U.S. patent application number 11/755067 was filed with the patent office on 2007-10-04 for pyrazolopyrimidine and pyrazolotriazine derivatives and pharmaceutical compositions containing them.
Invention is credited to Kristjan Gudmundsson, Brian A. Johns.
Application Number | 20070232623 11/755067 |
Document ID | / |
Family ID | 27805154 |
Filed Date | 2007-10-04 |
United States Patent
Application |
20070232623 |
Kind Code |
A1 |
Gudmundsson; Kristjan ; et
al. |
October 4, 2007 |
Pyrazolopyrimidine and Pyrazolotriazine Derivatives and
Pharmaceutical Compositions Containing Them
Abstract
The present invention provides compounds of formula (I):
##STR1## pharmaceutical compositions containing the same, processes
for preparing the same and their use as pharmaceutical agents.
Inventors: |
Gudmundsson; Kristjan;
(Durham, NC) ; Johns; Brian A.; (Durham,
NC) |
Correspondence
Address: |
GLAXOSMITHKLINE;CORPORATE INTELLECTUAL PROPERTY, MAI B475
FIVE MOORE DR., PO BOX 13398
RESEARCH TRIANGLE PARK
NC
27709-3398
US
|
Family ID: |
27805154 |
Appl. No.: |
11/755067 |
Filed: |
May 30, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10505386 |
Aug 20, 2004 |
7247626 |
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PCT/US03/05704 |
Feb 24, 2003 |
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11755067 |
May 30, 2007 |
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60362298 |
Mar 7, 2002 |
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Current U.S.
Class: |
514/259.3 ;
514/336; 544/180; 544/281; 546/272.7 |
Current CPC
Class: |
A61P 31/22 20180101;
C07D 487/04 20130101; A61P 31/12 20180101 |
Class at
Publication: |
514/259.3 ;
514/336; 544/180; 544/281; 546/272.7 |
International
Class: |
A61K 31/495 20060101
A61K031/495; A61K 31/4375 20060101 A61K031/4375; C07D 251/00
20060101 C07D251/00; C07D 487/00 20060101 C07D487/00 |
Claims
1. A compound of formula (I): ##STR90## wherein: R.sup.1 is
selected from the group consisting of H, halo, alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, --C(O)R.sup.9,
--C(O)Ay, --C(O)Het, --CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8,
--C(O)NR.sup.7Ay, --C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8,
--C(NH)NR.sup.7Ay, --OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8,
--NR.sup.7Ay, --NHHet, --S(O).sub.nR.sup.9, --S(O).sub.nAy,
--S(O).sub.nHet, --S(O).sub.2NR.sup.7R.sup.8,
--S(O).sub.2NR.sup.7Ay, --R.sup.10cycloalkyl, --R.sup.10Ay,
--R.sup.10Het, --R.sup.10OR.sup.9, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10C(O)R.sup.9, --R.sup.10C(O)Ay, --R.sup.10C(O)Het,
--R.sup.10CO.sub.2R.sup.9, --R.sup.10OC(O)R.sup.9,
--R.sup.10OC(O)Ay, --R.sup.10OC(O)Het,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2NHCOR.sup.9,
--R.sup.10OS(O).sub.nR.sup.9, cyano, nitro and azido; each R.sup.7
and R.sup.8 are the same or different and are independently
selected from the group consisting of H, alkyl, cycloalkyl,
alkenyl, cycloalkenyl, --C(O)R.sup.9, --CO.sub.2R.sup.9,
--C(O)NR.sup.9R.sup.11, --C(S)NR.sup.9R.sup.11,
--C(NH)NR.sup.9R.sup.11, --SO.sub.2R.sup.10,
--SO.sub.2NR.sup.9R.sup.11, --R.sup.10cycloalkyl, --R.sup.10Ay,
--R.sup.10Het, --R.sup.10C(O)R.sup.9, --R.sup.10CO.sub.2R.sup.9,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10OR.sup.9, --R.sup.10NR.sup.9R.sup.11,
--R.sup.10NHCOR.sup.9, --R.sup.10NHC(NH)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.10 and
--R.sup.10SO.sub.2NHCOR.sup.9; each R.sup.9 and R.sup.11 are the
same or different and are independently selected from the group
consisting of H, alkyl, cycloalkyl, --R.sup.10cycloalkyl,
--R.sup.10OH, --R.sup.10(OR.sup.10).sub.w where w is 1-10, and
--R.sup.10NR.sup.10R.sup.10; each R.sup.10 is the same or different
and is independently selected from the group consisting of alkyl,
cycloalkyl, alkenyl, cycloalkenyl, and alkynyl; n is 0, 1 or 2; Ay
is aryl; Het is a 5 or 6-membered heterocyclic or heteroaryl group;
Y.sup.1 is N; p is 0 or 1 when Y.sup.1 is N; each R.sup.6 is the
same or different and is independently selected from the group
consisting of H, halo, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, Ay, Het, --C(O)R.sup.9, --C(O)Ay, --C(O)Het,
--CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8, --C(O)NR.sup.7Ay,
--C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8, --C(NH)NR.sup.7Ay,
--OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8, --NR.sup.7Ay,
--NHHet, --S(O).sub.nR.sup.9, --S(O).sub.nAy, --S(O).sub.nHet,
--S(O).sub.2NR.sup.7R.sup.8, --S(O).sub.2NR.sup.7Ay,
--R.sup.10cycloalkyl, --R.sup.10Ay, --R.sup.10Het,
--R.sup.10OR.sup.9, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sub.7Ay, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10C(O)R.sup.9, --R.sup.10C(O)Ay, --R.sup.10C(O)Het,
--R.sup.10CO.sub.2R.sup.9, --R.sup.10OC(O)R.sup.9,
--R.sup.10OC(O)Ay, --R.sup.10OC(O)Het,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2NHCOR.sup.9,
--R.sup.10OS(O).sub.nR.sup.9, cyano, nitro and azido; Y is N or CH:
R.sup.2 is selected from the group consisting of halo, alkyl,
cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, --OR.sup.7, --OAy,
--OHet --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet
--S(O).sub.nR.sup.9, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8 and
--R.sup.10NR.sup.7Ay; R.sup.3 and R.sup.4 are the same or different
and are each independently selected from the group consisting of H,
halo, alkyl, alkenyl, cycloalkyl, Ay, Het, --C(O)R.sup.7, C(O)Ay,
--CO.sub.2R.sup.7, --CO.sub.2Ay, --OR.sup.7, --OAy,
--NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet, --SO.sub.2NHR.sup.9,
--R.sup.10OR.sup.7, --R.sup.10cycloalkyl, --R.sup.10OAy,
--R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay; Ring A is
selected from the group consisting of aryl, 5-10 membered
heterocyclic group and a 5-10 membered heteroaryl group; q is 0, 1,
2, 3, 4 or 5; and each R.sup.5 is the same or different and is
independently selected from the group consisting of halo, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, --C(O)R.sup.9,
--C(O)Ay, --C(O)Het, --CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8,
--C(O)NR.sup.7Ay, --C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8,
--C(NH)NR.sup.7Ay, --OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8,
--NR.sup.7Ay, --NHHet, --S(O).sub.nR.sup.9,
--S(O).sub.2NR.sup.7R.sup.8, --S(O).sub.2NR.sup.7Ay,
--R.sup.10cycloalkyl, --R.sup.10Het, --R.sup.10C(O)R.sup.9,
--R.sup.10CO.sub.2R.sup.9, --R.sup.10C(O)NR.sup.9R.sup.11,
--R.sup.10C(O)NR.sup.7Ay, --R.sup.10C(O)NHR.sup.10Het,
--R.sup.10C(S)NR.sup.9R.sup.11, --R.sup.10C(NH)NR.sup.9R.sup.11,
--R.sup.10OR.sup.9, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, --R.sup.10SO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2NHCOR.sup.9,
cyano, nitro and azido; or a pharmaceutically acceptable salt
thereof.
2. The compound according to claim 1 wherein R.sup.1 is selected
from the group consisting of halo, alkyl, cycloalkyl, Ay, Het,
--OR.sup.7, --OAy, --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet,
--S(O).sub.nR.sup.9, --R.sup.10cycloalkyl, --R.sup.10OR.sup.9,
--R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay.
3. The compound according to claim 1 wherein R.sup.1 is selected
from the group consisting of alkyl, Het, --OR.sup.7,
--NR.sup.7R.sup.8, --NR.sup.7Ay and --S(O).sub.nR.sup.9.
4-5. (canceled)
6. The compound according to claim 1 wherein p is 0 or 1.
7. The compound according to claim 1 wherein each R.sup.6 is the
same or different and is independently selected from the group
consisting of halo, alkyl, Ay, Het, --C(O)Het, --CO.sub.2R.sup.9,
--C(O)NR.sup.7R.sup.8, --C(O)NR.sup.7Ay, --OR.sup.7, --OAy,
--NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet, --S(O).sub.nR.sup.9,
--S(O).sub.nAy, --S(O).sub.nHet, --R.sup.10OR.sup.9 and cyano.
8. The compound according to claim 1 wherein each R.sup.6 is the
same or different and is independently selected from the group
consisting of halo, alkyl, Het, --NR.sup.7R.sup.8, --NHHet and
--S(O).sub.nR.sup.9.
9. The compound according to claim 1 wherein Y is CH.
10. The compound according to claim 1 wherein Y is N.
11. The compound according to claim 1 wherein R.sup.2 is selected
from the group consisting of Ay, Het, --OR.sup.7, --OAy, --OHet,
--NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet, --S(O).sub.nR.sup.9,
--S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8 and
--R.sup.10NR.sup.7Ay.
12. The compound according to claim 1 wherein R.sup.2 is selected
from the group consisting of --NR.sup.7R.sup.8, --NR.sup.7Ay and
--NHHet.
13. The compound according to claim 1 wherein R.sup.3 and R.sup.4
are the same or different and are each independently selected from
the group consisting of H, halo, alkyl, Ay, --CO.sub.2R.sup.7,
--OR.sup.7, --NR.sup.7R.sup.8, --R.sup.10OR.sup.7 and
--R.sup.10NR.sup.7R.sup.8.
14. The compound according to claim 1 wherein hu 3 and R.sup.4 are
both H.
15. The compound according to claim 1 wherein Ring A is selected
from the group consisting of aryl, a 5-6 membered heterocyclic or
heteroaryl group and a 9-membered heterocyclic or heteroaryl
group.
16. The compound according to claim 1 wherein Ring A is selected
from the group consisting of phenyl, naphthyl, furan, pyridine,
pyrimidine, thiazol, pyrazine, pyrrole, imidazole, oxazole,
benzimidazole, quinoline, isoquinoline and quinoxoline.
17. The compound according to claim 1 wherein Ring A is selected
from the group consisting of phenyl, furan, pyridine and
pyrimidine.
18. The compound according to claim 1 wherein Ring A is phenyl.
19. The compound according to claim 1 wherein q is 0, 1 or 2.
20. The compound according to claim 1 wherein each R.sup.5 is the
same or different and is independently selected from the group
consisting of halo, alkyl, alkenyl, Ay, Het, --CO.sub.2R.sup.9,
--C(O)NR.sup.7R.sup.8, --C(O)NR.sup.7Ay, --OR.sup.7, --OAy,
--NR.sup.7R.sup.8, --NR.sup.7Ay, --S(O).sub.2NR.sup.7R.sup.8,
cyano, nitro and azido.
21. The compound according to claim 1 wherein each R.sup.5 is the
same or different and is independently selected from the group
consisting of halo, alkyl, --OR.sup.7, --NR.sup.7R.sup.8 and
cyano.
22. A compound selected from the group consisting of:
N-Cyclopentyl-8-(2-fluoro-4-pyridinyl)-2-(methylsulfanyl)-7-phenylpyrazol-
o[1,5-a][1,3,5]triazin-4-amine;
N.sup.2,N.sup.4-Dicyclopentyl-8-[2-(cyclopentylamino)-4-pyridinyl]-7-phen-
ylpyrazolo[1,5-a][1,3,5]triazine-2,4-diamine; and
N-Cyclopentyl-8-[2-(cyclopentylamino)-4-pyrimidinyl]-7-phenylpyrazolo[1,5-
-a][1,3,5]triazin-4-amine; a pharmaceutically acceptable salt
thereof.
23. A pharmaceutical composition comprising a compound according to
claim 1 and a pharmaceutically acceptable carrier or diluent.
24-25. (canceled)
26. A method for the treatment of a herpes viral infection selected
from herpes simplex virus 1 and herpes simplex virus 2, in an
animal, said method comprising administering to the animal a
therapeutically effective amount of a compound according to claim
1.
27. (canceled)
28. A method for the treatment of a condition or disease associated
with a herpes viral infection selected from herpes simplex virus 1
and herpes simplex virus 2, in an animal, comprising administering
to the animal a therapeutically effective amount of the compound of
formula (I) according to claim 1.
29. (canceled)
30. A process for preparing a compound according to claim 1 wherein
Y is N; R.sup.2 is selected from the group consisting of alkyl,
cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, --OR.sup.7, --OAy,
--OHet --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet
--S(O).sub.nR.sup.9, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8 and
--R.sup.10NR.sup.7Ay; R.sup.3 is selected from the group consisting
of H, alkyl, alkenyl, cycloalkyl, Ay, Het, --C(O)R.sup.7, C(O)Ay,
--CO.sub.2R.sup.7, --CO.sub.2Ay, --OR.sup.7, --OAy,
--NR.sup.7R.sup.8 (where R.sup.7 and R.sup.8 are not H),
--NR.sup.7Ay (where R.sup.7 is H), --SO.sub.2NHR.sup.9,
--R.sup.10OR.sup.7, --R.sup.10cycloalkyl, --R.sup.10OAy,
--R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay; and R.sup.4 is
H said process comprising reacting a compound of formula (XXV):
##STR91## with a compound of formula (XXI): ##STR92##
31. A process for preparing a compound according to claim 1 wherein
Y is N and R.sup.2 is selected from the group consisting of alkyl,
cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, --OR.sup.7, --OAy,
--OHet --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet
--S(O).sub.nR.sup.9, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8 and
--R.sup.10NR.sup.7Ay, said process comprising the steps of: a)
reacting a compound of formula (XXVIII): ##STR93## with a compound
of formula (XXI): ##STR94## to prepare an intermediate compound;
and b) oxidizing the intermediate compound.
32. A process for preparing a compound according to claim 1
comprising reacting a compound of formula (XXX). ##STR95## wherein
X.sup.1 is chloro, bromo or iodo; with a compound of formula (X):
##STR96## wherein M.sup.1 is --B(OH).sub.2, --B(ORa).sub.2,
--B(Ra).sub.2, --Sn(Ra).sub.3, Zn-halide, ZnRa, or Mg-halide where
Ra is alkyl or cycloalkyl and halide is halo.
33-40. (canceled)
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to novel compounds,
pharmaceutical formulations comprising these compounds, and the use
of these compounds in therapy. More particularly, the present
invention relates to compounds for the prophylaxis and treatment of
herpes viral infections.
[0002] Of the DNA viruses, those of the herpes group are the
sources of the most common viral illnesses in man. The group
includes herpes simplex virus types 1 and 2 (HSV), varicella zoster
virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human
herpes virus type 6 (HHV-6), human herpes virus type 7 (HHV-7) and
human herpes virus type 8 (HHV-8). HSV-1 and HSV-2 are some of the
most common infectious agents of man. Most of these viruses are
able to persist in the host's neural cells; once infected,
individuals are at risk of recurrent clinical manifestations of
infection which can be both physically and psychologically
distressing.
[0003] Herpes simplex viruses (HSV-1 and -2) are the causative
agents of herpes labialis and genital herpes. HSV infection is
often characterised by extensive and debilitating lesions of the
skin, mouth and/or genitals. Primary infections may be subclinical
although tend to be more severe than infections in individuals
previously exposed to the virus. Ocular infection by HSV can lead
to keratitis or cataracts thereby endangering the host's sight.
Infection in the new-born, in immunocompromised patients or
penetration of the infection into the central nervous system can
prove fatal. In the US alone, 40 million individuals are infected
with HSV-2, a number that is expected to increase to 60 million by
2007. Over 80% of individuals infected with HSV-2 are unaware they
carry and spread the virus, and of those diagnosed less than 20%
received oral therapies. The net result is that less than 5% of the
infected population are treated. Likewise of the 530 million
individuals worldwide who carry HSV-1, 81% of the symptomatic
population remain untreated. No cure exists for HSV infection, and
once infected, individuals carry the virus for life in a dormant
state. Reactivation of the virus from latency occurs periodically
and may be triggered by stress, environmental factors, and/or
suppression of the host immune system. Currently, the use of
nucleoside analogs such as valaciclovir (VALTREX.RTM.) and
aciclovir (ZOVIRAX.RTM.) is the standard of care for managing
genital herpes virus outbreaks.
[0004] Varicella zoster virus (VZV) (also know as herpes zoster
virus) is a herpes virus which causes chickenpox and shingles.
Chickenpox is the primary disease produced in a host without
immunity, and in young children is usually a mild illness
characterised by a vesicular rash and fever. Shingles or zoster is
the recurrent form of the disease which occurs in adults who were
previously infected with VZV. The clinical manifestations of
shingles are characterised by neuralgia and a vesicular skin rash
that is unilateral and dermatomal in distribution. Spread of
inflammation may lead to paralysis or convulsions. Coma can occur
if the meninges become affected. VZV is of serious concern in
patients receiving immunosuppressive drugs for transplant purposes
or for treatment of malignant neoplasia and is a serious
complication of AIDS patients due to their impaired immune
system.
[0005] In common with other herpes viruses, infection with CMV
leads to a lifelong association of virus and host. Congenital
infection following infection of the mother during pregnancy may
give rise to clinical effects such as death or gross disease
(microcephaly, hepatosplenomegaly, jaundice, mental retardation),
retinitis leading to blindness or, in less severe forms, failure to
thrive, and susceptibility to chest and ear infections. CMV
infection in patients who are immunocompromised for example as a
result of malignancy, treatment with immunosuppressive drugs
following transplantation or infection with Human Immunodeficiency
Virus, may give rise to retinitis, pneumonitis, gastrointestinal
disorders and neurological diseases. CMV infection is also
associated with cardiovascular diseases and conditions including
restenosis and atherosclerosis.
[0006] The main disease caused by EBV is acute or chronic
infectious mononucleosis (glandular fever). Examples of other EBV
or EBV associated diseases include lymphoproliferative disease
which frequently occurs in persons with congenital or acquired
cellular immune deficiency, X-linked lymphoproliferative disease
which occurs namely in young boys, EBV-associated B-cell tumors,
Hodgkin's disease, nasopharyngeal carcinoma, Burkitt lymphoma,
non-Hodgkin lymphoma, thymomas and oral hairy leukoplakia. EBV
infections have also been found in association with a variety of
epithelial-cell-derived tumors of the upper and lower respiratory
tracts including the lung. EBV infection has also been associated
with other diseases and conditions including chronic fatigue
syndrome, multiple sclerosis and Alzheimer's disease.
[0007] HHV-6 has been shown to be a causative agent of infantum
subitum in children and of kidney rejection and interstitial
pneumonia in kidney and bone marrow transplant patients,
respectively, and may be associated with other diseases such as
multiple sclerosis. There is also evidence of repression of stem
cell counts in bone marrow transplant patients. HHV-7 is of
undetermined disease aetiology.
[0008] Hepatitis B virus (HBV) is a viral pathogen of world-wide
major importance. The virus is aetiologically associated with
primary hepatocellular carcinoma and is thought to cause 80% of the
world's liver cancer. Clinical effects of infection with HBV range
from headache, fever, malaise, nausea, vomiting, anorexia and
abdominal pains. Replication of the virus is usually controlled by
the immune response, with a course of recovery lasting weeks or
months in humans, but infection may be more severe leading to
persistent chronic liver disease outlined above.
BRIEF SUMMARY OF THE INVENTION
[0009] According to a first aspect of the invention there is
provided compounds of formula (I): ##STR2## wherein: [0010] R.sup.1
is selected from the group consisting of H, halo, alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, --C(O)R.sup.9,
--C(O)Ay, --C(O)Het, --CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8,
--C(O)NR.sup.7Ay, --C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8,
--C(NH)NR.sup.7Ay, --OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8,
--NR.sup.7Ay, --NHHet, --S(O).sub.nR.sup.9, --S(O).sub.nAy,
--S(O).sub.nHet, --S(O).sub.2NR.sup.7R.sup.8,
--S(O).sub.2NR.sup.7Ay, --R.sup.10cycloalkyl, --R.sup.10Ay,
--R.sup.10Het, --R.sup.10OR.sup.9, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10C(O)R.sup.9, --R.sup.10C(O)Ay, --R.sup.10C(O)Het,
--R.sup.10CO.sub.2R.sup.9, --R.sup.10OC(O)R.sup.9,
--R.sup.10OC(O)Ay, --R.sup.10OC(O)Het,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2NHCOR.sup.9,
--R.sup.10OS(O).sub.nR.sup.9, cyano, nitro and azido; [0011] each
R.sup.7 and R.sup.8 are the same or different and are independently
selected from the group consisting of H, alkyl, cycloalkyl,
alkenyl, cycloalkenyl, --C(O)R.sup.9, --CO.sub.2R.sup.9,
--C(O)NR.sup.9R.sup.11, --C(S)NR.sup.9R.sup.11,
--C(NH)NR.sup.9R.sup.11, --SO.sub.2R.sup.10,
--SO.sub.2NR.sup.9R.sup.11, --R.sup.10cycloalkyl, --R.sup.10Ay,
--R.sup.10Het, --R.sup.10C(O)R.sup.9, --R.sup.10CO.sub.2R.sup.9,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10OR.sup.9, --R.sup.10NR.sup.9R.sup.11,
--R.sup.10NHCOR.sup.9, --R.sup.10NHC(NH)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.10 and
--R.sup.10SO.sub.2NHCOR.sup.9; [0012] each R.sup.9 and R.sup.11 are
the same or different and are independently selected from the group
consisting of H, alkyl, cycloalkyl, --R.sup.10cycloalkyl,
--R.sup.10OH, --R.sup.10(OR.sup.10).sub.w where w is 1-10, and
--R.sup.10NR.sup.10R.sup.10; [0013] each R.sup.10 is the same or
different and is independently selected from the group consisting
of alkyl, cycloalkyl, alkenyl, cycloalkenyl, and alkynyl; [0014] n
is 0, 1 or 2; [0015] Ay is aryl; [0016] Het is a 5- or 6-membered
heterocyclic or heteroaryl group; [0017] Y.sup.1 is N or CH; [0018]
p is 0, 1 or 2 when Y.sup.1 is CH, [0019] p is 0 or 1 when Y.sup.1
is N; [0020] each R.sup.6 is the same or different and is
independently selected from the group consisting of H, halo, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, --C(O)R.sup.9,
--C(O)Ay, --C(O)Het, --CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8,
--C(O)NR.sup.7Ay, --C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8,
--C(NH)NR.sup.7Ay, --OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8,
--NR.sup.7Ay, --NHHet, --S(O).sub.nR.sup.9, --S(O).sub.nAy,
--S(O).sub.nHet, --S(O).sub.2NR.sup.7R.sup.8,
--S(O).sub.2NR.sup.7Ay, --R.sup.10cycloalkyl, --R.sup.10Ay,
--R.sup.10Het, --R.sup.10OR.sup.9, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10C(O)R.sup.9, --R.sup.10C(O)Ay, --R.sup.10C(O)Het,
--R.sup.10CO.sub.2R.sup.9, --R.sup.10OC(O)R.sup.9,
--R.sup.10OC(O)Ay, --R.sup.10OC(O)Het,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2NHCOR.sup.9,
--R.sup.10OS(O).sub.nR.sup.9, cyano, nitro and azido; [0021] or
when p is 2, two adjacent R.sup.6 groups together with the carbon
atoms to which they are bonded form a cycloalkyl or a 5- or
6-membered heterocyclic group containing 1 or 2 heteroatoms; [0022]
Y is N or CH; [0023] R.sup.2 is selected from the group consisting
of halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het,
--OR.sup.7, --OAy, --OHet --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet
--S(O).sub.nR.sup.9, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8 and
--R.sup.10NR.sup.7Ay; [0024] R.sup.3 and R.sup.4 are the same or
different and are each independently selected from the group
consisting of H, halo, alkyl, alkenyl, cycloalkyl, Ay, Het,
--C(O)R.sup.7, C(O)Ay, --CO.sub.2R.sup.7, --CO.sub.2Ay, --OR.sup.7,
--OAy, --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet,
--SO.sub.2NHR.sup.9, --R.sup.10OR.sup.7, --R.sup.10cycloalkyl,
--R.sup.10OAy, --R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay;
[0025] Ring A is selected from the group consisting of aryl, 5-10
membered heterocyclic group and a 5-10 membered heteroaryl group;
[0026] q is 0, 1, 2, 3, 4 or 5; and [0027] each R.sup.5 is the same
or different and is independently selected from the group
consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, Ay, Het, --C(O)R.sup.9, --C(O)Ay, --C(O)Het,
--CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8, --C(O)NR.sup.7Ay,
--C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8, --C(NH)NR.sup.7Ay,
--OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8, --NR.sup.7Ay,
--NHHet, --S(O).sub.nR.sup.9, --S(O).sub.2NR.sup.7R.sup.8,
--S(O).sub.2NR.sup.7Ay, --R.sup.10cycloalkyl, --R.sup.10Het,
--R.sup.10C(O)R.sup.9, --R.sup.10CO.sub.2R.sup.9,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10OR.sup.9,
--R.sup.10NR.sup.7R.sup.8, --R.sup.10NR.sup.7Ay,
--R.sup.10SO.sub.2R.sup.9, --R.sup.10SO.sub.2NR.sup.9R.sup.11,
--R.sup.10SO.sub.2NHCOR.sup.9, cyano, nitro and azido; and [0028]
pharmaceutically acceptable salts, solvates and physiologically
functional derivatives thereof.
[0029] According to another aspect, the present invention provides
a pharmaceutical composition comprising a compound of formula (I).
In one embodiment, the pharmaceutical composition further comprises
a pharmaceutically acceptable carrier or diluent. In one
embodiment, the pharmaceutical composition further comprises an
antiviral agent selected from the group consisting of aciclovir and
valaciclovir.
[0030] According to a third aspect, the present invention provides
a method for the prophylaxis or treatment of a herpes viral
infection in an animal. The method comprises administering to the
animal a therapeutically effective amount of a compound of formula
(I) or a pharmaceutically acceptable salt, solvate or
physiologically functional derivative thereof. The herpes viral
infection may be herpes simplex virus 1, herpes simplex virus 2,
cytomegalovirus, Epstein Barr virus, varicella zoster virus, human
herpes virus 6, human herpes virus 7, or human herpes virus 8.
[0031] According to a fourth aspect, the present invention provides
a method for the prophylaxis or treatment of a condition or disease
associated with a herpes viral infection in an animal. The method
comprises administering to the animal a therapeutically effective
amount of the compound of formula (I) or a pharmaceutically
acceptable salt, solvate or physiologically functional derivative
thereof.
[0032] According to a fifth aspect, the present invention provides
a process for preparing a compound of formula (I) wherein Y.sup.1
is CH; Y is N; R.sup.2 is selected from the group consisting of
alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, --OR.sup.7,
--OAy, --OHet --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet
--S(O).sub.nR.sup.9, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8 and
--R.sup.10NR.sup.7Ay; and R.sup.3 and R.sup.4 are H. The process
comprises reacting a compound of formula (XX): ##STR3## with a
compound of formula (XXI): ##STR4##
[0033] According to a sixth aspect, the present invention provides
a process for preparing a compound of formula (I) wherein Y is N;
R.sup.2 is selected from the group consisting of alkyl, cycloalkyl,
alkenyl, cycloalkenyl, Ay, Het, --OR.sup.7, --OAy, --OHet
--NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet --S(O).sub.nR.sup.9,
--S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay;
R.sup.3 is selected from the group consisting of H, alkyl, alkenyl,
cycloalkyl, Ay, Het, --C(O)R.sup.7, C(O)Ay, --CO.sub.2R.sup.7,
--CO.sub.2Ay, --OR.sup.7, --OAy, --NR.sup.7R.sup.8 (where R.sup.7
and R.sup.8 are not H), --NR.sup.7Ay (where R.sup.7 is H),
--SO.sub.2NHR.sup.9, --R.sup.10OR.sup.7, --R.sup.10cycloalkyl,
--R.sup.10OAy, --R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay;
and R.sup.4 is H. The process comprises reacting a compound of
formula (XXV): ##STR5## with a compound of formula (XXI):
##STR6##
[0034] According to a seventh aspect, the present invention
provides a process for preparing a compound of formula (I) wherein
Y is N and R.sup.2 is selected from the group consisting of alkyl,
cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, --OR.sup.7, --OAy,
--OHet --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet
--S(O).sub.nR.sup.9, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8 and
--R.sup.10NR.sup.7Ay. The process comprises the steps of:
[0035] a) reacting a compound of formula (XXVIII): ##STR7## with a
compound of formula (XXI): ##STR8## to prepare an intermediate
compound; and
[0036] b) oxidizing the intermediate compound.
[0037] According to an eighth aspect, the present invention
provides a process for preparing a compound of formula (I). The
process comprises reacting a compound of formula (XXX): ##STR9##
[0038] wherein X.sup.1 is chloro, bromo or iodo; with a compound of
formula (X): ##STR10## [0039] wherein M.sup.1 is --B(OH).sub.2,
--B(ORa).sub.2, --B(Ra).sub.2, --Sn(Ra).sub.3, Zn-halide, ZnRa, or
Mg-halide where Ra is alkyl or cycloalkyl and halide is halo.
[0040] As another aspect, the present invention provides a process
comprising the further step of converting the compound of formula
(I) to a pharmaceutically acceptable salt, solvate or
physiologically functional derivative thereof. In another aspect,
the present invention provides a process comprising the further
step of converting the compound of formula (I) or a
pharmaceutically acceptable salt, solvate or physiologically
functional derivative thereof to another compound of formula (I) or
a pharmaceutically acceptable salt, solvate or physiologically
functional derivative thereof.
