U.S. patent application number 11/538462 was filed with the patent office on 2007-12-13 for pyrazolopyridinyl pyridine.
Invention is credited to Jennifer G. Badiang, F. Leslie Boyd, Stanley D. Chamberlain, Mui Cheung, Kristjan Gudmundsson, Philip Anthony Harris, Brian A. Johns, David Kendall Jung, Michael Robert Peel, Connie Jo Sexton.
Application Number | 20070287721 11/538462 |
Document ID | / |
Family ID | 26944940 |
Filed Date | 2007-12-13 |
United States Patent
Application |
20070287721 |
Kind Code |
A1 |
Boyd; F. Leslie ; et
al. |
December 13, 2007 |
Pyrazolopyridinyl pyridine
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: |
Boyd; F. Leslie; (Durham,
NC) ; Chamberlain; Stanley D.; (Durham, NC) ;
Cheung; Mui; (Durham, NC) ; Gudmundsson;
Kristjan; (Durham, NC) ; Harris; Philip Anthony;
(Durham, NC) ; Johns; Brian A.; (Durham, NC)
; Jung; David Kendall; (Durham, NC) ; Peel;
Michael Robert; (Durham, NC) ; Badiang; Jennifer
G.; (Durham, NC) ; Sexton; Connie Jo; (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: |
26944940 |
Appl. No.: |
11/538462 |
Filed: |
October 4, 2006 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10433881 |
Jun 5, 2003 |
7163940 |
|
|
PCT/US01/44231 |
Nov 26, 2001 |
|
|
|
11538462 |
Oct 4, 2006 |
|
|
|
60255763 |
Dec 15, 2000 |
|
|
|
60274284 |
Mar 8, 2001 |
|
|
|
Current U.S.
Class: |
514/275 ;
514/256; 514/300; 544/331; 544/333; 546/121 |
Current CPC
Class: |
A61P 1/08 20180101; A61P
35/00 20180101; A61P 1/00 20180101; A61P 1/14 20180101; A61P 3/02
20180101; A61P 11/00 20180101; A61P 1/04 20180101; A61P 1/16
20180101; A61P 25/28 20180101; A61P 13/12 20180101; A61P 25/00
20180101; A61P 27/02 20180101; A61P 9/10 20180101; A61P 31/22
20180101; A61P 29/02 20180101; A61P 27/16 20180101; A61P 25/02
20180101; A61P 29/00 20180101; C07D 471/04 20130101; A61P 31/12
20180101 |
Class at
Publication: |
514/275 ;
514/256; 514/300; 544/331; 544/333; 546/121 |
International
Class: |
A61K 31/506 20060101
A61K031/506; A61K 31/437 20060101 A61K031/437; A61P 31/22 20060101
A61P031/22; C07D 401/14 20060101 C07D401/14; C07D 471/04 20060101
C07D471/04 |
Claims
1. A compound of formula (I): ##STR145## wherein: R.sup.1 is
selected from the group consisting of halo, --NR.sup.7R.sup.8, Ay,
--NR.sup.7Ay, Het, --NH(CH.sub.2).sub.mHet, and
--NH(CH.sub.2).sub.lAy; 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, alkylhydroxy,
amine, alkylamine, alkylcarboxy, alkylcarboxamide, alkyl
alkoxycarbonyl, alkylthioamide, alkylsulfonyl, alkylsulfonamide,
alkylether, --(CH.sub.2).sub.l-cycloalkyl,
--(CH.sub.2).sub.lNHCOR.sup.9 and
--(CH.sub.2).sub.mSO.sub.2NHCOR.sup.9; l is 1-6; m is 0-6; R.sup.9
is H, alkyl, cycloalkyl, alkylhydroxy, amine, alkylamine,
alkylcarboxy and alkylether; Ay is aryl; Het is a 5- or 6-membered
heterocyclic or heteroaryl group; R.sup.2 is selected from the
group consisting of H, halo, alkyl, cycloalkyl, alkenyl,
cycloalkenyl, --NR.sup.7R.sup.8, --OR.sup.7, --OAy,
--S(O).sub.nR.sup.7, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, Ay, Het, --NH(CH.sub.2).sub.mHet and
--O(CH.sub.2).sub.mHet; n is 0, 1 or 2; R.sup.10 is alkyl or
alkenyl; Y is CH; R.sup.3 and R.sup.4 are each independently
selected from the group consisting of H, halo, hydroxy, alkyl,
alkylhydroxy, alkylamine, alkylether, --OR.sup.7, --OAy,
--NR.sup.7R.sup.8, --NR.sup.7Ay, carboxy, carboxamide,
--SO.sub.2NHR.sup.9, Het and Ay; and R.sup.5 is halo; wherein when
Y is CH, R.sup.3 is not --NR.sup.7Ay; or a pharmaceutically
acceptable salt thereof.
2. The compound according to claim 1 wherein R.sup.1 is selected
from the group consisting of --NR.sup.7R.sup.8, --NR.sup.7Ay, Ay,
Het, --NH(CH.sub.2).sub.mHet, and --NH(CH.sub.2).sub.lAy.
3. The compound according to claim 1 wherein R.sup.1 is
--NR.sup.7R.sup.8.
4. The compound according to claim 1 wherein R.sup.2 is selected
from the group consisting of --NR.sup.7R.sup.8, --OR.sup.7, --OAy,
--S(O).sub.nR.sup.7, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, Ay, Het, --NH(CH.sub.2).sub.mHet and
--O(CH.sub.2).sub.mHet.
5. The compound according to claim 4 wherein R.sup.2 is selected
from the group consisting of --NR.sup.7R.sup.8 and Het.
6-7. (canceled)
8. The compound according to claim 1 wherein R.sup.3 and R.sup.4
are each independently selected from the group consisting of H,
hydroxy, alkyl, alkylhydroxy, alkylamine, alkylether,
--NR.sup.7R.sup.8, --NR.sup.7Ay, carboxy and Ay.
9. The compound according to claim 8 wherein R.sup.3 is selected
from the group consisting of H, alkyl, alkylhydroxy, alkylamine,
alkylether, and Ay.
10. The compound according to claim 8 wherein R.sup.4 is H.
11. The compound according to claim 1 wherein R.sup.5 is
fluoro.
12-17. (canceled)
18. A pharmaceutical formulation comprising a compound according to
claim 1.
19. The pharmaceutical formulation according to claim 18 further
comprising a pharmaceutically acceptable carrier or diluent.
20. The pharmaceutical formulation according to claim 18 further
comprising an antiviral agent selected from the group consisting of
aciclovir and valaciclovir.
21. 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.
22. (canceled)
23. A method for the treatment of a condition or disease associated
with a herpes viral infection selected from heroes simplex virus I
and herpes simplex virus 2 in an animal, comprising administering
to the animal a therapeutically effective amount of the compound
according to claim 1.
24-36. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is divisional of U.S. patent application
Ser. No.10/433,881, filed 5 Jun. 2003 (allowed), which is a 371
Application of PCT/US01/44231, filed 26 Nov. 2001, which claims
priority to U.S. Application Ser. No. 60/255,763, filed 15 Dec.
2000 and U.S. Application Ser. No. 60/274,284, filed 8 Mar.
2001.
BACKGROUND OF THE INVENTION
[0002] 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.
[0003] 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.
[0004] 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 the HSV-1 virus, 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.
[0005] VZV 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.
[0006] 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 atheroslcerosis.
[0007] 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 tumours,
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 tumours 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 and multiple sclerosis.
[0008] 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.
[0009] 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
[0010] According to a first aspect of the invention there is
provided the compound of formula (I): ##STR2## wherein: [0011]
R.sup.1 is selected from the group consisting of halo,
--NR.sup.7R.sup.8, --NR.sup.7Ay, Ay, Het, --NH(CH.sub.2).sub.mHet,
and --NH(CH.sub.2).sub.lAy; [0012] 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,
alkylhydroxy, amine, alkylamine, alkylcarboxy, alkylcarboxamide,
alkyl alkoxycarbonyl, alkylthioamide, alkylsulfonyl,
alkylsulfonamide, alkylether, --(CH.sub.2).sub.l-cycloalkyl,
--(CH.sub.2).sub.lNHCOR.sup.9 and
--(CH.sub.2).sub.mSO.sub.2NHCOR.sup.9;
[0013] l is 1-6; [0014] m is 0-6; [0015] R.sup.9 is H, alkyl,
cycloalkyl, alkylhydroxy, amine, alkylamine, alkylcarboxy and
alkylether; [0016] Ay is aryl; [0017] Het is a 5- or 6-membered
heterocyclic or heteroaryl group; [0018] R.sup.2 is selected from
the group consisting of H, halo, alkyl, cycloalkyl, alkenyl,
cycloalkenyl, --NR.sup.7R.sup.8, --OR.sup.7, --OAy,
--S(O).sub.nR.sup.7, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, Ay, Het, --NH(CH.sub.2).sub.mHet and
--O(CH.sub.2).sub.mHet; [0019] n is 0, 1 or 2; [0020] R.sup.10 is
alkyl or alkenyl; [0021] Y is N or CH; [0022] R.sup.3 and R.sup.4
are each independently selected from the group consisting of H,
halo, hydroxy, alkyl, alkylhydroxy, alkylamine, alkylether,
--OR.sup.7, --OAy, --NR.sup.7R.sup.8, --NR.sup.7Ay, carboxy,
carboxamide, --SO.sub.2NHR.sup.9, Het and Ay; and [0023] R.sup.5 is
halo; [0024] wherein when Y is CH, R.sup.3 is not --NR.sup.7Ay;
[0025] and pharmaceutically acceptable salts, solvates and
physiologically functional derivatives thereof.
[0026] In another aspect of the invention there is provided a
pharmaceutical formulation comprising a compound of formula (I). In
one embodiment, the pharmaceutical formulation further comprises a
pharmaceutically acceptable carrier or diluent. In one embodiment,
the pharmaceutical formulation further comprises an antiviral agent
selected from the group consisting of aciclovir and
valaciclovir.
[0027] In a third aspect of the invention, there is provided a
method for the prophylaxis or treatment of herpes viral infections
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 of physiologically
functional derivative thereof.
[0028] In a fourth aspect, there is provided a method for the
treatment or prophylaxis of conditions or diseases associated with
herpes viral infections 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.
[0029] In another aspect, there is provided a process for preparing
the compound of formula (I), wherein Y is N, R.sup.2 is selected
from the group consisting of H, alkyl, cycloalkyl, alkenyl,
cycloalkenyl, --NR.sup.7R.sup.8, --OR.sup.7, --OAy,
--S(O).sub.nR.sup.7, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, Ay, Het, --NH(CH.sub.2).sub.mHet and
--O(CH.sub.2).sub.mHet; and R.sup.3 and R.sup.4 are both H. The
process comprises reacting a compound of formula (IX): ##STR3##
[0030] with an amine of formula (X): ##STR4##
[0031] In another aspect, the present invention provides a process
for preparing the compound of formula (I) wherein Y is N; R.sup.2
is selected from the group consisting of H, alkyl, cycloalkyl,
alkenyl, cycloalkenyl, --NR.sup.7R.sup.8, --OR.sup.7, --OAy,
--S(O).sub.nR.sup.7, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, Ay, Het, --NH(CH.sub.2).sub.mHet and
--O(CH.sub.2).sub.mHet; R.sup.3 is selected from the group
consisting of H, alkyl, alkylhydroxy, alkylamine, alkylether,
--NR.sup.7R.sup.8 where R.sup.7 and R.sup.8 are not H, --NR.sup.7Ay
where R.sup.7 is not H, carboxy, carboxamide, --SO.sub.2NHR.sup.9,
Het and Ay; and R.sup.4 is H. The process comprises reacting a
compound of formula (XVI): ##STR5##
[0032] with an amine of formula (X): ##STR6##
[0033] In another aspect, the present invention provides a process
for preparing the compound of formula (I), wherein Y is N and
R.sup.2 is selected from the group consisting of H, alkyl,
cycloalkyl, alkenyl, cycloalkenyl, --NR.sup.7R.sup.8, --OR.sup.7,
--OAy, --S(O).sub.nR.sup.7, --S(O).sub.nAy,
--R.sup.10NR.sup.7R.sup.8, --R.sup.10NR.sup.7Ay, Ay, Het,
--NH(CH.sub.2).sub.mHet and --O(CH.sub.2).sub.mHet. The process
comprises the steps of: [0034] (a) reacting a compound of formula
(XX): ##STR7##
[0035] with an amine of formula (X): ##STR8##
[0036] to prepare an intermediate compound; and [0037] b) oxidizing
the intermediate compound.
[0038] In another aspect, the present invention provides a process
for preparing compounds of formula (I). The process comprises
reacting a compound of formula (XXII): ##STR9## [0039] wherein
X.sup.1 is chloro, bromo or iodo;
[0040] with a compound of formula (XXIV): ##STR10## [0041] wherein
M.sup.2 is selected from the group consisting of --B(OH).sub.2,
--B(ORa).sub.2, --B(Ra).sub.2, --Sn(Ra).sub.3, Zn-halide, ZnRa and
Mg-halide, where Ra is alkyl or cycloalkyl and halide is halo.
[0042] In 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 present invention provides a
tritiated compound of formula (I) or a pharmaceutically acceptable
salt, solvate or physiologically functional derivative thereof.
[0043] In another aspect, the present invention provides a compound
of formula (I) for use in therapy.
[0044] The present invention also provides a compound of formula
(I) for use in the prophylaxis or treatment of herpes viral
infections in an animal.
[0045] The present invention also provides a compound of formula
(I) for use in the prophylaxis or treatment of conditions or
diseases associated with herpes viral infections in an animal.
[0046] In yet another aspect, the present invention provides the
use of a compound of formula (I) for the preparation of a
medicament for the treatment of herpes viral infections in an
animal.
[0047] 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 conditions or diseases associated with herpes viral
infections in an animal.
DETAILED DESCRIPTION OF THE INVENTION
[0048] As used herein, "a compound of the invention" 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
compounds of formula (IX) (XVI), (XX), and (XXII), the phrase "a
compound of formula (number)" means a compound having that formula
and pharmaceutically acceptable salts, solvates and physiologically
functional derivatives thereof.
[0049] As used herein, the terms "alkyl" and "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. The alkyl groups may be
optionally substituted with alkylsulfenyl, alkylsulfinyl,
alkylsulfonyl, oxo, mercapto, nitro, cyano, halo, and
perfluoroalkyl. Trihalomethyl, such as trifluoromethyl, is one
preferred alkyl group.
[0050] As used herein, the term "cycloalkyl" 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 be optionally substituted with
substituents selected from a group consisting of mercapto, nitro,
cyano, halo, and perfluoroalkyl.
[0051] As used herein, the term "alkenyl" 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 be optionally substituted with mercapto, nitro,
cyano, halo, and perfluoroalkyl.
[0052] As used herein, the term "cycloalkenyl" refers to a
non-aromatic carbocyclic ring having from 3 to 8 carbon atoms and
from one to three carbon-carbon double bonds. "Cycloalkenyl"
includes by way of example cyclobutenyl, cyclopentenyl,
cyclohexenyl, cycloheptenyl and cyclooctenyl. "Cycloalkenyl" also
includes substituted cycloalkenyl. The cycloalkenyl may be
optionally substituted with substituents selected from a group
consisting of mercapto, nitro, cyano, halo, and perfluoroalkyl.
[0053] As used herein, the term "alkoxy" refers to the group RaO--,
where Ra is alkyl or cycloalkyl as defined above.
[0054] The term "alkylhydroxy" refers to the group --RaOH, where Ra
is alkyl or cycloalkyl as defined above.
[0055] The term "alkylamine" refers to the group --RaNH.sub.2,
where Ra is alkyl or cycloalkyl as defined above.
[0056] The term "alkylcarboxy" refers to the group --RaC(O)OH,
where Ra is alkyl or cycloalkyl as defined above.
[0057] The term "alkylether" refers to the group --RaORa, where Ra
is alkyl or cycloalkyl as defined above.
[0058] The term "alkyl alkoxycarbonyl" refers to a group
--Ra--C(O)--O--Ra, where Ra is alkyl or cycloalkyl as defined
above.
[0059] The term "alkylsulfonamide" refers to a group
--Ra--SO.sub.2--NH.sub.2, where Ra is alkyl or cycloalkyl as
defined above.
[0060] The term "halo" or "halogen" refers to the elements
fluorine, chlorine, bromine and iodine.
[0061] 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 substitued aryl groups. Aryl groups may be optionally
substituted with substituents selected from the group consisting of
halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, perfluoroalkyl,
alkoxy, amino, hydroxy, alkylhydroxy, alkylamine, alkylether
carboxy, carboxamide, sulfonamide, Het, amidine, cyano, nitro and
azido. Phenyl and substituted phenyl are preferred aryl groups.
[0062] The term "heterocyclic" refers to a monocyclic saturated or
unsaturated non-aromatic carbocyclic groups and fused bicyclic
non-aromatic carbocyclic groups, having the specified number of
members in a single ring 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. "Heterocycle" also includes
substituted heterocycle. The heterocyclic group may be optionally
substituted with substituents selected from a group consisting of
halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl, perfluoroalkyl,
alkoxy, amino, hydroxy, alkylhydroxy, alkylamine alkylether,
carboxy, carboxamide, sulfonamide, Het, amidine, cyano, nitro an
azido. Preferred heterocyclic groups include but are not limited to
pyrrolidine, piperidine, morpholine, thiomorpholine and
piperazine.
[0063] The term "heteroaryl" refers to aromatic monocyclic
heterocyclic 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 groups. The heteroaryl group may be
optionally substituted with substituents selected from a group
consisting of halo, alkyl, alkenyl, cycloalkyl, cycloalkenyl,
perfluoroalkyl, alkoxy, amino, hydroxy, alkylhydroxy, alkylamine,
alkylether, carboxy, carboxamide, sulfonamide, Het, amidine, cyano,
nitro and azido. Preferred heteroaryl groups include but are not
limited to pyridine, furan, thiophene, pyrrole, imidazole,
pyrazole, and pyrimidine.
[0064] 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.
[0065] The present invention provides compounds of formula (I):
##STR11##
[0066] wherein: [0067] R.sup.1 is selected from the group
consisting of halo, --NR.sup.7R.sup.8, Ay, --NR.sup.7Ay, Het,
--NH(CH.sub.2).sub.mHet, and --NH(CH.sub.2).sub.lAy; [0068] 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, alkylhydroxy, amine, alkylamine,
alkylcarboxy, alkylcarboxamide, alkyl alkoxycarbonyl,
alkylthioamide, alkylsulfonyl, alkylsulfonamide, alkylether,
--(CH.sub.2).sub.l-cycloalkyl, --(CH.sub.2).sub.lNHCOR.sup.9 and
--(CH.sub.2).sub.mSO.sub.2NHCOR.sup.9; [0069] l is 1-6; [0070] m is
0-6; [0071] R.sup.9 is H, alkyl, cycloalkyl, alkylhydroxy, amine,
alkylamine, alkylcarboxy and alkylether; [0072] Ay is aryl; [0073]
Het is a 5- or 6-membered heterocyclic or heteroaryl group; [0074]
R.sup.2 is selected from the group consisting of H, halo, alkyl,
cycloalkyl, alkenyl, cycloalkenyl, --NR.sup.7R.sup.8, --OR.sup.7,
--OAy, --S(O).sub.nR.sup.7, --S(O).sub.nAy,
--R.sup.10NR.sup.7R.sup.8, --R.sup.10NR.sup.7Ay, Ay, Het,
--NH(CH.sub.2).sub.mHet and --O(CH.sub.2).sub.mHet; [0075] n is 0,
1 or 2; [0076] R.sup.10 is alkyl or alkenyl; [0077] Y is N or CH;
[0078] R.sup.3 and R.sup.4 are each independently selected from the
group consisting of H, halo, hydroxy, alkyl, alkylhydroxy,
alkylamine, alkylether, --OR.sup.7, --OAy, --NR.sup.7R.sup.8,
--NR.sup.7Ay, carboxy, carboxamide, --SO.sub.2NHR.sup.9, Het and
Ay; and [0079] R.sup.5 is halo; [0080] wherein when Y is CH,
R.sup.3 is not --NR.sup.7Ay;
[0081] and pharmaceutically acceptable salts, solvates and
physiologically functional derivatives thereof.
[0082] Preferred compounds of formula (I) include those compounds
defined wherein at least one of R.sup.1 and R.sup.2 contain an
aryl, heterocyclic or heteroaryl moiety. The groups of Ay, --OAy,
--NR.sup.7Ay, --R.sup.10NR.sup.7Ay, --S(O).sub.nAy, Het,
--NH(CH.sub.2).sub.mHet, --NH(CH.sub.2).sub.lAy, and
--O(CH.sub.2).sub.mHet are some examples of groups containing an
aryl, heterocyclic or heteroaryl moiety. To illustrate, in such
embodiments, if R.sup.2 is defined as H, halo, alkyl, cycloalkyl,
alkenyl, cycloalkenyl, --NR.sup.7R.sup.8, --OR.sup.7,
--S(O).sub.nR.sup.7 or --R.sup.10NR.sup.7R.sup.8; then R.sup.1 is
selected from the group consisting of Ay, --NR.sup.7Ay, Het,
--NH(CH.sub.2).sub.mHet, and --NH(CH.sub.2).sub.lAy; and if R.sup.1
is halo or --NR.sup.7R.sup.8; then R.sup.2 is selected from the
group consisting of Ay, --OAy, --R.sup.10NR.sup.7Ay,
--S(O).sub.nAy, Het, --NH(CH.sub.2).sub.mHet, and
--O(CH.sub.2).sub.mHet. In one embodiment, compounds of the present
invention include those compounds defined wherein at least one of
R.sup.1 and R.sup.2 contain a heterocyclic or heteroaryl moiety
such as Het, --NH(CH.sub.2).sub.mHet and
--O(CH.sub.2).sub.mHet.
[0083] Another class of compounds of formula (I) include those
compounds defined wherein neither R.sup.1 nor R.sup.2 contain an
aryl, heterocyclic or heteroaryl moiety. In such embodiments,
R.sup.1 is preferably halo or --NR.sup.7R.sup.8, and R.sup.2 is
preferably selected from the group consisting of H, halo, alkyl,
cycloalkyl, alkenyl, cycloalkenyl, --NR.sup.7R.sup.8, --OR.sup.7,
--S(O).sub.nR.sup.7, and --R.sup.10NR.sup.7R.sup.8. More
preferably, neither of R.sup.1 and R.sup.2 contain a heterocyclic
or heteroaryl moiety, but may contain an aryl moiety.
[0084] In one preferred class of compounds of formula (I), Y is CH.
In another preferred class of compounds of formula (I), Y is N.
According to one preferred embodiment, when Y is CH, R.sup.3 is not
--NR.sup.7Ay.
[0085] Preferably, R.sup.1 is selected from the group consisting of
--NR.sup.7R.sup.8, Ay, --NR.sup.7Ay, Het, --NH(CH.sub.2).sub.mHet,
and --NH(CH.sub.2).sub.lAy, or any subset thereof. More preferably,
R.sup.1 is selected from the group consisting of --NR.sup.7R.sup.8,
Het and --NH(CH.sub.2).sub.mHet, or any subset thereof.
Particularly preferred compounds of formula (I) are defined wherein
R.sup.1 is --NR.sup.7R.sup.8.
[0086] In particular, R.sup.1 is preferably selected from the group
consisting of Cl, --NH.sub.2, --NHalkyl, --NHcycloalkyl,
--N(alkyl)(alkyl), Het, --Nalkyl-O-alkyl, and --NHAy, or any subset
thereof. Specific examples of some preferred R.sup.1 groups are
selected from the group consisting of Cl, --NH.sub.2, --NH-methyl,
--N(CH.sub.3).sub.2, --NH-cyclopentyl, --NH-cyclopropyl,
--NH-propyl, --NH-isopropyl, --NH-n-butyl, --NH-phenyl,
--NH(CH.sub.2).sub.2OCH.sub.3, and pyrrolidine, or any subset
thereof. In one embodiment R.sup.1 is --NH-cyclopentyl. In one
embodiment R.sup.1 is --NH-n-butyl. In one embodiment R.sup.1 is
--NH-cyclopropyl. In one embodiment R.sup.1 is pyrrolidine.
[0087] R.sup.2 is preferably selected from the group consisting of
--NR.sup.7R.sup.8, --OR.sup.7, --OAy, --S(O).sub.nR.sup.7,
--S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8, --R.sup.10NR.sup.7Ay,
Ay, Het, --NH(CH.sub.2).sub.mHet and --O(CH.sub.2).sub.mHet, or any
subset thereof. More preferably, R.sup.2 is selected from the group
consisting of --NR.sup.7R.sup.8, --R.sup.10NR.sup.7R.sup.8, Ay and
Het or any subset thereof. Particularly preferred compounds of
formula (I) are defined where R.sup.2 is selected from the group
consisting of --NR.sup.7R.sup.8 and Het, or any subset thereof.
[0088] More particularly, preferred embodiments of the present
invention include compounds of formula (I) wherein R.sup.2 is
selected from the group consisting of --NH.sub.2, --NH-alkyl,
--NH-cycloalkyl, Het and --NH-alkyl-Het. Particularly preferred
embodiments include those compounds of formula (I) wherein R.sup.2
is --NH.sub.2, --NH-propyl, --NH-isopropyl, --NH-cyclopropyl,
--NH-butyl, --NH-isobutyl, --NH-cyclobutyl, --NH-cyclopentyl,
--NH-cyclohexyl, --NH(CH.sub.2).sub.2OCH.sub.3, and pyrrolidine
(e.g., pyrrolidine bonded through N).
[0089] Preferably, R.sup.7 and R.sup.8 are each the same or
different and are independently selected from the group consisting
of H, alkyl, cycloalkyl, alkylhydroxy, amine, alkylamine, and
alkylcarboxy, or any subset thereof. More preferably, R.sup.7 and
R.sup.8 are each the same or different and are independently
selected from the group consisting of H, alkyl and cycloalkyl, or
any subset thereof.
[0090] Preferably, R.sup.3 and R.sup.4 are each the same or
different and are each independently selected from the group
consisting of H, hydroxy, alkyl, alkylhydroxy, alkylamine,
alkylether, --NR.sup.7R.sup.8, carboxy and Ay, or any subset
thereof. More preferably, R.sup.3 and R.sup.4 are each the same or
different and are each independently selected from the group
consisting of H, alkyl, alkylhydroxy, alkylamine, alkylether or Ay,
or any subset thereof.
[0091] More particularly, R.sup.3 and R.sup.4 are each the same or
different and are each independently selected from the group
consisting of H, F, Cl, Br, methyl, ethyl, propyl, O-methyl,
O-ethyl, O-isopropyl, --CH.sub.2--O-methyl, --NH.sub.2,
--NH(alkyl), --N(alkyl)(alkyl), --CH.sub.2--NH.sub.2,
--CH.sub.2--NH(alkyl), --CH.sub.2--N(alkyl)(alkyl), --CO.sub.2H,
--CO.sub.2-methyl and phenyl, or any subset thereof. More
preferably, R.sup.3 and R.sup.4 are each the same or different and
are each independently selected from the group consisting of H, F,
Cl, Br, methyl, ethyl, propyl, O-methyl, O-ethyl, O-isopropyl, and
--NH.sub.2, --NH(alkyl), --N(alkyl)(alkyl), or any subset
thereof.
[0092] In one preferred embodiment, R.sup.3 is H or alkyl; more
preferably H.
[0093] In one preferred embodiment, R.sup.4 is H or alkyl; more
preferably H.
[0094] Preferably, R.sup.5 is fluoro.
[0095] It is to be understood that the present invention includes
all combinations of the particular and preferred groups defined
hereinabove.
