13
[0318] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0319] wherein:
[0320] R.sup.2 is methoxy or fluoro; and
[0321] one of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
R.sup.14, R.sup.15, or R.sup.16 is methyl and the others are
hydrogen.
[0322] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0323] wherein:
[0324] R.sup.2 is methoxy; and
[0325] R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, and R.sup.16 are each hydrogen.
[0326] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0327] wherein:
[0328] one of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
R.sup.14, R.sup.15, or R.sup.16 is (R)-methyl and the others are
hydrogen.
[0329] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0330] wherein:
[0331] one of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
R.sup.14, R.sup.15, or R.sup.16 is (S)-methyl and the others are
hydrogen.
[0332] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0333] wherein:
[0334] R.sup.2 is methoxy, hydrogen, chloro, or fluoro; and
[0335] R.sup.4 is oxadiazole.
[0336] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0337] wherein:
[0338] R.sup.2 is methoxy, hydrogen, chloro or fluoro; and
[0339] R.sup.4 is oxadiazole substituted with a single fluoro,
chloro, amino or methyl group.
[0340] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0341] wherein:
[0342] A is selected from the group consisting of phenyl and
heteroaryl; wherein said heteroaryl is pyridinyl, furanyl or
thienyl; and said phenyl or said heteroaryl is optionally
substituted with one to two of the same or different amino,
C.sub.1-6alkyl, hydroxy, or halogen;
[0343] R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.15, and
R.sup.16 are each hydrogen;
[0344] R.sup.13 and R.sup.14are each independently hydrogen or
methyl with the proviso that only one is methyl;
[0345] Q is either: 14
[0346] R.sup.2 is selected from the group consisting of hydrogen,
halogen and methoxy; and
[0347] R.sub.3 is hydrogen; or
[0348] (b)Q is: 15
[0349] and R.sup.2 is halogen or hydrogen and R.sup.3 is
hydrogen;
[0350] and for both (a) and (b):
[0351] R.sup.4 is selected from the group consisting of B; and
[0352] B is selected from the group consisting of
--C(O)NR.sup.40R.sup.41, substituted phenyl, heteroaryl, oxazoline,
pyrazinone, methylene dioxy or ethylene dioxy fused to a benzene or
pyridine; wherein said heteroaryl or phenyl is optionally
substituted with one to three same or different halogens or from
one to two same or different substituents selected from the group
F.
[0353] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0354] wherein:
[0355] B is selected from the group consisting of
--C(O)NR.sup.40R.sup.41, substituted phenyl and heteroaryl; wherein
said phenyl is substituted and heteroaryl is optionally substituted
with one to three same or different halogens or from one to two
same or different substituents selected from the group F;
[0356] F is selected from the group consisting of (C.sub.1-6)alkyl,
(C.sub.3-6)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,
(C.sub.1-6)alkoxy, (C.sub.1-6)thioalkoxy, cyano, halogen,
--C(O)R.sup.57, benzyl, --NR.sup.42C(O)--(C.sub.1-6)alkyl,
--NR.sup.42C(O)--(C.sub.3-6)cy- cloalkyl, --NR.sup.42C(O)-aryl,
--NR.sup.42C(O)-heteroaryl, --NR.sup.42C(O)-heteroalicyclic, 4, 5,
or 6 membered ring cyclic N-lactam,
--NR.sup.42S(O).sub.2--(C.sub.1-6)alkyl, --NR.sup.42R.sup.43,
C(O)NR.sup.42R.sup.43 and COOR.sup.54; wherein said
(C.sub.1-6)alkyl, (C.sub.3-6)cycloalkyl, aryl, heteroaryl,
heteroalicyclic, (C.sub.1-6)alkoxy, are optionally substituted with
one to three same or different halogens or from one to two same or
different substituents selected from the group G;
[0357] G is selected from the group consisting of (C.sub.1-6)alkyl,
hydroxy, (C.sub.1-6)alkoxy, halogen,
--NR.sup.48C(O)--(C.sub.1-6)alkyl,
--NR.sup.48C(O)--(C.sub.3)cycloalkyl, 4, 5, or 6 membered ring
cyclic N-lactam, --NR.sup.48S(O).sub.2--(C.sub.1-6)alkyl,
NR.sup.48R.sup.49, (C.sub.1-6)alkyl C(O)NR.sup.48R.sup.49,
C(O)NR.sup.48R.sup.49 and (C.sub.1-6)alkylNR.sup.48R.sup.49;
[0358] R.sup.40 is hydrogen;
[0359] R.sup.41 is (C.sub.1-6)alkyl, (C.sub.3-7)cycloalkyl, phenyl,
or heteroaryl; wherein said (C.sub.1-6)alkyl,
(C.sub.3-7)cycloalkyl, phenyl, or heteroaryl are substituted with
one to three same or different halogens or one to two same or
different methyl, (C.sub.1-3)alkoxy, heteroaryl or aryl; wherein
said aryl or heteroaryl are optionally substituted with one to
three same or different halogens or from one to two same or
different substituents selected from the group consisting of
(C.sub.1-6)alkyl, hydroxy, (C.sub.1-6)alkoxy,
--NR.sup.42C(O)--(C.sub.1 6)alkyl, NR.sup.42R.sup.43 and
C(O)NR.sup.42R.sup.43 Another preferred embodiment of the invention
are compounds of Formula I, including pharmaceutically acceptable
salts thereof,
[0360] wherein:
[0361] A is selected from the group consisting of phenyl and
heteroaryl; wherein heteroaryl is pyridinyl, furanyl or thienyl;
and said phenyl or said heteroaryl is optionally substituted with
one to two of the same or different amino, C.sub.1-6alkyl, hydroxy,
or halogen;
[0362] R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
R.sup.15, and R.sup.16 are each independently hydrogen or methyl
with the proviso that only one is methyl;
[0363] Q is either: 16
[0364] wherein R.sup.2 is selected from the group consisting of
hydrogen, halogen and methoxy; and
[0365] R.sub.3 is hydrogen; or
[0366] (b) Q is: 17
[0367] wherein R.sup.2 is halogen or hydrogen; and R.sup.3 is
hydrogen;
[0368] and for both (a) and (b):
[0369] R.sup.4 is selected from the group consisting of B;
[0370] B is selected from the group consisting of
--C(O)NR.sup.40R.sup.41, substituted phenyl, heteroaryl, oxazoline,
pyrazinone, methylene dioxy or ethylene dioxy fused to a benzene or
pyridine; wherein said heteroaryl or phenyl is optionally
substituted with one to three same or different halogens or from
one to two same or different substituents selected from the group
F.
[0371] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0372] wherein:
[0373] B is selected from the group consisting of pyrazinone and
methylene dioxy or ethylene dioxy fused to a benzene ring; wherein
said group is optionally substituted with one to three same or
different halogens or a substituent selected from the group F
consisting of (C.sub.1-C.sub.6 alkyl), amino,
--NHC(O)--(C.sub.1-C.sub.6 alkyl), --NHS(0).sub.2--(C.sub.-
1-C.sub.6 alkyl), methoxy, --C(O)--NH.sub.2, C(O)NHMe, C(O)NMe2,
trifluoromethyl, --NHC(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, -heteroaryl and a 4, 5, or 6 membered cyclic
N-lactam.
[0374] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0375] wherein:
[0376] B is selected from the group consisting of oxadiazole,
triazole, pyrazole, pyrazine and pyrimidine; wherein said group is
optionally substituted with one to three same or different halogens
or a substituent selected from the group F consisting of
(C.sub.1-C.sub.6 alkyl), amino, --NHC(O)--(C.sub.1-C.sub.6 alkyl),
--NHS(O).sub.2--(C.sub.--C.sub.6 alkyl), methoxy, --C(O)--NH.sub.2,
C(O)NHMe, C(O)NMe2, trifluoromethyl, --NHC(C.sub.1-C.sub.6 alkyl),
--N(C.sub.1-C.sub.6 alkyl).sub.2, -heteroaryl, a 4, 5, or 6
membered cyclic N-lactam and (C.sub.1-6)alkylNR.sup.48R.sup.49.
[0377] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0378] wherein:
[0379] heteroaryl in B is selected from the group consisting of
pyrazine and pyrimidine.
[0380] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0381] wherein:
[0382] heteroaryl in B is selected from the group consisting of
pyrazine and pyrimidine.
[0383] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0384] wherein:
[0385] wherein R.sup.9, R.sup.10, R.sup.15 and R.sup.16 are each
hydrogen; and R.sup.11, R.sup.12, R.sup.13, and R.sup.14 are each
independently hydrogen or methyl with the proviso that up to one
can be methyl.
[0386] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0387] wherein:
[0388] one of R.sup.11, R.sup.12, R.sup.13, and R.sup.14 is
methyl.
[0389] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0390] wherein:
[0391] the carbon atom of the piperazine ring to which the methyl
group of R.sup.11, R.sup.12, R.sup.13, and R.sup.14 is attached has
an (R) configuration.
[0392] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0393] wherein:
[0394] R.sup.11, R.sup.12, R.sup.13, and R.sup.14 are each
hydrogen; and R.sup.9, R.sup.10, R.sup.15 and R.sup.16 are each
independently hydrogen or methyl with the proviso that up to one
can be methyl.
[0395] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0396] wherein:
[0397] one of R.sup.9, R.sup.10, R.sup.15 and R.sup.16 is
methyl.
[0398] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0399] wherein:
[0400] the carbon atom of the piperazine ring to which the methyl
group of R.sup.9, R.sup.10, R.sup.15 and R.sup.16 is attached has
an (R) configuration.
[0401] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof,
[0402] wherein:
[0403] R.sup.1 is hydrogen;
[0404] m is 2;
[0405] R.sup.5 is hydrogen;
[0406] R does not exist;
[0407] A is selected from the group consisting of C.sub.1-6alkoxy,
aryl and heteroaryl; wherein aryl is phenyl; heteroaryl is selected
from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl,
triazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl,
oxazolyl and isoxazolyl; and said aryl or heteroaryl is optionally
substituted with one or two of the same or different amino, cyano,
hydroxy C.sub.1-6alkoxy, C.sub.1-6alkyl, --NHC(O)CH.sub.3, halogen
and trifluoromethyl; and
[0408] represents a carbon-carbon bond.
[0409] A most preferred embodiment is a compound of Formula Ia,
including pharmaceutically acceptable salts thereof, 18
[0410] wherein:
[0411] R.sup.2 is methoxy, fluoro or chloro.
[0412] R.sup.4 is selected from the group consisting of either:
19
[0413] which is a 1,2,3 triazole directly attached via the nitrogen
atom of position 1 of the triazole wherein said 1,2,3 triazole is
substituted with D at position 4 or R.sup.4 is: 20
[0414] which is a 1,2,4 triazole attached via the nitrogen atom of
position 1 of the triazole wherein said 1,2,4 triazole is
substituted with E at position 3.
[0415] D is selected from hydrogen or C.sub.1-C.sub.3 alkyl.
[0416] E is selected from the group consisting hydrogen,
(C.sub.1-C.sub.3)alkyl, O(C.sub.1-C.sub.3)alkyl or
CH.sub.20CH.sub.3.
[0417] R.sup.11 is either hydrogen or methyl in which the
configuration to which the methyl is attached is (R) with the
proviso that when R.sup.4 is 1,2,3 triazole, then R.sup.11 is
hydrogen.
[0418] Another embodiment of the invention is a pharmaceutical
formulation comprising an antiviral effective amount of a compound
of Formula I, including pharmaceutically acceptable salts thereof
and a pharmaceutically acceptable carrier. When used for treating
HIV infection, said formulation can optionally additionally contain
an antiviral effective amount of an AIDS treatment agent selected
from the group consisting of: an AIDS antiviral agent; an
antiinfective agent; an immunomodulator; and HIV entry
inhibitors.
[0419] A third embodiment of the invention is a method for treating
mammals infected with a virus, such as HIV, comprising
administering to said mammal an antiviral effective amount of a
compound of Formula I, including pharmaceutically acceptable salts
thereof, a pharmaceutically acceptable carrier, optionally in
combination with an antiviral effective amount of an AIDS treatment
agent selected from the group consisting of: (a) an AIDS antiviral
agent; (b) an anti-infective agent; (c) an immunomodulator; and (d)
HIV entry inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
[0420] Since the compounds of the present invention, may possess
asymmetric centers and therefore occur as mixtures of diastereomers
and enantiomers, the present invention includes the individual
diastereoisomeric and enantiomeric forms of the compounds of
Formula I in addition to the mixtures thereof.
DEFINITIONS
[0421] The term "C.sub.1-6 alkyl" as used herein and in the claims
(unless specified otherwise) mean straight or branched chain alkyl
groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
t-butyl, amyl, hexyl and the like. "Halogen" refers to chlorine,
bromine, iodine or fluorine.
[0422] An "aryl" group refers to an all carbon monocyclic or
fused-ring polycyclic (i.e., rings which share adjacent pairs of
carbon atoms) groups having a completely conjugated pi-electron
system. Examples, without limitation, of aryl groups are phenyl,
napthalenyl and anthracenyl. The aryl group may be substituted or
unsubstituted. When substituted the substituted group(s) is
preferably one or more selected from alkyl, cycloalkyl, aryl,
heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,
heteroaryloxy, heteroalicycloxy, thiohydroxy, thioaryloxy,
thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,
carbonyl, 0-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,
0-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido,
amino and --NR.sup.xR.sup.Y, wherein R.sup.x and R.sup.y are
independently selected from the group consisting of hydrogen,
alkyl, cycloalkyl, aryl, carbonyl, C-carboxy, sulfonyl,
trihalomethyl, and, combined, a five- or six-member heteroalicyclic
ring.
[0423] As used herein, a "heteroaryl" group refers to a monocyclic
or fused ring (i.e., rings which share an adjacent pair of atoms)
group having in the ring(s) one or more atoms selected from the
group consisting of nitrogen, oxygen and sulfur and, in addition,
having a completely conjugated pi-electron system. Unless otherwise
indicated, the heteroaryl group may be attached at either a carbon
or nitrogen atom within the heteroaryl group. It should be noted
that the term heteroaryl is intended to encompass an N-oxide of the
parent heteroaryl if such an N-oxide is chemically feasible as is
known in the art. Examples, without limitation, of heteroaryl
groups are furyl, thienyl, benzothienyl, thiazolyl, imidazolyl,
oxazolyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, triazolyl,
tetrazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyranyl,
tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl, quinolinyl,
isoquinolinyl, purinyl, carbazolyl, benzoxazolyl, benzimidazolyl,
indolyl, isoindolyl, pyrazinyl. diazinyl, pyrazine,
triazinyltriazine, tetrazinyl, and tetrazolyl. When substituted the
substituted group(s) is preferably one or more selected from alkyl,
cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy,
aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioaryloxy,
thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,
carbonyl, 0-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,
0-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido,
amino, and --NR.sup.xR.sup.Y, wherein R.sup.x and R.sup.y are as
defined above.
[0424] As used herein, a "heteroalicyclic" group refers to a
monocyclic or fused ring group having in the ring(s) one or more
atoms selected from the group consisting of nitrogen, oxygen and
sulfur. The rings may also have one or more double bonds. However,
the rings do not have a completely conjugated pi-electron system.
Examples, without limitation, of heteroalicyclic groups are
azetidinyl, piperidyl, piperazinyl, imidazolinyl, thiazolidinyl,
3-pyrrolidin-1-yl, morpholinyl, thiomorpholinyl and
tetrahydropyranyl. When substituted the substituted group(s) is
preferably one or more selected from alkyl, cycloalkyl, aryl,
heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,
heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy,
thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano,
halogen, nitro, carbonyl, thiocarbonyl, 0-carbamyl, N-carbamyl,
0-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamido, N-amido,
C-carboxy, 0-carboxy, sulfinyl, sulfonyl, sulfonamido,
trihalomethanesulfonamido, trihalomethanesulfonyl, silyl, guanyl,
guanidino, ureido, phosphonyl, amino and --NRXRY, wherein Rx and RI
are as defined above.
[0425] An "alkyl" group refers to a saturated aliphatic hydrocarbon
including straight chain and branched chain groups. Preferably, the
alkyl group has 1 to 20 carbon atoms (whenever a numerical range;
e.g., "1-20", is stated herein, it means that the group, in this
case the alkyl group may contain 1 carbon atom, 2 carbon atoms, 3
carbon atoms, etc. up to and including 20 carbon atoms). More
preferably, it is a medium size alkyl having 1 to 10 carbon atoms.
Most preferably, it is a lower alkyl having 1 to 4 carbon atoms.
The alkyl group may be substituted or unsubstituted. When
substituted, the substituent group(s) is preferably one or more
individually selected from trihaloalkyl, cycloalkyl, aryl,
heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,
heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy,
thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halo,
nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl,
O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamido, N-amido,
C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido,
trihalomethanesulfonamido, trihalomethanesulfonyl, and combined, a
five- or sixmember heteroalicyclic ring.
[0426] A "cycloalkyl" group refers to an all-carbon monocyclic or
fused ring (i.e., rings which share and adjacent pair of carbon
atoms) group wherein one or more rings does not have a completely
conjugated pi-electron system. Examples, without limitation, of
cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane,
cyclopentene, cyclohexane, cyclohexadiene, cycloheptane,
cycloheptatriene and adamantane. A cycloalkyl group may be
substituted or unsubstituted. When substituted, the substituent
group(s) is preferably one or more individually selected from
alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,
heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy,
thioaryloxy, thioheteroarylloxy, thioheteroalicycloxy, cyano, halo,
nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl,
O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamido, N-amido,
C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalo-
methanesulfonamido, trihalomethanesulfonyl, silyl, guanyl,
guanidino, ureido, phosphonyl, amino and --NR.sup.xR.sup.y with
R.sup.x and R.sup.y as defined above.
[0427] An "alkenyl" group refers to an alkyl group, as defined
herein, consisting of at least two carbon atoms and at least one
carbon-carbon double bond.
[0428] An "alkynyl" group refers to an alkyl group, as defined
herein, consisting of at least two carbon atoms and at least one
carbon-carbon triple bond.
[0429] A "hydroxy" group refers to an --OH group.
[0430] An "alkoxy" group refers to both an --O-alkyl and an
--O-cycloalkyl group as defined herein.
[0431] An "aryloxy" group refers to both an --O-aryl and an
--O-heteroaryl group, as defined herein.
[0432] A "heteroaryloxy" group refers to a heteroaryl --O-- group
with heteroaryl as defined herein.
[0433] A "heteroalicycloxy" group refers to a heteroalicyclic --O--
group with heteroalicyclic as defined herein.
[0434] A "thiohydroxy" group refers to an --SH group.
[0435] A "thioalkoxy" group refers to both an S-alkyl and an
--S-cycloalkyl group, as defined herein.
[0436] A "thioaryloxy" group refers to both an --S-aryl and an
--S-heteroaryl group, as defined herein.
[0437] A "thioheteroaryloxy" group refers to a heteroaryl --S--
group with heteroaryl as defined herein.
[0438] A "thioheteroalicycloxy" group refers to a heteroalicyclic
--S-- group with heteroalicyclic as defined herein.
[0439] A "carbonyl" group refers to a --C(.dbd.O)--R" group, where
R" is selected from the group consisting of hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl (bonded through a
ring carbon) and heteroalicyclic (bonded through a ring carbon), as
each is defined herein.
[0440] An "aldehyde" group refers to a carbonyl group where R" is
hydrogen.
[0441] A "thiocarbonyl" group refers to a --C(.dbd.S)--R" group,
with R" as defined herein.
[0442] A "Keto" group refers to a --CC(.dbd.O)C-- group wherein the
carbon on either or both sides of the C.dbd.O may be alkyl,
cycloalkyl, aryl or a carbon of a heteroaryl or heteroaliacyclic
group.
[0443] A "trihalomethanecarbonyl" group refers to a
Z.sub.3CC(.dbd.O)-- group with said Z being a halogen.
[0444] A "C-carboxy" group refers to a --C(.dbd.O)O-R" groups, with
R" as defined herein.
[0445] An "O-carboxy" group refers to a R" C(--O)O-- group, with R"
as defined herein.
[0446] A "carboxylic acid" group refers to a C-carboxy group in
which R" is hydrogen.
[0447] A "trihalomethyl" group refers to a --CZ.sub.3, group
wherein Z is a halogen group as defined herein.
[0448] A "trihalomethanesulfonyl" group refers to an
Z.sub.3CS(.dbd.O).sub.2-- groups with Z as defined above.
[0449] A "trihalomethanesulfonamido" group refers to a
Z.sub.3CS(.dbd.O).sub.2NR.sup.x-- group with Z and R.sup.x as
defined herein.
[0450] A "sulfinyl" group refers to a --S(.dbd.O)-R" group, with R"
as defined herein and, in addition, as a bond only; i.e.,
--S(O)--.
[0451] A "sulfonyl" group refers to a --S(.dbd.O).sub.2R" group
with R" as defined herein and, in addition as a bond only; i.e.,
--S(O).sub.2--.
[0452] A "S-sulfonamido" group refers to a
--S(.dbd.O).sub.2NR.sup.XR.sup.- Y, with R.sup.X and R.sup.Y as
defined herein.
[0453] A "N--Sulfonamido" group refers to a
R"S(.dbd.O).sub.2NR.sup.x-- group with R.sup.x as defined
herein.
[0454] A "O-carbamyl" group refers to a --OC(.dbd.O)NR.sup.x RY as
defined herein.
[0455] A "N-carbamyl" group refers to a R.sup.xOC(.dbd.O)NR.sup.Y
group, with R.sup.x and R.sup.y as defined herein.
[0456] A "O-thiocarbamyl" group refers to a
--OC(.dbd.S)NR.sup.xR.sup.y group with R.sup.x and R.sup.y as
defined herein.
[0457] A "N-thiocarbamyl" group refers to a R.sup.xOC(.dbd.S)NR--
group with R.sup.x and R.sup.y as defined herein.
[0458] An "amino" group refers to an --NH.sub.2 group.
[0459] A "C-amido" group refers to a --C(.dbd.O)NR.sup.xR.sup.y
group with R.sup.x and R.sup.y as defined herein.
[0460] A "C-thioamido" group refers to a --C(.dbd.S)NR.sup.xR.sup.y
group, with R.sup.x and R.sup.y as defined herein.
[0461] A "N-amido" group refers to a R.sup.xC(.dbd.O)NR.sup.y--
group, with R.sup.x and R.sup.y as defined herein.
[0462] A cyclic 4, 5, or six membered ring N-lactam refers to rings
of 4, 5 or 6 atoms containing a single amide group as two of the
ring atoms which is linked to the parent molecule at the amide
nitrogen.
[0463] An "ureido" group refers to a
--NR.sup.xC(.dbd.O)NR.sup.yR.sup.y2 group with R.sup.x and R.sup.y
as defined herein and R.sup.y2 defined the same as R.sup.x and
R.sup.y.
[0464] A "guanidino" group refers to a
--R.sup.xNC(.dbd.N)NR.sup.yR.sup.y2 group, with R.sup.x, R.sup.y
and R.sup.y2 as defined herein.
[0465] A "guanyl" group refers to a R.sup.xR.sup.YNC(.dbd.N)--
group, with R.sup.x and R.sup.y as defined herein.
[0466] A "cyano" group refers to a --CN group.
[0467] A "silyl" group refers to a --Si(R").sub.3, with R" as
defined herein.
[0468] A "phosphonyl" group refers to a P(.dbd.O)(OR.sup.x).sub.2
with R.sup.x as defined herein.
[0469] A "hydrazino" group refers to a --NR.sup.xNR.sup.yR.sup.y2
group with R.sup.x, R.sup.y and R.sup.y2 as defined herein.
[0470] Any two adjacent R groups may combine to form an additional
aryl, cycloalkyl, heteroaryl or heterocyclic ring fused to the ring
initially bearing those R groups.
[0471] It is known in the art that nitogen atoms in heteroaryl
systems can be "participating in a heteroaryl ring double bond",
and this refers to the form of double bonds in the two tautomeric
structures which comprise five-member ring heteroaryl groups. This
dictates whether nitrogens can be substituted as well understood by
chemists in the art. The disclosure and claims of the present
invention are based on the known general principles of chemical
bonding. It is understood that the claims do not encompass
structures known to be unstable or not able to exist based on the
literature.
[0472] Physiologically acceptable salts and prodrugs of compounds
disclosed herein are within the scope of this invention. The term
"pharmaceutically acceptable salt" as used herein and in the claims
is intended to include nontoxic base addition salts. Suitable salts
include those derived from organic and inorganic acids such as,
without limitation, hydrochloric acid, hydrobromic acid, phosphoric
acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric
acid, lactic acid, sulfinic acid, citric acid, maleic acid, fumaric
acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid,
and the like. The term "pharmaceutically acceptable salt" as used
herein is also intended to include salts of acidic groups, such as
a carboxylate, with such counterions as ammonium, alkali metal
salts, particularly sodium or potassium, alkaline earth metal
salts, particularly calcium or magnesium, and salts with suitable
organic bases such as lower alkylamines (methylamine, ethylamine,
cyclohexylamine, and the like) or with substituted lower
alkylamines (e.g. hydroxyl-substituted alkylamines such as
diethanolamine, triethanolamine or tris(hydroxymethyl)-
aminomethane), or with bases such as piperidine or morpholine.
[0473] In the method of the present invention, the term "antiviral
effective amount" means the total amount of each active component
of the method that is sufficient to show a meaningful patient
benefit, i.e., healing of acute conditions characterized by
inhibition of the HIV infection. When applied to an individual
active ingredient, administered alone, the term refers to that
ingredient alone. When applied to a combination, the term refers to
combined amounts of the active ingredients that result in the
therapeutic effect, whether administered in combination, serially
or simultaneously. The terms "treat, treating, treatment" as used
herein and in the claims means preventing or ameliorating diseases
associated with HIV infection.
[0474] The present invention is also directed to combinations of
the compounds with one or more agents useful in the treatment of
AIDS. For example, the compounds of this invention may be
effectively administered, whether at periods of pre-exposure and/or
post-exposure, in combination with effective amounts of the AIDS
antivirals, immunomodulators, antiinfectives, or vaccines, such as
those in the following table.
1 Drug Name Manufacturer Indication ANTIVIRALS 097 Hoechst/Bayer
HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase (RT)
inhibitor) Amprenivir Glaxo Wellcome HIV infection, 141 W94 AIDS,
ARC GW 141 (protease inhibitor) Abacavir (1592U89) Glaxo Wellcome
HIV infection, GW 1592 AIDS, ARC (RT inhibitor) Acemannan
Carrington Labs ARC (Irving, TX) Acyclovir Burroughs Wellcome HIV
infection, AIDS, ARC, in combination with AZT AD-439 Tanox
Biosystems HIV infection, AIDS, ARC AD-519 Tanox Biosystems HIV
infection, AIDS, ARC Adefovir dipivoxil Gilead Sciences HIV
infection AL-721 Ethigen ARC, PGL (Los Angeles, CA) HIV positive,
AIDS Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIV in
combination w/Retrovir Ansamycin Adria Laboratories ARC LM 427
(Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced
Biotherapy AIDS, ARC Neutralizes pH Concepts Labile alpha aberrant
(Rockville, MD) Interferon AR177 Aronex Pharm HIV infection, AIDS,
ARC Beta-fluoro-ddA Nat'l Cancer Institute AIDS-associated diseases
BMS-232623 Bristol-Myers Squibb/ HIV infection, (CGP-73547)
Novartis AIDS, ARC (protease inhibitor) BMS-234475 Bristol-Myers
Squibb/ HIV infection, (CGP-61755) Novartis AIDS, ARC (protease
inhibitor) CI-1012 Warner-Lambert HIV-1 infection Cidofovir Gilead
Science CMV retinitis, herpes, papillomavirus Curdlan sulfate AJI
Pharma USA HIV infection Cytomegalovirus MedImmune CMV retinitis
Immune globin Cytovene Syntex Sight threatening Ganciclovir CMV
peripheral CMV retinitis Delaviridine Pharmacia-Upjohn HIV
infection, AIDS, ARC (RT inhibitor) Dextran Sulfate Ueno Fine Chem.
AIDS, ARC, HIV Ind. Ltd. (Osaka, positive Japan) asymptomatic ddC
Hoffman-La Roche HIV infection, AIDS, Dideoxycytidine ARC ddI
Bristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC;
combination with AZT/d4T DMP-450 AVID HIV infection, (Camden, NJ)
AIDS, ARC (protease inhibitor) Efavirenz DuPont Merck HIV
infection, (DMP 266) AIDS, ARC (-)6-Chloro-4-(S)- (non-nucleoside
RT cyclopropylethynyl- inhibitor) 4(S)-trifluoro-
methyl-1,4-dihydro- 2H-3,1-benzoxazin- 2-one, STOCRINE EL10 Elan
Corp, PLC HIV infection (Gainesville, GA) Famciclovir Smith Kline
herpes zoster, herpes simplex FTC Emory University HIV infection,
AIDS, ARC (reverse transcriptase inhibitor) GS 840 Gilead HIV
infection, AIDS, ARC (reverse transcriptase inhibitor) HBY097
Hoechst Marion HIV infection, Roussel AIDS, ARC (non-nucleoside
reverse transcriptase inhibitor) Hypericin VIMRx Pharm. HIV
infection, AIDS, ARC Recombinant Human Triton Biosciences AIDS,
Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARC Interferon
alfa-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIV
infection, AIDS, ARC, asymptomatic HIV positive, also in
combination with AZT/ddI/ddC ISIS 2922 ISIS Pharmaceuticals CMV
retinitis KNI-272 Nat'l Cancer Institute HIV-assoc. diseases
Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC (reverse
transcriptase inhibitor); also with AZT Lobucavir Bristol-Myers
Squibb CMV infection Nelfinavir Agouron HIV infection,
Pharmaceuticals AIDS, ARC (protease inhibitor) Nevirapine
Boeheringer HIV infection, Ingleheim AIDS, ARC (RT inhibitor)
Novapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH) Peptide T
Peninsula Labs AIDS Octapeptide (Belmont, CA) Sequence Trisodium
Astra Pharm. CMV retinitis, HIV Phosphonoformate Products, Inc.
infection, other CMV infections PNU-140690 Pharmacia Upjohn HIV
infection, AIDS, ARC (protease inhibitor) Probucol Vyrex HIV
infection, AIDS RBC-CD4 Sheffield Med. HIV infection, Tech
(Houston, TX) AIDS, ARC Ritonavir Abbott HIV infection, AIDS, ARC
(protease inhibitor) Saquinavir Hoffmann- HIV infection, LaRoche
AIDS, ARC (protease inhibitor) Stavudine; d4T Bristol-Myers Squibb
HIV infection, AIDS, Didehydrodeoxy- ARC thymidine Valaciclovir
Glaxo Wellcome Genital HSV & CMV infections Virazole
Viratek/ICN asymptomatic HIV Ribavirin (Costa Mesa, CA) positive,
LAS, ARC VX-478 Vertex HIV infection, AIDS, ARC Zalcitabine
Hoffmann-LaRoche HIV infection, AIDS, ARC, with AZT Zidovudine; AZT
Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi's sarcoma, in
combination with other therapies IMMUNOMODULATORS AS-101
Wyeth-Ayerst AIDS Bropirimine Pharmacia Upjohn Advanced AIDS
Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, TX) CL246, 738
American Cyanamid AIDS, Kaposi's Lederle Labs sarcoma EL10 Elan
Corp, PLC HIV infection (Gainesville, GA) FP-21399 Fuki ImmunoPharm
Blocks HIV fusion with CD4+ cells Gamma Interferon Genentech ARC,
in combination w/TNF (tumor necrosis factor) Granulocyte Genetics
Institute AIDS Macrophage Colony Sandoz Stimulating Factor
Granulocyte Hoechst-Roussel AIDS Macrophage Colony Immunex
Stimulating Factor Granulocyte Schering-Plough AIDS, Macrophage
Colony combination Stimulating Factor w/AZT HIV Core Particle Rorer
Seropositive HIV Immunostimulant IL-2 Cetus AIDS, in combination
Interleukin-2 w/AZT IL-2 Hoffman-LaRoche AIDS, ARC, HIV, in
Interleukin-2 Immunex combination w/AZT IL-2 Chiron AIDS, increase
in Interleukin-2 CD4 cell counts (aldeslukin) Immune Globulin
Cutter Biological Pediatric AIDS, in Intravenous (Berkeley, CA)
combination w/AZT (human) IMREG-1 Imreg AIDS, Kaposi's (New
Orleans, LA) sarcoma, ARC, PGL IMREG-2 Imreg AIDS, Kaposi's (New
Orleans, LA) sarcoma, ARC, PGL Imuthiol Diethyl Merieux Institute
AIDS, ARC Dithio Carbamate Alpha-2 Schering Plough Kaposi's sarcoma
Interferon w/AZT, AIDS Methionine- TNI Pharmaceutical AIDS, ARC
Enkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma
Muramyl-Tripeptide Granulocyte Amgen AIDS, in combination Colony
Stimulating w/AZT Factor Remune Immune Response Immunotherapeutic
Corp. rCD4 Genentech AIDS, ARC Recombinant Soluble Human CD4
rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS, ARC Soluble
Human CD4 Interferon Hoffman-La Roche Kaposi's sarcoma Alfa 2a
AIDS, ARC, in combination w/AZT SK&F106528 Smith Kline HIV
infection Soluble T4 Thymopentin Immunobiology HIV infection
Research Institute (Annandale, NJ) Tumor Necrosis Genentech ARC, in
combination Factor; TNF w/gamma Interferon ANTI-INFECTIVES
Clindamycin with Pharmacia Upjohn PCP Primaquine Fluconazole Pfizer
Cryptococcal meningitis, candidiasis Pastille Squibb Corp.
Prevention of Nystatin Pastille oral candidiasis Ornidyl Merrell
Dow PCP Eflornithine Pentamidine LyphoMed PCP treatment Isethionate
(IM & IV) (Rosemont, IL) Trimethoprim Antibacterial
Trimethoprim/sulfa Antibacterial Piritrexim Burroughs Wellcome PCP
treatment Pentamidine Fisons Corporation PCP prophylaxis
Isethionate for Inhalation Spiramycin Rhone-Poulenc Cryptosporidial
diarrhea Intraconazole- Janssen-Pharm. Histoplasmosis; R51211
cryptococcal Meningitis Trimetrexate Warner-Lambert PCP
Daunorubicin NeXstar, Sequus Kaposi's sarcoma Recombinant Human
Ortho Pharm. Corp. Severe anemia Erythropoietin assoc. with AZT
Therapy Recombinant Human Serono AIDS-related Growth Hormone
wasting, cachexia Megestrol Acetate Bristol-Myers Squibb Treatment
of Anorexia assoc. W/AIDS Testosterone Alza, Smith Kline
AIDS-related wasting Total Enteral Norwich Eaton Diarrhea and
Nutrition Pharmaceuticals malabsorption Related to AIDS
[0475] Additionally, the compounds of the invention herein may be
used in combination with another class of agents for treating AIDS
which are called HIV entry inhibitors. Examples of such HIV entry
inhibitors are discussed in DRUGS OF THE FUTURE 1999, 24(12), pp.
1355-1362; CELL, Vol. 9, pp. 243-246, Oct. 29, 1999; and DRUG
DISCOVERY TODAY, Vol. 5, No. 5, May 2000, pp. 183-194.
[0476] It will be understood that the scope of combinations of the
compounds of this invention with AIDS antivirals, immunomodulators,
anti-infectives, HIV entry inhibitors or vaccines is not limited to
the list in the above Table, but includes in principle any
combination with any pharmaceutical composition useful for the
treatment of AIDS.
[0477] Preferred combinations are simultaneous or alternating
treatments of with a compound of the present invention and an
inhibitor of HIV protease and/or a non-nucleoside inhibitor of HIV
reverse transcriptase. An optional fourth component in the
combination is a nucleoside inhibitor of HIV reverse transcriptase,
such as AZT, 3TC, ddC or ddI. A preferred inhibitor of HIV protease
is indinavir, which is the sulfate salt of N-(2(R)-hydroxy- I
-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5(1-(4-(-
3-pyridyl-methyl)-2(S)--N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide
ethanolate, and is synthesized according to U.S. Pat. No.
5,413,999. Indinavir is generally administered at a dosage of 800
mg three times a day. Other preferred protease inhibitors are
nelfinavir and ritonavir. Another preferred inhibitor of HIV
protease is saquinavir which is administered in a dosage of 600 or
1200 mg tid. Preferred non-nucleoside inhibitors of HIV reverse
transcriptase include efavirenz. The preparation of ddC, ddI and
AZT are also described in EPO 0,484,071. These combinations may
have unexpected effects on limiting the spread and degree of
infection of HIV. Preferred combinations include those with the
following (1) indinavir with efavirenz, and, optionally, AZT and/or
3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/or ddI
and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC;
(3) stavudine and 3TC and/or zidovudine; (4) zidovudine and
lamivudine and 141W94 and 1592U89; (5) zidovudine and
lamivudine.
[0478] In such combinations the compound of the present invention
and other active agents may be administered separately or in
conjunction. In addition, the administration of one element may be
prior to, concurrent to, or subsequent to the administration of
other agent(s).
[0479] The preparative procedures and anti-HIV-1 activity of the
novel azaindole piperazine diamide analogs of Formula I are
summarized below in Schemes 1-64.
Abbreviations
[0480] The following abbreviations, most of which are conventional
abbreviations well known to those skilled in the art, are used
throughout the description of the invention and the examples. Some
of the abbreviations used are as follows:
2 h = hour(s) rt = room temperature mol = mole(s) mmol =
millimole(s) g = gram(s) mg = milligram(s) mL = milliliter(s) TFA =
Trifluoroacetic Acid DCE = 1,2-Dichloroethane CH.sub.2Cl.sub.2 =
Dichloromethane TPAP = tetrapropylammonium perruthenate THF =
Tetrahydofuran DEPBT = 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazi-
n-4(3H)- one DMAP = 4-dimethylaminopyridine P-EDC = Polymer
supported 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide EDC =
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide DMF =
N,N-dimethylformamide Hunig`s Base = N,N-Diisopropylethylamine
mCPBA = meta-Chloroperbenzoic Acid azaindole = 1H-Pyrrolo-pyridine
4-azaindole = 1H-pyrrolo[3,2-b]pyridine 5-azaindole =
1H-Pyrrolo[3,2-c]pyridine 6-azaindole = 1H-pyrrolo[2,3-c]pyridine
7-azaindole = 1H-Pyrrolo[2,3-b]pyridine PMB = 4-Methoxybenzyl DDQ =
2,3-Dichloro-5,6-dicyano-1,4-be- nzoquinone OTf =
Trifluoromethanesulfonoxy NMM = 4-Methylmorpholine PIP-COPh =
1-Benzoylpiperazine NaHMDS = Sodium hexamethyldisilazide EDAC =
1-(3-Dimethylaminopropyl)-3-eth- ylcarbodiimide TMS =
Trimethylsilyl DCM = Dichloromethane DCE = Dichloroethane MeOH =
Methanol THF = Tetrahrdrofuran EtOAc = Ethyl Acetate LDA = Lithium
diisopropylamide TMP-Li = 2,2,6,6-tetramethylpiperidinyl lithium
DME = Dimethoxyethane DIBALH = Diisobutylaluminum hydride HOBT =
1-hydroxybenzotriazole CBZ = Benzyloxycarbonyl PCC = Pyridinium
chlorochromate Me = Methyl Ph = Phenyl
[0481] Chemistry
[0482] The present invention comprises compounds of Formula I,
their pharmaceutical formulations, and their use in patients
suffering from or susceptible to HIV infection. The compounds of
Formula I include pharmaceutically acceptable salts thereof.
[0483] General procedures to construct substituted azaindole
piperazine diamides of Formula I and intermediates useful for their
synthesis are described in the following Schemes, 1-81. 21
[0484] Step A in Scheme 1 depicts the synthesis of an aza indole
intermediate, 2a, via the well known Bartoli reaction in which
vinyl magnesium bromide reacts with an aryl or heteroaryl nitro
group, such as in 1, to form a five-membered nitrogen containing
ring as shown. Some references for the above transformation
include: Bartoli et al. a) Tetrahedron Lett. 1989, 30, 2129. b) J.
Chem. Soc. Perkin Trans. I 1991, 2757. c) J. Chem. Soc. Perkin
Trans. II 1991, 657. d) SynLett (1999), 1594. In the preferred
procedure, a solution of vinyl Magnesium bromide in THF (typically
1.0M but from 0.25 to 3.0M) is added dropwise to a solution of the
nitro pyridine in THF at -78.degree. under an inert atmosphere of
either nitrogen or Argon. After addition is completed, the reaction
temperature is allowed to warm to -20.degree. and then is stirred
for approximately 12h before quenching with 20% aq ammonium
chloride solution. The reaction is extracted with ethyl acetate and
then worked up in a typical manner using a drying agent such as
anhydrous magnesium sulfate or sodium sulfate. Products are
generally purified using chromatography over Silica gel. Best
results are generally achieved using freshly prepared vinyl
Magnesium bromide. In some cases, vinyl Magnesium chloride may be
substituted for vinyl Magnesium bromide.
[0485] Substituted azaindoles may be prepared by methods described
in the literature or may be available from commercial sources. Thus
there are many methods for carrying out step A in the literature
and the specific examples are too numerous to even list.
Alternative syntheses of aza indoles and general methods for
carrying out step A include, but are not limited to, those
described in the following references (a-k below): a) Prokopov, A.
A.; Yakhontov, L. N. Khim.-Farm. Zh. 1994, 28(7), 30-51; b)
Lablache--Combier, A. Heteroaromatics. Photoinduced Electron
Transfer 1988, Pt. C, 134-312; c) Saify, Zafar Said. Pak. J.
Pharmacol. 1986, 2(2), 43-6; d) Bisagni, E. Jerusalem Symp. Quantum
Chem. Biochem. 1972, 4, 439-45; e) Yakhontov, L. N. Usp. Khim.
1968, 37(7), 1258-87; f) Willette, R. E. Advan. Heterocycl. Chem.
1968, 9, 27-105; g) Mahadevan, I.; Rasmussen, M. Tetrahedron 1993,
49(33), 7337-52; h) Mahadevan, I.; Rasmussen, M. J. Heterocycl.
Chem. 1992, 29(2), 359-67; i) Spivey, A. C.; Fekner, T.; Spey, S.
E.; Adams, H. J. Org. Chem. 1999, 64(26), 9430-9443; j) Spivey,
A.C.; Fekner, T.; Adams, H. Tetrahedron Lett. 1998, 39(48),
8919-8922; k) Advances in Heterocyclic Chemistry (Academic press)
1991, Vol. 52, pg 235-236 and references therein.
[0486] Step B. Intermediate 3a can be prepared by reaction of
aza-indole, intermediate 2a, with an excess of ClCOCOOMe in the
presence of AlCl.sub.3 (aluminum chloride) (Sycheva et al, Ref. 26,
Sycheva, T.V.; Rubtsov, N.M.; Sheinker, Yu.N.; Yakhontov, L.N. Some
reactions of 5-cyano-6-chloro-7-azaindoles and lactam-lactim
tautomerism in 5-cyano-6-hydroxy-7-azaindolines. Khim. Geterotsikl.
Soedin., 1987, 100-106). Typically an inert solvent such as
CH.sub.2Cl.sub.2 is used but others such as THF, Et.sub.2O, DCE,
dioxane, benzene, or toluene may find applicability either alone or
in mixtures. Other oxalate esters such as ethyl or benzyl mono
esters of oxalic acid could also suffice for either method shown
above. More lipophilic esters ease isolation during aqueous
extractions. Phenolic or substituted phenolic (such as
pentafluorophenol) esters enable direct coupling of the
HW(C.dbd.O)A group, such as a piperazine, in Step D without
activation. Lewis acid catalysts, such as tin tetrachloride,
titanium IV chloride, and aluminum chloride are employed in Step B
with aluminum chloride being most preferred. Alternatively, the
azaindole is treated with a Grignard reagent such as MeMgI (methyl
magnesium iodide), methyl magnesium bromide or ethyl magnesium
bromide and a zinc halide, such as ZnCl.sub.2 (zinc chloride) or
zinc bromide, followed by the addition of an oxalyl chloride mono
ester, such as ClCOCOOMe (methyl chlorooxoacetate) or another ester
as above, to afford the aza-indole glyoxyl ester (Shadrina et al,
Ref. 25). Oxalic acid esters such as methyl oxalate, ethyl oxalate
or as above are used. Aprotic solvents such as CH.sub.2Cl.sub.2,
Et.sub.2O, benzene, toluene, DCE, or the like may be used alone or
in combination for this sequence. In addition to the oxalyl
chloride mono esters, oxalyl chloride itself may be reacted with
the azaindole and then further reacted with an appropriate amine,
such as a piperazine derivative (See Scheme 52, for example).
[0487] Step C. Hydrolysis of the methyl ester, (intermediate 3a,
Scheme 1) affords a potassium salt of intermediate 4a, which is
coupled with mono-benzoylated piperazine derivatives as shown in
Step D of Scheme 1. Some typical conditions employ methanolic or
ethanolic sodium hydroxide followed by careful acidification with
aqueous hydrochloric acid of varying molarity but 1M HCl is
preferred. The acidification is not utilized in many cases as
described above for the preferred conditions. Lithium hydroxide or
potassium hydroxide could also be employed and varying amounts of
water could be added to the alcohols. Propanols or butanols could
also be used as solvents. Elevated temperatures up to the boiling
points of the solvents may be utilized if ambient temperatures do
not suffice. Alternatively, the hydrolysis may be carried out in a
non polar solvent such as CH.sub.2Cl.sub.2 or THF in the presence
of Triton B. Temperatures of -78.degree. C. to the boiling point of
the solvent may be employed but -10.degree. C. is preferred. Other
conditions for ester hydrolysis are listed in reference 41 and both
this reference and many of the conditions for ester hydrolysis are
well known to chemists of average skill in the art.
[0488] Alternative Procedures for Step B and C:
[0489] Imidazolium Chloroaluminate:
[0490] We found that ionic liquid 1-alkyl-3-alkylimidazolium
chloroaluminate is generally useful in promoting the
Friedel--Crafts type acylation of indoles and azaindoles. The ionic
liquid is generated by mixing 1-alkyl-3-alkylimidazolium chloride
with aluminium chloride at room temperature with vigorous stirring.
1:2 or 1:3 molar ratio of 1-alkyl-3-alkylimidazolium chloride to
aluminium chloride is preferred. One particular useful imidazolium
chloroaluminate for the acylation of azaindole with methyl or ethyl
chlorooxoacetate is the 1-ethyl-3-methylimidazolium
chloroaluminate. The reaction is typically performed at ambient
temperature and the azaindoleglyoxyl ester can be isolated. More
conveniently, we found that the glyoxyl ester can be hydrolyzed in
situ at ambient temperature on prolonged reaction time (typically
overnight) to give the corresponding glyoxyl acid for amide
formation (Scheme 1). 22
[0491] A representative experimental procedure is as follows:
1-ethyl-3-methylimidazolium chloride (2 equiv.; purchased from TCI;
weighted under a stream of nitrogen) was stirred in an oven-dried
round bottom flask at r.t. under a nitrogen atmosphere, and added
aluminium chloride (6 equiv.; anhydrous powder packaged under argon
in ampules purchased from Aldrich preferred; weighted under a
stream of nitrogen). The mixture was vigorously stirred to form a
liquid, which was then added azaindole (1 equiv.) and stirred until
a homogenous mixture resulted. The reaction mixture was added
dropwise ethyl or methyl chlorooxoacetate (2 equiv.) and then
stirred at r.t. for 16 h. After which time, the mixture was cooled
in an ice-water bath and the reaction quenched by carefully adding
excess water. The precipitates were filtered, washed with water and
dried under high vacuum to give the azaindoleglyoxyl acid. For some
examples, 3 equivalents of 1-ethyl-3-methylimidazolium chloride and
chlorooxoacetate may be required.
[0492] Related references: (1) Welton, T. Chem Rev. 1999, 99, 2071;
(2) Surette, J. K. D.; Green, L.; Singer, R. D. Chem. Commun. 1996,
2753; (3) Saleh, R. Y. WO 0015594.
[0493] Step D. The acid intermediate, 4a, from step C of Scheme 1
is coupled with an amine A(C.dbd.O)WH preferably in the presence of
DEPBT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) and
N,N-diisopropylethylamine, commonly known as Hunig's base, to
provide azaindole piperazine diamides. DEPBT was prepared according
to the procedure of Ref. 28, Li, H.; Jiang, X.; Ye, Y.-H.; Fan, C.;
Romoff, T.; Goodman, M. Organic Lett., 1999, 1, 91-93. Typically an
inert solvent such as DMF or THF is used but other aprotic solvents
could be used. The group W as referred to herein is 23
[0494] The amide bond construction reaction could be carried out
using the preferred conditions described above, the EDC conditions
described below, other coupling conditions described in this
application, or alternatively by applying the conditions or
coupling reagents for amide bond construction described later in
this application for construction of substituents R.sub.y-R.sub.4.
Some specific nonlimiting examples are given in this
application.
[0495] The mono-substituted piperazine derivatives can be prepared
according to well established procedures such as those described by
Desai et al, Ref. 27(a), Adamczyk et al, Ref. 27(b), Rossen et al,
Ref. 27(c), and Wang et al, 27(d).
[0496] Additional procedures for synthesizing, modifying and
attaching groups: (C.dbd.O).sub.m-WC(O)-A are contained in PCT WO
00/71535. 24
[0497] Scheme 2 provides a more specific example of the
transformations previously described in Scheme 1. Intermediates
6-10 are prepared by the methodologies as described for
intermediates 1a-5a in Scheme 1. Scheme 2A is another embodiment of
the transformations described in Schemes 1 and 2. Conversion of the
phenol to the chloride (Step S, Scheme 2A) may be accomplished
according to the procedures described in Reimann, E.; Wichmann, P.;
Hoefner, G.; Sci. Pharm. 1996, 64(3), 637-646; and Katritzky, A.
R.; Rachwal, S.; Smith, T. P.; Steel, P. J.; J. Heterocycl. Chem.
15 1995, 32(3), 979-984. Step T of Scheme 2A can be carried out as
described for Step A of Scheme 1. The bromo intermediate can then
be converted into alkoxy, chloro, or fluoro intermediates as shown
in Step U of Scheme 2A. Scheme 2A describes the preferred method
for preparing intermediate 6c or other closely related compounds
containing a 4 methoxy group in the 6-azaindole system. When step U
is the conversion of the bromide into alkoxy derivatives, the
conversion may be carried out by reacting the bromide with an
excess of sodium methoxide in methanol with cuprous salts, such as
copper I bromide, copper I iodide, and copper I cyanide. The
temperature may be carried out at temperatures of between ambient
and 175.degree. but most likely will be around 115.degree. C. or
100.degree. C. The reaction may be run in a pressure vessel or
sealed tube to prevent escape of volatiles such as methanol. The
preferred conditions utilize 3eq of sodium methoxide in methanol,
CuBr as the reaction catalyst (0.2 to 3 equivalents with the
preferred being 1 eq or less), and a reaction temperature of
115.degree. C. The reaction is carried out in a sealed tube or
sealed reaction vessel. The conversion of the bromide into alkoxy
derivatives may also be carried out according to procedures
described in Palucki, M.; Wolfe, J. P.; Buchwald, S. L.; J. Am.
Chem. Soc. 1997, 119(14), 3395-3396; Yamato, T.; Komine, M.;
Nagano, Y.; Org. Prep. Proc. Int. 1997, 29(3), 300-303; Rychnovsky,
S. D.; Hwang, K.; J. Org. Chem. 1994, 59(18), 5414-5418. Conversion
of the bromide to the fluoro derivative (Step U, Scheme 2A) may be
accomplished according to Antipin, I. S.; Vigalok, A. I.;
Konovalov, A. I.; Zh. Org. Khim. 1991, 27(7), 1577-1577; and
Uchibori, Y.; Umeno, M.; Seto, H.; Qian, Z.; Yoshioka, H.; Synlett.
1992, 4, 345-346. Conversion of the bromide to the chloro
derivative (Step U, Scheme 2A) may be accomplished according to
procedures described in Gilbert, E. J.; Van Vranken, D. L.; J. Am.
Chem. Soc. 1996, 118(23), 5500-5501; Mongin, F.; Mongin, O.;
Trecourt, F.; Godard, A.; Queguiner, G.; Tetrahedron Lett. 1996,
37(37), 6695-6698; and O'Connor, K. J.; Burrows, C. J.; J. Org.
Chem. 1991, 56(3), 1344-1346. Steps V, W and X of Scheme 2A are
carried out according to the procedures previously described for
Steps B, C, and D of Scheme 1, respectively. The steps of Scheme 2A
may be carried out in a different order as shown in Scheme 2B and
Scheme 2C. 2526 2728 29 3031
[0498] S Scheme 3 shows the synthesis of 4-azaindole derivatives
1b-5b, 5-azaindole derivatives 1c-5c, and 7-azaindole derivatives
1d-5d. The methods used to synthesize 1b-5b, 1c-5c, and 1d-5d are
the same methods described for the synthesis of 1a-5a as described
in Scheme 1. It is understood, for the purposes of Scheme 3, that
1b is used to synthesize 2b-5b, 1c provides 2c-5c and 1d provides
2d-5d.
[0499] The compounds where there is a single carbonyl between the
azaindole and group W can be prepared by the method of Kelarev, V.
I.; Gasanov, S. Sh.; Karakhanov, R. A.; Polivin, Yu. N.;
Kuatbekova, K. P.; Panina, M. E.; Zh. Org. Khim 1992, 28(12),
2561-2568. In this method azaindoles are reacted with
trichloroacetyl chloride in pyridine and then subsequently with KOH
in methanol to provide the 3-carbomethoxy azaindoles shown in
Scheme 4 which can then be hydrolyzed to the acid and carried
through the coupling sequence with HW(C.dbd.O)A to provide the
compounds of Formula I wherein a single carbonyl links the
azaindole moiety and group W. 32
[0500] An alternative method for carrying out the sequence outlined
in steps B-D (shown in Scheme 5) involves treating an azaindole,
such as 11, obtained by procedures described in the literature or
from commercial sources, with MeMgI and ZnCl.sub.2, followed by the
addition of ClCOCOCl (oxalyl chloride) in either THF or Et.sub.2O
to afford a mixture of a glyoxyl chloride azaindole, 12a, and an
acyl chloride azaindole, 12b. The resulting mixture of glyoxyl
chloride azaindole and acyl chloride azaindole is then coupled with
mono-benzoylated piperazine derivatives under basic conditions to
afford the products of step D as a mixture of compounds, 13a and
13b, where either one or two carbonyl groups link the azaindole and
group W. Separation via chromatographic methods which are well
known in the art provides the pure 13a and 13b. This sequence is
summarized in Scheme 5, below. 33 34
[0501] Scheme 6 depicts a general method for modifying the
substituent A. Coupling of H-W-C(O)OtBu using the conditions
described previously for W in Scheme 1, Step D provides Boc
protected intermediate, 15. Intermediate 15 is then deprotected by
treatment with an acid such as TFA, hydrochloric acid or formic
acid using standard solvents or additives such as CH.sub.2Cl.sub.2,
dioxane, or anisole and temperatures between -78.degree. C. and
100.degree. C. Other acids such as aq hydrochloric or perchloric
may also be used for deprotection. Alternatively other nitrogen
protecting groups on W such as Cbz or TROC, may be utilized and
could be removed via hydrogenation or treatment with zinc
respectively. A stable silyl protecting group such as phenyl
dimethylsilyl could also be employed as a nitrogen protecting group
on W and can be removed with fluoride sources such as
tetrabutylammonium fluoride. Finally, the free amine is coupled to
acid A-C(O)OH using standard amine-acid coupling conditions such as
those used to attach group W or as shown below for amide formation
on positions R.sub.y-R.sub.4 to provide compound 16.
[0502] Some specific examples of general methods for preparing
functionalized azaindoles or for interconverting functionality on
aza indoles which will be useful for preparing the compounds of
this invention are shown in the following sections for illustrative
purposes. It should be understood that this invention covers
substituted 4, 5, 6, and 7 azaindoles and that the methodology
shown below may be applicable to all of the above series while
other shown below will be specific to one or more. A typical
practioner of the art can make this distinction when not
specifically delineated. Many methods are intended to be applicable
to all the series, particularly functional group installations or
interconversions. For example, a general strategy for providing
further functionality of this invention is to position or install a
halide such as bromo, chloro, or iodo, aldehyde, cyano, or a
carboxy group on the azaindole and then to convert that
functionality to the desired compounds. In particular, conversion
to substituted heteroaryl, aryl, and amide groups on the ring are
of particular interest.
[0503] General routes for functionalizing azaindole rings are shown
in Schemes 7, 8 and 9. As depicted in Scheme 7, the azaindole, 17,
can be oxidized to the corresponding N-oxide derivative, 18, by
using mCPBA (meta-Chloroperbenzoic Acid) in acetone or DMF (eq. 1,
Harada et al, Ref. 29 and Antonini et al, Ref. 34).
[0504] The N-oxide, 18, can be converted to a variety of
substituted azaindole derivatives by using well documented reagents
such as phosphorus oxychloride (POCl.sub.3) (eq. 2, Schneller et
al, Ref. 30), tetramethylammonium fluoride (Me.sub.4NF) (eq. 3),
Grignard reagents RMgX (R.dbd.alkyl or aryl, X .dbd.Cl, Br or I)
(eq. 4, Shiotani et al, Ref. 31), trimethylsilyl cyanide (TMSCN)
(eq. 5, Minakata et al, Ref. 32) or Ac.sub.2O (eq. 6, Klemm et al,
Ref. 33). Under such conditions, a chlorine (in 19), fluorine (in
20), nitrile (in 22), alkyl (in 21), aromatic (in 21) or hydroxyl
group (in 24) can be introduced to the pyridine ring. Nitration of
azaindole N-oxides results in introduction of a nitro group to
azaindole ring, as shown in Scheme 8 (eq. 7, Antonini et al, Ref.
34). The nitro group can subsequently be displaced by a variety of
nucleophilic agents, such as OR, NR.sup.1R.sup.2 or SR, in a well
established chemical fashion (eq. 8, Regnouf De Vains et al, Ref.
35(a), Miura et al, Ref. 35(b), Profft et al, Ref. 35(c)). The
resulting N-oxides, 26, are readily reduced to the corresponding
azaindole, 27, using phosphorus trichloride (PCl.sub.3) (eq. 9,
Antonini et al, Ref. 34 and Nesi et al, Ref. 36). Similarly,
nitro-substituted N-oxide, 25, can be reduced to the azaindole, 28,
using phosphorus trichloride (eq. 10). The nitro group of compound
28 can be reduced to either a hydroxylamine (NHOH), as in 29, (eq.
11, Walser et al, Ref. 37(a) and Barker et al, Ref. 37(b)) or an
amino (NH.sub.2) group, as in 30, (eq. 12, Nesi et al , Ref. 36 and
Ayyangar et al, Ref. 38) by carefully selecting different reducing
conditions. 3536 3738
[0505] The alkylation of the nitrogen atom at position 1 of the
azaindole derivatives can be achieved using NaH as the base, DMF as
the solvent and an alkyl halide or sulfonate as alkylating agent,
according to a procedure described in the literature (Mahadevan et
al, Ref. 9) (Scheme 9). 39
[0506] In the general routes for substituting the azaindole ring
described above, each process can be applied repeatedly and
combinations of these processes is permissible in order to provide
azaindoles incorporating multiple substituents. The application of
such processes provides additional compounds of Formula I. 40
[0507] The synthesis of 4-aminoazaindoles which are useful
precursors for 4, 5, and/or 7-substituted azaindoles is shown in
Scheme 10 above. The synthesis of 3, 5-dinitro-4-methylpyridine,
32, is described in the following two references by Achremowicz
et.al.: Achremowicz, Lucjan. Pr. Nauk. Inst. Chem. Org. Fiz.
Politech. Wroclaw. 1982, 23, 3-128; Achremowicz, Lucjan. Synthesis
1975, 10, 653-4. In the first step of Scheme 10, the reaction with
dimethylformamide dimethyl acetal in an inert solvent or neat under
conditions for forming Batcho-Leimgruber precursors provides the
cyclization precursor, 33, as shown. Although the step is
anticipated to work as shown, the pyridine may be oxidized to the
N-oxide prior to the reaction using a peracid such as MCPBA or a
more potent oxidant like meta-trifluoromethyl or meta nitro peroxy
benzoic acids. In the second step of Scheme 10, reduction of the
nitro group using for example hydrogenation over Pd/C catalyst in a
solvent such as MeOH, EtOH, or EtOAc provides the cyclized product,
34. Alternatively the reduction may be carried out using tin
dichloride and HCl, hydrogenation over Raney nickel or other
catalysts, or by using other methods for nitro reduction such as
described elsewhere in this application.
[0508] The amino indole, 34, can now be converted to compounds of
Formula I via, for example, diazotization of the amino group, and
then conversion of the diazonium salt to the fluoride, chloride or
alkoxy group. See the discussion of such conversions in the
descriptions for Schemes 17 and 18. The conversion of the amino
moiety into desired functionality could then be followed by
installation of the oxoacetopiperazine moiety by the standard
methodology described above. 5 or 7-substitution of the azaindole
can arise from N-oxide formation at position 6 and subsequent
conversion to the chloro via conditions such as POCl.sub.3 in
chloroform, acetic anhydride followed by POCl.sub.3 in DMF, or
alternatively TsCl in DMF. Literature references for these and
other conditions are provided in some of the later Schemes in this
application. The synthesis of 4-bromo-7-hydroxy or protected
hydroxy-4-azaindole is described below as this is a useful
precursor for 4 and/or 7 substituted 6-aza indoles.
[0509] The synthesis of 5-bromo-2-hydroxy-4-methyl-3-nitro
pyridine, 35, may be carried out as described in the following
reference:Betageri, R.; Beaulieu, P. L.; Llinas-Brunet, M; Ferland,
J. M.; Cardozo, M.; Moss, N.; Patel, U.; Proudfoot, J. R. PCT Int.
Appl. WO 9931066, 1999. Intermediate 36 is prepared from 35
according to the method as described for Step 1 of Scheme 10. PG is
an optional hydroxy protecting group such as triallylsilyl or the
like. Intermediate 37 is then prepared from 36 by the selective
reduction of the nitro group in the presence of bromide and
subsequent cyclization as described in the second step of Scheme
10. Fe(OH).sub.2 in DMF with catalytic tetrabutylammonium bromide
can also be utilized for the reduction of the nitro group. The
bromide may then be converted to fluoride via displacement with
fluoride anions or to other substituents. The compounds are then
converted to compounds of Formula I as above. 41
[0510] An alternate method for preparing substituted 6-azaindoles
is shown below in Schemes 12 and 13. It should be recognized that
slight modifications of the route depicted below are possible. For
example, acylation reactions of the 3 position of what will become
the azaindole five membered ring, prior to aromatization of the
azaindole, may be carried out in order to obtain higher yields. In
addition to a para-methoxybenzyl group (PMB), a benzyl group can be
carried through the sequence and removed during azaindole formation
by using TsOH, p-Chloranil, in benzene as the oxidant if DD
[0511] Q is not optimal. The benzyl intermediate, 38, has been
described by Ziegler et al. in J. Am. Chem. Soc. 1973, 95(22),
7458. The transformation of 38 to 40 is analogous to the
transformation described in Heterocycles 1984, 22, 2313. 42
[0512] Scheme 13 describes various transformations of intermediate
40 which ultimately provide compounds of Formula I. The conversions
of the phenol moiety to other functionality at position 4 (R.sub.2
position in Scheme 13) may be carried out by the following methods:
1) conversion of a phenol to methoxy group with silver oxide and
Mel or diazomethane; 2) conversion of a phenolic hydroxy group to
chloro using cat ZnCl.sub.2, and N,N dimethylaniline in
CH.sub.2Cl.sub.2 or PCl.sub.5 and POCl.sub.3 together; 3)
conversion of a phenolic hydroxy group to fluoro using
diethylamine-SF.sub.3 as in Org. Prep. Proc. Int. 1992, 24(1),
55-57. The method described in EP 427603, 1991, using the
chloroformate and HF will also be useful. Other transformations are
possible. For example the phenol can be converted to a triflate by
standard methods and used in coupling chemistries described later
in this application. 43
[0513] Step E. Scheme 14 depicts the nitration of an azaindole, 41,
(R.sub.2.dbd.H). Numerous conditions for nitration of the azaindole
may be effective and have been described in the literature.
N.sub.2O.sub.5 in nitromethane followed by aqueous sodium bisulfite
according to the method of Bakke, J. M.; Ranes, E.; Synthesis 1997,
3, 281-283 could be utilized. Nitric acid in acetic may also be
employed as described in Kimura, H.; Yotsuya, S.; Yuki, S.; Sugi,
H.; Shigehara, I.; Haga, T.; Chem. Pharm. Bull. 1995, 43(10),
1696-1700. Sulfuric acid followed by nitric acid may be employed as
in Ruefenacht, K.; Kristinsson, H.; Mattern, G.; Helv Chim Acta
1976, 59, 1593. Coombes, R. G.; Russell, L. W.; J. Chem. Soc.,
Perkin Trans. 1 1974, 1751 describes the use of a Titatanium based
reagent system for nitration. Other conditions for the nitration of
the azaindole can be found in the following references: Lever, O.
W. J.; Werblood, H. M.; Russell, R. K.; Synth. Comm. 1993, 23(9),
1315-1320; Wozniak, M.; Van Der Plas, H. C.; J. Heterocycl Chem.
1978, 15, 731. 44 45
[0514] Step F
[0515] As shown above in Scheme 15, Step F, substituted azaindoles
containing a chloride, bromide, iodide, triflate, or phosphonate
undergo coupling reactions with a boronate (Suzuki type reactions)
or a stannane to provide substituted azaindoles. Stannanes and
boronates are prepared via standard literature procedures or as
described in the experimental section of this application. The
substitututed indoles may undergo metal mediated coupling to
provide compounds of Formula I wherein R.sub.4 is aryl, heteroaryl,
or heteroalicyclic for example. The bromoazaindole intermediates,
(or azaindole triflates or iodides) may undergo Stille-type
coupling with heteroarylstannanes as shown in Scheme 15. Conditions
for this reaction are well known in the art and the following are
three example references a) Farina, V.; Roth, G.P. Recent advances
in the Stille reaction; Adv. Met. -Org. Chem. 1996, 5, 1-53. b)
Farina, V.; Krishnamurthy, V.; Scott, W. J. The Stille reaction;
Org. React. (N. Y.) 1997, 50, 1-652. and c) Stille, J. K. Angew.
Chem. Int. Ed. Engl. 1986, 25, 508-524. Other references for
general coupling conditions are also in the reference by Richard C.
Larock Comprehensive Organic Transformations 2nd Ed. 1999, John
Wiley and Sons New York. All of these references provide numerous
conditions at the disposal of those skilled in the art in addition
to the specific examples provided in Scheme 15 and in the specific
embodiments. It can be well recognized that an indole stannane
could also couple to a heterocyclic or aryl halide or triflate to
construct compounds of Formula I. Suzuki coupling (Norio Miyaura
and Akiro Suzuki Chem Rev. 1995, 95, 2457.) between a triflate,
bromo, or chloro azaindole intermediate and a suitable boronate
could also be employed and some specific examples are contained in
this application. Palladium catalyzed couplings of stannanes and
boronates between chloro azaindole intermediates are also feasible
and have been utilized extensively for this invention. Preferred
procedures for coupling of a chloro azaindole and a stannane employ
dioxane, stoichiometric or an excess of the tin reagent (up to 5
equivalents), 0.1 to 1 eq of Palladium (0) tetrakis triphenyl
phosphine in dioxane heated for 5 to 15 h at 110 to 120.degree..
Other solvents such as DMF, THF, toluene, or benzene could be
employed. Preferred procedures for Suzuki coupling of a chloro
azaindole and a boronate employ 1:1 DMF water as solvent, 2
equivalents of potassium carbonate as base stoichiometric or an
excess of the boron reagent (up to 5 equivalents), 0.1 to 1 eq of
Palladium (0) tetrakis triphenyl phosphine heated for 5 to 15 h at
110 to 120.degree.. If standard conditions fail new specialized
catalysts and conditions can be employed. Some references (and the
references therein) describing catalysts which are useful for
coupling with aryl and heteroaryl chlorides are:
[0516] Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000,
122(17), 4020-4028;
[0517] Varma, R. S.; Naicker, K. P. Tetrahedron Lett. 1999, 40(3),
439-442; Wallow, T. I.;
[0518] Novak, B. M. J. Org. Chem. 1994, 59(17), 5034-7; Buchwald,
S.; Old, D. W.;
[0519] Wolfe, J. P.; Palucki, M.; Kamikawa, K.; Chieffi, A.;
Sadighi, J. P.; Singer, R. A.;
[0520] Ahman, J PCT Int. Appl. WO 0002887 2000; Wolfe, J. P.;
Buchwald, S. L. Angew.
[0521] Chem., Int. Ed. 1999, 38(23), 3415; Wolfe, J. P.; Singer, R.
A.; Yang, B. H.;
[0522] Buchwald, S. L. J. Am. Chem. Soc. 1999, 121(41), 9550-9561;
Wolfe, J. P.;
[0523] Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38(16),
2413-2416; Bracher, F.;
[0524] Hildebrand, D.; Liebigs Ann. Chem. 1992, 12, 1315-1319; and
Bracher, F.;
[0525] Hildebrand, D.; Liebigs Ann. Chem. 1993, 8, 837-839.
[0526] Alternatively, the boronate or stannane may be formed on the
azaindole via methods known in the art and the coupling performed
in the reverse manner with aryl or heteroaryl based halogens or
triflates.
[0527] Known boronate or stannane agents could be either purchased
from commercial resources or prepared following disclosed
documents. Additional examples for the preparation of tin reagents
or boronate reagents are contained in the experimental section.
[0528] Novel stannane agents could be prepared from one of the
following routes. 46 47 48 49 50
[0529] Boronate reagents are prepeared as described in reference
71. Reaction of lithium or Grignard reagents with trialkyl borates
generates boronates. Alternatively, Palladium catalyzed couplings
of alkoxy diboron or alkyl diboron reagents with aryl or heteroaryl
halides can provide boron reagents for use in Suzuki type
couplings. Some example conditions for coupling a halide with
(MeO)BB(OMe)2 utilize PdCl2 (dppf), KOAc, DMSO, at 80.degree. C.
until reaction is complete when followed by TLC or HPLC
analysis.
[0530] Related examples are provided in the following experimental
section.
[0531] Methods for direct addition of aryl or heteroaryl
organometallic reagents to alpha chloro nitrogen containing
heterocyles or the N-oxides of nitrogen containing heterocycles are
known and applicable to the azaindoles. Some examples are Shiotani
et. Al. J. Heterocyclic Chem. 1997, 34(3), 901-907; Fourmigue
et.al. J.Org. Chem. 1991, 56(16), 4858-4864. 51 52
[0532] Direct displacements to install amine or N linked heteroaryl
substituents can also be used to prepare compounds of Formula I. As
shown in Schemes 15aa and 15bb, a mixture of halo-indole or
halo-azaindole intermediate, 1-2 equivalents of copper powder, with
1 equivalent preferred for the 4-F,6-azaindole series and 2
equivalents for the 4-methoxy, 6-azaindole series; 1-2 equivalents
of potassium carbonate, with 1 equivalent preferred for the
4-F,6-azaindole series and 2 equivalents for the
4-methoxy,6-azaindole series; and a 2-30 equivalents of the
corresponding heterocyclic reagent, with 10 equivalents preferred;
was heated at 135-160.degree. C. for 4 to 9 hours, with 5 hours at
160.degree. C. preferred for the 4-F,6-azaindole series and 7 hours
at 135.degree. C. preferred for the 4-methoxy,6-azaindole series.
The reaction mixture was cooled to room temperature and filtered
through filter paper. The filtrate was diluted with methanol and
purified either by preparative HPLC or silica gel. In many cases no
chromatography is necessary, the product can be obtained by
crystallization with methanol.
[0533] Alternatively, the installation of amines or N linked
heteroaryls may be carried out by heating 1 to 40 equivalents of
the appropriate amine and an equivalent of the appropriate aza
indole chloride, bromide or iodide with copper bronze (from 0.1 to
10equivalents (preferably about 2 equivalents) and from 1 to 10
equivalents of finely pulverized potassium hydroxide (preferably
about 2 equivalents).
[0534] Temperatures of 120.degree. to 200.degree. may be employed
with 140-160.degree. generally preferred. For volatile starting
materials a sealed reactor may be employed. The reaction is most
commonly used when the halogen being displaced is at the 7-position
of a 6-aza (or 4-azaindole, not shown) but the method can work in
the 5-azaseries or when the halogen is at a different position (4-7
position possible). As shown above the reaction can be employed on
azaindoles unsubstituted at position 3 or intermediates which
contain the dicarbonyl or the intact dicarbonyl piperazine urea or
thioureas contained in compounds of formula I. 53
[0535] The preparation of a key aldehyde intermediate, 43, using a
procedure adapted from the method of Gilmore et. Al. Synlett 1992,
79-80. Is shown in Scheme 16 above. The aldehyde substituent is
shown only at the R.sup.4 position for the sake of clarity, and
should not be considered as a limitation of the methodology. The
bromide or iodide intermediate is converted into an aldehyde
intermediate, 43, by metal-halogen exchange and subsequent reaction
with dimethylformamide in an appropriate aprotic solvent. Typical
bases used include, but are not limited to, alkyl lithium bases
such as n-butyl lithium, sec butyl lithium or tert butyl lithium or
a metal such as lithium metal. A preferred aprotic solvent is THF.