[0041] According to another aspect, the present invention provides
a radiolabeled compound of formula (I) or a pharmaceutically
acceptable salt, solvate or physiologically functional derivative
thereof. In one embodiment, the radiolabeled compound is tritiated.
In another aspect, the present invention provides a biotinylated
compound of formula (I) or a pharmaceutically acceptable salt,
solvate or physiologically functional derivative thereof.
[0042] According to another aspect, the present invention provides
a compound of formula (I) for use in therapy. The present invention
also provides a compound of formula (I) for the prophylaxis or
treatment of a herpes viral infection in an animal. The present
invention also provides a compound of formula (I) for the
prophylaxis or treatment of a condition or disease associated with
a herpes viral infection in an animal.
[0043] According to another aspect, the present invention provides
the use of a compound of formula (I) for the preparation of a
medicament for prophylaxis or treatment of a herpes viral infection
in an animal, preferably humans. The present invention also
provides the use of a compound of formula (I) for the preparation
of a medicament for the prophylaxis or treatment of a condition or
disease associated with a herpes viral infection in an animal,
preferably humans.
[0044] According to another aspect, the present invention provides
a pharmaceutical composition comprising a compound of formula (I)
for use in the prophylaxis or treatment of herpes viral infections
in an animal.
DETAILED DESCRIPTION OF THE INVENTION
[0045] As used herein, "a compound of the invention" or "a compound
of formula (I)" means a compound of formula (I) or a
pharmaceutically acceptable salt, solvate, or physiologically
functional derivative thereof. Similarly, with respect to
isolatable intermediates such as for example, compounds of formula
(IX), (XII), (XX), (XXV), (XXVIII) and (XXX), the phrase "a
compound of formula (number)" means a compound having that formula
and pharmaceutically acceptable salts, solvates and physiologically
functional derivatives thereof.
[0046] As used herein, the terms "alkyl" (or "alkylene") refer to
straight or branched hydrocarbon chains containing from 1 to 8
carbon atoms. Examples of "alkyl" as used herein include, but are
not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl,
isobutyl, isopropyl, and tert-butyl. Examples of "alkylene" as used
herein include, but are not limited to, methylene, ethylene,
propylene, butylene, and isobutylene. "Alkyl" also includes
substituted alkyl. The alkyl groups may be optionally substituted
with one or more substituents selected from the group consisting of
mercapto, nitro, cyano, azido and halo. Perhaloalkyl, such as
trifluoromethyl, is one preferred alkyl group.
[0047] As used herein, the term "cycloalkyl" (or "cycloalkylene")
refers to a non-aromatic carbocyclic ring having from 3 to 8 carbon
atoms and no carbon-carbon double bonds. "Cycloalkyl" includes by
way of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl and cyclooctyl. "Cycloalkyl" also includes substituted
cycloalkyl. The cycloalkyl may optionally be substituted on an
available carbon with one or more substituents selected from the
group consisting of mercapto, nitro, cyano, halo, and alkyl.
[0048] As used herein, the term "alkenyl" (or "alkenylene") refers
to straight or branched hydrocarbon chains containing from 2 to 8
carbon atoms and at least one and up to three carbon-carbon double
bonds. Examples of "alkenyl" as used herein include, but are not
limited to ethenyl and propenyl. "Alkenyl" also includes
substituted alkenyl. The alkenyl groups may optionally be
substituted on an available carbon with one or more substituents
selected from the group consisting of mercapto, nitro, cyano, halo,
and alkyl.
[0049] As used herein, the term "cycloalkenyl" (or
"cycloalkenylene") refers to refers to a non-aromatic carbocyclic
ring having from 3 to 8 carbon atoms (unless otherwise specified)
and up to 3 carbon-carbon double bonds. "Cycloalkenyl" includes by
way of example cyclobutenyl, cyclopentenyl and cyclohexenyl.
"Cycloalkenyl" also includes substituted cycloalkenyl. The
cycloalkenyl may optionally be substituted on an available carbon
with one or more substituents selected from the group consisting of
mercapto, nitro, cyano, halo, and alkyl.
[0050] As used herein, the term "alkynyl" (or "alkynylene") refers
to straight or branched hydrocarbon chains containing from 2 to 8
carbon atoms and at least one and up to three carbon-carbon triple
bonds. Examples of "alkynyl" as used herein include, but are not
limited to ethynyl and propynyl. "Alkynyl" also includes
substituted alkynyl. The alkynyl groups may optionally be be
substituted on an available carbon with one or more substituents
selected from the group consisting of mercapto, nitro, cyano, halo,
and alkyl.
[0051] The term "halo" or "halogen" refers to the elements
fluorine, chlorine, bromine and iodine.
[0052] The term "aryl" refers to monocyclic carbocyclic groups and
fused bicyclic carbocyclic groups having from 5 to 12 carbon atoms
and having at least one aromatic ring. Examples of particular aryl
groups include but are not limited to phenyl and naphthyl. "Aryl"
also includes substituted aryl. Aryl groups may optionally be
substituted on an available carbon with one or more substituents
selected from the group consisting of halo, alkyl (including
perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy,
cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine,
cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine,
cyano, nitro and azido. Preferred aryl groups according to the
invention include but are not limited to phenyl and substituted
phenyl.
[0053] The term "heterocyclic" (or "heterocycle") refers to a
monocyclic saturated or unsaturated non-aromatic groups and fused
bicyclic non-aromatic groups, having the specified number of
members and containing 1, 2, 3 or 4 heteroatoms selected from N, O
and S. Examples of particular heterocyclic groups include but are
not limited to tetrahydrofuran, dihydropyran, tetrahydropyran,
pyran, oxetane, thietane, 1,4-dioxane, 1,3-dioxane, 1,3-dioxalane,
piperidine, piperazine, tetrahydropyrimidine, pyrrolidine,
morpholine, thiomorpholine, thiazolidine, oxazolidine,
tetrahydrothiopyran, tetrahydrothiophene, and the like.
"Heterocyclic" also includes substituted heterocyclic. The
heterocyclic group may be optionally substituted on an available
carbon or heteroatom, with one or more substituents selected from
the group consisting of halo, alkyl (including perhaloalkyl),
alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, amino,
mercapto, hydroxy, alkylhydroxy, alkylamine, cycloalkylamine,
carboxy, carboxamide, sulfonamide, Het, amidine, cyano, nitro and
azido. Preferred heterocyclic groups according to the invention
include but are not limited to pyrrolidine, piperidine, morpholine,
thiomorpholine and piperazine and substituted variants thereof.
[0054] The term "heteroaryl" refers to aromatic monocyclic groups
and aromatic fused bicyclic groups having the specified number of
members and containing 1, 2, 3, or 4 heteroatoms selected from N, O
and S. Examples of particular heteroaryl groups include but are not
limited to furan, thiophene, pyrrole, imidazole, pyrazole,
triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole,
thiadiazole, isothiazole, pyridine, pyridazine, pyrazine,
pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene,
indole, and indazole. "Heteroaryl" also includes substituted
heteroaryl. The heteroaryl group may optionally be substituted on
an available carbon or heteroatom with one or more substituents
selected from the group consisting of halo, alkyl (including
perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy,
cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine,
cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine,
cyano, nitro and azido. Preferred heteroaryl groups according to
the invention include but are not limited to pyridine, furan,
thiophene, pyrrole, imidazole, pyrazole and pyrimidine, and
substituted variants thereof.
[0055] The term "members" or "membered" in the context of
heterocyclic and heteroaryl groups refers to the total atoms,
carbon and heteroatoms N, O and/or S, which form the ring. Thus, an
example of a 6-membered heterocyclic ring is piperidine and an
example of a 6-membered heteroaryl ring is pyridine.
[0056] As used herein, the term "optionally" means that the
subsequently described event(s) may or may not occur, and includes
both event(s) which occur and events that do not occur.
[0057] The present invention provides compounds of formula (I):
##STR11## wherein: [0058] R.sup.1 is selected from the group
consisting of H, halo, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, Ay, Het, --C(O)R.sup.9, --C(O)Ay, --C(O)Het,
--CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8, --C(O)NR.sup.7Ay,
--C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8, --C(NH)NR.sup.7Ay,
--OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8, --NR.sup.7Ay,
--NHHet, --S(O).sub.nR.sup.9, --S(O).sub.nAy, --S(O).sub.nHet,
--S(O).sub.2NR.sup.7R.sup.8, --S(O).sub.2NR.sup.7Ay,
--R.sup.10cycloalkyl, --R.sup.10Ay, --R.sup.10Het,
--R.sup.10OR.sup.9, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10C(O)R.sup.9, --R.sup.10C(O)Ay, --R.sup.10C(O)Het,
--R.sup.10CO.sub.2R.sup.9, --R.sup.10OC(O)R.sup.9,
--R.sup.10OC(O)Ay, --R.sup.10OC(O)Het,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2NHCOR.sup.9,
--R.sup.10OS(O).sub.nR.sup.9, cyano, nitro and azido; [0059] each
R.sup.7 and R.sup.8 are the same or different and are independently
selected from the group consisting of H, alkyl, cycloalkyl,
alkenyl, cycloalkenyl, --C(O)R.sup.9, --CO.sub.2R.sup.9,
--C(O)NR.sup.9R.sup.11, --C(S)NR.sup.9R.sup.11,
--C(NH)NR.sup.9R.sup.11, --SO.sub.2R.sup.10,
--SO.sub.2NR.sup.9R.sup.11, --R.sup.10cycloalkyl, --R.sup.10Ay,
--R.sup.10Het, --R.sup.10C(O)R.sup.9, --R.sup.10CO.sub.2R.sup.9,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10OR.sup.9, --R.sup.10NR.sup.9R.sup.11,
--R.sup.10NHCOR.sup.9, --R.sup.10NHC(NH)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.10 and
--R.sup.10SO.sub.2NHCOR.sup.9; [0060] each R.sup.9 and R.sup.11 are
the same or different and are independently selected from the group
consisting of H, alkyl, cycloalkyl, --R.sup.10cycloalkyl,
--R.sup.10OH, --R.sup.10(OR.sup.10).sub.w where w is 1-10, and
--R.sup.10NR.sup.10R.sup.10; [0061] each R.sup.10 is the same or
different and is independently selected from the group consisting
of alkyl, cycloalkyl, alkenyl, cycloalkenyl, and alkynyl; [0062] n
is 0, 1 or 2; [0063] Ay is aryl; [0064] Het is a 5- or 6-membered
heterocyclic or heteroaryl group; [0065] Y.sup.1 is N or CH; [0066]
p is 0, 1 or 2 when Y.sup.1 is CH, [0067] p is 0 or 1 when Y.sup.1
is N; [0068] each R.sup.6 is the same or different and is
independently selected from the group consisting of H, halo, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, --C(O)R.sup.9,
--C(O)Ay, --C(O)Het, --CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8,
--C(O)NR.sup.7Ay, --C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8,
--C(NH)NR.sup.7Ay, --OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8,
--NR.sup.7Ay, --NHHet, --S(O).sub.nR.sup.9, --S(O).sub.nAy,
--S(O).sub.nHet, --S(O).sub.2NR.sup.7R.sup.8,
--S(O).sub.2NR.sup.7Ay, --R.sup.10cycloalkyl, --R.sup.10Ay,
--R.sup.10Het, --R.sup.10OR.sup.9, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10C(O)R.sup.9, --R.sup.10C(O)Ay, --R.sup.10C(O)Het,
--R.sup.10CO.sub.2R.sup.9, --R.sup.10OC(O)R.sup.9,
--R.sup.10OC(O)Ay, --R.sup.10OC(O)Het,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2NHCOR.sup.9,
--R.sup.10OS(O).sub.nR.sup.9, cyano, nitro and azido; [0069] or
when p is 2 (and Y' is CH), two adjacent R.sup.6 groups together
with the carbon atoms to which they are bonded form a cycloalkyl or
a 5- or 6-membered heterocyclic group containing 1 or 2
heteroatoms; [0070] Y is N or CH; [0071] R.sup.2 is selected from
the group consisting of halo, alkyl, cycloalkyl, alkenyl,
cycloalkenyl, Ay, Het, --OR.sup.7, --OAy, --OHet --NR.sup.7R.sup.8,
--NR.sup.7Ay, --NHHet --S(O).sub.nR.sup.9, --S(O).sub.nAy,
--R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay; [0072] R.sup.3
and R.sup.4 are the same or different and are each independently
selected from the group consisting of H, halo, alkyl, alkenyl,
cycloalkyl, Ay, Het, --C(O)R.sup.7, C(O)Ay, --CO.sub.2R.sup.7,
--CO.sub.2Ay, --OR.sup.7, --OAy, --NR.sup.7R.sup.8, --NR.sup.7Ay,
--NHHet, --SO.sub.2NHR.sup.9, --R.sup.10OR.sup.7,
--R.sup.10cycloalkyl, --R.sup.10OAy, --R.sup.10NR.sup.7R.sup.8 and
--R.sup.10NR.sup.7Ay; [0073] Ring A is selected from the group
consisting of aryl, 5-10 membered heterocyclic group and a 5-10
membered heteroaryl group; [0074] q is 0, 1, 2, 3, 4 or 5; and
[0075] each R.sup.5 is the same or different and is independently
selected from the group consisting of halo, alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, --C(O)R.sup.9,
--C(O)Ay, --C(O)Het, --CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8,
--C(O)NR.sup.7Ay, --C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8,
--C(NH)NR.sup.7Ay, --OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8,
--NR.sup.7Ay, --NHHet, --S(O).sub.nR.sup.9,
--S(O).sub.2NR.sup.7R.sup.8, --S(O).sub.2NR.sup.7Ay,
--R.sup.10cycloalkyl, --R.sup.10Het, --R.sup.10C(O)R.sup.9,
--R.sup.10CO.sub.2R.sup.9, --R.sup.10C(O)NR.sup.9R.sup.11,
--R.sup.10C(O)NR.sup.7Ay, --R.sup.10C(O)NHR.sup.10Het,
--R.sup.10C(S)NR.sup.9R.sup.11, --R.sup.10C(NH)NR.sup.9R.sup.11,
--R.sup.10OR.sup.9, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, --R.sup.10SO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2NHCOR.sup.9,
cyano, nitro and azido; and pharmaceutically acceptable salts,
solvates and physiologically functional derivatives thereof.
[0076] In one embodiment of the invention R.sup.1 contains an aryl,
heterocyclic or heteroaryl moiety (e.g., R.sup.1 is selected from
the group consisting of Ay, Het, --C(O)Ay, --C(O)Het,
--C(O)NR.sup.7R.sup.8, --C(O)NR.sup.7Ay, --C(NH)NR.sup.7R.sup.8,
--C(NH)NR.sup.7Ay, --OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8,
--NR.sup.7Ay, --NHHet, --S(O).sub.nAy, --S(O).sub.nHet,
--S(O).sub.2NR.sup.7R.sup.8, --S(O).sub.2NR.sup.7Ay, --R.sup.10Ay,
--R.sup.10Het, --R.sup.10NR.sup.7R.sup.8, --R.sup.10NR.sup.7Ay,
--R.sup.10C(O)Ay, --R.sup.10C(O)Het, --R.sup.10OC(O)Ay,
--R.sup.10OC(O)Het, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het (where R.sup.7 or R.sup.8 is
appropriately defined to provide a group containing an aryl,
heterocyclic or heteroaryl moiety), or any subset thereof). In
another embodiment, compounds of formula (I) are defined wherein
R.sup.1 contains a heterocyclic or heteroaryl moiety (e.g., R.sup.1
is selected from the group consisting of Het, --C(O)Het,
--C(O)NR.sup.7R.sup.8, --C(O)NR.sup.7Ay, --C(NH)NR.sup.7R.sup.8,
--OR.sup.7, --OHet, --NR.sup.7R.sup.8, --NHHet, --S(O).sub.nHet,
--S(O).sub.2NR.sup.7R.sup.8, --R.sup.10Het,
--R.sup.10NR.sup.7R.sup.8, --R.sup.10C(O)Het, --R.sup.10OC(O)Het
and --R.sup.10C(O)NHR.sup.10Het (where R.sup.7 or R.sup.8 is
appropriately defined to provide a group containing a heterocyclic
or heteroaryl moiety), or any subset thereof). In yet another
embodiment, the compounds of formula (I) are defined wherein
R.sup.1 does not contain an aryl, heterocyclic or heteroaryl moiety
(e.g., R.sup.1 is selected from the group consisting of H, halo,
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, --C(O)R.sup.9,
--CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8, --C(S)NR.sup.9R.sup.11,
--C(NH)NR.sup.7R.sup.8, --OR.sup.7, --NR.sup.7R.sup.8,
--S(O).sub.nR.sup.9, --S(O).sub.2NR.sup.7R.sup.8,
--R.sup.10cycloalkyl, --R.sup.10OR.sup.9,
--R.sup.10NR.sup.7R.sup.8, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10C(O)R.sup.9, --R.sup.10CO.sub.2R.sup.9,
--R.sup.10OC(O)R.sup.9, --R.sup.10C(O)NR.sup.9R.sup.11,
--R.sup.10C(S)NR.sup.9R.sup.11, --R.sup.10C(NH)NR.sup.9R.sup.11,
--R.sup.10SO.sub.2R.sup.9, --R.sup.10SO.sub.2NR.sup.9R.sup.11,
--R.sup.10SO.sub.2NHCOR.sup.9, --R.sup.10OS(O).sub.nR.sup.9, cyano,
nitro and azido (where R.sup.7 and R.sup.8 are appropriately
defined to provide a group that does not contain an aryl,
heterocyclic or heteroaryl moiety), or any subset thereof). In
another embodiment, R.sup.1 may contain an aryl moiety but does not
contain a heteroaryl or heterocyclic moiety (e.g., R.sup.1 is
selected from the group consisting of H, halo, alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, Ay, --C(O)R.sup.9, --C(O)Ay,
--CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8, --C(O)NR.sup.7Ay,
--C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8, --C(NH)NR.sup.7Ay,
--OR.sup.7, --OAy, --NR.sup.7R.sup.8, --NR.sup.7Ay,
--S(O).sub.nR.sup.9, --S(O).sub.nAy, --S(O).sub.2NR.sup.7R.sup.8,
--S(O).sub.2NR.sup.7Ay, --R.sup.10cycloalkyl, --R.sup.10Ay,
--R.sup.10OR.sup.9, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10C(O)R.sup.9, --R.sup.10C(O)Ay, --R.sup.10CO.sub.2R.sup.9,
--R.sup.10OC(O)R.sup.9, --R.sup.10OC(O)Ay,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(S)NR.sup.9R.sup.11, --R.sup.10C(NH)NR.sup.9R.sup.11,
--R.sup.10SO.sub.2R.sup.9, --R.sup.10SO.sub.2NR.sup.9R.sup.11,
--R.sup.10SO.sub.2NHCOR.sup.9, --R.sup.10OS(O).sub.nR.sup.9, cyano,
nitro and azido (where R.sup.7 and R.sup.8 are appropriately
defined to provide a group that does not contain a heterocyclic or
heteroaryl moiety), or any subset thereof).
[0077] In one embodiment, R.sup.1 is selected from the group
consisting of halo, alkyl, cycloalkyl, Ay, Het, --OR.sup.7, --OAy,
--NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet, --S(O).sub.nR.sup.9,
--R.sup.10cycloalkyl, --R.sup.10OR.sup.9, --R.sup.10NR.sup.7R.sup.8
and --R.sup.10NR.sup.7Ay, or any subset thereof. More particularly,
R.sup.1 is selected from the group consisting of halo, alkyl, Het,
--OR.sup.7, --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet and
--S(O).sub.nR.sup.9, or any subset thereof. In one particular
embodiment R.sup.1 is selected from the group consisting of alkyl,
Het, --OR.sup.7, --NR.sup.7R.sup.8, --NR.sup.7Ay and
--S(O).sub.nR.sup.9, or any subset thereof. In one embodiment,
R.sup.1 is --NR.sup.7R.sup.8.
[0078] More specifically, particular compounds of formula (I) are
defined wherein R.sup.1 is selected from the group consisting of
halo, alkyl, --NH.sub.2, --NH-alkyl, --NH-cycloalkyl,
--N(alkyl)(alkyl), Het, --O-alkyl, --NHalkyl-O-alkyl, --NHAy and
--S-alkyl, or any subset thereof. More particularly, R.sup.1 is
selected from the group consisting of --NH-alkyl, --NH-cycloalkyl
and pyrrolidine or any subset thereof. Specific examples of some
R.sup.1 groups are selected from the group consisting of Cl, ethyl,
propyl, isopropyl, butyl, isobutyl, --NH-methyl,
--N(CH.sub.3).sub.2, --NH-cyclopentyl, --NH-cyclopropyl,
--NH-isopropyl, --NH-butyl, --NH-phenyl,
--NH(CH.sub.2).sub.2OCH.sub.3, methoxy, ethoxy, propoxy,
isopropoxy, butoxy, thiomethoxy, thioethoxy, thioisopropoxy and
pyrrolidine, or any subset thereof.
[0079] In one embodiment, R.sup.7 and R.sup.8 are each the same or
different and are each independently selected from the group
consisting of H, alkyl, cycloalkyl, --C(O)R.sup.9,
--R.sup.10-cycloalkyl, --R.sup.10Ay, --R.sup.10Het,
--R.sup.10OR.sup.9, --R.sup.10NR.sup.9R.sup.11, and
--R.sup.10CO.sub.2R.sup.9, or any subset thereof. More particularly
in such embodiment, R.sup.7 and R.sup.8 are each the same or
different and are each independently selected from the group
consisting of H, alkyl, cycloalkyl, --R.sup.10-cycloalkyl,
--R.sup.10Ay and --R.sup.10Het, or any subset thereof. In one
particular embodiment, R.sup.7 and R.sup.8 are each the same or
different and are each independently selected from the group
consisting of H, alkyl and cycloalkyl.
[0080] In the definition of R.sup.9 and R.sup.11,
"--R.sup.10(OR.sup.10).sub.w" refers to a PEG-like chain.
[0081] In one embodiment R.sup.9 and R.sup.11 are each the same or
different and are each independently selected from the group
consisting of H, alkyl, cycloalkyl, and --R.sup.10-cycloalkyl, or
any subset thereof. More particularly, R.sup.9 and R.sup.11 are
each the same or different and are each independently selected from
the group consisting of H and alkyl.
[0082] In one embodiment, R.sup.10 is alkyl or cycloalkyl; more
particularly alkyl.
[0083] In one class of compounds of formula (I), Y.sup.1 is CH. In
another embodiment, the compounds of formula (I) are defined
wherein Y.sup.1 is N.
[0084] When Y.sup.1 is CH, p is 0, 1 or 2 and R.sup.6 may be bonded
through Y.sup.1. When Y.sup.1 is N, p is 0 or 1 and R.sup.6 may not
be bonded through Y.sup.1. In one embodiment, p is 0 or 1. In one
particular embodiment, p is 0.
[0085] Compounds of formula (I) include those compounds defined
wherein R.sup.6 contains an aryl, heterocyclic or heteroaryl
moiety. In one embodiment, compounds of the present invention
include those compounds defined wherein R.sup.6 contains a
heterocyclic or heteroaryl moiety. Another class of compounds of
formula (I) includes those compounds defined wherein R.sup.6 does
not contain an aryl, heterocyclic or heteroaryl moiety. Yet another
class of compounds include those defined wherein R.sup.6 does not
contain a heterocyclic or heteroaryl moiety but may contain an aryl
moiety. Based on the guidance given above for R.sup.1, one skilled
in the art can readily determine the list of appropriate groups
defining R.sup.6 which contain or exclude aryl, heterocyclic or
heteroaryl moieties.
[0086] When Y.sup.1 is CH and p is 2, the two adjacent R.sup.6
groups (i.e., R.sup.6 bonded at C-4 and R.sup.6 bonded at C-5)
together with the atoms to which they are bonded may optionally
form a C.sub.5-6 cycloalkyl or a 5- or 6-membered heterocyclic
group containing 1 or 2 heteroatoms. By "two adjacent R.sup.6
groups" is meant that two R.sup.6 groups are bonded to adjacent
carbon atoms (C-4 and C-5). In the embodiments where two adjacent
R.sup.6 groups together with the atoms to which they are bonded
form a C.sub.5-6 cycloalkyl or a 5- or 6-membered heterocyclic
group containing 1 or 2 heteroatoms, each R.sup.6 group may be the
same or different and is preferably selected from the group
consisting of alkyl, alkenyl, --OR.sup.7, --NR.sup.7R.sup.8 and
--S(O).sub.nR.sup.9. For example, in one embodiment two adjacent
R.sup.6 groups are --OR.sup.7 and together with the atoms to which
they are bonded, they form a heterocyclic group such as:
##STR12##
[0087] In another embodiment, two adjacent R.sup.6 groups are alkyl
and together with the atoms to which they are bonded, they form a
cycloalkyl group such as: ##STR13##
[0088] In another embodiment two adjacent R.sup.6 groups are
defined as --OR.sup.7 and --NR.sup.7R.sup.8 respectively and
together with the atoms to which they are bonded, they form a
heterocyclic group such as: ##STR14##
[0089] From these examples, additional embodiments can be readily
ascertained by those skilled in the art. Preferably the compounds
of formula (I) are defined wherein when p is 2, two adjacent
R.sup.6 groups together with the atoms to which they are bonded do
not form a C.sub.5-6 cycloalkyl or a 5- or 6-membered heterocyclic
group containing 1 or 2 heteroatoms.
[0090] In one embodiment, R.sup.6 is the same or different and is
independently selected from the group consisting of halo, alkyl,
Ay, Het, --C(O)Het, --CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8,
--C(O)NR.sup.7Ay, --OR.sup.7, --OAy, --NR.sup.7R.sup.8,
--NR.sup.7Ay, --NHHet, --S(O).sub.nR.sup.9, --S(O).sub.nAy,
--S(O).sub.nHet, --R.sup.10OR.sup.9 and cyano. More particularly,
each R.sup.6 is the same or different and is independently selected
from the group consisting of halo, alkyl, Het, --OR.sup.7,
--NR.sup.7R.sup.8, --NHHet, --S(O).sub.nR.sup.9, and cyano, or any
subset thereof. In one embodiment each R.sup.6 is the same or
different and is independently selected from the group consisting
of halo, alkyl, Het, --NR.sup.7R.sup.8, --NHHet and and
--S(O).sub.nR.sup.9.
[0091] More specific examples of particular R.sup.6 groups include
but are not limited to --NH.sub.2, --NHalkyl, --NHR.sup.10OR.sup.9,
--NH-cycloalkyl, and --S(O).sub.nalkyl. In one embodiment, R.sup.6
is selected from the group consisting of --O-butyl, --NH.sub.2,
--NHCH(CH.sub.3).sub.2, --NH-cyclopropyl, --NH-n-propyl,
--NH-n-butyl, --NH-cyclopentyl, --NH-cyclohexyl,
--NH(CH.sub.2).sub.2--O--CH.sub.3, --S-methyl and --S-ethyl.
[0092] In one embodiment, compounds of formula (I) are defined
wherein, Y is CH. In another embodiment, the compounds of formula
(I) are defined wherein Y is N.
[0093] Compounds of formula (I) include those compounds defined
wherein R.sup.2 contains an aryl, heterocyclic or heteroaryl
moiety. In one embodiment, compounds of the present invention
include those compounds defined wherein R.sup.2 contains a
heterocyclic or heteroaryl moiety. Another class of compounds of
formula (I) includes those compounds defined wherein R.sup.2 does
not contain an aryl, heterocyclic or heteroaryl moiety. Yet another
class of compounds include those defined wherein R.sup.2 does not
contain a heterocyclic or heteroaryl moiety but may contain an aryl
moiety. Based on the guidance given above for R.sup.1, one skilled
in the art can readily determine the list of appropriate groups
defining R.sup.2 which contain or exclude aryl, heterocyclic or
heteroaryl moieties.
[0094] In one embodiment, R.sup.2 is selected from the group
consisting of Ay, Het, --OR.sup.7, --OAy, --OHet,
--NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet, --S(O).sub.nR.sup.9,
--S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay,
or any subset thereof. More particularly, R.sup.2 is selected from
the group consisting of Het, --NR.sup.7R.sup.8, --NR.sup.7Ay,
--NHHet, --R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay, or any
subset thereof. Particular compounds of formula (I) are defined
where R.sup.2 is selected from the group consisting of Het,
--NR.sup.7R.sup.8, --NR.sup.7Ay and --NHHet, or any subset thereof.
In one embodiment, R.sup.2 is selected from the group consisting of
--NR.sup.7R.sup.8, --NR.sup.7Ay and --NHHet, or any subset thereof.
In another embodiment, R.sup.2 is --NR.sup.7R.sup.8 or --NHHet. In
one particular embodiment, R.sup.2 is --NR.sup.7R.sup.8. In one
embodiment, R.sup.2 is not --NR.sup.7Ay, more specifically, R.sup.2
is not NH-phenyl.
[0095] More specifically, in one embodiment, R.sup.2 is selected
from the group consisting of --NH.sub.2, --NH-alkyl,
--NH-cycloalkyl, --N(alkyl)(alkyl), --NH-phenyl, --N(alkyl)-phenyl,
Het (e.g., pyrrolidine), --NHHet and --NH-alkyl-Het, or any subset
thereof. More particularly, R.sup.2 is selected from the group
consisting of --NH-alkyl, --NH-cycloalkyl and --NH-phenyl, or any
subset thereof. In one embodiment, R.sup.2 is --NH-alkyl or
--NH-cycloalkyl.
[0096] Specific examples of some particular R.sup.2 groups are
selected from the group consisting of --NH.sub.2, --NH-methyl,
--NH-ethyl, --NH-propyl, --NH-isopropyl, --NH-cyclopropyl,
--NH-butyl, --NH-isobutyl, --NH-cyclopentyl, --NH-cyclohexyl,
--NH(CH.sub.2).sub.2OCH.sub.3, --NH-phenyl, --N(methyl)-phenyl, and
pyrrolidine (e.g., pyrrolidine bonded through N). In one
embodiment, R.sup.2 is selected from the group consisting of
--NH.sub.2, --NH-methyl, --NH-ethyl, --NH-propyl, --NH-isopropyl,
--NH-cyclopropyl, --NH-butyl, --NH-isobutyl, --NH-cyclopentyl,
--NH-cyclohexyl, --NH(CH.sub.2).sub.2OCH.sub.3 and pyrrolidine
(e.g., pyrrolidine bonded through N).