[0096] Preferred compounds of formula (I) include but are not
limited to: [0097]
N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluoro-
phenyl)pyrazolo[1,5-a]pyridin-7-amine; [0098]
2-(4-Bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]-
pyridin-7-amine; [0099]
N-Butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a-
]pyridin-7-amine; [0100]
N-Butyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo-
[1,5-a]pyridin-7-amine; [0101]
N-Butyl-2-(4-fluorophenyl)-3-[2-(1-pyrrolidinyl)-4-pyrimidinyl]pyrazolo[1-
,5-a]pyridin-7-amine; [0102]
N-Butyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo-
[1,5-a]pyridin-7-amine; [0103]
4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
6-methyl-2-pyrimidinamine; [0104]
N-Cyclopentyl-3-[2-(cyclopentylamino)-6-methyl-4-pyrimidinyl]-2-(4-fluoro-
phenyl)pyrazolo[1,5-a]pyridin-7-amine; [0105]
2-(4-Bromophenyl)-N-butyl-3-[2-(1-pyrrolidinyl)-4-pyrimidinyl]pyrazolo[1,-
5-a]pyridin-7-amine; [0106]
2-(4-Bromophenyl)-N-butyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[-
1,5-a]pyridin-7-amine; [0107]
N-Cyclopentyl-3-[2-(dimethylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyraz-
olo[1,5-a]pyridin-7-amine; [0108]
3-(2-Amino-4-pyrimidinyl)-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-a]-
pyridin-7-amine; [0109]
N-Cyclopentyl-2-(4-fluorophenyl)-3-(2-{[3-(4-morpholinyl)propyl]amino}-4--
pyrimidinyl)pyrazolo[1,5-a]pyridin-7-amine; [0110]
N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-hydrazinopyrazolo[1,5-a]pyridin-3-y-
l]-6-methyl-2-pyrimidinamine; [0111]
N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(4-methyl-1-piperazinyl)pyrazolo[1,-
5-a]pyridin-3-yl]-6-methyl-2-pyrimidinamine; [0112]
N-Cyclopentyl-3-{2-(cyclopentylamino)-6-[(tetrahydro-2H-pyran-2-yloxy)met-
hyl]-4-pyrimidinyl}-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine;
[0113]
[6-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(cy-
clopentylamino)-4-pyrimidinyl]methanol; [0114]
[{4-[7-(Cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]--
2-pyrimidinyl}(methyl)amino]acetic acid; [0115]
N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(4-methyl-1-piperazinyl)pyrazolo[1,-
5-a]pyridin-3-yl]-6-phenyl-2-pyrimidinamine hydrochloride; [0116]
N.sup.1-[3-[2-(Cyclopentylamino)-6-phenyl-4-pyrimidinyl]-2-(4-fluoropheny-
l)pyrazolo-[1,5-a]pyridin-7-yl]-1,2-ethanediamine; [0117]
3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]p-
yridin-7-amine; [0118]
{2-(Cyclopentylamino)-6-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[-
1,5-a]pyridin-3-yl]-4-pyrimidinyl}methanol; [0119]
3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-(4-methoxyphe-
nyl)-pyrazolo[1,5-a]pyridin-7-amine; [0120] Methyl
{[3-[2-(cyclopentylamino)-6-methyl-4-pyrimidinyl]-2-(4-fluorophenyl)-pyra-
zolo[1,5-a]pyridin-7-yl]amino}acetate; [0121]
{[3-[2-(Cyclopentylamino)-6-methyl-4-pyrimidinyl]-2-(4-fluorophenyl)pyraz-
olo[1,5-a]pyridin-7-yl]amino}acetic acid; [0122]
4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
2-pyrimidinamine; [0123]
6-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(cyclopentyl-
amino)-4-pyrimidinecarboxylic acid; [0124]
N-Cyclopentyl-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-7--
amine; [0125]
N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(4-fluorophenyl)pyra-
zolo[1,5-a]pyridin-7-amine; [0126]
N-Cyclopentyl-2-(4-fluorophenyl)-3-(2-hydrazino-4-pyridinyl)pyrazolo[1,5--
a]pyridin-7-amine; [0127]
N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyri-
din-3-yl]-2-pyrimidinamine; [0128]
4-[2-(4-Fluorophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N--
dimethyl-2-pyrimidinamine; [0129]
3-[2-(Butylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-fluorophenyl)pyrazolo-
[1,5-a]pyridin-7-amine; [0130]
3-[2-(Butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N,N-dimethylpyrazolo[-
1,5-a]pyridin-7-amine; [0131]
N-Butyl-4-[2-(4-fluorophenyl)-7-(4-methyl-1-piperazinyl)pyrazolo[1,5-a]py-
ridin-3-yl]-2-pyrimidinamine; [0132]
N-Butyl-4-[2-(4-fluorophenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-y-
l]-2-pyrimidinamine; [0133]
N-Butyl-2-(4-fluorophenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1-
,5-a]pyridin-7-amine; [0134]
3-({4-[7-(Butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-py-
rimidinyl}amino)-1-propanol; [0135]
3-[2-(Allylamino)-4-pyrimidinyl]-N-butyl-2-(4-fluorophenyl)pyrazolo[1,5-a-
]pyridin-7-amine; [0136]
N-Butyl-2-(4-fluorophenyl)-3-[2-(4-morpholinyl)-4-pyrimidinyl]pyrazolo[1,-
5-a]pyridin-7-amine; [0137]
2-(4-{4-[7-(Butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2--
pyrimidinyl}-1-piperazinyl)ethanol; [0138]
N-Butyl-2-(4-fluorophenyl)-3-{2-[4-(2-methoxyethyl)-1-piperazinyl]-4-pyri-
midinyl}pyrazolo[1,5-a]pyridin-7-amine; [0139]
N-Butyl-2-(4-fluorophenyl)-3-{2-[(2-pyridinylmethyl)amino]-4-pyrimidinyl}-
pyrazolo[1,5-a]pyridin-7-amine; [0140]
N-Butyl-2-(4-fluorophenyl)-3-(2-{[3-(1H-imidazol-1-yl)propyl]amino}-4-pyr-
imidinyl)pyrazolo[1,5-a]pyridin-7-amine; [0141]
N-Butyl-2-(4-fluorophenyl)-3-(2-{[2-(4-morpholinyl)ethyl]amino}-4-pyrimid-
inyl)pyrazolo[1,5-a]pyridin-7-amine; [0142]
N-Butyl-2-(4-fluorophenyl)-3-{2-[2-(4-morpholinyl)ethoxy]-4-pyrimidinyl}p-
yrazolo-[1,5-a]pyridin-7-amine; [0143]
3-[2-(Butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-[2-(4-morpholinyl)e-
thyl]-pyrazolo[1,5-a]pyridin-7-amine; [0144]
3-[2-(Butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-(2-methoxyethyl)pyr-
azolo-[1,5-a]pyridin-7-amine; [0145]
3-[2-(Butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-methylpyrazolo[1,5--
a]-pyridin-7-amine; [0146]
4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
6-[(dimethylamino)methyl]-2-pyrimidinamine; [0147]
N-Cyclopentyl-3-{2-(cyclopentylamino)-6-[(dimethylamino)methyl]-4-pyrimid-
inyl}-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine; [0148]
4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
5-methyl-2-pyrimidinamine; [0149]
N-Cyclopentyl-3-[2-(cyclopentylamino)-5-methyl-4-pyrimidinyl]-2-(4-fluoro-
phenyl)pyrazolo[1,5-a]pyridin-7-amine; [0150]
N-Allyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-pyrazolo[1,5--
a]pyridin-7-amine; [0151]
3-[2-(Butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-propylpyrazolo[1,5--
a]pyridin-7-amine; [0152]
7-Chloro-2-(4-fluorophenyl)-3-pyridin-4-ylpyrazolo[1,5-a]pyridine;
[0153]
N-[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-7-yl]-
-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]amine; [0154]
2-(4-Fluorophenyl)-N-methyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-7-amine-
; [0155]
N,N-Diethyl-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]py-
ridin-7-amine; [0156]
2-(4-Fluorophenyl)-7-iodo-3-pyridin-4-ylpyrazolo[1,5-a]pyridine;
[0157]
7-Bromo-2-(4-fluorophenyl)-3-pyridin-4-ylpyrazolo[1,5-a]pyridine;
[0158]
N-Butyl-2-(4-fluorophenyl)-3-pyridin-4-ylpyrazolo[1,5-a]pyridin-7-amine;
[0159]
2-(4-Fluorophenyl)-7-(1H-imidazol-1-yl)-3-pyridin-4-ylpyrazolo[1-
,5-a]pyridine; [0160]
2-(4-Fluorophenyl)-3,7-bis(2-fluoropyridin-4-yl)pyrazolo[1,5-a]pyridine;
[0161]
N-{4-[3-{2-[(3-Aminopropyl)amino]pyridin-4-yl}-2-(4-fluorophenyl)-
pyrazolo[1,5-a]pyridin-7-yl]pyridin-2-yl}propane-1,3-diamine;
[0162]
4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propylpyridi-
n-2-amine; [0163]
N-Butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]pyridin-
-2-amine; [0164]
N-Butyl-2-(4-fluorophenyl)-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]pyr-
azolo[1,5-a]pyridin-7-amine; [0165]
2-(4-Fluorophenyl)-7-pyrrolidin-1-yl-3-(2-pyrrolidin-1-ylpyrimidin-4-yl)p-
yrazolo[1,5-a]pyridine; [0166]
3-[(4-{2-(4-Fluorophenyl)-7-[(3-hydroxypropyl)amino]pyrazolo[1,5-a]pyridi-
n-3-yl}pyrimidin-2-yl)amino]propan-1-ol; [0167]
N-Cyclohexyl-3-[2-(cyclohexylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyra-
zolo[1,5-a]pyridin-7-amine; [0168]
3-[2-(Cyclopentylamino)-6-methylpyrimidin-4-yl]-2-(4-fluorophenyl)pyrazol-
o[1,5-a]pyridin-7-amine; [0169]
7-Chloro-2-(4-fluorophenyl)-3-(2-phenylpyrimidin-4-yl)pyrazolo[1,5-a]pyri-
dine; [0170]
6-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
2-(cyclopentylamino)pyrimidine-4-carboxamide; [0171]
N-Cyclopentyl-2-(cyclopentylamino)-6-[7-(cyclopentylamino)-2-(4-fluorophe-
nyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidine-4-carboxamide; [0172]
7-Chloro-3-(2-cyclopropylpyrimidin-4-yl)-2-(4-fluorophenyl)pyrazolo[1,5-a-
]pyridine; [0173]
7-Chloro-2-(4-fluorophenyl)-3-(2-isopropylpyrimidin-4-yl)pyrazolo[1,5-a]p-
yridine; [0174]
N-Butyl-4-[2-(4-fluorophenyl)-7-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]pyri-
midin-2-amine; [0175]
4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylp-
yrimidin-2-amine; [0176]
2-(4-Chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]py-
razolo[1,5-a]pyridin-7-amine; [0177]
N-Cyclopentyl-3-[2-(dimethylamino)-6-methylpyrimidin-4-yl]-2-(4-fluorophe-
nyl)pyrazolo[1,5-a]pyridin-7-amine; [0178]
N-Cyclopentyl-3-[2-(cyclopentylamino)-6-phenylpyrimidin-4-yl]-2-(4-fluoro-
phenyl)pyrazolo[1,5-a]pyridin-7-amine; [0179]
N-Cyclopentyl-6-[2-(4-fluorophenyl)-7-(methylthio)pyrazolo[1,5-a]pyridin--
3-yl]pyrimidin-4-amine; and [0180]
N-cyclopentyl-3-[6-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)py-
razolo[1,5-a]pyridin-7-amine [0181] and pharmaceutically acceptable
salts, solvates and physiologically functional derivatives
thereof.
[0182] Particularly preferred compounds of formula (I) include but
are not limited to: [0183]
N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluoro-phenyl)p-
yrazolo[1,5-a]pyridin-7-amine; [0184]
2-(4-Bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo-[1,5-a-
]pyridin-7-amine; [0185]
N-Butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo-[1,5--
a]pyridin-7-amine; [0186]
N-Butyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-pyrazol-
o[1,5-a]pyridin-7-amine; [0187]
N-Butyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo-
[1,5-a]pyridin-7-amine; [0188]
N-Cyclopentyl-3-[2-(cyclopentylamino)-6-methyl-4-pyrimidinyl]-2-(4-fluoro-
phenyl)pyrazolo[1,5-a]pyridin-7-amine; [0189]
N-Cyclopentyl-3-[2-(dimethylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyraz-
olo[1,5-a]pyridin-7-amine; [0190]
3-(2-Amino-4-pyrimidinyl)-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo-[1,5-a-
]pyridin-7-amine; [0191]
3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]p-
yridin-7-amine; [0192]
3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-(4-methoxyphe-
nyl)pyrazolo[1,5-a]pyridin-7-amine; [0193]
N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(4-fluorophenyl)pyra-
zolo[1,5-a]pyridin-7-amine; [0194]
N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyri-
din-3-yl]-2-pyrimidinamine; [0195]
3-[2-(Butylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-fluorophenyl)pyrazolo-
[1,5-a]pyridin-7-amine; [0196]
3-[2-(Butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N,N-dimethylpyrazolo[-
1,5-a]pyridin-7-amine; [0197]
N-Butyl-4-[2-(4-fluorophenyl)-7-(4-methyl-1-piperazinyl)pyrazolo[1,5-a]py-
ridin-3-yl]-2-pyrimidinamine; [0198]
N-Butyl-4-[2-(4-fluorophenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-y-
l-2-pyrimidinamine; [0199]
3-[2-(Allylamino)-4-pyrimidinyl]-butyl-2-(4-fluorophenyl)pyrazolo-[1,5-a]-
pyridin-7-amine; [0200]
3-[2-(Butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-[2-(4-morpholinyl)e-
thyl]pyrazolo[1,5-a]pyridin-7-amine; [0201]
3-[2-(Butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-(2-methoxyethyl)pyr-
azolo[1,5-a]pyridin-7-amine; [0202]
N-Cyclopentyl-3-[2-(cyclopentylamino)-5-methyl-4-pyrimidinyl]-2-(4-fluoro-
phenyl)pyrazolo[1,5-a]pyridin-7-amine; [0203]
N-Allyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-pyrazolo[1,5--
a]pyridin-7-amine; [0204]
N-[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-7-yl]-N-[2-(1-
-methyl-2-pyrrolidinyl)ethyl]amine; [0205]
N-Butyl-4-[2-(4-fluorophenyl)-7-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]pyri-
midin-2-amine; and [0206]
2-(4-Chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]py-
razolo[1,5-a]pyridin-7-amine [0207] and pharmaceutically acceptable
salts, solvates and physiologically functional derivatives
thereof.
[0208] 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.
[0209] 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. Hereinafter, reference to a
compound of formula (I) is to the amorphous form of that compound,
unless another form or solvate thereof is specified.
[0210] 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, which upon administration to a mammal, such as a human, is
capable of providing (directly or indirectly) such a compound or an
active metabolite thereof. Such derivatives are clear to those
skilled in the art, without undue experimentation, and with
reference to the teaching of Burger's Medicinal Chemistry And Drug
Discovery, 5th Edition, Vol 1: Principles And Practice.
[0211] 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.
[0212] 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 (including but not limited to
compounds of formula (IX), (XVI), (XX), (XXII), (XXII-A) and
(XXII-B), 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).
[0213] 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 centers 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.
[0214] 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), herpes zoster virus (HZV), human herpes
virus 6 (HHV-6), human herpes virus 7 (HHV-7), and human herpes
virus 8 (HHV-8). Compounds of the invention are also useful in the
treatment or prophylaxis of the symptoms or effects of herpes virus
infections.
[0215] 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.
[0216] 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.
[0217] 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.
[0218] In addition, compounds of formula (I) may be useful in the
treatment or prophylaxis of hepatitis B and hepatitis C viruses,
human papilloma virus (HPV) and HIV.
[0219] 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
comprises administering to the animal a therapeutically effective
amount of the compound of formula (I).
[0220] As used herein, the term "prophylaxis" refers to the
complete prevention of infection, the prevention of occurrence of
symptoms in an infected subject, or a decrease in severity or
frequency of symptoms of viral infection, condition or disease in
the subject.
[0221] 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.
[0222] 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.
[0223] 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 viral
infection in the subject.
[0224] 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 and 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 and multiple sclerosis associated with latent
infection with a herpes virus.
[0225] 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).
[0226] 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).
[0227] 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).
[0228] 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).
[0229] 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 disease 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.
[0230] The compounds of formula (I) are conveniently administered
in the form of pharmaceutical compositions. Such compositions may
conveniently be presented for use in any conventional manner in
admixture with one or more physiologically acceptable carriers or
diluents.
[0231] 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. The carrier(s) must be "acceptable" in the sense of
being compatible with the other ingredients of the formulation and
not deleterious to the recipient thereof.
[0232] Accordingly, the present invention further provides for a
pharmaceutical composition or formulation comprising a compound of
formula (I) with one or more pharmaceutically acceptable carriers
therefore and, optionally, other therapeutic and/or prophylactic
ingredients.
[0233] 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.
[0234] Formulations suitable for oral administration may be
presented as discrete units such as capsules, cachets or tablets
(e.g. chewable tablets in particular for paediatric 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.
[0235] 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.
[0236] 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.
[0237] 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.
[0238] 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.
[0239] Formulations for rectal administration may be presented as a
suppository with the usual carriers such as cocoa butter, hard fat
or polyethylene glycol.
[0240] Formulations for topical administration in the mouth, for
example buccally or sublingually, include lozenges comprising the
active ingredient in a flavoured 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.
[0241] 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.
[0242] 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 flavouring
agents.
[0243] 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.
[0244] 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, famcyclovir, 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.
[0245] When the compounds of formula (I) are used in combination
with other therapeutic agents, the compounds may be administered
either sequentially or simultaneously by any convenient route.
[0246] 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.
[0247] 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.
[0248] 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.
[0249] Compounds of formula (I) wherein Y is N, R.sup.2 is selected
from the group consisting of H, alkyl, cycloalkyl, alkenyl,
cycloalkenyl, --NR.sup.7R.sup.8, --OR.sup.7, --OAy,
--S(O).sub.nR.sup.7, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, Ay, Het, --NH(CH.sub.2).sub.mHet and
--O(CH.sub.2).sub.mHet; and R.sup.3 and R.sup.4 are H, may be
conveniently prepared by a general process outlined in Scheme 1
below. ##STR12## ##STR13##
[0250] wherein: [0251] R.sup.1 is selected from the group
consisting of halo, --NR.sup.7R.sup.8, Ay, --NR.sup.7Ay, Het,
--NH(CH.sub.2).sub.mHet, and --NH(CH.sub.2).sub.lAy; [0252] 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, alkylhydroxy, amine, alkylamine,
alkylcarboxy, alkylcarboxamide, alkyl alkoxycarbonyl,
alkylthioamide, alkylsulfonyl, alkylsulfonamide, alkylether,
--(CH.sub.2).sub.l-cycloalkyl, --(CH.sub.2).sub.lNHCOR.sup.9 and
--(CH.sub.2).sub.mSO.sub.2NHCOR.sup.9; [0253] l is 1-6; [0254] m is
0-6; [0255] R.sup.9 is H, alkyl, cycloalkyl, alkylhydroxy, amine,
alkylamine, alkylcarboxy and alkylether; [0256] Ay is aryl; [0257]
Het is a 5- or 6-membered heterocyclic or heteroaryl group; [0258]
R.sup.2 is selected from the group consisting of H, alkyl,
cycloalkyl, alkenyl, cycloalkenyl, --NR.sup.7R.sup.8, --OR.sup.7,
--OAy, --S(O).sub.nR.sup.7, --S(O).sub.nAy,
--R.sup.10NR.sup.7R.sup.8, --R.sup.10NR.sup.7Ay, Ay, Het,
--NH(CH.sub.2).sub.mHet and --O(CH.sub.2).sub.mHet; [0259] n is 0,
1 or 2; [0260] R.sup.10 is alkyl or alkenyl; [0261] Y is N; [0262]
R.sup.3 and R.sup.4 are both H; [0263] R.sup.5 is halo; [0264] Rg
is Ay or Het as defined above; [0265] 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; [0266] Ra is alkyl or cycloalkyl and [0267] halide is
halo.
[0268] Generally, the process for preparing the compounds of
formula (I) wherein Y is N, R.sup.2 is selected from the group
consisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl,
--NR.sup.7R.sup.8, --OR.sup.7, --OAy, --S(O).sub.nR.sup.7,
--S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7R.sup.8, Ay, Het, --NH(CH.sub.2).sub.mHet and
--O(CH.sub.2).sub.mHet; and R.sup.3 and R.sup.4 are H, (all
formulas and all other variables having been defined above in
connection with Scheme 1) comprises the steps of: [0269] (a)
reacting 2-chloro-6-picoline with a benzoylating agent of formula
(II) to prepare a compound of formula (III); [0270] (b) reacting
the compound of formula (III) with a hydroxylamine source to
prepare a compound of formula (IV); [0271] (c) reacting the
compound of formula (IV) with an acylating or sulfonylating agent
to prepare a compound of formula (V); [0272] (d) rearranging the
compound of formula (V) to prepare a compound of formula (VI);
[0273] (e) acylating the compound of formula (VI) to prepare a
compound of formula (VII); [0274] (f) either: [0275] (1) replacing
the C-7 halogen of the compound of formula (VII) with an amine; or
[0276] (2) coupling the compound of formula (VII) with a metal
compound of the formula Rg-M.sup.3 to prepare a compound of formula
(VIII); [0277] (g) reacting the compound of formula (VIII) with a
dimethylformamide dialkyl acetal of formula
(CH.sub.3).sub.2NCH(ORa).sub.2 to prepare a compound of formula
(IX); and [0278] (h) reacting the compound of formula (IX) with a
compound of formula (X) to prepare the compounds of formula
(I).
[0279] More specifically, compounds of formula (I) wherein Y is N,
R.sup.2 is selected from the group consisting of H, alkyl,
cycloalkyl, alkenyl, cycloalkenyl, --NR.sup.7R.sup.8, --OR.sup.7,
--OAy, --S(O).sub.nR.sup.7, --S(O).sub.nAy,
--R.sup.10NR.sup.7R.sup.8, --R.sup.10NR.sup.7R.sup.8, Ay, Het,
--NH(CH.sub.2).sub.mHet and --O(CH.sub.2).sub.mHet; and R.sup.3 and
R.sup.4 are H can be prepared by reacting a compound of formula
(IX) with a compound of formula (X). ##STR14##
[0280] wherein all variables are as defined above in connection
with Scheme 1.
[0281] This general method can be readily carried out by mixing a
compound of formula (IX) with a compound of formula (X) 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
about 50-150.degree. C. Typical solvents include lower alcohols
such as methanol, ethanol, isopropanol, 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 dimethylformamide and the base is potassium carbonate,
or an amine base such as triethylamine.
[0282] Compounds of the formula (IX) may be conveniently prepared
by reacting a compound of formula (VIII) with a dimethylformamide
dialkyl acetal. ##STR15##
[0283] wherein all variables are as defined above in connection
with Scheme 1.
[0284] 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 (VIII) with
the dimethylformamide dialkyl acetal, optionally with heating.
[0285] Compounds of the formula (VIII) may be prepared by two
general methods. According to one method, compounds of formula
(VIII) are prepared from compounds of formula (VII) by replacement
of the C-7 halogen (chloro is depicted in formula (VII) but other
halogens are similarly useful) with an amine nucleophile.
##STR16##
[0286] wherein all variables are as defined above in connection
with Scheme 1.
[0287] Typically the replacement is carried out by mixing the
compound of formula (VII) with an amine nucleophile of formula
R.sup.1a where R.sup.1a is selected from the group consisting of
--NR.sup.7R.sup.8, --NR.sup.7Ay, Het, --NH(CH.sub.2).sub.mHet, and
--N(CH.sub.2).sub.lAy; and optionally heating the reaction.
[0288] The reaction can also be carried out via an adaptation of
procedures found in the literature (Wolfe, J. P.; Buchwald, S. L.
J. Org. Chem. 2000, 65, 1144) wherein a compound of the general
formula (VII) is treated with an amine, a palladium (0) or nickel
(0) source and a base in a suitable solvent. Suitable sources of
palladium (0) include but are not limited to palladium(II) acetate
and tris(dibenzylideneacetone) dipalladium (0). Typical bases for
use in the reaction include, for example sodium tert-butoxide and
cesium carbonate. Toluene is an example of a suitable solvent.
[0289] According to the second method, compounds of formula (VIII)
are prepared from compounds of formula (VII) by coupling with metal
compounds of the formula Rg-M.sup.3 wherein Rg is Ay or Het as
defined above and 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, wherein
Ra is alkyl or cycloalkyl and halide is halo. This general method
can be conveniently performed in an inert solvent, in the presence
of a palladium (0) catalyst, optionally with heating. Preferably
the reaction is performed by reacting equimolar amounts of a
compound of the general formula (VII) with the metal compound of
formula Rg-M.sup.3 or optionally adding an excess of the metal
compound. The palladium catalyst is preferably present in 1-10 mol
% compared to the compound of formula (VII). Palladium catalysts
that may be used may include, but are not limited to,
tetrakistriphenylphosphine palladium (0)
dichlorobis(triphenyl-phosphine)palladium(II), and
bis(diphenylphosphinoferrocene)palladium (II) dichloride. Inert
solvents for use in the reaction include but are not limited to,
N,N-dimethylformamide, toluene, tetrahydrofuran, dioxane and
1-methyl-2-pyrrolidinone.
[0290] When the metal compound of formula Rg-M.sup.3 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 metal compound.
[0291] Metal compounds of the formula Rg-M.sup.3 can be purchased
from commercial sources or prepared either as discreet isolated
compounds or generated in situ by 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.)
[0292] Compounds of the formula (VII) may be conveniently prepared
from compounds of formula (VI) using an acylation procedure.
##STR17##
[0293] wherein all variables are as defined above in connection
with Scheme 1.
[0294] Typically the acylation is carried out by treating the
compounds of formula (VI) 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.
[0295] Compounds of formula (VI) are conveniently prepared by
rearranging an azirine compound of formula (V). ##STR18##
[0296] wherein all variables are as defined above in connection
with Scheme 1.
[0297] The rearrangement of the azirines of formula (V) can be
accomplished by heating a solution of the azirine of formula (V) 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 (V) to
compounds of formula (VI) involves reacting the compound of formula
(V) with ferrous chloride (FeCl.sub.2) or ferric chloride
(FeCl.sub.3). This reaction is typically done in an inert solvent
with heating. A preferred solvent for this reaction is
1,2-dimethoxyethane and the like.
[0298] Typically the azirines of formula (V) are prepared from
oxime compounds of formula (IV) by treatment with acylating or
sulfonylating agents in the presence of a base. ##STR19##
[0299] wherein all variables are as defined above in connection
with Scheme 1.
[0300] 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, or the like. The reaction may be
carried out in an inert solvent such as for example, chloroform,
dichloromethane, toluene or the like.
[0301] The oxime compounds of formula (IV) are readily prepared by
treating ketone compounds of formula (III) with a hydroxylamine
source, in a suitable solvent, and optionally with a base.
##STR20##
[0302] wherein all variables are as defined above in connection
with Scheme 1.
[0303] Preferably 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.
[0304] The ketone compounds of formula (III) can be prepared by
treatment of 2-chloro-6-picoline with a benzoylating agent of
formula (II) in the presence of a base. ##STR21##
[0305] wherein all variables are as defined above in connection
with Scheme 1.
[0306] Preferred benzoylating agents of formula (II) include, but
are not limited to, benzoyl esters. 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).
[0307] In addition to the foregoing process for preparing certain
compounds of formula (I), the present invention also provides
certain intermediate compounds for use in the preparation of such
compounds of formula (I) according to the foregoing process.
[0308] As one aspect, the present invention provides compounds of
formula (III) ##STR22##
[0309] wherein R.sup.5 is halo.
[0310] As another aspect, the present invention provides compounds
of formula (IV) ##STR23##
[0311] wherein R.sup.5 is halo.
[0312] As another aspect, the present invention provides compounds
of formula (V) ##STR24##
[0313] wherein R.sup.5 is halo.
[0314] As another aspect, the present invention provides compounds
of formula (VI) ##STR25##
[0315] wherein R.sup.5 is halo.
[0316] As another aspect, the present invention provides compounds
of formula (VII) ##STR26##
[0317] wherein R.sup.5 is halo.
[0318] As another aspect, the present invention provides compounds
of formula (VIII) ##STR27##
[0319] wherein R.sup.1 and R.sup.5 are as defined above.
[0320] As another aspect, the present invention provides compounds
of formula (IX) ##STR28##
[0321] wherein R.sup.1 and R.sup.5 are as defined above.
[0322] In a further embodiment of the present invention, compounds
of formula (I) wherein Y is N; R.sup.2 is selected from the group
consisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl,
--NR.sup.7R.sup.8, --OR.sup.7, --OAy, --S(O).sub.nR.sup.7,
--S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7R.sup.8, Ay, Het, --NH(CH.sub.2).sub.mHet and
--O(CH.sub.2).sub.mHet; R.sup.3 is selected from the group
consisting of H, alkyl, alkylhydroxy, alkylamine, --NR.sup.7R.sup.8
where R.sup.7 and R.sup.8 are not H, --NR.sup.7Ay where R.sup.7 is
not H, carboxy, carboxamide, --SO.sub.2NHR.sup.9, Het and Ay; and
R.sup.4 is H, may be conveniently prepared by a general process
outlined in Scheme 2 below. ##STR29## ##STR30##
[0323] wherein R.sup.1 is selected from the group consisting of
halo, --NR.sup.7R.sup.8, --NR.sup.7Ay, Ay, Het,
--NH(CH.sub.2).sub.mHet, and --NH(CH.sub.2).sub.lAy; [0324] 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, alkylhydroxy, amine, alkylamine,
alkylcarboxy, alkylcarboxamide, alkyl alkoxycarbonyl,
alkylthioamide, alkylsulfonyl, alkylsulfonamide, alkylether,
--(CH.sub.2).sub.l-cycloalkyl, --(CH.sub.2).sub.lNHCOR.sup.9 and
--(CH.sub.2).sub.mSO.sub.2NHCOR.sup.9; [0325] l is 1-6; [0326] m is
0-6; [0327] R.sup.9 is H, alkyl, cycloalkyl, alkylhydroxy, amine,
alkylamine, alkylcarboxy and alkylether; [0328] Ay is aryl; [0329]
Het is a 5- or 6-membered heterocyclic or group; [0330] R.sup.2 is
selected from the group consisting of H, alkyl, cycloalkyl,
alkenyl, cycloalkenyl, --NR.sup.7R.sup.8, --OR.sup.7, --OAy,
--S(O).sub.nR.sup.7, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, Ay, Het, --NH(CH.sub.2).sub.mHet and
--O(CH.sub.2).sub.mHet; [0331] R.sup.3 is selected from the group
consisting of H, alkyl, alkylhydroxy, alkylamine, alkylether,
--NR.sup.7R.sup.8 where R.sup.7 and R.sup.8 are not H, --NR.sup.7Ay
where R.sup.7 is not H, carboxy, carboxamide, --SO.sub.2NHR.sup.9,
Het and Ay; [0332] R.sup.4 is H; [0333] R.sup.5 is halo; and [0334]
M.sup.1 is Li, Mg-halide or cerium-halide, wherein halide is
halo.
[0335] Generally, the process for preparing compounds of formula
(I) wherein Y is N; R.sup.2 is selected from the group consisting
of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, --NR.sup.7R.sup.8,
--OR.sup.7, --OAy, --S(O).sub.nR.sup.7, --S(O).sub.nAy,
--R.sup.10NR.sup.7R.sup.8, --R.sup.10NR.sup.7R.sup.8, Ay, Het,
--NH(CH.sub.2).sub.mHet and --O(CH.sub.2).sub.mHet; R.sup.3 is
selected from the group consisting of H, alkyl, alkylhydroxy,
alkylamine, alkylether, --NR.sup.7R.sup.8 where R.sup.7 and R.sup.8
are not H, --NR.sup.7Ay where R.sup.7 is not H, carboxy,
carboxamide, --SO.sub.2NHR.sup.9, Het and Ay; and R.sup.4 is H (all
formulas and all other variables having been defined above in
connection with Scheme 2), comprises the following steps: [0336]
(a) reacting a picoline with a benzoylating agent of formula (II)
to prepare a compound of formula (III-A); [0337] (b) reacting the
compound of formula (III-A) with a hydroxylamine source to prepare
a compound of formula (IV-A); [0338] (c) reacting the compound of
formula (IV-A) with an acylating or sulfonylating agent to prepare
a compound of formula (V-A); [0339] (d) rearranging the compound of
formula (V-A) to prepare a compound of formula (XII); [0340] (e)
formylating the compound of formula (XII) to prepare a compound of
formula (XIII); [0341] (f) reacting the compound of formula (XIII)
with a compound of formula (XIV) to prepare a compound of formula
(XV); [0342] (g) oxidizing the compound of formula (XV) to prepare
a compound of formula (XVI); and [0343] (h) reacting a compound of
formula (XVI) with a compound of formula (X) to prepare the
compound of formula (I).