Typically the transmetallation is initiated at -78.degree. C. The
reaction may be allowed to warm to allow the transmetalation to go
to completion depending on the reactivity of the bromide
intermediate. The reaction is then recooled to -78.degree. C. and
allowed to react with dimethylformamide. (allowing the reaction to
warm may be required to enable complete reaction) to provide an
aldehyde which is elaborated to compounds of Formula I. Other
methods for introduction of an aldehyde group to form intermediates
of formula 43 include transition metal catalyzed carbonylation
reactions of suitable bromo, trifluoromethane sulfonyl, or stannyl
azaindoles. Alternative the aldehydes can be introduced by reacting
indolyl anions or indolyl Grignard reagents with formaldehyde and
then oxidizing with MnO.sub.2 or TPAP/NMO or other suitable
oxidants to provide intermediate 43.
[0536] The methodology described in T. Fukuda et.al. Tetrahedron
1999, 55, 9151 and M. Iwao et. Al. Heterocycles 1992, 34(5), 1031
provide methods for preparing indoles with substituents at the
7-position. The Fukuda references provide methods for
functionalizing the C-7 position of indoles by either protecting
the indole nitrogen with 2,2-diethyl propanoyl group and then
deprotonating the 7-position with sec/Buli in TMEDA to give an
anion. This anion may be quenched with DMF, formaldehyde, or carbon
dioxide to give the aldehyde, benzyl alcohol, or carboxylic acid
respectively and the protecting group removed with aqueous t
butoxide. Similar tranformations can be achieved by converting
indoles to indoline, lithiation at C-7 and then reoxidation to the
indole such as described in the Iwao reference above. The oxidation
level of any of these products may be adjusted by methods well
known in the art as the interconversion of alcohol, aldehyde, and
acid groups has been well studied. It is also well understood that
a cyano group can be readily converted to an aldehyde. A reducing
agent such as DIBALH in hexane such as used in Weyerstahl, P.;
Schlicht, V.; Liebigs Ann/Recl. 1997, 1, 175-177 or alternatively
catecholalane in THF such as used in Cha, J. S.; Chang, S. W.;
Kwon, O. O.; Kim, J. M.; Synlett. 1996, 2, 165-166 will readily
achieve this conversion to provide intermediates such as 44 (Scheme
16). Methods for synthesizing the nitriles are shown later in this
application. It is also well understood that a protected alcohol,
aldehyde, or acid group could be present in the starting azaindole
and carried through the synthetic steps to a compound of Formula I
in a protected form until they can be converted into the desired
substituent at R.sub.1 through R.sub.4. For example, a benzyl
alcohol can be protected as a benzyl ether or silyl ether or other
alcohol protecting group; an aldehyde may be carried as an acetal,
and an acid may be protected as an ester or ortho ester until
deprotection is desired and carried out by literature methods.
54
[0537] Step G. Step 1 of Scheme 17 shows the reduction of a nitro
group on 45 to the amino group of 46. Although shown on position 4
of the azaindole, the chemistry is applicable to other nitro
isomers. The procedure described in Ciurla, H.; Puszko, A.; Khim
Geterotsikl Soedin 1996, 10, 1366-1371 uses hydrazine RaneyNickel
for the reduction of the nitro group to the amine. Robinson, R. P.;
DonahueO, K. M.; Son, P. S.; Wagy, S. D.; J. Heterocycl. Chem.
1996, 33(2), 287-293 describes the use of hydrogenation and Raney
Nickel for the reduction of the nitro group to the amine. Similar
conditions are described by Nicolai, E.; Claude, S.; Teulon, J. M.;
J. Heterocycl. Chem. 1994, 31(1), 73-75 for the same
transformation. The following two references describe some
trimethylsilyl sulfur or chloride based reagents which may be used
for the reduction of a nitro group to an amine. Hwu, J. R.; Wong,
F. F.; Shiao, M. J.; J. Org. Chem. 1992, 57(19), 5254-5255; Shiao,
M. J.; Lai, L. L.; Ku, W. S.; Lin, P. Y.; Hwu, J. R.; J. Org. Chem.
1993, 58(17), 4742-4744.
[0538] Step 2 of Scheme 17 describes general methods for conversion
of amino groups on azaindoles into other functionality. Scheme 18
also depicts transformations of an amino azaindole into various
intermediates and compounds of Formula I.
[0539] The amino group at any position of the azaindole, such as 46
(Scheme 17), may be converted to a hydroxy group using sodium
nitrite, sulfuric acid, and water via the method of Klemm, L. H.;
Zell, R.; J. Heterocycl. Chem. 1968, 5, 773. Bradsher, C. K.;
Brown, F. C.; Porter, H. K.; J. Am. Chem. Soc. 1954, 76, 2357
describes how the hydroxy group may be alkylated under standard or
Mitsonobu conditions to form ethers. The amino group may be
converted directly into a methoxy group by diazotization (sodium
nitrite and acid )and trapping with methanol.
[0540] The amino group of an azaindole, such as 46, can be
converted to fluoro via the method of Sanchez using HPF.sub.6,
NaNO.sub.2, and water by the method described in Sanchez, J. P.;
Gogliotti, R. D.; J. Heterocycl. Chem. 1993, 30(4), 855-859. Other
methods useful for the conversion of the amino group to fluoro are
described in Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G.;
Tetrahedron Lett. 1993, 34(18), 2937-2940 and Sanchez, J. P.;
Rogowski, J. W.; J. Heterocycl. Chem. 1987, 24, 215.
[0541] The amino group of the azaindole, 46, can also be converted
to a chloride via diazotization and chloride displacement as
described in Ciurla, H.; Puszko, A.; Khim Geterotsikl Soedin 1996,
10, 1366-1371 or the methods in Raveglia, L. F.; Giardina, G. A..;
Grugni, M.; Rigolio, R.; Farina, C.; J. Heterocycl. Chem. 1997,
34(2), 557-559 or the methods in Matsumoto, J. I.; Miyamoto, T.;
Minamida, A.; Mishimura, Y.; Egawa, H.; Mishimura, H.; J. Med.
Chem. 1984, 27(3), 292; or as in Lee, T. C.; Salemnick, G.; J. Org.
Chem. 1975, 24, 3608.
[0542] The amino group of the azaindole, 46, can also be converted
to a bromide via diazotization and displacement by bromide as
described in Raveglia, L. F.; Giardina, G. A..; Grugni, M.;
Rigolio, R.; Farina, C.; J. Heterocycl. Chem. 1997, 34(2), 557-559;
Talik, T.; Talik, Z.; Ban-Oganowska, H.; Synthesis 1974, 293; and
Abramovitch, R. A.; Saha, M.; Can. J. Chem. 1966, 44, 1765. 55
[0543] The preparation of 4-amino 4-azaindole and
7-methyl-4-azaindole is described by Mahadevan, I.; Rasmussen, M.
J. Heterocycl. Chem. 1992, 29(2), 359-67. The amino group of the
4-amino 4-azaindole can be converted to halogens, hydroxy,
protected hydroxy, triflate, as described above in Schemes 17-18
for the 4-amino compounds or by other methods known in the art.
Protection of the indole nitrogen of the 7-methyl-4-azaindole via
acetylation or other strategy followed by oxidation of the 7-methyl
group with potassium permanganate or chromic acid provides the
7-acid/4-N-oxide. Reduction of the N-oxide, as described below,
provides an intermediate from which to install various substituents
at position R.sub.4. Alternatively the parent 4-azaindole which was
prepared as described in Mahadevan, I.; Rasmussen, M. J.
Heterocycl. Chem. 1992, 29(2), 359-67 could be derivatized at
nitrogen to provide the 1-(2,2-diethylbutanoyl)azaindole which
could then be lithiated using TMEDA/sec BuLi as described in T.
Fukuda et. Al. Tetrahedron 1999, 55, 9151-9162; followed by
conversion of the lithio species to the 7-carboxylic acid or
7-halogen as described. Hydrolysis of the N-amide using aqueous
tert-butoxide in THF regenerates the free NH indole which can now
be converted to compounds of Formula I. The chemistry used to
functionalize position 7 can also be applied to the 5 and 6 indole
series.
[0544] Scheme 19 shows the preparation of a 7-chloro-4-azaindole,
50, which can be converted to compounds of Formula I by the
chemistry previously described, especially the palladium catalyzed
tin and boron based coupling methodology described above. The
chloro nitro indole, 49, is commercially available or can be
prepared from 48 according to the method of Delarge, J.; Lapiere,
C. L. Pharm. Acta Helv. 1975, 50(6), 188-91. 56
[0545] Scheme 20, below, shows another synthetic route to
substituted 4-aza indoles. The 3-aminopyrrole, 51, was reacted to
provide the pyrrolopyridinone, 52, which was then reduced to give
the hydroxy azaindole, 53. The pyrrolo[2,3-b]pyridines described
were prepared according to the method of Britten, A. Z.; Griffiths,
G. W. G. Chem. Ind. (London) 1973, 6, 278. The hydroxy azaindole,
53, can then be converted to the triflate then further reacted to
provide compounds of Formula I. 57
[0546] The following references describe the synthesis of 7-halo or
7 carboxylic acid, or 7-amido derivatives of 5-azaindoline which
can be used to construct compounds of Formula I. Bychikhina, N. N.;
Azimov, V. A.; Yakhontov, L. N. Khim. Geterotsikl. Soedin. 1983, 1,
58-62; Bychikhina, N. N.; Azimov, V. A.; Yakhontov, L. N. Khim.
Geterotsikl. Soedin. 1982, 3, 356-60; Azimov, V. A.; Bychikhina, N.
N.; Yakhontov, L. N. Khim. Geterotsikl. Soedin. 1981, 12, 1648-53;
Spivey, A. C.; Fekner, T.; Spey, S. E.; Adams, H. J. Org. Chem.
1999, 64(26), 9430-9443; Spivey, A. C.; Fekner, T.; Adams, H.
Tetrahedron Lett. 1998, 39(48), 8919-8922. The methods described in
Spivey et al. (preceding two references) for the preparation of
1-methyl-7-bromo-4-azaindoline can be used to prepare the
1-benzyl-7-bromo-4-azaindoline, 54, shown below in Scheme 21. This
can be utilized in Stille or Suzuki couplings to provide 55, which
is deprotected and dehydrogenated to provide 56. Other useful
azaindole intermediates, such as the cyano derivatives, 57 and 58,
and the aldehyde derivatives, 59 and 60, can then be further
elaborated to compounds of Formula I. 58
[0547] Alternatively the 7-functionalized 5-azaindole derivatives
may be obtained by functionalization using the methodologies of T.
Fukuda et.al. Tetrahedron 1999, 55, 9151 and M. Iwao et. Al.
Heterocycles 1992, 34(5), 1031described above for the 4 or 6
azaindoles. The 4 or 6 positions of the 5 aza indoles can be
functionalized by using the azaindole N-oxide.
[0548] The conversion of indoles to indolines is well known in the
art and can be carried out as shown or by the methods described in
Somei, M.; Saida, Y.; Funamoto, T.; Ohta, T. Chem. Pharm. Bull.
1987, 35(8), 3146-54; M. Iwao et. Al. Heterocycles 1992, 34(5),
1031; and Akagi, M.; Ozaki, K. Heterocycles 1987, 26(1), 61-4.
59
[0549] The preparation of azaindole oxoacetyl or oxo piperidines
with carboxylic acids can be carried out from nitrile, aldehyde, or
anion precursors via hydrolysis, oxidation, or trapping with
CO.sub.2 respectively. As shown in the Scheme 22, Step 1, or the
scheme below step a12 one method for forming the nitrile
intermediate, 62, is by cyanide displacement of a halide in the
aza-indole ring. The cyanide reagent used can be sodium cyanide, or
more preferably copper or zinc cyanide. The reactions may be
carried out in numerous solvents which are well known in the art.
For example DMF is used in the case of copper cyanide. Additional
procedures useful for carrying out step 1 of Scheme 24 are
Yamaguchi, S.; Yoshida, M.; Miyajima, I.; Araki, T.; Hirai, Y.; J.
Heterocycl. Chem. 1995, 32(5), 1517-1519 which describes methods
for copper cyanide; Yutilov, Y. M.; Svertilova, I. A.; Khim
Geterotsikl Soedin 1994, 8, 1071-1075 which utilizes potassium
cyanide; and Prager, R. H.; Tsopelas, C.; Heisler, T.; Aust. J.
Chem. 1991, 44 (2), 277-285 which utilizes copper cyanide in the
presence of MeOS(O).sub.2F. The chloride or more preferably a
bromide on the azaindole may be displaced by sodium cyanide in
dioxane via the method described in Synlett. 1998, 3, 243-244.
Alternatively, Nickel dibromide, Zinc, and triphenyl phosphine in
can be used to activate aromatic and heteroaryl chlorides to
displacement via potassium cyanide in THF or other suitable solvent
by the methods described in Eur. Pat. Appl., 831083, 1998.
[0550] The conversion of the cyano intermediate, 62, to the
carboxylic acid intermediate, 63, is depicted in step 2, Scheme 22
or in step a12, Scheme 23. Many methods for the conversion of
nitrites to acids are well known in the art and may be employed.
Suitable conditions for step 2 of Scheme 22 or the conversion of
intermediate 65 to intermediate 66 below employ potassium
hydroxide, water, and an aqueous alcohol such as ethanol. Typically
the reaction must be heated at refluxing temperatures for one to
100 h. Other procedures for hydrolysis include those described
in:
[0551] Shiotani, S.; Taniguchi, K.; J. Heterocycl. Chem. 1997,
34(2), 493-499; Boogaard, A. T.; Pandit, U. K.; Koomen, G.-J.;
Tetrahedron 1994, 50(8), 2551-2560; Rivalle, C.; Bisagni, E.;
Heterocycles 1994, 38(2), 391-397; Macor, J. E.; Post, R.; Ryan,
K.; J. Heterocycl. Chem. 1992, 29(6), 1465-1467.
[0552] The acid intermediate, 66 (Scheme 23), may then be
esterified using conditions well known in the art. For example,
reaction of the acid with diazomethane in an inert solvent such as
ether, dioxane, or THF would give the methyl ester. Intermediate 67
may then be converted to intermediate 68 according to the procedure
described in Scheme 2. Intermediate 68 may then be hydrolyzed to
provide intermediate 69. 60
[0553] As shown in Scheme 24, step a13 another preparation of the
indoleoxoacetylpiperazine 7-carboxylic acids, 69, is carried out by
oxidation of the corresponding 7-carboxaldehyde, 70. Numerous
oxidants are suitable for the conversion of aldehyde to acid and
many of these are described in standard organic chemistry texts
such as: Larock, Richard C., Comprehensive organic transformations
: a guide to functional group preparations 2nd ed. New York:
Wiley-VCH, 1999. One preferred method is the use of silver nitrate
or silver oxide in a solvent such as aqueous or anhydrous methanol
at a temperature of .about.25.degree. C. or as high as reflux. The
reaction is typically carried out for one to 48 h and is typically
monitored by TLC or LC/MS until complete conversion of product to
starting material has occurred. Alternatively, KmnO.sub.4 or
CrO.sub.3/H.sub.2SO.sub.4 could be utilized. 61
[0554] Scheme 25 gives a specific example of the oxidation of an
aldehyde intermediate, 70a, to provide the carboxylic acid
intermediate, 69a. 62
[0555] Alternatively, intermediate 69 can be prepared by the
nitrile method of synthesis carried out in an alternative order as
shown in Scheme 26. The nitrile hydrolyis step can be delayed and
the nitrile carried through the synthesis to provide a nitrile
which can be hydrolyzed to provide the free acid, 69, as above. 63
64
[0556] Step H. The direct conversion of nitriles, such as 72, to
amides, such as 73, shown in Scheme 27, Step H, can be carried out
using the conditions as described in Shiotani, S.; Taniguchi, K.;
J. Heterocycl. Chem. 1996, 33(4), 1051-1056 (describes the use of
aqueous sulfuric acid); Memoli, K. A.; Tetrahedron Lett. 1996,
37(21), 3617-3618; Adolfsson, H.; Waemmark, K.; Moberg, C.; J. Org.
Chem. 1994, 59(8), 2004-2009; and El Hadri, A.; Leclerc, G.; J.
Heterocycl. Chem. 1993, 30(3), 631-635. Step I. For NH2
[0557] Shiotani, S.; Taniguchi, K.; J. Heterocycl. Chem. 1997,
34(2), 493-499; Boogaard, A. T.; Pandit, U. K.; Koomen, G.-J.;
Tetrahedron 1994, 50(8), 2551-2560; Rivalle, C.; Bisagni, E.;
Heterocycles 1994, 38(2), 391-397; Macor, J. E.; Post, R.; Ryan,
K.; J. Heterocycl. Chem. 1992,29(6), 1465-1467.
[0558] Step J. 65
[0559] The following scheme (28A) shows an example for the
preparation of 4-fluoro-7substituted azaindoles from a known
starting materials. References for the Bartoli indole synthesis
were mentioned earlier. The conditions for tranformation to the
nitrites, acids, aldeheydes, heterocycles and amides have also been
described in this application. 66 67
[0560] Steps a16, a17, and a18 encompasses reactions and conditions
for 1.sup.0, 2.sup.0 and 3.sup.0 amide bond formation as shown in
Schemes 28 and 29 which provide compounds such as those of Formula
73.
[0561] The reaction conditions for the formation of amide bonds
encompass any reagents that generate a reactive intermediate for
activation of the carboxylic acid to amide formation, for example
(but not limited to), acyl halide, from carbodiimide, acyl iminium
salt, symmetrical anhydrides, mixed anhydrides (including
phosphonic/phosphinic mixed anhydrides), active esters (including
silyl ester, methyl ester and thioester), acyl carbonate, acyl
azide, acyl sulfonate and acyloxy N-phosphonium salt. The reaction
of the indole carboxylic acids with amines to form amides may be
mediated by standard amide bond forming conditions described in the
art. Some examples for amide bond formation are listed in
references 41-53 but this list is not limiting. Some carboxylic
acid to amine coupling reagents which are applicable are EDC,
Diisopropylcarbodiimide or other carbodiimides, PyBop
(benzotriazolyloxytris(dimethylamino) phosphonium
hexafluorophosphate), 2-(1H-benzotriazole-1-yl)-1, 1, 3,
3-tetramethyl uranium hexafluorophosphate (HBTU). A particularly
useful method for azaindole 7-carboxylic acid to amide reactions is
the use of carbonyl imidazole as the coupling reagent as described
in reference 53. The temperature of this reaction may be lower than
in the cited reference , from 80.degree. C. (or possibly lower) to
150.degree. C. or higher. A more specific application is depicted
in Scheme 30. 68
[0562] The following four general methods provide a more detailed
description for the preparation of indolecarboamides and these
methods were employed for the synthesis of compounds of Formula
I.
[0563] Method 1:
[0564] To a mixture of an acid intermediate, such as 69, (1 equiv.,
0.48 mmol), an appropriate amine (4 equiv.) and DMAP (58 mg, 0.47
mmol) dissolved CH.sub.2Cl.sub.2 (1 mL) was added EDC (90 mg, 0.47
mmol). The resulting mixture was shaken at rt for 12 h, and then
evaporated in vacuo. The residue was dissolved in MeOH, and
subjected to preparative reverse phase HPLC purification.
[0565] Method 2:
[0566] To a mixture of an appropriate amine (4 equiv.) and HOBT (16
mg, 0.12 mmol) in THF (0.5 mL) was added an acid intermediate, such
as 69, (25 mg, 0.06 mmol) and NMM (50 .mu.l, 0.45 mmol), followed
by EDC (23 mg, 0.12 mmol). The reaction mixture was shaken at rt
for 12 h. The volatiles were evaporated in vacuo; and the residue
dissolved in MeOH and subjected to preparative reverse phase HPLC
purification.
[0567] Method 3:
[0568] To a mixture of an acid intermediate, such as 69, (0.047
mmol), amine (4 equiv.) and DEPBT (prepared according to Li, H.;
Jiang, X. Ye, Y.; Fan, C.; Todd, R.; Goodman, M. Organic Letters
1999, 1, 91; 21 mg, 0.071 mmol) in DMF (0.5 mL) was added TEA (0.03
mL, 0.22 mmol). The resulting mixture was shaken at rt for 12 h;
and then diluted with MeOH (2 mL) and purified by preparative
reverse phase HPLC.
[0569] Method 4:
[0570] A mixture of an acid intermediate, such as 69, (0.047 mmol)
and 8.5 mg (0.052 mmol) of 1,1-carbonyldiimidazole in anhydrous THF
(2 mL) was heated to reflux under nitrogen. After 2.5 h, 0.052 mmol
of amine was added and heating continued. After an additional
period of 3.about.20 h at reflux, the reaction mixture was cooled
and concentrated in vacuo. The residue was purified by
chromatography on silica gel to provide a compound of Formula
I.
[0571] In addition, the carboxylic acid may be converted to an acid
chloride using reagents such as thionyl chloride (neat or in an
inert solvent) or oxalyl chloride in a solvent such as benzene,
toluene, THF, or CH.sub.2Cl.sub.2. The amides may alternatively, be
formed by reaction of the acid chloride with an excess of ammonia,
primary, or secondary amine in an inert solvent such as benzene,
toluene, THF, or CH.sub.2Cl.sub.2 or with stoichiometric amounts of
amines in the presence of a tertiary amine such as triethylamine or
a base such as pyridine or 2,6-lutidine. Alternatively, the acid
chloride may be reacted with an amine under basic conditions
(Usually sodium or potassium hydroxide) in solvent mixtures
containing water and possibly a miscible co solvent such as dioxane
or THF. Scheme 25B depicts a typical preparation of an acid
chloride and derivatization to an amide of Formula I. Additionally,
the carboxylic acid may be converted to an ester preferably a
methyl or ethyl ester and then reacted with an amine. The ester may
be formed by reaction with diazomethane or alternatively
trimethylsilyl diazomethane using standard conditions which are
well known in the art. References and procedures for using these or
other ester forming reactions can be found in reference 52 or
54.
[0572] Additional references for the formation of amides from acids
are: Norman, M. H.; Navas, F. III; Thompson, J. B.; Rigdon, G. C.;
J. Med. Chem. 1996, 39(24), 4692-4703; Hong, F.; Pang, Y.-P.;
Cusack, B.; Richelson, E.; J. Chem. Soc., Perkin Trans 1 1997, 14,
2083-2088; Langry, K. C.; Org. Prep. Proc. Int. 1994, 26(4),
429-438; Romero, D. L.; Morge, R. A.; Biles, C.; Berrios-Pena, N.;
May, P. D.; Palmer, J. R.; Johnson, P. D.; Smith, H. W.; Busso, M.;
Tan, C.-K.; Voorman, R. L.; Reusser, F.; Althaus, I. W.; Downey, K.
M.; et al.; J. Med. Chem. 1994, 37(7), 999-1014; Bhattacharjee, A.;
Mukhopadhyay, R.; Bhattacharjya, A.; Indian J. Chem., Sect B 1994,
33(7), 679-682. 69
[0573] Scheme 31 shows synthetic transformations on a chloro nitro
azaindole. Step F-1 of Scheme 31 can be carried may be carried out
according to the following procedures: Yamaguchi, S.; Yoshida, M.;
Miyajima, I.; Araki, T.; Hirai, Y.; J. Heterocycl. Chem. 1995,
32(5), 1517-1519;
[0574] Yutilov, Y. M.; Svertilova, I. A.; Khim Geterotsikl Soedin
1994, 8, 1071-1075; and Prager, R. H.; Tsopelas, C.; Heisler, T.;
Aust. J. Chem. 1991, 44(2), 277-285. Step F-2 of Scheme 31 may be
accomplished according to the procedures set forth in: Ciurla, H.;
Puszko, A.; Khim Geterotsikl Soedin 1996, 10, 1366-1371; Robinson,
R. P.; Donahue, K. M.; Son, P. S.; Wagy, S. D.; J. Heterocycl.
Chem. 1996, 33(2), 287-293; Nicolai, E.; Claude, S.; Teulon, J. M.;
J. Heterocycl. Chem. 1994, 31(1), 73-75; Hwu, J. R.; Wong, F. F.;
Shiao, M.-J.; J. Org. Chem. 1992, 57(19), 5254-5255; Shiao, M.-J.;
Lai, L.-L.; Ku, W.-S.; Lin, P.-Y.; Hwu, J. R.; J. Org. Chem. 1993,
58(17), 4742-4744.
[0575] The introduction of an alkoxy or aryloxy substituent onto
the azaindole (Step G, Scheme 31, R.sub.2 is alkoxy or aryloxy) may
be accomplished by the f procedures described in Klemm, L. H.;
Zell, R.; J. Heterocycl. Chem. 1968, 5, 773; Bradsher, C. K.;
Brown, F. C.; Porter, H. K.; J. Am. Chem. Soc. 1954, 76, 2357; and
Hodgson, H. H.; Foster, C. K.; J. Chem. Soc. 1942, 581.
[0576] The introduction of a fluorine substituent onto the
azaindole (Step G, Scheme 31) may be accomplished according to the
procedures as described in Sanchez, J. P.; Gogliotti, R. D.; J.
Heterocycl. Chem. 1993, 30(4), 855-859; Rocca, P.; Marsais, F.;
Godard, A.; Queguiner, G.; Tetrahedron Lett. 1993, 34(18),
2937-2940; and Sanchez, J. P.; Rogowski, J. W.; J. Heterocycl.
Chem. 1987, 24, 215.
[0577] The introduction of a chlorine substituent onto the
azaindole (Step G, Scheme 31) may be accomplished according to the
procedures as described in Ciurla, H.; Puszko, A.; Khim Geterotsikl
Soedin 1996, 10, 1366-1371; Raveglia, L. F.; Giardinal, G. A. M.;
Grugni, M.; Rigolio, R.; Farina, C.; J. Heterocycl. Chem. 1997,
34(2), 557-5 59; Matsumoto, J. I.; Miyamoto, T.; Minamida, A.;
Mishimura, Y.; Egawa, H.; Mishimura, H.; J. Med. Chem. 1984, 27(3),
292; Lee, T.-C.; Salemnick, G.; J. Org. Chem. 1975, 24, 3608.
[0578] The introduction of a bromine substituent onto the azaindole
(Step G, Scheme 31) may be accomplished according to the procedures
as described in Raveglia, L. F.; Giardina, G. A. M.; Grugni, M.;
Rigolio, R.; Farina, C.; J. Heterocycl. Chem. 1997, 34(2), 557-559;
Talik, T.; Talik, Z.; Ban-Oganowska, H.; Synthesis 1974, 293;
Abramovitch, R. A.; Saha, M.; Can. J. Chem. 1966, 44, 1765.
[0579] It is well known in the art that heterocycles may be
prepared from an aldehyde, carboxylic acid, carboxylic acid ester,
carboxylic acid amide, carboxylic acid halide, or cyano moiety or
attached to another carbon substituted by a bromide or other
leaving group such as a triflate, mesylate, chloride, iodide, or
phosponate. The methods for preparing such intermediates from
intermediates typified by the carboxylic acid intermediate, 69,
bromo intermediate, 76, or aldehyde intermediate, 70 described
above are known by a typical chemist practitioner. The methods or
types of heterocycles which may be constructed are described in the
chemical literature. Some representative references for finding
such heterocycles and their construction are included in reference
55 through 67 but should in no way be construed as limiting.
However, examination of these references shows that many versatile
methods are available for synthesizing diversely substituted
heterocycles and it is apparent to one skilled in the art that
these can be applied to prepare compounds of Formula I. Chemists
well versed in the art can now easily, quickly, and routinely find
numerous reactions for preparing heterocycles, amides, oximes or
other substituents from the above mentioned starting materials by
searching for reactions or preparations using a conventional
electronic database such as Scifinder (American Chemical Society),
Crossfire (Beilstein), Theilheimer, or Reaccs (MDS). The reaction
conditions identified by such a search can then be employed using
the substrates described in this application to produce all of the
compounds envisioned and covered by this invention. In the case of
amides, commercially available amines can be used in the synthesis.
Alternatively, the above mentioned search programs can be used to
locate literature preparations of known amines or procedures to
synthesize new amines. These procedures are then carried out by one
with typical skill in the art to provide the compounds of Formula I
for use as antiviral agents.
[0580] As shown below in Scheme 32, step a13, suitable substituted
azaindoles, such as the bromoazaindole intermediate, 76, may
undergo metal mediated couplings with aryl groups, heterocycles, or
vinyl stannanes to provide compounds of Formula I wherein R.sub.5
is aryl, heteroaryl, or heteroalicyclic for example. The
bromoazaindole intermediates, 76 (or azaindole triflates or
iodides) may undergo Stille-type coupling with heteroarylstannanes
as shown in Scheme 32, step a13. Conditions for this reaction are
well known in the art and references 68-70 as well as reference 52
provide numerous conditions in addition to the specific examples
provided in Scheme 14 and in the specific embodiments. It can be
well recognized that an indole stannane could also couple to a
heterocyclic or aryl halide or triflate to construct compounds of
Formula I. Suzuki coupling (reference 71) between the bromo
intermediate, 76, and a suitable boronate could also be employed
and some specific examples are contained in this application. 70
71
[0581] As shown in Scheme 34, step a14, aldehyde intermediates, 70,
may be used to generate numerous compounds of Formula I. The
aldehyde group may be a precursor for any of the substituents RI
through R.sub.5 but the transformation for R.sub.5 is depicted
above for simplicity. The aldehyde intermediate 70, may be reacted
to become incorporated into a ring as 72
[0582] described in the claims or be converted into an acyclic
group. The aldehyde, 70, may be reacted with a Tosmic based reagent
to generate oxazoles (references 42 and 43 for example). The
aldehyde, 70, may be reacted with a Tosmic reagent and than an
amine to give imidazoles as in reference 72 or the aldehyde
intermediate, 70, may be reacted with hydroxylamine to give an
oxime which is a compound of Formula I as described below.
Oxidation of the oxime with NBS, t-butyl hypochlorite, or the other
known reagents would provide the N-oxide which react with alkynes
or 3 alkoxy vinyl esters to give isoxazoles of varying
substitution. Reaction of the aldehyde intermediate 70, with the
known reagent, 77 (reference 70) shown below under basic conditions
would provide 4-aminotrityl oxazoles. 73
[0583] Removal of the trityl group would provide 4-amino oxazoles
which could be substitutued by acylation, reductive alkylation or
alkylation reactions or heterocycle forming reactions. The trityl
could be replaced with an alternate protecting group such as a
monomethoxy trityl, CBZ, benzyl, or appropriate silyl group if
desired. Reference 73 demonstrates the preparation of oxazoles
containing a triflouoromethyl moiety and the conditions described
therein demonstrates the synthesis of oxazoles with fluorinated
methyl groups appended to them.
[0584] The aldehyde could also be reacted with a metal or Grignard
(alkyl, aryl, or heteroaryl) to generate secondary alcohols. These
would be efficacious or could be oxidized to the ketone with TPAP
or MnO.sub.2 or PCC for example to provide ketones of Formula I
which could be utilized for treatment or reacted with metal
reagents to give tertiary alcohols or alternatively converted to
oximes by reaction with hydroxylamine hydrochlorides in ethanolic
solvents. Alternatively the aldehyde could be converted to benzyl
amines via reductive amination. An example of oxazole formation via
a Tosmic reagent is shown below in Scheme 35. The same reaction
would work with aldehydes at other positions and also in the 5 and
6 aza indole series. 74
[0585] Scheme 36 shows in step a15, a cyano intermediate, such as
62, which could be directly converted to compounds of Formula I via
heterocycle formation or reaction with organometallic reagents.
75
[0586] Scheme 37 shows a method for acylation of a cyanoindole
intermediate of formula 65 with oxalyl chloride which would give
acid chloride, 79, which could then be coupled with the appropriate
amine in the presence of base to provide 80. 76
[0587] The nitrile intermediate, 80, could be converted to the
tetrazole of formula 81, which could then be alkylated with
trimethylsilyldiazometh- ane to give the compound of formula 82
(Scheme 38). 77
[0588] Tetrazole alkylation with alkyl halides would be carried out
prior to azaindole acylation as shown in Scheme 39. Intermediate 65
could be converted to tetrazole, 83, which could be alkylated to
provide 84. Intermediate 84 could then be acylated and hydrolyzed
to provide 85 which could be subjected to amide formation
conditions to provide 86. The group appended to the tetrazole may
be quite diverse and still exhibit impressive potency. 78
[0589] Scheme 40 shows that an oxadiazole such as, 88, may be
prepared by the addition of hydroxylamine to the nitrile, 80,
followed by ring closure of intermediate 87 with phosgene.
Alkylation of oxadiazole, 88, with trimethylsilyldiazomethane would
give the compound of formula 89. 79
[0590] A 7-cyanoindole, such as 80, could be efficiently converted
to the imidate ester under conventional Pinner conditions using
1,4-dioxane as the solvent. The imidate ester can be reacted with
nitrogen, oxygen and sulfur nucleophiles to provide C7-substituted
indoles, for example: imidazolines, benzimidazoles,
azabenzimidazoles, oxazolines, oxadiazoles, thiazolines, triazoles,
pyrimidines and arnidines etc. For example the imidate may be
reacted with acetyl hydrazide with heating in a nonparticipating
solvent such as dioxane, THF, or benzene for example. (aqueous base
or aqueous base in an alcoholic solvent may need to be added to
effect final dehydrative cyclization in some cases) to form a
methyl triazine. Other hydrazines can be used. Triazines can also
be installed via coupling of stannyl triazines with 4,5,6, or
7-bromo or chloro azaindoles. The examples give an example of the
formation of many of these heterocycles.
[0591] References:
[0592] (1) Das, B. P.; Boykin, D. W. J. Med. Chem. 1977, 20,
531.
[0593] (2) Czarny, A.; Wilson, W. D.; Boykin, D. W. J. Heterocyclic
Chem. 1996, 33, 1393.
[0594] (3) Francesconi, I.; Wilson, W. D.; Tanious, F. A.; Hall, J.
E.; Bender, B. C.;
[0595] Tidwell, R. R.; McCurdy, D.; Boykin, D. W. J. Med. Chem.
1999, 42, 2260.
[0596] Scheme 41 shows addition of either hydroxylamine or
hydroxylamine acetic acid to aldehyde intermediate 90 may give
oximes of Formula 91. 80
[0597] An acid may be a precursor for substituents RI through
R.sub.5 when it occupies the corresponding position such as R.sub.5
as shown in Scheme 42. 8182 83
[0598] An acid intermediate, such as 69, may be used as a versatile
precursor to generate numerous substituted compounds. The acid
could be converted to hydrazonyl bromide and then a pyrazole via
reference 74. One method for general heterocycle synthesis would be
to convert the acid to an alpha bromo ketone (ref 75) by conversion
to the acid chloride using standard methods, reaction with
diazomethane, and finally reaction with HBr. The alpha bromo ketone
could be used to prepare many different compounds of Formula I as
it can be converted to many heterocycles or other compounds of
Formula I. Alpha amino ketones can be prepared by displacement of
the bromide with amines. Alternatively, the alpha bromo ketone
could be used to prepare heterocycles not available directly from
the aldeheyde or acid. For example, using the conditions of Hulton
in reference 76 to react with the alpha bromo ketone would provide
oxazoles. Reaction of the alpha bromoketone with urea via the
methods of reference 77 would provide 2-amino oxazoles. The alpha
bromoketone could also be used to generate furans using beta keto
esters(ref 78-80) or other methods, pyrroles (from beta dicarbonyls
as in ref 81 or by Hantsch methods (ref 82) thiazoles, isoxazoles
and imidazoles (ref 83) example using literature procedures.
Coupling of the aforementioned acid chloride with N-methyl0-methyl
hydroxyl amine would provide a "Weinreb Amide"which could be used
to react with alkyl lithiums or Grignard reagents to generate
ketones. Reaction of the Weinreb anion with a dianion of a hydroxyl
amine would generate isoxazoles (ref 84). Reaction with an
acetylenic lithium or other carbanion would generate alkynyl indole
ketones. Reaction of this alkynyl intermediate with diazomethane or
other diazo compounds would give pyrazoles (ref 85). Reaction with
azide or hydroxyl amine would give heterocycles after elimination
of water. Nitrile oxides would react with the alkynyl ketone to
give isoxazoles (ref 86). Reaction of the initial acid to provide
an acid chloride using for example oxalyl chloride or thionyl
chloride or triphenyl phosphine/carbon tetrachloride provides a
useful intermediate as noted above. Reaction of the acid chloride
with an alpha ester substituted isocyanide and base would give
2-substituted oxazoles (ref 87). These could be converted to
amines, alcohols, or halides using standard reductions or
Hoffman/Curtius type rearrangements.
[0599] Scheme 43 describes alternate chemistry for installing the
oxoacetyl piperazine moiety onto the 3 position of the azaindoles.
Step A'" in Scheme 43 depicts reaction with formaldehyde and
dimethylamine using the conditions in Frydman, B.; Despuy, M. E.;
Rapoport, H.; J. Am. Chem. Soc. 1965, 87, 3530 will provide the
dimethylamino compound shown.
[0600] Step B'" shows displacement with potassium cyanide would
provide the cyano derivative according to the method described in
Miyashita, K.; Kondoh, K.; Tsuchiya, K.; Miyabe, H.; Imanishi, T.;
Chem. Pharm. Bull. 1997, 45(5), 932-935 or in Kawase, M.;
Sinhababu, A. K.; Borchardt, R. T.; Chem. Pharm. Bull. 1990,
38(11), 2939-2946. The same transformation could also be carried
out using TMSCN and a tetrabutylammonium flouride source as in
Iwao, M.; Motoi, O.; Tetrahedron Lett. 1995, 36(33), 5929-5932.
Sodium cyanide could also be utilized. 84
[0601] Step C'" of Scheme 43 depicts hydrolysis of the nitrile with
sodium hydroxide and methanol would provide the acid via the
methods described in Iwao, M.; Motoi, O.; Tetrahedron Lett. 1995,
36(33), 5929-5932 for example. Other basic hydrolysis conditions
using either NaOH or KOH as described in Thesing, J.; et al.; Chem.
Ber. 1955, 88, 1295 and Geissman, T. A.; Armen, A.; J. Am. Chem.
Soc. 1952, 74, 3916. The use of a nitrilase enzyme to achieve the
same transformation is described by Klempier N, de Raadt A, Griengl
H, Heinisch G, J. Heterocycl. Chem., 1992 29, 93, and may be
applicable.
[0602] Step D'" of Scheme 43 depicts an alpha hydroxylation which
may be accomplished by methods as described in Hanessian, S.; Wang,
W.; Gai, Y.; Tetrahedron Lett. 1996, 37(42), 7477-7480; Robinson,
R. A.; Clark, J. S.; Holmes, A. B.; J. Am. Chem. Soc. 1993,
115(22), 10400-10401 (KN(TMS).sub.2 and then
camphorsulfonyloxaziridine or another oxaziridine; andDavis, F. A.;
Reddy, R. T.; Reddy, R. E.; J. Org. Chem. 1992, 57(24),
6387-6389.
[0603] Step E'" of Scheme 43 shows methods for the oxidation of the
alpha hydroxy ester to the ketone which may be accomplished
according to the methods described in Mohand, S. A.; Levina, A.;
Muzart, J.; Synth. Comm. 1995, 25 (14), 2051-2059. A preferred
method for step E'" is that of Ma, Z.; Bobbitt, J. M.; J. Org.
Chem. 1991, 56(21), 6110-6114 which utilizes 4-(NH-Ac)-TEMPO in a
solvent such as CH.sub.2Cl.sub.2 in the presence of para
toluenesulfonic acid. The method described in Corson, B. B.; Dodge,
R. A.; Harris, S. A.; Hazen, R. K.; Org. Synth. 1941, I, 241 for
the oxidation of the alpha hydroxy ester to the ketone uses
KmnO.sub.4 as oxidant. Other methods for the oxidation of the alpha
hydroxy ester to the ketone include those described in Hunaeus,;
Zincke,; Ber. Dtsch Chem. Ges. 1877, 10, 1489; Acree,; Am. Chem.
1913, 50, 391; and Claisen,; Ber. Dtsch. Chem. Ges. 1877, 10,
846.
[0604] Step F'" of Scheme 43 depicts the coupling reactions which
may be carried out as described previously in the application and
by a preferred method which is described in Li, H.; Jiang, X.; Ye,
Y.-H.; Fan, C.; Romoff, T.; Goodman, M. Organic Lett., 1999, 1,
91-93 and employs
3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT); a
new coupling reagent with remarkable resistance to racemization.
85
[0605] Scheme 44 depicts the preparation of Formula I compounds by
coupling HWC(O)A to the acid as described in Step F'" of Scheme 43,
followed by hydroxylation as in Step D'" of Scheme 43 and oxidation
as described in Step E'" of Scheme 43. 86
[0606] Scheme 45 depicts a method for the preparation which could
be used to obtain amido compounds of Formula I. Step G' represents
ester hydrolysis followed by amide formation (Step H' as described
in Step F'" of Scheme 43). Step I' of Scheme 45 depicts the
preparation of the N-oxide which could be accomplished according to
the procedures in Suzuki, H.; Iwata, C.; Sakurai, K.; Tokumoto, K.;
Takahashi, H.; Hanada, M.; Yokoyama, Y.; Murakami, Y.; Tetrahedron
1997, 53(5), 1593-1606; Suzuki, H.; Yokoyama, Y.; Miyagi, C.;
Murakami, Y.; Chem. Pharm. Bull. 1991, 39(8), 2170-2172; and
Ohmato, T.; Koike, K.; Sakamoto, Y.; Chem. Pharm. Bull. 1981, 29,
390. Cyanation of the N-oxide is shown in Step J' of Scheme 45
which may be accomplished according to Suzuki, H.; Iwata, C.;
Sakurai, K.; Tokumoto, K.; Takahashi, H.; Hanada, M.; Yokoyama, Y.;
Murakami, Y.; Tetrahedron 1997, 53(5), 1593-1606 and Suzuki, H.;
Yokoyama, Y.; Miyagi, C.; Murakami, Y.; Chem. Pharm. Bull. 1991,
39(8), 2170-2172. Hydrolysis of the nitrile to the acid is depicted
in Step K' of Scheme 45 according to procedures such as Shiotani,
S.; Tanigucchi, K.; J. Heterocycl. Chem. 1996, 33(4), 1051-1056;
Memoli, K. A.; Tetrahedron Lett. 1996, 37(21), 3617-3618;
Adolfsson, H.; Waermmark, K.; Moberg, C.; J. Org. Chem. 1994,
59(8), 2004-2009; and El Hadri, A.; Leclerc, G.; J. Heterocycl.
Chem. 1993, 30(3), 631-635. Step L' of Scheme 45 depicts a method
which could be utilized for the preparation of amido compounds of
Formula I from the cyano derivative which may be accomplished
according to procedures described in Shiotani, S.; Taniguchi, K.;
J. Heterocycl. Chem. 1997, 34(2), 493-499; Boogaard, A. T.; Pandit,
U. K.; Koomen, G.-J.; Tetrahedron 1994, 50(8), 2551-2560; Rivalle,
C.; Bisagni, E.; Heterocycles 1994, 38(2), 391-397; and Macor, J.
E.; Post, R.; Ryan, K.; J. Heterocycl. Chem. 1992, 29(6),
1465-1467. Step M' of Scheme 45 shows a method which could be used
for the preparation of amido compounds of Formula I from the acid
derivative which may be accomplished according to procedures
described in Norman, M. H.; Navas, F. III; Thompson, J. B.; Rigdon,
G. C.; J. Med. Chem. 1996, 39(24), 4692-4703; Hong, F.; Pang,
Y.-P.; Cusack, B.; Richelson, E.; J. Chem. Soc., Perkin Trans 1
1997, 14, 2083-2088; Langry, K. C.; Org. Prep. Proced. Int. 1994,
26(4)j 429-438; Romero, D. L.; Morge, R. A.; Biles, C.;
Berrios-Pena, N.; May, P. D.; Palmer, J. R.; Johnson, P. D.; Smith,
H. W.; Busso, M.; Tan, C.-K.; Voorman, R. L.; Reusser, F.; Althaus,
I. W.; Downey, K. M.; et al.; J. Med. Chem. 1994, 37(7), 999-1014
and Bhattacharjee, A.; Mukhopadhyay, R.; Bhattacharjya, A.; Indian
J. Chem., Sect B 1994, 33(7), 679-682. 87
[0607] Scheme 46 shows a method which could be used for the
synthesis of an azaindole acetic acid derivative. Protection of the
amine group could be effected by treatment with
di-tert-butyldicarbonate to introduce the t-Butoxycarbonyl (BOC)
group. Introduction of the oxalate moiety may then be accomplished
as shown in Step A of Scheme 46 according to the procedures
described in Hewawasam, P.; Meanwell, N. A.; Tetrahedron Lett.
1994, 35(40), 7303-7306 (using t-Buli, or s-buli, THF); or
Stanetty, P.; Koller, H.; Mihovilovic, M.; J. Org. Chem. 1992,
57(25), 6833-6837 (using t-Buli). The intermediate thus formed
could then be cyclized to form the azaindole as shown in Step B of
Scheme 46 according to the procedures described in Fuerstner, A.;
Ernst, A.; Krause, H.; Ptock, A.; Tetrahedron 1996, 52(21),
7329-7344 (using. TiCl3, Zn, DME); or Fuerstner, A.; Hupperts, A.;
J. Am. Chem. Soc. 1995, 117(16), 4468-4475 (using Zn, excess
Tms-Cl, TiCl3 (cat.), MeCN). 88
[0608] Scheme 47 describes an alternate synthesis which could be
used to prepare azaindole acetic acid derivatives. Step C of Scheme
47 could be accomplished by using the procedures described in
Harden, F. A.; Quinn, R. J.; Scammells, P. J.; J. Med. Chem. 1991,
34(9), 2892-2898 [use of 1. NaNO.sub.2, conc. HCl 2. SnCl.sub.2,
conc. HCl (cat.)]. Typically, 10 equivalents of NaNO.sub.2 and 1.0
equivalents of substrate reacted at 0.degree. C. for 0.25 to 1 h
and to this reaction mixture was added 3.5 equivalents of
SnCl.sub.2. Alternatively, the procedure described in De Roos, K.
B.; Salemink, C. A.; Recl. Trav. Chim. Pays-Bas 1971, 90, 1181 (use
of NaNO.sub.2, AcOH, H.sub.2O) could be used. The intermediate thus
formed could be further reacted and cyclized to provide azaindole
acetic acid derivatives as shown in Step D of Scheme 47 and
according to the procedures described in Atkinson, C. M.; Mattocks,
A. R.; J. Chem. Soc. 1957, 3722; Ain Khan, M.; Ferreira Da Rocha,
J.; Heterocycles 1978, 9, 1617; Fusco, R.; Sannicolo, F.;
Tetrahedron 1980, 36, 161[use of HCl (conc)]; Abramovitch, R. A.;
Spenser, I. D.; Adv. Heterocycl. Chem. 1964, 3, 79 (use of
ZnCl.sub.2, p-Cymene); and Clemo, G. R.; Holt, R. J. W.; J. Chem.
Soc. 1953, 1313; (use of ZnCl.sub.2, EtOH, Sealed tube). 89
[0609] Scheme 48 depicts another possible route to azaindole acetic
acid derivatives. Step E of Scheme 48 could be carried out as shown
or according to procedures such as those described in Yurovskaya,
M. A.; Khamlova, I. G.; Nesterov, V. N.; Shishkin, O. V.;
Struchkov, T.; Khim Geterotsikl Soedin 1995, 11, 1543-1550;
Grzegozek, M.; Wozniak, M.; Baranski, A.; Van Der Plas, H. C.; J.
Heterocycl. Chem. 1991, 28(4), 1075-1077 (use of NaOH, DMSO);
Lawrence, N. J.; Liddle, J.; Jackson, D. A.; Tetrahedron Lett.
1995, 36(46), 8477-8480 (use of. NaH, DMSO); Haglund, O.; Nilsson,
M.; Synthesis 1994, 3, 242-244; (use of 2.5 equiv. CuCl, 3.5 equiv.
TBu-OK, DME, Py); Makosza, M.; Sienkiewicz, K.; Wojciechowski, K.;
Synthesis 1990, 9, 850-852; (use of KO-tBu, DMF); Makosza, M.;
Nizamov, S.; Org. Prep. Proceed. Int. 1997, 29(6), 707-710; (use of
tBu-OK, THF). Step F of Scheme 48 shows the cyclization reaction
which could provide the azaindole acetic acid derivatives. This
reaction could be accomplished according to procedures such as
those described in Frydman, B.; Baldain, G.; Repetto, J. C.; J.
Org. Chem. 1973, 38, 1824 (use of H.sub.2, Pd-C, EtOH);
Bistryakova, I. D.; Smimova, N. M.; Safonova, T. S.; Khim
Geterotsikl Soedin 1993, 6, 800-803 (use of H.sub.2, Pd-C (cat.),
MeOH); Taga, M.; Ohtsuka, H.; Inoue, I.; Kawaguchi, T.; Nomura, S.;
Yamada, K.; Date, T.; Hiramatsu, H.; Sato, Y.; Heterocycles 1996,
42(1), 251-263 (use of SnCl.sub.2, HCl, Et.sub.2O); Arcari, M.;
Aveta, R.; Brandt, A.; Cecchetelli, L.; Corsi, G. B.; Dirella, M.;
Gazz. Chim. Ital. 1991, 121(11), 499-504 [use of
Na.sub.2S.sub.2O.sub.6, THF/EtOH/H.sub.2O(2:2:1)]; Moody, C. J.;
Rahimtoola, K. F.; J. Chem. Soc., Perkin Trans 1 1990, 673 (use of
TiCl.sub.3, NH.sub.4O ac, acetone, H.sub.2O).
[0610] Scheme 49 provides another route to azaindole intermediates
which could then be further elaborated to provide compounds of
Formula I, such as the amido derivatives shown. Steps G" and H" of
Scheme 49 may be carried out according to the procedures described
in Takahashi, K.; Shibasaki, K.; Ogura, K.; Iida, H.; Chem. Lett.
1983, 859; and Itoh, N.; Chem. Pharm. Bull. 1962, 10, 55.
Elaboration of the intermediate to the amido compound of Formula I
could be accomplished as previously described for Steps I'-M' of
Scheme 45. 90
[0611] Scheme 50 shows the preparation of azaindole oxalic acid
derivatives. The starting materials in Scheme 50 may be prepared
according to Tetrahedron Lett. 1995, 36, 2389-2392. Steps A', B',
C', and D' of Scheme 50 may be carried out according to procedures
described in Jones, R. A.; Pastor, J.; Siro, J.; Voro, T. N.;
Tetrahedron 1997, 53(2), 479-486; and Singh, S. K.; Dekhane, M.; Le
Hyaric, M.; Potier, P.; Dodd, R. H.; Heterocycles 1997, 44(1),
379-391. Step E' of Scheme 50 could be carried out according to the
procedures described in Suzuki, H.; Iwata, C.; Sakurai, K.;
Tokumoto, K.; Takahashi, H.; Hanada, M.; Yokoyama, Y.; Murakami,
Y.; Tetrahedron 1997, 53(5), 1593-1606; Suzuki, H.; Yokoyama, Y.;
Miyagi, C.; Murakami, Y.; Chem. Phanm. Bull. 1991, 39(8),
2170-2172; Hagen, T. J.; Narayanan, K.; Names, J.; Cook, J. M.; J.
Org. Chem. 1989, 54, 2170; Murakami, Y.; Yokoyama, Y.; Watanabe,
T.; Aoki, C.; et al.; Heterocycles 1987, 26, 875; and Hagen, T. J.;
Cook, J. M.; Tetrahedron Lett. 1988, 29(20), 2421. Step F' of
Scheme 50 shows the conversion of the phenol to a fluoro, chloro or
bromo derivative. Conversion of the phenol to the fluoro derivative
could be carried out according to procedures described in Christe,
K. O.; Pavlath, A. E.; J. Org. Chem. 1965, 30, 3170; Murakami, Y.;
Aoyama, Y.; Nakanishi, S.; Chem. Lett. 1976, 857; Christe, K. O.;
Pavlath, A. E.; J. Org. Chem. 1965, 30, 4104; and Christe, K. O.;
Pavlath, A. E.; J. Org. Chem. 1966, 31, 559. Conversion of the
phenol to the chloro derivative could be carried out according to
procedures described in Wright, S. W.; Org. Prep. Proc. Int. 1997,
29(1), 128-131; Hartmann, H.; Schulze, M.; Guenther, R.; Dyes Pigm
1991, 16(2), 119-136; Bay, E.; Bak, D. A.; Timony, P. E.;
Leone-Bay, A.; J. Org. Chem. 1990, 55, 3415; Hoffmann, H.; et al.;
Chem. Ber. 1962, 95, 523; and Vanallan, J. A.; Reynolds, G. A.; J.
Org. Chem. 1963, 28, 1022. Conversion of the phenol to the bromo
derivative may be carried out according to procedures described in
Katritzky, A. R.; Li, J.; Stevens, C. V.; Ager, D. J.; Org. Prep.
Proc. Int. 1994, 26(4), 439-444; Judice, J. K.; Keipert, S. J.;
Cram, D. J.; J. Chem. Soc., Chem. Commun. 1993, 17, 1323-1325;
Schaeffer, J. P.; Higgins, J.; J. Org. Chem. 1967, 32, 1607; Wiley,
G. A.; Hershkowitz, R. L.; Rein, R. M.; Chung, B. C.; J. Am. Chem.
Soc. 1964, 86, 964; and Tayaka, H.; Akutagawa, S.; Noyori, R.; Org.
Syn. 1988, 67, 20. 91
[0612] Scheme 51 describes methods for the preparation of azaindole
acetic acid derivatives by the same methods employed for the
preparation of azaindole oxalic acid derivatives as shown and
described in Scheme 50 above. The starting material employed in
Scheme 51 could be prepared according to J. Org. Chem. 1999, 64,
7788-7801. Steps Ay', B', C', D', and E' of Scheme 51 could be
carried out in the same fashion as previously described for Steps
Steps A', B', C', D', and E' of Scheme 50. 92
[0613] The remaining schemes provide additional background,
examples, and conditions for carrying out this invention. Specific
methods for preparing W and modifying A are presented. As shown in
Scheme 52, the azaindoles may be treated with oxalyl chloride in
either THF or ether to afford the desired glyoxyl chlorides
according to literature procedures (Lingens, F.; Lange, J. Justus
Liebigs Ann. Chem. 1970, 738, 46-53). The intermediate glyoxyl
chlorides may be coupled with benzoyl piperazines (Desai, M.;
Watthey, J. W. Org. Prep. Proc. Int. 1976, 8, 85-86) under basic
conditions to afford compounds of Formula I directly. 93
[0614] Alternatively, Scheme 52 treatment of the
azaindole-3-glyoxyl chloride, (Scheme 52) with tert-butyl
1-piperazinecarboxylate affords the piperazine coupled product. It
is apparent to one skilled in the art that use of an alternative
Boc protected piperazine which are synthesized as shown below would
provide compounds of formula I with alternative groups of formula
W. As discussed earlier, other amine protecting groups which do not
require acidic deprotection conditions could be utilized if
desired. Deprotection of the Boc group is effected with 20%
TFA/CH.sub.2Cl.sub.2 to yield the free piperazine. This product is
then coupled with carboxylic acid in the presence of polymer
supported 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (PEDC) to
afford products of Formula I. This sequence provides a general
method for synthesizing compounds of varied A in formula I. 94
[0615] An example for preparing compounds of Formula I which
possess substituents in A (or other parts of the molecule) which
might interfere with the standard reaction schemes reactions is
shown in Scheme 53. The piperazine derivative (Scheme 53) was
treated with Boc-protected aminobenzoic acid in the presence of EDC
to afford the piperazine diamide. A portion of the resulting
product was separated and subjected to TFA in order to remove the
Boc group, thus yielding amino derivatives. 95
[0616] Similarly, substituents which possess a reactive alcohol can
be incorporated as below. The piperazine derivative (Scheme 54) was
treated with acetoxybenzoic acid in the presence of EDC to afford
the piperazine diamide derivative. A portion of the resulting
product was separated and subjected to LiOH hydrolysis in order to
remove the acetate group, thus yielding hydroxy derivatives.
[0617] Examples containing substituted piperazines are prepared
using the general procedures outlined in Schemes 55-38. Substituted
piperazines are either commercially available from Aldrich, Co. or
prepared according to literature procedures (Behun et al, Ref.
88(a), Scheme 31, eq. 01). Hydrogenation of alkyl substituted
pyrazines under 40 to 50 psi pressure in EtOH afforded substituted
piperazines. When the substituent was an ester or amide, the
pyrazine systems could be partially reduced to the
tetrahydropyrazine (Rossen et al, Ref. 88(b), Scheme 55, eq. 02).
The carbonyl substituted piperazines could be obtained under the
same conditions described above by using commercially available
dibenzyl piperazines (Scheme 55, eq. 03). 96
[0618] 2-Trifluoromethylpiperazine (Jenneskens et al., Ref. 88c)
was prepared through a four step route (Scheme 56). Using Lewis
acid TiCl.sub.4, N,N'-dibenzylethylenediamine reacted with
trifluoropyruvates to afford the hemiacetal, which was reduced at
room temperature by Et.sub.3SiH in TFA to afford the lactam.
LiAlH.sub.4 treatment then reduced the lactam to
1,4-dibenzyl-2-trifluoromethylpiperazine. Finally, hydrogenation of
the dibenzyl-2-trifluoromethylpiperazine in HOAc gave the desired
product, 2trifluoromethylpiperazine. 97
[0619] Mono-benzoylation of symmetric substituted piperazines could
be achieved by using one of the following procedures (Scheme 57).
(a) Treatment of a solution of piperazine in acetic acid with
acetyl chloride afforded the desired mon-benzoylated piperazine
(Desai et al. Ref. 27, Scheme 57, eq. 04). (b) Symmetric
piperazines were treated with 2 equivalents of n-butyllithium,
followed by the addition of benzoyl chloride at room temperature
(Wang et al, Ref. 89, Scheme 57, eq. 05). 98
[0620] Mono-benzoylation of unsymmetric substituted piperazines
could be achieved by using one of the following procedures (Scheme
57), in which all the methods were exemplified by mono-alkyl
substituted piperazines. (a) Unsymmetric piperazines were treated
with 2 equivalents of n-butyllithium, followed by the addition of
benzoyl chloride at room temperature to afford a mixture of two
regioisomers, which could be separated by chromatography (Wang et
al, Ref. 89 and 90(b), Scheme 58 eq. 06); (b) Benzoic acid was
converted to its pentafluorophenyl ester, and then further reaction
with 2-alkylpiperazine to provide the monobenzoylpiperazines with
the benzoyl group at the less hindered nitrogen (Adamczyk et al,
Ref. 90(a), Scheme 58, eq. 07); (c) A mixture of piperazine and
methyl benzoate was treated with dialkylaluminum chloride in
methylene chloride for 2-4 days to yield the mono-benzoylpiperazine
with the benzoyl group at the less hindered nitrogen (Scheme 58 eq.
08); (d) Unsymmetric piperazines were treated with 2 equivalents of
n-butyllithium, followed by subsequent addition of triethylsilyl
chloride and benzoyl chloride in THF at room temperature to afford
mono-benzoylpiperazines with the benzoyl group at the more hindered
nitrogen (Wang et al, Ref. 90(b), Scheme 58, eq. 09). When the
substituent at position 2 was a ester or amide, the
mono-benzoylation with benzoyl chloride occurred at the less
hindered nitrogen of the piperazine with triethylamine as base in
THF (Scheme 58, eq. 10). 99
[0621] In the case of tetrahydropyrazines (Scheme 59, eq. 11),
mono-benzoylation occurred at the more hindered nitrogen under the
same conditions as those in equation 10 of Scheme 58, in the well
precedented manner. (Rossen et al, Ref. 88(b)). 100
[0622] Furthermore, the ester group can be selectively reduced by
NaBH.sub.4 in the presence of the benzamide (Masuzawa et al, Ref.
91), which is shown in Scheme 60. 101
[0623] The ester groups on either the piperazine linkers or on the
azaindole nucleus could be hydrolyzed to the corresponding acid
under basic conditions such as K.sub.2CO3 (Scheme 61, eq. 13) or
NaOMe (Scheme 61, eq. 14) as bases in MeOH and water. 102
[0624] Reaction of an azaindole glyoxyl chloride with substituted
benzoyl piperazines or tetrahydropyrazines in CH.sub.2Cl.sub.2
using I-Pr.sub.2Net as base afforded the coupled products as shown
in Scheme 62. 103
[0625] In the case of coupling reactions using
3-hydroxylmethyl-benzoylpip- erazine, the hydroxyl group was
temporarily protected as its TMS ether with BSTFA
(N,O-bistrimethylsilyl)trifluoroacetamide) (Furber et al, Ref. 92).
The unprotected nitrogen atom can then be reacted with glyoxyl
chlorides to form the desired diamides. During workup, the TMS
masking group was removed to give free hydroxylmethylpiperazine
diamides as shown in Scheme 63. 104
[0626] Piperazine intermediates were prepared using standard
chemistry as shown in Scheme 64. 105 106
[0627] Scheme 65 depicts some more specific methodology for
preparing 5-azindoles for use in prpeartion of the claimed
compounds. Some reductive cyclizations conditions include Fe in
acetic acid, Tin II chloride in aq HCl, or Zinc powder in acetic
acid. Hydrogenation condititons or other conditions used in
LeimGruber-Batch indole synthesis sequences can alo be employed.
107
[0628] Tautomers of nitrogen containing heterocycles are covered by
this patent application. For example, a hydroxy pyrazine is also
known to represent its corresponding tautomer as well as shown in
Scheme 66. 108
[0629] Scheme 67-74 provides some nonlimiting methodology for the
preparation of substituted pyrazines which can be incorporated into
substituents of compounds of claim 1, particularly as part of
R.sup.4. It should be noted that the nomenclature in these schemes
does not coincide with that of the claims but rather shows examples
of methods which can be used to prepare pieces which make up the
compounds of the claims. Thus R.sub.1 and R.sub.2 in these schemes
does not refer to the RI and R.sub.2 in the claims but for example
refers to chemically compatible groups which might be envisioned by
chemists skilled in the art and which can be utilized to prepare
compounds of the claims. 109110 111 112113 114115 116117 118 119
120
[0630] Throughout the chemistry discussion, chemical
transformations which are well known in the art have been
discussed. The average practioner in the art knows these
transformations well and a comprehensive list of useful conditions
for nearly all the transformations is available to organic chemists
and this list is contained in reference 52 authored by Larock and
is incorporated in its entirety for the synthesis of compounds of
Formula I.
[0631] Schemes 75-78 provide more specific examples of the general
synthesis described in Scheme 1. The examples describe the
synthesis of compounds of the invention in which the piperazine of
group W contains a substituent on the ring at a position next to
the nitrogen which comprises part of the amide attached to group A.
While other substitution patterns are important aspects of the
invention, we have found that compounds with a single group
adjacent to the amide attached to group A may have metabolic
stability advantages in humans and yet retain exceptional antiviral
properties. The specific substituted piperazines described in
Schemes 75-78 may be prepared as described in reference 90(b) or as
described for intermediates 17a-d in the experimental section. In
schemes 75 and 76 the most preferred groups for R.sub.9 and
R.sub.11, are C1-C6 alkyl groups. As shown in schemes 77 and 78 the
most preferred groups are methyl. As shown in schemes 75-78, the
compounds may be single isomers or enantiomers or may be used as a
racemic mixture or mixture of isomers. Preferred groups A as shown
in the schems 75-78 are the same as those described for the
invention. Most preferred groups A are 2-pyridyl or phenyl. In
Schemes 75 and 77, the most preferred groups for R.sub.2 are
methoxy, halogen, or hydrogen. In schemes 75-76 the most preferred
group for R1 and R3 is hydrogen. In scheme 76 the most preferred
group for R2 is hydrogen. In schemes 75-78, the most preferred
groups for R4 are phenyl, substituted phenyl, heteroaryl,
substituted heteroaryl, --C(O)NH2, --C(O)NHMe, or C(O)heteroaryl.
Most preferred substituents on the substituted aryl or heteroaryl
are methyl, amino, halogen, C(O)NHMe, COOH, COOMe, COOEt, or benzyl
but this list should not be construed to be rate limiting as the R4
position is extremely tolerant of broad substitution. Particular
groups at R4 of definite impotance are triazole, oxadiazole,
oxazole, pyrazole, pyrazine, pyrimidine, tetrazole, and phenyl but
should not be construed as limiting. 121 122 123 124
[0632] Schemes 79 provides examples and typical conditions for
forming intermediates 2 which contain an oxadiazole or substituted
oxadiazole. These intermediates can be converted to compounds of
claim 1 via the standard methodology described in Scheme 1 and the
rest of the application. An alternate sequence is shown in Scheme
79a which utilizes cyano substituted intermediates 5 to generate
the oxadiazoles of claim 1. Specific examples are given in the
experimental section. Other oxadiazole isomers may be prepared via
standard literature methodology. 125 126127
[0633] Scheme 80 is a preferred method for making compounds of
Formula I and Ia where R.sup.2 is fluoro. This is exemplified
specifically in the preparation of compound Example 216. The
synthesis of 2-hydroxy-3-nitro-5-fluoropyridine 5-80 as shown was
carried out generally via the methods of A. Marfat and R. P.
Robinson U.S. Pat. No. 5,811,432 (column 25, example 5) and Nesnow
and Heidleberger (J. Heterocyclic Chem. 1973, 10, pg 779) except
that a number of procedural enhancements were incorporated as noted
in the description of each step. 2-Hydroxy 5-fluoropyridine 4-80 is
also commercially available. The formation of diazonium
tetrafluoroborate salt 2-80 from 5-amino-2-methoxy pyridine 1-80
proceeded in essentially quantitative yield and was isolated via
filtration. The Schiemann reaction provided poor yields of the
desired 2-methoxy-fluoropyridine using the literature conditions
due mainly to significant contamination with 3-fluoro 1-(N)-methyl
pyridone and other byproducts. However, adoption of a procedure
similar to that described in Sanchez, J. P.; Rogowski, J. W.; J
Heterocycl Chem 1987, 24, 215 for a related compound provided very
high yields of essentially clean but volatile 2-methoxy-5-fluoro
pyridine 3-80 as a solution in toluene. In the interest of
expediency, demethylation was achieved on large scale using aqueous
HCl in pressure bottles at 140.degree. C. for 1 hr. Prior to
heating, the toluene solution was stirred with the aq HCl and then
the toluene was removed by decantation. The literature method for
carrying out this step using HBr at 100.degree. C. was also
successful on small scale and had the advantage of avoiding the use
of pressure bottles. Nitration of 4-80 as described by Marfat
provided lower than expected yields so the procedure was modified
slightly, using guidance from A. G. Burton, P. J. Hallis, and A. R.
Katritzky (Tetrahedron Letters 1971, 24, 2211-2212) on the control
of the regiochemistry of nitration of pyridones via modulation of
the acidity of the medium. The chemical yields of
2-hydroxy-3-nitro-5-fluoro pyridine 5-80 were significantly
improved using the procedure described in the experimental section.
Occasionally the product failed to precipitate during workup and
then considerable efforts were necessary to isolate this highly
water soluble compound from the aqueous layer. Using neat excess
POBr.sub.3, compound 5-80 was converted to 2-bromo-3-nitro-5-fluoro
pyridine 6 which could be used without further purification in the
subsequent azaindole forming reaction. Addition of the pyridine 6
to excess vinyl magnesium bromide in THF at low temperature
afforded the desired 4-fluoro-7-bromo-6-azaindol (precursor 5j) in
yields of up to 35% following acidic work up and isolation via
crystallization. A disadvantage of this method is the workup is
difficult due to the large amounts of salts formed as co-products
in the reaction and the low conversion to albeit clean product. The
reaction is also exothermic and thus would require care on larger
scales. Despite the moderate yields, as mentioned above the
reaction proceeds cleanly and provides pure product precursor 5j
without chromatography so it is anticipated that more detailed
studies of this chemistry could result in yield enhancements. A
selective copper/potassium carbonate mediated displacement of the
7-bromo group by commercially available 1,2,3-triazole provided an
approximately 1:1 mixture of triazoles from which the desired 7-80
was isolated via chromatography in 25-35% yields. Copper-bronze
rather than copper powder can also be used to carry out similar
transformations. This reaction must not be allowed to overheat
since concomitant displacement of the fluorine is possible and has
been observed. Acylation occurred most efficiently under conditions
that utilized excess acidic imidazolium chloro aluminate ionic
liquid to provide highly activated glyoxylating reagent (K. S.
Yeung et al. Tetrahedron Lett. 2002, 43, 5793). The acylation of
7-80 usually does not proceed to completion and typically results
in about 75% conversion as measured by LC/MS. An advantage to these
conditions is that the typical next step, ester hydrolysis,
proceeded in situ to provide the desired acid 8-80 which was
isolated directly by precipitation during workup. Coupling of the
piperazine benzamide was found to be cleaner and produced higher
yields of the compound of Example 216 using the depicted HATU based
coupling than with other standard coupling reagents such as EDC or
DEPBT. 128129
[0634] Chemistry
[0635] General:
[0636] Additional preparations of starting materials and precursors
are contained in Wang et. al. U.S. Ser. No. 09/912,710 filed Jul.
25, 2001 (which is a continuation-in-part of U.S. Ser. No.
09/765,189 filed Jan. 18, 2001, abandoned, corresponding to PCT WO
01/62255) which is incorporated by reference.
[0637] Chemistry
[0638] All Liquid Chromatography (LC) data were recorded on a
Shimadzu LC-10 AS liquid chromatograph using a SPD-10 AV UV-Vis
detector with Mass Spectrometry (MS) data determined using a
Micromass Platform for LC in electrospray mode.
3 LC/MS Method (i.e., compound identification) Column A: YMC ODS-A
S7 3.0 .times. 50 mm column Column B: PHX-LUNA C18 4.6 .times. 30
mm column Column C: XTERRA ms C18 4.6 .times. 30 mm column Column
D: YMC ODS-A C18 4.6 .times. 30 mm column Column E: YMC ODS-A C18
4.6 .times. 33 mm column Column F: YMC C18 S5 4.6 .times. 50 mm
column Column G: XTERRA C18 S7 3.0 .times. 50 mm column Column H:
YMC C18 S5 4.6 .times. 33 mm column Column I: YMC ODS-A C18 S7 3.0
.times. 50 mm column Column J: XTERRA C-18 S5 4.6 .times. 50 mm
column Column K: YMC ODS-A C18 4.6 .times. 33 mm column Column L:
Xterra MS C18 5 uM 4.6 .times. 30 mm column Column M: YMC ODS-A C18
S3 4.6 .times. 33 mm column
[0639] Standard LC Run Conditions (used unless otherwise
noted):
4 Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100%
Solvent B
[0640] Solvent A=10% MeOH-90% H.sub.2O-0.1% TFA, Solvent B=90%
MeOH-10% H.sub.2O-0.1% TFA; and R.sub.t in min. Gradient time: 2
minutes
5 Hold time 1 minute Flow rate: 5 mL/min Detector Wavelength: 220
nm Solvent A: 10% MeOH/90% H.sub.2O/0.1% Trifluoroacetic Acid
Solvent B: 10% H.sub.2O/90% MeOH/0.1% Trifluoroacetic Acid
[0641] Alternate LC Run Conditions B:
6 Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100%
Solvent B
[0642] Solvent A=10% MeOH-90% H.sub.2O-0.1% TFA, Solvent B=90%
MeOH-10% H.sub.2O-0. 1% TFA; and Rt in min. Gradient time: 4
minutes
7 Hold time 1 minute Flow rate: 4 mL/min Detector Wavelength: 220
nm Solvent A: 10% MeOH/90% H.sub.2O/0.1% Trifluoroacetic Acid
Solvent B: 10% H.sub.2O/90% MeOH/0.1% Trifluoroacetic Acid
[0643] Compounds purified by preparative HPLC were diluted in MeOH
(1.2 mL) and purified using the following methods on a Shimadzu
LC-10 A automated preparative HPLC system or on a Shimadzu LC-8A
automated preparative HPLC system with detector (SPD-10AV UV-VIS)
wavelength and solvent systems (A and B) the same as above.
[0644] Preparative HPLC Method (i.e., compound purification)
[0645] Purification Method: Initial gradient (40% B, 60% A) ramp to
final gradient (100% B, 0% A) over 20 minutes, hold for 3 minutes
(100% B, 0% A)
8 Solvent A: 10% MeOH/90% H.sub.2O/0.1% Trifluoroacetic Acid
Solvent B: 10% H.sub.2O/90% MeOH/0.1% Trifluoroacetic Acid Column:
YMC C18 S5 20 .times. 100 mm column Detector Wavelength: 220 nm
[0646] Typical Procedures and Characterization of Selected
Examples:
[0647] Preparation of Precursors: 130
[0648] 4-Methoxyphenylboronic acid (24.54 g),
4-chloro-3-nitropyridine hydrochloride (26.24 g),
Pd(Ph.sub.3P).sub.4 (4 g) and K.sub.2CO.sub.3 (111 g) were combined
in DME (500 mL). The reaction was heated to reflux for 10 hours.
After the mixture cooled down to room temperature, it was poured
into saturated aqueous NH.sub.4OAc (500 mL)solution. The aqueous
phase was extracted with EtOAc (3.times.200 mL). The combined
extract was concentrated to give a residue which was purified using
silica gel chromatography (10% to 30% EtOAc/PE) to afford 10.6 g of
Precursor 1, 3-Nitro-4-(4-methoxyphenyl)pyridin MS m/z: (M+H).sup.+
calcd for C.sub.12H.sub.11N.sub.2O.sub.3: 231.08; found 231.02.
