U.S. patent application number 10/654546 was filed with the patent office on 2007-02-15 for novel pyrazolopyrimidines as cyclin dependent kinase inhibitors.
This patent application is currently assigned to Schering Corporation. Invention is credited to Carmen S. Alvarez, Tin-Yau Chan, Lawrence W. Dillard, Ronald J. Doll, Michael P. Dwyer, Thierry O. Fischmann, Viyyoor M. Girijavallabhan, Timothy J. Guzi, Zhen Min He, Douglas Walsh Hobbs, Ray Anthony James, Kartik M. Keertikar, Vincent Madison, Alan Mallams, Vidyadhar M. Paradkar, Haengsoon Park, Kamil Paruch, Jocelyn Rivera, Vinh D. Tran.
Application Number | 20070037824 10/654546 |
Document ID | / |
Family ID | 33162933 |
Filed Date | 2007-02-15 |
United States Patent
Application |
20070037824 |
Kind Code |
A1 |
Guzi; Timothy J. ; et
al. |
February 15, 2007 |
Novel pyrazolopyrimidines as cyclin dependent kinase inhibitors
Abstract
In its many embodiments, the present invention provides a novel
class of pyrazolo[1,5-a]pyrimidine compounds as inhibitors of
cyclin dependent kinases, methods of preparing such compounds,
pharmaceutical compositions containing one or more such compounds,
methods of preparing pharmaceutical formulations comprising one or
more such compounds, and methods of treatment, prevention,
inhibition, or amelioration of one or more diseases associated with
the CDKs using such compounds or pharmaceutical compositions.
Inventors: |
Guzi; Timothy J.; (Chatham,
NJ) ; Paruch; Kamil; (Garwood, NJ) ; Dwyer;
Michael P.; (Scotch Plains, NJ) ; Doll; Ronald
J.; (Convent Station, NJ) ; Girijavallabhan; Viyyoor
M.; (Parsippany, NJ) ; Mallams; Alan;
(Hackettstown, NJ) ; Alvarez; Carmen S.;
(Livingston, NJ) ; Keertikar; Kartik M.; (East
Windsor, NJ) ; Rivera; Jocelyn; (Monmouth Junction,
NJ) ; Chan; Tin-Yau; (Edison, NJ) ; Madison;
Vincent; (Mountain Lakes, NJ) ; Fischmann; Thierry
O.; (Scotch Plains, NJ) ; Dillard; Lawrence W.;
(Skillman, NJ) ; Tran; Vinh D.; (Fountain Valley,
CA) ; He; Zhen Min; (Princeton, NJ) ; James;
Ray Anthony; (Bristol, PA) ; Park; Haengsoon;
(Plainsboro, NJ) ; Paradkar; Vidyadhar M.;
(Somerville, NJ) ; Hobbs; Douglas Walsh; (Yardley,
PA) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION;PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Assignee: |
Schering Corporation
Pharmacopeia, Inc.
|
Family ID: |
33162933 |
Appl. No.: |
10/654546 |
Filed: |
September 3, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60408027 |
Sep 4, 2002 |
|
|
|
60421959 |
Oct 29, 2002 |
|
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Current U.S.
Class: |
514/252.16 ;
514/259.3; 544/281 |
Current CPC
Class: |
A61P 35/00 20180101;
C07D 487/04 20130101; A61P 35/02 20180101; A61P 35/04 20180101 |
Class at
Publication: |
514/252.16 ;
544/281; 514/259.3 |
International
Class: |
A61K 31/519 20060101
A61K031/519; C07D 487/02 20060101 C07D487/02 |
Claims
1. A compound represented by the structural formula: ##STR2164## or
a pharmaceutically acceptable salt or solvate of said compound,
wherein: R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl,
cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl,
heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide
of said heteroaryl), --(CHR.sup.5).sub.n-aryl,
--(CHR.sup.5).sub.n-heteroaryl, ##STR2165## wherein each of said
alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and
heteroaryl can be unsubstituted or optionally substituted with one
or more moieties which can be the same or different, each moiety
being independently selected from the group consisting of halogen,
alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF.sub.3, OCF.sub.3,
CN, --OR.sup.5, --NR.sup.5R.sup.10,
--C(R.sup.4R.sup.5).sub.p--R.sup.9, --N(R.sup.5)Boc,
--(CR.sup.4R.sup.5).sub.pOR.sup.5, --C(O.sub.2)R.sup.5,
--C(O)R.sup.5, --C(O)NR.sup.5R.sup.10, --SO.sub.3H, --SR.sup.10,
--S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.5R.sup.10,
--N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and
--N(R.sup.5)C(O)NR.sup.5R.sup.10; R.sup.2 is selected from the
group consisting of R.sup.9, alkyl, alkenyl, alkynyl, CF.sub.3,
heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl,
arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl,
alkyl substituted with 1-6 R.sup.9 groups which can be the same or
different and are independently selected from the list of R.sup.9
shown below, aryl substituted with 1-3 aryl or heteroaryl groups
which can be the same or different and are independently selected
from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, aryl
fused with an aryl or heteroaryl group, heteroaryl substituted with
1-3 aryl or heteroaryl groups which can be the same or different
and are independently selected from phenyl, pyridyl, thiophenyl,
furanyl and thiazolo groups, heteroaryl fused with an aryl or
heteroaryl group, ##STR2166## wherein one or more of the aryl
and/or one or more of the heteroaryl in the above-noted definitions
for R.sup.2 can be unsubstituted or optionally substituted with one
or more moieties which can be the same or different, each moiety
being independently selected from the group consisting of halogen,
--CN, --OR.sup.5, --SR.sup.5, --S(O.sub.2)R.sup.6,
--S(O.sub.2)NR.sup.5R.sup.6, --NR.sup.5R.sup.6,
--C(O)NR.sup.5R.sup.6, CF.sub.3, alkyl, aryl and OCF.sub.3; R.sup.3
is selected from the group consisting of H, halogen,
--NR.sup.5R.sup.6, --OR.sup.6, --SR.sup.6, --C(O)N(R.sup.5R.sup.6),
alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl and heteroarylalkyl, ##STR2167##
wherein each of said alkyl, cycloalkyl, aryl, arylalkyl,
heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for
R.sup.3 and the heterocyclyl moieties whose structures are shown
immediately above for R.sup.3 can be unsubstituted or optionally
independently substituted with one or more moieties which can be
the same or different, each moiety being independently selected
from the group consisting of halogen, alkyl, aryl, cycloalkyl,
CF.sub.3, CN, --OCF.sub.3, --(CR.sup.4R.sup.5).sub.pOR.sup.5,
--OR.sup.5, --NR.sup.5R.sup.6,
--(CR.sup.4R.sup.5).sub.pNR.sup.5R.sup.6, --C(O.sub.2)R.sup.5,
--C(O)R.sup.5, --C(O)NR.sup.5R.sup.6, --SR.sup.6,
--S(O.sub.2)R.sup.6, --S(O.sub.2)NR.sup.5R.sup.6,
--N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and
--N(R.sup.5)C(O)NR.sup.5R.sup.6, with the proviso that no carbon
adjacent to a nitrogen atom on a heterocyclyl ring carries a
--OR.sup.5 moiety; R.sup.4 is H, halo or alkyl; R.sup.5 is H,
alkyl, aryl or cycloalkyl; R.sup.6 is selected from the group
consisting of H, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl,
cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and
heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl,
cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and
heteroarylalkyl can be unsubstituted or optionally substituted with
one or more moieties which can be the same or different, each
moiety being independently selected from the group consisting of
halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF.sub.3,
OCF.sub.3, CN, --OR.sup.5, --NR.sup.5R.sup.10,
--C(R.sup.4R.sup.5).sub.p--R.sup.9, --N(R.sup.5)Boc,
--(CR.sup.4R.sup.5).sub.pOR.sup.5, --C(O.sub.2)R.sup.5,
--C(O)R.sup.5, --C(O)NR.sup.5R.sup.10, --SO.sub.3H, --SR.sup.10,
--S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.5R.sup.10,
--N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and
--N(R.sup.5)C(O)NR.sup.5R.sup.10; R.sup.10 is selected from the
group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl,
heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl,
wherein each of said alkyl, aryl, arylalkyl, cycloalkyl,
heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl
can be unsubstituted or optionally substituted with one or more
moieties which can be the same or different, each moiety being
independently selected from the group consisting of halogen, alkyl,
aryl, cycloalkyl, heterocyclylalkyl, CF.sub.3, OCF.sub.3, CN,
--OR.sup.5, --NR.sup.4R.sup.5, --C(R.sup.4R.sup.5).sub.p--R.sup.9,
--N(R.sup.5)Boc, --(CR.sup.4R.sup.5).sub.pOR.sup.5,
--C(O.sub.2)R.sup.5, --C(O)NR.sup.4R.sup.5, --C(O)R.sup.5,
--SO.sub.3H, --SR.sup.5, --S(O.sub.2)R.sup.7,
--S(O.sub.2)NR.sup.4R.sup.5, --N(R.sup.5)S(O.sub.2)R.sup.7,
--N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.4R.sup.5; or
optionally (i) R.sup.5 and R.sup.10 in the moiety
--NR.sup.5R.sup.10, or (ii) R.sup.5 and R.sup.6 in the moiety
--NR.sup.5R.sup.6, may be joined together to form a cycloalkyl or
heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl
moiety being unsubstituted or optionally independently being
substituted with one or more R.sup.9 groups; R.sup.7 is selected
from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl,
heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and
heterocyclyl, wherein each of said alkyl, cycloalkyl,
heteroarylalkyl, aryl, heteroaryl and arylalkyl can be
unsubstituted or optionally independently substituted with one or
more moieties which can be the same or different, each moiety being
independently selected from the group consisting of halogen, alkyl,
aryl, cycloalkyl, CF.sub.3, OCF.sub.3, CN, --OR.sup.5,
--NR.sup.5R.sup.10, --CH.sub.2OR.sup.5, --C(O.sub.2)R.sup.5,
--C(O)NR.sup.5R.sup.10, --C(O)R.sup.5--SR.sup.10,
--S(O.sub.2)R.sup.10, --S(O.sub.2)NR.sup.5R.sup.10,
--N(R.sup.5)S(O.sub.2)R.sup.10, --N(R.sup.5)C(O)R.sup.10 and
--N(R.sup.5)C(O)NR.sup.5R.sup.10; R.sup.8 is selected from the
group consisting of R.sup.6, --OR.sup.6, --C(O)NR.sup.5R.sup.10,
--S(O.sub.2)NR.sup.5R.sup.10, --C(O)R.sup.7,
--C(.dbd.N--CN)--NH.sub.2, --C(.dbd.NH)--NHR.sup.5, heterocyclyl,
and --S(O.sub.2)R.sup.7; R.sup.9 is selected from the group
consisting of halogen, --CN, --NR.sup.5R.sup.10,
--C(O.sub.2)R.sup.6, --C(O)NR.sup.5R.sup.10, --OR.sup.6,
--SR.sup.6, --S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.5R.sup.10,
--N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and
--N(R.sup.5)C(O)NR.sup.5R.sup.10; m is 0 to 4; n is 1 to 4; and p
is 1 to 4, with the proviso that when R.sup.2 is phenyl, R.sup.3 is
not alkyl, alkynyl or halogen, and that when R.sup.2 is aryl, R is
not ##STR2168## and with the further proviso that when R is
arylalkyl, then any heteroaryl substituent on the aryl of said
arylalkyl contains at least three heteroatoms.
2. The compound of claim 1, wherein R is --(CHR.sup.5).sub.n-aryl,
--(CHR.sup.5).sub.n-heteroaryl, alkyl, cycloalkyl, heterocyclyl, or
heteroarylalkyl (including N-oxide of said heteroaryl), wherein
each of said alkyl, aryl, cycloalkyl, heterocyclyl and heteroaryl
can be unsubstituted or optionally substituted with one or more
moieties as stated in claim 1; R.sup.2 is halogen, alkyl,
haloalkyl, CN, cycloalkyl, heterocyclyl or alkynyl; R.sup.3 is H,
lower alkyl, aryl, heteroaryl, cycloalkyl, --NR.sup.5R.sup.6,
##STR2169## wherein said alkyl, aryl, heteroaryl, cycloalkyl and
the heterocyclyl structures shown immediately above for R.sup.3 are
optionally substituted with one or more moieties which can be the
same or different, each moiety being independently selected from
the group consisting of halogen, CF.sub.3, OCF.sub.3, lower alkyl,
CN, --C(O)R.sup.5, --S(O.sub.2)R.sup.5, --C(.dbd.NH)--NH.sub.2,
--C(.dbd.CN)--NH.sub.2, hydroxyalkyl, alkoxycarbonyl, --SR.sup.5,
and OR.sup.5, with the proviso that no carbon adjacent to a
nitrogen atom on a heterocyclyl ring carries a --OR.sup.5 moiety;
R.sup.4 is H or lower alkyl; R.sup.5 is H, lower alkyl or
cycloalkyl; n is 1 to 2; and p is 1 or 2.
3. The compound of claim 2, wherein R is hydroxyalkyl,
--(CHR.sup.5).sub.n-aryl, or --(CHR.sup.5).sub.n-heteroaryl,
wherein each of said aryl and heteroaryl is unsubstituted or
substituted with one or more groups which can be the same or
different, each group being independently selected from the group
consisting of heteroaryl, amine, heterocyclyl,
--C(O)N(R.sup.5R.sup.6), --S(O.sub.2)R.sup.5,
--S(O.sub.2)N(R.sup.5R.sup.6), alkoxy and halo.
4. The compound of claim 2, wherein R.sup.2 is Br, Cl, CF.sub.3,
CN, lower alkyl, cyclopropyl, alkynyl, alkyl substituted with
--OR.sup.6 or tetrahydrofuranyl.
5. The compound of claim 2, wherein R.sup.3 is H, lower alkyl,
aryl, heteroaryl, cycloalkyl, ##STR2170## wherein each of said
alkyl, aryl, heteroaryl, cycloalkyl and the heterocyclyl structures
shown immediately above for R.sup.3 are optionally substituted with
one or more moieties which moieties can be the same or different,
each moiety being independently selected from the group consisting
of halogen, CF.sub.3, OCF.sub.3, lower alkyl, CN and OR.sup.5, with
the proviso that no carbon adjacent to a nitrogen atom on a
heterocyclyl ring carries a --OR.sup.5 moiety.
6. The compound of claim 2, wherein R.sup.4 is H or lower
alkyl.
7. The compound of claim 2, wherein R.sup.5 is H.
8. The compound of claim 2, wherein n is 1.
9. The compound of claim 1, wherein p is 1.
10. The compound of claim 2, wherein R is benzyl or
hydroxyalkyl.
11. The compound of claim 2, wherein R is pyrid-3-ylmethyl, wherein
said pyridyl may be unsubstituted or optionally independently
substituted with one or more moieties as stated in claim 1.
12. The compound of claim 2, wherein R is pyrid-4-ylmethyl, wherein
said pyridyl may be unsubstituted or optionally independently
substituted with one or more moieties as stated in claim 1.
13. The compound 2, wherein R is the N-oxide of pyrid-2-ylmethyl,
pyrid-3-ylmethyl, or pyrid-4-ylmethyl, wherein each of said pyridyl
may be unsubstituted or optionally independently substituted with
one or more moieties as stated in claim 1.
14. The compound of claim 4, wherein said R.sup.2 is Br.
15. The compound of claim 4, wherein said R.sup.2 is Cl.
16. The compound of claim 4, wherein R.sup.2 is ethyl.
17. The compound of claim 4, wherein R.sup.2 is cyclopropyl.
18. The compound of claim 4, wherein R.sup.2 is ethynyl.
19. The compound of claim 2, wherein R.sup.3 is lower alkyl,
cycloalkyl, heterocyclyl, aryl or --N(R.sup.5R.sup.6).
20. The compound of claim 19, wherein R.sup.3 is isopropyl.
21. The compound of claim 19, wherein R.sup.3 is cyclohexyl or
norbornyl wherein each of said cyclohexyl or norbornyl can be
unsubstituted or substituted with one or more moieties which can be
the same or different, each moiety being independently selected
from the group consisting of alkyl and hydroxyalkyl.
22. The compound of claim 19, wherein R.sup.3 is unsubstituted
phenyl.
23. The compound of claim 19, wherein R.sup.3 is a phenyl
substituted with one or moieties which can be the same or
different, each moiety being independently selected from the group
consisting of F, Br, Cl and CF.sub.3.
24. The compound of claim 19, wherein R.sup.5 of said
--N(R.sup.5R.sup.6) is H or hydroxyalkyl, and R.sup.6 of said
--N(R.sup.5R.sup.6) is selected from the group consisting of alkyl,
hydroxyalkyl, cycloalkyl and methylenedioxy, wherein each of said
alkyl and cycloalkyl can be unsubstituted or substituted with one
or more moieties which can be the same or different, each moiety
being independently selected from the group consisting of amine,
ethoxycarbonyl, amide, hydroxyalkyl, hydroxy,
25. The compound of claim 19, wherein R.sup.5 and R.sup.6 of said
--N(R.sup.5R.sup.6) are joined together to form a heterocyclyl
moiety, wherein said heterocyclyl moiety can be unsubstituted or
optionally independently substituted with one or more groups which
can be the same or different, each group being selected from the
group consisting of hydroxyalkyl, amide, --C(O)R.sup.5,
>C(CH.sub.3).sub.2, --S(O.sub.2)R.sup.5,
--S(O.sub.2)N(R.sup.5R.sup.6), --C(.dbd.NH)N(R.sup.5R.sup.6) and
--C(.dbd.N--CN)N(R.sup.5R.sup.6).
26. The compound of claim 25, wherein said heterocyclyl moiety
formed by R.sup.5 and R.sup.6 is a pyrrolidine or piperidine
ring.
27. A compound of the formula: ##STR2171## ##STR2172## ##STR2173##
##STR2174## ##STR2175## ##STR2176## ##STR2177## ##STR2178##
##STR2179## ##STR2180## ##STR2181## ##STR2182## ##STR2183##
##STR2184## ##STR2185## ##STR2186## ##STR2187## ##STR2188##
##STR2189## ##STR2190## ##STR2191## ##STR2192## ##STR2193##
##STR2194## ##STR2195## ##STR2196## ##STR2197## ##STR2198##
##STR2199## ##STR2200## ##STR2201## ##STR2202## ##STR2203##
##STR2204## ##STR2205## ##STR2206## ##STR2207## ##STR2208##
##STR2209## ##STR2210## ##STR2211## ##STR2212## ##STR2213##
##STR2214## ##STR2215## ##STR2216## ##STR2217## ##STR2218##
##STR2219## ##STR2220## ##STR2221## ##STR2222## or a
pharmaceutically acceptable salt or solvate thereof.
28. A compound of the formula: ##STR2223## ##STR2224## ##STR2225##
##STR2226## ##STR2227## ##STR2228## ##STR2229## ##STR2230##
##STR2231## ##STR2232## ##STR2233## ##STR2234## ##STR2235##
##STR2236## ##STR2237## or a pharmaceutically acceptable salt or
solvate thereof.
29. A compound of the formula: ##STR2238## ##STR2239## ##STR2240##
##STR2241## ##STR2242## ##STR2243## ##STR2244## ##STR2245##
##STR2246## ##STR2247## ##STR2248## ##STR2249## ##STR2250##
##STR2251## or a pharmaceutically acceptable salt or solvate
thereof.
31. A method of inhibiting one or more cyclin dependent kinases,
comprising administering a therapeutically effective amount of at
least one compound of claim 1 to a patient in need of such
inhibition.
32. A method of treating one or more diseases associated with
cyclin dependent kinase, comprising administering a therapeutically
effective amount of at least one compound of claim 1 to a patient
in need of such treatment.
33. The method of claim 32, wherein said cyclin dependent kinase is
CDK2.
34. The method of claim 32, wherein said cyclin dependent kinase is
mitogen activated protein kinase (MAPK/ERK).
35. The method of claim 32, wherein said cyclin dependent kinase is
glycogen synthase kinase 3 (GSK3beta).
36. The method of claim 32, wherein said disease is selected from
the group consisting of: cancer of the bladder, breast, colon,
kidney, liver, lung, small cell lung cancer, esophagus, gall
bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and
skin, including squamous cell carcinoma; leukemia, acute
lymphocytic leukemia, acute lymphoblastic leukemia, B-cell
lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins
lymphoma, hairy cell lymphoma and Burkett's lymphoma; acute and
chronic myelogenous leukemia, myelodysplastic syndrome and
promyelocytic leukemia; fibrosarcoma, rhabdomyosarcoma;
astrocytoma, neuroblastoma, glioma and schwannomas; melanoma,
seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum,
keratoctanthoma, thyroid follicular cancer and Kaposi's
sarcoma.
37. A method of treating one or more diseases associated with
cyclin dependent kinase, comprising administering to a mammal in
need of such treatment an amount of a first compound, which is a
compound of claim 1, or a pharmaceutically acceptable salt or
solvate thereof; and an amount of at least one second compound,
said second compound being an anti-cancer agent; wherein the
amounts of the first compound and said second compound result in a
therapeutic effect.
38. The method of claim 37, further comprising radiation
therapy.
39. The method of claim 37, wherein said anti-cancer agent is
selected from the group consisting of a cytostatic agent,
cisplatin, doxorubicin, taxotere, taxol, etoposide, CPT-11,
irinotecan, camptostar, topotecan, paclitaxel, docetaxel,
epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, 5FU,
temozolomide, cyclophosphamide, SCH 66336, R115777, L778, 123, BMS
214662, Iressa, Tarceva, antibodies to EGFR, Gleevec, intron,
ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard,
Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman,
Triethylenemelamine, Triethylenethiophosphoramine, Busulfan,
Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine,
Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate,
oxaliplatin, leucovirin, ELOXATIN.TM., Pentostatine, Vinblastine,
Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin,
Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin,
Mitomycin-C, L-Asparaginase, Teniposide 17.alpha.-Ethinylestradiol,
Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone,
Dromostanolone propionate, Testolactone, Megestrolacetate,
Methylprednisolone, Methyltestosterone, Prednisolone,
Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,
Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate,
Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin,
Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane,
Mitoxantrone, Levamisole, Navelbene, CPT-11, Anastrazole,
Letrazole, Capecitabine, Reloxafine, Droloxafine, or
Hexamethylmelamine.
40. A pharmaceutical composition comprising a therapeutically
effective amount of at least one compound of claim 1 in combination
with at least one pharmaceutically acceptable carrier.
41. The pharmaceutical composition of claim 38, additionally
comprising one or more anti-cancer agents selected from the group
consisting of cytostatic agent, cisplatin, doxorubicin, taxotere,
taxol, etoposide, CPT-11, irinotecan, camptostar, topotecan,
paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil,
methoxtrexate, 5FU, temozolomide, cyclophosphamide, SCH 66336,
R115777, L778, 123, BMS 214662, Iressa, Tarceva, antibodies to
EGFR, Gleevec, intron, ara-C, adriamycin, cytoxan, gemcitabine,
Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil,
Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine,
Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine,
Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine,
Fludarabine phosphate, Pentostatine, Vinblastine, Vincristine,
Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin,
Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C,
L-Asparaginase, Teniposide 17.alpha.-Ethinylestradiol,
Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone,
Dromostanolone propionate, Testolactone, Megestrolacetate,
Methylprednisolone, Methyltestosterone, Prednisolone,
Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,
Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate,
Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin,
Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane,
Mitoxantrone, Levamisole, Navelbene, CPT-11, Anastrazole,
Letrazole, Capecitabine, Reloxafine, Droloxafine, or
Hexamethylmelamine.
42. A compound of claim 1 in purified form.
Description
[0001] This application claims benefit of priority from U.S.
provisional patent applications, Ser. No. 60/408,027 filed Sep. 4,
2002, and Ser. No. 60/421,959 filed Oct. 29, 2002.
FIELD OF THE INVENTION
[0002] The present invention relates to pyrazolo[1,5-a]pyrimidine
compounds useful as protein kinase inhibitors (such as for example,
the inhibitors of the cyclin-dependent kinases, mitogen-activated
protein kinase (MAPK/ERK), glycogen synthase kinase 3(GSK3beta) and
the like), pharmaceutical compositions containing the compounds,
and methods of treatment using the compounds and compositions to
treat diseases such as, for example, cancer, inflammation,
arthritis, viral diseases, neurodegenerative diseases such as
Alzheimer's disease, cardiovascular diseases, and fungal
diseases.
BACKGROUND OF THE INVENTION
[0003] Protein kinase inhibitors include kinases such as, for
example, the inhibitors of the cyclin-dependent kinases (CDKs),
mitogen activated protein kinase (MAPK/ERK), glycogen synthase
kinase 3 (GSK3beta), and the like. Protein kinase inhibitors are
described, for example, by M. Hale et al in WO02/22610 A1 and by Y.
Mettey et al in J. Med. Chem., (2003) 46 222-236. The
cyclin-dependent kinases are serine/threonine protein kinases,
which are the driving force behind the cell cycle and cell
proliferation. Individual CDK's, such as, CDK1, CDK2, CDK3, CDK4,
CDK5, CDK6 and CDK7, CDK8 and the like, perform distinct roles in
cell cycle progression and can be classified as either G1, S, or
G2M phase enzymes. Uncontrolled proliferation is a hallmark of
cancer cells, and misregulation of CDK function occurs with high
frequency in many important solid tumors. CDK2 and CDK4 are of
particular interest because their activities are frequently
misregulated in a wide variety of human cancers. CDK2 activity is
required for progression through G1 to the S phase of the cell
cycle, and CDK2 is one of the key components of the G1 checkpoint.
Checkpoints serve to maintain the proper sequence of cell cycle
events and allow the cell to respond to insults or to proliferative
signals, while the loss of proper checkpoint control in cancer
cells contributes to tumorgenesis. The CDK2 pathway influences
tumorgenesis at the level of tumor suppressor function (e.g. p52,
RB, and p27) and oncogene activation (cyclin E). Many reports have
demonstrated that both the coactivator, cyclin E, and the
inhibitor, p27, of CDK2 are either over- or underexpressed,
respectively, in breast, colon, nonsmall cell lung, gastric,
prostate, bladder, non-Hodgkin's lymphoma, ovarian, and other
cancers. Their altered expression has been shown to correlate with
increased CDK2 activity levels and poor overall survival. This
observation makes CDK2 and its regulatory pathways compelling
targets for the development years, a number of adenosine
5'-triphosphate (ATP) competitive small organic molecules as well
as peptides have been reported in the literature as CDK inhibitors
for the potential treatment of cancers. U.S. Pat. No. 6,413,974,
col. 1, line 23-col. 15, line 10 offers a good description of the
various CDKs and their relationship to various types of cancer.
[0004] CDK inhibitors are known. For example, flavopiridol (Formula
I) is a nonselective CDK inhibitor that is currently undergoing
human clinical trials, A. M. Sanderowicz et al, J. Clin. Oncol.
(1998) 16, 2986-2999. ##STR1##
[0005] Other known inhibitors of the CDKs include, for example,
olomoucine (J. Vesely et al, Eur. J. Biochem., (1994) 224, 771-786)
and roscovitine (I. Meijer et al, Eur. J. Biochem., (1997) 243,
527-536). U.S. Pat. No. 6,107,305 describes certain
pyrazolo[3,4-b]pyridine compounds as CDK inhibitors. An
illustrative compound from the '305 patent has the Formula II:
##STR2##
[0006] K. S. Kim et al, J. Med. Chem. 45 (2002) 3905-3927 and WO
02/10162 disclose certain aminothiazole compounds as CDK
inhibitors.
[0007] Pyrazolopyrimidines are known. For Example, WO92/18504,
WO02/50079, WO95/35298, WO02/40485, EP94304104.6, EP0628559
(equivalent to U.S. Pat. Nos. 5,602,136, 5,602,137 and 5,571,813),
U.S. Pat. No. 6,383,790, Chem. Pharm. Bull., (1999) 47 928, J. Med.
Chem., (1977) 20, 296, J. Med. Chem., (1976) 19 517 and Chem.
Pharm. Bull., (1962) 10 620 disclose various
pyrazolopyrimidines.
[0008] There is a need for new compounds, formulations, treatments
and therapies to treat diseases and disorders associated with CDKs.
It is, therefore, an object of this invention to provide compounds
useful in the treatment or prevention or amelioration of such
diseases and disorders.
SUMMARY OF THE INVENTION
[0009] In its many embodiments, the present invention provides a
novel class of pyrazolo[1,5-a]pyrimidine compounds as inhibitors of
cyclin dependent kinases, methods of preparing such compounds,
pharmaceutical compositions comprising one or more such compounds,
methods of preparing pharmaceutical formulations comprising one or
more such compounds, and methods of treatment, prevention,
inhibition or amelioration of one or more diseases associated with
the CDKs using such compounds or pharmaceutical compositions.
[0010] In one aspect, the present application discloses a compound,
or pharmaceutically acceptable salts or solvates of said compound,
said compound having the general structure shown in Formula III:
##STR3## wherein:
[0011] R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl,
cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl,
heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide
of said heteroaryl), --(CHR.sup.5).sub.n-aryl,
--(CHR.sup.5).sub.n-heteroaryl, ##STR4## wherein each of said
alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and
heteroaryl can be unsubstituted or optionally substituted with one
or more moieties which can be the same or different, each moiety
being independently selected from the group consisting of halogen,
alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF.sub.3, OCF.sub.3,
CN, --OR.sup.5, --NR.sup.5R.sup.10,
--C(R.sup.4R.sup.5).sub.p--R.sup.9, --N(R.sup.5)Boc,
--(CR.sup.4R.sup.5).sub.pOR.sup.5, --C(O.sub.2)R.sup.5,
--C(O)R.sup.5, --C(O)NR.sup.5R.sup.10, --SO.sub.3H, --SR.sup.10,
--S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.5R.sup.10,
--N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and
--N(R.sup.5)C(O)NR.sup.5R.sup.10;
[0012] R.sup.2 is selected from the group consisting of R.sup.9,
alkyl, alkenyl, alkynyl, CF.sub.3, heterocyclyl, heterocyclylalkyl,
halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl,
cycloalkyl, heteroaryl, alkyl substituted with 1-6 R.sup.9 groups
which can be the same or different and are independently selected
from the list of R.sup.9 shown below, aryl substituted with 1-3
aryl or heteroaryl groups which can be the same or different and
are independently selected from phenyl, pyridyl, thiophenyl,
furanyl and thiazolo groups, aryl fused with an aryl or heteroaryl
group, heteroaryl substituted with 1-3 aryl or heteroaryl groups
which can be the same or different and are independently selected
from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups,
heteroaryl fused with an aryl or heteroaryl group, ##STR5##
[0013] wherein one or more of the aryl and/or one or more of the
heteroaryl in the above-noted definitions for R.sup.2 can be
unsubstituted or optionally substituted with one or more moieties
which can be the same or different, each moiety being independently
selected from the group consisting of halogen, --CN, --OR.sup.5,
--SR.sup.5, --S(O.sub.2)R.sup.6, --S(O.sub.2)NR.sup.5R.sup.6,
--NR.sup.5R.sup.6, --C(O)NR.sup.5R.sup.6, CF.sub.3, alkyl, aryl and
OCF.sub.3;
[0014] R.sup.3 is selected from the group consisting of H, halogen,
--NR.sup.5R.sup.6, --OR.sup.6, --SR.sup.6, --C(O)N(R.sup.5R.sup.6),
alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl and heteroarylalkyl, ##STR6## wherein
each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl and heteroarylalkyl for R.sup.3 and
the heterocyclyl moieties whose structures are shown immediately
above for R.sup.3 can be unsubstituted or optionally independently
substituted with one or more moieties which can be the same or
different, each moiety being independently selected from the group
consisting of halogen, alkyl, aryl, cycloalkyl, CF.sub.3, CN,
--OCF.sub.3, --(CR.sup.4R.sup.5)OR.sup.5, --OR.sup.5,
--NR.sup.5R.sup.6, --(CR.sup.4R.sup.5).sub.pNR.sup.5R.sup.6,
--C(O.sub.2)R.sup.5, --C(O)R.sup.5, --C(O)NR.sup.5R.sup.6,
--SR.sup.6, --S(O.sub.2)R.sup.6, --S(O.sub.2)NR.sup.5R.sup.6,
--N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and
--N(R.sup.5)C(O)NR.sup.5R.sup.6, with the proviso that no carbon
adjacent to a nitrogen atom on a heterocyclyl ring carries a
--OR.sup.5 moiety;
[0015] R.sup.4 is H, halo or alkyl;
[0016] R.sup.5 is H, alkyl, aryl or cycloalkyl;
[0017] R.sup.6 is selected from the group consisting of H, alkyl,
alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of
said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be
unsubstituted or optionally substituted with one or more moieties
which can be the same or different, each moiety being independently
selected from the group consisting of halogen, alkyl, aryl,
cycloalkyl, heterocyclylalkyl, CF.sub.3, OCF.sub.3, CN, --OR.sup.5,
--NR.sup.5R.sup.10, --C(R.sup.4R.sup.5).sub.p--R.sup.9,
--N(R.sup.5)Boc, --(CR.sup.4R.sup.5).sub.pOR.sup.5,
--C(O.sub.2)R.sup.5, --C(O)R.sup.5, --C(O)NR.sup.5R.sup.10,
--SO.sub.3H, --SR.sup.10, --S(O.sub.2)R.sup.7,
--S(O.sub.2)NR.sup.5R.sup.10, --N(R.sup.5)S(O.sub.2)R.sup.7,
--N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.5R.sup.10;
[0018] R.sup.10 is selected from the group consisting of H, alkyl,
aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl,
arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,
and heteroarylalkyl can be unsubstituted or optionally substituted
with one or more moieties which can be the same or different, each
moiety being independently selected from the group consisting of
halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF.sub.3,
OCF.sub.3, CN, --OR.sup.5, --NR.sup.4R.sup.5,
--C(R.sup.4R.sup.5).sub.p--R.sup.9, --N(R.sup.5)Boc,
--(CR.sup.4R.sup.5).sub.pOR.sup.5, --C(O.sub.2)R.sup.5,
--C(O)NR.sup.4R.sup.5, --C(O)R.sup.5, --SO.sub.3H, --SR.sup.5,
--S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.4R.sup.5,
--N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and
--N(R.sup.5)C(O)NR.sup.4R.sup.5; [0019] or optionally (i) R.sup.5
and R.sup.10 in the moiety --NR.sup.5R.sup.10, or (ii) R.sup.5 and
R.sup.6 in the moiety --NR.sup.5R.sup.6, may be joined together to
form a cycloalkyl or heterocyclyl moiety, with each of said
cycloalkyl or heterocyclyl moiety being unsubstituted or optionally
independently being substituted with one or more R.sup.9
groups;
[0020] R.sup.7 is selected from the group consisting of alkyl,
cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl,
heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each
of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and
arylalkyl can be unsubstituted or optionally independently
substituted with one or more moieties which can be the same or
different, each moiety being independently selected from the group
consisting of halogen, alkyl, aryl, cycloalkyl, CF.sub.3,
OCF.sub.3, CN, --OR.sup.5, --NR.sup.5R.sup.10, --CH.sub.2OR.sup.5,
--C(O.sub.2)R.sup.5, --C(O)NR.sup.5R.sup.10, --C(O)R.sup.5,
--SR.sup.10, --S(O.sub.2)R.sup.10, --S(O.sub.2)NR.sup.5R.sup.10,
--N(R.sup.5)S(O.sub.2)R.sup.10, --N(R.sup.5)C(O)R.sup.10 and
--N(R.sup.5)C(O)NR.sup.5R.sup.10;
[0021] R.sup.8 is selected from the group consisting of R.sup.6,
--OR.sup.6, --O(O)NR.sup.5R.sup.10, --S(O.sub.2)NR.sup.5R.sup.10,
--C(O)R.sup.7, --C(.dbd.N--CN)--NH.sub.2, --C(.dbd.NH)--NHR.sup.5,
heterocyclyl, and --S(O.sub.2)R.sup.7;
[0022] R.sup.9 is selected from the group consisting of halogen,
--CN, --NR.sup.5R.sup.10, --C(O.sub.2)R.sup.6,
--C(O)NR.sup.5R.sup.10, --OR.sup.6, --SR.sup.6,
--S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.5R.sup.10,
--N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and
--N(R.sup.5)C(O)NR.sup.5R.sup.10;
[0023] m is 0 to 4;
[0024] n is 1 to 4; and
[0025] p is 1 to 4, with the proviso that when R.sup.2 is phenyl,
R.sup.3 is not alkyl, alkynyl or halogen, and that when R.sup.2 is
aryl, R is not ##STR7## and with the further proviso that when R is
arylalkyl, then any heteroaryl substituent on the aryl of said
arylalkyl contains at least three heteroatoms.
[0026] The compounds of Formula III can be useful as protein kinase
inhibitors and can be useful in the treatment and prevention of
proliferative diseases, for example, cancer, inflammation and
arthritis. They may also be useful in the treatment of
neurodegenerative diseases such Alzheimer's disease, cardiovascular
diseases, viral diseases and fungal diseases.
DETAILED DESCRIPTION
[0027] In one embodiment, the present invention discloses
pyrazolo[1,5-a]pyrimidine compounds which are represented by
structural Formula II, or a pharmaceutically acceptable salt or
solvate thereof, wherein the various moieties are as described
above.