[0344] More specifically, compounds of formula (I) wherein Y is N;
R.sup.2 is selected from the group consisting of H, alkyl,
cycloalkyl, alkenyl, cycloalkenyl, --NR.sup.7R.sup.8, --OR.sup.7,
--OAy, --S(O).sub.nR.sup.7, --S(O).sub.nAy,
--R.sup.10NR.sup.7R.sup.8, --R.sup.10NR.sup.7Ay, Ay, Het,
--NH(CH.sub.2).sub.mHet and --O(CH.sub.2).sub.mHet; R.sup.3 is
selected from the group consisting of H, alkyl, alkylhydroxy,
alkylamine, alkylether, --NR.sup.7R.sup.8 where R.sup.7 and R.sup.8
are not H, --NR.sup.7Ay where R.sup.7 is not H, carboxy,
carboxamide, --SO.sub.2NHR.sup.9, Het and Ay; and R.sup.4 is H, can
be prepared by reacting a compound of formula (XVI) with a compound
of formula (X). ##STR31##
[0345] wherein all variables are as defined above in connection
with Scheme 2.
[0346] This method can be readily carried out by mixing a compound
of formula (XVI) with a compound of formula (X) 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.
[0347] Compounds of formula (XVI) may be conveniently prepared by
oxidation of a compound of formula (XV). ##STR32##
[0348] wherein all variables are as defined above in connection
with Scheme 2.
[0349] Preferred 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.
[0350] Compounds of formula (XV) may be conveniently prepared by
reacting a compound of formula (XIII) with a compound of formula
(XIV). ##STR33##
[0351] wherein all variables are as defined above in connection
with Scheme 2.
[0352] Preferred metals (M.sup.1) in the compounds of formula (XIV)
include but are not limited to, lithium, magnesium(II) halides,
cerium(III) halides, and the like. Compounds of general formula
(XIV) may be purchased from commercial sources or prepared by
methods known to one skilled in the art.
[0353] Compounds of formula (XIII) may be conveniently prepared
from compounds of formula (XII) by a formylation procedure.
##STR34##
[0354] wherein all variables are as defined above in connection
with Scheme 2.
[0355] 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. Preferable
conditions include, but are not limited to treating compounds of
formula (XII) with a premixed solution of phosphorous oxychloride
in N,N-dimethylformamide optionally with heating the reaction to
50-150.degree. C.
[0356] The compounds of formula (XII) are prepared by a process
analogous to the process employed for the preparation of compounds
of formula (VI) in Scheme 1 above.
[0357] In addition to the foregoing process for preparing certain
compounds of formula (I), the present invention also provides
certain intermediate compounds for use in the preparation of such
compounds of formula (I) according to the foregoing process. Thus,
as one aspect, the present invention provides compounds of formula
(III-A) ##STR35## [0358] wherein R.sup.1 and R5 are as defined
above.
[0359] As another aspect, the present invention provides compounds
of formula (IV-A) ##STR36## [0360] wherein R.sup.1 and R.sup.5 are
as defined above.
[0361] As another aspect, the present invention provides compounds
of formula (V-A) ##STR37## [0362] wherein R.sup.1 and R.sup.5 are
as defined above.
[0363] As another aspect, the present invention provides compounds
of formula (XII) ##STR38## [0364] wherein R.sup.1 and R.sup.5 are
as defined above.
[0365] In another aspect, the present invention provides compounds
of formula (XIII) ##STR39## [0366] wherein R.sup.1 and R.sup.5 are
as defined above.
[0367] In another aspect, the present invention provides compounds
of formula (XV) ##STR40## [0368] wherein R.sup.1, R.sup.3 and
R.sup.5 are as defined above.
[0369] In another aspect, the present invention provides compounds
of formula (XVI) ##STR41## [0370] wherein R.sup.1, R.sup.3 and
R.sup.5 are as defined above.
[0371] Compounds of formula (I) wherein Y is N and R.sup.2 is
selected from the group consisting of H, alkyl, cycloalkyl,
alkenyl, cycloalkenyl, --NR.sup.7R.sup.8, --OR.sup.7, --OAy,
--S(O).sub.nR.sup.7, --S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8,
--R.sup.10NR.sup.7Ay, Ay, Het, --NH(CH.sub.2).sub.mHet and
--O(CH.sub.2).sub.mHet; may be conveniently prepared by a general
process outlined in Scheme 3 below. ##STR42##
[0372] wherein R.sup.1 is selected from the group consisting of
halo, --NR.sup.7R.sup.8, Ay, --NR.sup.7Ay, Het, [0373]
--NH(CH.sub.2).sub.mHet, and --NH(CH.sub.2).sub.lAy; [0374] 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, alkylhydroxy, amine, alkylamine,
alkylcarboxy, alkylcarboxamide, alkyl alkoxycarbonyl,
alkylthioamide, alkylsulfonyl, alkylsulfonamide, alkylether,
(CH.sub.2).sub.l-cycloalkyl, --(CH.sub.2).sub.lNHCOR.sup.9 and
--(CH.sub.2).sub.mSO.sub.2NHCOR.sup.9; [0375] l is 1-6; [0376] m is
0-6; [0377] R.sup.9 is H, alkyl, cycloalkyl, alkylhydroxy, amine,
alkylamine, alkylcarboxy and alkylether; [0378] Ay is aryl; [0379]
Het is a 5- or 6-membered heterocyclic or heteroaryl group; [0380]
R.sup.2 is selected from the group consisting of H, alkyl,
cycloalkyl, alkenyl, cycloalkenyl, --NR.sup.7R.sup.8, --OR.sup.7,
--OAy, --S(O).sub.nR.sup.7, --S(O).sub.nAy,
--R.sup.10NR.sup.7R.sup.8, R.sup.10NR.sup.7Ay, Ay, Het,
--NH(CH.sub.2).sub.mHet and --O(CH.sub.2).sub.mHet; [0381] n is 0,
1 or 2; [0382] R.sup.10 is alkyl or alkenyl; [0383] Y is N or CH;
[0384] R.sup.3 and R.sup.4 are each independently selected from the
group consisting of H, halo, hydroxy, alkyl, alkylhydroxy,
alkylamine, alkylether, --OR.sup.7, --OAy, NR.sup.7R.sup.8,
--NR.sup.7Ay, carboxy, carboxamide, --SO.sub.2NHR.sup.9, Het and
Ay; [0385] R.sup.5 is halo; and [0386] M.sup.1 is Li, Mg-halide or
cerium-halide, wherein halide is halo.
[0387] Generally, the process for preparing compounds of formula
(I) wherein Y is N and R.sup.2 is selected from the group
consisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl,
--NR.sup.7R.sup.8, --OR.sup.7, --OAy, --S(O).sub.nR.sup.7,
--S(O).sub.nAy, --R.sup.10NR.sup.7R.sup.8, --R.sup.10NR.sup.7Ay,
Ay, Het, --NH(CH.sub.2).sub.mHet and --O(CH.sub.2).sub.mHet; (all
formulas and all other variables having been defined above in
connection with Scheme 3), comprises the following steps: [0388]
(a) reacting a compound of formula (XIII) with a compound of
formula (XVIII) to prepare a compound of formula (XIX); [0389] (b)
oxidizing the compound of formula (XIX) to prepare a compound of
formula (XX); and [0390] (c) reacting a compound of formula (XX)
with a compound of formula (X) followed by oxidative aromatization
to prepare the compound of formula (I).
[0391] More specifically, compounds of formula (I) wherein Y is N
and R.sup.2 is selected from the group consisting of H, alkyl,
cycloalkyl, alkenyl, cycloalkenyl, --NR.sup.7R.sup.8, --OR.sup.7,
--OAy, --S(O).sub.nR.sup.7, --S(O).sub.nAy,
--R.sup.10NR.sup.7R.sup.8, --R.sup.10NR.sup.7Ay, Ay, Het,
--NH(CH.sub.2).sub.mHet and --O(CH.sub.2).sub.mHet; can be prepared
by reacting a compound of formula (XX) with a compound of formula
(X) followed by oxidative aromatization. ##STR43##
[0392] wherein all variables are as defined above in connection
with Scheme 3.
[0393] The condensation is conveniently carried out by treating the
compound of formula (XX) with a compound of formula (X) in an inert
solvent, optionally in the presence of a base. The reaction may be
heated to 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 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 amine
base such as triethylamine. The reaction produces a
dihydropyrimidine intermediate.
[0394] Preferably in the same reaction vessel, the
dihydropyrimidine intermediate may be oxidized to a compound of
formula (I) by the addition of an oxidizing agent. Preferably, the
oxidizing agent is oxygen (O.sub.2), palladium on carbon,
2,3-dichloro-5,6-dicyano-1,4-benzoquinone, or the like.
[0395] Compounds of formula (XX) may be conveniently prepared by
oxidation of compounds of formula (XIX). ##STR44##
[0396] wherein all variables are as defined above in connection
with Scheme 2.
[0397] Preferred oxidizing agents for the oxidation of compounds of
formula (XIX) 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, or the like.
[0398] Compounds of formula (XIX) may be conveniently prepared by
reacting a compound of formula (XIII) with a compound of formula
(XVIII). ##STR45## [0399] wherein all variables are as defined
above in connection with Scheme 2.
[0400] Compounds of formula (XVIII) may be purchased from
commercial sources or prepared by methods known to one skilled in
the art. The compounds of formula (XIII) may be prepared using the
methods described in connection with Scheme 2 above.
[0401] In addition to the foregoing process for preparing certain
compounds of formula (I), the present invention also provides
certain intermediate compounds for use in the preparation of such
compounds of formula (I) according to the foregoing process. Thus,
as one aspect, the present invention provides compounds of formula
(XIX) ##STR46## [0402] wherein all variables are as defined
above.
[0403] In another aspect, the present invention provides compounds
of formula (XX) ##STR47## [0404] wherein all variables are as
defined above.
[0405] Compounds of formula (I) wherein Y is CH or N, may be
conveniently prepared by a general process outlined in Scheme 4
below. ##STR48##
[0406] wherein: [0407] R.sup.1 is selected from the group
consisting of halo, --NR.sup.7R.sup.8, Ay, --NR.sup.7Ay, Het,
--NH(CH.sub.2).sub.mHet, and --NH(CH.sub.2).sub.lAy; [0408] 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, alkylhydroxy, amine, alkylamine,
alkylcarboxy, alkylcarboxamide, alkyl alkoxycarbonyl,
alkylthioamide, alkylsulfonyl, alkylsulfonamide, alkylether,
--(CH.sub.2).sub.l-cycloalkyl, --(CH.sub.2).sub.lNHCOR.sup.9 and
--(CH.sub.2).sub.mSO.sub.2NHCOR.sup.9; [0409] l is 1-6; [0410] m is
0-6; [0411] R.sup.9 is H, alkyl, cycloalkyl, alkylhydroxy, amine,
alkylamine, alkylcarboxy and alkylether; [0412] Ay is aryl; [0413]
Het is a 5- or 6-membered heterocyclic or heteroaryl group; [0414]
R.sup.2 is selected from the group consisting of H, halo, alkyl,
cycloalkyl, alkenyl, cycloalkenyl, --NR.sup.7R.sup.8, --OR.sup.7,
--OAy, --S(O).sub.nR.sup.7, --S(O).sub.nAy,
--R.sup.10NR.sup.7R.sup.8, --R.sup.10NR.sup.7Ay, Ay, Het,
--NH(CH.sub.2).sub.mHet and --O(CH.sub.2).sub.mHet; [0415] n is 0,
1 or 2; [0416] R.sup.10 is alkyl or alkenyl; [0417] Y is N or CH;
[0418] R.sup.3 and R.sup.4 are each independently selected from the
group consisting of H, halo, hydroxy, alkyl, alkylhydroxy,
alkylamine, alkylether, --OR.sup.7, --OAy, --NR.sup.7R.sup.8,
--NR.sup.7Ay, carboxy, carboxamide, --SO.sub.2NHR.sup.9, Het and
Ay; [0419] R.sup.5 is halo; [0420] X.sup.1 is chloro, bromo, or
iodo; and [0421] M.sup.2 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.
[0422] Generally, the process for preparing compounds of formula
(I) (all formulas and variables having been defined above in
connection with Scheme 4), comprises the following steps: [0423] a)
halogenating a compound of formula (XII) to prepare a compound of
formula (XXII); and [0424] b) reacting the compound of formula
(XXII) with a compound of formula (XXIV) to prepare the compound of
formula (I).
[0425] More specifically, compounds of formula (I) can be prepared
by reacting a compound of formula (XXII) with a compound of formula
(XXIV). ##STR49##
[0426] wherein all variables are as defined above in connection
with Scheme 4.
[0427] 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. Preferably the
reaction is performed by reacting equimolar amounts of a compound
of formula (XXII) with a Het-metal compound of formula (XXIV), but
the reaction may also be performed in the presence of an excess of
compound of the formula (XXIV). The palladium or nickel catalyst is
preferably present in 1-10 mol % compared to the compound of
formula (XXII). 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 Het-metal compound of formula (XXIV) 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 (XXIV). Het-metal
compounds of formula (XXIV) 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] Compounds of formula (XXII) can be prepared from compounds
of formula (XII) by a halogenation procedure. ##STR50##
[0429] wherein all variables are as defined above in connection
with Scheme 4.
[0430] Typically, the halogenation reaction is carried out by
subjecting the compounds of formula (XII) 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
monochloride, and the like. Suitable solvents include, for example,
N,N-dimethylformamide, tetrahydrofuran, dioxane,
1-methyl-2-pyrrolidinone, carbon tetrachloride, toluene,
dichloromethane, diethyl ether, or the like.
[0431] In the embodiments wherein the compound of formula (XXII) is
defined where R.sup.1 is chloro, (i.e., compounds of formula
(XXII-A)) and compounds of formula (I) where R.sup.1 is other than
chloro are desired, it may be desireable to convert the compounds
of formula (XXII-A) to compounds of formula (XXII-B) prior to
reacting with the Het-metal of formula (XXIV). Compounds of formula
(XXII-B) can be conveniently and surprisingly prepared from
compounds of formula (XXII-A) by an amination procedure.
##STR51##
[0432] wherein R.sup.1b is --NR.sup.7R.sup.8 or --NR.sup.7Ay and
all other variables are as defined above in connection with Scheme
4.
[0433] The ability to replace the chlorine in preference to the
bromine of the heterocyclic ring system is unexpected. Preferably,
a compound of formula (XXII-A) is reacted with a primary or
secondary amine having substitutions corresponding to those of
R.sup.1, in the presence of a palladium catalyst and a base. The
procedure represents a modification of procedures found in the
literature (Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65,
1144) wherein amines are cross-coupled to aryl halides. Suitable
palladium (0) catalysts include palladium(II) acetate and
tris(dibenzylideneacetone) dipalladium (0). Suitable bases include
sodium tert-butoxide and cesium carbonate. Solvents such as toluene
may be employed.
[0434] In addition to the foregoing process for preparing compounds
of formula (I), the present invention also provides certain
intermediate compounds for use in the preparation of compounds of
formula (I) according to the foregoing process. Thus, as one
aspect, the present invention provides compounds of formula (XXII)
##STR52## [0435] wherein all variables are as defined above.
[0436] Another method for the preparation of the compounds of
Formula (XXII) in this invention is the decarboxylation/bromination
sequence as shown below. ##STR53## [0437] wherein R.sup.1 and
R.sup.5 are as defined above in connection with Scheme 4.
[0438] This reaction can be achieved by treatment of a compound of
formula (XXV), dissolved in a suitable solvent, with a base
followed by a brominating agent and stirring the mixture at, or
about, 25.degree. C. until the reaction is judged complete by the
disappearance of (XXV). Suitable solvents include, but are not
limited to, dimethylformamide, dimethylacetamide, dioxane and the
like. Conveniently the base is sodium hydrogen carbonate and the
brominating agent can be, for example, N-bromosuccinimide.
[0439] Compounds of formula (XXV) can be prepared most readily by
simple hydrolysis of lower alkyl esters of formula (XXVI). Esters
such as (XXVI) may be prepared by a cycloaddition reaction between
compounds of formula (XXVII) and acetylenes of formula (XXVIII), as
summarized below. ##STR54## [0440] wherein R.sup.1 and R.sup.5 are
as defined above in connection with Scheme 4.
[0441] Cycloaddition reactions such as these are commonly known as
[3+2] dipolar cycloaddition reactions. Conveniently the reaction
may be carried out by mixing the reactants (XXVII) and (XXVIII), in
equimolar amounts, in an inert solvent and adding a suitable base.
The mixture is then stirred at between 20-100.degree. C. until the
reaction is judged complete by the disappearance of one of the
reactants. Preferred solvents include but are not limited to
acetonitrile, dioxane, tetrahydrofuran, dimethylformamide and the
like. Preferred bases include non-nucleophilic amines such as
1,8-diazabicyclo[5.4.0]undec-7-ene,
1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane and
the like.
[0442] Esters such as those of Formula (XXVI) can be conveniently
hydrolyzed to their corresponding carboxylic acids by standard
hydrolysis conditions employed to effect similar hydrolysis
reactions (Larock, Comprehensive Organic Transformations, 1989,
981). For example, treatment of a solution of a compound of formula
(XXVI) in a lower alcohol, for example methanol, with sodium
hydroxide followed by heating the mixture for an appropriate time
gives the compound of formula (XXV). Compounds of formula (XXVII)
are aminated pyridine derivatives and are either commercially
available or can be conveniently prepared by reacting a suitable
pyridine with an aminating reagent such as
O-(mesitylsulfonyl)hydroxylamine,
O-(diphenylphosphinyl)hydroxylamine, hydroxylamine-O-sulfonic acid
and the like.
[0443] Acetylenic esters such as those of general formula (XXVIII)
are either known compounds or can be prepared by methods described
in the literature. Preferred methods include the reaction of
acetylenes such as those of formula (XXIX) with a suitable base to
generate an acetylenic anion and subsequent reaction of the anion
with an alkoxycarbonylating agent, as summarized below. ##STR55##
[0444] wherein R.sup.5 is as defined above in connection with
Scheme 4.
[0445] Preferably the acetylene (XXIX) is dissolved in an inert
solvent, such as tetrahydrofuran, and the solution is cooled to
about -75.degree. C. A non-nuclephilic base is added in sufficient
quantity to effect deprotonation of the acetylene (XXIX). The
preferred bases include, but are not limited to, n-butyllithium,
lithium diisopropylamide, sodium bis(trimethylsilyl)amide and the
like. To the reaction mixture is then added a reagent capable of
reacting with an anion to introduce an alkoxycarbonyl group.
Preferred reagents include, but are not limited to, methyl
chloroformate, ethyl chloroformate, benzyl chloroformate and the
like.
[0446] Arylalkynes such as (XIX) are either known compounds or can
be prepared by literature methods such as those described in, for
example, Negishi, E. J. Org. Chem. 1997, 62, 8957.
[0447] Compounds of general formula (XXII) can also be prepared via
a number of other convenient routes. Disubstituted acetylenes as
represented by formula (XXX) can be treated with an aminating
agent, optionally in the presence of a base, to give compounds of
general formula (XII). The aminating agent is, preferably,
O-(mesitylsulfonyl)hydroxylamine and the base is potassium
carbonate. ##STR56## [0448] wherein R.sup.1 and R.sup.5 are as
defined above in connection with Scheme 4.
[0449] Disubstituted acetylenes such as (XXX) are readily prepared
by a palladium catalyzed coupling reaction between aryl acetylenes
and 2-halopyridines using methods described in the literature
(Yamanake et. al, Chem. Pharm. Bull 1988, 1890).
[0450] A compound of formula (XII) can be brominated to give a
compound of formula (XXII) as outlined previously.
[0451] As will be apparent to those skilled in the art, the
compounds of formula (I) may be converted to other compounds of
formula (I) using techniques well known in the art. For example,
one method of converting compounds of formula (I) to other
compounds of formula (I) comprises a) oxidizing the compound of
formula (I-A) to prepare a compound of formula (I-B) and then 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, --OAy,
Het attached through N, --NH(CH.sub.2).sub.mHet and
--O(CH.sub.2).sub.mHet to produce a compound of formula I wherein
R.sup.2 is selected from the group consisting of --NR.sup.7R.sup.8,
--OR.sup.7, --OAy, Het attached through N, --NH(CH.sub.2).sub.mHet
and --O(CH.sub.2).sub.mHet. ##STR57## [0452] wherein n' is 1 or 2
and all other variables are as defined according to any of the
processes described above.
[0453] More specifically, compounds of formula (I) wherein Y is N
or CH can be prepared by reacting a compound of formula (I-B)
(i.e., compounds of formula I wherein R.sup.2 is S(O).sub.n'R.sup.7
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
--NR.sup.7R.sup.8, --OR.sup.7, --OAy, Het attached through N,
--NH(CH.sub.2).sub.mHet and --O(CH.sub.2).sub.mHet. The reaction
may be carried out neat or in a suitable solvent and may be heated
to 50-150.degree. C. Typically the solvent is a lower alcohol such
as methanol, ethanol, isopropanol or the like, or solvent such as
N,N-dimethylformamide or tetrahydrofuran, or 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.
[0454] Compounds of formula (I-B) may be conveniently prepared by
reacting a compound of formula (I-A) (i.e., compounds of formula I
wherein R.sup.2 is S(O).sub.nR.sup.7 where n is 0) with an
oxidizing agent in an inert solvent, optionally in the presence of
a base. ##STR58## [0455] wherein the variables are as defined
above.
[0456] Typically the oxidizing agent is a peracid such as
m-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 or the like.
[0457] Compounds of formula (I-A) are prepared by methods described
above wherein R.sup.2.dbd.SR.sup.7 from from the reaction of
compounds selected from the group consisting of compounds of
formula (XVI), compounds of formula (IX) and compounds of formula
(XX) with a compound of formula (X-A) (i.e., the compound of
formula (X) wherein R.sup.2 is SR.sup.7). The requisite compound of
formula (X-A) can be obtained from commercial sources or prepared
by methods known to one skilled in the art.
[0458] Another particularly useful method for converting compounds
of formula (I) to other compounds 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 50-150.degree. C. to prepare a compound of formula
(I-D) (i.e., a compound of formula (I) wherein R.sup.2 is
--NR.sup.7R.sup.8). ##STR59## [0459] wherein all variables are as
defined in connection with any of the processes described
above.
[0460] This procedure may be carried out by mixing a compound of
formula (I-C) in an amine neat, or in a suitable solvent with an
excess of 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.
[0461] As a further example, compounds of formula (I-E) may be
converted to compounds of formula (I-F) using either of two
methods. ##STR60## [0462] wherein M.sup.3 is B(OH).sub.2,
B(ORa).sub.2, Sn(Ra).sub.3, Zn-halide, Zn--Ra or Mg-halide where Ra
is alkyl or cycloalkyl, halide is halo and all other variables are
as defined in connection with any process described above.
[0463] Such method can be carried out using the reaction and
conditions described above in connection with Scheme 1 and the
conversion of compounds of formula VII to compounds of formula
VIII. Thus, the present invention provides a process for converting
compounds of formula (I-E) to compounds of formula (I-F) which
comprises either: (1) replacing the C-7 halogen of the compound of
formula (I-E) with an amine; or (2) coupling the compound of
formula (I-E) with an aryl metal of the formula Ay-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.
[0464] 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.
[0465] The present invention also provides radiolabeled compounds
of formula (I). Radiolabeled 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).
[0466] In one preferred embodiment, the compounds of formula (I)
are tritiated.
[0467] The radiolabeled 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) to the target protein. More
specifically, suitable assay methods will include competition
binding assays. The radiolabeled compounds of formula (I) can be
employed in assays according to the methods conventional in the
art.
[0468] 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)-4-pyrimidinyl]-2-(4-fluoro-phenyl)py-
razolo[1,5-a]pyridin-7-amine
[0469] ##STR61##
a) 2-(6-Chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone
[0470] To a cold (0.degree. C.) solution of 6-chloro-2-picoline
(21.4 mL, 196.0 mmol) and ethyl 4-fluorobenzoate (57.5 mL, 391.2
mmol) in tetrahydrofuran (311 mL) was added lithium
bis(trimethylsilyl)amide (391 mL, 1.0 M in tetrahydrofuran, 391.0
mmol) dropwise via a pressure equalizing funnel over 1 hour. Upon
complete addition, the cold bath was removed and the resultant
solution was heated to 45.degree. C. for 15 hours. The mixture was
cooled to room temperature and quenched by the addition of water.
Ether was added and the organic layer was washed with brine. The
aqueous layer was extracted with ether and the combined organics
were dried over magnesium sulfate. Filtration and concentration
gave a solid residue which was purified by recrystallization from
ethyl acetate-hexanes to provide
2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (32.2 g, 66%)
as a tinted off-white solid existing as a keto-enol tautomeric
mixture. .sup.1H NMR (CDCl.sub.3): for the keto tautomer .delta.
8.11 (m, 2 H), 7.66 (t, 1 H), 7.30-7.25 (m 2 H), 7.17 (t, 2 H),
4.48 (s 2 H), .sup.19F NMR (CDCl.sub.3) .delta. -104.72 (keto),
-111.64 (enol); MS m/z 250 (M+1).
b) 2-(6-Chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime
[0471] To a solution of
2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (74.9 g, 299.8
mmol) in methanol (900 mL) was added hydroxylamine hydrochloride
(104 g, 1.49 mol) followed by sodium hydroxide (600 mL, 10%
aqueous, 1.5 mol). The resultant suspension was heated to reflux
for 2 hours and then cooled to room temperature. The mixture was
concentrated in vacuo and the residue taken up in ether and water.
The organic layer was washed with brine. The aqueous layer was
extracted with ether and the combined organics were dried over
magnesium sulfate. Filtration and concentration gave a solid
residue which was purified by recrystallization from ethyl
acetate-hexanes to provide
2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime (67.9 g,
86%) as a white solid. .sup.1H NMR (CDCl.sub.3): .delta. 8.69 (s, 1
H), 7.71 (dd, 2 H), 7.53 (t, 1 H), 7.18-7.16 (m, 2 H), 7.03 (t, 2
H), 4.37 (s, 2 H); .sup.19F NMR (CDCl.sub.3) .delta. -111.77; MS
m/z 265 (M+1).
c) 7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine
[0472] To a solution of
2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime (109.2 g,
414 mmol) in 1,2-dimethoxyethane (500 mL) at 0.degree. C. was added
trifluoroacetic anhydride (59 mL, 414 mmol), keeping the
temperature below 10.degree. C. After the addition was complete,
the reaction was warmed to 15.degree. C. The solution was then
cooled to 4.degree. C. and a solution of triethylamine (116 mL, 828
mmol) in 1,2-dimethoxyethane (60 mL) was added over 0.5 hours.
After warming to room temperature, the mixture was stirred for 1.5
hours. To this was added iron(II) chloride (0.52 g, 4.1 mmol) and
the reaction was heated to reflux for 3 hours. The reaction was
concentrated and the resulting solid was recrystallized from ethyl
acetate-hexanes to give
7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (69.7 g, 68%) as
off-white needles. .sup.1H NMR (CDCl.sub.3): .delta. 8.03 (m, 2 H),
7.54 (d, 1 H), 7.16 (m, 3 H), 6.93 (d, 1 H), 6.91 (s, 1 H); MS m/z
247 (M+1); mp 156-157.degree. C.
d)
1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone
[0473] To a solution of
7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (10.0 g, 40.5
mmol) in toluene (225 mL) at room temperature was added acetic
anhydride (4.6 mL, 48.6 mmol). Boron trifluoride diethyletherate
(5.6 mL, 44.6 mmol) was then added dropwise and the resultant
solution was heated to reflux for 3.5 hours. The reaction mixture
was cooled to room temperature and quenched by the dropwise
addition of aqueous sodium bicarbonate. Ether was added and the
organic layer was washed with brine. The aqueous layer was
extracted with ether and the combined organics were dried over
magnesium sulfate, filtered and concentrated. The residue was
purified by recrystallization from ethyl acetate-hexanes to give
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone
(9.0 g, 77%) as redish needles. .sup.1H NMR (CDCl.sub.3): .delta.
8.41 (d, 1 H), 7.59 (m, 2 H), 7.45 (dd, 1 H), 7.26-7.13 (m 3 H),
2.15 (s, 3 H); .sup.19F NMR (CDCl.sub.3) .delta. -112.06; MS m/z
289 (M+1).
e)
1-[7-(Cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]e-
thanone
[0474] To a solution of
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone
(2.7 g, 9.5 mmol) in toluene (50 mL) was added successively
racemic-BINAP (378 mg, 0.6 mmol), cesium carbonate (4.7 g, 14.3
mmol), cyclopentylamine (4.7 mL, 47.5 mmol), and palladium (II)
acetate (86 mg, 0.4 mmol). The resultant mixture was heated to
95.degree. C. for 2.5 hours at which time the reaction was judged
complete by thin layer chromatography. The solution was cooled to
room temperature and ether was added. The organic layer was washed
with water and brine. The aqueous layer was extracted with ether
and the combined organics dried over magnesium sulfate. Filtration
and concentration followed by flash chromatography (4:1
hexanes-ethyl acetate) provided
1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]eth-
anone (3.1 g, 95%) as a yellow solid. .sup.1H NMR (CDCl.sub.3):
.delta. 7.62 (d, 1 H), 7.55 (dd, 2 H), 7.40 (t, 1 H), 7.15 (t, 2
H), 6.10 (d, 1 H), 5.99 (d, 1 H), 3.94 (m, 1 H), 2.09 (s, 3 H),
2.12-2.04 (m, 2 H), 1.78-1.58 (m, 6 H); .sup.13C NMR (CDCl.sub.3)
.delta. 192.63, 163.28 (d, J.sub.CF=247.3 Hz), 154.89, 142.65,
142.38, 131.66 (d, J.sub.CF=8.3 Hz) 131.09, 130.03 (d, J.sub.CF=3.8
Hz), 115.33 (d, J.sub.CF=22.0 Hz), 111.32, 105.41, 91.97, 53.81,
33.21, 30.10, 23.96; .sup.19F NMR (CDCl.sub.3) .delta. -112.70; MS
m/z 338 (M+1).
f)
(2E)-1-[7-(Cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-
-yl]-3-(dimethylamino)-2-propen-1-one
[0475] A solution of
1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]eth-
anone (3.1 g, 9.2 mmol) in N,N-dimethylformamide dimethyl acetal
(25 mL) was heated to reflux for 6 days. The mixture was cooled to
room temperature, ethyl acetate was added followed by water. The
organic layer was washed with brine. The aqueous layer was
extracted with ethyl acetate and the combined organics were dried
over magnesium sulfate. Filtration and concentration followed by
flash chromatography (ethyl acetate) provided
(2E)-1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]py-
ridin-3-yl]-3-(dimethylamino)-2-propen-1-one (3.6 g, 99%) as a
tinted oil: .sup.1H NMR (CDCl.sub.3): .delta. 7.73-7.61 (m, 4 H),
7.32 (t, 1 H), 7.14 (t, 2 H), 6.03 (d, 1 H), 5.96 (d, 1 H), 5.05
(d, 1 H), 3.99 (m, 1 H), 5.15-2.42 (broad, 6 H), 2.19-2.08 (m, 2
H), 1.86-1.62 (m, 6 H); .sup.19F NMR (CDCl.sub.3) .delta. -113.75;
MS m/z 393 (M+1).
g) N-Cyclopentylguanidine hydrochloride
[0476] (prepared by modification of a procedure from Bannard, R. A.