[0097] In another embodiment, the compounds of formula (I) include
those compounds defined where at least one of R.sup.3 and R.sup.4
contain a heterocyclic or heteroaryl moiety. Another embodiment
includes those compounds of formula (I) where neither R.sup.3 nor
R.sup.4 contain a heterocyclic or heteroaryl moiety. Based on the
guidance given above for R.sup.1, one skilled in the art can
readily determine the list of appropriate groups defining R.sup.3
and R.sup.4 which contain or exclude aryl, heterocyclic or
heteroaryl moieties.
[0098] In one embodiment, R.sup.3 is preferably selected from the
group consisting of H, halo, alkyl, Ay, --CO.sub.2R.sup.7,
--OR.sup.7, --NR.sup.7R.sup.8, --R.sup.10OR.sup.7 and
--R.sup.10NR.sup.7R.sup.8, or any subset thereof. More
particularly, R.sup.3 is selected from the group consisting of H,
halo, alkyl, --OR.sup.7 and --NR.sup.7R.sup.8, or any subset
thereof. In one embodiment, R.sup.3 is H or alkyl. In one
embodiment R.sup.3 is H.
[0099] In one embodiment, R.sup.4 is selected from the group
consisting of H, halo, alkyl, Ay, --CO.sub.2R.sup.7,
--OR.sup.7.sub.8, --NR.sup.7R.sup.8, --R.sup.10OR.sup.7 and
--R.sup.10NR.sup.7R.sup.8, or any subset thereof. More particularly
R.sup.4 is selected from the group consisting of H, halo, alkyl
OR.sup.7 and --NR.sup.7R.sup.8, or any subset thereof. In one
embodiment, R.sup.4 is H or alkyl. In one embodiment, R.sup.4 is H.
##STR15## in formula (I) above is herein referred to as "Ring
A."
[0100] Ring A is aryl, a 5-10 membered heterocyclic group or a 5-10
membered heteroaryl group (including 1, 2, 3 or 4 heteroatoms
selected from N, O and S). Ring A may be bonded to the C-2 carbon
of the fused ring through any available atom including any
available heteroatom.
[0101] In one embodiment, Ring A is selected from the group
consisting of aryl, a 5-6 membered heterocyclic or heteroaryl group
and a 9-membered heterocyclic or heteroaryl group.
[0102] In one embodiment, Ring A is selected from the group
consisting of phenyl, naphthyl, furan, pyridine, pyrimidine,
thiazole, pyrazine, pyrrole, imidazole, oxazole, benzimidazole,
quinoline, isoquinoline, and quinoxoline, or any subset thereof.
More particularly, Ring A in formula (I) is selected from the group
consisting of phenyl, furan, pyridine and pyrimidine. In one
embodiment, Ring A contains at least one N atom and is bonded
through N. In another embodiment, Ring A is phenyl.
[0103] In one embodiment, q is 0, 1 or 2. In one particular
embodiment, q is 0. In one embodiment q is 1.
[0104] R.sup.5 may be bonded to any available carbon or heteroatom
of Ring A. Compounds of formula (I) include those compounds defined
wherein R.sup.5 contains an aryl, heterocyclic or heteroaryl
moiety. In one embodiment, compounds of the present invention
include those compounds defined wherein R.sup.5 contains a
heterocyclic or heteroaryl moiety. Another class of compounds of
formula (I) includes those compounds defined wherein R.sup.5 does
not contain an aryl, heterocyclic or heteroaryl moiety. Yet another
class of compounds include those defined wherein R.sup.5 does not
contain a heterocyclic or heteroaryl moiety but may contain an aryl
moiety. Based on the guidance given above for R.sup.1, one skilled
in the art can readily determine the list of appropriate groups
defining R.sup.5 which contain or exclude aryl, heterocyclic or
heteroaryl moieties.
[0105] In one embodiment, each R.sup.5 group is the same or
different and is independently selected from the group consisting
of halo, alkyl, alkenyl, Ay, Het, --CO.sub.2R.sup.9,
--C(O)NR.sup.7R.sup.8, --C(O)NR.sup.7Ay, --OR.sup.7, --OAy,
--NR.sup.7R.sup.8, --NR.sup.7Ay, --S(O).sub.2NR.sup.7R.sup.8,
cyano, nitro and azido, or any subset thereof. More particularly,
each R.sup.5 group is the same or different and is independently
selected from the group consisting of halo, alkyl, alkenyl,
--OR.sup.7, --NR.sup.7R.sup.8, Ay, Het, cyano and azido, or any
subset thereof. In one embodiment, each R.sup.5 group is the same
or different and is independently selected from the group
consisting of halo, alkyl, --OR.sup.7, --NR.sup.7R.sup.8 and cyano,
or any subset thereof. In one embodiment, R.sup.5 is halo, alkyl or
OR.sup.7.
[0106] In particular, specific embodiments of the compounds of
formula (I) are defined where R.sup.5 is halo (e.g., fluoro, chloro
or bromo), alkyl (e.g., methyl), O-alkyl (e.g., O-methyl,
O-isobutyl, and ##STR16## cyano, --NH--CH.sub.3, and
--N(CH.sub.3).sub.2.
[0107] It is to be understood that the present invention includes
all combinations and subsets of the particular and preferred groups
defined hereinabove.
[0108] Specific compounds of formula (I) include but are not
limited to: [0109]
N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluor-
ophenyl)pyrazolo-[1,5-c]pyrimidin-7-amine; [0110]
N-Cyclopentyl-3-[2-(cyclopropylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)py-
razolo-[1,5-c]pyrimidin-7-amine; [0111]
4-[2-(3-Chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidi-
n-2-amine; [0112]
4-[2-(3-Chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cycl-
opentylpyrimidin-2-amine; [0113]
2-(3-Chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]py-
razolo[1,5-c]pyrimidin-7-amine; [0114]
4-[2-(3-Chlorophenyl)-7-(4-morpholinyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-c-
yclopentyl-2-pyrimidinamine; [0115]
2-(3-Chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-(2-methoxyeth-
yl)pyrazolo[1,5-c]pyrimidin-7-amine; [0116]
2-(3-Chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-c]p-
yrimidin-7-ol; [0117]
N-Cyclopentyl-8-(2-fluoro-4-pyridinyl)-2-(methylsulfanyl)-7-phenylpyrazol-
o[1,5-a][1,3,5]triazin-4-amine; [0118]
N.sup.2,N.sup.4-Dicyclopentyl-8-[2-(cyclopentylamino)-4-pyridinyl]-7-phen-
ylpyrazolo[1,5-a][1,3,5]triazine-2,4-diamine; and [0119]
N-Cyclopentyl-8-[2-(cyclopentylamino)-4-pyrimidinyl]-7-phenylpyrazolo[1,5-
-a][1,3,5]triazin-4-amine; [0120]
3-[2-(Butylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo-
[1,5-c]pyrimidin-7-amine; [0121]
3-(2-Anilinopyrimidin-4-yl)-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5--
c]pyrimidin-7-amine; [0122]
3-[2-(1,3-Benzothiazol-2-ylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluor-
ophenyl)pyrazolo[1,5-c]pyrimidin-7-amine; [0123]
N-Cyclopentyl-2-(4-fluorophenyl)-3-{2-[(4-methyl-1,3-thiazol-2-yl)amino]p-
yrimidin-4-yl}pyrazolo[1,5-c]pyrimidin-7-amine; [0124]
3-[2-(1H-Benzimidazol-2-ylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluoro-
phenyl)pyrazolo[1,5-c]pyrimidin-7-amine; [0125]
N-Cyclopentyl-3-{2-[(4-fluorobenzyl)amino]pyrimidin-4-yl}-2-(4-fluorophen-
yl)pyrazolo[1,5-c]pyrimidin-7-amine; [0126]
N-Cyclopentyl-2-(4-fluorophenyl)-3-{2-[(2-phenylethyl)amino]pyrimidin-4-y-
l}pyrazolo[1,5-c]pyrimidin-7-amine; [0127]
3-[2-(tert-Butylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyr-
azolo[1,5-c]pyrimidin-7-amine; [0128]
N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyri-
midin-3-yl]pyrimidin-2-amine; [0129]
N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)p-
yrazolo[1,5-c]pyrimidin-7-amine; [0130]
4-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,-
5-c]pyrimidin-2-yl}phenol; [0131]
3-[2-(Cyclopentylamino)pyrimidin-4-yl]-N-cyclopropyl-2-(4-methoxyphenyl)p-
yrazolo-[1,5-c]pyrimidin-7-amine; [0132]
2-(4-Butoxyphenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]py-
razolo[1,5-c]pyrimidin-7-amine; [0133]
N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-isobutoxyphenyl-
)pyrazolo[1,5-c]pyrimidin-7-amine; [0134]
N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-[4-(2-methoxyethox-
y)phenyl]pyrazolo[1,5-c]pyrimidin-7-amine; [0135]
N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-propoxyphenyl)p-
yrazolo[1,5-c]pyrimidin-7-amine; [0136]
N-(tert-Butyl)-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)p-
yrazolo[1,5-c]pyrimidin-7-amine; [0137]
N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-pyrrolidin-1-ylpyrazolo[1,5-c]pyrim-
idin-3-yl]pyrimidin-2-amine; and [0138]
N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-piperidin-1-ylpyrazolo[1,5-c]pyrimi-
din-3-yl]pyrimidin-2-amine, or a pharmaceutically acceptable salt,
solvate or physiologically functional derivative thereof.
[0139] It will be appreciated by those skilled in the art that the
compounds of the present invention may also be utilized in the form
of a pharmaceutically acceptable salt or solvate thereof. The
pharmaceutically acceptable salts of the compounds of formula (I)
include conventional salts formed from pharmaceutically acceptable
inorganic or organic acids or bases as well as quaternary ammonium
salts. More specific examples of suitable acid salts include
hydrochloric, hydrobromic, sulfuric, phosphoric, nitric,
perchloric, fumaric, acetic, propionic, succinic, glycolic, formic,
lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic,
phenylacetic, glutamic, benzoic, salicylic, fumaric,
toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic,
benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic,
tannic and the like. Other acids such as oxalic, while not in
themselves pharmaceutically acceptable, may be useful in the
preparation of salts useful as intermediates in obtaining the
compounds of the invention and their pharmaceutically acceptable
salts. More specific examples of suitable basic salts include
sodium, lithium, potassium, magnesium, aluminium, calcium, zinc,
N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, N-methylglucamine and procaine
salts.
[0140] The term "solvate" as used herein refers to a complex of
variable stoichiometry formed by a solute (a compound of formula
(I)) and a solvent. Solvents, by way of example, include water,
methanol, ethanol, or acetic acid.
[0141] The term "physiologically functional derivative" as used
herein refers to any pharmaceutically acceptable derivative of a
compound of the present invention, for example, an ester or an
amide of a compound of formula (I), which upon administration to an
animal, particularly a mammal, such as a human, is capable of
providing (directly or indirectly) a compound of the present
invention or an active metabolite thereof. See, for example,
Burger's Medicinal Chemistry And Drug Discovery, 5th Edition, Vol
1: Principles And Practice.
[0142] Processes for preparing pharmaceutically acceptable salts,
solvates and physiologically functional derivatives of the
compounds of formula (I) are conventional in the art. See, e.g.,
Burger's Medicinal Chemistry And Drug Discovery 5th Edition, Vol 1:
Principles And Practice.
[0143] As will be apparent to those skilled in the art, in the
processes described below for the preparation of compounds of
formula (I), certain intermediates, may be in the form of
pharmaceutically acceptable salts, solvates or physiologically
functional derivatives of the compound. Those terms as applied to
any intermediate employed in the process of preparing compounds of
formula (I) have the same meanings as noted above with respect to
compounds of formula (I). Processes for preparing pharmaceutically
acceptable salts, solvates and physiologically functional
derivatives of such intermediates are known in the art and are
analogous to the process for preparing pharmaceutically acceptable
salts, solvates and physiologically functional derivatives of the
compounds of formula (I).
[0144] Certain compounds of formula (I) may exist in stereoisomeric
forms (e.g. they may contain one or more asymmetric carbon atoms or
may exhibit cis-trans isomerism). The individual stereoisomers
(enantiomers and diastereomers) and mixtures of these are included
within the scope of the present invention. The present invention
also covers the individual isomers of the compounds represented by
formula (I) as mixtures with isomers thereof in which one or more
chiral centres are inverted. Likewise, it is understood that
compounds of formula (I) may exist in tautomeric forms other than
that shown in the formula and these are also included within the
scope of the present invention.
[0145] The present invention further provides compounds of formula
(I) for use in medical therapy, e.g. in the treatment or
prophylaxis, including suppression of recurrence of symptoms, of a
viral disease in an animal, e.g. a mammal such as a human. The
compounds of formula (I) are especially useful for the treatment or
prophylaxis of viral diseases such as herpes viral infections.
Herpes viral infections include, for example, herpes simplex virus
1 (HSV-1), herpes simplex virus 2 (HSV-2), cytomegalovirus (CMV),
Epstein Barr virus (EBV), Varicella zoster virus (VZV), human
herpes virus 6 (HHV-6), human herpes virus 7 (HHV-7), and human
herpes virus 8 (HHV-8). Thus, the compounds of the invention are
also useful in the treatment or prophylaxis of the symptoms or
effects of herpes virus infections.
[0146] The compounds of the invention are useful in the treatment
or prophylaxis of conditions or diseases associated with herpes
virus infections, particularly conditions or diseases associated
with latent herpes virus infections in an animal, e.g., a mammal
such as a human. By conditions or diseases associated with herpes
viral infections is meant a condition or disease, excluding the
viral infection per se, which results from the presence of the
viral infection, such as chronic fatigue syndrome which is
associated with EBV infection; and multiple sclerosis which has
been associated with herpes viral infections such as EBV and HHV-6.
Further examples of such conditions or diseases are described in
the background section above.
[0147] In addition to those conditions and diseases, the compounds
of the present invention may also be used for the treatment or
prophylaxis of cardiovascular diseases and conditions associated
with herpes virus infections, in particular atherosclerosis,
coronary artery disease and restenosis and specifically restenosis
following angioplasty (RFA). Restenosis is the narrowing of the
blood vessels which can occur after injury to the vessel wall, for
example injury caused by balloon angioplasty or other surgical
and/or diagnostic techniques, and is characterized by excessive
proliferation of smooth muscle cells in the walls of the blood
vessel treated. It is thought that in many patients suffering from
RFA, viral infection, particularly by CMV and/or HHV-6 of the
patient plays a pivotal role in the proliferation of the smooth
muscle cells in the coronary vessel treated. Restenosis can occur
following a number of surgical and/or diagnostic techniques, for
example, transplant surgery, vein grafting, coronary by-pass
grafting and, most commonly following angioplasty.
[0148] There is evidence from work done both in vitro and in vivo,
indicating that restenosis is a multifactorial process. Several
cytokines and growth factors, acting in concert, stimulate the
migration and proliferation of vascular smooth muscle cells (SMC)
and production of extracellular matrix material, which accumulate
to occlude the blood vessel. In addition growth suppressors act to
inhibit the proliferation of SMC's and production of extracellular
matrix material.
[0149] In addition, compounds of formula (I) may be useful in the
treatment or prophylaxis of conditions or diseases associated with
hepatitis B or hepatitis C viruses, human papilloma virus (HPV) and
HIV.
[0150] Thus, the present invention provides a method for the
treatment or prophylaxis of a viral infection in an animal such as
a mammal (e.g., a human), particularly a herpes viral infection,
which method comprises administering to the animal a
therapeutically effective amount of the compound of formula
(I).
[0151] As used herein, the term "prophylaxis" refers to the
prevention of infection, the prevention of occurrence of symptoms
in an infected subject, the prevention of recurrence of symptoms in
an infected subject, or a decrease in severity or frequency of
symptoms of viral infection, condition or disease in the
subject.
[0152] As used herein, the term "treatment" refers to the partial
or total elimination of symptoms or decrease in severity of
symptoms of viral infection, condition or disease in the subject,
or the elimination or decrease of viral presence in the subject. As
used herein, the term "therapeutically effective amount" means an
amount of a compound of formula (I) which is sufficient, in the
subject to which it is administered, to treat or prevent the stated
disease, condition or infection. For example, a therapeutically
effective amount of a compound of formula (I) for the treatment of
a herpes virus infection is an amount sufficient to treat the
herpes virus infection in the subject.
[0153] The present invention also provides a method, for the
treatment or prophylaxis of conditions or diseases associated with
herpes viral infections in an animal such as a mammal (e.g., a
human), which comprises administering to the animal a
therapeutically effective amount of the compound of formula (I). In
one embodiment, the present invention provides a method for the
treatment or prophylaxis of chronic fatigue syndrome or multiple
sclerosis in an animal such as a mammal (e.g., a human), which
comprises administering to the animal a therapeutically effective
amount of a compound of formula (I). The foregoing method is
particularly useful for the treatment or prophylaxis of chronic
fatigue syndrome or multiple sclerosis associated with latent
infection with a herpes virus.
[0154] In another embodiment, the present invention provides a
method for the treatment or prophylaxis of a cardiovascular
condition such as atherosclerosis, coronary artery disease or
restenosis (particularly restenosis following surgery such as
angioplasty), which comprises administering to the animal a
therapeutically effective antiviral amount of the compound of
formula (I).
[0155] The present invention further provides a method for the
treatment or prophylaxis of hepatitis B or hepatitis C viruses in
an animal such as a mammal (e.g., a human), which comprises
administering to the animal a therapeutically effective amount of
the compound of formula (I).
[0156] The present invention further provides a method for the
treatment or prophylaxis of human papilloma virus in an animal such
as a mammal (e.g., a human), which comprises administering to the
animal a therapeutically effective amount of the compound of
formula (I).
[0157] The present invention further provides a method for the
treatment or prophylaxis of HIV in an animal such as a mammal
(e.g., a human), which comprises administering to the animal a
therapeutically effective amount of the compound of formula
(I).
[0158] The present invention also provides the use of the compound
of formula (I) in the preparation of a medicament for the treatment
or prophylaxis of a viral infection in an animal such as a mammal
(e.g., a human), particularly a herpes viral infection; the use of
the compound of formula (I) in the preparation of a medicament for
the treatment of conditions or diseases associated with a herpes
viral infection; and the use of the compound of formula (I) in the
preparation of a medicament for the treatment or prophylaxis of
hepatitis B or hepatitis C viruses, human papilloma virus and HIV.
In particular, the present invention also provides the use of a
compound of formula (I) in the preparation of a medicament for the
treatment or prophylaxis of chronic fatigue syndrome or multiple
sclerosis. In one embodiment, the present invention provides the
use of a compound of formula (I) in the preparation of a medicament
for the treatment or prophylaxis of cardiovascular disease, such as
restenosis and atherosclerosis.
[0159] The compounds of formula (I) are conveniently administered
in the form of pharmaceutical compositions. Such compositions may
conveniently be presented for use in conventional manner in
admixture with one or more physiologically acceptable carriers or
diluents.
[0160] While it is possible that compounds of the present invention
may be therapeutically administered as the raw chemical, it is
preferable to present the active ingredient as a pharmaceutical
formulation or composition. The pharmaceutical composition may
comprise a pharmaceutically acceptable carrier or diluent. The
carrier(s) or diluent(s) must be "acceptable" in the sense of being
compatible with the other ingredients of the formulation and not
deleterious to the recipient thereof.
[0161] Accordingly, the present invention further provides for a
pharmaceutical formulation or composition comprising a compound of
formula (I). In one embodiment, the pharmaceutical composition
further comprises one or more pharmaceutically acceptable carriers
or diluents and optionally, other therapeutic and/or prophylactic
ingredients.
[0162] The formulations include those suitable for oral, parenteral
(including subcutaneous e.g. by injection or by depot tablet,
intradermal, intrathecal, intramuscular e.g. by depot and
intravenous), rectal and topical (including dermal, buccal and
sublingual) administration although the most suitable route may
depend upon for example the condition, age, and disorder of the
recipient as well as the viral infection or disease being treated.
The formulations may conveniently be presented in unit dosage form
and may be prepared by any of the methods well known in the art of
pharmacy. All methods include the step of bringing into association
the compound(s) ("active ingredient") with the carrier which
constitutes one or more accessory ingredients. In general the
formulations are prepared by uniformly and intimately bringing into
association the active ingredient with liquid carriers or finely
divided solid carriers or both and then, if necessary, shaping the
product into the desired formulation. Formulations suitable for
oral administration may be presented as discrete units such as
capsules (including soft-gel capsules), cachets or tablets (e.g.
chewable tablets in particular for pediatric administration) each
containing a predetermined amount of the active ingredient; as a
powder or granules; as a solution or a suspension in an aqueous
liquid or a non-aqueous liquid; or as an oil-in-water liquid
emulsion or a water-in-oil liquid emulsion. The active ingredient
may also be presented as a bolus, electuary or paste.
[0163] A tablet may be made by compression or moulding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with other conventional excipients such as binding agents,
(for example, syrup, acacia, gelatin, sorbitol, tragacanth,
mucilage of starch or polyvinylpyrrolidone), fillers (for example,
lactose, sugar, microcrystalline cellulose, maize-starch, calcium
phosphate or sorbitol), lubricants (for example, magnesium
stearate, stearic acid, talc, polyethylene glycol or silica),
disintegrants (for example, potato starch or sodium starch
glycollate) or wetting agents, such as sodium lauryl sulfate.
Moulded tablets may be made by moulding in a suitable machine a
mixture of the powdered compound moistened with an inert liquid
diluent. The tablets may optionally be coated or scored and may be
formulated so as to provide slow or controlled release of the
active ingredient therein. The tablets may be coated according to
methods well-known in the art.
[0164] Alternatively, the compounds of the present invention may be
incorporated into oral liquid preparations such as aqueous or oily
suspensions, solutions, emulsions, syrups or elixirs, for example.
Moreover, formulations containing these compounds may be presented
as a dry product for constitution with water or other suitable
vehicle before use. Such liquid preparations may contain
conventional additives such as suspending agents such as sorbitol
syrup, methyl cellulose, glucose/sugar syrup, gelatin,
hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate
gel or hydrogenated edible fats; emulsifying agents such as
lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles
(which may include edible oils) such as almond oil, fractionated
coconut oil, oily esters, propylene glycol or ethyl alcohol; and
preservatives such as methyl or propyl p-hydroxybenzoates or sorbic
acid. Such preparations may also be formulated as suppositories,
e.g., containing conventional suppository bases such as cocoa
butter or other glycerides. Liquid preparations may also be
formulated as soft-gel capsules for oral administration, e.g.,
containing conventional soft-gel excipients such as polyethylene
glycol.
[0165] Formulations for parenteral administration include aqueous
and non-aqueous sterile injection solutions which may contain
anti-oxidants, buffers, bacteriostats and solutes which render the
formulation isotonic with the blood of the intended recipient; and
aqueous and non-aqueous sterile suspensions which may include
suspending agents and thickening agents.
[0166] The formulations may be presented in unit-dose or multi-dose
containers, for example sealed ampoules and vials, and may be
stored in a freeze-dried (lyophilised) condition requiring only the
addition of a sterile liquid carrier, for example,
water-for-injection, immediately prior to use. Extemporaneous
injection solutions and suspensions may be prepared from sterile
powders, granules and tablets of the kind previously described.
Formulations for rectal administration may be presented as a
suppository with the usual carriers such as cocoa butter, hard fat
or polyethylene glycol.
[0167] Formulations suitable for topical (e.g., dermal) or
intranasal application include ointments, creams, lotions, pastes,
gels, sprays, aerosols and oils. Suitable carriers for such
formulations include petroleum jelly, lanolin, polyethyleneglycols,
alcohols and combinations thereof.
[0168] Formulations for topical administration in the mouth, for
example buccally or sublingually, include lozenges comprising the
active ingredient in a flavored base such as sucrose and acacia or
tragacanth, and pastilles comprising the active ingredient in a
base such as gelatin and glycerin or sucrose and acacia.
[0169] The compounds may also be formulated as depot preparations.
Such long acting formulations may be administered by implantation
(for example subcutaneously or intramuscularly) or by intramuscular
injection. Thus, for example, the compounds may be formulated with
suitable polymeric or hydrophobic materials (for example as an
emulsion in an acceptable oil) or ion exchange resins, or as
sparingly soluble derivatives, for example, as a sparingly soluble
salt.
[0170] In addition to the ingredients particularly mentioned above,
the formulations may include other agents conventional in the art
having regard to the type of formulation in question, for example
those suitable for oral administration may include flavoring
agents.
[0171] It will be appreciated that the amount of a compound of the
invention required for use in treatment will vary with the nature
of the condition being treated and the age and the condition of the
patient and will be ultimately at the discretion of the attendant
physician or veterinarian. In general, however, doses employed for
adult human treatment will typically be in the range of 0.02-5000
mg per day, preferably 100-1500 mg per day. The desired dose may
conveniently be presented in a single dose or as divided doses
administered at appropriate intervals, for example as two, three,
four or more sub-doses per day. The formulations according to the
invention may contain between 0.1-99% of the active ingredient,
conveniently from 30-95% for tablets and capsules and 3-50% for
liquid preparations.
[0172] The compound of formula (I) for use in the instant invention
may be used in combination with other therapeutic agents for
example, non-nucleotide reverse transcriptase inhibitors,
nucleoside reverse transcriptase inhibitors, protease inhibitors
and/or other antiviral agents. The invention thus provides in a
further aspect the use of a combination comprising a compound of
formula (I) with a further therapeutic agent in the treatment of
viral infections. Particular antiviral agents which may be combined
with the compounds of the present invention include aciclovir,
valaciclovir, fameyclovir, gancyclovir, docosanol, miribavir,
amprenavir, lamivudine, zidovudine, and abacavir. Preferred
antiviral agents for combining with the compounds of the present
invention include aciclovir and valaciclovir. Thus the present
invention provides in a further aspect, a combination comprising a
compound of formula (i) and an antiviral agent selected from the
group consisting of aciclovir and valaciclovir; the use of such
combination in the treatment of viral infections and the
preparation of a medicament for the treatment of viral infections,
and a method of treating viral infections comprising administering
a compound of formula (I) and an antiviral agent selected from the
group consisting of aciclovir and valaciclovir.
[0173] When a compound of formula (I) is used in combination with
other therapeutic agents, the compounds may be administered either
sequentially or simultaneously by any convenient route.
[0174] The combinations referred to above may conveniently be
presented for use in the form of a pharmaceutical formulation and
thus pharmaceutical formulations comprising a combination as
defined above optionally together with a pharmaceutically
acceptable carrier or diluent comprise a further aspect of the
invention. The individual components of such combinations may be
administered either sequentially or simultaneously in separate or
combined pharmaceutical formulations. When combined in the same
formulation it will be appreciated that the two compounds must be
stable and compatible with each other and the other components of
the formulation and may be formulated for administration. When
formulated separately they may be provided in any convenient
formulation, in such a manner as are known for such compounds in
the art.
[0175] When a compound of formula (I) is used in combination with a
second therapeutic agent active against the viral infection, the
dose of each compound may differ from that when the compound is
used alone. Appropriate doses will be readily appreciated by those
skilled in the art.
[0176] Compounds of formula (I) wherein Y.sup.1 is N; R.sup.1 is
selected from the group consisting of Het, --OR.sup.7, --OAy,
--OHet, --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet,
--S(O).sub.nR.sup.9, --S(O).sub.nAy and --S(O).sub.nHet; p is 1 and
R.sup.6 is --SR.sup.9, may be prepared by the process outlined in
Scheme 1 below. ##STR17## ##STR18## wherein: [0177] R.sup.1 is
selected from the group consisting of Het, --OR.sup.7, --OAy,
--OHet, --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet,
--S(O).sub.nR.sup.9, --S(O).sub.nAy and --S(O).sub.nHet; [0178]
each R.sup.7 and R.sup.8 are the same or different and are
independently selected from the group consisting of H, alkyl,
cycloalkyl, alkenyl, cycloalkenyl, --C(O)R.sup.9,
--CO.sub.2R.sup.9, --C(O)NR.sup.9R.sup.11, --C(S)NR.sup.9R.sup.11,
--C(NH)NR.sup.9R.sup.11, --SO.sub.2R.sup.10,
--SO.sub.2NR.sup.9R.sup.11, --R.sup.10cycloalkyl, --R.sup.10Ay,
--R.sup.10Het, --R.sup.10C(O)R.sup.9, --R.sup.10CO.sub.2R.sup.9,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10OR.sup.9, --R.sup.10NR.sup.9R.sup.11,
--R.sup.10NHCOR.sup.9, --R.sup.10NHC(NH)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.10 and
--R.sup.10SO.sub.2NHCOR.sup.9; [0179] each R.sup.9 and R.sup.11 are
the same or different and are independently selected from the group
consisting of H, alkyl, cycloalkyl, --R.sup.10cycloalkyl,
--R.sup.10OH, --R.sup.10(OR.sup.10).sub.w where w is 1-10, and
--R.sup.10NR.sup.10R.sup.10; [0180] each R.sup.10 is the same or
different and is independently selected from the group consisting
of alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl; [0181] n
is 0, 1 or 2; [0182] Ay is aryl; [0183] Het is a 5- or 6-membered
heterocyclic or heteroaryl group; [0184] Y.sup.1 is N; [0185] p is
1; [0186] R.sup.6 is --SR.sup.9; [0187] Y is N or CH; [0188]
R.sup.2 is selected from the group consisting of halo, alkyl,
cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, --OR.sup.7, --OAy,
--OHet --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet
--S(O).sub.nR.sup.9, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8 and
--R.sup.10NR.sup.7Ay; [0189] R.sup.3 and R.sup.4 are the same or
different and are each independently selected from the group
consisting of H, halo, alkyl, alkenyl, cycloalkyl, Ay, Het,
--C(O)R.sup.7, C(O)Ay, --CO.sub.2R.sup.7, --CO.sub.2Ay, --OR.sup.7,
--OAy, --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet,
--SO.sub.2NHR.sup.9, --R.sup.10OR.sup.7, --R.sup.10cycloalkyl,
--R.sup.10OAy, --R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay;
[0190] Ring A is selected from the group consisting of aryl, 5-10
membered heterocyclic group and a 5-10 membered heteroaryl group;
[0191] q is 0, 1, 2, 3, 4 or 5; and [0192] each R.sup.5 is the same
or different and is independently selected from the group
consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, Ay, Het, --C(O)R.sup.9, --C(O)Ay, --C(O)Het,
--CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8, --C(O)NR.sup.7Ay,
--C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8, --C(NH)NR.sup.7Ay,
--OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8, --NR.sup.7Ay,
--NHHet, --S(O).sub.nR.sup.9, --S(O).sub.2NR.sup.7R.sup.8,
--S(O).sub.2NR.sup.7Ay, --R.sup.10cycloalkyl, --R.sup.10Het,
--R.sup.10C(O)R.sup.9, --R.sup.10CO.sub.2R.sup.9,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10OR.sup.9,
--R.sup.10NR.sup.7R.sup.8, --R.sup.10NR.sup.7Ay,
--R.sup.10SO.sub.2R.sup.9, --R.sup.10SO.sub.2NR.sup.9R.sup.11,
--R.sup.10SO.sub.2NHCOR.sup.9, cyano, nitro and azido; and [0193] X
is chloro, bromo or iodo; [0194] X.sup.1 is chloro, bromo, or iodo;
and [0195] M.sup.1 is --B(OH).sub.2, --B(ORa).sub.2, --B(Ra).sub.2,
--Sn(Ra).sub.3, Zn-halide, ZnRa, or Mg-halide where Ra is alkyl or
cycloalkyl and halide is halo.