[0028] In another embodiment, R is --(CHR.sup.5).sub.n-aryl,
--(CHR.sup.5).sub.n-heteroaryl, --(CHR.sup.5).sub.n-heteroaryl
(with said heteroaryl being substituted with an additional, same or
different, heteroaryl), --(CHR.sup.5).sub.n-heterocyclyl (with said
heterocyclyl being substituted with an additional, same or
different, heterocyclyl), or ##STR8##
[0029] In another embodiment, R.sup.2 is halogen, CF.sub.3, CN,
lower alkyl, alkyl substituted with --OR.sup.6, alkynyl, aryl,
heteroaryl or heterocyclyl.
[0030] In another embodiment, R.sup.3 is H, lower alkyl, aryl,
heteroaryl, cycloalkyl, --NR.sup.5R.sup.6, ##STR9## wherein said
alkyl, aryl, heteroaryl, cycloalkyl and the heterocyclyl structures
shown immediately above for R.sup.3 are optionally substituted with
one or more moieties which can be the same or different, each
moiety being independently selected from the group consisting of
halogen, CF.sub.3, OCF.sub.3, lower alkyl, CN, --C(O)R.sup.5,
--S(O.sub.2)R.sup.5, --C(.dbd.NH)--NH.sub.2,
--C(.dbd.CN)--NH.sub.2, hydroxyalkyl, alkoxycarbonyl, --SR.sup.5,
and OR.sup.5, with the proviso that no carbon adjacent to a
nitrogen atom on a heterocyclyl ring carries a --OR.sup.5
moiety.
[0031] In another embodiment, R.sup.4 is H or lower alkyl.
[0032] In another embodiment, R.sup.5 is H, lower alkyl or
cycloalkyl.
[0033] In another embodiment, n is 1 to 2.
[0034] In an additional embodiment, R is --(CHR.sup.5).sub.n-aryl,
--(CHR.sup.5).sub.n-heteroaryl.
[0035] In an additional embodiment, R.sup.2 is halogen, CF.sub.3,
CN, lower alkyl, alkynyl, or alkyl substituted with --OR.sup.6.
[0036] In an additional embodiment, R.sup.2 is lower alkyl, alkynyl
or Br.
[0037] In an additional embodiment, R.sup.3 is H, lower alkyl,
aryl, ##STR10## wherein said alkyl, aryl and the heterocyclyl
moieties shown immediately above for R.sup.3 are optionally
substituted with one or more moieties which can be the same or
different, each moiety being independently selected from the group
consisting of halogen, CF.sub.3, lower alkyl, hydroxyalkyl, alkoxy,
--S(O.sub.2)R.sup.5, and CN.
[0038] In an additional embodiment, R.sup.4 is H.
[0039] In an additional embodiment, R.sup.5 is H, ethyl,
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
[0040] In an additional embodiment, R.sup.8 is alkyl or
hydroxyalkyl.
[0041] In an additional embodiment, n is 1.
[0042] In an additional embodiment, p is 1 or 2.
[0043] Another embodiment discloses the inventive compounds shown
in Table 1, which exhibited CDK2 inhibitory activity of about
0.0001 .mu.M to >about 5 .mu.M. The assay methods are described
later (from page 333 onwards). TABLE-US-00001 TABLE 1 ##STR11##
##STR12## ##STR13## ##STR14## ##STR15## ##STR16## ##STR17##
##STR18## ##STR19## ##STR20## ##STR21## ##STR22## ##STR23##
##STR24## ##STR25## ##STR26## ##STR27## ##STR28## ##STR29##
##STR30## ##STR31## ##STR32## ##STR33## ##STR34## ##STR35##
##STR36## ##STR37## ##STR38## ##STR39## ##STR40## ##STR41##
##STR42## ##STR43## ##STR44## ##STR45## ##STR46## ##STR47##
##STR48## ##STR49## ##STR50## ##STR51## ##STR52## ##STR53##
##STR54## ##STR55## ##STR56## ##STR57## ##STR58## ##STR59##
##STR60## ##STR61## ##STR62## ##STR63## ##STR64## ##STR65##
##STR66## ##STR67## ##STR68## ##STR69## ##STR70## ##STR71##
##STR72## ##STR73## ##STR74## ##STR75## ##STR76## ##STR77##
##STR78## ##STR79## ##STR80## ##STR81## ##STR82## ##STR83##
##STR84## ##STR85## ##STR86## ##STR87## ##STR88## ##STR89##
##STR90## ##STR91## ##STR92## ##STR93## ##STR94## ##STR95##
##STR96## ##STR97## ##STR98## ##STR99## ##STR100## ##STR101##
##STR102## ##STR103## ##STR104## ##STR105## ##STR106## ##STR107##
##STR108## ##STR109## ##STR110## ##STR111## ##STR112## ##STR113##
##STR114## ##STR115## ##STR116## ##STR117## ##STR118## ##STR119##
##STR120## ##STR121## ##STR122## ##STR123## ##STR124## ##STR125##
##STR126## ##STR127## ##STR128## ##STR129## ##STR130## ##STR131##
##STR132##
##STR133## ##STR134## ##STR135## ##STR136## ##STR137## ##STR138##
##STR139## ##STR140## ##STR141## ##STR142## ##STR143## ##STR144##
##STR145## ##STR146## ##STR147## ##STR148## ##STR149## ##STR150##
##STR151## ##STR152## ##STR153## ##STR154## ##STR155## ##STR156##
##STR157## ##STR158## ##STR159## ##STR160## ##STR161## ##STR162##
##STR163## ##STR164## ##STR165## ##STR166## ##STR167## ##STR168##
##STR169## ##STR170## ##STR171## ##STR172## ##STR173## ##STR174##
##STR175## ##STR176## ##STR177## ##STR178## ##STR179## ##STR180##
##STR181## ##STR182## ##STR183## ##STR184## ##STR185## ##STR186##
##STR187## ##STR188## ##STR189## ##STR190## ##STR191## ##STR192##
##STR193## ##STR194## ##STR195## ##STR196## ##STR197## ##STR198##
##STR199## ##STR200## ##STR201## ##STR202## ##STR203## ##STR204##
##STR205## ##STR206## ##STR207## ##STR208## ##STR209## ##STR210##
##STR211## ##STR212## ##STR213## ##STR214## ##STR215## ##STR216##
##STR217## ##STR218## ##STR219## ##STR220## ##STR221## ##STR222##
##STR223## ##STR224## ##STR225## ##STR226## ##STR227## ##STR228##
##STR229## ##STR230## ##STR231## ##STR232## ##STR233## ##STR234##
##STR235## ##STR236## ##STR237## ##STR238## ##STR239##
[0044] Another embodiment of the invention discloses the following
compounds, which exhibited CDK2 inhibitory activity of about 0.0001
.mu.M to about 0.5 .mu.M: ##STR240## ##STR241## ##STR242##
##STR243## ##STR244## ##STR245## ##STR246## ##STR247## ##STR248##
##STR249## ##STR250## ##STR251## ##STR252## ##STR253##
##STR254##
[0045] Another embodiment of the invention discloses the following
compounds, which exhibited CDK2 inhibitory activity of about 0.0001
.mu.M to about 0.1 .mu.M: ##STR255## ##STR256## ##STR257##
##STR258## ##STR259## ##STR260## ##STR261## ##STR262## ##STR263##
##STR264## ##STR265## ##STR266## ##STR267## ##STR268##
##STR269##
[0046] As used above, and throughout this disclosure, the following
terms, unless otherwise indicated, shall be understood to have the
following meanings:
[0047] "Patient" includes both human and animals.
[0048] "Mammal" means humans and other mammalian animals.
[0049] "Alkyl" means an aliphatic hydrocarbon group which may be
straight or branched and comprising about 1 to about 20 carbon
atoms in the chain. Preferred alkyl groups contain about 1 to about
12 carbon atoms in the chain. More preferred alkyl groups contain
about 1 to about 6 carbon atoms in the chain. Branched means that
one or more lower alkyl groups such as methyl, ethyl or propyl, are
attached to a linear alkyl chain. "Lower alkyl" means a group
having about 1 to about 6 carbon atoms in the chain which may be
straight or branched. The term "substituted alkyl" means that the
alkyl group may be substituted by one or more substituents which
may be the same or different, each substituent being independently
selected from the group consisting of halo, alkyl, aryl,
cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, --NH(alkyl),
--NH(cycloalkyl), --N(alkyl).sub.2, carboxy and --C(O)O-alkyl.
Non-limiting examples of suitable alkyl groups include methyl,
ethyl, n-propyl, isopropyl and t-butyl.
[0050] "Alkynyl" means an aliphatic hydrocarbon group containing at
least one carbon-carbon triple bond and which may be straight or
branched and comprising about 2 to about 15 carbon atoms in the
chain. Preferred alkynyl groups have about 2 to about 12 carbon
atoms in the chain; and more preferably about 2 to about 4 carbon
atoms in the chain. Branched means that one or more lower alkyl
groups such as methyl, ethyl or propyl, are attached to a linear
alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon
atoms in the chain which may be straight or branched. Non-limiting
examples of suitable alkynyl groups include ethynyl, propynyl,
2-butynyl and 3-methylbutynyl. The term "substituted alkynyl" means
that the alkynyl group may be substituted by one or more
substituents which may be the same or different, each substituent
being independently selected from the group consisting of alkyl,
aryl and cycloalkyl.
[0051] "Aryl" means an aromatic monocyclic or multicyclic ring
system comprising about 6 to about 14 carbon atoms, preferably
about 6 to about 10 carbon atoms. The aryl group can be optionally
substituted with one or more "ring system substituents" which may
be the same or different, and are as defined herein. Non-limiting
examples of suitable aryl groups include phenyl and naphthyl.
[0052] "Heteroaryl" means an aromatic monocyclic or multicyclic
ring system comprising about 5 to about 14 ring atoms, preferably
about 5 to about 10 ring atoms, in which one or more of the ring
atoms is an element other than carbon, for example nitrogen, oxygen
or sulfur, alone or in combination. Preferred heteroaryls contain
about 5 to about 6 ring atoms. The "heteroaryl" can be optionally
substituted by one or more "ring system substituents" which may be
the same or different, and are as defined herein. The prefix aza,
oxa or thia before the heteroaryl root name means that at least a
nitrogen, oxygen or sulfur atom respectively, is present as a ring
atom. A nitrogen atom of a heteroaryl can be optionally oxidized to
the corresponding N-oxide. Non-limiting examples of suitable
heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl,
pyrimidinyl, pyridone (including N-substituted pyridones),
isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl,
furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl,
pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl,
imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,
indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,
imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,
pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,
1,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl"
also refers to partially saturated heteroaryl moieties such as, for
example, tetrahydroisoquinolyl, tetrahydroquinolyl and the
like.
[0053] "Aralkyl" or "arylalkyl" means an aryl-alkyl-group in which
the aryl and alkyl are as previously described. Preferred aralkyls
comprise a lower alkyl group. Non-limiting examples of suitable
aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl.
The bond to the parent moiety is through the alkyl.
[0054] "Alkylaryl" means an alkyl-aryl-group in which the alkyl and
aryl are as previously described. Preferred alkylaryls comprise a
lower alkyl group. Non-limiting example of a suitable alkylaryl
group is tolyl. The bond to the parent moiety is through the
aryl.
[0055] "Cycloalkyl" means a non-aromatic mono- or multicyclic ring
system comprising about 3 to about 10 carbon atoms, preferably
about 5 to about 10 carbon atoms. Preferred cycloalkyl rings
contain about 5 to about 7 ring atoms. The cycloalkyl can be
optionally substituted with one or more "ring system substituents"
which may be the same or different, and are as defined above.
Non-limiting examples of suitable monocyclic cycloalkyls include
cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
Non-limiting examples of suitable multicyclic cycloalkyls include
1-decalinyl, norbornyl, adamantyl and the like, as well as
partially saturated species such as, for example, indanyl,
tetrahydronaphthyl and the like.
[0056] "Halogen" means fluorine, chlorine, bromine, or iodine.
Preferred are fluorine, chlorine and bromine.
[0057] "Ring system substituent" means a substituent attached to an
aromatic or non-aromatic ring system which, for example, replaces
an available hydrogen on the ring system. Ring system substituents
may be the same or different, each being independently selected
from the group consisting of alkyl, alkenyl, alkynyl, aryl,
heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl,
heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy,
aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy,
alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio,
heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl,
heterocyclyl, --C(.dbd.N--CN)--NH.sub.2, --C(.dbd.NH)--NH.sub.2,
--C(.dbd.NH)--NH(alkyl), Y.sub.1Y.sub.2N--, Y.sub.1Y.sub.2N-alkyl-,
Y.sub.1Y.sub.2NC(O)--, Y.sub.1Y.sub.2NSO.sub.2-- and
--SO.sub.2NY.sub.1Y.sub.2, wherein Y.sub.1 and Y.sub.2 can be the
same or different and are independently selected from the group
consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring
system substituent" may also mean a single moiety which
simultaneously replaces two available hydrogens on two adjacent
carbon atoms (one H on each carbon) on a ring system. Examples of
such moiety are methylene dioxy, ethylenedioxy,
--C(CH.sub.3).sub.2-- and the like which form moieties such as, for
example: ##STR270##
[0058] "Heterocyclyl" means a non-aromatic saturated monocyclic or
multicyclic ring system comprising about 3 to about 10 ring atoms,
preferably about 5 to about 10 ring atoms, in which one or more of
the atoms in the ring system is an element other than carbon, for
example nitrogen, oxygen or sulfur, alone or in combination. There
are no adjacent oxygen and/or sulfur atoms present in the ring
system. Preferred heterocyclyls contain about 5 to about 6 ring
atoms. The prefix aza, oxa or thia before the heterocyclyl root
name means that at least a nitrogen, oxygen or sulfur atom
respectively is present as a ring atom. Any --NH in a heterocyclyl
ring may exist protected such as, for example, as an --N(Boc),
--N(CBz), --N(Tos) group and the like; such protections are also
considered part of this invention. The heterocyclyl can be
optionally substituted by one or more "ring system substituents"
which may be the same or different, and are as defined herein. The
nitrogen or sulfur atom of the heterocyclyl can be optionally
oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
Non-limiting examples of suitable monocyclic heterocyclyl rings
include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,
tetrahydrothiophenyl, lactam, lactone, and the like.
[0059] It should be noted that in hetero-atom containing ring
systems of this invention, there are no hydroxyl groups on carbon
atoms adjacent to a N, O or S, as well as there are no N or S
groups on carbon adjacent to another heteroatom. Thus, for example,
in the ring: ##STR271## there is no --OH attached directly to
carbons marked 2 and 5.
[0060] It should also be noted that tautomeric forms such as, for
example, the moieties: ##STR272## are considered equivalent in
certain embodiments of this invention.
[0061] "Alkynylalkyl" means an alkynyl-alkyl-group in which the
alkynyl and alkyl are as previously described. Preferred
alkynylalkyls contain a lower alkynyl and a lower alkyl group. The
bond to the parent moiety is through the alkyl. Non-limiting
examples of suitable alkynylalkyl groups include
propargylmethyl.
[0062] "Heteroaralkyl" means a heteroaryl-alkyl-group in which the
heteroaryl and alkyl are as previously described. Preferred
heteroaralkyls contain a lower alkyl group. Non-limiting examples
of suitable aralkyl groups include pyridylmethyl, and
quinolin-3-ylmethyl. The bond to the parent moiety is through the
alkyl.
[0063] "Hydroxyalkyl" means a HO-alkyl-group in which alkyl is as
previously defined. Preferred hydroxyalkyls contain lower alkyl.
Non-limiting examples of suitable hydroxyalkyl groups include
hydroxymethyl and 2-hydroxyethyl.
[0064] "Acyl" means an H--C(O)--, alkyl-C(O)-- or
cycloalkyl-C(O)--, group in which the various groups are as
previously described. The bond to the parent moiety is through the
carbonyl. Preferred acyls contain a lower alkyl. Non-limiting
examples of suitable acyl groups include formyl, acetyl and
propanoyl.
[0065] "Aroyl" means an aryl-C(O)-- group in which the aryl group
is as previously described. The bond to the parent moiety is
through the carbonyl. Non-limiting examples of suitable groups
include benzoyl and 1-naphthoyl.
[0066] "Alkoxy" means an alkyl-O-- group in which the alkyl group
is as previously described. Non-limiting examples of suitable
alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and
n-butoxy. The bond to the parent moiety is through the ether
oxygen.
[0067] "Aryloxy" means an aryl-O-- group in which the aryl group is
as previously described. Non-limiting examples of suitable aryloxy
groups include phenoxy and naphthoxy. The bond to the parent moiety
is through the ether oxygen.
[0068] "Aralkyloxy" means an aralkyl-O-- group in which the aralkyl
group is as previously described. Non-limiting examples of suitable
aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
The bond to the parent moiety is through the ether oxygen.
[0069] "Alkylthio" means an alkyl-S-- group in which the alkyl
group is as previously described. Non-limiting examples of suitable
alkylthio groups include methylthio and ethylthio. The bond to the
parent moiety is through the sulfur.
[0070] "Arylthio" means an aryl-S-- group in which the aryl group
is as previously described. Non-limiting examples of suitable
arylthio groups include phenylthio and naphthylthio. The bond to
the parent moiety is through the sulfur.
[0071] "Aralkylthio" means an aralkyl-S-- group in which the
aralkyl group is as previously described. Non-limiting example of a
suitable aralkylthio group is benzylthio. The bond to the parent
moiety is through the sulfur.
[0072] "Alkoxycarbonyl" means an alkyl-O--CO-- group. Non-limiting
examples of suitable alkoxycarbonyl groups include methoxycarbonyl
and ethoxycarbonyl. The bond to the parent moiety is through the
carbonyl.
[0073] "Aryloxycarbonyl" means an aryl-O--C(O)-- group.
Non-limiting examples of suitable aryloxycarbonyl groups include
phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent
moiety is through the carbonyl.
[0074] "Aralkoxycarbonyl" means an aralkyl-O--C(O)-- group.
Non-limiting example of a suitable aralkoxycarbonyl group is
benzyloxycarbonyl. The bond to the parent moiety is through the
carbonyl.
[0075] "Alkylsulfonyl" means an alkyl-S(O.sub.2)-- group. Preferred
groups are those in which the alkyl group is lower alkyl. The bond
to the parent moiety is through the sulfonyl.
[0076] "Arylsulfonyl" means an aryl-S(O.sub.2)-- group. The bond to
the parent moiety is through the sulfonyl.
[0077] The term "substituted" means that one or more hydrogens on
the designated atom is replaced with a selection from the indicated
group, provided that the designated atom's normal valency under the
existing circumstances is not exceeded, and that the substitution
results in a stable compound. Combinations of substituents and/or
variables are permissible only if such combinations result in
stable compounds. By "stable compound" or "stable structure" is
meant a compound that is sufficiently robust to survive isolation
to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent.
[0078] The term "optionally substituted" means optional
substitution with the specified groups, radicals or moieties.
[0079] The term "isolated" or "in isolated form" for a compound
refers to the physical state of said compound after being isolated
from a synthetic process or natural source or combination thereof.
The term "purified" or "in purified form" for a compound refers to
the physical state of said compound after being obtained from a
purification process or processes described herein or well known to
the skilled artisan, in sufficient purity to be characterizable by
standard analytical techniques described herein or well known to
the skilled artisan.
[0080] It should also be noted that any heteroatom with unsatisfied
valences in the text, schemes, examples and Tables herein is
assumed to have the hydrogen atom(s) to satisfy the valences.
[0081] When a functional group in a compound is termed "protected",
this means that the group is in modified form to preclude undesired
side reactions at the protected site when the compound is subjected
to a reaction. Suitable protecting groups will be recognized by
those with ordinary skill in the art as well as by reference to
standard textbooks such as, for example, T. W. Greene et al,
Protective Groups in organic Synthesis (1991), Wiley, New York.
[0082] When any variable (e.g., aryl, heterocycle, R.sup.2, etc.)
occurs more than one time in any constituent or in Formula III, its
definition on each occurrence is independent of its definition at
every other occurrence.
[0083] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts.
[0084] Prodrugs and solvates of the compounds of the invention are
also contemplated herein. The term "prodrug", as employed herein,
denotes a compound that is a drug precursor which, upon
administration to a subject, undergoes chemical conversion by
metabolic or chemical processes to yield a compound of Formula III
or a salt and/or solvate thereof. A discussion of prodrugs is
provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery
Systems (1987) 14 of the A.C.S. Symposium Series, and in
Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed.,
American Pharmaceutical Association and Pergamon Press, both of
which are incorporated herein by reference thereto.
[0085] "Solvate" means a physical association of a compound of this
invention with one or more solvent molecules. This physical
association involves varying degrees of ionic and covalent bonding,
including hydrogen bonding. In certain instances the solvate will
be capable of isolation, for example when one or more solvent
molecules are incorporated in the crystal lattice of the
crystalline solid. "Solvate" encompasses both solution-phase and
isolatable solvates. Non-limiting examples of suitable solvates
include ethanolates, methanolates, and the like. "Hydrate" is a
solvate wherein the solvent molecule is H.sub.2O.
[0086] "Effective amount" or "therapeutically effective amount" is
meant to describe an amount of compound or a composition of the
present invention effective in inhibiting the CDK(s) and thus
producing the desired therapeutic, ameliorative, inhibitory or
preventative effect.
[0087] The compounds of Formula III can form salts which are also
within the scope of this invention. Reference to a compound of
Formula III herein is understood to include reference to salts
thereof, unless otherwise indicated. The term "salt(s)", as
employed herein, denotes acidic salts formed with inorganic and/or
organic acids, as well as basic salts formed with inorganic and/or
organic bases. In addition, when a compound of Formula III contains
both a basic moiety, such as, but not limited to a pyridine or
imidazole, and an acidic moiety, such as, but not limited to a
carboxylic acid, zwitterions ("inner salts") may be formed and are
included within the term "salt(s)" as used herein. Pharmaceutically
acceptable (i.e., non-toxic, physiologically acceptable) salts are
preferred, although other salts are also useful. Salts of the
compounds of the Formula III may be formed, for example, by
reacting a compound of Formula III with an amount of acid or base,
such as an equivalent amount, in a medium such as one in which the
salt precipitates or in an aqueous medium followed by
lyophilization.
[0088] Exemplary acid addition salts include acetates, ascorbates,
benzoates, benzenesulfonates, bisulfates, borates, butyrates,
citrates, camphorates, camphorsulfonates, fumarates,
hydrochlorides, hydrobromides, hydroiodides, lactates, maleates,
methanesulfonates, naphthalenesulfonates, nitrates, oxalates,
phosphates, propionates, salicylates, succinates, sulfates,
tartarates, thiocyanates, toluenesulfonates (also known as
tosylates) and the like. Additionally, acids which are generally
considered suitable for the formation of pharmaceutically useful
salts from basic pharmaceutical compounds are discussed, for
example, by S. Berge et al, Journal of Pharmaceutical Sciences
(1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics
(1986) 33 201-217; Anderson et al, The Practice of Medicinal
Chemistry (1996), Academic Press, New York; and in The Orange Book
(Food & Drug Administration, Washington, D.C. on their
website). These disclosures are incorporated herein by reference
thereto.
[0089] Exemplary basic salts include ammonium salts, alkali metal
salts such as sodium, lithium, and potassium salts, alkaline earth
metal salts such as calcium and magnesium salts, salts with organic
bases (for example, organic amines) such as dicyclohexylamines,
t-butyl amines, and salts with amino acids such as arginine, lysine
and the like. Basic nitrogen-containing groups may be quarternized
with agents such as lower alkyl halides (e.g. methyl, ethyl, and
butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g.
decyl, lauryl, and stearyl chlorides, bromides and iodides),
aralkyl halides (e.g. benzyl and phenethyl bromides), and
others.
[0090] All such acid salts and base salts are intended to be
pharmaceutically acceptable salts within the scope of the invention
and all acid and base salts are considered equivalent to the free
forms of the corresponding compounds for purposes of the
invention.
[0091] Compounds of Formula II, and salts, solvates and prodrugs
thereof, may exist in their tautomeric form (for example, as an
amide or imino ether). All such tautomeric forms are contemplated
herein as part of the present invention.
[0092] All stereoisomers (for example, geometric isomers, optical
isomers and the like) of the present compounds (including those of
the salts, solvates and prodrugs of the compounds as well as the
salts and solvates of the prodrugs), such as those which may exist
due to asymmetric carbons on various substituents, including
enantiomeric forms (which may exist even in the absence of
asymmetric carbons), rotameric forms, atropisomers, and
diastereomeric forms, are contemplated within the scope of this
invention, as are positional isomers (such as, for example,
4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds
of the invention may, for example, be substantially free of other
isomers, or may be admixed, for example, as racemates or with all
other, or other selected, stereoisomers. The chiral centers of the
present invention can have the S or R configuration as defined by
the IUPAC 1974 Recommendations. The use of the terms "salt",
"solvate" "prodrug" and the like, is intended to equally apply to
the salt, solvate and prodrug of enantiomers, stereoisomers,
rotamers, tautomers, positional isomers, racemates or prodrugs of
the inventive compounds.
[0093] The compounds according to the invention have
pharmacological properties; in particular, the compounds of Formula
III can be inhibitors of protein kinases such as, for example, the
inhibitors of the cyclin-dependent kinases, mitogen-activated
protein kinase (MAPK/ERK), glycogen synthase kinase 3(GSK3beta) and
the like. The cyclin dependent kinases (CDKs) include, for example,
CDC2 (CDK1), CDK2, CDK4, CDK5, CDK6, CDK7 and CDK8. The novel
compounds of Formula III are expected to be useful in the therapy
of proliferative diseases such as cancer, autoimmune diseases,
viral diseases, fungal diseases, neurological/neurodegenerative
disorders, arthritis, inflammation, anti-proliferative (e.g.,
ocular retinopathy), neuronal, alopecia and cardiovascular disease.
Many of these diseases and disorders are listed in U.S. Pat. No.
6,413,974 cited earlier, the disclosure of which is incorporated
herein.
[0094] More specifically, the compounds of Formula III can be
useful in the treatment of a variety of cancers, including (but not
limited to) the following: carcinoma, including that of the
bladder, breast, colon, kidney, liver, lung, including small cell
lung cancer, esophagus, gall bladder, ovary, pancreas, stomach,
cervix, thyroid, prostate, and skin, including squamous cell
carcinoma;
[0095] hematopoietic tumors of lymphoid lineage, including
leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia,
B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins
lymphoma, hairy cell lymphoma and Burkett's lymphoma;
[0096] hematopoietic tumors of myeloid lineage, including acute and
chronic myelogenous leukemias, myelodysplastic syndrome and
promyelocytic leukemia;
[0097] tumors of mesenchymal origin, including fibrosarcoma and
rhabdomyosarcoma;
[0098] tumors of the central and peripheral nervous system,
including astrocytoma, neuroblastoma, glioma and schwannomas;
and
[0099] other tumors, including melanoma, seminoma, teratocarcinoma,
osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid
follicular cancer and Kaposi's sarcoma.
[0100] Due to the key role of CDKs in the regulation of cellular
proliferation in general, inhibitors could act as reversible
cytostatic agents which may be useful in the treatment of any
disease process which features abnormal cellular proliferation,
e.g., benign prostate hyperplasia, familial adenomatosis polyposis,
neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis,
psoriasis, glomerulonephritis, restenosis following angioplasty or
vascular surgery, hypertrophic scar formation, inflammatory bowel
disease, transplantation rejection, endotoxic shock, and fungal
infections.
[0101] Compounds of Formula III may also be useful in the treatment
of Alzheimer's disease, as suggested by the recent finding that
CDK5 is involved in the phosphorylation of tau protein (J. Biochem,
(1995) 117, 741-749).
[0102] Compounds of Formula III may induce or inhibit apoptosis.
The apoptotic response is aberrant in a variety of human diseases.
Compounds of Formula III, as modulators of apoptosis, will be
useful in the treatment of cancer (including but not limited to
those types mentioned hereinabove), viral infections (including but
not limited to herpevirus, poxvirus, Epstein-Barr virus, Sindbis
virus and adenovirus), prevention of AIDS development in
HIV-infected individuals, autoimmune diseases (including but not
limited to systemic lupus, erythematosus, autoimmune mediated
glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory
bowel disease, and autoimmune diabetes mellitus), neurodegenerative
disorders (including but not limited to Alzheimer's disease,
AIDS-related dementia, Parkinson's disease, amyotrophic lateral
sclerosis, retinitis pigmentosa, spinal muscular atrophy and
cerebellar degeneration), myelodysplastic syndromes, aplastic
anemia, ischemic injury associated with myocardial infarctions,
stroke and reperfusion injury, arrhythmia, atherosclerosis,
toxin-induced or alcohol related liver diseases, hematological
diseases (including but not limited to chronic anemia and aplastic
anemia), degenerative diseases of the musculoskeletal system
(including but not limited to osteoporosis and arthritis)
aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple
sclerosis, kidney diseases and cancer pain.
[0103] Compounds of Formula III, as inhibitors of the CDKs, can
modulate the level of cellular RNA and DNA synthesis. These agents
would therefore be useful in the treatment of viral infections
(including but not limited to HIV, human papilloma virus,
herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and
adenovirus).
[0104] Compounds of Formula III may also be useful in the
chemoprevention of cancer. Chemoprevention is defined as inhibiting
the development of invasive cancer by either blocking the
initiating mutagenic event or by blocking the progression of
pre-malignant cells that have already suffered an insult or
inhibiting tumor relapse.
[0105] Compounds of Formula III may also be useful in inhibiting
tumor angiogenesis and metastasis.
[0106] Compounds of Formula III may also act as inhibitors of other
protein kinases, e.g., protein kinase C, her2, raf 1, MEK1, MAP
kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, wee1
kinase, Src, Abl and thus be effective in the treatment of diseases
associated with other protein kinases.
[0107] Another aspect of this invention is a method of treating a
mammal (e.g., human) having a disease or condition associated with
the CDKs by administering a therapeutically effective amount of at
least one compound of Formula III, or a pharmaceutically acceptable
salt or solvate of said compound to the mammal.
[0108] A preferred dosage is about 0.001 to 500 mg/kg of body
weight/day of the compound of Formula III. An especially preferred
dosage is about 0.01 to 25 mg/kg of body weight/day of a compound
of Formula II, or a pharmaceutically acceptable salt or solvate of
said compound.
[0109] The compounds of this invention may also be useful in
combination (administered together or sequentially) with one or
more of anti-cancer treatments such as radiation therapy, and/or
one or more anti-cancer agents selected from the group consisting
of cytostatic agents, cytotoxic agents (such as for example, but
not limited to, DNA interactive agents (such as cisplatin or
doxorubicin)); taxanes (e.g. taxotere, taxol); topoisomerase II
inhibitors (such as etoposide); topoisomerase I inhibitors (such as
irinotecan (or CPT-11), camptostar, or topotecan); tubulin
interacting agents (such as paclitaxel, docetaxel or the
epothilones); hormonal agents (such as tamoxifen); thymidilate
synthase inhibitors (such as 5-fluorouracil); anti-metabolites
(such as methoxtrexate); alkylating agents (such as temozolomide
(TEMODAR.TM. from Schering-Plough Corporation, Kenilworth, N.J.),
cyclophosphamide); Farnesyl protein transferase inhibitors (such
as, SARASAR.TM.
(4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohept-
a[1,2-b]pyridin-11-yl-]-1-piperidinyl]-2-oxoehtyl]-1-piperidinecarboxamide-
, or SCH 66336 from Schering-Plough Corporation, Kenilworth, N.J.),
tipifarnib (Zarnestra.RTM. or R115777 from Janssen
Pharmaceuticals), L778, 123 (a farnesyl protein transferase
inhibitor from Merck & Company, Whitehouse Station, N.J.), BMS
214662 (a farnesyl protein transferase inhibitor from Bristol-Myers
Squibb Pharmaceuticals, Princeton, N.J.); signal transduction
inhibitors (such as, Iressa (from Astra Zeneca Pharmaceuticals,
England), Tarceva (EGFR kinase inhibitors), antibodies to EGFR
(e.g., C225), GLEEVEC.TM. (C-abl kinase inhibitor from Novartis
Pharmaceuticals, East Hanover, N.J.); interferons such as, for
example, intron (from Schering-Plough Corporation), Peg-Intron
(from Schering-Plough Corporation); hormonal therapy combinations;
aromatase combinations; ara-C, adriamycin, cytoxan, and
gemcitabine.
[0110] Other anti-cancer (also known as anti-neoplastic) agents
include but are not limited to Uracil mustard, Chlormethine,
Ifosfamide, Melphalan, Chlorambucil, Pipobroman,
Triethylenemelamine, Triethylenethiophosphoramine, Busulfan,
Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine,
Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate,
oxaliplatin, leucovirin, oxaliplatin (ELOXATIN.TM. from
Sanofi-Synthelabo Pharmaeuticals, France), Pentostatine,
Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin,
Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin,
Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide
17.alpha.-Ethinylestradiol, Diethylstilbestrol, Testosterone,
Prednisone, Fluoxymesterone, Dromostanolone propionate,
Testolactone, Megestrolacetate, Methylprednisolone,
Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene,
Hydroxyprogesterone, Aminoglutethimide, Estramustine,
Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene,
goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,
Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,
Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, or
Hexamethylmelamine.
[0111] If formulated as a fixed dose, such combination products
employ the compounds of this invention within the dosage range
described herein and the other pharmaceutically active agent or
treatment within its dosage range. For example, the CDC2 inhibitor
olomucine has been found to act synergistically with known
cytotoxic agents in inducing apoptosis (J. Cell Sci., (1995) 108,
2897. Compounds of Formula III may also be administered
sequentially with known anticancer or cytotoxic agents when a
combination formulation is inappropriate. The invention is not
limited in the sequence of administration; compounds of Formula III
may be administered either prior to or after administration of the
known anticancer or cytotoxic agent. For example, the cytotoxic
activity of the cyclin-dependent kinase inhibitor flavopiridol is
affected by the sequence of administration with anticancer agents.
Cancer Research, (1997) 57, 3375. Such techniques are within the
skills of persons skilled in the art as well as attending
physicians.
[0112] Accordingly, in an aspect, this invention includes
combinations comprising an amount of at least one compound of
Formula III, or a pharmaceutically acceptable salt or solvate
thereof, and an amount of one or more anti-cancer treatments and
anti-cancer agents listed above wherein the amounts of the
compounds/treatments result in desired therapeutic effect.
[0113] The pharmacological properties of the compounds of this
invention may be confirmed by a number of pharmacological assays.
The exemplified pharmacological assays which are described later
have been carried out with the compounds according to the invention
and their salts.
[0114] This invention is also directed to pharmaceutical
compositions which comprise at least one compound of Formula III,
or a pharmaceutically acceptable salt or solvate of said compound
and at least one pharmaceutically acceptable carrier.
[0115] For preparing pharmaceutical compositions from the compounds
described by this invention, inert, pharmaceutically acceptable
carriers can be either solid or liquid. Solid form preparations
include powders, tablets, dispersible granules, capsules, cachets
and suppositories. The powders and tablets may be comprised of from
about 5 to about 95 percent active ingredient. Suitable solid
carriers are known in the art, e.g., magnesium carbonate, magnesium
stearate, talc, sugar or lactose. Tablets, powders, cachets and
capsules can be used as solid dosage forms suitable for oral
administration. Examples of pharmaceutically acceptable carriers
and methods of manufacture for various compositions may be found in
A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18.sup.th
Edition, (1990), Mack Publishing Co., Easton, Pa.
[0116] Liquid form preparations include solutions, suspensions and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injection or addition of sweeteners
and opacifiers for oral solutions, suspensions and emulsions.
Liquid form preparations may also include solutions for intranasal
administration.
[0117] Aerosol preparations suitable for inhalation may include
solutions and solids in powder form, which may be in combination
with a pharmaceutically acceptable carrier, such as an inert
compressed gas, e.g. nitrogen.
[0118] Also included are solid form preparations that are intended
to be converted, shortly before use, to liquid form preparations
for either oral or parenteral administration. Such liquid forms
include solutions, suspensions and emulsions.
[0119] The compounds of the invention may also be deliverable
transdermally. The transdermal compositions can take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as are
conventional in the art for this purpose.
[0120] The compounds of this invention may also be delivered
subcutaneously.
[0121] Preferably the compound is administered orally.
[0122] Preferably, the pharmaceutical preparation is in a unit
dosage form. In such form, the preparation is subdivided into
suitably sized unit doses containing appropriate quantities of the
active component, e.g., an effective amount to achieve the desired
purpose.
[0123] The quantity of active compound in a unit dose of
preparation may be varied or adjusted from about 1 mg to about 100
mg, preferably from about 1 mg to about 50 mg, more preferably from
about 1 mg to about 25 mg, according to the particular
application.
[0124] The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage regimen for a
particular situation is within the skill of the art. For
convenience, the total daily dosage may be divided and administered
in portions during the day as required.