HPLC retention time: 1.07 minutes (column B). 131
[0649] 2-methoxy-5-bromo pyridine can be purchased from Aldrich (or
others) or prepared. Oxidation with 1.1 eq of MCPBA in
dichloromethane (20 ml per 10.6 mmol bromide) in the presence of
anhydrous MgSO4 (0.4 g per mL dichloromethane) with stirring from
0.degree. to ambient temperature for approximately 14 h provided
the N-oxide after workup and flash chromatographic purification
over silica gel using a 5% Etoac/Hexane gradient of increasing
EtOAc. The N-oxide (1.6 g) was dissolved in 10 mL 98% sulfuric acid
and cooled to 0.degree.. 10 mL of 69% nitric acid was added and
then allowed to warm to ambient temp with stirring. The reaction
was then heated and stirred at 80.degree. C. for 14 h and then
poured over ice, extracted with dichloromethane, washed with water,
and concentrated to give a yellow solid which was purified by flash
chromatography over Silica gel using 1:1EtOAc/hexane and then a
gradient to provide a yellow crystalline solid: ). .sup.1H NMR
(CDCl3) .delta.8.50 (s, 1H), 7.59 (s, 1H), 4.12 (3H, s). LC MS
showed desired M+H. The N-oxide was reduced by dissolving the
startingmaterial in dichloromethane (0.147M substrate) and cooling
to 0.degree.. A solution of 1.2 eq PCd.sub.3 (0.44M) in
dichloromethane was added slowly to keep the reaction at 0.degree..
Warm to ambient temp and stir for 72 h. Aqueous workup and
concentration provided a yellow solid which could be used in
subsequent reactions or purified by chromatography. Note: a similar
sequence could be used with 2-methoxy-5-chloro-pyridine as starting
material. 132
[0650] Typical procedure for preparing azaindole from
nitropyridine: Preparation of 7-chloro-6-azaindole, Precursor 2a,
is an example of Step A of Scheme 1. 2-chloro-3-nitropyridine (5.0
g, 31.5 mmol) was dissolved in dry THF (200 mL). After the solution
was cooled to -78.degree. C., vinyl magnesium bromide (1.0M in THF,
100 mL) was added dropwise. The reaction temperature was maintained
at -78.degree. C. for 1 h, and then at -20.degree. C. for another
12 h before it was quenched by addition of 20% NH.sub.4Cl aqueous
solution (150 mL). The aqueous phase was extracted with EtOAc
(3.times.150 mL). The combined organic layer was dried over
MgSO.sub.4, filtered and the filtrate was concentrated in vacuo to
give a residue which was purified by silica gel column
chromatography (EtOAc/Hexane, 1/10) to afford 1.5 g (31%) of
7-chloro-6-azaindole, Precursor 2a. .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta.7.84 (d, 1H, J=10.7 Hz), 7.55 (dd, 1H, J=10.9,
5.45 Hz), 6.62 (d, 1H, J=5.54 Hz), 4.89 (s, 1H). MS m/z:
(M+H).sup.+ calcd for C.sub.7H.sub.6ClN.sub.2: 153.02; found
152.93. HPLC retention time: 0.43 minutes (column A). 133
[0651] Precursor 2b, 7-(4-Methoxyphenyl)-4-azaindole, was prepared
by the same method as Precursor 2a starting from
3-Nitro-4-(4-methoxyphenyl)pyri- dine, Precursor 1. MS m/z:
(M+H).sup.+ calcd for C.sub.14H.sub.13N.sub.2O: 225.10; found
225.02. HPLC retention time: 1.39 minutes (column B). 134
[0652] Precursor 2c, 4-bromo-7-chloro-6-azaindole, was prepared by
the same method as Precursor 2a, starting from
2-Chloro-3-nitro-5-bromo-pyrid- ine (available from Aldrich, Co.).
MS m/z: (M+H).sup.+ calcd for C.sub.7H.sub.5BrClN.sub.2: 230.93;
found 231.15. HPLC retention time: 1.62 minutes (column B). 135
[0653] Precursor 2d, 4-fluoro-7-chloro-6-azaindole (above), was
prepared according to the following scheme: 136
[0654] It should be noted that 2-chloro-5-fluoro-3-nitro pyridine,
zz3', may be prepared by the method in example SB of the reference
Marfat, A.; and Robinson, R. P.; "Azaoxindole Derivatives" U.S.
Pat. No. 5,811,432 1998. The preparation below provides some
details which enhance the yields of this route.
[0655] In Step A, compound zzl' (1.2 g, 0.01 mol) was dissolved in
sulfuric acid (2.7 mL) at room temperature. Premixed fuming nitric
acid (1 mL) and sulfuric acid was added dropwise at 5-10.degree. C.
to the solution of compound zzl'. The reaction mixture was then
heated at 85.degree. C. for 1 hour, then was cooled to room
temperature and poured into ice (20 g). The yellow solid
precipitate was collected by filtration, washed with water and air
dried to provide 1.01 g of compound zz2'.
[0656] In Step B, compound zz2' (500 mg, 3.16 mmol) was dissolved
in phosphorous oxychloride (1.7 mL, 18.9 mmol) and dimethoxyethane
at room temperature. The reaction was heated to 110.degree. C. for
5 hours. The excess phosphorous oxychloride was then removed by
concentrating the reaction mixture in vacuo. The residue was
chromatographed on silica gel, eluted with chloroform (100%) to
afford 176 mg of product zz3'.
[0657] In Step C, compound zz3' (140 mg, 0.79 mmol) was dissolved
in THF (5 mL) and cooled to -78.degree. C. under a nitrogen
atmosphere. To this solution was added dropwise a solution of vinyl
magnesium bromide (1.2 mmol, 1.0 M in diethyl ether, 1.2 mL). The
reaction mixture was then kept at -20.degree. C. for 15 hours. The
reaction mixture was then quenched with saturated ammonium
chloride, and extracted with ethyl acetate. The combined organic
layers were washed with brine, dried over magnesium sulfate,
filtered, and the filtrate was concentrated in vacuo. The residue
was chromatographed on silica to provide 130 mg of precursor 2d
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta.7.78 (s, 1H), 7.60 (d, 1H,
J=3.0 Hz), 6.71 (d, 1H, J=3.05 Hz). MS m/z: (M+H).sup.+ calcd for
C.sub.7H.sub.5ClFN.sub.2: 171.10; found 171.00. HPLC retention
time: 1.22 minutes (column A).
[0658] Precursor 2d, 4-fluoro-7-chloro-6-azaindole, was prepared by
the same method as Precursor 2a, starting from
2-Chloro-3-nitro-5-fluoro-pyri- dine which was prepared according
to the procedure above. Experimental details for this preparation
are contained in Wang et. al. PCT WO 01/62255. .sup.1H NMR (500
MHz, CD.sub.3OD) 67 7.78 (s, 1H), 7.60 (d, 1H, J=3.0 Hz), 6.71 (d,
1H, J=3.05 Hz). MS m/z: (M+H).sup.30 calcd for
C.sub.7H.sub.5ClFN.sub.2: 171.10; found 171.00. HPLC retention
time: 1.22 minutes (column A). 137
[0659] Precursor 2e was prepared by either Method A or Method B,
below:
[0660] Method A: A mixture of 4-bromo-7-chloro-6-azaindole (1 g),
CuI (0.65 g) and NaOMe (4 mL, 25% in methanol) in MeOH (16 mL) was
heated at 110-120.degree. C. for 16 hours in a sealed tube. After
cooling to room temperature, the reaction mixture was neutralized
with 1N HCl to pH 7. The aqueous solution was extracted with EtOAc
(3.times.30 mL). Then the combined organic layer was dried over
MgSO.sub.4, filtered and the filtrate was concentrated in vacuo to
afford a residue, which was purified by using silica gel
chromotography to give 0.3 g of 4-methoxy-7-chloro-6-azaindole,
Precursor 2e. MS m/z: (M+H).sup.+ calcd for
C.sub.8H.sub.8ClN.sub.2O: 183.03; found 183.09. HPLC retention
time: 1.02 minutes (column B).
[0661] Method B : A mixture of 4-bromo-7-chloro-6-azaindole (6 g),
CuBr (3.7 g) and NaOMe (30 mL, 5% in MeOH) was heated at
110.degree. C. for 24 hours in a sealed tube. After cooling to room
temperature, the reaction mixture was added to saturated aqueous
NH4Cl. The resulting aqueous solution was extracted with EtOAc
(3.times.30 mL). The combined organic layer was dried over
MgSO.sub.4, filtered and the filtrate was concentrated in vacuo to
afford a residue, which was purified by using silica gel
chromotography to give 1.8 g of 4-methoxy-7-chloro-6-azaindole- ,
Precursor 2e. 138
[0662] Precursor 2f, 7-bromo-6-azaindole was prepared by the same
method as Precursor 2a, starting from 2-Bromo-3-nitro-pyridine
(available from Aldrich, Co.). MS m/z: (M+H).sup.+ calcd for
C.sub.7H.sub.6BrN.sub.2: 197.97; found 197.01. HPLC retention time:
0.50 minutes (column A). 139
[0663] Precursor 2g, 7-chloro-4-azaindole was prepared by the same
method as Precursor 2a, starting from 4-Chloro-3-nitro-pyridine
(HCl salt, available from Austin Chemical Company, Inc.). MS m/z:
(M+H).sup.+ calcd for C.sub.7H.sub.6ClN.sub.2: 153.02; found
152.90. HPLC retention time: 0.45 minutes (column A). 140
[0664] Precursor 2h, 5-chloro-7-methyl-4-azaindole was prepared by
the same method as Precursor 2a, starting from
2-Chloro-4-methyl-5-nitro-pyri- dine (available from Aldrich, Co.).
MS m/z: (M+H).sup.+ calcd for C.sub.8H.sub.8ClN.sub.2: 167.04;
found 166.99. HPLC retention time: 1.22 minutes (column B). 141
[0665] Precursor 2i, 4-fluoro-7-bromo-6-azaindole, was prepared by
the same method as Precursor 2e, using POBr.sub.3 in the step B
instead of POCl.sub.3. MS m/z: (M+H).sup.+ calcd for
C.sub.7H.sub.5BrFN.sub.2: 214.96; found 214.97. HPLC retention
time: 1.28 minutes (column G). 142
[0666] To a mixture of 5-bromo-2-chloro-3-nitropyridine (10 g, 42
mmol) in 1,4-dioxane (100 ml) was added pyrazole (5.8 g, 85 mmol).
The resulting mixture was stirred at 120.degree. C. for 26.5 h.,
and then evaporated after cooling to r.t. The crude material was
purified by flash chromatography (0 to 5% EtOAc/Hexanes) to give
the desired product 5-Bromo-3-nitro-2-pyrazol-1-yl-pyridine.
.sup.1H NMR: (CD.sub.3OD) .delta.8.77 (s, 1H), 8.56 (s, 1H), 8.45
(s, 1H), 7.73 (s, 1H), 6.57 (s, 1H); LC/MS: (ES.sup.30) m/z
(M+H).sup.+=269, 271, HPLC R.sub.t=1.223.
[0667] To a 250 mL round bottom flask was charged
5-Bromo-3-nitro-2-pyrazo- l-1-ylpyridine (1.02 g, 3.8 mmol) and THF
(30 ml). The mixture was then cooled to 78.degree. C., and added a
THF solution of vinylmagnesium bromide (23 mL, 18.4 mmol, 0.8 M).
After three minutes, the reaction mixture was warmed to -45.degree.
C. and remained stirring for 1 h. The reaction was then quenched
with ammonium chloride, and the resulting mixture extracted with
EtOAc. The combined extracts were evaporated in vacuo, and the
residue purified by flash column chromatography (5% EtOAc/Hexanes)
to give compound 2 (which by HPLC contained about 50% of a side
product, presumably 3-vinylamino of compound 1); .sup.1H NMR:
(CDCl.sub.3) .delta.10.75 (b s, 1H), 8.73 (s, 1H), 8.10 (s, 1H),
7.82 (s, 1H), 7.52 (s, 1H), 6.67 (s, 1H), LC/MS: (ES.sup.30) m/z
(M+H)=262,264; HPLC R.sub.t=1.670. 143
[0668] To a solution of 2-bromo-5-chloro-3-nitropyridine 5 (20 g,
84 mmol, prepared in 2 steps from 2-amino-5-chloropyridine as
described in WO9622990) in THF (300 ml) at -78.degree. C. was
charged a THF solution of vinylmagnesium bromide (280 ml, 252 mmol,
0.9 M). The resulting mixture was stirred at -78.degree. C. for one
hour, followed by quenching with aqueous ammonium chloride (500 ml,
sat.) and extracted with EtOAc (5.times.500 ml). The combined
organic extracts were washed with aqueous ammonium chloride
(2.times.500 ml, sat.) and water (3.times.500 ml), dried
(MgSO.sub.4) and evaporated to give a brownish residue. The crude
material was triturated with CH.sub.2Cl.sub.2, and the solid formed
filtered to give compound 6 as a yellow solid (8.0 g, 41%); .sup.1H
NMR: (DMSO-d.sub.6) 12.30 (b s, 1H), 7.99 (s, 1H), 7.80 (d, J=3.0,
1H), 6.71 (d, J=3.0, 1H); LC/MS: (ES.sup.30) m/z (M+H).sup.+=231,
233, 235; HPLC R.sub.t=1.833. 144
[0669] 4-Fluoro-7-Bromo-6-azaindole (500 mg, 1.74 mmol) was
dissolved in THF (5 ml) and cooled to -78.degree. C. and n-BuLi
(2.5 M, 2.1 ml) was added dropwise. The reaction mixture was
stirred at -78.degree. C. for 15 min, then stirred at 0.degree. C.
for 30 min. The reation was cooled to -78.degree. C. again, and
DMF(0.7 ml, 8.7 mmol) was added. After stirring for 30 min, water
was added to quench the reaction. The reaction mixture was
extracted with ethylacetate. The organic layer was dried over
MgSO.sub.4, filtered, concentrated and chromatographied to afford
208 mg of precursor 2m. LC/MS: (ES.sup.+) m/z (M+H).sup.+=164.98.
R.sub.t=0.44 min. 145
[0670] A mixture of precursor 2m (50 mg, 0.30 mmol), potassium
carbonate (42 mg, 0.30 mmol) and tosylmethyl isocyanide (60 mg,0.30
mmol) in MeOH(3 ml) was heated to reflux for about 2 hr. The
solvent was removed in vacuum and the residue was treated with ice
water and extracted with ether. The organic layer was washed with
an aqueous solution of HCl (2%), water and dried over magnesium
sulfate. After filtration and evaporation of the solvent, the
residue was purified on silica to afford the title compound (60
mg). LC/MS: (ES.sup.30) m/z (M+H).sup.+=204. R.sub.t=0.77 min.
146
[0671] 4-Fluoro-7-Bromo-6-azaindole (510 mg, 2.39 mmol) in
anhydrous DMF (5 mL) was treated with copper cyanide (430 mg, 4.8
mmol) at 150.degree. C. in a seal tube for 1 h. An aqueous solution
of NH.sub.4O H (10 mL) was added and the reaction was extracted
with diethylether (2.times.50 mL) and ethylacetate (2.times.50 mL).
The organic phases were combined and dried over sodium sulfate,
filtered, concentrated in vacuum and chromatographied on silica gel
(gradient elution AcOEt/Hexanes 0-30%) to afford the title compound
as a brownish solid (255 mg, 66%) LC/MS: (ES.sup.30) m/z
(M+H).sup.+=162. 147
[0672] Precursor 2o (82 mg, 0.51 mmol) was dissolved in absolute
ethanol (200% proof, 5 mL) and treated with hydroxylamine
hydrochloride (53 mg, 0.76 mmol) and triethylamine (140 .mu.L, 1.0
mmol) and the reaction mixture was heated up at 80.degree. C. in a
seal tube for 2 h. The solvent was removed in vacuum and the pale
yellow solid residue was washed with water to afford the title
compound. LC/MS: (ES.sup.30) m/z (M+H).sup.+=195. This compound was
taken to the next step without further purification. 148
[0673] Precursor 2p was dissolved in trimethylorthoformate (1 mL)
and heated at 85.degree. C. in a seal tube for 1 h, then it was
cooled to rt, the solvent was removed in vacuum and the residue was
chromatographied on silica gel (AcOEt/Hexanes, gradient elution
10-60%) to afford the title compound (54 mg, LC/MS: (ES.sup.30) m/z
(M+H).sup.+=205). 149
[0674] Precursor 2q (100 mg, 0.62 mmol, crude) in ethanol (5 mL)
was treated with an aqueous solution of sodium hydroxide (50%, 2
mL) and the reaction mixture was heated at 110.degree. C. overnight
in a seal tube. The pH was adjusted to 2 with HCl (6N) and a brown
precipitate was filtered off. The solution was concentrated to
dryness to afford the title compound as a pale yellow solid LC/MS:
(ES.sup.30) m/z (M+H).sup.+=181. This compound was used without
further purification. 150
[0675] Precursor 2r (0.62 mmol) was dissolved in DMF (1 mL) and
treated with 3-aminopyridine (58.3 mg, 0.62 mmol), DEBT (185 mg,
0.62) and Hunig's base (216 .mu.L, 1.26 mmol) and the reaction
mixture was stirred at room temperature for 18 h. Water was added
and the reaction was extracted with AcOEt (2.times.25 mL) and
CHCl.sub.3 (2.times.25 mL), dried over sodium sulfate, concentrated
and chromatographied on silica gel (AcOEt/Hexanes gradient elution
0-50%) to afford the title compound as a brownish solid LC/MS:
(ES.sup.30) m/z (M+H).sup.+=257. 151
[0676] Precursor 2h, 4-methoxy-7-bromo-5-azaindole was prepared by
the same method as Precursor 2a, starting from
2-methoxy-5-bromo-4-nitro-pyri- dine (precursor la). .sup.1H NMR
(CDCl3) .delta.8.52 (s, 1H), 7.84 (s, 1H), 7.12 (t, 1H), 6.68 (d,
1H), 3.99 (s, 3H). LC MS showed desired M+H. 152
[0677] A mixture of aldehyde precursor 2m (150 mg, 0.91 mmol),
sodium cyanide (44 mg, 0.091 mmol) and tosylmethyl isocyanide (177
mg, 0.91 mmol) in EtOH(3 ml) was stirred at room temperature for 30
min, then filtered and the crystals were washed with ether-hexane
(1:1) and dried. The obtained crystals, and a saturated solution of
ammonia in dry methanol (8 ml) were heated between 100-110.degree.
C. for 16 hr. The mixture was concentrated and chromatographed to
provide 20 mg of precursor 2. LC/MS: (ES.sup.30)
m/z(m+H).sup.+=203. Rt=0.64 min. 153
[0678] Typical procedure for acylation of azaindole: Preparation of
Methyl (7-chloro-6-azaindol-3-yl)-oxoacetate, Precursor 3a is an
example of Step B of Scheme 1. 7Chloro-6-azaindole, Precursor 2a
(0.5 g, 3.3 mmol) was added to a suspension of AlCl.sub.3 (2.2 g,
16.3 mmol) in CH.sub.2Cl.sub.2 (100 mL). Stirring was continued at
rt for 10 minutes before methyl chlorooxoacetate (2.0 g, 16.3 mmol)
was added dropwise. The reaction was stirred for 8 h. The reaction
was quenched with iced aqueous NH.sub.4OAc solution (10%, 200 mL).
The aqueous phase was extracted with CH.sub.2Cl.sub.2 (3.times.100
mL). The combined organic layer was dried over MgSO.sub.4, filtered
and the filtrate was concentrated in vacuo to give a residue which
was carried to the next step without further purification.
Precursor 2, Methyl (7-chloro-6-azaindol-3-yl)-oxoacetate: MS m/z:
(M+H).sup.+ calcd for C.sub.10H.sub.8ClN.sub.2O.sub.3: 239.02;
found 238.97. HPLC retention time: 1.07 minutes (column A). 154
[0679] Precursor 3b, Methyl (6-azaindol-3-yl)-oxoacetate, was
prepared by the same method as Precursor 3a, starting from
6-azaindole. MS m/z: (M+H).sup.+ calcd for
C.sub.10H.sub.9N.sub.2O.sub.3: 205.06; found 205.14. HPLC retention
time: 0.49 minutes (column A). 155
[0680] Precursor 3c, Methyl
(7-(4-methoxyphenyl)-4-azaindol-3-yl)-oxoaceta- te, was prepared by
the same method as Precursor 3a, starting from
7-(4-methoxyphenyl)-4-azaindole (Precursor 2b). MS m/z: (M+H).sup.+
calcd for C.sub.17H1.sub.5N.sub.2O.sub.4: 311.10; found 311.04.
HPLC retention time: 1.15 minutes (column A). 156
[0681] Precursor 3d, methyl
(7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetat- e was prepared by
the same method as Precursor 3a, starting from Precursor 2e,
4-methoxy7-chloro-6-azaindole. MS m/z: (M+H).sup.+ calcd for
C.sub.12H.sub.12ClN.sub.2O.sub.4: 283.05; found 283.22. HPLC
retention time: 1.37 minutes (column B). 157
[0682] Precursor 3e, Methyl
(7-chloro-4-fluoro-6-azaindol-3-yl)-oxoacetate was prepared by the
same method as Precursor 3a starting from Precursor 2d,
4-fluoro-7-chloro-6-azaindole.. .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta.8.63 (s, 1H), 8.00 (s, 1H), 3.95 (s, 3H). MS m/z:
(M+H).sup.+ calcd for C.sub.10H.sub.7ClFN.sub.2O.sub.3: 257.01;
found 257.00. HPLC retention time: 1.26 minutes (column A). 158
[0683] Precursor 3f, Methyl (7-chloro-4-azaindol-3-yl)-oxoacetate
was prepared by the same method as Precursor 3a, starting from
Precursor 2g, 7-chloro-4-azaindole. MS m/z: (M+H).sup.+ calcd for
C.sub.10H.sub.8ClN.sub.2O.sub.3: 239.02; found 238.97. HPLC
retention time: 0.60 minutes (column A). 159
[0684] Precursor 3g, Methyl
(5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetate was prepared by the
same method as Precursor 3a, starting from Precursor 2h,
5-chloro-7-methyl-4-azaindole. MS m/z: (M+H).sup.+ calcd for
C.sub.11H.sub.10ClN.sub.2O.sub.3: 253.04; found 252.97. HPLC
retention time: 1.48 minutes (column B). 160
[0685] Typical procedure of hydrolysis of ester: Preparation of
Potassium (7-chloro-6-azaindol-3-yl)-oxoacetate, Precursor 4a, is
an example of Step C of Scheme 1. Crude methyl
(7-chloro-6-azaindol-3-yl)-oxoacetate, Precursor 3a, and an excess
of K.sub.2CO.sub.3 (2 g) were dissolved in MeOH (20 mL) and
H.sub.2O(20 mL). After 8 h, the solution was concentrated and the
residue was purified by silica gel column chromatography to provide
200 mg of Potassium (7-chloro-6-azaindol-3-yl)-- oxoacetate. MS
m/z: (M+H).sup.+ of the corresponding acid was observed. Calc'd for
C.sub.9H.sub.6ClN.sub.2O.sub.3: 225.01; found 225.05. HPLC
retention time: 0.83 minutes (column A). 161
[0686] Potassium (6-azaindol-3-yl)oxoacetate, Precursor 4b, was
prepared by the same method as Precursor 4a, starting from Methyl
(6-azaindol-3-yl)oxoacetate, Precursor 3b. MS m/z: (M+H).sup.+ of
the corresponding acid was observed. Calc'd for
C.sub.9H.sub.7N.sub.2O.sub.3: 191.05; Found 190.99. HPLC retention
time: 0.12 minutes (column A). 162
[0687] Precursor 4c, Potassium
(7-(4-methoxyphenyl)-4-azaindol-3-yl)-oxoac- etate, was prepared by
the same method as Precursor 4a, starting from Methyl
(7-(4-methoxyphenyl)-4-azaindol-3-yl)-oxoacetate, Precursor 3c. MS
m/z: (M-K+H).sup.+ calcd for C.sub.16H.sub.13N.sub.2O.sub.4:
297.07; found 297.04. HPLC retention time: 1.00 minutes (column A).
163
[0688] Precursor 4d, Potassium
(7-chloro-4-methoxy-6-azaindol-3-yl)-oxoace- tate was prepared by
the same method as Precursor 4a starting from Methyl
(7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetate, Precursor 3d. MS
m/z: (M+H).sup.+ of the corresponding acid of compound 4d
(M-K+H).sup.+ calcd for C.sub.10H.sub.8ClN.sub.2O.sub.4: 255.02;
found 255.07. HPLC retention time: 0.74 minutes (column A). 164
[0689] Precursor 4e, Potassium
(7-chloro-4-azaindol-3-yl)-oxoacetate was prepared by the same
method as Precursor 4a, starting from Methyl
(7-chloro-4-azaindol-3-yl)-oxoacetate, Precursor 3f. MS m/z:
(M+H).sup.+ of the corresponding acid of compound 4e (M-K+H).sup.+
calcd for C.sub.9H.sub.6ClN.sub.2O.sub.3: 225.01; found 225.27.
HPLC retention time: 0.33 minutes (column A). 165
[0690] Precursor 4f, Potassium
(5-chloro-7-methyl-4-azaindol-3-yl)-oxoacet- ate was prepared by
the same method as Precursor 4a, starting from Methyl
(5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetate, Precursor 3g. MS
m/z: (M+H).sup.+ of the corresponding acid of compound 4f
(M-K+H).sup.+ calcd for C.sub.10H.sub.8ClN.sub.2O.sub.3: 239.02;
found 238.94. HPLC retention time: 1.24 minutes (column B). 166
[0691] Precursor 4g, Potassium (7-bromo-6-azaindol-3-yl)-oxoacetate
was prepared by the same method as Precursor 4a, starting from
Methyl (7-bromo-6-azaindol-3-yl)-oxoacetate (prepared according to
the method of Precursor 3a from 7-Bromo-6-azaindole, Precursor 2f).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.8.59 (s, 1H), 8.16 (d,
1H, J=5.3 Hz), 8.08 (d, 1H, J=5.45 Hz); .sup.13C NMR (125 MHz,
DMSO-d.sub.6) .delta.180.5, 164.0, 141.6, 140.4, 132.4, 125.3,
115.5, 113.0. 167
[0692] Precursor 4h, Potassium
(7-bromo-4-fluoro-6-azaindol-3-yl)-oxoaceta- te was prepared by the
same method as Precursor 4a, starting from Methyl
(7-bromo-4-fluoro-6-azaindol-3-yl)-oxoacetate (prepared according
to the method of Precursor 3a from 7-Bromo-4-fluoro-6-azaindole,
Precursor 2i). MS m/z: (M+H).sup.+ of the corresponding acid of
compound 4 g (M-K+H).sup.+ calcd for
C.sub.9H.sub.5BrFN.sub.2O.sub.3: 286.95; found 286.94. HPLC
retention time: 0.94 minutes (column A). 168
[0693] 1-ethyl-3-methylimidazolium chloride (0.172 g, 1.1 mmol) was
added to aluminum chloride (0.560 g, 4.2 mmol), and the mixture
vigorously stirred. Upon formation of a liquid, precursor 2j was
added, followed by ethyl chlorooxoacetate (0.12 ml, 1.1 mmol). The
mixture was allowed to stir at r.t. for 16 h, after which
additional chlorooxoacetate was added (0.12 ml, 1.1 mmol).
Following this addition, the reaction was allowed to stir at r.t.
for another 24 h. The flask was cooled to 0.degree. C. and water
added, upon which precipitates were formed. The solid material was
filtered, washed with water and methanol, and dried under high
vacuum to give compound 3; LC/MS: (ES.sup.30) m/z (M+H)=334, 336;
HPLC R.sub.t=1.390. 169
[0694] To 1-ethyl-3-methylimidazolium chloride (2.54 g, 17.3 mmol)
was added aluminum chloride (6.91 g, 51.8 mmol). The mixture was
stirred vigorously at ambient temperature for ten minutes. To the
resulting yellow liquid was added precursor 2k (2.0 g, 8.64 mmol)
and ethyl chlorooxoacetate (2.0 ml, 17.3 mmol), and was stirred at
ambient temperature for 16 h. The reaction mixture was then added
ice/water (300 ml) to give precipitates, which were filtered and
washed with water to give the title compound as a yellow solid
(1.98 g). The aqueous solution was extracted with EtOAc
(3.times.300 ml), and the extracts evaporated in vacuo to give a
second batch of compound 8 as a yellow solid (439 mg, total yield
92%); .sup.1H NMR: (DMSO-d.sub.6) 14.25 (b s, 1H), 13.37 (s, 1H),
8.56 (s, 1H), 8.18 (s, 1H); LC/MS: (ES.sup.+) m/z (M+H).sup.+=303,
305, 307; HPLC R.sub.t=1.360. 170
[0695] 1-Ethyl-3-methylimidazolium chloride (82 mg, 0.56 mmol) was
added to a flask which contained precursor 2n (56 mg, 0.28 mmol)
and the mixture was cooled to 0.degree. C. Aluminum chloride (336
mg, 2.52 mmol) was added in one portion followed by ClCOCOOEt (58
.mu.L, 0.56 mmol) and the reaction mixture was stirred at room
temperature for 2 days. Ice water was added to quench the reaction.
The reaction mixture was filtered. The solid was washed with water
and diethylether and dried in air to afford the title compound (58
mg). LC/MS: (ES.sup.30) m/z (M+H).sup.+=276. Rt=0.85 min. 171
[0696] 1-Ethyl-3-methylimidazolium chloride (73 mg, 0.52 mmol) and
aluminum chloride (198 mg, 1.56 mmol) were stirred together under
nitrogen for 1 h. To this solution was added intemediate 2q (54 mg,
0.26 mmol) and ethyloxalylchloride (58 .mu.L, 0.52 mmol) and the
reaction mixture was stirred at rt for 18 h. The reaction was
quenched with water and the mixture was stirred for 15 min. The
solid was collected by filtration and washed with water and
diethylether. LC/MS (ES.sup.30) m/z (M+H).sup.+=276. This compound
was used without further purification. 172
[0697] 1-Ethyl-3-methylimidazolium chloride (26 mg, 0.18 mmol) was
added to a flask which contained precursor 2t (18 mg, 0.09 mmol)
and the mixture was cooled to 0.degree. C. Aluminum chloride (92
mg, 0.54 mmol) was added in one portion followed by ClCOCOOEt (20
.mu.L, 0.18 mmol) and the reaction mixture was stirred at room
temperature for 2 days. Ice water was added to quench the reaction.
The reaction mixture was filtered. The solid was washed with water
and diethylether and dried in air to afford compound D (18 mg).
LC/MS: (ES.sup.30) m/z(m+H).sup.+=275. Rt=0.49 min. 173
[0698] Typical procedure for coupling piperazine derivative and
azaindole acid: Preparation of
1-benzoyl-3-(R)-methyl-4-[(7-chloro-6-azaindol-3-yl)-
-oxoacetyl]piperazine, Precursor 5, is an example of Step D of
Scheme 1. Potassium 7-chloro-6-azaindole 3-glyoxylate, Precursor
4a, (100 mg, 0.44 mmol), 3-(R)-methyl-1-benzoylpipe (107 mg, 0.44
mol), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one(DEPBT)
(101 mg, 0.44 mol) and Hunig's Base (diisopropylethylamine, 0.5 mL)
were combined in 5 mL of DMF. The mixture was stirred at rt for 8
h. DMF was removed via evaporation at reduced pressure and the
residue was purified using a Shimadzu automated preparative HPLC
System to give
1-(benzoyl)-3-(R)-methyl-4-[(7-chloro-6-azaindol-3-yl)-oxoacetyl]-piperaz-
ine (70 mg, 39%). MS m/z: (M+H).sup.+ Calc'd for
C.sub.21H.sub.20ClN.sub.4- O.sub.3: 411.12; Found 411.06. HPLC
retention time: 1.32 minutes (column A). 174
[0699] Precursor 5b,
1-benzoyl-4-[(7-chloro-4-methoxy-6-azaindol-3-yl)-oxo-
acetyl]piperazine was prepared by the same method as Precursor 5a
starting from Potassium
(7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetate, Precursor 4d, and
1-benzoylpiperazine. MS m/z: (M+H).sup.+ calcd for
C.sub.21H.sub.20C.sub.1N.sub.4O.sub.4: 427.12; found 427.12. HPLC
retention time: 1.28 minutes (column A). 175
[0700] Precursor 5c,
1-benzoyl-3-(R)-methyl-4-[(7-chloro-4-methoxy-6-azain-
dol-3yl)-oxoacetyl]piperzine was prepared by the same method as
Precursor 5a starting from Potassium
(7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetat- e, Precursor 4d,
and 1-benzoylpiperazine. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta.8.10 (s, 1H), 7.72 (s, 1H), 7.40 (s, 5H), 3.89 (s, 3H),
3.71-3.40 (m, 8H). MS m/z: (M+H).sup.+ calcd for
C.sub.22H.sub.22ClN.sub.4O.sub.4: 441.13; found 441.17. HPLC
retention time: 1.33 minutes (column A). 176
[0701] Precursor 5d,
1-benzoyl-3-(R)-methyl-4-[(7-chloro-4-azaindol-3-yl)--
oxoacetyl]piperazine was prepared by the same method as Precursor
5a, starting from Potassium (7-chloro-4-azaindol-3-yl)-oxoacetate,
Precursor 4e, and 1-benzoyl-3-(R)-methyl piperazine. MS m/z:
(M+H).sup.+ calcd for C.sub.21H.sub.20ClN.sub.4O.sub.3 411.12,
found 411.04. HPLC retention time: 1.10 minutes (column A). 177
[0702] Precursor 5e,
1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-methyl-4-azaind-
ol-3-yl)-oxoacetyl]piperazine was prepared by the same method as
Precursor 5a, starting from Potassium
(5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetat- e, Precursor 4f, and
1-benzoyl-3-(R)-methyl piperazine. MS m/z: (M+H).sup.+ calcd for
C.sub.22H.sub.22ClN.sub.4O.sub.3 425.24, found 425.04. HPLC
retention time: 1.72 minutes (column B). 178
[0703] Precursor 5f,
1-benzoyl-3-(R)-methyl-4-[(7-bromo-6-azaindol-3-yl)-o-
xoacetyl]piperazine was prepared by the same method as Precursor
5a, starting from (7-bromo-6-azaindol-3-yl)-oxoacetic acid
potassium salt, Precursor 4g, and 1-benzoyl-3-(R)-methylpiperazine.
MS m/z: (M+H).sup.+ calcd for C.sub.21H.sub.20BrN.sub.4O.sub.3:
455.07; found 455.14. HPLC retention time: 1.45 minutes (column B).
179
[0704] Precursor 5g,
1-benzoyl-4-[(7-bromo-6-azaindol-3-yl)-oxoacetyl]pipe- razine was
prepared by the same method as Precursor 5a, starting from
(7-bromo-6-azaindol-3-yl)-oxoacetic acid potassium salt, Precursor
4g, and 1-benzoylpiperazine. MS m/z: (M+H).sup.+ calcd for
C.sub.20H.sub.18BrN.sub.4O.sub.3: 441.06; found 441.07. HPLC
retention time: 1.43 minutes (column B). 180
[0705] Precursor 5h,
1-benzoyl-3-(R)-methyl-4-[(6-azaindol-3-yl)-oxoacetyl- ]piperazine
was prepared by the same method as Precursor 5a starting from
Potassium (6-azaindol-3-yl)oxoacetate, Precursor 4b, and
1-benzoyl-3-(R)-methylpiperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.21H.sub.21N.sub.4O.sub.3: 377.16; Found 377.10. HPLC
retention time: 0.88 minutes (column A). 181
[0706] Addition of precursor 2d to a solution of aluminum
trichloride in dichloromethane stirring at ambient temperature
followed 30 minutes later with chloromethyl or chloroethyl oxalate
(according to the method described for precursor 3a) provides
either the methyl or ethyl ester, respectively. Hydrolysis with KOH
(as in the standard hydrolysis procedure described for precursor
4a) provided potassium
(7-chloro-4-fluoro-6-azaindol-3-yl)oxoacetate. Potassium
(7-chloro-4-fluoro-6azaindol-3-yl)oxoacetate was then reacted with
1-benzoyl piperazine in the presence of DEPBT under the standard
conditions (as described for precursor 5a) to provide
1benzoyl-4-[(4-fluoro-7-chloro-6-azaindol-3-yl)-oxoacety]piperazine,precu-
rsor 5i. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.8.40 (s, 1H),
8.04 (s, 1H), 7.46 (bs, 5H), 3.80-3.50 (m, 8H); LC/MS (ES.sup.30)
m/z (M+H).sup.+ 415 observed; retention time 1.247 minutes; LC/MS
method: YMC ODS-A C18 S7 3.0.times.50 mm column; Start % B=0, Final
% B=100, Gradient time=2 minutes; Flow rate=5 mL/min; detector
wavelength=220 nm. 182
[0707]
1-benzoyl-3-(R)-methyl-4-[(4-fluoro-7-chloro-6-azaindol-3-yl)-oxoac-
etyl]-piperazine was prepared by coupling potassium
(7-chloro-4-fluoro-6-azaindol-3-yl)oxoacetate, prepared as
described above for precursor 5i, with
1-benzoyl-3-(R)-methylpiperazine in the presence of DEPBT under the
standard conditions (as described for precursor 5a) to provide
1-benzoyl-3-(R);methyl-4-[(4-fluoro-7-chloro-6-a-
zaindol-3-yl)-oxyoacetyl]piperazine, precursor 5j. .sup.1H NMR (500
MHz, CD.sub.3OD) .delta.8.42, 8.37 (s, s, 1H), 8.03 (s, 1H),
7.71-7.45 (m, 5H), 4.72-3.05 (m, 7H), 1.45-1.28 (m, 3H); LC/MS
(ES.sup.30) m/z (M+H).sup.+ 429 observed; retention time 1.297
minutes; LC/MS method: YMC ODS-A C18 S7 3.0.times.50 mm column;
Start % B=0, Final % B =100, Gradient time=2 minutes; Flow rate=5
mL/min; detector wavelength=220 nm. 183
[0708] Precursor 5k,
1-benzoyl-4-[(7-chloro-6-azaindol-3-yl)-oxoacetyl]pip- erazine was
prepared by the same method as Precursor 5a, starting from
(7-chloro-6-azaindol-3-yl)-oxoacetic acid potassium salt, Precursor
4a, and 1-benzoylpiperazine. MS m/z: (M+H).sup.+ calcd for
C.sub.20H1.sub.8ClN.sub.4O.sub.3: 397.11; found 396.97. HPLC
retention time: 2.37 minutes (column F, gradient time=3 min, flow
rate=4 mil/min). 184
[0709] Precursor 51,
1-picolinoyl-4-[(4-methoxy-7-chloro-6-azaindol-3-yl)--
oxoacetyl]piperazine was prepared by the same method as Precursor
5a starting from Potassium
(4-methoxy-7-chloro-6-azaindol-3-yl)oxoacetate, Precursor 4d, and
picolinoyl-piperazine. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta.8.63-7.45 (m, 7H), 3.94 (s, 3H), 3.82-2.50 (m, 8H). MS m/z:
(M+H).sup.+ Calc'd for C.sub.20H.sub.19ClN.sub.5O.sub.4: 428.11;
Found 428.11. HPLC retention time: 1.09 minutes (column A). 185
[0710] Precursor 5m,
(R)-1-picolinoyl-3-methyl-4-[(7-bromo-6-azaindol-3-yl-
)-oxoacetyl]piperazine was prepared by the same method as Precursor
5a starting from Potassium (7-bromo-6-azaindol-3-yl)oxoacetate,
Precursor 4g, and (R)-3-methyl-1-picolinoyl-piperazine. MS m/z:
(M+H).sup.+ Calc'd for C.sub.20H.sub.19BrN.sub.5O.sub.3: 456.07;
Found 456.11. HPLC retention time: 1.12 minutes (column A). 186
[0711] Precursor 5n,
(S)-1-picolinoyl-3-methyl-4-[(7-bromo-6-azaindol-3-yl-
)-oxoacetyl]piperazine was prepared by the same method as Precursor
5a starting from Potassium (7-bromo-6-azaindol-3-yl)oxoacetate,
Precursor 4g, and (S)-3-methyl-1-picolinoyl-piperazine. .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta.8.63-7.36 (m, 7H), 5.02-3.06 (m, 7H),
1.42-1.26 (m, 3H). 187
[0712] Precursor 5o,
(R)-1-picolinoyl-3-methyl-4-[(7-bromo-4-fluoro-6-azai-
ndol-3-yl)oxoacetyl]piperazine was prepared by the same method as
Precursor 5a starting from Potassium
(7-bromo-4-fluoro-6-azaindol-3-yl)ox- oacetate, Precursor 4h, and
(R)-3methyl-1-picolinoyl-piperazine. .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta.8.68-7.52 (m, 6H), 4.94-2.69 (m, 7H), 1.48-1.24
(m, 3H). MS m/z: (M+H).sup.+ Calc'd for C.sub.20H.sub.18BrFN.su-
b.5O.sub.3: 474.06; Found 474.23. HPLC retention time: 1.20 minutes
(column A). 188
[0713] Precursor 5p,
1-benzoyl-4-[(7-chloro-4-azaindol-3-yl)-oxoacetyl]pip- erazine was
prepared by the same method as Precursor 5a starting from Potassium
(7-chloro-4-fluoro-4-azaindol-3-yl)oxoacetate, Precursor 4e, and
1-benzoyl-piperazine. .sup.1H NMR (500 MHz, CD.sub.3OD) 88.83 (s,
1H), 8.63 (d, 1H, J=5.35 Hz), 7.91 (d, 1H, J=5.75 Hz), 7.47 (m,
5H), 3.80-3.30 (m, 3H). MS m/z: (M+H).sup.+ Calc'd for
C.sub.20H.sub.18ClN.sub- .4O.sub.3: 397.11; Found 397.02. HPLC
retention time: 1.20 minutes (column A). 189
[0714] Precursor 5q,
1-(4-Benzoyl-piperazin-1-yl)-2-(7-bromo-1H-pyrrolo[2,-
3-c]pyridin-3-yl)-ethan 1,2-dione To a solution of acid precursor
4j (2.4 g, 7.9 mmol) in DMF (40 ml) was added
3-(diethoxyphosphoryloxy)-1,2,3-ben- zotriazin-4(3H)-one (DEPBT,
5.96 g, 19.9 mmol), benzoylpiperazine hydrochloride (2.71 g, 11.9
mmol), and N,N-diisopropylethylamine (14 ml, 80.4 mmol). The
mixture was stirred at ambient temperature for 16 h. The reaction
mixture was then added water (400 ml) and extracted with EtOAc
(4.times.300 ml). The combined extracts were evaporated in vacuo to
give a brownish residue, which was triturated with MeOH to provide
the title compound as a white solid (2.8 g, 74%); .sup.1H NMR:
(DMSO-d.sub.6) 13.41 (s, 1H), 8.48 (s, 1H), 8.19 (s, 1H), 7.45 (b
s, 5H), 3.80-3.35 (b m, 8H); LC/MS: (ES+) m/z (M+H)+=475, 477, 479;
HPLC (alternate conditions B, column G) R.sub.t=1.953. 190
[0715] Precursor 5r was prepared by procedure used for 5q using
mono N-Boc piperazine. .sup.1H NMR: (CDCl.sub.3) .delta.8.26 (s,
1H), 8.19 (s, 1H), 3.71 (b s, 2H), 3.53 (b m, 6H), 1.48 (s, 9H);
LC/MS: (ES+) m/z (M+H)+=471, 473, 475; HPLC (alternate conditions
B, column G) R.sub.t=1.543. 191
[0716] Precursor 5s was prepared by procedure used for 5b using
mono N-Boc piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.19H.sub.24ClN.sub.4O.sub- .5: 423.14; Found 423.07 HPLC
retention time: 1.44 minutes (column L). 192
[0717] Precursor 5t, was prepared from Precursor 5s and the
pyrazin-2-yl stannane, via the procedure described in the later
section Preparation of Compounds of Formula I. MS m/z: (M+H).sup.+
Calc'd for C.sub.23H.sub.27N.sub.6O.sub.5: 467.20; found 467.47.
HPLC retention time: 1.57 minutes (column C). 193
[0718] Preparation of precursor 5u: Precursor 5t (30 mg) was
dissolved in TFA (0.5 g). After the reaction was stirred for 30
minutes, the mixture was concentrated in vacuo to give the desired
intermediae 5u which was used in further reactions without any
purification. MS m/z: (M+H)+Calc'd for
C.sub.18H.sub.19N.sub.6O.sub.5: 367.15; found 367.06. HPLC
retention time: 0.91 minutes (colurnn M). 194
[0719] Precursor 5v was prepared by procedure used for 5b using
2-methyl-1-picolinoylpiperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.21H.sub.21ClN.sub.5O.sub.4: 442.13; Found 442.11. HPLC
retention time: 1.01 minutes (column G). 195
[0720] Precursor 5xa was prepared by procedure used for 5b using
(R)-2-methyl-1-picolinoylpiperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.21H.sub.21ClN.sub.5O.sub.4: 442.13; Found 442.23. HPLC
retention time: 1.12 minutes (column L). 196
[0721] Precursor 5y was prepared by procedure used for 5b using
(R)-2-methyl-1-nicotinoylpiperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.21H.sub.21ClN.sub.5O.sub.4: 442.13; Found 442.15. HPLC
retention time: 0.87 minutes (column C). 197
[0722] Precursor 5z was prepared by procedure used for 5b using
(R)-2-methyl-1-benzoylpiperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.22H.sub.22ClN.sub.4O.sub.4: 441.13; Found 441.46. HPLC
retention time: 1.27 minutes (column C). 198
[0723] Typical procedure for N-Oxide formation: Preparation of
1-benzoyl-3-(R)-methyl-4-[(6-oxide-6-azaindol-3yl)-oxoacetyl]piperazine,
Precursor 6. 20 mg of
1-benzoyl-3-(R)-methyl-4-[(6-azaindol-3-yl)-oxoacet- yl]piperazine,
Precursor 5h, (0.053 mmol) was dissolved in CH.sub.2Cl.sub.2 (2
mL). 18 mg of mCPBA (0.11 mmol) was then added into the solution
and the reaction was stirred for 12 h at rt. CH.sub.2Cl.sub.2 was
removed via evaporation at reduced pressure and the residue was
purified using a Shimadzu automated preparative HPLC System to give
the compound shown above (5.4 mg, 26%). MS m/z: (M+H).sup.+ Calc'd
for C.sub.21H.sub.21N.sub.4O.sub.4: 393.16; Found 393.11. HPLC
retention time: 0.90 minutes (column A). 199
[0724] Preparation of
1-benzoyl-3-(R)-methyl-4-[(6-methyl-7-azaindol-3-yl)-
-oxoacetyl]-piperazine or
1-benzoyl-3-(R)-methyl-4-[(4-methyl-7-azaindol-3-
-yl)-oxoacetyl]-piperazine. An excess of MeMgI (3M in THF, 0.21 ml,
0.63 mmol) was added into a solution of
1-benzoyl-3-(R)-methyl-4-[(6-oxide-6-a-
zaindol-3-yl)oxoacetyl]piperazine, Precursor 6, (25 mg, 0.064
mmol). The reaction mixture was stirred at rt and then quenched
with MeOH. The solvents were removed under vacuum, the residue was
diluted with MeOH and purified using a Shimadzu automated
preparative HPLC System to give a compound shown above which was a
single isomer but regiochemistry was not definitively assigned.
(6.7 mg, 27%). MS m/z: (M+H).sup.+ Calc'd for
C.sub.22H.sub.23N.sub.4O.sub.3: 391.18; Found 391.17. HPLC
retention time: 1.35 minutes (column B).
Precursor 8
[0725] 200
[0726]
1-benzoyl-3-(R)-methyl-4-[(6-phenyl-7-azaindol-3-yl)-oxoacetyl]pipe-
razine or
1-benzoyl-3-(R)-methyl-4-[(4-phenyl-7-azaindol-3-yl)-oxoacetyl]p-
iperazine (regiochemistry was not definitively assigned) were
prepared by the method described for Example 7 starting with
1-benzoyl-3-(R)-methyl-4-
-[(6-oxide-6-azaindol-3-yl)oxoacetyl]piperazine Precursor 6, and
phenyl magnesium bromide (phenyl Grignard reagent). MS m/z:
(M+H).sup.+ Calc'd for C.sub.27H.sub.25N.sub.4O.sub.3: 453.19;
Found 454.20. HPLC retention time: 1.46 minutes (column B).
Precursor 9
[0727] 201
[0728] A mixture of Pd (10% on carbon, 100 mg), trifluoroacetic
acid (1 mL) and
1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-methyl-4-azaindol-3-yl)-oxo-
acetyl]piperazine, Precursor 5e (1.5 g) in MeOH (50 mL) and EtOAc
(50 mL) was shaken in a Parr reactor under a hydrogen atmosphere
(45 psi) for 48 hours. After solids were removed via filtration,
the filtrate was concentrated in vacuo to afford precursor 9 (1 g)
which was used without further purification. MS m/z: (M+H).sup.+
calcd for C.sub.21H.sub.21N.sub.4O.sub.3 391.18, found 391.15. HPLC
retention time: 1.15 minutes (column A).
Precursors 10 and 11
[0729] 202
[0730] Preparation of Precursor 10,
1-benzoyl-3-(R)-methyl-4-[(5-chloro-7--
carbonyl-4-azaindol-3-yl)-oxoacety]-piperazine and Precursor 11,
1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-hydroxycarbonyl-4-azaindol-3-yl)-ox-
oacety]-piperazine: A mixture of
1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-met-
hyl-4-azaindol-3-yl)-oxoacetyl]piperazine (1.78 g) and SeO.sub.2
(4.7 g) in dioxane/water (100:1) was refluxed for 10 hours. After
cooling to room temperature, the mixture was concentrated in vacuo
to provide a residue. The residue was purified by using silica gel
chromatography with EtOAc and MeOH as eluting solvents to afford
precursor 10 (350 mg) and precursor 11 (410 mg). Precursor 10,
1-benzoyl-3-(R)-methyl-4-[(5-chloro--
7-carbonyl-4-azaindol-3-yl)-oxoacetyl]-piperazin MS m/z:
(M+H).sup.+ calcd for C.sub.22H.sub.20ClN.sub.4O.sub.4: 439.12,
found 439.01. HPLC retention time: 1.37 minutes (column A);
Precursor 11,
1-benzoyl-3-(R)-methyl-4-[(5-chloro-5-7-hydroxycarbonyl-4-azaindol-3-yl)--
oxoacety]-piperazine: MS m/z: (M+H).sup.+ calcd for
C.sub.22H.sub.20ClN.sub.4O.sub.5: 455.11, found 455.10. HPLC reten
time: 1.44 minutes (column A).
Precursors 12 and 13
[0731] 203
[0732] Precursor 12,
1-benzoyl-3-(R)-methyl-4-[(7-carbonyl-4-azaindol-3-yl-
)-oxoacetyl]-piperazine and Precursor 13,
1-benzoyl-3-(R)-methyl-4-[(7-hyd-
roxycarbonyl-4-azaindol-3-yl)-oxoacetyl]-piperazine were made
according to the same procedure of preparing Precursors 10 and 11,
by using Precursor 9 as a starting material. Precursor 12,
1-benzoyl-3-(R)-methyl-4-[(7-carb-
onyl-4-azaindol-3-yl)-oxoacetyl]-piperazine: MS m/z: (M+H).sup.+
calcd for C.sub.22H.sub.21N.sub.4O.sub.4: 405.16, found 405.14.
HPLC retention time: 0.91 minutes (column A); Precursor 13,
1-benzoyl-3-(R)-methyl-4-[(7-
-hydroxycarbonyl-4-azaindol-3-yl)-oxoacetyl]-piperazine: MS m/z:
(M+H).sup.+ calcd for C.sub.22H.sub.21N.sub.4O.sub.5: 421.15, found
421.09. HPLC retention time: 1.02 minutes (column A).
Precursors 14a-1-14a-21
[0733] The following tin agents and boron agents can be purchased
from commercial resources and used without any further treatment
(Table I-1).
9TABLE I-1 Precursor Number Structure Company 14a-1 204 Frontier
Scientific, Inc. 14a-2 205 Maybridge Chem. Co. 14a-3 206 Frontier
Scientific, Inc. 14a-4 207 Matrix Scientific 14a-5 208 Matrix
Scientific 14a-6 209 Aldrich, Co. 14a-7 210 Aldrich, Co. 14a-8 211
Aldrich, Co. 14a-9 212 Aldrich, Co. 14a-10 213 Aldrich, Co. 14a-11
214 Lancaster 14a-12 215 Aldrich, Co. 14a-13 216 Aldrich, Co.
14a-14 217 Frontier Scientific, Inc. 14a-15 218 Matrix Scientific
14a-16 219 Frontier Scientific, Inc. 14a-17 220 Riedel-de Haen AG
14a-18 221 Lancaster 14a-19 222 Lancaster 14a-20 223 Aldrich, Co.
14a-21 224 Frontier Scientific, Inc.
[0734] Preparation of Tin Agents:
Precursors 14-1-14-65
[0735] The following known tin agents and boron agents could be
prepared according to the documented procedures indicated without
any modification (Table I-2):
10TABLE I-2 Precursor Number Structure Reference 14-1 225 Dondoni,
A., et al Synthesis, 1987, 693 14-2 226 Aldous, D. J., et al U.S.
Pat. No. 5,453,433 14-3 227 Sandosham, J., et al Tetrahedron 1994,
50, 275. 14-4 228 Lehn, L. M., et al. Chem. Eur. J. 2000, 6, 4133.
14-5 229 Jutzi, P., et al J. Organometallic Chem. 1983, 246, 163.
14-6 230 Jutzi, P., et al J. Organometallic Chem. 1983, 246, 163.
14-7 231 Graybill, T. L., et al Bioorg. Med. Chem. Lett. 1995,
5(4), 387. 14-8 232 Heldmann, D. K., et al Tetrahedron Lett. 1997,
38, 5791. 14-9 233 Kennedy, G., et al Tetrahedron Lett. 1996, 37,
7611. 14-10 234 Kondo, Y., et al Tetrahedron Lett. 1989, 30, 4249
14-11 235 Kondo, Y., et al Tetrahedron Lett. 1989, 30, 4249 14-12
236 Or, Y. S., et al U.S. Pat. No. 6,054,435 14-13 237 Or, Y. S.,
et al U.S. Pat. No. 6,054,435 14-14 238 Okada, T., et al WO-0123383
14-15 239 Okada, T., et al WO-0123383 14-16 240 Sandosham, J., et
al Tetrahedron 1994, 50, 275 14-17 241 Sandosham, J., et al Acta
Chem. Scand. 1989, 43, 684. 14-18 242 Nicolaou, K. C., et al
WO-9967252 14-19 243 Nicolaou, K. C., et al WO-9967252 14-20 244
Nicolaou, K. C., et al WO-9967252 14-21 245 Benheda, R., et al
Tetrahedron Lett. 1999, 40, 5701. 14-22 246 Collins, I., et al
Tetrahedron Lett. 1999, 40, 4069. 14-23 247 Fuss, R. W., et al
DE-19502178 14-24 248 Bunnage, M. E. et. al PCT Int. Appl. WO
0024745 A1 (2000); and Sandosham, J. et. Al Tetrahedron (1994),
50(1), 275-84. 14-25 249 From 5-iodo2-chloro-1,3 pyrimidine.
Fluoropyrimidines are obtained by fluorination of chloropyrimidines
with CsF in N-methyl-2- pyrrolidinone or DMF 2.5- 63 h at
80-150.degree. C. The iodo is then converted to the lithium reagent
with # tBuLi and trapped with Bu.sub.3SnCl. See Sandosham above.
14-26 250 Arukwe, J.; Benneche, T.; Undheim, K. J. Chem. Soc.,
Perkin Trans. 1 (1989), (2), 255-9. 14-27 251 Fruit, C.; et. al.
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Chem. Pharm. Bull. (1998), 46(3), 400-412. 14-34 258 Hayashi, K.;
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(1993). 14-36 260 Brown, A. D.; Dickinson, R. P.; Wythes, M. J. PCT
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North, P. C.; Wadman, S. N. PCT Int. Appl. WO 9408993 A1 (1994).
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(1994). 14-41 265 Achab, S.; Guyot, M.; Potier, P. Tetrahedron
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Muratake, H.; Tonegawa, M.; Natsume, M. Chem. Pharm. Bull. (1998),
46(3), 400-412. Dolle, R. E.; Graybill, T. L.; Osifo, I. K.;
Harris, A. L.; Miller, M. S.; Gregory, J. S. U.S. Pat. No. 5622967
(1997). 14-47 271 Henze, O.; Lehmann, U.; Schlueter, A. D.
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Gruett, M. D.; Saindane, M. T.; # et al. J. Med. Chem. (1995),
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M. R. Tetrahedron Lett. (1999), 40(3), 557-560. Sirisoma, N. S.;
Johnson, C. R. Tetrahedron Lett. (1998), 39(15), 2059-2062. Trost,
B. M.; Cook, G. R. Tetrahedron Lett. (1996), 37(42), 7485-7488.
14-50 274 Bunnage, M. E.; Maw, G. N.; Rawson, D. J.; Wood, A.;
Mathias, J. P.; Street, S. D. A. PCT Int. Appl. WO 0024745 A1
(2000). 14-51 275 Bunnage, M. E.; Maw, G. N.; Rawson, D. J.; Wood,
A.; Mathias, J. P.; Street, S. D. A. PCT Int. Appl. WO 0024745 A1
(2000). 14-52 276 Hayashi, K.; Kito, T.; Mitsuyama, J.; Yamakawa,
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39(15), 2059-2062. 14-53 277 Schnatterer, S.; Kern, M.; Sanft, U.
PCT Int. Appl. WO 9965901 A1 (1999). 14-54 278 Hayashi, K.; Kito,
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Appl. WO 9951588 A1 (1999). 14-55 279 Betageri, R.; Breitfelder,
S.; Cirillo, P. F.; Gilmore, T. A.; Hickey, E. R.; Kirrane, T. M.;
Moriak, M. H.; Moss, N.; Patel, U. R.; Proudfoot, J. R.; Regan, J.
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Appl. WO 0055139 A2 (2000). 14-56 280 Ueno, K.; Sasaki, A.; Kawano,
K.; Okabe, T.; Kitazawa, N.; Takahashi, K.; Yamamoto, N.; Suzuki,
Y.; Matsunaga, M.; Kubota, A. PCT Int. Appl. WO 9918077 A1 (1999).
14-57 281 Calderwood, D.; Arnold, L. D.; Mazdiyasni, H.; Hirst, G.;
Deng, B. B. PCT Int. Appl. WO 0017202 A1 (2000). 14-58 282 Hayashi,
K.; Kito, T.; Mitsuyama, J.; Yamakawa, T.; Kuroda, H.; Kawafuchi,
H. PCT Int. Appl. WO 9951588 A1 (1999). 14-59 283 Saji, H.;
Watanabe, A.; Magata, Y.; Ohmono, Y.; Kiyono, Y.; Yamada, Y.; Iida,
Y.; Yonekura, H.; Konishi, J.; Yokoyama, A. Chem. Pharm. Bull.
(1997), 45(2), 284-290. 14-60 284 Hayashi, K.; Kito, T.; Mitsuyama,
J.; Yamakawa, T.; Kuroda, H.; Kawafuchi, H. PCT Int. Appl. WO
9951588 A1 (1999); Reuman, M.; Daum, S. J.; Singh, B.; Wentland, M.
P.; Perni, R. B.; Pennock, P.; Carabateas, P. M.; Gruett, M. D.;
Saindane, M. T.; # et al. J. Med. Chem. (1995), 38(14), 2531-40.
14-61 285 Iino, Y.; Fujita, K.; Kodaira, A.; Hatanaka, T.;
Takehana, K.; Kobayashi, T.; Konishi, A.; Yamamoto, T. PCT Int.
Appl. WO 0102359 A1 (2001). 14-62 286 Iino, Y.; Fujita, K.;
Kodaira, A.; Hatanaka, T.; Takehana, K.; Kobayashi, T.; Konishi,
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Torrado, A.; Imperiali, B. J. Org. Chem. (1996), 61(25), 8940-8948.
14-64 288 Iino, Y.; Fujita, K.; Kodaira, A.; Hatanaka, T.;
Takehana, K.; Kobayashi, T.; Konishi, A.; Yamamoto, T. PCT Int.
Appl. WO 0102359 A1 (2001). 14-65 289 Gros, P.; Fort, Y. Synthesis
(1999), (5), 754-756 and Gros, P.; Fort, Y.; Caubere, P. J. Chem.
Soc., Perkin Trans. 1 (1997), (20), 3071-3080.
Precursor 14-66
[0736] 290
[0737] Preparation of 2,3-dicloro-5-(tri-n-butylstannyl)pyrazine
(An example of general procedure Tin-01, below): TMP-Li
(2,2,6,6-tetramethylpiperidinyl lithium) was prepared by addition
of n-butyl lithium (1.6 M, 6.25 mL) to a solution of
2,2,4,4-tetramethylpipe- ridine (1.4 g) in dry THF (180 mL) at
-78.degree. C. The solution was then allowed to warm to 0.degree.
C., was stirred at 0.degree. C. for 15 minutes, then was cooled to
-78.degree. C. To the solution was added 2,3-dichloropyrazine (1.35
g), and followed by an addition of tri-n-butyltin chloride (3.25 g)
in another 2 hours. The reaction was quenched with aqueous ammonium
chloride solution. The organic layer was separated, and aqueous
layer was extracted with ethyl acetate (3.times.100 mL). The
combined organic extract was dried over magnesium sulfate, filtered
and the filtrate 15 concentrated in vacuo. The residue was purified
by silica gel chromatography to afford
2,3-dicloro-5-(tri-n-butylstannyl)pyrazine (1 g).
Precursor 14-67
[0738] 291
[0739] Preparation of 2-(tri-n-butylstannyl)-pyrimidine: (Example
of the general procedure Tin-03, below) Tri-n-butylstannyl lithium
was prepared at 0.degree. C. in dry THF (20 mL) from tri-butyltin
hydride (2.2 mL) and LDA (lithium diisopropylamide, 2M, 4.09 mL).
The tri-n-butylstannyl lithium solution was then cooled to
-78.degree. C. and to it was added 2-bromopyrimidine (1 g). The
reaction mixture was then allowed to warm up to room temperature
over 8 hours. The reaction was then quenched with aqueous ammonium
chloride solution. The organic layer was separated, and aqueous
layer was extracted with ethyl acetate (3.times.20 mL). The
combined organic layer was dried over magnesium sulfate, filtered
and the filtrate concentrated in vacuo. The residue was purified by
silica gel chromatography to afford
2-(tri-n-butylstannyl)-pyrimidine (190 mg).
Precursor 14-68
[0740] 292
[0741] Preparation of 2-amino-6-(tri-n-butylstannyl)pyrazine
(Example of the general procedure Tin-04, below): To a sealed tube,
2-amino-6-chloro-pyrazine (1 g), bis(tri-butyltin) (3.92 mL) and
tetrakis-triphenylphosphine palladium, Pd(Ph.sub.3P).sub.4 (100 mg)
were combined in dioxane (10 mL). The reaction was heated at
110-120.degree. C. for 10 h. After the mixture cooled down to room
temperature, it was poured into 20 mL of water. The solution was
extracted with EtOAc (4.times.20 mL). The combined extract was
concentrated in vacuo to give a residue which was purified by
silica gel chromatography to afford
2-amino-6-(tri-n-butylstannyl)pyrazine (0.5 g)
Precursor 14-69
[0742] 293
[0743] Preparation of
2-methylsulfonylamino-5-(tri-n-butylstannyl)pyrazine (Example of
general procedure Tin-05, below): NaH (60%, 20 mg) was added into a
solution of 2-amino-5-(tri-n-butylstannyl)pyrazine (0.2 g) in THF
(30 mL) at room temperature. After the mixture stirred at room
temperature for 30 minutes, to it was added methylsulfonyl chloride
(63 mg). The reaction mixture was stirred at room temperature over
8 hours. The reaction was quenched with aqueous ammonium chloride
solution. The organic layer was separated, and the aqueous layer
was extracted with ethyl acetate (3.times.100 mL). The combined
organic extract was dried over magnesium sulfate, filtered and the
filtrate was concentrated in vacuo. The residue was purified by
silica gel chromatography to afford
2-methylsulfonylamino-5-(tri-n-butylstannyl)pyrazine (20 mg).
Precursors 14-70-14-129
[0744] The precursors 14-70-14-129 were prepared according to the
following general procedures designated Tin-01 through Tin-05
(Table I-3).
[0745] General Procedure Tin-01: 294
[0746] To a solution of a base (1.1 equivalents) selected from
lithium diisopropylamide, 2,2,6,6-tetramethylpiperidinyl lithium,
n-butyl lithium, sec-butyl lithium or tert-butyl lithium in a
solvent selected from tetrahydrofuran, diethyl ether or
dimethoxyethane (concentration of approximately 0.05 mmol base/mL
of solvent) at -78.degree. C. was added an appropriate aryl or
heteroaryl substrate (1.0 equivalents) followed by an addition of
tri-n-butyltin chloride or trimethyltin chloride (1.1 equivalents)
in another 2 hours. The reaction was quenched with aqueous ammonium
chloride solution. The organic layer was separated, and aqueous
layer was extracted with ethyl acetate. The combined organic
extract was dried over magnesium sulfate, filtered and the filtrate
concentrated in vacuo. The residue was purified by silica gel
chromatography to afford the desired stannane.
[0747] General Procedure Tin-02: 295
[0748] To a solution of a base (1.1 equivalents) selected from
n-butyl lithium, sec-butyl lithium or tert-butyl lithium in a
solvent selected from tetrahydrofuran, diethyl ether or
dimethoxyethane (concentration of approximately 0.05 mmol base/mL
of solvent) at -78.degree. C. was added an appropriate aryl or
heteroaryl bromide or aryl or heteroaryl iodide substrate (1.0
equivalents). The reaction mixture was stirred at -78.degree. C.
for a period suitable to generate the anion via metal-halogen
exchange then to it was added tri-n-butyltin chloride or
trimethyltin chloride (1.1 equivalents). The reaction was quenched
with aqueous ammonium chloride solution. The organic layer was
separated, and aqueous layer was extracted with ethyl acetate. The
combined organic extract was dried over magnesium sulfate, filtered
and the filtrate concentrated in vacuo. The residue was purified by
silica gel chromatography to afford the desired stannane.
[0749] General Procedure Tin-03: 296
[0750] Tri-n-butylstannyl lithium or trimethylstannyl lithium (1.3
equivalents) was prepared at 0.degree. C. in dry solvent selected
from THF, diethyl ether or dimethoxyethane (20 mL) from
tri-n-butyltin hydride or trimethyltin hydride, respectively (1.3
equivalents) and LDA (lithium diisopropylamide, 1.3 equivalents) at
a concentration of approximately 0.4 mmol of alkylstannyl
lithium/mL of solvent. The tri-n-butylstannyl lithium or
trimethylstannyl lithium solution was then cooled to -78.degree. C.
and to it was added an appropriate haloaryl or haloheteroaryl
substrate (1.0 equivalent). The reaction mixture was then allowed
to warm up to room temperature over 8 hours. The reaction was then
quenched with aqueous ammonium chloride solution. The organic layer
was separated, and aqueous layer was extracted with ethyl acetate
(3.times.20 mL). The combined organic layer was dried over
magnesium sulfate, filtered and the filtrate concentrated in vacuo.
The residue was purified by silica gel chromatography to afford the
desired stannane precursor.
[0751] General Procedure Tin-04: 297
[0752] To a sealed tube, an appropriate aryl or heteroaryl
substrate (1.0 equivalent), bis(tri-butyltin) or hexamethylditin
(1.0 equivalent) and tetrakis-triphenylphosphine palladium,
Pd(Ph.sub.3P).sub.4 (1.0 mol%) were combined in dioxane or toluene
(10 mL). The reaction was heated at 110-120.degree. C. for 10 h.
After the mixture cooled down to room temperature, it was poured
into water. The solution was extracted with ethyl acetate and the
combined extracts were concentrated in vacuo to give a residue
which was purified by silica gel chromatography to afford the
desired stannane product.
[0753] General Procedure Tin-05:
[0754] The following general reaction scheme depicts the
derivatization of stannane precursors in which the stannane has a
reactive ring NH group or reactive exocyclic amino, hydroxy or
thiol group. The starting stannane is treated with base in an
appropriate solvent then is reacted with suitable electrophiles
such as alkyl halides, acid chlorides, sulfonyl chlorides,
isocyanates and the like. 298
[0755] An appropriate base selected from sodium hydride, n-butyl
lithium, lithium diisopropylamide, potassium carbonate,
triethylamine, DBU, DMAP or sodium hexamethyldisilazide (1.0
equivalent) was added into a solution of an appropriate stannane
substrate (as depicted above, 1.0 equivalent) in an appropriate
solvent selected from dichloromethane, THF, diethyl ether or
N,N-dimethylformamide at a temperature between -78.degree. C. and
room temperature. After the mixture stirred for a period sufficient
to allow deprotonation, typically for 5 to 30 minutes, then to it
was added an appropriate electrophile such as an alkyl halide, acid
chloride, sulfonyl (1.0 equivalent). The reaction mixture was
stirred, typically at room temperature, over a period of 2 to 8
hours. The reaction was quenched with aqueous ammonium chloride
solution. The organic layer was separated, and the aqueous layer
was extracted with ethyl acetate (3.times.100 mL). The combined
organic extract was dried over magnesium sulfate, filtered and the
filtrate was concentrated in vacuo. The residue was purified by
silica gel chromatography to afford the desired stannane
precursor.
[0756] General Procedure Tin-06 299
[0757] An aryl hilide stannane agent was dissolved in appropriate
alcohol, either methanol or ethanol. After a cataylst (pt or pd)
was added into the solvent, the reaction mixture is placed in an
environment of hydrogen under normal or raised pressure. After
reaction finishes, the catalyst is filtered, and, concentration of
the mother solution provides a residue which is used in the further
reactions without any purification.
11TABLE I-3 Rf = retention time Intermed. Starting Method Number
Structure Material Applied Identification 14-70 300 301 Tin-04
R.sub.f = 2.33 min (Column A) .sup.1H NMR(500 MHz, CDCl3) .delta.
4.00(s, 6H), 1.63-0.85(m, 27H) 14-71 302 303 Tin-01 R.sub.f = 2.52
min (Column A) .sup.1H NMR(300 MHz, CDCl.sub.3) .delta. 7.02(s,
1H), 4.44(q, 2H, J=7.02 Hz), 1.63-0.85(m, 30H) 14-72 304 305 Tin-01
R.sub.f = 2.84 min (Column B) .sup.1H NMR(500 MHz, CDCl3) .delta.
9.48(s, 1H), 8.45(s, 1H), 2.03-0.88(m, 36H) 14-73 306 307 Tin-05
R.sub.f = 2.27 min (Column A) .sup.1H NMR(500 MHz, CDCl.sub.3)
.delta. 7.53(m, 1H), 6.29(m, 1H), 3.94(s, 3H), 1.56-0.87(m, 27H)
14-74 308 309 Tin-05 R.sub.f = 2.22 min (Column A) 14-75 310 311
Tin-01 R.sub.f = 2.44 min (Column B) .sup.1H NMR(500 MHz,
CDCl.sub.3) .delta. 8.89(s, 1H), 8.34(s, 1H), 1.61-0.85(m, 27H)
14-76 312 313 Tin-01 R.sub.f = 3.41 min (Column A, flow rate = 4
ml/min) .sup.1H NMR(300 MHz, CDCl3) .delta. 8.58(d, 1H, J=2.52 Hz),
8.13(d, 1H, J=2.52 Hz), 1.63-0.85(m, 27H) 14-77 314 315 Tin-01
R.sub.f = 3.89 min (Column A, flow rate = 4 ml/min) .sup.1H NMR(300
MHz, CDCl3) .delta. 8.63(s, 1H), 1.61-0.85(m, 27H) 14-78 316 317
Tin-01 R.sub.f = 3.86 min (Column A, flow rate = 4 ml/min) .sup.1H
NMR(300 MHz, CDCl3) .delta. 8.24(s, 1H), 1.61-0.85(m, 27H) 14-79
318 319 Tin-04 R.sub.f = 2.10 min (Column B) .sup.1H NMR(500 MHz,
CDCl3) .delta. 7.90(s, 1H), 7.26(s, 1H), 1.58-0.87(m, 27H) 14-80
320 321 Tin-04 R.sub.f = 1.83 min (Column A) 14-81 322 323 Tin-04
R.sub.f = 1.84 min (Column A) 14-82 324 325 Tin-04 R.sub.f = 1.84
min (Column A) 14-83 326 327 Tin-04 R.sub.f = 1.90 min (Column A)
14-84 328 329 Tin-01 R.sub.f = 2.23 min (Column A) 14-85 330 331
Tin-04 R.sub.f = 1.92 min (Column A) 14-86 332 333 Tin-03 R.sub.f =
2.01 min (Column A) 14-87 334 335 Tin-01 R.sub.f = 2.45 min (Column
A) 14-88 336 337 Tin-01 R.sub.f = 2.67 min (Column C) 14-89 338 339
Tin-01 R.sub.f = 2.31 min (Column C) 14-90 340 341 Tin-04 R.sub.f =
2.71 min (Column D) 14-91 342 343 Tin-01 R.sub.f = 2.49 min (Column
C) 14-92 344 345 Tin-01 R.sub.f = 2.42 min (Column C) 14-93 346 347
Tin-01 R.sub.f = 3.49 min (Column C) Flow Rate = 4 ml/min 14-94 348
349 Tin-01 R.sub.f = 2.46 min (Column C) 14-95 350 351 Tin-05 Rf =
2.15 min (Column A) 14-96 352 353 Tin-01 R.sub.f = 2.28 min (Column
C) 14-97 354 355 Tin-01 R.sub.f = 2.60 min (Column C) 14-98 356 357
Tin-01 R.sub.f = 2.37 min (Column A) 14-99 358 359 Tin-01 R.sub.f =
2.59 min (Column A) 14-100 360 361 Tin-01 R.sub.f = 2.49 min
(Column C) 14-101 362 363 Tin-04 R.sub.f = 2.41 min (Column A)
14-102 364 365 Tin-04 R.sub.f = 1.88 min (Column E) 14-103 366 367
Tin-04 R.sub.f = 1.92 min (Column E) 14-104 368 369 Tin-04 R.sub.f
= 2.01 min (Column E) 14-105 370 371 Tin-04 R.sub.f = 2.15 min
(Column E) 14-106 372 373 Tin-04 R.sub.f = 1.91 min (Column E)
14-107 374 375 Tin-04 Rf = 1.95 min (Column A) 14-108 376 377
Tin-04 Rf = 1.93 min (Column A) 12-109 378 379 Tin-01 Rf = 1.95 min
(Column A) 14-110 380 381 Tin-01 Rf = 1.83 min (Column A) .sup.1H
NMR(500 MHz, CDCl3) .delta. 9.03(d, 1H, J=5.15 Hz), 7.49(d, 1H,
J=7.95 Hz), 7.26(m, 1H), 1.61-0.86(m, 27H); .sup.13C NMR(125 MHz,
CDCl3) .delta. 175.3, 149.8, 133.2, 123.7, 29.0, 27.3, 13.6, 10.1.