[0196] Generally, the process for preparing the compounds of
formula (I) wherein Y.sup.1 is N; R.sup.1 is selected from the
group consisting of Het, --OR.sup.7, --OAy, --OHet,
--NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet, --S(O).sub.nR.sup.9,
--S(O).sub.nAy and --S(O).sub.nHet; p is 1 and R.sup.6 is
--SR.sup.9, (all formulas and all other variables having been
defined above in connection with Scheme 1) comprises the steps
of:
[0197] (a) reacting a compound of formula (II) with an
isothiocyanate of formula (III) to prepare a compound of formula
(IV);
[0198] (b) reacting the compound of formula (IV) with a base to
prepare a compound of formula (V);
[0199] (c) reacting the compound of formula (V) with a base and an
alkylating agent to prepare a compound of formula (VI);
[0200] (d) reacting a compound of formula (VI) with phosphorus
oxychloride to prepare a compound of formula (VII);
[0201] (e) reacting a compound of formula (VII) with a heteroatom
(N,O,S) nucleophile to prepare a compound of formula (VIII);
[0202] (f) halogenating a compound of formula (VIII) to prepare a
compound of formula (IX); and
[0203] (g) reacting a compound of formula (IX) with a compound of
formula (X) to prepare a compound of formula (I).
[0204] More specifically, compounds of formula (I) wherein Y.sup.1
is N; R.sup.1 is selected from the group consisting of Het,
--OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8, --NR.sup.7Ay,
--NHHet, --S(O).sub.nR.sup.9, --S(O).sub.nAy and --S(O).sub.nHet; p
is 1 and R.sup.6 is --SR.sup.9, can be prepared by reacting a
compound of formula (IX) with a compound of formula (X). ##STR19##
[0205] wherein all variables are as defined above in connection
with Scheme 1.
[0206] The reaction may be carried out in an inert solvent, in the
presence of a palladium (0) or nickel (0) catalyst. The reaction
may optionally be heated to about 50-150.degree. C. Typically the
reaction is performed by reacting equimolar amounts of a compound
of formula (IX) with a heteroaryl-metal compound of formula (X),
but the reaction may also be performed in the presence of an excess
of compound of the formula (X). The palladium or nickel catalyst is
typically present in 1-10 mol % compared to the compound of formula
(IX). Examples of suitable palladium catalysts include but are not
limited to, tetrakis(triphenylphosphine)palladium (0),
dichlorobis(triphenyl-phosphine)palladium(II),
tris(dibenzylideneacetone)dipalladium (0), and
bis(diphenylphosphinoferrocene)palladium (II) dichloride. Suitable
solvents include but are not limited to, N,N-dimethylformamide,
toluene, tetrahydrofuran, dioxane, and 1-methyl-2-pyrrolidinone.
When the heteroaryl-metal compound of formula (X) is an arylboronic
acid or ester or an arylborinate the reaction is more conveniently
carried out by adding a base in a proportion equivalent to, or
greater than, that of the compound of formula (X). Heteroaryl-metal
compounds of formula (X) may be obtained from commercial sources or
prepared either as discreet isolated compounds or generated in situ
using methods known to one skilled in the art. (Suzuki, A. J.
Organomet. Chem. 1999, 576, 147; Stille, J. Angew. Chem. Int. Ed.
Engl. 1986, 25, 508; Snieckus, V. J. Org. Chem. 1995, 60, 292.)
[0207] A compound of formula (IX) can be prepared from a compound
of formula (VIII) by a halogenation procedure. ##STR20## [0208]
wherein all variables are as defined above in connection with
Scheme 1.
[0209] Typically, the halogenation reaction is carried out by
subjecting the compound of formula (VIII) to a halogenating reagent
in a suitable solvent. Suitable halogenating reagents include but
are not limited to, N-bromosuccinimide, trialkylammonium
tribromides, bromine, N-chlorosuccinimide, N-iodosuccinimide,
iodine, iodine monochloride, and the like. Suitable solvents
include, for example, N,N-dimethylformamide, tetrahydrofuran,
dioxane, 1-methyl-2-pyrrolidinone, carbon tetrachloride, toluene,
dichloromethane, diethyl ether, and the like.
[0210] A compound of the formula (VIII) can be prepared from a
compound of formula (VII) through reaction with a heteroatom (i.e.,
N, O or S) nucleophile selected from the group consisting of Het,
--OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8, --NR.sup.7Ay,
--NHHet, --S(O).sub.nR.sup.9, --S(O).sub.nAy and --S(O).sub.nHet.
##STR21## [0211] wherein all variables are as defined above in
connection with Scheme 1.
[0212] Typically the chloro compound of formula (VII) can be
treated with the nucleophile in an inert solvent or the nucleophile
when suitable can be used as the solvent. By way of example some
suitable solvents include but are not limited to
1-methyl-2-pyrrolidinone, N,N-dimethylformamide, tetrahydrofuran,
dimethyl sulfoxide, and the lower alcohols such as methanol,
ethanol, isopropanol and the like. The reaction may be performed at
or below ambient temperature or if deemed necessary the reaction
may require heating to 50-200.degree. C.
[0213] A compound of formula (VII) can be conveniently prepared
from a compound of formula (VI) by treatment with phosphorus
oxychloride. ##STR22## [0214] wherein all variables are as defined
above in connection with Scheme 1.
[0215] Conveniently, this type of transformation can be carried out
using phosphorus oxychloride, optionally in the presence of a base.
This is performed by treating a compound of formula (VI) with
phosphorus oxychloride with optional heating. Typically an excess
of the dehydrating reagent is used and the reaction can be heated
up to reflux temperature of approximately 105.degree. C. By way of
example a suitable base is N,N-diethylaniline and the like.
[0216] A compound of the formula (VI) can be conveniently
synthesized from a compound of formula (V) by an alkylation
protocol. ##STR23## [0217] wherein all variables are as defined
above in connection with Scheme 1.
[0218] This sequence can be carried out by reacting a compound of
formula (V) with a base and an alkyl halide electrophile in an
inert solvent at room temperature or optionally with heating. A
typical base is aqueous sodium hydroxide or the like. Other bases
can be used under anhydrous conditions such as potassium carbonate,
sodium ethoxide, sodium hydride and the like. Electrophiles include
but are not limited to alkyl halides such as methyl iodide
(R.sup.9=methyl) and alkyl sulfates such as dimethyl sulfate, and
the like. A typical solvent system is ethanol/water, but other
solvents, with or without an aqueous co-solvent, can be used,
including 1-methyl-2-pyrrolidinone, N,N-dimethylformamide,
tetrahydrofuran, dimethyl sulfoxide, and the lower alcohols such as
methanol, ethanol, isopropanol, and the like. The reaction can
optionally be heated to 50-200.degree. C.
[0219] A compound of formula (V) can be prepared by an
intramolecular condensation ring closing reaction of a compound of
formula (IV). ##STR24## [0220] wherein all variables are as defined
above in connection with Scheme 1.
[0221] This condensation can be typically carried out by treating a
compound of formula (IV) with a base in an inert solvent. Typical
bases include but are not limited to sodium hydroxide, sodium
ethoxide, potassium carbonate, potassium tert-butoxide, and the
like. Solvents include water, the lower alcohols such as ethanol,
iospropanol, and the like. Additionally solvents can be chosen from
1-methyl-2-pyrrolidinone, N,N-dimethylformamide, tetrahydrofuran,
dimethyl sulfoxide, and the like.
[0222] A compound of the formula (IV) can be conveniently formed by
reaction of a compound of formula (II) with an isothiocyanate of
formula (III). ##STR25## [0223] wherein all variables are as
defined above in connection with Scheme 1.
[0224] This can be carried out by reacting a compound of formula
(II) with a commercially available isothiocyanate such as
ethoxycarbonyl isothiocyanate in a inert solvent optionally with
heating. A suitable solvent includes but is not limited to toluene.
The reaction may be heated to a temperature of from about
30-150.degree. C.
[0225] Compounds of the formula (II) can be purchased from
commercial sources or prepared using conventional techniques known
to one skilled in the art.
[0226] In a further embodiment of the present invention, a compound
of formula (I) wherein Y.sup.1 is N; R.sup.1 is selected from the
group consisting of of Het, --OR.sup.7, --OAy, --OHet,
--NR.sup.7R.sup.8, --NR.sup.7Ay and --NHHet and p is 0, may be
conveniently prepared by the process outlined in Scheme 2 below.
##STR26## wherein: [0227] R.sup.1 is selected from the group
consisting of Het, --OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8,
--NR.sup.7Ay and --NHHet; [0228] each R.sup.7 and R.sup.8 are the
same or different and are independently selected from the group
consisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl,
--C(O)R.sup.9, --CO.sub.2R.sup.9, --C(O)NR.sup.9R.sup.11,
--C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.9R.sup.11,
--SO.sub.2R.sup.10, --SO.sub.2NR.sup.9R.sup.11,
--R.sup.10cycloalkyl, --R.sup.10Ay, --R.sup.10Het,
--R.sup.10C(O)R.sup.9, --R.sup.10CO.sub.2R.sup.9,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10OR.sup.9, --R.sup.10NR.sup.9R.sup.11,
--R.sup.10NHCOR.sup.9, --R.sup.10NHC(NH)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.10 and
--R.sup.10SO.sub.2NHCOR.sup.9; [0229] each R.sup.9 and R.sup.11 are
the same or different and are independently selected from the group
consisting of H, alkyl, cycloalkyl, --R.sup.10cycloalkyl,
--R.sup.10OH, --R.sup.10(OR.sup.10).sub.w where w is 1-10, and
--R.sup.10NR.sup.10R.sup.10; [0230] each R.sup.10 is the same or
different and is independently selected from the group consisting
of alkyl, cycloalkyl, alkenyl, cycloalkenyl, and alkynyl; [0231] n
is 0, 1 or 2; [0232] Ay is aryl; [0233] Het is a 5- or 6-membered
heterocyclic or heteroaryl group; [0234] Y.sup.1 is N; [0235] p is
0; [0236] Y is N or CH; [0237] R.sup.2 is selected from the group
consisting of halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay,
Het, --OR.sup.7, --OAy, --OHet --NR.sup.7R.sup.8, --NR.sup.7Ay,
--NHHet --S(O).sub.nR.sup.9, --S(O).sub.nAy,
--R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay; [0238] R.sup.3
and R.sup.4 are the same or different and are each independently
selected from the group consisting of H, halo, alkyl, alkenyl,
cycloalkyl, Ay, Het, --C(O)R.sup.7, C(O)Ay, --CO.sub.2R.sup.7,
--CO.sub.2Ay, --OR.sup.7, --OAy, --NR.sup.7R.sup.8, --NR.sup.7Ay,
--NHHet, --SO.sub.2NHR.sup.9, --R.sup.10OR.sup.7,
--R.sup.10cycloalkyl, --R.sup.10OAy, --R.sup.10NR.sup.7R.sup.8 and
--R.sup.10NR.sup.7Ay; [0239] Ring A is selected from the group
consisting of aryl, 5-10 membered heterocyclic group and a 5-10
membered heteroaryl group; [0240] q is 0, 1, 2, 3, 4 or 5; and
[0241] each R.sup.5 is the same or different and is independently
selected from the group consisting of halo, alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, --C(O)R.sup.9,
--C(O)Ay, --C(O)Het, --CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8,
--C(O)NR.sup.7Ay, --C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8,
--C(NH)NR.sup.7Ay, --OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8,
--NR.sup.7Ay, --NHHet, --S(O).sub.nR.sup.9,
--S(O).sub.2NR.sup.7R.sup.8, --S(O).sub.2NR.sup.7Ay,
--R.sup.10cycloalkyl, --R.sup.10Het, --R.sup.10C(O)R.sup.9,
--R.sup.10CO.sub.2R.sup.9, --R.sup.10C(O)NR.sup.9R.sup.11,
--R.sup.10C(O)NR.sup.7Ay, --R.sup.10C(O)NHR.sup.10Het,
--R.sup.10C(S)NR.sup.9R.sup.11, --R.sup.10C(NH)NR.sup.9R.sup.11,
--R.sup.10OR.sup.9, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, --R.sup.10SO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2NHCOR.sup.9,
cyano, nitro and azido; and [0242] X.sup.1 is chloro, bromo, or
iodo; and [0243] M.sup.1 is --B(OH).sub.2, --B(ORa).sub.2,
--B(Ra).sub.2, --Sn(Ra).sub.3, Zn-halide, ZnRa, or Mg-halide where
Ra is alkyl or cycloalkyl and halide is halo.
[0244] Generally, the process for preparing a compound of formula
(I) wherein Y.sup.1 is N; R.sup.1 is selected from the group
consisting of of Het, --OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8,
--NR.sup.7Ay and --NHHet and p is 0 (all formulas and all other
variables having been defined above in connection with Scheme 2)
comprises the steps of:
[0245] a) reducing a compound of formula (VIII) to prepare a
compound of formula (XI);
[0246] b) halogenating the compound of formula (XI) to prepare a
compound of formula (XII); and
[0247] c) reacting a compound of formula (XII) with a compound of
formula (X) to prepare a compound of formula (I).
[0248] More specifically, a compound of formula (I) wherein Y.sup.1
is N; R.sup.1 is selected from the group consisting of of Het,
--OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8, --NR.sup.7Ay and
--NHHet and p is 0, can be prepared by reacting a compound of
formula (XII) with a compound of formula (X). ##STR27## [0249]
wherein all variables are as defined above in connection with
Scheme 1.
[0250] This reaction may be carried out using the same procedures
as described above in connection with Scheme 1, for the conversion
of a compound of formula (IX) to a compound of formula (I).
[0251] A compound of formula (XII) can be prepared from a compound
of formula (XI) by a halogenation procedure. ##STR28## [0252]
wherein all variables are as defined above in connection with
Scheme 1.
[0253] Typically, the halogenation reaction is carried out by
subjecting the compound of formula (XI) to a halogenating agent in
a suitable solvent. Suitable halogenating agents include but are
not limited to, N-bromosuccinimide, trialkylammonium tribromides,
bromine, N-chlorosuccinimide, N-iodosuccinimide, iodine, iodine
monochloride, and the like. Suitable solvents include, for example,
N,N-dimethylformamide, tetrahydrofuran, dioxane,
1-methyl-2-pyrrolidinone, carbon tetrachloride, toluene,
dichloromethane, diethyl ether, and the like.
[0254] A compound of formula (XI) can be conveniently prepared by
reduction of a compound of formula (VIII). ##STR29## [0255] wherein
all variables are as defined above in connection with Scheme 1 This
method can be carried out by treating a compound of formula (VIII)
with Raney-nickel in an alcohol solvent. A preferred solvent is
ethanol. The reaction may optionally require heating to
50-150.degree. C. Preparation of a compound of formula (VIII) is
described in connection with Scheme 1 above.
[0256] In a further embodiment of the present invention, a compound
of formula (I) wherein Y.sup.1 is CH; Y is N; R.sup.2 is selected
from the group consisting of alkyl, cycloalkyl, alkenyl,
cycloalkenyl, Ay, Het, --OR.sup.7, --OAy, --OHet --NR.sup.7R.sup.8,
--NR.sup.7Ay, --NHHet --S(O).sub.nR.sup.9, --S(O).sub.nAy,
--R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay; and R.sup.3 and
R.sup.4 are H, may be conveniently prepared by the process outlined
in Scheme 3 below. ##STR30## ##STR31## wherein: [0257] R.sup.1 is
selected from the group consisting of H, halo, alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, --C(O)R.sup.9,
--C(O)Ay, --C(O)Het, --CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8,
--C(O)NR.sup.7Ay, --C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8,
--C(NH)NR.sup.7Ay, --OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8,
--NR.sup.7Ay, --NHHet, --S(O).sub.nR.sup.9, --S(O).sub.nAy,
--S(O).sub.nHet, --S(O).sub.2NR.sup.7R.sup.8,
--S(O).sub.2NR.sup.7Ay, --R.sup.10cycloalkyl, --R.sup.10Ay,
--R.sup.10Het, --R.sup.10OR.sup.9, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10C(O)R.sup.9, --R.sup.10C(O)Ay, --R.sup.10C(O)Het,
--R.sup.10CO.sub.2R.sup.9, --R.sup.10OC(O)R.sup.9,
--R.sup.10OC(O)Ay, --R.sup.10OC(O)Het,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2NHCOR.sup.9,
--R.sup.10OS(O).sub.nR.sup.9, cyano, nitro and azido; [0258] each
R.sup.7 and R.sup.8 are the same or different and are independently
selected from the group consisting of H, alkyl, cycloalkyl,
alkenyl, cycloalkenyl, --C(O)R.sup.9, --CO.sub.2R.sup.9,
--C(O)NR.sup.9R.sup.11, --C(S)NR.sup.9R.sup.11,
--C(NH)NR.sup.9R.sup.11, --SO.sub.2R.sup.10,
--SO.sub.2NR.sup.9R.sup.11, --R.sup.10cycloalkyl, --R.sup.10Ay,
--R.sup.10Het, --R.sup.10C(O)R.sup.9, --R.sup.10CO.sub.2R.sup.9,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10OR.sup.9, --R.sup.10NR.sup.9R.sup.11,
--R.sup.10NHCOR.sup.9, --R.sup.10NHC(NH)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.10 and
--R.sup.10SO.sub.2NHCOR.sup.9; [0259] each R.sup.9 and R.sup.11 are
the same or different and are independently selected from the group
consisting of H, alkyl, cycloalkyl, --R.sup.10cycloalkyl,
--R.sup.10OH, --R.sup.10(OR.sup.10).sub.w where w is 1-10, and
--R.sup.10NR.sup.10R.sup.10; [0260] each R.sup.10 is the same or
different and is independently selected from the group consisting
of alkyl, cycloalkyl, alkenyl, cycloalkenyl, and alkynyl; [0261] n
is 0, 1 or 2; [0262] Ay is aryl; [0263] Het is a 5- or 6-membered
heterocyclic or heteroaryl group; [0264] p is 0, 1 or 2 when
Y.sup.1 is CH, [0265] p is 0 or 1 when Y.sup.1 is N; [0266] each
R.sup.6 is the same or different and is independently selected from
the group consisting of H, halo, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, Ay, Het, --C(O)R.sup.9, --C(O)Ay,
--C(O)Het, --CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8,
--C(O)NR.sup.7Ay, --C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8,
--C(NH)NR.sup.7Ay, --OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8,
--NR.sup.7Ay, --NHHet, --S(O).sub.nR.sup.9, --S(O).sub.nAy,
--S(O).sub.nHet, --S(O).sub.2NR.sup.7R.sup.8,
--S(O).sub.2NR.sup.7Ay, --R.sup.10cycloalkyl, --R.sup.10Ay,
--R.sup.10Het, --R.sup.10OR.sup.9, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10C(O)R.sup.9, --R.sup.10C(O)Ay, --R.sup.10C(O)Het,
--R.sup.10CO.sub.2R.sup.9, --R.sup.10OC(O)R.sup.9,
--R.sup.10OC(O)Ay, --R.sup.10OC(O)Het,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2NHCOR.sup.9,
--R.sup.10OS(O).sub.nR.sup.9, cyano, nitro and azido; [0267] or
when p is 2, two adjacent R.sup.6 groups together with the carbon
atoms to which they are bonded form a cycloalkyl or a 5- or
6-membered heterocyclic group containing 1 or 2 heteroatoms; [0268]
Y is N; [0269] R.sup.2 is selected from the group consisting of
alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, --OR.sup.7,
--OAy, --OHet --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet
--S(O).sub.nR.sup.9, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8 and
--R.sup.10NR.sup.7Ay; [0270] R.sup.3 and R.sup.4 are both H [0271]
Ring A is selected from the group consisting of aryl, 5-10 membered
heterocyclic group and a 5-10 membered heteroaryl group; [0272] q
is 0, 1, 2, 3, 4 or 5; [0273] each R.sup.5 is the same or different
and is independently selected from the group consisting of halo,
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het,
--C(O)R.sup.9, --C(O)Ay, --C(O)Het, --CO.sub.2R.sup.9,
--C(O)NR.sup.7R.sup.8, --C(O)NR.sup.7Ay, --C(S)NR.sup.9R.sup.11,
--C(NH)NR.sup.7R.sup.8, --C(NH)NR.sup.7Ay, --OR.sup.7, --OAy,
--OHet, --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet,
--S(O).sub.nR.sup.9, --S(O).sub.2NR.sup.7R.sup.8,
--S(O).sub.2NR.sup.7Ay, --R.sup.10cycloalkyl, --R.sup.10Het,
--R.sup.10C(O)R.sup.9, --R.sup.10CO.sub.2R.sup.9,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10OR.sup.9,
--R.sup.10NR.sup.7R.sup.8, --R.sup.10NR.sup.7Ay,
--R.sup.10SO.sub.2R.sup.9, --R.sup.10SO.sub.2NR.sup.9R.sup.11,
--R.sup.10SO.sub.2NHCOR.sup.9, cyano, nitro and azido; and [0274]
Ra is alkyl or cycloalkyl.
[0275] Generally, the process for preparing a compound of formula
(I) wherein Y.sup.1 is CH; Y is N; R.sup.2 is selected from the
group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay,
Het, --OR.sup.7, --OAy, --OHet --NR.sup.7R.sup.8, --NR.sup.7Ay,
--NHHet --S(O).sub.nR.sup.9, --S(O).sub.nAy,
--R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay; and R.sup.3 and
R.sup.4 are H (all formulas and all other variables having been
defined above in connection with Scheme 3), comprises the steps
of:
[0276] (a) reacting a 4-methylpyrimidine of formula (XIV) with an
ester of formula (XIII) to prepare a compound of formula (XV);
[0277] (b) reacting the compound of formula (XV) with a
hydroxylamine source to prepare a compound of formula (XVI);
[0278] (c) reacting the compound of formula (XVI) with an acylating
or sulfonylating agent to prepare a compound of formula (XVII);
[0279] (d) rearranging the compound of formula (XVII) to prepare a
compound of formula (XVIII);
[0280] (e) acylating the compound of formula (XVIII) to prepare a
compound of formula (XIX);
[0281] (f) reacting the compound of formula (XIX) with a
dimethylformamide dialkyl acetal of formula
(CH.sub.3).sub.2NCH(ORa).sub.2 to prepare a compound of formula
(XX); and
[0282] (g) reacting the compound of formula (XX) with a compound of
formula (XXI) to prepare a compound of formula (I).
[0283] More specifically, a compound of formula (I) wherein wherein
Y.sup.1 is CH; Y is N; R.sup.2 is selected from the group
consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het,
--OR.sup.7, --OAy, --OHet --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet
--S(O).sub.nR.sup.9, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8 and
--R.sup.10NR.sup.7Ay; and R.sup.3 and R.sup.4 are H, can be
prepared by reacting a compound of formula (XX) with a compound of
formula (XXI). ##STR32## [0284] wherein all variables are as
defined above in connection with Scheme 3.
[0285] This method can be readily carried out by mixing a compound
of formula (XX) with a compound of formula (XXI) in a suitable
solvent, optionally in the presence of a base (preferably when the
amidine is in a salt form), and heating the reaction to
50-150.degree. C. Typical solvents include lower alcohols such as
methanol, ethanol, isopropanol and N,N-dimethylformamide or the
like. The base is typically a sodium alkoxide, potassium carbonate,
or an amine base such as triethylamine. In one embodiment, the
solvent is N,N-dimethylformamide and the base is potassium
carbonate, or an amine base such as triethylamine.
[0286] A compound of formula (XX) may be conveniently prepared by
reacting a compound of formula (XIX) with a dimethylformamide
dialkyl acetal. ##STR33## [0287] wherein all variables are as
defined above in connection with Scheme 3.
[0288] Typical dimethylformamide dialkylacetal compounds for use in
this method include but are not limited to dimethylformamide
dimethylacetal and dimethylformamide di-tert-butylacetal. The
reaction is carried out by mixing a compound of formula (XIX) with
the dimethylformamide dialkyl acetal, optionally with heating.
[0289] The foregoing procedure for the conversion of a compound of
formula (XIX) to a compound of formula (I) can also be used for the
conversion of a compound of formula (VIII) to a compound of formula
(I) if desired.
[0290] A compound of formula (XIX) may be conveniently prepared
from a compound of formula (XVIII) using an acylation procedure.
##STR34## [0291] wherein all variables are as defined above in
connection with Scheme 3.
[0292] Typically the acylation is carried out by treating a
compound of formula (XVIII) with an acylating agent, optionally in
the presence of an acid or Lewis acid catalyst in an inert solvent
with optional heating. Typical acylating agents will be readily
determined by those skilled in the art. One preferred acylating
agent is acetic anhydride. Lewis acid catalysts are also known to
those skilled in the art. One preferred Lewis acid catalyst for use
in this reaction is boron trifluoride diethyl etherate. A suitable
solvent is toluene. Another preferred reaction condition is
catalytic sulfuric acid optionally in acetonitrile and optionally
with heating.
[0293] A compound of formula (XVIII) can be conveniently prepared
by rearranging an azirine compound of formula (XVII). ##STR35##
[0294] wherein all variables are as defined above in connection
with Scheme 3.
[0295] The rearrangement of the azirine of formula (XVII) can be
accomplished by heating a solution of the azirine of formula (XVII)
in a suitable solvent at a temperature of about 160-200.degree. C.
Suitable inert solvents include, but are not limited to,
1-methyl-2-pyrrolidinone and 1,2,4-trichlorobenzene. A more
preferred method for rearrangement of the azirine of formula (XVII)
to a compound of formula (XVIII) involves reacting the compound of
formula (XVII) with ferrous chloride (FeCl.sub.2) or ferric
chloride (FeCl.sub.3). See, PCT Publication No. WO 01/83479,
published 8 Nov. 2001 to GlaxoSmithKline Inc. This reaction is
typically done in an inert solvent with heating. A preferred
solvent for this reaction is 1,2-dimethoxyethane, or the like.
[0296] Typically the azirine of formula (XVII) can be prepared from
an oxime compound of formula (XVI) by treatment with an acylating
or sulfonylating agent in the presence of a base. ##STR36## [0297]
wherein all variables are as defined above in connection with
Scheme 3.
[0298] Typical acylating or sulfonylating agents include but are
not limited to, acetic anhydride, trifluoroacetic anhydride,
methanesulfonyl chloride, toluenesulfonyl chloride and the like.
Typical bases include, but are not limited to, triethylamine,
diisopropylethylamine, pyridine, and the like. The reaction may be
carried out in an inert solvent such as for example, chloroform,
dichloromethane, toluene or the like.
[0299] The oxime compounds of formula (XVI) are readily prepared by
treating ketone compounds of formula (XV) with a hydroxylamine
source, in a suitable solvent, and optionally with a base.
##STR37## [0300] wherein all variables are as defined above in
connection with Scheme 3.
[0301] Typically, the hydroxylamine is hydroxylamine hydrochloride
and the base is an aqueous solution of sodium hydroxide. Suitable
solvents include lower alcohols such as methanol, ethanol, or
isopropanol.
[0302] The ketone compounds of formula (XV) can be prepared by
treatment of a methylpyrimidine of formula (XIV) with an ester of
formula (XIII) in the presence of a base. ##STR38## [0303] wherein
all variables are as defined above in connection with Scheme 3.
[0304] An example of a suitable base is lithium
bis(trimethylsilyl)amide in an inert solvent such as
tetrahydrofuran. Ketones such as those of formula (III) can be
readily prepared using procedures known to one skilled in the art
and/or described in the literature (Cassity, R. P.; Taylor, L. T.;
Wolfe, J. F. J. Org. Chem. 1978, 2286).
