U.S. patent application number 10/979558 was filed with the patent office on 2005-06-09 for diazaindole-dicarbonyl-piperazinyl antiviral agents.
Invention is credited to Bender, John A., Kadow, John F., Meanwell, Nicholas A., Yang, Zhong.
Application Number | 20050124623 10/979558 |
Document ID | / |
Family ID | 34652366 |
Filed Date | 2005-06-09 |
United States Patent
Application |
20050124623 |
Kind Code |
A1 |
Bender, John A. ; et
al. |
June 9, 2005 |
Diazaindole-dicarbonyl-piperazinyl antiviral agents
Abstract
The invention comprises substituted
diazaindole-dicarbonyl-piperazinyl derivatives of general Formula I
1 wherein: Q is selected from the group consisting of 2 -- may
represent a bond; T is --C(O)-- or --CH(CN)--; and --Y-- is
selected from the group consisting of 3 compositions thereof and
their use for treating HIV infection.
Inventors: |
Bender, John A.;
(Middletown, CT) ; Yang, Zhong; (Middletown,
CT) ; Kadow, John F.; (Wallingford, CT) ;
Meanwell, Nicholas A.; (East Hampton, CT) |
Correspondence
Address: |
STEPHEN B. DAVIS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
34652366 |
Appl. No.: |
10/979558 |
Filed: |
November 2, 2004 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60525624 |
Nov 26, 2003 |
|
|
|
Current U.S.
Class: |
514/248 ;
514/265.1; 544/235; 544/280 |
Current CPC
Class: |
A61P 37/02 20180101;
A61P 31/18 20180101; C07D 487/04 20130101; A61P 31/00 20180101;
A61P 31/12 20180101 |
Class at
Publication: |
514/248 ;
514/265.1; 544/235; 544/280 |
International
Class: |
A61K 031/519; A61K
031/503; C07D 487/02 |
Claims
What is claimed is:
1. A compound of Formula I, including pharmaceutically acceptable
salts thereof, 379wherein: Q is selected from the group consisting
of 380T is --C(O)-- or --CH(CN)--; R.sup.1 is hydrogen or methyl;
R.sup.3 and R.sup.5 are independently selected from the group
consisting of hydrogen, halogen, cyano, nitro, COOR.sup.8, XR.sup.9
and B; R.sup.2 and R.sup.4 are independently O or do not exist with
the proviso that only one of R.sup.2 and R.sup.4 are O; R.sup.6 is
(CH.sub.2).sub.nH, wherein n is 0-1; -- represents a carbon-carbon
bond or does not exist; --Y-- is selected from the group consisting
of 381R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,R.sup.15,
R.sup.16 and R.sup.17 are each independently H or (C.sub.1-6)alkyl;
wherein said (C.sub.1-6)alkyl may optionally be substituted with
one to three same or different halogen, OH or CN; R.sup.18 is a
member selected from the group consisting of C(O)-phenyl,
C(O)-heteroaryl, pyridinyl, pyrimidinyl, quinolyl, isoquinolyl,
quinazolyl, quinoxalinyl, napthyridinyl, pthalazinyl, azabenzofuryl
and azaindolyl; wherein said member is optionally substituted with
from one to two substituents selected from the group consisting of
methyl, -amino, --NHMe, --NMe.sub.2, methoxy, hydroxymethyl and
halogen; D is selected from the group consisting of hydrogen,
cyano, S(O).sub.2R.sup.24, halogen, COOR.sup.20,
C(O)NR.sup.21R.sup.22, phenyl and heteroaryl; wherein said phenyl
or heteroaryl is independently optionally substituted with one to
three same or different halogens or from one to three same or
different substituents selected from F (as defined below); A is
selected from the group consisting of phenyl, pyridinyl, furanyl,
thienyl, isoxazole and oxazole; wherein said phenyl, pyridinyl,
furanyl, thienyl, isoxazole or oxazole is independently optionally
substituted with one to three same or different halogens or from
one to three same or different substituents selected from F; B is
selected from the group consisting of (C.sub.1-6)alkyl,
C(O)NR.sup.21R.sup.22, --C(O)CH.sub.3,
--N(CH.sub.2CH.sub.2).sub.2NC(O)pyrazolyl, phenyl and heteroaryl;
wherein said (C.sub.1-6)alkyl, phenyl and heteroaryl are
independently optionally substituted with one to three same or
different halogens or from one to three same or different
substituents selected from F; heteroaryl is selected from the group
consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,
furanyl, thienyl, benzothienyl, thiazolyl, oxazolyl, isoxazolyl,
imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl and
triazolyl; F is selected from the group consisting of
(C.sub.1-6)alkyl, (C.sub.1-6)alkenyl, phenyl, pyridinyl, hydroxy,
(C.sub.1-6)alkoxy, halogen, benzyl,
--NR.sup.23C(O)--(C.sub.1-6)alkyl, --NR.sup.24R.sup.25,
--S(O).sub.2NR.sup.24R.sup.25, COOR.sup.26, --COR.sup.27, and
--CONR.sup.24R.sup.25; wherein said (C.sub.1-6)alkyl or phenyl are
each optionally substituted with hydroxy, (C.sub.1-6)alkoxy,
(C.sub.1-6)alkyl, CF.sub.3, dimethylamino or from one to three same
or different halogen; R.sup.8, R.sup.9 and R.sup.26 are each
independently selected from the group consisting of hydrogen and
(C.sub.1-6)alkyl; X is selected from the group consisting of
NR.sup.26, O and S; R.sup.20, R.sup.21,R.sup.22, R.sup.23, R.sup.24
and R.sup.25 are independently selected from the group consisting
of hydrogen, (C.sub.1-6)alkyl, phenyl and heteroaryl; wherein said
phenyl and heteroaryl are each independently optionally substituted
with one to three same or different halogen or methyl; and R.sup.27
is piperazinyl, N-methyl piperazinyl, or 3-pyrazolyl.
2. A compound of claim 1 wherein T is 382
3. A compound of claim 2, wherein: R.sup.1 is hydrogen; --
represents a carbon-carbon bond; and R.sup.2 and R.sup.4 do not
exist. D is selected from the group consisting of hydrogen, cyano,
S(O).sub.2R.sub.24, halogen, COOR.sup.20, C(O)NH.sub.2, phenyl and
heteroaryl; wherein said phenyl or heteroaryl is independently
optionally substituted with one to three same or different halogens
or a member selected from the group consisting of (C.sub.1-6)alkyl,
(C.sub.1-6)alkenyl, hydroxy, (C.sub.1-6)alkoxy, halogen,
--NR.sup.24R.sup.25, --S(O).sub.2NR.sup.24R.s- up.25, COOR.sup.26
and --CONR.sup.24R.sup.25; wherein said (C.sub.1-6)alkyl is
optionally substituted with one to three same or different halogen
or a hydroxy; and A is selected from the group consisting of
phenyl, pyridinyl, furanyl, thienyl, isoxazole and oxazole; wherein
said phenyl, pyridinyl, furanyl, thienyl, isoxazole or oxazole are
independently optionally substituted with one to three same or
different halogens or a member selected from the group consisting
of (C.sub.1-4)alkyl, (C.sub.1-4)alkenyl, (C.sub.1-3)alkoxy, halogen
and --NH.sub.2; wherein said (C.sub.1-4)alkyl is optionally
substituted with one to three same or different halogens.
4. A compound of claim 3 wherein: R.sup.6 is hydrogen; and
R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15,
R.sup.16 and R.sup.17 are each independently H or methyl, with the
proviso that a maximum of two of R.sup.10--R.sup.17 is a
methyl.
5. A compound of claim 4 wherein: Q is a member selected from
groups (A), (B), and (C) consisting of (A) 383wherein R.sup.3 is
hydrogen, C.sub.1-C.sub.3 alkoxy, --NR.sup.26R.sup.9 or halogen;
(B) 384wherein R.sup.3 is hydrogen, methoxy or halogen; and (C)
385wherein R.sup.3 is hydrogen, methoxy or halogen.
6. A compound of claim 5 wherein: group(A) of Q is: 386wherein
R.sup.3 is hydrogen; and group (C) of Q is: 387wherein R.sup.5 is
hydrogen.
7. A compound of claim 5 wherein: Q is selected from group (A) or
(B); and R.sup.5 is selected from the group consisting of hydrogen,
halogen, heteroaryl, phenyl, cyano, methoxy, COOR.sup.8,
C(O)NH.sub.2, C(O)NHheteroaryl, and C(O)NHCH.sub.3; wherein said
C(O)NHheteroaryl, phenyl, and heteroaryl are independently
optionally substituted with one to three same or different halogens
or from one to three same or different substituents selected from
F.
8. A compound of claim 7 wherein: R.sup.5 is selected from the
group consisting of C(O)NH.sub.2, C(O)NHCH.sub.3 and
C(O)NHheteroaryl; wherein said C(O)NHheteroaryl is optionally
substituted with one to three same or different halogens or from
one to three same or different substituents selected from F.
9. A compound of claim 7 wherein: R.sup.5 is selected from the
group consisting of phenyl and heteroaryl; wherein said phenyl and
heteroaryl are independently optionally substituted with one to
three same or different halogens or from one to three same or
different substituents selected from F.
10. A compound of claim 9 wherein: heteroaryl is selected from the
group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,
furanyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl,
oxadiazolyl, thiadiazoyl, pyrazolyl, tetrazolyl and triazolyl;
wherein said heteroaryl is independently optionally substituted
with one to three same or different halogens or from one to three
same or different substituents selected from F.
11. A compound of claim 5, wherein: R.sup.18 is --C(O)phenyl or
--C(O)heteroaryl; wherein said heteroaryl is pyridinyl, furanyl or
thienyl; wherein heteroaryl is independently optionally substituted
with a member selected from the group consisting of halogen,
methyl, -amino, --NHMe, NMe.sub.2 and hydroxymethyl.
12. A compound of claim 5 wherein: --W-- is 388R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14,R.sup.15, R.sup.16 and R.sup.17 are
each independently H or methyl, with the proviso that not more than
one is methyl; and R.sup.18 is selected from the group consisting
of C(O)-phenyl and C(O)-heteroaryl; wherein each of C(O)-phenyl or
--C(O)-heteroaryl may be optionally substituted with from one to
two methyl, -amino, --NHMe, --NMe.sub.2, methoxy, hydroxymethyl or
halogen.
13. A compound of claim 5 wherein: --W-- is 389R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14,R.sup.15, R.sup.16 and R.sup.17 are
each independently H or methyl, with the proviso that not more than
one is methyl; and R.sup.18 is selected from the group consisting
of pyridinyl, pyrimidinyl, quinolyl, isoquinolyl, quinazolyl,
quinoxalinyl, napthyridinyl, pthalazinyl, azabenzofuryl and
azaindolyl, each of which may be optionally substituted with from
one to two substituents selected from the group consisting of
methyl, -amino, --NHMe, --NMe.sub.2, methoxy, hydroxymethyl and
halogen.
14. A compound of claim 5 wherein: --W-- is 390R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 are
each independently H or methyl, with the proviso that one is
methyl; D is selected from the group consisting of hydrogen, cyano,
S(O).sub.2R.sup.24, halogen, COOR.sup.20, C(O)NH.sub.2, phenyl and
heteroaryl; wherein said phenyl or heteroaryl is independently
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.sub.1-6)alkyl, (C.sub.1-6)alkenyl,
hydroxy, (C.sub.1-6)alkoxy, halogen, --NR.sup.24R.sup.25,
--S(O).sub.2NR.sup.24R.sup.25, COOR.sup.26 and
--CONR.sup.24R.sup.25; wherein said (C.sub.1-6)alkyl is optionally
substituted with one to three same or different halogen or a
hydroxy; and A is selected from the group consisting of phenyl,
pyridinyl, furanyl, thienyl, isoxazole and oxazole; wherein said
phenyl, pyridinyl, furanyl, thienyl, isoxazole or oxazole is
independently 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.sub.1-4)alkyl, (C.sub.1-4)alkenyl, (C.sub.1-3)alkoxy, halogen
and --NH.sub.2; wherein said (C.sub.1-4)alkyl is optionally
substituted with one to three same or different halogens.
15. A compound of claim 7 wherein: Q is selected from Group
(A).
16. A compound of claim 1 including pharmaceutically acceptable
salts thereof, 391wherein: Q is selected from the group consisting
of 392R.sup.1 is hydrogen or methyl; R.sup.3 and R.sup.5 are
independently selected from the group consisting of hydrogen,
halogen, cyano, nitro, COOR.sup.8, XR.sup.9 and B; R.sup.2 and
R.sup.4 are independently O or do not exist, with the proviso that
only one of R.sup.2 and R.sup.4 are O; R.sup.6 is
(CH.sub.2).sub.nH, wherein n is 0-1; -- represents a carbon-carbon
bond or does not exist; --Y-- is selected from the group consisting
of 393R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,R.sup.15,
R.sup.16 and R.sup.17 are each independently H or (C.sub.1-6)alkyl;
wherein said (C.sub.1-6)alkyl may optionally be substituted with
one to three same or different halogen, OH or CN; R.sup.18 is a
member selected from the group consisting of C(O)-phenyl,
C(O)-heteroaryl, pyridinyl, pyrimidinyl, quinolyl, isoquinolyl,
quinazolyl, quinoxalinyl, napthyridinyl, pthalazinyl, azabenzofuryl
and azaindolyl; wherein said member is optionally substituted with
from one to two substituents selected from the group consisting of
methyl, -amino, --NHMe, --NMe.sub.2, methoxy, hydroxymethyl and
halogen; D is selected from the group consisting of hydrogen,
cyano, S(O).sub.2R.sup.24, halogen, COOR.sup.20,
C(O)NR.sup.21R.sup.22, phenyl and heteroaryl; wherein said phenyl
or heteroaryl is independently optionally substituted with one to
three same or different halogens or from one to three same or
different substituents selected from F; A is selected from the
group consisting of phenyl, pyridinyl, furanyl, thienyl, isoxazole
and oxazole; wherein said phenyl, pyridinyl, furanyl, thienyl,
isoxazole or oxazole is independently optionally substituted with
one to three same or different halogens or from one to three same
or different substituents selected from F; B is selected from the
group consisting of (C.sub.1-6)alkyl, C(O)NR.sup.21R.sup.22, phenyl
and heteroaryl; wherein said (C.sub.1-6)alkyl, phenyl and
heteroaryl are independently optionally substituted with one to
three same or different halogens or from one to three same or
different substituents selected from F; heteroaryl is selected from
the group consisting of pyridinyl, pyrazinyl, pyridazinyl,
pyrimidinyl, furanyl, thienyl, thiazolyl, oxazolyl, isoxazolyl,
imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl and
triazolyl; F is selected from the group consisting of
(C.sub.1-6)alkyl, (C.sub.1-6)alkenyl, phenyl, pyridinyl, hydroxy,
(C.sub.1-6)alkoxy, halogen, benzyl,
--NR.sup.23C(O)--(C.sub.1-6)alkyl, --NR.sup.24R.sup.25,
--S(O).sub.2NR.sup.24R.sup.25, COOR.sup.26, --COR.sup.27, and
--CONR.sup.24R.sup.25; wherein said (C.sub.1-6)alkyl or phenyl are
each optionally substituted with hydroxy, (C.sub.1-6)alkoxy,
dimethylamino or from one to three same or different halogen;
R.sup.8, R.sup.9 and R.sup.26 are each independently selected from
the group consisting of hydrogen and (C.sub.1-6)alkyl; X is
selected from the group consisting of NR.sup.26, O and S; R.sup.20,
R.sup.21,R.sup.22, R.sup.23, R.sup.24 and R.sup.25 are
independently selected from the group consisting of hydrogen,
(C.sub.1-6)alkyl, phenyl and heteroaryl; wherein said phenyl and
heteroaryl are each independently optionally substituted with one
to three same or different halogen or methyl; and R.sup.27 is
piperazinyl, N-methylpiperazinyl or 3-pyrazolyl.
17. A compound of claim 6 wherein: Q is 394R.sup.5 is selected from
the group consisting of hydrogen, halogen, cyano, XR.sup.9,
heteroaryl, --N(CH.sub.2CH.sub.2).sub.2NC(O)pyrazolyl, and
--C(O)CH.sub.3, wherein said heteroaryl is optionally substituted
with one substituent selected from F; heteroaryl is selected from
the group consisting of pyridinyl, pyrazinyl, pyridazinyl,
pyrimidinyl, isoxazolyl, isoxazolyl, pyrazolyl, and triazolyl;
--Y-- is selected from the group consisting of 395R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.14,R.sup.15, R.sup.16 and
R.sup.17 are each hydrogen; A is phenyl or pyridinyl; R.sup.18 is
C(O)-phenyl, isoquinolyl or quinazolyl; D is cyano or oxadiazolyl;
F is selected from the group consisting of (C.sub.1-6)alkyl,
phenyl, pyridinyl, (C.sub.1-2)alkoxy, --COOR.sup.26--COR and
--CONR.sup.24R.sup.25; wherein said phenyl is optionally
substituted with one group selected from methyl, methoxy, fluoro,
or trifluoromethyl; X is selected from the group consisting of O;
R.sup.9 is (C.sub.1-2)alkyl; R.sup.26 is hydrogen, methyl, or
ethyl; R.sup.24 and R.sup.25 are independently selected from the
group consisting of hydrogen and methyl; and R.sup.27 is
piperazinyl, N-methyl piperazinyl, or 3-pyrazolyl.
18. A compound of claim 17 wherein: R.sup.5 is heteroaryl
optionally substituted with one halogen or one substituent selected
from F; --Y-- is 396R.sup.18 is C(O)-phenyl, isoquinolyl or
quinazolyl; and F is (C.sub.1-6)alkyl.
19. A compound of claim 18 wherein R.sup.18 is C(O)-phenyl.
20. A compound of claim 18 wherein R.sup.18 is isoquinolyl or
quinazolyl.
21. A compound of claim 17 wherein: R.sup.5 is heteroaryl
optionally substituted with one substituent selected from F;
heteroaryl is selected from the group consisting of pyridinyl,
pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, isoxazolyl,
pyrazolyl and triazolyl; and --Y-- is 397
22. A compound of claim 17 wherein: Q is 398R.sup.5 is heteroaryl
optionally substituted with one substituent selected from F; and
heteroaryl is selected from the group consisting of pyrazolyl and
triazolyl.
23. A compound of claim 22 wherein: F is selected from the group
consisting of methyl and --CONR.sup.24R.sup.25; and R.sup.24 and
R.sup.25 are independently selected from the group consisting of
hydrogen and methyl.
24. A compound of claim 23 wherein: F is methyl.
25. A pharmaceutical composition which comprises an antiviral
effective amount of a compound of Formula I, including
pharmaceutically acceptable salts thereof, as claimed in claim 1,
and one or more pharmaceutically acceptable carriers, excipients or
diluents.
26. The pharmaceutical composition of claim 25 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.
27. A method for treating a mammal infected with the HIV virus
comprising administering to said mammal an antiviral effective
amount of a compound of Formula I, including pharmaceutically
accceptable salts thereof, as claimed in claim 1, and one or more
pharmaceutically acceptable carriers, excipients or diluents.
28. The method of claim 27 comprising administering to said mammal
an antiviral effective amount of a compound of Formula I, including
pharmaceutically accceptable salts thereof, as claimed in claim 1,
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
an HIV entry inhibitor.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 60/525,624 filed Nov. 26, 2003.
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 new
diazaindole 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 ten 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) and Emtriva.RTM. (emtricitabine); three non-nucleoside
reverse transcriptase inhibitors: nevirapine (or Viramune.RTM.),
delavirdine (or Rescriptor.RTM.) and efavirenz (or Sustiva.RTM.),
nine peptidomimetic protease inhibitors or approved formulations:
saquinavir, indinavir, ritonavir, nelfinavir, amprenavir,
lopinavir, Kaletra.RTM. (lopinavir and Ritonavir), Atazanavir
(Reyataz.RTM.), Fosamprenavir.RTM. and one fusion inhibitor which
targets viral gp41 T-20 (FUZEON.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).
A recent overview of non-nucleoside reverse transcriptase
inhibitors: perspectives on novel therapeutic compounds and
strategies for the treatment of HIV infection. has appeared
(Buckheit, reference 99). A review covering both NRTI and NNRTIs
has appeared (De Clercq, reference 100). An overview of the current
state of the HIV drugs has been published (De Clercq, reference
101).
[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). 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).
[0008] Structurally related aza-indole amide derivatives have been
disclosed previously (Kato et al, Ref. 23(a); Levacher et al, Ref.
23(b); 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 monoaza-indole mono-amide rather than
oxoacetamide derivatives, and there is no mention of the use of
these compounds for treating viral infections, particularly
HIV.
[0009] New drugs for the treatment of HIV are needed for the
treatment of patients who become resistant to the currently
approved drugs described above which target reverse transcriptase
or the protease. One approach to obtaining these drugs is to find
molecules which inhibit new and different targets of the virus. A
general class of inhibitors which are under active study are HIV
entry inhibitors. This general classification includes drugs aimed
at several targets which include chemokine receptor (CCR5 or CXCR4)
inhibitors, fusion inhibitors targeting viral gp41, and inhibitors
which prevent attachment of the viral envelope, gp120, the its
human cellular target CD4. A number of reviews or general papers on
viral entry inhibitors have recently appeared and some selected
references are:
[0010] Chemokine receptor antagonists as HIV entry inhibitors.
Expert Opinion on Therapeutic Patents (2004), 14(2), 251-255.
[0011] Inhibitors of the entry of HIV into host cells. Meanwell,
Nicholas A.; Kadow, John F. Current Opinion in Drug Discovery &
Development (2003), 6(4), 451-461.
[0012] Virus entry as a target for anti-HIV intervention. Este,
Jose A. Retrovirology Laboratory irsiCaixa, Hospital Universitari
Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona,
Spain. Current Medicinal Chemistry (2003), 10(17), 1617-1632.
[0013] New antiretroviral agents. Rachline, A.; Joly, V. Service de
Maladies Infectieuses et Tropicales A, Hopital Bichat-Claude
Bernard, Paris, Fr. Antibiotiques (2003), 5(2), 77-82.
[0014] New antiretroviral drugs. Gulick, R. M. Cornell HIV Clinical
Trials Unit, Division of International Medicine and Infectious
Diseases, Weill Medical College of Cornell University, New York,
N.Y., USA. Clinical Microbiology and Infection (2003), 9(3),
186-193.
[0015] Sensitivity of HIV-1 to entry inhibitors correlates with
envelope/coreceptor affinity, receptor density, and fusion
kinetics. Reeves, Jacqueline D.; Gallo, Stephen A.; Ahmad, Navid;
Miamidian, John L.; Harvey, Phoebe E.; Sharron, Matthew; Pohlmann,
Stefan; Sfakianos, Jeffrey N.; Derdeyn, Cynthia A.; Blumenthal,
Robert; Hunter, Eric; Doms, Robert W. Department of Microbiology,
University of Pennsylvania, Philadelphia, Pa., USA. Proceedings of
the National Academy of Sciences of the United States of America
(2002), 99(25), 16249-16254. CODEN: PNASA6 ISSN: 0027-8424.
[0016] Opportunities and challenges in targeting HIV entry.
Biscone, Mark J.; Pierson, Theodore C.; Doms, Robert W. Department
of Microbiology, University of Pennsylvania, Philadelphia, Pa.,
USA. Current Opinion in Pharmacology (2002), 2(5), 529-533.
[0017] HIV entry inhibitors in clinical development. O'Hara, Bryan
M.; Olson, William C. Progenics Pharmaceuticals, Inc., Tarrytown,
N.Y., USA. Current Opinion in Pharmacology (2002), 2(5),
523-528.
[0018] Resistance mutation in HIV entry inhibitors. Hanna, Sheri
L.; Yang, Chunfu; Owen, Sherry M.; Lal, Renu B. HIV Immunology and
Diagnostics Branch, Division of AIDS, STD, Atlanta, Ga., USA. AIDS
(London, United Kingdom) (2002), 16(12), 1603-1608.
[0019] HIV entry: are all receptors created equal? Goldsmith, Mark
A.; Doms, Robert W. Genencor International, Inc., Palo Alto,
Calif., USA. Nature Immunology (2002), 3(8), 709-710. CODEN: NIAMCZ
ISSN: 1529-2908.
[0020] Peptide and non-peptide HIV fusion inhibitors. Jiang, Shibo;
Zhao, Qian; Debnath, Asim K. The New York Blood Center, Lindsley F.
Kimball Research Institute, New York, N.Y., USA. Current
Pharmaceutical Design (2002), 8(8), 563-580.
[0021] A series of recent publications and disclosures characterize
and describe a compound labelled as BMS-806, an initial member of a
class of viral entry inhibitors which target viral gp-120 and
prevent attachment of virus to host CD4.
[0022] A small molecule HIV-1 inhibitor that targets the HIV-1
envelope and inhibits CD4 receptor binding. Lin, Pin-Fang; Blair,
Wade; Wang, Tao; Spicer, Timothy; Guo, Qi; Zhou, Nannan; Gong,
Yi-Fei; Wang, H. -G. Heidi; Rose, Ronald; Yamanaka, Gregory;
Robinson, Brett; Li, Chang-Ben; Fridell, Robert; Deminie, Carol;
Demers, Gwendeline; Yang, Zheng; Zadjura, Lisa; Meanwell, Nicholas;
Colonno, Richard. Proceedings of the National Academy of Sciences
of the United States of America (2003), 100(19), 11013-11018.
[0023] Biochemical and genetic characterizations of a novel human
immunodeficiency virus type 1 inhibitor that blocks gp120-CD4
interactions. Guo, Qi; Ho, Hsu-Tso; Dicker, Ira; Fan, Li; Zhou,
Nannan; Friborg, Jacques; Wang, Tao; McAuliffe, Brian V.; Wang,
Hwei-gene Heidi; Rose, Ronald E.; Fang, Hua; Scarnati, Helen T.;
Langley, David R.; Meanwell, Nicholas A.; Abraham, Ralph; Colonno,
Richard J.; Lin, Pin-fang. Journal of Virology (2003), 77(19),
10528-10536.
[0024] Method using small heterocyclic compounds for treating HIV
infection by preventing interaction of CD4 and gp120. Ho, Hsu-Tso;
Dalterio, Richard A.; Guo, Qi; Lin, Pin-Fang. PCT Int. Appl.
(2003), WO 2003072028A2.
[0025] Discovery of
4-benzoyl-1-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-
oxoacetyl]-2-(R)-methylpiperazine (BMS-378806): A Novel HIV-1
Attachment Inhibitor That Interferes with CD4-gp120 Interactions.
Wang, Tao; Zhang, Zhongxing; Wallace, Owen B.; Deshpande, Milind;
Fang, Haiquan; Yang, Zheng; Zadjura, Lisa M.; Tweedie, Donald L.;
Huang, Stella; Zhao, Fang; Ranadive, Sunanda; Robinson, Brett S.;
Gong, Yi-Fei; Ricarrdi, Keith; Spicer, Timothy P.; Deminie, Carol;
Rose, Ronald; Wang, Hwei-Gene Heidi; Blair, Wade S.; Shi, Pei-Yong;
Lin, Pin-fang; Colonno, Richard J.; Meanwell, Nicholas A. Journal
of Medicinal Chemistry (2003), 46(20), 4236-4239.
[0026] Indole, azaindole and other oxo amide containing derivatives
have been disclosed in a number different PCT and issued U.S.
patent applications (Reference 93-95, 106, 108,109, 110, 111,112,
113, and 114). None of these applications discloses diazindole
compounds such as described in this invention. The extra nitrogen
of the diazaindole class of molecules provides altered properties
especially in combination with specific substituents that are
advantageous and not available from the azaindoles. The
diazaindoles are easier to access and thus offer the potential to
provide patients with lower cost treatments. A series of PCT
International Patent applications Bernd Nickel et.al. (reference
107a,b, and c) describes N-indolylglyoxamides for the treatment of
cancer. Although some of these compounds contain N-heteroaryl or
N-aryl piperazines, the substitution patterns at the other
positions are outside the scope of this invention.