[0125] The amount and frequency of administration of the compounds
of the invention and/or the pharmaceutically acceptable salts
thereof will be regulated according to the judgment of the
attending clinician considering such factors as age, condition and
size of the patient as well as severity of the symptoms being
treated. A typical recommended daily dosage regimen for oral
administration can range from about 1 mg/day to about 500 mg/day,
preferably 1 mg/day to 200 mg/day, in two to four divided
doses.
[0126] Another aspect of this invention is a kit comprising a
therapeutically effective amount of at least one compound of
Formula II, or a pharmaceutically acceptable salt or solvate of
said compound and a pharmaceutically acceptable carrier, vehicle or
diluent.
[0127] Yet another aspect of this invention is a kit comprising an
amount of at least one compound of Formula III, or a
pharmaceutically acceptable salt or solvate of said compound and an
amount of at least one anticancer therapy and/or anti-cancer agent
listed above, wherein the amounts of the two or more ingredients
result in desired therapeutic effect.
[0128] The invention disclosed herein is exemplified by the
following preparations and examples which should not be construed
to limit the scope of the disclosure. Alternative mechanistic
pathways and analogous structures will be apparent to those skilled
in the art.
[0129] Where NMR data are presented, .sup.1H spectra were obtained
on either a Varian VXR-200 (200 MHz, .sup.1H), Varian Gemini-300
(300 MHz) or XL-400 (400 MHz) and are reported as ppm down field
from Me.sub.4Si with number of protons, multiplicities, and
coupling constants in Hertz indicated parenthetically. Where LC/MS
data are presented, analyses was performed using an Applied
Biosystems API-100 mass spectrometer and Shimadzu SCL-10A LC
column: Altech platinum C18, 3 micron, 33 mm.times.7 mm ID;
gradient flow: 0 min--10% CH.sub.3CN, 5 min--95% CH.sub.3CN, 7
min--95% CH.sub.3CN, 7.5 min--10% CH.sub.3CN, 9 min--stop. The
retention time and observed parent ion are given.
[0130] The following solvents and reagents may be referred to by
their abbreviations in parenthesis:
Thin layer chromatography: TLC
dichloromethane: CH.sub.2Cl.sub.2
ethyl acetate: AcOEt or EtOAc
methanol: MeOH
trifluoroacetate: TFA
triethylamine: Et.sub.3N or TEA
butoxycarbonyl: n-Boc or Boc
nuclear magnetic resonance spectroscopy: NMR
liquid chromatography mass spectrometry: LCMS
high resolution mass spectrometry: HRMS
milliliters: mL
millimoles: mmol
microliters: .mu.l
grams: g
milligrams: mg
room temperature or rt (ambient): about 25.degree. C.
dimethoxyethane: DME
EXAMPLES
[0131] In general, the compounds described in this invention can be
prepared through the general routes described below in Scheme 1.
Treatment of the ##STR273## starting nitrile with potassium
t-butoxide and ethyl formate gives rise to the intermediate enol 2
which upon treatment with hydrazine gives the desired substituted
3-aminopyrazole. Condensation of compounds of type 3 with the
appropriately functionalized keto ester of type 5 gives rise to the
pyridones 6 as shown in Scheme 3. The keto esters used in this
general route are either commercially available or can be made as
illustrated in Scheme 2. ##STR274##
[0132] The chlorides of type 9 can be prepared by treatment of the
pyridones 8 with POCl.sub.3. When R.sup.2 is equal to H,
substitution in this position is possible on the compounds of type
9 by electrophilic halogenation, acylation, and various other
electrophilic aromatic substitutions.
[0133] Introduction of the N7-amino functionality can be
accomplished through displacement of the chloride of compounds of
type 9 by reaction with the appropriate amine as shown in Scheme 3.
##STR275##
[0134] Condensation of compounds of type 7 with the appropriately
functionalized malonate ester of type 11 gives rise to the
pyridones 13 as shown in Scheme 4.
[0135] The chlorides of type 14 can be prepared by treatment of the
pyridones 13 with POCl.sub.3. When R.sup.2 is H, substitution in
this position is possible on compounds of type 9 by electrophilic
halogenation, acylation, and various other electrophilic aromatic
substitutions.
[0136] Incorporation of the N7-amino functionality can be
accomplished through regioselective displacement of the chloride of
compounds of type 14. Incorporation of the N5-amino functionality
by addition of an appropriate amine at higher temperature.
##STR276##
[0137] Alternatively, condensations of the aminopyrazoles of type 7
with an appropriately functionalize keto ester as prepared in
Scheme 5, leads to compounds of type 13 as shown in Scheme 4.
##STR277##
[0138] The chlorides of type 14 can be prepared by treatment of the
pyridones 13 with POCl.sub.3. When R.sup.2 is equal to H,
substitution in this position is possible on compounds of type 14
by electrophilic halogenation, acylation, and various other
electrophilic aromatic substitutions.
[0139] Incorporation of the N7-amino functionality can be
accomplished through displacement of the chloride of compounds of
type 15.
Preparative Examples
Preparative Example 1
[0140] ##STR278## Step A: ##STR279##
[0141] A procedure in German patent DE 19834047 A1, p 19 was
followed. To a solution of KOtBu (6.17 g, 0.055 mol) in anhydrous
THF (40 mL) was added, dropwise, a solution of
cyclopropylacetonitrile (2.0 g, 0.025 mol) and ethyl formate (4.07
g, 0.055 mol) in anhydrous THF (4 mL). A precipitate formed
immediately. This mixture was stirred for 12 hr. It was
concentrated under vacuum and the residue stirred with Et.sub.2O
(50 mL). The resulting residue was decanted and washed with
Et.sub.2O (2.times.50 mL) and Et.sub.2O removed from the residue
under vacuum. The residue was dissolved in cold H.sub.2O (20 mL)
and pH adjusted to 4-5 with 12 N HCl. The mixture was extracted
with CH.sub.2Cl.sub.2 (2.times.50 mL). The organic layers were
combined, dried over MgSO.sub.4 and concentrated under vacuum to
give the aldehyde as a tan liquid. Step B: ##STR280##
[0142] The product from Preparative Example 1, Step A (2.12 g,
0.0195 mol), NH.sub.2NH.sub.2.H.sub.2O (1.95 g, 0.039 mol) and 1.8
g (0.029 mole) of glacial CH.sub.3CO.sub.2H (1.8 g, 0.029 mol) were
dissolved in EtOH (10 mL). It was refluxed for 6 hr and
concentrated under vacuum. The residue was slurried in
CH.sub.2Cl.sub.2 (150 mL) and the pH adjusted to 9 with 1N NaOH.
The organic layer was washed with brine, dried over MgSO.sub.4 and
concentrated under vacuum to give the product as a waxy orange
solid.
Preparative Examples 2-4
[0143] By essentially the same procedure set forth in Preparative
Example 1, only substituting the nitrile shown in Column 2 of Table
2, the compounds in Column 3 of Table 2 were prepared:
TABLE-US-00002 TABLE 2 Prep. Ex. Column 2 Column 3 2 ##STR281##
##STR282## 3 ##STR283## ##STR284## 3.10 ##STR285## ##STR286##
Preparative Example 4
[0144] ##STR287##
[0145] 2-Carbomethoxycyclopentanone (6.6 ml, 0.05 mol) in THF (15
ml) was added dropwise to a vigorously stirred suspension of NaH
(60% in mineral oil, 4 g, 0.1 mol) in THF (100 ml) at 0-10.degree.
C. When bubbling ceased, the reaction mixture was treated at the
same temperature with CICOOMe (7.8 ml, 0.1 mol) in THF (15 ml). The
resulted off-white suspension was stirred for 30 minutes at room
temperature and 30 minutes under reflux. The reaction was monitored
by TLC for disappearance of starting material. The reaction mixture
was quenched with water carefully and partitioned between ethyl
acetate and saturated solution of ammonium chloride in a funnel.
Shaken and separated, the organic layer was washed with brine and
dried over anhydrous sodium sulfate. Solvents were removed, and the
residue was purified by flash chromatography, eluted with 5% and
then 10% ethyl acetate in hexane. 9.4 g colorless oil was obtained
with 94% yield. .sup.1H NMR (CDCl.sub.3) .delta. 3.90(s, 3H),
3.73(s, 3H), 2.65(m, 4H), 1.98(m, 2H).
Preparative Example 5
[0146] ##STR288##
[0147] To lithium diisopropylamide solution in THF (2.0 N, 0.04
mol) at -65.degree. C., was added dropwise
2,2-dicarbomethoxycyclopentanone (4 g, 0.02 mol) in THF (60 ml).
The resulted reaction mixture was stirred at the same temperature
before adding methyl chloroformate (1.54 ml, 0.02 mol). Reaction
mixture stirred for an hour and poured into saturated ammonium
chloride solution with some ice. This solution was extracted three
times with ether, and the combined ethearal layers were dried over
sodium sulfate. Solvents were removed in vacuo, and the residue was
purified by flash chromatography, eluted with 30% increased to 50%
ethyl acetate in hexane. 2.3 g yellowish oil was obtained with 58%
yield. .sup.1H NMR (CDCl.sub.3) .delta. 3.77(s, 6H), 3.32(t, 1H),
3.60-3.10(m, 4H).
Preparative Example 6
[0148] ##STR289##
[0149] The reactions were done as outlined in (K. O. Olsen, J. Org.
Chem., (1987) 52, 4531-4536). Thus, to a stirred solution of
lithium diisopropylamide in THF at -65 to -70 C was added freshly
distilled ethyl acetate, dropwise. The resulting solution was
stirred for 30 min and the acid chloride was added as a solution in
THF. The reaction mixture was stirred at -65 to -70.degree. C. for
30 min and then terminated by the addition of 1 N HCl solution. The
resulting two-phased mixture was allowed to warm to ambient
temperature. The resulting mixture was diluted with EtOAc (100 mL)
the organic layer was collected. The aqueous layer was extracted
with EtOAc (100 mL). The organic layers were combined, washed with
brine, dried (Na.sub.2SO.sub.4), and concentrated in vacuo to give
the crude .beta.-keto esters, which were used in the subsequent
condensations.
Preparative Examples 7-19
[0150] By essentially the same procedure set forth in Preparative
Example 6 only substituting the acid chlorides shown in Column 2 of
Table 3, the .beta.-keto esters shown in Column 3 of Table 3 were
prepared: TABLE-US-00003 TABLE 3 Prep. Ex. Column 2 Column 3 DATA 7
##STR290## ##STR291## LCMS: MH.sup.+ = 223 8 ##STR292## ##STR293##
LCMS: MH.sup.+ = 253 9 ##STR294## ##STR295## LCMS: MH.sup.+ = 261
10 ##STR296## ##STR297## MH.sup.+ = 199 11 ##STR298## ##STR299## 12
##STR300## ##STR301## 13 ##STR302## ##STR303## LCMS: MH.sup.+ = 271
14 ##STR304## ##STR305## Yield = quant MH.sup.+ = 249 15 ##STR306##
##STR307## Yield = quant MH.sup.+ = 237 16 ##STR308## ##STR309##
Yield = quant MH.sup.+ = 262 17 ##STR310## ##STR311## Yield = 48
MH.sup.+ = 195 18 ##STR312## ##STR313## Yield = 99 MH.sup.+ = 199
19 ##STR314## ##STR315## Yield = 77% .sup.1H NMR (CDCl.sub.3)
.delta. 7.42(t, 1H), 6.68(d, 2H), 4.29(q, 2H), 3.97(d, 2H), 3.95(s,
3H), 1.38(t, 3H).
Preparative Example 20
[0151] ##STR316##
[0152] To a solution of the acid in THF was added Et.sub.3N,
followed by isobutyl chloroformate at -20 to -30.degree. C. After
the mixture was stirred for 30 min at -20 to -30.degree. C.,
triethylamine hydrochloride was filtered off under argon, and the
filtrate was added to the LDA-EtOAc reaction mixture (prepared as
outlined in Method A) at -65 to -70.degree. C. After addition of 1
N HCl, followed by routine workup of the reaction mixture and
evaporation of the solvents, the crude .beta.-keto esters were
isolated. The crude material was used in the subsequent
condensations.
Preparative Examples 21-28
[0153] By essentially the same conditions set forth in Preparative
Example 20 only substituting the carboxylic acid shown in Column 2
of Table 4, the compounds shown in Column 3 of Table 4 were
prepared: TABLE-US-00004 TABLE 4 Prep. Ex. Column 2 Column 3 CMPD
21 ##STR317## ##STR318## Yield = 99% MH.sup.+ = 213 22 ##STR319##
##STR320## Yield = 70% MH.sup.+ = 275 23 ##STR321## ##STR322##
Yield = quant MH.sup.+ = 213 24 ##STR323## ##STR324## Yield = quant
MH.sup.+ = 211 25 ##STR325## ##STR326## Yield = 99 MH.sup.+ = 334
26 ##STR327## ##STR328## Yield = 99 MH.sup.+ = 334 27 ##STR329##
##STR330## Yield = 99 MH.sup.+ = 334 28 ##STR331## ##STR332## Yield
= 77% .sup.1H NMR (CDCl.sub.3) .delta.4.21(q, 2H), 3.95(d, 2H),
3.93-3.79(m, 4H), 3.52(s, 2H), 2.65(m, 1H), 1.25(t, 3H),
1.23-1.2(m, 2H).
Preparative Example 29
[0154] ##STR333##
[0155] A solution of 3-aminopyrazole (2.0 g, 24.07 mmol) and ethyl
benzoylacetate (4.58 mL, 1.1 eq.) in AcOH (15 mL) was heated at
reflux for 3 hours. The reaction mixture was cooled to room
temperature and concentrated in vacuo. The resulting solid was
diluted with EtOAc and filtered to give a white solid (2.04 g, 40%
yield).
Preparative Examples 30-73
[0156] By essentially the same procedure set forth in Preparative
Example 29 only substituting the aminopyrazole shown in Column 2 of
Table 5 and the ester shown in Column 3 of Table 5, the compounds
shown in Column 4 of Table 5 were prepared: TABLE-US-00005 TABLE 5
Prep. Ex. Column 2 Column 3 Column 4 Column 5 30 ##STR334##
##STR335## ##STR336## 31 ##STR337## ##STR338## ##STR339## 32
##STR340## ##STR341## ##STR342## 33 ##STR343## ##STR344##
##STR345## 34 ##STR346## ##STR347## ##STR348## 35 ##STR349##
##STR350## ##STR351## 36 ##STR352## ##STR353## ##STR354## 37
##STR355## ##STR356## ##STR357## 37.10 ##STR358## ##STR359##
##STR360## 38 ##STR361## ##STR362## ##STR363## 39 ##STR364##
##STR365## ##STR366## 40 ##STR367## ##STR368## ##STR369## 41
##STR370## ##STR371## ##STR372## 42 ##STR373## ##STR374##
##STR375## 43 ##STR376## ##STR377## ##STR378## 44 ##STR379##
##STR380## ##STR381## 45 ##STR382## ##STR383## ##STR384## 46
##STR385## ##STR386## ##STR387## 47 ##STR388## ##STR389##
##STR390## 48 ##STR391## ##STR392## ##STR393## 49 ##STR394##
##STR395## ##STR396## 50 ##STR397## ##STR398## ##STR399## 51
##STR400## ##STR401## ##STR402## 52 ##STR403## ##STR404##
##STR405## 53 ##STR406## ##STR407## ##STR408## 54 ##STR409##
##STR410## ##STR411## 55 ##STR412## ##STR413## ##STR414## 56
##STR415## ##STR416## ##STR417## 57 ##STR418## ##STR419##
##STR420## 58 ##STR421## ##STR422## ##STR423## Yield = 68 MH.sup.+
= 152 59 ##STR424## ##STR425## ##STR426## Yield = 46 MH.sup.+ = 268
60 ##STR427## ##STR428## ##STR429## Yield = 63 MH.sup.+ = 255 61
##STR430## ##STR431## ##STR432## Yield = 80 MH.sup.+ = 280 62
##STR433## ##STR434## ##STR435## Yield = 72 MH.sup.+ = 214 63
##STR436## ##STR437## ##STR438## Yield = 51 MH.sup.+ = 218 64
##STR439## ##STR440## ##STR441## Yield = 82 MH.sup.+ = 218 65
##STR442## ##STR443## ##STR444## Yield = 39 MH.sup.+ = 232 66
##STR445## ##STR446## ##STR447## Yield = 30 MH.sup.+ = 230 67
##STR448## ##STR449## ##STR450## Yield = 80 MH.sup.+ = 353 68
##STR451## ##STR452## ##STR453## Yield = 49 MH.sup.+ = 353 69
##STR454## ##STR455## ##STR456## Yield = 42 MH.sup.+ = 353 70
##STR457## ##STR458## ##STR459## 71 ##STR460## ##STR461##
##STR462## 72 ##STR463## ##STR464## ##STR465## 73 ##STR466##
##STR467## ##STR468##
Preparative Example 74
[0157] ##STR469##
[0158] Ethyl benzoylacetate (1.76 mL, 1.1 eq.) and
3-amino-4-cyanopyrazole (1.0 g, 9.25 mmol) in AcOH (5.0 mL) and
H.sub.2O (10 mL) was heated at reflux 72 hours. The resulting
solution was cooled to room temperature, concentrated in vacuo, and
diluted with EtOAc. The resulting precipitate was filtered, washed
with EtOAc, and dried in vacuo (0.47 g, 21% yield).
Preparative Example 75
[0159] ##STR470##
[0160] A procedure in U.S. Pat. No. 3,907,799 was followed. Sodium
(2.3 g, 2 eq.) was added to EtOH (150 mL) portionwise. When the
sodium was completely dissolved, 3-aminopyrazole (4.2 g, 0.05 mol)
and diethyl malonate (8.7 g, 1.1 eq.) were added and the resulting
solution heated to reflux for 3 hours. The resulting suspension was
cooled to room temperature and filtered. The filter cake was washed
with EtOH (100 mL) and dissolved in water (250 mL). The resulting
solution was cooled in an ice bath and the pH adjusted to 1-2 with
concentrated HCl. The resulting suspension was filtered, washed
with water (100 mL) and dried under vacuum to give a white solid
(4.75 g, 63% yield).
Preparative Examples 76-78
[0161] By essentially the same procedure set forth in Preparative
Example 75 only substituting the compound shown in Column 2 of
Table 6, the compounds shown in Column 3 of Table 6 are prepared:
TABLE-US-00006 TABLE 6 Prep. Ex. Column 2 Column 3 76 ##STR471##
##STR472## 77 ##STR473## ##STR474## 78 ##STR475## ##STR476##
Preparative Example 79
[0162] ##STR477##
[0163] A solution of the compound prepared in Preparative Example
29 (1.0 g, 4.73 mmol) in POCl.sub.3 (5 mL) and pyridine (0.25 mL)
was stirred at room temperature 3 days. The resulting slurry was
diluted with Et.sub.2O, filtered, and the solid residue washed with
Et.sub.2O. The combined Et.sub.2O washings were cooled to 0.degree.
C. and treated with ice. When the vigorous reaction ceased, the
resulting mixture was diluted with H.sub.2O, separated, and the
aqueous layer extracted with Et.sub.2O. The combined organics were
washed with H.sub.2O and saturated NaCl, dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give a pale yellow
solid (0.86 g, 79% yield). LCMS: MH.sup.+=230.
Preparative Example 80-122
[0164] By essentially the same procedure set forth in Preparative
Example 79, only substituting the compound shown in Column 2 of
Table 7, the compounds shown in Column 3 of Table 7 were prepared:
TABLE-US-00007 TABLE 7 Prep. Ex. Column 2 Column 3 CMPD 80
##STR478## ##STR479## MS: MH.sup.+ = 248 81 ##STR480## ##STR481##
82 ##STR482## ##STR483## MS: MH.sup.+ = 298 83 ##STR484##
##STR485## MS: MH.sup.+ = 196 84 ##STR486## ##STR487## MS: MH.sup.+
= 210 85 ##STR488## ##STR489## 86 ##STR490## ##STR491## MS:
MH.sup.+ = 272 87 ##STR492## ##STR493## 87.10 ##STR494## ##STR495##
88 ##STR496## ##STR497## MS: MH.sup.+ = 255 89 ##STR498##
##STR499## 90 ##STR500## ##STR501## Yield = 65% MS: MH.sup.+ = 260
91 ##STR502## ##STR503## Yield = 35% MS: MH.sup.+ = 290 92
##STR504## ##STR505## Yield = 32% MS: MH.sup.+ = 298 93 ##STR506##
##STR507## Yield = 45% MS: MH.sup.+ = 236 94 ##STR508## ##STR509##
Yield = 100% LCMS: MH.sup.+ = 250 95 ##STR510## ##STR511## Yield =
88% MS: MH.sup.+ = 314 96 ##STR512## ##STR513## Yield = 43% MS:
MH.sup.+ = 223 97 ##STR514## ##STR515## Yield = 30% MS: MH.sup.+ =
295 98 ##STR516## ##STR517## Yield = 98% MS: MH.sup.+ = 244 99
##STR518## ##STR519## 100 ##STR520## ##STR521## 101 ##STR522##
##STR523## 102 ##STR524## ##STR525## 103 ##STR526## ##STR527## 104
##STR528## ##STR529## 105 ##STR530## ##STR531## 106 ##STR532##
##STR533## 107 ##STR534## ##STR535## 45% yield; MS: MH.sup.+ = 226
108 ##STR536## ##STR537## MS: MH.sup.+ = 308 109 ##STR538##
##STR539## Yield = quant MH = 286 110 ##STR540## ##STR541## Yield =
50 MH = 272 111 ##STR542## ##STR543## Yield = 85 MH.sup.+ = 299 112
##STR544## ##STR545## Yield = 97 MH.sup.+ = 231 113 ##STR546##
##STR547## Yield = 45 MH.sup.+ = 236 114 ##STR548## ##STR549##
Yield quant. MH.sup.+ = 236 115 ##STR550## ##STR551## Yield = 57
MH.sup.+ = 250 116 ##STR552## ##STR553## Yield = 89 MH.sup.+ = 248
117 ##STR554## ##STR555## Yield = 96 MH.sup.+ = 371 118 ##STR556##
##STR557## Yield = 99 MH.sup.+ = 371 119 ##STR558## ##STR559##
Yield = 50 MH.sup.+ = 371 120 ##STR560## ##STR561## Yield = 57%
LCMS: MH.sup.+ = 224 121 ##STR562## ##STR563## Yield = 34% LCMS:
MH.sup.+ = 226 122 ##STR564## ##STR565## Yield = 100% .sup.1H NMR
(CDCl.sub.3) .delta. 8.53(d, 1H), 7.66(t, 1H), 7.51(s, 1H), 7.45(d,
1H), 6.84(d, 2H).
Preparative Example 123
[0165] ##STR566##
[0166] POCl.sub.3 (62 mL) was cooled to 5.degree. C. under nitrogen
and dimethylaniline (11.4 g, 2.8 eq.) and the compound prepared in
Preparative Example 75 (4.75 g, 0.032 mol). The reaction mixture
was warmed to 60.degree. C. and stirred overnight. The reaction
mixture was cooled to 30.degree. C. and the POCl.sub.3 was
distilled off under reduced pressure. The residue was dissolved in
CH.sub.2Cl.sub.2 (300 mL) and poured onto ice. After stirring 15
minutes, the pH of the mixture was adjusted to 7-8 with solid
NaHCO.sub.3. The layers were separated and the organic layer was
washed with H.sub.2O (3.times.200 mL), dried over MgSO.sub.4,
filtered, and concentrated. The crude product was purified by flash
chromatography using a 50:50 CH.sub.2Cl.sub.2: hexanes solution as
eluent to elute the dimethyl aniline. The eluent was then changed
to 75:25 CH.sub.2Cl.sub.2:hexanes to elute the desired product
(4.58 g, 77% yield). MS: MH.sup.+=188.
Preparative Examples 124-126
[0167] By essentially the same procedure set forth in Preparative
Example 123 only substituting the compound in Column 2 of Table 8,
the compounds shown in Column 3 of Table 8 are prepared:
TABLE-US-00008 TABLE 8 Prep. Ex. Column 2 Column 3 124 ##STR567##
##STR568## 125 ##STR569## ##STR570## 126 ##STR571## ##STR572##
Preparative Example 127
[0168] ##STR573##
[0169] A solution of the compound prepared in Preparative Example
79 (0.10 g, 0.435 mmol) in CH.sub.3CN (3 mL) was treated with NBS
(0.085 g, 1.1 eq.). The reaction mixture was stirred at room
temperature 1 hour and concentrated under reduced pressure. The
crude product was purified by flash chromatography using a 20%
EtOAc-in-hexanes solution as eluent (0.13 g, 100% yield).
LCMS:MH.sup.+=308.
Preparative Examples 128-164
[0170] By essentially the same procedure set forth in Preparative
Example 127 only substituting the compounds shown in Column 2 of
Table 9, the compounds shown in Column 3 of Table 9 were prepared:
TABLE-US-00009 TABLE 9 Prep. Ex. Column 2 Column 3 CMPD 128
##STR574## ##STR575## MS: MH.sup.+ = 326 129 ##STR576## ##STR577##
MS: MH.sup.+ = 342 130 ##STR578## ##STR579## MS: MH.sup.+ = 376 131
##STR580## ##STR581## MS: MH.sup.+ = 274 132 ##STR582## ##STR583##
MS: MH.sup.+ = 288 133 ##STR584## ##STR585## 134 ##STR586##
##STR587## Yield = 75% MS: MH.sup.+ = 338 135 ##STR588## ##STR589##
Yield = 52% MS: MH.sup.+ = 368 136 ##STR590## ##STR591## Yield =
87% MS: MH.sup.+ = 376 137 ##STR592## ##STR593## Yield = 100% MS:
MH.sup.+ = 316 138 ##STR594## ##STR595## Yield = 92% MS: MH.sup.+ =
330 139 ##STR596## ##STR597## Yield = 82% MS: MH.sup.+ = 395 140
##STR598## ##STR599## Yield = 88% MS: MH.sup.+ = 308 141 ##STR600##
##STR601## Yield = 100% MS: MH.sup.+ = 322 142 ##STR602##
##STR603## MH.sup.+ = 266 143 ##STR604## ##STR605## 144 ##STR606##
##STR607## 145 ##STR608## ##STR609## 146 ##STR610## ##STR611## 147
##STR612## ##STR613## 148 ##STR614## ##STR615## 149 ##STR616##
##STR617## 150 ##STR618## ##STR619## 151 ##STR620## ##STR621##
LCMS: MH.sup.+ = 386 152 ##STR622## ##STR623## Yield = quant
MH.sup.+ = 364 153 ##STR624## ##STR625## Yield = quant MH.sup.+ =
353 154 ##STR626## ##STR627## Yield = 95 MH.sup.+ = 378 155
##STR628## ##STR629## Yield = 77 MH.sup.+ = 311 156 ##STR630##
##STR631## Yield = quant. MH.sup.+ = 314 157 ##STR632## ##STR633##
Yield = 99 MH.sup.+ = 328 158 ##STR634## ##STR635## Yield = 98
MH.sup.+ = 326 159 ##STR636## ##STR637## Yield = 99 MH.sup.+ = 449
160 ##STR638## ##STR639## Yield = 95 MH.sup.+ = 449 161 ##STR640##
##STR641## Yield = 72 MH.sup.+ = 449 162 ##STR642## ##STR643##
Yield = 98% LCMS: MH.sup.+ = 302 163 ##STR644## ##STR645## Yield =
95% LCMS: MH.sup.+ = 305 164 ##STR646## ##STR647## Yield = 50%
.sup.1H NMR (CDCl.sub.3) .delta.8.36(s, 1H), 7.72(d, 1H), 7.20(s,
1H), 6.82(d, 1H), 3.99(s, 3H), 3.90(s, 3H);
Preparative Example 165
[0171] ##STR648##
[0172] A solution of the compound prepared in Preparative Example
80 (0.3 g, 1.2 mmol) in CH.sub.3CN (15 mL) was treated with NCS
(0.18 g, 1.1 eq.) and the resulting solution heated to reflux 4
hours. Additional NCS (0.032 g, 0.2 eq.) added and the resulting
solution was stirred at reflux overnight. The reaction mixture was
cooled to room temperature, concentrated in vacuo and the residue
purified by flash chromatography using a 20% EtOAc in hexanes
solution as eluent (0.28 g, 83% yield). LCMS: MH.sup.+=282.
Preparative Example 166-167
[0173] By essentially the same procedure set forth in Preparative
Example 165 only substituting the compound shown in Column 2 of
Table 10, the compound shown in Column 3 of Table 10 was prepared:
TABLE-US-00010 TABLE 10 Prep. Ex. Column 2 Column 3 CMPD 166
##STR649## ##STR650## Yield = 82% LCMS: MH.sup.+ = 286 167
##STR651## ##STR652##
Preparative Example 167.10
[0174] ##STR653##
[0175] By essentially the same procedure set forth in Preparative
Example 165 only substituting N-iodosuccinimide, the above compound
was prepared.
Preparative Example 168
[0176] ##STR654##
[0177] To a solution of the compound from Preparative Example 79
(1.0 g, 4.35 mmol) in DMF (6 mL) was added POCl.sub.3 (1.24 mL,
3.05 eq.) and the resulting mixture was stirred at room temperature
overnight. The reaction mixture was cooled to 0.degree. C. and the
excess POCl.sub.3 was quenched by the addition of ice. The
resulting solution was neutralized with 1N NaOH, diluted with
H.sub.2O, and extracted with CH.sub.2Cl.sub.2. The combined
organics were dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The crude product was purified by flash
chromatography using a 5% MeOH in CH.sub.2Cl.sub.2 solution as
eluent (0.95 g, 85% yield). LCMS: MH.sup.+=258.
Preparative Example 169
[0178] ##STR655##
[0179] By essentially the same procedure set forth in Preparative
Example 168 only substituting the compound prepared in Preparative
Example 80, the above compound was prepared (0.45 g, 40%
yield).
Preparative Example 170
[0180] ##STR656##
[0181] To a solution of the product of Preparative Example 169
(0.25 g, 0.97 mmol) in THF was added NaBH.sub.4 (0.041 g, 1.1 eq.)
and the resulting solution was stirred at room temperature
overnight. The reaction mixture was quenched by the addition of
H.sub.2O and extracted with CH.sub.2Cl.sub.2. The combined organics
were dried over Na.sub.2SO.sub.4, filtered, and concentrated under
reduced pressure. The crude product was purified by flash
chromatography using a 60:40 hexanes:EtOAc mix as eluent (0.17 g,
69% yield). MS: MH.sup.+=260.
Preparative Example 171
[0182] ##STR657##
[0183] A solution of the compound prepared in Preparative Example
170 (0.12 g, 0.462 mmol), dimethyl sulfate (0.088 mL, 2.0 eq), 50%
NaOH (0.26 mL) and catalytic Bu.sub.4NBr in CH.sub.2Cl.sub.2 (4 mL)
was stirred at room temperature overnight. The reaction mixture was
diluted with H.sub.2O and extracted with CH.sub.2Cl.sub.2. The
combined organics were dried over Na.sub.2SO.sub.4, filtered, and
concentrated under reduced pressure. The crude product was purified
by flash chromatography using a 30% EtOAc-in-hexanes solution as
eluent (0.062 g, 48% yield).
Preparative Example 172
[0184] ##STR658##
[0185] To a solution of PPh.sub.3 (4.07 g, 4.0 eq.) and CBr.sub.4
(2.57 g, 2.0 eq.) in CH.sub.2Cl.sub.2 (75 mL) at 0.degree. C. was
added the compound prepared in Preparative Example 168 (1.0 g, 3.88
mmol). The resulting solution was stirred at 0.degree. C. for 1
hour and concentrated under reduced pressure. The residue was
purified by flash chromatography using a 20% EtOAc in hexanes
solution as eluent (1.07 g, 67% yield).
Preparative Example 173
[0186] ##STR659##
[0187] By essentially the same procedure set forth in Preparative
Example 172 only substituting the compound prepared in Preparative
Example 169 the above compound was prepared (0.5 g, 70% yield).
Preparative Example 174
[0188] ##STR660##
[0189] The compound prepared in Preparative Example 127 (3.08 g,
10.0 mmol), 2.0 M NH.sub.3 in 2-propanol (50 mL, 100.0 mmol), and
37% aqueous NH.sub.3 (10.0 mL) were stirred in a closed pressure
vessel at 50.degree. C. for 1 day. The solvent was evaporated and
the crude product was purified by flash chromatography using 3:1
CH.sub.2Cl.sub.2:EtOAc as eluent. Pale yellow solid (2.30 g, 80%)
was obtained. LCMS: M.sup.+=289.
Preparative Examples 175-180
[0190] By essentially the same procedure set forth in Preparative
Example 174 only substituting the compound shown in Column 2 of
Table 11, the compounds shown in Column 3 of Table 11 were
prepared. TABLE-US-00011 TABLE 11 Prep. Ex. Column 2 Column 3 175
##STR661## ##STR662## 176 ##STR663## ##STR664## 177 ##STR665##
##STR666## 178 ##STR667## ##STR668## 179 ##STR669## ##STR670## 180
##STR671## ##STR672##
Preparative Example 181
[0191] ##STR673##
[0192] The compound prepared in Preparative Example 80 (0.3 g, 1.2
mmol), K.sub.2CO.sub.3 (0.33 g, 2 eq.), and 4-aminomethylpyridine
(0.13 mL, 1.1 eq.) was heated to reflux overnight. The reaction
mixture was cooled to room temperature and concentrated under
reduced pressure. The residue was diluted with H.sub.2O and
extracted with CH.sub.2Cl.sub.2. The combined organics were dried
over Na.sub.2SO.sub.4, filtered and, concentrated. The crude
product was purified by flash chromatography using a 5% (10%
NH.sub.4OH in MeOH) solution in CH.sub.2Cl.sub.2 as eluent (0.051
g, 40% yield). LCMS: MH.sup.+=320.
Preparative Example 182
[0193] ##STR674##
[0194] By essentially the same procedure set forth in Preparative
Example 181 only substituting the compound described in Preparative
Example 92, the above compound was prepared. LCMS:
MH.sup.+=370.
Preparative Example 183
[0195] ##STR675##
[0196] To a solution of the compound prepared in Preparative
Example 123 (0.25 g, 1.3 mmol) in dioxane (5 mL) was added
iPr.sub.2NEt (0.47 mL, 2.0 eq.) and 3-aminomethylpyridine (0.15 ml,
1.1 eq.). The resulting solution was stirred at room temperature 72
hours. The reaction mixture was diluted with H.sub.2O and extracted
with EtOAc. The combined organics were washed with H.sub.2O and
saturated NaCl, dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography using a 5% MeOH in CH.sub.2Cl.sub.2 solution as
eluent (0.29 g, 83% yield). MS: MH.sup.+=260.
Preparative Examples 184-187
[0197] By essentially the same procedure set forth in Preparative
Example 183 only substituting the compound shown in Column 2 of
Table 12, the compounds shown in Column 3 of Table 12 are prepared.
TABLE-US-00012 TABLE 12 Prep. Ex. Column 2 Column 3 184 ##STR676##
##STR677## 184.1 ##STR678## ##STR679## 185 ##STR680## ##STR681##
186 ##STR682## ##STR683## 187 ##STR684## ##STR685## 187.1
##STR686## ##STR687## 187.11 ##STR688## ##STR689##
Preparative Example 188 and Preparative Example 189
[0198] ##STR690##
[0199] To a solution of the compound prepared in Preparative
Example 185 (1.18 g, 3.98 mmol) in THF (35 mL) at -78.degree. C.
was added LAH (4.78 mL, 1M in Et.sub.2O, 1.0 eq.) dropwise. The
reaction mixture was stirred at -78.degree. C. for 3 hours at which
time additional LAH (2.0 mL, 1M in Et.sub.2O, 0.42 eq.) was added
dropwise. The reaction mixture was stirred an additional 1.25 hours
and quenched by the addition of saturated Na.sub.2SO.sub.4 (8.5
mL). The reaction mixture was diluted with EtOAC (23 mL), H.sub.2O
(2 mL), and CH.sub.3OH (50 mL). The resulting slurry was filtered
through a plug of Celite. The Celite was washed with CH.sub.3OH and
the filtrate dried with Na.sub.2SO.sub.4, filtered, and
concentrated. The product was purified by flash chromatography
using a CH.sub.2Cl.sub.2:CH.sub.3OH (93:7) solution as eluent to
yield aldehyde as the first eluting product and alcohol as the
second eluting product.
Preparative Example 188: (Aldehyde)
[0200] 0.4 g, 39% yield. MS: MH.sup.+=254.
Preparative Example 189: (Alcohol)
[0201] 0.25 g, 24% yield. MS: MH.sup.+=256.
Preparative Example 190
[0202] ##STR691##
[0203] To a solution of the compound prepared in Preparative
Example 188 (0.075 g, 0.30 mmol) in THF (2.0 mL) at 0.degree. C.
was added CH.sub.3MgBr (0.3 mL, 3.0M solution in Et.sub.2O, 3.0
eq.) dropwise. The resulting solution was stirred at 0.degree. C.
an additional 1.5 hours, warmed to room temperature, and stirred
overnight. Additional CH.sub.3MgBr (0.15 mL, 3.0M in Et.sub.2O, 1.
eq.) was added and the resulting solution stirred an additional 1.5
hours. The reaction mixture was cooled to 0.degree. C. and quenched
by the addition of saturated NH.sub.4Cl. The resulting solution was
diluted with CH.sub.2Cl.sub.2 and H.sub.2O and extracted with
CH.sub.2Cl.sub.2. The combined organics were washed with saturated
NaCl and dried over Na.sub.2SO.sub.4, filtered, and concentrated.