[0305] In a further embodiment of the present invention, a compound
of formula (I) wherein Y is N; R.sup.2 is selected from the group
consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het,
--OR.sup.7, --OAy, --OHet --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet
--S(O).sub.nR.sup.9, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8 and
--R.sup.10NR.sup.7Ay; R.sup.3 is selected from the group consisting
of H, alkyl, alkenyl, cycloalkyl, Ay, Het, --C(O)R.sup.7, C(O)Ay,
--CO.sub.2R.sup.7, --CO.sub.2Ay, --OR.sup.7, --OAy,
--NR.sup.7R.sup.8 (where R.sup.7 and R.sup.8 are not H),
--NR.sup.7Ay (where R.sup.7 is H), --SO.sub.2NHR.sup.9,
--R.sup.10OR.sup.7, --R.sup.10cycloalkyl, --R.sup.10OAy,
--R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay; and R.sup.4 is
H, may be conveniently prepared by the process outlined in Scheme 4
below. ##STR39## wherein: [0306] R.sup.1 is selected from the group
consisting of H, halo, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, Ay, Het, --C(O)R.sup.9, --C(O)Ay, --C(O)Het,
--CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8, --C(O)NR.sup.7Ay,
--C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8, --C(NH)NR.sup.7Ay,
--OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8, --NR.sup.7Ay,
--NHHet, --S(O).sub.nR.sup.9, --S(O).sub.nAy, --S(O).sub.nHet,
--S(O).sub.2NR.sup.7R.sup.8, --S(O).sub.2NR.sup.7Ay,
--R.sup.10cycloalkyl, --R.sup.10Ay, --R.sup.10Het,
--R.sup.10OR.sup.9, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10C(O)R.sup.9, --R.sup.10C(O)Ay, --R.sup.10C(O)Het,
--R.sup.10CO.sub.2R.sup.9, --R.sup.10OC(O)R.sup.9,
--R.sup.10OC(O)Ay, --R.sup.10OC(O)Het,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2NHCOR.sup.9,
--R.sup.10OS(O).sub.nR.sup.9, cyano, nitro and azido; [0307] each
R.sup.7 and R.sup.8 are the same or different and are independently
selected from the group consisting of H, alkyl, cycloalkyl,
alkenyl, cycloalkenyl, --C(O)R.sup.9, --CO.sub.2R.sup.9,
--C(O)NR.sup.9R.sup.11, --C(S)NR.sup.9R.sup.11,
--C(NH)NR.sup.9R.sup.11, --SO.sub.2R.sup.10,
--SO.sub.2NR.sup.9R.sup.11, --R.sup.10cycloalkyl, --R.sup.10Ay,
--R.sup.10Het, --R.sup.10C(O)R.sup.9, --R.sup.10CO.sub.2R.sup.9,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10OR.sup.9, --R.sup.10NR.sup.9R.sup.11,
--R.sup.10NHCOR.sup.9, --R.sup.10NHC(NH)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.10 and
--R.sup.10SO.sub.2NHCOR.sup.9; [0308] each R.sup.9 and R.sup.11 are
the same or different and are independently selected from the group
consisting of H, alkyl, cycloalkyl, --R.sup.10cycloalkyl,
--R.sup.10OH, --R.sup.10(OR.sup.10).sub.w where w is 1-10, and
--R.sup.10NR.sup.10R.sup.10; [0309] each R.sup.10 is the same or
different and is independently selected from the group consisting
of alkyl, cycloalkyl, alkenyl, cycloalkenyl, and alkynyl; [0310] n
is 0, 1 or 2; [0311] Ay is aryl; [0312] Het is a 5- or 6-membered
heterocyclic or heteroaryl group; [0313] Y.sup.1 is N or CH; [0314]
p is 0, 1 or 2 when Y.sup.1 is CH, [0315] p is 0 or 1 when Y.sup.1
is N; [0316] each R.sup.6 is the same or different and is
independently selected from the group consisting of H, halo, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, --C(O)R.sup.9,
--C(O)Ay, --C(O)Het, --CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8,
--C(O)NR.sup.7Ay, --C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8,
--C(NH)NR.sup.7Ay, --OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8,
--NR.sup.7Ay, --NHHet, --S(O).sub.nR.sup.9, --S(O).sub.nAy,
--S(O).sub.nHet, --S(O).sub.2NR.sup.7R.sup.8,
--S(O).sub.2NR.sup.7Ay, --R.sup.10cycloalkyl, --R.sup.10Ay,
--R.sup.10Het, --R.sup.10OR.sup.9, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10C(O)R.sup.9, --R.sup.10C(O)Ay, --R.sup.10C(O)Het,
--R.sup.10CO.sub.2R.sup.9, --R.sup.10OC(O)R.sup.9,
--R.sup.10OC(O)Ay, --R.sup.10OC(O)Het,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2NHCOR.sup.9,
--R.sup.10OS(O).sub.nR.sup.9, cyano, nitro and azido; [0317] or
when p is 2, two adjacent R.sup.6 groups together with the carbon
atoms to which they are bonded form a cycloalkyl or a 5- or
6-membered heterocyclic group containing 1 or 2 heteroatoms; [0318]
Y is N; [0319] R.sup.2 is selected from the group consisting of
alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, --OR.sup.7,
--OAy, --OHet --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet
--S(O).sub.nR.sup.9, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8 and
--R.sup.10NR.sup.7Ay; [0320] R.sup.3 is selected from the group
consisting of H, alkyl, alkenyl, cycloalkyl, Ay, Het,
--C(O)R.sup.7, C(O)Ay, --CO.sub.2R.sup.7, --CO.sub.2Ay, --OR.sup.7,
--OAy, --NR.sup.7R.sup.8 (where R.sup.7 and R.sup.8 are not H),
--NR.sup.7Ay (where R.sup.7 is H), --SO.sub.2NHR.sup.9,
--R.sup.10OR.sup.7, --R.sup.10cycloalkyl, --R.sup.10OAy,
--R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay; [0321] R.sup.4
is H; [0322] Ring A is selected from the group consisting of aryl,
5-10 membered heterocyclic group and a 5-10 membered heteroaryl
group; [0323] q is 0, 1, 2, 3, 4 or 5; [0324] each R.sup.5 is the
same or different and is independently selected from the group
consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, Ay, Het, --C(O)R.sup.9, --C(O)Ay, --C(O)Het,
--CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8, --C(O)NR.sup.7Ay,
--C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8, --C(NH)NR.sup.7Ay,
--OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8, --NR.sup.7Ay,
--NHHet, --S(O).sub.nR.sup.9, --S(O).sub.2NR.sup.7R.sup.8,
--S(O).sub.2NR.sup.7Ay, --R.sup.10cycloalkyl, --R.sup.10Het,
--R.sup.10C(O)R.sup.9, --R.sup.10CO.sub.2R.sup.9,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10OR.sup.9,
--R.sup.10NR.sup.7R.sup.8, --R.sup.10NR.sup.7Ay,
--R.sup.10SO.sub.2R.sup.9, --R.sup.10SO.sub.2NR.sup.9R.sup.11,
--R.sup.10SO.sub.2NHCOR.sup.9, cyano, nitro and azido; and [0325]
M.sup.2 is Li, Mg-halide or cerium-halide.
[0326] Generally, the process for preparing a compound of formula
(I) wherein Y is N; R.sup.2 is selected from the group consisting
of alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, --OR.sup.7,
--OAy, --OHet --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet
--S(O).sub.nR.sup.9, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8 and
--R.sup.10NR.sup.7Ay; R.sup.3 is selected from the group consisting
of H, alkyl, alkenyl, cycloalkyl, Ay, Het, --C(O)R.sup.7, C(O)Ay,
--CO.sub.2R.sup.7, --CO.sub.2Ay, --OR.sup.7, --OAy,
--NR.sup.7R.sup.8 (where R.sup.7 and R.sup.8 are not H),
--NR.sup.7Ay (where R.sup.7 is H), --SO.sub.2NHR.sup.9,
--R.sup.10OR.sup.7, --R.sup.10cycloalkyl, --R.sup.10OAy,
--R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay; and R.sup.4 is
H, comprises the following steps:
[0327] (a) formylating a compound of formula (XVIII-A) to prepare a
compound of formula (XXII);
[0328] (b) reacting the compound of formula (XXII) with a compound
of formula (XXIII) to prepare a compound of formula (XXIV);
[0329] (c) oxidizing the compound of formula (XXIV) to prepare a
compound of formula (XXV); and
[0330] (d) reacting the compound of formula (XXV) with a compound
of formula (XXI) to prepare the compound of formula (I).
[0331] More specifically, a compound of formula (I) wherein Y is N;
R.sup.2 is selected from the group consisting of alkyl, cycloalkyl,
alkenyl, cycloalkenyl, Ay, Het, --OR.sup.7, --OAy, --OHet
--NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet --S(O).sub.nR.sup.9,
--S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay;
R.sup.3 is selected from the group consisting of H, alkyl, alkenyl,
cycloalkyl, Ay, Het, --C(O)R.sup.7, C(O)Ay, --CO.sub.2R.sup.7,
--CO.sub.2Ay, --OR.sup.7, --OAy, --NR.sup.7R.sup.8 (where R.sup.7
and R.sup.8 are not H), --NR.sup.7Ay (where R.sup.7 is H),
--SO.sub.2NHR.sup.9, --R.sup.10OR.sup.7, --R.sup.10cycloalkyl,
--R.sup.10OAy, --R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay;
and R.sup.4 is H, may be prepared by reacting a compound of formula
(XXV) with a compound of formula (XXI). ##STR40## [0332] wherein
all variables are as defined above in connection with Scheme 4.
[0333] This method can be readily carried out by mixing a compound
of formula (XXV) with a compound of formula (XXI) in a suitable
solvent, optionally in the presence of a base. The reaction may be
heated to 50-150.degree. C. or performed at ambient temperature.
Typical solvents include but are not limited to lower alcohols such
as methanol, ethanol, isopropanol and the like. Typical bases
include for example, sodium alkoxide, potassium carbonate, or an
amine base such as triethylamine. In another embodiment, the
solvent is N,N-dimethylformamide and the base is potassium
carbonate, or an amine base such as triethylamine.
[0334] A compound of formula (XXV) may be conveniently prepared by
oxidation of a compound of formula (XXIV). ##STR41## [0335] wherein
all variables are as defined above in connection with Scheme 4.
[0336] Typical oxidizing agents include but are not limited to,
manganese dioxide, and the like, in an inert solvent. Suitable
inert solvents include but are not limited to, dichloromethane,
chloroform, N,N-dimethylformamide, ether, and the like.
[0337] A compound of formula (XXIV) may be conveniently prepared by
reacting a compound of formula (XXII) with a compound of formula
(XXIII). ##STR42## [0338] wherein all variables are as defined
above in connection with Scheme 4.
[0339] Suitable metals (M.sup.2) in the compounds of formula
(XXIII) include but are not limited to, lithium, magnesium(II)
halides, cerium(III) halides, and the like. A compound of formula
(XXIII) may be purchased from commercial sources or prepared by
methods known to one skilled in the art. [0340] A compound of
formula (XXII) may be conveniently prepared from a compound of
formula (XVIII-A) by a formylation procedure. ##STR43## [0341]
wherein all variables are as defined above in connection with
Scheme 4.
[0342] Typically the formylation is carried out via the
Vilsmeier-Haack reaction. The Vilsmeier-Haack reagents can be
purchased from commercial sources or prepared in situ. Typical
conditions include, but are not limited to treating a compound of
formula (XVIII) with a premixed solution of phosphorus oxychloride
in N,N-dimethylformamide optionally with heating the reaction to
about 50-150.degree. C. The compounds of formula (XVIII-A) may be
prepared according to the process described in previous
Schemes.
[0343] A compound of formula (I) wherein Y is N; and R.sup.2 is
selected from the group consisting of alkyl, cycloalkyl, alkenyl,
cycloalkenyl, Ay, Het, --OR.sup.7, --OAy, --OHet --NR.sup.7R.sup.8,
--NR.sup.7Ay, --NHHet --S(O).sub.nR.sup.9, --S(O).sub.nAy,
--R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay, may be
conveniently prepared by the process outlined in Scheme 5 below.
##STR44## wherein: [0344] R.sup.1 is selected from the group
consisting of H, halo, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, Ay, Het, --C(O)R.sup.9, --C(O)Ay, --C(O)Het,
--CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8, --C(O)NR.sup.7Ay,
--C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8, --C(NH)NR.sup.7Ay,
--OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8, --NR.sup.7Ay,
--NHHet, --S(O).sub.nR.sup.9, --S(O).sub.nAy, --S(O).sub.nHet,
--S(O).sub.2NR.sup.7R.sup.8, --S(O).sub.2NR.sup.7Ay,
--R.sup.10cycloalkyl, --R.sup.10Ay, --R.sup.10Het,
--R.sup.10OR.sup.9, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10C(O)R.sup.9, --R.sup.10C(O)Ay, --R.sup.10C(O)Het,
--R.sup.10CO.sub.2R.sup.9, --R.sup.10OC(O)R.sup.9,
--R.sup.10OC(O)Ay, --R.sup.10OC(O)Het,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2NHCOR.sup.9,
--R.sup.10OS(O).sub.nR.sup.9, cyano, nitro and azido; [0345] each
R.sup.7 and R.sup.8 are the same or different and are independently
selected from the group consisting of H, alkyl, cycloalkyl,
alkenyl, cycloalkenyl, --C(O)R.sup.9, --CO.sub.2R.sup.9,
--C(O)NR.sup.9R.sup.11, --C(S)NR.sup.9R.sup.11,
--C(NH)NR.sup.9R.sup.11, --SO.sub.2R.sup.10,
--SO.sub.2NR.sup.9R.sup.11, --R.sup.10cycloalkyl, --R.sup.10Ay,
--R.sup.10Het, --R.sup.10C(O)R.sup.9, --R.sup.10CO.sub.2R.sup.9,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10OR.sup.9, --R.sup.10NR.sup.9R.sup.11,
--R.sup.10NHCOR.sup.9, --R.sup.10NHC(NH)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.10 and
--R.sup.10SO.sub.2NHCOR.sup.9; [0346] each R.sup.9 and R.sup.11 are
the same or different and are independently selected from the group
consisting of H, alkyl, cycloalkyl, --R.sup.10cycloalkyl,
--R.sup.10OH, --R.sup.10(OR.sup.10).sub.w where w is 1-10, and
--R.sup.10NR.sup.10R.sup.10; [0347] each R.sup.10 is the same or
different and is independently selected from the group consisting
of alkyl, cycloalkyl, alkenyl, cycloalkenyl, and alkynyl; [0348] n
is 0, 1 or 2; [0349] Ay is aryl; [0350] Het is a 5- or 6-membered
heterocyclic or heteroaryl group; [0351] Y.sup.1 is N or CH; [0352]
p is 0, 1 or 2 when Y.sup.1 is CH, [0353] p is 0 or 1 when Y.sup.1
is N; [0354] each R.sup.6 is the same or different and is
independently selected from the group consisting of H, halo, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, --C(O)R.sup.9,
--C(O)Ay, --C(O)Het, --CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8,
--C(O)NR.sup.7Ay, --C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8,
--C(NH)NR.sup.7Ay, --OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8,
--NR.sup.7Ay, --NHHet, --S(O).sub.nR.sup.9, --S(O).sub.nAy,
--S(O).sub.nHet, --S(O).sub.2NR.sup.7R.sup.8,
--S(O).sub.2NR.sup.7Ay, --R.sup.10cycloalkyl, --R.sup.10Ay,
--R.sup.10Het, --R.sup.10OR.sup.9, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10C(O)R.sup.9, --R.sup.10C(O)Ay, --R.sup.10C(O)Het,
--R.sup.10CO.sub.2R.sup.9, --R.sup.10OC(O)R.sup.9,
--R.sup.10OC(O)Ay, --R.sup.10OC(O)Het,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2NHCOR.sup.9,
--R.sup.10OS(O).sub.nR.sup.9, cyano, nitro and azido; [0355] or
when p is 2, two adjacent R.sup.6 groups together with the carbon
atoms to which they are bonded form a cycloalkyl or a 5- or
6-membered heterocyclic group containing 1 or 2 heteroatoms; [0356]
Y is N; [0357] R.sup.2 is selected from the group consisting of
alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, --OR.sup.7,
--OAy, --OHet --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet
--S(O).sub.nR.sup.9, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8 and
--R.sup.10NR.sup.7Ay; [0358] R.sup.3 and R.sup.4 are the same or
different and are each independently selected from the group
consisting of H, halo, alkyl, alkenyl, cycloalkyl, Ay, Het,
--C(O)R.sup.7, C(O)Ay, --CO.sub.2R.sup.7, --CO.sub.2Ay, --OR.sup.7,
--OAy, --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet,
--SO.sub.2NHR.sup.9, --R.sup.10OR.sup.7, --R.sup.10cycloalkyl,
--R.sup.10OAy, --R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay;
[0359] Ring A is selected from the group consisting of aryl, 5-10
membered heterocyclic group and a 5-10 membered heteroaryl group;
[0360] q is 0, 1, 2, 3, 4 or 5; [0361] each R.sup.5 is the same or
different and is independently selected from the group consisting
of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay,
Het, --C(O)R.sup.9, --C(O)Ay, --C(O)Het, --CO.sub.2R.sup.9,
--C(O)NR.sup.7R.sup.8, --C(O)NR.sup.7Ay, --C(S)NR.sup.9R.sup.11,
--C(NH)NR.sup.7R.sup.8, --C(NH)NR.sup.7Ay, --OR.sup.7, --OAy,
--OHet, --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet,
--S(O).sub.nR.sup.9, --S(O).sub.2NR.sup.7R.sup.8,
--S(O).sub.2NR.sup.7Ay, --R.sup.10cycloalkyl, --R.sup.10Het,
--R.sup.10C(O)R.sup.9, --R.sup.10CO.sub.2R.sup.9,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10OR.sup.9,
--R.sup.10NR.sup.7R.sup.8, --R.sup.10NR.sup.7Ay,
--R.sup.10SO.sub.2R.sup.9, --R.sup.10SO.sub.2NR.sup.9R.sup.11,
--R.sup.10SO.sub.2NHCOR.sup.9, cyano, nitro and azido; and [0362]
M.sup.2 is Li, Mg-halide or cerium-halide, wherein halide is
halo.
[0363] Generally, the process for preparing a compound of formula
(I) wherein Y is N and R.sup.2 is selected from the group
consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het,
--OR.sup.7, --OAy, --OHet --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet
--S(O).sub.nR.sup.9, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8 and
--R.sup.10NR.sup.7Ay, comprises the following steps:
[0364] (a) reacting a compound of formula (XXII) with a compound of
formula (XXVI) to prepare a compound of formula (XXII);
[0365] (b) oxidizing the compound of formula (XXVII) to prepare a
compound of formula (XXVIII); and
[0366] c) reacting a compound of formula (XXVIII) with a compound
of formula (XXI) followed by oxidative aromatization to prepare a
compound of formula (I).
[0367] More specifically, a compound of formula (I) wherein Y is N
and R.sup.2 is selected from the group consisting of alkyl,
cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, --OR.sup.7, --OAy,
--OHet --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet
--S(O).sub.nR.sup.9, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8 and
--R.sup.10NR.sup.7Ay, can be prepared by reacting a compound of
formula (XXVIII) with a compound of formula (XXI) followed by
oxidative aromatization. ##STR45## [0368] wherein all variables are
as defined above in connection with Scheme 5.
[0369] The condensation is conveniently carried out by treating the
compound of formula (XXVIII) with a compound of formula (XXI) in an
inert solvent, optionally in the presence of a base. The reaction
may be heated to about 50-150.degree. C. or performed at ambient
temperature. Suitable inert solvents include lower alcohols such
as, for example, methanol, ethanol, isopropanol and the like. The
base is typically a sodium alkoxide, potassium carbonate, or an
amine base such as triethylamine. In another embodiment, the
solvent is N,N-dimethylformamide and the base is potassium
carbonate, or an amine base such as triethylamine. The reaction
produces a dihydropyrimidine intermediate.
[0370] Conveniently in the same reaction vessel, the
dihydropyrimidine intermediate may be oxidized to a compound of
formula (I) by the addition of an oxidizing agent. The reaction may
be heated to 50-150.degree. C. or performed at ambient temperature.
Typically, the oxidizing agent is oxygen (O.sub.2), palladium on
carbon, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, or the like.
[0371] A compound of formula (XXVIII) may be conveniently prepared
by oxidation of a compound of formula (XXVII). ##STR46## [0372]
wherein all variables are as defined above in connection with
Scheme 5.
[0373] Typical oxidizing agents for the oxidation of a compound of
formula (XXVII) include but are not limited to manganese dioxide,
and the like. The oxidation is typically carried out in an inert
solvent such as for example, dichloromethane, chloroform,
N,N-dimethylformamide, ether, and the like. [0374] A compound of
formula (XXVII) may be conveniently prepared by reacting a compound
of formula (XXII) with a compound of formula (XXVI). ##STR47##
[0375] wherein all variables are as defined above in connection
with Scheme 5.
[0376] A compound of formula (XXVI) may be purchased from
commercial sources or prepared by methods known to one skilled in
the art. A compound of formula (XXII) may be prepared using the
methods described in connection with Schemes 3 and 4 above.
[0377] In a further embodiment of the invention, a compound of
formula (I), may be conveniently prepared by the process outlined
in Scheme 6 below. ##STR48## wherein: [0378] R.sup.1 is selected
from the group consisting of H, halo, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, Ay, Het, --C(O)R.sup.9, --C(O)Ay,
--C(O)Het, --CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8,
--C(O)NR.sup.7Ay, --C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8,
--C(NH)NR.sup.7Ay, --OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8,
--NR.sup.7Ay, --NHHet, --S(O).sub.nR.sup.9, --S(O).sub.nAy,
--S(O).sub.nHet, --S(O).sub.2NR.sup.7R.sup.8,
--S(O).sub.2NR.sup.7Ay, --R.sup.10cycloalkyl, --R.sup.10Ay,
--R.sup.10Het, --R.sup.10OR.sup.9, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10C(O)R.sup.9, --R.sup.10C(O)Ay, --R.sup.10C(O)Het,
--R.sup.10CO.sub.2R.sup.9, --R.sup.10OC(O)R.sup.9,
--R.sup.10OC(O)Ay, --R.sup.10OC(O)Het,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2NHCOR.sup.9,
--R.sup.10OS(O).sub.nR.sup.9, cyano, nitro and azido; [0379] each
R.sup.7 and R.sup.8 are the same or different and are independently
selected from the group consisting of H, alkyl, cycloalkyl,
alkenyl, cycloalkenyl, --C(O)R.sup.9, --CO.sub.2R.sup.9,
--C(O)NR.sup.9R.sup.11, --C(S)NR.sup.9R.sup.11,
--C(NH)NR.sup.9R.sup.11, --SO.sub.2R.sup.10,
--SO.sub.2NR.sup.9R.sup.11, --R.sup.10cycloalkyl, --R.sup.10Ay,
--R.sup.10Het, --R.sup.10C(O)R.sup.9, --R.sup.10CO.sub.2R.sup.9,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10OR.sup.9, --R.sup.10NR.sup.9R.sup.11,
--R.sup.10NHCOR.sup.9, --R.sup.10NHC(NH)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.10 and
--R.sup.10SO.sub.2NHCOR.sup.9; [0380] each R.sup.9 and R.sup.11 are
the same or different and are independently selected from the group
consisting of H, alkyl, cycloalkyl, --R.sup.10cycloalkyl,
--R.sup.10OH, --R.sup.10(OR.sup.10).sub.w where w is 1-10, and
--R.sup.10NR.sup.10R.sup.10; [0381] each R.sup.10 is the same or
different and is independently selected from the group consisting
of alkyl, cycloalkyl, alkenyl, cycloalkenyl, and alkynyl; [0382] n
is 0, 1 or 2; [0383] Ay is aryl; [0384] Het is a 5- or 6-membered
heterocyclic or heteroaryl group; [0385] Y.sup.1 is N or CH; [0386]
p is 0, 1 or 2 when Y.sup.1 is CH, [0387] p is 0 or 1 when Y.sup.1
is N; [0388] each R.sup.6 is the same or different and is
independently selected from the group consisting of H, halo, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, --C(O)R.sup.9,
--C(O)Ay, --C(O)Het, --CO.sub.2R.sup.9, --C(O)NR.sup.7R.sup.8,
--C(O)NR.sup.7Ay, --C(S)NR.sup.9R.sup.11, --C(NH)NR.sup.7R.sup.8,
--C(NH)NR.sup.7Ay, --OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8,
--NR.sup.7Ay, --NHHet, --S(O).sub.nR.sup.9, --S(O).sub.nAy,
--S(O).sub.nHet, --S(O).sub.2NR.sup.7R.sup.8,
--S(O).sub.2NR.sup.7Ay, --R.sup.10cycloalkyl, --R.sup.10Ay,
--R.sup.10Het, --R.sup.10OR.sup.9, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, --R.sup.10NHSO.sub.2R.sup.9,
--R.sup.10C(O)R.sup.9, --R.sup.10C(O)Ay, --R.sup.10C(O)Het,
--R.sup.10CO.sub.2R.sup.9, --R.sup.10OC(O)R.sup.9,
--R.sup.10OC(O)Ay, --R.sup.10OC(O)Het,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10SO.sub.2R.sup.9,
--R.sup.10SO.sub.2NR.sup.9R.sup.11, --R.sup.10SO.sub.2NHCOR.sup.9,
--R.sup.10OS(O).sub.nR.sup.9, cyano, nitro and azido; [0389] or
when p is 2, two adjacent R.sup.6 groups together with the carbon
atoms to which they are bonded form a cycloalkyl or a 5- or
6-membered heterocyclic group containing 1 or 2 heteroatoms; [0390]
Y is N or CH; [0391] R.sup.2 is selected from the group consisting
of halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het,
--OR.sup.7, --OAy, --OHet --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet
--S(O).sub.nR.sup.9, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8 and
--R.sup.10NR.sup.7Ay; [0392] R.sup.3 and R.sup.4 are the same or
different and are each independently selected from the group
consisting of H, halo, alkyl, alkenyl, cycloalkyl, Ay, Het,
--C(O)R.sup.7, C(O)Ay, --CO.sub.2R.sup.7, --CO.sub.2Ay, --OR.sup.7,
--OAy, --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet,
--SO.sub.2NHR.sup.9, --R.sup.10OR.sup.7, --R.sup.10cycloalkyl,
--R.sup.10OAy, --R.sup.10NR.sup.7R.sup.8 and --R.sup.10NR.sup.7Ay;
[0393] Ring A is selected from the group consisting of aryl, 5-10
membered heterocyclic group and a 5-10 membered heteroaryl group;
[0394] q is 0, 1, 2, 3, 4 or 5; [0395] each R.sup.5 is the same or
different and is independently selected from the group consisting
of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay,
Het, --C(O)R.sup.9, --C(O)Ay, --C(O)Het, --CO.sub.2R.sup.9,
--C(O)NR.sup.7R.sup.8, --C(O)NR.sup.7Ay, --C(S)NR.sup.9R.sup.11,
--C(NH)NR.sup.7R.sup.8, --C(NH)NR.sup.7Ay, --OR.sup.7, --OAy,
--OHet, --NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet,
--S(O).sub.nR.sup.9, --S(O).sub.2NR.sup.7R.sup.8,
--S(O).sub.2NR.sup.7Ay, --R.sup.10cycloalkyl, --R.sup.10Het,
--R.sup.10C(O)R.sup.9, --R.sup.10CO.sub.2R.sup.9,
--R.sup.10C(O)NR.sup.9R.sup.11, --R.sup.10C(O)NR.sup.7Ay,
--R.sup.10C(O)NHR.sup.10Het, --R.sup.10C(S)NR.sup.9R.sup.11,
--R.sup.10C(NH)NR.sup.9R.sup.11, --R.sup.10OR.sup.9,
--R.sup.10NR.sup.7R.sup.8, --R.sup.10NR.sup.7Ay,
--R.sup.10SO.sub.2R.sup.9, --R.sup.10SO.sub.2NR.sup.9R.sup.11,
--R.sup.10SO.sub.2NHCOR.sup.9, cyano, nitro and azido; and [0396]
X.sup.1 is chloro, bromo, or iodo; and [0397] M.sup.1 is
--B(OH).sub.2, --B(ORa).sub.2, --B(Ra).sub.2, --Sn(Ra).sub.3,
Zn-halide, ZnRa, or Mg-halide where Ra is alkyl or cycloalkyl and
halide is halo.
[0398] Generally, the process for preparing a compound of formula
(I) (all formulas and variables having been defined above in
connection with Scheme 6), comprises the following steps:
[0399] a) halogenating a compound of formula (XXIX) to prepare a
compound of formula (XXX); and
[0400] b) reacting the compound of formula (XXX) with a compound of
formula (X) to prepare a compound of formula (I).
[0401] More specifically, this sequence of reactions may be carried
out in an analogous manner as described above in connection with
Scheme 2. It should be noted that a compound of formula (XXX) is in
fact the same as a compound of formula (XII) described in Scheme 2
when Y.sup.1 is N and R.sup.6 is H. It should also be noted that a
compound of formula (XXIX) is in fact the same as a compound of
formula (XI) when Y.sup.1 is N and p is 0, and the same as a
compound of formula (XVIII) when Y.sup.1 is defined as CH. A
compound of the formula (XXIX) can be prepared using the methods
described above in connection with Schemes 1-4 using techniques
known to those in the art.
[0402] In each of the foregoing synthetic processes, the steps are
described in a specific order. However, one skilled in the art will
readily appreciate that various steps within each of the reaction
schemes may be conducted in a different order. Hence, the order in
which the steps of the process are performed is not critical to the
invention. The present invention contemplates and includes
analogous processes wherein the order of the steps differs from the
specific embodiment described herein.
[0403] As will be apparent to those skilled in the art, a compound
of formula (I) may be converted to another compound of formula (I)
using techniques well known in the art, i.e., a particular compound
of formula (I) may be used as an intermediate in processes for
preparing other compounds of formula (I). For example, one method
of converting a compound of formula (I) to another compound of
formula (I) comprises the steps of: a) oxidizing a compound of
formula (I-A) to prepare a compound of formula (I-B); and b)
optionally reacting a compound of formula (I-B) with an oxygen or
amine nucleophile of formula R.sup.2, wherein R.sup.2 is selected
from the group consisting of --NR.sup.7R.sup.8, --OR.sup.7, Het
attached through N, --NHHet, NHR.sup.10Het, OHet and --OR.sup.10Het
to prepare a compound of formula (I) wherein R.sup.2 is selected
from the group consisting of Het attached through N, --OR.sup.7,
--OHet, --NR.sup.7R.sup.8 and --NHHet. ##STR49##
[0404] wherein n' is 1 or 2;
[0405] R.sup.2 is selected from the group consisting of Het
attached through N, --OR.sup.7, --OHet, --NR.sup.7R.sup.8 and
--NHHet, all other variables are as defined according to any
process described above.