[0027] Structurally similar diazaindoles with a C-3 oxoacetyl group
have also been previously disclosed (Hutchison et al, Ref 5(d);
Resnyanskaya et al, Ref 24 (a); Cook et al, Ref 24(b)). However,
these molecules differ from those claimed in that they do not
contain the piperazine or piperidine moieties and there is no
mention of the use of these molecules as antiviral agents,
particularly against HIV.
[0028] Nothing in these references can be construed to disclose or
suggest the novel compounds of this invention and their use to
inhibit HIV infection.
References Cited
[0029] Patent Documents
[0030] 1. Greenlee, W. J.; Srinivasan, P. C. Indole reverse
transcriptase inhibitors. U.S. Pat. No. 5,124,327.
[0031] 2. Williams, T. M.; Ciccarone, T. M.; Saari, W. S.; Wai, J.
S.; Greenlee, W. J.; Balani, S. K.; Goldman, M. E.; Theohrides, A.
D. Indoles as inhibitors of HIV reverse transcriptase. European
Patent 530907.
[0032] 3. Romero, D. L.; Thomas, R. C.; Preparation of substituted
indoles as anti-AIDS pharmaceuticals. PCT WO 93/01181.
[0033] 4. Boschelli, D. H.; Connor, D. T.; Unangst, P. C.
Indole-2-carboxamides as inhibitors of cell adhesion. U.S. Pat. No.
5,424,329.
[0034] 5. (a) Mantovanini, M.; Melillo, G.; Daffonchio, L. Tropyl
7-azaindol-3-ylcarboxyamides as antitussive agents. PCT WO 95/04742
(Dompe Spa). (b) Cassidy, F.; Hughes, I.; Rahman, S.; Hunter, D. J.
Bisheteroaryl-carbonyl and carboxamide derivatives with 5HT 2C/2B
antagonists activity. PCT WO 96/11929. (c) Scherlock, M. H.; Tom,
W. C. Substituted 1H-pyrrolopyridine-3-carboxamides. U.S. Pat. No.
5,023,265. (d) Hutchison, D. R.; Martinelli, M. J.; Wilson, T. M.
Preparation or pyrrolo[2,3-d]pyrimidines as sPLA2 inhibitors PCT WO
00/00201.
[0035] Other Publications
[0036] 6. Larder, B. A.; Kemp, S. D. Multiple mutations in the
HIV-1 reverse transcriptase confer high-level resistance to
zidovudine (AZT). Science, 1989, 246,1155-1158.
[0037] 7. Gulick, R. M. Current antiretroviral therapy: An
overview. Quality of Life Research, 1997, 6, 471-474.
[0038] 8. Kuritzkes, D. R. HIV resistance to current therapies.
Antiviral Therapy, 1997, 2 (Supplement 3), 61-67.
[0039] 9. Morris-Jones, S.; Moyle, G.; Easterbrook, P. J.
Antiretroviral therapies in HIV-1 infection. Expert Opinion on
Investigational Drugs, 1997, 6(8),1049-1061.
[0040] 10. Schinazi, R. F.; Larder, B. A.; Mellors, J. W. Mutations
in retroviral genes associated with drug resistance. International
Antiviral News, 1997, 5,129-142.
[0041] 11. Vacca, J. P.; Condra, J. H. Clinically effective HIV-1
protease inhibitors. Drug Discovery Today, 1997, 2, 261-272.
[0042] 12. Flexner, D. HIV-protease inhibitors. Drug Therapy, 1998,
338, 1281-1292.
[0043] 13. Berkhout, B. HIV-1 evolution under pressure of protease
inhibitors: Climbing the stairs of viral fitness. J. Biomed. Sci.,
1999, 6, 298-305.
[0044] 14. Ren, S.; Lien, E. J. Development of HIV protease
inhibitors: A survey. Prog. Drug Res., 1998, 51, 1-31.
[0045] 15. Pedersen, O. S.; Pedersen, E. B. Non-nucleoside reverse
transcriptase inhibitors: the NNRTI boom. Antiviral Chem.
Chemother. 1999, 10, 285-314.
[0046] 16. (a) De Clercq, E. The role of non-nucleoside reverse
transcriptase inhibitors (NNRTIs) in the therapy of HIV-1
infection. Antiviral Research, 1998, 38, 153-179. (b) De Clercq, E.
Perspectives of non-nucleoside reverse transcriptase inhibitors
(NNRTIs) in the therapy of HIV infection. IL. Farmaco, 1999, 54,
26-45.
[0047] 17. Font, M.; Monge, A.; Cuartero, A.; Elorriaga, A.;
Martinez-Irujo, J. J.; Alberdi, E.; Santiago, E.; Prieto, I.;
Lasarte, J. J.; Sarobe, P. and Borras, F. Indoles and
pyrazino[4,5-b]indoles as nonnucleoside analog inhibitors of HIV-1
reverse transcriptase. Eur. J. Med. Chem., 1995, 30, 963-971.
[0048] 18. Romero, D. L.; Morge, R. A.; Genin, M. J.; Biles, C.;
Busso, M,; Resnick, L.; Althaus, I. W.; Reusser, F.; Thomas, R. C
and Tarpley, W. G. Bis(heteroaryl)piperazine (BHAP) reverse
transcriptase inhibitors: structure-activity relationships of novel
substituted indole analogues and the identification of
1-[(5-methanesulfonamido-1H-indol-2-yl)-carbony-
l]-4-[3-[1-methylethyl)amino]-pyridinyl]piperazine
momomethansulfonate (U-90152S), a second generation clinical
candidate. J. Med. Chem., 1993, 36, 1505-1508.
[0049] 19. Young, S. D.; Amblard, M. C.; Britcher, S. F.; Grey, V.
E.; Tran, L. O.; Lumma, W. C.; Huff, J. R.; Schleif, W. A.; Emini,
E. E.; O'Brien, J. A.; Pettibone, D. J. 2-Heterocyclic
indole-3-sulfones as inhibitors of HIV-reverse transcriptase.
Bioorg. Med. Chem. Lett., 1995, 5, 491-496.
[0050] 20. Genin, M. J.; Poel, T. J.; Yagi, Y.; Biles, C.; Althaus,
I.; Keiser, B. J.; Kopta, L. A.; Friis, J. M.; Reusser, F.; Adams,
W. J.; Olmsted, R. A.; Voorman, R. L.; Thomas, R. C. and Romero, D.
L. Synthesis and bioactivity of novel bis(heteroaryl)piperazine
(BHAP) reverse transcriptase inhibitors: structure-activity
relationships and increased metabolic stability of novel
substituted pyridine analogs. J. Med. Chem., 1996, 39,
5267-5275.
[0051] 21. Silvestri, R.; Artico, M.; Bruno, B.; Massa, S.;
Novellino, E.; Greco, G.; Marongiu, M. E.; Pani, A.; De Montis, A
and La Colla, P. Synthesis and biological evaluation of
5H-indolo[3,2-b][1,5]benzothiazepi- ne derivatives, designed as
conformationally constrained analogues of the human
immunodeficiency virus type 1 reverse transcriptase inhibitor
L-737,126. Antiviral Chem. Chemother. 1998, 9, 139-148.
[0052] 22. Fredenhagen, A.; Petersen, F.; Tintelnot-Blomley, M.;
Rosel, J.; Mett, H and Hug, P. J. Semicochliodinol A and B:
Inhibitors of HIV-1 protease and EGF-R protein Tyrosine Kinase
related to Asterriquinones produced by the fungus Chrysosporium
nerdarium. Antibiotics, 1997, 50, 395-401.
[0053] 23. (a) Kato, M.; Ito, K.; Nishino, S.; Yamakuni, H.;
Takasugi, H. New 5-HT.sub.3 (Serotonin-3) receptor antagonists. IV.
Synthesis and structure-activity relationships of
azabicycloalkaneacetamide derivatives. Chem. Pharm. Bull., 1995,
43, 1351-1357. (b) Levacher, V.; Benoit, R.; Duflos, J; Dupas, G.;
Bourguignon, J.; Queguiner, G. Broadening the scope of NADH models
by using chiral and non chiral pyrrolo[2,3-b]pyridine derivatives.
Tetrahedron, 1991, 47, 429-440.
[0054] 24. (a) Resnyanskaya, E. V.; Tverdokhlebov, A. V.;
Volovenko, Y. M.; Shishkin, O. V.; Zubatyuk, R. I. A simple
synthesis of 1-acyl-3-aryl-3H-pyrrolo[2',3',
:4,5]pyrimido[6,1-b]benzothiazol-6-ium-2-- olates: Betainic
derivatives of a novel heterocyclic system. Synthesis, 2002, 18,
2717-2724. (b) Cook, P. D.; Castle, R. N. Pyrrolopyridazines. 1.
Synthesis and reactivity of [2,3-d]pyridazine 5-oxides. J. Het.
Chem. 1973, 10(4), 551-557.
[0055] 25. Shadrina, L. P.; Dormidontov, Yu. P.; Ponomarev, V, G.;
Lapkin, I. I. Reactions of organomagnesium derivatives of 7-aza-
and benzoindoles with diethyl oxalate and the reactivity of
ethoxalylindoles. Khim. Geterotsikl. Soedin., 1987, 1206-1209.
[0056] 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.
[0057] 27. (a) Desai, M.; Watthey, J. W. H.; Zuckerman, M. A
convenient preparation of 1-aroylpiperazines. Org. Prep. Proced.
Int., 1976, 8, 85-86. (b) Adamczyk, M.; Fino, J. R. Synthesis of
procainamide metabolites. N-acetyl desethylprocainamide and
desethylprocainamide. Org. Prep. Proced. Int. 1996, 28, 470-474.
(c) Rossen, K.; Weissman, S. A.; Sager, J.; Reamer, R. A.; Askin,
D.; Volante, R. P.; Reider, P. J. Asymmetric Hydrogenation of
tetrahydropyrazines: Synthesis of (S)-piperazine
2-tert-butylcarboxamide, an intermediate in the preparation of the
HIV protease inhibitor Indinavir. Tetrahedron Lett., 1995, 36,
6419-6422. (d) Wang, T.; Zhang, Z.; Meanwell, N. A. Benzoylation of
Dianions: Preparation of mono-Benzoylated Symmetric Secondary
Diamines. J. Org. Chem., 1999, 64, 7661-7662.
[0058] 28. Li, H.; Jiang, X.; Ye, Y.-H.; Fan, C.; Romoff, T.;
Goodman, M. 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one
(DEPBT): A new coupling reagent with remarkable resistance to
racemization. Organic Lett., 1999, 1, 91-93.
[0059] 29. Harada, N.; Kawaguchi, T.; Inoue, I.; Ohashi, M.; Oda,
K.; Hashiyama, T.; Tsujihara, K. Synthesis and antitumor activity
of quaternary salts of 2-(2'-oxoalkoxy)-9-hydroxyellipticines.
Chem. Pharm. Bull., 1997, 45, 134-137.
[0060] 30. Schneller, S. W.; Luo, J.-K. Synthesis of
4-amino-1H-pyrrolo[2,3-b]pyridine (1,7-Dideazaadenine) and
1H-pyrrolo[2,3-b]pyridin-4-ol (1,7-Dideazahypoxanthine). J. Org.
Chem., 1980, 45, 4045-4048.
[0061] 31. Shiotani, S.; Tanigochi, K. Furopyridines. XXII [1].
Elaboration of the C-substitutents alpha to the heteronitrogen atom
of furo[2,3-b]-, -[3.2-b]-, -[2.3-c]- and -[3,2-c]pyridine. J. Het.
Chem., 1997, 34, 901-907.
[0062] 32. Minakata, S.; Komatsu, M.; Ohshiro, Y. Regioselective
functionalization of 1H-pyrrolo[2,3-b]pyridine via its N-oxide.
Synthesis, 1992, 661-663.
[0063] 33. Klemm, L. H.; Hartling, R. Chemistry of thienopyridines.
XXIV. Two transformations of thieno[2,3-b]pyridine 7-oxide (1). J.
Het. Chem., 1976, 13, 1197-1200.
[0064] 34. Antonini, I.; Claudi, F.; Cristalli, G.; Franchetti, P.;
Crifantini, M.; Martelli, S. Synthesis of
4-amino-1-.beta.-D-ribofuranosy- l-1H-pyrrolo[2,3-b]pyridine
(1-Deazatubercidin) as a potential antitumor agent. J. Med. Chem.,
1982, 25, 1258-1261.
[0065] 35. (a) Regnouf De Vains, J. B.; Papet, A. L.; Marsura, A.
New symmetric and unsymmetric polyfunctionalized 2,2'-bipyridines.
J. Het. Chem., 1994, 31, 1069-1077. (b) Miura, Y.; Yoshida, M.;
Hamana, M. Synthesis of 2,3-fused quinolines from 3-substituted
quinoline 1-oxides. Part II, Heterocycles, 1993, 36, 1005-1016. (c)
Profft, V. E.; Rolle, W. Uber 4-merkaptoverbindungendes
2-methylpyridins. J. Prakt. Chem., 1960, 283 (11), 22-34.
[0066] 36. Nesi, R.; Giomi, D.; Turchi, S.; Tedeschi, P.,
Ponticelli, F. A new one step synthetic approach to the
isoxazolo[4,5-b]pyridine system. Synth. Comm., 1992, 22,
2349-2355.
[0067] 37. (a) Walser, A.; Zenchoff, G.; Fryer, R. I. Quinazolines
and 1,4-benzodiazepines. 75. 7-Hydroxyaminobenzodiazepines and
derivatives. J. Med. Chem., 1976, 19, 1378-1381. (b) Barker, G.;
Ellis, G. P. Benzopyrone. Part I. 6-Amino- and
6-hydroxy-2-subtituted chromones. J. Chem. Soc., 1970,
2230-2233.
[0068] 38. Ayyangar, N. R.; Lahoti, R J.; Daniel, T. An alternate
synthesis of 3,4-diaminobenzophenone and mebendazole. Org. Prep.
Proced. Int., 1991, 23, 627-631.
[0069] 39. Mahadevan, I.; Rasmussen, M. Ambident heterocyclic
reactivity: The alkylation of pyrrolopyridines (azaindoles,
diazaindenes). Tetrahedron, 1993, 49, 7337-7352.
[0070] 40. Chen, B. K.; Saksela, K.; Andino, R.; Baltimore, D.
Distinct modes of human immunodeficiency type 1 proviral latency
revealed by superinfection of nonproductively infected cell lines
with recombinant luciferase-encoding viruses. J. Virol., 1994, 68,
654-660.
[0071] 41. Bodanszky, M.; Bodanszky, A. "The Practice of Peptide
Synthesis" 2.sup.nd Ed., Springer-Verlag: Berlin Heidelberg,
Germany, 1994.
[0072] 42. Albericio, F. et al. J. Org. Chem. 1998, 63, 9678.
[0073] 43. Knorr, R. et al. Tetrahedron Lett. 1989, 30, 1927.
[0074] 44. (a) Jaszay Z. M. et al. Synth. Commun., 1998 28, 2761
and references cited therein; (b) Bernasconi, S. et al. Synthesis,
1980, 385.
[0075] 45. (a) Jaszay Z. M. et al. Synthesis, 1989, 745 and
references cited therein; (b) Nicolaou, K. C. et al. Angew. Chem.
Int. Ed. 1999, 38, 1669.
[0076] 46. Ooi, T. et al. Synlett. 1999, 729.
[0077] 47. Ford, R. E. et al. J. Med. Chem. 1986, 29, 538.
[0078] 48. (a) Yeung, K.-S. et al. Bristol-Myers Squibb Unpublished
Results. (b) Wang, W. et al. Tetrahedron Lett. 1999, 40, 2501.
[0079] 49. Brook, M. A. et al. Synthesis, 1983, 201.
[0080] 50. Yamazaki, N. et al. Tetrahedron Lett. 1972, 5047.
[0081] 51. Barry A. Bunin "The Combinatorial Index" 1998 Academic
Press, San Diego/London pages 78-82.
[0082] 52. Richard C. Larock Comprehensive Organic Transormations
2nd Ed. 1999, John Wiley and Sons New York.
[0083] 53. M. D. Mullican et.al. J.Med. Chem. 1991, 34,
2186-2194.
[0084] 54. Protective groups in organic synthesis 3rd ed./Theodora
W. Greene and Peter G. M. Wuts. New York: Wiley, 1999.
[0085] 55. Katritzky, Alan R. Lagowski, Jeanne M. The principles of
heterocyclic ChemistryNew York: Academic Press, 1968.
[0086] 56. Paquette, Leo A. Principles of modern heterocyclic
chemistry New York: Benjamin.
[0087] 57. Katritzky, Alan R.; Rees, Charles W.; Comprehensive
heterocyclic chemistry: the structure, reactions, synthesis, and
uses of heterocyclic compounds 1st ed.Oxford (Oxfordshire); New
York: Pergamon Press, 1984. 8 v.
[0088] 58. Katritzky, Alan RHandbook of heterocyclic 1st edOxford
(Oxfordshire); New York: Pergamon Press, 1985.
[0089] 59. Davies, David I Aromatic Heterocyclic Oxford; New York:
Oxford University Press, 1991.
[0090] 60. Ellis, G. P. Synthesis of fused Chichester [Sussex]; New
York: Wiley, c1987-c1992. Chemistry of heterocyclic compounds; v.
47.
[0091] 61. Joule, J. A Mills, K., Smith, G. F. Heterocyclic
Chemistry, 3rd ed London; New York Chapman & Hall, 1995.
[0092] 62. Katritzky, Alan R., Rees, Charles W., Scriven, Eric F.
V. Comprehensive heterocyclic chemistry II: a review of the
literature 1982-1995.
[0093] 63. The structure, reactions, synthesis, and uses of
heterocyclic compounds 1st ed. Oxford; New York: Pergamon, 1996. 11
v. in 12: ill.; 28 cm.
[0094] 64. Eicher, Theophil, Hauptmann, Siegfried. The chemistry of
heterocycles: structure, reactions, syntheses, and applications
Stuttgart; New York: G. Thieme, 1995.
[0095] 65. Grimmett, M. R. Imidazole and benzimidazole Synthesis
London; San Diego: Academic Press, 1997.
[0096] 66. Advances in heterocyclic chemistry. Published in New
York by Academic Press, starting in 1963-present.
[0097] 67. Gilchrist, T. L. (Thomas Lonsdale) Heterocyclic
chemistry 3rd ed. Harlow, Essex: Longman, 1997, 414 p: ill.; 24
cm.
[0098] 68. Farina, Vittorio; Roth, Gregory P. Recent advances in
the Stille reaction; Adv. Met.-Org. Chem. 1996, 5, 1-53.
[0099] 69. Farina, Vittorio; Krishnamurthy, Venkat; Scott, William
J. The Stille reaction; Org. React. (N.Y.) (1997), 50, 1-652.
[0100] 70. Stille, J. K. Angew. Chem. Int. Ed. Engl. 1986, 25,
508-524.
[0101] 71. Norio Miyaura and Akiro Suzuki Chem Rev. 1995, 95,
2457.
[0102] 72. Home, D. A. Heterocycles 1994, 39, 139.
[0103] 73. Kamitori, Y. et.al. Heterocycles, 1994, 37(1), 153.
[0104] 74. Shawali, J. Heterocyclic Chem. 1976, 13, 989.
[0105] 75. a) Kende, A. S.et al. Org. Photochem. Synth. 1972, 1,
92. b) Hankes, L. V.; Biochem. Prep. 1966, 11, 63. c) Synth. Meth.
22, 837.
[0106] 76. Hulton et. al. Synth. Comm. 1979, 9, 789.
[0107] 77. Pattanayak, B. K. et.al. Indian J. Chem. 1978, 16,
1030.
[0108] 78. Chemische Berichte 1902, 35, 1545.
[0109] 79. Chemische Berichte Ibid 1911, 44, 493.
[0110] 80. Moubarak, I., Vessiere, R. Synthesis 1980, Vol. 1,
52-53.
[0111] 81. Ind J. Chem. 1973, 11, 1260.
[0112] 82. Roomi et.al. Can J. Chem. 1970, 48, 1689.
[0113] 83. Sorrel, T. N. J. Org. Chem. 1994, 59, 1589.
[0114] 84. Nitz, T. J. et. al. J. Org. Chem. 1994, 59,
5828-5832.
[0115] 85. Bowden, K. et.al. J. Chem. Soc. 1946, 953.
[0116] 86. Nitz, T. J. et. al. J. Org. Chem. 1994, 59,
5828-5832.
[0117] 87. Scholkopf et. al. Angew. Int. Ed. Engl. 1971, 10(5),
333.
[0118] 88. (a) Behun, J. D.; Levine, R. J. Org. Chem. 1961, 26,
3379. (b) Rossen, K.; Weissman, S. A.; Sager, J.; Reamer, R. A.;
Askin, D.; Volante, R. P.; Reider, P. J. Asymmetric Hydrogenation
of tetrahydropyrazines: Synthesis of (S)-piperazine
2-tert-butylcarboxamide, an intermediate in the preparation of the
HIV protease inhibitor Indinavir. Tetrahedron Lett., 1995, 36,
6419-6422. (c) Jenneskens, L. W.; Mahy, J.; den Berg, E. M. M. de
B.-v.; Van der Hoef, I.; Lugtenburg, J. Recl. Trav. Chim. Pays-Bas
1995, 114, 97.
[0119] 89. Wang, T.; Zhang, Z.; Meanwell, N. A. Benzoylation of
Dianions: Preparation of mono-Benzoylated Symmetric Secondary
Diamines. J. Org. Chem., 1999, 64, 7661-7662.
[0120] 90. (a) Adamczyk, M.; Fino, J. R. Synthesis of procainamide
metabolites. N-acetyl desethylprocainamide and
desethylprocainamide. Org. Prep. Proced. Int. 1996, 28, 470-474.
(b) Wang, T.; Zhang, Z.; Meanwell, N. A. Regioselective
mono-Benzoylation of Unsymmetrical Piperazines. J. Org. Chem., in
press.
[0121] 91. Masuzawa, K.; Kitagawa, M.; Uchida, H. Bull Chem. Soc.
Jpn. 1967, 40, 244-245.
[0122] 92. Furber, M.; Cooper, M. E.; Donald, D. K. Tetrahedron
Lett. 1993, 34, 1351-1354.
[0123] 93. Blair, Wade S.; Deshpande, Milind; Fang, Haiquan; Lin,
Pin-fang; Spicer, Timothy P.; Wallace, Owen B.; Wang, Hui; Wang,
Tao; Zhang, Zhongxing; Yeung, Kap-sun. Preparation of antiviral
indoleoxoacetyl piperazine derivatives U.S. Pat. No. 6,469,006.
Preparation of antiviral indoleoxoacetyl piperazine derivatives.
PCT Int. Appl. (PCT/US00/14359), WO 0076521 A1, filed May 24, 2000,
published Dec. 21, 2000.
[0124] 94. Wang, Tao; Wallace, Owen B.; Zhang, Zhongxing; Meanwell,
Nicholas A.; Bender, John A. Antiviral azaindole derivatives. U.S.
Pat. No. 6,476,034 and Wang, Tao; Wallace, Owen B.; Zhang,
Zhongxing; Meanwell, Nicholas A.; Bender, John A. Preparation of
antiviral azaindole derivatives. PCT Int. Appl. (PCT/US01/02009),
WO 0162255 A1, filed Jan. 19, 2001, published Aug. 30, 2001.
[0125] 95. Wallace, Owen B.; Wang, Tao; Yeung, Kap-Sun; Pearce,
Bradley C.; Meanwell, Nicholas A.; Qiu, Zhilei; Fang, Haiquan; Xue,
Qiufen May; Yin, Zhiwei. Composition and antiviral activity of
substituted indoleoxoacetic piperazine derivatives. U.S. Pat. No.
6,573,262 which is a continuation-in-part application of U.S. Ser.
No. 09/888,686 filed Jun. 25, 2001 (corresponding to PCT Int. Appl.
(PCT/US01/20300), WO 0204440 A1, filed Jun. 26, 2001, published
Jan. 17, 2002.
[0126] 96. J. L. Marco, S. T. Ingate, and P. M. Chinchon
Tetrahedron 1999, 55, 7625-7644.
[0127] 97. C. Thomas, F. Orecher, and P.Gmeiner Synthesis 1998,
1491.
[0128] 98. M. P. Pavia, S. J. Lobbestael, C. P. Taylor, F. M.
Hershenson, and D. W. Miskell.
[0129] 99. Buckheit, Robert W., Jr. Expert Opinion on
Investigational Drugs 2001, 10(8), 1423-1442.
[0130] 100. Balzarini, J.; De Clercq, E.. Antiretroviral Therapy
2001, 31-62.
[0131] 101. E. De clercq Journal of Clinical Virology, 2001, 22,
73-89.
[0132] 102. Merour, Jean-Yves; Joseph, Benoit. Curr. Org. Chem.
(2001), 5(5), 471-506.
[0133] 103. T. W. von Geldern et al. J. Med. Chem 1996, 39,
968.
[0134] 104. M. Abdaoui et al. Tetrahedron 2000, 56, 2427.
[0135] 105. W. J. Spillane et al. J. Chem. Soc., Perkin Trans. 1,
1982, 3, 677.
[0136] 106. Wang, Tao; Zhang, Zhongxing; Meanwell, Nicholas A.;
Kadow, John F.; Yin, Zhiwei; Xue, Qiufen May. (USA). Composition
and antiviral activity of substituted azaindoleoxoacetic piperazine
derivatives. U.S. patent application Publ. (2003), US 20030207910
A1 published Nov. 6, 2003 which is 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.
[0137] 107. a) Nickel, Bernd; Szelenyi, Istvan; Schmidt, Jurgen;
Emig, Peter; Reichert, Dietmar; Gunther, Eckhard; Brune, Kay.
Preparation of indolylglyoxylamides as antitumor agents. PCT Int.
Appl. (1999), 47 pp. CODEN: PIXXD2 WO 9951224, b) Emig, Peter;
Bacher, Gerald; Reichert, Dietmar; Baasner, Silke; Aue, Beate;
Nickel, Bernd; Guenther, Eckhard. Preparation of
N-(6-quinolinyl)-3-indolylglyoxylamides as antitumor agents. PCT
Int. Appl. (2002), 4WO 2002010152A2, c) Nickel, Bernd; Klenner,
Thomas; Bacher, Gerald; Beckers, Thomas; Emig, Peter; Engel,
Juergen; Bruyneel, Erik; Kamp, Guenter; Peters, Kirsten.
Indolyl-3-glyoxylic acid derivatives comprising therapeutically
valuable properties. PCT Int. Appl. (2001), WO 2001022954A2.
[0138] 108. Wang, Tao; Wallace, Owen B.; Meanwell, Nicholas A.;
Zhang, Zhongxing; Bender, John A.; Kadow, John F.; Yeung, Kap-Sun.
Preparation of indole, azaindole, and related heterocyclic
piperazinecarboxamides for treatment of AIDS. PCT Int. Appl. WO
2002085301A2, published Oct. 31, 2002; corresponding to U.S. patent
Publication U.S. 20030096825A1, published May 22, 2003.
[0139] 109. Kadow, John F.; Xue, Qiufen May; Wang, Tao; Zhang,
Zhongxing; Meanwell, Nicholas A. Preparation of indole, azaindole
and related heterocyclic pyrrolidine derivatives as antiviral
agents. PCT Int. Appl. WO 2003068221A1, published Aug. 21, 2003;
corresponding to U.S. patent Publication U.S. 20030236277A1.
[0140] 110. Wang, Tao; Wallace, Owen B.; Meanwell, Nicholas A.;
Kadow, John F.; Zhang, Zhongxing; Yang, Zhong. Preparation of
piperazine derivatives as antiviral agents. PCT Int. Appl. (2003),
WO 2003092695 A1; corresponding to U.S. patent Publication U.S.
20040009985A1, published Jan. 15, 2004.
[0141] 111. Kadow, John F.; Regueiro-Ren, Alicia; Xue, Qiufen May.
Preparation of indolyl-, azaindolyl-, and related heterocyclic
sulfonylureidopiperazines for treatment of HIV and AIDS. PCT Int.
Appl. (2003), WO 2004000210 A2; corresponding to U.S. patent
Publication U.S. 20040006090A1, published Jan. 8, 2004.