The crude product was purified by flash chromatography using a
CH.sub.2Cl.sub.2:CH.sub.3OH (90:10) solution as eluent (0.048 g,
60% yield). MS: MH.sup.+=270.
Preparative Example 191
[0204] ##STR692##
[0205] By essentially the same procedure set forth in Preparative
Example 190 only substituting the compound prepared in Preparative
Example 185 and using excess MeMgBr (5 eq.), the above compound was
prepared.
Preparative Example 192
[0206] ##STR693##
[0207] The compound prepared in Preparative Example 181 (0.29 g,
0.91 mmol), BOC.sub.2O (0.22 g, 1.1 eq), and DMAP (0.13 g, 1.1 eq.)
in dioxane (10 mL) was stirred at room temperature 3 days.
Additional BOC.sub.2O (0.10 g, 0.5 eq.) was added and the reaction
mixture was stirred 4 hours. The reaction mixture was concentrated
in vacuo, diluted with saturated NaHCO.sub.3 (15 mL), and extracted
with CH.sub.2Cl.sub.2 (2.times.100 mL). The combined organics were
dried over Na.sub.2SO.sub.4, filtered, and concentrated under
reduce pressure. The crude product was purified by flash
chromatography using a 5% (10% NH.sub.4OH in MeOH) solution in
CH.sub.2Cl.sub.2 as eluent (0.35 g, 91% yield). LCMS:
MH.sup.+=420.
Preparative Example 193
[0208] ##STR694##
[0209] By essentially the same procedure set forth in Preparative
Example 192 only substituting the compound prepared in Preparative
Example 183, the above compound was prepared. MS: MH.sup.+=360.
Preparative Example 193.10
[0210] ##STR695##
[0211] By essentially the same procedure set forth in Preparative
Example 192 only substituting the compound prepared in Preparative
Example 184.1, the above compound was prepared. MS:
MH.sup.+=454.
Preparative Example 194
[0212] ##STR696##
[0213] By essentially the same procedure set forth in Preparative
Example 192 only substituting the above compound prepared in
Preparative Example 187.11, the above compound was prepared (0.223
g, 88% yield). MS: MH.sup.+=528.
Preparative Example 195
[0214] ##STR697##
[0215] By essentially the same procedure set forth in Preparative
Example 127 only substituting the compound prepared in Preparative
Example 192, the above compound was prepared (0.38 g, 95% yield).
LCMS: MH.sup.+=498.
Preparative Example 196
[0216] ##STR698##
[0217] By essentially the same procedure set forth in Preparative
Example 195, only substituting the compound prepared in Preparative
Example 193, the above compound was prepared (0.3 g, 83% yield).
MS: MH.sup.+=438.
Preparative Example 197
[0218] ##STR699##
[0219] A solution of the compound prepared in Preparative Example
195 (0.15 g, 0.3 mmol), phenylboronic acid (0.073 g, 2.0 eq.),
K.sub.3PO.sub.4 (0.19 g, 3.0 eq.), and Pd(PPh.sub.3).sub.4 (0.017
g, 5 mol %) was heated at reflux in DME (16 mL) and H.sub.2O (4 mL)
7 hours. The resulting solution was cooled to room temperature,
diluted with H.sub.2O (10 mL), and extracted with CH.sub.2Cl.sub.2
(3.times.50 mL). The combined organics were dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The crude product was
purified by flash chromatography using a 2.5% (10% NH.sub.4OH in
MeOH) in CH.sub.2Cl.sub.2 solution as eluent (0.16 g, 100%
yield).
Preparative Example 198
[0220] ##STR700##
[0221] To a solution of 4-aminomethylpyridine (1.41 mL, 13.87 mmol)
in CH.sub.2Cl.sub.2 (50 mL) was added BOC.sub.2O (3.3 g, 1.1 eq.)
and TEA and the resulting solution was stirred a room temperature 2
hours. The reaction mixture was diluted with H.sub.2O (50 mL) and
extracted with CH.sub.2Cl.sub.2. The combined organics were dried
over Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure. The crude product was purified by flash chromatography
using a 5% (10% NH.sub.4OH in MeOH) solution in CH.sub.2Cl.sub.2 as
eluent to give a yellow solid (2.62 g, 91% yield). LCMS:
MH.sup.+=209.
Preparative Example 199
[0222] ##STR701##
[0223] By essentially the same procedure set forth in Preparative
Example 198 only substituting 3-aminomethylpyridine, the above
compound was prepared as a yellow oil (2.66 g, 92% yield). LCMS:
MH.sup.+=209.
Preparative Example 200
[0224] ##STR702##
[0225] To a solution of the compound prepared in Preparative
Example 198 (0.20 g, 0.96 mmol) in CH.sub.2Cl.sub.2 (5 mL) at
0.degree. C. was added m-CPBA (0.17 g, 1.0 eq) and the resulting
solution stirred at 0.degree. C. 2 hours and stored at 4.degree. C.
overnight at which time the reaction mixture was warmed to room
temperature and stirred 3 hours. The reaction mixture was diluted
with H.sub.2O and extracted with CH.sub.2Cl.sub.2. The combined
organics were dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The crude product was purified by flash
chromatography using a 10% (10% NH.sub.4OH in MeOH) solution as
eluent: LCMS: MH.sup.+=255.
Preparative Example 201
[0226] ##STR703##
[0227] A solution of oxone (58.6 g) in H.sub.2O (250 mL) was added
dropwise to the compound prepared in Preparative Example 199 (27 g,
0.13 mol) and NaHCO.sub.3 (21.8 g, 2.0 eq.) in MeOH (200 mL) and
H.sub.2O (250 mL). The resulting solution was stirred at room
temperature overnight. The reaction mixture was diluted with
CH.sub.2Cl.sub.2 (500 mL) and filtered. The layers were separated
and the aqueous layer extracted with CH.sub.2Cl.sub.2. The combined
organics were dried over Na.sub.2SO.sub.4, filtered, and
concentrated under reduced pressure to give a white solid (21.0 g,
72% yield). MS: MH.sup.+=255.
Preparative Example 202
[0228] ##STR704##
[0229] The compound prepared in Preparative Example 200 (0.29 g,
1.29 mmol) was stirred at room temperature in 4M HCl in dioxane
(0.97 mL) 2 hours. The reaction mixture was concentrated in vacuo
and used without further purification. LCMS: MH.sup.+=125.
Preparative Example 203
[0230] ##STR705##
[0231] By essentially the same procedure set forth in Preparative
Example 202 only substituting the compound prepared in Preparative
Example 201, the compound shown above was prepared. LCMS:
MH.sup.+=125.
Preparative Example 204
[0232] ##STR706##
[0233] To 4-N-t-Butoxycarbonylaminopiperidine (0.8 g, 4.0 mmol) in
CH.sub.2Cl.sub.2 (10 mL) at 0.degree. C. was added TEA (1.40 mL,
2.5 eq.) and 3-trifluoromethyl benzoyl chloride (1.05 g, 1.25 eq.).
The resulting solution was stirred 15 minutes and warmed to room
temperature and stirred 3 hours. The reaction mixture was diluted
with CH.sub.2Cl.sub.2 and washed with 5% Na.sub.2CO.sub.3
(2.times.100 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated to yield a pale yellow
solid (quantitative crude yield).
Preparative Example 205
[0234] ##STR707##
[0235] To a solution of the compound prepared in Preparative
Example 204 (1.0 g, 2.76 mmol) in CH.sub.2Cl.sub.2 (15 mL) at
0.degree. C. was added TFA (8 mL) and the resulting solution was
stirred at 0.degree. C. for 30 minutes and room temperature 1 hour.
The reaction mixture was poured onto Na.sub.2CO.sub.3 (40 g) and
H.sub.2O (400 mL) added and the resulting mixture was extracted
with CH.sub.2Cl.sub.2. The combined organics were dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatography
using a 20% (7N NH.sub.3 in MeOH) solution in CH.sub.2Cl.sub.2 as
eluent (0.6 g, 82% yield).
Preparative Examples 206
[0236] ##STR708## Step A:
[0237] To a solution of 6-chloronicotinamide (1 g, 6.39 mmol) in
isoamyl alcohol (15 mL) at rt was added Na.sub.2CO.sub.3 (0.81 g,
7.67 mmol) followed by methoxyethylamine (0.67 mL, 7.67 mmol). The
mixture was heat at 130.degree. C. for 16 h, cooled to rt, and was
filtered thru a medium glass-fritted filter. The resulting filtrate
was concentrated under reduced pressure and the resultant solid was
triturated with Et.sub.2O (2.times.10 mL). The crude solid was
placed under high vacuum to afford 1.2 g (96%) of a light yellow
solid. M+H=196.
Step B:
[0238] To a solution of amide (1.2 g, 6.12 mmol) from Preparative
Example 206, Step A in THF (5 mL) at 0.degree. C. was added a
solution of BH.sub.3-THF (43 mL; 43 mmol) dropwise over 10 min. The
resultant solution was warmed to rt and stirred for 14 h. The
mixture was cooled to 0.degree. C. and was sequentially treated
with 6M HCl (35 mL), water (30 mL), and MeOH (150 mL). The mixture
was stirred for 8 h and was concentrated under reduced pressure.
The crude residue was triturated with MeOH, concentrated under
reduced pressure, and placed under high vacuum to afford 1.6 g
(82%) of a white solid as the dihydrochloride salt. M+H (free
base)=182.0. This material was used crude in the coupling with 7-Cl
adducts.
Preparative Examples 207-211
[0239] By essentially the same known procedure set forth in
Preparative Example 206 only by utilizing the amines shown in
Column 2 of Table 13 and the amines shown in Column 3 of Table 13
were prepared: TABLE-US-00013 TABLE 13 Column 2 Column 3 CMPD
Prep.Ex. (Amine) (Amine) M + H (free base) 207 ##STR709##
##STR710## M + H = 138 208 ##STR711## ##STR712## M + H = 152 209
##STR713## ##STR714## M + H = 178 210 ##STR715## ##STR716## M + H =
195 211 ##STR717## ##STR718## M + H = 207
Preparative Example 212
[0240] ##STR719##
[0241] The above compound was prepared accordingly to the methods
described in WO 91/18904.
Preparative Example 213
[0242] ##STR720##
[0243] The above compound was prepared accordingly to the methods
described in U.S. Pat. No. 6,180,627 B1.
Preparative Example 214
[0244] ##STR721##
[0245] The known amine was prepared as described in J. Med. Chem.
(2001), 44, 4505-4508.
Preparative Example 215
[0246] ##STR722##
[0247] The known amine was prepared as described in J. Med. Chem.
(1997), 40, 3726-3733.
Preparative Example 216
[0248] ##STR723## Step A:
[0249] A solution of aldehyde (50 g, 0.41 mol) [WO 0232893] in MeOH
(300 mL) was cooled to 0.degree. C. and carefully treated with
NaBH.sub.4 (20 g, 0.53 mol in 6 batches) over 20 minutes. The
reaction was then allowed to warm to 20.degree. C. and was stirred
for 4 hours. The mixture was again cooled to 0.degree. C.,
carefully quenched with saturated aqueous NH.sub.4Cl, and
concentrated. Flash chromatography (5-10% 7N
NH.sub.3-MeOH/CH.sub.2Cl.sub.2) provided the primary alcohol (31 g,
62%) as a light yellow solid.
Step B:
[0250] A slurry of alcohol (31 g, 0.25 mol) from Preparative
Example 216, Step A in CH.sub.2Cl.sub.2 (500 mL) was cooled to
0.degree. C. and slowly treated with SOCl.sub.2 (55 mL, 0.74 mol
over 30 minutes). The reaction was then stirred overnight at
20.degree. C. The material was concentrated, slurried in acetone,
and then filtered. The resulting beige solid was dried overnight in
vacuo (38.4 g, 52%, HCl salt).
Step C
[0251] To a 15 mL pressure tube charged with a stir bar was added
chloride (150 mg, 0.83 mmol) from Preparative Example 216, Step B
followed by 7 M NH.sub.3/MeOH (10 mL). The resulting solution was
stirred for 48 h at rt where upon the mixture was concentrated
under reduced pressure to afford a light yellow solid (0.146 g,
83%). M+H (free base)=140.
Preparative Example 217
[0252] ##STR724##
[0253] The above compound was prepared accordingly to methods
described in WO 00/26210.
Preparative Example 218
[0254] ##STR725##
[0255] The above compound was prepared accordingly to methods
described in WO 99/10325.
Preparative Example 219
[0256] ##STR726##
[0257] The known amine dihydrochloride was prepared according to
methods described in WO 02/64211.
Preparative Example 220
[0258] ##STR727##
[0259] The above compound was prepared according to methods
described in WO 02/64211.
Preparative Example 221
[0260] ##STR728##
[0261] The known primary alcohol was prepared according to WO
00/37473 and was converted to the desired amine dihydrochloride in
analogous fashion as Preparative Example 220 according to WO
02/064211.
Preparative Example 222
[0262] ##STR729## Step A:
[0263] To a solution of aldehyde (WO 02/32893) (0.46 g, 2.07 mmol)
in MeOH/THF (2 mL/2 mL) at 0.degree. C. was added NaBH.sub.4 (94
mg, 2.48 mmol) in one portion. The resulting mixture was stirred
for 12 h at rt and was diluted with sat. aq. NH.sub.4Cl (3 mL). The
mixture was concentrated under reduced pressure and the resultant
aqueous layer was extracted with CH.sub.2Cl.sub.2 (3.times.5 mL).
The organic layers were combined, washed with brine (1.times.5 mL),
dried (Na.sub.2SO.sub.4), and filtered. The organic layer was
concentrated under reduced pressure to afford 417 mg (90% yield) of
a white solid. M+H=225.
Step B:
[0264] The crude alcohol from Preparative Example 222, step A (0.4
g, 1.78 mmol) in CH.sub.2Cl.sub.2 (4 mL) was added SOCl.sub.2 (0.65
mL, 8.91 mmol) and the mixture was stirred for 2 h at rt. The
mixture was concentrated under reduced pressure to afford 407 mg
(94%) of a light yellow solid. M+H=243. The crude product was taken
on without further purification.
Step C:
[0265] To a solution of crude chloride from Preparative Example
222, Step B (0.33 g, 1.36 mmol) in a pressure tube charged with 7M
NH.sub.3/MeOH (35 mL) and the mixture was stirred for 72 h. The
mixture was concentrated under reduced pressure to afford 257 mg
(85%) of a yellow semisolid. M+H (free base)=224.
Preparative Example 223
[0266] ##STR730##
[0267] To a round bottom flask charged with amine hydrochloride
(0.24 g, 1.1 mmol) from Preparative Example 222 and a stir bar was
added 4N HCl/dioxane (10 mL). The resulting solution was stirred
for 12 h at rt, concentrated under reduced pressure, and triturated
with CH.sub.2Cl.sub.2 (3.times.5 mL). The crude product was
filtered, washed with Et2O (2.times.5 mL), and dried under high
vacuum to afford 0.19 g (91%) as the dihydrochloride salt. M+H
(free base)=124.
Preparative Example 224
[0268] ##STR731##
[0269] Pd(PPh.sub.3).sub.4 (0.404 gm, 0.35 mmol) was added to a
degassed solution of 4-cyanobenzene boronic acid (1.029 g, 7 mmol)
and 2-bromopyridine (1.11 g, 7 mmol) in 75 mL acetonitrile. 0.4 M
sodium carbonate solution (35 mL) was added to the reaction mixture
and the resulting solution was refluxed at 90.degree. C. under Ar
for 24 hours (progress of reaction was monitored by TLC). The
reaction mixture was cooled and aqueous layer was separated. The
organic layer containing the product and spent catalyst was mixed
with silica gel (15 g) and concentrated to dryness. The
4-(2-pyridyl)-benzonitrile was isolated by column chromatography
(0.850 g, 68%). LCMS: MH.sup.+=181; .sup.1H NMR (CDCl.sub.3)
.delta. 8.85 (d, 1H), 8.7 (dd, 1H), 7.9 (dd, 1H), 7.75 (d, 2H), 7.7
(d, 2H), 7.4 (dd, 1H).
Preparative Examples 225-228
[0270] By following essentially same procedure described in
Preparative Example 224, only substituting the bromides in column 2
of Table 14, compounds in column 3 of Table 14 were prepared.
TABLE-US-00014 TABLE 14 Prep. Ex. Column 2 Column 3 Column 4 225
##STR732## ##STR733## Yield = 70% LCMS: MH.sup.+ = 187 226
##STR734## ##STR735## Yield = 60% LCMS: MH.sup.+ = 187 227
##STR736## ##STR737## Yield = 70% LCMS: MH.sup.+ = 186 228
##STR738## ##STR739## Yield = 70% LCMS: MH.sup.+ = 200
Preparative Example 229
[0271] ##STR740##
[0272] BH.sub.3-THF solution (1M, 24 mL, 5 eq) was added slowly to
a stirring solution of 4-(2-pyridyl)-benzonitrile (0.85 g, 4.72
mmol) in anhydrous THF (25 mL) under Ar, and the resulting solution
was refluxed for about 12 hr. The solution was cooled to 0.degree.
C. using ice-water. Methanol (15 mL) was added drop-wise to the
cold reaction mixture and stirred for 1 h to destroy excess
BH.sub.3. Added HCl-methanol (1M, 10 mL) slowly to the reaction
mixture and refluxed for 5 h. Concentrated the solution to dryness
and the residue was dissolved in 25 mL water and extracted with
ether to remove any un-reacted material. The aqueous solution was
neutralized with solid potassium carbonate to pH 10-11. The free
amine, thus formed was extracted with ether, dried over potassium
carbonate (0.45 g, 50%). LCMS: MH.sup.+=185; .sup.1H NMR
(CDCl.sub.3) .delta. 8.85 (d, 1H), 8.7 (dd, 1H), 7.9 (dd, 1H), 7.75
(d, 2H), 7.7 (d, 2H), 7.4 (dd, 1H), 3.7 (t, 2H), 1.7 (t, 2H).
Preparative Examples 230-233
[0273] By following essentially the same procedure set forth in
Preparative Example 229, compounds in column 3 of Table 15 were
prepared. TABLE-US-00015 TABLE 15 Prep. Ex. Column 2 Column 3
Column 4 230 ##STR741## ##STR742## Yield = 60% LCMS: MH.sup.+ = 191
231 ##STR743## ##STR744## Yield = 60% LCMS: MH.sup.+ = 191 232
##STR745## ##STR746## Yield = 70% LCMS: MH.sup.+ = 190 233
##STR747## ##STR748## Yield = 70% LCMS: MH.sup.+ = 204
Preparative Example 234
[0274] ##STR749## Step A:
[0275] A mixture 4-fluorobenzonitrile (3 g, 25 mmol) and imidazolyl
sodium (2.48 g, 27.5 mmol) in DMF (50 mL) was stirred at 80.degree.
C. under Ar for 12 h. Progress of reaction was monitored by TLC.
The reaction mixture was concentrated in vacuo and the residue was
diluted with 50 mL water and stirred. The aqueous mixture was
extracted with EtOAc (2.times.50 mL). Combined EtOAc extracts was
dried over anhydrous MgSO4, concentrated, and the
4-(1-imidazolyl)-benzonitrile was isolated by column chromatography
(3.6 g, 78%). LCMS: MH.sup.+=170; .sup.1H NMR (CDCl.sub.3) .delta.
8.0 (s, 1H), 7.5 (d, 2H), 7.4 (m, 3H), 7.3 (d, 1H).
Step B:
[0276] 4-(1-imidazolyl)-benzonitrile (1 g, 5.92 mmol) was dissolved
in anhydrous THF (10 mL) and added drop-wise to a stirring solution
of LAH-THF (1 M in THF, 18 mL) at room temperature. The reaction
mixture was refluxed under Ar for 2 h and the progress was
monitored by TLC. The mixture was cooled to 0.degree. C. and
quenched by drop-wise addition of a saturated
Na.sub.2SO.sub.4--H.sub.2O solution. The mixture was stirred for 1
h and filtered to remove lithium salts. The filtrate was dried over
anhydrous MgSO.sub.4 and concentrated to obtain
4-(1-imidazolyl)-benzylamine (0.8 g, 80%). LCMS: MH.sup.+=174.
Preparative Example 235
[0277] ##STR750##
[0278] A mixture of 4-(5-oxazolyl)benzoic acid (1.0 g, 5.46 mmol)
and Et.sub.3N (552 mg, 5.46 mmol) in 25 mL of THF was cooled to
0.degree. C. and ClCOOi-Bu (745 mg, 5.46 mmol) was added dropwise.
After the addition was over, the reaction mixture was stirred for
additional 5 min and then aq NH.sub.4OH (0.63 mL of 28% solution,
10.46 mmol) was added. After overnight stirring, the solvent was
evaporated, the residue was taken up in water and basified to pH 9.
The precipitated solid was filtered, washed with water and dried
over P.sub.2O.sub.5 in a vacuum desiccator to provide 500 mg (48%)
of the 4-(5-oxazolyl)-benzamide: .sup.1H NMR (DMSO-d6) .delta. 8.50
(s, 1H), 8.20-7.80 (m, 5H).
Preparative Example 236
[0279] ##STR751##
[0280] A suspension of 4-(5-oxazolyl)benzamide (500 mg, 2.657 mmol)
in 10 mL of dry THF was cooled to 0.degree. C. and 10 mL of 1 M
BH.sub.3.THF (10.00 mmol) was added. The contents were refluxed
overnight and the excess borane was destroyed by dropwise addition
of methanol. The solvent was evaporated and the residue was treated
with methanolic HCl to decompose the amine-borane complex. After
evaporation of the methanol, the residue was taken in water,
basified to pH 10 and the product was extracted in to DCM. The DCM
layer was dried (K.sub.2CO.sub.3) and the solvent was removed to
provide 150 mg (32%) of 4-(5-oxazolyl)benzylamine: .sup.1H NMR
(CDCl.sub.3) .delta. 7.90 (s, 1H), 7.60 (d, 2H), 7.40 (d, 2H), 7.30
(s, 1H), 3.90 (s, 2H).
Preparative Examples 237-239
[0281] By essentially the same procedures set forth above, the
compounds in Column 2 of Table 16 were reduced using the method
indicated in Column 3 of Table 16 to give the amine indicated in
Column 4 of Table 16. TABLE-US-00016 TABLE 16 Prep. Ex. Column 2
Column 3 Column 4 CMPD 237 ##STR752## BH.sub.3 ##STR753## .sup.1H
NMR (CDCl.sub.3) .delta.7.15-6.90 (m, 3H), 3.85 (s, 2H), 1.45 (s,
2H) 238 ##STR754## H.sub.2 ##STR755## .sup.1H NMR (CDCl.sub.3)
.delta.8.40 (s, 1H), 7.55 (dd, 1H), 7.10 (d, 1H), 3.85 (s, 2H),
2.50 (s, 3H), 1.70 (bs, 2H) 239 ##STR756## BH.sub.3 ##STR757##
Preparative Example 240
[0282] ##STR758##
[0283] Prepared by the literature procedure (PCT Int. Appl, WO
0105783): .sup.1H NMR (CDCl.sub.3) .delta. 7.35 (d, 1H), 7.24-7.10
(m, 2H), 7.02 (d, 1H), 3.95 (t, 1H), 3.70 (d, 1H), 3.37 (d, 1H),
2.65 (m, 2H), 2.45 (s, 3H), 1.90 (bs, 2H).
Preparative Example 241
3-(AMINOMETHYL)PIPERIDINE-1-CARBOXAMIDE
[0284] ##STR759##
A. 3-(tert-BUTOXYCARBONYLAMINOMETHYL)PIPERIDINE-1-CARBOXAMIDE
[0285] ##STR760##
[0286] 3(R/S)-(tert-Butoxycarbonylaminomethyl)piperidine (3 g, 14.0
mmoles) was dissolved in anhydrous dichloromethane (50 mL) and
trimethylsilylisocyanate (9.68 g, 11.4 mL, 84.0 mmoles) was added.
The mixture was stirred under argon at 25.degree. C. for 68 h.
Additional trimethylsilylisocyanate (4.84 g, 5.7 mL, 42.0 mmoles)
was added and the mixture was stirred at 25.degree. C. for a total
of 90 h. The mixture was evaporated to dryness and chromatographed
on a silica gel column (30.times.5 cm) using 2% (10% conc. ammonium
hydroxide in methanol)-dichloromethane as the eluant to give
3-(tert-butoxycarbonylaminomethyl)piperidine-1-carboxamide (3.05 g,
85%): FABMS: m/z 258.1 (MH.sup.+); HRFABMS: m/z 258.1816
(MH.sup.+). Calcd. for C.sub.12H.sub.24O.sub.3N.sub.3: m/z
258.1818; .delta..sub.H (CDCl.sub.3) 1.22 91H, m, CH.sub.2), 1.42
(9H, s, --COOC(CH.sub.3).sub.3), 1.48 (1H, m, CH.sub.2), 1.67 (2H,
m, CH.sub.2), 1.78 (1H, m, CH), 2.80 (1H, m, CH.sub.2), 2.99, 3H,
m, CH.sub.2), 3.59 (1H, m, CH.sub.20 3.69 (1H, m, CH.sub.2), 4.76
(2H, bm, CONH.sub.2) and 4.98 ppm (1H, bm, NH); .delta..sub.C
(CDCl.sub.3) CH.sub.3: 28.5, 28.5, 28.5; CH.sub.2: 24.0, 28.3,
43.2, 45.1, 47.8; CH: 36.5; C: 79.4, 156.3, 158.5.
B. 3-(AMINOMETHYL)PIPERIDINE-1-CARBOXAMIDE
[0287] ##STR761##
[0288] 3-(tert-Butoxycarbonylaminomethyl)piperidine-1-carboxamide
(150 mg, 0.583 mmoles) (prepared as described in Preparative
Example 241, Step A above) was dissolved in methanol (3 mL). 10%
conc. sulfuric acid in 1,4-dioxane (7.9 mL) was added and the
mixture was stirred at 25.degree. C. for 1 h. The mixture was
diluted with methanol and BioRad AG1-X8 resin (OH-form) was added
until the pH was basic. The resin was filtered off, washed with
methanol, evaporated to dryness and chromatographed on a silica gel
column (15.times.2 cm) using dichloromethane followed by 15% (10%
conc, ammonium hydroxide in methanol)-dichloromethane as the eluant
to give the 3-(aminomethyl)piperidine-1-carboxamide (80 mg, 87%):
FABMS: m/z 158.1 (MH.sup.+); HRFABMS: m/z 158.1294 (MH.sup.+).
Calcd. for C.sub.7H.sub.16N.sub.3O: m/z 158.1293; .delta..sub.H
(CDCl.sub.3+drop CD.sub.3OD) 1.20 (1H, m, CH.sub.2), 1.48 (1H, m,
CH.sub.2), 1.60 (1H, m, CH), 1.68 (1H, m, CH.sub.2), 1.83 (1H, m,
CH.sub.2), 2.64 (bm, 2H, --CH.sub.2NH.sub.2), 2.82 (1H, m,
CH.sub.2), 3.02 (1H, m, CH.sub.2), 2.98 (2H, m, CH.sub.2), 3.70
(1H, m, --CH.sub.2NH.sub.2), 3.78 (1H, m, --CH.sub.2NH.sub.2) and
5.24 ppm (1H, bs, NH); .delta..sub.C (CDCl.sub.3+drop CD.sub.3OD)
CH.sub.2: 24.1, 28.6, 44.0, 44.8, 47.9; CH: 38.3; C: 159.0.
Preparative Example 242
3-(2-AMINOETHYL)PIPERIDINE-1-CARBOXAMIDE
[0289] ##STR762##
A. 3-(2-tert-BUTOXYCARBONYLAMINOETHYL)PIPERIDINE-1-CARBOXAMIDE
[0290] ##STR763##
[0291] 3-(2-tert-Butoxycarbonylaminoethyl)piperidine (500 mg, 2.19
mmoles) was dissolved in anhydrous dichloromethane (10 mL) and
trimethylsilylisocyanate (2.96 mL, 21.9 mmoles) was added. The
mixture was stirred under argon at 25.degree. C. for 3.35 h. The
mixture was diluted with dichloromethane and washed with saturated
aqueous sodium bicarbonate. The organic layer was dried
(MgSO.sub.4), filtered, evaporated to dryness and chromatographed
on a silica gel column (15.times.5 cm) using 5% (10% conc. ammonium
hydroxide in methanol)-dichloromethane as the eluant to give
3-(2-tert-butoxycarbonylaminoethyl)piperidine-1-carboxamide (417.7
mg, 70%): FABMS: m/z 272.0 (MH.sup.+); HRFABMS: m/z 272.1979
(MH.sup.+). Calcd. for C.sub.13H.sub.26O.sub.3: m/z 272.1974;
.delta..sub.H (CDCl.sub.3) 1.16 (1H, m, CH.sub.2), 1-30-1.60 (5H,
m, CH/CH.sub.2), 1.46 (9H, s, --COOC(CH.sub.3).sub.3), 1.68 (1H, m,
CH.sub.2), 1 84 (1H, m, CH.sub.2), 2.54 (1H, dd, CH.sub.2), 2.73
(1H, m, CH.sub.2), 3.08 (1H, m, CH.sub.2), 3.42 (1H, m, CH.sub.2),
4.02 (1H, m, CH.sub.2), 4.10 (1H, m, CH.sub.2), 4.84 (1H, m, NH)
and 4.96 ppm (2H, bm, CONH.sub.2); .delta..sub.C (CDCl.sub.3)
CH.sub.3: 28.5, 28.5, 28.5; CH.sub.2: 25.2, 31.7, 34.9, 37.3, 44.6,
50.3; CH: 32.9; C: 79.5, 156.4, 158.2.
B. 3-(2-AMINOETHYL)PIPERIDINE-1-CARBOXAMIDE
[0292] ##STR764##
[0293] 3-(2-tert-Butoxycarbonylaminoethyl)piperidine-1-carboxamide
(392.7 mg, 1.45 mmoles) (prepared as described in Preparative
Example 242, Step A above) was dissolved in methanol (7.5 mL) and
10% conc. sulfuric acid in 1,4-dioxane (19.5 mL) was added. The
mixture was stirred at 25.degree. C. for 1.25 h. The mixture was
diluted with methanol and BioRad AG1-X8 resin (OH.sup.- form) was
added until the pH was basic. The resin was filtered off, washed
with methanol, evaporated to dryness and chromatographed on a
silica gel column (30.times.2.5 cm) using 15% (10% conc, ammonium
hydroxide in methanol)-dichloromethane as the eluant to give
3-(2-aminoethyl)piperidine-1-carboxamide (233 mg, 94%): FABMS: m/z
172.1 (MH.sup.+); HRFABMS: m/z 172.1444(MH.sup.+). Calcd for
C.sub.8H.sub.18N.sub.3O requires: m/z 172.1450; .delta..sub.H
(CDCl.sub.3+3% CD.sub.3OD) 1.14 (1H, m, CH.sub.2), 1.40 (2H, m,
CH.sub.2), 1.49 (1H, m, CH), 1.58 (1H, m, CH.sub.2), 1.69 (1H, m,
CH.sub.2), 1.85 (1H, m, CH.sub.2), 2.55 (1H, m, CH.sub.2), 2.67
(5H, m, CH.sub.2/NH.sub.2), 2.76 (1H, bm, CH.sub.2), 2.84 (1H, m,
CH.sub.2) and 3.82 ppm (2H, m, CONH.sub.2); .delta..sub.C
(CDCl.sub.3+3% CD.sub.3OD) CH.sub.2: 24.8, 30.9, 36.6, 38.9, 44.9,
50.0; CH: 33.4.
Preparative Example 243
4-(2-AMINOETHYL)PIPERIDINE-1-CARBOXAMIDE
[0294] ##STR765##
A. 4-(2-tert-BUTOXYCARBONYLAMINOETHYL)PIPERIDINE-1-CARBOXAMIDE
[0295] ##STR766##
[0296] 4-(2-tert-Butoxycarbonylaminoethyl)piperidine (500 mg, 2.19
mmoles) was dissolved in anhydrous dichloromethane (10 mL) and
trimethylsilylisocyanate (2.96 mL, 21.9 mmoles) was added. The
mixture was stirred under argon at 25.degree. C. for 3.25 h. The
mixture was diluted with dichloromethane and washed with saturated
aqueous sodium bicarbonate. The organic layer was dried
(MgSO.sub.4), filtered, evaporated to dryness and chromatographed
on a silica gel column (15.times.5 cm) using 5% (10% conc. ammonium
hydroxide in methanol)-dichloromethane as the eluant to give
4-(2-tert-butoxycarbonylaminoethyl)piperidine-1-carboxamide (308.2
mg, 52%): FABMS: m/z 272.0 (MH.sup.+); HRFABMS: m/z 272.1965
(MH.sup.+). Calcd. for C.sub.13H.sub.26O.sub.3N.sub.3: m/z
272.1974; .delta..sub.H (CDCl.sub.3) 1.20 (2H, m, CH.sub.2), 1.47
(9H, s, --COOC(CH.sub.3).sub.3), 1.45-1.55 (3H, m, CH/CH.sub.2),
1.75 (2H, m, CH.sub.2), 2.82 (2H, m, CH.sub.2), 3.19 (2H, m,
CH.sub.2), 3.96 (2H, m, CH.sub.2), 4.64 (2H, m, CH.sub.2) and 4.70
ppm (1H, bm, NH); .delta..sub.C (CDCl.sub.3) CH.sub.3: 28.5, 28.5,
28.5; CH.sub.2: 31.8, 31.8, 36.7, 38.0, 44.5, 44.5; CH: 33.4; C:
79.2, 156.7, 158.1.
A. 3-(2-AMINOETHYL)PIPERIDINE-1-CARBOXAMIDE
[0297] ##STR767##
[0298] 4-(2-tert-Butoxycarbonylaminoethyl)piperidine-1-carboxamide
(283.3 mg, 1.04 mmoles) (prepared as described in Preparative
Example 243, Step A above) was dissolved in methanol (5.4 mL) and
10% conc. sulfuric acid in 1,4-dioxane (14.2 mL) was added and the
mixture was stirred at 25.degree. C. for 1.25 h. The mixture was
diluted with methanol and BioRad AG1-X8 resin (OH.sup.- form) was
added until the pH was basic. The resin was filtered off, washed
with methanol, evaporated to dryness and chromatographed on a
silica gel column (30.times.2.5 cm) using 15% (10% conc, ammonium
hydroxide in methanol)-dichloromethane as the eluant to give the
3-(2-aminoethyl)piperidine-1-carboxamide (170 mg, 95%): FABMS: m/z
172.1 (MH.sup.+); HRFABMS: m/z 172.1442. Calcd for
C.sub.8H.sub.18N.sub.3O requires: m/z 172.1450; .delta..sub.H
(CDCl.sub.3+3% CD.sub.3OD) 1.16 (2H, m, CH.sub.2), 1.43 (2H, m,
CH.sub.2), 1.52 (1H, m, CH), 1.70 (2H, m, CH.sub.2), 2.70-2.85 (8H,
m, CH.sub.2) and 3.92 ppm (2H, m, CONH.sub.2); .delta..sub.C
(CDCl.sub.3+3% CD.sub.3OD) CH.sub.2: 31.9, 31.9, 39.0, 39.7, 44.4,
44.4; CH: 33.5; C: 158.7.
Preparative Example 244
3-(AMINOMETHYL)-1-METHYLPIPERIDINE
[0299] ##STR768##
A. 3-(BROMOMETHYL)-1-METHYLPIPERIDINE
[0300] ##STR769##
[0301] 3-(Hydroxymethyl)-1-methylpiperidine (2 g, 15.5 mmoles) was
dissolved in anhydrous acetonitrile (32 mL) and anhydrous pyridine
(2.02 mL, 24.8 mmoles) was added and the solution was cooled to
0.degree. C. Dibromotriphenylphosphorane (8.49 g, 20.2 mmoles) was
added at 0.degree. C. and the mixture was allowed to warm up to
25.degree. C. and was stirred for 94 h. The mixture was evaporated
to dryness and the residue was chromatographed on a silica gel
column (30.times.5 cm) using gradient elution with dichloromethane,
35% diethyl ether in dichloromethane and 5-10% methanol in
dichloromethane as the eluant to give
3-(bromomethyl)-1-methylpiperidine (3.13 g, 100%): FABMS: m/z 192.1
(MH.sup.+); .delta..sub.H (CDCl.sub.3) 1.52 (1H, m, CH.sub.2), 1.99
(2H, m, CH.sub.2), 2.43 (1H, m, CH.sub.2), 2.75 (2H, m, CH.sub.2),
2.82 (1H, m, CH), 2.86/2.88 (3H, s, NCH.sub.3), 3.42/3.49 (2H, dd,
--CH.sub.2Br) and 3.56 ppm (2H, m, CH.sub.2); .delta..sub.C
(CDCl.sub.3) CH.sub.3: 44.3; CH.sub.2: 22.1, 26.6, 35.4, 54.8,
58.2; CH: 34.6.