B.; Casselman, A. A.; Cockburn, W. F.; and Brown, G. M. Can. J.
Chem. 1958, 36, 1541-1549). To a solution of
2-methyl-2-thiopseudourea sulfate (13.9 g, 50.0 mmol) in water (40
mL) was added cyclopentylamine (14.8 mL, 150 mmol). The resultant
mixture was heated to 55.degree. C. for 20 minutes and then to
reflux for 2.5 hours. The mixture was cooled to room temperature
and concentrated in vacuo and azeotroped with methanol. Water was
added (.about.100 mL) and Amberlite IRA 400 (Cl.sup.-) resin was
added. The mixture was stirred for 1 hour and then the resin was
removed by filtration. The solution was concentrated in vacuo and
azeotroped with methanol. The residue was recrystallized from
methanol-acetone to yield N-cyclopentylguanidine hydrochloride (7.0
g, 86%) as a fine white solid. .sup.1H NMR (D.sub.2O): .delta. 3.62
(m, 1 H), 1.75 (m, 2 H), 1.52-1.32 (m, 6 H); .sup.13C NMR
(D.sub.2O) .delta. 156.23, 53.11, 32.15, 23.13; MS m/z 128
(M+1).
h)
N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-
pyrazolo[1,5-a]pyridin-7-amine
[0477] To a solution of
(2E)-1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-y-
l]-3-(dimethylamino)-2-propen-1-one (3.5 g, 8.9 mmol) in
tetrahydrofuran (36 mL, 0.25 M) was added N-cyclopentylguanidine
hydrochloride (1.89 g, 11.6 mmol), followed by solid potassium
tert-butoxide (2.6 g, 23.2 mmol) in two portions. The resultant
solution was heated to reflux for 23 hours. Upon cooling to room
temperature, ether was added followed by water. The organics were
washed with brine, and the aqueous layer was extracted with ether.
The combined organics were dried over magnesium sulfate, filtered
and concentrated in vacuo. The residue was purified by flash
chromatography on silica to give
N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)py-
razolo[1,5-a]pyridin-7-amine (3.7 g, 91%) as an off white solid.
.sup.1H NMR (CDCl.sub.3): .delta. 7.97 (d, 1 H), 7.68 (d, 1 H),
7.59 (dd, 2 H), 7.27 (t, 1 H), 7.10 (t, 2 H), 6.24 (d, 1 H), 5.99
(d, 1 H), 5.96 (d, 1 H), 5.01 (d, 1 H), 4.28 (m, 1 H), 3.97 (m, 1
H), 2.12-1.99 (m, 4 H), 1.79-1.44 (m, 12 H); .sup.13C NMR
(CDCl.sub.3) .delta. 163.12 (d, J.sub.CF=246.6 Hz), 162.09, 161.53,
156.67, 152.15, 142.66, 141.09, 131.46 (d, J.sub.CF=8.0 Hz), 129.92
(d, J.sub.CF=3.1 Hz), 128.39, 115.45(d, J.sub.CF=21.3 Hz),108.68,
107.13, 105.15, 90.13, 53.84, 52.87, 33.50, 33.30, 24.05, 23.70;
.sup.19F NMR (CDCl.sub.3) .delta. -113.49; MS m/z 457 (M+1); Anal.
Calcd for C.sub.27H.sub.29FN.sub.6: C, 71.03; H, 6.40; N, 18.41.
Found: C, 71.20; H, 6.37; N, 18.52.
EXAMPLE 2
2-(4-Bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo-[1,5-a]-
pyridin-7-amine
[0478] ##STR62##
a) 1-(4-Bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone
[0479] In a similar manner as described in Example 1, from ethyl
4-bromobenzoate (12.8 mL, 78.3 mmol) and 6-chloro-2-picoline (4.3
mL, 39.2 mmol), 1-(4-bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone
(9.6 g, 82%) was obtained as a crystalline solid existing as a
keto-enol tautomeric mixture. .sup.1H NMR (CDCl.sub.3): for the
keto tautomer .delta. 7.95 (d, 2 H), 7.74-7.56 (m, 3 H), 7.27 (m, 2
H), 4.47 (s, 2 H); MS m/z 310 (M+1).
b) 1-(4-Bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime
[0480] In a similar manner as described in Example 1, from
1-(4-bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone (9.5 g, 30.6
mmol) was obtained
1-(4-bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime (10.0 g,
99%) as a white solid. .sup.1H NMR (CDCl.sub.3): .delta. 9.78
(broad, 1 H), 7.74-7.47 (m, 5 H), 7.21-7.17 (m, 2 H), 4.39 (s, 2
H); MS m/z 325 (M+1).
c) 2-(4-Bromophenyl)-7-chloropyrazolo[1,5-a]pyridine
[0481] In a similar manner as described in Example 1, from
1-(4-bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime (45.2 g,
139 mmol), 2-(4-bromophenyl)-7-chloropyrazolo[1,5-a]pyridine (30.5
g, 72%) was obtained as a pale yellow crystalline solid. .sup.1H
NMR (CDCl.sub.3): .delta. 7.85 (dd, 2 H), 7.54 (dd, 2 H), 7.46 (d,
1 H), 7.04 (m, 1 H), 6.87 (m, 2 H); MS m/z 307 (M+1).
d)
1-[2-(4-Bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone
[0482] In a similar manner as described in Example 1, from
2-(4-bromophenyl)-7-chloropyrazolo[1,5-a]pyridine (10.0 g, 32.5
mmol),
1-[2-(4-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone
(7.63 g, 67%) was obtained as pink needles. .sup.1H NMR
(CDCl.sub.3): .delta. 8.37 (d, 1 H), 7.62 (d, 2 H), 7.43 (m, 3 H),
7.14 (d, 1 H), 2.13 (s, 3 H); MS m/z 349 (M+1).
e)
1-[2-(4-Bromophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone
[0483] In a similar manner as described in Example 1, from
1-[2-(4-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone
(2.55 g, 7.3 mmol),
1-[2-(4-bromophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone
(2.15 g, 76%) was obtained as a yellow oil. .sup.1H NMR
(CDCl.sub.3): .delta. 7.61 (m, 3 H), 7.43 (m, 3 H), 6.08 (d, 1 H),
6.02 (bs, 1 H), 3.33 (q, 2 H), 2.12 (s, 3 H), 1.70 (m, 2 H), 1.44
(m, 2 H), 0.94 (t, 3 H); MS m/z 386 (M+1).
f)
(2E)-1-[2-(4-Bromophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-3--
(dimethylamino)-2-propen-1-one
[0484] In a similar manner as described in Example 1, from
1-[2-(4-bromophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone
(5.5 g, 14.2 mmol),
(2E)-1-[2-(4-bromophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(d-
imethylamino)-2-propen-1-one (5.78 g, 92%) was obtained as a brown
oil. .sup.1H NMR (CDCl.sub.3): .delta. 7.57 (m, 6 H), 7.28 (t, 1
H), 5.95 (m, 2 H), 5.03 (d, 1 H), 3.32 (q, 2 H), 2.92 (bs, 3 H),
2.52 (bs, 3 H), 1.71 (m, 2 H), 1.44 (m, 2 H), 0.94 (t, 3 H); MS m/z
441 (M+1).
g)
2-(4-Bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5--
a]pyridin-7-amine
[0485] In a similar manner as described in Example 1, from
(2E)-1-[2-(4-bromophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(d-
imethylamino)-2-propen-1-one (5.78 g, 13.1 mmol) and
N-butylguanidine sulfate (Weiss, S.; Krommer, H. Chem.-Zgt. 1974,
98, 617-618) was obtained
2-(4-bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazo-
lo[1,5-a]pyridin-7-amine (5.18 g, 80%) as a pale yellow solid.
.sup.1H NMR (CDCl.sub.3): .delta. 7.98 (d, 1 H), 7.71 (d, 1 H),
7.56 (m, 4 H), 7.33 (t, 1 H), 6.35 (d, 1 H), 6.03 (m, 2 H), 3.46
(q, 2 H), 3.38 (q, 2 H), 1.81-1.40 (m, 8 H), 0.98 (m, 6 H); MS m/z
493 (M+1).
EXAMPLE 3
N-Butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo-[1,5-a-
]pyridin-7-amine
[0486] ##STR63##
a)
1-[7-(Butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanon-
e
[0487] A mixture of
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone
(969 mg, 3.4 mmol) and potassium carbonate (9.6 g, 69.4 mmol) in
n-butylamine (20 mL) was heated to reflux for 5 hours. The mixture
was cooled to room temperature and concentrated in vacuo. The
residue was taken up in ethyl acetate and water. The organic layer
was washed with brine. The aqueous layer was extracted with ethyl
acetate and the combined organics were dried over sodium sulfate.
Filtration and concentration followed by flash chromatography (2:1
hexanes-ethyl acetate) provided
1-[7-(butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone
(921 mg, 84%) as a tinted oil. .sup.1H NMR (CDCl.sub.3): .delta.
7.71 (d, 1 H), 7.63 (dd, 2 H), 7.49 (t, 1 H), 7.23 (t, 2 H), 6.16
(d, 1 H), 6.10 (m, 1 H), 3.40 (m, 2 H), 2.18 (s, 3 H), 1.78 (m, 2
H), 1.52 (m, 2 H), 1.02 (t, 3 H); MS m/z 326 (M+1); R.sub.f 0.6
(1:1 hexanes:ethyl acetate).
b)
(2E)-1-[7-(Butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-
-(dimethylamino)-2-propen-1-one
[0488] In a similar manner as described in Example 1, from
1-[7-(butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone
(880 mg, 2.7 mmol) was formed
(2E)-1-[7-(butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(-
dimethylamino)-2-propen-1-one (971 mg, 95%) as yellow foam. .sup.1H
NMR (CDCl.sub.3): .delta. 7.67 (dd, 2 H), 7.60 (d, 1 H), 7.53 (d, 1
H), 7.27 (t, 1 H), 7.09 (t, 2 H), 5.96-5.93 (m 2 H), 5.01 (d, 1 H),
3.30 (m, 2 H), 3.10-2.30 (broad, 6 H), 1.69 (m, 2 H), 1.43 (m, 2
H), 0.93 (t, 3 H); MS m/z 381 (M+1).
c)
N-Butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-
-a]pyridin-7-amine
[0489] In a similar manner as described in Example 1, from
(2E)-1-[7-(butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(-
dimethylamino)-2-propen-1-one (34 mg, 0.09 mmol), N-butylguanidine
sulfate and potassium carbonate in N,N-dimethylformamide was
obtained
N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a-
]pyridin-7-amine (33 mg, 85%) as a yellow solid. .sup.1H NMR
(CDCl.sub.3): .delta. 7.98 (d, 1 H), 7.68 (d, 1 H), 7.59 (m, 2 H),
7.27 (t, 1 H), 7.10 (t, 2 H), 6.25 (d, 1 H), 6.00-5.96 (m, 2 H),
5.05 (m, 1 H), 3.41 (m, 2 H), 3.33 (m, 2 H), 1.71 (m, 2 H), 1.60
(m, 2 H), 1.50-1.36 (m, 4 H), 0.97-0.91 (m, 6 H); MS m/z 433 (M+1);
R.sub.f 0.67 (1:1 hexanes-ethyl acetate).
EXAMPLE 4
N-Butyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-pyrazolo-
[1,5-a]pyridin-7-amine
[0490] ##STR64##
[0491] In a similar manner as described in Example 1, from
(2E)-1-[7-(butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(-
dimethylamino)-2-propen-1-one (71mg, 0.19 mmol),
N-cyclopropylguanidine sulfate and potassium carbonate in
dimethylformamide was obtained
N-butyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo-
[1,5-a]pyridin-7-amine (57 mg, 73%) as a white solid. .sup.1H NMR
(CDCl.sub.3): .delta. 8.09 (d, 1 H), 7.92 (d, 1 H), 7.67 (dd, 2 H),
7.34 (t, 1 H), 7.18 (t, 2 H), 6.37 (d, 1 H), 6.09-6.04 (m, 2 H),
5.53 (broad, 1 H), 3.40 (m, 2 H), 2.88 (m, 1 H), 1.79 (m, 2 H),
1.52 (m, 2 H), 1.02 (t, 3 H), 0.88 (m, 2 H), 0.64 (m, 2 H); MS m/z
417 (M+1); R.sub.f 0.55 (1:1 hexanes:ethyl acetate).
EXAMPLE 5
N-Butyl-2-(4-fluorophenyl)-3-[2-(1-pyrrolidinyl)-4-pyrimidinyl]pyrazolo[1,-
5-a]pyridin-7-amine
[0492] ##STR65##
[0493] In a similar manner as described in Example 1, from
(2E)-1-[7-(butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(-
dimethylamino)-2-propen-1-one (70 mg, 0.18 mmol),
1-pyrrolidinecarboximidamide sulfate and potassium carbonate in
dimethylformamide was obtained
N-butyl-2-(4-fluorophenyl)-3-[2-(1-pyrrolidinyl)-4-pyrimidinyl]pyrazolo[1-
,5-a]pyridin-7-amine (64 mg, 81%) as a yellow solid. .sup.1H NMR
(CDCl.sub.3): .delta. 8.03 (d, 1 H), 7.76 (d, 1 H), 7.59 (m, 2 H),
7.26 (t, 1 H), 7.09 (t, 2 H), 6.20 (d, 1 H), 5.99-5.95 (m, 2 H),
3.61 (m, 4 H), 3.32 (m, 2 H), 1.98 (m, 4 H), 1.70 (m, 2 H), 1.44
(m, 2 H), 0.94 (t, 3 H); .sup.13C NMR (CDCl.sub.3) .delta. 163.07
(d, J.sub.CF=246.5 Hz), 161.04, 160.48, 156.56, 152.19, 143.01,
141.13, 131.45 (d, J.sub.CF=8.4 Hz), 130.05 (d, J.sub.CF=3.0 Hz),
128.34, 115.38 (d, J.sub.CF=21.2 Hz), 107.46, 107.22, 105.50,
89.19, 46.59, 42.33, 31.11, 25.55, 20.19, 13.75; MS m/z 431
(M+1).
EXAMPLE 6
N-Butyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[-
1,5-a]pyridin-7-amine
[0494] ##STR66##
[0495] In a similar manner as described in Example 1, from
(2E)-1-[7-(butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(-
dimethylamino)-2-propen-1-one (258 mg, 0.68 mmol) was obtained
N-butyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo-
[1,5-a]pyridin-7-amine (260 mg, 87%) as a yellow solid. .sup.1H NMR
(CDCl.sub.3): .delta. 8.01 (d, 1 H), 7.73 (d, 1 H), 7.62 (m, 2 H),
7.29 (t, 1 H), 7.12 (t, 2 H), 6.28 (d, 1 H), 6.05 (m, 1 H), 5.98
(d, 1 H), 5.27 (broad, 1 H), 4.32 (m, 1 H), 3.34 (m, 2 H),
2.10-2.00 (m, 2 H), 1.77-1.41 (m, 10 H), 0.97 (t, 3 H); .sup.13C
NMR (CDCl.sub.3) .delta. 163.03 (d, J.sub.CF=244.5 Hz), 162.14,
161.41, 156.74, 152.10, 142.99, 141.02, 131.36 (d, J.sub.CF=8.0 Hz)
129.92 (d, J.sub.CF=3.0 Hz), 128.31, 115.36 (d, J.sub.CF=21.0 Hz),
108.58, 107.9, 105.17, 89.21, 52.79, 42.27, 33.40, 31.06, 23.65,
20.13, 13.70; .sup.19F NMR (CDCl.sub.3) .delta. -113.42; MS m/z 445
(M+1).
EXAMPLE 7
4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-6-
-methyl-2-pyrimidinamine
[0496] ##STR67##
a)
7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde
[0497] N,N-Dimethylformamide (100 mL) was cooled to 0.degree. C.
and treated with phosphorous oxychloride (5.7 mL, 60.8 mmol). After
the addition was complete, the mixture was warmed to room
temperature and stirred for 1 hour. To this was added
7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (10.0 g, 40.5
mmol) and the resultant solution was stirred overnight. Water was
added, followed by dichloromethane. The aqueous layer was extracted
with dichloromethane. The combined organics were washed with brine,
dried over magnesium sulfate, filtered and concentrated. The
residue was recrystallized from diethyl ether and hexanes to give
7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde
(10.6 g, 95%) as a fluffy white solid. .sup.1H NMR (CDCl.sub.3):
.delta. 10.07 (s, 1 H), 8.37 (d, 1 H), 7.78 (m, 2 H), 7.48 (t, 1
H), 7.20 (m, 3 H); .sup.19F NMR (CDCl.sub.3) .delta. -111.25; MS
m/z 275 (M+1); Anal. Calcd for C.sub.14H.sub.8ClFN.sub.2O: C,
61.22; H, 2.94; N, 10.20. Found: C, 61.34; H, 2.90; N, 10.15; mp
212-213.degree. C. (decomp.).
b)
1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn-1-ol
[0498] To a cold (-78.degree. C.) suspension of
7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde
(1.50 g, 5.47 mmol) in tetrahydrofuran (10 mL) was added 1-propynyl
magnesium bromide (12.0 mL, 0.5 M in tetrahydrofuran, 6.02 mmol)
dropwise. The reaction mixture was stirred at -78.degree. C. for 1
hour, then at 0.degree. C. for 2 hours. The resultant solution was
poured into saturated aqueous sodium bicarbonate and extracted with
ethyl acetate. The organic layer was washed with water and brine
and the combined organics were dried over magnesium sulfate.
Filtration and concentration followed by flash chromatography (4:1
hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate) provided
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn-1-ol
(1.3 g, 72%) as a white solid. R.sub.f 0.44 (2:1 hexanes:ethyl
acetate); .sup.1H NMR (CDCl.sub.3) .delta. 7.99 (d, 1H), 7.78 (m,
2H), 7.14 (m, 3H), 6.95 (d, 1H), 5.70 (m, 1H), 2.21 (d, 1H), 1.85
(d, 3H); MS m/z 315 (M+1).
c)
1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn-1-on-
e
[0499] To a solution of
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn-1-ol
(1.04 g, 3.30 mmol) in chloroform (50 mL) was added manganese
dioxide (5.70 g, 65.6 mmol). The reaction mixture was stirred at
room temperature for 3 hours. The suspension was filtered through a
pad of Celite and the filtrate was concentrated in vacuo to give
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn-1-one
(950 mg, 91%). R.sub.f 0.44 (3:1 hexanes:ethyl acetate); .sup.1H
NMR (CDCl.sub.3) .delta. 8.49 (d, 1H), 7.73 (m, 2H), 7.50 (t, 1H),
7.19 (m, 3H), 1.71 (3H); .sup.19F NMR (CDCl.sub.3) .delta. -112.58;
mp 182-183.degree. C.
d)
4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopenty-
l-6-methyl-2-pyrimidinamine
[0500] To a dry round bottom flask was added sodium metal (81 mg,
3.5 mmol). Ethanol (20 mL) was added and allowed to react with
sodium at room temperature until completely dissolved.
N-Cyclopentylguanidine hydrochloride (572 mg, 3.5 mmol) was added
and the mixture was allowed to stir at room temperature for 10
minutes. To the resultant mixture was added
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn--
1-one (842 mg, 2.69 mmol) and the reaction mixture was allowed to
stir at room temperature for 72 hours, then heated to 70.degree. C.
for 12 hours. The reaction mixture was cooled to room temperature
and diluted with water. The mixture was extracted with ethyl
acetate, and the combined extracts were washed with water and
brine. The organic layer was dried over magnesium sulfate.
Filtration and concentration followed by flash chromatography (4:1
hexanes:ether to 3:2 hexanes:ether) provided
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
6-methyl-2-pyrimidinamine (1.11 g, 98%) as a yellow foam. R.sub.f
0.45 (3:1 hexanes:ethyl acetate). .sup.1H NMR (CDCl.sub.3) .delta.
8.35 (d, 1H), 7.64 (m, 2H), 7.24 (m, 1H), 7.13 (m, 2H), 7.03 (d,
1H), 6.22 (s, 1H), 5.10 (m, 1H), 4.35 (m, 1H), 2.19 (s, 3H), 2.03
(m, 2H), 1.60 (m, 6H); MS m/z 422 (M+1).
EXAMPLE 8
N-Cyclopentyl-3-[2-(cyclopentylamino)-6-methyl-4-pyrimidinyl]-2-(4-fluorop-
henyl)pyrazolo[1,5-a]pyridin-7-amine
[0501] ##STR68##
[0502] In a similar manner as described in Example 1, from
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
6-methyl-2-pyrimidinamine (58 mg, 0.14 mmol) and cyclopentylamine
was formed
N-cyclopentyl-3-[2-(cyclopentylamino)-6-methyl-4-pyrimidinyl]-2-(4-
-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine (41 mg, 64%) as a
clear oil. .sup.1H NMR (CDCl.sub.3): .delta. 7.69-7.62 (m, 3 H),
7.28 (t, 1 H), 7.12 (t, 2 H), 6.21 (s, 1 H), 6.02-5.99 (m, 2 H),
5.05 (d, 1 H), 4.33 (m, 1 H), 3.99 (m, 1 H), 2.15 (s, 3 H),
2.15-1.45 (m, 16 H); .sup.19F NMR (CDCl.sub.3) .delta. -113.70; MS
m/z 471 (M+1). This material was treated with anhydrous
hydrochloric acid in ether to provide a hydrochloride salt as a
yellow solid.
EXAMPLE 9
2-(4-Bromophenyl)-N-butyl-3-[2-(1-pyrrolidinyl)-4-pyrimidinyl]pyrazolo-[1,-
5-a]pyridin-7-amine
[0503] ##STR69##
[0504] In a similar manner as described in Example 1, from
(2E)-1-[2-(4-bromophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(d-
imethylamino)-2-propen-1-one (47 mg, 0.11 mmol) and
1-pyrrolidinecarboximidamide sulfate was obtained
2-(4-bromophenyl)-N-butyl-3-[2-(1-pyrrolidinyl)-4-pyrimidinyl]pyrazolo[1,-
5-a]pyridin-7-amine (34 mg, 66%) as a yellow solid. .sup.1H NMR
(CDCl.sub.3): .delta. 8.05 (d, 1 H), 7.74 (d, 1 H), 7.52 (ABq, 4
H), 7.27 (t, 1 H), 6.22 (d, 1 H), 5.99-5.95 (m, 2 H), 3.61 (m, 4
H), 3.33 (m, 2 H), 1.98 (m, 4 H), 1.71 (m, 2 H), 1.44 (m, 2 H),
0.94 (t, 3 H); MS m/z 491 (M+1).
EXAMPLE 10
2-(4-Bromophenyl)-N-butyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1-
,5-a]pyridin-7-amine
[0505] ##STR70##
[0506] In a similar manner as described in Example 1, from
(2E)-1-[2-(4-bromophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(d-
imethylamino)-2-propen-1-one (299 mg, 0.68 mmol) was obtained
2-(4-bromophenyl)-N-butyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[-
1,5-a]pyridin-7-amine (251 mg, 74%) as a yellow crystalline solid.
.sup.1H NMR (CDCl.sub.3): .delta. 8.07 (d, 1 H), 7.74 (d, 1 H),
7.60 (ABq, 4 H), 7.35 (t, 1 H),6.34 (d, 1 H), 6.07-6.04 (m, 2 H),
5.09 (d, 1 H), 4.34 (m, 1 H), 3.41 (m, 2 H), 2.10 (m, 2 H),
1.85-1.47 (m, 10 H), 1.02 (t, 3 H); MS m/z 505 (M+1).
EXAMPLE 11
N-Cyclopentyl-3-[2-(dimethylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazo-
lo[1,5-a]pyridin-7-amine
[0507] ##STR71##
[0508] In a similar manner as described in Example 1, from
(2E)-1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-y-
l]-3-(dimethylamino)-2-propen-1-one (250 mg, 0.64 mmol) and
N,N-dimethylguanidine sulfate was obtained
/cyclopentyl-3-[2-(dimethylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazo-
lo[1,5-a]pyridin-7-amine (233 mg, 87%) as a white solid. .sup.1H
NMR (CDCl.sub.3): .delta. 8.13 (d, 1 H), 7.75 (d, 1 H), 7.67 (dd, 2
H), 7.33 (t, 1 H), 7.16 (t, 2 H), 6.30 (d, 1 H), 6.06-6.04 (m, 2
H), 4.02 (m, 1 H), 3.26 (s, 6 H), 2.16 (m, 2 H), 1.84-1.65 (m, 6
H); MS m/z 417 (M+1).
EXAMPLE 12
3-(2-Amino-4-pyrimidinyl)-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo-[1,5-a]-
pyridin-7-amine
[0509] ##STR72##
[0510] In a similar manner as described in Example 1, from
(2E)-1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-y-
l]-3-(dimethylamino)-2-propen-1-one (375 mg, 0.96 mmol) and
guanidine hydrochloride was obtained
3-(2-amino-4-pyrimidinyl)-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-a]-
pyridin-7-amine (220 mg, 60%) as a white solid. .sup.1H NMR
(CDCl.sub.3): .delta. 7.98 (d, 1 H), 7.66 (d, 1 H), 7.59 (m, 2 H),
7.28 (t, 1 H), 7.10 (t, 2 H), 6.31 (d, 1 H), 6.00 (d, 1 H), 5.96
(d, 1 H), 4.97 (broad s, 2 H), 3.96 (m, 1 H), 2.14-2.06 (m, 2 H),
1.83-1.63 (m, 6 H); .sup.13C NMR (CDCl.sub.3) .delta. 163.39 (d,
J.sub.CF=246.6 Hz), 163.20, 162.25, 157.27, 152.33, 142.88, 141.32,
131.64 (d, J.sub.CF=8.4 Hz), 129.91 (d, J.sub.CF=3.8 Hz), 128.84,
115.75 (d, J.sub.CF=22.0 Hz), 110.31, 106.85, 105.31, 90.53, 54.06,
33.53, 24.27; .sup.19F NMR (CDCl.sub.3) .delta. -113.20; MS m/z 389
(M+1); Anal. Calcd for C.sub.22H.sub.21FN.sub.6: C, 68.03; H, 5.45;
N, 21.63. Found: C, 67.96; H, 5.50; N, 21.82.
EXAMPLE 13
N-Cyclopentyl-2-(4-fluorophenyl)-3-(2-{[3-(4-morpholinyl)propyl]-amino}-4--
pyrimidinyl)pyrazolo[1,5-a]pyridin-7-amine
[0511] ##STR73##
[0512] In a similar manner as described in Example 1, from
(2E)-1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-y-
l]-3-(dimethylamino)-2-propen-1-one (250 mg, 0.64 mmol) and
N-[3-(4-morpholinyl)propyl]guanidine sulfate was obtained
N-cyclopentyl-2-(4-fluorophenyl)-3-(2-{[3-(4-morpholinyl)propyl]amino}-4--
pyrimidinyl)pyrazolo[1,5-a]pyridin-7-amine (200 mg, 61%) as a tan
solid. .sup.1H NMR (CDCl.sub.3): .delta. 7.97 (d, 1 H), 7.69 (d, 1
H), 7.59 (dd, 2 H), 7.26 (t, 1 H), 7.10 (t, 2 H), 6.24 (d, 1 H),
6.00 (d, 1 H), 5.96 (d, 1 H), 5.70 (broad, 1 H), 3.97 (m, 1 H),
3.71 (m, 4 H), 3.49 (m, 2 H), 2.48-2.45 (m, 6 H), 2.10 (m, 2 H),
1.83-1.59 (m, 8 H); .sup.19F NMR (CDCl.sub.3) .delta. -113.46; MS
m/z 516 (M+1).
EXAMPLE 14
N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-hydrazinopyrazolo[1,5-a]pyridin-3-yl-
]-6-methyl-2-pyrimidinamine
[0513] ##STR74##
[0514] To a solution of
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
6-methyl-2-pyrimidinamine (100 mg, 0.237 mmol) in ethanol (1 mL)
was added hydrazine (500 uL, 15.9 mmol). The reaction mixture was
heated in a sealed tube at 90.degree. C. for 72 hours. The mixture
was cooled and diluted with ethyl acetate and washed with saturated
aqueous sodium bicarbonate, water and brine. The combined organics
were dried over magnesium sulfate. Filtration and concentration
followed by flash chromatography (38:2 dichloromethane-methanol)
provided
N-cyclopentyl-4-[2-(4-fluorophenyl)-7-hydrazinopyrazolo[1,5-a]pyridin-3-y-
l]-6-methyl-2-pyrimidinamine (45 mg, 46%) as a yellow solid.
R.sub.f 0.43 (38:2 CH.sub.2Cl.sub.2-MeOH); .sup.1H NMR (CDCl.sub.3)
.delta. 7.78 (1H), 7.62 (2H), 7.35 (1H), 7.20 (1H), 7.12 (2H), 6.45
(1H), 6.24 (1H), 5.03 (1H), 4.35 (1H), 3.85 (2H), 2.18 (3H), 2.02
(2H), 1.62 (6H); MS m/z 418 (M+1).