[0142] 112. Regueiro-Ren, Alicia; Xue, Qiufen May; Kadow, John F.;
Taylor, Malcolm. Preparation of indolyl-, azaindolyl-, and related
heterocyclic ureido and thioureido piperazines for treatment of HIV
and AIDS. PCT Int. Appl. (2004), WO 2004011425 A2; corresponding to
U.S. patent Publication U.S. 20040063746A1, published Apr. 1,
2004.
[0143] 113. Wang, Tao; Zhang, Zhongxing; Meanwell, Nicholas A.;
Kadow, John F.; Yin, Zhiwei; Xue, Qiufen May; Regueiro-Ren, Alicia;
Matiskella, John D.; Ueda, Yasutsugu. Composition and antiviral
activity of substituted azaindoleoxoacetic piperazine derivatives.
U.S. patent application Publ. (2004), US 2004110785 A1; published
Jun. 10, 2004.
[0144] 114. Wang, Tao; Kadow, John F.; Meanwell, Nicholas A.;
Yeung, Kap-Sun; Zhang, Zhongxing; Yin, Zhiwei; Qiu, Zhilei; Deon,
Daniel H.; James, Clint A.; Ruediger, Edward H.; Bachand, Carol.
Preparation and pharmaceutical compositions of indole, azaindole
and related heterocyclic 4-alkenyl piperidine amides. U.S. patent
application Publ. (2004), US 20040063744 A1; published Apr. 1,
2004; corresponding to PCT Intl. Appln. (2004), WO 2004/04337.
SUMMARY OF THE INVENTION
[0145] The present invention comprises compounds of Formula I,
their pharmaceutical formulations, and their use in patients
suffering from or susceptible to a virus such as HIV. The compounds
of Formula I, which include nontoxic pharmaceutically acceptable
salts thereof, have the formula and meaning as described below.
[0146] The present invention comprises compounds of Formula I,
including pharmaceutically acceptable salts thereof, which are
effective antiviral agents, particularly as inhibitors of HIV.
4
[0147] wherein:
[0148] Q is selected from the group consisting of 5
[0149] T is --C(O)-- or --CH(CN)--;
[0150] R.sup.1 is hydrogen or methyl;
[0151] R.sup.3 and R.sup.5 are independently selected from the
group consisting of hydrogen, halogen, cyano, nitro, COOR.sup.8,
XR.sup.9 and B;
[0152] R.sup.2 and R.sup.4 are independently O or do not exist with
the proviso that only one of R.sup.2 and R.sup.4 are O;
[0153] R.sup.6 is (CH.sub.2).sub.nH, wherein n is 0-1;
[0154] -- represents a carbon-carbon bond or does not exist;
[0155] --Y-- is selected from the group consisting of 6
[0156] R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,R.sup.15,
R.sup.16 and R.sup.17 are each independently H or (C.sub.1-6)alkyl;
wherein said (C.sub.1-6)alkyl may optionally be substituted with
one to three same or different halogen, OH or CN;
[0157] R.sup.18 is a member selected from the group consisting of
C(O)-phenyl, C(O)-heteroaryl, pyridinyl, pyrimidinyl, quinolyl,
isoquinolyl, quinazolyl, quinoxalinyl, napthyridinyl, pthalazinyl,
azabenzofuryl and azaindolyl; wherein said member is optionally
substituted with from one to two substituents selected from the
group consisting of methyl, -amino, --NHMe, --NMe.sub.2, methoxy,
hydroxymethyl and halogen;
[0158] D is selected from the group consisting of hydrogen, cyano,
S(O).sub.2R.sup.24, halogen, COOR.sup.20, C(O)NR.sup.21R.sup.22,
phenyl and heteroaryl; wherein said phenyl or heteroaryl is
independently optionally substituted with one to three same or
different halogens or from one to three same or different
substituents selected from F (as defined below);
[0159] A is selected from the group consisting of phenyl,
pyridinyl, furanyl, thienyl, isoxazole and oxazole; wherein said
phenyl, pyridinyl, furanyl, thienyl, isoxazole or oxazole is
independently optionally substituted with one to three same or
different halogens or from one to three same or different
substituents selected from F;
[0160] B is selected from the group consisting of (C.sub.1-6)alkyl,
C(O)NR.sup.21R.sup.22, --C(O)CH.sub.3,
--N(CH.sub.2CH.sub.2).sub.2NC(O)py- razolyl, phenyl and heteroaryl;
wherein said (C.sub.1-6)alkyl, phenyl and heteroaryl are
independently optionally substituted with one to three same or
different halogens or from one to three same or different
substituents selected from F;
[0161] heteroaryl is selected from the group consisting of
pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl,
benzothienyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl,
oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl and triazolyl;
[0162] F is selected from the group consisting of (C.sub.1-6)alkyl,
(C.sub.1-6)alkenyl, phenyl, pyridinyl, hydroxy, (C.sub.1-6)alkoxy,
halogen, benzyl, --NR.sup.23C(O)--(C.sub.1-6)alkyl,
--NR.sup.24R.sup.25, --S(O).sub.2NR.sup.24R.sup.25, COOR.sup.26,
--COR.sup.27, and --CONR.sup.24R.sup.25; wherein said
(C.sub.1-6)alkyl or phenyl are each optionally substituted with
hydroxy, (C.sub.1-6)alkoxy, (C.sub.1-6)alkyl, CF.sub.3,
dimethylamino or from one to three same or different halogen;
[0163] R.sup.8, R.sup.9 and R.sup.26 are each independently
selected from the group consisting of hydrogen and
(C.sub.1-6)alkyl;
[0164] X is selected from the group consisting of NR.sup.26, O and
S;
[0165] R.sup.20, R.sup.21,R.sup.22, R.sup.23, R.sup.24 and R.sup.25
are independently selected from the group consisting of hydrogen,
(C.sub.1-6)alkyl, phenyl and heteroaryl; wherein said phenyl and
heteroaryl are each independently optionally substituted with one
to three same or different halogen or methyl; and
[0166] R.sup.27 is piperazinyl, N-methyl piperazinyl, or
3-pyrazolyl.
[0167] A preferred embodiment includes compounds where T is 7
[0168] Another preferred embodiment of the invention are compounds
of Formula I, including pharmaceutically acceptable salts
thereof
[0169] wherein:
[0170] R.sup.1 is hydrogen;
[0171] -- represents a carbon-carbon bond; and
[0172] R.sup.2 and R.sup.4 do not exist.
[0173] D is selected from the group consisting of hydrogen, cyano,
S(O).sub.2R.sub.24, halogen, COOR.sup.24, C(O)NH.sub.2, phenyl and
heteroaryl; wherein said phenyl or heteroaryl is independently
optionally substituted with one to three same or different halogens
or a member selected from the group consisting of (C.sub.1-6)alkyl,
(C.sub.1-6)alkenyl, hydroxy, (C.sub.1-6)alkoxy, halogen,
--NR.sup.24R.sup.25, --S(O).sub.2NR.sup.24R.sup.25, COOR.sup.26 and
--CONR.sup.24R.sup.25; wherein said (C.sub.1-6)alkyl is optionally
substituted with one to three same or different halogen or a
hydroxy; and
[0174] A is selected from the group consisting of phenyl,
pyridinyl, furanyl, thienyl, isoxazole and oxazole; wherein said
phenyl, pyridinyl, furanyl, thienyl, isoxazole or oxazole are
independently optionally substituted with one to three same or
different halogens or a member selected from the group consisting
of (C.sub.1-4)alkyl, (C.sub.1-4)alkenyl, (C.sub.1-3)alkoxy, halogen
and --NH.sub.2; wherein said (C.sub.1-3)alkyl is optionally
substituted with one to three same or different halogens.
[0175] Another preferred embodiment are compounds I wherein:
[0176] R.sup.6 is hydrogen; and
[0177] R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,R.sup.15,
R.sup.16, R.sup.17 are each independently H or methyl with the
proviso that a maximum of two of R.sup.10--R.sup.17 is a
methyl.
[0178] Another preferred embodiment of the invention are compounds
of Formula I, as above including pharmaceutically acceptable salts
thereof,
[0179] wherein:
[0180] Q is a member selected from groups (A), (B), and (C)
consisting of
[0181] (A) 8
[0182] wherein R.sup.3 is hydrogen, C.sub.1-C.sub.3 alkoxy,
--NR.sup.26R.sup.9 or halogen;
[0183] (B) 9
[0184] wherein R.sup.3 is hydrogen, methoxy or halogen; and
[0185] (C) 10
[0186] wherein R.sup.3 is hydrogen, methoxy or halogen.
[0187] Another preferred embodiment of the invention are compounds
of Formula I, as above including pharmaceutically acceptable salts
thereof, wherein:
[0188] group(A) of Q is:
[0189] (A) 11
[0190] wherein R.sup.3 is hydrogen; and
[0191] group (C) of Q is: 12
[0192] wherein:
[0193] R.sup.5 is hydrogen.
[0194] In another preferred embodiment of the invention, Q is
selected from group (A) or (B), and
[0195] R.sup.5 is selected from the group consisting of hydrogen,
halogen, heteroaryl, phenyl, cyano, methoxy, COOR.sup.8,
C(O)NH.sub.2, C(O)NHheteroaryl, and C(O)NHCH.sub.3; wherein said
C(O)NHheteroaryl, phenyl, and heteroaryl are independently
optionally substituted with one to three same or different halogens
or from one to three same or different substituents selected from
F.
[0196] Other preferred embodiments are compounds I:
[0197] wherein heteroaryl is selected from the group consisting of
pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl,
thiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,
thiadiazoyl, pyrazolyl, tetrazolyl and triazolyl; wherein said
heteroaryl is independently optionally substituted with one to
three same or different halogens or from one to three same or
different substituents selected from F;
[0198] R.sup.18 is --C(O)phenyl or --C(O)heteroaryl; wherein said
heteroaryl is pyridinyl, furanyl or thienyl; wherein heteroaryl is
independently optionally substituted with a member selected from
the group consisting of halogen, methyl, -amino, --NHMe, NMe.sub.2
and hydroxymethyl;
[0199] --W-- is 13
[0200] R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,R.sup.15,
R.sup.16 and R.sup.17 are each independently H or methyl with the
proviso that not more than one is methyl; and
[0201] R.sup.18 is selected from the group consisting of
C(O)-phenyl or C(O)-heteroaryl wherein each of C(O)-phenyl or
--C(O)-heteroaryl may be optionally substituted with from one to
two methyl, -amino, --NHMe, --NMe.sub.2, methoxy, hydroxymethyl or
halogen groups; or
[0202] R.sup.18 is selected from the group consisting of pyridyl,
pyrimidinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl,
napthyridinyl, pthalazinyl, azabenzofuryl and azaindolyl, each of
which may be optionally substituted with from one to two methyl,
-amino, --NHMe, --NMe.sub.2, methoxy, hydroxymethyl or halogen
groups.
[0203] In another preferred embodiment:
[0204] --W-- is selected from the group consisting of 14
[0205] R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,R.sup.15,
R.sup.16 and R.sup.17 are each independently H or methyl, with the
proviso that one is methyl;
[0206] D is selected from the group consisting of hydrogen, cyano,
S(O).sub.2R.sup.24, halogen, COOR.sup.20, C(O)NH.sub.2, phenyl, or
heteroaryl; wherein said phenyl or heteroaryl is independently
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.sub.1-6)alkyl, (C.sub.1-6)alkenyl,
hydroxy, (C.sub.1-6)alkoxy, halogen, --NR.sup.24R.sup.25,
--S(O).sub.2NR.sup.24R.sup.25, COOR.sup.26 and
--CONR.sup.24R.sup.25; wherein said (C.sub.1-6)alkyl is optionally
substituted with one to three same or different halogen or a
hydroxy; and
[0207] A is selected from the group consisting of phenyl,
pyridinyl, furanyl, thienyl, isoxazole and oxazole; wherein said
phenyl, pyridinyl, furanyl, thienyl, isoxazole or oxazole is
independently 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.sub.1-4)alkyl, (C.sub.1-4)alkenyl, (C.sub.1-3)alkoxy, halogen
and --NH.sub.2; wherein said (C.sub.1-4)alkyl is optionally
substituted with one to three same or different halogens.
[0208] In another preferred embodiment:
[0209] Q is selected from Group (A).
[0210] Another preferred embodiment are compounds of Formula I,
including pharmaceutically acceptable salts thereof, 15
[0211] wherein:
[0212] Q is selected from the group consisting of 16
[0213] R.sup.1 is hydrogen or methyl;
[0214] R.sup.3 and R.sup.5 are independently selected from the
group consisting of hydrogen, halogen, cyano, nitro, COOR.sup.8,
XR.sup.9 and B;
[0215] R.sup.2 and R.sup.4 are independently O or do not exist,
with the proviso that only one of R.sup.2 and R.sup.4 are O;
[0216] R.sup.6 is (CH.sub.2).sub.nH, wherein n is 0-1;
[0217] -- represents a carbon-carbon bond or does not exist;
[0218] --Y-- is selected from the group consisting of 17
[0219] R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,R.sup.15,
R.sup.16 and R.sup.17 are each independently H or (C.sub.1-6)alkyl;
wherein said (C.sub.1-6)alkyl may optionally be substituted with
one to three same or different halogen, OH or CN;
[0220] R.sup.18 is a member selected from the group consisting of
C(O)-phenyl, C(O)-heteroaryl, pyridinyl, pyrimidinyl, quinolyl,
isoquinolyl, quinazolyl, quinoxalinyl, napthyridinyl, pthalazinyl,
azabenzofuryl and azaindolyl; wherein said member is optionally
substituted with from one to two substituents selected from the
group consisting of methyl, -amino, --NHMe, --NMe.sub.2, methoxy,
hydroxymethyl and halogen;
[0221] D is selected from the group consisting of hydrogen, cyano,
S(O).sub.2R.sup.24, halogen, COOR.sup.20, C(O)NR.sup.21R.sup.22,
phenyl and heteroaryl; wherein said phenyl or heteroaryl is
independently optionally substituted with one to three same or
different halogens or from one to three same or different
substituents selected from F;
[0222] A is selected from the group consisting of phenyl,
pyridinyl, furanyl, thienyl, isoxazole and oxazole; wherein said
phenyl, pyridinyl, furanyl, thienyl, isoxazole or oxazole is
independently optionally substituted with one to three same or
different halogens or from one to three same or different
substituents selected from F;
[0223] B is selected from the group consisting of (C.sub.1-6)alkyl,
(C.sub.3-6)cycloalkyl, C(O)NR.sup.21R.sup.22, --C(O)CH.sub.3,
--N(CH.sub.2CH.sub.2).sub.2NC(O)pyrazolyl, phenyl and heteroaryl;
wherein said (C.sub.1-6)alkyl, phenyl and heteroaryl are
independently optionally substituted with one to three same or
different halogens or from one to three same or different
substituents selected from F;
[0224] heteroaryl is selected from the group consisting of
pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl,
thiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,
thiadiazolyl, pyrazolyl, tetrazolyl and triazolyl;
[0225] F is selected from the group consisting of (C.sub.1-6)alkyl,
(C.sub.1-6)alkenyl, phenyl, pyridinyl, hydroxy, (C.sub.1-6)alkoxy,
halogen, benzyl, --NR.sup.23C(O)--(C.sub.1-6)alkyl,
--NR.sup.24R.sup.25, --S(O).sub.2NR.sup.24R.sup.25, COOR.sup.26,
--COR.sup.27, and --CONR.sup.24R.sup.25; wherein said
(C.sub.1-6)alkyl or phenyl are each optionally substituted with
hydroxy, (C.sub.1-6)alkoxy, dimethylamino or from one to three same
or different halogen;
[0226] R.sup.8, R.sup.9 and R.sup.26 are each independently
selected from the group consisting of hydrogen and
(C.sub.1-6)alkyl;
[0227] X is selected from the group consisting of NR.sup.26, O and
S;
[0228] R.sup.20, R.sup.21,R.sup.22, R.sup.23,R.sup.24 and R.sup.25
are independently selected from the group consisting of hydrogen,
(C.sub.1-6)alkyl, phenyl and heteroaryl; wherein said phenyl and
heteroaryl are each independently optionally substituted with one
to three same or different halogen or methyl; and
[0229] R.sup.27 is piperazinyl, N-methylpiperazinyl or
3-pyrazolyl.
[0230] In another embodiment are Compounds I, including
pharmaceutically acceptable salts, wherein:
[0231] Q is 18
[0232] R.sup.5 is selected from the group consisting of hydrogen,
halogen, cyano, XR.sup.9, heteroaryl,
--N(CH.sub.2CH.sub.2).sub.2NC(O)pyrazolyl, and --C(O)CH.sub.3,
wherein said heteroaryl is optionally substituted with one
substituent selected from F;
[0233] heteroaryl is selected from the group consisting of
pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl,
isoxazolyl, pyrazolyl, and triazolyl;
[0234] --Y-- is selected from the group consisting of 19
[0235] R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,R.sup.15,
R.sup.16 and R.sup.17 are each hydrogen;
[0236] A is phenyl or pyridinyl;
[0237] R.sup.18 is C(O)-phenyl, isoquinolyl or quinazolyl;
[0238] D is cyano or oxadiazolyl;
[0239] F is selected from the group consisting of (C.sub.1-6)alkyl,
phenyl, pyridinyl, (C.sub.1-2)alkoxy, --COOR.sup.26--COR.sup.27 and
--CONR.sup.24R.sup.25; wherein said phenyl is optionally
substituted with one group selected from methyl, methoxy, fluoro,
or trifluoromethyl;
[0240] X is selected from the group consisting of O;
[0241] R.sup.9 is (C.sub.1-2)alkyl;
[0242] R.sup.26 is hydrogen, methyl, or ethyl;
[0243] R.sup.24 and R.sup.25 are independently selected from the
group consisting of hydrogen and methyl; and
[0244] R.sup.27 is piperazinyl, N-methyl piperazinyl, or
3-pyrazolyl.
[0245] Another embodiment of the present invention is a method for
treating mammals infected with the HIV virus, comprising
administering to said mammal an antiviral effective amount of a
compound of Formula I, including pharmaceutically acceptable salts
thereof, and one or more pharmaceutically acceptable carriers,
excipients or diluents; optionally the compound of Formula I can be
administered 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.
[0246] Another embodiment of the present invention is a
pharmaceutical composition comprising an antiviral effective amount
of a compound of Formula I, including pharmaceutically acceptable
salts thereof, and one or more pharmaceutically acceptable
carriers, excipients, diluents and 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
[0247] 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
[0248] 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.
[0249] "Halogen" refers to chlorine, bromine, iodine or
fluorine.
[0250] 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, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,
O-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.
[0251] 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, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,
O-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.
[0252] 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. Rings are selected from those which provide stable
arrangements of bonds and are not intended to encomplish systems
which would not exist. 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, O-carbamyl, N-carbamyl,
O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamido, N-amido,
C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido,
trihalomethanesulfonamido, trihalomethanesulfonyl, silyl, guanyl,
guanidino, ureido, phosphonyl, amino and --NR.sup.xR.sup.y, wherein
R.sup.x and R.sup.y are as defined above.
[0253] 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 six-member heteroalicyclic ring.
[0254] 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, 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,
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.
[0255] 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.
[0256] 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.
[0257] A "hydroxy" group refers to an --OH group.
[0258] An "alkoxy" group refers to both an --O-alkyl and an
--O-cycloalkyl group as defined herein.
[0259] An "aryloxy" group refers to both an --O-aryl and an
--O-heteroaryl group, as defined herein.
[0260] A "heteroaryloxy" group refers to a heteroaryl-O-- group
with heteroaryl as defined herein.
[0261] A "heteroalicycloxy" group refers to a heteroalicyclic-O--
group with heteroalicyclic as defined herein.
[0262] A "thiohydroxy" group refers to an --SH group.
[0263] A "thioalkoxy" group refers to both an S-alkyl and an
--S-cycloalkyl group, as defined herein.
[0264] A "thioaryloxy" group refers to both an --S-aryl and an
--S-heteroaryl group, as defined herein.
[0265] A "thioheteroaryloxy" group refers to a heteroaryl-S-- group
with heteroaryl as defined herein.
[0266] A "thioheteroalicycloxy" group refers to a
heteroalicyclic-S-- group with heteroalicyclic as defined
herein.
[0267] 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.
[0268] An "aldehyde" group refers to a carbonyl group where R" is
hydrogen.
[0269] A "thiocarbonyl" group refers to a --C(.dbd.S)--R" group,
with R" as defined herein.
[0270] 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.
[0271] A "trihalomethanecarbonyl" group refers to a
Z.sub.3CC(.dbd.O)-- group with said Z being a halogen.
[0272] A "C-carboxy" group refers to a --C(.dbd.O)O--R" groups,
with R" as defined herein.
[0273] An "O-carboxy" group refers to a R"C(.dbd.O)O-group, with R"
as defined herein.
[0274] A "carboxylic acid" group refers to a C-carboxy group in
which R" is hydrogen.
[0275] A "trihalomethyl" group refers to a --CZ.sub.3, group
wherein Z is a halogen group as defined herein.
[0276] A "trihalomethanesulfonyl" group refers to an
Z.sub.3CS(.dbd.O).sub.2-- groups with Z as defined above.
[0277] 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.
[0278] 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)--.
[0279] 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--.
[0280] 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.
[0281] A "N-Sulfonamido" group refers to a
R"S(.dbd.O).sub.2NR.sub.X-- group with R.sub.x as defined
herein.
[0282] A "O-carbamyl" group refers to a --OC(.dbd.O)NR.sup.xR.sup.y
as defined herein.
[0283] 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.
[0284] 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.
[0285] A "N-thiocarbamyl" group refers to a
R.sup.xOC(.dbd.S)NR.sup.y-- group with R.sup.x and R.sup.y as
defined herein.
[0286] An "amino" group refers to an --NH.sub.2 group.
[0287] 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.
[0288] 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.
[0289] 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.
[0290] 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.
[0291] An "thioureido" group refers to a
--NR.sup.xC(.dbd.S)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.
[0292] 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.
[0293] 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.
[0294] A "cyano" group refers to a --CN group.
[0295] A "silyl" group refers to a --Si(R").sub.3, with R" as
defined herein.
[0296] A "phosphonyl" group refers to a P(.dbd.O)(OR.sup.x).sub.2
with R.sup.x as defined herein.
[0297] 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.
[0298] 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.
[0299] 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.
[0300] 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.
[0301] 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.
[0302] 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 trans- criptase
(RT) inhibitor) Amprenivir Glaxo Wellcome HIV infection, 141 W94
AIDS, ARC GW 141 (protease inhibitor) Abacavir Glaxo Wellcome HIV
infection, (1592U89) AIDS, ARC GW 1592 (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 Gilead Sciences HIV infection
dipivoxil Ethigen ARC, PGL AL-721 (Los Angeles, CA) HIV positive,
AIDS Alpha Glaxo Wellcome Kaposi's sarcoma, Interferon 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
(Rockville, MD) aberrant Interferon AR177 Aronex Pharm HIV
infection, AIDS, ARC Beta-fluoro- Nat'l Cancer Institute
AIDS-associated ddA 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 AJI Pharma USA HIV infection sulfate
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 Ueno Fine Chem. AIDS, ARC, HIV Sulfate 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- (non-nucleoside RT 4-(S)-cyclo- inhibitor)
propylethynyl- 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 Triton Biosciences AIDS, Kaposi's Human (Almeda, CA)
sarcoma, ARC Interferon Beta Interferon Interferon Sciences ARC,
AIDS alfa-n3 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, Glaxo Wellcome HIV infection, 3TC
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 Phosphono- Products, Inc.
infection, other CMV formate infections PNU-140690 Pharmacia Upjohn
HIV infection, AIDS, ARC (protease inhibitor) Probucol Vyrex HIV
infection, AIDS RBC-CD4 Sheffield Med. Tech HIV infection,
(Houston, TX) AIDS, ARC Ritonavir Abbott HIV infection, AIDS, ARC
(protease inhibitor) Saquinavir Hoffmann-LaRoche HIV infection,
AIDS, ARC (protease inhibitor) Stavudine; d4T Bristol-Myers Squibb
HIV infection, AIDS, Didehydro- ARC deoxythymidine 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;
Glaxo Wellcome HIV infection, AIDS, AZT ARC, Kaposi's sarcoma, in
combination with other therapies Tenofovir Gilead HIV infection,
AIDS, disoproxil, (reverse transcriptase fumarate salt inhibitor)
(Viread .RTM.) Combivir .RTM. GSK HIV infection, AIDS, (reverse
transcriptase inhibitor) abacavir GSK HIV infection, AIDS,
succinate (reverse transcriptase (or Ziagen .RTM.) inhibitor)
Reyataz .RTM. (or Bristol-Myers Squibb HIV infection AIDs,
atazanavir) protease inhibitor Fuzeon .RTM. Roche/Trimeris HIV
infection AIDs, (or T-20) viral Fusion inhibitor 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 Genentech ARC, in
combination Interferon w/TNF (tumor necrosis factor) Granulocyte
Genetics Institute AIDS Macrophage Sandoz Colony Stimulating Factor
Granulocyte Hoechst-Roussel AIDS Macrophage Immunex Colony
Stimulating Factor Granulocyte Schering-Plough AIDS, combination
Macrophage w/AZT Colony Stimulating Factor HIV Core Rorer
Seropositive HIV Particle Immuno- stimulant IL-2 Cetus AIDS, in
Interleukin-2 combination 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
Cutter Biological Pediatric AIDS, in Globulin (Berkeley, CA)
combination w/AZT Intravenous (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 Merieux Institute
AIDS, ARC Diethyl 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 Colony
combination w/AZT Stimulating 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 Pharmacia Upjohn PCP with Primaquine
Fluconazole Pfizer Cryptococcal meningitis, candidiasis Pastille
Squibb Corp. Prevention of Nystatin oral candidiasis Pastille
Ornidyl Merrell Dow PCP Eflornithine Pentamidine LyphoMed PCP
treatment Isethionate (Rosemont, IL) (IM & IV) Trimethoprim
Antibacterial Trimethoprim/ Antibacterial sulfa 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 Ortho Pharm. Corp. Severe anemia Human assoc. with AZT
Erythropoietin therapy Recombinant Serono AIDS-related Human
wasting, cachexia Growth Hormone Megestrol Bristol-Myers Squibb
Treatment of Acetate anorexia assoc. W/AIDS Testosterone Alza,
Smith Kline AIDS-related wasting Total Enteral Norwich Eaton
Diarrhea and Nutrition Pharmaceuticals malabsorption related to
AIDS
[0303] 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 and
Inhibitors of the entry of HIV into host cells. Meanwell, Nicholas
A.; Kadow, John F. Current Opinion in Drug Discovery &
Development (2003), 6(4), 451-461. Specifically the compounds can
be utilized in combination with other attachment inhibitors, fusion
inhibitors, and chemokine receptor antagonists aimed at either the
CCR5 or CXCR4 coreceptor.
[0304] 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.
[0305] Preferred combinations are simultaneous or alternating
treatments 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 Reyataz.RTM. (active ingredient Atazanavir). Typically a dose of
300 to 600 mg is administered once a day. This may be
co-administered with a low dose of Ritonavir (50 to 500 mgs).
Another preferred inhibitor of HIV protease is Kaletra.RTM..
Another useful inhibitor of HIV protease is indinavir, which is the
sulfate salt of
N-(2(R)-hydroxy-1-(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.
[0306] 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).