14-111 382 383 Tin-01 Rf = 2.18 min (Column E) .sup.1H NMR(500 MHz,
CDCl3) .delta. 9.22(s, 1H), 8.46(d, 1H, J=4.80 Hz), 7.42(d, 1H,
J=4.75 Hz), 1.56-0.86(m, 27H); .sup.13C NMR(125 MHz, CDCl3) .delta.
185.4, 158.0, 153.2, 130.6, 28.9, 27.2, 13.5, 9.9. 14-112 384 385
Tin-04 Rf = 1.96 min (Column A) 14-113 386 387 Tin-01 Rf = 2.61 min
(Column A) 14-114 388 389 Tin-01 Rf = 2.85 min (Column A) 14-115
390 391 Tin-05 Rf = 2.09 min (Column A) .sup.1H NMR(500 MHz, CDCl3)
.delta. 8.12(s, 1H), 7.95(s, 1H), 4.11(s, 1H), 2.95(s, 3H),
2.03-0.85(m, 27H) 14-116 392 393 Tin-05 Rf = 2.16 min (Column A)
.sup.1H NMR(500 MHz, CDCl3) .delta. 8.08(s, 1H), 7.92(s, 1H),
4.49(s, 1H), 3.35(m, 2H), 1.63-0.85(m, 30H) 14-117 394 395 Tin-04
Rf = 2.19 min (Column A) 14-118 396 397 Tin-04 Rf = 2.18 min
(Column A) 14-119 398 399 Tin-04 Rf = 2.47 min (Column A) .sup.1H
NMR(500 MHz, CDCl3) .delta. 7.85(s, 1H), 4.91(s, 2H), 2.16-0.87(m,
27H) 14-120 400 401 Tin-04 Rf = 2.61 min (Column A) 14-121 402 403
Tin-04 Rf = 2.92 min (Column A) 14-122 404 405 Tin-04 Rf = 1.93 min
(Column A) 14-123 406 407 Tin-01 Rf = 2.20 min (Column A) 14-124
408 409 Tin-01 Rf = 2.50 min (Column A) .sup.1H NMR(500 MHz, CDCl3)
.delta. 9.07(s, 1H), 7.87(s, 1H), 1.59-0.85(m, 27H) 12-125 410 411
Tin-04 Rf = 1.97 min (Column A) 14-126 412 413 Tin-04 Rf = 1.97 min
(Column A) 14-127 414 415 Tin-01 Rf = 2.70 min (Column E) .sup.1H
NMR(500 MHz, CDCl3) .delta. 8.11(d, 1H, J=5.2 Hz), 7.41(d, 1H,
J=5.2 Hz), 6.94(s, 1H), 1.62-0.89(m, 27H) 14-128 416 417 Tin-06
.sup.1H NMR(500 MHz, CDCl3) .delta. 8.12(d, 1H, J=5.2 Hz), 7.78(s,
1H), 7.46(d, 1H, J=5.2 Hz), 6.84(s, 1H), 1.98-0.85(m, 27H) 14-129
418 419 Tin-01 Rf = 1.86 min (Column A)
[0758] The following Table I-4 contains novel stannane reagents
which can be prepared by the methodology described above and then
could be used to prepare compounds of formula I.
12TABLE I-4 Precursor Number Structure Reference 420 From
5-iodo2-chloro- 1,3 pyrimidine. Fluoropyrimidines are obtained by
fluorination of chloropyrimidines with CsF in N-methyl-
2-pyrrolidinone or DMF 2.5-63 h at 80-150.degree. C. The iodo is
then converted to the # lithium reagent with tBuLi and trapped with
Bu3SnCl. See Sandosham above. 421 422 423 424 425 426 427 428 429
430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446
Turck, A.; et. al Lab.. J. Organomet. Chem. (1991), 412(3), 301-10.
Metallation of 2,6- dicloropyrazine and quench with Bu3SnCl 447
Analogous to Lehn, L. M., et al. Chem. Eur. J. 2000, 6, 4133. 448
449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465
466 467 468 469 470 471 472 473 474 475 476 477 Metallation of
1-trityl- 4-iodo imidazole (prepared in Takahashi, Kazuyuki; Kirk,
Kenneth L.; Cohen, Louis A. Lab. Chem., Natl. Inst. Arthritis
Diabetes Dig. Kidney Dis., Bethesda, MD, USA. J. Labelled Compd.
Radiopharm. # (1986), 23(1), 1-8) using tBuLi in THF at -78 and
quenching with Bu.sub.3SnCl. Detritylate with TFA or aq HCl after
coupling to azaindole core. 478 Metallation of 1- methyl-4-iodo
imidazole (prepared in Takahashi, Kazuyuki; Kirk, Kenneth L.;
Cohen, Louis A. Lab. Chem., Natl. Inst. Arthritis Diabetes Dig.
Kidney Dis., Bethesda, MD, USA. J. Labelled Compd. Radiopharm.
(1986), # 23(1), 1-8) using tBuLi in THF at -78 and quenching with
Bu.sub.3SnCl. El Borai, M.; Moustafa, A. H.; Anwar, M.; Abdel Hay,
F. I. The bromo derivative is described in Pol. J. Chem. (1981),
55(7-8), 1659-65 and can be used to # generate the tin reagent via
transmetallation. 479 480 4,5difluoroimidazole prepared as in
Dolensky, Bohumil; et. al, USA. J. Fluorine Chem. (2001), 107(1),
147-148. 481 Dolensky, Bohumil; et. al, USA. J. Fluorine Chem.
(2001), 107(1), 147-148. 482
[0759] Select General Procedures, via S.sub.NAr Reactions, for the
Preparation of Starting Materials for Tin Agents
[0760] a. Preparation of 2-bromo-5-substituted-pyrazine,
5-bromo-2-subsitutedthiazole, 2-substituted-thiazaole,
4-chloro-6-substituted-pyrimidine and
5-bromo-2-substituted-pyrimidine 483
[0761] To a flask, an appropriate pyrazine, pyrimidine or thiazole
(1.0 equivalent) and a nucleophile (Nu), such as amine, alcohol or
thio-derivatives in one equivalence or an exess amount were
combined in a solvent such as THF, DMF or alcohol, with or without
an addition of NaH. The reaction was either stirred at room
temperature or under heating for one to three days. After all the
solvents were removed, the residue was partitioned between
saturated NaHCO.sub.3 and EtOAc. The aqueous layer was extracted
with ethyl acetate and the combined extracts were concentrated in
vacuo to give a residue, which was purified by silica gel
chromatography to afford the desired product.
13 Starting Reaction Rf MS MS Material Product Condition (minutes)
(M + H) + Cald. (M + H) + Obsv. 484 485 SM-01 (2 g) Piperazine (10
g), THF (50 ml), r.t 0.56 (column G) 342.02 243.03 486 487 SM-01 (1
g), MeNH.sub.2 (2M in THF, 100 ml), r.t. 0.89 (column E) 187.93
187.98 488 489 SM-01 (1 g), Me.sub.2NH 2M in THF, 100 ml), r.t.
1.19 (column E) 201.92 202.00 490 491 SM-01 (1 g), MeONa (0.5M in
MeOH, 100 ml), r.t. 1.05 (column E) 188.91 188.97 492 493 SM-01 (50
mg), NaH (17 mg), 2- amino-1,3,4- thiadiazole (25 mg), DMF 5 ml)
r.t. 1.21 (column E) 257.94 257.89 494 495 SM-01 (50 mg), NaH (17
mg), N- benzylpiperazine 25 mg), DMF 5 ml) r.t. 1.04 (column E)
333.07 332.99 496 497 SM-01 (50 mg), NaH (17 mg), N,N-
diethylamino- ethanol (0.033 ml), DMF 5 ml) r.t. 0.72 (column E)
274.06 273.97 498 499 SM-02 (2 g) Piperazine (10 g), THF (50 ml),
r.t. 0.89 (column E) 247.99 247.97 500 501 SM-05 (1 g), Me.sub.2NH
(2M in THF, 100 ml), r.t. 0.65 (column E) 206.89 206.96 502 503
SM-02 (1 g), MeONa (0.5M in MeOH, 100 ml), r.t. 1.35 (column E)
193.93 193.84 504 505 SM-03 (50 mg), NaH (16 mg), imidazole (77
mg), DMF 5 ml) r.t. 0.89 (column E) 229.94 229.83 506 507 SM-02 (50
mg), NaH (16 mg), N-benzylpiperazine (30 mg), DMF 5 ml) r.t. 1.02
(column E) 338.03 337.98 508 509 SM-02 (50 mg), NaH (16 mg),
N,N-diethylamino- ethanol (0.033 ml), DMF 5 ml) r.t. 0.83 (column
E) 279.02 278.95 510 511 SM-03 (50 mg), NaH (25 mg), imidazole (25
mg), DMF 5 ml) r.t. 0.31 (column E) 151.9 152.03 512 513 SM-03 (50
mg), NaH (25 mg), N-benzylpiperazine (37 mg) DMF 5 ml) r.t. 0.66
(column E) 260.07 260.12 514 515 SM-03 (50 mg), NaH (25 mg),
N,N-diethylamino- ethanol (0.05 ml), DMF 5 ml) r.t. 0.46 (column E)
201.11 201.02 516 517 SM-04 (1 g), MeONa (0.5M in MeOH, 13.52 ml).
r.t. 0.86 (column E) 145.02 144.99 518 519 SM-04 (1 g), MeNH.sub.2
(2M in THF, 100 ml), r.t. 0.46 (column E), 144.03 143.96 520 521
SM-05 (1 g), MeONa (0.5M in MeOH, 100 ml), 1 day, r.t. 0.91 (column
E) 188.97 188.91 522 523 SM-05 (1 g), MeNH.sub.2 (2M in THF, 100
ml), r.t. 0.84 (column E) 187.99 187.94 524 525 SM-05 (1 g),
Me.sub.2NH (2M in THF, 100 ml), r.t. 1.24 (column E) 202.00
201.98
[0762] b. Preparation of 2-bromo-5,6-disubstituted-pyrazine 526
[0763] Step One
[0764] To a flask, an appropriate pyrazine (1.0 equivalent) and a
nucleophile, such as amine or sodium alkoxide in an exess amount
were combined in a solvent such as water or THF or without solvent.
The reaction was either stirred at room temperature or under
heating for one to three days. After all the solvents were removed,
a residue was collected and used in the further steps without any
purification.
14 Starting Reaction Rf MS MS Material Product Condition (minutes)
(M + H) + Cald. (M + H) + Obsv. 527 528 SM-06 (100 mg), propylamine
(2 ml), r.t. 1.28 (column C) 172.06 172.09 529 530 SM-06 (100 mg),
Me.sub.2NH (2M in THF, 10 ml) or Me.sub.2NH (40% in water, 10 ml),
r.t. 1.21 (column C) 158.05 158.07 531 532 SM-06 (100 mg), Me2NH
(40% in water, 10 ml), 100.degree. C. 0.49 (column C) 167.13 167.19
533 534 SM-06 (100 mg), MeNH.sub.2 (2M in THF, 10 ml), r.t. 0.72
(column C) 144.03 144.07 535 536 SM-06 (100 mg), NH.sub.4OH (10
ml), 100.degree. C. 0.41 (column C) 162.04 (M + Me OH + H).sup.+
162.06 (M + meO H + H).sup.+
[0765] Step Two
[0766] To a flask, the crude pyrazine derivative obtained from the
step one (1.0 equivalent) and a nucleophile, such as amine or
sodium alkoxide in an exess amount were combined in a solvent such
as water or THF or without solvent. The reaction was either stirred
at room temperature or under heating for one to three days. After
all the solvents were removed, a residue was collected and used in
the further steps without any purification.
15 Starting Reaction RF MS MS Material Product Condition (minutes)
(M + H) + Cald. (M + H) + Obsv. 537 538 SM-07 (2 g), MeONa 12.5 wt
%, 100 ml, 100.degree. C. 0.28 (column C) 140.08 140.14 539 540
SM-08 (2 g), MeONa 12.5 wt %, 20 ml), 100.degree. C. 0.28 (column
C) 158.13 158.09 541 542 SM-07 (2 g), MeNH.sub.2 (40% in water, 100
ml), 110.degree. C. 0.34 (column C) 139.10 139.13
[0767] Step Three
[0768] To a flask, the crude pyrazine derivative obtained from the
step two (1.0 equivalent) was dissolved in methylene chloride. A
slightly excess of bromine was then added into the mixed solution.
The reaction was stirred at room temperature for ten hours. After
all the solvents were removed, a residue was collected and purified
by silica gel chromatography to afford the desired product.
16 Starting Reaction Rf MS MS Material Product Condition (minutes)
(M + H) + Cald. (M + H) + Obsv. 543 544 SM-09 (5 g), bromine (1.34
ml), CH.sub.2Cl.sub.2 (100 ml) 1.77 (column C) 249.97 250.02 545
546 SM-10 (2 g), bromine (0.72 ml), CH.sub.2Cl.sub.2 (20 ml) 1.13
(column C) 217.99 217.98 547 548 SM-11 (2 g), bromine (0.72 ml),
CH.sub.2Cl.sub.2 (20 ml) 0.98 (column C) 203.98 203.99
[0769] General Procedure of the Preparation of
2-alkyl-5-bromo-pyrimide: 549
[0770] To a sealed tube, 5-bromo-2-iodopyrimidine (1.0 equivalent),
trialkylalumimun (1.5 equivalent) and tetrakis-triphenylphosphine
palladium, Pd(Ph.sub.3P).sub.4 (1.0 mol %) were combined in
dioxane(10 mL). The reaction was heated at 110-120.degree. C. for
10 h. After the mixture cooled down to room temperature, it was
poured into water. The solution was extracted with ethyl acetate
and the combined extracts were concentrated in vacuo to give a
residue which was purified by silica gel chromatography to afford
the desired 2-alkyl-5-bromopyrimidine product.
17 MS MS Rf (M + H) + (M + H)+ R3Al Product (minutes) Cald. Obsv.
Me.sub.3Al 550 0.90 (column E) 172.94 172.97 (i-Bu).sub.3Al 551
1.45 (column E) 215.02 214.99
[0771] Prep of triazine stannane for Stille coupling to prepare
examples of claim 1. (the sulfur can thenbe removed with Raney
Nickel to give additional desulfurized triazines). 552
[0772] 2,2,6,6-tetramethylpiperidine (2.0 ml, 11.81 mmol) in 30 ml
of THF was cooled to -78.degree. C. and treated with n-butyllithium
(4.7 ml, 11.81 mmol, 2.5M in hexane). After stirring 30 min at
0.degree. C., the reaction was cooled to -78.degree. C. again and
3-methylthio-1,2,4-triazi- ne (1.0 g, 7.87 mmol) was added. The
resulting solution was stirred at -78.degree. C. for 30 min before
tributyltin chloride (2.1 ml, 7.87 mmol) was added. The reaction
was kept at -78.degree. C. for lhr, then quenched with water. The
THF solvent was removed on rotarory evaporator and the remaining
solution was extracted with ethylacetate. The organic layer was
dried over MgSO4, filtered and the filtrate was concentrated. The
residue was chromatographed to afford 96 mg of
3-methylthio-6-tributyltin-1,2,4-t- riazine.
[0773] 1H NMR (300 Hz, CHCl3): 8.83 (s, 1H); 2.62 ( s, 3H);
2.04-0.79 (m, 27H). LC/MS: (ES+) M/Z (M+H)+=418, RT=2.29 min.
Precursor 13a
[0774] 553
[0775] To a mixture of 5q (50 mg, 105 .mu.mol) and
Pd(PPh.sub.3).sub.4 (25 mg, 21 .mu.mol) was added 1,4-dioxane (1
ml) and vinyl tributylstannane (50 mg, 158 .mu.mol). The reaction
mixture was heated in a sealed tube at 145.degree. C. for 3 hours.
After cooling to ambient temperature, the reaction mixture was
added MeOH (4 ml) and then filtered. The filtrate was purified by
preparative reverse phase HPLC to give the TFA salt of Precursor
13a using the method: Start % B=30, Final % B=75, Gradient time=20
min, Flow Rate=25 ml/min, Column: YMC C18 5um 20.times.100 mm,
Fraction Collection: 7.92-8.58 min. .sup.1H NMR: (CD.sub.3OD)
.delta.8.61 (s, 1H), 8.37 (s, 1H), 7.47 (b s, 5H), 7.31 (dd,
J=17.3, 11.3, 1H), 6.50 (d, J=17.3, 1H), 5.97 (d, J=11.3, 1H),
3.97- 3.38 (b m, 8H); LC/MS: (ES+) m/z (M+H).sup.+=423,425; HPLC
R.sub.t=1.887.
Precursor 14
[0776] 554
[0777] To a mixture of precursor 5q (30 mg, 63 .mu.mol) and
Pd(PPh.sub.3).sub.4 (20 mg, 17 .mu.mol) was added 1,4-dioxane (1
ml) and 1-tributylstannyl propyne (40 mg, 122 .mu.mol). The
reaction mixture was heated in a sealed tube at 145.degree. C. for
2 hours. After cooling to ambient temperature, the reaction mixture
was added MeOH (4 ml) and then filtered. The filtrate was purified
by preparative reverse phase HPLC to give the TFA salt of precursor
14 (1-(4-Benzoyl-piperazin-1-yl)-2-(4-chlo- ro-7-prop-1-ynyl-1H
-pyrrolo[2,3-c]pyridin-3-yl)-ethane-1,2-dione) using the method:
Start % B=20, Final % B=80, Gradient time=20 min, Flow Rate=25
ml/min, Column: YMC C18 5 um 20.times.100 mm, Fraction Collection:
8.74-9.00 min. .sup.1H NMR: (CD.sub.3OD) .delta.8.47 (s, 1H), 8.27
(s, 1H), 7.46 (b s, 5H), 3.82-3.34 (b m, 8H), 2.26 (s, 3H); LC/MS:
(ES+) m/z (M+H).sup.+=435, 437; HPLC (alternate conditions B,
column G) R.sub.t=2.123.
Precursor 15
[0778] 555
[0779] To a solution of precursor 5q (50 mg, 0.11 mmol) in DMF (1
ml) was added CuCN (30 mg, 0.335 mmol). The reaction mixture was
heated at 170.degree. C. for 30 min. After cooling to ambient
temperature, the reaction mixture was diluted with MeOH (15 ml),
filtered under gravity, and the filtrate evaporated in vacuo to
afforded a brownish residue. To the residue in EtOH (3 ml) at
ambient temperature was bubbled hydrogen chloride gas for 10
minutes to give a yellow solution, which was purified by
preparative reverse phase HPLC using the method: Start % B=15,
Final % B=85, Gradient time=15 min, Flow Rate=40 ml/min, Column:
XTERRA C18 5 um 30.times.100 mm, Fraction Collection: 10.40-10.85
min; .sup.1H NMR: (CD.sub.3OD) 8.35 (s, 1H), 8.33 (s, 1H), 7.42 (b
s, 5H), 3.95-3.41 (b m, 8H); LC/MS: (ES+) m/z (M+H).sup.+=440, 442;
HPLC (alternate conditions B, column G) R.sub.t =1.820.
Precursor 16
[0780] 556
[0781] Preparation of Precursor 16:
[0782] To a suspension of precursor 15 (6 mg, 13 .mu.mol) in a
mixture of AcOH (0.5 ml) and Ac.sub.2O (1.0 ml) at 0.degree. C. was
charged with sodium nitrite (17 mg, 246 .mu.mol). The reaction
mixture was stirred at 0.degree. C. for 30 min. and then at ambient
temperature for 1 hour. After addition of MeOH (4 ml), the reaction
mixture was purified by preparative reverse phase HPLC to give the
TFA solvate of the title compound using the method: Start % B=15,
Final % B=80, Gradient time=15 min, Flow Rate=25 ml/min, Column:
YMC C18 5 um 20.times.100 mm, Fraction Collection: 9.48-10.03 min.
.sup.1H NMR: (DMSO-d.sub.6) .delta.12.76 (s, 1H), 8.48 (s, 1H),
8.32 (d, J=3.0, 1H), 7.44 (b s, 5H), 3.97-3.47 (b m, overlapping
with water peak, 8H); LC/MS: (ES+) m/z (M+H).sup.+=441, 443; HPLC
(alternate conditions B, column G) R.sub.t=1.530. Ref: Amide
hydrolysis: Evans, D. A.; Carter, P. H.; Dinsmore, C. J.; Barrow,
J. C.; Katz, J. L.; Kung, D. W. Tetrahedron Lett. 1997, 38, 4535
and references cited therein.
[0783] Additional Piperazine Precursors
[0784] N-(Benzoyl)-2-methylpiperazine, Precursor 17a, was prepared
according to the procedure described in Ref. 90(b). .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta.7.47 (m, 5H), 3.30-2.70 (m, 7H), 1.36
(d, 3H, J=6.90 Hz); .sup.13C NMR (75 MHz, CD.sub.3OD) .delta.171.0,
135.4, 129.7, 128.5, 126.3, 48.5, 44.3,14.5; .sup.2 HRMS m/z:
(M+H).sup.+ calcd for C.sub.12H.sub.17N.sub.2O 205.1341, found
205.1341.
[0785] (R)-N-(Benzoyl)-2-methylpiperazine, Precursor 17b, was
prepared according to the procedure described in Ref. 90(b).
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta.7.41 (m, 5H), 3.31-2.70
(m, 7H), 1.35 (d, 3H, J=6.90 Hz). MS m/z: (M+H).sup.+ Calc'd for
C.sub.12H.sub.17N.sub.2O: 205.13; Found 205.16. HPLC retention
time: 0.51 minutes (column L).
[0786] (S)-N-(Benzoyl)-2-methylpiperazine, Precursor 17c, was
prepared according to the procedure described in Ref. 90(b).
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta.7.41 (m, 5H), 3.31-2.72
(m, 7H), 1.35 (d, 3H, J=6.90 Hz). MS m/z: (M+H).sup.+ Calc'd for
C.sub.12H.sub.17N.sub.2O: 205.13; Found 205.16. HPLC retention
time: 0.50 minutes (column L).
[0787] .sup.2Some carbon peaks are missing due to the overlap of
signals.
[0788] N-(Benzoyl)-2-ethylpiperazine, Precursor 17d, was prepared
according to the procedure described in Ref. 90(b).. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta.7.49 (m, 5H), 3.34-2.80 (m, 7H),
2.10-1.70 (m, 2H), 0.85 (b, 3H); .sup.13C NMR (75 MHz, CD.sub.3OD)
.delta.171.5, 135.1, 129.8, 128.5, 126.5, 48.5, 46.0, 43.9, 21.8,
9.6; .sup.2 HRMS m/z: (M+H).sup.+ calcd for
C.sub.13H.sub.19N.sub.2O 219.1497, found 219.1501.
Preparation of Compounds of Formula I
EXAMPLE 1
[0789] 557
[0790] Typical procedure for coupling azaindole with aromatic boron
reagent (An example of the general procedure described below for
examples 2-14): Preparation of
1-benzoyl-3-(R)-methyl-4-[(7-(4-fluorophenyl)-6-aza-
indol-3-yl)-oxoacetyl]-piperazine is an example of Step E as
described in Scheme 15. To a sealed tube,
1-(benzoyl)-3-(R)-methyl-4-[(7-chloro-6-azai-
ndol-3-yl)-oxoacetyl]piperazine, Precursor 5a, (20 mg, 0.049 mmol),
4-fluorophenylboronic acid, Precursor 14a-9, (8.2 mg, 0.059 mmol),
Pd(Ph.sub.3P).sub.4 (5 mg) and K.sub.2CO.sub.3 (20 mg, 0.14 mmol)
were combined in 1.5 mL of DMF and 1.5 mL of water. The reaction
was heated at 110-120.degree. C. for 10 h. After the mixture cooled
down to rt, it was poured into 20 mL of water. The solution was
extracted with EtOAc (4.times.20 mL). The combined extract was
concentrated to give a residue which was purified using a Shimadzu
automated preparative HPLC System to give compound
1-benzoyl-3-(R)-methyl-4-[(7-(4-fluorophenyl)-6-azaindol-3--
yl)-oxoacetyl]piperazine (1.8 mg, 7.9%). MS m/z: (M+H).sup.+ Calc'd
for C.sub.27H.sub.24FN.sub.4O.sub.3: 471.18; found 471.08. HPLC
retention time: 1.12 minutes (column A).
EXAMPLES 2-14
[0791] Examples 2-14 were prepared according to the following
general method in a manner analogous to the preparation of Example
1.
[0792] Typical procedure for coupling azaindole with aromatic boron
reagent: To a sealed tube, an appropriately substituted azaindole
precursor (0.049 mmol), an appropriate boronic acid derivative
(0.059 mmol), Pd(Ph.sub.3P).sub.4 (5 mg) and K.sub.2CO.sub.3 (20
mg, 0.14 mmol) were combined in 1.5 mL of DMF and 1.5 mL of water.
The reaction was heated at 110-120.degree. C. for 10 h. After the
mixture cooled down to rt, it was poured into 20 mL of water. The
solution was extracted with EtOAc (4.times.20 mL). The combined
extract was concentrated in vacuo to give a residue which was
purified using a Shimadzu automated preparative HPLC System to
provide the desired compound.
EXAMPLE 2
[0793] 558
[0794] Example 2, was prepared according to the general method
described above starting from Precursor 5g and 4-chlorophenyl
boronic acid, Precursor 14a-10, to provide
1-benzoyl-4-[(7-(4-chlorophenyl)-6-azaindol--
3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.27H.sub.24FN.sub.4O.sub.3: 473.14; found 473.13. HPLC
retention time: 1.43 minutes (column B).
EXAMPLE 3
[0795] 559
[0796] Example 3, was prepared according to the general method
described above starting from Precursor 5a and
3-amino-4-methylphenyl boronic acid, Precursor 14a-11, to provide
1-benzoyl-3-.RTM.-methyl-4-[(7-(3-amino-4-me-
thylphenyl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z:
(M+H).sup.+ Calc'd for C.sub.27H.sub.24ClN.sub.4O.sub.3: 482.22;
found 482.25. HPLC retention time: 1.35 minutes (column B).
EXAMPLE 4
[0797] 560
[0798] Example 4, was prepared according to the general method
described above starting from Precursor 5g and
4-hydroxycarbonylphenyl boronic acid, Precursor 14a-12, to provide
1-benzoyl-4-[(7-(4-carboxy-phenyl)-6-a-
zaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.27H.sub.24ClN.sub.4O.sub.3: 483.17; found 483.10. HPLC
retention time: 1.00 minutes (column A).
EXAMPLE 5
[0799] 561
[0800] Example 5, was prepared according to the general method
described above from
1-benzoyl-3-methyl-4-[(7-chloro-6-azaindol-3-yl)-oxoacetyl]pip-
erazine and 3,4-methylenedioxyphenyl boronic acid, Precursor
14a-13, to provide
1-benzoyl-3-methyl-4-[(7-(3,4-methylenedioxyphenyl)-6-azaindol-3--
yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.28H.sub.25N.sub.4O.sub.5: 497.18; found 497.03. HPLC
retention time: 1.41 minutes (column B).
EXAMPLE 6
[0801] 562
[0802] Example 6, was prepared according to the general method
described above starting from Precursor 5a and furan-2-yl boronic
acid to provide
1-benzoyl-3-.RTM.-methyl-4-[(7-(furan-2-yl)-6-azaindol-3-yl)-oxoacetyl]pi-
perazine; MS m/z: (M+H).sup.+Calc'd for
C.sub.25H.sub.23N.sub.4O.sub.4: 443.17; found 443.12. HPLC
retention time: 1.20 minutes (column A).
EXAMPLE 7
[0803] 563
[0804] Example 7, was prepared according to the general method
described above starting from Precursor 5g and furan-2-yl boronic
acid to provide
1-benzoyl-4-[(7-(furan-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine
MS m/z: (M+H).sup.+ Calc'd for C.sub.24H.sub.12N.sub.4O.sub.4:
429.16; found 428.98. HPLC retention time: 1.36 minutes (column
A).
EXAMPLE 8
[0805] 564
[0806] Example 8, was prepared according to the general method
described above starting from Precursor 5g and benzofuran-2-yl
boronic acid to provide
1-benzoyl-4-[(7-(benzofuran-2-yl)-6-azaindol-3-yl)-oxoacetyl]pipe-
razine MS m/z: (M+H).sup.+ Calc'd for
C.sub.28H.sub.23N.sub.4O.sub.4: 479.17; found 479.09. HPLC
retention time: 1.67 minutes (column B).
EXAMPLE 9
[0807] 565
[0808] Example 9, was prepared according to the general method
described above starting from Precursor 5a and thien-2-yl boronic
acid to provide
1-(benzoyl)-3-.RTM.-methyl-4-[(7-(thien-2-yl-6-azaindol-3-yl)-oxoacetyl]p-
iperazine MS m/z: (M+H).sup.+Calc'd for
C.sub.25H.sub.23N.sub.4O.sub.3S: 459.15; found 459.10. HPLC
retention time: 1.20 minutes (column A).
EXAMPLE 10
[0809] 566
[0810] Example 10, was prepared according to the general method
described above starting from Precursor 5g and pyridin-4-yl boronic
acid to provide
1-(benzoyl)-4-[(7-(pyridin-4-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine
MS m/z: (M+H).sup.+ Calc'd for C.sub.25H.sub.22N.sub.5O.sub.3:
440.17; found 440.10. HPLC retention time: 0.97 minutes (column
A).
EXAMPLE 11
[0811] 567
[0812] Example 11, was prepared according to the general method
described above starting from Precursor 5g and quinolin-8-yl
boronic acid, Precursor 14a-14, to provide
1-benzoyl-4-[(7-(quinolin-8-yl)-6-azaindol-3-
-yl)-oxoacetyl]piperazine MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.22N.sub.5O.sub.3: 490.19; found 490.09. HPLC
retention time: 1.34 minutes (column B).
EXAMPLE 12
[0813] 568
[0814] Example 12, was prepared according to the general method
described above starting from Precursor 5a and
2,4-dimethoxypyrimidin-5-yl boronic acid, Precursor 14a-4, to
provide 1-benzoyl-3-.RTM.-methyl-4-[(7-(2,4-dim-
ethoxy-pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine MS
m/z: (M+H).sup.+ Calc'd for C.sub.27H.sub.27N.sub.6O.sub.5: 515.20;
found 515.28. HPLC retention time: 1.17 minutes (column B).
EXAMPLE 13
[0815] 569
[0816] Example 13, was prepared according to the general method
described above starting from Precursor 5b and
2,4-dimethoxypyrimidin-5-yl boronic acid, Precursor 14a-4, to
provide 1-benzoyl-4-[(4-methoxy-7-(2,4-dimethox-
y-pyrimidin-5-yl)-6-azaindol-3-oxoacetyl]piperazine .sup.1H NMR
(500 MHz, CD.sub.3OD) .delta.8.71 (s, 1H), 8.64 (s, 1H), 8.21 (s,
1H), 7.48 (s, 5H), 4.15 (s, 3H), 4.13 (s, 3H), 3.84 (s 3H),
3.64-3.34 (m, 8H). MS m/z: (M+H).sup.+ Calc'd for
C.sub.29H.sub.35N.sub.6O.sub.6: 531.20; found 531.26. HPLC
retention time: 1.09 minutes (column A).
EXAMPLE 14
[0817] 570
[0818] Example 14, was prepared according to the general method
described above starting from Precursor 5b and pyridin-4-yl boronic
acid to provide
1-benzoyl-4-[(4-methoxy-7-(pyridin-4-yl)-6-azaindol-3yl)-oxoacetyl]pipera-
zine MS m/z: (M+H).sup.+ Calc'd for C.sub.26H.sub.24N.sub.5O.sub.4:
470.18; found 470.32. HPLC retention time: 1.02 minutes (column
A).
EXAMPLE 15
[0819] 571
[0820] Typical procedure for coupling azaindole with aromatic tin
reagent (An example of the general procedure described below for
examples 16-53):
[0821] Preparation of Example 15,
1-benzoyl-4-[(4-methoxy-7-(2-(1,1-dimeth-
ylethylaminocarbonyl)-pyrazin-5-yl)-6-azaindol-3yl)-oxoacetyl]piperazine
is an example of Step E as described in Scheme 15. To a sealed
tube,
1-benzoyl-4-[(7-chloro-4-methoxy-6-azaindol-3yl)-oxoacetyl]piperazine
Precursor 5b, (20 mg),
2-(1,1-dimethylethylaminocarbonyl)-5-tributylstann- yl-pyrazine
(1.2 equivalents, 27 mg.) and Pd(Ph.sub.3P).sub.4 (1 mg) were
combined in 1.5 mL of dioxane. The reaction was heated at
110-120.degree. C. for 10 h. After the mixture cooled down to room
temperature, it was poured into 5 mL of water. The solution was
extracted with EtOAc (4.times.5 mL). The combined extract was
concentrated in vacuo to give a residue which was purified using a
Shimadzu automated preparative HPLC System to give compound
1-benzoyl-4-[(4-methoxy-7-(2-(1,1-dimethylethylam-
inocarbonyl)-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine (1
mg); MS m/z: (M+H).sup.+ Calc'd for C.sub.30H.sub.32N.sub.7O.sub.5:
570.25; found 570.43. HPLC retention time: 1.83 minutes (column
B).
EXAMPLES 16-54
[0822] Examples 16-54 were prepared according to the following
general procedure by a method analogous to the method described for
the preparation of Example 15.
[0823] Typical procedure for coupling azaindole with aromatic tin
reagent: To a sealed tube, an appropriate azaindole (0.049 mmol),
an appropriate stannane (0.059 mmol) and Pd(Ph.sub.3P).sub.4 (1 mg)
were combined in 1.5 mL of dioxane. The reaction was heated at
110-120.degree. C. for 10 h. After the mixture cooled down to rt,
it was poured into 5 mL of water. The solution was extracted with
EtOAc (4.times.5 mL). The combined extract was concentrated to give
a residue which was purified using a Shimadzu automated preparative
HPLC System to provide the desired compound.
EXAMPLE 16
[0824] 572
[0825] Example 16, was prepared according to the general method
described above starting from Precursor 5a and pyriridin-5-yl
tributyltin, Precursor 14-9, to provide
1-benzoyl-3-(R)-methyl-4-[(7-(pyrimidin-5-yl)--
6-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd
for C.sub.25H.sub.23N.sub.6O.sub.3: 455.18; found 455.17. HPLC
retention time: 1.33 minutes (column B).
EXAMPLE 17
[0826] 573
[0827] Example 17, was prepared according to the general method
described above starting from Precursor 5g and pyrimidin-5-yl
tributyltin, Precursor 14-9, to provide
1-benzoyl-4-[(7-(pyrimidin-5-yl)-6-azaindol-3--
yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.23N.sub.6O.sub.3: 441.17; found 441.07. HPLC
retention time: 1.30 minutes (column B).
EXAMPLE 18
[0828] 574
[0829] Example 18, was prepared according to the general method
described above starting from Precursor 5a and pyridin-3-yl
tributyltin, Precursor 14a-2, to provide
1-benzoyl-3-(R)-methyl-4-[(7-(pyrimidin-3-yl)-6-azaindo-
l-3-yl)-oxoacetyl]piperazine MS m/z: (M+H).sup.+ Calc'd for
C.sub.26H.sub.24N.sub.5O.sub.3: 454.19; found 454.17. HPLC
retention time: 1.11 minutes (column A).
EXAMPLE 19
[0830] 575
[0831] Example 19, was prepared according to the general method
described above starting from Precursor 5g and pyridin-2-yl
tributyltin, Precursor 14a-19, to provide
1-benzoyl-4-[(7-(pyridin-2-yl)-6-azaindol-3-yl)-oxoace-
tyl]piperazine MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.22N.sub.5O.sub- .3: 440.17; found 440.07. HPLC
retention time: 1.40 minutes (column B).
EXAMPLE 20
[0832] 576
[0833] Example 20, was prepared according to the general method
described above starting from Precursor 5a and thiazol-2-yl
tributyltin, Precursor 14a-21, to provide
1-benzoyl-3-(R)-methyl-4-[(7-(thiazol-2-yl)-6-azaindol-
-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.22N.sub.5O.sub.3S: 460.14; found 460.15. HPLC
retention time: 1.48 minutes (column B).
EXAMPLE 21
[0834] 577
[0835] Example 21, was prepared according to the general method
described above starting from Precursor 5g and thiazol-2-yl
tributyltin, Precursor 14a-21, to provide
1-benzoyl-4-[(7-(thiazol-2-yl)-6-azaindol-3-yl)-oxoace-
tyl]piperazine MS m/z: (M+H).sup.+ Calc'd for
C.sub.23H.sub.20N.sub.5O.sub- .3S: 446.13; found 446.03. HPLC
retention time: 1.44 minutes (column B).
EXAMPLE 22
[0836] 578
[0837] Example 22, was prepared according to the general method
described above starting from Precursor 5b and 1-methylpyrazol-3-yl
tributyltin, to provide
1-benzoyl-4-[(4-methoxy-7-(1-methyl-pyrazol-3-yl)-6-azaindol-3-yl-
)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.25N.sub.6O.sub.4: 473.19; found 473.28. HPLC
retention time: 1.18 minutes (column B).
EXAMPLE 23
[0838] 579
[0839] Example 23, was prepared according to the general method
described above starting from Precursor 5b and Intermeidiate 14-9
to provide
1-benzoyl-4-[(4-methoxy-7-(pyridazin-4-yl)-6-azaindol-3-yl)-oxoacetyl]pip-
erazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.23N.sub.6O.sub.4: 471.18; found 471.26. HPLC
retention time: 1.20 minutes (column B).
EXAMPLE 24
[0840] 580
[0841] Example 24, was prepared according to the general method
described above starting from Precursor 5b and
2-aminopyrimidin-5-yl tributyltin, to provide
1-benzoyl-4-[(4-methoxy-7-(2-amino-pyrimidin-5-yl))-azaindol-3-
-yl)-oxoacetyl]piperazine MS m/z: (M+H).sup.+ Calc'd for for
C.sub.25H.sub.24N.sub.7O.sub.4: 486.19: found 486.24. HPLC
retention time: 1.19 minutes (column A).
EXAMPLE 25
[0842] 581
[0843] Example 25, was prepared according to the general method
described above starting from Precursor 5b and pyridin-3-yl
tributyltin, Precursor 14a-2, to provide
1-benzoyl-4-[(4-methoxy)-7-(pyridin-3-yl)-6-azaindol-3--
yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.26H.sub.24N.sub.5O.sub.4: 470.18; found 470.19. HPLC
retention time: 1.04 minutes (column A).
EXAMPLE 26
[0844] 582
[0845] Example 26, was prepared according to the general method
described above starting from Precursor 5b and 2-aminopyrazin-5-yl
trimethyltin, Precursor 14-28, to provide
1-benzoyl-4-[(4-methoxy-7-(2-amino-pyrazin-5--
yl))-6-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+
Calc'd for C.sub.25H.sub.24N.sub.7O.sub.4: 486.19; found 470.19.
HPLC retention time: 1.13 minutes (column B).
EXAMPLE 27
[0846] 583
[0847] Example 27, was prepared according to the general method
described above starting from Precursor 5b and
1-methylimidazol-2-yl trimethyltin, Precursor 14-5, to provide
1-benzoyl-4-[(4-methoxy-7-(1-methyl-imidazol-2-
-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+
Calc'd for C.sub.25H.sub.25N.sub.6O.sub.4: 473.18; found 473.27.
HPLC retention time: 1.07 minutes (column B).
EXAMPLE 28
[0848] 584
[0849] Example 28, was prepared according to the general method
described above starting from Precursor 5b and 1-methylpyrrol-2-yl
tributyltin, Precursor 14a-15, to provide
1-benzoyl-4-[(4-methoxy-7-(1-methyl-pyrrol-2-
-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+
Calc'd for C.sub.26H.sub.26N.sub.5O.sub.4: 472.20; found 470.26.
HPLC retention time: 1.11 minutes (column A).
EXAMPLE 29
[0850] 585
[0851] Example 29, was prepared according to the general method
described above starting from Precursor 5i and 1-methylpyrazol-3-yl
tributyltin, to provide
1-benzoyl-4-[(4-fluoro-7(1-methyl-pyrazol-3-yl)-6-azaindol-3-yl)--
oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.22FN.sub.6O.sub.3: 461.17; found 461.24. HPLC
retention time: 1.36 minutes (column A).
EXAMPLE 30
[0852] 586
[0853] Example 30, was prepared according to the general method
described above starting from Precursor 5i and pyridazin-4-yl
tributyltin, Precursor 14-8, to provide
1-benzoyl-4-[(4-fluoro-7(pyridazin-4-yl)-6-aza-
indol-3-yl)-oxoacetyl]piperazine .sup.1 H NMR (500 MHz, CD.sub.3OD)
.delta.9.72 (s, 1H), 9.39 (s, 1H), 8.42 (m, 2H), 8.22 (s, 1H), 7.47
(s, 5H), 3.84-3.38 (m, 8H). MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.20FN.sub.6O.sub.3: 459.16; found 459.25. HPLC
retention time: 1.26 minutes (column A).
EXAMPLE 32
[0854] 587
[0855] Example 32, was prepared according to the general method
described above starting from Precursor 5b and pyrazin-2-yl
tributyltin, Precursor 14a-1, to provide
1-benzoyl-4-[(4-methoxy-7-(pyrazin-2-yl)-6-azaindol-3-y-
l)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.23N.sub.6O.sub.3: 471.18; found 471.17. HPLC
retention time: 1.35 minutes (column A).
EXAMPLE 33
[0856] 588
[0857] Example 33, was prepared according to the general method
described above starting from Precursor 5a and pyrazin-2-yl
tributyltin, Precursor 14a-1, to provide
1-benzoyl-3-(R)-methyl-4-[(7-(pyrazin-2-yl)-6-azaindol--
3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.23N.sub.6O.sub.3: 455.18; found 455.26. HPLC
retention time: 1.46 minutes (column A).
EXAMPLE 34
[0858] 589
[0859] Example 34, was prepared according to the general method
described above starting from Precursor 5g and pyrazin-2-yl
tributyltin, Precursor 14a-1, to provide
1-benzoyl-4-[(7-(pyrazin-2-yl)-6-azaindol-3-yl)-oxoacet-
yl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.21N.sub.6O.sub- .3: 441.17; found 441.22. HPLC
retention time: 1.22 minutes (column A).
EXAMPLE 35
[0860] 590
[0861] Example 35, was prepared according to the general method
described above starting from Precursor 5b and thiazol-2-yl
tributyltin, Precursor 14a-2 1, to provide
1-(benzoyl)-4-[(4-(4-methoxy-7-(thiazol-2-yl)-6-azain-
dol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.22N.sub.5O.sub.3S: 476.14; found 476.20. HPLC
retention time: 1.25 minutes (column B).
EXAMPLE 36
[0862] 591
[0863] Example 36, was prepared according to the general method
described above starting from Precursor 5b and pyridin-2-yl
tributyltin, Precursor 14a-19, to provide
1-benzoyl-4-[(4-methoxy-7-(pyridin-2-yl)-6-azaindol-3--
yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.26H.sub.24N.sub.5O.sub.4: 470.18; found 470.17. HPLC
retention time: 1.04 minutes (column A).
EXAMPLE 37
[0864] 592
[0865] Example 37, was prepared according to the general method
described above starting from Precursor 5j and thiazol-2-yl
tributyltin, Precursor 14a-21, to provide
1-benzoyl-3-(R)-methyl-4-[(4-fluoro-7-(thiazol-2-yl)-6-
-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd
for C.sub.24H.sub.21FN.sub.5O.sub.3S: 478.13; found 478.13. HPLC
retention time: 1.34 minutes (column A).
EXAMPLE 38
[0866] 593
[0867] Example 38, was prepared according to the general method
described above starting from Precursor 5i and pyrazol-3-yl
tributyltin, to provide
1-benzoyl-4-[(4-fluoro-7-(pyrazol-3yl)-6-azaindol-3-yl)-oxoacetyl]piperaz-
ine MS m/z: (M+H).sup.+ Calc'd for C.sub.23H.sub.20FN.sub.6O.sub.3:
447.16; found 447.15. HPLC retention time: 1.26 minutes (column
A).
EXAMPLE 39
[0868] 594
[0869] Example 39, was prepared according to the general method
described above starting from Precursor 5b and pyrazol-3-yl
tributyltin, to provide
1-benzoyl-4-[(4-methoxy-7-(pyrazol-3-yl)-6-azaindol-3-yl)-oxoacetyl]piper-
azine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.23N.sub.6O.sub.4: 459.18; found 459.21. HPLC
retention time: 1.11 minutes (column A).
EXAMPLE 40
[0870] 595
[0871] Example 40, was prepared according to the general method
described above starting from Precursor 5b and pyrimidin-5-yl
tributyltin, Precursor 14-9, to provide
1-benzoyl-4-[(4-methoxy-7-(pyrimidin-5-yl)-6-a-
zaindol-3-yl)-oxoacetyl]piperazine MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.23N.sub.6O.sub.4: 471.18; found 471.20. HPLC
retention time: 1.61 minutes (column A).
EXAMPLE 41
[0872] 596
[0873] Example 41, was prepared according to the general method
described above starting from Precursor 5j and pyrimidin-5-yl
tributyltin, Precursor 14-9, to provide
1-benzoyl-3-(R)-methyl-4-[(4-fluoro-7-(pyrimid-
in-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; .sup.1 H NMR (500
MHz, CD.sub.3OD) .delta.9.26 (m, 3H), 8.39 (m, 2H), 7.56 (m, 5H),
4.72-3.12 (m, 7H), 1.40-0.91 (m, 3H). MS m/z: (M+H).sup.+ Calc'd
for C.sub.25H.sub.22FN.sub.6O.sub.3: 473.17; found 473.17. HPLC
retention time: 1.34 minutes (column A).
EXAMPLE 42
[0874] 597
[0875] Example 42, was prepared according to the general method
described above starting from Precursor 5i and pyrimidin-5-yl
tributyltin, Precursor 14-9, to provide
1-benzoyl-4-[(4-fluoro-7-(pyrimidin-5-yl)-6-az-
aindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.20FN.sub.6O.sub.3: 459.16; found 459.14. HPLC
retention time: 1.28 minutes (column A).
Example 43
[0876] 598
[0877] Example 43,
(R)-1-(benzoyl)-3-methyl-4-[(7-(2,4-dimethoxy-pyrinidin-
-5-yl)-6-azaindol-3yl)-oxoacetyl]piperazine MS m/z: (M+H).sup.+
Calc'd for C.sub.27H.sub.27N.sub.6O.sub.5: 515.20; found 515.28.
HPLC retention time: 1.17 minutes (column B).
EXAMPLE 44
[0878] 599
[0879] Example 44, was prepared according to the general method
described above starting from Precursor 5a and
2,3-dichloropyrazin-5-yl tributyltin, Precursor 14-66, to provide
1-benzoyl-3-(R)-methyl-4-[(7-(2,-
3-dichloro-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS
m/z: (M+Na).sup.+ Calc'd for
C.sub.25H.sub.20Cl.sub.2NaN.sub.6O.sub.3: 545.09; found 545.29.
HPLC retention time: 1.87 minutes (column B).
EXAMPLE 45
[0880] 600
[0881] Example 45, was prepared according to the general method
described above starting from Precursor 5b and 2-ethoxythiazol-5-yl
tributyltin, Precursor 14-71, to provide
1-benzoyl-4-[(4-methoxy-7-(2-ethoxy-thiazol-5-
-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+
Calc'd for C.sub.26H.sub.26N.sub.5O.sub.5S: 520.17; found 520.24.
HPLC retention time: 1.32 minutes (column A).
EXAMPLE 46
[0882] 601
[0883] Example 46, was prepared according to the general method
described above starting from Precursor 5b and the
2-amino-pyrazin-6-yl stannane, Precursor 14-68, to provide
1-benzoyl-4-[(4-methoxy-7-(2-amino-pyrazin-6--
yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+
Calc3 d for C.sub.25H.sub.24N.sub.7O.sub.4: 486.19; found 486.31.
HPLC retention time: 1.22 minutes (column B).
EXAMPLE 47
[0884] 602
[0885] Example 47, was prepared according to the general method
described above starting from Precursor 5b and
2-methylsulfonylamino-5-(tri-n-butyl- stannyl)pyrazine, Precursor
14-69, to provide 1-benzoyl-4-[(7-(2-methylsul-
fonylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine MS
m/z: (M+H).sup.+ Calc'd for C.sub.26H.sub.26N.sub.7O.sub.6S:
564.17; found 564.21. HPLC retention time: 1.24 minutes (column
A).
EXAMPLE 48
[0886] 603
[0887] Example 48, was prepared according to the general method
described above starting from Precursor 5b and
2,4-dimethoxy-1,3,5-triazin-6-yl tributyltin, Precursor 14-70, to
provide 1-benzoyl-4-[(7-(2,4-dimethoxy-1-
,3,5-triazin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine MS m/z:
(M+H).sup.+ Calc'd for C.sub.26H.sub.26N.sub.7O.sub.6: 532.19;
found 532.12. HPLC retention time: 1.28 minutes (column A).
EXAMPLE 49
[0888] 604
[0889] Example 49, was prepared according to the general method
described above starting from Precursor 5b and pyrimidin-2-yl
tributyltin, Precursor 14-67, to provide
1-benzoyl-4-[(4-methoxy-7-(pyrimidin-2-yl)-6--
azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.23N.sub.6O.sub.4: 471.18; found 471.29. HPLC
retention time: 1.21 minutes (column A).
EXAMPLE 50
[0890] 605
[0891] Example 50, was prepared
froml-(pyridin-2-yl)-4-[(4-methoxy-7-chlor-
o-6-azaindol-3-yl)-oxoacetyl]piperazine and thiazol-2-yl
tributyltin, Precursor 14a-21, according to the general method
above to provide
1-(pyridin-2-yl)-4-[(4-methoxy-7-(thiazol-2-yl)-6-azaindol-3yl)-oxoacetyl-
]piperazine MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.25N.sub.6O.sub.4S- : 477.13; found 477.22. HPLC
retention time: 0.98 minutes (column A).
EXAMPLE 51
[0892] 606
[0893] Example 51, was prepared according to the general method
described above starting from Precursor 5d and pyrimidin-5-yl
tributyltin, Precursor 14-9, to provide
1-benzoyl-3-(R)-methyl-4-[(7-(pyrimidin-5-yl)--
4-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd
for C.sub.25H.sub.23N.sub.6O.sub.3: 455.18; found 455.16. HPLC
retention time: 0.98 minutes (column A).
EXAMPLE 52
[0894] 607
[0895] Example 52, was prepared according to the general method
described above starting from Precursor 5d and pyrimidin-2-yl
tributyltin, Precursor 14a-1, to provide
1-benzoyl-3-(R)-methyl-4-[(7-(pyrazin-2-yl)-4-
-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd
for C.sub.25H.sub.23N.sub.6O.sub.3: 455.18; found 455.16. HPLC
retention time: 1.09 minutes (column A).
EXAMPLE 53
[0896] 608
[0897] Example 53, was prepared according to the general method
described above starting from Precursor 5d and thiazol-2-yl
tributyltin, Precursor 14a-21, to provide
1-benzoyl-3-(R)-methyl-4-[(7-(thiazol-2-yl)-4-azaindol-
-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.22N.sub.5O.sub.3S: 460.14; found 460.26. HPLC
retention time: 1.02 minutes (column A).
EXAMPLE 54
[0898] 609
[0899] Example 54, was prepared according to the general method
described above starting from Precursor 5d and 2-ethoxythiazol-5-yl
tributyltin, Precursor 14-71, to provide
1-benzoyl-3-(R)-methyl-4-[(7-(2-ethoxy-thiazo-
l-5-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+
Calc'd for C.sub.26H.sub.26N.sub.5O.sub.4S: 504.17; found 4504.18.
HPLC retention time: 1.26 minutes (column A).
EXAMPLE 55
[0900] 610
[0901] The compound of Example 15,
1-benzoyl-4-[(4-methoxy-7-(2-(1,1-dimet-
hylethylaminocarbonyl)-pyrazin-5-yl)-azaindol-3-yl)-oxoacetyl]piperazine
(20 mg) was dissolved in 1 drop of concentrated sulfuric acid.
After 30 minutes, the mixture was diluted with 2 mL of methanol.
The resulting solution was injected into a Shimadzu automated
preparative HPLC System and the HPLC purification afforded the
compound of Example 55,
1-benzoyl-4-[(4-methoxy-7-(2-aminocarbonyl-pyrazin-5-yl)-6-azaindol-3-yl)-
-oxoacetyl]piperazine (1 mg); MS m/z: (M+H).sup.+ Calc'd for
C.sub.26H.sub.24N.sub.7O.sub.5: 514.78; found 514.22. HPLC
retention time: 1.44 minutes (column B).
EXAMPLE 56
[0902] 611
[0903] An excess of NH.sub.4Cl (27 mg) was added into a solution of
1-(benzoyl)-3-(R)-methyl-4-[(6-cyano-7-azaindol-3-yl)-oxoacetyl]piperazin-
e (20 mg) and NaN.sub.3 (16 mg) in DMF. The reaction was heated to
reflux for 12 h. After cooling down, the mixture was concentrated
under reduced pressure and the residue was purified using Shimadzu
automated preparative HPLC System to give
1-benzoyl-3-(R)-methyl-4-[(6-(tetrazol-1--
yl)-7-azaindol-3-yl)-oxoacetyl]piperazine (6.3 mg). MS m/z:
(M+H).sup.+ Calc'd for C.sub.22H.sub.21N.sub.8O.sub.3: 445.17;
Found 3445.16. HPLC retention time: 1.42 minutes (column B); Column
B: PHX-LUNA C18 4.6.times.30 mm.
EXAMPLE 57
[0904] 612
[0905] Preparation of
1-benzoyl-3-(R)-methyl-4-[(7-(methoxymethylamino)car-
bonyl)-4-azaindol-3-yl)-oxoacetyl]piperazine: A mixture of
Precursor 13 (267 mg), N,O-dimethylhydroxylamine hydrogen chloride
(248 mg), carbon tetrabromide (844 mg), pyridine (202 mg) and
triphenylphosphine (668 mg) in dichloromethane (10 mL) was stirred
at room temperature for 10 hours. After solvent was removed under
vaccum, the residue was purified by using silica gel chromatography
to afford 1-(benzoyl)-3-(R)-methyl-4-[(7-(metho-
xymethylamino)carbonyl)-4-azaindol-3-yl)-oxoacetyl]piperazine (56
mg); MS m/z: (M+H).sup.+ Calc'd for C.sub.24H.sub.26N.sub.5O.sub.5:
464.19; found 464.25. HPLC retention time: 1.02 minutes (column
A).
EXAMPLE 58
[0906] 613
[0907] Example 58 was prepared according to the same procedure used
in preparing Example 57 with the exception of using Precursor 11 as
a starting material instead of Precursor 13. The procedure provided
1-benzoyl-3-(R)-methyl-4-[(5-chloro-(7-(methoxymethylamino)carbonyl)-4-az-
aindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.25ClN.sub.5O.sub.5: 498.15; found 498.12. HPLC
retention time: 1.39 minutes (column A).
[0908] General Procedure A to Prepare CO-NR1R2 fromCOOH
EXAMPLE 59
[0909] 614
[0910] Preparation of
1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(methylamino)c-
arbonyl)-4-azaindol-3-yl)-oxoacetyl]piperazine: A mixture of
Precursor 11 (25 mg), methylamine (2M in THF, 0.08 mL), EDC (26
mg), HOBT (11.2 mg) and diisopropylethylamine (43 mg) in
tetrahydrofuran (5 mL) was stirred at room temperature for 10
hours. After the solvent was removed under vaccum, the residue was
purified by using silica gel chromatography to afford
1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(methylamino)carbonyl)-4-aza-
indol-3-yl)-oxoacetyl]piperazine (13.6 mg); MS m/z: (M+H).sup.+
Calc'd for C.sub.23H.sub.23ClN.sub.5O.sub.4: 468.14; found 468.03.
HPLC retention time: 1.33 minutes (column A).
[0911] This general produre A is applied to prepare examples 94 and
135:
EXAMPLE 94
[0912] 615
[0913] Example
94,1-benzoyl-4-[(4-methoxy-7-(2-methylaminocarbonyl-furan-5-
-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta.8.37 (s, 1H), 8.06 (s, 1H), 7.48-7.26 (m, 7H),
4.08 (s, 3H), 3.83-3.44 (m, 8H), 2.96 (s, 3H). MS m/z: (M+H).sup.+
Calc'd for C.sub.29H.sub.26N.sub.5O.sub.6: 516.19; found 516.14.
HPLC retention time: 1.35 minutes (column A).
EXAMPLE 135
[0914] 616
[0915] Example 135, (R)-
1-benzoyl-3-methyl-4-[(7-(4-trifluoromethylbenzyl- amino)
carbonyl-4-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+
Calc'd for C.sub.30H.sub.27F.sub.3N.sub.5O.sub.4: 578.20; found
578.39. HPLC retention time: 1.47 minutes (column G).
[0916] General Procedure B to Prepare CO-NR1R2 fromCOOH 617
[0917] Preparation of Example 136,
(R)-1-benzoyl-3-methyl-4-[(7-(4-methylt-
hiazol-2-yl)aminocarbonyl-4-azaindol-3-yl)-oxoacetyl]piperazine:
[0918] To a solution of
(R)-1-benzoyl-3-methyl-4-[(7-hydroxylcarbonyl-4-az-
aindol-3-yl)-oxoacetyl]piperazine (146 mg) in DMF (5 ml) at room
temperature was added pentafluorophenyl (70.3 mg) followed by EDC
(73.23 mg). The reaction mixture was stirred at room temperature
for 8 hours. The crude product was diluted with methylene chloride
and was washed with water, 0.1N HCl and brine. The organic phase
was dried over MgSO4, filtered and concentrated. The
pentafluorophenyl ester was used in the following reaction without
further purification.
[0919] To a stirred solution of 4-methyl-2-amino-thiazole (39.6 mg)
and Hunig's base (49.4 mg) in DMF (5 ml) at room temperature was
added a solution of pentafluorophenyl ester (1/3 of the product
obtained in the previous step described above) in DMF (2 ml). The
reaction mixture was stirred at room temperature for 16 hours. The
crude product was diluted with methylene chloride and was washed
with Na2CO3 (sat.) and brine. The organic phase was dried over
MgSO4, filtered and concentrated. The residue was purified using
Shimadzu automated preparative HPLC System to give
(R)-1-benzoyl-3-methyl-4-[(7-(4-methylthiazol-2-yl)aminocarbonyl-4-a-
zaindol-3-yl)-oxoacetyl]piperazine (3.6 mg). MS m/z: (M+H).sup.+
Calc'd for C.sub.26H.sub.25N.sub.6O.sub.4S: 517.17; found 517.41.
HPLC retention time: 1.25 minutes (column A).
[0920] This general produre B is applied to prepare example
137:
EXAMPLE 137
[0921] 618
[0922] Example 137, (R)-
1-benzoyl-3-methyl-4-[(7-(thiazol-2-yl)aminocarbo-
nyl-4-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+
Calc'd for C.sub.25H.sub.23N.sub.6O.sub.4S: 503.15; found 503.29.
HPLC retention time: 1.33 minutes (column A).
EXAMPLE 60
[0923] 619
[0924] Preparation of
1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(imidazol-2-yl-
)-4-azaindol-3-yl)-oxoacetyl]piperazine: A mixture of Precursor 10
(34 mg), glyoxal (40% in water, 0.2 mL) and ammonia acetate (139
mg) in methanol was heated up to reflux for 10 hours. After cooling
down, the mixture was concentrated under reduced pressure and the
residue was purified using Shimadzu automated preparative HPLC
System to provide
1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(imidazol-2-yl)-4-azaindol-3-yl)-ox-
oacetyl]piperazine (1.8 mg); MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.22ClN.sub.6O.sub.3: 477.14; found 477.13. HPLC
retention time: 1.17 minutes (column A).
EXAMPLE 61
[0925] 620
[0926] Example 61 was prepared according to the same procedure used
for preparing Example 60 with the exception of using methylglyoxal
as a starting material instead of glyoxal to
providel-benzoyl-3-(R)-methyl-4-[-
(5-chloro-7-(4-methyl-imidazol-2-yl)-4-azaindol-3yl)-oxoacetyl]piperazine
MS m/z: (M+H).sup.+ Calc'd for C.sub.25H.sub.24ClN.sub.6O.sub.3:
491.16; found 491.13. HPLC retention time: 1.26 minutes (column
A).
EXAMPLE 62
[0927] 621
[0928] Example 62 was prepared according to the same procedure used
for preparing Example 60 with the exception of using
dimethylglyoxal as a starting material instead of glyoxal to
provide 1-benzoyl-3-(R)-methyl-4--
[(5-chloro-7-(4,5-dimethyl-imidazol-2-yl)-4-azaindol-3yl)-oxoacetyl]pipera-
zine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.26H.sub.26ClN.sub.6O.sub.3: 505.18; found 505.10. HPLC
retention time: 1.24 minutes (column A).
EXAMPLE 63
[0929] 622
[0930] Preparation of
1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(oxazol-5-yl)--
4-azaindol-3-yl)-oxoacetyl]piperazine: A mixture of Precursor 10
(27.6 mg), tosylmethyl isocyanide (12.3 mg) and K.sub.2CO.sub.3
(8.7 mg) in MeOH was heated up to reflux for 10 hours. After
cooling down, the mixture was concentrated under reduced pressure
and the residue was purified using Shimadzu automated preparative
HPLC System to provide
1-(benzoyl)-3-(R)-methyl-4-[(5-chloro-7-(oxazol-5-yl)-4-azaindol-3-yl)-ox-
oacetyl]piperazine (17.7 mg); MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.21ClN.sub.5O.sub.4: 478.13; found 478.03. HPLC
retention time: 1.48 minutes (column A).
EXAMPLE 64
[0931] 623
[0932] Step 1: Preparation of I-64,
1-benzoyl-3-(R)-methyl-4-[(7-(2-propyn-
yl)carbonyl-4-azaindol-3yl)-oxoacetyl]piperazine Propynyllithium
(21 mg) was added to a solution of Example 52 (41 mg) in
tetrahydrofuran (5 ml) a -78.degree. C. The reaction was quenched
with methanol at -25.degree. C. in 2 hours. After solvents were
removed under vaccum, the residue was carried to the further
reactions without any purification. I-64,
1-benzoyl-3-(R)-methyl-4-[(7-(2-propynyl)carbonyl-4-azaindol-3-yl)-oxoace-
tyl]piperazine MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.22ClN.sub.4O.s- ub.4: 477.13; found 477.17. HPLC
retention time: 1.46 minutes (column A).
[0933] Step 2: Preparation of Example 64: 624
[0934] Example 64
[0935] Preparation of Example 64,
1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(3-
methyl-pyrazol-5-yl)-4-azaindol-3yl)-oxoacetyl]piperazine: A
mixture of I-64 (crude product from Step 1) and hydrazine (0.22 mL)
in EtOAc (2 mL) and water (2 mL) was stirred at room temperature
for 24 hours. Then solvents were removed under vaccum, and the
residue was purified using Shimadzu automated preparative HPLC
System to give
1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-(3-methyl-pyrazol-5-yl)-4-azaindol--
3-yl)-oxoacetyl]piperazine (9 mg); MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.24ClN.sub.6O.sub.3: 491.16; found 491.19. HPLC
retention time: 1.42 minutes (column A).
EXAMPLES 65-67
[0936] The procedure for the preparation of Examples 65-67 is the
same as that described previously for the preparation of Precursor
5a and is as follows: Potassium
7-(4-methoxyphenyl)-4-azaindole-3-glyoxylate, Precursor 4c (147 mg,
0.44 mmol), an appropriate 1-benzoylpiperazine derivative (0.44
mmol), 3(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H--
one-(DEPBT) (101 mg, 0.44 mol) and Hunig's Base (0.5 mL) were
combined in 5 mL of DMF. The mixture was stirred at rt for 8 h. DMF
was removed via evaporation at reduced pressure and the residue was
purified using a Shimadzu automated preparative HPLC System to give
the corresponding
1-benzoyl-4-[(7-(4-methoxyphenyl)-4-azaindol-3-yl)-oxoacetyl]-piperazine
derivative.
EXAMPLE 65
[0937] 625
[0938] Example 19,
1-(benzoyl)-4-[(7-(4-methoxy)-4-azaindol-3-yl)oxoacetyl-
]piperazine was prepared from potassium
7-(4-methoxyphenyl)-4-azaindole-3-- glyoxylate and
1-(benzoyl)piperazine according to the above general procedure. MS
m/z: (M+H).sup.+ Calc'd for C.sub.27H.sub.25N.sub.4O.sub.4: 469.19;
found 469.16. HPLC retention time: 1.26 minutes (column A).
EXAMPLE 66
[0939] 626
[0940] Example 66,
1-benzoyl-3-(S)-methyl-4-[(7-(4-methoxy)-4-azaindol-3-y-
l)oxoacetyl]piperazine was prepared from potassium
7-(4-methoxyphenyl)-4-a- zaindole-3-glyoxylate and the
corresponding 1-(benzoyl)-3-methylpiperazine according to the above
general procedure. MS m/z: (M+H).sup.+ Calc'd for
C.sub.28H.sub.27N.sub.4O.sub.4: 483.20; found 483.17. HPLC
retention time: 1.30 minutes (column A).
EXAMPLE 67
[0941] 627
[0942] Example 67,
1-benzoyl-3-(R)-methyl-4-[(7-(4-methoxyphenyl)-4-azaind-
ol-3-yl)oxoacetyl]piperazine was prepared from potassium
7-(4-methoxyphenyl)-4-azaindole-3-glyoxylate and the corresponding
1-benzoyl-3-methylpiperazine according to the above general
procedure. MS m/z: (M+H).sup.+ Calc'd for
C.sub.28H.sub.27N.sub.4O.sub.4: 483.20; found 483.16. HPLC
retention time: 1.28 minutes (column A).
EXAMPLES 68-79 and 81
[0943] Examples 68-79 and 81 were prepared according to the same
general method as previously described for Examples 16-54.
EXAMPLE 68
[0944] 628
[0945] Example 68, was prepared from Precursor 5b and the
2,4-dimethoxypyrimidin-6-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-
-(2,6-dimethoxy-pyrimidin-4-yl)-6-azaindol-3yl)-oxoacetyl]piperazine.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta.8.20 (s, 1H), 8.13 (s,
1H), 7.52 (s, 1H), 7.42 (m, 5H), 4.11 (s, 3H), 4.06 (s, 3H),
4.00-3.40 (m, 8H). MS m/z: (M+H).sup.+ Calc'd for
C.sub.27H.sub.27N.sub.6O.sub.6: 531.20; found 531.24. HPLC
retention time: 1.54 minutes (column A).
EXAMPLE 69
[0946] 629
[0947] Example 69, was prepared from Precursor 5b and the
6-methoxypyridin-3-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(6-me-
thoxy-pyridin-3-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta.8.69 (s, 1H), 8.63 (s, 1H), 8.11
(m, 2H), 7.49 (m, 5H), 7.10 (d, 1H, J=8.65 Hz), 4.16 (s, 3H), 4.06
(s,3H), 4.00-3.40 (m, 8H). MS m/z: (M+H).sup.+ Calc'd for
C.sub.27H.sub.26N.sub.5- O.sub.5: 500.09; found 500.20. HPLC
retention time: 1.11 minutes (column A).
EXAMPLE 70
[0948] 630
[0949] Example 70, was prepared from Precursor 5b and the
2-diethylamino-thiazol-4-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-
-(2-diethylamino-thiazol-4-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta.8.47 (s, 1H), 7.97 (m,
2H), 7.49 (m, 5H), 4.08 (s, 3H), 3.64 (m, 12H), 1.35 (m, 6H). MS
m/z: (M+H).sup.+ Calc'd for C.sub.28H.sub.31N.sub.6O.sub.4S:
547.21; found 547.22. HPLC retention time: 1.35 minutes (column
A).
EXAMPLE 71
[0950] 631
[0951] Example 71, was prepared from Precursor 5b and the
thiazol-5-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(thioazol-5-yl)-6-azaindol--
3-yl)-oxoacetyl]piperazine. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta.9.19 (s, 1H), 8.64 (s, 1H), 8.34 (s, 1H), 8.11 (s, 1H), 7.46
(m, 5H), 4.00 (s, 3H), 3.55 (m, 8H). MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.22N.sub.5O.sub.4S: 476.14; found 476.17. HPLC
retention time: 1.13 minutes (column A).
EXAMPLE 72
[0952] 632
[0953] Example 72, was prepared from Precursor 5b and the
2-dimethylamino-pyrazin-5-yl stannane to provide
1-(benzoyl)-4-[(4-methox-
y-7-(2-dimethylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS m/z: (M+H).sup.+ Calc'd for C.sub.27H.sub.28N.sub.7O.sub.4:
514.22; found 514.29. HPLC retention time: 1.27 minutes (column
A).
EXAMPLE 73
[0954] 633
[0955] Example 73, was prepared from Precursor 5b and the
furan-2-yl stannane to provide
1-(benzoyl)-4-[(4-methoxy-7-(furan-2-yl)-6-azaindol-3-
-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.23N.sub.4O.sub.5: 459.17; found 459.25. HPLC
retention time: 1.15 minutes (column A).
EXAMPLE 74
[0956] 634
[0957] Example 74, was prepared from Precursor 5b and the
oxazol-2-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(oxazol-2-yl)-6-azaindol-3--
yl)-oxoacetyl]piperazine. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta.9.19 (s, 1H), 8.64 (s, 1H), 8.34 (s, 1H), 8.11 (s, 1H), 7.46
(m, 5H), 4.00 (s, 3H), 3.55 (m, 8H). MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.22N.sub.5- O.sub.5: 460.16; found 460.23. HPLC
retention time: 1.22 minutes (column A).
EXAMPLE 75
[0958] 635
[0959] Example 75, was prepared from Precursor 5b and the
6-aminopyridin-2-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(2-amin-
opyridin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z:
(M+H).sup.+ Calc'd for C.sub.26H.sub.25N.sub.6O.sub.4: 485.19;
found 485.24. HPLC retention time: 1.15 minutes (column A).
EXAMPLE 76
[0960] 636
[0961] Example 76, was prepared from Precursor 5b and the
6-methylpyridin-2-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(2-met-
hyl-pyridin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z:
(M+H).sup.+ Calc'd for C.sub.27H.sub.26N.sub.5O.sub.4: 484.20;
found 484.22. HPLC retention time: 1.24 minutes (column A).
EXAMPLE 77
[0962] 637
[0963] Example 77, was prepared from Precursor 5b and the
6-methoxypyridin-2-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(2-me-
thoxy-pyridin-6-yl)-6-azaindol3-yl)-oxoacetyl]piperazine. MS m/z:
(M+H).sup.+ Calc'd for C.sub.27H.sub.26N.sub.5O.sub.5: 500.19;
found 500.23. HPLC retention time: 1.26 minutes (column A).
EXAMPLE 78
[0964] 638
[0965] Example 78, was prepared from Precursor 5b and the
2-acetylamino-thiazol-5-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7--
(2-acetylamino-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS m/z: (M+H).sup.+ Calc'd for C.sub.26H2.sub.5N.sub.6O.sub.5S:
533.16; found 533.18. HPLC retention time: 1.21 minutes (column
A).
EXAMPLE 79
[0966] 639
[0967] Example 79, was prepared from Precursor 5b and the
2-ethylamino-pyrazin-5-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(-
2-ethylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS m/z: (M+H).sup.+ Calc'd for C.sub.27H.sub.28N.sub.7O.sub.4:
514.22; found 514.18. HPLC retention time: 1.31 minutes (column
A).
EXAMPLE 88
[0968] 640
[0969] Example 88, was prepared from Precursor 5b and the
2-ethyl-thiazol-5-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(2-eth-
yl-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z:
(M+H).sup.+ Calc'd for C.sub.26H.sub.26N.sub.5O.sub.4S: 504.17;
found 514.32. HPLC retention time: 1.50 minutes (column A).
EXAMPLE 89
[0970] 641
[0971] Example 89, was prepared from Precursor 5k and the
2-isobutyl-thiazol-5-yl stannane to provide
1-benzoyl-4-[(7-(2-isobutyl-t-
hiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z:
(M+H).sup.+ Calc'd for C.sub.27H.sub.28N.sub.5O.sub.3S: 502.19;
found 502.26. HPLC retention time: 1.56 minutes (column E).
EXAMPLE 90
[0972] 642
[0973] Example 90, was prepared from Precursor 5b and the
2-isobutyl-thiazol-5-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(2--
isobutyl-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS
m/z: (M+H).sup.+ Calc'd for C.sub.28H.sub.30N.sub.5O.sub.4S:
532.20; found 532.27. HPLC retention time: 1.57 minutes (column
E).