EXAMPLE 15
N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(4-methyl-1-piperazinyl)-pyrazolo[1,-
5-a]pyridin-3-yl]-6-methyl-2-pyrimidinamine
[0515] ##STR75##
[0516] In a similar manner to Example 14, from
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
6-methyl-2-pyrimidinamine (100 mg, 0.237 mmol) and
N-methylpiperazine (1 mL, 9.01 mmol) was formed
N-cyclopentyl-4-[2-(4-fluorophenyl)-7-(4-methyl-1-piperazinyl)pyrazolo[1,-
5-a]pyridin-3-yl]-6-methyl-2-pyrimidinamine (80 mg, 70%) as a clear
oil. R.sub.f 0.31 (3:2 hexanes:ethyl acetate) .sup.1H NMR
(CDCl.sub.3) .delta. 8.00 (d, 1H), 7.66 (m, 2H), 7.25 (d, 1H), 7.08
(t, 2H), 6.31 (d, 1H), 6.27 (s, 1H), 5.02 (d, 1H), 4.34 (m, 1H),
3.50 (m, 4H), 2.72 (m, 4H), 2.41 (s, 3H), 2.18 (s, 3H), 2.03 (m,
2H), 1.65 (m, 6H); MS m/z 486 (M+1). This material was taken up in
ether and treated with hydrochloric acid in ether to yield an
orange precipitate which was isolated by filtration as a
hydrochloride salt.
EXAMPLE 16
N-Cyclopentyl-3-{2-(cyclopentylamino)-6-[(tetrahydro-2H-pyran-2-yloxy)meth-
yl]-4-pyrimidinyl}-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine
[0517] ##STR76##
a)
1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-4-(tetrahydr-
o-2H-pyran-2-yloxy)-2-butyn-1-ol
[0518] To a cold (-78.degree. C.) solution of
tetrahydro-2-(2-propynyloxy)-2H-pyran (0.5 mL, 3.6 mmol) in
tetrahydrofuran (10 mL) was added n-butyllithium (2.05 mL, 1.6 M in
hexanes, 3.3 mmol) dropwise. The reaction mixture was allowed to
warm to 0.degree. C., then cooled to -78.degree. C. A separate
solution of
7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde
(200 mg, 0.73 mmol) in tetrahydrofuran (5 mL) was cooled to
0.degree. C. The alkynyllithium solution was added to the aldehyde
solution via canula. The reaction mixture was allowed to warm to
room temperature and stirred for 1 hour. Water was added followed
by ether. The organic layer was washed with water and brine. The
aqueous layer was extracted with ether and the combined organics
were dried over magnesium sulfate. Filtration and concentration
followed by flash chromatography (2:1 hexanes:ethyl acetate)
provided
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-4-(tetrahydro--
2H-pyran-2-yloxy)-2-butyn-1-ol (301 mg, 99%) as a mixture of
diastereomers. .sup.1H NMR (CDCl.sub.3) .delta. 8.00 (d, 1H), 7.79
(m, 2H), 7.17 (m 3 H), 6.99 (m, 1 H), 5.79 (s, 1 H), 4.81-4.74 (m,
1 H), 4.39-4.25 (m, 2 H), 3.81 (m, 1 H), 3.52 (m, 1 H), 3.15
(broad, 1 H), 1.90-1.48 (m, 6 H); .sup.19F NMR (CDCl.sub.3) .delta.
-113.01; MS m/z 437 (M+Na.sup.+).
b)
1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-4-(tetrahydr-
o-2H-pyran-2-yloxy)-2-butyn-1-one
[0519] In a similar manner as described in Example 7, from
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-4-(tetrahydro--
2H-pyran-2-yloxy)-2-butyn-1-ol (301 mg, 0.73 mmol) was formed
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-4-(tetrahydro--
2H-pyran-2-yloxy)-2-butyn-1-one (280 mg, 93%) as a white solid.
.sup.1H NMR (CDCl.sub.3) .delta. 8.48 (d, 1H), 7.71 (m, 2H), 7.50
(m, 1H), 7.17 (m, 3H), 4.59 (m, 1H), 4.11 (s, 2H), 3.72 (m, 1H),
3.49 (m, 1H), 1.82-1.50 (m, 6H); .sup.19F NMR (CDCl.sub.3) .delta.
-111.89; MS m/z 435 (M+Na.sup.+).
c)
4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopenty-
l-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-pyrimidinamine
[0520] In a similar manner as described in Example 7, from
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-4-(tetrahydro--
2H-pyran-2-yloxy)-2-butyn-1-one (186 mg, 0.45 mmol) was formed
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-pyrimidinamine (165 mg,
71%) as a clear oil. R.sub.f 0.12 (4:1 hexanes:ethyl acetate);
.sup.1H NMR (CDCl.sub.3) .delta. 8.46 (d, 1H), 7.65 (m, 2H), 7.24
(m, 1H), 7.11 (t, 2H), 7.02 (d, 1H), 6.51 (s, 1H), 5.09 (d, 1H),
4.58 (m, 1H), 4.50 (d, 1H), 4.37 (m, 1H), 4.08 (d, 1H), 3.66 (m,
1H), 3.45 (m, 1H), 2.06 (m, 2H), 1.58 (m, 12H); .sup.19F NMR
(CDCl.sub.3) .delta. -113.16; MS m/z 522 (M+1).
d)
N-Cyclopentyl-3-{2-(cyclopentylamino)-6-[(tetrahydro-2H-pyran-2-yloxy)--
methyl]-4-pyrimidinyl}-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine
[0521] In a similar manner as described in Example 8, from
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-pyrimidinamine (163 mg,
0.31 mmol) was formed
N-cyclopentyl-3-{2-(cyclopentylamino)-6-[(tetrahydro-2H-pyran-2-yloxy)met-
hyl]-4-pyrimidinyl}-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine
(146 mg, 82%) as a white solid. .sup.1H NMR (CDCl.sub.3) .delta.
7.80 (d, 1 H), 7.68 (m, 2 H), 7.37-7.13 (m, 3 H), 6.53 (s, 1 H),
6.06 (m, 2 H), 5.04 (d, 1 H), 4.63 (broad, 1 H), 4.53 (d, 1 H),
4.40 (m, 1 H), 4.31 (d, 1 H), 4.05 (m, 1 H), 3.74 (m, 1 H), 3.50
(m, 1 H), 2.24-1.44 (m, 22 H); .sup.19F NMR (CDCl.sub.3) .delta.
-113.75; MS m/z 571 (M+1).
EXAMPLE 17
[6-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(cyclopentyl-
amino)-4-pyrimidinyl]methanol
[0522] ##STR77##
[0523] To a solution of
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-pyrimidinamine (1.18 g,
2.26 mmol) in tetrahydrofuran (20 mL) at 0.degree. C. was added
hydrochloric acid (8 mL, 4 N aqueous, 32 mmol). The reaction
mixture was allowed to warm to room temperature and was stirred for
48 hours. The solution was diluted and extracted with ethyl
acetate. The organic layer was washed with water and brine and
dried over magnesium sulfate. Filtration and concentration followed
by flash chromatography (2:1 hexanes:ethyl acetate) provided
[6-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(cyclopenty-
lamino)-4-pyrimidinyl]methanol (815 mg, 82%) as a solid. R.sub.f
0.21 (2:1 hexanes:ethyl acetate); .sup.1H NMR (CDCl.sub.3) .delta.
8.31 (d, 1H), 7.60 (m, 2H), 7.22 (m, 1H), 7.10 (m, 2H), 7.01 (d,
1H), 6.23 (s, 1H), 5.37 (d, 1H), 4.33 (m, 3H), 3.95 (br, 1H), 2.03
(m, 2H), 1.62 (m, 6H); .sup.19F NMR (CDCl.sub.3) .delta. -112.70;
MS m/z 438 (M+1).
EXAMPLE 18
[{4-[7-(Cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-
-pyrimidinyl}(methyl)amino]acetic acid
[0524] ##STR78##
[0525] In a similar manner as described in Example 1, from
(2E)-1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-y-
l]-3-(dimethylamino)-2-propen-1-one (200 mg, 0.51 mmol) and
creatine was obtained
[{4-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrid-
in-3-yl]-2-pyrimidinyl}(methyl)amino]acetic acid (30 mg, 13%) as a
yellow solid. .sup.1H NMR (DMSO-d.sub.6; all peaks broad) .delta.
8.03 (1 H), 7.61 (3 H), 7.29 (3 H), 6.58 (1 H), 6.17 (2 H), 4.17 (2
H), 4.00 (1 H), 3.12 (s, 3 H), 2.03 (2 H), 1.66 (6 H); .sup.19F NMR
(DMSO-d.sub.6) .delta. -113.51; MS m/z 461 (M+1).
EXAMPLE 19
N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(4-methyl-1-piperazinyl)pyrazolo[1,5-
-a]pyridin-3-yl]-6-phenyl-2-pyrimidinamine hydrochloride
[0526] ##STR79##
a)
1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-phenyl-2-p-
ropyn-1-ol
[0527] In a similar manner to Example 16 from
7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde
(190 mg, 0.69 mmol) and phenylacetylene was formed
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-phenyl-2-pro-
pyn-1-ol (250 mg, 96%) as a white solid. .sup.1H NMR (CDCl.sub.3)
.delta. 8.10 (d, 1 H), 7.87 (dd, 2 H), 7.44-7.41 (m, 2 H),
7.37-7.33 (m, 3 H), 7.25-7.19 (m, 3 H), 7.02 (d, 1 H), 6.02 (d, 1
H), 2.66 (d, 1 H); .sup.19F NMR (CDCl.sub.3) .delta. -113.02; MS
m/z 399 (M+Na.sup.+).
b)
1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-phenyl-2-p-
ropyn-1-one
[0528] In a similar manner to Example 7, from
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-phenyl-2-pro-
pyn-1-ol (250 mg, 0.66 mmol) was formed
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-phenyl-2-pro-
pyn-1-one (246 mg, 99%) as a white solid. .sup.1H NMR (CDCl.sub.3)
.delta. 8.47 (d, 1 H), 7.76 (dd, 2 H), 7.47 (dd, 1 H), 7.34 (t, 1
H), 7.24 (m, 2 H), 7.16 (d, 1 H), 7.13-7.05 (m, 4 H).
c)
4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopenty-
l-6-phenyl-2-pyrimidinamine
[0529] To a solution of
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-phenyl-2-pro-
pyn-1-one (246 mg, 0.66 mmol) in N,N-dimethylformamide (10 mL) was
added N-cyclopentylguanidine hydrochloride (320 mg, 1.97 mmol)
followed by solid potassium carbonate (274 mg, 1.97 mmol). The
resultant mixture was heated to 75.degree. C. for 4 hours The
reaction mixture was cooled to room temperature, diluted with water
and ether was added. The organic layer was washed with brine. The
aqueous layer was extracted with ether and the combined organics
were dried over magnesium sulfate. Filtration and concentration
followed by flash chromatography (4:1, hexanes:ethyl acetate)
provided
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
6-phenyl-2-pyrimidinamine (265 mg, 84%) as a solid. .sup.1H NMR
(CDCl.sub.3) .delta. 8.49 (d, 1 H), 7.80-7.75 (m, 4 H), 7.44-7.41
(m, 3 H), 7.33 (m, 1 H), 7.22 (t, 2 H), 7.09 (d, 1 H), 6.82 (s, 1
H), 5.25 (d, 1 H), 4.49 (m, 1 H), 2.22-2.12 (m, 2 H), 1.88-1.61 (m,
6 H); .sup.19F NMR (CDCl.sub.3) .delta. -112.89; MS m/z 484
(M+1).
d)
N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(4-methyl-1-piperazinyl)pyrazolo[-
1,5-a]pyridin-3-yl]-6-phenyl-2-pyrimidinamine hydrochloride
[0530] In a similar manner as described in Example 1, from
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
6-phenyl-2-pyrimidinamine (60 mg, 0.12 mmol) and N-methylpiperazine
was formed
N-cyclopentyl-4-[2-(4-fluorophenyl)-7-(4-methyl-1-piperazinyl)pyra-
zolo[1,5-a]pyridin-3-yl]-6-phenyl-2-pyrimidinamine (70 mg, 99%) as
an oil. This material was taken up in ether and treated with
hydrochloric acid in ether to yield a yellow precipitate which was
isolated by filtration as an hydrochloride salt. .sup.1H NMR
(DMSO-d.sub.6) .delta. 11.18 (broad, 1 H), 8.22 (d, 1 H), 7.78-7.73
(m, 4 H), 7.63-7.36 (m, 6 H), 6.77 (s, 1 H), 4.29 (broad, 1 H),
4.19-4.16 (m, 2 H), 3.55 (m, 2 H), 3.39-3.29 (m, 4 H), 2.83 (d, 3
H), 1.95 (m, 2 H), 1.73-1.59 (m, 6 H); .sup.19F NMR (DMSO-d.sub.6)
.delta. -112.68; MS m/z 548 (M+1).
EXAMPLE 20
N.sup.1-[3-[2-(Cyclopentylamino)-6-phenyl-4-pyrimidinyl]-2-(4-fluorophenyl-
)pyrazolo[1,5-a]pyridin-7-yl]-1,2-ethanediamine
[0531] ##STR80##
[0532] In a similar manner as described in Example 1, from
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
6-phenyl-2-pyrimidinamine (60 mg, 0.12 mmol) and ethylenediamine
was formed
N.sup.1-[3-[2-(cyclopentylamino)-6-phenyl-4-pyrimidinyl]-2-(4-fluo-
rophenyl)pyrazolo[1,5-a]pyridin-7-yl]-1,2-ethanediamine (30 mg,
48%) as an oil. .sup.1H NMR (CDCl.sub.3) .delta. 7.84-7.72 (m, 6H),
7.42-7.40 (m, 3 H), 7.33 (t, 1 H), 7.18 (t, 1 H), 6.80 (s, 1 H),
6.44 (m, 1 H), 6.05 (d, 1 H), 5.26 (d, 1 H), 4.47 (m, 1 H), 3.48
(m, 2 H), 3.09 (broad, 2 H), 2.93 (broad, 2 H), 2.13 (m, 2 H),
1.83-1.56 (m, 6 H); .sup.19F NMR (CDCl.sub.3) .delta. -113.21; MS
m/z 508 (M+1). This material was taken up in ether and treated with
hydrochloric acid in ether to yield an orange precipitate which was
isolated by filtration as a hydrochloride salt.
EXAMPLE 21
3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a
pyridin-7-amine
[0533] ##STR81##
[0534] To a solution of
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
2-pyrimidinamine (53 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL)
was added sodium azide (85 mg, 1.3 mmol). The resultant mixture was
heated to 100.degree. C. for 18 hours. The reaction mixture was
cooled to room temperature and ether was added. The organic layer
was washed with brine. The aqueous layer was extracted with ether
and the combined organics dried over magnesium sulfate. Filtration
and concentration followed by flash chromatography (2:1 to 1:1
hexanes:ethyl acetate) provided
3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]p-
yridin-7-amine (30 mg, 60%) as an oil. .sup.1H NMR (CDCl.sub.3)
.delta. 7.97 (d, 1 H), 7.77 (d, 1 H), 7.60 (m, 2 H), 7.22 (m, 1 H),
7.10 (t, 2 H), 6.26 (d, 1 H), 6.14 (d, 1 H), 5.26 (s, 2 H), 5.09
(d, 1 H), 4.29 (m, 1 H), 2.06-1.99 (m, 2 H), 1.75-1.45 (m, 6 H); MS
m/z 389 (M+1). This material was taken up in ether and treated with
hydrochloric acid in ether to yield a yellow precipitate which was
isolated by filtration as a hydrochloride salt.
EXAMPLE 22
{2-(Cyclopentylamino)-6-[7-(cyclopentylamino)-2-(4-fluorophenyl)-pyrazolo[-
1,5-a]pyridin-3-yl]-4-pyrimidinyl}methanol
[0535] ##STR82##
[0536] To a solution of
N-cyclopentyl-3-{2-(cyclopentylamino)-6-[(tetrahydro-2H-pyran-2-yloxy)met-
hyl]-4-pyrimidinyl}-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine
(134 mg, 2.23 mmol) in tetrahydrofuran (8 mL) was added
hydrochloric acid (4 mL, 4 N aqueous, 32 mmol). After 30 minutes,
the solution was made basic with sodium bicarbonate and ether was
added. The organic layer was washed with water and brine and dried
over magnesium sulfate. Filtration and concentration followed by
flash chromatography (2:1 to 1:1 hexanes:ethyl acetate) provided
{2-(cyclopentylamino)-6-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[-
1,5-a]pyridin-3-yl]-4-pyrimidinyl}methanol (80 mg, 71%). This
material was taken up in ether and treated with anhydrous
hydrochloric acid in ether to yield upon filtration a yellow solid.
.sup.1H NMR of hydrochloride salt (CDCl.sub.3) .delta. 8.00-7.94
(broad, 1 H), 7.78 (d, 1 H), 7.54-7.44 (m, 3 H), 7.17 (m, 2 H),
6.22 (s, 1 H), 6.19 (d, 1 H), 6.07 (d, 1 H), 4.74-4.60 (broad, 1
H), 4.47 (s, 2 H), 4.36 (m, 1 H), 3.99 (m, 1 H), 2.16-2.00 (m, 4
H), 1.82-1.59 (m, 12 H); .sup.19F NMR (CDCl.sub.3) .delta. -111.26;
MS m/z 487 (M+1 of free base).
EXAMPLE 23
3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-(4-methoxyphen-
yl)pyrazolo[1,5-a]pyridin-7-amine
[0537] ##STR83##
[0538] In a similar manner as described in Example 1, from
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
2-pyrimidinamine (48 mg, 0.12 mmol) and p-anisidine was formed
3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-(4-methoxyphe-
nyl)pyrazolo[1,5-a]pyridin-7-amine (35 mg, 60%) as a white solid.
.sup.1H NMR (CDCl.sub.3) .delta. 7.99 (d, 1 H), 7.84 (d, 1 H),
7.70-7.64 (m, 3 H), 7.32-7.26 (m, 3 H), 7.17 (t, 2 H), 9.67 (d, 2
H), 6.34-6.31 (m, 2 H), 5.43 (broad, 1 H), 4.35 (m, 1 H), 3.85 (s,
3 H), 2.11-2.03 (m, 2 H), 1.83-1.55 (m, 6 H); .sup.19F NMR
(CDCl.sub.3) .delta. -112.97; MS m/z 495 (M+1).
EXAMPLE 24
Methyl
{[3-[2-(cyclopentylamino)-6-methyl-4-pyrimidinyl]-2-(4-fluorophenyl-
)pyrazolo[1,5-a]pyridin-7-yl]amino}acetate
[0539] ##STR84##
[0540] In a similar manner as described in Example 1, from
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
6-methyl-2-pyrimidinamine (94 mg, 0.22 mmol) and methyl glycinate
hydrochloride was formed methyl
{[3-[2-(cyclopentylamino)-6-methyl-4-pyrimidinyl]-2-(4-fluorophenyl)pyraz-
olo[1,5-a]pyridin-7-yl]amino}acetate (95 mg, 90%) as a yellow foam.
.sup.1H NMR (CDCl.sub.3) .delta. 7.74 (d, 1 H), 7.67 (dd, 2 H),
7.30 (m, 1 H), 7.13 (m, 2 H), 6.56 (m, 1 H), 6.24 (s, 1 H), 5.90
(d, 1 H), 5.07 (broad, 1 H), 4.35 (m, 1 H), 4.17 (d, 2 H), 3.82 (s,
3 H), 2.17 (s, 3 H), 2.03 (m, 2 H), 1.75-1.50 (m, 6 H); .sup.19F
NMR (CDCl.sub.3) .delta. -113.61; MS m/z 475 (M+1).
EXAMPLE 25
{[3-[2-(Cyclopentylamino)-6-methyl-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazo-
lo[1,5-a]pyridin-7-yl]amino}acetic acid
[0541] ##STR85##
[0542] To a room temperature solution of methyl
{[3-[2-(cyclopentylamino)-6-methyl-4-pyrimidinyl]-2-(4-fluorophenyl)pyraz-
olo[1,5-a]pyridin-7-yl]amino}acetate (76 mg, 0.16 mmol) in
tetrahydrofuran (3 mL) and methanol (1 mL) was added lithium
hydroxide (1 mL, 1.0 M in water, 1 mmol). The resultant mixture was
stirred at room temperature for 24 hours then concentrated in
vacuo. The residue was suspended in ether and acidified with
aqueous hydrochloric acid (4N). The solids were filtered and
azeotroped twice with methanol in vacuo to provide the
hydrochloride salt of
{[3-[2-(cyclopentylamino)-6-methyl-4-pyrimidinyl]-2-(4-fluorophenyl)pyraz-
olo[1,5-a]pyridin-7-yl]amino}acetic acid (70 mg, 95%) as a yellow
solid. .sup.1H NMR (CDCl.sub.3) .delta. 7.72-7.34 (m, 7 H),
6.40-6.26 (m, 2 H), 4.17-4.04 (m, 3 H), 2.20 (s, 3 H), 1.88 (m, 2
H), 1.69 (m, 2 H), 1.54 (m, 4 H);.sup.19F NMR (CDCl.sub.3) .delta.
-112.96; MS m/z 461 (M+1).
EXAMPLE 26
4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-
-pyrimidinamine
[0543] ##STR86##
a)
1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-o-
l
[0544] In a similar manner as described in Example 7 from
7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde
(5.49 g, 20.0 mmol) and ethynylmagnesium bromide (100 mL, 0.5 M in
tetrahydrofuran, 50.0 mmol) at 0.degree. C., recrystallized from
dichloromethane, was obtained
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol
(5.3 g, 88%) as a pale yellow crystalline solid. .sup.1H NMR
(CDCl.sub.3): .delta. 8.04 (d, 1 H), 7.79 (m, 2 H), 7.20 (m, 3 H),
7.01 (d, 1 H), 5.77 (m, 1 H), 2.69 (d, 1 H), 2.32 (d, 1 H); MS m/z
301 (M+1).
b)
1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-o-
ne
[0545] In a similar manner as described in Example 7, from
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol
(5.30 g, 17.6 mmol) was obtained
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one
(4.04 g, 77%) as a yellow solid. .sup.1H NMR (CDCl.sub.3): .delta.
8.45 (d, 1 H), 7.67 (m, 2 H), 7.50 (t, 1 H), 7.19 (d, 1 H), 7.12
(t, 2 H), 2.93 (s, 1 H); MS m/z 299 (M+1).
c)
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopenty-
l-2-pyrimidinamine
[0546] In a similar manner as described in Example 7
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one
(210 mg, 0.70 mmol), cyclopentylguanidine hydrochloride (291 mg,
2.1 mmol), and potassium carbonate (345 mg, 2.1 mmol) were heated
at 120.degree. C. for 1.5 hours in 1-methyl-2-pyrrolidinone (8 mL)
to form
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
2-pyrimidinamine (125 mg, 44%) as a white foam. .sup.1H NMR
(CDCl.sub.3) .delta. 8.42 (d, 1 H), 8.09 (d, 1 H), 7.67 (dd, 2 H),
7.30 (m, 1 H), 7.17 (t, 2 H), 7.06 (d, 1 H), 6.33 (d, 1 H), 5.30
(d, 1 H), 4.35 (m, 1 H), 2.18-2.05 (m, 2 H), 1.84-1.52 (m, 6 H);
.sup.19F NMR (CDCl.sub.3) .delta. -112.78; MS m/z 408 (M+1).
EXAMPLE 27
6-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(cyclopentyla-
mino)-4-pyrimidinecarboxylic acid
[0547] ##STR87##
[0548] A solution of
[6-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(cyclopenty-
lamino)-4-pyrimidinyl]methanol (50 mg, 0.11 mmol) in
dichloromethane (5 mL) was treated with manganese dioxide (397 mg,
4.6 mmol). The resultant heterogeneous mixture was stirred for 5
hours at which time an additional quantity of manganese dioxide
(397 mg, 4.6 mmol) was added. After stirring for 3 hours the
suspension was filtered through a plug of Celite and eluted
sequentially with methanol and then chloroform:isopropanol (3:1).
The eluents were removed in vacuo to provide
6-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(cyclopentyl-
amino)-4-pyrimidinecarboxylic acid (54 mg, 99%) as a white solid.
.sup.1H NMR (DMSO-d.sub.6) .delta. 8.28 (d, 1 H), 7.63 (dd, 2 H),
7.49 (t, 1 H), 7.37 (d, 1 H), 7.30 (t, 2 H), 7.10 (broad, 1 H),
6.89 (broad, 1 H), 4.09 (m, 1 H), 1.90-1.83 (m, 2 H), 1.73-1.62 (m,
2 H), 1.56-1.43 (m, 4 H); .sup.19F NMR (DMSO-d.sub.6) .delta.
-113.40; MS m/z 452 (M+1).
EXAMPLE 28
N-cyclopentyl-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-7-a-
mine
[0549] ##STR88##
a) 3-bromo-7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine
[0550] To a cold (0.degree. C.) solution of
7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (5.0 g, 20.2
mmol) in tetrahydrofuran (81 mL) was added N-bromosuccinimide (3.79
g, 21.2 mmol) in two portions. The solution solidified after 5
minutes and additional tetrahydrofuran was added (20 mL). The
resultant solution was stirred for 15 minutes. Saturated aqueous
sodium bicarbonate and ether were added and the layers separated.
The organic layer was washed with brine. The aqueous layers were
extracted with ethyl acetate and the combined organics were dried
over magnesium sulfate. Filtration and concentration followed by
recrystallization from ethyl acetate-hexane-methanol provided
3-bromo-7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (5.7 g,
87%) as a crystalline solid. .sup.1H NMR (CDCl.sub.3) .delta. 8.07
(dd, 2 H), 7.53 (d, 1 H), 7.23-7.16 (m, 3 H), 6.98 (d, 1 H);
.sup.19F NMR (CDCl.sub.3) .delta. -112.60; MS m/z 325 (M+1).
b)
3-Bromo-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine
[0551] To a solution of
3-bromo-7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (1.26 g,
3.9 mmol) in toluene (39 mL) was added successively racemic-BINAP
(153 mg, 0.23 mmol), cesium carbonate (1.44 g, 3.9 mmol),
cyclopentylamine (1.14 mL, 11.5 mmol), and palladium (II) acetate
(35 mg, 0.15 mmol). The resultant mixture was heated at 95.degree.
C. for 2.5 hours at which time the reaction was judged complete by
thin layer chromatography. The solution was cooled to room
temperature and ether was added. The organic layer was washed with
water and brine. The aqueous layer was extracted with ether and the
combined organics dried over magnesium sulfate. Filtration and
concentration followed by flash chromatography (100:1 to 40:1
hexanes:ether) provided
3-bromo-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine
(1.2 g, 83%) as a white crystalline solid upon standing. .sup.1H
NMR (CDCl.sub.3): .delta. 8.05 (dd, 2 H), 7.22-7.14 (m, 3 H), 6.87
(d, 1 H), 5.95-5.92 (m, 2 H), 4.00 (m, 1 H), 2.13 (m, 2 H),
1.84-1.67 (m, 6 H); .sup.19F NMR (CDCl.sub.3) .delta. -113.44; MS
m/z 374 (M+1).
c)
N-Cyclopentyl-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin--
7-amine
[0552] To a solution of
3-bromo-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine
(106 mg, 0.28 mmol) in N,N-dimethylformamide (5 mL) was added
4-pyridinylboronic acid (70 mg, 0.56 mmol), sodium carbonate (0.28
mL, 2 M aqueous, 0.56 mmol) and
dichlorobis(triphenylphosphine)palladium(II) (10 mg, 0.01 mmol).
The resultant solution was heated to 100.degree. C. for 18 hours.
The reaction mixture was cooled to room temperature and ether was
added. The organic layer was washed with water and brine. The
aqueous layer was extracted with ether and the combined organics
dried over magnesium sulfate. Filtration and concentration followed
by flash chromatography (2:1 hexanes:ether) provided
N-cyclopentyl-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-7--
amine (48 mg, 46%) as a yellow solid. .sup.1H NMR (CDCl.sub.3):
.delta. 8.50 (d, 2 H), 7.53 (m, 2 H), 7.22-7.18 (m, 3 H), 7.06-6.97
(m, 3 H), 6.00 (d, 1 H), 5.95 (d, 1 H), 3.99 (m, 1 H), 2.16-2.08
(m, 2 H), 1.83-1.66 (m, 6 H); .sup.13C NMR (CDCl.sub.3) .delta.
162.99 (d, J.sub.CF=246.6 Hz), 150.07, 149.98, 142.77, 141.98,
140.13, 131.02 (d, J.sub.CF=8.0 Hz), 129.04, 127.64, 123.98, 115.56
(d, J.sub.CF=21.2 Hz), 106.51, 102.22, 89.25, 53.88, 33.36, 24.05;
.sup.19F NMR (CDCl.sub.3) .delta. -113.49; MS m/z 373 (M+1).