Abbreviations
[0307] 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:
[0308] h=hour(s)
[0309] r.t.=room temperature
[0310] mol=mole(s)
[0311] mmol=millimole(s)
[0312] g=gram(s)
[0313] mg=milligram(s)
[0314] mL=milliliter(s)
[0315] TFA=Trifluoroacetic Acid
[0316] DCE=1,2-Dichloroethane
[0317] CH.sub.2Cl.sub.2=Dichloromethane
[0318] TPAP=tetrapropylammonium perruthenate
[0319] THF=Tetrahydofuran
[0320]
DEPBT=3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one
[0321] DMAP=4-dimethylaminopyridine
[0322] P-EDC=Polymer supported
1-(3-dimethylaminopropyl)-3-ethylcarbodiimi- de
[0323] EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
[0324] DMF=N,N-dimethylformamide
[0325] Hunig's Base=N,N-Diisopropylethylamine
[0326] MCPBA=meta-Chloroperbenzoic Acid
[0327] azaindole=1H-Pyrrolo-pyridine
[0328] 4-azaindole=1H-pyrrolo[3,2-b]pyridine
[0329] 5-azaindole=1H-Pyrrolo[3,2-c]pyridine
[0330] 6-azaindole=1H-pyrrolo[2,3-c]pyridine
[0331] 7-azaindole=1H-Pyrrolo[2,3-b]pyridine
[0332] 4,6-diazaindole=5H-Pyrrolo[3,2-d]pyrimidine
[0333] 5,6-diazaindole=1H-Pyrrolo[2,3-d]pyridazine
[0334] 5,7-diazaindole=7H-Pyrrolo[2,3-d]pyrimidine
[0335] PMB=4-Methoxybenzyl
[0336] DDQ=2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
[0337] OTf=Trifluoromethanesulfonoxy
[0338] NMM=4-Methylmorpholine
[0339] PIP-COPh=1-Benzoylpiperazine
[0340] NaHMDS=Sodium hexamethyldisilazide
[0341] EDAC=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
[0342] TMS=Trimethylsilyl
[0343] DCM=Dichloromethane
[0344] DCE=Dichloroethane
[0345] MeOH=Methanol
[0346] THF=Tetrahydrofuran
[0347] EtOAc=Ethyl Acetate
[0348] LDA=Lithium diisopropylamide
[0349] TMP-Li=2,2,6,6-tetramethylpiperidinyl lithium
[0350] DME=Dimethoxyethane
[0351] DIBALH=Diisobutylaluminum hydride
[0352] HOBT=1-hydroxybenzotriazole
[0353] CBZ=Benzyloxycarbonyl
[0354] PCC=Pyridinium chlorochromate
[0355] Chemistry
[0356] 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.
[0357] The synthesis procedures and anti-HIV-1 activities of
substituted diazaindole oxoacetic and piperidine containing analogs
are described below.
[0358] Scheme A depicts one of the preferred methods for preparing
the compounds of the invention. In this method, as shown in Step A,
a functionalized diazaindole which also has a carboxy ester
appended to the three position is condensed with an acetonitrile
anion functionalized with Y to provide the alpha cyano ketone
examples of the invention. Oxidation of these compounds as shown in
Step B, provides further compounds of the invention. 20
[0359] Step A. The carboxylic ester intermediates Z-CO.sub.2R or
more preferably the acid chlorides Z-CO.sub.2Cl from Scheme A are
condensed with a cyanomethyl intermediate YCH.sub.2CN under basic
conditions to form the .alpha.-cyanoketo intermediate ZC(O)CH(CN)Y.
The base KHMDS in THF at r.t. is employed most often, but other
amide bases such as NaHMDS could be utilized. The typical solvent
utilized is THF but DMF can be employed for less soluble molecules.
Typically the reaction with an acid chloride Z-CO.sub.2Cl is
conducted with the reaction flask immersed in a dry ice acetone
cooling bath (.about.-78.degree. C.) when THF is the solvent and an
acetonitrile/acetone cooling bath (.about.-42.degree. C.) when DMF
is the solvent but temperatures between -78.degree. and 50.degree.
C. could be employed in appropriate cases. The reaction is stirred
between 1 h and 1 day. Typically the reaction when judged to be
complete by TLC or LC or LC/MS is maintained at the cold
temperature and oxidant added directly to the reaction as described
in Step B. Alternatively the reaction could be allowed to attain
ambient temperature and either allowed to react further if
necessary and then quenched or be immediately quenched with
saturated aqueous sodium bicarbonate. The mixture could then be
extracted with EtOAc, concentrated and the .alpha.-cyanoketo
intermediate ZC(O)CH(CN)Y could be purified by preparative HPLC.
When the same reaction is carried out with an ester Z-CO2R as the
reactant, the alkylation reaction is initiated and then is usually
allowed to warm to ambient temperature for further reaction.
Typically R is methyl or ethyl or less ideally another lower alkyl
group. Phenoxy, pentafluorophenoxy, or Weinreb esters
(R.dbd.--NH.sub.2OMe) might also be employed. As mentioned above,
in the event that the carboxylic ester intermediates Z-CO.sub.2R
are less reactive than desired under the standard condensation
conditions, they may be activated by the intial conversion to an
acid chloride Z-COCl (OR where R=H converted to Cl). This is
currently the preferred method for diazaindole esters of this
invention. The preparation of the acid chlorides from Z-CO.sub.2R--
is accomplished by initial hydrolysis of the ester to the analogous
carboxylic acid Z-CO.sub.2H. A typical procedure involves stirring
the ester with LiOH in THF and water at 100.degree. C. for 6 h to 2
days, concentrating the crude mixture and recrystallizing the
carboxylic acid from water. The carboxylic acid Z-CO.sub.2H is then
dissolved or more typically suspended as a slurry in
dichloromethane and stirred with oxalyl chloride and a catalytic
amount of DMF from 4-24 h but typically overnight. The solvents are
removed in vacuo and the acid chloride used directly. Possible
alternative solvents are benzene or toluene. A possible alternative
method for conversion of the carboxylic acid to an acid chloride
entails reacting thionyl choride in benzene at 100.degree. C.
between 2 h and 6 h with the acid in the presence of catalytic DMF
followed by concentration in vacuo to yield the acid chloride
Z-CO.sub.2Cl. As mentioned above, the acid chloride Z-CO.sub.2Cl is
the preferred reactant for conducting step A for the preparation of
diazindole compounds of formula I. Alternatively, the acid may be
converted to an acid anhydrides which may also find utility in the
alkylation reaction.
[0360] Step B. The preferred method for accomplishing step B, the
conversion of the .alpha.-cyanoketo intermediate ZC(O)CH(CN)Y to
the diacarbonyl compounds of formula I or ketoamide intermediates
to prepare compounds of formula I is to to add 1-20 equivalents but
most preferably 5 equivalents of a commercially available solution
of 32% peracetic acid in dilute aq acetic acid tb the reaction
flask containing the completed reaction described in Step A. The
reaction is typically stirred at the same temperature at which the
alkylation reaction was conducted (for the Step A reactions with an
acid chloride in THF .about.-78.degree. and for the step A
reactions in DMF .about.-42.degree.) for a period of 1 h and then
allowed to warm to ambient temperature if not already at that
tmeperature. The reaction mixture is then either allowed to react
further or immediately diluted with saturated aq. ammonium chloride
and EtOAc. For relatively insoluble acid products which
precipatate, the resultant precipitate is isolated by filtration as
the oxoacetyl product ZC(O)C(O)Y. For organic soluble acid
products, the acid is extracted into the organic layer and the
layers separated. The organic layer is concentrated in vacuo and
the product purified via preparative HPLC. The .alpha.-cyanoketo
intermediate ZC(O)CH(CN)Y, if isolated, can be oxidized to the
oxoacetyl product ZC(O)C(O)Y using a variety of oxidants including
mCPBA, NaOCl (bleach), peracetic acid, or nickel peroxide. In a
typical procedure a solution of peracetic acid in acetic acid is
added to a solution of .alpha.-cyanoketo intermediate ZC(O)CH(CN)Y
in THF and the reaction is stirred at between r.t and -70.degree.
C. for between 30 min and 2 h. The reaction mixture is then diluted
with saturated aq. ammonium chloride and EtOAc and the resultant
precipitate is isolated by filtration as the oxoacetyl product
ZC(O)C(O)Y. Step A and Step B can be combined into a one pot
reaction by adding the oxidant directly to the reaction pot after
the completion of step A without isolating the .alpha.-cyanoketo
intermediate ZC(O)CH(CN)Y.
[0361] Scheme B depicts a typical method for preparing the
cyanomethyl piperazine or piperidine analogues utilized in scheme
A. Two general literature references for some of the chemistry
depicted in these initial schemes are Takahashi, K.; Shibasaki, K.;
Ogura, K.; Iida, H.; Chem Lett. 1983, 859 or Yang; Z.; Zhang, Z.;
Meanwell, N. A.; Kadow, J. F.; Wang, T.; Org. Lett. 2002, 4, 1103.
21
[0362] Step C. The secondary amine of a functionalized piperazine
or piperidine can be alkylated with a haloacetonitrile under basic
conditions to yield a cyanomethyl piperazine or piperidine
analogue. In a typical procedure N-benzoyl piperazine was added to
a solution of chloroacetonitrile and TEA in THF and stirred at r.t.
for between 2 and 5 days. A resulting precipitate is removed by
filtration, the filtrate is concentrated in vacuo, and the residue
purified via chromatography to yield the cyanomethyl intermediate
YCH.sub.2CN. The alkylation with haloacetonitrile can also be
carried out with an alternate base, such as 4-methylmorpholine or
diisopropylethyl amine.
[0363] The diazaindole carboxylic ester condensation partners
Z-C(O)OR utilized in Scheme A can be prepared as shown in the
following schemes:
[0364] One preferred method for preparing 4,6 diazaindole is shown
in Scheme C. 22
[0365] Step D. The reaction of an (alkoxymethylene)cyanoacetate
with an amino malonate under basic conditions is known to yield a
2,4-dicarboxylic ester-3-aminopyrrole. As shown in Scheme C, step D
is carried out by reacting an amino malonate with an 2-alkoxy
1-cyano acrylate in the presence of a base such as sodium ethoxide.
For a representive example see; Elliot, A. J.; Montgomery, J. A.,
and Walsh, D. A. Tetrahedron Lett, 1996, 37(25), 4339-4340. A
typical procedure and conditions is is described in the
experimental section.
[0366] Step E. The 3-Aminopyrrole 2-carboxylic ester resulting from
step D can be cyclized to the desired 7-hydroxyl-4,6-diazaindole
using a number of reagents including formamides, dialkyl acetal
formamides, nitriles and formamidines. In a typical procedure
3-aminopyrrole-2,4-dicarboxylic acid diethyl ester and formidine
acetate are heated at reflux in EtOH for 1 to 3 days. The reaction
solution is filtered hot and the product usually crystallized upon
cooling and is then rinsed with diethyl ether.
[0367] Step F. A 3-carboxylic ester 7-hydroxyl-4,6-diazaindole can
then be converted to a 7-chloro analogue by treatment with a
chlorinating reagent such as POCl.sub.3 or SOCl.sub.2. In a typical
reaction procedure 3-ethylester-7-hydroxyl-4,6-diazaindole and
POCl.sub.3 are combined and heated at 105.degree. C. for between 3
and 5 h, cooled to r.t. and diluted with diethyl ether. The
precipitate that forms is collected by filtration and was shown to
be the 7-chloro-4,6-diazaindole. Alternatively, when greater
reactivity is desired for further functionalization and for
carrying out step G, the corresponding 7-bromo-4,6-diazindole may
be prepared by substituting POBr.sub.3 for the chlorinating agents
described above.
[0368] Step G. A 7-chloro-4,6-diazaindole can be displaced with a
variety of nucleophiles to form the claimed R.sup.5 substituents or
intermediates from which the claimed R.sup.5 substituents can be
formed. Included in these are cyanide, alkoxides, amines, alcohols
and various metallated species (cuprates, lithiates, zincates and
Grignard reagents). In a typical procedure
3-ethylester-7-chloro-4,6-diazaindole and 3-methyl pyrazole in EtOH
are heated at between 100.degree. C. and 140.degree. C. for 20 min
to 1 h. Upon cooling the reaction is concentrated and purified by
silica gel chromatography or by preparative HPLC. This step may
also be carried out after the initial coupling and oxidation steps
(steps A and B) have been preformed on the
3-ethylester-7-chloro-4,6-diazaindole intermediate. A cyano moiety
could be introduced and converted to acids, esters, amides,
imidates, or heteraromatics. Typical amide coupling methodology
could be used to prepare amides from acids. It should also be noted
that the halogen moiety may be carried through until compounds of
the invention are realized and then the conditions described in
Step G may frequently be used to prepare further compounds of the
invention.
[0369] Alternatively, a 7-chloro or 7-bromo-4,6-diazaindole could
be coupled to a heteroaryl stannane or boronic ester via Stille or
Suzuki methodology respectively. Other metal catalyzed methodology
such as copper mediated displacements could also be used to prepare
N linked heteraromatic or heteroalicyclic derivatives. In general,
substituted diazaindoles containing a chloride, bromide, iodide,
triflate, or phosphonate should undergo coupling reactions with a
boronate (Suzuki type reactions) or a stannane to provide
substituted diazaindoles. Stannanes and boronates are prepared via
standard literature procedures or as described in the experimental
section of this application. The vinyl bromides, chlorides,
triflates, or phosphonates may undergo metal mediated coupling to
provide compounds of formula W-H. Stille or Suzuki couplings are
particularly useful. A detailed discussion of the references and
best conditions for these kinds of metal mediated coupling is
described later in this application where the discussion is
combined with a description of how these types of reactions may
also be used to funtionalize diazaindoles. In additions,
applications incorporated in their entirety elsewhere in this
application contain methods for preparing heteroaryls from
funtional groups appended to indoles and azaindoles. This
methodology is also applicable to diazaindoles.
[0370] One potential method for preparing the 5,6-diazaindoles
QCOOR is shown in Scheme D. 23
[0371] Step H. A TMS-isocyanide would be reacted with an acid
fluoride in the presence of a dialkyl acetylene dicarboxylate to
form a substituted pyrrole. For representative examples see:
Livinghouse, T.; Smith, R.; J. Chem. Soc, Chem. Commun 1983, 5,
210. In a typical procedure, trimethylsilylmethyl isocyanide
(generated from the lithiation of methyl isocyanide, followed by
silylation with TMSCl) would be stirred with an aryl acid fluoride
and dimethyl acetylenedicarboxylate in toluene at 80.degree. C.
After a standard workup a functionalized pyrrole where R.sup.1 is
hydrogen and R.sup.5 is aryl would be realized.
[0372] Step I. A mixture of the keto-diester-pyrrole and hydrazine
dihydrochloride in ethanol heated at reflux should result in the
formation of the desired 4-hydroxyl-5,6-diazaindole. Alternatively,
the keto-diester-pyrrole, hydrazine hydrate and a catalytic amount
of p-toluenesulfonic acid could be heated to reflux in toluene or
benzene in the presence of a Dean-Stark trap and upon dehydration,
the desired 4-hydroxyl-5,6-diazaindole should form.
[0373] Step J, Step K and Step L. A 4-hydroxyl-5,6-diazaindole
intermediate could be converted to the intermediates in which
R.sup.3 is modified by direct functionalization of the hydroxyl
group or by conversion of the hydroxyl group to a leaving group
(halogen or triflate) followed by nucleophilic displacement or a
metal (Pd or Cu) mediated coupling. These step(s) might also be
carried out after the initial coupling and oxidation steps (steps A
and B) have been preformed on the 4-hydroxyl-5,6-diazaindole
intermediate. The conditions described for step G could also be
utilized for this system. 2425
[0374] As shown in Scheme DD pyrrole 2,3 di-carboxylic ethyl ester
prepared as in either of the following two references: Roeder,
Erhard; Wiedenfeld, Helmut; Bourauel, Thomas. Synthesis of ethyl
2,3-bis(ethoxycarbonyl)-1H-pyrrole-1-propionate. Liebigs Annalen
der Chemie (1987), (12), 1117-19. and Swan, George A.; Waggott, A.
Chemistry of melanins. VI. Syntheses of 3-carboxypyrrole-2-acetic
acid, 3,5-dicarboxypyrrole-2-acetic acid, and related compounds.
Journal of the Chemical Society [Section] C: Organic (1970), (2),
285-90. could be reacted with hydrazine in ethanol between RT and
reflux to provide the cyclized product of step DD1. Reaction with
phosphoryl chloride (2.2 to 5 equivalents should provide the
dichloride as shown in step DD2. In step DD3, selective reaction of
the C-7 chloride could occur by using benzyl alcohol and
triethylamine in a cosolvent such as THF. In step DD4, the 4-chloro
group might then be displaced with sodium or potassium methoxide in
solvents such as methanol or toluene or a mixture. Stoichiometric
copper I iodide could be added to speed slow reactions. In step
DD5, selective hydrogenation of the benzyl group using 5 to 10%
Pd/C in EtOH under a balloon pressure of hydrogen brovides the
7-hydroxy compound. Alternatively the benzyl group may be cleaved
selectively with TMSI in acetonitrile at temperatures from 0 to
65.degree. C. or using HBr in 1,2,dichloroethane at temps from -20
to 50.degree. C. An alternate prep is to react the
dichlorointemrediate above with methoxide rather than benzyl
alcohol and then to selectivel cleave the C-7 ether using
conditions described for the benzyl cleavage. Reacting the C-7
hydroxy group /amide tautomer with POCl3 or POBr3 would generate
the chloride or bromide selectively which may be functionalized as
described in step G of Scheme C for the 4,6-diazindoles. Step DD6
describes acylation of the functionalized intermediate and is done
using the same procedures described in step O of Scheme F. Step
DD7, amide copuling with piperazine or piperidine is carried out
according to the general procedures described in Step P of Scheme F
to provide compounds of the invention. It should be understood that
the order of steps DD5-DD7 could be switched to determine which
order provides best yields.
[0375] The 5,7-diazaindole could be prepared as shown in Scheme E.
Intermediate M1 is a known compound whose synthesis has been
described in the literature in the following references: Olsen,
David B.; Lafemina, Robert L.; Eldrup, Anne B.; Bera, Sanjib.
Methods of inhibiting orthopoxvirus replication with nucleoside
compounds. PCT Int. Appl. (2003), 99 pp. WO 2003068244A1 Mekouar,
Khalid; Deziel, Robert; Mounir, Samir; Iyer, Radhakrishnan P.
Preparation of 7-deaza L-nucleosides as antiviral agents against
the hepatitis B virus. PCT Int. Appl. (2003), WO 2003055896A2
Carroll, Steven S.; Lafemina, Robert L.; Hall, Dawn L.;
Himmelberger, Amy L.; Kuo, Lawrence C.; Maccoss, Malcolm; Olsen,
David B.; Rutkowski, Carrie A.; Tomassini, Joanne E.; An, Haoyun;
Bhat, Balkrishen; Bhat, Neelima; Cook, Phillip Dan; Eldrup, Anne
B.; Guinosso, Charles J.; Prhavc, Marija; Prakash, Thazha P.
Preparation of nucleoside derivatives as inhibitors of
RNA-dependent RNA viral polymerase. PCT Int. Appl. (2002), 235 pp.
CODEN: PIXXD2 WO 2002057425A2 Carroll, Steven S.; Maccoss, Malcolm;
Olsen, David B.; Bhat, Balkrishen; Bhat, Neelima; Cook, Phillip
Dan; Eldrup, Anne B.; Prakash, Thazha P.; Prhavc, Marija; Song,
Quanlai. Preparation of nucleoside derivatives as inhibitors of
RNA-dependent RNA viral polymerase. PCT Int. Appl. (2002), WO
2002057287A2. 26
[0376] Intermediate M2 where R is ethyl is a known compound which
could be prepared as described in the following three literature
references:
[0377] Ugarkar, Bheemarao G.; DaRe, Jay M.; Kopcho, Joseph J.;
Browne, Clinton E., III; Schanzer, Juergen M.; Wiesner, James B.;
Erion, Mark D. Adenosine Kinase Inhibitors. 1. Synthesis, Enzyme
Inhibition, and Anti-seizure Activity of 5-Iodotubercidin
Analogues. Journal of Medicinal Chemistry (2000), 43(15),
2883-2893.
[0378] Firestein, Gary Steven; Ugarkar, Bheemarao Ganapatrao;
Miller, Leonard Paul; Gruber, Harry Edward; Bullough, David Andrew;
Erion, Mark David; Castellino, Angelo John. Preparation of
adenosine kinase-inhibiting purine nucleoside analogs as
antiinflammatory agents. PCT Int. Appl. WO 9417803A1.
[0379] Browne, Clinton E.; Ugarkar, Bheemarao G.; Mullane, Kevin
M.; Gruber, Harry E.; Bullough, David A.; Erion, Mark D.;
Castellino, Angelo. Adenosine kinase inhibitors. Eur. Pat. Appl. EP
496617A1.
[0380] Step N. Nucleophilic or metal catalyzed substitution of the
4-chloro-5,7-diazaindole will yield the R.sup.3 substituents of
claim 1.
[0381] The diazaindole core may be coupled to the functionalized
piperidine or piperazine through an oxoacetate or through an
acylation/amidation process as shown in Scheme F. 27
[0382] Step O. Conversion of a specific 3H-diazaindole to the
depicted ketoacid might be accomplished via several methods. Method
a for step O: One successful method has been to use Fridel-Crafts
acylation conditions mediated by an ionic liquid. In particular the
ionic liquid 1-alkyl-3-alkylimidazolium chloroaluminate is
generally useful in promoting the Friedel-Crafts type acylation and
does work with some diazainoles. 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 diazaindoles with methyl or ethyl chlorooxoacetate
would be the 1-ethyl-3-methylimidazolium chloroaluminate. The
reaction would typically be performed at ambient temperature and
the diazaindoleglyoxyl ester would be expected to be isolated. The
resulting ester could then be hydrolyzed using the hydrolysis
methods for Step O described below.
[0383] More conveniently, it is probable that the glyoxyl ester
could be hydrolyzed in situ at ambient temperature upon prolonged
reaction time (typically overnight) to give the corresponding
glyoxyl acid which would be ready for amide formation.
[0384] A representative experimental procedure is as follows:
1-ethyl-3-methylimidazolium chloride (2 equiv.; purchased from TCI;
weighted under a stream of nitrogen) would be stirred in an
oven-dried round bottom flask at r.t. under a nitrogen atmosphere,
and then aluminium chloride (6 equiv.; anhydrous powder packaged
under argon in ampules purchased from Aldrich preferred would be
added; after weighing under a stream of nitrogen). The mixture
would be vigorously stirred to form a liquid, to which would then
be added diazaindole (1 equiv.) followed by stirring until a
homogenous mixture resulted. To the reaction mixture would then be
added dropwise ethyl or methyl chlorooxoacetate (2 equiv.) and then
stirring would be continued at r.t. for 2 to 24 h, probably
approximately 16 h. After stirring was completed, the mixture an
ice-water bath and the reaction would be quenched by carefully
adding excess water. The precipitates would be filtered, washed
with water and dried under high vacuum to give the
diazaindoleglyoxylic acid. For some examples, 3 or even equivalents
of 1-ethyl-3-methylimidazolium chloride and chlorooxoacetate may be
required. A more comprehensive reference with analogous examples
with non diazaindoles but with conditions that could be utilized
with diazaindoles is contained in: Yeung, Kap-Sun; Farkas, Michelle
E.; Qiu, Zhilei; Yang, Zhong. Friedel-Crafts acylation of indoles
in acidic imidazolium chloroaluminate ionic liquid at room
temperature. Tetrahedron Letters (2002), 43(33), 5793-5795.4
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 00/15594.
[0385] Step O method B. The diazaindole could be treated with a
Grignard reagent such as MeMgI (methyl magnesium iodide), methyl
magnesium bromide or ethyl magnesium bromide and then 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 diaza-indole glyoxyl ester. 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, THF, dioxane or the like could potentially be used alone or in
combination for this sequence.
[0386] Step O method c: A Lewis acid catalyzed Friedel-Crafts
reaction under standard conditions with an alkyl chloroacetoacetate
might be utilized. This could be followed by in situ by hydrolysis
of the ester my the method described below to form the diazaindole
ketocarboxylic acid (cite previous patent(s)). Thus the diazindole
ketoester precursors to the depicted acid could be prepared by
reaction of diazaindoles with an excess of ClCOCOOMe in the
presence of AlCl.sub.3 (aluminum chloride). Some further
descriptions of the exact procedures to carry out this reaction but
on indoles or azaindoles are contained in a) Zhang, Zhongxing;
Yang, Zhong; Wong, Henry; Zhu, Juliang; Meanwell, Nicholas A.;
Kadow, John F.; Wang, Tao. "An Effective Procedure for the
Acylation of Azaindoles at C-3." J. Org. Chem. 2002, 67(17),
6226-6227; b) Tao Wang et. al. U.S. Pat. No. 6,476,034 B2
"Antiviral Azaindole derivatives" published Nov. 5, 2002; c) W.
Blair et al. PCT patent application WO 00/76521 A1 published Dec.
21,2000; d) O. Wallace et. al. PCT application WO 02/04440A1
published Jan. 17, 2002. 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 would
be 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. Lewis
acid catalysts, such as tin tetrachloride, titanium IV chloride,
and aluminum chloride could be employed with this transformation
with aluminum chloride being most preferred.
[0387] Hydrolysis methods for Step O. Hydrolysis of a diazindole
keto methyl ester would afford a potassium salt of the acid product
shown as the product for Step O in Scheme F and this would then be
ready for coupling with amines as shown in the next step.
Acidification during workup, typically with aqueous HCl would
provide the acid products from Step O as shown. 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.
[0388] Step P. The ketocarboxylic acid may be coupled with
functionalized piperidines or piperazines using a number of
standard amide bond or peptide bond forming coupling reagents. The
acid intermediate Z-C(O)(O)OH from Scheme F could be coupled with
either a substituted piperazine or piperidine, H--Y using standard
amide bond or peptide bond forming coupling reagents. The
combination of EDAC and triethylamine in tetrahydrofuran or BOPCl
and diisopropyl ethyl amine in chloroform could be utilized but
DEPBT, or other coupling reagents such as PyBop could be utilized.
Another useful coupling condition employs HATU (L. A. Carpino et.
al. J.Chem.Soc. Chem Comm. 1994, 201-203; A. Virgilio et.al. J.Am.
Chem. Soc. 1994, 116,11580-11581). A general procedure for using
this reagent is Acid (1 eq) and H--Y or H--W-Boc or HCl salt (2 eq)
in DMF are stirred at rt for between 1 h and 2 days. HATU (2 eq) is
added in one portion and then DMAP(3 eq). The reaction could be
stirred at rt for 2 to 15 h (reaction progress monitored by
standard methods ie TLC, LC/MS). The mixture is filtered through
filter paper to collect the solid. The filtrate is concentrated and
water is added. The mixture is filtered again and the solid is
washed with water. The solid is conbined and washed with water.
Many reagents for amide bond couplings are known by an organic
chemist skilled in the art and nearly all of these are applicable
for realizing coupled amide products.
[0389] DEPBT
(3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) and
N,N-diisopropylethylamine, commonly known as Hunig's base,
represents another efficient method to form the amide bond (step
P). DEPBT is either purchased from Adrich or 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.
[0390] 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 in
incorporated applications for construction of substituents
R.sub.2--R.sub.5 on indoles or azaindoles. Some specific
nonlimiting examples are given in this application.
[0391] Alternatively, the acid could be converted to a methyl ester
using excess diazomethane in THF/ether. The methyl ester in dry THF
could be reacted with the lithium amide of intermediate H--Y. The
lithium amide of H--Y, Li--Y is formed by reacting H--Y with
lithium bistrimethylsilylamide in THF for 30 minutes in an ice
water cooling bath. Sodium or potassium amides could be formed
similarly and utilized if additional reactivity is desired. Other
esters such as ethyl, phenyl, or pentafluorophenyl could be
utilized and would be formed using standard methodology.
[0392] In addition, the acid can be converted to the acid chloride
using oxalyl chloride in a solvent such as benzene or thionyl
chloride either neat or containing a catalystic amount of DMF.
Temperatures between 0.degree. C. and reflux may be utilized
depending on the substrate. Compounds of Formula I can be obtained
from the resultant compounds of formula Z-C(O)(O)Cl by reaction
with the appropriate H--Y in the presence of a tertiary amine (3-10
eq.) such as triethylamine or diisopropylethylamine in an anhydrous
aprotic solvent such as dichloromethane, dichloroethane, diethyl
ether, dioxane, THF, acetonitrile, DMF or the like at temperatures
ranging from 0.degree. C. to reflux. Most preferred are
dichloromethane, dichloroethane, or THF. The reaction can be
monitored by LC/MS. The 3H-diazaindoles may also be prepared under
Bartoli or Liemgruber-Batchko reaction conditions as shown in
schemeG. Conditions for carrying out these reactions were contained
in the incorporated patent applications.