EXAMPLE 91
[0974] 643
[0975] Example 91, was prepared from Precursor 5b and the
2-(2-butyl)-thiazol-5-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(2-
-(2-butyl)-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS
m/z: (M+H).sup.+ Calc'd for C.sub.28H.sub.30N.sub.5O.sub.4S:
532.20; found 532.27. HPLC retention time: 1.57 minutes (column
E).
EXAMPLE 92
[0976] 644
[0977] Example 92, was prepared from Precursor 5b and the
2-(thiazol-2-yl)-thiazol-5-yl stannane to provide
1-benzoyl-4-[(4-methoxy-
-7-(2-(thiazol-2-yl)-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS m/z: (M+H).sup.+ Calc'd for
C.sub.27H.sub.23N.sub.6O.sub.4S.sub.2: 559.12; found 559.18. HPLC
retention time: 1.55 minutes (column E).
EXAMPLE 93
[0978] 645
[0979] Example 93, was prepared from Precursor 5b and the
2-methylthio-thiazol-5-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(-
2-methylthio-thiazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.24N.sub.5O.sub.4S.sub.2: 522.13; found 522.17. HPLC
retention time: 1.45 minutes (column E).
EXAMPLE 95
[0980] 646
[0981] Example 95, was prepared from Precursor 5i and the
pyrazin-2-yl stannane to provide
1-benzoyl-4-[(4-fluoro-7-(pyrazin-2-yl)-6-azaindol-3--
yl)-oxoacetyl]piperazine. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta.9.89 (s, 1H), 8.70-8.34 (m, 4H), 7.46 (m, 5H), 3.80-3.50 (m,
8H). MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.20FN.sub.6O.sub.3: 459.16; found 459.33. HPLC
retention time: 1.46 minutes (column G).
EXAMPLE 100
[0982] 647
[0983] Example 100, was prepared from Precursor 5b and the
2-methylamino-3methoxy-pyrazin-5-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(2-methylamino-3-methoxy-pyrazin-5-yl)-6-azaind-
ol-3-yl)-oxoacetyl]piperazine. .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta.8.65 (s, 1H), 8.43 (s, 1H), 7.95 (s, 1H), 7.45 (m, 5H), 4.21
(s, 3H), 4.12 (s, 3H), 3.89-3.32 (m, 8H), 3.06 (s, 3H). MS m/z:
(M+H).sup.+ Calc'd for C.sub.27H.sub.28N.sub.7O.sub.5: 530.22;
found 530.19. HPLC retention time: 1.31 minutes (column A).
EXAMPLE 101
[0984] 648
[0985] Example 101, was prepared from Precursor 5b and the
2-amino-3-methoxypyrazin-5-yl stannane to provide
1-benzoyl-4-[(4-methoxy-
-7-(2-amino-3-methoxy-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta.8.67 (s, 1H), 8.34 (s,
1H), 7.96 (s, 1H), 7.48 (m, 5H), 4.22 (s, 3H), 4.12 (s, 3H),
3.92-3.32 (m, 8H). MS m/z: (M+H).sup.+ Calc'd for
C.sub.26H.sub.26N.sub.7O.sub.5: 516.20; found 516.23. HPLC
retention time: 1.27 minutes (column A).
EXAMPLE 102
[0986] 649
[0987] Example 102, was prepared from Precursor 51 and the
pyrazin-2-yl stannane to provide
1-picolinoyl-4-[(4-methoxy-7-(pyrazin-2-yl)-6-azaindo-
l-3-yl)-oxoacetyl]piperazine. .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta.9.59 (s, 1H), 8.79-7.51 (m, 8H), 4.13 (s, 3H), 3.95-3.34 (m,
8H). MS m/z: (M+H).sup.+ Calc'for C.sub.24H.sub.22N.sub.7O.sub.4:
472.17; found 472.25. HPLC retention time: 1.15 minutes (column
A).
EXAMPLE 103
[0988] 650
[0989] Example 103, was prepared from Precursor 51 and the
2-dimethylamino-pyrazin-5-yl stannane to provide
1-picolinoyl-4-[(4-metho-
xy-7-(2-dimethylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS m/z: (M+H).sup.+ Calc'd for C.sub.26H.sub.27N.sub.8O.sub.4:
515.22; found 515.16. HPLC retention time: 1.29 minutes (column
A).
EXAMPLE 104
[0990] 651
[0991] Example 104, was prepared from Precursor 5b and the
6-aza-benzofuran-2-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(6-az-
a-benzofuran-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. .sup.1H
NMR (500 MHz, CDCl.sub.3) 88.48 (d, 1H, J=8.5 Hz), 8.36 (s, 1H),
8.30 (s, 1H), 8.02 (s, 1H), 7.64 (d, 1H, J=8.55 Hz), 7.41 (m, 4H),
6.92 (s, 1H), 4.12 (s, 3H), 3.87-3.38 (m, 8H). MS m/z: (M+H).sup.+
Calc'd for C.sub.28H.sub.24N.sub.5O.sub.5: 510.18; found 510.33.
HPLC retention time: 1.33 minutes (column A).
EXAMPLE 105
[0992] 652
[0993] Example 105, was prepared from Precursor 5m and the
2-dimethylamino-pyrazin-5-yl stannane to provide
(R)-1-picolinoyl-3-methy-
l-4-[(7-(2-dimethylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazi-
ne. MS m/z: (M+H).sup.+ Calc'd for C.sub.26H.sub.27N.sub.8O.sub.3:
499.22; found 499.27. HPLC retention time: 1.17 minutes (column
A).
EXAMPLE 106
[0994] 653
[0995] Example 106, was prepared from Precursor 5n and the
2-dimethylamino-pyrazin-5-yl stannane to provide
(S)-1-picolinoyl-3-methy-
l-4-[(7-(2-dimethylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazi-
ne. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.9.08-7.49 (m, 9H),
5.00-3.15 (m, 13H), 1.44-1.27 (m, 3H). MS m/z: (M+H).sup.+Calc'd
for C.sub.26H.sub.27N.sub.8O.sub.3: 499.22; found 499.27. HPLC
retention time: 1.19 minutes (column A).
EXAMPLE 109
[0996] 654
[0997] Example 109, was prepared from Precursor 5m and the
thiazol-5-yl stannane to provide
(R)-1-picolinoyl-3-methyl-4-[(7-(thiazol-5-yl)-6-azai-
ndol-3-yl)-oxoacetyl]piperazine.. .sup.1H NMR (500 MHz, CD.sub.3OD)
89.42-7.49 (m, 9H), 4.98-3.14 (m, 7H), 1.43-1.26 (m, 3H). MS m/z:
(M+H).sup.+ Calc'd for C.sub.23H.sub.21N.sub.6O.sub.3S: 461.14;
found 461.28. HPLC retention time: 1.11 minutes (column A).
EXAMPLE 110
[0998] 655
[0999] Example 110, was prepared from Precursor 5n and the
thiazol-5-yl stannane to provide
(S)-1-picolinoyl-3-methyl-4-[(7-(thiazol-5-yl)-6-azai-
ndol-3-yl)-oxoacetyl]piperazine.. .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta.9.44-7.48 (m, 9H), 4.98-3.15 (m, 7H), 1.43-1.26 (m, 3H). MS
m/z: (M+H).sup.+ Calc'd for C.sub.23H.sub.21N.sub.6O.sub.3S:
461.14; found 461.27. HPLC retention time: 1. 13 minutes (column
A).
EXAMPLE 111
[1000] 656
[1001] Example 111, was prepared from Precursor 5f and the
2-amino-pyrazin-6-yl stannane to provide
(R)-1-benzoyl-3-methyl-4-[(7-(2--
amino-pyrazin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta.8.68-7.45 (m, 10H), 4.89-3.13 (m,
7H), 1.39-0.99 (m, 3H). MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.24N.sub.7- O.sub.3: 470.19; found 470.31. HPLC
retention time: 1.30 minutes (column A).
EXAMPLE 112
[1002] 657
[1003] Example 112, was prepared from Precursor 5f and the
2-amino-pyridin-6-yl stannane to provide
(R)-1-benzoyl-3-methyl-4-[(7-(2--
amino-pyridin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta.8.65-6.89 (m, 11H), 4.90-3.12 (m,
7H), 1.39-0.99 (m, 3H). MS m/z: (M+H).sup.+ Calc'd for
C.sub.26H.sub.25N.sub.6- O.sub.3: 469.20; found 469.32. HPLC
retention time: 1.26 minutes (column A).
EXAMPLE 113
[1004] 658
[1005] Example 113, was prepared from Precursor 5f and the
2-amino-pyridin-5-yl stannane to provide
(R)-1-benzoyl-3-methyl-4-[(7-(2--
amino-pyridin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. .sup.1H
NMR (500 MHz, CD.sub.3OD) 88.75-7.19 (m, 11H), 4.91-3.12 (m, 7H),
1.38-1.25 (m, 3H). MS m/z: (M+H).sup.+ Calc'd for
C.sub.26H.sub.25N.sub.6O.sub.3: 469.20; found 469.34. HPLC
retention time: 1.05 minutes (column A).
EXAMPLE 114
[1006] 659
[1007] Example 114, was prepared from Precursor 5f and the
5-amino-pyridin-2-yl stannane to provide
(R)-1-benzoyl-3-methyl-4-[(7-(5--
amino-pyridin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta.8.67-7.20 (m, 11H), 4.88-3.13 (m,
7H), 1.39-1.25 (m, 3H). MS m/z: (M+H).sup.+ Calc'd for
C.sub.26H.sub.25N.sub.6- O.sub.3: 469.20; found 469.33. HPLC
retention time: 1.22 minutes (column A).
EXAMPLE 115
[1008] 660
[1009] Example 115, was prepared from Precursor 5b and the
2-methylamino-pyrazin-5-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7--
(2-methylamino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta.8.90 (s, 1H), 8.61 (s,
1H), 8.18 (s, 1H), 7.92 (s, 1H), 7.46 (m, 5H), 4.12 (s, 3H),
3.85-3.40 (m, 8H), 3.02 (s, 3H). MS m/z: (M+H).sup.+ Calc'd for
C.sub.26H.sub.26N.sub.7O.sub- .4: 500.20; found 500.23. HPLC
retention time: 1.24 minutes (column A).
EXAMPLE 116
[1010] 661
[1011] Example 116, was prepared from Precursor 5b and the
2-(2-pyrrolidinon-1-yl)-thiazol-5-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-((2-pyrrolidinon-1-yl)-thiazol-5-yl)-6-azaindol-
-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.28H.sub.27N.sub.6O.sub.5S.sub.2: 559.18; found 559.11. HPLC
retention time: 1.39 minutes (column E).
EXAMPLE 117
[1012] 662
[1013] Example 117, was prepared from Precursor 5b and the
2-methoxy-pyrimidin-5-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(2-
-methoxy-pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS
m/z: (M+H).sup.+ Calc'd for C.sub.26H.sub.25N.sub.6O.sub.5: 501.19;
found 501.12. HPLC retention time: 1.21 minutes (column E).
EXAMPLE 118
[1014] 663
[1015] Example 118, was prepared from Precursor 5b and the
2-(pyrrol-1-yl)-pyrimidin-5-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(2-(pyrrol-1-yl)-pyrimidin-5-yl)-6-azaindol-3-y-
l)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.29H.sub.26N.sub.7O.sub.4: 536.20; found 536.33. HPLC
retention time: 1.44 minutes (column C).
EXAMPLE 119
[1016] 664
[1017] Example 119, was prepared from Precursor 5b and the
pyrimidin-4-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(pyrimidin-5-yl)-6-azaindol-
-3-yl)-oxoacetyl]piperazine. .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta.9.29 (s, 1H), 8.88 (d, 1H, J=5.4 Hz), 8.48 (d, 1H, J=5.25
Hz), 8.26 (s, 1H), 8.18 (s, 1H), 7.43 (m, 5H), 4.13 (s, 3H),
3.85-3.47 (m, 8H). MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.23N.sub.6O.sub.4: 471.18; found 471.32. HPLC
retention time: 1.35 minutes (column G).
EXAMPLE 120
[1018] 665
[1019] Example 119, was prepared from Precursor 5b and the
pyridazin-3-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(pyridazin-3-yl)-6-azaindol-
-3-yl)-oxoacetyl]-piperazine. .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta.9.16 (s, 1H), 8.77 (d, 1H, J=8.5 Hz), 8.26 (d, 1H, J=3.05
Hz), 8.18 (s, 1H), 7.68 (m, 1H), 7.43 (m, 5H), 4.13 (s, 3H),
3.85-3.47 (m, 8H). MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.23N.sub.6O.sub.4: 471.18; found 471.16. HPLC
retention time: 1.35 minutes (column G).
EXAMPLE 125
[1020] 666
[1021] Example 125, was prepared from Precursor 5i and the
pyrimidin-4-yl stannane to provide
1-benzoyl-4-[(4-fluoro-7-(pyrimidin-5-yl)-6-azaindol--
3-yl)-oxoacetyl]piperazine. .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta.9.36 (s, 1H), 8.96 (d, 1H, J=5.35 Hz), 8.58 (d, 1H, J=5.10
Hz), 8.43 (s, 1H), 8.38 (s, 1H), 7.43 (m, 5H), 3.85-3.47 (m, 8H).
MS m/z: (M+H).sup.+ Calc'd for C.sub.24H.sub.20FN.sub.6O.sub.2:
459.16; found 459.15. HPLC retention time: 1.48 minutes (column
A).
EXAMPLE 126
[1022] 667
[1023] Example 126, was prepared from Precursor 5i and the
oxazol-2-yl stannane to provide
(R)-1-benzoyl-3-Methyl-4-[7-(oxazol-2-yl)-4-azaindol--
3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.22N.sub.5O.sub.4: 444.17; found 444.25. HPLC
retention time: 1.13 minutes (column A).
EXAMPLE 131
[1024] 668
[1025] Example 131, was prepared from Precursor 5p and the
thiazol-2-yl stannane to provide
1-benzoyl-4-[7-(thiazol-2-yl)-4-azaindol-3-yl)-oxoace-
tyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.23H.sub.20N.sub.5O.su- b.3S: 446.13; found 446.04. HPLC
retention time: 1.12 minutes (column A).
EXAMPLE 80
[1026] 669
[1027] Preparation of Example 80,
1-benzoyl-4-[(4-methoxy-7-(2-amino-thioa-
zol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. A mixture of
Example 78 (9 mg), TFA (3 mL) and water (1 mL) was stirred at
80.degree. C. for 10 hours. After solvent was removed under vaccum,
the residue was purified by using silica gel chromatography to
afford 1-benzoyl-4-[(4-methoxy-7-(2-
-amino-thioazol-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine (3 mg);
MS m/z: (M+H).sup.+ Calc'd for C.sub.24H.sub.23N.sub.6O.sub.5S:
491.15; found 491.21. HPLC retention time: 1.20 minutes (column
A).
EXAMPLE 81
[1028] 670
[1029] Example 81, was prepared from Precursor 5b and the
furan-3-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(furan-3-yl)-6-azaindol-3-y-
l)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.23N.sub.40.sub.5: 459.17; found 459.24. HPLC
retention time: 1.13 minutes (column A).
EXAMPLE 150
[1030] 671
[1031] Example 150, was prepared from Precursor 5f and the
5-amino-pyrazin-2-yl stannane to provide
(R)-1-benzoyl-3-methyl-4-[(7-(5--
amino-pyrazin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z:
(M+H).sup.+ Calc'd for C.sub.25H.sub.24N.sub.7O.sub.3: 470.19;
found 470.19. HPLC retention time: 1.14 minutes (column G).
EXAMPLE 153
[1032] 672
[1033] Example 153, was prepared from Precursor 5f and the
2-amino-pyrimidin-5-yl stannane to provide
(R)-1-benzoyl-3-methyl-4-[(7-(-
2-amino-pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS
m/z: (M+H).sup.+ Calc'd for C.sub.25H.sub.24N.sub.7O.sub.3: 470.19;
found 470.22. HPLC retention time: 1.07 minutes (column G).
EXAMPLE 170
[1034] 673
[1035] Example 170, was prepared from Precursor 5f and the
4-borono-bezoic acid to provide
(R)-1-benzoyl-3-methyl-4-[(7-(hydoxylcarbonyl-benzen-4-yl-
)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd
for C.sub.28H.sub.25N.sub.4O.sub.5: 497.18; found 497.10. HPLC
retention time: 1.25 minutes (column H).
EXAMPLE 171
[1036] 674
[1037] Example 171, was prepared from Precursor 5b and the
2-methyl-pyrimidin-5-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(2--
methyl-pyrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS
m/z: (M+H).sup.+ Calc'd for C.sub.26H.sub.25N.sub.6O.sub.4: 485.19;
found 485.20. HPLC retention time: 1.14 minutes (column C).
EXAMPLE 172
[1038] 675
[1039] Example 172, was prepared from Precursor 5l and the 5-indole
boronic acid to provide
1-picolinoyl-4-[(4-methoxy-7-(indol-5-yl)-6-azain-
dol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.28H.sub.25N.sub.6O.sub.4: 509.19; found 509.33. HPLC
retention time: 1.14 minutes (column J).
EXAMPLE 173
[1040] 676
[1041] Example 173, was prepared from Precursor 5l and the
thiazol-4-yl stannane to provide 1-picolinoyl
-4-[(4-methoxy-7-(thiazol-4-yl)-6-azaind-
ol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.23H.sub.21N.sub.6O.sub.4S: 477.13; found 477.06. HPLC
retention time: 0.92 minutes (column G).
EXAMPLE 174
[1042] 677
[1043] Example 174, was prepared from Precursor 5b and the
thiazol-4-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(thiazol-4-yl)-6-azaindol-3-
-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.22N.sub.5O.sub.4S: 476.14; found 476.13. HPLC
retention time: 1.12 minutes (column G).
EXAMPLE 175
[1044] 678
[1045] Example 175, was prepared from Precursor 5b and the
2-(N-diethylaminoethyl-N-methyl)aminopyrazin-5-yl stannane to
provide
1-benzoyl-4-[(4-methoxy-7-(2-(N-diethylaminoethyl-N-methyl)aminopyrazin-5-
-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+
Calc'd for C.sub.32H.sub.39N.sub.8O.sub.4: 599.31; found 599.29.
HPLC retention time: 1.11 minutes (column G).
EXAMPLE 176
[1046] 679
[1047] Example 176, was prepared from Precursor 5b and the
2-(N-dimethylaminoethyl-N-methyl)aminopyrazin-5-yl stannane to
provide
1-benzoyl-4-[(4-methoxy-7-(2-(N-dimethylaminoethyl-N-methyl)aminopyrazin--
5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+
Calc'd for C.sub.30H.sub.35N.sub.8O.sub.4: 571.28; found 571.23.
HPLC retention time: 1.06 minutes (column G).
EXAMPLE 177
[1048] 680
[1049] Example 177, was prepared from Precursor 5b and the
2-(N-piperazinyl)pyrazin-5-yl stannane to provide
1-benzoyl-4-[(4-methoxy-
-7-(2-(N-piperazinyl)-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS m/z: (M+H).sup.+ Calc'd for C.sub.29H.sub.31N.sub.8O.sub.4:
555.25; found 555.19. HPLC retention time: 1.05 minutes (column
G).
EXAMPLE 178
[1050] 681
[1051] Example 178, was prepared from Precursor 5b and the
2-(4-morpholinyl)-pyrazin-5-yl stannane to provide
1-benzoyl-4-[(4-methoxy-7-(2-(4-morpholinyl)-pyrazin-5-yl)-6-azaindol-3-y-
l)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.29H.sub.30N.sub.7O.sub.5: 556.23; found 556.18. HPLC
retention time: 1.27 minutes (column G).
EXAMPLE 179
[1052] 682
[1053] Example 179, was prepared from Precursor 5l and the
2-ethylaminopyrazin-5-yl stannane to provide
1-picolinoyl-4-[(4-methoxy-7-
-(2-ethylaminopyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS m/z: (M+H).sup.+ Calc'd for C.sub.26H.sub.27N.sub.8O.sub.4:
515.22; found 515.14. HPLC retention time: 1.13 minutes (column
G).
EXAMPLE 180
[1054] 683
[1055] Example 180, was prepared from Precursor 5l and the
2-methylpyrazin-5-yl stannane to provide
1-picolinoyl-4-[(4-methoxy-7-(2--
methylpyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z:
(M+H).sup.+ Calc'd for C.sub.25H.sub.24N.sub.7O.sub.4: 486.19;
found 486.16. HPLC retention time: 1.08 minutes (column G).
EXAMPLE 181
[1056] 684
[1057] Example 181, was prepared from Precursor 5l and the
2-cyclopropanyl-pyrazin-5-yl stannane to provide
1-picolinoyl-4-[(4-metho-
xy-7-(2-cyclopropanyl-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine.
MS m/z: (M+H).sup.+ Calc'd for C.sub.27H.sub.26N.sub.7O.sub.4:
512.20; found 512.12. HPLC retention time: 1.35 minutes (column
G).
EXAMPLE 182
[1058] 685
[1059] Example 182, was prepared from Precursor 5l and the
2-methoxy-pyrazin-5-yl stannane to provide
1-picolinoyl-4-[(4-methoxy-7-(-
2-methoxy-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS
m/z: (M+H).sup.+ Calc'd for C.sub.25H.sub.24N.sub.7O.sub.5: 502.18;
found 502.08. HPLC retention time: 1.15 minutes (column G).
EXAMPLE 183
[1060] 686
[1061] Example 183, was prepared from Precursor 5l and the
2-benzofuran boronic acid to provide
1-picolinoyl-4-[(4-methoxy-7-(benzofuran-2-yl)-6--
azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.28H.sub.24N.sub.5O.sub.5: 510.18; found 510.08. HPLC
retention time: 1.33 minutes (column G).
EXAMPLE 184
[1062] 687
[1063] Example 184, was prepared from Precursor 5l and the
2-diethylaminocarbonyl-pyrazin-5-yl stannane to provide
1-picolinoyl-4-[(4-methoxy-7-(2-diethylaminocarbonyl-pyrazin-5-yl)-6-azai-
ndol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.29H.sub.31N.sub.8O.sub.5: 571.24; found 571.19. HPLC
retention time: 1.55 minutes (column J).
EXAMPLE 185
[1064] 688
[1065] Example 185, was prepared from Precursor 5l and the
2-(N-pyrrolinyl)-pyrazin-5-yl stannane to provide
1-picolinoyl-4-[(4-meth-
oxy-7-(2-(N-pyrrolinyl)-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazin-
e. MS m/z: (M+H).sup.+ Calc'd for C.sub.28H.sub.29N.sub.8O.sub.4:
541.23; found 541.18. HPLC retention time: 1.30 minutes (column
J).
EXAMPLE 186
[1066] 689
[1067] Example 186, was prepared from Precursor 5l and the
quinoxalin-2-yl stannane to provide
1-picolinoyl-4-[(4-methoxy-7-(quinoxakin-2-yl)-6-azai-
ndol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.28H.sub.24N.sub.7O.sub.4: 522.19; found 522.14. HPLC
retention time: 1.68 minutes (column J).
EXAMPLE 194
[1068] 690
[1069] Example 194, was prepared from Precursor 5v and the
pyrazin-2-yl stannane to provide
2-methyl-1-picolinoyl-4-[(4-methoxy-7-(pyrazin-2-yl)--
6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd
for C.sub.25H.sub.24N.sub.7O.sub.4: 486.19; found 486.14. HPLC
retention time: 1.50 minutes (column G).
EXAMPLE 147
[1070] 691
[1071] Precursor 5i (16.5 mg, 0.05 mmol) in DMF (1 mL) was treated
with N-benzoylpiperazine hydrochloride, DEBPT (15 mg, 0.05 mmol)
and Hunig's base (34 .mu.L, 0.2 mmol) at rt for 18 h. The solvent
was removed in vacuum and the residue was purified by reverse phase
preparative HPLC. The fractions showing the right LC/MS(ES+) m/z
(M+H).sup.+=501 were collected, concentrated and purified again
using a preparative TLC (5% MeOH/CH.sub.2Cl.sub.2) to afford the
title compound as a white solid. .sup.1H-NMR (500 MHz, CDCl.sub.3)
.delta.11.2 (s, 1H), 10.0 (s, 1H), 9.21 (s, 1H), 8.51 (s, 1H), 8.41
(s, 1H), 8.40 (m, 1H), 8.32 (s, 1H), 7.62 (m, 1H), 7.45 (m, 5H),
3.90-3.50 (bm, 8H).
EXAMPLE 156
[1072] 692
[1073] Example 156, was prepared from Precursor 5b and the
4,4-dimethyloxazolin-2-yl stannane to provide
1-benzoyl-4-[(7-(4,4-dimeth-
yloxazolin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z:
(M+H).sup.+ Calc'd for C.sub.27H.sub.28N.sub.5O.sub.5: 490.21;
found 490.22. HPLC retention time: 1.20 minutes (column C).
EXAMPLE 169
[1074] 693
[1075] Example 169, was prepared from Precursor 5b and the
2-(4-pyridinecarboxamido)-thiazol-5-yl stannane to provide
1-benzoyl-4-[(7-(2-(4-pyridinecarboxamido)-thiazol-5-yl)-6-azaindol-3-yl)-
-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.30H.sub.26N.sub.7O.sub.5S: 596.17; found 596.14. HPLC
retention time: 1.32 minutes (column C).
EXAMPLES 82-86, 98, 107, 108, 129, 130, 132, 133, 134
[1076] Examples 82-86, 98, 107,108, 127, 128, 129, 130, 132, 133
and 134 were prepared according to the general procedure as
previously described for Examples 2-14.
EXAMPLE 82
[1077] 694
[1078] Example 82, was prepared from Precursor 5b and thien-2-yl
boronic acid to provide
1-benzoyl-4-[(4-methoxy-7-(thiophen-2-yl)-6-azaindol-3-yl-
)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.23N.sub.4O.sub.4S: 475.14; found 475.31. HPLC
retention time: 1.14 minutes (column A).
EXAMPLE 83
[1079] 695
[1080] Example 83, was prepared from Precursor 5b and thien-2-yl
boronic acid to provide
1-benzoyl-4-[(4-methoxy-7-(thiophen-3-yl)-6-azaindol-3-yl-
)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.23N.sub.4O.sub.4S: 475.14; found 475.33. HPLC
retention time: 1.16 minutes (column A).
EXAMPLE 84
[1081] 696
[1082] Example 84, was prepared from Precursor 5b and
5-carbonylthien-2-yl boronic acid to provide
1-benzoyl-4-[(4-methoxy-7-(5-carbonyl-thiophen-2--
yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+
Calc'd for C.sub.26H.sub.23N.sub.4O.sub.5S: 503.14; found 503.23.
HPLC retention time: 1.31 minutes (column A).
EXAMPLE 85
[1083] 697
[1084] Example 76, was prepared from Precursor 5b and
5-carbonylfuran-2-yl boronic acid to provide
1-(benzoyl)-4-[(4-methoxy-7-(5-carbonyl-furan-2-y-
l)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+
Calc'd for C.sub.26H.sub.23N.sub.4O.sub.6: 487.16; found 487.28.
HPLC retention time: 1.44 minutes (column A).
EXAMPLE 86
[1085] 698
[1086] Example 86, was prepared from Precursor 5d and
4-methylthien-2-yl boronic acid to provide
1-benzoyl-3-(R)-methyl-4-[(7-(4-methyl-thiophen-2-
-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+
Calc'd for C.sub.26H.sub.25N.sub.4O.sub.3S: 473.16; found 473.26.
HPLC retention time: 1.28 minutes (column A).
EXAMPLE 98
[1087] 699
[1088] Example 98, was prepared from Precursor 5d and
2-benzofuranyl boronic acid to provide
1-benzoyl-3-(R)-methyl-4-[(7-(benzofuran-2-yl)-4--
azaindol-3-yl)-oxoacetyl]piperazine. .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta.8.24 (s, 1H), 8.09 (s, 1H), 7.70-7.26 (m, 1OH),
4.03 (s, 3H), 3.97-3.49 (m, 8H). MS m/z: (M+H).sup.+ Calc'd for
C.sub.29H.sub.25N.sub.4- O.sub.5: 509.18; found 509.18. HPLC
retention time: 1.50 minutes (column A).
EXAMPLE 107
[1089] 700
[1090] Example 107, was prepared from Precursor 5m and
2-benzofuranyl boronic acid to provide
(R)-1-picolinoyl-3-methyl-4-[(7-(benzofuran-2-yl)-
-6-azaindol-3-yl)-oxoacetyl]piperazine. .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta.8.77-7.38 (m, 12H), 4.99-3.16 (m, 7H), 1.44-1.27
(m, 3H). MS m/z: (M+H).sup.+ Calc'd for
C.sub.28H.sub.24N.sub.5O.sub.4: 494.18; found 494.24. HPLC
retention time: 1.35 minutes (column A).
EXAMPLE 108
[1091] 701
[1092] Example 108, was prepared from Precursor 5n and
2-benzofuranyl boronic acid to provide
(S)-1-picolinoyl-3-methyl-4-[(7-(benzofuran-2-yl)-
-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd
for C.sub.28H.sub.24N.sub.5O.sub.4: 494.18; found 494.23. HPLC
retention time: 1.37 minutes (column A).
EXAMPLE 127
[1093] 702
[1094] Example 127, was prepared from Precursor 5i and the
benzothiophen-2-yl boronic acid to provide
(R)-1-benzoyl-3-Methyl-4-[7-(b-
enzothiophen-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z:
(M+H).sup.+ Calc'd for C.sub.29H.sub.25N.sub.4O.sub.3S: 509.16;
found 509.21. HPLC retention time: 1.42 minutes (column A).
EXAMPLE 128
[1095] 703
[1096] Example 128, was prepared from Precursor 5i and the
thiophen-2-yl boronic acid to provide
(R)-1-benzoyl-3-Methyl-4-[7-(thiophen-2-yl)-4-aza-
indol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.23N.sub.4O.sub.3S: 459.15; found 459.27. HPLC
retention time: 1.22 minutes (column A).
EXAMPLE 129
[1097] 704
[1098] Example 129, was prepared from Precursor 5i and the
thiophen-3-yl boronic acid to provide
(R)-1-benzoyl-3-Methyl-4-[7-(thiophen-3-yl)-4-aza-
indol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.23N.sub.4O.sub.3S: 459.15; found 459.34. HPLC
retention time: 1.31 minutes (column A).
EXAMPLE 130
[1099] 705
[1100] Example 130, was prepared from Precursor 5i and the
2,5-dimethyl-isoxazol4-yl boronic acid to provide
(R)-1-benzoyl-3-Methyl--
4-[7-(2,5-dimethyl-isoxazol-4-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine.
MS m/z: (M+H).sup.+ Calc'd for C.sub.26H.sub.26N.sub.5O.sub.4:
472.20; found 472.28. HPLC retention time: 1.14 minutes (column
A).
EXAMPLE 132
[1101] 706
[1102] Example 132, was prepared from Precursor 5p and the
2-methylcarbonyl-thiophen-5-yl boronic acid to provide
1-benzoyl-4-[7-(2-methylcarbonyl-thiophen-5-yl)-4-azaindol-3-yl)-oxoacety-
l]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.26H.sub.23N.sub.4O.sub.- 4S: 487.14; found 487.20. HPLC
retention time: 1.14 minutes (column A).
EXAMPLE 133
[1103] 707
[1104] Example 133, was prepared from Precursor 5p and the
2-carbonyl-thiophen-5-yl boronic acid to provide
1-benzoyl-4-[7-(2-carbon-
yl-thiophen-5-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z:
(M+H).sup.+ Calc'd for C.sub.25H.sub.21N.sub.4O.sub.4S: 473.13;
found 473.11. HPLC retention time: 1.14 minutes (column A).
EXAMPLE 134
[1105] 708
[1106] Example 134, was prepared from Precursor 5p and the
4-methyl-thiophen-2-yl boronic acid to provide
1-benzoyl-4-[7-(4-methyl-t-
hiophen-2-yl)-4-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z:
(M+H).sup.+ Calc'd for C.sub.25H.sub.23N.sub.4O.sub.3S: 459.15;
found 459.08. HPLC retention time: 1.26 minutes (column G).
EXAMPLE 152
[1107] 709
[1108] Preparation of Example 152: To a mixture of acid precursor
16 (30 mg, 68 .mu.mol), 3-aminopyridine (26 mg, 0.27 mmol) and DMAP
(50 mg, 0.41 mmol) was added THF (2 ml), and then EDC (60 mg, 0.31
mmol). The reaction mixture was stirred at ambient temperature for
16 hours. The LC/MS analysis indicated that the major product was
the activated ester. The reaction mixture was then added into a DMF
(2 ml) solution of 3-aminopyridine (400 mg, 4.25 mmol) and stirred
at ambient temperature for 16 hours. After addition of MeOH (4 ml),
the reaction mixture was purified by preparative reverse phase HPLC
to give the TFA salt of the title compound using the method: Start
% B=30, Final % B=75, Gradient time=25 min, Flow Rate=25 ml/min,
Column: YMC C18 5 .mu.m 20.times.100 mm, Fraction Collection:
10.41-11.08 min. .sup.1H NMR: (DMSO-d.sub.6) .delta.13.04 (s, 1H),
11.17 (s, 1H), 9.17 (s, 1H), 8.53 (s, 1H), 8.35 (m, 3H), 7.44 (b s,
6H), 3.75-3.37 (b m, 8H); LC/MS: (ES+) m/z (M+H).sup.+=517, 519;
HPLC R.sub.t=1.653.
EXAMPLE 143
[1109] 710
[1110] Prep of Example 143: To a mixture of precursor 5q (31 mg, 65
.mu.mol) and Pd(PPh.sub.3).sub.4 (20 mg, 17 mol) was added
1,4-dioxane (1 ml) and ii (30 mg, 78 .mu.mol). The reaction mixture
was heated in a sealed tube at 145.degree. C. for 4 hours. After
cooling to ambient temperature, the reaction mixture was added MeOH
(4 ml) and then filtered. The filtrate was purified by preparative
reverse phase HPLC to give the TFA salt of the title compound using
the method: Start % B=25, Final % B=90, Gradient time=20 min, Flow
Rate=25 ml/min, Column: YMC C18 5 .mu.m 20.times.100 mm, Fraction
Collection: 11.14-11.92 min. .sup.1H NMR: (DMSO-d.sub.6)
.delta.12.71 (s, 1H), 9.01 (s, 1H), 8.36 (s, 1H), 8.27 (s, 1H),
8.08 (s, 1H), 7.44 (b s, 5H), 7.44 (b s, 2H), 3.75-3.37 (b m, 8H);
LC/MS: (ES+) m/z (M+H).sup.+=490, 492; HPLC R.sub.t=2.250.
EXAMPLE 149
[1111] 711
[1112] Preparation of Example 49: To a suspension of compound of
Example 143 (12 mg, 24 .mu.mol) in sulfuric acid (5%, 2 ml), was
charged sodium nitrite (22 mg, 0.32 mol) at 0.degree. C. The
reaction mixture was stirred at 0.degree. C. for 30 minutes and
then at ambient temperature for 1 hour. After addition of MeOH (4
ml), the reaction mixture was purified by preparative reverse phase
HPLC to give a TFA solvate of title compound using the method:
Start % B=20, Final % B=85, Gradient time=15 min, Flow Rate=25
ml/min, Column: YMC C18 5 .mu.m 20.times.100 mm, Fraction
Collection: 10.67-11.36 min. .sup.1H NMR: (DMSO-d.sub.6)
.delta.12.62 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 8.29 (s, 1H),
8.18 (s, 1H), 7.44 (b s, 5H), 3.80-3.30 (b m, 8H); LC/MS: (ES+) m/z
(M+H).sup.+=491, 493; HPLC R.sub.t=2.193.
EXAMPLE 144
[1113] 712
[1114] Preparation of Example 144: To a mixture of precursor 5q (50
mg, 105 .mu.mol) and Pd(PPh.sub.3).sub.4 (50 mg, 43 .mu.mol) was
added 1,4-dioxane (1 ml) and iii (77 mg, 210 .mu.mol). The reaction
mixture was heated in a sealed tube at 145.degree. C. for 16 hours.
After cooling to ambient temperature, the reaction mixture was
added MeOH (4 ml) and then filtered. The filtrate was purified by
reverse phase HPLC to give the TFA salt of the title compound of
using the method: Start % B=15, Final % B=100, Gradient time=20
min, Flow Rate=25 ml/min, Column: YMC C18 5 .mu.m 20.times.100 mm,
Fraction Collection: 11.80-12.31 min. .sup.1H NMR: (CD.sub.3OD)
.delta.9.32 (s, 1H), 9.25 (s, 2H), 8.50 (s, 1H), 8.44 (s, 1H), 7.47
(b s, 5H), 4.00-3.44 (b m, 8H); LC/MS: (ES+) m/z (M+H).sup.+=475,
477; HPLC R.sub.t=1.833.
EXAMPLE 87
[1115] 713
[1116] Preparation of Example 87,
1-benzoyl-4-[(4-methoxy-7-(2-hydroxycarb-
onyl-furan-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine: A mixture
of the compound of Example 85 (19 mg), NaClO.sub.2 (9.2 mg) in a
mixed solution of CH.sub.3CN (3 mL) and water (0.5 mL) was stirred
at room temperature for 24 hours. After the reaction was quenched
by 1N NaOH solution (1 ml), the mixture was extracted with diethyl
ether (3.times.10 mL). The aqueous phase was acidified with 1N HCl
to give a yellow solid precipitate (5 mg) which was the product
shown. MS m/z: (M+H).sup.+ Calc'd for
C.sub.26H.sub.23N.sub.6O.sub.7: 503.16; found 503.19. HPLC
retention time: 1.37 minutes (column A).
[1117] General Procedure of Converting --NH.sub.2 Group to --NHCOR
Group 714
[1118] Preparation of Example 99,
1-(benzoyl)-4-[(4-methoxy-7-(2-acetylami-
nopyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine:
1-(benzoyl)-4-[(4-methoxy-7-(2-amino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoac-
etyl]piperazine (4 mg) and acetic anhydride (20 mg) were dissolved
in pyridine (0.5 ml). The reaction was stirred for three hours at
room temperature. After reaction was quenched with MeOH (1 ml),
solvents were concentrated to give a residue which was purified
using a Shimadzu automated preparative HPLC System to provide 3.0
mg of the desired compound,
1-(benzoyl)-4-[(4-methoxy-7-(2-acetylamino-pyrazin-5-yl)-6-azai-
ndol-3-yl)-oxoacetyl]piperazine. .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta.9.58 (s, 1H), 9.25 (s, 1H), 8.45 (s, 1H), 8.10 (s, 1H), 7.49
(m, 5H), 4.12 (s, 3H), 3.84-3.35 (m, 8H); 2.27 (s, 3H). MS m/z:
(M+H).sup.+ Calc'd for C.sub.27H.sub.26N.sub.7O.sub.5: 528.20;
found 528.22. HPLC retention time: 1.33 minutes (column A).
[1119] General Procedure of Converting --NH.sub.2 Group to --OH
Group Preparation of Example 97,
1-(benzoyl)-4-[(4-methoxy-7-(2-hydroxyl-pyrazi-
n-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine:
1-(benzoyl)-4-[(4-methoxy-7-
-(2-amino-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine (15
mg) and NaNO.sub.2 (10 mg) was added into a H.sub.2SO.sub.4
solution (0.1 ml of concentrated H.sub.2SO.sub.4 diluted with 0.3
ml of water). The reaction was stirred at room temperature for one
hour. Then, the reaction mixture was neutralized with a saturated
Na.sub.2CO.sub.3 solution (10 ml). The solvents were concentrated
to give a residue which was purified using a Shimadzu automated
preparative HPLC System to provide 4.2 mg of the desired compound,
1(benzoyl)-4-[(4-methoxy-7-(2-hydroxyl-pyrazin-5-yl)-6--
azaindol-3-yl)-oxoacetyl]piperazine. .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta.8.55 (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 8.01
(s, 1H), 7.49 (m, 5H), 4.12 (s, 3H), 3.84-3.64 (m, 8H). MS m/z:
(M+H).sup.+ Calc'd for C.sub.25H.sub.23N.sub.6O.sub.5: 487.17;
found 487.22. HPLC retention time: 1.13 minutes (column A). 715
[1120] This general procedure is applied to prepare examples 121,
122,123,124,155, 157, and 162.
EXAMPLE 121
[1121] 716
[1122] Example 121,
(R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(2-hydroxyl-p-
yrazin-6-yl)-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z:
(M+H).sup.+ Calc'd for C.sub.25H.sub.23N.sub.6O.sub.4: 471.18;
found 471.17. HPLC retention time: 1.39 minutes (column G).
EXAMPLE 121-2
[1123] 717
[1124] Example 121-2,
(R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(2-hydroxyl-
-4oxo-pyrazin-6-yl)-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine was
isolated during the preparation of Example 121. MS m/z: (M+H).sup.+
Calc'd for C.sub.25H.sub.23N.sub.6O.sub.5: 487.17; found 487.17.
HPLC retention time: 1.08 minutes (column G).
EXAMPLE 122
[1125] 718
[1126] Example 122,
(R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(2-hydroxyl-p-
yridin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z:
(M+H).sup.+ Calc'd for C.sub.26H.sub.24N.sub.5O.sub.4: 470.18;
found 470.17. HPLC retention time: 1.03 minutes (column G).
EXAMPLE 123
[1127] 719
[1128] Example 123,
(R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(2-hydroxyl-p-
yridin-6-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z:
(M+H).sup.+ Calc'd for C.sub.26H.sub.24N.sub.5O.sub.4: 470.18;
found 470.14. HPLC retention time: 1.28 minutes (column G).
EXAMPLE 124
[1129] 720
[1130] Example 124,
(R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(5-hydroxyl-p-
yridin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z:
(M+H).sup.+ Calc'd for C.sub.26H.sub.24N.sub.5O.sub.4: 470.18;
found 470.13. HPLC retention time: 1.21 minutes (column G).
[1131] Preparation of Example 138 721
[1132] Preparation of Example 138,
1-(benzoyl)-4-[(4-methoxy-7-(1-methylpy-
razin-2-on-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine:
1-(benzoyl)-4-[(4-methoxy-7-(2-hydroxyl-pyrazin-5-yl)-6-azaindol-3-yl)-ox-
oacetyl]piperazine (6 mg), MeI (5 mg) and K.sub.2CO.sub.3 (4
mg)were dissolved in acetone (5 ml). The reaction was stirred for
four hours at room temperature. After solid was filtered away, the
mother liquid was concentrated to give a residue which was purified
using a Shimadzu automated preparative HPLC System to provide 3.0
mg of the desired compound,
1-(benzoyl)-4-[(4-methoxy-7-(1-methylpyrazin-2-on-5-yl)-6-azain-
dol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.26H.sub.25N.sub.6O.sub.5: 501.19; found 501.14. HPLC
retention time: 1.08 minutes (column G).
EXAMPLE 139
[1133] 722
[1134] Precursor 4i was dissolved in DMF (2 ml), and to which
N-benzoyl-(R)-methylpiperazine hydrochloride (0.092 g, 0.45 mmol)
and 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT,
0.180 g, 0.60 mmol) were added, followed by
N,N-diisopropylethylamine (0.15 ml, 0.87 mmol). The reaction
mixture was stirred for 2 h at r.t., and then the volatile
evaporated under high vacuum. Water was added to the mixture to
induce precipitation, and the solids were filtered and dried in
vacuo. Purification of the crude solid by preparative thin layer
chromatography (5% MeOH/CH.sub.2Cl.sub.2), and subsequent washing
with ether gave the title compound; .sup.1H NMR: (CDCl.sub.3)
.delta.8.78 (s, 1H), 8.32 (s, 1H), 8.28 (s, 1H) 7.84 (s, 1H), 7.44
(b s, 5H), 6.56 (s, 1H), 5.00-3.00 (b m, 7H), 1.45-1.20 (b s, 3H);
LC/MS: (ES+) m/z (M+H).sup.+=521, 523; HPLC R.sub.t=1.677.
[1135] Preparation of N-linked Azaindole Heterocylic Derivatives
from the Corresponding Bromide or Chloride. An Example of a Typical
Procedure:
[1136] A General Reaction Condition is Shown with the Preparation
of Example 187. Other Analogs, Examples 188-193, were Preparaed Via
the Same Reaction Condition.
EXAMPLE 187
[1137] 723
[1138] Preparation of compound of Example 187: Precursor 5b (30
mg), 1,2,4-triazole (145 mg), Cu (4.4 mg) and K2CO3 (9.6 mg) were
combined in a sealed tube which was degassed before being sealed.
The mixture was heated to 160.degree. C. for 8 hours. After being
allowed to cool down to ambient temperature, the mixture was
diluted with MeOH (14 ml) and dichloromethane (7 ml). After
filtration, the filtrate was concentrated to give a residue which
was purified using a Shimadzu automated preparative HPLC System to
provide 12.9 mg of the desired compound 187,
1-benzoyl-4-[(4-methoxy-7-(1,2,4-triazol-1-yl)-6-azaindol-3-yl)-oxoacetyl-
]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.23H.sub.22N.sub.7O.sub.4- : 460.17; found 460.33. HPLC
retention time: 1.45 minutes (column J).
EXAMPLE 188 and EXAMPLE 188A
[1139] 724
[1140] Example 188 and 188A, were prepared according to the general
method described above starting from Precursor 5z and
1,2,3-triazole to provide Example 188 and Example 188A.
[1141] Precursor 5z (0.050 g), 0.050 g Cu powder, 0.025 g K2CO3 and
6 equivalents of 1,2,3 triazole were heated at 150.degree. C. for
16 hrs. The reaction was allow to cool to ambient temperature and
was dissolved in MeOH and purified by Prep HPLC as described above
in the general methods to provide Example 188 (0.0237 g brown
solid,yield 44%) and the the other isomer Example 188a.
[1142] Example 188,
1-benzoyl-4-[(4-methoxy-7-(1,2,3-triazol-1-yl)-6-azain-
dol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.23H.sub.22N.sub.7O.sub.4: 460.17; found 460.34. HPLC
retention time: 1.50 minutes (column J); 1.29 minutes (column L).
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta.8.86 (s, 1H), 8.34 (s,
1H), 7.97 (m, 2H), 7.48 (b, 5H), 4.08 (s, 3H), 3.89-3.56 (m,
8H).
[1143] Example 188A,
1-benzoyl-4-[(4-methoxy-7-(1,2,3-triazol-2-yl)-6-azai-
ndol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.23H.sub.22N.sub.7O.sub.4: 460.17; found 460.34. HPLC
retention time: 1.39 minutes (column J). .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta.8.32 (s, 1H), 7.76 (s, 1H), 7.45 (b, 7H), 4.07
(s, 3H), 3.80-3.30 (m, 8H).
EXAMPLE 189
[1144] 725
[1145] Example 189, was prepared from Precursor 5b and pyrazole to
provide
1-benzoyl-4-[(4-methoxy-7-(1-pyrazolyl)-6-azaindol-3-yl)-oxoacetyl]pipera-
zine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.23N.sub.6O.sub.4: 459.18; found 459.01. HPLC
retention time: 0.92 minutes (column G).
EXAMPLE 190
[1146] 726
[1147] Example 190, was prepared from Precursor 5b and
3-methylpyrazole to provide
1-benzoyl-4-[(.sup.4-methoxy-7-(3-methylpyrazol-1-yl)-6-azaindol--
3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.25N.sub.6O.sub.4: 473.19; found 473.09. HPLC
retention time: 1.49 minutes (column G).
EXAMPLE 191
[1148] 727
[1149] Example 191, was prepared from Precursor 5b and
4-methylpyrazole to provide
1-benzoyl-4-[(4-methoxy-7-(4-methylpyrazol-1-yl)-6-azaindol-3-yl)-
-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.25N.sub.6O.sub.4: 473.19; found 473.09. HPLC
retention time: 1.52 minutes (column G).
EXAMPLE 192
[1150] 728
[1151] Example 192, was prepared from Precursor 5b and
3-trifluoromethylpyrazole to provide
1-benzoyl-4-[(4-methoxy-7-(3-trifluo-
romethylpyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS
m/z: (M+H).sup.+ Calc'd for C.sub.25H.sub.22F.sub.3N.sub.6O.sub.4:
527.17; found 527.09. HPLC retention time: 1.64 minutes (column
G).
EXAMPLE 193
[1152] 729
[1153] Example 193, was prepared from Precursor 5b and imidazole to
provide
1-benzoyl-4-[(4-methoxy-7-(1-imidazolyl)-6-azaindol-3-yl)-oxoacet-
yl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.23N.sub.6O.sub- .4: 459.18; found 459.26. HPLC
retention time: 1.22 minutes (column G).
EXAMPLE 140
[1154] 730
[1155] The title compound was prepared according to general
procedures described before (Sn-coupling). H NMR: 8.41(m, 1H);
8.33(m, 1H); 8.16(m, 1H); 7.53(m, 1H); 7.47(bs, 5H); 3.97-3.54(m,
8H). LC/MS: (ES.sup.+) m/z(m+H).sup.+=448, Rt=1.28 min.
EXAMPLE 141
[1156] 731
[1157] The title compound was prepared according to general
procedures described before (Sn-coupling). .sup.1H-NMR:
9.71-9.70(m, 1H); 8.80-8.79(m, 1H); 8.66-8.42(m, 2H); 8.41-8.35(m,
2H); 7.99-7.92(m,1H), 7.69-7.53(m, 1H); 7.48-7.44(m, 1H);
5.05-3.15(m, 8H). LC/MS: (ES.sup.+) m/z (m+H).sup.+=474.
R.sub.t=1.26 min.
EXAMPLE 144
[1158] 732
[1159] Preparation of Example 144: To a mixture of precursor 5q (50
mg, 105 .mu.mol) and Pd(PPh.sub.3).sub.4 (50 mg, 43 .mu.mol) was
added 1,4-dioxane (1 ml) and iii (77 mg, 210 .mu.mol). The reaction
mixture was heated in a sealed tube at 145.degree. C. for 16 hours.
After cooling to ambient temperature, the reaction mixture was
added MeOH (4 ml) and then filtered. The filtrate was purified by
reverse phase HPLC to give the TFA salt of the title compound of
using the method: Start % B=15, Final % B=100, Gradient time=20
min, Flow Rate=25 ml/min, Column: YMC C18 5 .mu.m 20.times.100 mm,
Fraction Collection: 11.80-12.31 min. .sup.1H NMR: (CD.sub.3OD)
.delta.9.32 (s, 1H), 9.25 (s, 2H), 8.50 (s, 1H), 8.44 (s, 1H), 7.47
(b s, 5H), 4.00-3.44 (b m, 8H); LC/MS: (ES+) m/z (M+H).sup.+=475,
477; HPLC R.sub.t=1.833.
EXAMPLE 145
[1160] 733
[1161] The title compound was prepared following the procedure
described before for example 146 and precursor 4k. .sup.1H NMR:
8.35-8.33(m, 2H); 8.1 l(s, 1H); 7.89(s, 1H); 7.43(bs, 5H);
3.89-3.49(m, 8H). LC/MS: (ES.sup.+) m/z (M+H).sup.+=448.
Rt=1.18min.
EXAMPLE 146
[1162] 734
[1163] Precursor 4m (0.26 mmol) was dissolved in DMF (1 mL) and
treated with N-benzoylpiperazine hydrochloride (59 mg, 0.26 mmol),
DEBPT (79 mg, 0.26 mmol) and Hunig's base ( 90 .mu.L, 0.52 mmol)
and the reaction mixture was stirred at rt for 18 h. The solvent
was removed in vacuum and the residue was purified by reverse phase
preparative HPLC. The fractions showing the right LC/MS:(ES.sup.+)
m/z (M+H).sup.+=449 were collected, concentrated and purified again
using a preparative TLC (5% MeOH/CH.sub.2Cl.sub.2) to afford the
title compound as a white solid. .sup.1H-NMR (500 MHz, CDCl.sub.3)
.delta.10.7 (s, 1H), 9.00 (s, 1H), 8.54 (s, 1H), 8.39 (s, 1H), 7.45
(m, 5H), 3.9-3.5 (bm, 8H).
EXAMPLE 148
[1164] 735
[1165] The title compound was prepared from precursor 4n using the
same coupling conditions described for the last step of the
preparation of precursor 5i. .sup.1H NMR: 8.82(m, 1H); 8.48-8.45(m,
1H); 8.37-8.33(m, 1H); 8.26-8.23(m, 1H); 7.47(bs, 5H); 3.97-3.54(m,
8H). LC/MS: (ES.sup.+) m/z(m+H).sup.+=447 Rt=0.94 min.
EXAMPLE 151
[1166] 736
[1167] Example 151, was prepared from Precursor 5l and the
thiazol-5-yl stannane to provide
1-picolinoyl-4-[(4-methoxy-7-(thiazol-5-yl)-6-azaindo-
l-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.23H.sub.21N.sub.6O.sub.4S: 477.13; found 477.13. HPLC
retention time: 0.94 minutes (column G).
EXAMPLE 154
[1168] 737
[1169] The title compound was prepared according to general
procedures described before (Sn-coupling). .sup.1H-NMR: 9.23-9.22
(m, 1H); 8.83-8.81(m, 1H); 8.43 (m, 1H); 8.36 (m, 1H); 7.75-7.73
(m, 1H), 7.44 (bs, SH); 3.85-3.49 (m, 8H). LC/MS: (ES.sup.+) m/z
(M+H).sup.+=459. Rt=1.39 min.
EXAMPLE 155
[1170] 738
[1171] Example 155,
1-(benzoyl)-4-[(4-methoxy-7-(2-hydroxyl-pyrazin-5-yl)--
6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd
for C.sub.25H.sub.23N.sub.6O.sub.5: 487.17; found 487.14. HPLC
retention time: 1.30 minutes (column G).
EXAMPLE 157
[1172] 739
[1173] Example 157,
(R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(5-hydroxyl-p-
yrazin-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z:
(M+H).sup.+ Calc'd for C.sub.25H.sub.23N.sub.6O.sub.4: 471.18;
found 471.16. HPLC retention time: 1.09 minutes (column G).
EXAMPLE 161
[1174] 740
[1175] Example 161 was prepared from precursor 5p and
3-phenyl-5-tributylstannyl1,2,3-triazole using the general tin
coupling procedure provided earlier: .sup.1H NMR (500 MHz, DMSO)
.delta.9.67 (s, 1H), 8.81 (s, 1H), 8.72 (d, J=5.4 Hz, 1H), 8.25 (d,
J=6.1 Hz, 1H), 8.00 (dd, J=8.2, 1.8 Hz, 1H), 7.68 (dd, J=8.2, 7.4
Hz, 2H), 7.60 (tt, J=7.4, 1.8 Hz, 2H), 7.48 (br s, 5H), 4.04-3.46
(m, 8H). MS nm/z: (M+H).sup.+calcd for
C.sub.28H.sub.24N.sub.7O.sub.3: 506.19; found 506.15. HPLC
retention time: 1.21 minutes (XTERRA C18 S7 3.0.times.50 mm)).
EXAMPLE 162
[1176] 741
[1177] Example 162,
(R)-1-(benzoyl)-3-methyl-4-[(4-methoxy-7-(2-hydroxyl-p-
yrimidin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z:
(M+H).sup.+ Calc'd for C.sub.25H.sub.23N.sub.6O.sub.4: 471.18;
found 471.13. HPLC retention time: 0.95 minutes (column G).
EXAMPLE 163
[1178] 742
[1179] To a solution of precursor 5q (50 mg, 0.11 mmol) in DMF (1
ml) was added CuCN (30 mg, 0.335 mmol). The reaction mixture was
heated at 170.degree. C. for 30 min. After cooling to ambient
temperature, the reaction mixture was diluted with MeOH (15 ml),
filtered under gravity, and the filtrate evaporated in vacuo to
afforded a brownish residue which is a cyanoprecursor. To the
residue in DMF (1 ml) was added sodium azide (61 mg, 0.95 mmol) and
ammonium chloride (50 mg, 0.95 mmol). The mixture was heated at
90.degree. C. for one hour. The reaction mixture was then diluted
with MeOH (4 ml), filtered, and the filtrate purified by
preparative reverse phase HPLC using the method: Start % B=20,
Final % B=80, Gradient time=15 min, Flow Rate=40 ml/min, Column:
XTERRA C18 5 um 30.times.100 mm, Fraction Collection: 11.26-11.71
min. The material was homogenous by .sup.1H NMR and HPLC, although
the mass spectrum indicated an extra peak at (M+H).sup.+=431;
.sup.1H NMR: (CD.sub.3OD) 8.41 (s, 1H), 8.12 (s, 1H), 7.47 (b s,
5H), 3.97-3.47 (b m, 8H); LC/MS: (ES+) m/z (M+H).sup.+=465, 467;
HPLC R.sub.t=1.937
EXAMPLE 164
[1180] 743
[1181] Example 164, was prepared from Precursor 5a and the
4-hydroxycarbonylphenyl boronic acid to provide
1-benzoyl-4-[7-(4-hydroxy-
carbonylphenyl)-4-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z:
(M+H).sup.+ Calc'd for C.sub.28H.sub.25N.sub.4O.sub.5: 497.18;
found 497.22. HPLC retention time: 1.20 minutes (column C).
EXAMPLE 165
[1182] 744
[1183] Compound of Example 165 was prepared in a similar manner to
compound of Example 143 starting with precursor 5r, but at
125.degree. C. for 22 hours and purification by preparative thin
layer chromatography (4% MeOH/CH.sub.2Cl.sub.2). .sup.1H NMR:
(CDCl.sub.3) .delta.11.85 (s, 1H), 9.91 (d, J=1.6 Hz, 1H), 8.70 (d,
J=2.6 Hz, 1H), 8.65 (dd, J=1.6, 2.6 Hz, 1H), 8.52 (s, 1H), 8.35 (d,
J=3.1 Hz, 1H), 3.73 (b m, 2H), 3.56 (b m, 4H), 3.53 (b m, 2H), 1.48
(s, 9H); LC/MS: (ES+) m/z (M+H).sup.+=471, 473; HPLC
R.sub.t=1.690.
EXAMPLE 167
[1184] 745
[1185] Precursor 4m (0.098 mmol) was dissolved in DMF (1 mL) and
treated with N-[5-(2-Bromofuroyl)]piperazine hydrochloride (30 mg,
0.098 mmol), DEBPT (60 mg, 0.19 mmol ) and Hunig's base (70 .mu.L,
0.19 mmol) and the reaction mixture was stirred at rt for 18 h. The
solvent was removed in vacuum and the residue was purified by
reverse phase preparative HPLC. The fractions showing the right
LC/MS:(ES.sup.+) m/z (M+H).sup.+=518,520 were collected,
concentrated and purified again using a preparative TLC (5%
MeOH/CH.sub.2Cl.sub.2) to afford the title compound as a white
solid. .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta.10.7 (s, 1H), 9.00
(s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 7.06 (d, J=3.4 Hz, 1H), 6.46
06 (d, J=3.4 Hz, 1H), 3.90-3.66 (bm, 8H).
EXAMPLE 168
[1186] 746
[1187] Example 168,
1-benzoyl-3-(R)-methyl-4-[(7-(2-thienylcarbonyl)-4-aza-
indol-3-yl)-oxoacetyl]piperazine, was prepared from a reaction
1-benzoyl-3-(R)-methyl-4-[(7-(methoxymethylamino)carbonyl)-azaindol-3-yl)-
-oxoacetyl]piperazine and 2thienyl lithium by using the same
procedure for the preapartion of 1-64,
1-benzoyl-3(R)-methyl-4-[(7-(2-propynyl)carbonyl-
-4-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd
for C.sub.26H.sub.23N.sub.4O.sub.4S: 487.14; found 487.11. HPLC
retention time: 1.31 minutes (column A).
[1188] General Procedure for the Preparation of Piperazine Amides
or Carbamides:
[1189] The free nitrogen atom of piperazine could be masked as
amides or carbamides via reactions of piperazine with acyl halides,
acyl acids or acyl halo formates, which are shown in the following
schemes 80 and 81. 747 748
[1190] Example 195-199 were prepared via a procedure demonstrated
in Scheme 80. The typical procedure is presented in the synthesis
of Example 195.
EXAMPLE 195
[1191] 749
[1192] Example 195: Precursor 5u (40 mg), pyrazine carbonyl
chloride (50 mg) and I-Pr.sub.2NEt (0.2 g) were combined in 1 ml of
THF. After the reaction was stirred at room temperature for 16 h,
the mixture was concentrated in vacuo to give a residue which was
purified using a Shimadzu automated preparative HPLC System to
provide the desired compound 195 (4.7 mg). MS m/z: (M+H).sup.+
Calc'd for C.sub.23H.sub.21N.sub.8O.sub.4: 473.17; found 473.42.
HPLC retention time: 1.14 minutes (column C).
EXAMPLE 196
[1193] 750
[1194] Example 196, was prepared from Precursor 5u and 4-isoxazole
carbonyl chloride. MS m/z: (M+H).sup.+ Calc'd for
C.sub.22H.sub.20N.sub.7- O.sub.5: 462.15; found 462.41. HPLC
retention time: 1.09 minutes (column C).
EXAMPLE 197
[1195] 751
[1196] Example 197, was prepared from Precursor 5u and
4-(1,2,3-thiodiazole)-carbonyl chloride. MS m/z: (M+H).sup.+ Calc'd
for C.sub.21H.sub.19N.sub.8O.sub.4S: 479.12; found 479.31. HPLC
retention time: 1.17 minutes (column C).
EXAMPLE 198
[1197] 752
[1198] Example 198, was prepared from Precursor 5u and
5-(3-amino-1,2,4-triazole)-carbonyl chloride. MS m/z: (M+H).sup.+
Calc'd for C.sub.21H.sub.21N.sub.10O.sub.4: 477.17; found 477.36.
HPLC retention time: 0.97 minutes (column C).
EXAMPLE 199
[1199] 753
[1200] Example 199, was prepared from Precursor 5u and propanyl
chloro formate. MS m/z: (M+H).sup.+ Calc'd for
C.sub.22H.sub.25N.sub.6O.sub.5: 453.19; found 453.17. HPLC
retention time: 1.53 minutes (column M).
[1201] Example 200-201 were prepared via a procedure demonstrated
in Scheme 81. The typical procedure is presented in the synthesis
of Example 200.
EXAMPLE 200
[1202] 754
[1203] Example 200: 3-methyl-2-picolinic acid (140 mg), EDAC (190
mg) pentafluorophenol (180 mg) were combined in DMF, and, the
reaction was stirred for 12 hours. Precursor 3u was then added and
resulted mixture was stirred at room temperature for another 16
hours. Solvents were removed in vacuo to give a residue which was
purified using a Shimadzu automated preparative HPLC System to
provide the desired compound 200 (28 mg). MS m/z: (M+H).sup.+
Calc'd for C.sub.25H.sub.24N.sub.7O.sub.4: 486.19; found 486.14.
HPLC retention time: 1.08 minutes (column G).
EXAMPLE 201
[1204] 755
[1205] Example 201, was prepared from Precursor 5u and
6-methyl-2-picolinic acid. MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.24N.sub.7O.sub.4: 486.19; found 486.28. HPLC
retention time: 1.44 minutes (column G).
EXAMPLE 202
[1206] 756
[1207] Example 202, was prepared from Precursor 5p and the ethyl
pyrazol-5-yl stannane carboxylate to provide
5-{3-[2-(4-Benzoyl-piperazin-
-1-yl)-2-oxo-acetyl]-1H-pyrrolo[3,2-b]pyridin-7-yl}-2H-pyrazole-3-carboxyl-
ic acid ethyl ester. MS m/z: (M+H).sup.+ Calc'd for
C.sub.26H.sub.25N.sub.6O.sub.5: 501.18; found 501.13. HPLC
retention time: 1.14 minutes (column G).
EXAMPLE 203
[1208] 757
[1209] Example 202, was prepared from Precursor 5p and the
benzofuran-2-yl stannane to provide
1-(7-benzofuran-2-yl-1H-pyrrolo[3,2-b]pyridin-3-yl)-2-
-(4-benzoyl-piperazin-1-yl)-ethane-1,2-dione. MS m/z: (M+H).sup.+
Calc'd for C.sub.28H.sub.21N.sub.4O.sub.4: 479.16; found 479.07.
HPLC retention time: 1.31 minutes (column G).
EXAMPLE 204
[1210] 758
[1211] Example 204, was prepared from Precursor 5p and the
oxazol-2-yl stannane to provide
1-benzoyl-4-[7-(oxazol-2-yl)-4-azaindol-3-yl)-oxoacet-
yl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.23H.sub.20N.sub.5O.sub- .4: 430.14; found 430.07. HPLC
retention time: 2.08 minutes (column E, 10 minute gradient).
EXAMPLE 205 and EXAMPLE 206
[1212] 759
[1213] Example 205 and 206. In a sealed tube
-(4-benzoyl-piperazin-1-yl)-2-
-(7-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione (30 mg,
0.076 mmol), 1H1,2,3-triazole (160 mg, 2.3 mmol), Cu (0) (10 mg,
0.16 mmol) and K.sub.2CO.sub.3 (11 mg, 0.080 mmol) were heated at
160.degree. C. for 16 h. The reaction mixture was diluted with
MeOH, filtered through celite and concentrated. The reaction
mixture was diluted with MeOH, filtered through celite and
concentrated. The residue was purified by preparative HPLC to
provide 1-(4-benzoyl-piperazin-1-yl)-2-(7-[1,2,3]triazol-2-yl-1H--
pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione: .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta.8.79 (d, J=6.6 Hz, 1H), 8.79 (s, 1H), 8.48 (d,
J=6.6 Hz, 1H), 8.40 (s, 2H), 7.48 (br s, 5H), 4.00-3.55 (m, 8H). MS
m/z (M+H).sup.+ calcd for C.sub.22H.sub.20N.sub.7O.sub.3: 430.15;
found 430.29. HPLC retention time 0.91 min (Column G); and
1-(4-benzoyl-piperazin-1-yl)-2-(7-[1,2,3]triazol-1-yl-1H-pyrrolo[3,2-b]py-
ridin-3-yl)-ethane-1,2-dione: .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta.8.97 (d, J=81.2 Hz, 1H), 8.70 (d, J=5.6 Hz, 1H), 8.48 (s,
1H), 8.06 (d, J=1.2 Hz, 1H), 7.80 (d, J=5.6 Hz, 1H), 7.47 (br s,
5H), 4.00-3.45 (m, 8H). MS m/z (M+H).sup.+ calcd for
C.sub.22H.sub.20N.sub.7O.- sub.3: 430.15; found 430.29. HPLC
retention time 0.90 min (Column G).
EXAMPLE 207
[1214] 760
[1215] Example 207, was prepared as in Example 205 from Precursor
5p and 1,2,4-triazole to provide
1-(4-benzoyl-piperazin-1-yl)-2-(7-[1,2,4]triazo-
l-1-yl-1H-pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta.9.73 (s, 1H), 8.82 (d, J=6.6 Hz, 1H),
8.77 (s, 1H), 8.55 (s, 1H), 8.32 (d, J=6.6 Hz, 1H), 7.48 (br s,
SH), 4.00-3.45 (m, 8H). MS m/z (M+H).sup.+ calcd for
C.sub.22H.sub.20N.sub.7O.sub.3: 430.15; found 430.27. HPLC
retention time 0.87 min (Column G).
EXAMPLE 208
[1216] 761
[1217] Example 208, was prepared as in Example 205 from Precursor
5p and pyrazole to provide
1-(4-Benzoyl-piperazin-1-yl)-2-(7-pyrazol-1-yl-1H-pyr-
rolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta.8.87 (d, J=2.7 Hz, 1H), 8.70 (s, 1H), 8.68 (d,
J=6.6 Hz, 1H), 8.18 (d, J=1.5 Hz, 1H), 8.14 (d, J=6.6 Hz, 1H), 7.48
(br s, 5H), 6.85 (dd, J=2.7, 1.5 Hz, 1H), 4.00-3.50 (m, 8H). MS m/z
(M+H).sup.+ calcd for C.sub.23H.sub.21N.sub.6O.sub.3: 429.16; found
429.23. HPLC retention time 0.87 min (Column G).
EXAMPLE 209
[1218] 762
[1219] The compound of Example 209 was prepared according to the
general method described above starting from Precursor 5i and
pyrazol-3-carboxylic ethyl ester-5-tributyltin prepared as
described in the following reference: Heterocycles, 1992, 33(2),
813-18. After cooling to ambient temperature, the reaction mixture
was concentrated in vacuum. The residue was filtered through filter
paper and washed with methanol. The resulting yellow solid was
dried in air to provide Compound X; .sup.1H NMR (500MHz,
CDCl.sub.3): 8.33 (s, 1H); 8.31 (s, 1H); 7.66 (s, 1H); 7.46-7.39
(m, 5H); 4.47-4.42 (q, 2H); 3.98-3.45 (m, 8H); 1.43-1.40 (t, 3H).
LC/MS: (ES.sup.+) m/z (M+H).sup.+=519. Rt=1.43 min.
EXAMPLES 210-213
[1220] 763
[1221] General procedure for the preparation of Examples
210-213
[1222] The compound of Example 209 was treated with an excess
(>5eq.) of the corresponding amine and stirred in a sealed tube
at ambient temperature or 70.degree. C. (R=NH.sub.2) for 20 hr. The
resulting solution was concentrated on a rotary evaporator and
purified by reverse phase preparative HPLC.
EXAMPLES 210 and 214
[1223] 764
[1224] Compounds of Example 210 and 214 were prepared from compound
of Example 209 and ammonium hydroxide following the procedure
described above. X1a: .sup.1H NMR (500 MHz, CD.sub.3OD.sub.3):
8.40-8.37 (m, 1H); 8.28-8.27 (m, 1H); 7.58-7.39 (m, 6H); 3.97-3.43
(m, 8H). LC/MS: (ES.sup.+) m/z (M+H).sup.+=490. Rt=1.14 min. X1b:
8.43 (s, 1H); 8.29 (s, 1H); 7.56 (s, 1H); 7.45-7.55 (m, 5H);
3.99-3.45 (m, 8H). LC/MS: (ES.sup.+) m/z (M+H).sup.+=491. Rt=1.12
min.
EXAMPLE 211
[1225] 765
[1226] The compound od Example 211 was prepared from the compound
of Example 209 and methylamine following the procedure described
above. .sup.1H NMR (500MHz, CD.sub.3OD.sub.3): 8.43 (s, 1H); 8.31
(s, 1H); 7.49 (bs, 5H); 7.45 (s, 1H) 3.97-3.48 (m, 8H); 2.97 (s,
3H). LC/MS: (ES.sup.+) m/z (M+H).sup.+=504. Rt=1.31 min.
EXAMPLE 212
[1227] 766
[1228] The compound of example 212 was prepared from the compound
of example 209 and dimethylamine following the procedure described
above. LC/MS: (ES.sup.+) m/z (M+H).sup.+=518. Rt=122 min.
COMPOUND 213
[1229] 767
[1230] The compound of Example 213 was prepared from the compound
of Example 209 and N-aminoethylmorpholine following the procedure
described above. .sup.1H NMR (500 MHz, CD.sub.3OD.sub.3): 8.41 (s,
1H); 8.31 (s, 1H); 7.52-7.49 (m, 6H); 4.19-3.20 (m, 20H); LC/MS:
(ES.sup.+) m/z (M+H).sup.+=603. Rt=1.03 min.
COMPOUNDS OF EXAMPLES 215-222
[1231] 768
[1232] General Procedure for the Preparation of Compounds of
Examples 215-222
[1233] A mixture of precursor 5i, 30 equivalents of the
corresponding amine, 1 equivalent of copper powder and 1 equivalent
of potassium carbonate was heated at 160.degree. C. for 4-7 hr in a
sealed tube. The reaction was cooled to room temperature and
filtered through filter paper. The filtrate was diluted with
methanol and purified by preparative HPLC.
EXAMPLE 215
[1234] 769
[1235] Example 215 was prepared from precursor 5i and
1,2,4-triazole following the procedure described above. .sup.1H NMR
(500 MHz, CDCl.sub.3): 11.15 (bs, 1H); 9.28 (s, 1H); 8.33-8.34 (m,
1H); 8.22 (s, 1H); 8.10 (s, 1H); 7.46-7.42 (m, 5H); 3.90-3.48 (m,
8H). LC/MS: (ES.sup.+) m/z (M+H).sup.+=448. Rt=1.21 min.
EXAMPLE 216
[1236] 770
[1237] Example 216 was prepared from precursor 5i and
1,2,3-triazole following the procedure described above. .sup.1H NMR
(500 MHz, CDCl.sub.3): 11.16 (bs, 1H); 8.75 (s, 1H); 8.37-8.37 (s,
1H); 8.15 (s, 1H); 7.92 (s, 1H); 7.43 (bs, 5H); 3.99-3.48 (m, 8H).
LC/MS: (ES.sup.+) m/z (M+H).sup.+=448. Rt=1.28 min.
EXAMPLE 217
[1238] 771
[1239] Example 217 was prepared from precursor 5i and
1,2,3-triazole following the procedure described above. .sup.1H NMR
(500 MHz, CDCl.sub.3): 11.12 (bs, 1H); 8.78-8.77 (m, 1H); 8.37-8.36
(m, 1H); 8.02-8.0 (m, 2H); 7.45-7.41 (m, 5H); 4.11-3.45 (m, 8H).
LC/MS: (ES.sup.+) m/z (M+H).sup.+=448. Rt=1.03 min.
EXAMPLE 218
[1240] 772
[1241] Example 218 was prepared from precursor 5i and imidazole
following the procedure described above. .sup.1H NMR (500 MHz,
CDCl.sub.3): 13.35 (bs, 1H); 9.49 (s, 1H); 8.35-8.30 (m, 1H); 8.20
(s, 1H); 7.97 (s, 1H); 7.56-7.53 (m, 1H); 7.46-7.41 (m, 5H);
3.98-3.40 (m, 8H). LC/MS: (ES.sup.+) m/z (M+H).sup.+=447. Rt=1.25
min.