A. 3-(Di-tert-BUTOXYCARBONYLAMINOMETHYL)-1-METHYLPIPERIDINE
[0302] ##STR770##
[0303] 3-(Bromomethyl)-1-methylpiperidine (1.5 g, 7.81 mmoles)
(from Preparative Example 244, Step A above) and
di-tert-butyliminodicarboxylate (1.697 g, 7.81 mmoles) were
dissolved in anhydrous acetonitrile (25 mL). Cesium carbonate (5.1
g, 15.6 mmoles) and lithium iodide (52 mg, 0.391 mmoles) were added
and the mixture was stirred at 70.degree. C. for 20 h. The mixture
was evaporated to dryness and the residue was partitioned between
dichloromethane and saturated aqueous sodium bicarbonate. The
organic layer was dried (MgSO.sub.4), filtered and evaporated to
dryness. the residue was chromatographed on a silica gel column
(30.times.5 cm) using 3% methanol in dichloromethane as the eluant
to give 3-(di-tert-butoxycarbonylamino)-1-methylpiperidine (1.331
g, 52%): FABMS: m/z 329.2 (MH.sup.+); HRFABMS: m/z 329.2438
(MH.sup.+). Calcd. for C.sub.17H.sub.33N.sub.2O.sub.4: m/z
329.2440; .delta..sub.H (CDCl.sub.3) 1.10 (1H, m, CH.sub.2), 1.54
(18H, s, --COOC(CH.sub.3).sub.3), 1.86 (2H, m, CH.sub.2), 2.01 (1H,
m, CH.sub.2), 2.19 (1H m, CH), 2.34 (2H, bm, CH.sub.2), 2.59 (3H,
--NCH.sub.3), 3.19 (2H, m, CH.sub.2) and 3.52/3.52 ppm (2H,
--CH.sub.2N--); .delta..sub.C (CDCl.sub.3) CH.sub.3: 28.5, 28.5,
28.5, 28.5, 28.5, 28.5, 47.2; CH.sub.2: 25.4, 28.3, 50.4, 56.8,
60.8; CH: 37.2; C: 83.0, 83.0, 153.5, 153.5.
A. 3-(AMINOMETHYL)-1-METHYLPIPERIDINE
[0304] ##STR771##
[0305] 3-(Di-tert-butoxycarbonylamino)-1-methylpiperidine (500 mg,
1.52 mmoles) (from Preparative Example 244, Step B above) was
dissolved in methanol (7.5 mL) and 10% (v/v) conc. sulfuric acid in
1,4-dioxane (19.75 mL) was added. The solution was stirred at
25.degree. C. for 0.5 h. Methanol (300 mL) was added, followed by
BioRad AG1-X8 resin (OH.sup.- form) until the pH was .about.10. The
resin was filtered off and washed with methanol (2.times.200 mL).
The combined eluates were evaporated to dryness and the residue was
chromatographed on a silica gel column (30.times.2.5 cm) using 10%
(10% conc. ammonium hydroxide in methanol)-dichloromethane as the
eluant to give 3-(aminomethyl)-1-methylpiperidine (69.2 mg, 35%):
FABMS: m/z 129.1 (MH.sup.+); HRFABMS: m/z 129.1392 (MH.sup.+).
Calcd. for C.sub.7H.sub.17N.sub.2: m/z 129.1392; .delta..sub.H
(CDCl.sub.3) 0.90 (2H, m, CH.sub.2), 1.65 (2H, m, CH.sub.2), 1.72
(1H, m, CH), 1.79 (1H, m, CH.sub.2), 1.91 (1H, m, CH.sub.2), 2.30
(3H, s, --NCH.sub.3), 2.64 (2H, m, CH.sub.2), 2.82 (1H, m,
--CH.sub.2NH.sub.2) and 2.92 ppm (1H, m, -CH.sub.2NH.sub.2);
.delta..sub.C (CDCl.sub.3) CH.sub.3: 46.7; CH.sub.2: 25.2, 28.0,
46.3, 56.4, 60.3; CH: 39.9.
Preparative Example 245
4-(AMINOMETHYL)-1-METHYLPIPERIDINE
[0306] ##STR772##
A. 1-METHYLISONIPECOTAMIDE
[0307] ##STR773##
[0308] Isonipecotamide (10 g, 78.0 mmoles) was dissolved in
distilled water (100 mL) and 37% aqueous formaldehyde (7.6 mL,
equivalent to 2.81 g HCHO, 93.6 mmoles) was added. Wet 10% Pd--C (8
spoon spatulas) was added under argon and the mixture was
hydrogenated at 25.degree. C. and 50 psi for 43 h. The catalyst was
filtered off through Celite and the latter was washed with water
and methanol. The combined filtrates were evaporated to dryness and
the residue was chromatographed on a silica gel column (60.times.5
cm) using 8%-10%-20% (10% conc. ammonium hydroxide in
methanol)dichloromethane as the eluant to give
1-methylisonipecotamide (7.15 g, 64%): FABMS: m/z 143.1 (MH.sup.+);
HRFABMS: m/z 143.1184 (MH.sup.+). Calcd. for
C.sub.7H.sub.15N.sub.2O: m/z 143.1184; .delta..sub.H (d.sub.6-DMSO)
1.50/1.57 (4H, m, CH.sub.2), 1.76/1.94 (4H, m, CH.sub.2), 2.10 (3H,
s, --NCH.sub.3), 2.72 (1H, m, CH) and 6.68/7.18 ppm (2H, m,
CONH.sub.2); .delta..sub.C (d.sub.6-DMSO)CH.sub.3: 41.2; CH.sub.2:
28.5, 28.5, 54.9, 54.9; CH: 46.2; C: 176.7.
B. 4-(AMINOMETHYL)-1-METHYLPIPERIDINE
[0309] ##STR774##
[0310] 1-Methylisonipecotamide (6.75 g, 47.5 mmoles) (prepared as
described in Preparative Example 245, Step A above) was dissolved
in anhydrous THF (350 mL) and the resulting mixture was added in
portions to a stirred slurry of lithium aluminum hydride (1.8 g,
47.5 mmoles) in anhydrous THF (100 mL) at 0.degree. C. under
nitrogen. The mixture was stirred at 0.degree. C. for 30 min and
then heated at 66.degree. C. for 25 h under nitrogen. Distilled
water (1.88 mL) was added dropwise to the stirred mixture at
0.degree. C., followed by 20% aqueous sodium hydroxide (1.42 mL)
and then distilled water (6.75 mL) and the mixture was stirred for
15 min. The mixture was filtered and the solids were washed with
THF and dichloromethane. The combined filtrates were evaporated to
dryness and chromatographed on a silica gel column (30.times.5 cm)
using 15%-20% (10% conc. ammonium hydroxide in
methanol)-dichloromethane as the eluant to give
4-(aminomethyl)-1-methylpiperidine (0.678 g, 11%): FABMS: m/z 129.1
(MH.sup.+); HRFABMS: m/z 129.1389 (MH.sup.+). Calcd. for
C.sub.7H.sub.17N.sub.2: m/z 129.1392; .delta..sub.H (d.sub.6-DMSO):
2.08 ppm (3H, s, --NCH.sub.3); .delta..sub.C (d.sub.6-DMSO):
CH.sub.3: under DMSO peaks; CH.sub.2: 29.6, 29.6, 46.7, 55.2, 55.2;
CH: 46.2.
Preparative Example 246
3-(AMINOMETHYL)BENZONITRILE
[0311] ##STR775##
A. 3-(Di-tert-BUTOXYCARBONYLAMINO)BENZONITRILE
[0312] ##STR776##
[0313] 3-(Bromomethyl)benzonitrile (9 g, 25.5 mmoles) and
di-tert-butyliminodicarboxylate (5.54 g, 25.5 mmoles) were
dissolved in anhydrous THF (50 mL) and cesium carbonate (16.62 g,
25.5 mmoles) and lithium iodide (170.5 mg, 1.275 mmoles) were
added. The mixture was stirred at 70.degree. C. for 22 h and the
reaction was worked up as described in Preparative Example 89, Step
B above. The residue was chromatographed on a silica gel column
(60.times.5 cm) using 5% ethyl acetate in hexane as the eluant to
give 3-(di-tert-butoxycarbonylamino)benzonitrile (7.39 g, 87%):
FABMS: m/z 333.2 (MH.sup.+); HRFABMS: m/z 333.1815 (MH.sup.+);
Calcd. for C.sub.18H.sub.25N.sub.2O.sub.4: m/z 333.1814;
.delta..sub.H (CDCl.sub.3) 1.52 (18H, s, --COOC(CH.sub.3).sub.3),
4.84 (2H, s, CH.sub.2), 7.48 (1H, m, Ar--H), 7.60 (2H, m, Ar--H)
and 7.65 ppm (1H, m, Ar--H); .delta..sub.C (CDCl.sub.3) CH.sub.3:
28.1, 28.1, 28.1, 28.1, 28.1, 28.1; CH.sub.2: 48.4; CH: 129.2,
131.0, 131.0, 131.9; C: 83.2, 83.2, 112.5, 118.8, 140.1, 152.5,
152.5.
B. 3-(AMINOMETHYL)BENZONITRILE
[0314] ##STR777##
[0315] 3-(Di-tert-butoxycarbonylamino)benzonitrile (2 g, 6.0
mmoles) (prepared as described in Preparative Example 246, Step A
above) was dissolved in methanol (30 mL) and 10% (v/v) (10% conc.
sulfuric acid in 1,4-dioxane) (79 mL) was added. The solution was
stirred at 25.degree. C. for 0.25 h and worked up as described in
Preparative Example 89, Step C above). The residue was
chromatographed on a silica gel column (15.times.5 cm) using 3%
(10% conc. ammonium hydroxide in methanol)-dichloromethane as the
eluant to give the title compound (651.4 mg, 82%): FABMS: m/z 133.1
(MH.sup.+); HRFABMS: m/z 133.0762 (MH.sup.+). Calcd. for
C.sub.8H.sub.9N.sub.2: m/z 133.0766; .delta..sub.H (CDCl.sub.3)
2.57 (2H, s, --CH.sub.2NH.sub.2), 3.92 (2H, s, --CH.sub.2NH.sub.2),
7.46 (1H, m, Ar--H), 7.57 (2H, m, Ar--H) and 7.64 ppm (1H, m,
Ar--H); .delta..sub.C (CDCl.sub.3) CH.sub.2: 45.2; CH: 129.4,
130.7, 130.7, 131.8; C: 112.4, 118.8, 143.8.
Preparative Example 247
4-(AMINOMETHYL)BENZONITRILE
[0316] ##STR778##
A. 3-(Di-tert-BUTOXYCARBONYLAMINOMETHYL)BENZONITRILE
[0317] ##STR779##
[0318] 4-(Bromomethyl)benzonitrile (5 g, 25.5 mmoles) and
di-tert-butyliminodicarboxylate (5.54 g, 25.5 mmoles) were
dissolved in anhydrous THF (50 mL) and cesium carbonate (16.62 g,
25.5 mmoles) and lithium iodide (170.5 mg, 1.275 mmoles) were
added. The mixture was stirred at 70.degree. C. for 23 h and the
reaction was worked up as described in Preparative Example 244,
Step B above. The residue was chromatographed on a silica gel
column (50.times.5 cm) using 5% ethyl acetate in hexane as the
eluant to give 4-(di-tert-butoxycarbonylaminomethyl)benzonitrile
(7.07 g, 83%): FABMS: m/z 333.2 (MH.sup.+); HRFABMS: m/z 333.1816
(MH.sup.+). Calcd. for C.sub.18H.sub.25N.sub.2O.sub.4: m/z
333.1814; .delta..sub.H (CDCl.sub.3) 1.45 (18H, s,
--COOC(CH.sub.3).sub.3), 4.81 (2H, s, CH.sub.2), 7.37 (2H, d,
Ar--H) and 7.62 ppm (2H, d, Ar--H); .delta..sub.C (CDCl.sub.3)
CH.sub.3: 28.1, 28.1, 28.1, 28.1, 28.1, 28.1; CH.sub.2: 49.2; CH:
127.8, 127.8, 132.3, 132.3; C: 83.2, 83.2, 111.1, 118.9, 144.1,
152.4, 152.4.
B. 4-(AMINOMETHYL)BENZONITRILE
[0319] ##STR780##
[0320] 4-(Di-tert-butoxycarbonylaminomethyl)benzonitrile (2 g, 6.0
mmoles) (prepared as described in Preparative Example 247, Step A
above) was dissolved in TFA (4 mL) and the solution was stirred at
25.degree. C. for 0.25 h. The reaction mixture was diluted with
dichloromethane and extracted with 1N sodium hydroxide. The organic
layer was dried (MgSO.sub.4), filtered and evaporated to dryness.
The residue was chromatographed on a silica gel column (15.times.5
cm) using 3% (10% conc. ammonium hydroxide in
methanol)-dichloromethane as the eluant to give
4-(aminomethyl)benzonitrile (108 mg, 68%): FABMS: m/z 133.1
(MH.sup.+); HRFABMS: m/z133.0764 (MH.sup.+). Calcd. for
C.sub.8H.sub.9N.sub.2: m/z 133.0766; .delta..sub.H (CDCl.sub.3)
2.04 (2H, s, --CH.sub.2NH.sub.2), 3.89 (2H, s, --CH.sub.2NH.sub.2),
7.40 (2H, d, Ar--H) and 7.59 ppm (2H, d, Ar--H); .delta..sub.C
(CDCl.sub.3)CH.sub.2: 45.7; CH: 127.8, 127.8, 132.4, 132.4; C:
110.6, 118.9, 148.0.
Preparative Example 248
[0321] ##STR781##
[0322] To a solution of (1S,2S)-2-benzyloxycyclopentyl amine (1.5
g, 7.84 mmol) in MeOH (50 mL) at rt was added 10% Pd/C (50% wet,
1.0 g) followed by dropwise addition of conc. HCl (0.7 mL). The
mixture was stirred under a balloon of H.sub.2 for 14 h and the
catalyst was filtered off thru a pad of Celite. The pad of Celite
was washed with MeOH (2.times.10 mL) and the resulting filtrate was
concentrated under reduced pressure to afford 0.97 g (90%) of a
yellow semisolid; M+H (free base)=102
Preparative Examples 249-251
[0323] In an analogous fashion to Preparative Example 248, the
benzyl protected cycloalkyl amines (Column 2) were converted to the
desired aminocycloalkanol hydrochloride derivatives (Column 3) as
listed in Table 17. TABLE-US-00017 TABLE 17 Column 2 Column 3 CMPD
Ex. (Amine) (Cleavage method) M + H 249 ##STR782## ##STR783## M + H
= 102 (free base) 250 ##STR784## ##STR785## M + H = 116 (free base)
251 ##STR786## ##STR787## M + H = 116 (free base)
Preparative Example 252
[0324] ##STR788##
[0325] To a solution of ester (prepared according to J. Org. Chem.
(1999), 64, 330) (0.5 g, 2.43 mmol) in THF (8 mL) at 0.degree. C.
was added LiAlH.sub.4 (0.37 g, 9.74 mmol) in one portion. The
resulting mixture was heated at reflux for 12 h and was cooled to
0.degree. C. The mixture was treated sequentially with H.sub.2O (1
mL), 1 M NaOH (1 mL), and H.sub.2O (3 mL). CH.sub.2Cl.sub.2 (10 ml)
was added to the mixture which was stirred vigorously for 30 min.
The mixture was filtered thru a pad of Celite which was washed
generously with CH.sub.2Cl.sub.2 (3.times.5 mL). The resulting
filtrate was concentrated under reduced pressure to afford 0.41 g
(85%) of a yellow/orange solid. M+H=142.
Preparative Example 253
[0326] ##STR789## Step A:
[0327] To a solution of L-proline methyl ester hydrochloride (0.50
g, 3.0 mmol) in CH.sub.2Cl.sub.2 (15 mL) at 0.degree. C. was added
Et.sub.3N (1.1 mL, 7.55 mmol) followed by TFAA (0.56 mL, 3.92
mmol). The mixture was stirred for 12 h at rt and 1N HCl (25 mL)
was added. The layers were separated and the organic layer was
washed sequentially with sat. aq. NaHCO.sub.3 (1.times.25 mL), and
brine (1.times.25 mL). The organic layer was dried
(Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure to afford 0.72 g (100%) of a yellow oil. M+H=226. The
crude material was taken onto Step B without further
purification.
Step B:
[0328] To a solution of the compound prepared in Preparative
Example 253, Step A (0.68 g, 3.0 mmol) in THF (20 mL) at 0.degree.
C. was added MeMgl (5.1 mL, 3.0M in Et.sub.2O) dropwise over 10
min. The resulting solution was stirred for 16 h at rt whereupon
the mixture was quenched by addition of sat. aq. NH.sub.4Cl. The
mixture was concentrated to dryness and the resultant residue was
stirred with EtOAc (100 mL) for 45 min and filtered. The filtrate
was concentrated under reduced pressure to afford 0.68 g (100%) of
a yellow/orange oil. M+H=226. The crude material was taken onto
Step C without further purification.
Step C:
[0329] To a solution of the compound prepared in Preparative
Example 253, Step B (0.68 g, 3.0 mmol) in MeOH (5 mL) was added a
solution of KOH (0.68 g, 12.1 mmol) in MeOH (5 mL). The mixture was
stirred at reflux for 12 h and rt for 72 h whereupon the mixture
was concentrated to dryness. The crude residue was suspended in
EtOAc (50 mL) and was stirred vigorously for 30 min and was
filtered. This procedure was repeated 2.times. more and the
resultant filtrate was concentrated under reduced pressure to
afford 128 mg (33%) of a maroon/orange oil. M+H=130. This material
was used without purification in the subsequent coupling step.
Preparative Example 254
[0330] ##STR790##
[0331] The aldehyde was prepared according to the procedure of
Gupton (J. Heterocyclic Chem. (1991), 28, 1281).
Preparative Example 255
[0332] ##STR791##
[0333] Using the aldehyde from Preparative Example 254, the
procedure of Gupton (J. Heterocyclic Chem. (1991), 28, 1281) was
employed to prepare the title aldehyde.
Preparative Example 256
[0334] ##STR792##
[0335] The title aldehyde was prepared according to the procedure
of Ragan et. al Synlett (2000), 8, 1172-1174.
Preparative Example 257
[0336] ##STR793##
[0337] The reaction of known cyclopentyl guanidine hydrochloride
(Org. Lett. (2003), 5, 1369-1372) under the conditions of Ragan
(Synlett (2000), 8, 1172-1174) afforded the title aldehyde.
Preparative Example 258
[0338] ##STR794##
[0339] The title compound was prepared according to known
literature Monatshefte fur Chemie (1973), 104, 1372-1382.
Examples
Example 1
[0340] ##STR795##
[0341] A solution of the product from Preparative Example 127 (0.27
g, 0.875 mmol), 4-aminomethylpyridine (0.12 g, 1.3 eq.), and
K.sub.2CO.sub.3 (0.24 g, 2 eq.) in CH.sub.3CN (5 mL) was stirred at
room temperature 48 hours. The reaction mixture was diluted with
H.sub.2O and extracted with CH.sub.2Cl.sub.2. The combined organics
were dried over Na.sub.2SO.sub.4, filtered and concentrated. The
crude product was purified by flash chromatography using a 4% MeOH
in CH.sub.2Cl.sub.2 solution as eluent (0.28 g, 93% yield). LCMS:
MH.sup.+=380; mp=>205.degree. C. (dec).
Examples 2-210
[0342] By following essentially the same procedure set forth in
Example 1 only substituting the chlorides shown in Column 2 of
Table 18 and the amines shown in Column 3 of Table 18, the
compounds in Column 4 of Table 18 were prepared: TABLE-US-00018
TABLE 18 Ex. Column 2 Column 3 Column 4 Data 2 ##STR796##
##STR797## ##STR798## LCMS: MH.sup.+ = 380; mp =175-176.degree. C.
3 ##STR799## ##STR800## ##STR801## LCMS: MH.sup.+ = 398; mp
=156-157.degree. C. 4 ##STR802## ##STR803## ##STR804## LCMS:
MH.sup.+ = 398; mp =45-49.degree. C. 5 ##STR805## ##STR806##
##STR807## LCMS: MH.sup.+ = 354; mp =43-46.degree. C. 6 ##STR808##
##STR809## ##STR810## LCMS: MH.sup.+ = 354; mp =149-150.degree. C.
7 ##STR811## ##STR812## ##STR813## LCMS: MH.sup.+ = 414; mp
=86-92.degree. C. 8 ##STR814## ##STR815## ##STR816## LCMS: MH.sup.+
= 414; mp =185-186.degree. C. 9 ##STR817## ##STR818## ##STR819##
LCMS: MH.sup.+ = 448; mp =167-168.degree. C. 10 ##STR820##
##STR821## ##STR822## LCMS: MH.sup.+ = 346; mp =57-58.degree. C. 11
##STR823## ##STR824## ##STR825## LCMS: MH.sup.+ = 347; mp
=122.9-125.3.degree. C. 12 ##STR826## ##STR827## ##STR828## LCMS:
MH.sup.+ = 360; mp =127-128.degree. C. 13 ##STR829## ##STR830##
##STR831## LCMS: MH.sup.+ = 342; mp =133-135.degree. C. 14
##STR832## ##STR833## ##STR834## LCMS: MH.sup.+ = 344; mp
=152-155.degree. C. 15 ##STR835## ##STR836## ##STR837## LCMS:
MH.sup.+ = 362; mp =164-167.degree. C. 16 ##STR838## ##STR839##
##STR840## LCMS: MH.sup.+ = 327; mp =146-155.degree. C. 17
##STR841## ##STR842## ##STR843## LCMS: MH.sup.+ = 332; mp
=71-82.degree. C. 17.1 ##STR844## ##STR845## ##STR846## MS:
MH.sup.+ = 332. 18 ##STR847## ##STR848## ##STR849## LCMS: MH.sup.+
= 346; mp =58-65.degree. C. 19 ##STR850## ##STR851## ##STR852##
LCMS: MH.sup.+ = 414; mp =211-213.degree. C. 20 ##STR853##
##STR854## ##STR855## LCMS: MH.sup.+ = 414; mp =194-197.degree. C.
21 ##STR856## ##STR857## ##STR858## MS: MH.sup.+ = 414 m.p.
211-216.degree. C. 22 ##STR859## ##STR860## ##STR861## LCMS:
MH.sup.+ = 544; mp =104-107.degree. C. 23 ##STR862## ##STR863##
##STR864## Yield = 83% LCMS: MH.sup.+ = 410. 24 ##STR865##
##STR866## ##STR867## Yield = 84% LCMS: MH.sup.+ = 410. 25
##STR868## ##STR869## ##STR870## Yield = 96% LCMS: MH.sup.+ = 440.
26 ##STR871## ##STR872## ##STR873## Yield = 99% LCMS: MH.sup.+ =
440. 27 ##STR874## ##STR875## ##STR876## Yield = 89% LCMS: MH.sup.+
= 448. 28 ##STR877## ##STR878## ##STR879## Yield = 78% LCMS:
MH.sup.+ = 448. 30 ##STR880## ##STR881## ##STR882## Yield = 96%
LCMS: MH.sup.+ = 483. 31 ##STR883## ##STR884## ##STR885## Yield =
35% LCMS: MH.sup.+ = 483. 32 ##STR886## ##STR887## ##STR888## Yield
= 77% LCMS: MH.sup.+ = 515. 33 ##STR889## ##STR890## ##STR891##
Yield = 100% m.p. 179.degree. C. LCMS: MH.sup.+ = 388 34 ##STR892##
##STR893## ##STR894## Yield = 99% m.p. 186.degree. C. LCMS:
MH.sup.+ = 456 35 ##STR895## ##STR896## ##STR897## Yield = 98% m.p.
181.degree. C. LCMS: MH.sup.+ = 401 36 ##STR898## ##STR899##
##STR900## Yield = 63% m.p. 192.degree. C. LCMS: MH.sup.+ = 480 37
##STR901## ##STR902## ##STR903## Yield = 75% m.p. 126-127.degree.
C. LCMS: MH.sup.+ = 400 38 ##STR904## ##STR905## ##STR906## Yield =
94% m.p. 132-133.degree. C. LCMS: MH.sup.+ = 400 39 ##STR907##
##STR908## ##STR909## Yield = 95% m.p. 121-122.degree. C. LCMS:
MH.sup.+ = 400 40 ##STR910## ##STR911## ##STR912## Yield = 98%
LCMS: MH.sup.+ = 460 41 ##STR913## ##STR914## ##STR915## Yield =
87% m.p. 170-171.degree. C. LCMS: MH.sup.+ = 464 42 ##STR916##
##STR917## ##STR918## Yield = 84% m.p. 216-217.degree. C. LCMS:
MH.sup.+ = 464 43 ##STR919## ##STR920## ##STR921## Yield = 96% m.p.
214.degree. C. LCMS: MH.sup.+ = 464 44 ##STR922## ##STR923##
##STR924## Yield = 95% m.p. 158.degree. C. LCMS: MH.sup.+ = 522 45
##STR925## ##STR926## ##STR927## Yield = 90% LCMS: MH.sup.+ = 278
46 ##STR928## ##STR929## ##STR930## Yield = 100%; LCMS: MH.sup.+ =
394 47 ##STR931## ##STR932## ##STR933## LCMS: MH.sup.+ = 473 m.p.
84-87.degree. C. 48 ##STR934## ##STR935## ##STR936## MS: MH.sup.+ =
396 m.p. 91.5-93.3.degree. C. 49 ##STR937## ##STR938## ##STR939##
MS: MH.sup.+ = 396 m.p. 196-199.degree. C. 50 ##STR940## ##STR941##
##STR942## MS: MH.sup.+ = 430 m.p. 242-244.degree. C. 51 ##STR943##
##STR944## ##STR945## MS: MH.sup.+ = 430 m.p. 218.degree. C. 52
##STR946## ##STR947## ##STR948## MS: MH.sup.+ = 430 m.p.
230-233.degree. C. 54 ##STR949## ##STR950## ##STR951## MS: MH.sup.+
= 405 m.p. 185-188.degree. C. 55 ##STR952## ##STR953## ##STR954##
MS: MH.sup.+ = 370 m.p. 229-232.degree. C. 56 ##STR955## ##STR956##
##STR957## MS: MH.sup.+ = 370 m.p. 85-90.degree. C. 57 ##STR958##
##STR959## ##STR960## MS: MH.sup.+ = 386 m.p. 227-230.degree. C. 58
##STR961## ##STR962## ##STR963## MS: MH.sup.+ = 372 m.p.
212-215.degree. C. 59 ##STR964## ##STR965## ##STR966## MS: MH.sup.+
= 318 m.p. 169-171.degree. C. 60 ##STR967## ##STR968## ##STR969##
MS: MH.sup.+ = 332 m.p. 170-173.degree. C. 61 ##STR970## ##STR971##
##STR972## MS: MH.sup.+ = 346 m.p. 156-159.degree. C. 62 ##STR973##
##STR974## ##STR975## MS: MH.sup.+ = 360 m.p. 114-116.degree. C. 63
##STR976## ##STR977## ##STR978## MS: MH.sup.+ = 348 m.p.
197-200.degree. C. 64 ##STR979## ##STR980## ##STR981## 1. mp
=230-232 2. M + H =396 65 ##STR982## ##STR983## ##STR984## 1. mp
=205-207 2. M + H =402 66 ##STR985## ##STR986## ##STR987## 1. mp
=220-223 2. M + H =414 67 ##STR988## ##STR989## ##STR990## 1. mp
=191-193 2. M + H =431 68 ##STR991## ##STR992## ##STR993## 1. mp
=235-237 2. M + H =397 69 ##STR994## ##STR995## ##STR996## 1. mp
=>250 2. M + H =403 70 ##STR997## ##STR998## ##STR999## 1. mp
=230-232 2. M + H =415 71 ##STR1000## ##STR1001## ##STR1002## 1. mp
=235-238 2. M + H =431 72 ##STR1003## ##STR1004## ##STR1005## 1. mp
=186-188 2. M + H =410 73 ##STR1006## ##STR1007## ##STR1008## 1. mp
=136-138 2. M + H =424 74 ##STR1009## ##STR1010## ##STR1011## 1. mp
=192-195 2. M + H =450 75 ##STR1012## ##STR1013## ##STR1014## 1. mp
=88-90 2. M + H =454 76 ##STR1015## ##STR1016## ##STR1017## 1. mp
=230-232 2. M + H =467 77 ##STR1018## ##STR1019## ##STR1020## 1. mp
=131-133 2. M + H =479 78 ##STR1021## ##STR1022## ##STR1023## 1. mp
=85-88 2. M + H =376 79 ##STR1024## ##STR1025## ##STR1026## 1. mp
=131-133 2. M + H =388 80 ##STR1027## ##STR1028## ##STR1029## 1. mp
=206-208 2. M + H =408 81 ##STR1030## ##STR1031## ##STR1032## 1. mp
=108-110 2. M + H =502 82 ##STR1033## ##STR1034## ##STR1035## 1. mp
=83-85 2. M + H =402 83 ##STR1036## ##STR1037## ##STR1038## 1. mp
=220 2. M + H =414 84 ##STR1039## ##STR1040## ##STR1041## 1. mp
=154-156 2. M + H =426 85 ##STR1042## ##STR1043## ##STR1044## 1. mp
=152-153 2. M + H =438 86 ##STR1045## ##STR1046## ##STR1047## 1. mp
=159-161 2. M + H =420 87 ##STR1048## ##STR1049## ##STR1050## 1. mp
=>220 2. M + H =455 88 ##STR1051## ##STR1052## ##STR1053## 1. mp
=223-225 2. M + H =425 89 ##STR1054## ##STR1055## ##STR1056## 1. mp
=199-201 2. M + H =419 90 ##STR1057## ##STR1058## ##STR1059## 1. mp
=184-186 2. M + H =426 91 ##STR1060## ##STR1061## ##STR1062## 1. mp
=196-198 2. M + H =420 92 ##STR1063## ##STR1064## ##STR1065## 1. mp
=156-159 2. M + H =440
93 ##STR1066## ##STR1067## ##STR1068## 1. mp =173-176 2. M + H =434
94 ##STR1069## ##STR1070## ##STR1071## 1. mp =173-175 2. M + H =452
95 ##STR1072## ##STR1073## ##STR1074## 1. mp =174-176 2. M + H =469
96 ##STR1075## ##STR1076## ##STR1077## 1. mp =230-234 2. M + H =434
97 ##STR1078## ##STR1079## ##STR1080## 1. mp =191-193 2. M + H =441
98 ##STR1081## ##STR1082## ##STR1083## 1. mp =202-205 2. M + H =434
99 ##STR1084## ##STR1085## ##STR1086## 1. mp =209-212 2. M + H =453
100 ##STR1087## ##STR1088## ##STR1089## 1. mp =219-221 2. M + H
=469 101 ##STR1090## ##STR1091## ##STR1092## 1. mp =64-66 2. M + H
=403 102 ##STR1093## ##STR1094## ##STR1095## 1. mp =168-170 2. M +
H =420 103 ##STR1096## ##STR1097## ##STR1098## 1. mp =213-216 2. M
+ H =411 104 ##STR1099## ##STR1100## ##STR1101## 1. mp =98-100 2. M
+ H =561 105 ##STR1102## ##STR1103## ##STR1104## 1. mp 70-72 2. M +
H =608 106 ##STR1105## ##STR1106## ##STR1107## 1. mp 168-170 2. M +
H =538 107 ##STR1108## ##STR1109## ##STR1110## 1. mp 189-191 2. M +
H =592 108 ##STR1111## ##STR1112## ##STR1113## LCMS: MH.sup.+ =
458; 109 ##STR1114## ##STR1115## ##STR1116## Yield = 89 LCMS:
MH.sup.+ = 418 m. p. =131-132.degree. C. 110 ##STR1117##
##STR1118## ##STR1119## Yield = 95% LCMS: MH.sup.+ = 347 111
##STR1120## ##STR1121## ##STR1122## Yield = 91% 3H); LCMS: MH.sup.+
= 484 112 ##STR1123## ##STR1124## ##STR1125## Yield = 87% LCMS:
MH.sup.+ = 427 113 ##STR1126## ##STR1127## ##STR1128## Yield = 80%
LCMS: MH.sup.+ = 427 114 ##STR1129## ##STR1130## ##STR1131## Yield
= 91% LCMS: MH.sup.+ = 378 115 ##STR1132## ##STR1133## ##STR1134##
Yield = 92%, 3H); LCMS: MH.sup.+ = 520 116 ##STR1135## ##STR1136##
##STR1137## Yield = 98% LCMS: MH.sup.+ = 536 117 ##STR1138##
##STR1139## ##STR1140## Yield = 82% LCMS: MH.sup.+ = 410 118
##STR1141## ##STR1142## ##STR1143## Yield = 95% LCMS: MH.sup.+ =
347 121 ##STR1144## ##STR1145## ##STR1146## Yield = 65% LCMS:
MH.sup.+ = 481.02 126 ##STR1147## ##STR1148## ##STR1149## Yield =
71% MH.sup.+ = 486 127 ##STR1150## ##STR1151## ##STR1152## Yield =
71% MH.sup.+ = 495.1 128 ##STR1153## ##STR1154## ##STR1155## Yield
= 55% MH.sup.+ = 463 129 ##STR1156## ##STR1157## ##STR1158## Yield
= 77% LCMS: MH.sup.+ = 455 130 ##STR1159## ##STR1160## ##STR1161##
.sup.1H NMR (Yield = 75% LCMS: MH.sup.+ = 379 131 ##STR1162##
##STR1163## ##STR1164## Yield = 75% LCMS: MH.sup.+ = 407 132
##STR1165## ##STR1166## ##STR1167## Yield = 75% LCMS: MH.sup.+ =
421 133 ##STR1168## ##STR1169## ##STR1170## Yield = 70% LCMS:
MH.sup.+ = 421 134 ##STR1171## ##STR1172## ##STR1173## Yield = 78%
LCMS: MH.sup.+ = 475 135 ##STR1174## ##STR1175## ##STR1176## Yield
= 75% LCMS: MH.sup.+ = 476 136 ##STR1177## ##STR1178## ##STR1179##
Yield = 65% LCMS: MH.sup.+ = 455 137 ##STR1180## ##STR1181##
##STR1182## Yield = 55% LCMS: MH.sup.+ = 473) 138 ##STR1183##
##STR1184## ##STR1185## Yield = 60% LCMS: MH.sup.+ = 439 139
##STR1186## ##STR1187## ##STR1188## Yield = 65% LCMS: MH.sup.+ =
441 140 ##STR1189## ##STR1190## ##STR1191## Yield = 80% LCMS:
MH.sup.+ = 432 141 ##STR1192## ##STR1193## ##STR1194## Yield = 60%
LCMS: MH.sup.+ = 429 142 ##STR1195## ##STR1196## ##STR1197## LCMS:
MH.sup.+ = 330; mp =109-111.degree. C. 143 ##STR1198## ##STR1199##
##STR1200## LCMS: MH.sup.+ = 346; mp =186-188.degree. C. 144
##STR1201## ##STR1202## ##STR1203## LCMS: MH.sup.+ = 384; mp
=148-150.degree. C. 145 ##STR1204## ##STR1205## ##STR1206## LCMS:
MH.sup.+ = 400; mp =186-188.degree. C. 146 ##STR1207## ##STR1208##
##STR1209## LCMS: M2H.sup.+ = 390; mp =192-194.degree. C. 147
##STR1210## ##STR1211## ##STR1212## LCMS: M.sup.+ = 404; mp
=220-222.degree. C. 148 ##STR1213## ##STR1214## ##STR1215## LCMS:
MH.sup.+ = 369; mp >230.degree. C. 149 ##STR1216## ##STR1217##
##STR1218## LCMS: MH.sup.+ = 364; mp =186-188.degree. C. 150
##STR1219## ##STR1220## ##STR1221## LCMS: MH.sup.+ = 312; mp
=138-140.degree. C. 151 ##STR1222## ##STR1223## ##STR1224## LCMS:
M.sup.+ = 380; mp =172-174.degree. C. 152 ##STR1225## ##STR1226##
##STR1227## LCMS: MH.sup.+ = 352; mp =201-203.degree. C. 153
##STR1228## ##STR1229## ##STR1230## LCMS: MH.sup.+ = 348; mp
=166-168.degree. C. 154 ##STR1231## ##STR1232## ##STR1233## LCMS:
M2H.sup.+ = 531; mp =78-80.degree. C. 155 ##STR1234## ##STR1235##
##STR1236## LCMS: M2H.sup.+ = 474; mp =161-163.degree. C. 156
##STR1237## ##STR1238## ##STR1239## LCMS: M.sup.+ = 444; mp
=48-51.degree. C. 157 ##STR1240## ##STR1241## ##STR1242## MH.sup.+
= 542.1 158 ##STR1243## ##STR1244## ##STR1245## MH.sup.+ = 520.1
159 ##STR1246## ##STR1247## ##STR1248## MH.sup.+ = 542.1 160
##STR1249## ##STR1250## ##STR1251## MH.sup.+ = 480.1 161
##STR1252## ##STR1253## ##STR1254## MH.sup.+ = 506.1 162
##STR1255## ##STR1256## ##STR1257## MH.sup.+ = 480.1 163
##STR1258## ##STR1259## ##STR1260## MH.sup.+ = 494.1 164
##STR1261## ##STR1262## ##STR1263## MH.sup.+ = 466.1 165
##STR1264## ##STR1265## ##STR1266## MH.sup.+ = 494.1 166
##STR1267## ##STR1268## ##STR1269## MH.sup.+ = 508.1 167
##STR1270## ##STR1271## ##STR1272## MH.sup.+ = 520.1 168
##STR1273## ##STR1274## ##STR1275## MH.sup.+ = 528.1 169
##STR1276## ##STR1277## ##STR1278## MH.sup.+ = 520.1 170
##STR1279## ##STR1280## ##STR1281## MH.sup.+ = 528.1 171
##STR1282## ##STR1283## ##STR1284## LCMS: MH.sup.+ = 474; 172
##STR1285## ##STR1286## ##STR1287## LCMS: MH.sup.+ = 437; 173
##STR1288## ##STR1289## ##STR1290## LCMS: MH.sup.+ = 472; 174
##STR1291## ##STR1292## ##STR1293## LCMS: MH.sup.+ = 428.1 175
##STR1294## ##STR1295## ##STR1296## LCMS: MH.sup.+ = 426.2 176
##STR1297## ##STR1298## ##STR1299## LCMS: MH.sup.+ = 442.0 177
##STR1300## ##STR1301## ##STR1302## LCMS: MH.sup.+ = 452.0 178
##STR1303## ##STR1304## ##STR1305## Yield = 90 MH.sup.+ = 436 m.
pt. =89.1.degree. C. 179 ##STR1306## ##STR1307## ##STR1308##
MH.sup.+ = 424 m. pt. =188.2.degree. C. 180 ##STR1309## ##STR1310##
##STR1311## MH.sup.+ = 448 m. pt. =211.3.degree. C. 181 ##STR1312##
##STR1313## ##STR1314## Yield = quant. MH.sup.+ = 464 182
##STR1315## ##STR1316## ##STR1317## MH.sup.+ = 382 m. pt.