[0393] Note: For the purposes of brevity, the following symbol is
taken to represent the following systems: 28 29
[0394] Step Q. Step Q in Scheme G depicts a potential synthesis of
a diazaindole intermediate, via the well known Bartoli reaction in
which vinyl magnesium bromide reacts with an aryl or heteroaryl
nitro groups, to form a five-membered nitrogen containing ring as
shown. Some references for the above transformation to form an
indole ring include: Bartoli et al. a) Tetrahedron Lett. 1989, 30,
2129. b) J. Chem. Soc. Perkin Trans. 1 1991, 2757. c) J. Chem. Soc.
Perkin Trans. II 1991, 657. d) SynLett (1999), 1594. In the
preferred procedure, which could be applied to diazaindole
synthesis, 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 12 h 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.
[0395] Step R. Reaction with dimethylformamide dimethyl acetal in
an inert solvent or neat under conditions for forming
Batcho-Leimgruber precursors would provide the cyclization
precursor, 33, as shown. A typical condition would employ 20% DMF
dimethyl acetal in DMF heated to 105-110 degrees C. 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.
[0396] Step S. Reduction of the nitro group using for example
hydrogenation over Pt on/C catalyst in a solvent such as MeOH,
EtOH, or EtOAc could provide the cyclized product. Generally only a
slight positive pressure of hydrogen would be required (a stream)
but higher pressures may be needed (1.5 atm). 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.
[0397] Another possible method for preparation of 5,6-diazaindoles
is shown in scheme H. 30
[0398] Step T. 1,2,3,4-Tetrazines have been shown to react with
pyrrole and substituted pyrroles to form 5,6-diazaindole products.
This reaction proceeds through a [4+2]-cycloaddition followed by a
retro-[4+2]-cycloaddition to release nitrogen gas and a subsequent
oxidation to establish aromaticity. For representative examples
see: Seitz, Z.; Kaempchen, T.; Arch. Pharm. 1978, 311, 728.
Takahashi, M; Ishida, H.; Kohmoto, M. Bull. Chem. Soc. Japan 1976,
49, 1725. Benson, S. C.; Palabrica, C. A.; Snyder, J. K. J. Org.
Chem. 1987, 52, 4610. Gonzalez, J. C.; Lobo-Antunes, J;
Perez-Lourido, P.; Santana, L.; Uriate, E. Synthesis 2002, 4,
475-478.
[0399] Another possible method for preparing a 5,6-diazaindole with
a C-3 oxoacetate is shown in Scheme I (Cook, P. D.; Castle, R. N.
J. Het. Chem. 1973, 10, 551. 31
[0400] Step U. The starting pyridazine N-oxide would initially be
nitrated and the resulting nitro group then would be reduced under
standard conditions to an amine. The chloro would then be removed
under hydrogentation conditions. Alternatively, the chloro could
remain in the molecule and be carried through the subsequent steps.
This should allow for the formation of a 4-chloro-5,6-diazaindole.
The chloro could then be converted to a methoxy or an amino group
by nucleophilic displacement or copper catalyzed assisted coupling.
This would result in an intermediate that could be converted to
molecules claimed within this application via previously described
amide bond coupling.
[0401] Step V The amine could then be functionalized with ethyl
orthoformate under acidic conditions to form an ethoxyimine. In a
typical procedure the amine and triethyl orthoformate were
dissolved into a solution of DMF and ethanol that had been adjusted
to pH 1 with anhydrous hydrogen chloride. The reaction was then
heated to 150-160.degree. C. and ethanol was collected by
distillation resulting in the formation of the desired
ethoxyimine.
[0402] Step W Deprotonation of the methyl group followed by
acylation with diethyl oxalate would yield a ketoester intermediate
that could be used to form a 3-oxoacetate-5,6-diazaindole (Step X)
or could be used to make a 2-carboxylate-5,6-diazaindole by
hydrolysis of the imine, followed by condensation of the amine onto
the ketone five centers away.
[0403] Step X. The ketoester could then be cyclized onto the
ethoxyimine under basic conditions to arrive at the
3-oxoacetate-5,6-diazaindole. To form the molecules of this claim,
functionalized piperazine or piperidones could be coupled to the
ester through standard amide bond forming reactions. This general
scheme should also allow for the preparation of other
5,6-diazaindole intermediates with different R.sup.3 and R.sup.5
substituents by displacement or coupling to the chloro or
displacement of the methoxy at some point in the sequence.
Preparations of Functionalized Piperazines and Piperidines are
Described later in the Application.
[0404] 32
[0405] As shown above in Scheme 15, Step F15, substituted
diazaindoles containing a chloride, bromide, iodide, triflate, or
phosphonate could undergo coupling reactions with a boronate
(Suzuki type reactions) or a stannane to provide substituted
diazaindoles. Stannanes and boronates are prepared via standard
literature procedures or as described in the experimental section
of this application. The substitututed diazindoles may undergo
metal mediated coupling to provide compounds of Formula I wherein
R.sub.4 is aryl, heteroaryl, or heteroalicyclic for example. The
bromo or chloro diazaindole intermediates, (or diazaindole
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 diazaindole 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 diazaindole 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 diazaindole intermediates are also
feasible and have been utilized extensively for this invention.
Preferred procedures for coupling of a chloro diazaindole 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 diazaindole 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 (O) tetrakis triphenyl
phosphine heated for 5 to 15 h at 110 to 120.degree.. Some
references (and the references therein) describing catalysts which
are useful for coupling with aryl and heteroaryl chlorides are:
[0406] Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000,
122(17), 4020-4028;
[0407] Varma, R. S.; Naicker, K. P. Tetrahedron Lett. 1999, 40(3),
439-442; Wallow, T. I.;
[0408] Novak, B. M. J. Org. Chem. 1994, 59(17), 5034-7; Buchwald,
S.; Old, D. W.;
[0409] Wolfe, J. P.; Palucki, M.; Kamikawa, K.; Chieffi, A.;
Sadighi, J. P.; Singer, R. A.;
[0410] Ahman, J. PCT Int. Appl. WO 0002887 2000; Wolfe, J. P.;
Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38(23), 3415; Wolfe,
J. P.; Singer, R. A.; Yang, B. H.;
[0411] Buchwald, S. L. J. Am. Chem. Soc. 1999, 121(41), 9550-9561;
Wolfe, J. P.;
[0412] Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38(16),
2413-2416; Bracher, F.;
[0413] Hildebrand, D.; Liebigs Ann. Chem. 1992, 12, 1315-1319; and
Bracher, F.;
[0414] Hildebrand, D.; Liebigs Ann. Chem. 1993, 8, 837-839.
[0415] Alternatively, the boronate or stannane could potentially be
formed on the diazaindole via methods known in the art and the
coupling performed in the reverse manner with aryl or heteroaryl
based halogens or triflates.
[0416] 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.
[0417] Novel stannane agents could be prepared from one of the
following routes. 33 34 35 36 37
[0418] Boronate reagents are prepared 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.
[0419] Related examples are provided in the following experimental
section.
[0420] 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 diazaindoles. 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. 38 39
[0421] Direct displacements to install amine or N linked heteroaryl
substituents could also be used to prepare compounds of Formula I.
As shown in Schemes 15aa and 15bb, a mixture of halo-diazaindole
intermediate, 1-2 equivalents of copper powder; 1-2 equivalents of
potassium carbonate, 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. 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.
[0422] Alternatively, the installation of amines or N linked
heteroaryls could be carried out by heating 1 to 40 equivalents of
the appropriate amine and an equivalent of the appropriate
diazaindole chloride, bromide or iodide with copper bronze (from
0.1 to 10 equivalents (preferably about 2 equivalents) and from 1
to 10 equivalents of finely pulverized potassium hydroxide
(preferably about 2 equivalents). Temperatures of 120.degree. to
200.degree. might be employed with 140-160.degree. generally
preferred. For volatile starting materials a sealed reactor may be
employed. The reaction would most often be applicable when the
halogen being displaced is at the 7-position of a diazaindole but
the method could work when the halogen is at a different position
(4-7 position possible). As shown above the reaction could be
employed on diazaindoles unsubstituted at position 3 or
intermediates which contain the dicarbonyl or the intact dicarbonyl
piperazine urea or thioureas contained in compounds of formula I.
40
[0423] A possible 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 one position for the sake of clarity,
and should not be considered as a limitation of the methodology.
The bromide or iodide intermediate would be converted into an
aldehyde intermediate, 43, by metal-halogen exchange and subsequent
reaction with dimethylformamide in an appropriate aprotic solvent.
Typical bases used could include, but would not be 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 would be
initiated at -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
diazaindoles.
[0424] As shown in Scheme 52, the pieces HW--R.sup.18 can be
prepared by a number of different methods. One useful way is by
reacting a mono protected piperazine with a heteroaryl chloride,
bromide, iodide, or triflate. This reaction is typically carried
out at elevated temperature (50 to 250 degrees celsius) in a
solvent such as ethylene glycol, DME, dioxane, NMP, or DMF. A
tertiary amine base such as triethyl amide or diisopropyl ethyl
amine is typically employed and usually 2 to 4 equivalents are
employed. At least 2 equivalents are used if a salt of HW R.sup.18
is utilized. The piperazine is typically monoprotected with a BOC
group since this material is commercially available. Removal of the
Boc group is typically done using HCl (typically 1 to 6N) in
dioxane to provide the HCl salt. TFA may also be used to generate
the TFA salt. Alternatively, the conditions for coupling
heterocycles using copper catalysis discussed earlier in Scheme 12
may be used to couple W to R.sup.18 via displacement of X in
X--R.sup.18. Alternatively Palladium catalysis in the presence of a
bidentate catalyst via the procedures of Buchwald or the use of a
ferrocenyl catalyst via the methods of Hartwig could be used to
couple the piperazine to the heteroaryl (R.sup.18). 41 42
[0425] Scheme 53 describes how a protected piperazine can be
coupled to Q-COOH via standard methodology. Conditions for removal
of the amine protecting group which could be tBoc or other groups
is protecting group specific. As shown in Scheme 53 where tBoc is
the preferred protecting group used to exemplify the strategy,
standard conditions for removal such as TFA in dichloromethane or
alternatively aqueous HCl can provide the free amine. The free
amine is coupled to heteraromatic R.sup.18 using the conditions
described in Scheme 52 for step F"".
[0426] General Schemes:
[0427] Scheme D1 describes a possible method for preparing the
compounds described by H--W where Y is as defined in the
description and claims of the invention. Typically, this
methodology will work best when D is a group which lowers the PKA
of the hydrogens on the adjacecent methylene moiety. For example
cyano, sulfonyl, amido and the like as specified in the claim. A
preferably could be aryl or heteroaryl moieties as described in
claim 1. A could also be other groups described in claim 1.
Alkoxide bases of C1 to C4 alcohols can be utilzed but other bases
such as lithium, sodium, or potassium dialkyl amides or the
corresponding bistrimethylsilyl amides could also be utilized.
Preparation of Intermediates:
[0428] 43
[0429] Note as shown in Scheme D1, the piperazine or piperidine
moiety of Y may be substituted as defined by the invention. In the
interest of clarity, unsubstituted piperidines and piperazines are
used in the Schemes to keep them readable. It is understood
substituents could be incorporated. 44
[0430] As shown in Scheme E1, addition of an organometallic reagent
to a ketone can provide an intermediate tertiary alkoxide which
undergoes protonation and acid catalyzed elimination to form the
desired double bond. A number of organo metallic reagents could
suffice as shown but an extra equivalent (at least two total) could
be needed to compensate for deprotection of the amine nitrogen in
many cases. 45
[0431] Standard olefination conditions such as Wittig, Horner
Emmons, Petersen or Arsenic based could be used to convert the
ketone to the desired products. Some general reviews of this
methodology and directions for use are contained in the following
references: Wadsworth, W. S, Jr., in "Organic Reactions", Dauben,
W. G., Ed., Wiley, New York, 1977, 25, 73. McMurry, J. E. Acct.
Chem. Res. 1983, 16, 405. Cushman, M., et al. Bioorg. Med. Chem.
2002, 10, 2807. When Z=triphenyl phosphine, butyl lithium or LDA
could be used to generate the phosphorus ylide in THF and then the
ylide reacted with the ketone ot provide the desired product. The
phosphinate or phosphine oxide based reagents could be used with
similar bases or with sodium or postassium methoxide or ethoxide in
the corresponding alcohol solvents. 46 47
[0432] As shown above in Scheme H1, a chloride, bromide, iodide,
triflate, or phosphonate undergo coupling reactions with a boronate
(Suzuki type reactions). Stannanes and boronates are prepared via
standard literature procedures or as described in the experimental
section of this application. The vinyl bromides, chlorides,
triflates, or phosphonates may undergo metal mediated coupling to
provide compounds of formula W--H. Stille or Suzuki couplings are
particularly useful. A detailed discussion of the references and
best conditions for these kinds of metal mediated coupling is
described later in this application where the discussion is
combined with a description of how these types of reactions may
aslo be used to funtionalize diazaindoles.
[0433] When Ar is benzene, starting materials are commerially
available 48
[0434] Alternatively, the compounds Y--H could potentially be
prepared via olefin metathesis using highly active Rhodium
catalysts. The methylene starting material can be prepared via
simple Wittig methylenation of the precursor ketone which is
prepared via literature methods. The olefin metathesis is
preferably carried out using 1% of the imadazoylidene ruthenium
benzylidene catalyst described in the following reference. The
reaction is carried out starting at low temperatures (-40.degree.)
or similar. Starting methylene material is mixed with excess olefin
(5 to 100 equivalents) and the reaction is warmed to 40.degree. C.
Synthesis of Symmetrical Trisubstituted Olefins by Cross
Metathesis. Chatterjee, Arnab K.; Sanders, Daniel P.; Grubbs,
Robert H. Organic Letters ACS ASAP.
[0435] Additional references are listed below which show additional
conditions and substrates which could be used with this
catalyst.
[0436] Functional group diversity by ruthenium-catalyzed olefin
cross-metathesis. Toste, F. Dean; Chatterjee, Arnab K.; Grubbs,
Robert H. The Arnold and Mabel Beckman Laboratory of Chemical
Synthesis, Division of Chemistry and Chemical Engineering,
California Institute of Technology, Pasadena, Calif., USA. Pure and
Applied Chemistry (2002), 74(1), 7-10. A Versatile Precursor for
the Synthesis of New Ruthenium Olefin Metathesis Catalysts.
Sanford, Melanie S.; Love, Jennifer A.; Grubbs, Robert H.. Arnold
and Mabel Beckman Laboratories for Chemical Synthesis Division of
Chemistry and Chemical Engineering, California Institute of
Technology, Pasadena, Calif., USA. Organometallics (2001), 20(25),
5314-5318. Olefin metathesis with 1,1-difluoroethylene. Trnka, Tina
M.; Day, Michael W.; Grubbs, Robert H.. Arnold and Mabef Beckman
Lab. of Chemical Synthesis, California Institute of Technology,
Pasadena, Calif., USA. Angewandte Chemie, International Edition
(2001), 40(18), 3441-3444.
[0437] Scheme K1 shows a sequence in which a piperidone is coverted
to a monofuntionalized olefin via Wittig olefination. Bromination
and dehydrobromination provides a versatile vinyl bromide
intermediate. This intermediate is coupled to the QC(O)C(O)OH acid
with BOPCl to provide a compound of formula I. This intermediate is
then functionalized using palladium mediated couplings to either
boronates or stannanes. Conditions for these couplings are
described in this application. 49
[0438] Scheme L1 shows specific examples of general Scheme K1 which
are some of those described in the experimental section. 50
[0439] Scheme M1 shows how a protected vinyl bromide can be
converted to a carboxylic acid via lithium bromide exchange and
reaction with carbon dioxide. As described in this application and
the incorporated ones, carboxylic acids are excellent precursors to
many heterocyles or amides. The rest of Scheme M1 shows conversion
to funtionalized oxadiazoles. Other chemistry described in this
application depicts other methods for converting acids to groups of
other compounds of the invention. 51
[0440] Scheme N1 depicts a more specific example of Scheme M1.
52
[0441] Scheme P depicts methods for functionalizing the vinyl
bromide to install groups D (or A). Either a modified Stille
coupling or a zinc mediated coupling are depicted. Details of these
tranformations are discussed later in the section on metal
couplings. 53
[0442] Scheme Q depicts some specific examples of Scheme P. 54
[0443] Scheme R depicts methods for functionalizing the vinyl
bromide to install groups D (or A). Either a modified Stille
coupling, zinc mediated coupling, or a Suzuki boronic acid coupling
are depicted. A method for converting the vinyl bromide to vinyl
idodide is shown. If the vinyl bromide fails to undergo efficient
reaction, the more reactive iodide can be prepared as a better
partner. Details of these tranformations are discussed later in the
section on metal couplings. 55
[0444] Scheme S provides specific examples of Scheme R. 56
[0445] Scheme T shows methods for converting the vinyl bromide into
more funtionalized groups D (or A). A key aldehyde intermediate is
generated from the vinyl bromide and can be used to generate
heteroaryls such as the oxazole via reaction with Tosmic. 57
[0446] Scheme U shows how a hydrazide (gnerated from the acid) can
be used to prepare oxadiazoles with diffferent substituents. 58
[0447] Scheme V provides more specific examples of Scheme U. 59
[0448] Scheme W shows some other methods for installing D (or A).
60
[0449] Scheme X shows a particular example where a functionalized
heteroaryl or in this case aryl are coupled and then further
functionalization can occurr (in this case redcution of an ester to
an alcohol). 61
[0450] Scheme Y provides more specific examples of Scheme X. 62
[0451] Procedures for coupling piperazine amides to oxoacetyl
derivatives are described in the Blair, Wang, Wallace, or Wang
references 93-95 and 106 respectively. In addition, these
applications describe preparations of heteroaryls and methods for
funtionalizing heteraromatic systems in the presence of oxoacetyl
amides. The entire disclosures in U.S. Pat. No. 6,469,006 granted
Oct. 22, 2002; U.S. Pat. No. 6,476,034 granted Nov. 5, 2002; U.S.
patent application Ser. No. 10/027,612 filed Dec. 19, 2001, which
is a continuation-in-part of U.S. Ser. No. 09/888,686 filed Jun.
25, 2001 (corresponding to PCT WO 02/04440, published Jan. 17,
2002); and U.S. patent application Ser. No. 10/214,982 filed Aug.
7, 2002, which is a continuation-in-part of U.S. Ser. No.
10/038,306 filed Jan. 2, 2002 (corresponding to PCT WO 02/62423
published Aug. 15, 2002) are incorporated by reference herein. The
procedures used to couple diazaindole oxoacetic acids to piperazine
amides in these references could potentially be used analogously to
form the compounds of this invention except the H--Y are used in
place of the piperazine benzamides. 63
[0452] Scheme 54a depict a general method suitable for the
synthesis of many of the compounds of formula I. As shown in these
schemes, a suitable protected piperazine derivative, PG-YH, of
Formula VI, (wherein PG is an appropriate amine protecting group)
is acylated with an appropriate acylating agent, R.sup.18C(O)L,
(wherein L is a suitable leaving group) to provide the protected
acylated piperazine derivative of Formula V. Compound V is then
deprotected using standard methods to provide the acylated
piperazine derivative of Formula IV. For example, when PG
represents tertiary-butoxycarbonyl the compound of Formula V can be
deprotected to provide a compound of Formula IV by treatment with a
strong acid, such as neat cold trifluoroacetic acid or aqueous
hydrochloric acid, in an appropriate solvent such as
dichloromethane. Alternatively, when PG represents benzyl the
deprotection may be effected by hydrogenation.
[0453] 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). 64
[0454] 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). 65
[0455] 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 mono-benzoylpiperazines 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). 66
[0456] Piperazine intermediates could be prepared using standard
chemistry as shown in Scheme 64. 67 68
[0457] 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 65 which provide compounds such as those of Formula 73.
Compounds of formula 73 represent intermediates for the preparation
of Compounds I or compounds I depending on the identity of T and
Y.
[0458] 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 diazaindole 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
uronium 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. An example of more specific conditions
which are likely to be successful are depicted in Scheme 66. 69
[0459] The following four general methods provide a more detailed
description of procedures potentially useful for the preparation of
diazindoleindolecarboxamides and these methods could potentially be
employed for the synthesis of intermediates 73 useful for the
preparation of compounds I or for the preparation of compounds of
Formula I themselves.
[0460] Method 1:
[0461] To a mixture of an acid intermediate, such as 74, (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) should be added EDC (90 mg,
0.47 mmol). The resulting mixture should be shaken at rt for 12 h,
and then evaporated in vacuo. The residue could be dissolved in
MeOH, and subjected to preparative reverse phase HPLC
purification.
[0462] Method 2:
[0463] To a mixture of an appropriate amine (4 equiv.) and HOBT (16
mg, 0.12 mmol) in THF (0.5 mL) could be added an acid intermediate,
such as 74, (25 mg, 0.06 mmol) and NMM (50 .mu.l, 0.45 mmol),
followed by EDC (23 mg, 0.12 mmol). The reaction mixture could be
shaken at rt for 12 h. The volatiles could be evaporated in vacuo;
and the residue dissolved in MeOH and subjected to preparative
reverse phase HPLC purification.
[0464] Method 3:
[0465] To a mixture of an acid intermediate, such as 74, (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) could be added TEA
(0.03 mL, 0.22 mmol). The resulting mixture could be shaken at rt
for 12 h; and then diluted with MeOH (2 mL) and purified by
preparative reverse phase HPLC.
[0466] Method 4:
[0467] A mixture of an acid intermediate, such as 74, (0.047 mmol)
and 8.5 mg (0.052 mmol) of 1,1-carbonyldiimidazole in anhydrous THF
(2 mL) could be heated to reflux under nitrogen. After 2.5 h, 0.052
mmol of amine could be added and heating continued. After an
additional period of 3.about.20 h at reflux, the reaction mixture
could be cooled and concentrated in vacuo. The residue could be
purified by chromatography on silica gel to provide a compound of
Formula I.
[0468] In addition, the carboxylic acid could 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 could 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 could 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 could be converted to
an ester preferably a methyl or ethyl ester and then reacted with
an amine. The ester could 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.
[0469] 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. 70
[0470] Scheme 67 shows possible synthetic transformations on a
chloro diazazaindole. Step F-1 of Scheme 31 could 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 in which they use 1 eq of Chloride, 1.9 eq
Cu(I)CN, in dry DMF and reflux for 48 h. The concentration of
chloride in DMF is preferably 0.094 mmol per mL of solvent.
Reaction times of 1-48 h may be approrpiate depending on substrate
and reaction temperatures between 80.degree. C. and reflux
(156.degree. C.) may be employed. An alternate procedure for
carrying out step F-1 as described in the experimental section for
Example 12 occurrs via reaction of the chloride intermediate with
potassium cyanide (0.9 to 5 eqs, preferably 1.5 eqs) in a solvent
such as DMF in the presence of catalytic sodium 4-toluene sulfinate
at an elevate temperature such as 100.degree. C. for 3 h. Reaction
temperature may vary between 50 and 200.degree. C. depending on
substrate and reaction time from 30 min to 48 h. Reactions may be
conducted in a sealed tube to minimize escape of volatiles if
necessary.
[0471] Transformation step I, the hydrolysis of the nitrile to the
acid may be carried out using acidic conditions such as MeOH and
HCl at ambient temp followed by heating the intermediate imididate
in the Methanol which provides the intermediate methyl ester which
can then be hydrolyzed using potassium carbonate MeOH or LiOH or
KOH in Methanol. This method is preferred to produce intact
Compounds I. Alternatively, KOH/in ethanol or methanol may be
utilized to achieve this transformation in step I. Other methods
for this tranformations are well known in the literature or in the
references incorporated in the experimental section.
[0472] Transformation step H can be used to directly produce
unsubstituted carboxamides (R.sup.1.dbd.R.sup.2=hydrogen)via
stirring in cold concentrated sulfuric acid or at ambient
tmeperature for 0.5 to 15 days. Alternatively stirring with MeOH
and HCl at room temperature followed by a hydrolytic workup (water
and theyl acetate or dichloromethane, may produce the same
product.
[0473] Step J the amide coupling is carried out as described above
in the discussions for Scheme 65 and 66.
[0474] Chemistry
[0475] General:
[0476] Additional preparations of starting materials and precursors
particulalry those for appending heteroaryls or carboxamides and
for construction of substituted piperazines and alkenyl piperidines
have been disclosed in a number different PCT and issued U.S.
patents/applications (Reference 93-95, 106, 108,109, 110, 111,112,
113 and 114) and U.S. application Ser. No. 10/871,931 filed Jun.
18, 2004, which are hereby incorporated by reference.
[0477] All Liquid Chromatography (LC) data were recorded on a
Shimadzu LC-10AS liquid chromatograph using a SPD-10AV UV-Vis
detector with Mass Spectrometry (MS) data determined using a
Micromass Platform for LC in electrospray mode.
[0478] LC/MS Method (Compound Identification)
[0479] Column A: YMC ODS-A S7 3.0.times.50 mm column
[0480] Column B: PHX-LUNA C18 4.6.times.30 mm column
[0481] Column C: XTERRA ms C18 4.6.times.30 mm column
[0482] Column D: YMC ODS-A C18 4.6.times.30 mm column
[0483] Column E: YMC ODS-A C18 4.6.times.33 mm column
[0484] Column F: YMC C18 S5 4.6.times.50 mm column
[0485] Column G: XTERRA C18 S7 3.0.times.50 mm column
[0486] Column H: YMC C18 S5 4.6.times.33 mm column
[0487] Column I: YMC ODS-A C18 S7 3.0.times.50 mm column
[0488] Column J: XTERRA C-18 S5 4.6.times.50 mm column
[0489] Column K: YMC ODS-A C18 4.6.times.33 mm column
[0490] Column L: Xterra MS C18 5 uM 4.6.times.30 mm column
[0491] Column M: YMC ODS-A C18 S3 4.6.times.33 mm column
[0492] Column N: XTERRA MS C18 7 u 3.0.times.50 mm column
[0493] Column O: Phenomenex 10 u 4.6.times.50 mm column
[0494] Column P: Waters Atlantis 4.6.times.50 mm C18 Sum column
[0495] Column Q: Phenomenex 5 u 4.6.times.50 mm C18 column
[0496] Column R: Phenomenex Lina C18 5 um 3.0.times.50 mm
column
[0497] Column S: Phenomenex C18 10 u 3.0.times.50 mm column
[0498] Standard LC Run Conditions A (used Unless Otherwise
Noted):
[0499] Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100%
Solvent B
[0500] Gradient time: 2 minutes
[0501] Hold time: 1 minute
[0502] Flow rate: 5 mL/min
[0503] Detector Wavelength: 220 nm
[0504] Solvent A: 10% MeOH/90% H.sub.2O/0.1% Trifluoroacetic
Acid
[0505] Solvent B: 10% H.sub.2O/90% MeOH/0.1% Trifluoroacetic
Acid
[0506] Alternate LC Run Conditions B:
[0507] Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100%
Solvent B
[0508] Gradient time: 2 minutes
[0509] Hold time: 1 minute
[0510] Flow rate: 5 ml/min
[0511] Detector Wavelength: 220 nm
[0512] Solvent A: 5% CH.sub.3CN /95% H.sub.2O/10 mM Ammonium
Acetate
[0513] Solvent B: 95% CH.sub.3CN/55% H.sub.2O/10 mM Ammonium
Acetate
[0514] Compounds purified by preparative HPLC were diluted in MeOH
and/or DMSO (1-2 mL) and purified using the following methods on a
Shimadzu LC-10A 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.