[0406] More specifically, a compound of formula (I) wherein R.sup.2
is selected from the group consisting of Het attached through N,
--OR.sup.7, --OHet, --NR.sup.7R.sup.8 and --NHHet; can be prepared
by reacting a compound of formula (I-B) (i.e., a compound of
formula (I) wherein R.sup.2 is S(O).sub.nR.sup.9 where n' is 1 or
2, with an oxygen or amine nucleophile of formula R.sup.2, wherein
R.sup.2 is selected from the group consisting of Het attached
through N, --OR.sup.7, --OHet, --NR.sup.7R.sup.8 and --NHHet. The
reaction may be carried out neat or in a suitable solvent and may
be heated to about 50-150.degree. C. Typically the solvent is a
lower alcohol such as methanol, ethanol, isopropanol and the like
or solvent such as N,N-dimethylformamide or tetrahydrofuran, and
the like. Optionally a base may be used to facilitate the reaction.
Typically the base can be potassium carbonate, or an amine base
such as triethylamine.
[0407] A compound of formula (I-B) may be conveniently prepared by
reacting a compound of formula (I-A) (i.e., a compound of formula
(I) wherein R.sup.2 is --S(O).sub.nR.sup.9 where n is 0) with an
oxidizing agent in an inert solvent, optionally in the presence of
a base. Typically the oxidizing agent is a peracid such as
3-chloroperbenzoic acid or the like optionally with a base such as
sodium bicarbonate. Careful monitoring of the stoichiometry between
the oxidizing agent and the substrate allows the product
distribution between sulfoxide (n=1), and sulfone (n=2) to be
controlled. Suitable solvents include but are not limited to,
dichloromethane, chloroform and the like. If the compound of
formula (I-A) contains oxidizeable nitrogens, it may be preferred
to perform the oxidation under acidic conditions. Acetic acid, or
other suitable acids known to those skilled in the art can be added
to make the solution acidic.
[0408] Compounds of formula (I-A) are prepared by methods described
above in Schemes 1 through 6 wherein R.sup.2.dbd.SR.sup.9.
[0409] In an analogus procedure, a compound of formula (I) wherein
at least one R.sup.6 is --SR.sup.9, may be converted to another
compound of formula (I) wherein at least one R.sup.6 is selected
from the group consisting Het attached through N, --OR.sup.7,
--OHet --NR.sup.7R.sup.8 and --NHHet. The process comprises the
steps of: a) oxidizing a compound of formula (I-AA) to prepare a
compound of formula (I-BB); and b) optionally reacting a compound
of formula (I-BB) with an oxygen or amine nucleophile of formula
R.sup.6, wherein R.sup.6 is selected from the group consisting of
Het attached through N, --OR.sup.7, --OHet --NR.sup.7R.sup.8 and
--NHHet to prepare a compound of formula I wherein at least one
R.sup.6 is selected from the group consisting Het attached through
N, --OR.sup.7, --OHet --NR.sup.7R.sup.8 and --NHHet. ##STR50##
[0410] wherein p' is 0 when Y.sup.1 is N or p' is 0 or 1 when
Y.sup.1 is CH;
[0411] at least one R.sup.6 is selected from the group consisting
of Het attached through N, --OR.sup.7, --OHet --NR.sup.7R.sup.8 and
--NHHet; and
[0412] all other variables are as defined according to any process
described above.
[0413] Compounds of formula (I-AA) are prepared by methods
described above in Schemes 1 through 6 wherein at least one
R.sup.6.dbd.SR.sup.9.
[0414] Another particularly useful method for converting a compound
of formula (I) to another compound of formula (I) comprises
reacting a compound of formula (I-C) (i.e., a compound of formula
(I) wherein R.sup.2 is fluoro) with an amine, and optionally
heating the mixture to about 50-150.degree. C. to prepare a
compound of formula (I-D) (i.e., a compound of formula (I) wherein
R.sup.2 is Het bonded through N, --NR.sup.7R.sup.8, --NR.sup.7Ay
and --NHHet). ##STR51## [0415] wherein all other variables are as
defined in any process described above.
[0416] This procedure may be carried out by mixing a compound of
formula (I-C) in a neat amine (i.e., R.sup.2), or in a suitable
solvent with an excess of an amine to produce a compound of formula
(I-D). Typically the solvent is a lower alcohol such as methanol,
ethanol, isopropanol or the like. Other suitable solvents may
include N,N-dimethylformamide, 1-methyl-2-pyrrolidine or the
like.
[0417] As a further example, a compound of formula (I-E) may be
converted to a compound of formula (I-F) using either of two
methods. ##STR52## wherein M.sup.3 is B(OH).sub.2, B(ORa).sub.2,
B(Ra).sub.2, Sn(Ra).sub.3, Zn-halide; Zn--Ra or Mg-halide, Rg is Ay
or Het, and all other variables are as defined in any process
described above.
[0418] Thus, the present invention provides a process for
converting a compound of formula (I-E) to a compound of formula
(I-F) which comprises either: (1) replacing a halogen of the
compound of formula (I-E) with an amine; or (2) coupling the
compound of formula (I-E) with a metal compound of the formula
Rg-M.sup.3 where M.sup.3 is B(OH).sub.2, B(ORa).sub.2, B(Ra).sub.2,
Sn(Ra).sub.3, Zn-halide; Zn--Ra or Mg-halide.
[0419] As a further example, a compound of formula (I-G) (i.e., a
compound of formula (I) wherein q is 1 or more and at least one
R.sup.5 is O-methyl) may be converted to a compound of formula
(I-H) (i.e., a compound of formula (I) wherein q is 1 or more and
at least one R.sup.5 is OH) using conventional demethylation
techniques. Additionally, a compound of formula (I-H) may
optionally be converted to a compound of formula (I-J) (i.e., a
compound of formula (I) wherein q is 1 or more and at least one
R.sup.5 is OR.sup.10). For example, the foregoing conversions are
represented schematically as follows: ##STR53## wherein q' is 0, 1,
2, 3 or 4; Me is methyl and all other variables are defined
according to any process described above.
[0420] The demethylation reaction may be carried out by treating a
compound of formula (I-G) in a suitable solvent with a Lewis acid
at a temperature of about -78.degree. C. to room temperature, to
produce a compound of formula (I-H). Typically the solvent is an
inert solvent such as dichloromethane, chloroform, acetonitrile,
toluene or the like. The Lewis acid may be boron tribromide,
trimethylsilyl iodide or the like.
[0421] Optionally, the compound of formula (I-H) may be further
converted to a compound of formula (I-J) by an alkylation reaction.
The alkylation reaction may be carried out by treating a compound
of formula (I-H) in suitable solvent with an alkyl halide of
formula R.sup.10-halo where R.sup.10 is as defined above, to form
another compound of formula (I-J). The reaction is typically
carried out in the presence of a base and with optionally heating
to about 50-200.degree. C. The reaction may be carried out in
solvents such as N,N-dimethylformamide, dimethylsulfoxide and the
like. Typically the base is potassium carbonate, cesium carbonate,
sodium hydride or the like. Additionally, as will be apparent to
those skilled in the art, the alkylation reaction can be carried
out under Mitsunobu conditions.
[0422] As a further example of methods for converting a compound of
formula (I) to another compound of formula (I), a compound of
formula (I-K) (i.e., a compound of formula (I) wherein q is 1 or
more and at least one R.sup.5 is halo) may be converted to a
compound of formula (I-L) (i.e., a compound of formula (I) wherein
q is 1 or more and at least one R.sup.5 is Ay, Het or a
nitrogen-linked substituent). For example, the conversion of a
compound of formula (I-K) to a compound of formula (I-L) is shown
schematically below. ##STR54## wherein: [0423] q' is 0, 1, 2, 3 or
4; [0424] R.sup.5' is selected from the group consisting of Ay,
Het, --NR.sup.7R.sup.8, --NR.sup.7Ay and --NHHet; [0425] M.sup.4 is
selected from the group consisting of --B(OH).sub.2,
--B(ORa).sub.2, --B(Ra).sub.2, and --Sn(Ra).sub.2 wherein Ra is
alkyl or cycloalkyl; and [0426] all other variables are as defined
according to any process described above.
[0427] The conversion of a compound of formula (I-K) to a compound
of formula (I-L) is carried out by heating a compound of formula
(I-K) with a compound of formula H--R.sup.5' or coupling the
compound of formula (I-K) with a compound of formula
R.sup.5'-M.sup.4, where M.sup.4 is --B(OH).sub.2, --B(ORa).sub.2,
--B(Ra).sub.2, --Sn(Ra).sub.2 wherein Ra is alkyl or cycloalkyl.
The reaction may be carried out in an inert solvent, in the
presence of a palladium (0) source. The reaction may optionally be
heated to about 50-150.degree. C. Preferably the reaction is
performed by reacting equimolar amounts of a compound of formula
(I-K) with a compound of formula R.sup.5'-M.sup.4. The reaction may
also be performed in the presence of an excess R.sup.5'-M.sup.4.
The palladium (0) catalyst is typically present in 1-25 mol %
compared to the compound of formula (I-K). Examples of suitable
palladium catalysts include but are not limited to,
tetrakis(triphenylphosphine)palladium (0),
dichlorobis(triphenyl-phosphine)palladium(II), and
bis(diphenylphosphinoferrocene)palladium (II) dichloride. Suitable
solvents include but are not limited to, N,N-dimethylformamide,
toluene, tetrahydrofuran, dioxane, and 1-methyl-2-pyrrolidinone.
When the compound of formula R.sup.5'-M.sup.4 is a boronic acid or
ester or a borinate the reaction is more conveniently carried out
by adding a base in a proportion equivalent to, or greater than,
that of the compound of formula R.sup.5'-M.sup.4. Compounds of
formula R.sup.5'-M.sup.4 may be obtained from commercial sources or
prepared either as discreet isolated compounds or generated in situ
using methods known to one skilled in the art. (Suzuki, A. J.
Organomet. Chem. 1999, 576, 147; Stille, J. Angew. Chem. Int. Ed.
Engl. 1986, 25, 508; Snieckus, V. J. Org. Chem. 1995, 60, 292.)
[0428] In yet another example, a compound of formula (I-K) (i.e., a
compound of formula (I) wherein q is 1 or more and at least one
R.sup.5 is halo) are converted to a compound of formula (I-N)
(i.e., a compound of formula (I) wherein q is 1 or more and at
least one R.sup.5 is NH.sub.2). Optionally, a compound of formula
(I-N) may then be converted to a compound of formula (I-O) (i.e., a
compound of formula (I) wherein q is 1 or more and at least one
R.sup.5 is --NR.sup.7R.sup.8 where R.sup.7 and R.sup.8 are not both
H). For example, the foregoing conversions are represented
schematically as follows: ##STR55## wherein q' is 0, 1, 2, 3 or 4,
and all other variables are defined according to any process
described above.
[0429] The process of converting a compound of formula (I-K) to a
compound of formula (I-N) is carried out by reacting a compound of
formula (I-K) with an imine in the presence of a palladium (0)
source, a base and a suitable ligand, followed by hydrolysis to
give a compound of formula (I-N). See J. Wolfe, et al., Tetrahedron
Letters 38:6367-6370 (1997). Typically the imine is
benzophenoneimine, the palladium (0) source is
tris(dibenzylideneacetone)dipalladium(0), the base is sodium
tert-butoxide and the ligand is
racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl. Suitable
solvents include N,N-dimethylformamide and the like.
[0430] Reaction of a compound of formula (I-N) with compound of
formula R.sup.7-halogen in a suitable solvent in the presence of
base, optionally with heating may be used to prepare a compound of
formula (I-O). Typically the base is triethylamine or pyridine and
the solvent is N,N-dimethylformamide and the like. Other
transformations well known to those skilled in the art for use with
anilines may be used to convert a compound of formula (I-N) to a
compound of formula (I-O). Additional compounds of formula (I-O)
can be obtained by reductive amination of a compound of formula
(I-N) with ketones or aldehydes. See, A. Abdel-Magid, et al., J.
Org. Chem. 61:3849-3862 (1996). Typically a compound of formula
(I-N) is treated with an aldehyde or a ketone in the presence of an
acid, such as acetic acid, and a reducing agent, such as sodium
triacetoxyborohydride and the like, in an inert solvent such as
dichloroethane and the like.
[0431] As previously described, another method for converting a
compound of formula (I-K) directly to a compound of formula (I-O)
involves heating a compound of formula (I-K) with a amine to
thermally displace the halogen.
[0432] In the embodiment where a compound of formula (I) is defined
where R.sup.1 is H, the compound of formula (I-P) may be converted
to a compound of formula (I-Q). For example, a compound of formula
(I-P) may be converted to a compound of formula (I-Q) by a
deprotonation/electrophile quench protocol. For example, reaction
of a compound of formula (I-P) with a base, such as n-butyllithium,
followed by reacting with an electrophilic agent gives a compound
of formula (I-Q). ##STR56## [0433] wherein E is selected from halo,
alkyl, --C(O)R.sup.9, --C(O)Ay, --C(O)Het, --CO.sub.2R.sup.9,
--C(O)NR.sup.7R.sup.8, --C(O)NR.sup.7Ay, --S(O).sub.nR.sup.9 and
--R.sup.10cycloalkyl, and all other variables are as defined in
connection with any processes described above.
[0434] Electrophiles which may be used in this process include, but
are not limited to: halogens (E=iodo, bromo, chloro), alkyl halides
(E=methyl, benzyl etc.); aldehydes (E=CH(OH)R.sup.10);
dimethylformamide (E=CHO); dialkyl disulfide (E=SMe, SEt,
S-isopropyl etc); carbon dioxide (E=CO.sub.2H); dimethylcarbamoyl
chloride (E=C(O)NMe.sub.2) and the like.
[0435] Typically a compound of formula (I-P) in an inert solvent
such as tetrahydrofuran at about -78.degree. C. is treated with a
nonnucleophilic base. This reaction is subsequently quenched by
addition of an electrophile. Suitable nonnucleophilic bases
include, but are not limited to, n-butyllithium, lithium
diisopropylamide, lithium tetramethylpiperidide and the like.
[0436] Further, a compound of formula (I) wherein R.sup.1 is H, may
be converted to another compound of formula (I), by a
deprotonation/electrophile quench/nucleophilic displacement
protocol. For example, reaction of a compound of formula (I-P) with
a base, such as n-butyllithium, followed by quenching with an
electrophilic halogenating agent gives a compound of formula (I-Q
where E is halogen) as outlined in the previous scheme. Treatment
of a compound of formula (I-Q, where E is halogen) with a
nucloephile (Z.sup.1) in a suitable solvent optionally with heating
and optionally in the presence of a base gives a compound of
formula (I-R). ##STR57## wherein Z.sup.1 is selected from the group
consisting of Het, --OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8,
--NR.sup.7Ay, --NHHet --S(O).sub.nR.sup.9 (where n is 0) and cyano
and all other variables are as defined according to any process
described above.
[0437] Solvents for use in this reaction include but are not
limited to tetrahydrofuran, diethylether, and
1-methyl-2-pyrrolidinone. The base may be sodium hydride,
sodium-tert-butoxide, potassium carbonate or the like.
[0438] As another example, one method of converting a compound of
formula (I) to another compound of formula (I) comprises a)
oxidizing the compound of formula (I-S), where R.sup.1 is
--SR.sup.15 and R.sup.15 is alkyl, cycloalkyl or Ay, to prepare a
compound of formula (I-T) and then b) optionally reacting a
compound of formula (I-T) with a nucleophile Z.sup.1 selected from
the group consisting of Het, --OR.sup.7, --OAy, --OHet,
--NR.sup.7R.sup.8, --NR.sup.7Ay, --NHHet --S(O).sub.nR.sup.9 (where
n is 0) and cyano, to prepare a compound of formula (I-U).
##STR58## wherein Z.sup.1 is selected from the group consisting of
Het, --OR.sup.7, --OAy, --OHet, --NR.sup.7R.sup.8, --NR.sup.7Ay,
--NHHet --S(O).sub.nR.sup.9 (where n is 0) and cyano; R.sup.15 is
alkyl, cycloalkyl or Ay; and all other variables are as defined
according to any processes described above.
[0439] An analogous method can be used for the conversion of a
compound of formula (I) wherein at least one R.sup.5 is --SR.sup.15
to a compound of formula (I) wherein at least one R.sup.5 is
Z.sup.1.
[0440] Based upon this disclosure and the examples contained herein
one skilled in the art can readily convert compounds of formula (I)
or a pharmaceutically acceptable salt, solvate or physiologically
functional derivative thereof into other compounds of formula (I),
or salts, solvates or physiologically functional derivatives
thereof.
[0441] The present invention also provides radiolabeled compounds
of formula (I) and biotinylated compounds of formula (I).
Radiolabeled compounds of formula (I) and biotinylated compounds of
formula (I) can be prepared using conventional techniques. For
example, radiolabeled compounds of formula (I) can be prepared by
reacting the compound of formula (I) with tritium gas in the
presence of an appropriate catalyst to produce radiolabeled
compounds of formula (I).
[0442] In one preferred embodiment, the compounds of formula (I)
are tritiated.
[0443] The radiolabeled compounds of formula (I) and the
biotinylated compounds of formula (I) are useful in assays for the
identification of compounds for the treatment or prophylaxis of
viral infections such as herpes viral infections. Accordingly, the
present invention provides an assay method for identifying
compounds which have activity for the treatment or prophylaxis of
viral infections such as herpes viral infections, which method
comprises the step of specifically binding the radiolabeled
compound of formula (I) or a biotinylated compound of formula (I)
to the target protein. More specifically, suitable assay methods
will include competition binding assays. The radiolabeled compounds
of formula (I) and biotinylated compounds of formula (I) can be
employed in assays according to the methods conventional in the
art.
[0444] The following examples are intended for illustration only
and are not intended to limit the scope of the invention in any
way. Reagents are commercially available or are prepared according
to procedures in the literature. Example numbers refer to those
compounds listed in the tables above. .sup.1H and .sup.13C NMR
spectra were obtained on Varian Unity Plus NMR spectrophotometers
at 300 or 400 MHz, and 75 or 100 MHz respectively. .sup.19F NMR
were recorded at 282 MHz. Mass spectra were obtained on Micromass
Platform, or ZMD mass spectrometers from Micromass Ltd. Altrincham,
UK, using either Atmospheric Chemical Ionization (APCI) or
Electrospray Ionization (ESI). Analytical thin layer chromatography
was used to verify the purity of some intermediates which could not
be isolated or which were too unstable for full characterization,
and to follow the progress of reactions. Unless otherwise stated,
this was done using silica gel (Merck Silica Gel 60 F254). Unless
otherwise stated, column chromatography for the purification of
some compounds, used Merck Silica gel 60 (230-400 mesh), and the
stated solvent system under pressure. All compounds were
characterized as their free-base form unless otherwise stated. On
occasion the corresponding hydrochloride salts were formed to
generate solids where noted.
EXAMPLE 1
N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyr-
azolo[1,5-c]pyrimidin-7-amine
[0445] ##STR59##
a) 4-Methyl-2-(methylsulfanyl)pyrimidine
[0446] 4-Methylpyrimidine-2-thiol (79.4 g, 488 mmol) was added to
1M aqueous sodium hydroxide (NaOH) (1.02 L, 1.02 mol). To the
stirring mixture was added iodomethane (76.2 g, 540 mmol) and the
reaction-stirred at room temperature overnight. The mixture was
extracted with dichloromethane (3.times.300 mL). The organic phase
was dried over magnesium sulfate and concentrated to yield 66.8 g
(98%) of 4-methyl-2-(methylsulfanyl)pyrimidine. .sup.1H NMR
(CDCl.sub.3): .delta. 8.39 (d, 1H), 6.84 (d, 1H), 2.59 (s, 3H),
2.48 (s, 3H); MS m/z 141 (M+1).
b)
1-(4-Fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone
[0447] To a 0.degree. C. solution of
4-methyl-2-(methylsulfanyl)pyrimidine (66.8 g, 477 mmol) and ethyl
4-fluorobenzoate (80.2 g, 477 mmol) in tetrahydrofuran (390 mL) was
added a solution of 1M lithium bis(trimethylsilyl)amide (954 mL,
954 mmol) in tetrahydrofuran (THF) dropwise via an addition funnel.
The reaction was stirred for 10 minutes and allowed to warm to room
temperature. The reaction was stirred at room temperature for 1.5
hours and then carefully quenched with water. The mixture was
extracted with ethyl acetate (3.times.300 mL) before the organic
phase was dried over magnesium sulfate, filtered and concentrated.
The residue was recrystallized from dichloromethane and hexanes to
yield 91.4 g (75%) of
1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone as
a mixture of tautomers. Tautomer A: .sup.1H NMR (CDCl.sub.3):
.delta. 8.50 (d, 1H), 8.12 (dd, 2H), 7.18 (m, 2H), 7.02 (d, 1H),
4.39 (s, 2H), 2.56 (s, 3H). MS m/z 263 (M+1). Tautomer B: .sup.1H
NMR (CDCl.sub.3): .delta. 8.35 (d, 1H), 7.87 (dd, 2H), 7.16 (m,
3H), 6.68 (d, 1H), 5.96 (s, 1H), 2.65 (s, 3H). MS m/z 263
(M+1).
c) 1-(4-Fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone
oxime
[0448] To a solution of
1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone
(91.4 g, 348 mmol) in acetonitrile (1.8 L) was added hydroxylamine
hydrochloride (121 g, 1.7 mol) and sodium acetate (139 g, 1.7 mol).
The reaction was stirred for 24 hours before 100 mL of water was
added. The reaction was stirred for 24 hours. The mixture was
filtered through a glass frit and the filtrate partitioned between
dichloromethane and water. The layers were separated and the
aqueous phase extracted with dichloromethane (2.times.500 mL). The
organic layers were combined, washed with saturated aqueous sodium
bicarbonate (300 mL), washed with brine (300 mL), dried over
magnesium sulfate, filtered and concentrated. The residue was
recrystallized from dichloromethane and hexanes to yield 66.4 g
(69%) of
1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone
oxime. .sup.1H NMR (CDCl.sub.3): .delta. 8.75 (m, 1H), 8.42 (d,
1H), 7.75 (dd, 2H), 7.09 (t, 2H), 6.98 (d, 1H), 4.29 (s, 2H), 2.54
(s, 3H). MS m/z 278 (M+1).
d)
2-(4-Fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidine
[0449] To a 0.degree. C. solution of
1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone
oxime (4.0 g, 14 mmol) in ethylene glycol dimethyl ether (40 mL)
was added trifluoroacetic anhydride (3.0 g, 14 mmol) dropwise. The
reaction was allowed to warm to 20.degree. C., then re-cooled to
0.degree. C. Triethylamine (2.9 g, 29 mmol) was added dropwise so
that the internal reaction temperature did not exceed 10.degree. C.
The reaction was allowed to warm to room temperature and was
stirred for 2 hours. Iron (II) chloride (18 mg, 0.14 mmol) was
added and the mixture heated to 80.degree. C. for 2 hours. An
additional portion of iron (II) chloride (18 mg, 0.14 mmol) was
added and the mixture heated at 80.degree. C. for 2 hours. An
additional portion of iron (II) chloride (18 mg, 0.14 mmol) was
added and the mixture heated at 80.degree. C. for 4 hours. The
reaction was allowed to cool to room temperature and stirred
overnight. The mixture was partitioned between ethyl acetate and
water. The aqueous phase was extracted with ethyl acetate
(2.times.20 mL) and the organic layers combined. The organic phase
was washed with brine, dried over magnesium sulfate, filtered and
concentrated. The residue was purified by silica chromatography
eluting with 1% acetone in dichloromethane to yield 2.54 g (68%) of
2-(4-fluorophenyl)-7-(methylsulfanyl)-pyrazolo[1,5-c]pyrimidine.
.sup.1H NMR (CDCl.sub.3): .delta. 8.04 (dd, 2H), 7.80 (d, 1H), 7.20
(m, 3H), 6.79 (s, 1H), 2.76 (s, 3H). MS m/z 260 (M+1).
e)
1-[2-(4-Fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]e-
thanone
[0450] To a solution of
2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidine (150
mg, 0.58 mmol) in toluene (10 mL) was added acetic anhydride (0.065
mL, 0.69 mmol), followed by boron trifluoride diethyl etherate
(0.080 mL, 0.64 mmol). An additional 10 mL of toluene was added and
the mixture heated to 90.degree. C. Acetonitrile (10 mL) was added
to the reaction and the mixture heated at 70.degree. C. for
additional 16 hours. Additional acetic anhydride (0.11 mL, 1.1
mmol) and boron trifluoride diethyl etherate (0.15 mL, 1.2 mmol)
were added dropwise to the reaction mixture at 90.degree. C. The
reaction was stirred for 1 hour, cooled to room temperature,
stirred for 16 hours, and partitioned between ethyl acetate and
saturated aqueous sodium bicarbonate. The ethyl acetate layer was
washed with brine, dried over magnesium sulfate, filtered,
concentrated, and the residue purified by silica gel chromatography
eluting with 10% ethyl acetate in hexanes to yield 110 mg (63%) of
1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]eth-
anone. .sup.1H NMR (CDCl.sub.3): .delta. 8.13 (d, 1H), 7.98 (d,
1H), 7.65 (dd, 2H), 7.27 (m, 2H), 2.77 (s, 3H), 2.23 (s, 3H). MS
m/z 302 (M+1).
ee)
1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]-
ethanone
[0451] To a slurry of
2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidine
(11.8 g, 45.5 mmol) in acetic anhydride (250 mL) was added 10 drops
of sulfuric acid (H.sub.2SO.sub.4). The mixture was heated at
reflux for 2 hours. Additional 20 drops of sulfuric acid were added
and the reaction heated at reflux for additional 2 hours. The
mixture was allowed to cool and was poured into water (300 mL). The
mixture was extracted with ethyl acetate (3.times.200 mL). The
organic phase was washed with saturated aqueous sodium bicarbonate
and brine, dried over magnesium sulfate, filtered and concentrated.
The residual was co-evaporated with toluene and then dissolved in
methylene chloride (CH.sub.2Cl.sub.2). The solution was diluted
with hexanes and the resulting precipitate collected by filtration.
The solids were dissolved in dichloromethane, passed through a
silica plug with 2% acetone in dichloromethane. The wash was
concentrated to yield 7.5 g of product. The filtrate from the
initial filtration was concentrated and the residue purified by
silica chromatography, eluting with 2% acetone in dichloromethane
to yield additional 1.3 g of product. The two portions were
combined to yield 8.8 g (64%) of
1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]eth-
anone.
f)
1-[7-(Cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl-
]ethanone
[0452] To a 0.degree. C. solution of
1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]eth-
anone (400 mg, 1.33 mmol) in dichloromethane (10 mL) was added
sodium bicarbonate (110 mg, 1.33 mmol) and 3-chloroperoxybenzoic
acid (340 mg, 2.00 mmol). The reaction was allowed to warm to room
temperature and stirred for 2 hours. The mix was diluted with
dichloromethane and the organic phase was washed with saturated
aqueous sodium bicarbonate. The phases were separated and the
organic phase concentrated. The residue was dissolved in
cyclopentylamine (10 mL) and stirred for 2 hours. The reaction was
concentrated and the residue purified by silica gel chromatography
eluting with 2% acetone in dichloromethane to give 200 mg (44%) of
1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimid-
in-3-yl]ethanone. .sup.1H NMR (CDCl.sub.3): .delta. 7.93 (d, 1H),
7.64 (dd, 2H), 7.47 (d, 1H), 7.26 (m, 2H), 6.44 (d, 1H), 4.56 (q,
1H), 2.23 (m, 5H), 1.56-1.90 (m, 6H). MS m/z 339 (M+1).
g)
1-[7-(Cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl-
]-3-(dimethylamino)prop-2-en-1-one
[0453] To
1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimi-
din-3-yl]ethanone (200 mg, 0.59 mmol) was added
1,1-di-tert-butoxy-N,N-dimethylmethanamine (4 mL) and the mixture
heated to 80.degree. C. for 30 minutes. The reaction was let cool
to room temperature and was partitioned between ethyl acetate and
water. The aqueous layer was extracted with ethyl acetate and the
combined organic layers washed with water and brine. The ethyl
acetate solution was dried over magnesium sulfate, filtered and
concentrated. The resulting residue was purified by silica
chromatography eluting with ethyl acetate to yield 160 mg (69%) of
1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]--
3-(dimethylamino)prop-2-en-1-one. .sup.1H NMR (CDCl.sub.3): .delta.
7.77 (m, 4H), 7.44 (d, 1H), 7.19 (t, 2H), 6.41 (d, 1H), 5.09 (d,
1H), 4.57 (m, 1H), 3.07 (m, 3H), 2.60 (m, 3H), 2.25 (m, 2H), 1.85
(m, 6H). MS m/z 394 (M+1).
h)
N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)-
-pyrazolo[1,5-c]pyrimidin-7-amine
[0454] To a solution of
1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]--
3-(dimethylamino)prop-2-en-1-one (160 mg, 0.41 mmol) in
N,N-dimethylformamide (10 mL) was added N-cyclopentylguanidine
hydrochloride (130 mg, 0.82 mmol). Freshly ground anhydrous
potassium carbonate (56 mg, 0.41 mmol) was added and the reaction
heated to 140.degree. C. for 4 hours. Additional freshly ground
anhydrous potassium carbonate (120 mg, 0.87 mmol) and
N-cyclopentylguanidine hydrochloride (75 mg, 0.46 mmol) were added
and the reaction heated for additional 3 hours. The reaction was
allowed to cool and was stirred at room temperature for 16 hours.
The mixture was quenched with water, extracted with ethyl acetate
(2.times.), washed with brine, concentrated, and the residue
purified by silica chromatography eluting with 5% acetone in
dichloromethane to yield 140 mg (75%) of
N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)py-
razolo[1,5-c]pyrimidin-7-amine. .sup.1H NMR (CDCl.sub.3): .delta.