EXAMPLE 29
N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(4-fluorophenyl)pyraz-
olo[1,5-a]pyridin-7-amine
[0553] ##STR89##
a) 2-Fluoropyridin-4-ylboronic acid
[0554] To a stirred solution of n-butyl lithium (3.2 mL, 2.5M, 8.0
mmol) in dry diethyl ether (20 mL) at -78.degree. C. was added a
solution of 2-fluoro-4-iodopyridine (1.5 g, 6.7 mmol) in dry ether
(10 mL) and the reaction mixture was stirred at -78.degree. C. for
10 minutes. Tributyl borate (2.4 mL, 2.01 g, 8.7 mmol) was added
and the reaction mixture was allowed to warm to room temperature
over 2 hours. Water (5 mL) was added followed by 2N aqueous sodium
hydroxide solution (10 mL) to dissolve the solids. The organic
phase was separated. The aqueous phase was acidified to pH3 using
6N hydrochloric acid and the resulting white solid was collected by
filtration and dried under vacuum to give the title compound, 0.74
g (78%). .sup.1H NMR (DMSO-d.sub.6) .delta. 8.65 (br s, 2H), 8.21
(d, 1H), 7.59 (t, 1H), 7.37 (d, 1H).
b)
N-Cyclopentyl-2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a-
]pyridin-7-amine
[0555] In a similar manner to that in Example 28, from
3-bromo-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine
(240 mg, 0.64 mmol) and 2-fluoropyridin-4-ylboronic acid (271 mg,
1.92 mmol) after heating to 100.degree. C. for 1.5 hours was formed
N-cyclopentyl-2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]p-
yridin-7-amine (180 mg, 72%) as a greenish solid. .sup.1H NMR
(CDCl.sub.3): .delta. 8.12 (d, 1 H), 7.56 (m, 2 H), 7.27 (m, 1 H),
7.13-7.02 (m, 4 H), 6.90 (s, 1 H), 6.05-6.01 (m, 2 H), 4.02 (m, 1
H), 2.16 (m, 2 H), 1.86-1.68 (m, 6 H); .sup.19F NMR (CDCl.sub.3)
.delta. -68.65, -113.06; MS m/z 391 (M+1).
c)
N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(4-fluorophenyl)py-
razolo[1,5-a]pyridin-7-amine
[0556] A solution of
N-cyclopentyl-2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]p-
yridin-7-amine (37 mg, 0.10 mmol) in cyclopentylamine (4 mL) was
heated to 150.degree. C. in a sealed tube for 12 hours. Upon
cooling to room temperature, the mixture was concentrated in vacuo
and the residue was taken up in ether and washed with water and
then brine. The aqueous layer was extracted with ether and the
combined organics were dried over magnesium sulfate. Filtration and
concentration followed by flash chromatography (4:1 to 2:1
hexanes:ethyl acetate) provided
N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(4-fluorophenyl)pyra-
zolo[1,5-a]pyridin-7-amine (31 mg, 72%) as a solid. .sup.1H NMR
(CDCl.sub.3): .delta. 8.01 (d, 1 H), 7.64 (dd, 2 H), 7.21 (t, 1 H),
7.10-7.02 (m, 3 H), 6.57 (d, 1 H), 6.34 (s, 1 H), 6.01 (d, 1 H),
5.97 (d, 1 H), 4.63 (broad, 1 H), 4.02 (m, 1 H), 3.79 (m, 1 H),
2.16 (m, 2 H), 1.96-1.42 (m, 14 H); .sup.19F NMR (CDCl.sub.3)
.delta. -114.06; MS m/z 456 (M+1).
EXAMPLE 30
N-Cyclopentyl-2-(4-fluorophenyl)-3-(2-hydrazino-4-pyridinyl)pyrazolo[1,5-a-
]pyridin-7-amine
[0557] ##STR90##
[0558] In a similar manner as described in Example 29, from
N-cyclopentyl-2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]p-
yridin-7-amine (45 mg, 0.12 mmol) and anhydrous hydrazine (0.5 mL)
in ethanol (4 mL) at 100.degree. C. for 13 hours was formed
N-cyclopentyl-2-(4-fluorophenyl)-3-(2-hydrazino-4-pyridinyl)pyrazolo[1,5--
a]pyridin-7-amine (30 mg, 65%) as a solid. .sup.1H NMR
(CDCl.sub.3): .delta. 8.05 (d, 1 H), 7.61 (m, 2 H), 7.20 (t, 1 H),
7.09-6.99 (m, 4 H), 6.71 (s, 1 H), 6.63 (d, 1 H), 6.03-5.96 (m, 3
H), 4.01 (broad m, 2 H), 2.14 (m, 2 H), 1.84-1.68 (m, 6 H);
.sup.19F NMR (CDCl.sub.3) .delta. -113.66; MS m/z 403 (M+1).
EXAMPLE 31
N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyrid-
in-3-yl]-2-pyrimidinamine
[0559] ##STR91##
a)
1-[2-(4-Fluorophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]eth-
anone
[0560] In a similar manner as described in Example 1, from
1-[7-chloro-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridin-3-yl]ethanone
(0.30 g, 1.0 mmol) and pyrrolidine (0.43 mL, 5.2 mmol),
1-[2-(4-fluorophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]ethan-
one (0.30 g, 91%) was obtained as a yellow solid. .sup.1H NMR
(CDCl.sub.3): .delta. 7.78 (d, 1 H), 7.56 (m, 2 H), 7.36 (t, 1 H),
7.13 (t, 2 H), 6.16 (d, 1 H), 3.72 (m, 4 H), 2.11 (s, 3 H), 1.99
(m, 4 H); MS m/z 324 (M+1).
b)
(2E)-3-(Dimethylamino)-1-[2-(4-fluorophenyl)-7-(1-pyrrolidinyl)pyrazolo-
[1,5-a]pyridin-3-yl]-2-propen-1-one
[0561] In a similar manner as described in Example 1, from
1-[2-(4-fluorophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]ethan-
one (0.28 g, 0.86 mmol),
(2E)-3-(dimethylamino)-1-[2-(4-fluorophenyl)-7-(1-pyrrolidinyl)pyrazolo[1-
,5-a]pyridin-3-yl]-2-propen-1-one (0.25 g, 76%) was obtained as a
yellow foam. .sup.1H NMR (CDCl.sub.3): .delta. 7.75 (m, 3 H), 7.58
(d, 1 H), 7.25 (t, 1 H), 7.11 (t, 2 H), 6.09 (d, 1 H), 5.09 (d, 1
H), 3.73 (m, 4 H), 2.93 (bs, 3 H), 2.62 (bs, 3 H), 2.02 (m, 4 H);
MS m/z 379 (M+1).
c)
N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]py-
ridin-3-yl]-2-pyrimidinamine
[0562] In a similar manner as described in Example 1, from
(2E)-3-(dimethylamino)-1-[2-(4-fluorophenyl)-7-(1-pyrrolidinyl)pyrazolo[1-
,5-a]pyridin-3-yl]-2-propen-1-one (75 mg, 0.20 mmol),
N-cyclopentylguanidine hydrochloride and potassium carbonate in
N,N-dimethylformamide was obtained
N-cyclopentyl-4-[2-(4-fluorophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyri-
din-3-yl]-2-pyrimidinamine (28.7 mg, 33%) as a yellow solid.
.sup.1H NMR (CDCl.sub.3): .delta. 7.95 (d, 1 H), 7.82 (d, 1 H),
7.61 (m, 2 H), 7.22 (t, 1 H), 7.08 (t, 2 H), 6.28 (d, 1 H), 6.07
(d, 1 H), 5.25 (bs, 1 H), 4.31 (m, 1 H), 3.72 (m, 4 H), 2.02 (m, 6
H), 1.75-1.49 (m, 6 H); MS m/z 443 (M+1).
EXAMPLE 32
4-[2-(4-Fluorophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-d-
imethyl-2-pyrimidinamine
[0563] ##STR92##
[0564] In a similar manner as described in Example 1, from
(2E)-3-(dimethylamino)-1-[2-(4-fluorophenyl)-7-(1-pyrrolidinyl)pyrazolo[1-
,5-a]pyridin-3-yl]-2-propen-1-one (75 mg, 0.20 mmol),
N,N-dimethylguanidine sulfate and potassium carbonate in
N,N-dimethylformamide was obtained
4-[2-(4-fluorophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N--
dimethyl-2-pyrimidinamine (19.8 mg, 25%) as a yellow crystalline
solid. .sup.1H NMR (CDCl.sub.3): .delta. 8.05 (d, 1 H), 7.81 (d, 1
H), 7.61 (m, 2 H), 7.21 (t, 1 H), 7.07 (t, 2 H), 6.27 (d, 1 H),
6.06 (d, 1 H), 3.71 (m, 4 H), 3.21 (s, 6 H), 2.01 (m, 4 H); MS m/z
403 (M+1).
EXAMPLE 33
3-[2-(Butylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-fluorophenyl)pyrazolo[-
1,5-a]pyridin-7-amine
[0565] ##STR93##
a)
N-Butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-py-
rimidinamine
[0566] In a similar manner as described in Example 7 from
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one
(0.50 g, 1.7 mmol), N-butylguanidine sulfate and sodium ethoxide
(0.81 mL, 21 wt % in ethanol, 2.2 mmol) at room temperature was
obtained
N-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyri-
midinamine (0.39 g, 59%) as a fluffy pale yellow solid. .sup.1H NMR
(CDCl.sub.3): .delta. 8.40 (d, 1 H), 8.07 (d, 1 H), 7.65 (m, 2 H),
7.29 (m, 1 H), 7.15 (t, 2 H), 7.06 (d, 1 H), 6.32 (d, 1 H), 5.16
(bs, 1 H), 3.49 (q, 2 H), 1.71-1.41 (m, 4 H), 0.99 (t, 3 H);
.sup.19F NMR (CDCl.sub.3) .delta. -112.77; MS m/z 396 (M+1).
b)
3-[2-(Butylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-fluorophenyl)pyrazo-
lo[1,5-a]pyridin-7-amine
[0567] In a similar manner as described in Example 1, from
N-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyri-
midinamine (46 mg, 0.12 mmol) and cyclopropylamine was obtained
3-[2-(butylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-fluorophenyl)pyrazolo-
[1,5-a]pyridin-7-amine (36.5 mg, 75%) as a yellow foam. .sup.1H NMR
(CDCl.sub.3): .delta. 7.95 (d, 1 H), 7.75 (d, 1 H), 7.58 (m, 2 H),
7.32 (t, 1 H), 7.11 (t, 2 H), 6.36 (d, 1 H), 6.27 (s, 1 H), 6.24
(d, 1H), 5.15 (bs, 1 H), 3.43 (q, 2 H), 2.63 (m, 1 H), 1.61 (m, 2
H), 1.42 (m, 2 H), 0.94 (t, 3 H), 0.84 (m, 2 H), 0.71 (m, 2 H); MS
m/z 417 (M+1).
EXAMPLE 34
3-[2-(Butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N,N-dimethylpyrazolo[1-
,5-a]pyridin-7-amine
[0568] ##STR94##
a)
(2E)-1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dime-
thylamino)-2-propen-1-one
[0569] In a similar manner as described in Example 1, from
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone
(1.83 g, 6.3 mmol) was obtained
(2E)-1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimeth-
ylamino)-2-propen-1-one (1.47 g, 67%) as a yellow solid. .sup.1H
NMR (acetone-d.sub.6): .delta. 8.21 (d, 1 H), 7.79 (m, 2 H), 7.50
(d, 1 H), 7.38 (t, 1 H), 7.23 (m, 3 H), 5.07 (d, 1 H), 3.04 (bs, 3
H), 2.54 (bs, 3 H); MS m/z 344 (M+1).
b)
3-[2-(Butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N,N-dimethylpyrazol-
o[1,5-a]pyridin-7-amine
[0570] In a similar manner as described in Example 1, from
(2E)-1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimeth-
ylamino)-2-propen-1-one (1.47 g, 4.3 mmol), N-butylguanidine
sulfate and potassium carbonate in N,N-dimethylformamide was
obtained
3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N,N-dimethylpyrazolo[-
1,5-a]pyridin-7-amine (0.40 g, 24%) as a yellow solid. .sup.1H NMR
(CDCl.sub.3): .delta. 8.00 (m, 2 H), 7.62 (m, 2 H), 7.28 (t, 1 H),
7.08 (t, 2 H), 6.29 (m, 2 H), 5.24 (bs, 1 H), 3.44 (m, 2 H), 3.09
(s, 6 H), 1.65-1.38 (m, 4 H), 0.94 (t, 3 H); MS m/z 405 (M+1).
EXAMPLE 35
N-Butyl-4-[2-(4-fluorophenyl)-7-(4-methyl-1-piperazinyl)pyrazolo[1,5-a]pyr-
idin-3-yl]-2-pyrimidinamine
[0571] ##STR95##
[0572] In a similar manner as described in Example 1, from
N-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyri-
midinamine (50 mg, 0.13 mmol) and 1-methylpiperazine was prepared
N-butyl-4-[2-(4-fluorophenyl)-7-(4-methyl-1-piperazinyl)pyrazolo[1,5-a]py-
ridin-3-yl]-2-pyrimidinamine (28 mg, 48%) as an off-white foam.
.sup.1H NMR (DMSO-d.sub.6): .delta. 7.98 (m, 2 H), 7.58 (t, 2 H),
7.35 (t, 1 H), 7.26 (t, 2 H), 7.04 (bs, 1 H), 6.46 (d, 1 H), 6.14
(bs, 1 H), 3.37 (bs, 4 H), 3.20 (d, 2 H), 2.49 (s, 4 H), 2.20 (s, 3
H), 1.46 (m, 2 H), 1.28 (m, 2 H), 0.84 (t, 3 H); .sup.19F NMR
(DMSO-d.sub.6) .delta. -113.56; MS m/z 460 (M+1).
EXAMPLE 36
N-Butyl-4-[2-(4-fluorophenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl-
]-2-pyrimidinamine
[0573] ##STR96##
[0574] In a similar manner as described in Example 1, from
N-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyri-
midinamine (50 mg, 0.13 mmol) and morpholine was prepared
N-butyl-4-[2-(4-fluorophenyl)-7-(4-morpholinyl)-pyrazolo[1,5-a]pyridin-3--
yl]-2-pyrimidinamine (24 mg, 44%) as an off-white foam. .sup.1H NMR
(CDCl.sub.3): .delta. 8.14 (d, 1 H), 8.03 (m, 1 H), 7.68 (m, 2 H),
7.37 (t, 1 H), 7.17 (t, 2 H), 6.39 (m, 2 H), 5.52 (bs, 1 H), 4.04
(m, 4 H), 3.66 (m, 6 H), 1.70 (m, 2 H), 1.52 (m, 2 H), 1.02 (t, 3
H); MS m/z 447 (M+1).
EXAMPLE 37
N-Butyl-2-(4-fluorophenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]-pyrazolo[1-
,5-a]pyridin-7-amine
[0575] ##STR97##
a)
4-[7-(Butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyri-
midinethiolate
[0576] A solution of
(2E)-1-[7-(butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(-
dimethylamino)-2-propen-1-one (5.92 g, 15.6 mmol), thiourea (2.37
g, 31.1 mmol) and potassium hydroxide (15.6 mL, 1.0 N in ethanol)
in 200 mL of ethanol was heated to reflux until starting material
was consumed. The reaction was cooled to room temperature and the
resulting precipitate was isolated by filtration. After washing
with ethyl acetate,
4-[7-(butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimi-
dinethiolate (1.68 g, 44%) was isolated as a tan solid as the
potassium salt. .sup.1H NMR (DMSO-d.sub.6): .delta. 7.68-7.61 (m, 4
H), 7.29-7.23 (m, 3 H), 6.88 (m, 1 H), 6.08 (d, 1 H), 6.00 (d, 1
H), 3.32-3.22 (m, 2 H), 1.59 (m, 2 H), 1.34 (m, 2 H), 0.87 (t, 3
H); MS m/z 392 (M+1).
b)
N-Butyl-2-(4-fluorophenyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo-
[1,5-a]pyridin-7-amine
[0577] A mixture of
4-[7-(butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimi-
dinethiolate (2.87 g, 6.9 mmol) in 50 mL water was treated with
iodomethane (0.86 mL, 13.8 mmol) and sodium hydroxide (4.1 mL, 5 N
aqueous solution) and allowed to stir at room temperature for 4
hours. The mixture was diluted with additional water and extracted
with dichloromethane. The organic layers were washed with brine,
dried over magnesium sulfate and concentrated. Flash column
chromatography eluting with 9:1 hexanes-ethyl acetate afforded
N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1-
,5-a]pyridin-7-amine (1.64 g, 56%) as a yellow foam. .sup.1H NMR
(CDCl.sub.3): .delta. 8.15 (d, 1 H), 7.73 (d, 1 H), 7.56 (m, 2 H),
7.33 (t, 1 H), 7.13 (t, 2 H), 6.62 (d, 1 H), 6.02 (m, 2 H), 3.35
(q, 2 H), 2.55 (s, 3 H), 1.76-1.41 (m, 4 H), 0.95 (t, 3 H);
.sup.19F NMR (CDCl.sub.3): .delta. -112.75; MS m/z 408 (M+1).
c)
N-Butyl-2-(4-fluorophenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo-
[1,5-a]pyridin-7-amine
[0578] To a cold (0.degree. C.) solution of
N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1-
,5-a]pyridin-7-amine (1.51 g, 3.7 mmol) in 50 mL chloroform was
added m-chloroperbenzoic acid (0.87 g, 70-75%, 3.7 mmol). The
reaction was allowed to warm to rt. After stirring for 5h, another
0.2 g m-chloroperbenzoic acid was added and the reaction was
stirred for 15 min. The reaction was diluted with aqueous sodium
bicarbonate and extracted with dichloromethane. The organic
extracts were washed with brine, dried over magnesium sulfate and
concentrated. The crude product was recrystallized from ethyl
acetate-hexanes to afford
N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1-
,5-a]pyridin-7-amine (0.95 g, 60%) as an orange solid. .sup.1H NMR
(CDCl.sub.3): .delta. 8.40 (broad, 1 H), 7.99 (d, 1 H), 7.58 (m, 2
H), 7.45 (t, 1 H), 7.20 (t, 2 H), 6.94 (d, 1 H), 6.13 (d, 1 H),
6.10 (broad, 1 H), 3.38 (m, 2 H), 2.98 (s, 3 H), 1.79-1.42 (m, 4
H), 0.97 (t, 3 H); MS m/z 422 (M-1).
EXAMPLE 38
3-({4-[7-(Butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyr-
imidinyl}amino)-1-propanol
[0579] ##STR98##
[0580] A solution of
N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1-
,5-a]pyridin-7-amine (50 mg, 0.12 mmol) and 3-amino-1-propanol
(0.45 mL, 5.9 mmol) in 2 mL tetrahydrofuran was heated to reflux
for 4 hours, then the mixture was cooled to room temperature and
concentrated. Flash column chromatography eluting with a gradient
of 0% to 100% ethyl acetate in hexanes afforded
3-({4-[7-(butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-py-
rimidinyl}amino)-1-propanol (46.3 mg, 90%) as a yellow foam.
.sup.1H NMR (CDCl.sub.3): .delta. 7.97 (d, 1 H), 7.67-7.61 (m, 3
H), 7.35 (t, 1 H), 7.16 (t, 2 H), 6.34 (d, 1 H), 6.04 (m, 2 H),
3.67-3.60 (m, 4 H), 3.39 (q, 2 H), 1.79-1.45 (m, 6 H), 1.00 (t, 3
H); .sup.19F NMR (CDCl.sub.3): .delta. -113.10; MS m/z 435
(M+1).
EXAMPLE 39
3-[2-(Allylamino)-4-pyrimidinyl]-N-butyl-2-(4-fluorophenyl)pyrazolo-[1,5-a-
]pyridin-7-amine
[0581] ##STR99##
[0582] In a similar manner as described in Example 38, from
N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1-
,5-a]pyridin-7-amine (50 mg, 0.12 mmol) and allylamine, heated at
60.degree. C. for 24 h was prepared
3-[2-(allylamino)-4-pyrimidinyl]-N-butyl-2-(4-fluorophenyl)pyrazolo[1,5-a-
]pyridin-7-amine (44.6 mg, 91%) as a yellow foam. .sup.1H NMR
(CDCl.sub.3): .delta. 7.99 (d, 1 H), 7.74 (d, 1 H), 7.63 (m, 2 H),
7.34 (t, 1 H), 7.17 (t, 2 H), 6.33 (d, 1 H), 6.06-5.98 (m, 3 H),
5.32 (dd, 1 H), 5.19 (dd, 1 H), 4.15 (t, 2 H), 3.39 (q, 2 H),
1.80-1.46 (m, 4 H), 1.00 (t, 3 H); .sup.19F NMR (CDCl.sub.3):
.delta. -113.17 MS m/z 417 (M+1).
EXAMPLE 40
N-Butyl-2-(4-fluorophenyl)-3-[2-(4-morpholinyl)-4-pyrimidinyl]pyrazolo[1,5-
-a]pyridin-7-amine
[0583] ##STR100##
[0584] In a similar manner as described in Example 38, from
N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1-
,5-a]pyridin-7-amine (50 mg, 0.12 mmol) and morpholine was prepared
N-butyl-2-(4-fluorophenyl)-3-[2-(4-morpholinyl)-4-pyrimidinyl]pyrazolo[1,-
5-a]pyridin-7-amine (43.0 mg, 82%) as an off-white foam. .sup.1H
NMR (DMSO-d.sub.6): .delta. 8.09 (d, 1 H), 7.56 (dd, 2 H), 7.44 (d,
1 H), 7.35 (t, 1 H), 7.26 (t, 2 H), 7.06 (t, 1 H), 6.30 (d, 1 H),
6.14 (d, 1 H), 3.59 (m, 8 H), 3.28 (m, 2 H), 1.59 (m, 2 H), 1.33
(m, 2 H), 0.87 (t, 3 H); .sup.19F NMR (DMSO-d.sub.6): .delta.
-113.70; MS m/z 447 (M+1).
EXAMPLE 41
2-(4-{4-[7-(Butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-p-
yrimidinyl}-1-piperazinyl)ethanol
[0585] ##STR101##
[0586] In a similar manner as described in Example 38, from
N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1-
,5-a]pyridin-7-amine (50 mg, 0.12 mmol) and
1-(2-hydroxyethyl)piperazine was prepared
2-(4-{4-[7-(butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2--
pyrimidinyl}-1-piperazinyl)ethanol (47.8 mg, 83%) as a pale yellow
solid. .sup.1H NMR (DMSO-d.sub.6): .delta. 8.12 (d, 1 H), 7.61 (m,
2 H), 7.48 (d, 1 H), 7.39 (t, 1 H), 7.30 (t, 2 H), 7.09 (t, 1 H),
6.31 (d, 1 H), 6.18 (d, 1 H), 4.43 (broad, 1 H), 3.64 (broad, 4 H),
3.53 (q, 2 H), 3.38-3.27 (m, 4 H), 2.44 (broad, 4 H), 1.63 (m, 2
H), 1.37 (m, 2 H), 0.91 (t, 3 H); .sup.19F NMR (CDCl.sub.3):
.delta. -113.30; MS m/z 490 (M+1).
EXAMPLE 42
N-Butyl-2-(4-fluorophenyl)-3-{2-[4-(2-methoxyethyl)-1-piperazinyl]-4-pyrim-
idinyl}pyrazolo[1,5-a]pyridin-7-amine
[0587] ##STR102##
[0588] In a similar manner as described in Example 38, from
N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1-
,5-a]pyridin-7-amine (50 mg, 0.12 mmol) and
1-(2-methoxyethyl)piperazine was prepared
N-butyl-2-(4-fluorophenyl)-3-{2-[4-(2-methoxyethyl)-1-piperazinyl]-4-pyri-
midinyl}pyrazolo[1,5-a]pyridin-7-amine (59.9 mg, 100%) as a pale
yellow oil. .sup.1H NMR (DMSO-d.sub.6): .delta. 8.11 (d, 1 H), 7.61
(dd, 2 H), 7.48 (d, 1 H), 7.40 (t, 1 H), 7.30 (t, 2 H), 7.09 (t, 1
H), 6.31 (d, 1 H), 6.18 (d, 1 H), 3.64 (broad, 4 H), 3.46 (t, 2 H),
3.38-3.22 (m, 7 H), 2.44 (broad, 4 H), 1.63 (m, 2 H), 1.38 (m, 2
H), 0.92 (t, 3 H); .sup.19F NMR (CDCl.sub.3): .delta. -113.59 MS
m/z 504 (M+1). This material was treated with anhydrous
hydrochloride in ether to provide a hydrochloride salt as an orange
solid.
EXAMPLE 43
N-Butyl-2-(4-fluorophenyl)-3-{2-[(2-pyridinylmethyl)amino]-4-pyrimidinyl}p-
yrazolo[1,5-a]pyridin-7-amine
[0589] ##STR103##
[0590] In a similar manner as described in Example 38, from
N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1-
,5-a]pyridin-7-amine (89 mg, 0.21 mmol), 2-picolylamine (0.6 mL,
5.8 mmol) and potassium carbonate (64 mg, 0.46 mmol) in xylenes at
140.degree. C. for 24 h was prepared
N-butyl-2-(4-fluorophenyl)-3-{2-[(2-pyridinylmethyl)amino]-4-pyrimidinyl}-
pyrazolo[1,5-a]pyridin-7-amine (39.2 mg, 40%) as a solid. .sup.1H
NMR (CDCl.sub.3): .delta. 8.62 (d, 1 H), 8.05 (d, 1 H), 7.65 (m, 3
H), 7.38 (d, 1 H), 7.27-7.12 (m, 4 H), 6.37 (d, 1 H), 6.13 (broad,
1 H), 6.02-6.00 (m, 2 H), 4.83 (d, 2 H), 3.38 (q, 2 H), 1.75 (m, 2
H), 1.49 (m, 2 H), 0.99 (t, 3 H); .sup.19F NMR (CDCl.sub.3):
.delta. -113.22 MS m/z 468 (M+1). This material was treated with
anhydrous hydrochloride in ether to provide a hydrochloride salt as
a brown solid.
EXAMPLE 44
N-Butyl-2-(4-fluorophenyl)-3-(2-{[3-(1H-imidazol-1-yl)propyl]amino}-4-pyri-
midinyl)pyrazolo[1,5-a]pyridin-7-amine
[0591] ##STR104##
[0592] In a similar manner as described in Example 38, from
N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1-
,5-a]pyridin-7-amine (50 mg, 0.12 mmol) and
1-(3-aminopropyl)imidazole in ethanol in a sealed tube at
90.degree. C. was prepared
N-butyl-2-(4-fluorophenyl)-3-(2-{[3-(1H-imidazol-1-yl)propyl]amino}-4-pyr-
imidinyl)pyrazolo[1,5-a]pyridin-7-amine (43.8 mg, 77%) as a yellow
oil. .sup.1H NMR (CDCl.sub.3): .delta. 8.01 (d, 1 H), 7.65-7.61 (m,
3 H), 7.54 (s, 1 H), 7.34 (t, 1 H), 7.15 (t, 2 H), 7.08 (s, 1 H),
6.97 (s, 1 H), 6.37 (d, 1 H), 6.07-6.03 (m, 2 H), 5.32 (broad, 1
H), 4.08 (t, 2 H), 3.48 (q, 2 H), 3.39 (q, 2 H), 2.14 (m, 2 H),
1.77 (m, 2 H), 1.51 (m, 2 H), 1.00 (t, 3 H); MS m/z 485 (M+1). This
material was treated with anhydrous hydrochloride in ether to
provide a hydrochloride salt as a gold solid.
EXAMPLE 45
N-Butyl-2-(4-fluorophenyl)-3-(2-{[2-(4-morpholinyl)ethyl]amino}-4-pyrimidi-
nyl)pyrazolo[1,5-a]pyridin-7-amine
[0593] ##STR105##
[0594] In a similar manner as described in Example 38, from
N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1-
,5-a]pyridin-7-amine (50 mg, 0.12 mmol) and
4-(2-aminoethyl)morpholine in ethanol in a sealed tube at
90.degree. C. was prepared
N-butyl-2-(4-fluorophenyl)-3-(2-{[2-(4-morpholinyl)ethyl]amino}-4-pyrimid-
inyl)-pyrazolo[1,5-a]pyridin-7-amine (47.0 mg, 81%) as a yellow
solid. .sup.1H NMR (CDCl.sub.3): .delta. 8.02 (d, 1 H), 7.72 (d, 1
H), 7.63 (dd, 2 H), 7.33 (t, 1 H), 7.14 (t, 2 H), 6.31 (d, 1 H),
6.03-6.01 (m, 2 H), 5.65 (broad, 1 H), 3.75 (broad, 4 H), 3.57 (q,
2 H), 3.39 (q, 2 H), 2.65 (t, 2 H), 2.53 (broad, 4 H), 1.81-1.46
(m, 4 H), 0.99 (t, 3 H); .sup.19F NMR (CDCl.sub.3): .delta. -113.31
MS m/z 490 (M+1).
EXAMPLE 46
N-Butyl-2-(4-fluorophenyl)-3-{2-[2-(4-morpholinyl)ethoxy]-4-pyrimidinyl}py-
razolo[1,5-a]pyridin-7-amine
[0595] ##STR106##
[0596] In a similar manner as described in Example 38, from
N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1-
,5-a]pyridin-7-amine (50 mg, 0.12 mmol),
4-(2-hydroxyethyl)morpholine (71 .mu.L, 0.59 mmol) and potassium
t-butoxide (0.24 mL, 1.0 M in t-butanol, 0.24 mmol) in
tetrahydrofuran at room temperature was prepared
N-butyl-2-(4-fluorophenyl)-3-{2-[2-(4-morpholinyl)ethoxy]-4-pyrimidinyl}p-
yrazolo[1,5-a]pyridin-7-amine (37.0 mg, 64%) as a yellow oil.
.sup.1H NMR (CDCl.sub.3): .delta. 8.19 (d, 1 H), 7.77 (d, 1 H),
7.60 (m, 2 H), 7.37 (t, 1 H), 7.17 (t, 2 H), 6.65 (d, 1 H),
6.08-6.03 (m, 2 H), 4.55 (broad, 2 H), 3.76 (broad, 4 H), 3.39 (q,
2 H), 2.88 (broad, 2 H), 2.63 (broad, 4 H), 1.81-1.46 (m, 4 H),
1.00 (t, 3 H); .sup.19F NMR (CDCl.sub.3): .delta. -112.88 MS m/z
491 (M+1). This material was treated with anhydrous hydrochloride
in ether to provide a hydrochloride salt as an orange solid.
EXAMPLE 47
3-[2-(Butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-[2-(4-morpholinyl)et-
hyl]pyrazolo[1,5-a]pyridin-7-amine
[0597] ##STR107##
[0598] In a similar manner as described in Example 1, from
N-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyri-
midinamine (52.5 mg, 0.13 mmol) and 4-(2-aminoethyl)morpholine was
prepared
3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-[2-(4-morp-
holinyl)ethyl]pyrazolo[1,5-a]pyridin-7-amine (30.0 mg, 46%) as a
yellow solid. .sup.1H NMR (CDCl.sub.3): .delta. 7.97 (broad, 1 H),
7.76 (d, 1 H), 7.65 (m, 2 H), 7.34 (t, 1 H), 7.16 (t, 2 H), 6.54
(t, 1 H), 6.32 (d, 1 H), 6.04 (d, 1 H), 3.76 (t, 4 H), 3.48 (m, 4
H), 2.78 (t, 2 H), 2.55 (broad, 4 H), 1.68-1.44 (m, 4 H), 0.98 (t,
3 H); MS m/z 490 (M+1).
EXAMPLE 48
3-[2-(Butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-(2-methoxyethyl)pyra-
zolo[1,5-a]pyridin-7-amine
[0599] ##STR108##
[0600] A mixture of
N-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyri-
midinamine (56 mg, 0.14 mmol) and 2-methoxyethylamine (5 mL) was
heated to reflux for 24 hours, then cooled and concentrated. Flash
column chromatography eluting with 3:1 hexanes:ethyl acetate
afforded
3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-(2-methoxyethyl)pyr-
azolo[1,5-a]pyridin-7-amine (57.1 mg, 93%) as a yellow foam.