=185.8.degree. C. 183 ##STR1318## ##STR1319## MH.sup.+ = 387 m. pt.
=181-182.degree. C. 184 ##STR1320## ##STR1321## ##STR1322##
MH.sup.+ = 453 185 ##STR1323## ##STR1324## ##STR1325## MH.sup.+ =
401 m. pt. =178.3.degree. C. 186 ##STR1326## ##STR1327##
##STR1328## MH.sup.+ = 402 187 ##STR1329## ##STR1330## ##STR1331##
Yield = 91 MH.sup.+ = 386 m. pt. =148.3.degree. C. 188 ##STR1332##
##STR1333## ##STR1334## Yield = 65 MH.sup.+ = 402 m. pt.
=174.5.degree. C. 189 ##STR1335## ##STR1336## ##STR1337## MH.sup.+
= 379 m. pt. =82-83.degree. C. 190 ##STR1338## ##STR1339##
##STR1340## MH.sup.+ = 379 m. pt. =50.7.degree. C. 191 ##STR1341##
##STR1342## ##STR1343## Yield = 89 MH.sup.+ = 469 m. pt.
=186.7.degree. C. 192 ##STR1344## ##STR1345## ##STR1346## Yield =
93 MH.sup.+ = 410 m. pt. =86.7.degree. C. 193 ##STR1347##
##STR1348## ##STR1349## Yield = 76 MH.sup.+ = 333 m. pt.
=120.3.degree. C. 194 ##STR1350## ##STR1351## ##STR1352## Yield =
86 MH.sup.+ = 353 m. pt. =188.9.degree. C. 195 ##STR1353##
##STR1354## ##STR1355## Yield = 11% LCMS: 374
MH.sup.+ = 390 196 ##STR1356## ##STR1357## ##STR1358## Yield = 88%
LCMS: 374 MH.sup.+ = 346 197 ##STR1359## ##STR1360## ##STR1361##
Yield = 88% LCMS: 374 MH.sup.+ = 346 198 ##STR1362## ##STR1363##
##STR1364## Yield =MH.sup.+ = 400 m. pt. =111.5-112.2.degree. C.
199 ##STR1365## ##STR1366## ##STR1367## MH.sup.+ = 416 200
##STR1368## ##STR1369## ##STR1370## MH.sup.+ = 415 201 ##STR1371##
##STR1372## ##STR1373## MH.sup.+ = 398 m.p. =156.5.degree. C. 202
##STR1374## ##STR1375## ##STR1376## MH.sup.+ = 414 m.p.
=89.5.degree. C. 203 ##STR1377## ##STR1378## ##STR1379## MH.sup.+ =
413 204 ##STR1380## ##STR1381## ##STR1382## Yield = 86 MH.sup.+ =
521 m.p. =79.9.degree. C. 204.10 ##STR1383## ##STR1384##
##STR1385## 204.11 ##STR1386## ##STR1387## ##STR1388## Yield = 87
MH.sup.+ = 521 m.p. =128.6.degree. C. 205 ##STR1389## ##STR1390##
##STR1391## Yield = 99 MH.sup.+ = 537 m.p. =83.5.degree. C. 206
##STR1392## ##STR1393## ##STR1394## Yield = 94 MH.sup.+ = 598 m.p.
=110.8.degree. C. 207 ##STR1395## ##STR1396## ##STR1397## Yield =
quant. MH.sup.+ = 545 208 ##STR1398## ##STR1399## ##STR1400## Yield
= 96 MH.sup.+ = 468 m.p. =69.2.degree. C. 209 ##STR1401##
##STR1402## ##STR1403## MH.sup.+ = 498 m.p. =226.5.degree. C. 210
##STR1404## ##STR1405## ##STR1406## MH.sup.+ = 564 m.p.
=174.2.degree. C.
Additional data for select examples given below.
Example 23
[0343] .sup.1H NMR (CD.sub.3OD) .delta. 8.63 (d, J=5.7 Hz, 2H),
8.18 (s, 1H), 7.81 (dd, J=8.1 Hz, 2.1 Hz, 1H), 7.58 (d, J=6.0 Hz,
2H), 7.48 (m, 1H), 7.15-7.10 (m, 2H), 6.50 (s, 1H), 4.86 (s, 2H),
3.70 (s, 3H).
Example 24
[0344] .sup.1H NMR (CDCl.sub.3) .delta. 8.82 (s, 1H), 8.73 (d,
J=4.2 Hz, 1H), 8.11 (s, 1H), 8.06 (dd, J=7.8 Hz, 1.8 Hz, 1H), 7.91
(d, J=8.1 Hz, 1H), 7.53-7.47 (m, 2H), 7.20 (m, 1H), 7.08 (d, J=8.1
Hz, 1H), 6.75 (s, 1H), 4.81 (d, J=4.5 Hz, 2H), 3.86 (s, 3H).
Example 25
[0345] .sup.1H NMR (CDCl.sub.3) .delta. 8.75 (d, J=5.7 Hz, 2H),
8.12 (s, 1H), 7.81 (d, J=2.1 Hz, 1H), 7.53 (dd, J=8.4, 2.1 Hz, 1H),
7.45 (d, J=6.0 Hz, 2H), 6.96 (t, J=6.0 Hz, 2H), 6.33 (s, 1H), 4.85
(d, J=6.0 Hz, 2H), 4.09 (s, 3H), 4.03 (s, 3H).
Example 26
[0346] .sup.1H NMR (CDCl.sub.3) .delta. 8.82 (s, 1H), 8.72 (s, 1H),
8.09 (m, 1H), 7.87-7.83 (m, 2H), 7.60 (m, 1H), 7.45 (m, 1H), 7.03
(d, J=8.4 Hz, 1H), 6.87 (s, 1H), 6.43 (s, 1H), 4.83 (d, J=4.5 Hz,
2H), 4.11 (s, 3H), 4.04 (s, 3H).
Example 27
[0347] .sup.1H NMR (CDCl.sub.3) .delta. 8.75 (d, J=4.5 Hz, 2H),
8.19 (s, 1H), 7.63 (d, J=7.8 Hz, 2H), 7.44-7.40 (m, 3H), 7.07 (m,
1H), 6.26 (s, 1H), 4.83 (d, J=5.1 Hz, 2H).
Example 28
[0348] .sup.1H NMR (CDCl.sub.3) .delta. 8.86 (s, 1H), 8.74 (m, 1H),
8.17 (s, 1H), 7.97 (m, 1H), 7.66-7.63 (m, 2H), 7.62 (m, 1H), 7.41
(m, 1H), 7.07 (m, 1H), 6.35 (s, 1H), 4.87 (d, J=6.0 Hz, 2H).
Example 30
[0349] .sup.1H NMR (CDCl.sub.3) .delta. 8.16 (s, 1H), 7.66-7.62 (m,
2H), 7.41 (m, 1H), 7.33-7.22 (m, 3H), 6.96 (t, J=6.0 Hz, 1H), 6.33
(s, 1H), 4.73 (d, J=6.0 Hz, 2H).
Example 31
[0350] .sup.1H NMR (CDCl.sub.3) .delta. 8.13 (s, 1H), 7.66 (d,
J=7.8 Hz, 2H), 7.45-7.40 (m, 2H), 7.10-7.04 (m, 2H), 6.93 (t, J=6.6
Hz, 1H), 6.60 (s, 1H), 4.84 (d, J=6.6 Hz, 2H).
Example 32
[0351] .sup.1H NMR (CDCl.sub.3) .delta. 8.16 (s, 1H), 7.66-7.62 (m,
2H), 7.57-7.55 (m, 2H), 7.41 (t, J=7.8 Hz, 1H), 7.31 (dd, J=7.8,
1.8 Hz, 1H), 6.99 (t, J=6.0 Hz, 1H), 6.32 (s, 1H), 4.73 (d, J=6.0
Hz, 2H).
Example 40
[0352] .sup.1H NMR (CDCl.sub.3) .delta. 8.01 (s, 1H), 7.31-7.24 (d,
J=8.2 Hz, 1H), 6.72-6.64 (br t, J=5.4 Hz, 1H), 6.62-6.52 (m, 2H),
6.05-6.01 (s, 1H), 5.56-4.64 (d, J=6.0 Hz, 2H), 4.03-3.93 (s, 3H),
3.94-3.86 (s, 3H), 2.79-2.70 (d, J=8.1 Hz, 2H), 2.02-1.66 (m, 6H),
1.43-1.22 (m, 3H), 1.20-1.02 (m, 2H).
Example 45
[0353] .sup.1H NMR (CDCl.sub.3) .delta. 8.73(d, 2H), 8.54(s, 1H),
7.41(d, 2H), 7.02(br, 1H), 5.90(s, 1H), 4.80(s, 2H), 4.48(q, 2H),
2.75(s, 2H), 1.50(t, 2H), 1.06(s, 9H);
Example 46
[0354] .sup.1H NMR (CDCl.sub.3) .delta. 8.79 (s, 1H), 8.72 (d, 1H),
8.14(s, 1H), 7.84(d, 1H), 7.54-7.33(m, 4H), 6.97(t, 1H), 6.18(s,
1H), 4.79(d, 2H), 2.47(s, 3H).
Example 108
[0355] .sup.1H NMR (CDCl.sub.3) .delta. 8.79 (s, 1H), 8.72 (d,
J=3.0 Hz, 1H), 8.16 (s, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.74 (d, J=7.5
Hz, 2H), 7.55-7.35 (m, 3H), 6.92 (t, J=6.3 Hz, 1H), 6.42 (s, 1H),
4.81 (d, J=6.3 Hz, 2H).
Example 110
[0356] .sup.1H NMR (CDCl.sub.3) .delta. 8.18(t, 1H), 8.03(s, 1H),
7.44(m, 1H), 7.30(t, 1H), 7.17(q, 1H), 6.66(s, 1H), 6.56(br, 1H),
4.28(d, 2H), 2.38(s, 1H).
Example 111
[0357] .sup.1H NMR (CDCl.sub.3) .delta. 8.72(br, 1H), 8.59(d, 1H),
8.11 (t, 1H), 8.06(s, 1H), 7.73(d, 1H), 7.44(d, 1H), 7.42-7.21(m,
3H), 7.07(q, 1H), 6.39(d, 1H), 5.21(q, 1H), 4.16(q, 2H), 3.08(d,
2H), 1.22(t, 3H).
Example 112
[0358] .sup.1H NMR (CDCl.sub.3) .delta. 8.22(t, 1H), 8.15(s, 1H),
7.51-7.33(m, 7H), 7.21(q, 1H), 6.82(d, 1H), 6.51(s, 1H), 4.68(q,
1H), 2.18(m, 2H), 1.17(t, 3H).
Example 113
[0359] .sup.1H NMR (CDCl.sub.3) .delta. 8.22(t, 1H), 8.14(s, 1H),
7.51-7.33(m, 7H), 7.21(q, 1H), 6.82(d, 1H), 6.51(s, 1H), 4.68(q,
1H), 2.18(m, 2H), 1.17(t, 3H).
Example 114
[0360] .sup.1H NMR (CDCl.sub.3) .delta. 8.81(s, 1H), 8.75(d, 1H),
8.21(s, 1H), 7.84(d, 1H), 7.47(q, 1H), 6.96(s, 1H), 6.94(t, 1H),
4.85(d, 2H), 4.60(q, 2H), 1.58(t, 3H).
Example 115
[0361] .sup.1H NMR (CDCl.sub.3) .delta. 8.77(s, 1H), 8.72(d, 1H),
8.14(s, 1H), 7.83(d, 1H), 7.65(d, 1H), 7.44(q, 1H), 7.80(t, 1H),
7.6(d, 1H), 6.18(s, 1H), 4.75(d, 2H), 3.91 (s, 3H), 3.81(s,
3H).
Example 116
[0362] .sup.1H NMR (CDCl.sub.3) .delta. 8.67(s, 1H), 8.55(d, 1H),
8.50(s, 1H), 7.92(d, 1H), 7.90(d, 1H), 7.78(t, 1H), 7.10(d, 1H),
6.97(s, 1H), 5.11(s, 2H), 3.77(s, 6H).
Example 117
[0363] .sup.1H NMR (CDCl.sub.3) .delta. 8.38(s, 1H), 8.30(d, 1H),
8.17(s, 1H), 7.52-7.37(m, 6H), 6.97(t, 1H), 6.13(s, 1H), 4.77(d,
2H), 2.50(s, 3H).
Example 118
[0364] .sup.1H NMR (CDCl.sub.3) .delta. 8.18(t, 1H), 8.03(s, 1H),
7.44(m, 1H), 7.30(t, 1H), 7.17(q, 1H), 6.66(s, 1H), 6.56(br, 1H),
4.28(d, 2H), 2.38(s, 1H);
Example 121
[0365] .sup.1H NMR (CDCl.sub.3) .delta. 8.6 (S, 1H), 8.15 (dt, 1H),
8.1 (s, 1H), 8.0 (d, 2H), 7.5 (d, 2H), 7.4 (dd, 1H), 7.2 (d, 1H),
7.15 (dd, 1H), 6.8 (t, 1H), 6.6 (s, 1H), 4.75 (d, 2H).
Example 126
[0366] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.5 (d, 1H), 7.42-7.35 (m, 2H), 7.3-7.2 (m, 2H), 7.15 (dd, 1H), 7.1
(dd, 1H), 7.0 (t, 1H), 6.6 (s, 1H), 4.8 (d, 2H).
Example 127
[0367] .sup.1H NMR (CDCl.sub.3) .delta. 8.2 (dt, 1H), 8.0 (s, 1H),
7.4 (dd, 1H), 7.3-7.25 (m, 3H), 7.1 (dd, 1H), 6.9-6.85 (m, 2H), 6.7
(t, 1H), 6.6 (s, 1H), 4.6 (d, 2H), 3.2 (m, 4H), 2.6 (m, 4H), 2.3
(s, 3H).
Example 128
[0368] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.1 (s, 1H),
8.0 (d, 2H), 7.5 (d, 2H), 7.4 (m, 2H), 7.25 (d, 1H), 7.2 (s, 1H),
7.15 (dd, 1H), 7.0 (s, 1H), 6.8 (t, 1H), 6.6 (s, 1H), 4.75 (d,
2H).
Example 129
[0369] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.05 (s,
1H), 8.0 (d, 2H), 7.5 (d, 2H), 7.4 (m, 1H), 7.3 (dd, 1H), 7.15 (dd,
1H), 6.9 (t, 1H), 6.5 (s, 1H), 4.75 (d, 2H), 3.85 (s, 3H).
Example 130
[0370] .sup.1H NMR (CDCl.sub.3) .delta. 8.2 (dt, 1H), 8.0 (s, 1H),
7.4 (dd, 1H), 7.3(dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1H), 6.4 (s, 1H),
4.2 (d, 2H), 3.8 (s, 3H).
Example 131
[0371] .sup.1H NMR (CDCl.sub.3) .delta. 8.2 (dt, 1H), 8.0 (s, 1H),
7.4-7.15 (m, 3H), 6.7 (t, 1H), 4.2 (q, 2H), 3.8 (dt, 2H), 2.8 (t,
2H), 1.2 (t, 3H).
Example 132
[0372] .sup.1H NMR (CDCl.sub.3) .delta. 8.2 (dt, 1H), 8.0 (s, 1H),
7.4-7.15 (m, 3H), 6.7 (t, 1H), 4.2 (q, 2H), 3.8 (dt, 2H), 2.8 (t,
2H), 2.05 (m, 2H) 1.2 (t, 3H).
Example 133
[0373] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.4 (m, 1H), 7.3 (dd 1H), 7.2 (dd, 1H), 6.5 (s, 1H), 6.4 (t, 1H),
3.7 (s, 3H), 3.5 (dd, 2H), 2.4 (t, 2H), 1.8 (m, 4H).
Example 134
[0374] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.95 (d, 2H), 7.6 (d, 2H), 7.4 (m, 1H), 7.25 (dd, 1H), 7.1 (dd,
1H), 6.9 (t, 1H), 6.5 (s, 1H), 4.8 (d, 2H), 3.0 (s, 3H).
Example 135
[0375] .sup.1H NMR (DMSO d6) .delta. 9.1 (bs, 2H), 8.4 (s, 1H), 8.0
(t, 1H), 7.85 (d, 2H), 7.7 (d, 2H), 7.6 (m, 1H), 7.4 (m, 2H), 6.6
(s, 1H), 4.8 (bs, 2H).
Example 136
[0376] .sup.1H NMR (CDCl.sub.3) .delta. 8.2 (dt, 1H), 8.0 (s, 1H),
7.4 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.9 (m, 3H), 6.7 (t,
1H), 6.5 (s, 1H), 4.5 (d, 2H), 4.2 (s, 4H).
Example 137
[0377] .sup.1H NMR (CDCl.sub.3) .delta. 8.2 (dt, 1H), 8.0 (s, 1H),
7.4 (m, 1H), 7.3 (dd, 1H), 7.2 (dd, 1H), 6.9 (dd, 1H), 6.8 (t, 1H),
6.7 (m, 1H), 6.6 (s, 1H), 5.3 (s, 2H), 4.85 (s, 2H), 4.6 (d,
2H).
Example 138
[0378] .sup.1H NMR (CDCl.sub.3) .delta. 8.2 (dt, 1H), 8.0 (s, 1H),
7.9 (d, 1H), 7.8 (d, 1H), 7.4 (m, 2H), 7.3 (dd, 1H), 7.1 (dd, 1H),
6.9 (t, 1H), 6.6 (s, 1H), 4.8 (d, 2H).
Example 139
[0379] .sup.1H NMR (CDCl.sub.3) .delta. 8.2 (dt, 1H), 8.0 (s, 1H),
7.4 (m, 1H), 7.3 (m, 2H), 7.2 (dd, 1H), 7.1 (dd, 1H), 6.8 (d, 1H),
6.7 (t, 1H), 6.6(s, 1H), 4.6 (m, 4H), 3.2 (t, 2H).
Example 140
[0380] .sup.1H NMR (CDCl.sub.3) .delta. 8.45 (s, 1H), 8.2 (dt, 1H),
8.0 (s, 1H), 7.7 (dd, 1H), 7.4-7.3 (m, 3H), 7.15 (dd, 1H), 6.8 (t,
1H), 6.6 (s, 1H), 4.7 (d, 2H).
Example 141
[0381] .sup.1H NMR (CDCl.sub.3) .delta. 8.2 (dt, 1H), 8.0 (s, 1H),
7.45-7.1 (m, 7H), 6.6 (s, 1H), 4.4 (dt, 2H), 2.6 (t, 2H), 1.8 (m,
2H), 1.4 (m, 2H).
Example 171
[0382] .sup.1H NMR (CD.sub.3OD) .delta. 8.41 (s, 1H), 8.25 (d,
J=6.3 Hz, 1H), 8.15 (s, 1H), 7.67 (d, J=7.8 Hz, 2H), 7.55-7.48 (m,
2H), 7.45 (dd, J=7.5, 1.2 Hz, 1H), 7.34 (dd, J=7.5, 1.8 Hz, 1H),
6.28 (s, 1H), 4.79 (s, 2H).
Example 172
[0383] .sup.1H NMR (CDCl.sub.3) .delta. 8.64 (s, 1H), 7.68-7.64 (m,
2H), 7.52 (m, 1H), 7.43 (t, J=7.8 Hz, 1H), 6.89 (t, J=6.0 Hz, 1H),
6.51 (s, 1H), 6.48 (m, 2H), 4.74 (d, J=6.0 Hz, 2H).
Example 173
[0384] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.86 (s, 1H), 8.46 (s,
1H), 8.32-8.28 (m, 2H), 7.97 (m, 1H), 7.87 (m, 1H), 7.52 (m, 1H),
7.35-7.24 (m, 2H), 6.57 (s, 1H), 6.46 (m, 1H), 3.65 (m, 4H).
Example 174
[0385] .sup.1H NMR (CDCl.sub.3) d 8.37 (s, 1H), 8.16 (t, J=7.5 Hz,
1H), 7.45-7.35 (m, 1H), 7.32-7.20 (m, 3H), 7.17-7.07 (m, 1H), 6.92
(t, J=6 Hz, 1H), 6.48 (s, 1H), 4.65 (d, 2H), 2.50 (s, 3H).
Example 175
[0386] .sup.1H NMR (CDCl.sub.3) d 8.16 (t, J=9 Hz, 1H), 8.00 (s,
1H), 7.49 (d, J=9 Hz, 1H), 7.46-7.36 (m, 1H), 7.18-7.08 (m, 1H),
7.00 (d, J=9 Hz, 1H), 6.62-6.50 (m, 2H), 2.60 (s, 3H), 2.55 (s,
3H).
Example 176
[0387] .sup.1H NMR (CDCl.sub.3) d 8.15 (t, J=9 Hz, 1H), 8.00 (s,
1H), 7.45-7.35 (m, 1H), 7.32-7.20 (m, 1H), 7.20-7.05 (m, 3H), 6.80
(t, 1H), 6.50 (s, 1H), 4.65 (d, 2H), 2.65 (s, 3H), 2.50 (s,
3H).
Example 177
[0388] .sup.1H NMR (CDCl.sub.3) d 8.20 (t, 1H), 7.90 (s, 1H),
7.50-7.05 (m, 8H), 6.80 (s, 1H), 5.05-4.90 (m, 2H), 3.80 (d, 1H),
3.45 (d, 1H), 3.00 (dd, 1H), 2.90 (dd, 1H), 2.50 (s, 3H).
Example 181
[0389] .sup.1H NMR (300 MHz, CDCl.sub.3) .quadrature. 8.41 (s, 1H),
8.28-8.23 (d, 1H), 8.15 (s, 1H), 7.69-7.60 (d, 1H), 7.62-7.50 (m,
3H), 7.50-7.47 (dd, 1H), 6.35 (s, 1H), 5.36 (s, 1H), 4.80 (s,
2H).
Example 184
[0390] .sup.1H NMR (300 MHz, CDCl.sub.3) .quadrature.
.quadrature.8.96-8.90 (s, 1H), 8.08 (s, 1H), 8.04 (d, 1H), 7.72 (d,
1H), 7.70-7.61 (dd, 1H), 7.24-7.20 (dd, 1H), 6.92-6.84 (t, 1H),
6.36 (s, 1H), 4.96-4.89 (d, 2H).
Example 186
[0391] .sup.1H NMR (300 MHz, CDCl.sub.3) .quadrature.
.quadrature.8.96-8.90 (s, 1H), 8.08 (s, 1H), 8.44 (s, 1H),
8.27-8.24 (d, 1H), 8.02 (s, 1H), 7.78-7.76 (d, 1H), 7.73-7.70 (d,
1H), 7.58-7.51 (m, 2H), 7.13-7.08 (dd, 1H), 5.51 (s, 2H).
Example 195
[0392] .sup.1H NMR (CD.sub.3OD) .delta. 8.40(s, 1H), 8.27(d, 1H),
8.03(s, 1H), 7.75-7.50(m, 2H), 6.10(s, 1H), 4.76(s, 2H), 4.05(m,
2H), 3.88(m, 2H), 3.52(m, 1H), 2.33(m, 1H), 2.20(m, 1H).
Example 196
[0393] .sup.1H NMR (CD.sub.3OD) .delta. 8.73(d, 1H), 8.58(q, 1H),
8.12(s, 1H), 8.00(d, 1H), 7.54(q, 1H), 6.19(s, 1H), 4.86(s, 2H),
4.22-4.08(m, 2H), 4.03-3.93(m, 2H), 3.63(m, 1H), 2.50-2.39(m, 1H),
2.32-2.21 (m, 1H).
Example 197
[0394] .sup.1H NMR (CD.sub.3OD) .delta. 8.73(d, 1H), 8.58(q, 1H),
8.12(s, 1H), 8.00(d, 1H), 7.54(q, 1H), 6.19(s, 1H), 4.86(s, 2H),
4.22-4.08(m, 2H), 4.03-3.93(m, 2H), 3.63(m, 1H), 2.50-2.39(m, 1H),
2.32-2.21 (m, 1H).
Example 199
[0395] .sup.1H NMR (300 MHz, CDCl.sub.3) .quadrature.
.quadrature.8.29 (s, 1H), 8.15 (br s, 1H), 7.95 (s, 1H), 7.28 (d,
1H), 7.05-6.95 (appt t, 1H), 5.70 (s, 1H), 4.62 (d, 2H), 2.90 (m,
1H), 2.30 (m, 1H), 1.9-1.2 (m, 8H), 0.65 (d, 3H).
Example 200
[0396] .sup.1H NMR (300 MHz, CDCl.sub.3) .quadrature. .quadrature.
8.71 (s, 2H), 8.00 (s, 1H), 6.13 (s, 1H), 3.59 (s, 2H), 3.01-2.58
(m, 1H), 2.51-2.45 (m, 1H), 2.44-2.30 (m, 1H), 2.20 (s, 3H),
2.09-1.95 (m, 2H), 1.85-1.70 (m, 2H), 0.80-0.76 (d, 3H).
Example 203
[0397] .sup.1H NMR (300 MHz, CDCl.sub.3) .quadrature.
.quadrature.8.10 (s, 1H), 8.08 (s, 1H), 6.27 (s, 2H), 4.95 (s, 2H),
3.00-2.90 (dd, 2H), 2.60 (m, 2H), 2.48 (br s, 1H), 2.39 (s, 3h),
2.25 m, 1H), 1.95-1.70 (m, 3H).
Example 211
[0398] ##STR1407##
[0399] To a solution of the compound prepared in Example 156 (100
mg, 0.23 mmol) in dry THF (4 mL) was added LiAlH.sub.4 (1.0 M in
THF, 0.110 mL, 0.110 mmol) at 0.degree. C. under N.sub.2. The
mixture was stirred at 0.degree. C. for 1 hr, warmed to 25.degree.
C., then additional LiAlH.sub.4 (1.0 M in THF, 0.400 mL) was added,
the mixture was stirred for 20 min and then quenched with MeOH (2.0
mL). The solvent was evaporated and the crude product was purified
by flash chromatography using 10:1 CH.sub.2Cl.sub.2:MeOH as eluent.
White solid (46 mg, 49%) was obtained. LCMS: M.sup.+=416.
Mp=71-72.degree. C.
Example 212
[0400] ##STR1408##
[0401] To a solution of the compound prepared in Example 156 (70
mg, 0.16 mmol) in dry THF (3 mL) was added MeMgBr (3.0 M in
Et.sub.20, 1.10 mL, 3.20 mmol) under N.sub.2. The mixture was
stirred at 25.degree. C. for 45 min and then quenched with
saturated aqueous NH.sub.4Cl (5.0 mL). The mixture was poured into
saturated aqueous NH.sub.4Cl (30 mL) and extracted with
CH.sub.2Cl.sub.2 (3.times.20 mL). The extracts were dried over
Na.sub.2SO.sub.4 and filtered. The solvent was evaporated and the
crude product was purified by flash chromatography using 20:1
CH.sub.2Cl.sub.2:MeOH as eluent. White solid (25 mg, 36%) was
obtained. LCMS: M.sup.+=444. Mp=76-80.degree. C.
Example 213
[0402] ##STR1409##
[0403] Anhydrous DMF (40 mL) was added under N.sub.2 to the
compound prepared in Preparative Example 174 (2.50 g, 8.65 mmol)
and 60% NaH in mineral oil (346 mg, 8.65 mmol). The mixture was
stirred at 25.degree. C. for 1 hr, then
2-chloro-5-chloromethylpyridine N-oxide (1.54 g, 8.65 mmol) in
anhydrous DMF (20 mL) was added slowly. The mixture was stirred at
25.degree. C. for 18 hr, the solvent was evaporated and the crude
product was purified by flash chromatography using 30:1
CH.sub.2Cl.sub.2:MeOH as eluent. So obtained solid was triturated
by 50 mL of 1:1 EtOAc:hexane. Pale yellow solid (1.25 g, 34%) was
obtained. LCMS: MH.sup.+=432. Mp=224-226.degree. C.
Examples 214-217
[0404] By essentially the same procedure set forth in Example 213
combining the compounds shown in Column 2 of Table 19 with
compounds in Column 3 of Table 19, the compounds shown in Column 3
of Table 19 were prepared. TABLE-US-00019 TABLE 19 Ex. Column 2
Column 3 Column 4 CMPD 214 ##STR1410## ##STR1411## ##STR1412##
LCMS: MH.sup.+ = 380; mp = .degree. C. 215 ##STR1413## ##STR1414##
##STR1415## LCMS: MH.sup.+ = 450; mp =218-222.degree. C. 216
##STR1416## ##STR1417## ##STR1418## LCMS: MH.sup.+ = 466; mp
=126-128.degree. C. 217 ##STR1419## ##STR1420## ##STR1421## LCMS:
M.sup.+ = 523
Example 218
[0405] ##STR1422##
[0406] CF.sub.3CH.sub.2OH (3.0 mL) was added under N.sub.2 to 60%
NaH in mineral oil (40 mg, 1.0 mmol), the mixture was stirred for
20 min, then the product prepared in Example 213 (50 mg, 0.12 mmol)
was added. The mixture was refluxed for 20 hr, the solvent was
evaporated, and the residue was purified by flash chromatography
using 20:1 CH.sub.2Cl.sub.2:MeOH as eluent to yield pale yellow
solid (35 mg, 61%). LCMS: M2H+=496. Mp=208-210.degree. C.
Examples 219-225
[0407] By essentially the same procedure set forth in Example 218
combining the compounds shown in Column 1 of Table 20 with the
appropriate alcohol, the compounds shown in Column 2 of Table 20
were prepared. TABLE-US-00020 TABLE 20 Ex. Column 1 Column 2 Data
219 ##STR1423## ##STR1424## LCMS: M.sup.+ = 426; mp
=126-128.degree. C. 220 ##STR1425## ##STR1426## LCMS: M.sup.+ =
483; mp =89-91.degree. C. 221 ##STR1427## ##STR1428## LCMS:
M2H.sup.+ = 442; mp =112-114.degree. C. 222 ##STR1429## ##STR1430##
LCMS: MH.sup.+ = 462; mp =121-123.degree. C. 223 ##STR1431##
##STR1432## LCMS: MH.sup.+ = 444; mp =112-114.degree. C. 224
##STR1433## ##STR1434## LCMS: M.sup.+ = 376; mp = .degree. C. 225
##STR1435## ##STR1436## LCMS: MH.sup.+ =; mp = .degree. C.
Example 226
[0408] ##STR1437##
[0409] A mixture of the product prepared in Example 213 (100 mg,
0.23 mmol) and KOH (95 mg, 1.70 mmol) in 1,2-dimethoxyethane (3 mL)
and H.sub.2O (1.5 mL) was refluxed under N.sub.2 for 20 hr,
quenched with acetic acid (0.30 mL), and the solvent was
evaporated. The residue was suspended in H.sub.2O (15 mL), filtered
and the solid was washed with H.sub.2O (15 mL) and Et.sub.2O (10
mL). Then it was mixed with CH.sub.2Cl.sub.2 (2 mL) and Et.sub.2O
(2 mL) and filtered. Et.sub.2O (5 mL) was added to the filtrate and
the mixture was allowed to stand overnight. The solid was removed
by filtration, washed with Et.sub.2O and then dissolved in MeOH (5
mL). The solution was filtered and the solvent from the filtrate
was evaporated. Off-white solid (5 mg, 5%) was obtained. LCMS:
M.sup.+=412. Mp=206-208.degree. C.
Example 227
[0410] ##STR1438##
[0411] A mixture of the product prepared in Example 213 (129 mg,
0.30 mmol), N,N-dimethylethylenediamine (0.165 mL, 1.50 mmol), and
diisopropylethylamine (0.10 mL) in anhydrous N-methylpyrrolidinone
(1.0 mL) was stirred at 100.degree. C. for 24 hr. The solvent was
evaporated, and the residue was purified by flash chromatography
using 20:1 CH.sub.2Cl.sub.2: 7N NH.sub.3 in MeOH as eluent to yield
pale yellow solid (110 mg, 76%). LCMS: M.sup.+=482.
Mp=76-78.degree. C.
Examples 228-233
[0412] By essentially the same procedure set forth in Example 227
combining the compounds shown in Column 1 of Table 21 with the
appropriate amine, the compounds shown in Column 2 of Table 21 were
prepared. TABLE-US-00021 TABLE 21 Ex. Column 1 Column 2 Data 228
##STR1439## ##STR1440## LCMS: M2H.sup.+ = 467; mp 126-128 =
.degree. C. 229 ##STR1441## ##STR1442## LCMS: M.sup.+ = 481; mp
=128-130.degree. C. 230 ##STR1443## ##STR1444## LCMS: M.sup.+ =
494; mp =108-110.degree. C. 231 ##STR1445## ##STR1446## LCMS:
M2H.sup.+ = 482; mp =129-133.degree. C. 232 ##STR1447## ##STR1448##
LCMS: M2H.sup.+ = 482; mp =124-126.degree. C. 233 ##STR1449##
##STR1450## LCMS: M2H.sup.+ = 471; mp =88-90.degree. C.
Example 234
[0413] ##STR1451##
[0414] A mixture of the product prepared in Example 213 (80 mg,
0.19 mmol) and 2.0 M methylamine in THF was stirred in a closed
pressure vessel at 50.degree. C. for 72 hr. The solvent was
evaporated, and the residue was purified by flash chromatography
using 10:1 CH.sub.2Cl.sub.2: MeOH as eluent to yield pale yellow
solid (40 mg, 51%). LCMS: M2H.sup.+=427. Mp=217-219.degree. C.
Example 235
[0415] ##STR1452##
[0416] By essentially the same procedure set forth in Example 234,
the compound shown above was prepared. LCMS: M2H.sup.+=441.
Mp=98-101.degree. C.
Example 236
[0417] ##STR1453##
[0418] The compound prepared in Preparative Example 174 (140 mg,
0.48 mmol) and the aldehyde (71 mg, 0.58 mmol) were stirred in
anhydrous THF (4 mL) at 50.degree. C. under N.sub.2. Ti(OiPr).sub.4
(0.574 mL, 1.92 mmol) was added, the mixture was stirred at
50.degree. C. 3 hr, and cooled to 25.degree. C. NaBH.sub.3CN (181
mg, 2.88 mmol) was added, the mixture was stirred for 2 more hr,
then poured into 10% aqueous Na.sub.2CO.sub.3 (100 mL), and
extracted with CH.sub.2Cl.sub.2 (3.times.50 mL). Combined extracts
were dried over Na.sub.2SO.sub.4, filtered, and the solvent was
evaporated. The residue was purified by flash chromatography using
15:1 CH.sub.2Cl.sub.2:MeOH as eluent to yield pale yellow solid (40
mg, 21%). LCMS: MH.sup.+=398. Mp>230.degree. C.
Examples 237-256
[0419] By essentially the same procedure set forth in Example 236
combining the compounds shown in Column 2 and 3 of Table 22, the
compounds shown in Column 4 of Table 22 were prepared.