8.09 (d, 1H), 7.80 (d, 1H), 7.66 (dd, 2H), 7.54 (d, 1H), 7.19 (t,
2H), 6.42 (d, 1H), 6.30 (d, 1H), 5.14 (d, 1H), 4.57 (m, 1H), 4.34
(m, 1H), 2.22 (m, 2H), 2.09 (m, 2H), 1.52-1.89 (m, 12H).
EXAMPLE 2
N-Cyclopentyl-3-[2-(cyclopropylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyr-
azolo[1,5-c]pyrimidin-7-amine
[0455] ##STR60##
[0456] The title compound was prepared in a similar manner as
described in Example 1 to give a light yellow solid. .sup.1H NMR
(CDCl.sub.3): .delta. 8.09 (d, 1 H), 7.77 (d, 1 H), 7.68-7.61 (m, 3
H), 7.17 (t, 2 H), 6.38 (d, 1 H), 6.33 (d, 1 H), 5.43 (broad, 1 H),
4.55 (m, 1 H), 2.85 (m, 1 H), 2.19 (m, 2 H), 1.83-1.62 (m, 6 H),
0.87 (m, 2 H), 0.63 (m, 2 H); .sup.19F NMR (CHCl.sub.3) .delta.
-112.35; MS m/z 430 (M+1).
EXAMPLE 3
4-[2-(3-Chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-
-2-amine
[0457] ##STR61##
a) 1-(3-Chlorophenyl)-2-(4-pyrimidinyl)ethenol
[0458] To a cold (0.degree. C.) solution of 4-methylpyrimidine
(4.56 mL, 50.1 mmol) and ethyl 3-chlorobenzoate (7.90 mL, 50.1
mmol) in tetrahydrofuran (50 mL) was added lithium
bis(trimethylsilyl)amide (100 mL, 1.0 M in tetrahydrofuran, 100
mmol) dropwise over 30 minutes. The resultant mixture was warmed to
room temperature and stirred 16 hours. The reaction mixture was
concentrated in vacuo. The resultant oil was diluted with methanol.
Upon standing, a solid precipitated, which was collected on a
filter to provide 1-(3-chlorophenyl)-2-(4-pyrimidinyl)ethenol (11.2
g, 93%) as a yellow solid. R.sub.f 0.31 (3:1 hexanes:ethyl
acetate); .sup.1H NMR (d.sub.6-DMSO) .delta. 8.37 (s, 1H), 7.98 (m,
1H), 7.81-7.76 (m, 2H), 7.38-7.32 (m, 2H), 6.71 (br, 1H), 5.65 (s,
1H); MS m/z 233 (M+1).
b) 1-(3-Chlorophenyl)-2-(4-pyrimidinyl)ethanone oxime
[0459] To a suspension of
1-(3-chlorophenyl)-2-(4-pyrimidinyl)ethenol (9.0 g, 38.7 mmol) in
methanol (100 mL) was added hydroxylamine hydrochloride (11.5 g,
165 mmol) and sodium hydroxide (60 mL, 2.8 M in water, 166 mmol).
The reaction mixture was refluxed 4 hours. After cooling, the
excess methanol was removed in vacuo. Ice water (.about.300 mL) was
added to the resultant mixture and the ice was allowed to melt. The
aqueous mixture was extracted with ethyl acetate. The organic layer
was washed with water and brine, then dried over magnesium sulfate.
Filtration and concentration followed by flash chromatography (3:1
to 2:1 hexanes:ethyl acetate) provided
1-(3-chlorophenyl)-2-(4-pyrimidinyl)ethanone oxime (6.5 g, 68%) as
a white solid. R.sub.f 0.14 (3:1 hexanes:ethyl acetate): .sup.1H
NMR (CDCl.sub.3) .delta. 9.50 (br, 1H), 9.18 (s, 1H), 8.61 (d, 1H),
7.78 (s, 1H), 7.58 (d, 1H), 7.38-7.25 (m, 3H), 4.38 (s, 2H); MS m/z
248 (M+1).
c) 2-(3-Chlorophenyl)pyrazolo[1,5-c]pyrimidine
[0460] To a cold (0.degree. C.) solution of
1-(3-chlorophenyl)-2-(4-pyrimidinyl)ethanone oxime (5.0 g, 20.2
mmol) in ethylene glycol dimethyl ether (50 mL) was added
trifluoroacetic anhydride (2.85 mL, 20.2 mmol) dropwise). The
reaction mixture was warmed to room temperature and stirred 10
minutes then recooled to 0.degree. C. A solution of triethylamine
(5.63 mL, 40.4 mmol) in ethylene glycol dimethyl ether was added
and the resultant solution was stirred at room temperature 1.5
hours. Iron (II) chloride (25 mg, 0.20 mmol) was added and the
reaction mixture was refluxed 3 hours. The reaction mixture was
cooled to room temperature and the excess ethylene glycol dimethyl
ether was removed in vacuo. The resultant oil was chromatographed
(9:1 to 4:1 hexanes:ethyl acetate) to provide
2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidine (3.2 g, 69%) as a pale
yellow solid. R.sub.f 0.27 (4:1 hexanes:ethyl acetate); .sup.1H NMR
(CDCl.sub.3) .delta. 9.25 (s, 1H), 8.00 (s, 1H), 7.88-7.81 (m, 2H),
7.46-7.39 (m, 3H), 6.81 (s, 1H); MS m/z 230 (M+1).
d) 2-(3-Chlorophenyl)pyrazolo[1,5-c]pyrimidine-3-carbaldehyde
[0461] To a cold (0.degree. C.) solution of phosphorus oxychloride
(1.22 mL, 13.1 mmol) in N,N-dimethylformamide (50 mL) was added a
solution of 2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidine (2.00 g,
8.71 mmol) in N,N-dimethylformamide (25 mL). The reaction mixture
was stirred at room temperature overnight. To the reaction mixture
was added a cold (0.degree. C.) solution of phosphorus oxychloride
(1.22 mL, 13.1 mmol) in N,N-dimethylformamide (50 mL) and the
resultant mixture was stirred at room temperature 4 days. The
reaction contents were poured onto ice. After the ice had melted,
the precipitated solids were collected on a filter to provide
2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidine-3-carbaldehyde (1.5 g,
67%) as a white solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 10.11 (s,
1H), 9.86 (s, 1H), 8.37 (d, 1H), 8.22 (d, 1H), 7.99 (s, 1H), 7.91
(d, 1H), 7.70-7.59 (m, 2H); MS m/z 258 (M+1).
e)
1-[2-(3-Chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-2-propyn-1-ol
[0462] To a solution of
2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidine-3-carbaldehyde (1.5 g,
5.82 mmol) in tetrahydrofuran (50 mL) was added ethynylmagnesium
bromide (17 mL, 0.5 M in tetrahydrofuran, 8.73 mmol). The reaction
mixture was stirred 4 hours at room temperature then quenched with
water. The mixture was extracted with ethyl acetate. The organic
layer was washed with water and brine, then dried over magnesium
sulfate. Filtration and concentration followed by flash
chromatography (2:1 hexanes:ethyl acetate) provided
1-[2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-2-propyn-1-ol
(1.41 g, 85%). R.sub.f 0.17 (2:1 hexanes:ethyl acetate); .sup.1H
NMR (CDCl.sub.3) .delta. 9.27 (s, 1H), 7.93-7.90 (m, 2H), 7.83 (s,
1H), 7.73 (d, 1H), 7.50-7.41 (m, 2H), 5.78 (s, 1H), 2.99 (br, 1H),
2.71 (s, 1H); MS m/z 284 (M+1).
f)
1-[2-(3-Chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-2-propyn-1-one
[0463] To a cold (0.degree. C.) solution of
1-[2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-2-propyn-1-ol
(1.41 g, 4.97 mmol) in chloroform (600 mL) was added manganese
dioxide (30.3 g, 0.348 mol). The reaction mixture was stirred at
0.degree. C. for 10 minutes then filtered through a pad of celite.
The filtrate was concentrated in vacuo to provide
1-[2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-2-propyn-1-one
(1.40 g, 100%) as a white solid. R.sub.f 0.37 (2:1 hexanes:ethyl
acetate); .sup.1H NMR (CDCl.sub.3) .delta. 9.39 (s, 1H), 8.37 (d,
1H), 8.28 (d, 1H), 7.78 (s, 1H), 7.62 (d, 1H), 7.52-7.40 (m, 2H),
3.17 (s, 1H); MS m/z 282 (M+1).
g)
4-[2-(3-Chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimi-
din-2-amine
[0464] To a mixture of cyclopentyl guanidine hydrochloride (1.05 g,
6.43 mmol) in ethanol (60 mL) was added sodium ethoxide (2.15 mL, 3
M in ethanol, 6.43 mmol). The mixture was stirred at room
temperature for 30 minutes then cooled to 0.degree. C. A solution
of
1-[2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-2-propyn-1-one
(1.4 g, 4.97 mmol) in ethanol (100 mL) was added and the reaction
mixture was stirred at room temperature 16 hours. The reaction
mixture was diluted with water (200 mL) then concentrated to about
two thirds the original volume. The precipitated solids were
collected on a filter to provide
4-[2-(3-Chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidi-
n-2-amine (1.25 g, 64%) as a white solid. R.sub.f 0.19 (4:1
hexanes:ethyl acetate); .sup.1H NMR (CDCl.sub.3) .delta. 9.32 (s,
1H), 8.22 (d, 1H), 8.13 (d, 1H), 8.01 (d, 1H), 7.72 (s, 1H),
7.55-7.39 (m, 3H), 6.38 (d, 1H), 5.19 (d, 1H), 4.33 (m, 1H), 2.08
(m, 2H), 1.80-1.52 (m, 6H); MS m/z 391 (M+1).
EXAMPLE 4
4-[2-(3-Chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclo-
pentylpyrimidin-2-amine
[0465] ##STR62##
[0466] To a cold (-78.degree. C.) solution of
4-[2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentyl-2-pyrim-
idinamine (267 mg, 0.683 mmol) in tetrahydrofuran (8 mL) was added
lithium diisopropylamide (12.8 mL, 0.16 M in tetrahydrofuran, 2.05
mmol, made from 5 mL n-BuLi (1.6 M in hexanes) and 1.19 mL
diisopropylamine in 43.5 mL tetrahydrofuran at 0.degree. C.)
dropwise. The reaction mixture was stirred at -78.degree. C. for 10
minutes followed by the addition of methyl disulfide (246 .mu.L,
2.73 mmol). The resultant mixture was stirred at -78.degree. C. for
10 minutes then quenched with water. Upon warming to room
temperature, the mixture was extracted with ethyl acetate. The
organic layer was washed with water and brine, then dried over
magnesium sulfate. Filtration and concentration followed by flash
chromatography (4:1 to 3:1 hexanes:ethyl acetate) provided
4-[2-(3-chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cycl-
opentylpyrimidin-2-amine (171 mg, 57%) as a white solid. R.sub.f
0.10 (4:1 hexanes:ethyl acetate); .sup.1H NMR (CDCl.sub.3) .delta.
8.12 (d, 1H), 7.99-7.91 (m, 2H), 7.73 (s, 1H), 7.51 (d, 1H),
7.48-7.34 (m, 2H), 6.35 (d, 1H), 5.19 (d, 1H), 4.30 (m, 1H), 2.76
(s, 3H), 2.05 (m, 2H), 1.82-1.50 (m, 6H); MS m/z 437 (M+1).
EXAMPLE 5
2-(3-Chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyr-
azolo[1,5-c]pyrimidin-7-amine
[0467] ##STR63##
[0468] To a cold (0.degree. C.) solution of
4-[2-(3-chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cycl-
opentylpyrimidin-2-amine (40 mg, 0.0915 mmol) in dichloromethane (3
mL) was added m-chloroperoxybenzoic acid (24 mg, 0.139 mmol). The
reaction mixture was stirred 1.5 hours at 0.degree. C. then diluted
with dichloromethane and washed with saturated aqueous sodium
bicarbonate solution. The organic layer was washed with water and
brine, then dried over magnesium sulfate. Filtration and
concentration provided a crude oil which was heated in
cyclopentylamine (2 mL, 20 mmol) at 85.degree. C. in a sealed tube
for 16 hours. The reaction mixture was diluted with ethyl acetate
and washed with saturated aqueous sodium bicarbonate solution. The
organic layer was washed with brine and dried over magnesium
sulfate. Filtration and concentration followed by flash
chromatography (4:1 to 3:1 hexanes:ethyl acetate) provided
2-(3-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]py-
razolo[1,5-c]pyrimidin-7-amine (28 mg, 65%) as a beige solid.
R.sub.f 0.27 (3:1 hexanes:ethyl acetate); .sup.1H NMR (CDCl.sub.3)
.delta. 8.09 (d, 1H), 7.78 (d, 1H), 7.71 (s, 1H), 7.51-7.35 (m,
4H), 6.41 (d, 1H), 6.30 (d, 1H), 5.15 (d, 1H), 4.53 (m, 1H), 4.29
(m, 1H), 2.20 (m, 2H), 2.04 (m, 2H), 1.83-1.50 (m, 12 H); MS m/z
474 (M+1).
EXAMPLE 6
4-[2-(3-Chlorophenyl)-7-(4-morpholinyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cy-
clopentyl-2-pyrimidinamine
[0469] ##STR64##
[0470] In a similar manner as described in Example 5 from
4-[2-(3-chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cycl-
opentylpyrimidin-2-amine (40 mg, 0.091 mmol),
4-[2-(3-chlorophenyl)-7-(4-morpholinyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-c-
yclopentyl-2-pyrimidinamine (29 mg, 67%) was obtained as a yellow
solid. R.sub.f 0.18 (2:1 hexanes:ethyl acetate); .sup.1H NMR
(CDCl.sub.3) .delta. 8.10 (d, 1H), 7.78-7.73 (m, 2H), 7.68 (t, 1H),
7.52-7.37 (m, 3H), 6.32 (d, 1H), 5.19 (d, 1H), 4.30 (m, 1H), 4.04
(m, 4H), 3.93 (m, 4H), 2.05 (m, 2H), 1.79-1.50 (m, 6H); MS m/z 476
(M+1).
EXAMPLE 7
2-(3-Chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-(2-methoxyethy-
l)pyrazolo[1,5-c]pyrimidin-7-amine
[0471] ##STR65##
[0472] In a similar manner as described in Example 5 from
4-[2-(3-chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cycl-
opentylpyrimidin-2-amine (40 mg, 0.091 mmol),
2-(3-chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-(2-methoxyeth-
yl)pyrazolo[1,5-c]pyrimidin-7-amine (22 mg, 52%) was obtained as a
white solid. R.sub.f 0.05 (3:1 hexanes:ethyl acetate); .sup.1H NMR
(CDCl.sub.3) .delta. 8.09 (d, 1H), 7.76-7.69 (m, 2H), 7.52-7.36 (m,
4H), 6.74 (t, 1H), 6.32 (d, 1H), 5.13 (d, 1H), 4.29 (m, 1H), 3.87
(m, 2H), 3.68 (t, 2H), 3.43 (s, 3H), 2.05 (m, 2H), 1.79-1.48 (m,
6H); MS m/z 464 (M+1).
EXAMPLE 8
2-(3-Chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-c]py-
rimidin-7-ol
[0473] ##STR66##
[0474] To a cold (0.degree. C.) solution of
4-[2-(3-chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cycl-
opentylpyrimidin-2-amine (90 mg, 0.206 mmol) in dichloromethane (10
mL) was added m-chloroperoxybenzoic acid (54 mg, 0.313 mmol). The
reaction mixture was stirred 1.5 hours at 0.degree. C. then diluted
with dichloromethane and washed with saturated aqueous sodium
bicarbonate. The organic layer was washed with water and brine,
then dried over magnesium sulfate. Filtration and concentration
provided a crude oil. In a separate flask, a solution of sodium
butoxide was prepared by reacting sodium (35 mg, 1.52 mmol) with
n-butanol (2 mL). The sodium butoxide solution was added to the
crude oil and the resulting solution was heated in a sealed tube at
120.degree. C. for 16 hours. The reaction mixture was cooled and
concentrated in vacuo. The resulting oil was partitioned between
water and ethyl acetate. The organic layer was washed with water
and brine, then dried over magnesium sulfate. Filtration and
concentration provided a crude oil which was diluted with ethyl
acetate (.about.5 mL). Upon standing 7 hours, a solid had
precipitated, which was collected on a filter to provide
2-(3-chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-c]p-
yrimidin-7-ol (22 mg, 26%) as a pale yellow solid. .sup.1H NMR
(CDCl.sub.3) .delta. 8.00 (d, 1H), 7.60 (s, 1H), 7.42 (d, 1H), 7.36
(d, 1H), 7.30 (d, 1H), 7.25 (s, 1H), 7.14 (d, 1H), 7.02 (d, 1H),
6.24 (d, 1H), 4.19 (m, 1H), 1.99 (m, 2H), 1.78-1.42 (m, 6H); MS m/z
407 (M+1).
EXAMPLE 9
N-Cyclopentyl-8-(2-fluoro-4-pyridinyl)-2-(methylsulfanyl)-7-phenylpyrazolo-
[1,5-a][1,3,5]triazin-4-amine
[0475] ##STR67##
a) Ethyl [(3-phenyl-1H-pyrazol-5-yl)amino]carbothioylcarbamate
[0476] To a cold (0.degree. C.) solution of
3-amino-5-phenylpyrazole (10.0 g, 62.8 mmol) in toluene (100 mL)
was added ethoxycarbonyl isothiocyanate (8.3 mL, 70 mmol) dropwise
via a pressure equalizing funnel. Upon complete addition, the cold
bath was removed and the resulting solution was stirred at room
temperature for 15 hours, at which time a heavy white precipitate
had formed. The precipitate was collected by filtration and dried
to give ethyl [(3-phenyl-1H-pyrazol-5-yl)amino]carbothioylcarbamate
(11 g, 60%) as a white solid. .sup.1H-NMR (DMSO-d.sub.6): .delta.
13.25 (s, 1H), 12.06 (s, 1H), 11.40 (s, 1H), 7.75 (d, 2H), 7.5-7.3
(m, 4H), 4.25 (q, 2H), 1.29 (t, 3H); MS m/z 291 (M+1).
b)
7-Phenyl-2-thioxo-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one
[0477] Ethyl [(3-phenyl-1H-pyrazol-5-yl)amino]carbothioylcarbamate
(8.4 g, 29 mmol) was dissolved in aqueous sodium hydroxide (100 mL,
2N solution) and the resulting solution was stirred at room
temperature overnight. This solution was acidified to pH=1 with
concentrated sulfuric acid, resulting in heavy precipitation. This
precipitate was collected by filtration and dried to give
7-phenyl-2-thioxo-2,3-dihydropyrazolo-[1,5-a][1,3,5]triazin-4(1H)-one
(5.7 g, 80%) as a white solid. .sup.1H-NMR (DMSO-d.sub.6): .delta.
7.97 (m, 2H), 7.48 (m, 3H), 6.41 (s, 1H); MS m/z 245 (M+1).
c)
2-(Methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4(3H)-one
[0478]
7-Phenyl-2-thioxo-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-o-
ne (6.4 g, 26.2 mmol) was dissolved in absolute ethanol (150 mL).
To this solution was added aqueous sodium hydroxide (2.1 g, 53 mmol
in 50 mL of water) and finally iodomethane (1.7 mL, 27.3 mmol) was
added dropwise. The resulting solution was stirred at room
temperature for 3 hours and then concentrated to a white solid.
This solid was suspended in water and the mixture acidified (to
pH=1) with concentrated sulfuric acid. The resulting precipitate
was collected by filtration, washed with water and dried to give
2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4(3H)-one
(5.5 g, 81%) as a white solid. .sup.1H-NMR (DMSO-d.sub.6): .delta.
7.99 (d, 2H), 7.5 (m, 3H), 6.93 (s, 1H), 2.58 (s, 3H); MS m/z 259
(M+1).
d)
4-Chloro-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazine
[0479]
2-(Methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4(3H)-one
(5.4 g, 21 mmol) was added to a mixture of phosphorus oxychloride
(100 mL) and diethylaniline (2.5 mL). The resulting mixture was
heated at reflux for 3 hours. The excess phosphorus oxychloride was
removed in vacuo and the dark syrup residue was added slowly to
-crushed ice with good stirring. Dichloromethane and water were
added and the phases separated. The organic phase was washed with
water and brine, dried over magnesium sulfate, filtered and
concentrated to give a crude solid (5 g, 86%). A portion of this
solid was purified by silica gel chromatography (ethyl
acetate:hexane 1:1) go give a white solid. .sup.1H-NMR
(CDCl.sub.3): .delta. 8.04 (m, 2H), 7.54 (m, 3H), 6.83 (s, 1H),
2.66 (s, 3H); MS m/z 277 (M+1).
e)
N-Cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin--
4-amine
[0480]
4-Chloro-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazine
(2.5 g, 9 mmol) was dissolved in cyclopentylamine (30 mL) and the
resulting solution heated to 80.degree. C. for 2 hours. Excess
cyclopentylamine was removed in vacuo and the residue was dissolved
in ethyl acetate. The organic phase was washed with water and
brine, dried over magnesium sulfate, filtered and concentrated to
give a foam. This foam was purified by silica gel chromatography
(ethyl acetate:hexane 1:1) go give 2.3 g (78%) of
N-cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4--
amine as a solid. .sup.1H-NMR (CDCl.sub.3): .delta. 7.96 (m, 2H),
7.47 (m, 3H), 6.63 (d, 1H), 6.56 (s, 1H), 4.54 (m, 1H), 2.61 (s,
3H), 2.2-2.0 (m, 2H), 1.9-1.5 (m, 6H); MS m/z 326 (M+1).
f)
8-Bromo-N-cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]-
triazin-4-amine
[0481]
N-Cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]tri-
azin-4-amine (0.49 g, 1.5 mmol) was dissolved in dichloromethane.
To this solution was added N-bromosuccinimide (330 mg, 1.85 mmol)
and the resulting solution was stirred at room temperature for 30
minutes. Additional dichloromethane was added and the reaction
mixture was extracted with 1N aqueous sodium hydroxide and with
water. The organic phase was dried (magnesium sulfate), filtered
and concentrated to give a solid. This solid was purified by silica
gel chromatography (ethyl acetate:hexane 1:2) to give 0.5 g (82%)
of
8-bromo-N-cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]tr-
iazin-4-amine as a solid. .sup.1H-NMR (CDCl.sub.3): .delta. 8.05
(m, 2H), 7.55 (m, 3H), 6.52 (d, 1H), 4.60 (m, 1H), 2.66 (s, 3H),
2.3-2.1 (m, 2H), 2.0-1.6 (m, 6H); MS m/z 405 (M+1).
g)
N-Cyclopentyl-8-(2-fluoro-4-pyridinyl)-2-(methylsulfanyl)-7-phenylpyraz-
olo[1,5-a][1,3,5]triazin-4-amine
[0482]
8-Bromo-N-cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1-
,3,5]triazin-4-amine (0.20 g, 0.50 mmol) was dissolved in
N,N-dimethylformamide. To this solution was added
dichlorobis(triphenylphosphine)palladium (II] (70 mg, 0.2 equiv),
anhydrous sodium carbonate (105 mg, 2 equiv),
2-fluoro-4-pyridinylboronic acid (91 mg, 1.3 equiv) and a few drops
of water. The reaction mixture was heated at 100.degree. C. for 12
hours, at which time no starting material remained in the reaction
mixture. Ethyl acetate and water were added to the reaction
mixture. The phases were separated and the organic phase was washed
with water, dried over magnesium sulfate, filtered and
concentrated. Purification by silica gel chromatography (ethyl
acetate:hexane 1:1) gave 70 mg (33%) of
N-cyclopentyl-8-(2-fluoro-4-pyridinyl)-2-(methylsulfanyl)-7-phenylpyrazol-
o[1,5-a][1,3,5]triazin-4-amine as a white foam. .sup.1H-NMR
(CDCl.sub.3): .delta. 8.10 (d, 1H), 7.60 (m, 2H), 7.52 (m, 3H),
7.37 (m, 1H), 7.29 (s, 1H), 6.55 (d, 1H), 4.63 (m, 1H), 2.66 (s,
3H), 2.3-2.1 (m, 2H), 2.0-1.6 (m, 6H); F-NMR (CDCl.sub.3): .delta.
-69.01; MS m/z 421 (M+1).
EXAMPLE 10
N.sup.2,N.sup.4-Dicyclopentyl-8-[2-(cyclopentylamino)-4-pyridinyl]-7-pheny-
lpyrazolo[1,5-a][1,3,5]triazine-2,4-diamine
[0483] ##STR68##
[0484]
N-Cyclopentyl-8-(2-fluoro-4-pyridinyl)-2-(methylsulfanyl)-7-phenyl-
pyrazolo[1,5-a][1,3,5]triazin-4-amine (60 mg, 0.14 mmol) was
dissolved in cyclopentylamine and heated at 160.degree. C. in a
glass pressure vessel for 24 hours. The resulting solution was
concentrated in vacuo to give a residue that was purified by silica
gel chromatography (ethyl acetate:hexane 1:1 to ethyl acetate) to
yield 25 mg (34%) of
N.sup.2,N.sup.4-dicyclopentyl-8-[2-(cyclopentylamino)-4-pyridinyl]-7-phen-
ylpyrazolo[1,5-a][1,3,5]triazine-2,4-diamine as a foam. .sup.1H-NMR
(CDCl.sub.3): .delta. 7.94 (d, 1H), 7.60 (m, 2H), 7.45 (m, 3H),
6.81 (d, 1H), 6.36 (m, 1H), 5.13 (d, 1H), 4.60 (m, 1H), 4.44 (m,
2H), 3.74 (m, 1H), 2.1-1.4 (m, 24H); MS m/z 523 (M+1).
EXAMPLE 11
N-Cyclopentyl-8-[2-(cyclopentylamino)-4-pyrimidinyl]-7-phenylpyrazolo[1,5--
a][1,3,5]triazin-4-amine
[0485] ##STR69##
a) N-Cyclopentyl-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine
[0486]
N-Cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]tri-
azin-4-amine (300 mg, 0.92 mmol, from Example 9) was dissolved in
absolute ethanol (30 mL). To this mixture was added Raney nickel
(approximately 2-3 g) and the reaction was heated at reflux for 6
hours. The Raney nickel was removed by filtering the reaction
mixture through a Celite pad, and the Celite was washed with
ethanol (150 mL). The combined organic phase was concentrated to
dryness. The resulting residue was purified by silica gel
chromatography (ethyl acetate:hexane 1:1) to give 200 mg (78%) of
N-cyclopentyl-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine as a
yellow foam. .sup.1H-NMR (CDCl.sub.3): .delta. 8.24 (s, 1H), 7.98
(m, 2H), 7.51 (m, 3H), 6.75 (s, 1H), 6.67 (d, 1H), 4.60 (m, 1H),
2.3-2.1 (m, 2H), 2.0-1.6 (m, 6H); MS m/z 280 (M+1).
b)
N-Cyclopentyl-8-iodo-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine
[0487] N-Cyclopentyl-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine
(0.25 g, 0.90 mmol) was dissolved in dichloromethane. To this
solution was added N-iodosuccinimide (300 mg, 1.33 mmol) and the
resulting solution was stirred at room temperature for 30 minutes.
Additional dichloromethane was added and the reaction mixture was
extracted with 1N aqueous sodium hydroxide and with water. The
organic phase was dried (magnesium sulfate), filtered and
concentrated to give a solid. This solid was purified by silica gel
chromatography (ethyl acetate:hexane 1:1) to give 310 mg (85%) of
N-cyclopentyl-8-iodo-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine
as a yellow solid. .sup.1H-NMR (CDCl.sub.3): .delta. 8.35 (s, 1H),
7.98 (m, 2H), 7.55 (m, 3H), 6.64 (d, 1H), 4.60 (m, 1H), 2.3-2.1 (m,
2H), 2.0-1.6 (m, 6H); MS m/z 406 (M+1).
c)
N-Cyclopentyl-8-[2-(cyclopentylamino)-4-pyrimidinyl]-7-phenylpyrazolo[1-
,5-a][1,3,5]triazin-4-amine
[0488]
N-Cyclopentyl-8-iodo-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine
(80 mg, 0.20 mmol) was dissolved in anhydrous toluene (5 mL). To
this solution was added
2-(methylsulfanyl)-4-(tributylstannyl)pyrimidine (100 mg, 0.24
mmol,) and dichlorobis(triphenylphosphine)palladium (II] (14 mg,
0.1 equiv) and the resulting mixture heated at 100.degree. C. for
24 hours. Ethyl acetate and water were added to the reaction
mixture. The phases were separated and the organic phase washed
with water, dried over magnesium sulfate, filtered and
concentrated. Purification by silica gel chromatography (ethyl
acetate:hexane 1:1) gave an inseparable mixture of the desired
N-cyclopentyl-8-[2-(methylsulfanyl)-4-pyrimidinyl]-7-phenylpyrazolo[1,5-a-
][1,3,5]triazin-4-amine contaminated with
N-cyclopentyl-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine. This
mixture was dissolved in dichloromethane (15 mL) and
3-chloroperoxybenzoic acid (113 mg, 57-86%) was added. The
resulting reaction mixture was stirred at room temperature for 1
hour. Dichloromethane and saturated aqueous potassium carbonate
were added and the phases separated. The organic phase was washed
with additional saturated aqueous potassium carbonate, water, dried
over magnesium sulfate, filtered and concentrated to give a foam.
This foam was dissolved in cyclopentylamine and the solution was
heated at 60.degree. C. for 3 hours. The mixture was concentrated
in vacuo and the residue purified by silica gel chromatography
(ethyl acetate:hexane 1:1) to give 20 mg (23% for 3 steps) of
N-cyclopentyl-8-[2-(cyclopentylamino)-4-pyrimidinyl]-7-phenylpyrazolo[1,5-
-a][1,3,5]triazin-4-amine as a white foam. .sup.1H-NMR
(CDCl.sub.3): .delta. 8.39 (s, 1H), 8.28 (d, 1H), 7.67 (m, 2H),
7.46 (3H), 6.71 (d, 1H), 5.01 (d, 1H), 4.64 (m, 1H), 3.80 (m, 1H),
1.2-2.3 (m, 16H); MS m/z 441 (M+1).