EXAMPLE 219
[1242] 773
[1243] Example 219 was prepared from precursor 5i and pyrazole
following the procedure described above. .sup.1H NMR (500 MHz,
CDCl.sub.3): 11.52 (bs, 1H); 8.65-8.64 (m, 1H); 8.27-8.26 (m, 1H);
8.05-8.04 (m, 1H); 7.81-7.80 (m, 1H); 7.50-7.35 (m, 5H); 6.54-6.53
(m, 1H); 4.01-3.47 (m, 8H). LC/MS: (ES.sup.+) m/z (M+H).sup.+=447.
Rt=1.25 min.
EXAMPLE 220
[1244] 774
[1245] Example 220 was prepared from precursor 5i and pyrrole
following the procedure described above. .sup.1H NMR (300 MHz,
CD.sub.3OD.sub.3): 8.33-8.29 (m, 2H); 7.49-7.40 (m, 5H); 7.38-7.37
(m, 2H); 6.42-6.41 (m, 2H); 3.91-3.40 (m, 8H). LC/MS: (ES.sup.+)
m/z (M+H).sup.+=446. Rt=1.34 min.
EXAMPLE 221
[1246] 775
[1247] Example 221 was prepared from precursor 5i and pyrrolidine
following the procedure described above. .sup.1H NMR (300 MHz,
CD.sub.3OD.sub.3): 8.37 (s, 1H); 7.61-7.59 (m, 1H); 7.51-7.38 (m,
5H); 4.08-3.23 (m, 12H); 2.25-2.15 (m, 4H). LC/MS: (ES.sup.+) m/z
(M+H).sup.+=450. Rt=0.89 min.
EXAMPLE 222
[1248] 776
[1249] Compound of example 222 was prepared from precursor 5i and
morpholine following the procedure described above. .sup.1H NMR
(300 MHz, CD.sub.3OD.sub.3): 8.38 (s, 1H); 7.86-7.84 (m, 1H);
4.14-3.25 (m, 16H). LC/MS: (ES.sup.+) m/z (M+H).sup.+=466. Rt=0.988
min. 777
[1250] Preparation of Precursor 5w: To a mixture of 2u (2.0 g, 7.3
mmol) and CuCN (1.0 g, 11 mmol) was added DMF (20 ml). The reaction
mixture was heated at 150.degree. C. for 1 hour. After cooling to
room temperature, the reaction mixture was added NaOMe (20 ml, 25
wt. % solution in MeOH), and was heated at 110.degree. C. for 10
minutes. After cooling to room temperature, the reaction mixture
was poured into an aqueous solution of ammonium acetate (sat. 500
ml). The resulting mixture was filtered through a short Celite.RTM.
pad. The filtrate was extracted with EtOAc (500 ml.times.4). The
combined extracts were dried over MgSO.sub.4 and evaporated in
vacuo to give a brownish residue, which was triturated with MeOH (5
ml.times.3) to provide precursor 2v as a yellow solid (317 mg,
25%). The structure was supported by NOE experiments. .sup.1H NMR:
(DMSO-d.sub.6) 12.47 (s, 1H), 8.03 (s, 1H), 7.65 (t, J=2.8, 1H),
6.70 (dd, J=2.8, 1.8, 1H), 4.08 (s, 3H); LC/MS: (ES+) m/z
(M+H).sup.+=174; HPLC (alternate conditions B, column G)
R.sub.t=1.320.
[1251] Preparation of Precursor 3h: To 1-ethyl-3-methylimidazolium
chloride (85 mg, 0.58 mmol) in a capped vial was quickly added
aluminum chloride (231 mg, 1.73 mmol). The mixture was vigorously
stirred at room temperature until the formation of the ionic
liquid. After cooling to room temperature, the ionic liquid was
added compound 2v (50 mg, 0.29 mmol) and ethyl chlorooxoacetate
(0.2 ml, 1.79 mmol). The reaction mixture was stirred at room
temperature for three hours, cooled to 0.degree. C. and quenched by
carefully adding ice-water (15 ml). The precipitates were filtered,
washed with water (5 ml.times.3) and dried in vacuo to give 3h as a
grayish yellow solid (50 mg, 63%). .sup.1H NMR: (DMSO-d.sub.6)
13.73 (s, 1H), 8.54 (s, 1H), 8.26 (s, 1H), 4.35 (q, J=7.0, 2H),
4.06 (s, 3H), 1.29 (t, J=7.0, 3H); LC/MS: (ES+) m/z
(M+H).sup.+=274; HPLC (alternate conditions B, column G)
R.sub.t=1.527.
[1252] Preparation of Precursor 4p: To a mixture of 3h (200 mg,
0.73 mmol) in MeOH (1 ml) was added NaOH (2.5 ml, 1N aqueous). The
reaction mixture was stirred at room temperature for 30 minutes,
and then acidified with hydrochloric acid (1N, .about.3 ml) to pH
about 2. The solid was filtered, washed with water (5 ml.times.4),
and dried in vacuo to give 4p as a brownish solid (160 mg, 89%).
Compound 4p was used directly in the following reaction without
further purification. LC/MS: (ES+) m/z (M+H).sup.+=246; HPLC
(alternate conditions B, column G) R.sub.t=0.777.
[1253] Preparation of Precursor 5w: To a mixture of 4p (160 mg,
0.65 mmol), DEPBT (390 mg, 1.31 mmol) and benzoylpiperazine
hydrochloride (222 mg, 0.98 mmol) was added DMF (2 ml) and
N,N-diisopropylethylamine (1.2 ml, 6.9 mmol). The reaction mixture
was stirred at room temperature for 16 hours, and concentrated to
remove most of the solvent. The residue was diluted with MeOH (10
ml) and then filtered. The filtrate was purified by preparative
reverse phase HPLC using the method: Start % B=15, Final % B=70,
Gradient time=30 min, Flow Rate=40 ml/min, Wavelength=220 nm,
Column XTERRA C18 5 .mu.m 30.times.100 mm, A=10% MeOH,-90%
H.sub.2O-0.1% TFA, B=90% MeOH-10% H.sub.2O-0.1% TFA, Fraction
Collection: 14.03-15.43 min. The structure was supported by NOE
experiments. .sup.1H NMR: (DMSO-d.sub.6) 13.66 (s, 1H), 8.45 (s,
1H), 8.25 (s, 1H), 7.45 (s, 5H), 4.07 (s, 3H), 3.80-3.40 (b m, 8H);
LC/MS: (ES+) m/z (M+H).sup.+=418 HPLC (alternate conditions B,
column G) R.sub.t=1.447. 778
[1254] Preparation of Example 223: To a mixture of 5w (15 mg, 0.036
mmol), NaN.sub.3 (24 mg, 0.36 mmol), and NH.sub.4Cl (19 mg, 0.36
mmol) was added DMF (1 ml). The reaction mixture was heated at
100.degree. C. for three hours. After cooling to room temperature,
the reaction mixture was added MeOH (4 ml) and then filtered. The
filtrate was purified by preparative reverse phase HPLC using the
method: Start % B=15, Final % B=75, Gradient time=15 min, Flow
Rate=40 ml/min, Wavelength=220 nm, Column: XTERRA C18 5 .mu.m
30.times.100 mm, A=10% MeOH,-90% H.sub.2O-0.1% TFA, B=90% MeOH-10%
H.sub.2)-0.1% TFA, Fraction Collection: 8.48-9.78 min. .sup.1H NMR:
(DMSO-d.sub.6) 12.68 (b s, 1H), 8.26 (s, 1H), 8.24 (s, 1H), 7.46
(s, 5H), 4.09 (s, 3H), 3.86-3.30 (b m, overlapping with broad water
peak, 8H), one exchangeable proton was not observed due to the
presence of water in the sample. LC/MS: (ES+) m/z (M+H).sup.+=461
HPLC (alternate conditions B, column G) R.sub.t=1.392.
[1255] Preparation of Examples 224 and 225: To the mixture of 5w
(10 mg, 0.022 mmol) in MeOH (0.2 ml) and benzene (0.4 ml) was added
TMSCHN.sub.2 (0.4 ml, 0.1 M*). The reaction mixture was stirred at
room temperature for 1.5 hours, followed by purification on
preparative TLC (1.times.20.times.20 cm, 500 microns) with 10%
MeOH/CH.sub.2Cl.sub.2 to give the two compounds as white solids.
Example 224 (2.7 mg, 26%); .sup.1H NMR: (DMSO-d.sub.6) 12.60 (b s,
1H), 8.31 (s, 1H), 8.23 (s, 1H), 7.46 (s, 5H), 4.50 (s, 3H), 4.15
(s, 3H), 3.80-3.30 (b m, 8H); LC/MS: (ES+) m/z (M+H).sup.+=475,
HPLC (alternate conditions B, column G) R.sub.t=1.672. Example 225
(1.4 mg, 13%), .sup.1H NMR: (DMSO-d.sub.6) 12.40 (b s, 1H), 8.22
(s, 1H), 8.20 (s, 1H), 7.46 (s, 5H), 4.52 (s, 3H), 4.04 (s, 3H),
3.80-3.30 (b m 8H); LC/MS: (ES+) m/z (M+H).sup.+=475, HPLC
(alternate conditions B, column G) R.sub.t=1.373. These two
structures were further supported by nitrogen HMBC analysis.
*TMSCHN.sub.2 (0.1 M) was prepared by diluting commercially
available TMSCHN.sub.2 (0.2 ml, 2.0 M) with hexane (3.8 ml).
EXAMPLE 226
[1256] 779
[1257] Reaction scheme for prep of example 226 780
[1258] Preparation of Example 226
[1259] To a mixture of 5w (85 mg, 0.204 mmol) and hydroxylamine
hydrochloride (22 mg, 0.305 mmol) in anhydrous ethanol (3 ml, 200
proof) was added triethylamine (60 .mu.l, 0.4 mmol). The reaction
mixture was heated in a capped vial at 100.degree. C. for 6
hours.
[1260] Removal of solvent gave precursor 5x as a white solid, to
which was added triethyl orthoformate (3 ml). The mixture was then
heated in a capped vial at 100.degree. C. for 12 hours. After
removal of most of the excess triethyl orthoformate, the residue
was diluted with MeOH (6 ml), followed by filtration. The filtrate
was purified by preparative reverse phase HPLC using the method:
Start % B=30, Final % B=50, Gradient time=20 min, Flow Rate=40
ml/min, Column: XTERRA C18 5 .mu.m 30.times.100 mm, Fraction
Collection: 7.57-7.98 min. .sup.1H NMR: (DMSO-d.sub.6) 12.41 (s,
1H), 9.87 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 7.45 (s, 5H), 4.06
(s, 3H), 3.68-3.20 (b m, overlapping with broad water peak, 8H);
The following HPLC conditions for the analytical LCMS were used:
Column: Xterra C18 S7 3.times.50 mm; Gradient Time=3 min; Flow
rate=4 ml/min. LC/MS: (ES+) m/z (M+H).sup.+=461 HPLC R.sub.t=1.390.
Product from a similar run provided the following 1H NMR spectra
(methanol-d6) .delta.9.32 (s, 1H), 8.28 (s, 2H), 7.83 (s, 1H), 7.45
(narrow multiplet, 6H), 4.05 (s, 3H), 3.80 (bm, 4H), 3.56 (bm,
4H).
EXAMPLES 227 to 229
[1261] Examples 227 to 230 (Table 2-1) were prepared analogously to
Example 194 except that the appropriate substituted piperazine was
utilized. The preparation of the appropriate substituted
piperazines is described for precursors 17a-d or in reference
90b.
[1262] General Procedures for the Preparation of Pyrazoles
[1263] 3-Substituted pyrazoles can be prepared via the following
routes: 781
[1264] Alkyne (1 eq.) was dissolved in a 2M solution of
diazomethane (5-10 eq.) in hexane and resulting mixture was heated
to 110-1 15.degree. C. for 12 hours. After reaction was quenched
with MeOH, removal of solvents provided a residue which was used in
the next step without any purification. 782
[1265] Methyl ketone (1 eq.) was added into a solution of
dimethoxy-DMF (5-10 eq.) in DMF and the resulting mixture was
heated to 110-115.degree. C. for 12 hours. Solvents were then
removed under vaccum to provide a residue.
[1266] The above residue was mixed with hydrazine (5-10 eq.) in
ethanol and the reaction was kept in refluxing for 12 hours.
Removal of solvents in vacco gave a residue, which was carried onto
further reactions without purification. 783
[1267] Hydrazine (10-20 eq.) was added into a solution of alkenone
or alkenal (1 eq.) in THF and the resulting mixture was heated to
110-115.degree. C. for 12 hours. After the mixture cooled down to
room temperature, an excess of NiO2-2H2O ( 5-10 eq.) was then added
into the reaction mixture and the reaction was stirred at room
temperature for another 12 hours. Insoluble materials were then
filtered away and concentration under vaccum provided a residue
that was used in the further reactions without purification.
18TABLE I-5 Preparation of Pyrazoles Method HPLC R.sub.f
(column)/MS Compound.sup.# Structure Used (M + H).sup.+or (M +
Na).sup.+ Pyrazole-001 784 P-A 0.35 min (column L) Pyrazole-002 785
P-A 0.59 min (column L) Pyrazole-003 786 P-A 1.07 min (column L)/
MS (M + H).sup.+: Calc'd 139.12 Found 139.18 Pyrazole-004 787 P-A,
P-B, P-C 0.35 min (column L) Pyrazole-005 788 P-B 0.48 min (column
L) Pyrazole-006 789 P-A 0.63 min (column L) Pyrazole-007 790 P-A
0.21 min (column G) Pyrazole-008 791 P-A 0.81 min (column L)/ MS (M
+ H).sup.+: Calc'd 197.13 Found 197.18 Pyrazole-009 792 P-A
Pyrazole-010 793 P-A 0.34 min (column L) Pyrazole-011 794 P-A 0.47
min (column L)/ MS (M + H).sup.+: Calc'd 155.08 Found 155.06
Pyrazole-012 795 P-A 0.38 min (column G) Pyrazole-013 796 P-A
Pyrazole-014 797 P-A Pyrazole-015 798 P-A 0.26 min (column L)/ MS
(M + Na).sup.+: Calc'd 149.07 Found 149.11 Pyrazole-016 799 P-A
0.31 min (column L)/ MS (M + H).sup.+: Calc'd 141.10 Found 141.17
Pyrazole-017 800 P-A 0.27 min (column L)/ MS (M + Na).sup.+: Calc'd
149.07 Found 149.13 Pyrazole-018 801 P-A 0.22 min (column L)
Pyrazole-019 802 P-A 0.61 min (column L)/ MS (M + Na).sup.+: Calc'd
175.08 Found 175.14 Pyrazole-020 803 P-A 0.79 min (column L)/ MS (M
+ Na).sup.+: Calc'd 189.10 Found 189.17 Pyrazole-021 804 P-A 0.59
min (column L)/ MS (M + H).sup.+: Calc'd 141.10 Found 141.18
Pyrazole-022 805 P-A 0.22 (column L) Pyrazole-023 806 P-A 0.34 min
(column L)/ MS (M + Na).sup.+: Calc'd 193.10 Found 193.14
Pyrazole-024 807 P-A 1.05 min (column L)/ MS (M + H).sup.+: Calc'd
228.08 Found 228.14
[1268] General Procedure Si--Cu
[1269] Silicon Masked General Procedure for Attaching Pyrazoles,
Imidazoles and Triazoles with Melting-points Higher Than
160.degree. C. to C-7 Position of Azaindoles:
[1270] In cases where the meltingpoints of the nitrogen heterocycle
to be attached to the azaindole have melting points higher than
160.degree. C., an excess of the heterocycle (usually greater than
3 equivalents) is heated with a larger excess of
hexamethydisilazane or chloro trimethylsilane (>10 equivalents)
at temperatures up to 140.degree. C. for approximately 12 h. The
excess silylating reagent is removed in vacuo and the mixture is
combined with the azaindole halide and the copper catalyzed
reaction is conducted as below.
[1271] A mixture of halo-indole or halo-azaindole intermediate, 1-2
equivalents of copper powder, with 1 equivalent preferred for the
4-F,6-azaindole series and 2 equivalents for the
4-methoxy,6-azaindole series; 1-2 equivalents of potassium
carbonate, and the the corresponding silylated heterocyclic reagent
as prepared above, was heated at 135-160.degree. C. for 4 to 9
hours, with 5 hours at 160.degree. C. preferred for the
4F,6-azaindole series and 7 hours at 135.degree. C. preferred for
the 4-methoxy,6-azaindole series. The reaction mixture was cooled
to room temperature and filtered through filter paper. The filtrate
was diluted with methanol and purified either by preparative HPLC
or silica gel. In many cases no chromatography is necessary, the
product can be obtained by crystallization with methanol.
19TABLE I-6 N-containing Heterocycles Applied under General
Procedure Si--Cu (Silicon-Masking Conditions) Entry N-Containing
Heterocycle HM-01 808 HM-02 809 HM-03 810 HM-04 811 HM-05 812 HM-06
813 HM-07 814
[1272] Examples 230 Through Example 258, Were Prepared Using the
Same Conditions and Method Used for Synthesizing, Example 187:
EXAMPLE 230
[1273] 815
[1274] Example 230, was prepared according to the general method
described above starting from Precursor 5z and Pyrazole-001 to
provide
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-ethyl-pyrazol-1-yl)-6-azaindol--
3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.27H.sub.29N.sub.6O.sub.4: 501.23; found 501.17. HPLC
retention time: 2.30 minutes (column G, flow rate 4 ml/min,
gradient time 3 min).
EXAMPLE 231
[1275] 816
[1276] Example 231, was prepared according to the general method
described above starting from Precursor 5z and Pyrazole-002 to
provide
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-propyl-pyrazol-1-yl)-6-azaindol-
-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.28H.sub.31N.sub.6O.sub.4: 515.24; found 515.19. HPLC
retention time: 2.47 minutes (column G, flow rate 4 ml/min,
gradient time 3 min).
EXAMPLE 232
[1277] 817
[1278] Example 232, was prepared according to the general method
described above starting from Precursor 5z and Pyrazole-006 to
provide
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-cycloputyl-pyrazol-1-yl)-6-azai-
ndol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.29H.sub.31N.sub.6O.sub.4: 527.24; found 527.16. HPLC
retention time: 2.53 minutes (column G, flow rate 4 ml/min,
gradient time 3 min).
EXAMPLE 233
[1279] 818
[1280] Example 233, was prepared according to the general method
described above starting from Precursor 5z and Pyrazole-012 to
provide
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-ethoxy-pyrazol-1-yl)-6-azaindol-
-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.27H.sub.29N.sub.6O.sub.5: 517.22; found 517.17. HPLC
retention time: 2.26 minutes (column G, flow rate 4 ml/min,
gradient time 3 min).
EXAMPLE 234
[1281] 819
[1282] Example 234, was prepared according to the general method
described above starting from Precursor 5z and Pyrazole-011 to
provide
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-(3-hydroxylcarbonylethan-1-yl)--
pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z:
(M+H).sup.+ Calc'd for C.sub.28H.sub.29N.sub.6O.sub.4: 545.21;
found 545.15. HPLC retention time: 2.08 minutes (column G, flow
rate 4 ml/min, gradient time 3 min).
EXAMPLE 235
[1283] 820
[1284] Example 235, was prepared according to the general method
described above starting from Precursor 5z and Pyrazole-009 to
provide
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-(1-hydroxylethyl)-pyrazol-1-yl)-
-6-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd
for C.sub.27H.sub.29N.sub.6O.sub.5: 517.22; found 517.15. HPLC
retention time: 1.43 minutes (column G).
EXAMPLES 236 AND 237
[1285] 821
[1286] Examples 236 and 237, were prepared according to the general
method described above starting from Precursor 5z and Pyrazole-007
to provide Example 236,
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-hydroxylmethyl-pyr-
azol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine and Example 237,
(R)-1-benzoyl-3-methyl-4-[(4
methoxy-7-(4-hydroxylmethyl-pyrazol-1-yl)-6--
azaindol-3-yl)-oxoacetyl]piperazine.
[1287] Example 236,
(R)-1-benzoyl-3-methyl-4-[(4-methoxy-7-(3-hydroxylmeth-
yl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine: MS m/z:
(M+H).sup.+ Calc'd for C.sub.26H.sub.27N.sub.6O.sub.5: 503.20;
found 503.20. HPLC retention time: 1.87 minutes (column G, flow
rate 4 ml/min, gradient time 3 min).
[1288] Example 237,
(R)-1-benzoyl-3-methyl-4-[(4-methoxy-7-(4-hydroxylmeth-
yl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine: MS m/z:
(M+H).sup.+ Calc'd for C.sub.26H.sub.27N.sub.6O.sub.5: 503.20;
found 503.25. HPLC retention time: 1.31 minutes (column G, flow
rate 4 ml/min, gradient time 3 min).
EXAMPLE 238
[1289] 822
[1290] Example 238, was prepared according to the general method
described above starting from Precursor 5z and Pyrazole-013 to
provide
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-methoxymethyl-pyrazol-1-yl)-6-a-
zaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.27H.sub.29N.sub.6O.sub.5: 517.22; found 517.23. HPLC
retention time: 1.95 minutes (column G, flow rate 4 ml/min,
gradient time 3 min).
EXAMPLE 239
[1291] 823
[1292] Example 239, was prepared according to the general method
described above starting from Precursor 5z and Pyrazole-014 to
provide
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-(N,N-dimethylamino)methyl-pyraz-
ol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+
Calc'd for C.sub.28H.sub.32N.sub.7O.sub.4: 530.25; found 530.25.
HPLC retention time: 1.45 minutes (column G, flow rate 4 ml/min,
gradient time 3 min).
EXAMPLES 190 AND 240
[1293] 824
[1294] Examples 190 and 240, were prepared according to the general
method described above starting from Precursor 5b and
3-methylpyrazole to provide example Example 190 and Example
240.
[1295] Example 240,
1-benzoyl-4-[(4-methoxy-7-(5-methyl-pyrazol-1-yl)-6-az-
aindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.25N.sub.6O.sub.4: 473.19; found 473.19. HPLC
retention time: 1.35 minutes (column G).
[1296] Example 190,
1-benzoyl-4-[(4-methoxy-7-(3-methyl-pyrazol-1-yl)-6-az-
aindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.25N.sub.6O.sub.4: 473.19; found 473.17. HPLC
retention time: 1.50 minutes (column G).
EXAMPLES 241 AND 242
[1297] 825
[1298] Examples 241 and 242, were prepared according to the general
method described above starting from Precursor 5z and
3-methylpyrazole.
[1299] Example 241,
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-methyl-pyraz-
ol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+
Calc'd for C.sub.26H.sub.26N.sub.6O.sub.4: 487.21; found 486.20.
HPLC retention time: 1.54 minutes (column G).
[1300] Example 242,
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(5-methyl-pyraz-
ol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+
Calc'd for C.sub.26H.sub.27N.sub.6O.sub.4: 487.21; found 486.20.
HPLC retention time: 1.41 minutes (column G).
EXAMPLE 243
[1301] 826
[1302] Example 243, was prepared according to the general method
described above starting from Precursor 5z and 3-t-butylpyrazole to
provide
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-t-butyl-pyrazol-1-yl)-6-azaindo-
l-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.29H.sub.30N.sub.6O.sub.4: 529.26; found 529.29. HPLC
retention time: 1.86 minutes (column G).
EXAMPLE 244
[1303] 827
[1304] Example 244, was prepared according to the general method
described above starting from Precursor 5z and
3-trifluoromethylpyrazole to provide
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-trifluoromethyl-pyrazol-1-yl)-6-
-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd
for C.sub.26H.sub.24F.sub.3N.sub.6O.sub.4: 541.18; found 541.25.
HPLC retention time: 1.71 minutes (column G).
EXAMPLE 245
[1305] 828
[1306] Example 245, was prepared according to the general method
described above starting from Precursor 5z and 1,2,4-triazole to
provide
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(1,2,4-triazol-1-yl)-6-azaindol-3--
yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.24N.sub.7O.sub.4: 474.19; found 474.23. HPLC
retention time: 1.29 minutes (column G).
EXAMPLE 246
[1307] 829
[1308] Example 246, was prepared according to the general method
described above starting from Precursor 5z and 1,2,3-benzotriazole
to provide
(R)-1-benzoyl-2methyl-4-[(4-methoxy-7-(1,2,3-benzotriazol-1-yl)-6-azaindo-
l-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.28H.sub.26N.sub.7O.sub.4: 524.20; found 524.27. HPLC
retention time: 1.68 minutes (column G).
EXAMPLE 247
[1309] 830
[1310] Example 247, was prepared according to the general method
described above starting from Precursor 5b and Pyrazole-010 to
provide
1-benzoyl-4-[(4-methoxy-7-(3-(1-hydroxyl-1-methylethyl)-pyrazol-1-yl)-6-a-
zaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.27H.sub.29N.sub.6O.sub.5: 517.22; found 517.37. HPLC
retention time: 1.38 minutes (column L).
EXAMPLE 248
[1311] 831
[1312] Example 248, was prepared according to the general method
described above starting from Precursor 5b and Pyrazole-008 to
provide
1-benzoyl-4-[(4-methoxy-7-(3-(3-hydroxylethyl)-pyrazol-1-yl)-6-azaindol-3-
-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.26H.sub.27N.sub.6O.sub.5: 503.20; found 503.27. HPLC
retention time: 1.16 minutes (column L).
EXAMPLE 249
[1313] 832
[1314] Example 249, was prepared according to the general method
described above starting from Precursor 5b and Pyrazole-004 to
provide
1-benzoyl-4-[(4-methoxy-7-(3-iso-propyl-pyrazol-1-yl)-6-azaindol-3-yl)-ox-
oacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.27H.sub.29N.sub.6- O.sub.4: 501.23; found 501.34. HPLC
retention time: 1.74 minutes (column L).
EXAMPLE 250
[1315] 833
[1316] Example 250, was prepared according to the general method
described above starting from Precursor 5b and Pyrazole-003 to
provide
1-benzoyl-4-[(4-methoxy-7-(3-n-pentyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoa-
cetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.29H.sub.33N.sub.6O.- sub.4: 529.26; found 529.34. HPLC
retention time: 1.96 minutes (column L).
EXAMPLES 251 AND APP 252
[1317] 834
[1318] Examples 251 and 252, were prepared according to the general
method described above starting from Precursor 5b and
3-aminopyrazole.
[1319] Example 251,
1-benzoyl-4-[(4-methoxy-7-(3-amino-pyrazol-1-yl)-6-aza-
indol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.24N.sub.7O.sub.4: 474.29; found 474.24. HPLC
retention time: 1.58 minutes (column G).
[1320] Example 252,
1-benzoyl-4-[(4-methoxy-7-(5-amino-pyrazol-1-yl)-6-aza-
indol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.24N.sub.7O.sub.4: 474.29; found 474.22. HPLC
retention time: 1.59 minutes (column G).
EXAMPLES 253 AND 254
[1321] 835
[1322] Examples 253 and 254, were prepared according to the general
method described above starting from Precursor 5z and
3-aminopyrazole.
[1323] Example 253,
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-amino-pyrazo-
l-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+
Calc'd for C.sub.25H.sub.26N.sub.7O.sub.4: 488.20; found 488.25.
HPLC retention time: 1.65 minutes (column G, flow rate=4 ml/min,
gradient time=3 min).
[1324] Example 254,
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(5-amino-pyrazo-
l-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+
Calc'd for C.sub.25H.sub.26N.sub.7O.sub.4: 488.20; found 488.25.
HPLC retention time: 1.74 minutes (column G, flow rate=4 ml/min,
gradient time=3 min).
EXAMPLES 255 AND 256
[1325] 836
[1326] Examples 255 and 256, were prepared according to the general
method described above starting from Precursor 5z and
1,2,3-triazole. Precursor 5z (0.056 g), 0.056 g Cu powder,0.025 g
K2CO3 and 10 equivalents of 1,2,3 triazole were heated at
155-170.degree. C. for 4 hrs. The reaction was allowed to cool to
ambient temperature and the residue was dissolved in MeOH and
purifed by Prep HPLC. as described above in the general methods to
provide Example 255 (0.020 g) as a brown solid,yield 34% and the
other isomer Example 256.
[1327] Example 255,
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(1,2,3-triazol--
1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+
Calc'd for C.sub.24H.sub.24N.sub.7O.sub.4: 474.19; found 474.21.
HPLC retention time: 1.84 minutes (column G, flow rate=4 ml/min,
gradient time=3 min). .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.8.85
(s, 1H), 8.32 (ss, 1H), 7.94 (m, 2H), 7.48 (m, 5H), 4.07 (ss, 3H),
4.00-3.00 (m, 7H), 1.33 (m, 3H).
[1328] Example 256,
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(1,2,3-triazol--
2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+
Calc'd for C.sub.24H.sub.24N.sub.7O.sub.4: 474.19; found 474.21.
HPLC retention time: 1.66 minutes (column G, flow rate=4 ml/min,
gradient time=3 min). .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.8.33
(ss, 1H), 8.13 (s, 1H), 7.46 (m, 7H), 4.07 (ss, 3H), 4.00-3.00 (m,
7H), 1.32 (m, 3H).
EXAMPLE 257
[1329] 837
[1330] Example 257, was prepared according to the general method
described above starting from Precursor 5z and 3-hydroxylpyrazole
to provide
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-hydroxylpyrazol-1-yl)-6-azaindo-
l-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.25N.sub.6O.sub.5: 489.19; found 489.15. HPLC
retention time: 1.38 minutes (column G).
EXAMPLE 258
[1331] 838
[1332] Example 258, was prepared according to the general method
described above starting from Precursor 5z and
3-amino-1,2,4-triazole to provide
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-amino-1,2,4-triazol-1-yl)-6-aza-
indol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.24H.sub.25N.sub.8O.sub.4: 489.20; found 489.24. HPLC
retention time: 1.69 minutes (column G).
[1333] Examples 259 Through 265, Were Prepared According to the
General Procedure Si-Cu (Silicon-Masking conditions) Described
Above:
EXAMPLE 259
[1334] 839
[1335] Example 259, was prepared according to the general method
Si--Cu(Silicon-Masking) described above starting from Precursor 5z
and 3-methylcarbonylpyrazole to provide
(R)-1-benzoyl-2-methyl-4-[(4-methoxy--
7-(3-methylcarbonyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS m/z: (M+H).sup.+ Calc'd for C.sub.27H.sub.27N.sub.6O.sub.5:
515.20; found 515.15. HPLC retention time: 1.51 minutes (column
G).
EXAMPLE 260
[1336] 840
[1337] Example 260, was prepared according to the general method
Si--Cu (Silicon-Masking) described above starting from Precursor 5z
and 3-phenylpyrazole to provide
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-phe-
nyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyly]piperazine; MS m/z:
(M+H).sup.+ Calc'd for C.sub.31H.sub.29N.sub.6O.sub.4: 549.23;
found 549.18. HPLC retention time: 1.82 minutes (column G).
EXAMPLE 261
[1338] 841
[1339] Example 261, was prepared according to the general method
Si--Cu (Silicon-Masking) described above starting from Precursor 5z
and 3-(3-pyridinemethylamino)-1,2,4-triazole to provide
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(3-(3-pyridinemethylamino)-1,2,4-t-
riazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z:
(M+H).sup.+ Calc'd for C.sub.30H.sub.30N.sub.9O.sub.4: 580.24;
found 580.14. HPLC retention time: 1.15 minutes (column G).
EXAMPLE 262
[1340] 842
[1341] Example 262, was prepared according to the general method
Si--Cu (Silicon-Masking) described above starting from Precursor 5z
and 3-acetylaminopyrazole to provide
(R)-1-benzoyl-2-methyl-4-[(4-methoxy-7-(-
3-acetylamino-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS m/z: (M+H).sup.+ Calc'd for C.sub.27H.sub.28N.sub.7O.sub.5:
530.22; found 530.15. HPLC retention time: 1.41 minutes (column
G).
EXAMPLE 263
[1342] 843
[1343] Example 263 was prepared according to the general method
Si--Cu (Silicon-Masking) described above starting from Precursor 5z
and 3-(2-methylpyridin-5-yl)pyrazole to provide
(R)-1-benzoyl-2-methyl-4-[(4--
methoxy-7-(3-(2-methylpyridin-5-yl)pyrazol-1-yl)-6-azaindo-3-yl)-oxoacetyl-
]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.31H.sub.30N.sub.7O.sub.4- : 564.24; found 564.26. HPLC
retention time: 1.22 minutes (column C).
EXAMPLE 264
[1344] 844
[1345] Example 264 was prepared according to the general method
Si--Cu (Silicon-Masking) described above starting from Precursor 5b
and 3-(2-methylpyridin-5-yl)pyrazole to provide
1-benzoyl-4-[(4-methoxy-7-(3--
(2-methylpyridin-5-yl)pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS m/z: (M+H).sup.+ Calc'd for C.sub.30H.sub.28N.sub.7O.sub.4:
550.22; found 550.26. HPLC retention time: 1.20 minutes (column
C).
EXAMPLE 265
[1346] 845
[1347] Example 265 was prepared according to the general method
Si--Cu (Silicon-Masking) described above starting from Precursor 5z
and 3-(1,2,4-triazol-1-yl)ethyl-pyrazole to provide
(R)-1-benzoyl-2-methyl-4--
[(4-methoxy-7-(3-(1,2,4-triazol-1-yl)ethyl-pyrazol-1-yl)-6-azaindol-3-yl)--
oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.29H.sub.30N.sub.9O.sub.4: 568.24; found 568.13. HPLC
retention time: 1.44 minutes (column G).
[1348] Examples 266 to 270, Were Prepared According to a Procedure
Analogous to the Procedure used Synthesize Example 15:
EXAMPLE 266
[1349] 846
[1350] Example 266, was prepared according to the general method
described above starting from Precursor 5z and 2-amino-pyrazin-5-yl
tributyltin, to provide
(R)-1-benzoyl-2-methyl-4-[(7-(2-amino-pyrazin-5-yl)-6-azaindol-3--
yl-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.26H.sub.26N.sub.7O.sub.4: 500.20; found 500.26. HPLC
retention time: 1.11 minutes (column G).
EXAMPLE 267
[1351] 847
[1352] Example 267, was prepared according to the general method
described above starting from Precursor 5za and
2-amino-pyrazin-5-yl tributyltin, to provide
(R)-1-picolinoyl-2-methyl-4-[(7-(2-amino-pyrazin-5-yl)-6-azain-
dol-3-yl-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.25N.sub.8O.sub.4: 501.20; found 501.30. HPLC
retention time: 1.04 minutes (column J).
EXAMPLE 268
[1353] 848
[1354] Example 268, was prepared according to the general method
described above starting from Precursor 5xa and
4-methylsulfonylphenyl boronic acid, to provide
(R)-1-picolinoyl-2-methyl-4-[(7-(4-methylsulfonyl-phenyl-
-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+
Calc'd for C.sub.28H.sub.28N.sub.5O.sub.6S: 562.18; found 562.19.
HPLC retention time: 0.86 minutes (column G).
EXAMPLE 269
[1355] 849
[1356] Example 269, was prepared according to the general method
described above starting from Precursor 5xa and tri-butylstannyl
pyrazine, to provide
(R)-1-picolinoyl-2-methyl-4-[(7-pyrazinyl-6-azaindol-3-yl-oxoacet-
yl]piperazine; MS m/z: (M+H).sup.+ Calc'd for C25H24N.sub.7O.sub.4:
486.19; found 486.32. HPLC retention time: 1.07 minutes (column
G).
EXAMPLE 270
[1357] 850
[1358] Example 270, was prepared according to the general method
described above starting from Precursor 5y and tri-butylstannyl
pyrazine, to provide
(R)-1-nicotinoyl-2-methyl-4-[(7-pyrazinyl-6-azaindol-3-yl-oxoacet-
yl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.24N.sub.7O.sub- .4: 486.19; found 486.10. HPLC
retention time: 0.96 minutes (column L).
[1359] Examples 271 through 272, Were Prepared using the "General
Procedure of Converting --NH.sub.2 Group to --OH Group",
Examplified by the Preparation of Example 97:
EXAMPLE 271
[1360] 851
[1361] Example 271, was prepared according to the general method
described above starting from Example 266 to provide
(R)-1-benzoyl-2-methyl-4-[(7-(-
5-hydroxyl-pyrazin-1-yl)-6-azaindol-3-yl-oxoacetyl]piperazine; MS
m/z: (M+H).sup.+ Calc'd for C.sub.26H.sub.25N.sub.6O.sub.5: 501.19;
found 501.21. HPLC retention time: 1.08 minutes (column G).
EXAMPLE 272
[1362] 852
[1363] Example 272, was prepared according to the general method
described above starting from Example 267 to provide
(R)-1-picolinoyl-2-methyl-4-[(-
7-(5-hydroxyl-pyrazin-1-yl)-6-azaindol-3-yl-oxoacetyl]piperazine;
MS m/z: (M+H).sup.+ Calc'd for C.sub.25H.sub.24N.sub.7O.sub.5:
502.18; found 502.19. HPLC retention time: 0.88 minutes (column
G).
EXAMPLE 273
[1364] 853
[1365] Example 273, was prepared from Precursor 5b and
1H-[1,2,4]-triazole-3-carboxylic acid ethylamide to provide
1-benzoyl-4-[(4-methoxy-7-(3-ethylaminocarbonyl-1,2,4-triazol-1-yl)-6-aza-
indol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.26H.sub.27N.sub.8O.sub.5: 531.21; found 531.21. HPLC
retention time: 1.75 minutes (column G). .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta.9.35 (s, 1H), 8.34 (s, 1H), 7.86 (s, 1H), 7.48
(b, 5H), 4.06 (s, 3H), 4.00-3.49 (m, 10H), 1.30 (t, 3H, J=7.5
Hz).
EXAMPLE 274
[1366] 854
[1367] Example 274, was prepared from Precursor 5b and
1H-[1,2,4]-triazole-3-carboxylic acid methylamide to provide
1-benzoyl-4-[(4-methoxy-7-(3-methylaminocarbonyl-1,2,4-triazol-1-yl)-6-az-
aindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.25H.sub.25N.sub.8O.sub.5: 517.19; found 517.18. HPLC
retention time: 1.67 minutes (column G). .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta.9.36 (s, 1H), 8.35 (s, 1H), 7.88 (s, 1H), 7.48
(b, 5H), 4.06 (s, 3H), 3.80-3.60 (m, 8H), 3.02 (s, 3H).
EXAMPLE 275
[1368] 855
[1369] Example 275, was prepared from Precursor 5b and
1H-[1,2,4]-triazole-3-caroxylic acid dimethylamide to provide
1-benzoyl-4-[(4-methoxy-7-(3-dimethylaminocarbonyl-1,2,4-triazol-1-yl)-6--
azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.26H.sub.27N.sub.8O.sub.5: 531.21; found 531.28. HPLC
retention time: 1.71 minutes (column G).
EXAMPLE 276
[1370] 856
[1371] Example 276, was prepared from Precursor 5b and
1H-pyrazole-3-caroxylic acid methylamide to provide
1-benzoyl-4-[(4-methoxy-7-(3-methylaminocarbonyl-pyrazol-1-yl)-6-azaindol-
-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.26H.sub.26N.sub.7O.sub.5: 516.20; found 516.27. HPLC
retention time: 1.86 minutes (column G).
EXAMPLE 277
[1372] 857
[1373] Example 277, was prepared from Precursor 5b and
1-(1H-pyrazol-3-yl)propan-2-ol to provide
1-benzoyl-4-[(4-methoxy-7-(3-(2-
-hydroxylpropyl)-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS m/z: (M+H).sup.+ Calc'd for C.sub.27H.sub.29N.sub.6O.sub.5:
517.22; found 517.38. HPLC retention time: 1.42 minutes (column
L).
EXAMPLE 278
[1374] 858
[1375] Example 278, was prepared from Precursor 5b and
3-cyclohex-1-enyl-1H-pyrazole to provide
1-benzoyl-4-[(4-methoxy-7-(3-(cy-
clohexen-1-yl)-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS m/z: (M+H).sup.+ Calc'd for C.sub.30H.sub.31N.sub.6O.sub.4:
539.24; found 539.26. HPLC retention time: 1.96 minutes (column
L).
EXAMPLE 279
[1376] 859
[1377] Example 279, was prepared from Precursor 5b and
4-(1H-pyrazol-3-yl)-butyronitrile to provide
1-benzoyl-4-[(4-methoxy-7-(3-
-(3-cyano-propan-1-yl)-pyrazol-1-yl)-6-azaindol-3-yl-oxoacetyl]piperazine;
MS m/z: (M+H).sup.+ Calc'd for C.sub.28H.sub.28N.sub.7O.sub.4:
526.22; found 526.35. HPLC retention time: 1.51 minutes (column
L).
EXAMPLE 280
[1378] 860
[1379] Example 280, was prepared from Precursor 5b and
4-(1H-pyrazol-3-ylmethyl)-thiomorpholine 1,1-dioxide to provide
1-benzoyl-4-[(4-methoxy-7-(3-(1,1-dioxo-thiomorpholin-4-yl)methyl-pyrazol-
-1-yl-6-azaindol-3-yl-oxoacetyl]piperazine; MS m/z: (M+H).sup.+
Calc'd for C.sub.29H.sub.32N.sub.7O.sub.6S: 606.21; found 606.34.
HPLC retention time: 1.01 minutes (column L).
EXAMPLE 281
[1380] 861
[1381] Example 281, was prepared from Precursor 5b and
3-isobutyl-1H-pyrazole to provide
1-benzoyl-4-[(4-methoxy-7-(3-isobutyl-p-
yrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z:
(M+H).sup.+ Calc'd for C.sub.28H.sub.31N.sub.6O.sub.4: 515.24;
found 515.35. HPLC retention time: 1.90 minutes (column L).
EXAMPLE 282
[1382] 862
[1383] Example-282, was prepared from Precursor 5b and
1-(1H-pyrazol-3-yl)-cyclopentanol to provide
1-benzoyl-4-[(4-methoxy-7-(3-
-(1-hydroxy-cyclopentyl)-pyrazol-1-yl)-6-azaindol-3-yl-oxoacetyl]piperazin-
e; MS m/z: (M+H).sup.+ Calc'd for C.sub.29H.sub.31N.sub.6O.sub.5:
543.24; found 543.43. HPLC retention time: 1.51 minutes (column
L).
EXAMPLE 283
[1384] 863
[1385] Example 283, was prepared from Precursor 5b and
methyl-(1H-pyrazol-3-ylmethyl)-amine to provide
1-benzoyl-4-[(4-methoxy-7-
-(3-methylaminomethyl-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS m/z: (M+H).sup.+ Calc'd for C.sub.26H.sub.28N.sub.7O.sub.4:
502.22; found 502.31. HPLC retention time: 1.51 minutes (column
L).
EXAMPLE 284
[1386] 864
[1387] Example 284, was prepared from Precursor 5b and
2-methyl-1-(1H-pyrazol-3-yl)-propan-1-ol to provide
1-benzoyl-4-[(4-methoxy-7-(3-(1-hydroxy-2-methyl-propyl)-pyrazol-1-yl)-6--
azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H).sup.+ Calc'd for
C.sub.28H.sub.31N.sub.6O.sub.5: 531.24; found 531.43. HPLC
retention time: 1.63 minutes (column L).
EXAMPLE 285
[1388] 865
[1389] Example 285, was prepared according to the general method
described above starting from Precursor 5b and Pyrazole-025 to
provide
1-benzoyl-4-[(4-methoxy-7-(3-(4-ethoxycarbonyl-phenyl)oxymethyl-pyrazol-1-
-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+
Calc'd for C.sub.34H.sub.33N.sub.6O.sub.7: 637.24; found 637.34.
HPLC retention time: 1.87 minutes (column G). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta.8.61 (s, 1H), 8.16 (s, 1H), 8.02 (d, 2H, J=15
Hz), 7.76 (s, 1H), 7.43 (b, 5H), 7.05 (d, 2H, J=14.5 Hz), 6.60 (s,
1H), 5.29 (s, 2H), 4.33 (q, 2H, J=12 Hz), 4.03 (s, 3H), 3.80-3.57
(m, 8H), 1.38 (t, 3H, J=12.0 Hz).
EXAMPLE 286
[1390] 866
[1391] Example 286, was prepared according to the general method
described above starting from Precursor 5b and
3-(toluene-4-sulfonyl)-1H-pyrazole to provide
1-benzoyl-4-[(4-methoxy-7-(3-(toluene-4-sulfonyl)-pyrazol-1-yl-
)-6-azaindol-3-yl)oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd
for C.sub.31H.sub.29N.sub.6O.sub.6S: 613.19; found 613.28. HPLC
retention time: 1.69 minutes (column G). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta.8.64 (s, 1H), 8.21 (s, 1H), 7.94 (d, 2H, J=8.00
Hz), 7.74 (s, 1H), 7.43 (b, 5H), 7.34 (d, 2H, J=8.00 Hz), 6.94 (s,
1H), 4.04 (s, 3H), 4.00-3.40 (m, 8H), 2.42 (s, 3H).
EXAMPLE 287
[1392] 867
[1393] Example 287, was prepared according to the general method
described above starting from Precursor 5b and
3-(3-trifluoromethyl-phenyl)-1H-pyra- zole to provide
1-benzoyl-4-[(4-methoxy-7-(3-(3-trifluoromethyl-phenyl)-py-
razol-1-yl)-6-azaindol-3-yl-oxoacetyl]piperazine; MS m/z:
(M+H).sup.+ Calc'd for C.sub.31H.sub.26F.sub.3N.sub.6O.sub.4:
603.20; found 603.32. HPLC retention time: 1.94 minutes (column G).
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta.8.67 (s, 1H), 8.26 (s,
1H), 8.09-7.42 (m, 10H), 6.87 (s, 1H), 4.01 (s, 3H), 4.00-3.62 (m,
8H).
EXAMPLE 288
[1394] 868
[1395] Example 288, was prepared according to the general method
described above starting from Precursor 5b and
3-(4-trifluoromethyl-phenyl)-1H-pyra- zole to provide
1-benzoyl-4-[(4-methoxy-7-(3-(4-trifluoromethyl-phenyl)-py-
razol-1-yl)-6-azaindol-3-yl-oxoacetyl]piperazine; MS m/z:
(M+H).sup.+ Calc'd for C.sub.31H.sub.26F.sub.3N.sub.6O.sub.4:
603.20; found 603.32. HPLC retention time: 1.96 minutes (column G).
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta.8.69 (s, 1H), 8.26 (s,
1H), 8.09-7.43 (m, 10H), 6.87 (s, 1H), 4.01 (s, 3H), 4.00-3.62 (m,
8H).
EXAMPLE 289
[1396] 869
[1397] Example 289, was prepared according to the general method
described above starting from Precursor 5b and
3-propylsulfanyl-1H-[1,2,4]triazole to provide
1-benzoyl-4-[(4-methoxy-7-(3-propylsulfanyl-[1,2,4]triazol-1-y-
l)-6-azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+
Calc'd for C.sub.26H.sub.28N.sub.7O.sub.4S: 534.19; found 534.32.
HPLC retention time: 1.65 minutes (column G). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta.9.09 (s, 1H), 8.18 (s, 1H), 7.70 (s, 1H), 7.37
(m, 5H), 4.05 (s, 3H), 3.90-3.30 (m, 8H), 3.18 (t, 2H, J=11.5 Hz),
1.74 (m, 2H), 1.02 (t, 3H, J=12.5 Hz).
EXAMPLE 290
[1398] 870
[1399] Example 290 (18 mg) was dissolved in 1 ml of AcOOH (37% in
AcOH) at room temperature and the mixture was kept stirring for 10
hours. Removal of solvents under vaccum provided a redicue, which
was purified using Shimadzu automated preparative HPLC System to
provide Example 290,
1-benzoyl-4-[(4-methoxy-7-(3-(propane-1-sulfonyl)-[1,2,4]triazol-1-yl)-6--
azaindol-3-yl)-oxoacetyl]piperazine; MS m/z: (M+H).sup.+ Calc'd for
C.sub.26H.sub.28N.sub.7O.sub.6S: 566.18; found 566.30. HPLC
retention time: 1.44 minutes (column G). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta.9.33 (s, 1H), 8.24 (s, 1H), 7.80 (s, 1H), 7.43
(m, 5H), 4.08 (s, 3H) 3.90-3.50 (m, 8H), 3.42 (t, 2H, J=8.00 Hz),
1.90 (m, 2H), 1.09 (t, 3H, J=7.50 Hz).
EXAMPLE 291
[1400] 871
[1401] Example 290, obtained from the previous stage, was dissolved
in 5 ml of MeONa (8 wt % in MeOH) at room temperature and the
mixture was heated to 90.degree. C. for 10 hours to form 291,
1-benzoyl-4-[(4-methoxy-
-7-(3-methoxy-[1,2,4]triazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS m/z: (M+H).sup.+ Calc'd for C.sub.24H.sub.24N.sub.7O.sub.5:
490.18; found 490.29. HPLC retention time: 1.36 minutes (column
G).
EXAMPLE 292
[1402] 872
[1403] Example 288 (8 mg) was dissolved in 0.2 ml of concentrated
at room temperature and the mixture was heated to 70.degree. C. for
6 hours. Then the mixture was quenched with water (2 ml) to form
Example 292, which was purified using Shimadzu automated
preparative HPLC System (2.1 mg of Example 292 obtained). Example
292, 1-benzoyl-4-[(4-methoxy-7-(3-(4-hydro-
xylcarbonylphenyl)-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS m/z: (M+H).sup.+ Calc'd for C.sub.31H.sub.27N.sub.6O.sub.6:
579.20; found 579.28. HPLC retention time: 1.72 minutes (column G).
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta.8.71 (s, 1H), 8.29 (s,
1H), 8.15 (d, 2H, J=8.00 Hz), 7.97 (d, 2H, J=8.00 Hz), 7.80 (s,
1H), 7.45 (m, 5H), 6.90 (s, 1H), 4.05 (s, 3H), 4.02-3.49 (m,
8H).
EXAMPLE 293
[1404] 873
[1405] Example 288 (8 mg) was dissolved in 0.2 ml of concentrated
at room temperature and the mixture was heated to 70.degree. C. for
6 hours. Then the mixture was quenched with MeOH (2 ml) to form
Example 293, which was purified using Shimadzu automated
preparative HPLC System (1.1 mg of Example 293 obtained). Example
293, 1-benzoyl-4-[(4-methoxy-7-(3-(4-metho-
xycarbonylphenyl)-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS m/z: (M+H).sup.+ Calc'd for C.sub.32H.sub.29N.sub.6O.sub.6:
593.21; found 593.32. HPLC retention time: 1.84 minutes (column G).
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta.8.74 (s, 1H), 8.29 (s,
1H), 8.16 (d, 2H, J=8.00 Hz), 7.94 (d, 2H, J=8.00 Hz), 7.79 (s,
1H), 7.44 (m, 5H), 6.89 (s, 1H), 4.05 (s, 3H), 3.96 (s, 3H),
3.90-3.40 (m, 8H).
EXAMPLE 294
[1406] 874
[1407] Example 287 (6 mg) was dissolved in 0.2 ml of concentrated
at room temperature and the mixture was heated to 70.degree. C. for
6 hours. Then the mixture was quenched with water (2 ml) to form
Example 294, which was purified using Shimadzu automated
preparative HPLC System (2.7 mg of Example 294 obtained). Example
294, 1-benzoyl-4-[(4-methoxy-7-(3-(3-hydro-
xylcarbonylphenyl)-pyrazol-1-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine;
MS m/z: (M+H).sup.+ Calc'd for C.sub.31H.sub.27N.sub.6O.sub.6:
579.20; found 579.28. HPLC retention time: 1.74 minutes (column G).
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta.8.76 (s, 1H), 8.56 (s,
1H), 8.30 (s, 1H), 8.10 (m, 2H), 7.77 (m, 1H), 7.80 (s, 1H), 7.45
(m, 5H), 6.87 (s, 1H), 4.04 (s, 3H), 4.00-3.40 (m, 8H).
EXAMPLE 295
[1408] 875
[1409] Example 136 (6 mg), succinic anhydride (20 mg) and DMAP (5
ml) were dissolved in 5 ml of anhydrous pyridine at room
temperature and the mixture was heated to reflux for 10 hours. Then
the mixture was quenched with MeOH and solvents were removed under
vaccum to provide a residue, which was purified using Shimadzu
automated preparative HPLC System to give Example 295 (2.4 mg),
2,2-Dimethyl-succinic acid
4-(1-{3-[2-(4-benzoyl-3-methyl-piperazin-1-yl)-2-oxoacetyl]-4-methoxy-1H--
pyrrolo[2,3-c]pyridin-7-yl}-1H-pyrazol-3-ylmethyl) ester; MS m/z:
(M+H).sup.+ Calc'd for C.sub.32H.sub.35N.sub.6O.sub.8: 631.25;
found 631.34. HPLC retention time: 1.64 minutes (column G).
EXAMPLE 296
[1410] 876
[1411] Example 111 (10 mg), trans-epoxysuccinyl chloride (20 mg)
and Et.sub.3N (0.2 ml) were dissolved in 2 ml of anhydrous THF at
room temperature and the mixture was kept stirring for 10 hours.
Then the mixture was quenched with water and solvents were removed
under vaccum to provide a residue, which was purified using
Shimadzu automated preparative HPLC System to give Example 296 (2
mg),
3-(6-{3[2-(4-Benzoyl-2-methyl-piperazin-1-yl)-2-oxo-acetyl]-1H-pyrrolo[2,-
3-c]pyridin-7-yl-} -pyrazin-2-ylcarbamoyl)-oxirane-2-carboxylic
acid; MS m/z: (M+H).sup.+ Calc'd for
C.sub.29H.sub.26N.sub.7O.sub.7: 584.19; found 584.36. HPLC
retention time: 1.44 minutes (column G).
EXAMPLE 297
[1412] 877
[1413] Example 112 (10 mg), trans-epoxysuccinyl chloride (20 mg)
and Et.sub.3N (0.2 ml) were dissolved in 2 ml of anhydrous THF at
room temperature and the mixture was kept stirring for 10 hours.
Then the mixture was quenched with water and solvents were removed
under vaccum to provide a residue, which was purified using
Shimadzu automated preparative HPLC System to give Example 297 (5
mg),
3-(6-{3-[2-(4-Benzoyl-2-methyl-piperazin-1-yl)-2-oxo-acetyl]-1H-pyrrolo[2-
,3-c]pyridin-7-yl}-pyridin-2-ylcarbamoyl)-oxirane-2-carboxylic
acid; MS m/z: (M+H).sup.+ Calc'd for
C.sub.30H.sub.27N.sub.6O.sub.7: 583.19; found 583.34. HPLC
retention time: 1.31 minutes (column G). 878
[1414] Precursor 2p (200 mg, 1.0 mmol) was dissolved in
trichloroacetic anhydride (1.2 mL) and heated at 80.degree. C. for
3 h. MeOH (10 mL) was added and the mixture was stirred at rt for
30 min. The volatiles were removed in vacuo. The residue was
diluted with AcOEt (25 mL) and washed with water (2.times.25 mL).
The organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated. The resulting crude oil was dissolved in DMF (1 mL)
and treated with a 2M solution of MeNH.sub.2 in MeOH (2 mL). The
reaction mixture was stirred at rt for 18 h. LC/MS: (ES.sup.+) m/z
(M+H).sup.+=234. The volatiles were removed in vacuo and the crude
(134 mg) was taken to next step without further purification.
879
[1415] Precursor 4p was prepared from precursor 2u following the
procedure described to prepare precursor 4m. LC/MS: (ES.sup.+) m/z
(M+H).sup.+=306. Taken to next step without further
purification.
EXAMPLE 298
[1416] 880
[1417] Example 298 was prepared from precursor 4p by treatment with
EDC (434 mg, 2.3 mmol), HOBt (308 mg, 2.3 mmol) and
benzoylpiperazine (304 mg, 1.36 mmol) in DMF (2 mL). The mixture
was stirred at rt for 18 h and then concentrated in vacuo and
purified using reverse phase HPCL to afford the title compound.
LC/MS: (ES.sup.+) m/z (M+H).sup.+=478; rt =1.25 min. 881
[1418] To a diethylether (10 mL) solution of
trimethylsilyldiazomethane (2 M in hexane, 5.3 mL) was added n-BuLi
(2.5 M in hexane, 4.2 mL) at 0.degree. C. After stirring for 20
min, the resulting mixture was added into a diethylether (5 ml)
solution of 4-fluoro-7-bromo-6-azaindole (340 mg, 2.1 mmol). The
reaction was stirred at 0.degree. C. for 60 min and then, quenched
with water (20 mL). The reaction mixture was extracted with ethyl
acetate (2.times.40 mL). The organic layers were combined, dried
over MgSO.sub.4, filtered and concentrated. The residue was
triturated with ethyl acetate. The solid was filtered and dried in
air to give precursor 2v as a white solid (35 mg). .sup.1HNMR
(300MHz, CD.sub.3OD): 8.43 (bs, 1H); 8.09-8.08 (m, 1H); 7.64-7.63
(m, 1H); 6.72-6.71 (m, 1H). LC/MS: (ES.sup.+) m/z (M+H).sup.+=204.
Rt=0.50 min. The filtrate was concentrated and purified on silica
gel column eluting with 5-10% of ethyl acetate/hexane to afford
precursor 2vv as a yellow solid (422 mg). .sup.1HNMR (300MHz,
CDCl.sub.3): 8.09-8.08 (m, 1H); 7.47-7.45 (m, 1H); 6.69-6.67 (m,
1H); 0.45 (s, 9H). LC/MS: (ES.sup.+) m/z (M+H).sup.+=276. Rt=1.39
min. 882
[1419] Precursor 4q was prepared following the procedure described
before for compound 4m. LC/MS: (ES.sup.+) m/z(M+H).sup.+=276.
Rt=0.42 min.
EXAMPLE 299
[1420] 883
[1421] The title compound was prepared following the coupling
procedure previously described before for precursor 5a .sup.1HNMR
(300MHz, DMSO): 8.44(m, 1H); 8.33-8.31 (m, 2H); 7.44(m, 5H);
3.87-3.40(m, 8H). LC/MS: (ES.sup.+) m/z(M+H).sup.+=448. Rt=1.04
min.
N-Hydroxy-Acetamidine
[1422] 884
[1423] Sodium ethoxide solution (32.5 mL, 21% w/v) was added over 1
h to a solution of hydrochloride (3.5 g, 0.05 mol) and
phenolphthalein (5 mg) in ethanol (20 mL). After stirring for 3 hr
at room temperature, acetonitrile (1.4 g) was added. The reaction
was stirred for 2 h and then heated at 40.degree. C. for 48 h. The
reaction mixture was cooled to room temperature and concentrated
under vacuum. The residue was kept at room temperature for 48 h,
purified on silica gel column eluting with 9:1 dichloromethane:
methanol to give N-Hydroxy-acetamidine (1.8 g, 73%). .sup.1HNMR
(300MHz, DMSO): 8.60 (s, 1H); 5.51 (bs, 2H); 1.60 (s, 3H). 885
[1424] A solution of 4-fluoro-7-bromo-6-azaindole (100 mg, 0.46
mmol), N-Hydroxy-acetamidine (170 mg, 2.3 mmol),
tetrakis(triphenylphosphine)pal- ladium (200 mg, 0.17 mmol) and
triethylamine (0.2 mL, 1.4 mmol) in toluene (2.5 mL) was heated at
reflux under an atmosphere of carbon monoxide for 18 h. The
reaction mixture was cooled to room temperature and concentrated
under vacuum. The residue was diluted with ethyl acetate (10 mL)
and washed with water (2.times.25 mL). The organic layer was
concentrated and purified on preparative HPLC to give precursor 2y
(5 mg, 5%). .sup.1HNMR (300MHz, CDCl.sub.3): 10.22 (bs, 1H);
8.32-8.31 (m, 1H); 7.55-7.53 (m, 1H); 6.81-6.79 (m, 1H); 2.55 (s,
3H). LC/MS: (ES.sup.+) m/z(M+H).sup.+=219. Rt=1.15 min. 886
[1425] Precursor 4r was prepared following the procedure previously
described for compound 4k LC/MS: (ES.sup.+) m/z (M+H).sup.+=291.
Rt=0.87 min.
EXAMPLE 300
[1426] 887
[1427] The title compound was prepared following the general
coupling procedure described before for precursor 5a and using
precursor 4k and benzoyl piperazine as the inputs. .sup.1HNMR
(300MHz, CDCl.sub.3): 10.92 (bs, 1H); 8.51-8.50 (m, 1H); 8.41-8.40
(m, 1H); 7.43 (m, 5H); 3.97-3.50 (m, 8H); 2.58 (s, 3H). LC/MS:
(ES.sup.+) m/z(m+H).sup.+=463. Rt=1.24 min. 888
[1428] 1-Methyl-1,2,4-triazole (249 mg, 3 mmol) was dissolved in
anhydrous THF (3 mL) and cooled to -78.degree. C. n-BuLi (2.5 M in
hexane, 1.2 ml) was added via a syringe. After stirring for 10 min,
ZnCl.sub.2 (0.5 M in hexane, 6 mL) was added. The reaction mixture
was stirred at -78.degree. C. for 20 min, then warmed to room
temperature. The resulting mixture was transferred via a syringe
into a pressure flask which contained a mixture of
4-fluoro-7-bromo-6-azaindole (215 mg, 1.0 mmol),
tetrakis(triphenylphosphine)palladium (127 mg, 0.11 mmol) and
dioxane (6 mL). The reaction mixture was heated at 120.degree. C.
in the sealed flask for 15 h, and then cooled to room temperature.
Ethyl acetate (100 mL) was added to quench the reaction. The
resulting mixture was washed with water (2.times.20 mL). The
organic layer was concentrated and purified on preparative HPLC.
Final crystallization in methanol/water gave Precursor 2z (80 mg,
37%). .sup.1HNMR (300MHz, CDCl.sub.3): 11.10 (bs, 1H); 8.18-8.17
(m, 1H); 8.02-8.01 (m, 1H); 7.50-7.48 (m, 1H); 6.74-6.72 (m, 1H);
4.52 (s, 3H). LC/MS: (ES.sup.+) m/z(M+H).sup.+=218. Rt=1.23 min.
889
[1429] Precursor 4s was prepared following the procedure described
before for precursor 4m. LC/MS: (ES.sup.+) m/z(M+H).sup.+=293.
Rt=0.92 min.
EXAMPLE 301
[1430] 890
[1431] The title compound was prepared following the example
coupling procedure described before for precursor 5a and using
precursor 4s and (benzoyl piperazine as inputs. .sup.1HNMR (300MHz,
CDCl.sub.3): 11.86 (bs, 1H); 8.37-8.36 (m, 1H); 8.32-8.31 (m, 1H);
8.02-8.01 (m, 1H); 7.42(m, 5H); 4.51 (s, 3H); 3.95-3.51 (m, 8H).
LC/MS: (ES.sup.+) m/z(M+H).sup.+=462 Rt=1.32 min.
PREPARATION OF PRECURSOR 4T
[1432] 891
[1433] To a solution of 1-ethyl-3-methyl imidazolium chloride (2.7
g, 18.6 mmol) and aluminum chloride (7.5 g, 55.8 mmol) was added
precursor 2i (2.0 g, 9.3 mmol) followed by slow addition of
ethyloxalylacetate (2.1 ml, 18.6 mmol) at room temperature. The
reaction was then stirred at room temperature for 20 h, and
quenched by slow addition of ice water (20 mL). A light brown solid
precipitated out and was collected by filtration and dried in air
to provide compound precursor 4t (2.2 g, 82%). LC/MS: (ES.sup.+)
m/z (M+H).sup.+=289. Rt=0.85 min.
PREPARATION OF PRECURSOR 5AB
[1434] 892
[1435] A mixture of compound precursor 4t (500 mg, 1.74 mmol),
benzylpiperazine hydrochloride (395 mg, 1.74 mmol), DEBPT (520 mg,
1.74 mg) and diisopropylethylamine (0.61 ml, 3.48 mmol) in 3 ml of
DMF was stirred at rt for 20 h. The reaction mixture was diluted
with EtOAc (50 ml) and washed with water (50 ml). The aqueous layer
was extracted with EtOAc (3.times.50 ml). The organic extracts were
combined and dried over Mg.sub.2SO.sub.4, filtered and concentrated
to dryness. The residue was redissolved in EtOAc and precursor 5ab
crystallized out as a pale brownish solid and was collected by
filtration (221 mg, 27%). .sup.1HNMR (d, MeOD): 8.4 (s, 1H), 8.1
(s, 1H), 7.5 (bs, 5H), 3.82-3.53 (m, 8H); MS m/z 461 (MH); Rt=1.24
min.
GENERAL PROCEDURE FOR PREPARING EXAMPLES 302-315
[1436] 893
General Procedure for the Preparation of 7-N-linked
Heterocycles
[1437] A mixture of precursor 5ab for examples 302-313 or 5ac for
Examples 314-315, 15-30 equivalents of the corresponding amine,
preferably 30 equivalents were used, 1 equivalent of copper powder
and 1 equivalent of potassium carbonate was heated at 160.degree.
C. for 4-7 hr in a sealed tube. The reaction was cooled to room
temperature, diluted with EtOAc and filtered through filter paper.
The solvent was removed in vacuo and the residue was diluted with
methanol and purified by preparative HPLC.
EXAMPLE 303
[1438] 894
[1439] Example 303 was prepared from precursor 5ab and
1,2,4-triazole following the procedure described above. .sup.1H NMR
(500 MHz, CDCl.sub.3): 11.15 (bs, 1H); 9.28 (s, 1H); 8.33-8.34 (m,
1H); 8.22 (s, 1H); 8.10 (s, 1H); 7.46-7.42 (m, 5H); 3.90-3.48 (m,
8H). LC/MS: (ES.sup.+) m/Z (M+H).sup.+=448. Rt=1.21 min.
EXAMPLE 304
[1440] 895
[1441] Example 304 was prepared from precursor 5ab and imidazole
following the procedure described above. .sup.1H NMR (500MHz,
CDCl.sub.3): 13.35 (bs, 1H); 9.49 (s, 1H); 8.35-8.30 (m, 1H); 8.20
(s, 1H); 7.97 (s, 1H); 7.56-7.53 (m, 1H); 7.46-7.41 (m, 5H);
3.98-3.40 (m, 8H). LC/MS: (ES.sup.+) m/z (M+H).sup.+=447. Rt=1.25
min.
EXAMPLE 305
[1442] 896
[1443] Example 305 was prepared from precursor 5ab and pyrazole
following the procedure described above. .sup.1H NMR (500MHz,
CDCl.sub.3): 11.52 (bs, 1H); 8.65-8.64 (m, 1H); 8.27-8.26 (m, 1H);
8.05-8.04 (m, 1H); 7.81-7.80 (m, 1H); 7.50-7.35 (m, 5H); 6.54-6.53
(m, 1H); 4.01-3.47 (m, 8H). LC/MS: (ES.sup.+) m/z (M+H).sup.+=447.
Rt=1.25 min. Compound of example 222 was prepared from precursor 5i
and morpholine following the procedure described above. .sup.1H NMR
(300 MHz, CD.sub.3OD.sub.3): 8.38 (s, 1H); 7.86-7.84 (m, 1H);
4.14-3.25 (m, 16H). LC/MS: (ES.sup.+) m/z (M+H).sup.+=466. Rt=0.988
min.
EXAMPLES 306 and 307
[1444] 897
[1445] Examples 306 and 307 were prepared from precursor 5ab using
the general procedure previously described above using
3-methyltriazole. Example 306: .sup.1HNMR (500 MHz, CDCl.sub.3):
9.14 (s, 1H); 8.32 (s, 1H); 8.06 (s, 1H); 7.42 (m, 5H); 3.75-3.85
(m, 4H); 3.55-3.70 (m, 4H); 2.57 (s, 3H). LC/MS: (ES.sup.+) m/z
(M+H).sup.+=462; rt =1.27 min. Example 307: .sup.1HNMR (500 MHz,
CDCl.sub.3): 8.29 (s, 1H); 8.17 (s, 1H); 8.05 (s, 1H); 7.42 (m,
5H); 4.75-4.85 (m, 4H); 4.55-5.70 (m, 4H); 3.02 (s, 3H). LC/MS:
(ES.sup.+) m/z (M+H).sup.+=462; rt=1.27 min.
EXAMPLE 308
[1446] 898
[1447] Example 308 was prepared from precursor 5ab and pyrrole
following the procedure described above. .sup.1H NMR (300 MHz,
CD.sub.3OD.sub.3): 8.33-8.29 (m, 2H); 7.49-7.40 (m, 5H); 7.38-7.37
(m, 2H); 6.42-6.41 (m, 2H); 3.91-3.40 (m, 8H). LC/MS: (ES.sup.+)
m/z (M+H).sup.+=446. Rt=1.34 min.
EXAMPLE 309
[1448] 899
[1449] The title compound was prepared from precursor 5ab using the
general procedure previously described using 3-aminopyrazole.
.sup.1HNMR (300 MHz, DMSO):12.42 (bs, 1H); 8.34-8.33 (m, 1H);
8.31-8.30 (m, 1H); 8.04-8.03 (m, 1H); 7.44 (bs, 5H); 5.93-5.92
(m,1H); 3.80-3.16 (m, 8H). LC/MS: (ES.sup.+) m/z (M+H).sup.+=462.
Rt=1.26 min.
EXAMPLE 310
[1450] 900
[1451] The title compound was prepared from precursor 5ab according
to the general procedure previously described using
3-methylpyrazole. .sup.1HNMR (500 MHz, CDCl.sub.3): 11.59 (bs, 1H);
8.53-8.52 (m, 1H); 8.27-8.26 (m, 1H); 8.02-8.01 (m, 1H); 7.46-7.42
(m, 5H); 6.32-6.31 (m,1H); 3.82-3.48 (m, 8H); 2.43 (s, 3H). LC/MS:
(ES.sup.+) m/z (M+H).sup.+=461. Rt=1.50 min.
EXAMPLE 311
[1452] 901
[1453] The title compound was prepared from precursor 5ab according
to the general procedures previously described. .sup.1HNMR (500
MHz, CDCl.sub.3): 11.92 (bs, 1H); 8.28-8.27 (m, 1H); 8.08-8.07 (m,
1H); 7.47-7.42 (m, 5H); 6.73-6.72 (m,1H); 4.45-4.38 (m, 2H);
4.0-3.49 (m, 8H); 2.84 (s, 3H); 1.44-1.37 (m, 3H). LC/MS:
(ES.sup.+) m/z (m+h).sup.+=533. Rt=1.67 min.
EXAMPLE 312
[1454] 902
[1455] Example 312 was prepared from precursor 5ab according to the
general procedure previously described using 3-methylpyrazole.
.sup.1HNMR (300 MHz, CDCl.sub.3): 11.61 (bs, 1H); 8.23-8.22 (m,
1H); 8.06-8.05 (m, 1H); 7.67-7.66 (m, 1H); 7.42 (m, 5H); 6.25 (m,
1H); 3.89-3.48 (m, 8H); 2.82 (s, 3H). LC/MS: (ES.sup.+) m/z
(M+H).sup.+=461. Rt=1.41 min.
EXAMPLE 313
[1456] 903
[1457] Example 313 was prepared from precursor 5ab according to the
general procedure previously described using
3-amino-1,2,4-triazole. .sup.1HNMR (500 MHz, CDCl.sub.3): 11.12
(bs, 1H); 8.89-8.88 (m, 1H); 8.29-8.28 (m, 1H); 8.03-8.02 (m, 1H);
7.58-7.51 (m, 5H), 3.87-3.50 (m, 8H). LC/MS: (ES.sup.+) m/z
(M+H).sup.+=463. Rt=1.16 min. 904
[1458] Precursor 5ac was prepared from precursor 4t following the
procedure described for precursor 5ab using
1-benzoyl-3-(R)-methylpiperaz- ine instead of benzylpiperazine.
LC/MS: (ES.sup.+) m/z (M+H).sup.+=474-475. Rt=1.20 min.
EXAMPLE 314
[1459] 905
[1460] Example 314 was prepared from Precursor 5ac following the
general procedure described above for 7-N-linked heterocycles.
.sup.1HNMR (500 MHz, CDCl.sub.3): 8.75 (s, 1H); 8.36 (m, 1H); 8.08
(m, 1H); 7.45-7.38 (m, 5H); 4.75-2.947 (series of multiplets, 7H);
1.37-1.30 (m, 3H).
EXAMPLE 315
[1461] 906
[1462] Example 315 was prepared from Precursor 5ac following the
general procedure described above for 7-N-linked heterocycles.
.sup.1HNMR (500 MHz, CDCl.sub.3): 9.15 (s, 1H); 8.32 (d, J=3.0 Hz,
1H); 8.16 (m, 1H); 7.92 (s, 1H); 7.45-7.38 (m, 5H) 4.72-2.94
(series of multiplets, 7H); 2.57 (s, 3H); 1.37-1.30 (m, 3H); LC/MS:
(ES.sup.+) m/z (M+H).sup.+=476. Rt=1.29 min. 907
[1463] Synthetic Experimental Procedures for Best Preparation of
Example 216 (Scheme 80) 908
[1464] 5-Amino 2 methoxypyridine (50 g, 0.4 mol ) was added to a
stirring mixture of absolute ethanol (280 ml) and HBF.sub.4 (48% in
water, 172 ml) and cooled to 0.degree. C. Sodium nitrite (129 g)
was dissolved in water (52 ml) and added portion-wise over 1 h).
The stirring was continued at 0.degree. C. for 2 hr. The reaction
mixture was diluted with ether (1 L). The solid product was
collected by filtration and washed with 500 ml of 50:50 EtOH/ether
and subsequently several times with ether until the product was
slightly pinkish in color. The pale pink solid 90 g (.about.100%
yield) was kept in a dessicator over P.sub.2O.sub.5.