.sup.1H NMR (CDCl.sub.3): .delta. 8.02 (d, 1 H), 7.76 (d, 1 H),
7.65 (m, 2 H), 7.32 (t, 1 H), 7.15 (t, 2 H), 6.29 (m, 2 H), 6.05
(d, 1 H), 5.10 (broad, 1 H), 3.72 (t, 2 H), 3.57 (q, 2 H), 3.47 (q,
2 H), 3.43 (s, 3 H), 1.69-1.44 (m, 4 H), 0.98 (t, 3 H); MS m/z 435
(M+1).
EXAMPLE 49
3-[2-(Butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-methylpyrazolo[1,5-a-
]pyridin-7-amine
[0601] ##STR109##
[0602] In a similar manner as described in Example 14, from
N-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyri-
midinamine (53 mg, 0.13 mmol) and methylamine (5 mL, 40% aqueous)
in a sealed tube was obtained
3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-methylpyrazolo[1,5--
a]pyridin-7-amine (40.5 mg, 77%) as a pale yellow solid. .sup.1H
NMR (CDCl.sub.3): .delta. 8.01 (d, 1 H), 7.75 (d, 1 H), 7.62 (m, 2
H), 7.34 (t, 1 H), 7.13 (t, 2 H), 6.30 (d, 1 H), 6.03-5.99 (m, 2
H), 5.11 (broad, 1 H), 3.46 (q, 2 H), 3.10 (d, 3 H), 1.69-1.42 (m,
4 H), 0.97 (t, 3 H); .sup.19F NMR (CDCl.sub.3) .delta. -113.39; MS
m/z 391 (M+1).
EXAMPLE 50
4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-6-
-[(dimethylamino)methyl]-2-pyrimidinamine
[0603] ##STR110##
a)
4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopenty-
l-6-(iodomethyl)-2-pyrimidinamine
[0604]
[6-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(cyc-
lopentylamino)-4-pyrimidinyl]methanol (215 mg, 0.49 mmol) was
dissolved in a mixture of benzene (4 mL) and ether (8 mL).
Imidazole (134 mg, 2.0 mmol) and triphenylphosphine (191 mg, 0.73
mmol) were added sequentially. A solution of iodine (179 mg, 0.71
mmol) in ether (5 mL) was added dropwise to the reaction mixture
over 10 minutes. The resultant solution was stirred for an
additional 20 minutes then diluted with 10 mL of ether. The mixture
was filtered to remove solids. Concentration followed by flash
chromatography (4:1 hexanes:ethyl acetate) provided
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
6-(iodomethyl)-2-pyrimidinamine (160 mg, 60%) as a solid. R.sub.f
0.47 (4:1 hexanes:ethyl acetate); .sup.1H NMR (CDCl.sub.3) .delta.
8.38 (d, 1H), 7.67 (m, 2H), 7.28 (m, 1H), 7.18 (t, 2H), 7.03 (d,
1H), 6.38 (s, 1H), 5.19 (d, 1H), 4.35 (m, 1H), 4.02 (s, 2H), 2.10
(m, 2H), 2.67 (m, 6H).
b)
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopenty-
l-6-[(dimethylamino)methyl]-2-pyrimidinamine
[0605] To a solution of
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
6-(iodomethyl)-2-pyrimidinamine (160 mg, 0.29 mmol) in
tetrahydrofuran (2 mL) was added dimethylamine (730 .mu.L, 2 M in
THF, 1.5 mmol) and the reaction mixture was allowed to stir at room
temperature for 16 hours. The reaction mixture was diluted with
ethyl acetate and washed with saturated aqueous sodium bicarbonate
solution, water, and brine. The organic layer was dried over
magnesium sulfate. Filtration and concentration provided the crude
amine (120 mg, 88%). A portion of the crude amine (26 mg) was
purified by flash chromatography (38:2 dichloromethane:methanol to
37:3 dichloromethane-methanol) to provide
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
6-[(dimethylamino)methyl]-2-pyrimidinamine (15 mg). R.sub.f 0.32
(37:3 dichloromethane:methanol); .sup.1H NMR (CDCl.sub.3) .delta.
8.37 (d, 1H), 7.66 (m, 2H), 7.26 (m, 1H), 7.11 (t, 2H), 7.03 (d,
1H), 6.39 (s, 1H), 5.18 (d, 1H), 4.35 (m, 1H), 3.23 (s, 2H), 2.22
(s, 6H), 2.07 (m, 2H), 1.80-1.45 (m, 6H); MS m/z 465 (M+1); mp
68-75.degree. C.
EXAMPLE 51
N-Cyclopentyl-3-{2-(cyclopentylamino)-6-[(dimethylamino)methyl]-4-pyrimidi-
nyl}-2-(4-fluorophenyl)[pyrazolo[1,5-a]pyridin-7-amine
[0606] ##STR111##
[0607] A solution of
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
6-[(dimethylamino)methyl]-2-pyrimidinamine (60 mg, 0.13 mmol) in
cyclopentylamine (2 mL) was heated in a sealed tube at 95.degree.
C. for 16 hours followed by heating at 100.degree. C. for 72 hours.
After cooling to room temperature, the reaction mixture was diluted
with ethyl acetate and washed with a saturated aqueous sodium
bicarbonate solution. The organic layer was concentrated and
chromatographed (37:3 dichloromethane:methanol) to provide
N-cyclopentyl-3-{2-(cyclopentylamino)-6-[(dimethylamino)methyl]-4-pyrimid-
inyl}-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine (10 mg,
15%). .sup.1H NMR (CDCl.sub.3) .delta. 7.70 (d, 1H), 7.65 (m, 2H),
7.31 (t, 1H), 7.12 (t, 2H), 6.37 (s, 1H), 6.05-5.95 (m, 2H), 5.13
(d, 1H), 4.35 (m, 1H), 4.01 (m, 1H), 3.20 (s, 2H), 2.20 (s, 6H),
2.15 (m, 2H), 2.05 (m, 2H), 1.90-1.50 (m, 12H); MS m/z 514
(M+1).
EXAMPLE 52
4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-5-
-methyl-2-pyrimidinamine
[0608] ##STR112##
a)
1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-methyl-2-p-
ropen-1-ol
[0609] In a similar manner as described in Example 7, from
7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde
(510 mg, 1.9 mmol) and isopropenyl magnesium bromide was obtained
1-[7-chloro-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-methyl-2-pr-
open-1-ol (530 mg, 90%) as an off-white solid. R.sub.f 0.26 (4:1
hexanes:ethyl acetate); .sup.1H NMR (CDCl.sub.3) .delta. 7.81-7.70
(m, 3H), 7.21-7.08 (m, 3H), 6.95 (d, 1H), 5.41 (s, 1H), 5.30 (s,
1H), 5.08 (s, 1H), 1.62 (s, 3H); MS m/z 317 (M+1).
b)
1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-methyl-2-p-
ropen-1-one
[0610] In a similar manner as described in Example 7, from
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-methyl-2-pro-
pen-1-ol (530 mg, 1.7 mmol) was formed
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-methyl-2-pro-
pen-1-one (390 mg, 74%) as a white solid. R.sub.f 0.29 (4:1
hexanes:ethyl acetate); .sup.1H NMR (CDCl.sub.3) .delta. 7.96 (d,
1H), 7.59 (m, 2H), 7.34 (t, 1H), 7.18-7.07 (m, 3H), 5.48 (s, 1H),
5.40 (s, 1H), 1.98 (s, 3H).
c)
4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopenty-
l-5-methyl-2-pyrimidinamine
[0611] To a suspension of N-cyclopentylguanidine hydrochloride (68
mg, 0.42 mmol) in ethanol (1 mL) was added sodium ethoxide (138
.mu.L, 3 M in ethanol, 0.41 mmol). A solution of
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-methyl-2-pro-
pen-1-one in ethanol (1 mL) was added and the reaction mixture was
allowed to stir at room temperature for 16 hours. An additional
aliquot of N-cyclopentylguanidine hydrochloride (68 mg, 0.42 mmol)
and sodium ethoxide (138 .mu.L, 3 M in ethanol, 0.41 mmol) in
ethanol (1 mL) was added to reaction mixture and allowed to stir an
additional 24 hours. Palladium on carbon (10%, 30 mg) was added to
reaction mixture and allowed to stir at room temperature for 30
minutes under an atmosphere of air, at which point additional
palladium on carbon (10%, 100 mg) was added. The reaction mixture
was allowed to stir at room temperature 16 hours. The suspension
was diluted with ethyl acetate and filtered through Celite.
Concentration followed by flash chromatography (4:1 hexanes:ethyl
acetate) provided
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
5-methyl-2-pyrimidinamine (57 mg, 43%) as a clear oil. R.sub.f 0.24
(4:1 hexanes:ethyl acetate); .sup.1H NMR (CDCl.sub.3) .delta. 8.14
(s, 1H), 7.64 (m, 2H), 7.57 (d, 1H), 7.17 (m, 1H), 7.08 (t, 2H),
7.00 (d, 1H), 5.09 (d, 1H), 4.26 (m, 1H), 2.03 (m, 2H), 1.82-1.45
(m, 9H); MS m/z 422 (M+1). To a solution of the product in ether
was added 1 M hydrochloride in ether. The precipitated solid was
isolated to give the corresponding hydrochloride salt.
EXAMPLE 53
N-Cyclopentyl-3-[2-(cyclopentylamino)-5-methyl-4-pyrimidinyl]-2-(4-fluorop-
henyl)pyrazolo[1,5-a]pyridin-7-amine
[0612] ##STR113##
[0613] In a similar manner as described in Example 7, from
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
5-methyl-2-pyrimidinamine (52 mg, 0.12 mmol) and cyclopentylamine
was formed
N-cyclopentyl-3-[2-(cyclopentylamino)-5-methyl-4-pyrimidinyl]-2-(4-
-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine (47 mg, 90%) as a
yellow oil. R.sub.f 0.15 (4:1 hexanes:ethyl acetate); .sup.1H NMR
(DMSO-d.sub.6) .delta. 8.51 (broad, 1H), 8.27 (s, 1H), 7.65 (m,
2H), 7.41 (t, 1H), 7.28 (t, 2H), 6.97 (d, 1H), 6.74 (br, 1H), 6.25
(d, 1H), 4.14 (br, 1H), 4.05 (br, 1H), 2.09 (m, 2H), 1.96-1.42 (m,
17H); MS m/z 471 (M+1). To a solution of the product in ether was
added 1 M hydrochloride in ether. The precipitated solid was
isolated to give the corresponding hydrochloride salt.
EXAMPLE 54
N-Allyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-pyrazolo[1,5-a-
]pyridin-7-amine
[0614] ##STR114##
[0615] A solution of
N-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyri-
midinamine (0.15 g, 0.38 mmol) in allylamine (5 mL, 67 mmol) was
heated at 85.degree. C. in a sealed tube for 88 hours. After
cooling and concentrating the reaction mixture, flash
chromatography (4:1 hexanes-ethyl acetate) afforded
N-allyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a-
]pyridin-7-amine (0.14 g, 88%) as a pale yellow foam. .sup.1H NMR
(CDCl.sub.3): .delta. 7.89 (broad, 1 H), 7.78 (d, 1 H), 7.62 (m, 2
H), 7.36 (t, 1 H), 7.16 (t, 2 H), 6.31-6.26 (m, 2 H), 6.09-5.92 (m,
2 H), 5.39-5.24 (m, 2 H), 4.06 (t, 2 H), 3.50 (q, 2 H), 1.72-1.41
(m, 4 H), 0.98 (t, 3 H); .sup.19F NMR (CDCl.sub.3) .delta. -113.16;
MS m/z 417 (M+1); Anal. Calcd for C.sub.24H.sub.25FN.sub.6: C,
69.21; H, 6.05; N, 20.18. Found: C, 69.27; H, 6.07; N, 20.03.
EXAMPLE 55
3-[2-(Butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-propylpyrazolo[1,5-a-
]pyridin-7-amine
[0616] ##STR115##
[0617] To a solution of
N-allyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a-
]pyridin-7-amine (80 mg, 0.19 mmol) in ethanol (5 mL) was added
palladium on carbon (10%, 8 mg). The mixture was stirred overnight
at room temperature under a balloon filled with hydrogen. The
reaction was filtered through a pad of Celite and concentrated to
give
3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-propylpyrazolo[1,5--
a]pyridin-7-amine (79 mg, 99%) as a gold foam. .sup.1H NMR
(CDCl.sub.3): .delta. 8.03 (d, 1 H), 7.74 (d, 1 H), 7.69 (m, 2 H),
7.33 (t, 1 H), 7.15 (t, 2 H), 6.30 (d, 1 H), 6.08-6.01 (m, 2H),
5.08 (broad, 1 H), 3.47 (q, 2 H), 3.37 (q, 2 H), 1.87-1.41 (m, 6
H), 1.08 (t, 3 H), 0.99 (t, 3 H); .sup.19F NMR (CDCl.sub.3) .delta.
-113.44; MS m/z 419 (M+1).
EXAMPLE 56
7-Chloro-2-(4-fluorophenyl)-3-pyridin-4-ylpyrazolo[1,5-a]pyridine
[0618] ##STR116##
a) 1-(4-Fluorophenyl)-2-trimethylsilylacetylene
[0619] 4-Fluoroiodobenzene (112 mL, 0.97 mol) and triethylamine
(176 mL, 1.26 mol) are dissolved in dry tetrahydrofuran (1.2 L) and
nitrogen gas was bubbled through the solution for about 20 min.
Copper (I) iodide (1.08 g, 5.7 mmol) and
bis(triphenyphosphine)palladium dichloride (2.15 g, 3 mmol) are
added and then trimethylsilylacetylene (178 mL, 1.3 mol) was added
dropwise over about 40 min with the temperature being maintained at
about 23.degree. C. A large amount of precipitate forms which
necessitates mechanical stirring. Following complete addition of
the trimethylsilylacetylene the mixture was allowed to stir at room
temperature for about 18 hours. The mixture was filtered and the
solid washed with cyclohexane. The combined filtrates are
concentrated under reduce pressure to give a brown oil.
[0620] Application of this oil to a pad of silica gel followed by
elution with cyclohexane gave a yellow solution. Removal of the
solvent gave the title compound as a yellow oil; 182.8 g (95%).
b) Methyl 3-(4-fluorophenyl)propiolate
[0621] A solution of 1-(4-fluorophenyl)-2-trimethylsilylacetylene
(64 g, 0.33 mol) in dry diethyl ether (400 mL) was cooled to
0.degree. C. under a nitrogen atmosphere. To this solution was
added, dropwise over 45 minutes, a solution of tetrabutylammonium
fluoride (1M in tetrahydrofuran, 330 mL, 0.33 mol) via a dropping
funnel maintaining the internal temperature below 2.degree. C. The
mixture was allowed to warm to room temperature over about 1 hour.
Diethyl ether (300 mL) was added to the mixture and the organic
solution was washed with water, saturated brine and then dried over
anhydrous magnesium sulfate. The magnesium sulfate was removed by
filtration and the filtrate was cooled to about -78.degree. C.
n-Butyl lithium (1.6M in hexanes, 450 mL, 0.72 mol) was added
dropwise via a dropping funnel over about 1 h while the temperature
was maintained below -66.degree. C. After complete addition the
mixture was stirred at -78.degree. C. for about 1 h and then a
precooled solution of methyl chloroformate (110 mL, 1.4 mol) in dry
diethyl ether (200 mL) was added in a continuous stream as fast as
possible. The mixture was allowed to cool to -78.degree. C. and
then allowed to warm to room temperature over 1.5 h. The organic
reaction mixture was washed with water and saturated brine and then
dried over anhydrous magnesium sulfate. The solvents are remove
under reduced pressure and the residue dried under reduced pressure
to give the title compound as a brown solid, 36.5 g (61%). .sup.1H
NMR (CDCl.sub.3) .delta. 7.58 (dd, 2H, J=9, 5.4 Hz), 7.07 (t, 2H,
J=8.5 Hz), 3.84 (s, 3H). MS (+ve ion electrospray) 178 (30),
(M.sup.+).
c) Methyl
2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylate
[0622] A stirred solution of methyl 3-(4-fluorophenyl)propiolate
(8.02 g, 45 mmol) and 1-aminopyridinium iodide (10 g, 45 mmol) in
dry acetonitrile (150 mL) was cooled to about 0.degree. C. A
solution of 1,8-diazabicycloundec-7-ene (13.7 g, 90 mmol) in dry
acetonitrile (50 mL) was added dropwise over 1 hour. The mixture
was allowed to stir at room temperature for about 18 h. The
reaction mixture was cooled in an ice bath for about 30 min and the
precipitate was collected by filtration and washed with cold
acetonitrile (10 mL). The solid was dried under reduced pressure to
give the title compound as a white solid, 8.48 g (70%). .sup.1H NMR
(CDCl.sub.3) .delta. 8.50 (d, 1H, J=8.4 Hz), 8.18 (d, 1H, J=8.8
Hz), 7.78 (m, 2H), 7.42 (t, 1H, J=8.4 Hz), 7.13 (t, 2H, J=8.8 Hz),
6.97 (td, 1H, J=6.8, 1 Hz).). MS (+ve ion electrospray) 271 (100),
(MH.sup.+).
d) 2-(4-Fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid
[0623] A solution of methyl
2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylate (5.0 g,
18.5 mmol) in 2N aqueous sodium hydroxide (50 ml) and methanol (30
mL) was heated at reflux for about 3 h. The mixture was filtered
and the filtrate was washed with diethyl ether (20 mL) and then
concentrated under reduced pressure to about half the original
volume. Concentrated hydrochloric acid was added to adjust the pH
to about 2 and the resulting solid was collected by filtration and
washed with water and dried under vacuum to give the title compound
as a white solid, 4.8 g (ca. 100%). .sup.1H NMR (d.sub.6 DMSO)
.delta. 12.43 (br s, 1 h), 8.84 (d, 1H, J=6.9 Hz), 8.14 (d, 1H, J=9
Hz), 7.82 (m, 2H), 7.57 (t, 1H, J=8.1 Hz), 7.28 (t, 2H, J=9 Hz),
7.15 (td, 1H, J=6.9, 1.2 Hz). MS (+ve ion electrospray) 257 (100),
(MH.sup.+).
e) 2-(4-Fluorophenyl)-3-bromopyrazolo[1,5-a]pyridine
[0624] To a solution of
2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.96
g, 3.75 mmol) in dry N,N-dimethylformamide (10 mL) was added sodium
bicarbonate (0.95 g, 11.3 mmol) followed by N-bromosuccinimide
(0.667 g, 3.75 mmol) and the mixture was stirred at room
temperature under a nitrogen atmosphere for about 90 min. The
mixture was poured into water (300 mL) and the resulting solid was
collected by filtration and washed with water. The solid was
dissolved in 10:1 chloroform-methanol (10 mL) and filtered through
a pad (0.5 cm) of silica gel using 10:1 chloroform:methanol as
eluent. The filtrate was evaporated to leave the title compound as
a tan solid, 0.87 g (80%). .sup.1H NMR (d.sub.6 DMSO) .delta. 8.7
(d, 1H, J=6.9 Hz), 8.02 (dd, 2H, J=8.7, 5.7 Hz), 7.61 (d, 1H, J=8.4
Hz), 7.40 (t, 1H, J=6 Hz), 7.38 (t, 2H, J=9 Hz), 7.04 (t, 1H, J=6.9
Hz). MS (+ve ion electrospray) 293 (100), (MH.sup.+).
f) 2-(4-Fluorophenyl)-3-(4-pyridyl)-pyrazolo[1,5-a]pyridine
[0625] To a solution of
2-(4-fluorophenyl)-3-bromopyrazolo[1,5-a]pyridine (0.2 g, 0.68
mmol) and 4-(tributylstannyl)pyridine (0.38 g, 1 mmol) in dry
toluene (10 mL) was added tetrakis(triphenylphosphine)palladium (0)
(0.03 g, 0.03 mmol) and the mixture was heated at reflux
temperature under a nitrogen atmosphere for about 48 hours. The
mixture was cooled to room temperature and diluted with diethyl
ether (40 mL). The mixture was poured into a 10% aqueous solution
of potassium fluoride (20 mL) and the mixture was stirred for 1
hour. The biphasic mixture was filtered through a pad of
diatomaceous earth and the organic phase was separated. The aqueous
phase was extracted with diethyl ether (10 mL) and the combined
organic phases are washed with brine, dried over anhydrous
magnesium sulfate, filtered and the solvent evaporated under
reduced pressure. The residue was purified using silica gel
chromatography with 20% ethyl acetate in hexanes, followed by 50%
ethyl acetate in hexanes, as eluent to give the title compound as
an off white solid, 0.16 g (80%). .sup.1H NMR (CDCl.sub.3) .delta.
8.58 (br s, 2H), 8.50 (d, 1H, J=7.2 Hz), 7.63 (d, 1H, 9 Hz), 7.52
(m, 2H), 7.27-7.20 (m, 3H), 7.06 (t, 2H, 8.7 Hz), 6.86 dt, 1H, J=7,
1 Hz). MS (+ve ion electrospray) 290 (100), (MH.sup.+).
g)
7-Chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine
[0626] To a stirred solution of
2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine (100 mg,
0.346 mmol) in 4 ml of tetrahydrofuran at -78.degree. C. under
N.sub.2 was added 2.5 M n-butyllithium in hexanes (22 .mu.l, 2 eq).
The mixture was stirred at -78.degree. C. for 30 min and
N-chlorosuccinimide (2.2 eqv) was then added. The mixture was
allowed to warm to room temperature after 30 min and was stirred at
room temperature for 1 hr. The mixture was diluted with ether and
washed with 1N hydrochloric acid solution. The aqueous layer was
basified with 1N sodium hydroxide solution and extracted thoroughly
with ether. The combined organic layers were dried on anhydrous
magnesium sulfate, filtered and evaporated. Purification by
chromatography yielded
7-chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine
(71%).
[0627] When the electrophile is N-chlorosuccinimide in 1 ml of
tetrahydrofuran,
7-chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine
was isolated as yellow solid in 72% yield. When the electrophile is
p-toluenesulfonyl chloride in 1 ml of tetrahydrofuran,
7-chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine
was isolated as yellow solid in 79% yield. .sup.1H NMR
(CDCl.sub.3): .delta. 8.65 (d, 2H, J=5.8 Hz), 7.55-7.69 (m, 3H),
7.30 (d, 2H, J=5.8 Hz), 7.11-7.21 (m, 1H), 7.04-7.13 (m, 3H); MS
(ES +ve): 326 (25, M+3), 323 (50, M.sup.+), 290 (100).
EXAMPLE 57
N-[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-7-yl]-N-[2-(1--
methyl-2-pyrrolidinyl)ethyl]amine
[0628] ##STR117##
[0629] To a stirred solution of
7-chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine
(50 mg, 0.154 mmol) in 1 mL of isopropanol was added excess of
2-(1-methylpyrrolidin-2-yl)ethanamine (1 mL). The mixture was
heated to reflux at 85.degree. C. overnight. The mixture was
evaporated to dryness and purified by preparative thin layer
chromatography to give
N-[2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-7-yl]-N[2-(1--
methyl-2-pyrrolidinyl)ethyl]amine as peach solid in 17% yield
(28.3% yield based on recovered starting material). .sup.1H NMR
(CDCl.sub.3): .delta. 8.58 (dd, 2H, J=1.4, 4.6 Hz), 7.59-7.62 (m,
2H), 7.25-7.32 (m, 3H), 7.04-7.14 (m, 3H), 6.83 (t, 1H, J=5.3 Hz),
5.98 (d, 1H, J=7.4 Hz), 3.40-3.55 (m, 2H), 3.13-3.19 (m, 1H), 2.43
(s, 3H), 2.36-2.43 (m, 1H), 2.20-2.29 (m, 1H), 1.66-2.20 (m, 6H);
MS (ES +ve): 418 (10, M+3), 417 (20, M+2), 416 (60, M+1), 112
(100).
EXAMPLE 58
2-(4-Fluorophenyl)-N-methyl-3-(4-pyridinyl)pyrazolo1,5-a]pyridin-7-amine
[0630] ##STR118##
[0631]
7-Chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine
(25 mg, 0.077 mmol) and excess of methylamine in alcohol (1 mL) in
sealed tube was heated at 120.degree. C. for overnight. The mixture
was evaporated to dryness and purified by preparative thin layer
chromatography to give
2-(4-fluorophenyl)-N-methyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-7-amine
a peach solid in 77.3% yield. .sup.1H NMR (CDCl.sub.3): .delta.
8.59 (d, 2H, J=5.4 Hz), 7.58-7.62 (m, 2H), 7.28-7.30 (m, 3H),
7.07-7.14 (m, 3H), 6.11 (bs, 1H), 6.00 (d, 1H, J=7.4 Hz), 3.16 (d,
3H, J=5.0 Hz); MS (ES +ve): 320 (18, M+2), 319 (20, M+1), 318 (100,
M.sup.+).
EXAMPLE 59
N,N-Diethyl-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-7-ami-
ne
[0632] ##STR119##
[0633]
7-Chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine
and excess of diethylamine in alcohol (1 mL) in sealed tube was
heated at 120.degree. C. for overnight. The mixture was evaporated
to dryness and purified by preparative thin layer chromatography to
give
N,N-diethyl-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-7-am-
ine. .sup.1H NMR (CDCl.sub.3): .delta. 8.61 (d, 2H, J=6.0 Hz),
7.61-7.66 (m, 2H), 7.22-7.34 (m, 4H), 7.09 (t, 2H, J=8.7 Hz), 6.32
(d, 1H, J=6.1 Hz), 3.64 (q, 4H, J=7.0 Hz), 1.26 (t, 6H, J=7 Hz). MS
(ES +ve): 362 (25, M+2), 361 (100, M+1).
EXAMPLE 60
2-(4-Fluorophenyl)-7-iodo-3-pyridin-4-ylpyrazolo[1,5-a]pyridine
[0634] ##STR120##
[0635] To a stirred solution of
2-(4-fluorophenyl)-3-(4-pyridyl)-pyrazolo[1,5-a]pyridine (100 mg,
0.346 mmol) in 4 mL of tetrahydrofuran at -78.degree. C. under
N.sub.2 was added 2.5 M n-butyllithium in hexanes (2 eq.). The
mixture was stirred at -78.degree. C. for 30 min and
N-iodosuccinimide (2.2 eq.) was then added. The mixture was allowed
to warm to room temperature after 30 min and was stirred at room
temperature for 1 hour. The mixture was diluted with ether and
washed with 1N hydrochloric acid solution. The aqueous layer was
basified with 1N sodium hydroxide solution and extracted thoroughly
with ether. The combined organic layers were dried on anhydrous
magnesium sulfate, filtered and evaporated. Purification by
chromatography yielded
2-(4-fluorophenyl)-7-iodo-3-pyridin-4-ylpyrazolo[1,5-a]pyridine as
a yellow solid. .sup.1H NMR (CDCl.sub.3): .delta. 8.54 (d, 2H,
J=5.8 Hz), 7.50-7.57 (m, 3H), 7.37 (d, 1H, J=7.1 Hz), 7.20 (d, 2H,
J=5.8 Hz), 7.00 (t, 2H, J=8.6 Hz), 6.90 (t, 1H, J=7.8 Hz); MS m/z
416 (M+1).
EXAMPLE 61
7-Bromo-2-(4-fluorophenyl)-3-pyridin-4-ylpyrazolo[1,5-a]pyridine
[0636] ##STR121##
[0637] To a stirred solution of of
2-(4-fluorophenyl)-3-(4-pyridyl)-pyrazolo[1,5-a]pyridine (100 mg,
0.346 mmol) in 4 ml of tetrahydrofuran at -78.degree. C. under
N.sub.2 was added 2.5 M n-butyllithium in hexanes (2 eq.). The
mixture was stirred at -78.degree. C. for 30 min and
N-bromosuccinimide (2.2 eq.) was then added. The mixture was
allowed to warm to room temperature after 30 min and was stirred at
room temperature for 1 hr. The mixture was diluted with ether and
washed with 1N hydrochloric acid solution. The aqueous layer was
basified with 1N sodium hydroxide solution and extracted thoroughly
with ether. The combined organic layers were dried on anhydrous
magnesium sulfate, filtered and evaporated. Purification by
chromatography yielded
7-bromo-2-(4-fluorophenyl)-3-pyridin-4-ylpyrazolo[1,5-a]pyridine as
a yellow solid. .sup.1H NMR (CDCl.sub.3): .delta. 8.65 (d, 2H,
J=5.0 Hz), 7.56-7.68 (m, 3H), 7.31 (d, 2H, J=5.0 Hz), 7.11-7.30 (m,
4H; MS m/z 368 (M+1).
EXAMPLE 62
N-Butyl-2-(4-fluorophenyl)-3-pyridin-4-ylpyrazolo[1,5-a]pyridin-7-amine
[0638] ##STR122##
[0639] A mixture of of
7-chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine
in toluene (2 mL) and excess of butylamine (1 mL) in sealed tube
was heated at 110.degree. C. for overnight. The mixture was
evaporated to dryness and purified by preparative thin layer
chromatography to give
N-butyl-2-(4-fluorophenyl)-3-pyridin-4-ylpyrazolo[1,5-a]pyridin-7-amine.
.sup.1H NMR (CDCl.sub.3): .delta. 8.53 (d, 2H, J=5.1 Hz), 7.54-7.57
(m, 2H), 7.20-7.24 (m, 3H), 7.06 (t, 2H, J=8.6 Hz), 7.02-7.00 (m,
1H), 6.04 (bs, 1H), 5.95 (d, 1H, J=7.7 Hz), 3.39 (q, 2H, J=6.4 Hz),
1.74-1.78 (m, 2H), 1.47-1.56 (m, 2H), 0.99 (t, 3H, J=7.4 Hz); MS
m/z 361 (M+1).