[0515] Preparative HPLC Method (i.e., Compound Purification)
[0516] Purification Method: Initial gradient (10% B, 90% A) ramp to
final gradient (100% B, 0% A) over 20 minutes, hold for 3 minutes
(100% B, 0% A)
[0517] Solvent A: 10% MeOH/90% H.sub.2O/0.1% Trifluoroacetic
Acid
[0518] Solvent B: 10% H.sub.2O/90% MeOH/0.1% Trifluoroacetic
Acid
[0519] Column: YMC C18 S5 20.times.100 mm column
[0520] Detector Wavelength: 220 nm
[0521] Starting materials, can be purchased from commercial sources
or prepared using literature procedures. 71
[0522] To a mixture of diethyl aminomalonate hydrochloride (8.0 g,
47.3 mmol) and ethyl (ethoxymethylene)cyanoacetate (10.0 g, 47.2
mmol) in ethanol (60 ml) at r.t. was added a 21 wt. % solution of
sodium ethoxide in ethanol (62 ml, 165.4 mmol). The reaction
mixture was then stirred at reflux for 20 h. After cooling to r.t.,
the mixture was neutralized with AcOH (6.75 ml, 118 mmol),
concentrated, diluted with H.sub.2O (250 mL) and extracted with
CHCl.sub.3 (3.times.250 mL). The combined organics were dried
(MgSO.sub.4), filtered, concentrated and purified by flushing
through a pad of silical gel (10 g, EtOAc) to yield amino pyrrole 3
(10.2 g, 45.1 mmol, 95%) as a yellow solid. .sup.1H NMR: (500 MHz,
DMSO-d.sub.6) .delta. 11.55 (br s, 1H), 7.21 (d, J=4.0, 1H,), 5.57
(s, 2H), 4.21 (q, J=7.5 Hz, 2H), 4.18 (q, J=7.8 Hz, 2H), 1.27 (t,
J=7.5 Hz, 2H), 1.25 (t, J=7.8 Hz, 2H); LC/MS: (ES+) m/z
(M-OEt).sup.+=181; HPLC R.sub.t=0.96, column N.
Preparation of 4-hydroxy-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic
acid ethyl ester 4
[0523] 72
[0524] A mixture of amino pyrrole 3. (10.0 g, 44.2 mmol) and
formamidine acetate (13.8 g, 133 mmol) in ethanol (100 ml) was
heated at 105.degree. C. for 20 h. The reaction mixture was
filtered while still hot to collect solids that were rinsed with
EtOH. The filtrate was allowed to cool to r.t., filtered to collect
solids that were washed with EtOH. The combined solids were
slurried with Et.sub.2O, filtered and dried under vacuum to yield
4,6-diazaindole 4 (6.60 g 31.9 mmol, 72%) as a pale yellow solid
which was used without further purification. .sup.1H NMR: (500 MHz,
DMSO-d.sub.6) .delta. 7.91 (s, 1H), 7.89 (s, 1H), 4.22 (q, J=7.2
Hz, 2H), 3.17 (s, 2H), 1.27 (t, J=7.2 Hz, 3H); LC/MS: (ES+) m/z
(M+H).sup.+=208; HPLC R.sub.t=0.55 min., column N.
Preparation of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic
acid ethyl ester 5
[0525] 73
[0526] 4,6-Diazaindole 4 (2.74 g, 13.2 mmol) was slurried in
POCl.sub.3 (37 mL, 400 mmol) and heated at 105.degree. C. for 3.5
h. The reaction mixture was cooled, diluted with Et.sub.2O (150 mL)
and the resulting precipitate was collected by filtration, rinsed
with EtOAc and Et.sub.2O and dried under vacuum to yield
7-chloro-4,6-diazaindole 5 (2.48 g, 11.0 mmol, 83%) as a yellow
powder which was used without further purification. LC/MS: (ES+)
m/z (M+H).sup.+=226; HPLC R.sub.t=0.84 min., column N.
Preparation of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic
acid 6
[0527] 74
[0528] To a solution of 7-chloro-4,6-diazaindole 5 (4.0 g, 18 mmol)
in THF (90 mL) was added a solution of LiOH.H.sub.2O (2.5 g, 59
mmol) in H.sub.2O (60 mL). The reaction mixture was stirred at
100.degree. C. for 1 d, concentrated and recrystallized from
H.sub.2O (20 mL). The crystals were collected by filtration, washed
with H.sub.2O and dried under high vacuum. The off-white solid was
shown to be the lithium salt of the diazaindole carboxylic acid 6
(quantitative), which was used without further purification.
.sup.1H NMR: (500 MHz, DMSO-d.sub.6) .delta. 8.28 (s, 1H), 8.14 (s,
1H); LC/MS: (ES+) m/z (M+H).sup.+=198; HPLC R.sub.t=0.47 min.,
column G.
Preparation of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carbonyl
chloride 7
[0529] 75
[0530] A solution of the lithium salt of the diazaindole carboxylic
acid 6 (1.3 g, 6.6 mmol) in thionyl chloride (22 mL, 300 mmol) and
benzene (30 mL) was heated at 105.degree. C. for 3 h. The reaction
was cooled and concentrated under vacuum. The light yellow solid
residue was shown to be acid chloride 7 and was used without
further purification. The acid chloride 7 was identified by
quenching a small amount with methanol to make the analogous methyl
ester or with aniline to make the phenyl amide, each of which could
be verified by LCMS. Methyl ester: LC/MS: (ES+) m/z
(M+H).sup.+=212; HPLC R.sub.t=0.90 min., column G. Phenyl amide:
LC/MS: (ES+) m/z (M+H).sup.+=269; HPLC R.sub.t=01.56 min., column
G.
PREPARATION OF EXAMPLE 1
2-(4-Benzoyl-piperazin-1-yl)-3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)--
3-oxo-propionitrile (Compound 9)
[0531] 76
EXAMPLE 1
[0532] To a solution of acid chloride 7 (0.5 mmol) and
cyanomethylpiperazine 8 (150 mg, 0.66 mmol) in THF (4 mL) stirring
at -35.degree. C. was slowly added a solution of 0.5 M KHMDS in
toluene (3.2 mL, 1.6 mmol). The reaction mixture was stirred at
-35.degree. C. for 1 h, quenched with sat. aqueous NaHCO.sub.3 (50
mL) and extracted with EtOAc (2.times.50 mL). The combined organics
were concentrated and the residue purified by prep HPLC to yield
the ketocyano intermediate 9 (39 mg, 0.96 mmol, 19%) as a yellow
solid. .sup.1H NMR: (500 MHz, DMSO-d.sub.6) .delta. 8.80 (s, 0.5H),
8.80 (s, 0.5H), 8.65 (s, 0.5H), 8.64 (s, 0.5H), 7.50-7.36 (m, 5H),
4.82-4.77 (m, 1H) 3.80-3.25 (m, 4H) 3.02-2.55 (m, 4H); LC/MS: (ES+)
m/z (M+H).sup.+=407; HPLC R.sub.t=0.94 min., column G, conditions
B.
PREPARATION OF EXAMPLE 2
1-(4-Benzoyl-piperazin-1-yl)-2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)--
ethane-1,2-dione (Compound 10)
[0533] 77
EXAMPLE 2
[0534] To a solution of acid chloride 7 (6.6 mmol) and
cyanomethylpiperazine 8 (1.96 g, 8.58 mmol) in THF (45 mL) stirring
at -78.degree. C. was slowly added a solution of 0.5 M KHMDS in
toluene (42 mL, 21 mmol). The reaction mixture was stirred at
-78.degree. C. for 2 h and then a solution of 32 wt. % peracetic
acid in dilute AcOH (12 ml, 57 mmol) was added and the reaction was
stirred at r.t. for 1 h. The reaction mixture was quenched with
sat. aqueous NH.sub.4Cl (150 mL) and stirred with EtOAc (200 mL).
The resultant precipitate was collected by filtration, rinsed with
H.sub.2O and EtOAc, dried under vacuum and shown to be dicarbonyl
intermediate 10 (813 mg, 2.05 mmol, 24%) as an off-white solid.
.sup.1H NMR: (500 MHz, DMSO-d.sub.6) .delta. 13.71 (s, 1H), 8.85
(s, 1H), 8.76 (s, 1H), 7.51-7.25 (m, 5H), 3.89-3.20 (m, 8H); LC/MS:
(ES+) m/z (M+H).sup.+=398; HPLC R.sub.t=0.80 min., column G,
conditions B.
PREPARATION OF EXAMPLE 3
1-(4-Benzoyl-piperazin-1-yl)-2-[4-(3-methyl-pyrazol-1-yl)-5H-pyrrolo[3,2-d-
]pyrimidin-7-yl]-ethane-1,2-dione (Compound 11)
EXAMPLE 3
[0535] 78
[0536] In a sealed tube dicarbonyl intermediate 10 (50 mg, 0.13
mmol), 3-methylpyrazole (31 mg, 0.38 mmol) and ethanol (1 mL) were
combined and heated to 140.degree. C. with microwaves for 45 min.
The reaction was diluted with MeOH (2 mL), filtered and the
filtrate was purified by preparative HPLC to yield 11 (36 mg, 0.08
mmol, 65%) as a light yellow solid. .sup.1H NMR: (300 MHz,
CD.sub.3OD) .delta. 8.83 (s, 1H), 8.83 (d, J=2.8 Hz, 1H), 8.52 (s,
1H), 7.50-7.41 (m, 5H), 6.50 (d, J=2.8 Hz, 1H), 3.95-3.45 (m, 8H),
2.45 (s, 3H); LC/MS: (ES+) m/z (M+H).sup.+=444; HPLC R.sub.t=0.97
min., column G, conditions B.
PREPARATION OF EXAMPLE 4
1-(4-Benzoyl-piperazin-1-yl)-2-[4-(4-methyl-pyrazol-1-yl)-5H-pyrrolo[3,2-d-
]pyrimidin-7-yl]-ethane-1,2-dione (Compound 12)
EXAMPLE 4
[0537] 79
[0538] In a sealed tube dicarbonyl intermediate 10 (50 mg, 0.13
mmol), 4-methylpyrazole (31 mg, 0.38 mmol) and ethanol (1 mL) were
combined and heated to 140.degree. C. with microwaves for 30 min.
The reaction was diluted with MeOH (2 mL), filtered and the
filtrate was purified by preparative HPLC to yield 12 (34 mg, 0.08
mmol, 61%) as a white solid. .sup.1H NMR: (300 MHz, CDCl.sub.3)
.delta. 12.13 (br s), 9.17 (s, 1H), 8.74 (s, 1H), 8.40 (s, 1H),
7.85 (s, 1H), 7.46-7.36 (m, 5H), 3.85-3.55 (m, 8H), 2.20 (s, 3H);
LC/MS: (ES+) m/z (M+H).sup.+=444; HPLC R.sub.t=0.97 min., column G,
conditions B.
PREPARATION OF EXAMPLE 5
1-(4-Benzoyl-piperazin-1-yl)-2-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-
-ethane-1,2-dione (Compound 13)
EXAMPLE 5
[0539] 80
[0540] To a solution of dicarbonyl intermediate 10 (50 mg, 0.13
mmol) in MeOH (1 mL) was added KOMe (79 mg, 1.1 mmol). The reaction
was heated at 90.degree. C. for 0.5 h, cooled, diluted with MeOH (2
mL) and H.sub.2O (1 mL) and purified by preparative HPLC to yield
13 (24 mg, 0.06 mmol, 48%) as a white solid. .sup.1H NMR: (500 MHz,
CD.sub.3OD) .delta. 8.93 (s, 1H), 8.62 (s, 1H), 7.53-7.40 (m, 5H),
4.39 (s, 3H) 3.98-3.46 (m, 8H); LC/MS: (ES+) m/z (M+H).sup.+=394;
HPLC R.sub.t=0.79 min., column G, conditions B.
PREPARATION OF EXAMPLE 6
1-(4-Benzoyl-piperazin-1-yl)-2-(4-pyrazol-1-yl-5H-pyrrolo[3,2-d]pyrimidin--
7-yl)-ethane-1,2-dione (Compound 14)
EAXAMPLE 6
[0541] 81
[0542] In a sealed tube dicarbonyl intermediate 10 (50 mg, 0.13
mmol), pyrazole (26 mg, 0.38 mmol) and ethanol (1 mL) were combined
and heated at 140.degree. C. with microwaves for 45 min. The
reaction was diluted with MeOH (3 mL), filtered and the filtrate
was purified by preparative HPLC to yield 14 (13 mg, 0.03 mmol,
24%) as a white solid. .sup.1H NMR: (500 MHz, CD.sub.3OD) .delta.
8.87 (s, 1H), 8.81 (s, 1H), 8.53 (s, 1H), 8.04 (s, 1H), 7.53-7.39
(m, 5H), 6.69 (s, 1H), 3.98-3.46 (m, 8H); LC/MS: (ES+) m/z
(M+H).sup.+=430; HPLC R.sub.t=0.95 min., column G, conditions
B.
PREPARATION OF EXAMPLE 7
1-(4-Benzoyl-piperazin-1-yl)-2-[4-(3-methyl-[1,2,4]triazol-1-yl)-5H-pyrrol-
o[3,2-d]pyrimidin-7-yl]-ethane-1,2-dione (Compound 15)
EXAMPLE 7
[0543] 82
[0544] In a sealed tube dicarbonyl intermediate 10 (50 mg, 0.13
mmol), 3-methyl-1,2,4-triazole (22 mg, 0.38 mmol) and ethanol (1
mL) were combined and heated at 140.degree. C. with microwaves for
45 min. The reaction was diluted with MeOH/DMF (1:1, 3 mL),
filtered and the filtrate was purified by preparative HPLC to yield
15 (9 mg, 0.02 mmol, 17%) as a white solid. .sup.1H NMR: (500 MHz,
DMSO-d.sub.6) .delta. 12.74 (br s, 1H), 9.54 (s, 1H), 8.94 (s, 1H),
8.54 (s, 1H), 7.55-7.35 (m, 5H), 3.90-3.22 (m, 8H), 2.53 (s, 3H);
LC/MS: (ES+) m/z (M+H).sup.+=445; HPLC R.sub.t=0.88 min., column G,
conditions B.
PREPARATION OF EXAMPLE 8
1-(4-(2H-1,2,3-Triazol-2-yl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-2-(4-benzoyl-
piperazin-1-yl)ethane-1,2-dione (Compound 16)
EXAMPLE 8
[0545] 83
[0546] In a sealed tube dicarbonyl intermediate 10 (50 mg, 0.13
mmol), 3-methyl-1,2,4-triazole (52 mg, 0.75 mmol) and copper powder
(16 mg, 0.25 mmol) were combined and heated at 140.degree. C. with
microwaves for 1 h. The reaction was diluted with MeOH (3 mL),
filtered through celite and the filtrate was purified by
preparative HPLC to yield 16 (3 mg, 0.007 mmol, 5%) as a yellow
solid. .sup.1H NMR: (500 MHz, CD.sub.3OD) .delta. 8.97 (s, 1H),
8.61 (s, 1H), 8.28 (s, 1H), 8.27 (s, 1H), 7.52-7.40 (m, 5H),
4.02-3.44 (m, 8H); LC/MS: (ES+) m/z (M+H).sup.+=431; HPLC
R.sub.t=0.82 min., column G, conditions B.
PREPARATION OF EXAMPLE 9
1-{7-[2-(4-Benzoyl-piperazin-1-yl)-2-oxo-acetyl]-5H-pyrrolo[3,2-d]pyrimidi-
n-4-yl}-1H-pyrazole-3-carboxylic acid (Compound 17)
EXAMPLE 9
[0547] 84
[0548] In a sealed tube dicarbonyl intermediate 10 (30 mg, 0.076
mmol) and 3-pyrazolecarboxylic acid (26 mg, 0.23 mmol), copper
powder (10 mg, 0.16 mmol) and K.sub.2CO.sub.3 (52 mg, 0.38 mmol)
were combined and heated at 150.degree. C. with microwaves for 2 h.
The reaction was diluted with MeOH (3 mL), filtered through celite,
concentrated, dissolved into DMSO and purified by preparative HPLC
to yield 17 (5 mg, 0.01 mmol, 14%) as a white solid. .sup.1H NMR:
(500 MHz, DMSO-d.sub.6) .delta. 13.32 (br s, 1H), 12.55 (br s, 1H),
8.98-8.96 (m, 2H), 8.71 (s, 1H), 7.51-7.38 (m, 5H), 7.13 (d, J=2.4
Hz, 1 H), 3.90-3.20 (m, 8H); LC/MS: (ES+) m/z (M+H).sup.+=474; HPLC
R.sub.t=0.76 min., column G, conditions B.
PREPARATION OF EXAMPLE 10
1-(4-Benzoylpiperazin-1-yl)-2-(4-ethoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)et-
hane-1,2-dione (Compound 18)
EXAMPLE 10
[0549] 85
[0550] In a sealed tube dicarbonyl intermediate 10 (30 mg, 0.076
mmol) and 3-pyrazolecarboxylic acid (26 mg, 0.23 mmol), copper
powder (10 mg, 0.16 mmol) and K.sub.2CO.sub.3 (52 mg, 0.38 mmol) in
EtOH (1.0 mL) were combined and heated at 150.degree. C. with
microwaves for 2 h. The reaction was diluted with MeOH (3 mL),
filtered through celite, concentrated, dissolved into DMSO and
purified by preparative HPLC to yield 18 (1 mg, 0.002 mmol, 3%) as
a white solid. .sup.1H NMR: (500 MHz, CD.sub.3OD) .delta. 8.73 (s,
1H), 8.45 (s, 1H), 7.57-7.40 (m, 5H), 4.77 (q, J=7.3 Hz, 2H),
4.04-3.42 (m, 8H), 1.53 (t, J=7.3 Hz, 3H); LC/MS: (ES+) m/z
(M+H).sup.+=408; HPLC R.sub.t=0.85 min., column G, conditions
B.
PREPARATION OF EXAMPLE 11
1-(4-Acetyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-2-(4-benzoylpiperazin-1-yl)et-
hane-1,2-dione (Compound 19)
EXAMPLE 11
[0551] 86
[0552] In a sealed tube dicarbonyl intermediate 10 (600 mg, 1.5
mmol), tributyl(1-ethoxyvinyl)stannane (1.5 mL 4.5 mmol),
tetrakis(triphenylphosphine)palladium(O) (350 mg, 0.30 mmol) and
1,4-dioxane (15 mL) were combined and heated at 120.degree. C. with
microwaves for 2 h. The reaction mixture was divided and 25% v/v
was concentrated diluted with MeOH/CH.sub.2Cl.sub.2 (2:1, 1.5 mL)
and IN aqueous HCl (0.5 mL). The reaction was stirred overnight,
neutralized with 1N aqueous NaOH (0.5 mL) and concentrated. The
residue was dissolved into DMSO, filtered and purified by
preparative HPLC to yield 19 (79 mg, 0.20 mmol, 53%) as a pink
solid. .sup.1H NMR: (500 MHz, CD.sub.3OD) .delta. 9.19 (s, 1H),
8.62 (s, 1H), 7.52-7.40 (m, 5H), 3.92-3.41 (m, 8H), 2.80 (s, 3H);
LC/MS: (ES+) m/z (M+H).sup.+=406; HPLC R.sub.t=0.79 min., column
N.
PREPARATION OF EXAMPLE 12
7-(2-(4-Benzoylpiperazin-1-yl)-2-oxoacetyl)-5H-pyrrolo[3,2-d]pyrimidine-4--
carbonitrile (Compound 20)
EXAMPLE 12
[0553] 87
[0554] In a sealed tube dicarbonyl intermediate 10 (40 mg, 0.10
mmol), potassium cyanide (10 mg, 0.15 mmol), sodium
4-toluenesulfinate (20 mg, 0.11 mmol) and DMF (0.8 mL) were
combined and heated at 100.degree. C. for 3 h. The crude reaction
mixture was partitioned between aqueous 5% Na.sub.2CO.sub.3 (0.5
mL) and EtOAc (4 mL). The organic layer was washed with aqueous 5%
Na.sub.2CO.sub.3 (0.7 mL), concentrated, dissolved into MeOH/DMSO
(3:1, 2 mL) and purified by preparative HPLC to yield 20 (10 mg,
0.03 mmol, 26%) as a white solid. .sup.1H NMR: (500 MHz,
DMSO-d.sub.6) .delta. 14.16 (br s, 1H), 9.20 (s, 1H), 8.96 (s, 1H),
7.52-7.36 (m, 5H), 3.90-3.28 (m, 8H); LC/MS: (ES+) m/z
(M+H).sup.+=389; HPLC R.sub.t=0.92 min., column P, conditions
B.
PREPARATION OF EXAMPLE 13
1-(7-(2-(4-Benzoylpiperazin-1-yl)-2-oxoacetyl)-5H-pyrrolo[3,2-d]pyrimidin--
4-yl)-N,N-dimethyl-1H-pyrazole-3-carboxamide (Compound 21)
EXAMPLE 13
[0555] 88
[0556] In a sealed tube dicarbonyl intermediate 10 (50 mg, 0.13
mmol), N,N-dimethyl-1H-pyrazole-3-carboxamide (53 mg, 0.38 mmol),
copper(0) (10 mg) and 1,4-dioxane (0.8 mL) were combined and heated
at 150.degree. C. with microwaves for 2 h. The reaction mixture was
concentrated, diluted with MeOH and DMSO, filtered and purified by
preparative HPLC to yield 21 (2.3 mg, 0.005 mmol, 4%) as a yellow
solid. .sup.1H NMR: (500 MHz, CD.sub.3OD) .delta. 8.94-8.87 (m,
2H), 8.59 (s, 1H), 7.56-7.36 (m, 5H), 6.94 (d, J=2.8 Hz, 1H),
4.07-3.43 (m, 8H), 3.29 (s, 3H), 3.19 (s, 3H); LC/MS: (ES+) m/z
(M+H).sup.+=501; HPLC R.sub.t=1.16 min., column N.
PREPARATION OF EXAMPLE 14
1-(4-Benzoylpiperazin-1-yl)-2-(4-(3-(1-methylpiperazine-4-carbonyl)-1H-pyr-
azol-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)ethane-1,2-dione
(Compound 22)
EXAMPLE 14
[0557] 89
[0558] Carboxylic acid 17 (34 mg, 0.73 mmol), N-methylpiperazine
(15 mg, 0.15 mmol), N,N-diisopropylethylamine (0.13 mL, 94 mg, 0.73
mmol) and bis(2-oxo-3-oaxzolidinyl)phosphinic chloride (41 mg, 0.16
mmol) were dissolved into CH.sub.2Cl.sub.2 (0.5 mL) and stirred for
20 h. The reaction mixture was concentrated, diluted with MeOH (1.7
mL) filtered and purified by preparative HPLC to yield 22 (41 mg,
0.73 mmol, 99%) as a white solid .sup.1H NMR: (500 MHz, CD.sub.3OD)
.delta. 8.93 (d, J=2.8 Hz, 1H), 8.90 (s, 1H), 8.60 (s, 1H),
7.54-7.37 (m, 5H), 6.98 (d, J=2.8 Hz, 1H), 4.06-3.12 (m, 16H), 2.97
(s, 3H); LC/MS: (ES+) m/z (M+H).sup.+=556; HPLC R.sub.t=1.03 min.,
column P., conditions B.
PREPARATION OF EXAMPLE 15
1-(4-Benzoylpiperazin-1-yl)-2-(4-(3-phenyl-1H-pyrazol-1-yl)-5H-pyrrolo[3,2-
-d]pyrimidin-7-yl)ethane-1,2-dione (Compound 23)
EAXMAPLE 15
[0559] 90
[0560] In a sealed tube dicarbonyl intermediate 10 (50 mg, 0.13
mmol), 3-phenyl-1H-pyrazole (80 mg, 0.56 mmol) and 1,4-dioxane (2.5
mL) were combined and heated at 170.degree. C. with microwaves for
20 min. The reaction was concentrated and triturated with MeOH (3
mL). The resulting solids were washed with MeOH and with Et.sub.2O
to yield 23 (33 mg, 0.07 mmol, 50%) as a tan solid. .sup.1H NMR:
(500 MHz, DMSO-d.sub.6) .delta. 12.42 (br s, 1H), 8.95 (d, J=2.8
Hz, 1H), 8.92 (s, 1H), 8.57 (br d, J=3.1 Hz, 1H), 8.27 (d, J=7.3
Hz, 2H), 7.55 (dd, J=7.3, 7.3 Hz, 2H), 7.48 (t, J=7.3 Hz, 1H),
7.51-7.38 (m, 5H), 7.30 (d, J=2.8 Hz, 1H), 3.92-3.21 (m, 8H);
LC/MS: (ES+) m/z (M+H).sup.+=505; HPLC R.sub.t=1.40 min., column Q,
conditions B.
PREPARATION OF EXAMPLE 16
1-(4-Benzoylpiperazin-1-yl)-2-(4-(3-(4-fluorophenyl)-1H-pyrazol-1-yl)-5H-p-
yrrolo[3,2-d]pyrimidin-7-yl)ethane-1,2-dione (Compound 24)
EXAMPLE 16
[0561] 91
[0562] In a sealed tube dicarbonyl intermediate 10 (50 mg, 0.13
mmol), 3-(4-fluorophenyl)-1H-pyrazole (150 mg, 0.93 mmol) and
1,4-dioxane (2 mL) were combined and heated at 160.degree. C. with
microwaves for 20 min. The reaction was concentrated, diluted with
MeOH (3 mL), neutralized with saturated aqueous NaHCO.sub.3 and 24
(15 mg, 0.03 mmol, 22%) was collected by filtration as a tan solid.
.sup.1H NMR: (500 MHz, DMSO-d.sub.6) .delta. 12.48 (br s, 1H), 8.96
(d, J=2.8 Hz, 1H), 8.91 (s, 1H), 8.58 (br s, 1H), 8.34 (dd, J=8.7,
5.6 Hz, 2H), 7.50-7.39 (m, 5H), 7.88 (t, J=8.7 Hz, 2H), 7.80 (d,
J=2.8 Hz, 1H), 3.91-3.23 (m, 8H); LC/MS: (ES+) m/z (M+H).sup.+=524;
HPLC R.sub.t=1.42 min., column Q, conditions B.
PREPARATION OF EXAMPLE 17
1-(4-Benzoylpiperazin-1-yl)-2-(4-(3-(4-methoxyphenyl)-1H-pyrazol-1-yl)-5H--
pyrrolo[3,2-d]pyrimidin-7-yl)ethane-1,2-dione (Compound 25)
EAXMAPLE 17
[0563] 92
[0564] In a sealed tube dicarbonyl intermediate 10 (50 mg, 0.13
mmol), 3-(4-methoxyphenyl)-1H-pyrazole (105 mg, 0.60 mmol) and
1,4-dioxane (2.5 mL) were combined and heated at 170.degree. C.
with microwaves for 20 min. The reaction was concentrated and
triturated with MeOH (3 mL). The resulting solids were washed with
MeOH and with Et.sub.2O to yield 25 (43 mg, 0.08 mmol, 61%) as a
tan solid. .sup.1H NMR: (500 MHz, DMSO-d.sub.6) .delta. 12.41 (br
s, 1H), 8.91 (d, J=2.8 Hz, 1H), 8.89 (s, 1H), 8.55 (br d, J=3.4 Hz,
1H), 8.20 (d, J=8.7 Hz, 2H), 7.51-7.39 (m, 5H), 7.23 (d, J=2.8 Hz,
1H), 7.08 (d, J=8.7 Hz, 2H), 3.85 (s, 3H), 3.92-3.21 (m, 8H);
LC/MS: (ES+) m/z (M+H).sup.+=535; HPLC R.sub.t=1.40 min., column Q,
conditions B.
PREPARATION OF EXAMPLE 18
1-(4-Benzoylpiperazin-1-yl)-2-(4-(3-(2-methoxyphenyl)-1H-pyrazol-1-yl)-5H--
pyrrolo[3,2-d]pyrimidin-7-yl)ethane-1,2-dione (Compound 26)
EAXMAPLE 18
[0565] 93
[0566] In a sealed tube dicarbonyl intermediate 10 (51 mg, 0.13
mmol), 3-(2-methoxyphenyl)-1H-pyrazole (109 mg, 0.60 mmol) and
1,4-dioxane (2 mL) were combined and heated at 170.degree. C. with
microwaves for 20 min. The reaction was concentrated and triturated
with MeOH (3 mL). The resulting solids were washed with MeOH and
with Et.sub.2O to yield 26 (32 mg, 0.06 mmol, 47%) as a tan solid.