[1465] The same procedure was followed to perform the reaction on
larger scale:
[1466] (1) (200 g, 1.6 mol); HBF.sub.4 (688 ml); NaNO.sub.2 (116
g); ETOH (1.12 L); H.sub.2O (208 ml)
[1467] The reaction was run 4 times (total 800 grams (1-80)). The
product was dried over P.sub.2O.sub.5 for 48 hr. (only 24 hr for
first batch).
[1468] A total of 1,293 g of (2-80) was obtained, (91% yield).
[1469] Ref: J. Heterocyclic Chem., 10, 779, 1973 (for above
Reactions, Including Analytical Data) 909
[1470] The decomposition of the diazonium salt was run in 3 batches
of:
[1471] 206 g, 219 g and 231 g using 1.3 L, 1.4 L and 1.6 L of
anhydrous toluene respectively.
[1472] The toluene was preheated under nitrogen to 100.degree. C.
(internal temperature) in a 2 L 3-neck round bottom flask provided
with a mechanical stirrer. The solid was added solid portion-wise
via a scoop through a powder funnel which was attached to an
adapter with slight outward positive nitrogen flow. During
addition, the temperature was maintained between 99-102.degree. C.
(set at 100.degree. C.) and stirred vigorously. Total addition time
was 60 min. for the smaller two batches and 70 min. for the last
one. After the addition was finished, each stirring reaction was
heated at 110.degree. C. for 1 hr. The heating mantle was removed
and stirring was stopped. The reactions were allowed to stand for 2
hr (ambient temp achieved). Safety Note: The reaction contains BF3
so working with the reaction hot exposes vapors which caused skin
irritation with some people. No incidents were noted at ambient
temperature (6 different people). The hot toluene from the reaction
was poured into a 4 L Erlenmeyer (a dark brown oil and residue
remained in the flask). The residue was washed with 50 ml of
toluene and poured into the original toluene extracts.
[1473] Add 1.5 L of 1N NaOH to toluene layer, extract and wash with
.about.100 ml of sat aq. NaCl.
[1474] Combine NaCl with NaOH layer, re-extract with 150 ml of
toluene, wash with 50 ml of sat NaCl.
[1475] Combine toluene layers.
[1476] Add 1 L of 1N NaOH to residue in reaction flask and swirl to
dissolve as much residue as possible then add 500 ml Et2O and pour
into Erlenmeyer.
[1477] Add .about.500 ml more of 1 N NaOH to reaction flask and
swirl .about.500 ml of Et2O.
[1478] Combine dark Et2O and NaOH washings in erlenmyer flask.
[1479] Et2O/NaOH mixture was poured through powder funnel
containing plug of glass wool to collect dark viscous solid. (Add
.about.500 ml more ether to wash) into 6 L sep funnel.
[1480] Extract. Wash ether layer with .about.200 ml of H.sub.2O and
then 100 ml of sat NaCl.
[1481] Combine all washings with original NaOH aq. Layer and
re-extract with 500 ml of ether. Wash with 100 ml H.sub.2O and 100
ml of NaCl.
[1482] Combine ether extracts. Toluene and ether extracts were
checked by LC/MS clean product.
[1483] The ether was concentrated on a rotovap and the residue was
combined with the toluene extracts to make a homogeneous solution
which is taken to next step as is.
[1484] The other two rxns were combined and worked up in the same
way.
[1485] All aqueous layers were checked by LC/MS=no product.
[1486] Ref: J. Heterocyclic Chem., 10, 779, 1973 (for above
Reactions, Including Analytical Data) 910
[1487] A total of 4.6 L of toluene solution containing 3-80 was
placed in several sealed tubes and treated with 900 ml of 35% HCl
at 145.degree. C. for 2 hr. LC/MS showed no starting material, only
4. The toluene solution was decanted and discarded. The aqueous
phase was washed with EtOAc and concentrated down to remove
volatiles to afford a brown solid containing the desired
fluoro-hydroxypyridine 4-80.
[1488] A total of 244 g of this solid was collected and taken to
next step as is (it was not completely dry).
[1489] Note: We have subsequently run this by decanting the toluene
layer first prior to heating to reduce volumes. Same reaction was
carried out using HBr (48% in H2O) at 100.degree. C. for 6 h with
similar result to the literature procedure 49% yield.
[1490] Ref: J. Heterocyclic Chem., 10, 779, 1973 (for above
Reactions, Including Analytical Data) 911
[1491] The solid from above containing (4-80) was divided in 4
batches and treated with H.sub.2SO.sub.4 and fuming HNO.sub.3 as
shown below. The amounts used were:
20 batch 1 batch 2 batch 3 batch 4 (1) 25 g 54 g 75 g 90 g fuming
HNO.sub.3 20.8 ml 45 ml 62.4 ml 75 ml H.sub.2SO.sub.4.(for
addition) 5.6 ml+ 12 ml+ 16.8 ml+ 20 ml+ (for soln) 56 ml 120 ml
168 ml 200 ml
[1492] Compound 4-80 was dissolved in sulfuric acid (the larger
amounts indicated above) at rt and then heated to 65.degree. C. A
preformed solution of fuming nitric acid and sulfuric acid (the
smaller amount indicated above) was added dropwise. The temperature
was kept between 65.degree. C. and 80.degree. C. (rxn is exothermic
and although the bath is at 65.degree. C., temperature goes higher,
usually 75, sometimes 80.degree. C.). After the addition was
complete, the reaction mixture was heated at 65.degree. C. for an
additional hr. The reaction mixture was then cooled to rt and
poured in a flask containing ice) (20 g of ice/gr compound,
evolution of gas occurred). A solid precipitated out and it was
collected by filtration (.sup.1HNM" showed 4-80 and something else
(discarded)).
[1493] The aqueous layer was extracted with AcOEt several times
(3-5) and concentrated on a rotary evaporator under vacuum to
afford a solid that was triturated with ether to afford 5-80 as a
bright yellow solid. A total of 117 g of desired product was
collected in the first crop (27% yield from diazonium salt). A
portion did not crystallize: this oil was triturated with MeOH and
Et.sub.2O to afford 3.6 g of 5-80; another precipitation from the
mother liquid afforded an additional 6.23 g of the desired product
5-80
[1494] Total:117.0+3.6+6.23 =126.83. 30.4%). Yield for 3 steps
(decomposition of diazonium salt; deprotection and nitration).
[1495] Analytical data from Notebook: 53877-115:
.sup.1HNMR(.delta., MeOD): 8.56-8.27 (dd, J=7.5, 3.3 Hz, 1H), 8.01
(d, J=3.3 Hz, 1H); LC/MS(M+1).sup.+=158.9; rt=0.15 min.
[1496] Note: A portion of the aqueous acidic solution was taken and
neutralized with Na.sub.2CO.sub.3 until effervescence stopped and
then it was extracted with AcOEtA different product was obtained.
No desired product in these extracts. 912
[1497] A total of 117 g of 5-80 was divided in 4 batches of 30
g.times.3 and 27 g.times.1 and treated with POBr.sub.3 (3 equiv.;
163 g.times.3 and 155 g.times.1) and a catalytic amount of DMF (15
ml) at rt (DMF was added carefully gas evolution). After 5 min. at
room temperature, the solutions were heated at 110.degree. C. for 3
hr. LC/MS showed starting material had been consumed. The reaction
mixtures were allowed to cool to rt. The reaction flasks were
placed in an ice bath; and then ice was added very slowly and
carefully portionwise into the flask, gas evolution was due to HBr
formation; the liquid and black solid that formed was poured into a
beaker with ice. EtOAc was added and the mixture was then extracted
several times with EtOAc. The organic layer was washed with
saturated aq. NaHCO.sub.3; H.sub.2O and brine; dried over
Na.sub.2SO.sub.4 and filtered. The product was dried in the pump
overnight to provide 123 g of 6-80 as a brown solid (77%
yield).
[1498] Note: Reaction is completed within 1 h.
[1499] .sup.1HNMR(.delta., CDCl.sub.3):8.52 (m, 1H), 7.93 (m, 1H).
913
[1500] 800 ml of vinyl magnesium bromide (1M in THF, Aldrich) was
cooled below -60.degree. C. with vigorous stirring under N.sub.2.
2-bromo-5-fluoro-3-nitro pyridine (43.3 g, 0.196 mol) in 200 ml THF
was added dropwise via addition funnel at such a rate that the temp
was kept below -60.degree. C. This took .about.1.25 hr. The
reaction mixture was warmed to -40 to -50.degree. C. and stirred
for 1 hr more. Then 1 L of saturated aqueous NH.sub.4Cl was added
slowly and cautiously. At first, foaming occurred and considerable
solid was present, but this essentially dissolved as the addition
was completed and the material warmed to rt. The layers were
separated and the aqueous layer extracted 3 times with ethyl
acetate. The organic extracts were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford .about.50 g
of a black gummy solid. HPLC indicated 57-58% product. To this was
added CH.sub.2Cl.sub.2 and the solid was collected by filtration
and washed with CH.sub.2Cl.sub.2 to afford 12.5 g of product as a
brown solid. The reaction was repeated on exactly the same scale
and worked up in the same manner. From CH.sub.2Cl.sub.2 trituration
there was obtained 12.4 g of Precursor 2i (HPLC .about.97% pure).
The crude was recovered and allowed to stand in dichloromethane.
Upon standing 3.6 g of additional product separated and was
recovered by filtration.
[1501] Total yield=29.5 g (35%).
[1502] .sup.1HNMR (.delta., CDCl.sub.3): 8.69(bs, 1H), 7.92 (d,
J=1.8 Hz, 1H), 7.41 (m, 1H), 6.77 (m,1H);
LC/MS(M+1).sup.+=216-217.9; rt=1.43 min. 914
[1503] Reaction was carried in a 250 ml flask (foaming occurred
upon heating and the big size flask is more convenient). A mixture
of precursor 2i (3 g, 13.95 mmol), 1,2,3-triazole (15 g, 217.6
mmol, 15 eq), K.sub.2CO.sub.3 (1.9 g, 13.95 mmol, 1 eq) and
Cu(0)(0.9 g, 13.9 mmol, 1 eq) was heated at 160.degree. C. for 7 hr
(from rt to 160.degree. C. total 7 hr) under N.sub.2 (depending on
the Cu(0) lot, reaction time may vary from 2 hr to 7 hr). The
resulting mixture was diluted with MeOH, filtered through filter
paper (to remove the copper). Washed with MeOH (20 ml) and water
(30 ml).
[1504] The filtrate was concentrated (remove solvent in rotovap)
and diluted with ethylacetate. The aqueous layer was extracted with
ethylacetate. The combined organic layer was dried over sodium
sulfate, filtered and concentrated. The residue was dissolved in
MeOH (20 ml), 7-80 (750 mg) crystallized from the methanol as a
white solid and was collected by filtration. (Slow gradient volume,
silica gel hex/AcOEt (0.fwdarw.18%) of the mother liquids usually
affords 5-10% more of 7-80.
[1505] .sup.1HNMR (.delta., CDCl.sub.3): 10.47 (bs, 1H), 8.76 (s,
1H), 7.94 (s, 1H), 7.89 (s, 1H), 7.53 (m, 1H), 6.78 (m, 1H);
LCMS(M+1).sup.+=204; rt=1.29 min. 915
[1506] Ethyl methylimidazolium chloride (4.3 g, 29.6 mmol, 3 eq)
was placed in a 250 ml flask. AlCl.sub.3 (11.8 g, 88.6 mmol, 9 eq)
was added into the flask in one portion. A liquid suspension was
formed (some of AlCl.sub.3 remained as solid). After stirring for
5-10 min. compound (1) (2.0 g, 9.85 mmol) was added in one portion
followed by slow addition (via a syringe) of ethyl
chlorooxalacetate (3.3 ml, 29.6 mmol, 3 eq). The reaction was
stirred at room temperature for 20 hr. LCMS indicated compound
8-80: compound 7-80=6:2. (Compound I has strong UV absorption) The
reaction was quenched by carefully adding ice water (.about.75 ml)
at 0.degree. C. A yellow solid precipitated at this point. The
resulting suspension was filtered and the solid was washed with
water. MeOH and ethyl acetate (to remove unreacted SM) and the
solid was dried in air. (LCMS purity 70%.about.80%) 2 g of solid
containing 8-80 was obtained and taken to the next step without
further purification. LCMS(M+1).sup.+=276; rt=0.97 min. 916
[1507] A mixture of compound 8-80 (4.9 g, 17.8 mmol) &
N-benzoylpiperazine hydrochloride 8a-80 (HCl salt; 6.0 g, 26.7
mmol, 1.5 eq) in DMF (30 ml) was stirred at RT overnight (16 hr). A
slurry was formed. An additional 20 ml of DMF was added into the
slurry. Then HATU (12.2 g, 26.7 mmol, 1.5 eq) was added followed by
DMAP (4.3 g, 35.6 mmol, 2 eq). The reaction mixture was stirred for
30 min. LCMS indicated the starting material 8-80 was completely
converted to product (EXAMPLE 216). The resulting mixture was
filtered and the solid washed with water. The filtrate was
concentrated in vacuo. Water was added to the residue and the solid
was collected by filtration. The solids were combined and washed
with water, MeOH and EtOAc. Then the solid was dried in air. LCMS
& HPLC showed BMS-585248, >99% pure. The solid product was
further purified by precipitation and crystallization in
5.about.10% CH.sub.3OH/CHCl.sub.3.
Purification of Example 216
[1508] Crude compound of Example 216 obtained as above (15.3 g) was
dissolved in 10% MeOH/CHCl.sub.3 (600 ml). A light brown suspension
was formed, filtered through filter paper and washed with MeOH a
twice. The brownish solid was discarded (.about.1.2 g). Example 216
was crystallized in the filtrate, the solid was collected by
filtration and the white solid was dried in air. The filtrate was
used to repeat the crystallization several times. The solid
obtained from each filtration was analyzed by HPLC. All the pure
fractions were combined. The not so pure fractions were resubjected
to crystallization with MeOH & CHCl.sub.3. A total of 12.7 g of
Example 216 was obtained from recrystallization and precipitation.
The mother liquid was concentrated and purified on silica gel
column (EtOAc, then CHCl.sub.3/MeOH (0-2%)) to provide 506 mg of
product) as a white solid.
[1509] .sup.1HNMR (d, DMSO) 13.1 (bs, 1H), 9.0 (s, 1H), 8.4 (s,
1H), 8.3 (s, 1H), 8.2 (s, 1H), 7.4 (bs, 5H), 3.7 (bs, 4H), 3.5 (bs,
4H); MS m/z 448 (MH). Anal: Calc for
C.sub.22H.sub.18FN.sub.7O.sub.3; C 59.05, H 4.05, N 21.91, F 4.24.
Found; C 57.28, H 4.14, N 21.22; F 4.07%.
[1510] Scheme 81 is a preferred method for making compounds of
Formula I and Ia where R2 is methoxy. This is specifically
exemplified for the preparation of compound Example 316 and 317.
917918
Preparation of 3-methyl-1,2,4-triazole (2-81)
[1511] 919
[1512] Procedure: A solid mixture of formic hydrazide (68 g, 1.13
mol) and thioacetamide (85 g, 1.13 mol) in a 500 mL-RBF was heated
with stirring at 150.degree. C. (oil bath temp.) for 1.5 hrs with a
gentle stream of nitrogen, removing H.sub.2S and water (about 18 mL
of liquid collected) formed during the reaction. The reaction
mixture was distilled under reduced pressure, collecting 60.3 g
(0.726 mol, Y. 63.3%) of the title compound at 102.degree.
C./0.35-1 mmHg as white solid after removing a liquid forerun.:
.sup.1H NMR (CDCl.sub.3) .delta. ppm 2.51 (3H, s, 3-Me), 8.03 (1H,
s, 5-H), 9.5 (1H, br, NH); TLC Rf (10% MeOH/CH.sub.2Cl.sub.2)=0- .3
(phosphomolybdate-charring, white spot). Reference: Vanek, T.;
Velkova, V.; Gut, Jiri Coll. Czech. Chem. Comm. 1985, 49, 2492.
920
[1513] Procedure: A 500 mL round bottom flask was loaded with
4-methoxy-7-chloro-6-azaindole precursor 2e (9.1 g, 50 mmol; dried
in vacuo), potassium carbonate (13.8 g, 100 mmol, 2 eq.), copper
powder (6.35 g, 100 mmol, 2 eq.), and 3-methyl-1,2,4-triazole (83
g, 1.0 mol, 20 eq.). The solid mixture was heated to melt at
170-175.degree. C. (external oil bath temperature) under gentle
stream of anhydrous nitrogen for 12 h, by which time HPLC analysis
indicates the amount of the peak for the starting material becomes
5-30% and the desired product peak becomes about 45% with isomeric
by-product peak becomes 15%. As the reaction mixture cools, MeOH
(150 mL) was added slowly to the stirred warm mixture. Upon
cooling, the insoluble material (copper powder) was filtered
through a Celite pad, and rinsed with methanol. The filtrate was
concentrated in vacuo to a thick paste which was diluted with water
(1 L) and extracted with EtOAc (3.times.150 mL). The EtOAc extracts
were dried (MgSO.sub.4), filtered and concentrated to obtain about
8 g of crude residue which was crystallized by dissolving in hot
CH.sub.3CN (50 mL), followed by diluting with water (100 mL) and
cooling at 0.degree. C. to collect 1.45 g (12.7%) of the title
compound as white solid. The filtrate was purified by C-18 reverse
phase silica gel (YMC ODS-A 75 .mu.m) eluted with 15-30%
CH.sub.3CN/H.sub.2O. Appropriate fractions were combined and the
aqueous solution after removing CH.sub.3CN by rotary evaporator was
lyophilized to give additional 1.15 g of the title compound 3-81.
The crude aqueous layer was further extracted with EtOAc several
times. The ethyl acetate extracts were dried (MgSO4), filtered,
concentrated, and crystallized from MeOH to give additional 200 mg
of the title compound 3-81. The total yield: 2.8 g (12.2 mmol, Y.
24.5%); MS m/z 230 (MH), HRMS (ESI) m/z calcd for
C.sub.11H.sub.12N.sub.5O (M+H), 230.1042, found 230.1038
(.DELTA.-1.7 ppm); .sup.1H NMR (CDCl.sub.3) .delta. ppm 2.54 (3H,
s, CH.sub.3), 4.05 (3H, s, OCH.sub.3), 6.73 (1H, s, H-3), 7.40 (1H,
s, H-2), 7.56 (1H, s, H-5), 9.15 (1H, s, triazole-H-5); .sup.13C
NMR (CDCl.sub.3, 125.7 MHz) .delta. ppm 14.2 (triazole-Me), 56.3
(OMe), 100.5 (C-3), 116.9 (C-5), 123.5, 127.2, 127.5 (C-2), 129.5
(C-7), 141.2 (C-5'), 149.5 (C-4), 161.8 (C-3'); Anal. Calcd for
C.sub.11H11N.sub.5O:C 57.63, H 4.83, N 30.55, found C 57.37, H
4.64, N 30.68.
[1514] The structure was confirmed by a single X-ray
crystallographic analysis using crystals obtained from C-18 column
fractions. A portion of C-18 column fractions containing a mixture
of the desired 3-methyl-1,2,4-triazolyl analog 3-81 and isomeric
5-methy-1,2,4-triazolyl analog 4-81 was further purified by C-18
reverse phase column eluting with 8-10% CH.sub.3CN/H.sub.2O.
Appropriate fractions were extracted with CH.sub.2Cl.sub.2, and
slow evaporation of the solvent gave crystalline material of the
isomeric 7-(5-methy-1,1,2,4-triazolyl)-4-methoxy-6-azaind- ole
(4-81): MS m/z 230 (MH), .sup.1H NMR (CDCl.sub.3) .delta. ppm 3.05
(3H, s, CH.sub.3), 4.07 (3H, s, OCH.sub.3), 6.74 (1H, q, J=2.4,
H-2), 7.37 .sup.(1H, t, J=2.4, H-3), 7.65 (1H, s, H-5), 8.07 (1H,
s, triazole-H-3). The structure was confirmed by a single X-ray
crystallographic analysis.
Preparation of 5-81
[1515] 921
[1516] Procedure: AlCl.sub.3 (40 g, 0.3 mol, 15 eq.) was dissolved
in a solution of CH.sub.2Cl.sub.2 (100 mL) and nitromethane (20 mL)
under dry nitrogen. To this solution was added compound 3-81 (4.58
g, 0.02 mol) under stirring and under N.sub.2, followed by methyl
chlorooxoacetate (9.8 g, 0.08 mol, 4 eq.). The mixture was stirred
under N.sub.2 at room temperature for 1.5 h. The mixture was added
drop-wise to a cold and stirred solution of 20% aqueous ammonium
acetate solution (750 mL). The mixture was stirred for 20 min and
the resultant precipitate was filtered, washed thoroughly with
water and dried in vacuo to obtain 4.7 g (0.015 mol, Y. 75%) of the
title compound 5-81 as white solid: MS m/z 316 (MH); HRMS (ESI) m/z
calcd for C.sub.14H.sub.14N.sub.5O.sub.4 (M+H), 316.1046; found
316.1041 (.DELTA.-1.6 ppm); .sup.1H NMR (CDCl.sub.3,500 MHz)
.delta. ppm 2.58 (3H, s, CH.sub.3), 3.96 (3H, s, OCH.sub.3), 4.05
(3H, s, OCH.sub.3), 7.76 (1H, s, H-5), 8.34 (1H, d, J=3 Hz, H-2),
9.15 (1H, s, triazole-H-5), 11.0 (1H, brs, NH). More title compound
5-81 and hydrolyzed acid 6-81 can be obtained from the filtrate by
acid-base extraction with EtOAc.
Preparation of 6-81
[1517] 922
[1518] Procedure: To a suspension of the methyl ester 5-81 (2.2 g,
7.0 mmol) in MeOH (50 mL) was added 0.25M NaOH solution in water
(56 mL, 14 mmol, 2 eq.) at room temperature and the mixture stirred
for 15 min by which time HPLC indicated the hydrolysis was
complete. The mixture was concentrated in vacuo quickly to remove
MeOH, and to the residual solution was added water (100 mL) and 1N
HCl (14 mL) with stirring to neutralize the mixture. The resultant
fine precipitate was filtered, washed with water and dried in vacuo
to obtain 1.98 g (6.58 mmol, Y. 94%) of the title compound 6-81 as
off-white solid: MS m/z 302 (MH); .sup.1H NMR (DMSO-d.sub.6,500
MHz) .delta. ppm 2.50 (3H, s, overlapped with DMSO peaks), 3.98
(3H, s, CH.sub.3O), 7.87 (1H, s, H-5), 8.29 (1H, d, J=3.5 Hz, H-2),
9.25 (1H, s, triazole-H-5), 12.37 (1H, s, NH).
[1519] Alternative procedure: To a suspension of the methyl ester
5-81 (10.7 g, 34 mmol) in MeOH (150 mL) was added 0.25M NaOH
solution in water (272 mL, 68 mmol, 2 eq.) at room temperature and
the mixture stirred for 20 min by which time HPLC indicated the
hydrolysis was complete. The mixture was concentrated in vacuo
quickly to remove MeOH, and the residual solution was extracted
with EtOAc to remove any neutral impurities. To the aqueous phase
was added 1N HCl (68 mL, 68 mmol) to neutralize the product. The
resultant mixture was frozen and lyophilized to obtain 14.1 g (33.7
mmol, Y. 99.2%) of the title compound 6-81, containing 2 mole
equivalents of NaCl as off-white solid. This material was used in
the subsequent reaction without further purification. The sodium
salt of the title compound 6-81 was obtained by C-18 reverse phase
column chromatography after sodium bicarbonate treatment:
HPLC>97% (AP, uv at 254nm); HRMS (Na salt, ESI ) m/z calcd for
C.sub.13H.sub.10N.sub.5O.sub.4 (M-H), 300.0733; found 300.0724
(.DELTA.-3 ppm); .sup.1H NMR (Na salt, DMSO-d.sub.6,500 MHz)
.delta. ppm 2.37 (3H, s, Me), 3.83 (3H, s, CH.sub.3O), 7.56 (1H, s,
H-5), 8.03 (1H, s, H-2), 9.32 (1H, s, triazole-H-5); .sup.13C NMR
(Na salt, DMSO-d.sub.6,125.7 MHz) .delta. ppm 13.8 (triazole-Me),
57.2 (OMe), 114.8 (C-3), 120.0 (C-5), 125.1, 143.5 (C-5'), 149.8
(C-4), 160.0 (C-3'), 171.7, 191.3.
Preparation of Example 316
[1520] 923
[1521] Procedure: To a solution of the acid 6-81 (3.01 g, 10 mmol)
and benzoylpiperazine hydrochloride (3.39 g, 15 mmol) in DMF (50
mL) was added triethylamine (10.1 g, 100 mmol, 10 eq.), followed by
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC;
5.75 g, 30 mmol) under N.sub.2 and the mixture stirred at room
temperature for 22 h after sonication and at 40.degree. C. for 2 h.
The mixture was concentrated in vacuo to remove DMF and TEA, and to
the residual solution was added water (200 mL) under stirring and
sonication. The precipitates formed were collected, washed with
water and dried in vacuo to obtain 2.8 g (5.9 mmol, Y. 59%) of the
title compound Example 316 as off-white solid. The filtrate was
extracted with CH.sub.2Cl.sub.2 (.times.2). The CH.sub.2Cl.sub.2
extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated
to gum which was triturated with Et.sub.2O to obtain a solid. This
solid was suspended and triturated with MeOH to obtain 400 mg of
the title compound Example 316 as off-white solid. Total yield: 3.2
g (6.8 mmol, Y. 68%): MS m/z 474 (MH); HRMS (ESI) m/z calcd for
C.sub.24H.sub.24N.sub.7O.sub.4 (M+H) 474.1890, found 474.1884
(.DELTA.-1.2 ppm); .sup.1H NMR (DMSO-d6) .delta. ppm 2.50 (3H, s,
overlapped with DMSO peaks), 3.43 (4H, br, CH.sub.2N), 3.68 (4H,
br, CH.sub.2N), 3.99 (3H, s, CH.sub.3O), 7.46 (5H, br, s, Ar-Hs),
7.88 (1H, s, indole-H-5), 8.25 (1H, s, indole-H-2), 9.25 (1H, s,
triazole-H-5), 12.40 (1H, s, NH); .sup.13C-NMR (DMSO-d6) .delta.
ppm 13.78, 40.58, 45.11, 56.78, 114.11, 120.95, 122.71, 123.60,
126.98, 128.34, 129.6, 135.43, 138.52, 142.10, 149.15, 161.29,
166.17, 169.22, 185.42; UV (MeOH) .lambda.max 233.6 nm (.epsilon.
3.43.times.10.sup.4), 314.9 nm (.epsilon. 1.73.times.10.sup.4);
Anal: Calc for C.sub.24H.sub.24N.sub.7O.sub.4.1/5H.- sub.2O; C
60.42, H 4.94, N 20.55, Found; C 60.42, H 5.03, N 20.65; KF
(H.sub.2O) 0.75%.
[1522] This reaction can also be performed by use of HATU and DMAP
to provide more consistent yield of the title compound: To a
suspension of the acid 6-81 (15.6 mmol) and HATU
[O-(7-azabenzotriazol-1-yl)-N,N,N',N'-- tetramethyluronium
hexafluorophos phonate] (8.90 g, 23.4 mmol; 1.5 eq.) in DMF (60 mL)
and CH.sub.2Cl.sub.2 (60 mL) was added a mixture of DMAP (5.72 g,
46.8 mmol, 3 eq.) and benzoylpiperazine hydrochloride (5.30 g, 23.4
mmol; 1.5 eq.) in DMF (60 mL) at room temperature and the mixture
was stirred under nitrogen atmosphere for 4 hrs. The mixture was
concentrated in vacuo to remove CH.sub.2Cl.sub.2 and most of DMF,
and to the residual solution was added water under stirring and
sonication. The precipitates formed were collected, washed with
water and dried in vacuo to obtain 5.38 g (11.4 mmol, Y. 72.8%) of
the title compound Example 316 as off-white solid: HPLC >95%
(AP, uv at 254 nm).
Preparation of Example 317
[1523] 924
[1524] Procedure: To a solution of the acid 6-81, containing 2 mole
equivalent of NaCl (4.1 g, 9.8 mmol) in CH.sub.2Cl.sub.2 (30 mL)
and DMF (30 mL) was added at -10.degree. C. under anhydrous
nitrogen HATU
[O-(7-azabenzotriazol-1yl)-N,N,N',N'-tetrmethyluronium
hexafluorophosphate] (5.59 g, 14.7 mmol; 1.5 eq.), and stirred at
-10.degree. C. for 30 min. To this mixture was added a solution of
2-(R)-methyl-N-benzoylpiperazine trifluoroacetate (4.7 g, 14.7
mmol; 1.5 eq.) and dimethylaminopyridine (3.5 g, 29 mmol; 3 eq.) in
DMF (30 mL) and CH.sub.2Cl.sub.2 (30 mL) and the mixture stirred at
room temperature overnight, by which time HPLC analysis indicated
reaction was essentially complete. The mixture was concentrated in
vacuo to remove valatiles and DMF, and to the residue was added
water (.about.150 mL) under stirring and sonication. The
precipitates formed were collected, washed with water and dried in
vacuo to obtain 4.3 g of the title compound Example 317 as
off-white solid. This was dissolved in 20% MeOH in CH.sub.2Cl.sub.2
(about 250 mL), removing any insoluble material, and the filtrate
was concentrated in vacuo to remove more volatile CH2Cl2. The
resultant precipitate was collected, washed with MeOH and then with
Et.sub.2O to obtain 3.5 g (7.18 mmol, Y. 73.2%; AP>99%) of the
title compound Example 317 as off-white solid: LC/MS m/z 488 (MH);
.sup.1H NMR (DMSO-d6) .delta. ppm 1.15, 1.22 (3H, 2d, J=7 Hz), 2.50
(3H, s, overlapped with DMSO peaks), 3-4.3 (8H, m, CH.sub.2N),
3.98, 4.00 (3H, s, CH.sub.3O), 7.45 (5H, m, Ar-Hs), 7.89 (1H, s,
indole-H-5), 8.19, 8.26 (1H, 2s, indole-H-2), 9.24, 9.25 (1H, 2s,
triazole-H-5), 12.40 (1H, br.s, NH); Anal: Calc for
C.sub.25H.sub.25N.sub.7O.sub.4; C 61.59, H 5.16, N 20.11, Found; C
61.69, H 5.27, N 20.10; KF (H.sub.2O) <0.1%.
[1525] Notes:
[1526] The following compounds, Examples 187, 245, and 241, were
also prepared by the method described above using appropriate
azoles (1,2,4-triazole for Example 187, and Example 245;
3-methylpyrazole for Example 241. 925
Preparation of Example 316
Alternate Preparation of Example 316
[1527] 926
[1528] A mixture of compound precursor 5b (150 mg, 0.35 mmol),
3-methyl-1,2,4-triazole (581 mg, 7 mmol; 20 eq.; prepared by the
method described in Coll. Czech. Chem. Comm. 1985, 49, 2492),
copper powder (45 mg, 0.7 mmol; 2 eq.), potassium carbonate (97 mg,
0.7 mmol; 2 eq.) was flushed with anhydrous nitrogen and heated in
a sealed tube at 160.degree. C. for 11 h. Upon cooling, to the
mixture was added MeOH, and the insoluble material was filtered.
The filtrate was concentrated in vacuo and purified by C-18 reverse
phase column (Prep. System eluting with MeOH-water containing 0.1%
TFA) to obtain 19 mg (0.040 mmol, Y. 11%) of the title compound
Example 216 as amorphous powder (TFA salt): MS m/e 474 (MH);
.sup.1H NMR (DMSO-d6) .delta. ppm 2.50 (3H, s, overlapped with DMSO
peaks), 3.44 (4H, br, CH.sub.2N), 3.68 (4H, br, CH.sub.2N), 4.00
(3H, s, CH.sub.3O), 7.46 (5H, br. s, Ar-Hs), 7.89 (1H, s), 8.25
(1H, s), 9.24 (1H, s), 12.41 (1H, s, NH).
Alternate Preparation of Example 317
[1529] 927
[1530] A mixture of compound 5z (220 mg, 0.5 mmol),
3-methyl-1,2,4-triazole (830 mg, 10 mmol; 20 eq.; prepared by the
method described in Coll. Czech. Chem. Comm. 1985, 49, 2492),
copper powder (63.5 mg, 1 mmol; 2 eq.), potassium carbonate (138
mg, 1 mmol; 2 eq.) was flushed with anhydrous nitrogen and heated
in a sealed tube at 160.degree. C. for 11 h. Upon cooling, to the
mixture was added MeOH, and the insoluble material was filtered.
The filtrate was concentrated in vacuo and purified by C-18 reverse
phase column (Prep. System eluting with gradient 0-70% MeOH-water
containing 0.1% TFA) to obtain 24 mg (0.049 mmol, Y. 9.8%) of the
title compound Example 317 as amorphous powder (TFA salt): MS m/e
488 (MH); .sup.1H NMR (CD.sub.3OD) .delta. ppm 1.30, 1.35 (3H, 2d,
J=7 Hz), 2.54 (3H, s, CH.sub.3), 3-4.5 (8H, m, CH.sub.2N), 4.04,
4.05 (3H, 2s, CH.sub.3O), 7.46, 7.47 (5H, 2s, Ar-Hs), 7.85, 7.86
(1H, 2s), 8.28, 8.31 (1H, 2s), 9.22 (1H, s).
Preparation of Example 318
[1531] 928
[1532] A mixture of compound 5b (150 mg, 0.35 mmol),
4-methylimidazole (517 mg, 6.2 mmol; 18 eq.; Aldrich), copper
powder (26 mg, 0.42 mmol; 1.2 eq.), potassium carbonate (57 mg,
0.42 mmol; 1.2 eq.) was flushed with anhydrous nitrogen and heated
in a sealed tube at 160.degree. C. for 6 h. Upon cooling, to the
mixture was added MeOH, and the insoluble material was filtered.
The filtrate was concentrated in vacuo and purified by C-18 reverse
phase column eluting with 15% CH.sub.3CN-water containing 0.1% TFA
to obtain 32 mg (0.068 mmol, Y. 19%) of the title compound Example
318 as amorphous powder (TFA salt). H-NMR indicates contamination
of about 30% of the isomeric product, 5-methylimidazolyl analog: MS
(ES) m/e 473 (MH); .sup.1H NMR (CD.sub.3OD) .delta. ppm 2.25 (s),
2.51 (3H, s, CH.sub.3), 3.63 (4H, br, CH.sub.2N), 3.9 (4H, br,
CH.sub.2N), 4.13 (3H, s, CH.sub.3O), 4.15 (s), 7.50 (5H, br. s,
Ar-Hs), 7.60 (s), 7.89 (1H, s), 8.03 (1H, s), 8.11 (s), 8.43 (1H,
s), 9.35 (s), 9.42 (1H, s).
Preparation of Example 319
[1533] 929
[1534] A mixture of precursor 4-81b (30 mg, 0.11 mmol; prepared
from 7-(5-methyl-1,2,4-triazolyl)-4-methoxy-6-azaindole by the
method used for the best mode-preparation of Example 316),
benzoylpiperazine hydrochloride (39 mg, 0.17 mmol), triethylamine
(200 mg, 1.9 mmol; 18 eq.),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC;
77 mg, 0.45 mmol) in 1:1 DMF-NMP (1 mL) was stirred under N.sub.2
at room temperature for 20 h. The mixture was concentrated in vacuo
to remove DMF and to the residue was added water and the mixture
stirred to form precipitates which were collected and dried to
obtain 14 mg (0.030 mmol, Y. 27%) of the title compound Example 319
as amorphous powder: MS m/e 474 (MH); .sup.1H NMR (DMSO-d6) .delta.
ppm 2.67 (3H, s, CH.sub.3), 3.44 (4H, br, CH.sub.2N), 3.68 (4H, br,
CH.sub.2N), 4.02 (3H, s, CH.sub.3O), 7.46 (5H, br. s, Ar-Hs), 7.98
(1H, s), 8.21 (1H, s), 8.24 (1H, s), 12.57 (1H, s, NH).
Preparation of Example 320
[1535] 930
[1536] A mixture of compound 4-81b (30 mg, 0.11 mmol; prepared from
7-(5-methyl-1,2,4-triazolyl)-4-methoxy-6-azaindole by the method
used for the best mode-preparation of Example 316),
2R-methyl-1-benzoylpiperazine trifluoroacetate (54 mg, 0.17 mmol),
triethylamine (200 mg, 1.9 mmol; 18 eq.),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC;
77 mg, 0.45 mmol) in 1:1 DMF-NMP (1 mL) was stirred under N.sub.2
at room temperature for 20 h. More EDC (20 mg) was added to the
mixture and stirred for additional 6 h. The mixture was
concentrated in vacuo to remove DMF and to the residue was added
water and the product was extracted with EtOAc twice. The EtOAc
extracts were dried (MgSO4), filtered and concentrated. The residue
was purified by silica gel column chromatography eluting with 5%
MeOH-CH.sub.2Cl.sub.2 to obtain 10 mg (0.021 mmol, Y. 19%) of the
title compound Example 320 as amorphous powder: MS m/e 488 (MH);
.sup.1H NMR (CDCl.sub.3) .delta. ppm 1.33, 1.36 (3H, 2d, J=7 Hz),
3.00 (3H, s, CH.sub.3), 3-4.6 (8H, m, CH.sub.2N), 4.05 (3H, s,
CH.sub.3O), 7.38-7.44 (5H, m, Ar-Hs), 7.81 (1H, s), 8.02 (1H, s),
8.16, 8.17, 8.18, 8.19 (1H, 4s), 11.10 (1H, s, NH).
Preparation of Example 321 and Example 322
[1537] 931932
Preparation of 3-methyl-1,2,4-triazole (2-82)
[1538] 933
[1539] Procedure: A solid mixture of formic hydrazide (6.0 g, 0.1
mol; Aldrich) and thiopropionamide (8.92 g, 0.1 mol; TCI) was
heated with stirring at 150.degree. C. (oil bath temp.) for 2 hrs
with a gentle stream of nitrogen. It was cooled and stored at room
temperature overnight. The solid reaction mixture was suspended in
20% EtOAc/CH.sub.2Cl.sub.2, removing insoluble solid and the
filtrate was concentrated. The residue was purified by column
chromatography, eluting first with 50-80% EtOAc/CH.sub.2Cl.sub.2,
removing by-products, and then with 10% MeOH/CH.sub.2Cl.sub.2,
collecting 5.4 g (0.056 mol, Y. 56%) of the title compound as a
solid: MS (ESI -) m/z 96 (M-H); .sup.1H NMR (CDCl.sub.3) .delta.
ppm 1.37 (3H, t, J=7.5 Hz), 2.88 (2H, q, J=7.5 Hz), 8.06 (1H, s,
5-H), 9.4 (1H, br, NH). Reference: Vanek, T.; Velkova, V.; Gut,
Jiri Coll. Czech. Chem. Comm. 1985, 49, 2492.
Preparation of 3-82
[1540] 934
[1541] Procedure: A mixture of 4-methoxy-7-chloro-6-azaindole 2e
(910 mg, 5.0 mmol), potassium carbonate (1.38 g, 10 mmol, 2 eq.),
copper powder (635 mg, 10 mmol, 2 eq.), and 3-ethyl-1,2,4-triazole
(2.4 g, 25 mmol, 5 eq.) in a sealed tube was heated at
145-150.degree. C. (external oil bath temperature) for 52 h, by
which time HPLC analysis indicated no more reaction progressed.
After cooling, MeOH was added, the insoluble material (copper
powder) was filtered through a Celite pad, and rinsed with
methanol. The filtrate was concentrated in vacuo. The residue was
purified by silica gel column chromatography (50%
EtOAc/CH.sub.2Cl.sub.2) to obtain 450 mg of the products as an
about 4:1 mixture of two regio-isomers. This was further separated
by C-18 reverse phase silica gel (YMC, ODS-A 75 .mu.m) eluted with
15% CH.sub.3CN/H.sub.2O containing 0.1% TFA. The fractions
containing the major isomer were concentrated in vacuo to remove
acetonitrile and the aqueous solution was extracted with CH2C12
after neutralizing with aqueous sodium bicarbonate to obtain the
title compound 3-82 (305 mg, 1.25 mmol; Y. 25%): HPLC>97% (AP at
254 nm); MS (LC/MS) m/z 244 (M+H); .sup.1H NMR (CDCl.sub.3) .delta.
ppm 1.43 (3H, t, J=7.5 Hz; CH.sub.3), 2.91 (2H, q, J=7.5 Hz;
CH.sub.2), 4.05 (3H, s, OCH.sub.3), 6.71 (1H, dd, J=6, 2.4 Hz,
H-3), 7.57 (1H, t, J=3 Hz, H-2), 7.57 (1H, s, H-5), 9.16 (1H, s,
triazole-H-5), 10.3 (1H, br, NH).
Preparation of 4-82
[1542] 935
[1543] Procedure: AlCl.sub.3 (2.50 g, 18.8 mmol, 15 eq.) was
dissolved in a solution of CH.sub.2Cl.sub.2 (8 mL) and nitromethane
(2 mL) under dry nitrogen. To this solution was added compound 3-82
(305 mg, 1.26 mmol) under stirring and under N.sub.2, followed by
methyl chlorooxoacetate (612 mg, 5.0 mol, 4 eq.). The mixture was
stirred under N.sub.2 at room temperature for 1.5 h. The mixture
was added drop-wise to a cold and stirred solution of 20% aqueous
ammonium acetate solution (120 mL). The mixture was stirred for 30
min and the resultant precipitate was filtered, washed thoroughly
with water and dried in vacuo to obtain 320 mg (0.97 mmol, Y. 77%)
of the title compound 5-82 as a solid: HPLC purity 97% (AP at 254
nm); LC/MS m/z 330 (M+H); .sup.1H NMR (DMSO-d.sub.6) .delta. ppm
1.35 (3H, t, J=7.5 Hz, CH.sub.3), 2.85 (2H, q, J=7.5 Hz, CH.sub.2),
3.89 (3H, s, OCH.sub.3), 3.99 (3H, s, OCH.sub.3), 7.90 (1H, s,
H-5), 8.35 (1H, s, H-2), 9.25 (1H, s, triazole-H-5), 12.4 (1H, brs,
NH).
Preparation of 5-82
[1544] 936
[1545] Procedure: To a suspension of the methyl ester 4-82 (315 mg,
0.957 mmol) in MeOH (8 mL) was added 0.25M NaOH solution in water
(7.6 mL, 1.9 mmol, 2 eq.) at room temperature and the mixture
stirred for 15 min by which time HPLC indicated the hydrolysis was
complete. The mixture was concentrated in vacuo quickly to remove
MeOH, and to the residual solution was added water (10 mL) and 1N
HCl (2 mL) with stirring to neutralize the mixture. The resultant
fine precipitate was filtered, washed with water and dried in vacuo
to obtain 285 mg (0.904 mmol, Y. 94%) of the title compound 5-82 as
off-white solid: HPLC purity>96% (AP at 254 nm); LC/MS m/z 316
(M+H); .sup.1H NMR (DMSO-d.sub.6) .delta. ppm 1.35 (3H, t, J=7.5
Hz, Me), 2.85 (2H, q, J=7.5 Hz, CH.sub.2), 3.97 (3H, s, CH.sub.3O),
7.88 (1H, s, H-5), 8.30 (1H, d, J=3 Hz, H-2), 9.24 (1H, s,
triazole-H-5), 12.28 (1H, s, NH).
Preparation of Example 321
[1546] 937
[1547] Procedure: A mixture of the acid 5-82 (126 mg, 0.4 mmol) and
HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphonate, 228 mg, 0.6 mmol; 1.5 eq.) in a mixture of
CH.sub.2Cl.sub.2 (2 mL) and DMF (2 mL) was stirred for 30 min under
N.sub.2. To this mixture was added a mixture of benzoylpiperazine
hydrochloride (136 mg, 0.60 mmol; 1.5 eq.) and DMAP
(dimethylaminipyridine, 147 mg, 1.2 mmol; 3 eq.) in DMF (2 mL), and
the mixture ws stirred at room temperature under N.sub.2 for 15
min, by which time HPLC indicated the reaction was complete. The
mixture was quickly concentrated in vacuo to remove DMF and all
volatile materials, and to the residue was added water (50 mL)
under stirring and sonication. The precipitates formed were
collected, washed with water and dried in vacuo to obtain 160 mg
(0.328 mmol, Y. 82%) of the title compound Example 321 as off-white
solid: HPLC purity 100% (AP, at 254 nm); LC/MS m/z 488 (M+H);
.sup.1H NMR (DMSO-d6) .delta. ppm 1.35 (3H, t, J=7.5 Hz, Me), 2.85
(2H, q, J=7.5 Hz, CH.sub.2), 3.43 (4H, br, CH.sub.2N), 3.68 (4H,
br, CH.sub.2N), 4.00 (3H, s, CH.sub.3O), 7.46 (5H, br. s, Ar-HS),
7.89 (1H, s, indole-H-5), 8.26 (1H, s, indole-H-2), 9.25 (1H, s,
triazole-H-5), 12.32 (1H, br.s, NH).
Preparation of Example 322
[1548] 938
[1549] Procedure: A mixture of the acid 5-82 (79 mg, 0.25 mmol) and
HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphonate, 142 mg, 0.375 mmol; 1.5 eq.) in a mixture of
CH.sub.2Cl.sub.2 (1 mL) and DMF (1 mL) was stirred for 30 min under
N.sub.2. To this mixture was added a mixture of benzoylpiperazine
hydrochloride (136 mg, 0.60 mmol; 1.5 eq.) and DMAP
(dimethylaminipyridine, 92 mg, 0.75 mmol; 3 eq.) in DMF (1 mL), and
the mixture was stirred at room temperature under N.sub.2 for 15
min, by which time HPLC indicated the reaction was complete. The
mixture was quickly concentrated in vacuo to remove all solvents,
CH.sub.2Cl.sub.2 and DMF, and to the residue was added water
(.about.25 mL) under stirring and sonication. The resultant gum
were further washed with water and collected by decantation. The
residual gum was dried in vacuo. The solution of this gum in
isopropanol was concentrated in vavuo to remove any residual water.
Addition of anhydrous diethyl ether and trituaration gave 90 mg
(0.18 mmol, Y. 72%) of the title compound Example 322 as off-white
solid: HPLC purity 95% (AP, at 254 nm); LC/MS m/z 502 (M+H);
.sup.1H NMR (DMSO-d6) .delta. ppm 1.15, 1.22 (3H, 2d, J=6.6 Hz,
Me), 1.35 (3H, t, J=7.5 Hz, Me), 2.85 (2H, q, J=7.5 Hz, CH.sub.2),
2.9-4.4 (7H, m, CH.sub.2N, CHN), 3.99, 4.00 (3H, 2s, CH.sub.3O),
7.45 (5H, br. s, Ph-Hs), 7.89 (1H, s, indole-H-5), 8.20, 8.25 (1H,
2s, indole-H-2), 9.24, 9.25 (1H, 2s, triazole-H-5), 12.29, 12.32
(1H, 2br.s, NH).
[1550] The following compounds, Example 323, and Example 324, were
prepared by the method described above using
3-(methoxymethyl)-1,2,4-tria- zole (10-83). 939 940941
Preparation of 3-methoxymethyl-1,2,4-triazole (10-83)
[1551] 942
[1552] Procedure: To a mixture of methoxyacetonitrile (25 g, 0.35
mol: Aldrich) and diethylamine (1 g, 8.6 mmol) was condensed
H.sub.2S (50 mL), and the mixture was sealed, and heated at
50.degree. C. for 14 hrs. After cooling volatile materials were
evaporated and the residue was dissolved in water, extracted with
EtOAc several times. The combined organic extracts were washed with
brine, dried over anhydrous Na.sub.2SO.sub.4, and concentrated in
vacuo. The residue was purified by column chromatography
(EtOAc:CH.sub.2Cl.sub.2=1: 10) to obtain 13 g (0.12 mol, Y. 35%) of
the title compound as a dark oil: GC/MS m/z 105 (M); .sup.1H NMR
(CDCl.sub.3) .delta. ppm 3.43 (3H, s, CH.sub.3), 4.26 (2H, s,
CH.sub.2).
Preparation of 3-methoxymethyl-1,2,4-triazole (10-83)
[1553] 943
[1554] Procedure: A solid mixture of formic hydrazide (4.58 g,
0.0763 mol) and methoxythioacetamide (8.92 g, 0.1 mol) was heated
with stirring at 150.degree. C. (oil bath temp.) for 2 hrs with a
gentle stream of nitrogen. It was cooled and stored at room
temperature overnight. The solid reaction mixture was suspended in
20% EtOAc/CH2Cl2, removing insoluble solid and the filtrate was
concentrated. The residue was purified by column chromatography,
eluting first with 50-80% EtOAc/CH.sub.2Cl.sub.2, removing
by-products, and then with 10% MeOH/CH.sub.2Cl.sub.2, collecting
3.8 g (0.034 mol, Y. 44%) of the title compound 10-83 as a solid:
.sup.1H NMR (CDCl.sub.3) .delta. ppm 3.48 (3H, s, MeO), 4.67 (2H,
s, CH.sub.2), 8.10 (1H, s, 5-H). 944
[1555] Y. 9%: HPLC>98% (AP at 254 nm); MS (LC/MS) m/z 260 (M+H);
.sup.1H NMR (CDCl.sub.3) .delta. ppm 3.53 (3H, s, MeO), 4.06 (3H,
s, 4-OCH.sub.3), 4.69 (2H, s, CH.sub.2), 6.73 (1H, dd, J=3, 2.4 Hz,
H-3), 7.40 (1H, t, J=2.7 Hz, H-2), 7.58 (1H, s, H-5), 9.16 (1H, s,
triazole-H-5), 10.2 (1H, br, NH). 945
[1556] Y. 78%: HPLC 100% (AP at 254 nm); MS (LC/MS) m/z 346 (M+H);
.sup.1H NMR (CD.sub.3OD) .delta. ppm 3.51 (3H, s, MeO), 3.94 (3H,
s, MeO), 4.05 (3H, s, MeO), 4.71 (2H, s, CH.sub.2), 7.87 (1H, s),
8.35 (1H, s), 9.33 (1H, s, triazole-H-5). 946
[1557] Y. 97%: HPLC 98% (AP at 254 nm); MS (LC/MS) m/z 332 (M+H);
.sup.1H NMR (CDCl.sub.3) .delta. ppm 3.49 (1H, s, OH), 3.55 (3H, s,
MeO), 4.10 (3H, s, MeO), 4.72 (2H, s, CH.sub.2), 7.84 (1H, s, H-5),
9.13 (1H, d, J=3.3 Hz), 9.21 (1H, s, triazole-H-5), 11.15 (1H, br,
NH).
EXAMPLE 323
[1558] 947
[1559] Y. 79%: HPLC 100% (AP at 254 nm); MS (LC/MS) m/z 504 (M+H);
.sup.1H NMR (DMSO-d.sub.6) .delta. ppm 3.39 (3H, s, MeO), 3.42 (4H,
br, CH.sub.2N), 3.68 (4H, br, CH.sub.2N), 4.01 (3H, s, 4-MeO), 4.61
(2H, s, CH.sub.2), 7.46 (5H, s, Ph-Hs), 7.92 (1H, s), 8.27 (1H, s),
9.36 (1H, s, triazole-H-5), 12.42 (1H, br.s, NH).
EXAMPLE 324
[1560] 948
[1561] Y. 69%: HPLC>97% (AP at 254 nm); MS (LC/MS) m/z 518
(M+H); .sup.1H NMR (DMSO-d.sub.6) .delta. ppm 1.15, 1.22 (3H, 2d,
J=7 Hz, Me), 2.9-4.4 (7H, m, CH.sub.2N, CHN), 3.39 (3H, s, MeO),
4.00, 4.01 (3H, 2s, CH.sub.3O), 4.61 (2H, s, CH.sub.2), 7.4-7.5
(5H, m, Ph-Hs), 7.92 (1H, s, indole-H-5), 8.21, 8.29 (1H, 2s,
indole-H-2), 9.35, 9.36 (1H, 2s, triazole-H-5), 12.4 (1H, br,
NH).
[1562] The following compounds, Examples 325, 326, 327, and 328,
were prepared by the method described above using
4-methyl-1,2,3-triazole (19-84). 949 950
Preparation of 4-methyl-1,2,3-triazole (19-84)
[1563] 951
[1564] Procedure:
[1565] This compound 19-84 was prepared by the method described in
M. Begtrup J. Chem Soc., Perkin Transactions II, 1976, 736.
[1566] A mixture of m-nitrobenzoyl azide (38.4 g, 0.200 mol;
prepared from m-nitrobenzoyl chloride and sodium azide following
the procedure described in Org. Syn. Coll. Vol. IV, 1963, p. 715)
and 1-triphenylphosphoranylidene-2-propanone (63.6 g, 0.200 mol:
Aldrich) in CH.sub.2Cl.sub.2 (300 mL) was stirred at room
temperature for 2 hrs. The mixture was concentrated in vacuo to
obtain a solid. This solid was dissolved in MeOH, and the solution
was stirred at room temperature for 30 min, and the precipitates
formed were removed. The filtrate was concentrated in vacuo, and
the residue was extracted with water (500 mL) containing TFA (17
mL). This solution was washed once with a small amount of
CH.sub.2Cl.sub.2 to remove the most of triphenylphosphine, and the
aqueous phase neutralized with NaHCO3 to pH 7 and extracted five
times with CH.sub.2Cl.sub.2 (total of 500 mL). The combined
extracts were dried over Na2SO4, concentrated to obtain 7.6 g
(0.091 mol, Y. 46%) of the title compound 19-84 as a yellow oil:
.sup.1H NMR (CDCl.sub.3) .delta. ppm 2.37 (3H, s, Me), 7.50 (1H, s,
5-H), 10.41 (1H, br, NH). 952
[1567] Yield 5-9%: HPLC purity 100% (RT 1.89 min, AP at 254 nm); MS
(LC/MS) m/z 230 (M+H); .sup.1H NMR (CDCl.sub.3) .delta. ppm 2.47
(3H, s, Me), 4.07 (3H, s, 4-OCH.sub.3), 6.74 (1H, t J=2.7 Hz, H-3),
7.42 (1H, t, J=2.7 Hz, H-2), 7.62 (1H, s, H-5), 8.41 (1H, s,
triazole-H-5), 10.3 (1H, br, NH).
[1568] The structure was confirmed by a single X-ray
crystallographic analysis. 953
[1569] Yield 11-14%: HPLC purity 100% (RT 1.36 min, AP at 254 nm);
MS (LC/MS) m/z 230 (M+H); .sup.1H NMR (CDCl.sub.3) .delta. ppm 2.48
(3H, s, Me), 4.06 (3H, s, 4-OCH.sub.3), 6.74 (1H, dd, J=3, 2.4 Hz,
H-3), 7.39 (1H, t, J=3 Hz, H-2), 7.68 (1H, s, H-5), 7.72 (1H, br,
triazole-H-5), 10.25 (1H, br, NH). 954
[1570] Yield 79%: HPLC purity 94% (AP at 254 nm); MS (LC/MS) m/z
316 (M+H); .sup.1H NMR (CDCl.sub.3) .delta. ppm 2.49 (3H, s, Me),
3.96 (3H, s, OMe), 4.07 (3H, s, OMe), 7.81 (1H, s, H-5), 8.38 (1H,
d, J=3.3 Hz, H-2), 8.42 (1H, s, triazole-H-5), 11.07 (1H, br, NH).
955
[1571] Yield 81%: HPLC purity>95% (AP at 254 nm); MS (LC/MS) m/z
316 (M+H); .sup.1H NMR (CDCl.sub.3) .delta. ppm 2.49 (3H, s, Me),
4.00 (3H, s, OMe), 4.05 (3H, s, OMe), 7.72 (1H, s, H-5), 7.89 (1H,
br.s, triazole-H-5), 8.33 (1H, d, J=3 Hz, H-2), 11 (1H, br, NH).
956
[1572] Yield 83%: HPLC purity 98% (AP at 254 nm); MS (LC/MS) m/z
302 (M+H); .sup.1H NMR (CD.sub.3OD) .delta. ppm 2.46 (3H, s, Me),
4.06 (3H, s, OMe), 7.89 (1H, s, H-5), 8.39 (1H, d, J=3.3 Hz, H-2),
8.58 (1H, s, triazole-H-5). 957
[1573] Yield 74%: HPLC purity 100% (AP at 254 nm); MS (LC/MS) m/z
302 (M+H); .sup.1H NMR (CD.sub.3OD) .delta. ppm 2.50 (3H, s, Me),
4.05 (3H, s, OMe), 7.84 (1H, s), 7.90 (1H, s), 8.39 (1H, s).
EXAMPLE 325
[1574] 958
[1575] Y. 76%: HPLC 98% (AP at 254 nm); MS (LC/MS) m/z 474 (M+H);
.sup.1H NMR (DMSO-d.sub.6) .delta. ppm 2.40 (3H, s, Me), 3.44 (4H,
br, CH.sub.2N), 3.68 (4H, br, CH.sub.2N), 4.02 (3H, s, 4-MeO), 7.46
(5H, s, Ph-Hs), 7.96 (1H, s), 8.21 (1H, s), 8.68 (1H, s,
triazole-H-5), 12.72 (1H, br, s, NH).
EXAMPLE 326
[1576] 959
[1577] Y. 62%: HPLC 97% (AP at 254 nm); MS (LC/MS) m/z 488 (M+H);
.sup.1H NMR (DMSO-d.sub.6) .delta. ppm 1.14, 1.21 (3H, 2d, J=7 Hz,
Me), 2.40 (3H, s, Me), 2.9-4.4 (7H, m, CH.sub.2N, CHN), 4.01, 4.02
(3H, 2s, CH.sub.3O), 7.46 (5H, s, Ph-Hs), 7.96 (1H, s), 8.16, 8.23
(1H, 2s), 8.675, 8.68 (1H, 2d, J=2.5 Hz), 12.72 (1H, br.s, NH).
COMPOUND EXAMPLE 327
[1578] 960
[1579] Y. 73%: HPLC 96% (AP at 254 nm); MS (LC/MS) m/z 474 (M+H);
.sup.1H NMR (DMSO-d.sub.6) .delta. ppm 2.45 (3H, s, Me), 3.44 (4H,
br, CH.sub.2N), 3.68 (4H, br, CH.sub.2N), 4.01 (3H, s, 4-MeO), 7.46
(5H, s, Ph-Hs), 7.93 (1H, s), 8.04 (1H, s), 8.24 (1H, d, J=3 Hz,
H-2), 12.51 (1H, br.s, NH).
EXAMPLE 328
[1580] 961
[1581] Y. 74%: HPLC 99% (AP at 254 nm); MS (LC/MS) m/z 488 (M+H);
.sup.1H NMR (DMSO-d.sub.6) .delta. ppm 1.15, 1.22 (3H, 2d, J=7 Hz,
Me), 2.45 (3H, s, Me), 2.9-4.4 (7H, m, CH.sub.2N, CHN), 4.00, 4.01
(3H, 2s, CH.sub.3O), 7.45 (5H, s, Ph-Hs), 7.92 (1H, s), 8.03 (1H,
s), 8.18, 8.26 (1H, 2s), 12.5 (1H, br.s, NH).
Preparation of Example 329
[1582] 962
[1583] A mixture of compound 5b (128 mg, 0.3 mmol),
imidazole-4-propionic acid (1.26 g, 9 mmol; 30 eq.; prepared from
urocanic acid by catalytic hydrogenation using 10% Pd-C in acetic
acid, following the procedure described in J. Altman, N. Shoef, M.
Wilchek, and A. Warshawsky J. Chem. Soc., Perkin Trans. I, 1984,
59), copper powder (38 mg, 0.6 mmol; 2 eq.), potassium carbonate
(83 mg, 0.6 mmol; 2 eq.) was flushed with anhydrous nitrogen and
heated in a sealed tube at 190.degree.-200.degree. C. (oil bath
temp.) for 2 h. Upon cooling, to the mixture was added MeOH, and
the insoluble material was filtered. The filtrate was concentrated
in vacuo and purified by C-18 reverse phase column (YMC, eluting
with 15% CH.sub.3CN-water containing 0.1% TFA) to obtain 12 mg
(0.023 mmol, Y. 7.5%) of the title compound Example 329 as
amorphous powder (about 1:1 mixture of two regio-isomers): HPLC
purity 96% (AP, at 254 nm); MS (LC/MS) m/z 531 (M+H); .sup.1H NMR
(CD.sub.3OD) .delta. ppm 2.74, 3.00 (2H, 2t, J=7 Hz), 2.82, 3.11
(2H, 2t, J=7 Hz), 3.59 (4H, br, CH.sub.2N), 3.79 (4H, br,
CH.sub.2N), 3.79, 4.10 (3H, 2s, CH.sub.3O), 6.73 (s), 7.33 (s),
7.48 (5H, br. s, Ar-Hs), 7.93 (br.s), 8.00 (s), 8.10 (s), 8.40 (s),
8.77 (s), 9.43 (br.s).
[1584] The following compounds, Examples 330 and 331 were similarly
prepared by following the above procedure.
EXAMPLE 330
[1585] 963
[1586] Y. 10% (150.degree. C., 7 h): HPLC 93% (AP at 254 nm); MS
(LC/MS) m/z 485 (M+H); .sup.1H NMR (CD.sub.3OD, 500 MHz) .delta.
ppm 3.63 (4H, br, CH.sub.2N), 3.84 (4H, br, CH.sub.2N), 4.05 (3H,
s, 4-MeO), 7.32 (2H, m, pyr-Hs), 7.52 (5H, s, Ph-Hs), 7.71 (1H, s),
8.06 (1H, t, J=7.5 Hz, pyr-H), 8.48 (1H, d, J=4.5 Hz), 8.60 (1H,
s).
EXAMPLE 331
[1587] 964
[1588] Y. 10% (150.degree. C., 7 h): HPLC 93% (AP at 254 nm); MS
(LC/MS) m/z 563 (M+H); .sup.1H NMR (CDCl.sub.3) .delta. ppm 2.76 (3
h. S, Me), 3.55 (4H, br, CH.sub.2N), 3.78 (4H, br, CH.sub.2N), 4.09
(3H, s, 4-MeO), 6.71 (1H, t, J=7 Hz, pyr-H), 7.43 (5H, s, Ph-Hs),
7.68 (1H, t, J=7 Hz, pyr-H), 7.82 (1H, t, J=7 Hz, pyr-H), 7.91(1H,
s), 8.15 (1H, s), 10.84 (1H, br, NH). 965
[1589] A mixture of precursor 5w (71.5 mg, 0.17 mmol) in MeOH (1.5
mL) was cooled to 0.degree. C., and saturated with hydrogen
chloride gas over the course of 10 min. The volatiles were then
evaporated via blowing N.sub.2 overnight to provide precursor 5wa.
.sup.1H NMR: (DMSO-d.sub.6) .delta.12.45 (s, 1H), 8.12 (s, 2H),
8.07 (s, 1H), 7.65 (s, 1H), 7.45 (s, 5H), 4.04 (s, 3H), 3.80-3.30
(b m, 8H); LC/MS: (ES.sup.+) m/z (M+H).sup.+=436, HPLC
R.sub.t=1.357 (Column G). 966
[1590] To a mixture of precursor 5wa (10 mg, 23 .mu.mol) in acetic
acid (0.4 mL) and acetic anhydride (0.75 mL) at 0.degree. C., was
added NaNO.sub.2 (30 mg, 0.43 mmol). The reaction mixture was
stirred at 0.degree. C. for 30 min, and allowed to warm to ambient
temperature. After stirring for an additional 1.5 hr, the mixture
was filtered and the residue dried under vacuum to give the desired
compound 5wb an off-white solid. .sup.1H NMR: (CD.sub.3OD)
.delta.8.44 (s, 1H), 8.08 (s, 1H), 7.48 (b s, 5H), 4.14-3.27 (m,
8H), 4.14 (s, 3H); LC/MS: (ES.sup.+) m/z (M+H).sup.+=437, HPLC
Rt=0.750 (Column G). 967
[1591] A flask was charged with precursor 5wb (2.6 mg, 6.0
.mu.mol), DMF (0.5 mL), tert-butyl carbazate (1.2 mg, 8.9 .mu.mol),
DEPBT (5.4 mg, 18 .mu.mol), and N,N-diisopropylethylamine (10
.mu.L, 30 .mu.mol). The reaction mixture was allowed to stir at
ambient temperature overnight. The product 5wc was separated using
the following reverse phase preparative HPLC method: Start % B=0,
Final % B=100, Gradient time=6 min, Flow Rate=30 mL/min, Column:
Xerra Prep MS C18 5 .mu.m19=50 mm, Fraction Collection: 4.38-4.59
min. .sup.1H NMR: (CD.sub.3OD) .delta.8.29 (s, 1H), 8.11 (s, 1H),
7.47 (b s, 5H), 4.11-3.28 (m, 8H), 4.10 (s, 3H), 1.50 (b s, 9H);
LC/MS: (ES+) m/z (M+H).sup.+=551, HPLC Rt=1.203 (Column G). 968
[1592] To precursor 5wc (57 mg, 0.104 mmol) was added a solution of
HCl in 1,4-dioxane (4 M, 0.25 mL), and the reaction mixture was
stirred overnight at room temperature. The deprotection afforded
the desired product precursor 5wd cleanly. The excess reagent and
solvent were evaporated via blowing N.sub.2, and the product dried
under vacuum. LC/MS: (ES.sup.+) m/z (M+H).sup.+=451, HPLC Rt=0.803
(Column G). 969
[1593] A solution of precursor 5we (106 mg, 0.25 mmol) in MeOH (2.5
mL) in a sealed tube at 0.degree. C. was flushed with N.sub.2, and
saturated with HCl gas for 10 min. The tube was closed and the
reaction mixture was stirred at 70.degree. C. for 50 minutes. After
cooling to ambient temperature, the volatiles were evaporated in
vacuo to give precursor 5wf. .sup.1H NMR: (CD.sub.3OD) .delta.8.33,
8.30 (s, 1H), 8.13, 8.12 (s, 1H), 7.48-7.44 (m, 5H), 4.60-3.10 (b
m, 7H), 4.12, 4.11 (s, 3H) 4.06 (s, 3H), 1.35,1.29 (d, J=6.5, 7.0,
3H); LC/MS: (ES.sup.+) m/z (M+H).sup.+=465, HPLC Rt=0.993 (Column
G). 970
[1594] To a solution of precursor 5wf (65 mg, 0.14 mmol) in MeOH (1
mL) was added NaOH (1.5 mL, 1 N aq.). The mixture was stirred for 2
hours, and upon which time HCl (1.5 mL, 1 N aq.) was added to
quench the reaction. The volatiles were evaporated in vacuo to give
precursor 5wg. .sup.1H NMR: (TFA solvate, CD.sub.3OD) .delta.8.54,
8.51 (s, 1H), 8.11 (b s, 1H), 7.57-7.48 (b s, 5H), 4.60-3.10 (b m,
7H), 4.17, 4.16 (s, 3H), 1.37,1.33 (d, J=6.5, 6.0, 3H); LC/MS:
(ES.sup.+) m/z (M+H).sup.+=451, HPLC R.sub.t=0.837 (Column G).
971
[1595] To a mixture of precursor 5wg (22 mg, 0.048 mmol) in DMF (1
mL) were added tert-butyl carbazate (14 mg, 0.11 mmol), DEPBT (53
mg, 0.18 mmol), and N,N-diisopropylethylamine (40 .mu.L, 0.23
mmol). The reaction mixture was stirred overnight, and the desired
compound precursor 5wh was isolated via preparative reverse phase
HPLC using the following conditions: Start % B=0, Final % B=100,
Gradient time=6 min, Flow Rate=30 mL/min, Column: Xerra Prep MS C18
5 .mu.m 19.times.50 mm, Fraction Collection: 4.37-4.98 min. .sup.1H
NMR: (CD.sub.3OD) .delta.8.28, 8.26 (s, 1H), 8.08 (b s, 1H),
7.47-7.43 (m, 5H), 4.75-3.26 (m, 7H), 4.10 (s, 3H), 1.50 (b s, 9H),
1.36-1.27 (m, 3H); LC/MS: (ES.sup.+) m/z (M+H).sup.+=565, HPLC
R.sub.t=1.207 (Column G). 972
[1596] A mixture of precursor 5wh in a solution of HCl in
1,4-dioxane (0.2 mL, 4 M) was stirred for 3.5 hr at ambient
temperature. The volatiles were evaporated in vacuo, and the crude
mixture was purified via reverse phase preparative HPLC using the
following method: Start % B=0, Final % B=100, Gradient time=6 min,
Flow Rate=30 mL/min, Column: Xerra Prep MS C18 5.mu.m19.times.50
mm, Fraction Collection: 3.20-3.80 min. .sup.1H NMR: (CD.sub.3OD)
.delta.8.74, 8.71 (s, 1H), 8.31, 8.28 (s, 1H), 7.47-7.44 (m, 5H),
4.46-3.35 (m, 7H), 4.18, 4.10 (s, 3H), 1.38-1.22 (m, 3H); LC/MS:
(ES.sup.+) m/z (M+H).sup.+=465, HPLC R.sub.t=0.850 (Column G).
EXAMPLE 333 AND EXAMPLE 334
[1597] 973
[1598] Thioacetamide (2 mg, 22 .mu.mol) was added to Example 333
(10 mg, 20 .mu.mol, HCl salt) in a round-bottom flask. The mixture
was heated to 150.degree. C. for 20 minutes, after which it was
cooled to ambient temperature, and diluted with MeOH. Purification
of the desired compound Example 334 was performed via preparative
reverse phase HPLC using the following method: Start % B=0, Final %
B=100, Gradient time=6 min, Flow Rate=30 mL/min, Column: Xerra Prep
MS C18 5 .mu.m19.times.50 mm, Fraction Collection: 3.47-3.86 min.
.sup.1H NMR: (CD.sub.3OD) .delta.8.64, 8.62 (s, 1H), 8.04 (b s,
1H), 7.49-7.44 (m, 5H), 4.37-3.44 (m, 7H), 4.16, 4.14 (s, 3H), 2.63
(s, 3H), 1.36-1.32 (m, 3H); LC/MS: (ES.sup.+) m/z (M+H).sup.+=488,
HPLC Rt=0.973 (column G).
[1599] The following examples were prepared in a similar manner as
above.
EXAMPLE 335
[1600] 974
Preparation of Example 335
[1601] .sup.1H NMR: (CD.sub.3OD) .delta.8.60, 8.58 (s, 1H), 8.12
(d, J=3, 1H), 7.71-7.67 (m, 1H), 7.59-7.54 (m, 4H), 7.50-7.46 (m,
5H), 4.37-3.44 (m, 7H), 4.16, 4.14 (s, 3H), 1.37, 1.33 (d J=6.5,
3H); LC/MS: (ES.sup.+) m/z (M+H).sup.+=550, HPLC Rt=1.283(column
G).
EXAMPLE 336
[1602] 975
[1603] .sup.1H NMR: (CD.sub.3OD) .delta.8.66, 8.64 (s, 1H), 8.04
(d, J=3, 1H), 7.49-7.40 (m, 5H), 4.41-3.44 (m, 7H), 4.16, 4.14 (s,
3H), 3.00 (q, J=7.5, 2H), 1.46 (t, J=7.5, 3H), 1.36-1.32 (m, 3H);
LC/MS: (ES.sup.+) m/z (M+H).sup.+=502, HPLC R.sub.t=1.007(column
G).
EXAMPLE 337
[1604] 976
[1605] .sup.1H NMR: (CD.sub.3OD) .delta.8.59, 8.57 (s, 1H), 8.11 (b
d, 1H), 7.48-7.40 (m, 9H), 4.46-3.39 (m, 7H), 4.16, 4.14 (s, 3H),
2.45 (s, 3H), 1.40-1.29 (m, 3H); LC/MS: (ES.sup.+) m/z
(M+H).sup.+=564, HPLC R.sub.t=1.363 (column G).
EXAMPLE 338
[1606] 977
[1607] .sup.1H NMR: (CD.sub.3OD) .delta.9.62 (s, 1H), 9.11 (s, 1H),
8.82 (d, J=5.5, 1H), 8.47 (d, J=8.5, 1H), 8.19 (s, 1H), 7.98 (s,
1H), 7.49-7.46 (m, 5H), 4.64-3.35 (m, 7H), 4.14, 4.13 (s, 3H),
1.37, 1.32 (d, J=7, 3H); LC/MS: (ES.sup.+) m/z (M+H).sup.+=551,
HPLC R.sub.t=1.090 (column G).
EXAMPLE 339
[1608] 978
[1609] .sup.1H NMR: (CD.sub.3OD) .delta.8.50 (s, 1H), 8.17 (b d,
1H), 7.53-7.45 (m, 9H), 4.64-3.35 (m, 7H), 4.14, 4.13 (s, 3H),
1.37, 1.32 (d, J=6.5, 7, 3H); LC/MS: (ES.sup.+) m/z
(M+H).sup.+=584, HPLC R.sub.t=1.427 (column G).
EXAMPLE 340
[1610] 979
[1611] .sup.1H NMR: (CD.sub.3OD) .delta.8.56, 8.55 (s, 1H), 8.36
(s, 1H), 8.10 (s, 1H), 7.72 (s, 1H), 7.48-7.45 (m, 5H), 7.09 (s,
1H), 4.64-3.44 (m, 7H), 4.15, 4.14 (s, 3H), 1.36-1.32 (m, 3H);
LC/MS: (ES.sup.+) m/z (M+H).sup.+=540, HPLC R.sub.t=1.133 (column
G).
EXAMPLE 341
[1612] 980
[1613] .sup.1H NMR: (CD.sub.3OD) .delta.8.54, 8.51 (s, 1H), 8.20
(s, 1H), 8.14 (s, 1H), 7.48-7.39 (m, 5H), 4.71-3.44 (m, 7H), 4.14,
4.13 (s, 3H), 2.85 (s, 3H), 1.37-1.29 (m, 3H); LC/MS: (ES.sup.+)
m/z (M+H).sup.+=571, HPLC R.sub.t=1.450 (column G).