EXAMPLE 12
3-[2-(Butylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[-
1,5-c]pyrimidin-7-amine
[0489] ##STR70##
[0490] In a similar manner as described in Example 1 above,
3-[2-(butylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo-
[1,5-c]pyrimidin-7-amine (80 mg, 72%) was prepared from
1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]--
3-(dimethylamino)prop-2-en-1-one and N-butylguanidine. .sup.1H NMR
(CDCl.sub.3): .delta. 8.04 (d, 1H), 7.74 (d, 1H), 7.60 (dd, 2H),
7.48 (d, 1H), 7.13 (t, 2H), 6.36 (d, 1H), 6.25 (d, 1H), 5.05 (t,
1H), 4.51 (m, 1H), 3.42 (qt, 2H), 2.16 (m, 2H), 1.78 (m, 2H),
1.56-1.70 (m, 6H), 1.43 (m, 2H), 0.95 (t, 3H). MS m/z 446
(M+1).
EXAMPLE 13
3-(2-Anilinopyrimidin-4-yl)-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo-[1,5--
c]pyrimidin-7-amine
[0491] ##STR71##
[0492] In a similar manner as described above,
3-(2-anilinopyrimidin-4-yl)-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5--
c]pyrimidin-7-amine (70 mg, 60%) was prepared from
1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]--
3-(dimethylamino)prop-2-en-1-one and N-cyclopentylguanidine.
.sup.1H NMR (CDCl.sub.3): .delta. 8.19 (d, 1H), 7.72 (d, 1H), 7.62
(dd, 2H), 7.57 (d, 2H), 7.44 (d, 1H), 7.30 (t, 2H), 7.15 (t, 2H),
7.08 (s, 1H), 7.03 (t, 1H), 6.47 (d, 1H), 6.38 (d, 1H), 4.52 (m,
1H), 2.12-2.24 (m, 2H), 1.79 (m, 2H), 1.60-1.72 (m, 4H). MS m/z 466
(M+1).
EXAMPLE 14
3-[2-(1,3-Benzothiazol-2-ylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluoro-
phenyl)pyrazolo[1,5-c]pyrimidin-7-amine
[0493] ##STR72##
[0494] In a similar manner as described above,
3-[2-(1,3-benzothiazol-2-ylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluor-
ophenyl)pyrazolo[1,5-c]pyrimidin-7-amine (38 mg, 29%) was prepared
from
1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]--
3-(dimethylamino)prop-2-en-1-one and
N-(1,3-benzothiazol-2-yl)guanidine. .sup.1H NMR (CDCl.sub.3):
.delta. 10.58 (bs, 1H), 8.49 (d, 1H), 7.90 (d, 1H), 7.75 (d, 1H),
7.73 (d, 1H), 7.64 (dd, 2H), 7.47 (d, 1H), 7.40 (t, 1H), 7.23 (t,
1H), 7.15 (t, 2H), 6.69 (d, 1H), 6.41 (d, 1H), 4.54 (m, 1H),
2.14-2.24 (m, 2H), 1.58-1.85 (m, 6H). MS m/z 523 (M+1).
EXAMPLE 15
N-Cyclopentyl-2-(4-fluorophenyl)-3-{2-[(4-methyl-1,3-thiazol-2-yl)amino]py-
rimidin-4-yl}pyrazolo[1,5-c]pyrimidin-7-amine
[0495] ##STR73##
[0496] In a similar manner as described above,
N-cyclopentyl-2-(4-fluorophenyl)-3-{2-[(4-methyl-1,3-thiazol-2-yl)amino]p-
yrimidin-4-yl}pyrazolo[1,5-c]pyrimidin-7-amine (65 mg, 53%) was
prepared from
1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-
-yl]-3-(dimethylamino)prop-2-en-1-one and
N-(4-methyl-1,3-thiazol-2-yl)guanidine. .sup.1H NMR (CDCl.sub.3):
.delta. 9.16 (s, 1H), 8.33 (d, 1H), 7.76 (d, 1H), 7.61 (dd, 2H),
7.45 (d, 1H), 7.14 (t, 2H), 6.58 (d, 1H), 6.40 (s, 1H), 6.39 (d,
1H), 4.53 (m, 1H), 2.35, (s, 3H), 2.13-2.24 (m, 2H), 1.60-1.84 (m,
6H). MS m/z 487 (M+1).
EXAMPLE 16
3-[2-(1H-Benzimidazol-2-ylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorop-
henyl)pyrazolo[1,5-c]pyrimidin-7-amine
[0497] ##STR74##
[0498] In a similar manner as described above,
3-[2-(1H-benzimidazol-2-ylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluoro-
phenyl)pyrazolo[1,5-c]pyrimidin-7-amine (18 mg, 14%) was prepared
from
1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]--
3-(dimethylamino)prop-2-en-1-one and
N-(1H-benzimidazol-2-yl)guanidine. .sup.1H NMR (CDCl.sub.3):
.delta. 8.40 (m, 1H), 7.80 (d, 1H), 7.66 (m, 3H), 7.37 (m, 1H),
7.17 (m, 7H), 6.71 (m, 1H), 6.44 (m, 1H), 4.56 (m, 1H), 2.18 (m,
2H), 1.62-1.87 (m, 6H). MS m/z 506 (M+1).
EXAMPLE 17
N-Cyclopentyl-3-{2-[(4-fluorobenzyl)amino]pyrimidin-4-yl}-2-(4-fluoropheny-
l)pyrazolo[1,5-c]pyrimidin-7-amine
[0499] ##STR75##
[0500] In a similar manner as described above,
N-cyclopentyl-3-{2-[(4-fluorobenzyl)amino]pyrimidin-4-yl}-2-(4-fluorophen-
yl)pyrazolo[1,5-c]pyrimidin-7-amine (21 mg, 17%) was prepared from
1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]--
3-(dimethylamino)prop-2-en-1-one and N-(4-fluorobenzyl)guanidine
trifluoroacetate. .sup.1H NMR (CDCl.sub.3): .delta. 8.07 (d, 1H),
7.64 (d, 1H), 7.59 (dd, 2H), 7.33 (dd, 2H), 7.21 (bs, 1H), 7.13 (t,
2H), 7.02 (t, 2H), 6.34 (d, 1H), 6.31 (d, 1H), 5.42 (t, 1H), 4.62
(d, 2H), 4.49 (m, 1H), 2.11-2.20 (m, 2H) 1.74-1.83 (m, 2H),
1.59-1.72 (m, 4H). MS m/z 498 (M+1).
EXAMPLE 18
N-Cyclopentyl-2-(4-fluorophenyl)-3-{2-[(2-phenylethyl)amino]pyrimidin-4-yl-
}pyrazolo[1,5-c]pyrimidin-7-amine
[0501] ##STR76##
[0502] In a similar manner as described above,
N-cyclopentyl-2-(4-fluorophenyl)-3-{2-[(2-phenylethyl)amino]pyrimidin-4-y-
l}pyrazolo[1,5-c]pyrimidin-7-amine (9 mg, 7%) was prepared from
1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]--
3-(dimethylamino)prop-2-en-1-one and N-(2-phenylethyl)guanidine
sulfate. .sup.1H NMR (CDCl.sub.3): .delta. 8.05 (d, 1H), 7.73 (d,
1H), 7.61 (dd, 2H), 7.48 (d, 1H), 7.31 (m, 2H), 7.23 (m, 3H), 7.13
(t, 2H), 6.37 (d, 1H), 6.28 (d, 1H). 5.14 (t, 1H), 4.51 (m, 1H),
3.71 (q, 2H), 2.94 (t, 2H), 2.16 (m, 2H), 1.75-1.85 (m, 2H),
1.62-1.73 (m, 4H). MS m/z 494 (M+1).
EXAMPLE 19
3-[2-(tert-Butylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyra-
zolo[1,5-c]pyrimidin-7-amine
[0503] ##STR77##
a) Methyl N-(tert-butyl)imidothiocarbamate hydroiodide
[0504] To a solution of t-butylthiourea (1.35 g, 10.2 mmol) in
methanol (150 mL) was added iodomethane (2.13 g, 15.0 mmol). The
solution was stirred overnight at room temperature. The reaction
mixture was concentrated under reduced pressure to yield the title
compound (2.8 g, >99%) as a yellow solid. .sup.1H NMR
(CDCl.sub.3): .delta. 9.07 (s, 1 H), 8.6 (bs, 2H), 2.63 (s, 3H),
1.40 (s, 9H). MS m/z 147 (M+1).
b) N-(tert-Butyl)guanidine hydroiodide
[0505] N-(tert-Butyl)imidothiocarbamate hydroiodide (2.8 g, 10
mmol) was dissolved in a 2M NH3 solution in methanol (100 mL). The
reaction mixture was heated to reflux for 3 hours and then removed
from heat to stir at room temperature for 48 hours. The reaction
mixture was concentrated under reduced pressure to leave the title
compound (2.4 g, >99%) as a solid.
c)
3-[2-(tert-Butylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)p-
yrazolo[1,5-c]pyrimidin-7-amine
[0506] In a similar manner as described above,
3-[2-(tert-butylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyr-
azolo[1,5-c]pyrimidin-7-amine (29 mg, 26%) was prepared from
1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]--
3-(dimethylamino)prop-2-en-1-one and N-(tert-butyl)guanidine
hydroiodide. .sup.1H NMR (CDCl.sub.3): .delta. 8.10 (d, 1H), 7.78
(d, 1H), 7.64 (dd, 2H), 7.45 (d, 1H), 7.17 (t, 2H), 6.42 (d, 1H),
6.31 (d, 1H), 5.16 (s, 1H), 4.56 (m, 1H), 2.22 (m, 2H), 1.63-1.90
(m, 15H). MS m/z 446 (M+1).
EXAMPLE 20
N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrim-
idin-3-yl]pyrimidin-2-amine
[0507] ##STR78##
a)
1-[2-(4-Fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]e-
thanone
[0508] To a slurry of
2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidine (1.5
g, 5.9 mmol) in acetic anhydride (10 mL) was added 4 drops of
sulfuric acid. The reaction mixture was heated to 80.degree. C. for
2 hours, to 110.degree. C. for 2 hours, and to reflux for 2 hours.
The solution was allowed to cool to room temperature and stirred
for 4 days. The mixture was poured into water (350 mL) and
extracted with ethyl acetate (2.times.75 mL). The organic phase was
washed with brine and concentrated under reduced pressure. The
residue was purified by silica gel chromatography eluting with 2:98
acetone:dichloromethane to yield
1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]eth-
anone (1.24 g, 70%). .sup.1H NMR (DMSO): .delta. 8.12 (d, 1H), 7.98
(d, 1H), 7.65 (dd, 2H), 7.24 (m, 2H), 2.77 (s, 3H), 2.23 (s, 3H).
MS m/z 302 (M+1).
b)
(2E)-3-(Dimethylamino)-1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo-
-[1,5-c]pyrimidin-3-yl]prop-2-en-1-one
[0509] To
1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidi-
n-3-yl]ethanone (1.24 g, 4.12 mmol) was added
1,1-di-tert-butoxy-N,N-dimethylmethanamine (15 mL) and the mixture
heated to 120.degree. C. for 1 hour. The reaction was allowed to
cool to room temperature and stirred for 16 hours. The mixture was
diluted with hexanes. The precipitate was collected by filtration
and air dried to yield
(2E)-3-(dimethylamino)-1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyra-
zolo[1,5-c]pyrimidin-3-yl]prop-2-en-1-one (880 mg, 60%). .sup.1H
NMR (DMSO): .delta. 8.03 (d, 1H), 7.72-7.82 (m, 3H), 7.57 (d, 1H),
7.37 (t, 2H), 5.08 (d, 1H), 3.04 (bs, 3H), 2.71 (s, 3H), 2.52 (bs,
3H). MS m/z 357 (M+1).
c)
N-cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]py-
rimidin-3-yl]pyrimidin-2-amine
[0510] To a solution of
(2E)-3-(dimethylamino)-1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1-
,5-c]pyrimidin-3-yl]prop-2-en-1-one (660 mg, 1.85 mmol) and
N-cyclopentylguanidine hydrochloride (600 mg, 3.71 mmol) in
N,N-dimethylformamide (10 mL) was added potassium carbonate (760
mg, 5.55 mmol). The reaction mixture was heated to 100.degree. C.
for 1 hour and then to 115.degree. C. for 4 hours. The reaction was
allowed to cool to room temperature and diluted with water. The
mixture was extracted with ethyl acetate, washed with brine, dried
over magnesium sulfate, filtered and concentrated. The residue was
purified using silica gel chromatography eluting with 5% acetone in
dichloromethane to yield
N-cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyri-
midin-3-yl]pyrimidin-2-amine (210 mg, 32%). .sup.1H NMR
(CDCl.sub.3): .delta. 8.05 (d, 1H), 7.94 (m, 2H), 7.64 (dd, 2H),
7.13 (t, 2H), 6.29 (d, 1H), 5.21 (bs, 1H), 4.31 (m, 1H), 2.72 (s,
3H), 2.06 (m, 2H), 1.49-1.82 (m, 6H). MS m/z 421 (M+1).
EXAMPLE 21
N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)py-
razolo[1,5-c]pyrimidin-7-amine
[0511] ##STR79##
[0512] In a similar manner as described above
N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)p-
yrazolo[1,5-c]pyrimidin-7-amine (610 mg, 66%) was prepared as a
brown solid. .sup.1H NMR (CDCl.sub.3) .delta. 8.02 (d, 1H), 7.73
(d, 1H), 7.57-7.52 (m, 3H), 6.98 (d, 2H), 6.40 (d, 1H), 6.30 (d,
1H), 5.12 (d, 1H), 4.51 (m, 1H), 4.32 (m, 1H), 3.87 (s, 3H),
2.18-2.03 (m, 4H), 1.81-1.49 (m, 12H); MS m/z 470 (M+1).
EXAMPLE 22
4-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,5-
-c]pyrimidin-2-yl}phenol
[0513] ##STR80##
[0514] In a similar manner as described above
4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,-
5-c]pyrimidin-2-yl}phenol (535 mg, 90%) was prepared as a yellow
solid. .sup.1H NMR (DMSO) .delta. 9.82 (s, 1H), 8.02 (d, 1H),
7.84-7.77 (m, 2H), 7.40 (d, 2H), 6.88 (d, 2H), 6.27 (m, 1H),
4.51-4.44 (m, 1H), 1.99-1.93 (m, 3H), 1.73-1.55 (m, 11H), 1.27-1.24
(m, 3H), 0.88-0.83 (m, 2H); MS m/z 456 (M+1).
EXAMPLE 23
N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-[4-(cyclopropylmeth-
oxy)phenyl]pyrazolo[1,5-c]pyrimidin-7-amine
[0515] ##STR81##
[0516] In a similar manner as described above
N-cyclopentyl-3-[2-(cyclopentylamino)-pyrimidin-4-yl]-2-[4-(cyclopropylme-
thoxy)phenyl]pyrazolo[1,5-c]pyrimidin-7-amine (170 mg, 76%) was
prepared as a brown solid. .sup.1H NMR (CDCl.sub.3) .delta. 8.02
(d, 1H), 7.73 (d, 1H), 7.55-7.52 (m, 3H), 6.99-6.96 (m, 2H), 6.39
(d, 1H), 6.30 (d, 1H), 5.05 (d, 1H), 4.54-4.49 (m, 1H), 4.35-4.30
(m, 1H), 3.86 (d, 2H), 2.18-2.05 (m, 3H), 1.80-1.60 (m, 7H),
1.56-1.51 (m, 7H), 0.68-0.65 (m, 2H), 0.39-0.37 (m, 2H); MS m/z 510
(M+1).
EXAMPLE 24
3-[2-(Cyclopentylamino)pyrimidin-4-yl]-N-cyclopropyl-2-(4-methoxyphenyl)py-
razolo[1,5-c]pyrimidin-7-amine
[0517] ##STR82##
[0518] In a similar manner as described above
3-[2-(cyclopentylamino)pyrimidin-4-yl]-N-cyclopropyl-2-(4-methoxyphenyl)p-
yrazolo[1,5-c]pyrimidin-7-amine (150 mg, 56%) was prepared as a
white solid. .sup.1H NMR (CDCl.sub.3) .delta. 8.03 (d, 1H), 7.813
(d, 1H), 7.60 (m, 1H), 7.55-7.52 (m, 2H), 6.99-6.96 (m, 2H), 6.63
(m, 1H), 6.30 (d, 1H), 5.09 (m, 1H), 4.33 (m, 1H), 3.87 (s, 3H),
2.99 (m, 1H), 2.09-2.04 (m, 3H), 1.77-1.65 (m, 5H), 0.97-0.92 (m,
2H), 0.78-0.74 (m, 2H); MS m/z 442 (M+1).
EXAMPLE 25
2-(4-Butoxyphenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyr-
azolo[1,5-c]pyrimidin-7-amine
[0519] ##STR83##
[0520] In a similar manner as described above
2-(4-butoxyphenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]py-
razolo[1,5-c]pyrimidin-7-amine was prepared as a white solid.
.sup.1H NMR (CDCl.sub.3) .delta. 8.02 (d, 1H), 7.73 (d, 1H),
7.55-7.52 (m, 3H), 6.97 (m, 2H), 6.40 (d, 1H), 6.31 (d, 1H), 5.09
(d, 1H), 4.51 (m, 1H), 4.32 (m, 1H), 4.02 (t, 2H), 2.19-2.04 (m,
5H), 1.85-1.48 (m, 15H), 0.99 (m, 3H); MS m/z 512 (M+1).
EXAMPLE 26
N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-isobutoxyphenyl)-
pyrazolo[1,5-c]pyrimidin-7-amine
[0521] ##STR84##
[0522] In a similar manner as described above
N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-isobutoxyphenyl-
)pyrazolo[1,5-c]pyrimidin-7-amine was prepared as a tan solid.
.sup.1H NMR (CDCl.sub.3) .delta. 8.02 (d, 1H), 7.73 (d, 1H),
7.55-7.52 (m, 3H), 6.97 (m, 2H), 6.39 (d, 1H), 6.31 (d, 1H), 5.07
(d, 1H), 4.51 (m, 1H), 4.33 (m, 1H), 3.77 (d, 2H), 2.19-2.04 (m,
5H), 1.79-1.49 (m, 12H), 1.05 (d, 6H); MS m/z 512 (M+1).
EXAMPLE 27
N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-[4-(2-methoxyethoxy-
)phenyl]pyrazolo[1,5-c]pyrimidin-7-amine
[0523] ##STR85##
[0524] In a similar manner as described above
N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-[4-(2-methoxyethox-
y)phenyl]pyrazolo[1,5-c]pyrimidin-7-amine was prepared as a yellow
solid. .sup.1H NMR (CDCl.sub.3) .delta. 8.02 (d, 1H), 7.73 (d, 1H),
7.55-7.52 (m, 3H), 7.00 (m, 2H), 6.39 (d, 1H), 6.27 (d, 1H), 5.10
(d, 1H), 4.51 (m, 1H), 4.33 (m, 1H), 4.18 (m, 2H), 3.78 (m, 2H),
3.47 (s, 3H), 2.18-2.03 (m, 4H), 1.78-1.49 (m, 12H); MS m/z 514
(M+1).
EXAMPLE 28
N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-propoxyphenyl)py-
razolo[1,5-c]pyrimidin-7-amine
[0525] ##STR86##
[0526] In a similar manner as described above
N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-propoxyphenyl)p-
yrazolo[1,5-c]pyrimidin-7-amine was prepared as a yellow solid.
.sup.1H NMR (CDCl.sub.3) .delta. 8.02 (d, 1H), 7.73 (d, 1H),
7.55-7.52 (m, 3H), 6.97 (m, 2H), 6.40 (d, 1H), 6.31 (d, 1H), 5.10
(d, 1H), 4.51 (m, 1H), 4.33 (m, 1H), 3.98 (t, 2H), 2.19-2.05 (m,
4H), 1.87-1.51 (m, 14H), 1.06 (t, 3H); MS m/z 498 (M+1).
EXAMPLE 29
N-(tert-Butyl)-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)py-
razolo[1,5-c]pyrimidin-7-amine
[0527] ##STR87##
[0528] To a solution of
N-cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyri-
midin-3-yl]pyrimidin-2-amine (40 mg, 0.095 mmol) in dichloromethane
(2 mL) was added 3-chloroperoxybenzoic acid (12 mg, 0.14 mmol) and
the reaction mixture stirred at room temperature for 1 hour.
t-Butylamine (3 mL) was added and heated to reflux for 3 hours. The
reaction was allowed to cool and diluted with water. The mixture
was extracted with ethyl acetate and the organic phase washed with
brine before being concentrated under vacuum. The residue was
purified by silica gel chromatography eluting with 5% acetone in
dichloromethane to yield a 1:1 mixture of starting material and
product. The residue was dissolved in dichloromethane (2 mL) and
3-chloroperoxybenzoic acid (18 mg, 0.21 mmol) was added. The
mixture was stirred for 2 hours and then t-butylamine (3 mL) was
added. The reaction mixture was stirred for 3 hours, diluted with
water, extracted with ethyl acetate, washed with brine,
concentrated, and the residue purified by silica gel chromatography
eluting with 5% acetone in dichloromethane to yield
N-(tert-butyl)-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)p-
yrazolo[1,5-c]pyrimidin-7-amine (6 mg, 14%). .sup.1H NMR
(CDCl.sub.3): .delta. 8.02 (d, 1H), 7.72 (d, 1H), 7.60 (dd, 2H),
7.47 (d, 1H), 7.13 (t, 2H), 6.42 (s, 1H), 6.25 (d, 1H), 5.14 (bs,
1H), 4.28 (m, 1H), 2.04 (m, 2H), 1.45-1.78 (m, 15H). MS m/z 446
(M+1).
EXAMPLE 30
N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-pyrrolidin-1-ylpyrazolo[1,5-c]pyrimi-
din-3-yl]pyrimidin-2-amine
[0529] ##STR88##
[0530] To a solution of
N-cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyri-
midin-3-yl]pyrimidin-2-amine (24 mg, 0.057 mmol) in dichloromethane
(3 mL) was added 3-chloroperoxybenzoic acid (15 mg, 0.086 mmol) and
the reaction mixture stirred for 1 hour. Pyrrolidine (3 mL) was
added and the reaction mixture stirred for 2 hours before being
diluted with dichloromethane. The organic phase was washed with
saturated sodium bicarbonate, washed with brine, and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography eluting with 5% acetone in dichloromethane to yield
N-cyclopentyl-4-[2-(4-fluorophenyl)-7-pyrrolidin-1-ylpyrazolo[1,5-c]pyrim-
idin-3-yl]pyrimidin-2-amine (15 mg, 59%). .sup.1H NMR (CDCl.sub.3):
.delta. 8.05 (d, 1H), 7.65 (d, 1H), 7.60 (dd, 2H), 7.43 (d, 1H),
7.10 (t, 2H), 6.27 (d, 1H), 5.05 (d, 1H), 4.29 (m, 1H), 4.09 (t,
4H), 1.99 (m, 6H), 1.45-1.78 (m, 6H). MS m/z 444 (M+1).
EXAMPLE 31
N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-piperidin-1-ylpyrazolo[1,5-c]pyrimid-
in-3-yl]pyrimidin-2-amine
[0531] ##STR89##
[0532] In a similar manner as described above,
N-cyclopentyl-4-[2-(4-fluorophenyl)-7-piperidin-1-ylpyrazolo[1,5-c]pyrimi-
din-3-yl]pyrimidin-2-amine (25 mg, 45%) was prepared from
N-cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyri-
midin-3-yl]pyrimidin-2-amine and piperidine. .sup.1H NMR
(CDCl.sub.3): .delta. 8.06 (d, 1H), 7.73 (d, 1H), 7.63 (m, 3H),
7.11 (t, 2H), 6.29 (d, 1H), 5.08 (m, 1H), 4.29 (m, 1H), 3.91 (m,
4H), 2.05 (m, 2H), 1.68-1.80 (m, 9H), 1.63 (m, 1H), 1.51 (m, 2H).).
MS m/z 458 (M+1).
EXAMPLE 32
Biological Activity
[0533] In the following example, "MEM" means Minimal Essential
Media; "FBS" means Fetal Bovine Serum; "NP40" and "Igepal" are
detergents; "MOI" means Multiplicity of Infection; "NaOH" means
sodium hydroxide; "MgCl.sub.2" means magnesium chloride; "dATP"
means deoxyadenosine 5' triphosphate; "dUTP" means deoxyuridine 5'
triphosphate; "dCTP" means dexoxycytidine 5' triphosphate; "dGTP"
means deoxyguanosine 5' triphosphate; "GuSCN" means Guanidinium
thiocyanate; "EDTA" means ethylenediamine tetraacetic acid; "TE"
means-Tris-EDTA; "SCC" means sodium chloride/sodium citrate; "APE"
means a solution of ammonia acetate, ammonia phosphate, EDTA; "PBS"
means phosphate buffered saline; and "HRP" means horseradish
peroxidase.
[0534] a) Tissue Culture and HSV Infection.
[0535] Vero 76 cells were maintained in MEM with Earle's salts,
L-glutamine, 8% FBS (Hyclone, A-1111-L) and 100 units/mL
Penicillin-100 .mu.g/mL Streptomycin. For assay conditions, FBS was
reduced to 2%. Cells are seeded into 96-well tissue culture plates
at a density of 5.times.10.sup.4 cells/well after being incubated
for 45 min at 37.degree. C. in the presence of HSV-1 or HSV-2
(MOI=0.001). Test compounds are added to the wells and the plates
are incubated at 37.degree. C. for 40-48 hours. Cell lysates are
prepared as follows: media was removed and replaced with 150
.mu.L/well 0.2 N NaOH with 1% Igepal CA 630 or NP-40. Plates were
incubated up to 14 days at room temperature in a humidified chamber
to prevent evaporation.
[0536] (b) Preparation of Detection DNA.
[0537] For the detection probe, a gel-purified,
digoxigenin-labeled, 710-bp PCR fragment of the HSV UL-15 sequence
was utilized. PCR conditions included 0.5 .mu.M primers, 180 .mu.M
dTTP, 20 .mu.M dUTP-digoxigenin (Boehringer Mannheim 1558706), 200
.mu.M each of dATP, dCTP, and dGTP, 1.times.PCR Buffer II (Perkin
Elmer), 2.5 mM MgCl.sub.2, 0.025 units/.mu.L of AmpliTaq Gold
polymerase (Perkin Elmer), and 5 ng of gel-purified HSV DNA per 100
.mu.L Extension conditions were 10 min at 95.degree. C., followed
by 30 cycles of 95.degree. C. for 1 min, 55.degree. C. for 30 sec.
and 72.degree. C. for 2 min. The amplification was completed with a
10-min incubation at 72.degree. C. Primers were selected to amplify
a 728 bp probe spanning a section of the HSV1 UL15 open reading
frame (nucleotides 249-977). Single-stranded transcripts were
purified with Promega M13 Wizard kits. The final product was mixed
1:1 with a mixture of 6 M GuSCN, 100 mM EDTA and 200 .mu.g/mL
herring sperm DNA and stored at 4.degree. C.
[0538] (c) Preparation of Capture Plates.
[0539] The capture DNA plasmid (HSV UL13 region in pUC) was
linearized by cutting with Xba I, denatured for 15 min at
95.degree. C. and diluted immediately into Reacti-Bind DNA Coating
Solution (Pierce, 17250, diluted 1:1 with TE buffer, pH 8) at 1
ng/.mu.L. 75 .mu.L/well were added to Corning (#3922 or 9690) white
96-well plates and incubated at room temperature for at least 4 hrs
before washing twice with 300 .mu.L/well 0.2.times.SSC/0.05%
Tween-20 (SSC/T buffer). The plates were then incubated overnight
at room temperature with 150 .mu.L/well 0.2 N NaOH, 1% IGEPAL and
10 .mu.g/mL herring sperm DNA.
[0540] (d) Hybridization.
[0541] Twenty-seven (27) .mu.L of cell lysate was combined with 45
.mu.L of hybridization solution (final concentration: 3M GuSCN, 50
mM EDTA, 100 .mu.g/ml salmon sperm DNA, 5.times. Denhardt's
solution, 0.25.times.APE, and 5 ng of the digoxigenin-labeled
detection probe). APE is 1.5 M NH.sub.4-acetate, 0.15 M
NH.sub.4H.sub.2 phosphate, and 5 mM EDTA adjusted to pH 6.0.
Mineral oil (50 .mu.L) was added to prevent evaporation. The
hybridization plates were incubated at 95.degree. C. for 10 minutes
to denature the DNA, then incubated at 42.degree. C. overnight. The
wells were washed 6.times. with 300 .mu.L/well SSC/T buffer then
incubated with 75 .mu.L/well anti-digoxigenin-HRP-conjugated
antibody (Boehringer Mannheim 1207733, 1:5000 in TE) for 30 min at
room temperature. The wells were washed 6.times. with 300
.mu.L/well with PBS/0.05% Tween-20 before 75 .mu.L/well SuperSignal
LBA substrate (Pierce) was added. The plates were incubated at room
temperature for 30 minutes and chemiluminescence was measured in a
Wallac Victor reader.
[0542] e) Results.
[0543] The following results were obtained for HSV-1.
TABLE-US-00001 Example No. IC.sub.50 (.mu.M) 1 0.72 2 5.5 3 3.9 4
11.3 5 0.46 6 0.20 7 0.30 8 2.5 9 7.1 10 0.12 11 6.4 12 1 13 1.5 14
>40 15 >40 16 >40 17 2 18 3.5 19 3 20 >40 21 0.4 22 4
23 0.5 24 1 25 0.6 26 0.5 27 1 28 0.5 29 7 30 2 31 1
[0544] The results demonstrate that the compounds of the present
invention are useful for the treatment and prophylaxis of herpes
viral infections.
* * * * *