.sup.1H NMR: (500 MHz, DMSO-d.sub.6) .delta. 12.34 (br s, 1H), 8.91
(s, 1H), 8.90 (d, J=2.8 Hz, 1H), 8.55 (br d, J=3.4 Hz, 1H), 8.37
(dd, J=7.8, 1.5 Hz, 1H), 7.50-7.39 (m, 5H), 7.47 (ddd, J=8.2, 7.0,
1.5 Hz, 1H), 7.21 (d, J=2.8 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 7.14
(dd, J=7.8, 7.0 Hz, 1H), 3.94 (s, 3H), 3.91-3.23 (m, 8H); LC/MS:
(ES+) m/z (M+H).sup.+=535; HPLC R.sub.t=1.42 min., column Q,
conditions B.
PREPARATION OF EXAMPLE 19
1-(4-Benzoylpiperazin-1-yl)-2-(4-(3-(3-(trifluoromethyl)phenyl)-1H-pyrazol-
-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)ethane-1,2-dione (Compound
27)
EAXMAPLE 19
[0567] 94
[0568] In a sealed tube dicarbonyl intermediate 10 (50 mg, 0.13
mmol), 3-(3-(trifluoromethyl)phenyl)-1H-pyrazole (150 mg, 0.70
mmol) and 1,4-dioxane (2 mL) were combined and heated at
160.degree. C. with microwaves for 20 min. The reaction was
concentrated, dissolved into MeOH (3 mL) and purified by
preparative HPLC to yield 27 (34 mg, 0.06 mmol, 46%) as a white
solid. .sup.1H NMR: (500 MHz, DMSO-d.sub.6) .delta. 12.63 (br s,
1H), 9.00 (d, J=2.8 Hz, 1H), 8.94 (s, 1H), 8.64 (s, 1H), 8.62 (d,
J=7.9 Hz, 1H), 8.54 (s, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.79 (dd,
J=7.9, 7.6 Hz, 1H), 7.52-7.36 (m, 5H), 7.47 (d, J=2.8 Hz, 1H),
3.90-3.25 (m, 8H); LC/MS: (ES+) m/z (M+H).sup.+=574; HPLC
R.sub.t=1.77 min., column Q, conditions B.
PREPARATION OF EXAMPLE 20
1-(4-(1H-1,2,4-Triazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-2-(4-benzoyl-
piperazin-1-yl)ethane-1,2-dione (Compound 28)
EXAMPLE 20
[0569] 95
[0570] In a sealed tube dicarbonyl intermediate 10 (50 mg, 0.13
mmol), 1,2,4-triazole (26 mg, 0.44 mmol), copper(0) (8 mg, 0.13
mmol), K.sub.2CO.sub.3 (23 mg, 0.17 mmol) and 1,4-dioxane (0.8 mL)
were combined and heated at 140.degree. C. with microwaves for 6 h.
The reaction mixture was diluted with MeOH/CH.sub.2Cl.sub.2 (1:1, 2
mL), filtered, concentrated, dissolved into MeOH/DMSO (5:4, 1.8 mL)
and purified by preparative HPLC. The resulting yellow solid was
triturated with MeOH to yield 28 (15 mg, 0.03 mmol, 28%) as a light
yellow solid. .sup.1H NMR: (500 MHz, DMSO-d.sub.6) .delta. 12.95
(s, 1H), 9.71 (s, 1H), 8.98 (s, 1H), 8.61 (s, 1H), 8.56 (br s, 1H),
7.52-7.36 (m, 5H), 3.92-3.23 (m, 8H); LC/MS: (ES+) m/z
(M+H).sup.+=431; HPLC R.sub.t=0.98 min., column C.
PREPARATION OF EXAMPLE 21
1-(4-(1H-1,2,3-Triazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-2-(4-benzoyl-
piperazin-1-yl)ethane-1,2-dione (Compound 29)
EXAMPLE 21
[0571] 96
[0572] In a sealed tube dicarbonyl intermediate 10 (60 mg, 0.15
mmol) and 1,2,3-triazole (95 mg, 1.4 mmol) in 1,4-dioxane (3 mL)
were combined and heated at 170.degree. C. with microwaves for 20
min. The reaction was concentrated and the residue was triturated
with MeOH to yield 29 (10 mg, 0.023 mmol, 16%) as a yellow solid.
.sup.1H NMR: (500 MHz, CD.sub.3OD) .delta. 9.08 (s, 1H), 9.04 (s,
1H), 8.66 (s, 1H), 8.07 (s, 1H), 7.57-7.41 (m, 5H), 4.08-3.43 (m,
8H); LC/MS: (ES+) m/z (M+H).sup.+=431; HPLC R.sub.t=0.95 min.,
column O, conditions B.
PREPARATION OF EXAMPLE 22
1-(4-(1H-Pyrazol-3-yl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-2-(4-benzoylpipera-
zin-1-yl)ethane-1,2-dione (Compound 30)
EXAMPLE 22
[0573] 97
[0574] In a sealed tube dicarbonyl intermediate 10 (50 mg, 0.13
mmol), 3-(tributylstannyl)pyrazole (188 mg, 0.52 mmol),
tetrakis(triphenylphosph- ine)-palladium(0) (72 mg, 0.06 mmol) and
1,4-dioxane (0.8 mL) were combined and heated at 110.degree. C.
with microwaves for 1 h. The reaction mixture was diluted with
MeOH/CH.sub.2Cl.sub.2 (1:1, 2 mL) and filtered to collect solids.
The solids were dissolved into DMSO and purified by preparative
HPLC to yield 30 (28 mg, 0.07 mmol, 52%) as a white solid. .sup.1H
NMR: (500 MHz, DMSO-d.sub.6) .delta. 13.63 (br s, 1H), 12.41 (s,
1H), 9.03 (s, 1H), 8.44 (d, J=2.3 Hz, 1H), 8.03 (d, J=2.3 Hz, 1H),
7.50-7.37 (m, 5H), 7.13 (d, J=1.8 Hz, 1H), 3.90-3.23 (m, 8H);
LC/MS: (ES+) m/z (M+H).sup.+=430; HPLC R.sub.t=0.87 min., column R,
conditions B.
PREPARATION OF EXAMPLE 23
1-(4-Benzoylpiperazin-1-yl)-2-(4-(3-methylisoxazol-5-yl)-5H-pyrrolo[3,2-d]-
pyrimidin-7-yl)ethane-1,2-dione (Compound 31)
EXAMPLE 23
[0575] 98
[0576] In a sealed tube dicarbonyl intermediate 10 (50 mg, 0.13
mmol), 3-methyl-5-(tributylstannyl)isoxazole (141 mg, 0.38 mmol),
tetrakis(triphenylphosphine)-palladium(0) (30 mg, 0.03 mmol) and
1,4-dioxane (1 mL) were combined and heated at 110.degree. C. with
microwaves for 2 h, and then heated at 120.degree. C. for 2 h. The
reaction was repeated as described above and the reaction solution
was heated at 110.degree. C. with microwaves for 5 h. The two
reactions were combined, diluted with MeOH/DMSO, filtered and
purified by preparative HPLC. The resulting yellow solid was
triturated with MeOH to yield 31 (4 mg, 0.008 mmol, 3%) as a white
solid. .sup.1H NMR: (500 MHz, CD.sub.3OD) .delta. 9.11 (s, 1H),
8.66 (s, 1H), 7.56-7.42 (m, 5H), 7.27 (s, 1H), 4.06-3.45 (m, 8H),
2.47 (s, 3H); LC/MS: (ES+) m/z (M+H).sup.+=445; HPLC R.sub.t=1.23
min., column L.
PREPARATION OF EXAMPLE 24
1-(4-Benzoylpiperazin-1-yl)-2-(4-(pyridin-2-yl)-5H-pyrrolo[3,2-d]pyrimidin-
-7-yl)ethane-1,2-dione (Compound 32)
EXAMPLE 24
[0577] 99
[0578] In a sealed tube dicarbonyl intermediate 10 (50 mg, 0.13
mmol), 2-(tributylstannyl)pyridine (140 mg, 0.38 mmol),
tetrakis(triphenylphosph- ine)-palladium(0) (30 mg, 0.03 mmol) and
1,4-dioxane (0.8 mL) were combined and heated at 110.degree. C.
with microwaves for 1 h. The reaction mixture was concentrated,
diluted with MeOH, filtered and purified by preparative HPLC to
yield 32 (8 mg, 0.02 mmol, 14%) as a yellow waxy solid. .sup.1H
NMR: (500 MHz, CD.sub.3OD) .delta. 9.15-9.10 (m, 1H), 8.89 (br s,
1H), 8.70 (d, J=7.9 Hz, 1H), 8.62 (s, 1H), 8.09-8.05 (m, 1H),
7.61-7.55 (m, 1H), 7.54-7.37 (m, 5H), 4.05-3.42 (m, 8H); LC/MS:
(ES+) m/z (M+H).sup.+=441; HPLC R.sub.t=1.54 min., column P.
PREPARATION OF EXAMPLE 25
1-(4-Benzoylpiperazin-1-yl)-2-(4-(pyridin-3-yl)-5H-pyrrolo[3,2-d]pyrimidin-
-7-yl)ethane-1,2-dione (Compound 33)
EXAMPLE 25
[0579] 100
[0580] In a sealed tube dicarbonyl intermediate 10 (50 mg, 0.13
mmol), 3-(tributylstannyl)pyridine (160 mg, 0.43 mmol),
tetrakis(triphenylphosph- ine)-palladium(0) (40 mg, 0.03 mmol) and
1,4-dioxane (0.8 mL) were combined and heated at 130.degree. C. for
4 h. The reaction mixture was concentrated to dryness and
partitioned between EtOAc (5 mL) and saturated aqueous NaHCO.sub.3
with cesium fluoride. The biphasic suspension was filtered,
separated and the aqueous layer was concentrated to dryness. The
residue was diluted with MeOH (2 mL) and DMSO (0.5 mL), filtered
and purified by preparative HPLC to yield 33 (7 mg, 0.02 mmol, 12%)
as a yellow solid. .sup.1H NMR: (500 MHz, CD.sub.3OD) .delta. 9.41
(s, 1H), 9.20 (s, 1H), 8.96 (d, J=5.5 Hz, 1H), 8.91 (d, J=7.6 Hz,
1H), 8.73 (s, 1H), 8.05 (dd, J=7.6, 5.5 Hz, 1H), 7.56-7.42 (m, 5H),
4.10-3.43 (m, 8H); LC/MS: (ES+) m/z (M+H).sup.+=441; HPLC
R.sub.t=0.92 min., column S.
PREPARATION OF EXAMPLE 26
1-(4-Benzoylpiperazin-1-yl)-2-(4-(pyridin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-
-7-yl)ethane-1,2-dione (Compound 34)
EXAMPLE 26
[0581] 101
[0582] In a sealed tube dicarbonyl intermediate 10 (50 mg, 0.13
mmol), 4-(tributylstannyl)pyridine (140 mg, 0.38 mmol),
tetrakis(triphenylphosph- ine)-palladium(0) (30 mg, 0.03 mmol) and
1,4-dioxane (0.8 mL) were combined and heated at 110.degree. C.
with microwaves for 2 h, and then at 120.degree. C. for 2 h. The
reaction mixture was concentrated, diluted with MeOH/DMSO, filtered
and purified by preparative HPLC to yield 34 (22 mg, 0.08 mmol,
38%) as a yellow solid. .sup.1H NMR: (500 MHz, CD.sub.3OD) .delta.
9.24 (s, 1H), 9.04 (d, J=5.8 Hz, 2H), 8.75 (s, 1H), 8.52 (d, J=5.8
Hz, 2H), 7.57-7.40 (m, 5H), 4.12-3.44 (m, 8H); LC/MS: (ES+) m/z
(M+H).sup.+=441; HPLC R.sub.t=0.78 min., column L.
PREPARATION OF EXAMPLE 27
1-(4-Benzoylpiperazin-1-yl)-2-(4-(pyrazin-2-yl)-5H-pyrrolo[3,2-d]pyrimidin-
-7-yl)ethane-1,2-dione (Compound 35)
EXAMPLE 27
[0583] 102
[0584] In a sealed tube dicarbonyl intermediate 10 (50 mg, 0.13
mmol), 2-(tributylstannyl)pyrazine (160 mg, 0.43 mmol),
tetrakis(triphenylphosph- ine)-palladium(0) (30 mg, 0.03 mmol) and
1,4-dioxane (0.8 mL) were combined and heated at 120.degree. C.
with microwaves for 2 h, and then at 130.degree. C. for 2 h. The
reaction mixture was concentrated to dryness, diluted with MeOH
(2.5 mL) and DMSO (0.5 mL), filtered and purified by preparative
HPLC. The resulting yellow solid was triturated with MeOH to yield
35 (8 mg, 0.02 mmol, 15%) as a light yellow solid. .sup.1H NMR:
(500 MHz, DMSO-d.sub.6) .delta. 12.93 (br s, 1H), 9.75 (d, J=1.2
Hz, 1H), 9.21 (s, 1H), 8.93 (dd, J=2.4, 1.2 Hz, 1H), 8.90 (d, J=2.4
Hz, 1H), 8.64 (br s, 1H), 7.53-7.35 (m, 5H), 3.96-3.21 (m, 8H);
LC/MS: (ES+) m/z (M+H).sup.+=442; HPLC R.sub.t=1.15 min., column
S.
PREPARATION OF EXAMPLE 28
1-(4-Benzoylpiperazin-1-yl)-2-(4-(pyrimidin-5-yl)-5H-pyrrolo[3,2-d]pyrimid-
in-7-yl)ethane-1,2-dione (Compound 36)
EXAMPLE 28
[0585] 103
[0586] In a sealed tube dicarbonyl intermediate 10 (50 mg, 0.13
mmol), 5-(tributylstannyl)pyrimidine (160 mg, 0.43 mmol),
tetrakis(triphenylphosphine)-palladium(0) (30 mg, 0.03 mmol) and
1,4-dioxane (0.8 mL) were combined and heated at 130.degree. C.
with microwaves for 2 h. The reaction mixture was concentrated,
diluted with MeOH/DMSO, filtered and purified by preparative HPLC.
The resulting orange solid was triturated with acetone to yield 36
(36.3 mg, 0.08 mmol, 63%) as a yellow solid. .sup.1H NMR: (500 MHz,
DMSO-d.sub.6) .delta. 13.48 (br s, 1H), 9.42 (s, 1H), 9.41 (s, 2H),
9.18 (s 1H), 7.52-7.39 (m, 5H), 3.91-3.24 (m, 8H); LC/MS: (ES+) m/z
(M+H).sup.+=442; HPLC R.sub.t=0.90 min., column S.
PREPARATION OF EXAMPLE 29
1-(4-Benzoylpiperazin-1-yl)-2-(4-(pyridazin-4-yl)-5H-pyrrolo[3,2-d]pyrimid-
in-7-yl)ethane-1,2-dione (Compound 37)
EXAMPLE 29
[0587] 104
[0588] In a sealed tube dicarbonyl intermediate 10 (50 mg, 0.13
mmol), 4-(tributylstannyl)pyridazine (160 mg, 0.43 mmol),
tetrakis(triphenylphosphine)-palladium(0) (30 mg, 0.03 mmol) and
1,4-dioxane (0.8 mL) were combined and heated at 130.degree. C.
with microwaves for 2 h. The reaction mixture was concentrated,
diluted with MeOH, filtered and purified by preparative HPLC. The
resulting black oil was repurified by preparative HPLC and the
resulting yellow solid was triturated with acetone to yield 37
(18.7 mg, 0.04 mmol, 33%) as an off-white solid. .sup.1H NMR: (500
MHz, DMSO-d.sub.6) .delta. 13.48 (br s, 1H), 9.82 (br s, 1H), 9.54
(dd, J=5.2, 1.1 Hz, 1H), 9.22 (s 1H), 8.85 (br s, 1H), 8.29 (dd,
J=5.2, 2.0 Hz, 1H), 7.54-7.37 (m, 5H), 3.91-3.25 (m, 8H); LC/MS:
(ES+) m/z (M+H).sup.+=442; HPLC R.sub.t=0.89 min., column S.
Preparation of 2-(4-(isoquinolin-1-yl)piperazin-1-yl)acetonitrile
38
[0589] 105
[0590] To a solution of 1-(piperazin-1-yl)isoquinoline (459 mg,
2.15 mmol) in THF (15 mL) was added NEt.sub.3 (3.6 mL, 27 mmol) and
chloroacetonitrile (1.8 mL, 28 mmol) and the reaction was stirred 3
h. The reaction mixture was filtered, concentrated and the residue
purified by silica gel chromatography (Biotage 25-short, 25%
EtOAc/hexanes to 100% EtOAc/hex) to yield 38 (188 mg, 0.75 mmol,
35%) as a white solid. LC/MS: (ES+) m/z (M+H).sup.+=253; HPLC
R.sub.t=1.23 min., column Q, conditions B.
PREPARATION OF EXAMPLE 30
1-(4-Chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-2-(4-(isoquinolin-1-yl)pipera-
zin-1-yl)ethane-1,2-dione (Compound 39)
EXAMPLE 30
[0591] 106
[0592] To a slurry of acid chloride intermediate 7 (115 mg, 0.53
mmol) and 2-(4-(isoquinolin-1-yl)piperazin-1-yl)acetonitrile 38
(188 mg, 0.75 mmol) in THF (5 mL), at -78.degree. C., was added 0.5
M KHMDS in toluene (3.4 mL, 1.7 mmol). The reaction was stirred 2
h. and the presence of the desired cyanoketone intermediate was
verified by LCMS. A solution of 32% peracetic acid in dilute
aqueous acetic acid (0.5 mL, 2.4 mmol) was added and the reaction
mixture was allowed to warm to ambient temperature overnight. The
reaction mixture was diluted with EtOAc (10 mL) and saturated
aqueous NH.sub.4Cl (10 mL) and filtered. The layers were separated
and the aqueous layer extracted with EtOAc (25 mL). The combined
organic layers were concentrated and purified by preparative HPLC
to yield 39 (102 mg, 0.24 mmol, 45%) as a bright yellow solid.
.sup.1H NMR: (500 MHz, CD.sub.3OD) .delta. 8.84 (s, 1H), 8.70 (s,
1H), 8.38 (d, J=7.9 Hz, 1H), 8.06 (d, J=7.2 Hz, 1H), 7.99 (dd,
J=7.9, 7.6 Hz, 1H), 7.89 (d, J=6.7 Hz, 1H), 7.83 (dd, J=7.6, 7.2
Hz, 1H), 7.62 (d, J=6.7 Hz, 1H), 4.20-3.79 (m, 8H); LC/MS: (ES+)
m/z (M+H).sup.+=421; HPLC R.sub.t=0.83 min., column S.
PREPARATION OF EXAMPLE 31
1-(4-(Isoquinolin-1-yl)piperazin-1-yl)-2-(4-(pyrazin-2-yl)-5H-pyrrolo[3,2--
d]pyrimidin-7-yl)ethane-1,2-dione (Compound 40)
EXAMPLE 31
[0593] 107
[0594] In a sealed tube dicarbonyl intermediate 39 (40 mg, 0.10
mmol), 2-(tributylstannyl)pyrazine (105 mg, 0.28 mmol),
tetrakis(triphenylphosph- ine)-palladium(0) (30 mg, 0.03 mmol) and
1,4-dioxane (0.8 mL) were combined and heated at 130.degree. C.
with microwaves for 2 h. The reaction mixture was diluted with MeOH
(1 mL) and DMSO (1 mL), filtered through celite and purified by
preparative HPLC to yield 40 (12 mg, 0.03 mmol, 27%) as a yellow
solid. .sup.1H NMR: (500 MHz, CD.sub.3OD) .delta. 9.85 (s, 1H),
9.21 (s, 1H), 8.93 (br s, 1H), 8.83 (d, J=2.4 Hz, 1H), 8.72 (s,
1H), 8.42 (d, J=8.9 Hz, 1H), 8.09 (d, J=7.9 Hz, 1H), 8.05 (dd,
J=8.0, 7.0 Hz, 1H), 7.87 (dd, J=8.9, 8.0 Hz, 1H), 7.85 (d, J=7.0
Hz, 1H), 7.66(d, J=6.7 Hz, 1H), 4.24-4.20 (m, 2H), 4.14-4.04 (m,
2H), 3.99-3.91 (m, 4H); LC/MS: (ES+) m/z (M+H).sup.+=465; HPLC
R.sub.t=0.92 min., column S.
PREPARATION OF EXAMPLE 32
1-(4-(1H-Pyrazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-2-(4-(isoquinolin--
1-yl)piperazin-1-yl)ethane-1,2-dione (Compound 41)
EXAMPLE 32
[0595] 108
[0596] In a sealed tube dicarbonyl intermediate 39 (41 mg, 0.10
mmol), pyrazole (26 mg, 0.38 mmol), copper(0) (10 mg) and
1,4-dioxane (0.8 mL) were combined and heated at 140.degree. C.
with microwaves for 50 min. The reaction mixture was diluted with
MeOH (1 mL) and DMSO (1 mL), filtered through celite and purified
by preparative HPLC to yield 41 (11 mg, 0.02 mmol, 23%) as a light
yellow solid. .sup.1H NMR: (500 MHz, CD.sub.3OD) .delta. 8.90 (br
s, 1H), 8.85 (d, J=2.5 Hz, 1H), 8.61 (s, 1H), 8.42 (d, J=8.5 Hz,
1H), 8.09 (d, J=7.9 Hz, 1H), 8.08 (s, 1H), 8.04 (dd, J=7.6, 7.3 Hz,
1H), 7.89-7.85 (m, 1H), 7.85 (d, J=6.7 Hz, 1H), 7.66 (d, J=7.0 Hz,
1H), 6.72 (dd, J=2.5, 1.6 Hz, 1H), 4.22-4.18 (m, 2H), 4.12-4.07 (m,
2H), 3.97-3.89 (m, 4H); LC/MS: (ES+) m/z (M+H).sup.+=453; HPLC
R.sub.t=0.97 min., column S.
Preperation of
2-(1-(cyanomethyl)piperidin-4-ylidene)-2-phenylacetonitrile 42
[0597] 109
[0598] To a solution of
2-phenyl-2-(piperidin-4-ylidene)acetonitrile (6.8 g, 34 mmol) in
THF (150 mL) was added NEt.sub.3 (40 mL, 300 mmol) and
chloroacetonitrile (20 mL, 315 mmol) and the reaction was stirred
16 h. The precipitates was filtered away and the filtrate
concentrated to dryness. The residues was purified by silica gel
chromatography (Biotage 40-short, 20% EtOAc/Hex to 50% EtOAc/Hex)
to yield 42 (1.7 g, 7.2 mmol, 21%) as a yellow waxy solid. .sup.1H
NMR: (500 MHz, CDCl.sub.3) .delta. 7.44-7.34 (m, 3H), 7.30-7.27 (m,
2H), 3.65 (s, 2H), 2.96 (t, J=5.3 Hz, 2H), 2.90 (t, J=5.3 Hz, 2H),
2.70 (t, J=5.6 Hz, 2H), 2.62 (t, J=5.6 Hz, 2H); LC/MS: (ES+) m/z
(M+H).sup.+=238; HPLC R.sub.t=1.33 min., column O, conditions
B.
PREPARATION OF EXAMPLE 33
2-(1-(2-(4-Chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-2-oxoacetyl)piperidin-4-
-ylidene)-2-phenylacetonitrile (Compound 43)
EXAMPLE 33
[0599] 110
[0600] To a slurry of acid chloride intermediate 7 (100 mg, 0.46
mmol) and phenylcyanoalkene intermediate 42 (143 mg, 0.60 mmol) in
THF (4 mL) at -78.degree. C. was added a solution of 0.5 M KHMDS in
toluene (3.0 mL, 1.5 mmol). The reaction was stirred 2 h and the
presence of the desired cyanoketone intermediate was verified by
LCMS. A solution of 32% peracetic acid in dilute aqueous acetic
acid (0.44 mL, 2.1 mmol) was added to the reaction mixture and then
allowed to warm to ambient temperature overnight. The reaction
mixture was diluted with EtOAc (15 mL) and saturated aqueous
NH.sub.4Cl (10 mL). The layers were separated and the aqueous layer
extracted with EtOAc (2.times.20 mL). The combined organic layers
were concentrated, the residue was purified by preparative HPLC and
the resulting yellow solid was triturated with MeOH to yield 43
(18.6 mg, 0.04 mmol, 10%) as a white solid. .sup.1H NMR: (500 MHz,
DMSO-d.sub.6) .delta. 13.73 (s, 1H), 8.85 (s, 0.5H), 8.84 (s,
0.5H), 8.79 (s, 0.5H), 8.76 (s, 0.5H), 7.54-7.30 (m, 5H), 3.86 (t,
J=5.8 Hz, 1H), 3.70 (t, J=5.8 Hz, 1H), 3.56 (t, J=5.8 Hz, 1H), 3.38
(t, J=5.8 Hz, 1H), 2.93 (t, J=5.8 Hz, 1H), 2.65 (t, J=5.8 Hz, 1H),
2.63 (dd, J=5.8 Hz, 1H), 2.36 (t, J=5.8 Hz, 1H); LC/MS: (ES+) m/z
(M+H).sup.+=406; HPLC R.sub.t=1.28 min., column S.
PREPARATION OF EXAMPLE 34
2-(1-(2-Oxo-2-(4-(pyrimidin-5-yl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)acetyl)p-
iperidin-4-ylidene)-2-phenylacetonitrile (Compound 44)
EXAMPLE 34
[0601] 111
[0602] In a sealed tube dicarbonyl intermediate 33 (30 mg, 0.074
mmol), 5-(tributylstannyl)pyrimidine (82 mg, 0.22 mmol),
tetrakis(triphenylphosp- hine)-palladium(0) (20 mg, 0.02 mmol) and
1,4-dioxane (0.8 mL) were combined and heated at 130.degree. C.
with microwaves for 2 h. The reaction mixture was diluted with
MeOH/DMSO, filtered and purified by preparative HPLC to yield 44 (8
mg, 0.02 mmol, 30%) as a yellow solid. .sup.1H NMR: (500 MHz,
CD.sub.3OD) .delta. 9.47 (s, 1H), 9.45 (s, 1H), 9.40 (s, 0.5H),
9.39 (s, 0.5H), 9.19 (s, 0.5H), 9.18 (s, 0.5H), 8.72 (s, 0.5H),
8.69 (s, 0.5H), 7.53-7.31 (m, 5H), 4.02 (dd, J=6.1, 5.8 Hz, 1H),
3.84 (dd, J=6.1, 5.8 Hz, 1H), 3.75 (dd, J=5.8, 5.8 Hz, 1H), 3.57
(dd, J=6.1, 5.8 Hz, 1H), 3.07 (dd, J=6.1, 5.8 Hz, 1H), 2.86 (dd,
J=5.8, 5.8 Hz, 1H), 2.74 (dd, J=6.1, 5.8 Hz, 1H), 2.54 (dd, J=6.1,
5.8 Hz, 1H); LC/MS: (ES+) m/z (M+H).sup.+=450; HPLC R.sub.t=1.48
min., column O.
Preparation of
2-(4-((1,3,4-oxadiazol-2-yl)(phenyl)methylene)piperidin-1-y-
l)acetonitrile 45
[0603] 112
[0604] tert-Butyl
4-((1,3,4-oxadiazol-2-yl)(phenyl)methylene)piperidine-1--
carboxylate (100 mg, 0.29 mmol) was diluted with 4 M HCl in
1,4-dioxane (1.2 mL, 4.8 mmol) and stirred 1 h. The reaction was
concentrated and the residue diluted with THF (1.5 mL),
triethylamine (0.5 mL, 3.8 mmol) and chloroacetonitrile (0.25 mL,
3.9 mmol). The reaction was stirred 3 d, concentrated, diluted with
MeOH, filtered and purified by preparative HPLC to yield 45 (43 mg,
0.15 mmol, 53%) as a white solid. .sup.1H NMR: (500 MHz,
CDCl.sub.3) .delta. 8.27 (s, 1H), 7.41-7.31 (m, 3H), 7.20-7.16 (m,
2H), 3.55 (s, 2H), 3.02 (t, J=5.8 Hz, 2H), 2.75 (t, J=5.8 Hz, 2H),
2.61 (t, J=5.8 Hz, 2H), 2.39 (t, J=5.8 Hz, 2H); LC/MS: (ES+) m/z
(M+H).sup.+=281; HPLC R.sub.t=0.97 min., column G, conditions
B.