EXAMPLE 63
2-(4-Fluorophenyl)-7-(1H-imidazol-1-yl)-3-pyridin-4-ylpyrazolo[1,5-a]pyrid-
ine
[0640] ##STR123##
[0641] A mixture of
7-chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine
(100 mg) and imidazole (5 eq.) in dimethylsulfoxide (2 mL) in
sealed tube was heated at 120.degree. C. overnight. The mixture was
evaporated to dryness and purified by preparative thin layer
chromatography to give
2-(4-fluorophenyl)-7-(1H-imidazol-1-yl)-3-pyridin-4-ylpyrazolo[1,5-a]pyri-
dine. .sup.1H NMR (CDCl.sub.3): .delta. 8.65 (d, 2H, J=5.6 Hz),
7.96 (s, 1H), 7.60 (d, 1H, J=9.5 Hz), 7.44-7.47 (m, 2H), 7.34-7.38
(m, 4H), 7.28 (d, 2H, J=5.7 Hz), 7.02 (m, 2H); MS m/z 356
(M+1).
EXAMPLE 64
2-(4-Fluorophenyl)-3,7-bis(2-fluoropyridin-4-yl)pyrazolo[1,5-a]pyridine
[0642] ##STR124##
[0643] In a similar manner to that in Example 28, from
3-bromo-7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (305 mg,
0.94 mmol) and 2-fluoropyridin-4-ylboronic acid (182 mg, 1.30 mmol)
after heating to 100.degree. C. for 1.5 hours was formed
2-(4-fluorophenyl)-3,7-bis(2-fluoropyridin-4-yl)pyrazolo[1,5-a]pyridine
(90 mg, 24%). .sup.1H NMR (CDCl.sub.3): .delta. 8.47 (d, 1 H), 8.29
(d 1 H), 7.89 (br d, 1 H), 7.78 (d, 1 H), 7.72 (s, 1 H), 7.58 (dd,
2 H), 7.44 (dd, 1 H), 7.20 (br d, 1 H), 7.15 (d, 1 H), 7.13 (t, 2
H), 7.05 (s, 1 H); MS m/z 403 (M+1).
EXAMPLE 65
N-{4-[3-{2-[(3-Aminopropyl)amino]pyridin-4-yl}-2-(4-fluorophenyl)pyrazolo[-
1,5-a]pyridin-7-yl]pyridin-2-yl}propane-1,3-diamine
[0644] ##STR125##
[0645] A solution of
2-(4-fluorophenyl)-3,7-bis(2-fluoropyridin-4-yl)pyrazolo[1,5-a]pyridine
(34 mg, 0.08 mmol) in 1,3-diaminopropane (1 mL) was heated at
150.degree. C. for 0.25 hours. Upon cooling to room temperature,
the mixture was concentrated in vacuo and the residue was
triturated with hot ethyl acetate. The resulting solids were
collected on filter, washed with ethyl ether and dried to provide
N-{4-[3-{2-[(3-aminopropyl)amino]pyridin-4-yl}-2-(4-fluorophenyl)pyrazolo-
[1,5-a]pyridin-7-yl]pyridin-2-yl}propane-1,3-diamine as a light
yellow powder (19 mg, 46%). .sup.1H NMR (CD.sub.3OD): .delta. 8.18
(d, 1 H), 8.03 (d, 1 H), 7.78 (d, 1 H), 7.65 (dd, 2 H), 7.45 (dd, 1
H), 7.30 (s, 1 H), 7.1-7.2 (m, 4 H), 6.60 (s, 1 H), 6.59 (d, 1 H),
3.55 (t, 2 H), 3.47 (t, 2 H), 3.0 (q, 4 H), 1.88-2.04 (m, 4 H); MS
m/z 511 (M+1).
EXAMPLE 66
4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propylpyridin-
-2-amine
[0646] ##STR126##
[0647] Prepared in a similar manner as Example 56. .sup.1H NMR
(d.sub.6-acetone): .delta. 8.04 (d, 1 H), 7.68-7.76 (m, 3 H), 7.35
(dd, 1 H), 7.16-7.24 (m, 3H), 6.46-6.50(m, 2 H), 3.28 (t, 2 H),
1.60 (sextet, 2 H), 0.85 (t, 3 H); MS m/z 381 (M+1).
EXAMPLE 67
N-Butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]pyridin--
2-amine
[0648] ##STR127##
[0649] Prepared in a similar manner as Example 56. .sup.1H NMR
(d.sub.6-acetone): .delta. 8.04 (d, 1 H), 7.68-7.76 (m, 3 H), 7.35
(dd, 1 H), 7.17-7.25 (m, 3H), 6.46-6.50(m, 2 H), 3.32 (t, 2 H),
1.57 (m, 2 H), 1.40 (m, 2 H), 0.82 (t, 3 H); MS m/z 395 (M+1).
EXAMPLE 68
N-Butyl-2-(4-fluorophenyl)-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]pyra-
zolo[1,5-a]pyridin-7-amine
[0650] ##STR128##
[0651] In a similar manner as described in Example 38, from
N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1-
,5-a]pyridin-7-amine (50 mg, 0.12 mmol), 2,2,2-trifluoroethanol
(0.43 mL, 5.9 mmol) and potassium t-butoxide (0.24 mL, 1.0 M in
t-butanol, 0.24 mmol) at room temperature for 1 h was prepared
N-butyl-2-(4-fluorophenyl)-3-[2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]pyr-
azolo[1,5-a]pyridin-7-amine (52.4 mg, 97%) as an off-white solid.
.sup.1H NMR (CDCl.sub.3): .delta. 8.22 (d, 1 H), 7.73 (d, 1 H),
7.59 (m, 2 H), 7.43 (t, 1 H), 7.19 (t, 2 H), 6.75 (d, 1 H),
6.11-6.07 (m, 2 H), 4.79 (q, 2 H), 3.40 (q, 2 H), 1.77 (m, 2 H),
1.51 (m, 2 H), 1.00 (t, 3 H); .sup.19F NMR (CDCl.sub.3): .delta.
-74.03, -112.61; MS m/z 460 (M+1).
EXAMPLE 69
2-(4-Fluorophenyl)-7-pyrrolidin-1-yl-3-(2-pyrrolidin-1-ylpyrimidin-4-yl)py-
razolo[1,5-a]pyridine
[0652] ##STR129##
[0653] The title compound can be synthesized in a similar manner to
the methods described in previous examples. .sup.1H NMR
(acetone-d.sub.6): .delta. 8.11 (d, 1 H), 7.98 (d, 1 H), 7.76 (dd,
2H), 7.35 (t, 1 H), 7.28 (t, 2 H), 6.33 (d, 1 H), 6.21 (d, 1 H),
3.84 (m, 4 H), 3.64 (br. s, 4 H), 2.06 (m, 8 H); MS m/z 429
(M+1).
EXAMPLE 70
3-[(4-{2-(4-Fluorophenyl)-7-[(3-hydroxypropyl)amino]-pyrazolo[1,5-a]pyridi-
n-3-yl}pyrimidin-2-yl)amino]propan-1-ol
[0654] ##STR130##
[0655] The title compound can be synthesized in a similar manner to
the methods described in previous examples. .sup.1H NMR
(acetone-d.sub.6): .delta. 8.04 (d, 1 H), 7.83 (d, 1 H), 7.76 (m,
2H), 7.40 (t, 1 H), 7.30 (t, 2 H), 6.86 (t,1H), 6.4 (br. s, 1H),
6.33 (d, 1 H), 6.24 (d, 1 H), 3.89 (br. s, 1H), 3.81 (br.s, 2H),
3.62 (m, 5 H), 2.03 (m, 2 H), 1.84 (m, 2H); MS m/z 437 (M+1).
EXAMPLE 71
N-Cyclohexyl-3-[2-(cyclohexylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyraz-
olo[1,5-a]pyridin-7-amine
[0656] ##STR131##
[0657] The title compound can be synthesized in a similar manner to
the methods described in previous examples. .sup.1H NMR
(acetone-d.sub.6): .delta. 7.98 (d, 1 H), 7.75 (d, 1 H), 7.65 (m,
2H), 7.33 (t, 1 H), 7.24 (t, 2 H), 6.28 (m, 2H), 6.19 (d, 1H), 3.81
(br.s, 1H), 3.61 (br. s, 1H), 2.13 (s, 2 H), 2.04 (m, 4H), 1.79 (m,
4H), 1.65 (m, 2H), 1.47 (m, 4H), 1.32 (m, 8H); MS m/z 485
(M+1).
EXAMPLE 72
3-[2-(Cyclopentylamino)-6-methylpyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo-
[1,5-a]pyridin-7-amine
[0658] ##STR132##
[0659] In a similar manner as described in Example 21 from
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
6-methyl-2-pyrimidinamine (100 mg, 0.237 mmol) and sodium azide (19
mg, 0.29 mmol) was formed
3-[2-(cyclopentylamino)-6-methylpyrimidin-4-yl]-2-(4-fluorophenyl)pyrazol-
o[1,5-a]pyridin-7-amine (9 mg, 9%). .sup.1H NMR (CDCl.sub.3)
.delta. 7.79 (d, 1H), 7.67 (m, 2H), 7.26 (t, 1H), 7.14 (t, 2H),
6.23 (s, 1H), 6.19 (d, 1H), 5.28 (s, 2H), 5.19 (br, 1H), 4.35 (m,
1H), 2.17 (s, 3H), 2.03 (m, 2H), 1.76-1.50 (m, 6H); .sup.19F NMR
(CDCl3) .delta. -113.52; MS m/z 403 (M+1). This material was
treated with anhydrous hydrochloric acid in ether to provide a
hydrochloride salt as a yellow solid.
EXAMPLE 73
7-Chloro-2-(4-fluorophenyl)-3-(2-phenylpyrimidin-4-yl)pyrazolo[1,5-a]pyrid-
ine
[0660] ##STR133##
[0661] To a suspension of
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one
(36 mg, 0.12 mmol) and benzamidine hydrochloride (25 mg, 0.16 mmol)
in ethanol (500 .mu.L) was added sodium ethoxide (52 .mu.L, 3 M in
ethanol, 0.16 mmol). The reaction mixture was stirred at room
temperature 16 hours. The reaction mixture was diluted with water
and 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 hexanes-ethyl
acetate) provided
7-chloro-2-(4-fluorophenyl)-3-(2-phenylpyrimidin-4-yl)pyrazolo[1,5-a]pyri-
dine (34 mg, 71%). R.sub.f 0.36 (3:1 hexanes-ethyl acetate);
.sup.1H NMR (CDCl.sub.3) .delta. 8.60-8.56 (m, 2H), 8.52-8.48 (m,
2H), 7.67 (m, 2H), 7.56-7.52 (m, 3H), 7.39 (m, 1H), 7.22-7.11 (m,
3H), 6.93 (d, 1H); .sup.19F NMR (CDCl.sub.3) .delta. -112.30; MS
m/z 401 (M+1).
EXAMPLE 74
6-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-
-(cyclopentylamino)pyrimidine-4-carboxamide
[0662] ##STR134##
a) Methyl
6-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(cy-
clopentylamino)pyrimidine-4-carboxylate
[0663] To a solution of
6-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(cyclopentyl-
amino)-4-pyrimidinecarboxylic acid (340 mg, 0.752 mmol) in methanol
(20 mL) was added (trimethylsilyl)diazomethane (376 .mu.L, 2.0 M in
hexanes, 0.752 mmol). The reaction mixture was stirred at room
temperature for 16 hours. Excess (trimethylsilyl)diazomethane was
added and the reaction mixture was stirred 3 days. The reaction
mixture was quenched with saturated aqueous sodium bicarbonate
solution and 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 (49-1
to 29-1 dichloromethane-methanol) provided methyl
6-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(cyclopentyl-
amino)pyrimidine-4-carboxylate (45 mg, 13%). .sup.1H NMR
(CDCl.sub.3) .delta. 8.44 (d, 1H), 7.65 (m, 2H), 7.34 (t, 1H), 7.17
(t, 2H), 7.11 (d, 1H), 7.03 (s, 1H), 5.43 (br, 1H), 4.36 (m, 1H),
3.89 (s, 3H), 2.05 (m, 2H), 1.76-1.55 (m, 6H); MS m/z 466
(M+1).
b)
6-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopenty-
l-2-(cyclopentylamino)pyrimidine-4-carboxamide
[0664] A solution of methyl
6-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-(cyclopentyl-
amino)pyrimidine-4-carboxylate (45 mg, 0.097 mmol) in
cyclopentylamine (1 mL) was heated at 85.degree. C. in a sealed
tube for 24 hours. The reaction mixture was cooled and the excess
cyclopentylamine was removed in vacuo. The resulting residue was
partitioned between ethyl acetate and saturated aqueous sodium
bicarbonate solution. The organic layer was washed with water and
brine, then dried over magnesium sulfate. Filtration and
concentration followed by flash chromatography (4:1 hexanes:ethyl
acetate) provided
6-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
2-(cyclopentylamino)pyrimidine-4-carboxamide (35 mg, 70%). .sup.1H
NMR (CDCl.sub.3) .delta. 8.34 (d, 1H), 7.78 (br, 1H), 7.65 (m, 2H),
7.31-7.26 (m, 2H), 7.14 (t, 2H), 7.07 (d, 1H), 5.16 (br, 1H),
4.34-4.24 (m, 2H), 2.07-2.00 (m, 4H), 1.80-1.48 (m, 12H); MS m/z
519 (M+1). A portion of this material was treated with anhydrous
hydrochloric acid in ether to provide a hydrochloride salt as a
yellow solid.
EXAMPLE 75
N-Cyclopentyl-2-(cyclopentylamino)-6-[7-(cyclopentylamino)-2-(4-fluorophen-
yl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidine-4-carboxamide
[0665] ##STR135##
[0666] In a similar manner as described Example 1 from
6-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
2-(cyclopentylamino)pyrimidine-4-carboxamide (31 mg, 0.060 mmol)
and cyclopentylamine (1 mL) was formed
N-cyclopentyl-2-(cyclopentylamino)-6-[7-4-carboxamide (24 mg, 71%).
.sup.1H NMR (CDCl.sub.3) .delta. 7.79 (br, 1H), 7.70 (d, 1H), 7.63
(m, 2H), 7.32 (t, 1H), 7.24 (s, 1H), 7.14 (t, 2H), 6.06-6.03 (m,
2H), 5.05 (d, 1H), 4.35-4.20 (m, 2H), 4.00 (m, 1H), 2.18-1.96 (m,
6H), 1.83-1.47 (m, 18H); MS m/z 568 (M+1).
EXAMPLE 76
7-Chloro-3-(2-cyclopropylpyrimidin-4-yl)-2-(4-fluorophenyl)pyrazolo[1,5-a]-
pyridine
[0667] ##STR136##
[0668] In a similar manner as described in Example 73, from
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one
(100 mg, 0.335 mmol), cyclopropylcarbamidine hydrochloride (53 mg,
0.436 mmol), and sodium ethoxide (145 .mu.L, 3 M in ethanol, 0.436
mmol) was formed
7-chloro-3-(2-cyclopropylpyrimidin-4-yl)-2-(4-fluorophenyl)pyrazol-
o[1,5-a]pyridine (75 mg, 61%). .sup.1H NMR (CDCl.sub.3) .delta.
8.45 (d, 1H), 8.31 (d, 1H), 7.62 (m, 2H), 7.33 (m, 1H), 7.18-7.07
(m, 3H), 6.78 (d, 1H), 2.32 (m, 1H), 1.25-1.09 (m, 4H); MS m/z 365
(M+1).
EXAMPLE 77
7-Chloro-2-(4-fluorophenyl)-3-(2-isopropylpyrimidin-4-yl)pyrazolo[1,5-a]py-
ridine
[0669] ##STR137##
[0670] In a similar manner as described in Example 73, from
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one
(100 mg, 0.335 mmol), isopropylcabamidine hydrochloride (53 mg,
0.436 mmol), and sodium ethoxide (145 .mu.L, 3 M in ethanol, 0.436
mmol) was formed
7-chloro-2-(4-fluorophenyl)-3-(2-isopropylpyrimidin-4-yl)pyrazolo[-
1,5-a]pyridine (83 mg, 67%). .sup.1H NMR (CDCl.sub.3) .delta. 8.55
(d, 1H), 8.41 (d, 1H), 7.63 (m, 2H), 7.33 (m, 1H), 7.19-7.07 (m,
3H), 6.84 (d, 1H), 3.28 (m, 1H), 1.44 (d, 6H); MS m/z 367
(M+1).
EXAMPLE 78
N-Butyl-4-[2-(4-fluorophenyl)-7-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]pyrim-
idin-2-amine
[0671] ##STR138##
[0672] A solution of
N-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimid-
in-2-amine (35 mg, 0.089 mmol), 2-furylboronic acid (30 mg, 0.27
mmol), sodium carbonate (155 .mu.L, 2.0 M aqueous, 0.31 mmol), and
dichlorobis(triphenyl-phosphine)palladium(II) (3 mg, 0.004 mmol)
was heated at 90.degree. C. for 4 hours. The reaction mixture was
cooled to room temperature, diluted with water, and 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 hexanes:ethyl acetate)
provided
N-butyl-4-[2-(4-fluorophenyl)-7-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]pyri-
midin-2-amine (15 mg, 39%) as a yellow solid. R.sub.f 0.19 (4:1
hexanes:ethyl acetate); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.35 (d, 1H), 8.11-8.07 (m, 2H), 7.73 (m, 2H), 7.63 (s, 1H), 7.57
(d, 1H), 7.43 (t, 1H), 7.16 (t, 2H), 6.66 (m, 1H), 6.41 (d, 1H),
5.17 (m, 1H), 3.50 (q, 2H), 1.67 (m, 2H), 1.49 (m, 2H), 0.99 (t,
3H); MS m/z 428 (M+1).
EXAMPLE 79
4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylpy-
rimidin-2-amine
[0673] ##STR139##
[0674] In a similar manner as described in Example 7, from
1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one
(2.65 g, 8.9 mmol) and N-cyclopropylguanidine sulfate (2.27 g, 11.5
mmol) was prepared
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl--
2-pyrimidinamine (1.59 g, 47%) as a yellow solid. .sup.1H NMR
(CDCl.sub.3): .delta. 8.66 (m, 1 H), 8.03 (m, 1 H), 7.66 (m, 2 H),
7.35 (t, 1 H), 7.18 (m, 3 H), 6.40 (d, 1 H), 6.06 (broad, 1 H),
2.90 (m, 1 H), 0.91 (m, 2 H), 0.70 (m, 2 H); .sup.19F NMR
(CDCl.sub.3) .delta. -112.22; MS m/z 380 (M+1).
EXAMPLE 80
2-(4-Chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyr-
azolo[1,5-a]pyridin-7-amine
[0675] ##STR140##
a) 1-(3-Bromo-4-chlorophenyl)-2-(6-chloro-2-pyridinyl)ethanone
[0676] In a similar manner as described in Example 1 from ethyl
3-bromo-4-chlorobenzoate (42.6 g, 171 mmol) and 6-chloro-2-picoline
(18.7 mL, 171 mmol),
1-(3-bromo-4-chlorophenyl)-2-(-6-chloro-2-pyridinyl)ethanone was
obtained as a pale yellow solid existing as a mixture of ketone and
enol tautomers. .sup.1H NMR (CDCl.sub.3) of ketone: .delta. 8.30
(d, 1H), 7.92 (dd, 1H), 7.69-7.54 (m, 2H), 7.24 (m, 2H), 4.42 (s,
2H); MS m/z 344 (M+1).
b) 1-(3-Bromo-4-chlorophenyl)-2-(6-chloro-2-pyridinyl)ethanone
oxime
[0677] In a similar manner as described in Example 1 from
1-(3-bromo-4-chlorophenyl)-2-(6-chloro-2-pyridinyl)ethanone was
obtained
1-(3-bromo-4-chlorophenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime
(22.0 g, yield 36% for the two steps) as a white solid. .sup.1H NMR
(CDCl.sub.3): .delta. 8.20 (b, 1H), 8.06 (d, 1H), 7.62-7.53 (m,
2H), 7.42 (d, 1H), 7.18-7.14 (m, 2H), 4.32 (s, 2H); MS m/z 359
(M+1).
c) 2-(3-Bromo-4-chlorophenyl)-7-chloropyrazolo[1,5-a]pyridine
[0678] In a similar manner as described in Example 1 from
1-(3-bromo-4-chlorophenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime
(17.57 g, 48.8 mmol) was obtained
2-(3-bromo-4-chlorophenyl)-7-chloropyrazolo[1,5-a]pyridine (13.7 g,
82%). .sup.1H NMR (CDCl.sub.3): .delta. 8.28 (d, 1H), 7.99 (dd,
1H), 7.52 (m, 2H), 7.10 (t, 1H), 6.94-6.90 (m, 2H); MS m/z 341
(M+1).
d)
1-[2-(3-Bromo-4-chlorophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethan-
one
[0679] In a similar manner as described in Example 1 from
2-(3-bromo-4-chlorophenyl)-7-chloropyrazolo[1,5-a]pyridine (13.9 g,
40.8 mmol),
1-[2-(3-bromo-4-chlorophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-
ethanone (12.5 g, 80%) was obtained as a tan solid. .sup.1H NMR
(CDCl.sub.3): .delta. 8.40 (d, 1H), 7.92 (d, 1H), 7.61-7.44 (m,
3H), 7.19 (d, 1H), 2.21(s, 3H); MS m/z 383 (M+1).
e)
1-[2-(3-Bromo-4-chlorophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridi-
n-3-yl]ethanone
[0680] In a similar manner as described in Example 1
1-[2-(3-bromo-4-chlorophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanon-
e (12.5 g, 32.5 mmol),
1-[2-(3-bromo-4-chlorophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin--
3-yl]ethanone was obtained as a yellow foam. .sup.1H NMR
(CDCl.sub.3): .delta. 7.91 (d, 1H), 7.62-7.41 (m, 4H), 6.16 (d,
1H), 6.02 (d, 1H), 4.00 (m, 1H), 2.22 (s, 3H), 2.13 (m, 2H),
1.82-1.65 (m, 6H); MS m/z 432 (M+1).
f)
(2E)-1-[2-(3-Bromo-4-chlorophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]p-
yridin-3-yl]-3-(dimethylamino)-2-propen-1-one
[0681] In a similar manner as described in Example 1 from
1-[2-(3-bromo-4-chlorophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin--
3-yl]ethanone,
(2E)-1-[2-(3-bromo-4-chlorophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyr-
idin-3-yl]-3-(dimethylamino)-2-propen-1-one (6.45 g, combined yield
for steps e and f 41%) was obtained as a brown syrup. .sup.1H NMR
(CDCl.sub.3): .delta. 8.08 (d, 1H), 7.69-7.57 (m, 3H), 7.51 (d,
1H), 7.32 (t, 1H), 6.04 (d, 1H), 5.96 (d, 1H), 5.13 (d, 1H), 4.00
(m, 1H), 3.0 (b, 3H), 2.62 (b, 3H), 2.13 (m, 2H), 1.84-1.68 (m,
6H); MS m/z 487 (M+1).
g)
2-(3-Bromo-4-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyri-
midinyl]pyrazolo[1,5-a]pyridin-7-amine
[0682] In a similar manner as described in Example 1 from
(2E)-1-[2-(3-bromo-4-chlorophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyr-
idin-3-yl]-3-(dimethylamino)-2-propen-1-one (3.00 g, 6.15 mmol),
2-(3-bromo-4-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimi-
dinyl]pyrazolo[1,5-a]pyridin-7-amine (2.71 g, 80%) was obtained as
a yellow solid. .sup.1H NMR (CDCl.sub.3): .delta. 8.08 (d, 1H),
8.02 (s, 1H), 7.64 (d, 1H), 7.50 (m, 2H), 7.53 (t, 1H), 6.38 (d,
1H), 6.05 (d, 1H), 6.00 (d, 1H), 5.13 (d, 1H), 4.28 (m, 1H), 4.01
(m, 1H), 2.15 (m, 2H), 2.04 (m, 2H), 1.83-1.49 (m, 12H); MS m/z 551
(M+1).
h)
2-(4-Chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-
-pyrazolo[1,5-a]pyridin-7-amine
[0683] To a solution of
2-(3-bromo-4-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimi-
dinyl]pyrazolo[1,5-a]pyridin-7-amine (200 mg, 0.36 mmol) in toluene
(15 mL) was added 2,2'-azobisisobutyronitril (30 mg, 0.18 mmol) and
tributyltin hydride (282 mg, 97 mmol). After heated at reflux for
24 hours, the reaction mixture was cooled to room temperature.
Concentration followed by purification with flash chromatograph
(30:70 ethyl acetate/hexanes) gave
2-(4-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]py-
razolo[1,5-a]pyridin-7-amine as a white foam. .sup.1H NMR
(CDCl.sub.3): .delta. 8.02 (d, 1H), 7.72 (m, 1H), 7.60 (d, 2H),
7.41 (d, 2H), 7.35 (m, 1H), 6.31 (d, 1H), 6.03 (m, 2H), 5.17 (br,
1H), 4.32 (m, 1H), 4.00 (m, 1H), 2.18-2.05 (m, 4H), 1.82-1.50 (m,
12H). MS m/z 474 (M+1).
EXAMPLE 81
N-Cyclopentyl-3-[2-(dimethylamino)-6-methylpyrimidin-4-yl]-2-(4-fluorophen-
yl)pyrazolo[1,5-a]pyridin-7-amine
[0684] ##STR141##
[0685] The title compound was synthesized in an similar manner to
that described in Example 8 to give a clear oil. .sup.1H NMR
(CDCl.sub.3): .delta. 7.63-7.60 (m, 3 H), 7.24 (m, 1 H), 7.07 (t, 2
H), 6.14 (s, 1 H), 5.98-5.96 (m, 2 H), 3.96 (m, 1 H), 3.17 (s, 6
H), 2.16 (s, 3 H), 2.14-2.06 (m, 2 H), 1.78-1.59 (m, 6 H). MS m/z
431 (M+1). This material was treated with anhydrous hydrogen
chloride in ether to give the corresponding HCl salt as a yellow
solid.
EXAMPLE 82
N-Cyclopentyl-3-[2-(cyclopentylamino)-6-phenylpyrimidin-4-yl]-2-(4-fluorop-
henyl)pyrazolo[1,5-a]pyridin-7-amine
[0686] ##STR142##
[0687] In a similar manner as described in Example 1 from
4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl--
6-phenylpyrimidin-2-amine (60 mg, 0.12 mmol) and cyclopentylamine
(1 mL) was formed N-cyclopentyl-3-[2-(cyclopentylamino)-6-phenyl
pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine
(64.1 mg, 97%) as a clear oil. .sup.1H NMR (CDCl.sub.3): .delta.
7.84-7.46 (m, 5 H), 7.44-7.33 (m, 4 H), 7.22 (t, 2 H), 6.81 (s, 1
H), 6.10-6.07 (m, 2 H), 5.24 (d, 1 h), 4.49 (m, 1 H), 4.05 (m, 1
H), 2.17 (m, 4 H), 1.87-1.59 (m, 12 H). .sup.19F NMR (CDCl.sub.3):
.delta. -113.49; MS m/z 533 (M+1). This material was treated with
anhydrous hydrogen chloride in ether to give the corresponding HCl
salt as a orange solid.
EXAMPLE 83
N-Cyclopentyl-6-[2-(4-fluorophenyl)-7-(methylthio)pyrazolo[1,5-a]pyridin-3-
-yl]pyrimidin-4-amine
[0688] ##STR143##
[0689] The title compound could be synthesized in a similar manner
to that described in Example 56 to give a peach solid. .sup.1H NMR
(CDCl.sub.3) .delta. 8.60 (s, 1H), 8.26 (d, 1H), 7.86 (m, 2H), 7.32
(t, 1H), 7.15 (t, 2H), 6.70 (d, 1H), 6.08 (s, 1H), 4.95 (br, 1H),
3.58 (br, 1H), 2.65 (s, 3H), 1.85-1.50 (m, 6H), 1.38-1.22 (m, 2H);
MS m/z 420 (M+1).
EXAMPLE 84
N-cyclopentyl-3-[6-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyr-
azolo[1,5-a]pyridin-7-amine
[0690] ##STR144##
[0691] The title compound could be synthesized in a similar manner
to that described in previous examples to give a light brown solid.
R.sub.f 0.18 (3:1 hexanes-ethyl acetate); .sup.1H NMR (CDCl.sub.3)
.delta. 8.58 (s, 1H), 7.74-7.64 (m, 3H), 7.32 (d, 1H), 7.16 (t,
2H), 6.05-5.98 (m, 3H), 4.98 (br, 1H), 4.02 (m, 1H), 3.53 (br, 1H),
2.18-2.13 (m, 2H), 1.84-1.55 (m, 12 H), 1.38-1.33 (m, 2H); MS m/z
457 (M+1).
EXAMPLE 85
Biological Activity
[0692] 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.
a) Tissue Culture and HSV Infection.
[0693] 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.
(b) Preparation of Detection DNA.
[0694] 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).
[0695] 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.
(c) Preparation of Capture Plates.
[0696] 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.
(d) Hybridization.
[0697] 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 ammonium
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.
e) Results.
[0698] The following results were obtained for HSV-1.
TABLE-US-00001 Example No. IC.sub.50 (.mu.M) 1 0.3 2 0.7 3 0.5 4
0.6 5 5.0 6 0.2 7 3.9 8 0.8 9 8.0 10 5.0 11 1.0 12 0.5 13 6.0 14
5.0 15 5.0 16 40.0 17 3.0 18 20.0 19 2.5 20 3.0 21 1.0 22 5.0 23
1.0 24 10.0 25 15.0 26 1.5 27 1.3 28 2.0 29 0.3 30 5.0 31 1.0 32
5.0 33 0.2 34 0.3 35 0.9 36 0.8 37 15.0 38 5.0 39 1.0 40 15.0 41
6.0 42 10.0 43 3.0 44 4.0 45 5.0 46 7.0 47 0.4 48 0.3 49 1.2 50 5.0
51 5.0 53 1.0 54 0.5 55 1.2 57 0.7 58 10.5 59 4.0 61 >20 68
>20 69 4.2 72 4.4 73 >20 74 >20 75 >20 76 >20 77
>20 78 0.95 79 >20 80 0.54 81 >20 82 >20 83 1.3 84
1.3
[0699] The results demonstrate that the compounds of the present
invention are useful for the treatment and prophylaxis of herpes
viral infections.
* * * * *