TABLE-US-00022 TABLE 22 Ex. Column 2 Column 3 Column 4 Data 237
##STR1454## ##STR1455## ##STR1456## LCMS: M.sup.+ = 381; mp >
200.degree. C. 238 ##STR1457## ##STR1458## ##STR1459## LCMS:
M.sup.+ = 387; mp = .degree. C. 239 ##STR1460## ##STR1461##
##STR1462## LCMS: MH.sup.+ = 413; mp =157-159.degree. C. 240
##STR1463## ##STR1464## ##STR1465## LCMS: M2H.sup.+ = 419; mp
=77-79.degree. C. 241 ##STR1466## ##STR1467## ##STR1468## LCMS:
M2H.sup.+ = 385; mp =214-216.degree. C. 242 ##STR1469## ##STR1470##
##STR1471## LCMS: MH.sup.+ =; mp = .degree. C. 243 ##STR1472##
##STR1473## ##STR1474## LCMS: M.sup.+ = 416; mp =80-82.degree. C.
244 ##STR1475## ##STR1476## ##STR1477## 245 ##STR1478## ##STR1479##
##STR1480## 246 ##STR1481## ##STR1482## ##STR1483## LCMS: M.sup.+ =
452; mp =54-56.degree. C. 247 ##STR1484## ##STR1485## ##STR1486##
LCMS: MH.sup.+ = 401; mp > 200.degree. C. 248 ##STR1487##
##STR1488## ##STR1489## LCMS: M2H.sup.+ = 474; mp >200.0.degree.
C. dec. 249 ##STR1490## ##STR1491## ##STR1492## LCMS: MH.sup.+ =
377; mp =65-67.degree. C. 250 ##STR1493## ##STR1494## ##STR1495##
LCMS: M2H.sup.+ = 421; mp =87-93.degree. C. 251 ##STR1496##
##STR1497## ##STR1498## LCMS: MH.sup.+ = 361; mp > 225.degree.
C. 252 ##STR1499## ##STR1500## ##STR1501## LCMS: MH.sup.+ = 346; mp
=270-271.degree. C. 253 ##STR1502## ##STR1503## ##STR1504## LCMS:
MH.sup.+ = 402; mp =250-255.degree. C. 254 ##STR1505## ##STR1506##
##STR1507## LCMS: MH.sup.+ = 416; mp =210-215.degree. C. 255
##STR1508## ##STR1509## ##STR1510## LCMS: MH.sup.+ = 428; mp =
145.degree. C. 256 ##STR1511## ##STR1512## ##STR1513## LCMS:
MH.sup.+ =; mp = .degree. C.
Example 257
[0420] ##STR1514##
[0421] A mixture of the compound prepared in Example 242 (100 mg,
0.24 mmol), conc. aqueous HCl (1.0 mL) and acetic acid (2.0 mL)
were stirred at 100.degree. C. under N.sub.2 for 2 hr, then poured
onto Na.sub.2CO.sub.3 (15 g), and extracted with 1:1
acetone:CH.sub.2Cl.sub.2 (3.times.30 mL). Combined extracts were
filtered, and the solvent was evaporated. The residue was purified
by flash chromatography using 10:1 CH.sub.2Cl.sub.2:MeOH as eluent
to yield pale yellow solid (36 mg, 37%). LCMS: M2H.sup.+=398.
Examples 258-260
[0422] By essentially the same procedure set forth in Example 257
starting from the compounds shown in Column 1 of Table 23, the
compounds shown in Column 2 of Table 23 were prepared.
TABLE-US-00023 TABLE 23 Ex. Column 1 Column 2 Data 258 ##STR1515##
##STR1516## LCMS: M.sup.+ = 402; mp =229-231.degree. C. 259
##STR1517## ##STR1518## LCMS: MH.sup.+ = 416; mp =215-218.degree.
C. 260 ##STR1519## ##STR1520## LCMS: M2H.sup.+ = 398; mp >
230.degree. C.
Example 261
[0423] ##STR1521##
[0424] To a stirred solution of the compound prepared in Example
239 (41 mg, 0.10 mmol) in CH.sub.2Cl.sub.2 was added 1.0 M
BBr.sub.3 (0.30 mL, 0.30 mmol) in CH.sub.2Cl.sub.2 at -78.degree.
C. The mixture was stirred at -78.degree. C. for 5 min, then at
24.degree. C. for 3 hr, then MeOH (2.0 mL) was added and the
mixture was stirred for 10 min. The solvent was evaporated and the
residue was purified by flash chromatography using 5:1:0.1
CH.sub.2Cl.sub.2:MeOH:conc. NH.sub.4OH as eluent to yield white
solid (39 mg, 99%). LCMS: M.sup.+=397. Mp>230.degree. C.
Example 262
[0425] ##STR1522##
[0426] A mixture of the product prepared in Example 217 (40 mg,
0.077 mmol) and 5.0 M aqueous NaOH (0.8 mL) in MeOH (3.0 mL) was
refluxed under N.sub.2 for 1 hr. NaHCO.sub.3 (700 mg) was added,
the solvent evaporated, and the residue was purified by flash
chromatography using 10:1:0.1 CH.sub.2Cl.sub.2: MeOH: conc.
NH.sub.4OH as eluent to yield white solid (10 mg, 35%). LCMS:
M2H.sup.+=371. Mp=237-239.degree. C.
Examples 263-264
[0427] By essentially the same procedure set forth in Example 262
starting from the compounds shown in Column 1 of Table 24, the
compounds shown in Column 2 of Table 24 were prepared.
TABLE-US-00024 TABLE 24 Ex. Column 1 Column 2 Data 263 ##STR1523##
##STR1524## LCMS: M2H.sup.+ = 370; mp =166-168.degree. C. 264
##STR1525## ##STR1526## LCMS: M2H.sup.+ = 371; mp =180-182.degree.
C.
Example 265
[0428] ##STR1527##
[0429] TFA (0.5 mL) was added to a solution of the compound
prepared in Preparative Example 197 (0.08 g, 0.16 mmol) in
CH.sub.2Cl.sub.2 (2.0 mL) at 0.degree. C. and the resulting
solution stirred 2.5 hours and stored at 4.degree. C. overnight at
which time additional TFA (0.5 mL) was added. The resulting
solution was stirred 4 hours and concentrated in vacuo. The residue
was neutralized with 1N NaOH and extracted with CH.sub.2Cl.sub.2.
The combined organics were dried over Na.sub.2SO.sub.4, filtered,
and concentrated under reduced pressure. The crude product was
purified by flash chromatography using a 2.5% (10% NH.sub.4OH in
MeOH) in CH.sub.2Cl.sub.2 solution as eluent (0.009 g, 15% yield).
LCMS: MH.sup.+=396; mp=53-54.degree. C.
Example 266
[0430] ##STR1528##
[0431] A solution of the compound prepared in Preparative Example
182 (26 mg, 0.070 mmol) and potassium thiocyanate (13 mg, 0.14
mmol) in MeOH (1 mL) was cooled in a cold water bath. To it was
added a solution of bromine (22 mg, 0.14 mmol) in MeOH (0.7 mL)
dropwise. The resulting reaction mixture was stirred for 4 h at
room temperature and the volatiles were removed under reduced
pressure. The residue obtained was suspended in a small amount of
CH.sub.2Cl.sub.2. The potassium bromide was filtered off and pH of
the filtrate was adjusted to about 7 by the addition of aqueous
ammonia. It was concentrated under reduced pressure and the
residual oil was purified by preparative thin-layer chromatography
using 15% MeOH in CH.sub.2Cl.sub.2 as eluent (26 mg, 87%
yield).
[0432] .sup.1H NMR (CDCl.sub.3) .delta. 8.75 (d, J=4.2 Hz, 2H),
8.38 (s, 1H), 7.68-7.64 (m, 2H), 7.46-7.39 (m, 3H), 7.22 (t, J=6.3
Hz, 1H), 6.43 (s, 1H), 4.84 (d, J=6.3 Hz, 2H); LCMS:
MH.sup.+=427.
Example 267
[0433] ##STR1529##
[0434] Boron tribromide (1 M in CH.sub.2Cl.sub.2, 0.60 mL, 0.60
mmol) was added dropwise to an ice-cold stirred solution of the
compound prepared in Example 24 (50 mg, 0.12 mmol) in
CH.sub.2Cl.sub.2 (1.5 mL) under an argon atmosphere. The resulting
reaction mixture was stirred at 0.degree. C. for 30 minutes,
allowed to warm up to room temperature, and stirred overnight. The
mixture was quenched by the addition of a small amount of water and
extracted with CH.sub.2Cl.sub.2. The organic layer was dried over
magnesium sulfate and concentrated in vacuo (45 mg, 94% yield).
.sup.1H NMR (CD.sub.3OD) .delta. 9.16 (s, 1H), 8.95 (s, 1H), 8.88
(d, J=8.1 Hz, 1H), 8.24 (t, J=6.9 Hz, 1H), 8.18 (s, 1H), 7.95 (d,
J=7.8 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.00-6.96 (m, 2H), 6.86 (s,
1H), 5.28 (s, 2H); LCMS: MH.sup.+=396.
Example 268
[0435] ##STR1530##
[0436] A solution of the compound from Preparative Example 184
(0.05 g, 0.15 mmol), N-methylpiperazine (20 .mu.L, 1.2 eq.) and
iPr.sub.2Et (52 .mu.L, 2.0 eq.) in dioxane (1 mL) was heated to
70.degree. C. overnight. The reaction mixture was cooled to room
temperature and diluted with H.sub.2O and saturated NaHCO.sub.3.
The resulting mixture was extracted with CH.sub.2Cl.sub.2, the
combined organics dried over Na.sub.2SO.sub.4, filtered, and
concentrated under reduced pressure. The crude product was purified
by Preparative TLC using a 5% (10% NH.sub.4OH in MeOH) in
CH.sub.2Cl.sub.2 solution as eluent (0.028 g, 47% yield). MS:
MH.sup.+=402. mp=210.degree. C. (dec.)
Examples 269-275
[0437] By essentially the same procedure set forth in Example 268
only substituting the amine in Column 2 of Table 25 and the
chlorides in Column 3 of Table 25, the compounds shown in Column 4
of Table 25 are prepared: TABLE-US-00025 TABLE 25 Ex. Column 2
Column 3 Column 4 CMPD 269 ##STR1531## ##STR1532## ##STR1533## MS:
MH.sup.+ = 387 m.p. 182-183.degree. C. 270 ##STR1534## ##STR1535##
##STR1536## MS: MH.sup.+ = 373 m.p. 190-191.degree. C. 271
##STR1537## ##STR1538## ##STR1539## MS: MH.sup.+ = 403 m.p.
227-230.degree. C. 272 ##STR1540## ##STR1541## ##STR1542## MS:
MH.sup.+ = 388 m.p. 198-201.degree. C. 273 ##STR1543## ##STR1544##
##STR1545## MS: MH.sup.+ = 430 m.p. 100-103.degree. C. 274
##STR1546## ##STR1547## ##STR1548## MS: MH.sup.+ = 456 m.p.
175-178.degree. C. 275 ##STR1549## ##STR1550## ##STR1551## MS:
MH.sup.+ = 403 m.p. 218.degree. C.
Example 276
[0438] Step A: ##STR1552##
[0439] 4-Fluorophenyl magnesium bromide (0.68 mL, 1.2 eq.) was
added to the compound prepared in Preparative Example 193 (0.20 g,
0.55 mmol) and PdCl.sub.2(dppf).sub.2 (0.037 g, 10 mol %) in THF
and the resulting solution was stirred at room temperature 72
hours. The reaction mixture was dilute with saturated NH.sub.4Cl
and extracted with EtOAc. The combined organics were washed with
saturated NaCl, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The crude product was purified by flash
chromatography using neat EtOAc as eluent (0.15 g, 65% yield). MS:
MH.sup.+=420. Step B: ##STR1553##
[0440] By essentially the same procedure set forth in Preparative
Example 127 only substituting the compound prepared in Example 276,
Step A, the above compound was prepared (0.17 g, 94% yield). Step
C: ##STR1554##
[0441] By essentially the same procedure set forth in Preparative
Example 200 only substituting the compound prepared in Example 276,
Step B, the above compound was prepared (0.1 g, 100% yield). Step
D: ##STR1555##
[0442] By essentially the same procedure set forth in Example 265
only substituting the compound prepared in Example 276, Step C, the
above compound was prepared (0.049 g, 62% yield). MS: MH.sup.+=414;
mp=110-115.degree. C.
Example 277
[0443] Step A: ##STR1556##
[0444] Pd(PPh.sub.3).sub.4 (0.065 g, 10 mol %) was added to
3-cyanophenyl zinc iodide (2.2 mL, 0.5 M solution in THF, 2 eq.)
and the compound prepared in Preparative Example 193 (0.2 g, 0.56
mmol) in DMF (2.0 mL) and the resulting solution heated to
80.degree. C. g for 144 hours. The reaction mixture was cooled to
room temperature, diluted with saturated NH.sub.4Cl and extracted
with EtOAc. The combined organics were washed with H.sub.2O and
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated
under reduced pressure. The crude product was purified by flash
chromatography using a neat EtOAC solution as eluent (0.07 g, 29%
yield). MS: MH.sup.+=427. Step B Through Step D: ##STR1557##
[0445] By essentially the same procedures set forth in Example 276,
Step B through Step D, the above compound was prepared (0.023 g,
53% yield). MS: MH.sup.+=421; mp=230.degree. C. (dec.)
Example 278
[0446] ##STR1558##
[0447] By essentially the same procedure set forth in Example 276
only substituting the appropriate cyclopropylmagnesium bromide in
Step A, the compound was prepared. MS: MH.sup.+=372; m.
p.=96-98.degree. C.
Example 279
[0448] ##STR1559##
[0449] The palladium-catalyzed zinc cross-coupling reaction was
carried out in a manner similar to the procedure described in J.
Org. Chem. (1999), 453. A solution of the chloropyrazolopyrimidine
(200 mg, 0.458 mmol), Pd(PPh.sub.3).sub.4 (53 mg, 0.046 mmol), and
exo-2-norbonylzinc bromide (0.5 M in THF, 0.95 mL, 0.47 mmol) in
DMF (2 mL) was refluxed at 100.degree. C. (oil bath temp.)
overnight. The reaction mixture was quenched with half-saturated
NH.sub.4Cl and extracted with CH.sub.2Cl.sub.2. The organic phase
was dried over MgSO.sub.4 and concentrated under reduced pressure.
The residue was purified by flash chromatography using a 50% EtOAc
in hexanes solution as eluent. A solution of the obtained
N--Boc-protected product (121 mg, 53% yield, LCMS: MH.sup.+=498)
and TFA (1 mL) in CH.sub.2Cl.sub.2 (2 mL) was stirred at room
temperature for 2 hr. The volatiles were removed under reduced
pressure. The residue was dissolved in CH.sub.2Cl.sub.2,
neutralized with saturated NaHCO.sub.3, and extracted with
CH.sub.2Cl.sub.2. The organic phase was dried over MgSO.sub.4 and
concentrated in vacuo (96 mg, 99% yield). LCMS: MH.sup.+=398;
.sup.1H NMR (CDCl.sub.3) .delta. 8.78 (s, 1H), 8.71 (d, J=4.2 Hz,
1H), 8.04 (d, J=3.9 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.44 (m, 1H),
6.73 (m, 1H), 5.98 (d, J=7.5 Hz, 1H), 4.74 (d, J=5.4 Hz, 2H),
3.40-1.00 (m, 11H).
Examples 280-294
[0450] By following essentially the same procedure set forth in
Example 279 only substituting the chlorides shown in Column 2 of
Table 26 and the organozinc reagents shown in Column 3 of Table 26,
the compounds in Column 4 of Table 26 were prepared: TABLE-US-00026
TABLE 26 Ex. Column 2 Column 3 Column 4 Data 280 ##STR1560##
##STR1561## ##STR1562## LCMS: MH.sup.+ = 395 281 ##STR1563##
##STR1564## ##STR1565## LCMS: MH.sup.+ = 400 282 ##STR1566##
##STR1567## ##STR1568## LCMS: MH.sup.+ = 412 283 ##STR1569##
##STR1570## ##STR1571## LCMS: MH.sup.+ = 452 284 ##STR1572##
##STR1573## ##STR1574## LCMS: MH.sup.+ = 422 285 ##STR1575##
##STR1576## ##STR1577## LCMS: MH.sup.+ = 408 286 ##STR1578##
##STR1579## ##STR1580## LCMS: MH.sup.+ = 404 287 ##STR1581##
##STR1582## ##STR1583## LCMS: MH.sup.+ = 404 288 ##STR1584##
##STR1585## ##STR1586## LCMS: MH.sup.+ = 408 289 ##STR1587##
##STR1588## ##STR1589## LCMS: MH.sup.+ = 386 290 ##STR1590##
##STR1591## ##STR1592## LCMS: MH.sup.+ = 464 291 ##STR1593##
##STR1594## ##STR1595## LCMS: MH.sup.+ = 480 292 ##STR1596##
##STR1597## ##STR1598## LCMS: MH.sup.+ = 424 293 ##STR1599##
##STR1600## ##STR1601## LCMS: MH.sup.+ = 424 294 ##STR1602##
##STR1603## ##STR1604## LCMS: MH.sup.+ = 426
Additional data for select compounds is shown below.
Example 280
[0451] .sup.1H NMR (CDCl.sub.3) .delta. 8.65 (s, 1H), 8.57 (d,
J=4.2 Hz, 1H), 8.50 (d, J=4.5 Hz, 1H), 8.01 (s, 1H), 7.69 (d, J=7.5
Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.31-7.22 (m, 2H), 6.77 (m, 2H),
4.71 (d, J=5.4 Hz, 2H), 2.68 (s, 3H).
Example 281
[0452] .sup.1H NMR (CDCl.sub.3) .delta. 8.80 (s, 1H), 8.72 (d,
J=4.8 Hz, 1H), 8.08 (s, 1H), 7.85-7.40 (m, 3H), 7.02 (d, J=5.1 Hz,
1H), 6.90 (t, J=6.0 Hz, 1H), 6.29 (s, 1H), 4.79 (d, J=6.0 Hz, 2H),
2.61 (s, 3H).
Example 282
[0453] .sup.1H NMR (CDCl.sub.3) .delta. 8.67 (s, 1H), 8.61 (d,
J=3.9 Hz, 1H), 8.03 (s, 1H), 7.72-7.31 (m, 3H), 7.22-7.00 (m, 2H),
6.81 (t, J=6.0 Hz, 1H), 6.03 (s, 1H), 4.68 (d, J=6.0 Hz, 2H), 2.28
(s, 3H).
Example 283
[0454] .sup.1H NMR (CDCl.sub.3) .delta. 8.68 (s, 1H), 8.63 (d,
J=4.0 Hz, 1H), 8.00 (s, 1H), 7.80-7.72 (m, 2H), 7.54-7.47 (m, 3H),
7.35 (m, 1H), 6.74 (t, J=6.0 Hz, 1H), 6.19 (s, 1H), 4.67 (d, J=6.0
Hz, 2H), 4.21 (q, J=7.2 Hz, 2H), 1.13 (t, J=7.2 Hz, 3H).
Example 284
[0455] .sup.1H NMR (CDCl.sub.3) .delta. 7.97 (s, 1H), 7.65 (d,
J=7.2 Hz, 1H), 7.33-7.15 (m, 5H), 6.73 (t, J=5.4 Hz, 1H), 5.99 (s,
1H), 4.61 (d, J=5.4 Hz, 2H), 3.09 (sept, J=6.9 Hz, 1H), 1.11 (d,
J=6.9 Hz, 6H).
Example 285
[0456] .sup.1H NMR (CDCl.sub.3) .delta. 8.56-8.55 (m, 2H), 7.94 (s,
1H), 7.54 (m, 1H), 7.30-7.22 (m, 6H), 6.59 (t, J=5.7 Hz, 1H), 5.66
(s, 1H), 4.47 (d, J=5.7 Hz, 2H), 4.26 (q, J=7.2 Hz, 1H), 1.68 (d,
J=7.2 Hz, 3H).
Example 286
[0457] .sup.1H NMR (CDCl.sub.3) .delta. 8.67 (m, 2H), 7.94 (s, 1H),
7.69 (d, J=7.8 Hz, 1H), 7.34 (m, 1H), 6.63 (t, J=5.7 Hz, 1H), 5.87
(s, 1H), 4.62 (d, J=5.7 Hz, 2H), 3.64 (s, 3H), 3.13 (m, 2H), 2.82
(m, 1H), 1.22 (m, 3H).
Example 287
[0458] .sup.1H NMR (CDCl.sub.3) .delta. 8.66 (m, 2H), 7.94 (s, 1H),
7.68 (d, J=7.8 Hz, 1H), 7.34 (m, 1H), 6.62 (t, J=6.0 Hz, 1H), 5.87
(s, 1H), 4.62 (d, J=6.0 Hz, 2H), 3.64 (s, 3H), 3.13 (m, 2H), 2.81
(m, 1H), 1.22 (m, 3H).
Example 288
[0459] .sup.1H NMR (CDCl.sub.3) .delta. 8.64 (s, 1H), 8.60 (d,
J=3.6 Hz, 1H), 8.04 (s, 1H), 7.68 (m, 1H), 7.31 (m, 1H), 7.16 (m,
1H), 7.07-7.05 (m, 2H), 6.80 (t, J=6.3 Hz, 1H), 5.93 (s, 1H), 4.64
(d, J=6.3 Hz, 2H), 2.08 (s, 6H).
Example 289
[0460] .sup.1H NMR (CDCl.sub.3) .delta. 8.72 (s, 1H), 8.62 (d,
J=4.8 Hz, 1H), 7.99-7.97 (m, 2H), 7.73-7.69 (m, 2H), 7.40-7.33 (m,
2H), 6.67 (t, J=6.0 Hz, 1H), 6.29 (s, 1H), 4.71 (d, J=6.0 Hz,
2H).
Example 290
[0461] .sup.1H NMR (CDCl.sub.3) .delta. 8.73 (s, 1H), 8.62 (d,
J=4.5 Hz, 1H), 8.01 (s, 1H), 7.76 (m, 1H), 7.41 (d, J=5.1 Hz, 1H),
7.34 (dd, J=8.1, 5.1 Hz, 1H), 7.05 (d, J=5.1 Hz, 1H), 7.01 (s, 1H),
6.79 (t, J=6.0 Hz, 1H), 4.74 (d, J=6.0 Hz, 2H).
Example 291
[0462] .sup.1H NMR (DMSO-d.sub.6) .delta. 9.12 (s, 1H), 8.40 (s,
1H), 8.33 (s, 1H), 8.13 (m, 1H), 7.82 (d, J=5.1 Hz, 1H), 7.40-7.39
(m, 2H), 7.22 (d, J=5.1 Hz, 1H), 6.86 (s, 1H), 4.86 (s, 2H).
Example 292
[0463] .sup.1H NMR (CDCl.sub.3) .delta. 8.23 (s, 1H), 8.16 (d,
J=6.0 Hz, 1H), 8.06 (s, 1H), 7.31-7.05 (m, 5H), 6.86 (m, 1H), 5.87
(s, 1H), 4.62 (d, J=6.3 Hz, 2H), 2.09 (s, 6H).
Example 293
[0464] .sup.1H NMR (CDCl.sub.3) .delta. 8.14 (s, 1H), 8.12 (d,
J=6.3 Hz, 1H), 7.94 (s, 1H), 7.29-7.16 (m, 6H), 7.07 (m, 1H), 6.78
(t, J=6.0 Hz, 1H), 5.54 (s, 1H), 4.44 (d, J=6.0 Hz, 2H), 4.24 (t,
J=7.2 Hz, 1H), 1.68 (d, J=7.2 Hz, 3H).
Example 294
[0465] .sup.1H NMR (CDCl.sub.3) .delta. 8.67 (s, 1H), 8.59 (d,
J=4.8 Hz, 1H), 8.01 (s, 1H), 7.71 (m, 1H), 7.52 (dd, J=7.8, 1.8 Hz,
1H), 7.40-7.19 (m, 4H), 6.78 (t, J=6.0 Hz, 1H), 6.32 (s, 1H), 4.67
(d, J=6.0 Hz, 2H), 2.38 (s, 3H).
Example 295
[0466] ##STR1605##
[0467] To a suspension of lithium aluminum hydride (10 mg, 0.26
mmol) in anhydrous THF (2 mL) at 0.degree. C. was added dropwise a
solution of the compound prepared in Example 283 (20 mg, 0.044
mmol) in anhydrous THF (2 mL). The resulting mixture was refluxed
for 1 hr and stirred at room temperature overnight, neutralized
with dilute sulfuric acid, and extracted with EtOAc. The organic
phase was dried over MgSO.sub.4 and concentrated under reduced
pressure. The crude product was purified by preparative thin-layer
chromatography using a 5% MeOH in EtOAc solution as eluent (15 mg,
83% yield). LCMS: MH.sup.+=410; .sup.1H NMR (CDCl.sub.3) .delta.
8.69 (s, 1H), 8.61 (d, J=3.9 Hz, 1H), 8.05 (d, J=2.1 Hz, 1H), 7.74
(d, J=7.8 Hz, 1H), 7.52-7.31 (m, 5H), 6.97 (t, J=6.3 Hz, 1H), 6.55
(d, J=2.7 Hz, 1H), 6.20 (s, 1H), 4.71 (d, J=6.3 Hz, 2H), 4.52 (s,
2H).
Example 296
[0468] ##STR1606##
[0469] To a solution of the N--Boc-protected compound prepared in
Example 294 (45 mg, 0.085 mmol) in CH.sub.2Cl.sub.2 (4 mL) at
-50.degree. C. was added m-CPBA (18 mg, 0.10 mmol). After stirring
for 1 hr at -50.degree. C. more m-CPBA (4 mg, 0.02 mmol) was added.
The mixture was stirred for a further 2 hr, diluted with
CH.sub.2Cl.sub.2 (20 mL), and washed with saturated NaHCO.sub.3 (20
mL). The organic phase was dried over MgSO.sub.4 and concentrated
under reduced pressure. The residue was purified by preparative
thin-layer chromatography using a 2.5% MeOH in CH.sub.2Cl.sub.2
solution as eluent. A solution of the obtained N-Boc-protected
product (37 mg, 80% yield, LCMS: MH.sup.+=542) and TFA (1 mL) in
CH.sub.2Cl.sub.2 (2 mL) was stirred at room temperature for 2 hr.
The volatiles were removed under reduced pressure. The residue was
dissolved in CH.sub.2Cl.sub.2, neutralized with saturated
NaHCO.sub.3, and extracted with CH.sub.2Cl.sub.2. The organic phase
was dried over MgSO.sub.4 and concentrated under reduced pressure.
The crude product was purified by preparative thin-layer
chromatography using a 5% MeOH in EtOAc solution as eluent (26 mg,
89% yield). LCMS: MH.sup.+=442; .sup.1H NMR (CDCl.sub.3) .delta.
8.71 (s, 1H), 8.64 (d, J=3.9 Hz, 1H), 8.41 (m, 1H), 8.03 (s, 1H),
7.75-7.54 (m, 4H), 7.36 (dd, J=8.1, 5.1 Hz, 1H), 6.81 (t, J=6.0 Hz,
1H), 6.34 (s, 1H), 4.74 (d, J=6.0 Hz, 2H), 3.25 (s, 3H).
Example 297
[0470] ##STR1607##
[0471] To a solution of the N--Boc-protected compound prepared in
Example 294 (56 mg, 0.11 mmol) in CH.sub.2Cl.sub.2 (4 mL) at
0.degree. C. was added m-CPBA (42 mg, 0.24 mmol). After stirring
for 2 hr at room temperature more m-CPBA (13 mg, 0.075 mmol) was
added. The mixture was stirred at room temperature overnight,
diluted with CH.sub.2Cl.sub.2 (20 mL), and washed with saturated
NaHCO.sub.3 (20 mL). The organic phase was dried over MgSO.sub.4
and concentrated under reduced pressure. The residue was purified
by preparative thin-layer chromatography using a 2.5% MeOH in EtOAc
solution as eluent. A solution of the obtained N-Boc-protected
product (29 mg, 49% yield, LCMS: MH.sup.+=558) and TFA (1 mL) in
CH.sub.2Cl.sub.2 (2 mL) was stirred at room temperature for 2 hr.
The volatiles were removed under reduced pressure. The residue was
dissolved in CH.sub.2Cl.sub.2, neutralized with saturated
NaHCO.sub.3, and extracted with CH.sub.2Cl.sub.2. The organic phase
was dried over MgSO.sub.4 and concentrated under reduced pressure.
The crude product was purified by preparative thin-layer
chromatography using a 2.5% MeOH in EtOAc solution as eluent (21
mg, 90% yield). LCMS: MH.sup.+=458; .sup.1H NMR (CDCl.sub.3)
.delta. 8.64 (s, 2H), 8.20 (m, 1H), 8.01 (s, 1H), 7.73-7.60 (m,
3H), 7.46 (m, 1H), 7.35 (s, 1H), 6.82 (t, J=5.9 Hz, 1H), 6.17 (s,
1H), 4.65 (d, J=5.7 Hz, 2H), 3.60 (s, 3H).
Example 298
[0472] ##STR1608##
[0473] By essentially the same procedure set forth in Preparative
Example 127 only substituting the compound prepared in Preparative
Example 189, the above compound was prepared. MS: MH.sup.+=334;
mp=170-173.degree. C.
Examples 299-300
[0474] By essentially the same procedure set forth in Example 298
only substituting the compound shown in Table 27, Column 2, the
compounds shown in Table 27, Column 3 were prepared: TABLE-US-00027
TABLE 27 Ex. Column 2 Column 3 CMPD 299 ##STR1609## ##STR1610## MS:
MH.sup.+ = 348 m.p. = 73-83.degree. C. 300 ##STR1611## ##STR1612##
MS: MH.sup.+ = 362 m.p. = 165-175.degree. C.
Example 301
[0475] ##STR1613##
[0476] To a solution of the compound prepared in Preparative
Example 186 (0.1 g, 0.21 mmol) in THF (4.0 mL) at -78.degree. C.
was added nBuLi (0.57 mL, 2.16M in hexanes, 5.0 eq.) at -78.degree.
C. The reaction mixture was stirred 2 hours at -78.degree. C.,
quenched with H.sub.2O, warmed to room temperature, and extracted
with EtOAc. The combined organics were dried over Na.sub.2SO.sub.4,
filtered, and concentrated under reduced pressure. The crude
product was purified by Preparative TLC using a 2.5% (10%
NH.sub.4OH in CH.sub.3OH) solution in CH.sub.2Cl.sub.2 as eluent
(0.013 g, 20% yield). MS: MH.sup.+=326; mp=71-72.degree. C.
Example 302
[0477] ##STR1614##
[0478] By essentially the same procedure set forth in Example 301
only substituting the compound from Preparative Example 187, the
above compound was prepared (0.049 g, 68% yield). MS: MH.sup.+=344;
mp=69-71.degree. C.
Example 303
[0479] ##STR1615##
[0480] To a solution of 3-H adduct from Preparative Example 187.1
(0.70 g, 2.32 mmol) in DMF (4.2 mL) at 0.degree. C. was added
POCl.sub.3 (0.67 mL, 7.2 mmol) dropwise. The mixture was stirred
for 14 h at rt, cooled to 0.degree. C., and was quenched by
addition of ice. 1N NaOH was carefully added to adjust pH to 8 and
the mixture was extracted with CH.sub.2Cl.sub.2 (3.times.25 mL).
The organic layers were combined, dried (Na.sub.2SO.sub.4),
filtered, and concentrated under reduced pressure. The crude
product was recrystallized from EtOAc to afford 0.43 g (56%) of a
yellow solid. mp 181-183.degree. C.; M+H=330.
Example 304
[0481] ##STR1616## Step A:
[0482] To a solution of aldehyde (100 mg, 0.30 mmol) from Example
303 in THF (1 mL) at 0.degree. C. was added cyclohexyl magnesium
bromide (0.46 mL, 2.0M in Et.sub.2O) dropwise over 5 min. The
resulting mixture was stirred at 0.degree. C. for 2 h and at rt for
12 h. The mixture was cooled to 0.degree. C. and was treated with
sat. aq. NH.sub.4Cl (3 mL) and CH.sub.2Cl.sub.2 (5 mL). The layers
were separated and the aqueous layer was extracted with
CH.sub.2Cl.sub.2 (2.times.5 mL). The organic layers were combined,
washed with brine (1.times.5 mL), dried (Na.sub.2SO4), filtered and
concentrated under reduced pressure to afford 110 mg (89%) of a
light yellow semisolid. M+H=414. This material was carried on crude
to Step B without further purification.
Step B:
[0483] To a solution of alcohol (53 mg, 0.13 mmol) in
CH.sub.2Cl.sub.2 (0.5 mL) at 0.degree. C. was added Et.sub.3SiH (24
.mu.L, 0.15 mmol) followed by TFA (24 .mu.L, 0.30 mmol). The
mixture was stirred for 2 h at 0.degree. C. and rt for 2 h
whereupon additional portions of Et.sub.3SiH (24 .mu.L, 0.15 mmol)
and TFA (24 .mu.L, 0.30 mmol) were added and the mixture was
stirred for 3 h at rt (until complete by TLC). The mixture was
concentrated under reduced pressure and the crude residue was
partitioned between CH.sub.2Cl.sub.2 (5 mL) and sat. aq.
NaHCO.sub.3 (2.5 mL). The layers were separated and the aqueous
layer was extracted with CH.sub.2Cl.sub.2 (2.times.5 mL). The
organic layers were combined, washed with brine (1.times.5 mL),
dried (Na.sub.2SO4), filtered and concentrated under reduced
pressure. The crude product was purified by prep TLC (8.times.1000
mM) eluting with CH.sub.2Cl.sub.2/MeOH (22:1) to afford 29 mg (56%)
of a yellow semisolid. M+H=398.
Examples 305-312
[0484] By essentially the same procedure set forth in Example 304,
utilizing the aldehyde from Example 303 and substituting the
Grignard or organolithium reagents shown in Column 2 of Table 28,
the compounds in Column 3 of Table 28 were prepared: TABLE-US-00028
TABLE 28 CMPD Column 2 Column 3 1. mp (.degree. C.) Ex.
(Organometallic) (Final Structure) 2. M + H 305 ##STR1617##
##STR1618## 1. yellow oil 2. M + H = 392 306 ##STR1619##
##STR1620## 1. red oil 2. M + H = 353 307 ##STR1621## ##STR1622##
1. red oil 2. M + H = 398 308 ##STR1623## ##STR1624## 1. yellow oil
2. M + H = 406 309 ##STR1625## ##STR1626## 1. yellow semisolid 2. M
+ H = 384 310 ##STR1627## ##STR1628## 1. semisolid 2. M + H = 340
311 ##STR1629## ##STR1630## 1. mp = 141-143 2. M + H = 358 312
##STR1631## ##STR1632## 1. mp = 148-150 2. M + H = 372
Example 313
[0485] ##STR1633##
[0486] To solution of aldehyde (81 mg, 0.25 mmol) from Example 303
in benzene (2.5 mL) was added carboethoxymethylene triphenyl
phosphorane (0.12 g, 0.33 mmol) in one portion. The mixture was
heated at reflux for 24 h, cooled to rt, and concentrated under
reduced pressure. The mixture was diluted CH.sub.2Cl.sub.2 (5 mL),
brine (2 mL) was added, and the layers were separated. The aqueous
layer was extracted with CH.sub.2Cl.sub.2 (2.times.4 mL). The
organic layers were combined, dried (Na.sub.2SO.sub.4), filtered,
and concentrated under reduced pressure. The crude product was
purified by preparative TLC (8.times.1000 .mu.M) eluting with
CH.sub.2Cl.sub.2/MeOH (20:1) to afford 98 mg (100%) of white solid.
mp 151-153.degree. C.; M+H=400.
Example 314
[0487] ##STR1634##
[0488] To a mixture of benzyltriphenylphosphonium bromide (0.59 g,
1.37 mmol) in THF (3 mL) was added NaH (55 mg, 1.37 mmol) and the
mixture was stirred for 30 min. The aldehyde (0.15 g, 0.46 mmol)
from Example 303 was added in a single portion and the mixture was
heated at reflux for 36 h. The mixture was cooled to rt and was
concentrated under reduced pressure. The mixture was diluted
CH.sub.2Cl.sub.2 (5 mL), brine (2 mL) was added, and the layers
were separated. The aqueous layer was extracted with
CH.sub.2Cl.sub.2 (2.times.4 mL). The organic layers were combined,
dried (Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure. The crude product was purified by preparative TLC
(8.times.1000 .mu.M) eluting with CH.sub.2Cl.sub.2/MeOH (20:1) to
afford 58 mg (32%) of yellow solid. mp 138-141.degree. C.;
M+H=404.