PREPARATION OF EXAMPLE 35
1-(4-((1,3,4-Oxadiazol-2-yl)(phenyl)methylene)piperidin-1-yl)-2-(4-(1H-1,2-
,4-triazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)ethane-1,2-dione
(Compound 46)
EXAMPLE 35
[0605] 113
[0606] To a slurry of acid chloride intermediate 7 (600 mg, 2.8
mmol) and
2-(4-((1,3,4-oxadiazol-2-yl)(phenyl)methylene)piperidin-1-yl)acetonitrile
45 (800 mg, 2.9 mmol) in THF (5 mL), at -78.degree. C. was added a
solution of 0.5 M KHMDS in toluene (17.2 mL, 8.6 mmol). The
reaction was stirred 2 h. A solution of 32% peracetic acid in
dilute aqueous acetic acid (2.8 mL, 13 mmol) was added and the
reaction mixture was allowed to warm to ambient temperature over 1
h. The reaction mixture was diluted with EtOAc (30 mL) and brine
(25 mL) and filtered. The layers were separated and the organic
layer concentrated. The residue was triturated with Et.sub.2O to
yield 46 (340 mg, 0.76 mmol, 27%) as an orange/yellow solid.
.sup.1H NMR: (500 MHz, DMSO-d.sub.6) .delta. 13.73 (s, 1H), 9.17
(s, 0.5H), 9.10 (s, 0.5H), 8.83 (s, 0.5H), 8.82 (s, 0.5H), 8.76 (s,
0.5H), 8.74 (s, 0.5H), 7.49-7.15 (m, 5H), 3.80 (t, J=5.8 Hz, 1H),
3.71 (t, J=5.8 Hz, 1H), 3.49 (t, J=5.8 Hz, 1H), 3.40 (t, J=5.8 Hz,
1H), 3.02 (t, J=5.8 Hz, 1H), 2.75 (t, J=5.8 Hz, 1H), 2.52 (t, J=5.8
Hz, 1H), 2.25 (t, J=5.8 Hz, 1H); LC/MS: (ES+) m/z (M+H).sup.+=449;
HPLC R.sub.t=1.10 min., column P, conditions B.
PREPARATION OF EXAMPLE 36
1-(4-((1,3,4-Oxadiazol-2-yl)(phenyl)methylene)piperidin-1-yl)-2-(4-(1H-1,2-
,4-triazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)ethane-1,2-dione
(Compound 47)
EXAMPLE 36
[0607] 114
[0608] In a sealed tube dicarbonyl intermediate 46 (30 mg, 0.07
mmol), 1,2,4-triazole (28 mg, 0.41 mmol), copper(0) (8 mg, 0.13
mmol), K.sub.2CO.sub.3 (20 mg, 0.14 mmol) and 1,4-dioxane (1 mL)
were combined and heated at 140.degree. C. with microwaves for 2 h.
The reaction mixture was diluted with MeOH/DMSO (2:3, 1 mL) and
purified by preparative HPLC to yield 47 (4 mg, 0.008 mmol, 12%) as
a yellow solid. .sup.1H NMR: (500 MHz, CD.sub.3OD) .delta. 9.62 (s,
0.5H), 9.62 (s, 0.5H), 8.87 (s, 0.5H), 8.79 (s, 0.5H), 8.60 (s,
0.5H), 8.58 (s, 0.5H), 8.44 (s, 0.5H), 8.43 (s, 0.5H), 7.48-7.14
(m, 6H), 3.95 (dd, J=6.1, 5.8 Hz, 1H), 3.83 (dd, J=6.1, 5.8 Hz,
1H), 3.68 (dd, J=6.1, 5.5 Hz, 1H), 3.58 (dd, J=5.8, 5.8 Hz, 1H),
3.10 (dd, J=6.1, 5.8 Hz, 1H), 2.90 (dd, J=6.1, 5.5 Hz, 1H), 2.61
(dd, J=6.1, 5.8 Hz, 1H), 2.42 (dd, J=6.1, 5.5 Hz, 1H); LC/MS: (ES+)
m/z (M+H).sup.+=482; HPLC R.sub.t=1.13 min., column P, conditions
B.
PREPARATION OF EXAMPLE 37
1-(4-((1,3,4-Oxadiazol-2-yl)(phenyl)methylene)piperidin-1-yl)-2-(4-(1H-pyr-
azol-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)ethane-1,2-dione
(Compound 48)
EXAMPLE 37
[0609] 115
[0610] In a sealed tube dicarbonyl intermediate 46 (30 mg, 0.07
mmol), pyrazole (34 mg, 0.5 mmol) and 1,4-dioxane (0.7 mL) were
combined and heated at 140.degree. C. with microwaves for 50 min.
The reaction mixture was diluted with MeOH/DMSO (1:1, 1.2 mL) and
purified by preparative HPLC to yield 48 (10 mg, 0.02 mmol, 32%) as
a yellow solid. .sup.1H NMR: (500 MHz, CD.sub.3OD) .delta. 8.86 (s,
1H), 8.85 (s, 0.5H), 8.82 (d, J=2.8 Hz, 0.5H), 8.81 (d, J=2.8 Hz,
0.5H), 8.79 (s, 0.5H), 8.53 (s, 0.5H), 8.51 (s, 0.5H), 8.04 (d,
J=1.5 Hz, 0.5H), 8.03 (d, J=1.5 Hz, 0.5H), 7.46-7.16 (m, 5H),
6.71-6.67 (m, 1H), 3.94 (dd, J=6.1, 5.8 Hz, 1), 3.81 (dd, J=6.1,
5.8 Hz, 1H), 3.69 (dd, J=6.1, 5.8 Hz, 1H), 3.57 (dd, J=5.8, 5.8 Hz,
1H), 3.08 (dd, J=5.8, 5.8 Hz, 1H), 2.91 (dd, J=6.1, 5.8 Hz, 1H),
2.59 (dd, J=6.1, 5.8 Hz, 1H), 2.43 (dd, J=6.1, 5.8 Hz, 1H); LC/MS:
(ES+) m/z (M+H).sup.+=481; HPLC R.sub.t=1.27 min., column P,
conditions B.
Preparation of ethyl
4-(1H-pyrazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-car- boxylate
49
[0611] 116
[0612] In a sealed tube
4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carbonyl chloride 5 (2.0 g,
8.9 mmol), pyrazole (1.8 g, 26.5 mmol) and 1,4 dioxane (10 mL) were
heated at 138.degree. C. for 2 h. Upon cooling to ambient
temperature a precipitate formed which was collected and washed
with saturated aqueous NaHCO.sub.3 and diethyl ether to yield 49
(340 mg, 1.3 mmol) as a white solid. The filtrate was treated with
saturated aqueous NaHCO.sub.3 (20 ml) and the resulting precipitate
was washed with saturated aqueous NaHCO.sub.3 and diethyl ether to
yield additional 49 (2.0 g, 7.8 mmol, 99% total yield). .sup.1H
NMR: (500 MHz, CD.sub.3OD) .delta. 8.99 (br s, 1H), 8.78 (br s,
1H), 8.29 (s, 1H), 8.06 (br s, 1H), 6.72 (br s, 1H), 4.30 (q, J=7.0
Hz, 2H), 1.33 (t, J=7.0 Hz, 3H); LC/MS: (ES+) m/z (M+H).sup.+=258;
HPLC R.sub.t=1.20 min., column L.
Preparation of
4-(1H-pyrazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxyli- c acid
50
[0613] 117
[0614] To a solution of
4-(1H-pyrazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-- carboxylate 49
(2.0 g, 7.8 mmol) in THF (45 mL) was added a solution of
LiOH.H.sub.2O (1.3 g, 31 mmol) in H.sub.2O (30 mL) and the reaction
was stirred at 100.degree. C. for 16 h. Additional LiOH.H.sub.2O
(2.0 g, 48 mmol) was added, heating continued for 2 h, MeOH was
added (10 mL) and heating continued at 100.degree. C. for 1 d. The
reaction mixture was cooled, filtered, concentrated to 20% volume
and neutralized with ice and conc HCl. The white precipitate that
formed was collected by filtration and washed with brine, H.sub.2O,
EtOAc, and Et.sub.2O to yield 50 (quantitative), which was used
without further purification. .sup.1H NMR: (500 MHz, DMSO-d.sub.6)
.delta. 12.07 (br s, 1H), 8.89 (br s, 1H), 8.75 (s, 1H), 8.14 (s,
1H), 8.09 (br s, 1H), 6.76-6.73 (m, 1H); LC/MS: (ES+) m/z
(M+H).sup.+=230; HPLC R.sub.t=0.75 min., column S.
Preparation of
4-(1H-pyrazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carbonyl chloride
51
[0615] 118
[0616] Oxalyl chloride (4.5 mL, 51 mmol) was added to a solution of
diazaindole carboxylic acid 50 (1.08 g, 4.7 mmol) in
CH.sub.2Cl.sub.2 (8 mL) and the reaction mixture was stirred 14 h.
Catalytic DMF (3 drops) was added to the reaction mixture and after
3 h the reaction was quenched with MeOH. The crude reaction mixture
was concentrated to dryness to yield 51 (1.21 g, 49 mmol, 96%) as a
tan solid with was used without further purification. .sup.1H NMR:
(500 MHz, DMSO-d.sub.6) .delta. 12.45 (br s, 1H), 8.87 (s, 1H),
8.87 (d, J=2.6 Hz, 1H), 8.32 (d, J=3.3 Hz, 1H), 8.14 (d, J=1.5 Hz,
1H), 6.77 (dd, J=2.6, 1.5 Hz, 1H); Methyl ester (obtained by
stirring 51 in MeOH): LC/MS: (ES+) m/z (M+H).sup.+=244; HPLC
R.sub.t=0.95 min., column O, conditions B.
Preparation of
2-(1-(cyanomethyl)piperidin-4-ylidene)-2-(pyridin-2-yl)acet-
onitrile 52
[0617] 119
[0618] To a solution of
2-(piperidin-4-ylidene)-2-(pyridin-2-yl)acetonitri- le (560 mg, 2.8
mmol) in THF (20 mL) was added NEt.sub.3 (5 mL, 38 mmol) and
chloroacetonitrile (3 mL, 47 mmol) and the reaction was stirred 16
h. The resulting precipitates were filtered away and the filtrate
concentrated to dryness. The residues was purified by silica gel
chromatography (Biotage 40-short, 50% EtOAc/hexanes to 100%
EtOAc/hexanes) to yield 52 (470 mg, 2.0 mmol, 71%) as a yellow
solid. .sup.1H NMR: (500 MHz, CDCl.sub.3) .delta. 8.64 (br d, J=4.9
Hz, 1H), 7.77 (ddd, J=7.9, 7.6, 1.9 Hz, 1H), 7.50 (d, J=7.9 Hz,
1H), 7.27 (dd, J=7.6, 4.9 Hz, 1H), 3.58 (s, 2H), 2.94 (t, J=5.8 Hz,
2H), 2.91 (t, J=5.8 Hz, 2H), 2.83 (t, J=5.8 Hz, 2H), 2.67 (t, J=5.8
Hz, 2H); LC/MS: (ES+) m/z (M+H).sup.+=239; HPLC R.sub.t=0.99 min.,
column O, conditions B.
PREPARATION OF EXAMPLE 38
2-(1-(2-(4-(1H-pyrazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-2-oxoacetyl)-
piperidin-4-ylidene)-2-(pyridin-2-yl)acetonitrile (Compound 53)
EXAMPLE 38
[0619] 120
[0620] To a slurry of acid chloride pyrazole intermediate 51 (100
mg, 0.40 mmol) and 3-pyridinylcyanoalkene intermediate 52 (100 mg,
0.42 mmol) in THF (4 mL) at -78.degree. C. was added a solution of
0.5 M KHMDS in toluene (3.0 mL, 1.5 mmol). The reaction mixture was
stirred at -78.degree. C. for 3 h and the presence of the desired
cyanoketone intermediate was verified by LCMS. A solution of 32%
peracetic acid in dilute aqueous acetic acid (0.44 mL, 2.1 mmol)
was added to the reaction mixture and then allowed to warm to
ambient temperature overnight. The reaction mixture was diluted
with H.sub.2O (5 mL) and saturated aqueous NH.sub.4Cl (5 mL) and
extracted with EtOAc (3.times.20 mL). The layers were separated and
the aqueous layer extracted with EtOAc (2.times.20 mL). The
combined organic layers were concentrated, the residue was purified
by preparative HPLC to yield 53 (7.3 mg, 0.02 mmol, 4%) as a yellow
solid. .sup.1H NMR: (500 MHz, CD.sub.3OD) .delta. 8.95 (s, 0.5H),
8.93 (s, 0.5H), 8.88 (d, J=2.8 Hz, 0.5H), 8.86 (d, J=3.1 Hz, 0.5H),
8.71 (br d, J=4.9 Hz, 0.5H), 8.64-8.61 (m, 1H), 8.60 (s, 0.5H),
8.11 (br s, 0.5H), 8.10 (br s, 0.5H), 8.03 (ddd, J=7.9, 7.6, 1.5
Hz, 0.5H), 7.97 (ddd, J=7.9, 7.6, 1.5 Hz, 0.5H), 7.65 (d, J=7.9 Hz,
0.5H), 7.60 (d, J=7.9 Hz, 0.5H), 7.52 (dd, J=7.9, 4.9 Hz, 0.5H),
7.46 (dd, J=7.9, 4.9 Hz, 0.5H), 6.76-6.72 (m, 1H), 4.03 (dd, J=6.1,
6.1 Hz, 1H), 3.86 (dd, J=6.1, 5.8 Hz, 1H), 3.81 (dd, J=6.1, 5.5 Hz,
1H), 3.64 (dd, J=5.8, 5.8 Hz, 1H), 3.10 (dd, J=6.1, 5.8 Hz, 1H),
2.94 (dd, J=6.1, 5.5 Hz, 1H), 2.90 (dd, J=6.1, 5.8 Hz, 1H), 2.75
(dd, J=5.8, 5.8 Hz, 1H); LC/MS: (ES+) m/z (M+H).sup.+=439; HPLC
R.sub.t=1.37 min., column O.
PREPARATION OF EXAMPLE 39
1-(4-Benzoylpiperazin-1-yl)-2-(4-(3-(pyridin-2-yl)-1H-pyrazol-1-yl)-5H-pyr-
rolo[3,2-d]pyrimidin-7-yl)ethane-1,2-dione (Compound 54)
EXAMPLE 39
[0621] 121
[0622] In a sealed tube dicarbonyl intermediate 10 (52 mg, 0.13
mmol), 2-(1H-pyrazol-3-yl)pyridine (104 mg, 0.71 mmol) and
1,4-dioxane (2.0 mL) were combined and heated at 150.degree. C.
with microwaves for 1 h. The reaction mixture was concentrated,
diluted with MeOH, filtered and purified by preparative HPLC to
yield 54 (31 mg, 0.06 mmol, 47%) as an off-white solid. .sup.1H
NMR: (500 MHz, DMSO-d.sub.6) .delta. 12.60 (br s, 1H), 8.97 (d,
J=1.8 Hz, 1H), 8.94 (s, 1H), 8.73-8.66 (m, 2H), 8.61 (br s, 1H),
8.02 (t, J=7.0 Hz, 1H), 7.54-7.38 (m, 6H), 7.31 (d, J=1.8 Hz, 1H),
3.92-3.13 (m, 8H); LC/MS: (ES+) m/z (M+H).sup.+=507; HPLC
R.sub.t=1.19 min., column N.
Preparation of 2-(4-(quinazolin-4-yl)piperazin-1-yl)acetonitrile
55
[0623] 122
[0624] To a solution of 4-(piperazin-1-yl)quinazoline (1.8 g, 8.3
mmol) in THF (50 mL) was added NEt.sub.3 (20 mL, 150 mmol) and
chloroacetonitrile (12 mL, 190 mmol) and the reaction was stirred
16 h. The reaction mixture was quenched with 50% saturated aqueous
NaHCO.sub.3 and extracted with EtOAc (3.times.200 mL). The combined
organics were purified by silica gel chromatography (50%
EtOAc/hexanes to 80% EtOAc/hexanes) to yield 55 (1.6 g, 6.1 mmol,
73%) as an viscous yellow oil. .sup.1H NMR: (500 MHz, CDCl.sub.3)
.delta. 8.74 (s, 1H), 8.06 (d, J=8.6 Hz, 1H), 7.90 (d, J=8.5 Hz,
1H), 7.82-7.55 (m, 1H), 7.54-7.50 (m, 1H), 3.94-3.88 (m, 4H), 3.63
(s, 2H), 2.86-2.81 (m, 4H); LC/MS: (ES+) m/z (M+H).sup.+=254; HPLC
R.sub.t=0.71 min., column O.
PREPARATION OF EXAMPLE 40
1-(4-(1H-Pyrazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-2-(4-(quinazolin-4-
-yl)piperazin-1-yl)ethane-1,2-dione (Compound 56)
EXAMPLE 40
[0625] 123
[0626] To a slurry of acid chloride pyrazole intermediate 51 (100
mg, 0.40 mmol) and
2-(4-(quinazolin-4-yl)piperazin-1-yl)acetonitrile 55 (98 mg, 0.39
mmol) in THF (4 mL), at -78.degree. C. was added a solution of 0.5
M KHMDS in toluene (3.0 mL, 1.5 mmol). The reaction mixture was
stirred 3 h and the presence of the desired cyanoketone
intermediate was verified by LCMS. The reaction was treated with a
solution of 32% peracetic acid in dilute aqueous acetic acid (0.40
mL, 1.9 mmol) and then allowed to warm to ambient temperature
overnight. The reaction mixture was diluted with saturated aqueous
NH.sub.4Cl (5 mL) and extracted with EtOAc (3.times.20 mL). The
combined organic layers were concentrated, the residue was purified
by preparative HPLC to yield 56 (33 mg, 0.07 mmol, 18%) as a yellow
solid. .sup.1H NMR: (500 MHz, CD.sub.3OD) .delta. 8.86 (s, 1H), 8.5
(d, J=2.7 Hz, 1H), 8.75 (s, 1H), 8.61 (s, 1H), 8.30 (d, J=8.2 Hz,
1H), 8.09-8.05 (m, 2H), 7.84 (d, J=8.5 Hz, 1H), 7.79 (dd, J=8.2,
7.6 Hz, 1H), 6.72 (br s, 1H), 4.62-4.56 (m, 2H), 4.43-4.38 (m, 2H),
4.12-4.07 (m, 2H), 3.91-3.86 (m, 2H); LC/MS: (ES+) m/z
(M+H).sup.+=439; HPLC R.sub.t=1.06 min., column O.
PREPARATION OF EXAMPLE 41
1-(4-(4-(1H-Pyrazole-3-carbonyl)piperazin-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-
-7-yl)-2-(4-benzoylpiperazin-1-yl)ethane-1,2-dione (Compound
57)
EXAMPLE 41
[0627] 124
[0628] In a sealed tube dicarbonyl intermediate 10 (50 mg, 0.13
mmol), (4-methylpiperazin-1-yl)(1H-pyrazol-3-yl)methanone (75 mg,
0.39 mmol) and copper powder (10 mg, 0.16 mmol) were combined and
heated at 150.degree. C. with microwaves for 2 h. The reaction was
purified by preparative HPLC to yield 57 (65 mg, 0.12 mmol, 92%) as
a white solid. .sup.1H NMR: (500 MHz, CD.sub.3COCD.sub.3) .delta.
10.31 (br s, 2H), 8.82 (s, 1H), 8.85 (s, 1H), 7.80 (s, 1H),
7.50-7.40 (m, 5H), 6.74 (s, 1H), 4.50-4.37 (m, 6H), 4.09-3.96 (m,
2H), 3.86-3.60 (m, 8H); LC/MS: (ES+) m/z (M+H).sup.+=542; HPLC
R.sub.t=0.85 min., column G, conditions B.
PREPARATION OF EXAMPLE 42
2-(1-(2-(4-(1H-Pyrazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-2-oxoacetyl)-
piperidin-4-ylidene)-2-phenylacetonitrile (Compound 58)
EXAMPLE 42
[0629] 125
[0630] In a sealed tube dicarbonyl intermediate 33 (31 mg, 0.077
mmol), pyrazole (20 mg, 0.29 mmol) and 1,4-dioxane (0.8 mL) were
combined and heated at 140.degree. C. with microwaves for 50 min.
The reaction mixture was diluted with MeOH/DMSO (2:1, 1.5 mL),
filtered and purified by preparative HPLC to yield 58 (10 mg, 0.024
mmol, 31%) as an orange solid. .sup.1H NMR: (500 MHz, CD.sub.3OD)
.delta. 8.90 (s, 0.5H), 8.88 (s, 0.5H), 8.86 (d, J=2.8 Hz, 0.5H),
8.84 (d, J=2.8 Hz, 0.5H), 8.57 (s, 0.5H), 8.54 (s, 0.5H), 8.08 (br
s, 0.5H), 8.06 (br s, 0.5H), 7.53-7.31 (m, 5H), 6.74-6.70 (m, 1H),
4.00 (t, J=5.8 Hz, 1H), 3.82 (t, J=5.8 Hz, 1H), 3.75 (t, J=5.8 Hz,
1H), 3.56 (t, J=5.8 Hz, 1H), 3.05 (t, J=5.8 Hz, 1H), 2.87 (t, J=5.8
Hz, 1H), 2.72 (t, J=5.8 Hz, 1H), 2.55 (t, J=5.8 Hz, 1H); LC/MS:
(ES+) m/z (M+H).sup.+=438; HPLC R.sub.t=1.73 min., column O.
PREPARATION OF EXAMPLE 43
2-(1-(2-(4-(1H-pyrazol-3-yl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-2-oxoacetyl)-
piperidin-4-ylidene)-2-phenylacetonitrile (Compound 59)
EXAMPLE 43
[0631] 126
[0632] In a sealed tube dicarbonyl intermediate 33 (33 mg, 0.081
mmol), 3-(tributylstannyl)-1H-pyrazole (73 mg, 0.20 mmol),
tetrakis(triphenylphosphine)-palladium(0) (20 mg, 0.02 mmol) and
1,4-dioxane (0.8 mL) were combined and heated at 130.degree. C.
with microwaves for 2 h. The reaction mixture was diluted with
MeOH/DMSO (2:1, 1.5 mL), filtered and purified by preparative HPLC
to yield 59 (3.4 mg, 0.008 mmol, 10%) as a yellow solid. .sup.1H
NMR: (500 MHz, CD.sub.3COCD.sub.3) .delta. 11.84 (br s, 1H), 9.06
(s, 0.5H), 9.05 (s, 0.5H), 8.58 (s, 0.5H), 8.55 (s, 0.5H), 8.01 (d,
J=2.7 Hz, 0.5H), 8.01 (d, J=2.7 Hz, 0.5H), 7.55-7.32 (m, 5H), 7.24
(d, J=2.7 Hz, 0.5H), 7.23 (d, J=2.7 Hz, 0.5H), 4.01 (t, J=5.8 Hz,
1H), 3.84 (t, J=5.8 Hz, 1H), 3.74 (t, J=5.8 Hz, 1H), 3.56 (t, J=5.8
Hz, 1H), 3.07 (t, J=5.8 Hz, 1H), 2.84 (t, J=5.8 Hz, 1H), 2.78 (t,
J=5.8 Hz, 1H), 2.54 (t, J=5.8 Hz, 1H); LC/MS: (ES+) m/z
(M+H).sup.+=438; HPLC R.sub.t=1.29 min., column L.
[0633] Biology
[0634] ".mu.M" means micromolar;
[0635] "mL" means milliliter;
[0636] ".mu.l" means microliter;
[0637] "mg" means milligram;
[0638] The materials and experimental procedures used to obtain the
results reported in Tables 1-3 are described below.
[0639] Cells:
[0640] 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.).
[0641] 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.).
[0642] 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.).
[0643] Experiment
[0644] 1. Compound was added to HeLa CD4 CCR5 cells plated in 96
well plates at a cell density of 1.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.
[0645] 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.
[0646] 3. Samples were harvested 72 h after infection.
[0647] 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.
[0648] 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.
[0649] 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.
[0650] 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.
[0651] 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.
[0652] Results
2TABLE 1 Biological Data Key for EC.sub.50s Compounds with
Compounds EC50 >50 nM Compounds* with but not yet Compounds with
EC.sub.50s >1 .mu.M tested at higher with EC.sub.50s >5 .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.
[0653]
3TABLE 2 127 Examples EC.sub.50 Group from Example Compound Table
Number Number R3 R5 Y 1 Example 2 10 H Cl 128 A Example 3 11 H 129
130 A Example 4 12 H 131 132 A Example 5 13 H 133 134 A Example 6
14 H 135 136 A Example 7 15 H 137 138 A Example 8 16 H 139 140 A
Example 9 17 H 141 142 A
[0654]
4TABLE 3 143 Examples EC.sub.50 Group Example Cmpd. from No. No. R3
R5 Y Table 1 Example 1 9 H Cl 144 A Example 10 18 H 145 146 A
Example 11 19 H 147 148 A Example 12 20 H 149 150 A Example 13 21 H
151 152 A Example 14 22 H 153 154 A Example 15 23 H 155 156 A
Example 16 24 H 157 158 A Example 17 25 H 159 160 A Example 18 26 H
161 162 A Example 19 27 H 163 164 A Example 20 28 H 165 166 A
Example 21 29 H 167 168 A Example 22 30 H 169 170 A Example 22 30 H
171 172 A Example 24 32 H 173 174 A Example 25 33 H 175 176 A
Example 26 34 H 177 178 A Example 27 35 H 179 180 A Example 28 36 H
181 182 A Example 29 37 H 183 184 A Example 30 39 H Cl 185 A
Example 31 40 H 186 187 A Example 32 41 H 188 189 A Example 33 43 H
Cl 190 A Example 34 44 H 191 192 A Example 35 46 H Cl 193 A Example
36 47 H 194 195 A Example 37 48 H 196 197 A Example 38 53 H 198 199
A Example 39 54 H 200 201 A Example 40 56 H 202 203 A Example 41 57
H 204 205 A Example 42 58 H 206 207 A Example 43 59 H 208 209 A
[0655] Table 4 shows other compounds of the invention which could
be prepared by the methodology described herein and which are
expected to have antiviral activity.
5TABLE 4 210 EC.sub.50 Group Example Cmpd. from No. No. R3 R5 Y
Table 1 Example # # H 211 212 H 213 214 H 215 216 H 217 218 H 219
220 H 221 222 H 223 224 H 225 226 227 228 H 229 230 H 231 232 H 233
234 H 235 236 H 237 238 H 239 240 H 241 242 H 243 244 H 245 246 H
247 248 H 249 250 H 251 252 H 253 254 H 255 256 H 257 258 H 259 260
H 261 262 H 263 264 H 265 266 H 267 268 H 269 270 H 271 272 H 273
274 H 275 276 H 277 278 H 279 280 H 281 282 283 284 H 285 286 H 287
288 H 289 290 H 291 292 H 293 294 H 295 296 H 297 298 H 299 300 H
301 302 H 303 304 H 305 306 H 307 308 H 309 310 H 311 312 H 313 314
H 315 316 H 317 318 H 319 320 321 322 H 323 324 H 325 326 H 327 328
H 329 330 H 331 332 H 333 334 H 335 336 H 337 338 339 340 H 341 342
H 343 344 H 345 346 H 347 348 H 349 350 H 351 352 H 353 354 H 355
356 H 357 358 H 359 360 H 361 362 H 363 364 H 365 366 H 367 368 H
369 370 H 371 372 H 373 374 H 375 376 H 377 378
[0656] 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.
[0657] 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.
[0658] 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.
[0659] 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.
[0660] 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.
[0661] 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.
* * * * *