EXAMPLE 342
[1614] 981
[1615] .sup.1H NMR: (CD.sub.3OD) .delta.8.64 (s, 1H), 8.04 (s, 1H),
7.48 (s, 5H), 4.16 (s, 3H), 3.92-3.39 (m, 8H), 2.64 (s, 3H); LC/MS:
(ES.sup.+) m/z (M+H).sup.+=474, HPLC R.sub.t=0.903 (column G).
EXAMPLES 343 AND 344
[1616] 982
[1617] Precursor 5b (60 mg, 0.14 mmol), 4-fluoropyrazole (0.30 mL)
(prepared as described in Molines, H.; Wakselman, C. J. Org. Chem.
1989, 54, 5618-5620), copper(0) (8.0 mg, 0.13 mmol),
K.sub.2CO.sub.3 (15 mg, 0.11 mmol) and EtOH (0.30 mL) were combined
in a sealed tube flushed with nitrogen and heated at 170.degree. C.
with microwave irradiation for 1.5 h. The reaction was cooled,
filtered and concentrated. The residue was purified by preparative
HPLC under the standard conditions described above to provide (6.6
mg,0.014 mmol) of Example 343 as a yellow solid and Example 344
(3.1 mg. 0.006 mmol) as a greenish solid.
EXAMPLE 343
[1618] .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.8.56 (d, J=4.3 Hz,
1H), 8.27 (s, 1H), 7.82-7.79 (m, 2H), 7.47 (br s, 5H), 4.03 (s,
3H), 3.97-3.45 (m, 8H). MS m/z: (M+H).sup.+ calcd for
C.sub.24H.sub.21FN.sub.6O.sub.2: 477.16; found 477.16. HPLC
retention time: 1.45 minutes (column G).
EXAMPLE 344
[1619] .sup.1H NMR (500 MHz, CDCl.sub.3) 6 11.16 (br s, 1H), 8.59
(s 1H), 8.19 (s, 1H), 7.78-7.62 (m, 2H), 7.43 (br s, 5H), 4.04 (s,
3H), 3.987-3.40 (m, 8H). MS m/z: (M+H).sup.+ calcd for
C.sub.24H.sub.21ClN.sub- .6O.sub.2: 493.13; found 493.12. HPLC
retention time: 1.59 minutes (column G).
EXAMPLE 353
[1620] 983
[1621] Example 353 was prepared from the corresponding 7-chloro
precursor 5mn and 2-tributyl stannyl oxazole via the standard
Stille coupling conditions described above. The 7-chloro precursor
was prepared similarly to precursor 5d except that 2-(R) methyl
piperazine benzamide (precursor 17b) was utilized. Example 353,
4-azaindole-7-(2'-oxazole): .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta.8.68 (s, 0.5H), 8.67 (s, 0.5H), 8.45 (s, 0.5H), 8.43 (s,
0.5H), 8.18 (s, 1H), 7.86 (d, J=4.9 Hz, 0.5H), 7.85 d, J=4.9 Hz,
0.5H), 7.55 (s, 1H), 7.50-7.40 (m, 5H), 4.45-3.06 (m, 7H), 1.48 (d,
J=6.7 Hz, 1.5H) 1.24 (d, J=6.7 Hz, 1.5H). MS m/z: (M+H).sup.+ calcd
for C.sub.24H.sub.22N.sub.5O.sub.4: 444.16; found 444.23. HPLC
retention time: 0.90 minutes (column G).
EXAMPLE 354
[1622] 984
[1623] Example 354 was prepared from the corresponding 7-chloro
precursor 5mn and 2-tributyl stannyl thiazole via the standard
Stille coupling conditions described above. The 7-chloro precursor
was prepared similarly to precursor 5d except that 2-(R) methyl
piperazine benzamide (precursor 17b) was utilized. example 354:
4-azaindole-7-(2'-thiazole): .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta.8.80 (s, 0.5H), 8.74-8.71 (m, 1.5H), 8.35 (d, J=3.5 Hz,
0.5H), 8.35 (d, J=3.5 Hz, 0.5H), 8.26 (d, J=3.5 Hz, 0.5H), 8.25 (d,
J=3.5 Hz, 0.5H), 8.14 (d, J=3.1 Hz, 0.5H), 8.14 (d, J=3.1 Hz,
0.5H), 7.50-7.42 (m, 5H), 4.48-3.08 (m, 7H), 1.36 (d, J=6.7 Hz,
1.5H) 1.32 (d, J=6.7 Hz, 1.5H). MS m/z: (M+H).sup.+ calcd for
C.sub.24H.sub.22N.sub.5O.sub.3S: 460.14; found 460.20. HPLC
retention time: 0.94 minutes (column G).
EXAMPLE 355
[1624] 985
[1625] Example 355 was prepared via the procedure used for Example
205 from the corresponding 7-chloro precursor 5 mn and
1,2,3,-triazole. The 7-chloro precursor was prepared similarly to
precursor 5d except that 2-(R) methyl piperazine benzamide
(precursor 17b) was utilized. Example 355,
4-azaindole-7-(2'-triazole): .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta.8.79-8.76 (m, 1H), 8.78 (s, 0.5H), 8.70 (s, 0.5H), 8.44 (d,
J=5.9 Hz, 0.5H), 8.43 (d, J=5.9 Hz, 0.5H), 8.38 (s, 1H), 8.38 (s,
1H), 7.51-7.42 (m, 5H), 4.50-3.21 (m, 7H), 1.37 (d, J=6.7 Hz, 1.5H)
1.32 (d, J=6.7 Hz, 1.5H). MS m/z: (M+H).sup.+ calcd for
C.sub.23H.sub.22N.sub.7O.s- ub.3: 444.17; found 444.26. HPLC
retention time: 0.90 minutes (column G).
EXAMPLE 356
[1626] 986
[1627] Example 356 was prepared via the procedure used for Example
205 from the corresponding 7-chloro precursor 5mn and 3-methyl
pyrazole. The 7-chloro precursor was prepared similarly to
precursor 5d except that 2-(R) methyl piperazine
benzamide(precursor 17b)was utilized. Example
356,4-azaindole-7-(3'-methyl-2'pyrazole): .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta.8.73-8.71 (m, 1H), 8.70 (s, 0.5H), 8.63 (s,
0.5H), 8.64-8.60 (m, 1H), 8.06 (s, 0.5H), 8.04 (s, 0.5H), 7.52-7.42
(m, 5H), 6.68 (s, 0.5H), 6.67 (s, 0.5H), 4.61-3.21 (m, 7H), 2.51
(s, 3H), 1.35 (d, J=6.5 Hz, 1.5H 1.32 (d, J=6.5 Hz, 1.5H). MS m/z:
(M+H).sup.+ calcd for C.sub.25H.sub.25N.sub.6O.sub.3: 457.19; found
457.33. HPLC retention time: 1.04 minutes (column G).
[1628] Biology
[1629] ".mu.M" means micromolar;
[1630] "mL" means milliliter;
[1631] ".mu.l" means microliter;
[1632] "mg" means milligram;
[1633] The materials and experimental procedures used to obtain the
results reported in Tables 1-5 are described below.
[1634] Cells:
[1635] Virus production--Human embryonic Kidney cell line, 293,
propagated in Dulbecco's Modified Eagle Medium (Life Technologies,
Gaithersburg, Md.) containing 10% fetal Bovine serum (FBS, Sigma,
St. Louis, Mo.).
[1636] Virus infection--Human epithelial cell line, HeLa,
expressing the HIV-1 receptors CD4 and CCR5 was propagated in
Dulbecco's Modified Eagle Medium (Life Technologies, Gaithersburg,
Md.) containing 10% fetal Bovine serum (FBS, Sigma, St. Louis, Mo.)
and supplemented with 0.2 mg/mL Geneticin (Life Technologies,
Gaithersburg, Md.) and 0.4 mg/mL Zeocin (Invitrogen, Carlsbad,
Calif.).
[1637] Virus--Single-round infectious reporter virus was produced
by co-transfecting human embryonic Kidney 293 cells with an HIV-1
envelope DNA expression vector and a proviral cDNA containing an
envelope deletion mutation and the luciferase reporter gene
inserted in place of HIV-1 nef sequences (Chen et al, Ref. 41).
Transfections were performed using lipofectAMINE PLUS reagent as
described by the manufacturer (Life Technologies, Gaithersburg,
Md.).
[1638] Experiment
[1639] 1. Compound was added to HeLa CD4 CCR5 cells plated in 96
well plates at a cell density of 5.times.10.sup.4 cells per well in
100 .mu.l Dulbecco's Modified Eagle Medium containing 10% fetal
Bovine serum at a concentration of <20 .mu.M.
[1640] 2. 100 .mu.l of single-round infectious reporter virus in
Dulbecco's Modified Eagle Medium was then added to the plated cells
and compound at an approximate multiplicity of infection (MOI) of
0.01, resulting in a final volume of 200 .mu.l per well and a final
compound concentration of <10 .mu.M.
[1641] 3. Samples were harvested 72 h after infection.
[1642] 4. Viral infection was monitored by measuring luciferase
expression from viral DNA in the infected cells using a luciferase
reporter gene assay kit (Roche Molecular Biochemicals,
Indianapolis, Ind.). Infected cell supernatants were removed and 50
.mu.l of Dulbecco's Modified Eagle Medium (without phenol red) and
50 .mu.l of luciferase assay reagent reconstituted as described by
the manufacturer (Roche Molecular Biochemicals, Indianapolis, Ind.)
was added per well. Luciferase activity was then quantified by
measuring luminescence using a Wallac microbeta scintillation
counter.
[1643] 5. The percent inhibition for each compound was calculated
by quantifying the level of luciferase expression in cells infected
in the presence of each compound as a percentage of that observed
for cells infected in the absence of compound and subtracting such
a determined value from 100.
[1644] 6. An EC.sub.50 provides a method for comparing the
antiviral potency of the compounds of this invention. The effective
concentration for fifty percent inhibition (EC.sub.50) was
calculated with the Microsoft Excel Xlfit curve fitting software.
For each compound, curves were generated from percent inhibition
calculated at 10 different concentrations by using a four
paramenter logistic model (model 205). The EC.sub.50 data for the
compounds is shown in Tables 2-4. Table 1 is the key for the data
in Tables 2-4.
[1645] Cytoxicity assays were conducted with the same HeLa using
methodology well known in the art. This method has been described
in the literature (S Weislow, R Kiser, D L Fine, J Bader, R H
Shoemaker and M R Boyd: New soluble-formazan assay for HIV-1
cytopathic effects: application to high-flux screening of synthetic
and natural products for AIDS-antiviral activity. Journal of the
National Cancer Institute. 81(8):577-586, 1989.
[1646] Cells were incubated in the presence of drug for six days,
after which cell viability was measured using a dye reduction assay
(MTT) and determined as a CC50. This assay measures the
intracellular reducing activity present in actively respiring
cells.
[1647] Results
21TABLE 1 Biological Data Key for EC.sub.50s Compounds with
Compounds EC50 > 50 nM with but not yet Compounds Compounds*
EC.sub.50s > 1 .mu.M tested at higher with with EC.sub.50s >
5 .mu.M .mu.M but < 5 .mu.M concentrations EC50 < 1 .mu.M
Group C Group B Group A' Group A *Some of these compounds may have
been tested at a concentration lower than their EC.sub.50 but
showed some ability to cause inhibition and thus should be
evaluated at a higher concentration to determine the exact
EC.sub.50.
[1648] In Tables 2-5, X.sub.2, X.sub.4 etc. indicates the point of
attachment.
22TABLE 2 Examples 987 Table Entry (Example EC.sub.50 Group
Number.) R2 R3 R4 R9 A from Table 1 1 (Example 1) H H 988 CH.sub.3
989 A 2 (Example 2) H H 990 CH.sub.3 991 A 4 (Example 4) H H 992 H
993 A 5 (Example 5) H H 994 CH.sub.3 995 A 6 (Example 6) H H 996
CH.sub.3 997 A 7 (Example 7) H H 998 H 999 A 8 (Example 8) H H 1000
H 1001 A 9 (Example 9) H H 1002 CH.sub.3 1003 A 10 (Example 16) H H
1004 CH.sub.3 1005 A 11 (Example 17) H H 1006 H 1007 A 12 (Example
18) H H 1008 CH.sub.3 1009 A 13 (Example 10) H H 1010 H 1011 A 14
(Example 19) H H 1012 H 1013 A 15 (Example 11) H H 1014 H 1015 A'
16 (Example 20) H H 1016 CH.sub.3 1017 A 17 (Example 21) H H 1018 H
1019 A 18 (Example 22) OMe H 1020 H 1021 A 19 (Example 23) OMe H
1022 H 1023 A 20 (Example 24) OMe H 1024 H 1025 A 21 (Example 25)
OMe H 1026 H 1027 A 22 (Example 26) OMe H 1028 H 1029 A 23 (Example
27) OMe H 1030 H 1031 A 24 (Example 28) OMe H 1032 H 1033 A 25
(Example 29) F H 1034 H 1035 A 26 (Example 30) F H 1036 H 1037 A 27
(Example 15) OMe H 1038 H 1039 A 28 (Example 32) OMe H 1040 H 1041
A 29 (Example 33) H H 1042 Me 1043 A 30 (Example 34) H H 1044 H
1045 A 31 (Example 35) OMe H 1046 H 1047 A 32 (Example 36) OMe H
1048 H 1049 A 33 (Example 37) F H 1050 Me 1051 A 34 (Example 38) F
H 1052 H 1053 A 35 (Example 39) OMe H 1054 H 1055 A 36 (Example 40)
OMe H 1056 H 1057 A 37 (Example 41) F H 1058 Me 1059 A 38 (Example
42) F H 1060 H 1061 A 41 (Example 45) OMe H 1062 H 1063 A 42
(Example 46) OMe H 1064 H 1065 A 43 (Example 47) OMe H 1066 H 1067
A 45 (Example 49) OMe H 1068 H 1069 A 46 (Example 13) OMe H 1070 H
1071 A 47 (Example 55) OMe H 1072 H 1073 A 48 (Example 50) OMe H
1074 H 1075 A 49 (Example 14) OMe H 1076 H 1077 A 50 (Example 68)
OMe H 1078 H 1079 A 51 (Example 69) OMe H 1080 H 1081 A 52 (Example
70) OMe H 1082 H 1083 A 53 (Example 71) OMe H 1084 H 1085 A 54
(Example 72) OMe H 1086 H 1087 A 55 (Example 82) OMe H 1088 H 1089
A 56 (Example 73) OMe H 1090 H 1091 A 57 (Example 83) OMe H 1092 H
1093 A 58 (Example 84) OMe H 1094 H 1095 A 59 (Example 85) OMe H
1096 H 1097 A 60 (Example 74) OMe H 1098 H 1099 A 61 (Example 75)
OMe H 1100 H 1101 A 62 (Example 76) OMe H 1102 H 1103 A 63 (Example
77) OMe H 1104 H 1105 A 64 (Example 78) OMe H 1106 H 1107 A 65
(Example 80) OMe H 1108 H 1109 A 66 (Example 79) OMe H 1110 H 1111
A 67 (Example 87) OMe H 1112 H 1113 A 68 (Example 81) OMe H 1114 H
1115 A 69 (Example 88) OMe H 1116 H 1117 A 70 (Example 89) H H 1118
H 1119 A 71 (Example 90) OMe H 1120 H 1121 A 72 (Example 91) OMe H
1122 H 1123 A 72 (Example 92) OMe H 1124 H 1125 A 73 (Example 93)
OMe H 1126 H 1127 A 74 (Example 94) OMe H 1128 H 1129 A 75 (Example
95) OMe H 1130 H 1131 A 76 (Example 96) OMe H 1132 H 1133 A 77
(Example 97) OMe H 1134 H 1135 A 78 (Example 98) OMe H 1136 H 1137
A 79 (Example 99) OMe H 1138 H 1139 A 80 (Example 100) OMe H 1140 H
1141 A 81 (Example 101) OMe H 1142 H 1143 A 82 (Example 102) OMe H
1144 H 1145 A 83 (Example 103) OMe H 1146 H 1147 A 84 (Example 104)
OMe H 1148 H 1149 A 85 (Example 105) H H 1150 (R)-Me 1151 A 86
(Example 106) H H 1152 (S)-Me 1153 A 87 (Example 107) H H 1154
(R)-Me 1155 A 88 (Example 108) H H 1156 (S)-Me 1157 A 89 (Example
109) H H 1158 (R)-Me 1159 A 90 (Example 110) H H 1160 (S)-Me 1161 A
91 (Example 111) H H 1162 (R)-Me 1163 A 92 (Example 112) H H 1164
(R)-Me 1165 A 93 (Example 113) H H 1166 (R)-Me 1167 A 94 (Example
114) H H 1168 (R)-Me 1169 A 95 (Example 115) OMe H 1170 H 1171 A 96
(Example 116) OMe H 1172 H 1173 A 97 (Example 117) OMe H 1174 H
1175 A 98 (Example 118) OMe H 1176 H 1177 A 99 (Example 119) OMe H
1178 H 1179 A 100 (Example 120) OMe H 1180 H 1181 A 101 (Example
121) H H 1182 (R)-Me 1183 A 102 (Example 121-2) H H 1184 (R)-Me
1185 A 103 (Example 122) H H 1186 (R)-Me 1187 A 104 (Example 123) H
H 1188 (R)-Me 1189 A 105 (Example 124) H H 1190 (R)-Me 1191 A 106
(Example 125) F H 1192 H 1193 A 107 (Example 138) OMe H 1194 H 1195
A 108 (Example 139) Br H 1196 (R)-Me 1197 A 109 (Example 140) F H
1198 H 1199 A 110 (Example 141) F H 1200 (R)-Me 1201 A 111 112
(Example 143) Cl H 1202 H 1203 A 113 (Example 144) Cl H 1204 H 1205
A 114 (Example 145) F H 1206 H 1207 A 115 (Example 146) F H 1208 H
1209 A 116 (Example 147) F H 1210 H 1211 A 117 (Example 148) F H
1212 H 1213 A 118 (Example 149) Cl H 1214 H 1215 A 119 (Example
150) H H 1216 (R)-Me 1217 A 120 (Example 151) OMe H 1218 H 1219 A
121 (Example 152) Cl H 1220 H 1221 A 122 (Example 153) H H 1222
(R)-Me 1223 A 123 (Example 154) F H 1224 H 1225 A 124 (Example 155)
OMe H 1226 H 1227 A 125 (Example 156) OMe H 1228 H 1229 A 126
(Example 157) H H 1230 (R)-Me 1231 A 127 (Example 165) Cl H 1232 H
1233 A 128 (Example 166) F H 1234 H 1235 129 (Example 167) F H 1236
H 1237 130 (Example 162) H H 1238 (R)-Me 1239 A 131 (Example 163)
Cl H 1240 H 1241 A 132 (Example 164) H H 1242 (R)-Me 1243 A 133
(Example 169) OMe H 1244 H 1245 134 (Precursor 5t) OMe H 1246 H
1247 A 135 (Example 170) H H 1248 (R)-Me 1249 A 136 (Example 171)
OMe H 1250 H 1251 A 137 (Example 172) OMe H 1252 H 1253 A 138
(Example 173) OMe H 1254 H 1255 A 139 (Example 174) OMe H 1256 H
1257 A 140 (Example 175) OMe H 1258 H 1259 A 141 (Example 176) OMe
H 1260 H 1261 A 142 (Example 177) OMe H 1262 H 1263 A 143 (Example
178) OMe H 1264 H 1265 A 144 (Example 179) OMe H 1266 H 1267 A 145
(Example 180) OMe H 1268 H 1269 A 146 (Example 181) OMe H 1270 H
1271 A 147 (Example 182) OMe H 1272 H 1273 A 148 (Example 183) OMe
H 1274 H 1275 A 149 (Example 184) OMe H 1276 H 1277 A 150 (Example
185) OMe H 1278 H 1279 A 151 (Example 186) OMe H 1280 H 1281 A 152
(Example 187) OMe H 1282 H 1283 A 153 (Example 188) OMe H 1284 H
1285 A 154 (Example 189) OMe H 1286 H 1287 A 155 (Example 190) OMe
H 1288 H 1289 A 156 (Example 191) OMe H 1290 H 1291 A 157 (Example
192) OMe H 1292 H 1293 A 158 (Example 193) OMe H 1294 H 1295 A 159
(Example 195) OMe H 1296 H 1297 A 160 (Example 196) OMe H 1298 H
1299 A 161 (Example 197) OMe H 1300 H 1301 A 162 (Example 198) OMe
H 1302 H 1303 A 163 (Example 199) OMe H 1304 H 1305 A 164 (Example
200) OMe H 1306 H 1307 A 165 (Example 201) OMe H 1308 H 1309 A 166
(Example 209) F H 1310 H 1311 A 167 (Example 210) F H 1312 H 1313 A
168 (Example 211) F H 1314 H 1315 A 169 (Example 212) F H 1316 H
1317 A 170 (Example 213) F H 1318 H 1319 A 171 (Example 214) F H
1320 H 1321 A 172 (Example 215) F H 1322 H 1323 A 173 (Example 216)
F H 1324 H 1325 A 174 (Example 217) F H 1326 H 1327 A 175 (Example
218) F H 1328 H 1329 A 176 (Example 219) F H 1330 H 1331 A 177
(Example 220) F H 1332 H 1333 A 178 (Example 221) F H 1334 H 1335 A
179 (Example 222) F H 1336 H 1337 A 180 (Example 223) OMe H 1338 H
1339 A 181 (Example 224) OMe H 1340 H 1341 A 182 (Example 225) OMe
H 1342 H 1343 A 183 (Example 226) OMe H 1344 H 1345 A 185 (Example
240) OMe H 1346 H 1347 A 186 (Example 247) OMe H 1348 H 1349 A 187
(Example 248) OMe H 1350 H 1351 A 188 (Example 249) OMe H 1352 H
1353 A 189 (Example 250) OMe H 1354 H 1355 A 190 (Example 251) OMe
H 1356 H 1357 A 191 (Example 252) OMe H 1358 H 1359 A 192 (Example
264) OMe H 1360 H 1361 A 193 (Example 273) OMe H 1362 H 1363 A 194
(Example 274) OMe H 1364 H 1365 A 195 (Example 275) OMe H 1366 H
1367 A 196 (Example 276) OMe H 1368 H 1369 A 197 (Example 277) OMe
H 1370 H 1371 A 198 (Example 278) OMe H 1372 H 1373 A 199 (Example
279) OMe H 1374 H 1375 A 200 (Example 280) OMe H 1376 H 1377 A 201
(Example 281) OMe H 1378 H 1379 A 202 (Example 282) OMe H 1380 H
1381 A 203 (Example 283) OMe H 1382 H 1383 A 204 (Example 284) OMe
H 1384 H 1385 A 205 (Example 285) OMe H 1386 H 1387 A 206 (Example
286) OMe H 1388 H 1389 A 207 (Example 287) OMe H 1390 H 1391 A 208
(Example 288) OMe H 1392 H 1393 A 209 (Example 289) OMe H 1394 H
1395 A 210 (Example 290) OMe H 1396 H 1397 A 211 (Example 291) OMe
H 1398 H 1399 A 212 (Example 292) OMe H 1400 H 1401 A 213 (Example
293) OMe H 1402 H 1403 A 214 (Example 294) OMe H 1404 H 1405 A 215
(Example 295) OMe H 1406 H 1407 A 216 (Example 296) OMe H 1408 H
1409 A 217 (Example 297) OMe H 1410 H 1411 A 218 (Example 298) F H
1412 H 1413 A 219 (Example 299) F H 1414 H 1415 A 220 (Example 300)
F H 1416 H 1417 A 221 (Example 301) F H 1418 H 1419 A 222 (Example
303) F H 1420 H 1421 A 223 (Example 304) F H 1422 H 1423 A 223
(Example 305) F H 1424 H 1425 A 224 (Example 306) F H 1426 H 1427 A
225 (Example 307) F H 1428 H 1429 A 226 (Example 308) F H 1430 H
1431 A 227 (Example 309) F H 1432 H 1433 A 228 (Example 310) F H
1434 H 1435 A 229 (Example 311) F H 1436 H 1437 A 230 (Example 312)
F H 1438 H 1439 A 231 (Example 313) F H 1440 H 1441 A 232 (Example
316) MeO H 1442 H 1443 A 233 (Example 318) MeO H 1444 H 1445 A 234
(Example 319) MeO H 1446 H 1447 A 234 (Example 321) MeO H 1448 H
1449 A 235 (Example 323) MeO H 1450 H 1451 A 236 (Example 325) MeO
H 1452 H 1453 A 237 (Example 327) MeO H 1454 H 1455 A 238 (Example
329) MeO H 1456 H 1457 A 239 (Example 330) MeO H 1458 H 1459 A 240
(Example 331) MeO H 1460 H 1461 B 241 (Example 342) MeO H 1462 H
1463 A 242 (Example 341) MeO H 1464 H 1465 C 243 (Example 343) MeO
H 1466 H 1467 A 244 (Example 344) MeO H 1468 H 1469 A 245 (Example
346) MeO H 1470 H 1471 A 246 (Example 349) MeO H 1472 H 1473 A 247
(Example 351) MeO H 1474 H 1475 A
[1649]
23TABLE 2-1 1476 EC.sub.50 Table Entry Group (Example from Number.)
R2 R3 R4 R A Table 1 1 (Example 194) OMe H 1477 Me 1478 A 2
(Example 227) OMe H 1479 (R)--Me 1480 A 3 (Example 228) OMe H 1481
(S)--Me 1482 A 4 (Example 229) OMe H 1483 Et 1484 A 5 (Example 230)
OMe H 1485 (R)--Me 1486 A 6 (Example 231) OMe H 1487 (R)--Me 1488 A
7 (Example 232) OMe H 1489 (R)--Me 1490 A 7 (Example 233) OMe H
1491 (R)--Me 1492 A 8 (Example 234) OMe H 1493 (R)--Me 1494 A 8
(Example 235) OMe H 1495 (R)--Me 1496 A 9 (Example 236) OMe H 1497
(R)--Me 1498 A 10 (Example 237) OMe H 1499 (R)--Me 1500 A 11
(Example 238) OMe H 1501 (R)--Me 1502 A 12 (Example 239) OMe H 1503
(R)--Me 1504 A 13 (Example 241) OMe H 1505 (R)--Me 1506 A 14
(Example 242) OMe H 1507 (R)--Me 1508 A 15 (Example 243) OMe H 1509
(R)--Me 1510 A 16 (Example 244) OMe H 1511 (R)--Me 1512 A 17
(Example 245) OMe H 1513 (R)--Me 1514 A 18 (Example 246) OMe H 1515
(R)--Me 1516 A 19 (Example 253) OMe H 1517 (R)--Me 1518 A 20
(Example 254) OMe H 1519 (R)--Me 1520 A 21 (Example 255) OMe H 1521
(R)--Me 1522 A 22 (Example 256) OMe H 1523 (R)--Me 1524 A 23
(Example 257) OMe H 1525 (R)--Me 1526 A 24 (Example 258) OMe H 1527
(R)--Me 1528 A 25 (Example 259) OMe H 1529 (R)--Me 1530 A 26
(Example 260) OMe H 1531 (R)--Me 1532 A 27 (Example 261) OMe H 1533
(R)--Me 1534 A 28 (Example 262) OMe H 1535 (R)--Me 1536 A 29
(Example 263) OMe H 1537 (R)--Me 1538 A 30 (Example 265) OMe H 1539
(R)--Me 1540 A 31 (Example 266) OMe H 1541 (R)--Me 1542 A 32
(Example 267) OMe H 1543 (R)--Me 1544 A 33 (Example 268) OMe H 1545
(R)--Me 1546 A 34 (Example 269) OMe H 1547 (R)--Me 1548 A 35
(Example 270) OMe H 1549 (R)--Me 1550 A 36 (Example 271) OMe H 1551
(R)--Me 1552 A 37 (Example 272) OMe H 1553 (R)--Me 1554 A 38
(Example 314) F H 1555 (R)--Me 1556 A 39 (Example 315) F H 1557
(R)--Me 1558 A 40 (Example 317) OMe H 1559 (R)--Me 1560 A 41
(Example 322) MeO H 1561 (R)--Me 1562 A 42 (Example 324) MeO H 1563
(R)--Me 1564 A 43 (Example 326) MeO H 1565 (R)--Me 1566 A 44
(Example 328) MeO H 1567 (R)--Me 1568 A 45 (Example 334) MeO H 1569
(R)--Me 1570 A 46 (Example 335) MeO H 1571 (R)--Me 1572 A 47
(Example 336) MeO H 1573 (R)--Me 1574 A 48 (Example 337) MeO H 1575
(R)--Me 1576 A 49 (Example 338) MeO H 1577 (R)--Me 1578 A 50
(Example 339) MeO H 1579 (R)--Me 1580 A 51 (Example 340) MeO H 1581
(R)--Me 1582 A 52 (Example 341) MeO H 1583 (R)--Me 1584 A 53
(Example 345) MeO H 1585 (R)--Me 1586 A 54 (Example 347) MeO H 1587
(R)--Me 1588 A 55 (Example 348) MeO H 1589 (R)--Me 1590 A 56
(Example 350) MeO H 1591 (R)--Me 1592 A 57 (Example 352) MeO H 1593
(S)--Me 1594 A
[1650]
24TABLE 3 1595 EC.sub.50 Table Entry Group (Example from number) R2
R3 R4 R9 A Table 1 1 (Example 56) H H 1596 CH.sub.3 1597 B
[1651]
25TABLE 4 1598 EC.sub.50 Group Table Entry from (Example No.) R2 R3
R4 R9 A Table 1 1 (Example 65) H H 1599 H 1600 A 2 (Example 66) H H
1601 (S)--CH.sub.3 1602 A 3 (Example 67) H H 1603 (R)--Me 1604 A 4
(Example 57) H H 1605 (R)--Me 1606 A 6 (Example 64) Cl H 1607
(R)--Me 1608 A 7 (Example 58) Cl H 1609 (R)--Me 1610 A 8 (Example
60) Cl H 1611 (R)--Me 1612 A 9 (Example 61) Cl H 1613 (R)--Me 1614
A 10 (Example 62) Cl H 1615 (R)--Me 1616 A 11 (Example 63) Cl H
1617 (R)--Me 1618 A 12 13 (Example 51) H H 1619 (R)--Me 1620 A 14
(Example 52) H H 1621 (R)--Me 1622 A 15 (Example 53) H H 1623
(R)--Me 1624 A 16 (Example 54) H H 1625 (R)--Me 1626 A 17 (Example
86) H H 1627 (R)--Me 1628 A 18 (Example 126) H H 1629 (R)--Me 1630
A 19 (Example 127) H H 1631 (R)--Me 1632 A 20 (Example 128) H H
1633 (R)--Me 1634 A 21 (Example 129) H H 1635 (R)--Me 1636 A 22
(Example 130) H H 1637 (R)--Me 1638 A 23 (Example 131) H H 1639 H
1640 A 24 (Example 132) H H 1641 H 1642 A 25 (Example 133) H H 1643
H 1644 A 26 (Example 134) H H 1645 H 1646 A 27 (Example 135) H H
1647 (R)--Me 1648 A 28 (Example 136) H H 1649 (R)--Me 1650 A 29
(Example 137) H H 1651 (R)--Me 1652 A 30 (Example 158) H H 1653 H
1654 A 31 (Example 159) H H 1655 H 1656 A 32 (Example 160) H H 1657
H 1658 A 33 (Example 161) H H 1659 H 1660 A 34 (Example 202) H H
1661 H 1662 A 35 (Example 203) H H 1663 H 1664 A 36 (Example 204) H
H 1665 H 1666 A 37 (Example 168) H H 1667 H 1668 A 38 (Example 205)
H H 1669 H 1670 A 39 (Example 206) H H 1671 H 1672 A 40 (Example
207) H H 1673 H 1674 A 41 (Example 208) H H 1675 H 1676 A
[1652]
26TABLE 4-1 1677 EC.sub.50 Group Table Entry from (Example No.) R2
R3 R4 R9 A Table 1 1 (Example 353) H H 1678 H 1679 A 2 (Example
354) H H 1680 (S)--CH.sub.3 1681 A 3 (Example 355) H H 1682 (R)--Me
1683 A 4 (Example 356) H H 1684 (R)--Me 1685 A 6 (Example 357) Cl H
1686 (R)--Me 1687 A 7 (Example 358) Cl H 1688 (R)--Me 1689 A 8
(Example 359) Cl H 1690 (R)--Me 1691 A 9 (Example 360) Cl H 1692
(R)--Me 1693 A 10 (Example 361) Cl H 1694 (R)--Me 1695 A
[1653] Method for Extrapolating % Inhibition at 10 .mu.M
[1654] The compounds of Table 5 below were all found to be very
potent in the assay described above using % inhibition as a
criteria. In Table 5, X.sub.2, X.sub.4 etc. indicates the point of
attachment. The vast majority of the compounds exhibited greater
than 98% inhibition at a concentration of 10 .mu.M. The data at 10
.mu.M was calculated in the following manner:
[1655] Method for extrapolating % inhibition at 10 .mu.M
[1656] The data in Table 5 was obtained using the general
procedures above and by the following methods. Data is not reported
for all compounds since data for all the compounds is reported by
the alternate method in the previous Tables 1-4. The percent
inhibition for each compound was calculated by quantifying the
level of luciferase expression in cells infected in the presence of
compound as a percentage of that observed for cells infected in the
absence of compound and subtracting such a determined value from
100. For compounds tested at concentrations less than 10 .mu.M, the
percent inhibition at 10 .mu.M was determined by extrapolation
using the XLfit curve fitting feature of the Microsoft Excel
spreadsheet software. Curves were obtained from 10 data points (%
inhibition determined at 10 concentrations of compound) by using a
four parameter logistic model (XLfit model 205:
y=A+((B-A)/(1+((C/x).sup.D))), where, A=minimum y, B=maximum y,
C=logEC.sub.50, D=slope factor, and x and y are known data values.
Extrapolations were performed with the A and B parameters
unlocked.
[1657] Thus the compounds of this invention are all potent
antiviral inhibitors based on this assay.
27TABLE 5 1696 1697 Average % inhibition Compound # at 10 .mu.M
Precursor 8 85% Example 1 56%
[1658] Other Compounds of the Invention:
[1659] The 5-aza inhibitors shown in Table 6 should also be active
antiviral agents. They are also part of the invention and could be
prepared from precursors 1a or 2s or the corresponding
7-desbromo-7-chloro precursors which are prepared analogously and
the methods herein or by using other methods described herein.
28TABLE 6 1698 Table Entry (Example Number.) R2 R3 R4 R9 A 1 MeO H
1699 H 1700 2 MeO H 1701 H 1702 3 MeO H 1703 H 1704 4 MeO H 1705 H
1706
[1660] The compounds in the following Tables exemplify without
restriction some of the many additional inhibitors which could be
prepared by using methodology contained herein or exemplified in
the preparation of the compounds of the invention.
29TABLE 2a R2 R3 R4 R9 A OMe H 1707 H 1708 F H 1709 H 1710 Cl H
1711 H 1712 F H 1713 H 1714 OMe H 1715 H 1716 OMe H 1717 H 1718 F H
1719 H 1720 F H 1721 H 1722 F H 1723 H 1724 OMe H 1725 H 1726 F H
1727 H 1728 Cl H 1729 H 1730 Cl H 1731 (R)--Me 1732 F H 1733 H 1734
OMe H 1735 H 1736 OMe H 1737 H 1738 OMe H 1739 H 1740 OMe H 1741 H
1742 OMe H 1743 H 1744 OMe H 1745 H 1746 OMe H 1747 H 1748 OMe H
1749 H 1750 OMe H 1751 H 1752 OMe H 1753 H 1754 OMe H 1755 H 1756
OMe H 1757 H 1758 OMe H 1759 H 1760 H H 1761 (R)--Me 1762 OMe H
1763 H 1764 OMe H 1765 H 1766 OMe H 1767 H 1768 OMe H 1769 H 1770
OMe H 1771 H 1772 OMe H 1773 H 1774 OMe H 1775 H 1776 OMe H 1777 H
1778 OMe H 1779 H 1780 OMe H 1781 H 1782 OMe H 1783 H 1784 OMe H
1785 H 1786 OMe H 1787 H 1788 OMe H 1789 H 1790 OMe H 1791 H 1792
OMe H 1793 H 1794 OMe H 1795 H 1796 OMe H 1797 H 1798 OMe H 1799 H
1800 F H 1801 H 1802 F H 1803 H 1804 F H 1805 H 1806 OMe H 1807 H
1808 OMe H 1809 H 1810 OMe H 1811 H 1812 OMe H 1813 H 1814 OMe H
1815 H 1816 OMe H 1817 H 1818 OMe H 1819 H 1820 OMe H 1821 H 1822
OMe H 1823 H 1824 OMe H 1825 H 1826 OMe H 1827 H 1828 OMe H 1829 H
1830 OMe H 1831 H 1832 OMe H 1833 H 1834 OMe H 1835 H 1836 OMe H
1837 H 1838 OMe H 1839 H 1840 OMe H 1841 H 1842 OMe H 1843 H 1844
OMe H 1845 H 1846 OMe H 1847 H 1848 OMe H 1849 H 1850 OMe H 1851 H
1852 OMe H 1853 H 1854 OMe H 1855 H 1856 OMe H 1857 H 1858 OMe H
1859 H 1860 OMe H 1861 H 1862 OMe H 1863 H 1864 OMe H 1865 H 1866
OMe H 1867 H 1868 OMe H 1869 H 1870 OMe H 1871 H 1872 OMe H 1873 H
1874 OMe H 1875 H 1876 OMe H 1877 H 1878 OMe H 1879 H 1880 OMe H
1881 H 1882 OMe H 1883 H 1884 OMe H 1885 H 1886 OMe H 1887 H 1888
OMe H 1889 H 1890 OMe H 1891 H 1892 OMe H 1893 H 1894 OMe H 1895 H
1896 OMe H 1897 H 1898 OMe H 1899 H 1900 OMe H 1901 H 1902 OMe H
1903 H 1904 OMe H 1905 H 1906 OMe H 1907 H 1908 OMe H 1909 H 1910
OMe H 1911 H 1912 OMe H 1913 H 1914 OMe H 1915 H 1916 OMe H 1917 H
1918 OMe H 1919 H 1920 OMe H 1921 H 1922 OMe H 1923 H 1924 OMe H
1925 H 1926 OMe H 1927 H 1928 OMe H 1929 H 1930 OMe H 1931 H 1932
OMe H 1933 H 1934 OMe H 1935 H 1936 OMe H 1937 H 1938 OMe H 1939 H
1940 OMe H 1941 H 1942 OMe H 1943 H 1944 OMe H 1945 H 1946 OMe H
1947 H 1948 OMe H 1949 H 1950 OMe H 1951 H 1952 OMe H 1953 H 1954
OMe H 1955 H 1956 OMe H 1957 H 1958 OMe H 1959 H 1960 OMe H 1961 H
1962 OMe H 1963 H 1964 OMe H 1965 H 1966 OMe H 1967 H 1968 OMe H
1969 H 1970 OMe H 1971 H 1972 OMe H 1973 H 1974 OMe H 1975 H 1976
OMe H 1977 H 1978 OMe H 1979 H 1980 OMe H 1981 H 1982 OMe H 1983 H
1984 OMe H 1985 H 1986 OMe H 1987 H 1988 OMe H 1989 H 1990 OMe H
1991 H 1992 OMe H 1993 H 1994 OMe H 1995 H 1996 OMe H 1997 H 1998
OMe H 1999 H 2000 OMe H 2001 H 2002 OMe H 2003 H 2004 OMe H 2005 H
2006 OMe H 2007 H 2008 OMe H 2009 H 2010
[1661] The inhibitors in Table 4a could be prepared using analogous
procedures which were demonstrated to prepare the examples in Table
4.
30TABLE 4a 2011 Other inhibitors Table Entry R2 R3 R4 R9 A 1 H H
2012 H.sub.3 2013 2 H H 2014 H 2015 3 H H 2016 H 2017 4 H H 2018 H
2019 5 H H 2020 H 2021 6 H H 2022 H 2023 7 H H 2024 H 2025 8 H H
2026 H 2027 9 H H 2028 H 2029 2030 R2 R3 R4 R9 A OMe H 2031 (R) or
(S) Me 2032 F H 2033 (R) or (S) Me 2034 Cl H 2035 (R) or (S) Me
2036 F H 2037 (R) or (S) Me 2038 OMe H 2039 (R) or (S) Me 2040 OMe
H 2041 (R) or (S) Me 2042 F H 2043 (R) or (S) Me 2044 F H 2045 (R)
or (S) Me 2046 F H 2047 (R) or (S) Me 2048 OMe H 2049 (R) or (S) Me
2050 F H 2051 (R) or (S) Me 2052 Cl H 2053 (R) or (S) Me 2054 Cl H
2055 (R) or (S) Me 2056 F H 2057 (R) or (S) Me 2058 OMe H 2059 (R)
or (S) Me 2060 OMe H 2061 (R) or (S) Me 2062 OMe H 2063 (R) or (S)
Me 2064 OMe H 2065 (R) or (S) Me 2066 OMe H 2067 (R) or (S) Me 2068
OMe H 2069 (R) or (S) Me 2070 OMe H 2071 (R) or (S) Me 2072 OMe H
2073 (R) or (S) Me 2074 OMe H 2075 (R) or (S) Me 2076 OMe H 2077
(R) or (S) Me 2078 OMe H 2079 (R) or (S) Me 2080 OMe H 2081 (R) or
(S) Me 2082 OMe H 2083 (R) or (S) Me 2084 H H 2085 (R) or (S) Me
2086 OMe H 2087 (R) or (S) Me 2088 OMe H 2089 (R) or (S) Me 2090
OMe H 2091 (R) or (S) Me 2092 OMe H 2093 (R) or (S) Me 2094 OMe H
2095 (R) or (S) Me 2096 OMe H 2097 (R) or (S) Me 2098 OMe H 2099
(R) or (S) Me 2100 OMe H 2101 (R) or (S) Me 2102 OMe H 2103 (R) or
(S) Me 2104 OMe H 2105 (R) or (S) Me 2106 OMe H 2107 (R) or (S) Me
2108 OMe H 2109 (R) or (S) Me 2110 OMe H 2111 (R) or (S) Me 2112
OMe H 2113 (R) or (S) Me 2114 OMe H 2115 (R) or (S) Me 2116 OMe H
2117 (R) or (S) Me 2118 OMe H 2119 (R) or (S) Me 2120 OMe H 2121
(R) or (S) Me 2122 OMe H 2123 (R) or (S) Me 2124 F H 2125 (R) or
(S) Me 2126 F H 2127 (R) or (S) Me 2128 F H 2129 (R) or (S) Me 2130
OMe H 2131 (R) or (S) Me 2132 OMe H 2133 (R) or (S) Me 2134 OMe H
2135 (R) or (S) Me 2136 OMe H 2137 (R) or (S) Me 2138 OMe H 2139
(R) or (S) Me 2140 OMe H 2141 (R) or (S) Me 2142 OMe H 2143 (R) or
(S) Me 2144 OMe H 2145 (R) or (S) Me 2146 OMe H 2147 (R) or (S) Me
2148 OMe H 2149 (R) or (S) Me 2150 OMe H 2151 (R) or (S) Me 2152
OMe H 2153 (R) or (S) Me 2154 OMe H 2155 (R) or (S) Me 2156 OMe H
2157 (R) or (S) Me 2158 OMe H 2159 (R) or (S) Me 2160 OMe H 2161
(R) or (S) Me 2162 OMe H 2163 (R) or (S) Me 2164 OMe H 2165 (R) or
(S) Me 2166 OMe H 2167 (R) or (S) Me 2168 OMe H 2169 (R) or (S) Me
2170 OMe H 2171 (R) or (S) Me 2172 OMe H 2173 (R) or (S) Me 2174
OMe H 2175 (R) or (S) Me 2176 OMe H 2177 (R) or (S) Me 2178 OMe H
2179 (R) or (S) Me 2180 OMe H 2181 (R) or (S) Me 2182 OMe H 2183
(R) or (S) Me 2184 OMe H 2185 (R) or (S) Me 2186 F H 2187 (R) or
(S) Me 2188 F H 2189 (R) or (S) Me 2190 F H 2191 (R) or (S) Me 2192
F H 2193 (R) or (S) Me 2194 OMe H 2195 (R) or (S) Me 2196 OMe H
2197 (R) or (S) Me 2198 OMe H 2199 (R) or (S) Me 2200 OMe H 2201
(R) or (S) Me 2202 OMe H 2203 (R) or (S) Me 2204 OMe H 2205 (R) or
(S) Me 2206 OMe H 2207 (R) or (S) Me 2208 OMe H 2209 (R) or (S) Me
2210 OMe H 2211 (R) or (S) Me 2212 OMe H 2213 (R) or (S) Me 2214
OMe H 2215 (R) or (S) Me 2216 OMe H 2217 (R) or (S) Me 2218 OMe H
2219 (R) or (S) Me 2220 OMe H 2221 (R) or (S) Me 2222 OMe H 2223
(R) or (S) Me 2224 OMe H 2225 (R) or (S) Me 2226 OMe H 2227 (R) or
(S) Me 2228 OMe H 2229 (R) or (S) Me 2230 OMe H 2231 (R) or (S) Me
2232 OMe H 2233 (R) or (S) Me 2234 OMe H 2235 (R) or (S) Me 2236
OMe H 2237 (R) or (S) Me 2238 OMe H 2239 (R) or (S) Me 2240 OMe H
2241 (R) or (S) Me 2242 OMe H 2243 (R) or (S) Me 2244 OMe H 2245
(R) or (S) Me 2246 OMe H 2247 (R) or (S) Me 2248 OMe H 2249 (R) or
(S) Me 2250 OMe H 2251 (R) or (S) Me 2252 OMe H 2253 (R) or (S) Me
2254 OMe H 2255 (R) or (S) Me 2256 OMe H 2257 (R) or (S) Me 2258
OMe H 2259 (R) or (S) Me 2260 OMe H 2261 (R) or (S) Me 2262 OMe H
2263 (R) or (S) Me 2264 OMe H 2265 (R) or (S) Me 2266 OMe H 2267
(R) or (S) Me 2268 OMe H 2269 (R) or (S) Me 2270 OMe H 2271 (R) or
(S) Me 2272 OMe H 2273 (R) or (S) Me 2274 OMe H 2275 (R) or (S) Me
2276 OMe H 2277 (R) or (S) Me 2278 OMe H 2279 (R) or (S) Me 2280
OMe H 2281 (R) or (S) Me 2282 OMe H 2283 (R) or (S) Me 2284 OMe H
2285 (R) or (S) Me 2286 OMe H 2287 (R) or (S) Me 2288 OMe H 2289
(R) or (S) Me 2290 OMe H 2291 (R) or (S) Me 2292 OMe H 2293 (R) or
(S) Me 2294 OMe H 2295 (R) or (S) Me 2296 OMe H 2297 (R) or (S) Me
2298 OMe H 2299 (R) or (S) Me 2300 OMe H 2301 (R) or (S) Me 2302
OMe H 2303 (R) or (S) Me 2304 OMe H 2305 (R) or (S) Me 2306 OMe H
2307 (R) or (S) Me 2308 OMe H 2309 (R) or (S) Me 2310 OMe H 2311
(R) or (S) Me 2312 OMe H 2313 (R) or (S) Me 2314 OMe H 2315 (R) or
(S) Me 2316 OMe H 2317 (R) or (S) Me 2318 OMe H 2319 (R) or (S) Me
2320 OMe H 2321 (R) or (S) Me 2322 OMe H 2323 (R) or (S) Me 2324
OMe H 2325 (R) or (S) Me 2326 OMe H 2327 (R) or (S) Me 2328 OMe H
2329 (R) or (S) Me 2330 OMe H 2331 (R) or (S) Me 2332 OMe H 2333
(R) or (S) Me 2334 OMe H 2335 (R) or (S) Me 2336 OMe H 2337 (R) or
(S) Me 2338 OMe H 2339 (R) or (S) Me 2340 OMe H 2341 (R) or (S) Me
2342 OMe H 2343 (R) or (S) Me 2344 OMe H 2345 (R) or (S) Me 2346
OMe H 2347 (R) or (S) Me 2348 OMe H 2349 (R) or (S) Me 2350 2351
Other inhibitors R4 R9 A 2352 (R) or (S) Me 2353 2354 (R) or (S) Me
2355 2356 (R) or (S) Me 2357 2358 (R) or (S) Me 2359 2360 (R) or
(S) Me 2361 2362 (R) or (S) Me 2363 2364 (R) or (S) Me 2365 2366
(R) or (S) Me 2367
[1662] Metabolic Stability Studies of compounds in Liver
Microsomes. The metabolic stability of compounds were investigated
in pooled liver microsomes from humans. The human liver microsomes
were obtained from BD Gentest (Lot #16, Woburn, MA) with a protein
concentration of 20 mg/ml and a total cytochrome P450 (CYP)
concentration of 0.55 nmol/mg protein.
[1663] A stock solution of drug was prepared in acetonitrile at 1
mM. An aliquot of the stock solution was added to the incubation
media to give a final concentration of 3 .mu.M of drug, and the
acetonitrile concentration not exceeding 1% in the incubation. The
incubation media consisted of potassium phosphate buffer (0.1 M, pH
7.4), liver microsomes (final concentration 0.9 mg/ml), magnesium
chloride (0.033 mM), and a NADPH-regenerating system. The cofactors
of the NADPH-regenerating system consisted of NADPH (final
concentration 0.425 mg/ml), glucose-6-phosphate (final
concentration 0.512 mg/ml), and glucose-6-phosphate dehydrogenase
(final concentration 0.6 unit/ml). The test compound was
pre-incubated in the media for 2 min. The reaction was initiated by
the addition of the cofactors. The incubation was carried out at
37.degree. C. for 10 min. The reaction was terminated by drawing an
aliquot of 100 .mu.L from the incubation and adding into 200 .mu.L
of acetonitrile containing a reference compound as an external
analytical standard. Following vortex-mixing and centrifugation, an
aliquot of 10 .mu.L of the supernatant was analyzed by LC/MS.
[1664] GUIDELINES can be used to categorized test substances as
low, intermediate or highly cleared compounds.
31 Rate (nmol/min/mg) Clearance Estimate 0-0.100 Low 0.101-0.200
Intermediate 0.201-0.300 High
[1665] Rat Pharmacokinetic Studies:
[1666] For the IV and PO pharmacokinetic studies of compounds in
rats, the compound was dissolved in PEG-400/ethanol (90/10) as a
solution.
[1667] Rat. Male Sprague-Dawley rats (300-350 g, Hilltop Lab
Animals, Inc., Scottdale, Pa.) with cannulas implanted in the
jugular vein were used. The rats were fasted overnight in the PO
pharmacokinetic studies. Blood samples of 0.3 ml were collected
from the jugular vein in EDTA-containing microtainer tubes (Becton
Dickinson, Franklin Lakes, N.J.), and centrifuged to separate
plasma.
[1668] In the IV study, the test compound was delivered at 1 mg/kg
as a bolus over 0.5 min (n=3). Serial blood samples were collected
before dosing and 2, 10, 15, 30, 45, 60, 120, 240, 360, 480, and
1440 min after dosing.
[1669] In the PO study of the test compound, the rats (n=3)
received an oral dose of 5 mg/kg of BMS-585248. Serial blood
samples were collected before dosing and 15, 30, 45, 60, 120, 240,
360, 480, and 1440 min after dosing.
[1670] Quantitation of Compounds in Plasma. Aliquots of plasma
samples from rat, studies were prepared for analysis by
precipitating plasma proteins with two volumes of acetonitrile
containing an internal standard of a similar compound. The
resulting supernates were separated from the precipitated proteins
by centrifugation for 10 minutes and transferred to autosampler
vials. Samples were either prepared manually, or with the use of
the Tomtec automated liquid handler.. An aliquot of 5 .mu.L was
injected for analysis.
[1671] The HPLC system consisted of two Shimadzu LC1OAD pumps
(Columbia, Md.), a Shimadzu SIL-HTC autosampler (Columbia, Md.),
and a Hewlett Packard Series 1100 column compartment (Palo Alto,
Calif.). The column was a YMC Pro C18 (2.0.times.50 mm, 3 .mu.m
particles, Waters Co., Milford, Mass.), maintained at 60.degree. C.
and a flow rate of 0.3 mil/min. The mobile phase consisted of 10 mM
ammonium formate and 0.1% formic acid in water (A) and 100% 10 mM
ammonium formate and 0.1% formic acid in methanol (B). The initial
mobile phase composition was 95% A. After sample injection, the
mobile phase was changed to 15% A/85% B over 2 minutes and held at
that composition for an additional 1 minute. The mobile phase was
then returned to initial conditions and the column re-equilibrated
for 1 minute. Total analysis time was 4 minutes.
[1672] The HPLC was interfaced to a Micromass Quattro LC. Ultra
high purity nitrogen was used as the nebulizing and desolvation gas
at flow rates of 100 L/hr for nebulization and 1100 L/hr for
desolvation. The desolvation temperature was 300.degree. C. and the
source temperature was 150.degree. C. Data acquisition utilized
selected reaction monitoring (SRM). Ions representing the
(M+H).sup.+ species for the compound and the internal standard were
selected in MS1 and collisionally dissociated with argon at a
pressure of 2.times.10.sup.-3 torr to form specific product ions
which were subsequently monitored by MS2.
[1673] The compounds of the present invention may be administered
orally, parenterally (including subcutaneous injections,
intravenous, intramuscular, intrasternal injection or infusion
techniques), by inhalation spray, or rectally, in dosage unit
formulations containing conventional non-toxic
pharmaceutically-acceptable carriers, adjuvants and vehicles.
[1674] Thus, in accordance with the present invention there is
further provided a method of treating and a pharmaceutical
composition for treating viral infections such as HIV infection and
AIDS. The treatment involves administering to a patient in need of
such treatment a pharmaceutical composition comprising a
pharmaceutical carrier and a therapeutically-effective amount of a
compound of the present invention.
[1675] The pharmaceutical composition may be in the form of
orally-administrable suspensions or tablets; nasal sprays, sterile
injectable preparations, for example, as sterile injectable aqueous
or oleagenous suspensions or suppositories.
[1676] When administered orally as a suspension, these compositions
are prepared according to techniques well-known in the art of
pharmaceutical formulation and may contain microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweetners/flavoring agents known in the art. As immediate release
tablets, these compositions may contain microcrystalline cellulose,
dicalcium phosphate, starch, magnesium stearate and lactose and/or
other excipients, binders, extenders, disintegrants, diluents and
lubricants known in the art.
[1677] The injectable solutions or suspensions may be formulated
according to known art, using suitable non-toxic,
parenterally-acceptable diluents or solvents, such as mannitol,
1,3-butanediol, water, Ringer's solution or isotonic sodium
chloride solution, or suitable dispersing or wetting and suspending
agents, such as sterile, bland, fixed oils, including synthetic
mono- or diglycerides, and fatty acids, including oleic acid.
[1678] The compounds of this invention can be administered orally
to humans in a dosage range of 1 to 100 mg/kg body weight in
divided doses. One preferred dosage range is 1 to 10 mg/kg body
weight orally in divided doses. Another preferred dosage range is 1
to 20 mg/kg body weight orally in divided doses. It will be
understood, however, that the specific dose level and frequency of
dosage for any particular patient may be varied and will depend
upon a variety of factors including the activity of the specific
compound employed, the metabolic stability and length of action of
that compound, the age, body weight, general health, sex, diet,
mode and time of administration, rate of excretion, drug
combination, the severity of the particular condition, and the host
undergoing therapy.
[1679] Scheme 41a depicts methodology for converting a carboxylic
acid to an alkynyl ketone. The alkynyl ketone precursors can then
be converted to pyrazoles or isoxazoles upon reaction with
hydrazines or hydroxyl amines, respectively.
[1680] The invention is intended to cover isomers, diasteroisomers,
stereoisomers, and enantiomers of the depicted formulas when one or
more asymmetric carbons are present in the molecules. An asymmetric
carbon is one in which the carbon is attached to four different
substitutions. In particular, the invention is intended to cover
isomers or a single enantiomer especially when one enantiomer
displays superior properties. Enantiomers differ from one another
in that the spacial arrangement of the substituents around the
chiral centers of the asymmetric carbons result in each molecule
being a nonsuperimposable mirror image of the other. In this
application, the configuration of the substituents around an
asymmetric carbon are defined unambiguously as either (R) which is
a standard representation which stands for Latin rectus, right or
(S) which is the standard representation for Latin sinister, left
in the Cahn-Ingold-Prelog nomenclature system which has been in use
since the 1960s. Standard rules for defining the configuration of
these centers are found in any basic organic chemistry textbook. In
particular, for this application and based on initial examples,
when W contains a single methyl group as depicted below, when the
carbon bearing the methyl group is in the (R) configuration it may
show a potency advantage over the (S) enantiomer. Occasionally the
(R)-methyl piperazine may show a potency advantage over the
unsubstituted piperazine. These observations are compound specific
effect and are not always present. The unsubstituted piperazine and
(S) enantiomers are still potent antiviral compounds despite
occasionally being less potent than the (R) enantiomer. 2368
[1681] When the configuration of a methyl piperazine shown as below
is (R) the methyl group may improve the metabolic stability of the
adjacent amide as compared to the (S) methyl piperazine or the
unsubstituted piperazine. However, the metabolic stability of the
amide bond is compound specific and a methyl substituent is not
necessarily required for optimal properties. 2369
[1682] It has now also been surprisingly found that compounds of
Formula Ia, in which specifically R.sub.4 is an N-linked triazolyl
group, attached at the 1-nitrogen position, are particularly
effective for inhibiting HIV. This is discussed more fully
below.
[1683] The effective treatment of HIV and other viruses requires
compounds that are potent inhibitors of the virus, are selective
for the virus, and have the properties which allow them to safely
achieve and maintain plasma level concentrations which are a
maximum number multiples above the concentration required to
minimally inhibit the virus. Higher exposures suppress viral
replication and reduced rates of replication mean that strains of
virus with resistance to the drug treatment will develop at a
slower rate. Potent drugs exhibit equivalent activity from a lower
concentration or lower dose than that needed to achieve the same
effect from a less potent drug. Drugs which intrinsically produce
higher exposures from an equivalent dose in animal models or
patients (as determined by pharmacokinetic measurements such as AUC
(the sum of the concentration of drug over a particular time),
Cmax, or Cmin will also provide greater benefit to the patient.
Drugs which have higher stability in the presence of metabolizing
pathways and enzymes will maintain their concentrations longer and
thus require less frequent dosing or dosing of smaller quantities.
In animals or people the rate of clearance is a frequently measured
parameter to assess this property but mean retention time is also
used. For accuracy, the determined measure of viral inhibition is
an EC50; but the minimum plasma concentrations which should be
maintained in a patient is generally believed to be at least four
or five fold higher. Thus the antiviral or anti HIV drug candidates
which will be most likely to provide maximum benefits in patients
and those that preclinical research programs strive to identify
will exhibit 1) maximum potency 2) no general cytotoxicity vs the
cell line used for the assay 3) low predicted rates of metabolism
in human based on in vitro models 4) high exposure after oral
dosing. Many other properties of potential drug candidates are
evaluated in order to determine which compounds will have the best
chance of showing optimal utility in human patients but the
compounds of this invention were evaluated initially in part by
determining:
[1684] 1) Potency vs HIV as determined by an EC50 in an initial
pseudotype assay as described in the biology section.
[1685] 2) Lack of general cytotoxicity vs a Hela cell line. >100
uM was used as an arbitrary cut off for safety.
[1686] 3) Measurement of the rate of metabolism vs human liver
microsomal preparations and from this data projecting human rate of
clearance. Lower is better.
[1687] 4) Estimating potential exposure in man by measuring
parameters such as AUC and rate of clearance by oral and iv dosing
in rats. High exposure and low clearance was desired.
[1688] Aazaindole oxoacetic piperazine amides have been disclosed
in two series of patent applications. The first series discloses
azaindole derivatives which have promising potential as antiviral
agents (hereinafter called, reference 94) Wang, Tao et al, U.S.
Pat. No. 6,476,034 and WO 0162255 A1, filed Jan. 19, 2001,
published Aug. 30, 2001. The second series (hereinafter called,
reference 106) Wang, Tao, et al discloses HIV Antiviral Activity of
Substituted Azaindoleoxoacetic Piperazine Derivatives in U.S.
patent application Ser. No. 10/214,982 filed Aug. 7, 2002, which is
a continuation-in-part application of U.S. Ser. No. 10/038,306
filed Jan. 2, 2002 (corresponding to PCT Int. Appl.
(PCT/US02/00455), WO 02/062423 A1, filed Jan. 2, 2002, published
Aug. 15, 2002. All of the references for these two series are
incorporated by reference herein. Reference 106 describes in part
C-7 heteroaryl, aryl or substituted 4,5,6, or 7-azaindoles as
antiviral agents and is the most relevant prior art.
[1689] We have evaluated the properties of many compounds covered
within the scope of references 94 and 106 and have found that the
compounds having C-7, N-linked triazole groups are surprisingly and
unexpectedly superior.
[1690] We initially evaluated compounds to determine which showed
maximum potency or the lowest EC50 using the pseudotype assay
described in the biology section of this application. In our case
compounds with EC50s less than 0.20 nM were considered of most
interest since this covered the most potent compounds and accounted
for assay variability of our initial screen. The stability of
compounds were also evaluated to determine metabolic stability when
incubated in in vitro preparations of human liver microsomes (HLM).
This is one commonly used predictive system for evaluating the
potential for human metabolism and projecting clearance rates in
man. Compounds with low clearance rates were most desireable.
Intermediate and high clearance compounds would be more likely to
have difficulty achieving feasible dosing regimen's in man vs low
clearance compounds. Compounds for which accurate determinations
could not be made were also not advanced.
[1691] Surprisingly, when the most promising compounds from the
potency and metabolic stability criterias were evaluated in rats to
measure their pharmacokinetic properties, one class of C-7
substituents, N linked triazoles of Formula Ia showed very low
clearance and very high AUCs (exposure) when compared to the
compounds of references 94 and 106.
[1692] The compounds I having Formula Ia are described below:
2370
[1693] wherein:
[1694] R.sup.2 is methoxy, fluoro or chloro; 2371
[1695] D is hydrogen or C.sub.1-C.sub.3 alkyl;
[1696] E is selected from the group consisting of hydrogen,
(C.sub.1-C.sub.3)alkyl, O(C.sub.1-C.sub.3)alkyl or
CH.sub.2OCH.sub.3.
[1697] R.sup.11 is either hydrogen or methyl in which the
configuration to which the methyl is attached is (R) with the
proviso that when R.sup.4 is 1,2,3-triazole, then R.sup.11 is
hydrogen.
[1698] The C-7 N-linked triazoles thus showed surprising properties
as they were essentially equivalent in potency to the most potent
compounds covered by references 94 and 106 that we have evaluated
to date. They showed metabolic stability in human liver microsomes
that was equivalent to the best compounds from the application.
Unexpectedly, they showed clearance rates in rats that were much
lower, usually 10 fold lower than the best compounds from those
described in the applications of reference 94 and were the best of
any compounds evaluated in reference 106. Even more surprisingly,
they were the only class of compounds to show significantly
increased exposure in rats as shown by their AUCs.
[1699] In summation, these N-linked triazoles exhibited a
surprising combination of properties that would not be obvious to
one skilled in the art relying on the disclosure of references 94
and 106. Only a single triazole is disclosed in WO 02/06423. This
compound has an R.sup.4 substiuent which is a C-linked triazole,
and not an N-linked triazole, and exhibited potency which was not
comparable to the N-linked triazoles. No N-linked triazoles were
described in the examples of the published PCT application from
reference 106.
[1700] The following data tables summarize the potency, predicted
human clearance based on human liver microsomes, and the AUC and
clearance determined by pharmacokinetic studies in rats for these
N-linked triazoles of the invention herein compared with
representative compounds and close analogs contained in PCT
application WO 02/062423 A1, filed Jan. 2, 2002, published Aug. 15,
2002 and the published applications and patents contained in
reference 94. As seen in the following tables the N linked
triazoles herein identified as most preferred groups exhibit
surprising superiority especially in terms of displaying maximum
potency, metabolic stability equivalent to best in class and
uniquely a high AUC (exposure) and low clearance in rats which is
determined by oral and iv dosing at 5 mg/kg and 1 mg/kg
respectively. The rat model is an initial model used to assess
potential for exposure in man.
[1701] The utility of compounds in the triazole class is
surprisingly very dependent on the substituion patterns as
depicted. For example the 1,2,3 triazoles attached at the
2-position nitrogen atom have to date shown significantly reduced
AUC (exposure) in rats compared to the compounds depicted. In
addition, moving the E group when E is methyl, in the
1,2,4-N-linked triazole from position 3 to 5 provides compounds
with significantly reduced potency. As can be seen in Table A2, the
N-linked triazoles specified showed high potency in an initial
antiviral assay.
[1702] As evidenced by Tables A3-A8 of Comparator compounds, the
metabolic stability of the N-linked triazole compounds Ia of the
invention is surprisingly equivalent to or better than any of the
compounds covered in either series of published azaindole
applications (i.e. references 94 and 106).
[1703] As dramatically shown in the tables, the low clearance and
high exposure seen in rats for the compounds in table A2 was
surprising and unexpected since the prior art taught compounds did
not exhibit these properties as one would have expected.
[1704] In the tables that follow these terms have the following in
meanings: "NT" meant not tested.
[1705] "Difficulties" means results could not be interpreted (i.e.
in HLM test).
[1706] Result
32TABLE A1 Biological Data Key for EC.sub.50s in Tables A2-A7
Compounds Compounds* with EC.sub.50s > 0.2 Compounds with with
EC.sub.50s > 1 .mu.M nM but < 1 .mu.M EC50 .ltoreq. 0.20 nM
Group 3 Group 2 Group 1
[1707]
33TABLE A2 N linked Triazoles as R4 with Surprising Superior
Properties HLM predicted CC50 > human Example EC50 100 clearance
AUC 24 h CL, iv Number category uM class (ug .multidot. hr/mL)
(mL/min/kg) 216 1 Yes Low 32 .+-. 12 1.6 .+-. 0.2 188 1 Yes Low 20
.+-. 4.6 2.4 .+-. 0.08 187 1 Yes Low 22.4 .+-. 7.2 2.4 .+-. 0.5
215, 303 1 Yes Low 83.7 .+-. 9.8 0.7 .+-. 0.12 245 1 Yes Low 12.1
.+-. 1.3 5.6 .+-. 1.8 313 1 Yes Low 316 1 Yes Low 52 .+-. 12 1.3
.+-. 0.19 317 1 Yes Low 43 .+-. 12 1.9 .+-. 0.26 306 1 Yes Low 160
.+-. 11 0.39 .+-. 0.07 321 1 Yes Low 322 1 Yes Low 82 .+-. 23 1.8
.+-. 0.4 314 1 Yes Low 315 1 Yes Low 352 1 Yes Low 325 1 Yes Low
326 1 Yes Low 9.8 .+-. 2.9 8.3 274 1 Yes Low 273 1 Yes Low 324 1
Yes Low 275 1 Yes Low
[1708]
34TABLE A3 Some Other Alternatively Substituted N linked Triazoles
at R4 as Comparators HLM predicted CC50 > human Example EC50 100
clearance AUC 24 h CL, iv Number category uM class (ug .multidot.
hr/mL) (mL/min/kg) 217 2 Yes NT NT NT 307 2 Yes NT NT NT 256 2 Yes
NT NT NT 350 2 Yes Low NT NT 327 2 Yes Low NT NT 328 1 Yes Low NT
NT 351 NT NT Low 1.5 .+-. 0.14 16.6 .+-. 1.4
[1709]
35TABLE A4 Some Other Relevant N linked Heteroaryls at R4 as
Comparators HLM predicted Example EC50 CC50 > human clearance
AUC 24 h CL, iv Number category 100 uM class (ug .multidot. hr/mL)
(mL/min/kg) 139 2 Yes High 219, 305 1 Yes High 193 1 No Low 14 .+-.
8 4.5 .+-. 0.4 189 2 Yes Low 222 2 Yes Low 221 2 Yes Low 220 2 Yes
NT 218, 304 2 Yes Low 190 1 Yes Low 7.4 .+-. 3.4* 3.7 .+-. 1.0 191
2 Yes NT 309 1 Yes Low 0.09 .+-. 0.05 34.3 .+-. 2.6 318 2 Yes Low
310 1 Yes Low 2.1 .+-. 0.4* 16.5 .+-. 3.3 241 1 Yes Low 6.4 .+-.
4.2* 11.2 .+-. 0.9 312 2 Yes Low 241 1 Yes Low 0.0086 .+-. 0.005**
131 .+-. 4.3 236 1 Yes Low 0.56 .+-. 0.25 29 .+-. 6.7 251 1 Yes Low
230 1 Yes Intermediate 343 1 Yes Low 344 2 No Low 276 1 Yes NT 255
1 Yes Intermediate 258 1 Yes Low 314 1 Yes Low 315 1 Yes Low 352 1
Yes Low 326 1 Yes Low 9.8 .+-. 2.9 8.3 274 1 Yes 273 1 Yes 275 1
Yes
[1710]
36TABLE A5 Some Relevant C linked Heteroaryl Comparators HLM
predicted EC50 CC50 > human clearance AUC 24 h CL, iv Example
Number category 100 uM class (ug .multidot. hr/mL) (mL/min/kg) 40 2
No Low 42 2 Yes Low 22 1 No Intermediate 35 1 Yes Intermediate 37 1
No NT 38 1 No Low 39 2 No Intermediate 28 3 No NT 29 2 No High 22 2
No High 74 2 No Intermediate 71 1 Yes Intermediate 73 1 Yes
Intermediate 78 2 Yes Intermediate 94 1 Yes NT 102 2 Yes Low 6.9
.+-. 1.3 12 .+-. 5.5 163 2 Yes Difficulties 95 1 Yes Intermediate
140 2 Yes Intermediate 146 2 Yes Intermediate 145 1 Yes
Difficulties 12 .+-. 3.8 1.4 .+-. 0.29 148 2 Yes NT 210 1 Yes
Intermediate 211 1 No Intermediate 212 1 Yes Low 223 2 Yes Low 224
2 Yes Low 225 2 Yes NT 227 2 Yes Low 3.8 .+-. 0.83 8.8 .+-. 3.7 226
1 Yes Low 0.5 .+-. 0.13* 24.5 .+-. 3 299 1 No Low 300 2 Yes Low 266
1 Yes Low 0.16 .+-. 0.04* 37.4 .+-. 3.2 345 2 Yes Low 301 2 Yes NT
346 2 Yes NT 347 2 Yes Low 334 2 Yes NT 348 2 Yes Low 349 2 Yes NT
342 1 Yes Low
[1711]
37TABLE A6 Some Relevant 4-azaindole Comparators and data HLM
predicted Example EC50 CC50 human clearance AUC 24 h CL, iv Number
category >100 uM class (ug .multidot. hr/mL) (mL/min/kg) 204 2
Yes Low 1.2 .+-. 1.4 1.0 .+-. 1.3 161 1 Yes High 205 2 Yes Low 9.6
.+-. 1.2 5.4 .+-. 0.4 207 2 Yes Low 206 2 Yes NT 208 2 Yes NT 353 2
Yes Low 1363 .+-. 307 5.6 .+-. 1.1* 354 2 Yes Low 1.26 11.2 .+-.
0.8 0.18* 355 2 Yes Low 3.3 .+-. 0.77* 13.9 .+-. 5.3 356 2 Yes Low
357 2 Yes Intermediate 358 2 Yes High 359 2 Yes NT 360 2 Yes Low
361 2 Yes NT
[1712]
38TABLE A7 Some Relevant Comparators and data from U.S. Pat. No.
6476034 (Reference 94) HLM Reference predicted Com- EC50 CC50 >
human pound cate- 100 clearance AUC 24 h CL, iv Number gory uM?
class (ug .multidot. hr/mL) (mL/min/kg) 1 2 Yes Low 0.5 32 .+-. 1.8
2 2 Yes Intermediate 3 2 Yes Low 6.3 .+-. 2.7 13 .+-. 4.0 4 2 Yes
Low 5 1 Yes Intermediate 6 2 Yes Low 1.7 .+-. 0.58 31 .+-. 5.9 7 1
Yes Low 2.6 .+-. 0.12* 19.3 .+-. 0.65 8 1 Yes Low 1.03 .+-. 0.07*
47.2 .+-. 11.5 9 2 Yes Low 5.9 .+-. 2.2 5.9 .+-. 2.2 10 2 Yes Low
2.9 .+-. 0.3 11.7 .+-. 1.0 11 1 Yes 1.4 .+-. 0.2* 24.8 .+-. 0.41 12
1 Yes Low 4.7 .+-. 1.1 11.9 .+-. 1.8 13 2 Yes NT
[1713] Structures of Reference Compounds as a Key for Table A7
2372
39TABLE A8 (Reference compounds structures 2-9) 2373 Reference
Compound Number R2 R3 R4 R9 A 2 OMe H X.sub.2--OMe (R)--Me 2374 3
OMe H X.sub.2--OMe H 2375 4 OMe H X.sub.2--OH H 2376 5 Cl H 2377 H
2378 6 F H 2379 H 2380 7 F H 2381 H 2382 8 MeO H 2383 H 2384 9 MeO
H 2385 H 2386
[1714]
40TABLE A9 (Reference compounds 10-12) 2387 Reference Compound
Number R2 R3 R4 R11 A 10 MeO H X.sub.2--OMe (R)--Me 2388 11 MeO H
2389 (R)--Me 2390 12 MeO H 2391 (R)--Me 2392
[1715] In Tables A8 and A9, X.sub.2 and X.sub.4 refer to point of
attachment.
* * * * *