Example 315
[0489] ##STR1635##
[0490] To a solution of aldehyde (0.20 g, 0.60 mmol) from Example
303 in THF (3 mL) was added Ti (i-OPr).sub.4 (0.36 mL, 1.21 mmol)
dropwise followed by addition of
(S)-(-)-2-methyl-2-propanesulfinamide (74 mg, 0.61 mmol). The
resulting mixture was stirred for 18 h at reflux, cooled to rt, and
quenched with brine (2 mL). The mixture was filtered thru a pad of
Celite which was washed with EtOAc (2.times.2 mL). The layers were
separated and the aqueous layer was extracted with EtOAc (2.times.4
mL). The organic layers were combined, dried (Na.sub.2SO.sub.4),
filtered, and concentrated under reduced pressure. The crude
product was purified by preparative TLC (8.times.1000 .mu.M)
eluting with CH.sub.2Cl.sub.2/MeOH (20:1) to afford 0.21 g (80%) of
yellow solid. mp 108-110.degree. C.; M+H=433.
Example 316
[0491] ##STR1636##
[0492] Prepared in the same fashion as Example 315 except
substituting (R)-(-)-2-methyl-2-propanesulfinamide to afford 0.25 g
(94%) as a yellow solid. mp 107-109.degree. C.; M+H=433.
Example 317
[0493] ##STR1637## Step A:
[0494] To a solution of sulfinimine (50 mg, 0.12 mmol) from Example
316 in CH.sub.2Cl.sub.2 (2.5 mL) at -40.degree. C. was added MeMgBr
(96 mL, 0.29 mmol) dropwise. The mixture was stirred for 5 h at
-40.degree. C. and was stirred at rt for 12 h. An additional
portion of MeMgBr (96 mL, 0.29 mmol) and the mixture was stirred
for 12 h. Sat. aq. NH.sub.4Cl (2 mL) was added and the mixture was
extracted with EtOAc (3.times.4 mL). The organic layers were
combined, dried (Na.sub.2SO.sub.4), filtered, and concentrated
under reduced pressure to afford 30 mg (58%) of crude residue. This
material was taken onto the next step without purification.
Step B:
[0495] The crude material from Step A (30 mg, 0.067 mmol) in MeOH
(2 mL) was added conc. HCl (2 mL). The mixture was stirred at rt
for 12 h and the mixture was concentrated to dryness. The crude
material was partitioned between CH.sub.2Cl.sub.2 (3 mL) and sat.
aq. NaHCO.sub.3 (2 mL) and the layers were separated. The aqueous
layer was extracted with CH.sub.2Cl.sub.2 (2.times.3 mL) and the
organic layers were combined. The organic layer was dried
(Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure to afford 6 mg (24%) of the title compound as a light
yellow solid. mp 100-102.degree. C.; M+H=345.
Example 318
[0496] ##STR1638##
[0497] To a solution of aldehyde (75 mg, 0.23 mmol) from Example
300 in THF/CH.sub.2Cl.sub.2 (5 mL/1 mL) at rt was added
MeONH.sub.2.HCl (38 mg, 0.46 mmol) followed by dropwise addition of
pyridine (46 .mu.L, 0.57 mmol). The mixture was stirred for 72 h at
rt whereupon the mixture was concentrated to dryness. The crude
material was partitioned between CH.sub.2Cl.sub.2 (3 mL) and sat.
aq. NaHCO.sub.3 (2 mL) and the layers were separated. The aqueous
layer was extracted with CH.sub.2Cl.sub.2 (2.times.3 mL) and the
organic layers were combined. The organic layer was dried
(Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure. The crude product was purified by preparative TLC
(3.times.1000 .mu.M) eluting with CH.sub.2Cl.sub.2/MeOH (22:1) to
afford 90 mg (100%) of light yellow solid. mp 173-175.degree. C.;
M+H=359.
Example 319
[0498] ##STR1639##
[0499] To solution of aldehyde (60 mg, 0.18 mmol) from Example 303
at EtOH (2.5 mL) was added oxindole (48 mg, 0.37 mmol) followed by
piperidine (3 drops). The mixture was heated at reflux for 14 h and
the mixture was cooled to rt. The resultant precipitate was
filtered and washed with cold EtOH (2.times.2 mL). The product was
dried under high vacuum to afford 81 mg (100%) of the title
compound as an orange/brown solid. mp 182-185.degree. C.;
M+H=445.
Example 320
[0500] ##STR1640##
[0501] To a solution of 3-H analog (106 mg, 0.35 mmol) from
Preparative Example 187.10 in AcOH (2 mL) was added 37% aqueous
formaldehyde (1.5 ml; 1.40 mmol) followed by piperidine (100 .mu.L;
0.37 mmol). The resulting mixture was stirred at rt for 24 h and
the AcOH was removed under reduced pressure. The mixture was
diluted with water (2 mL) and neutralized with 2M NaOH until pH=8.
The aqueous layer was extracted with CH.sub.2Cl.sub.2 (3.times.7
mL) and the organic layers were combined. The organic layer was
washed with brine (1.times.4 mL), dried (Na.sub.2SO.sub.4),
filtered, and concentrated under reduced pressure to afford 96 mg
(69%) of an off-white solid. mp 88-90.degree. C.; M+H 399.
Examples 321-322
[0502] By essentially the same procedure set forth in Example 320
only substituting the amines in Column 2 of Table 29 and employing
the 3-H adduct from Preparative Example 187.10, the compounds in
Column 3 of Table 29 were prepared: TABLE-US-00029 TABLE 29 CMPD
Column 2 Column 3 1. mp (.degree. C.) Ex. (Amine) (Final Structure)
2. M + H 321 ##STR1641## ##STR1642## 1. mp = 178-180 2. M + H = 401
322 ##STR1643## ##STR1644## 1. mp = 102-104 2. M + H = 414
Example 323
[0503] ##STR1645##
[0504] To a solution of 3-H analog (113 mg, 0.38 mmol) from
Preparative Example 187.10 in CH.sub.2Cl.sub.2 (5 mL) at rt was
added AlCl.sub.3 (215 mg, 1.61 mmol) followed by AcCl (100 mL, 1.40
mmol). The mixture was heated at reflux for 12 h and was cooled to
rt. The mixture was treated sequentially with 3M HCl (3 mL)
followed by sat. aq. NaHCO.sub.3 (until pH=8). The layers were
separated and the aqueous layer was extracted with CH.sub.2Cl.sub.2
(2.times.5 mL). The organic layers were combined, dried
(Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure. The crude product was purified by preparative TLC
(8.times.1000 mM) eluting with CH.sub.2Cl.sub.2/MeOH (20:1) to
afford 68 mg (52%) of white solid. mp 220-221.degree. C.;
M+H=344.
Example 324
[0505] ##STR1646##
[0506] Utilizing the method described in Example 323, except
employing benzoyl chloride, the title compound was prepared in 61%
yield as a white solid. mp 172-175.degree. C.; M+H=406.
Example 325
[0507] ##STR1647##
[0508] To a solution of ketone (100 mg, 0.29 mmol) from Example 323
in CH.sub.2Cl.sub.2 (2.5 mL) at 0.degree. C. was added MeMgBr (0.35
mL, 3.0M in Et.sub.2O) dropwise. The resulting mixture was stirred
for 18 h at rt and was carefully quenched by addition of sat. aq.
NH.sub.4Cl (2 mL) and CH.sub.2Cl.sub.2 (2 mL) were added. The
layers were separated and the aqueous layer was extracted with
CH.sub.2Cl.sub.2 (2.times.4 mL). The organic layers were combined,
dried (Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure. The crude product was purified by preparative TLC
(8.times.1000 .mu.M) eluting with CH.sub.2Cl.sub.2/MeOH (10:1) to
afford 68 mg (52%) of a yellow solid. mp 160-162.degree. C.;
M+H=360.
Example 326
[0509] ##STR1648##
[0510] To a solution of ketone (84 mg, 0.24 mmol) from Example 323
in MeOH/THF (1:1; 2 mL total) at 0.degree. C. was added NaBH.sub.4
(12 mg, 0.30 mmol) in one portion. The resulting mixture was
stirred for 18 h at rt whereupon and additional portion of
NaBH.sub.4 (12 mg, 0.30 mmol) was added. The mixture was stirred
for 12 h whereupon the mixture was quenched with ice followed by
addition of 1M NaOH to adjust the pH=9. The mixture was diluted
with CH.sub.2Cl.sub.2 (5 mL). The layers were separated and the
aqueous layer was extracted with CH.sub.2Cl.sub.2 (2.times.4 mL).
The organic layers were combined, dried (Na.sub.2SO.sub.4),
filtered, and concentrated under reduced pressure. The crude
product was purified by preparative TLC (8.times.1000 .mu.M)
eluting with CH.sub.2Cl.sub.2/MeOH (10:1) to afford 25 mg (30%) of
a yellow solid. mp 148-150.degree. C.; M+H=346.
Example 327
[0511] ##STR1649##
[0512] Using the same procedure as outlined in Example 326, the
ketone (84 mg, 0.21 mmol) was converted to 53 mg (62%) as a light
yellow solid. mp 78-80.degree. C.; M+H=408.
Example 328
[0513] ##STR1650##
[0514] To a solution of 3-H adduct (1.3 g, 4.31 mmol) from
Preparative Example 187.10 in CH.sub.2Cl.sub.2(50 mL) was added
Eschenmoser's salt (0.79 g, 4.31 mmol) followed by dropwise
addition of TFA (0.56 mL, 7.33 mmol). The mixture was stirred at rt
for 48 h and was diluted with CH.sub.2Cl.sub.2 (250 mL). The
organic layer was washed with sat. aq. NaHCO.sub.3 (2.times.125 mL)
to afford 1.41 h (92%) of a yellow solid. mp 231-233.degree. C.;
M+H=359.
Example 329
[0515] ##STR1651##
[0516] To a solution of tertiary amine adduct (100 mg, 0.28 mmol)
from Example 328 in 50% aq. DMF (5 mL) in a pressure tube was added
KCN (0.15 g, 2.32 mmol). The tube was capped and heated at
100.degree. C. for 96 h. The mixture was cooled to rt and was
diluted with EtOAc (25 mL). The organic layer was washed with brine
(1.times.5 mL) and water (1.times.5 mL). The organic layers was
dried (Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure. The crude product was purified by preparative TLC
(4.times.1000 .mu.M) eluting with EtOAc to afford 21 mg (30%) of
brown solid. mp 152-155.degree. C.; M+H=341.
Example 330
[0517] ##STR1652##
[0518] To a solution of alcohol (45 mg, 0.14 mmol) from Example
17.10 in CH.sub.2Cl.sub.2 (0.7 mL) at 0.degree. C. was added
Et.sub.3SiH (26 .mu.L, 0.16 mmol) followed by TFA (25 .mu.L, 0.33
mmol). The mixture was stirred for 2 h at 0.degree. C. and rt for 2
h whereupon additional portions of Et.sub.3SiH (26 .mu.L, 0.16
mmol) and TFA (25 .mu.L, 0.33 mmol) were added and the mixture was
stirred for 4 h at rt (until complete by TLC). The mixture was
concentrated under reduced pressure and the crude residue was
partitioned between CH.sub.2Cl.sub.2 (3 mL) and sat. aq.
NaHCO.sub.3 (1.5 mL). The layers were separated and the aqueous
layer was extracted with CH.sub.2Cl.sub.2 (2.times.4 mL). The
organic layers were combined, washed with brine (1.times.5 mL),
dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure. The crude product was purified by prep TLC (4.times.1000
mM) eluting with CH.sub.2Cl.sub.2/MeOH (20:1) to afford 21 mg (48%)
of a yellow solid. mp 146-148.degree. C.; M+H=316.
Example 331
[0519] ##STR1653##
[0520] To a solution of 3-H adduct (90 mg, 0.30 mmol) from
Preparative Example 187.10 in conc. H.sub.2SO.sub.4 (2 mL) at
0.degree. C. was added fuming HNO.sub.3 (30 .mu.L, 0.72 mmol)
dropwise. The resulting mixture was stirred for 1 h at 0.degree. C.
whereupon ice (.about.1 g) was added to the mixture. The resulting
precipitate was collected and was washed with water (2.times.2 mL)
and CH.sub.2Cl.sub.2 (2.times.2 mL). The crude product was dried
under high vacuum to afford 67 mg (60%) of the monosulfate salt as
a yellow/orange solid. mp 250.degree. C.; M+H (free base)=392.
Example 332
[0521] Step A: ##STR1654##
[0522] To a solution of aldehyde (0.10 g, 0.39 mmol) from
Preparative Example 168 in THF (2.5 mL) at 0.degree. C. was added
CF.sub.3TMS (64 mL, 0.43 mmol) followed by CsF (10 mg). The
resulting mixture was stirred for 2 h at 0.degree. C. and 2 h at
rt. 1M HCl (5 mL) was added and the mixture was diluted with
CH.sub.2Cl.sub.2 (10 mL). The layers were separated, the aqueous
layer was extracted with CH.sub.2Cl.sub.2 (2.times.10 mL), and the
organic layers were combined. The organic layer was washed with
brine (1.times.10 mL), dried (Na.sub.2SO.sub.4), filtered, and
concentrated under reduced pressure to afford 127 mg (99%) of a
yellow semisolid. M+H=328. The crude product was carried on without
further purification. Step B: ##STR1655##
[0523] By utilizing the general procedure set forth in Example 1,
the 7-Cl adduct (127 mg, 0.39 mmol) from Example 332, Step A was
reacted with 3-(aminomethyl)pyridine (73 .mu.L, 0.43 mmol) to
afford 80 mg (51%) of the title compound as a light yellow solid.
mp 68-72.degree. C.; M+H=400.
Example 333
[0524] ##STR1656##
[0525] To a solution of aniline (200 mg, 0.69 mmol) from
Preparative Example 174 in THF (6 mL) at rt was added aldehyde (114
mg, 0.83 mmol) from Preparative Example 256 followed by dropwise
addition of Ti(i-OPr).sub.4 (0.82 mL, 2.77 mmol). The mixture was
stirred at reflux for 4 h and was cooled to rt. NaCNBH.sub.3 (347
mg, 5.53 mmol) was added and the mixture was stirred for 2 h at rt.
The mixture was cooled to 0 oC, treated with 1M NaOH (4 mL) and
brine (1 mL) and stirred for 30 min. The mixture was extracted with
CH.sub.2Cl.sub.2 (3.times.10 mL) and the organic layers were
combined. The organic layer was washed with brine (1.times.7 mL),
dried (Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure. The crude product was purified by preparative thin-layer
chromatography (8.times.1000 .upsilon.M plates) eluting with
CH.sub.2Cl.sub.2/MeOH (25:1) to afford 89 mg (31%) of the title
compound as a yellow solid. mp 210-213.degree. C.; M+H=411.
Examples 334-337
[0526] By essentially the same procedure set forth in Example 333
only by utilizing the anilines shown in Column 2 of Table 30 and
the aldehydes shown in Column 3 of Table 30, the compounds in
Column 4 of Table 30 were prepared: TABLE-US-00030 TABLE 30 CMPD
Column 2 Column 3 Column 4 1. mp (.degree. C.) Ex. (Aniline)
(Aldehyde) (Final Structure) 2. M + H 334 ##STR1657## ##STR1658##
##STR1659## 1. mp = 85-87 2. M + H = 425 335 ##STR1660##
##STR1661## ##STR1662## 1. mp = 160-162 2. M + H = 451 336
##STR1663## ##STR1664## ##STR1665## 1. mp = 117-119 2. M + H = 382
337 ##STR1666## ##STR1667## ##STR1668## 1. mp = 171-175 2. M + H =
400
Example 338
[0527] ##STR1669## ##STR1670## Step A:
[0528] Reaction of aniline (0.20 g, 0.69 mmol) with aldehyde (0.13
g, 0.83 mmol) under the reaction conditions described in Example
333 afforded 70 mg (23%) of thiomethyl derivative as a yellow
solid. M+H=428.
Step B:
[0529] To a solution of thiomethyl derivative (60 mg, 0.14 mmol)
from Example 338, Step A in dioxane (2 mL) was added Boc.sub.2O (61
mg, 0.28 mmol) followed by DMAP (21 mg, 0.17 mmol). The mixture was
stirred for 14 h at rt and was concentrated under reduced pressure.
The crude product was purified by preparative thin-layer
chromatography (6.times.1000 .mu.M plates) eluting with
hexanes/EtOAc (4:1) to afford 61 mg (83%) of the title compound as
a yellow solid. M+H=528.
Step C:
[0530] To a solution of thiomethyl derivative from Example 338,
Step B (41 mg, 0.078 mmol) in CH.sub.2Cl.sub.2 (2 mL) was added
MCPBA (33 mg, 0.19 mmol) in one portion. The resulting mixture was
stirred for 3 h at rt and the mixture was diluted with
CH.sub.2Cl.sub.2 (5 mL) and sat. aq. NaHCO.sub.3 (2.5 mL). The
layers were separated, the aqueous layer was extracted with
CH.sub.2Cl.sub.2 (2.times.5 mL), and the organic layers were
combined. The organic layer was dried (Na.sub.2SO.sub.4), filtered,
and concentrated under reduced pressure to afford 40 mg (92%) of
the sulfone adduct as a light yellow solid. M+H=560.
Step D:
[0531] To a flask charged with sulfone from Example 338, Step C (75
mg, 0.13 mmol) and a stir bar was added morpholine (2 ml; 22 mmol).
The mixture was heated at reflux for 12 h, cooled to rt, and
concentrated to dryness under high vacuum. The crude product was
purified by preparative thin-layer chromatography (6.times.1000
.mu.M plates) eluting with CH.sub.2Cl.sub.2/MeOH (40:1) to afford
41 mg (68%) of the title compound as a yellow solid. mp
209-210.degree. C.; M+H=466.
Example 339
[0532] ##STR1671##
[0533] The title compound was prepared according to the procedure
outlined in Example 338 except using benzyl amine to afford 12 mg
(70%) of a white solid. mp 194-196; M+H=487.
Example 340
[0534] ##STR1672## Step A:
[0535] To a solution of 5-chloro adduct (0.15 g, 0.34 mmol) in
dioxane/DIPEA (2.5 mL/1.0 mL) at rt was added cyclopentylamine
(0.041 .mu.L, 0.41 mmol) dropwise. The resulting solution was
stirred at reflux for 16 h, cooled to rt, and concentrated under
reduced pressure. The crude material was purified by preparative
thin-layer chromatography (8.times.1000 .mu.M) eluting with
CH.sub.2Cl.sub.2/MeOH (25:1) to afford 148 mg (89%) of a yellow
oil. M+H=489.
Step B: Removal of the T-Butoxycarbonyl Protecting Group with
TFA
[0536] To a solution of the compound prepared in Example 340, Step
A (135 mg, 0.28 mmol) in CH.sub.2Cl.sub.2 (2 mL) at rt was added
TFA (0.54 mL, 7.0 mmol) dropwise. The resulting solution was
stirred for 18 h at rt and was concentrated under reduced pressure.
The crude material was redissolved in CH.sub.2Cl.sub.2 (5 mL) and
the organic layer was sequentially washed with sat. aq. NaHCO.sub.3
(2.times.2 mL) and brine (1.times.2 mL). The organic layer was
dried (Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure. The crude material was purified by preparative thin-layer
chromatography (8.times.1000 .mu.M) eluting with
CH.sub.2Cl.sub.2/MeOH (20:1) to afford 105 mg (97%) of white solid.
mp 120-122.degree. C.; M+H=389.
Example 341
[0537] ##STR1673## Step A:
[0538] By essentially the same procedure set forth in Example 340
only substituting the appropriate amine, the above compound was
prepared. MS: MH.sup.+=431. Step B: Removal to T-butoxycarbonyl
Protecting Group with KOH. ##STR1674##
[0539] To a mixture of the compound prepared in Example 341, Step A
(0.14 g, 0.26 mmol) in EtOH:H.sub.2O (3 mL, 2:1) was added KOH
(0.29 g, 20 eq.) in one portion. The resulting solution was stirred
at reflux 14 hours, cooled to room temperature, and concentrated
under reduced pressure. The residue was taken up in
CH.sub.2Cl.sub.2 (5 mL) and diluted with saturated NaHCO.sub.3 (2
mL). The layers were separated and the aqueous layer extracted with
CH.sub.2Cl.sub.2 (2.times.4 mL). The combined organics were washed
with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated
under reduced pressure. The crude product was purified by
preparative TLC (8.times.1000 .mu.M) eluting with 5% MeOH in
CH.sub.2Cl.sub.2 solution (0.066 g, 59% yield). MS: MH.sup.+=432;
mp=219-221.degree. C.
Examples 342-397
[0540] By essentially the same procedure set forth in Example 340
only substituting the chlorides in Column 2 of Table 31 and
removing the t-butoxycarbonyl protecting group by the method shown
in Column 3 of Table 31, the compounds shown in Column 4 of Table
31 were prepared. TABLE-US-00031 TABLE 31 Ex. Column 2 Column 3
Column 4 CMPD 342 ##STR1675## HCI ##STR1676## MS: MH.sup.+ = 403
m.p. 151-157.degree. C. 343 ##STR1677## HCI ##STR1678## MS:
MH.sup.+ = 466 m.p. 212-217.degree. C. 344 ##STR1679## HCI
##STR1680## MS: MH.sup.+ = 405 m.p. 53-58.degree. C. 345
##STR1681## HCI ##STR1682## MS: MH.sup.+ = 405 m.p. 63-69.degree.
C. 346 ##STR1683## HCI ##STR1684## MS: MH.sup.+ = 363 m.p.
170-171.degree. C. 347 ##STR1685## HCI ##STR1686## MS: MH.sup.+ =
407 m.p. 148-151.degree. C. 348 ##STR1687## HCI ##STR1688## MS:
MH.sup.+ = 435 m.p. 56-59.degree. C. 349 ##STR1689## HCI
##STR1690## MS: MH.sup.+ = 445 m.p. 66-68.degree. C. 350
##STR1691## KOH ##STR1692## MS: MH.sup.+ = 417 m.p. 149-151.degree.
C. 351 ##STR1693## KOH ##STR1694## MS: MH.sup.+ = 431 m.p.
111-114.degree. C. 352 ##STR1695## KOH ##STR1696## MS: MH.sup.+ =
417 m.p. 53-58.degree. C. 353 ##STR1697## KOH ##STR1698## MS:
MH.sup.+ = 456 m.p. 186-189.degree. C. 354 ##STR1699## KOH
##STR1700## MS: MH.sup.+ = 416 m.p. 210-213.degree. C. 355
##STR1701## TFA ##STR1702## 1. mp = 68-70 2. M + H = 494 356
##STR1703## KOH ##STR1704## 1. mp = 181-183 2. M + H = 404 357
##STR1705## TFA ##STR1706## 1. mp = 69-71 2. M + H = 494 358
##STR1707## KOH ##STR1708## 1. mp = 182-184 2. M + H = 404 359
##STR1709## KOH ##STR1710## 1. mp = 202-204 2. M + H = 418 360
##STR1711## TFA ##STR1712## 1. mp = 160-162 2. M + H = 402 361
##STR1713## TFA ##STR1714## 1. mp = 151-153 2. M + H = 416 362
##STR1715## KOH ##STR1716## 1. mp = 140-143 2. M + H = 418 363
##STR1717## KOH ##STR1718## 1. mp = 139-142 2. M + H = 418 364
##STR1719## KOH ##STR1720## 1. mp = 115-117 2. M + H = 418 366
##STR1721## TFA ##STR1722## 1. mp = 102-104 2. M + H = 445 367
##STR1723## TFA ##STR1724## 1. mp = 118-120 2. M + H = 474 368
##STR1725## TFA ##STR1726## 1. mp = 106-108 2. M + H = 474 369
##STR1727## TFA ##STR1728## 1. mp = 160-161 2. M + H = 464 370
##STR1729## TFA ##STR1730## 1. mp = 93-95 2. M + H = 432 371
##STR1731## KOH ##STR1732## 1. mp = 108-110 2. M + H = 432 372
##STR1733## KOH ##STR1734## 1. mp = 180-182 2. M + H = 418 373
##STR1735## TFA ##STR1736## 1. mp = 169-170 2. M + H = 417 374
##STR1737## TFA ##STR1738## 1. mp = 77-79 2. M + H = 479 375
##STR1739## TFA ##STR1740## 1. mp = 76-79 2. M + H = 479 376
##STR1741## TFA ##STR1742## 1. mp = 105-107 2. M + H = 389 377
##STR1743## TFA ##STR1744## 1. mp = 105-107 2. M + H = 389 378
##STR1745## TFA ##STR1746## 1. mp = 130-133 2. M + H = 389 379
##STR1747## TFA ##STR1748## 1. mp = 132-135 2. M + H = 431 380
##STR1749## TFA ##STR1750## 1. mp = 135-137 2. M + H = 372 381
##STR1751## KOH ##STR1752## 1. mp = 78-82 2. M + H = 432 382
##STR1753## TFA ##STR1754## 1. mp = 101-103 2. M + H = 432 383
##STR1755## TFA ##STR1756## 1. mp = 92-95 2. M + H = 472 384
##STR1757## TFA ##STR1758## 1. mp = 107-111 2. M + H = 444 384.10
##STR1759## TFA ##STR1760## 1. mp =2. M + H = 417 384.11
##STR1761## TFA ##STR1762## 1. mp = 210-212 2. M + H = 391 385
##STR1763## TFA ##STR1764## 1. mp = 122-124 2. M + H = 403 386
##STR1765## TFA ##STR1766## 1. mp = 186-188 2. M + H = 491 387
##STR1767## TFA ##STR1768## 1. mp = 173-175 2. M + H = 483 388
##STR1769## TFA ##STR1770## 1. mp = 167-169 2. M + H = 450 389
##STR1771## TFA ##STR1772## 1. mp = 90-92 2. M + H = 374 390
##STR1773## TFA ##STR1774## 1. mp = 113-115 2. M + H = 404 391
##STR1775## TFA ##STR1776## 1. mp = 114-116 2. M + H = 404 392
HNMe.sub.2 TFA ##STR1777## LCMS: MH.sup.+ = 347; 393 H.sub.2NMe TFA
##STR1778## LCMS: MH.sup.+ = 333; 394 ##STR1779## TFA ##STR1780##
LCMS: MH.sup.+ = 359; 395 ##STR1781## TFA ##STR1782## LCMS:
MH.sup.+ = 405; 396 ##STR1783## TFA ##STR1784## LCMS: MH.sup.+ =
405; 397 ##STR1785## TFA ##STR1786## LCMS: MH.sup.+ = 391;
Additional data for select example shown below:
Example 392
[0541] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.65 (s, 1H), 8.46 (d,
J=3.3 Hz, 1H), 8.21 (t, J=6.6 Hz, 1H), 7.90 (s, 1H), 7.80 (d, J=7.8
Hz, 1H), 7.35 (dd, J=7.8, 4.8 Hz, 1H), 5.46 (s, 1H), 4.61 (d, J=6.9
Hz, 2H), 3.01 (s, 6H).
Example 393
[0542] .sup.1H NMR (CDCl.sub.3) .delta. 8.65 (s, 1H), 8.60 (d,
J=4.8 Hz, 1H), 7.76 (s, 1H), 7.70 (m, 1H), 7.32 (dd, J=8.1, 4.8 Hz,
1H), 6.43 (t, J=6.0 Hz, 1H), 5.08 (s, 1H), 4.80 (m, 1H), 4.56 (d,
J=6.0 Hz, 2H), 2.96 (d, J=5.1 Hz, 3H).
Example 394
[0543] .sup.1H NMR (CDCl.sub.3) .delta. 8.68 (s, 1H), 8.60 (d,
J=4.8 Hz, 1H), 7.76 (s, 1H), 7.72 (m, 1H), 7.32 (dd, J=7.8, 5.4 Hz,
1H), 6.55 (t, J=5.7 Hz, 1H), 5.53 (s, 1H), 5.35 (s, 1H), 4.62 (d,
J=5.7 Hz, 2H), 2.49 (m, 1H), 0.75 (m, 2H), 0.51 (m, 2H).
Example 395
[0544] .sup.1H NMR (CDCl.sub.3) .delta. 8.65 (s, 1H), 8.60 (d,
J=4.0 Hz, 1H), 7.75 (s, 1H), 7.69 (m, 1H), 7.33 (dd, J=8.1, 5.1 Hz,
1H), 6.45 (t, J=6.0 Hz, 1H), 5.07 (s, 1H), 4.69 (m, 1H), 4.54 (d,
J=6.0 Hz, 2H), 3.98 (m, 1H), 3.79 (dd, J=10.8, 2.4 Hz, 1H), 3.59
(dd, J=11.1, 7.2 Hz, 1H), 1.59-1.36 (m, 4H), 0.94 (t, J=6.9 Hz,
3H).
Example 396
[0545] .sup.1H NMR (CDCl.sub.3) .delta. 8.60 (s, 1H), 8.56 (d,
J=4.2 Hz, 1H), 7.73 (s, 1H), 7.66 (m, 1H), 7.31 (dd, J=7.8, 4.8 Hz,
1H), 6.51 (t, J=6.0 Hz, 1H), 5.05 (s, 1H), 4.86 (d, J=6.6 Hz, 1H),
4.50 (d, J=6.0 Hz, 2H), 3.94 (m, 1H), 3.78 (dd, J=11.1, 2.4 Hz,
1H), 3.57 (dd, J=11.1, 7.2 Hz, 1H), 1.57-1.34 (m, 4H), 0.91 (t,
J=7.2 Hz, 3H).
Example 397
[0546] .sup.1H NMR (CDCl.sub.3) .delta. 8.65 (s, 1H), 8.59 (d,
J=4.5 Hz, 1H), 7.75 (s, 1H), 7.69 (m, 1H), 7.31 (m, 1H), 6.43 (t,
J=6.0 Hz, 1H), 5.06 (s, 1H), 4.88 (m, 1H), 4.55 (d, J=6.0 Hz, 2H),
3.70 (m, 2H), 3.38 (m, 2H), 1.79-1.61 (m, 4H).
Examples 398-416
[0547] By essentially the same conditions set forth in Example 341,
Steps A and B only substituting the compound prepared in
Preparative Example 193.10, the compounds in Column 4 of Table 32
were prepared. TABLE-US-00032 TABLE 32 Ex. Column 2 Column 3 Column
4 CMPD 398 ##STR1787## ##STR1788## MS: MH.sup.+ = 419 m.p.
102-105.degree. C. 399 ##STR1789## ##STR1790## MS: MH.sup.+ = 421
m.p. 79-81.degree. C. 400 ##STR1791## ##STR1792## MS: MH.sup.+ =
421 m.p. 78-79.degree. C. 401 ##STR1793## ##STR1794## MS: MH.sup.+
= 433 m.p. 228-231.degree. C. 402 ##STR1795## ##STR1796## MS:
MH.sup.+ = 447 m.p. 97-102.degree. C. 403 ##STR1797## ##STR1798##
MS: MH.sup.+ = 421 m.p. .degree. C. 404 ##STR1799## ##STR1800## MS:
MH.sup.+ = 421 m.p. .degree. C. 405 ##STR1801## ##STR1802## MS:
MH.sup.+ = 386 m.p. .degree. C. 407 ##STR1803## KOH ##STR1804## 1.
mp = 98-100 2. M + H = 390 408 ##STR1805## TFA ##STR1806## 1. mp =
170-173 2. M + H = 404 409 ##STR1807## KOH ##STR1808## 1. mp =
219-221 2. M + H = 420 410 ##STR1809## KOH ##STR1810## 1. mp =
110-112 2. M + H = 448 411 ##STR1811## TFA ##STR1812## 1. mp =
81-83 2. M + H = 448 412 ##STR1813## TFA ##STR1814## 1. mp =
136-138 2. M + H = 448 413 NaOMe KOH ##STR1815## 1. mp = 107-110 2.
M + H = 351 414 ##STR1816## ##STR1817## LCMS: MH.sup.+ = 375;
Additional data for select examples shown below:
Example 414
[0548] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.26 (s, 1H), 8.23 (m,
1H), 8.13 (m, 1H), 7.90 (s, 1H), 7.40-7.27 (m, 3H), 5.34 (s, 1H),
4.49 (d, J=6.3 Hz, 2H), 2.56 (m, 1H), 0.67 (m, 2H), 0.35 (m,
2H).
Example 403
[0549] .sup.1H NMR (DMSO-d.sub.6+CDCl.sub.3) .delta. 8.08 (s, 1H),
7.90 (d, J=6.3 Hz, 1H), 7.49 (s, 1H), 7.34 (t, J=6.3 Hz, 1H),
7.16-7.09 (m, 2H), 5.65 (d, J=6.6 Hz, 1H), 4.97 (s, 1H), 4.90 (s,
1H), 4.29 (d, J=6.3 Hz, 2H), 3.70 (m, 1H), 3.46 (m, 1H), 3.34 (m,
1H), 1.35-1.17 (m, 4H), 0.71 (t, J=7.2 Hz, 3H).
Example 404
[0550] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.21 (s, 1H), 8.12 (d,
J=6.61 Hz, 1H), 8.06 (m, 1H), 7.86 (s, 1H), 7.38 (t, J=7.8 Hz, 1H),
7.30 (d, J=7.5 Hz, 1H), 6.73 (d, J=8.7 Hz, 1H), 5.28 (s, 1H), 4.70
(t, J=5.1 Hz, 1H), 4.41 (d, J=6.6 Hz, 2H), 4.00 (s, 1H), 3.39 (m,
1H), 1.53 (m, 1H), 1.36-1.25 (m, 3H), 0.86 (t, J=7.0 Hz, 3H).
Examples 417-421
[0551] By the procedure set forth in Chem. Pharm. Bull. 1999, 47,
928-938. utilizing the oxygen or sulfur nucleophiles shown in
Column 2 as described of Table 33 and by employing the cleavage
method listed in Column 3 of Table 33, the compounds in Column 4 of
Table 33 were prepared: TABLE-US-00033 TABLE 33 Column 3 CMPD
Column 2 (Cleavage Column 4 1. mp. Ex. (Nucleophile) method) (Final
Structure) 2. M + H 417 NaSMe TFA ##STR1818## 1. mp = 172-175 2. M
+ H = 351 418 NaSt-Bu TFA ##STR1819## 1. mp = 165-168 2. M + H =
392 419 NaSPh TFA ##STR1820## 1. mp = 154-156 2. M + H = 412 420
NaOMe TFA ##STR1821## 1. mp = 161-163 2. M + H = 335 421 NaOPh TFA
##STR1822## 1. mp = 64-66 2. M + H = 397
Example 422
[0552] ##STR1823##
[0553] To a solution of amino compound (18 mg, 0.043 mmol) from
Example 373 in CH.sub.2Cl.sub.2 (1 mL) at rt was added DIPEA (10
.mu.L, 0.056 mmol) followed by MeSO.sub.2Cl (4 mL, 0.052 mmol). The
mixture was stirred at rt for 12 h and was diluted with
CH.sub.2Cl.sub.2 (2 mL) and sat. aq. NaHCO.sub.3 (2 mL). The layers
were separated and the organic layer was extracted with brine
(1.times.2 mL). The organic layer was dried (Na.sub.2SO.sub.4),
filtered, and concentrated under reduced pressure. The crude
material was purified by preparative thin-layer chromatography
(4.times.1000 .mu.M) eluting with CH.sub.2Cl.sub.2/MeOH (20:1) to
afford 16 mg (75%) of white solid. mp 152-154.degree. C.;
M+H=495.
Examples 423-424
[0554] Utilizing the procedure outlined in Example 422, the amino
compounds (Column 2) were converted to the corresponding
methylsulfonamides (Column 3) in Table 34. TABLE-US-00034 TABLE 34
CMPD Column 2 Column 3 1. mp. Ex. (Amine) (Final Structure) 2. M +
H 423 ##STR1824## ##STR1825## 1. mp = 166-168 2. M + H = 467 424
##STR1826## ##STR1827## 1. mp = 165-168 2. M + H = 467
Example 425
[0555] Step A ##STR1828##
[0556] A mixture of the compound prepared in Preparative Example
194 (132 mg, 0.25 mmol), tributylvinyltin (95 mg, 0.30 mmol) and
tetrakis(triphenylphospine)palladium (29 mg, 0.025 mmol) in
anhydrous dioxane (5 mL) was refluxed under N.sub.2 for 24 hr. The
solvent was evaporated and the residue was purified by flash
chromatography using 2:1 CH.sub.2Cl.sub.2:EtOAc as eluent to yield
yellow waxy solid (53 mg, 50%). LCMS: MH.sup.+=428. Step B:
##STR1829##
[0557] A mixture of the compound prepared in Example 425, Step A
(50 mg, 0.12 mmol) and KOH (100 mg, 1.80 mmol) in ethanol (3 mL)
and H.sub.2O (0.6 mL) was stirred at 70.degree. C. under N.sub.2
for 24 hr. NaHCO.sub.3 (1.0 g), Na.sub.2SO.sub.4 (2.0 g), and
CH.sub.2Cl.sub.2 (20 mL) were added, the mixture was shaken and
then filtered. The solvent was evaporated and the residue was
purified by flash chromatography using 20:1:0.1
CH.sub.2Cl.sub.2:MeOH:conc.NH.sub.4OH as eluent to yield yellow
waxy solid (17 mg, 45%). LCMS: MH.sup.+=328. Mp=48-51.degree.
C.
Example 426
[0558] Step A: ##STR1830##
[0559] By essentially the same procedure set forth in Example 425,
Step A only using tributylmethylethynyltin, the compound shown
above was prepared. Step B: ##STR1831##
[0560] A mixture of the compound prepared in Example 426, Step A
(150 mg, 0.34 mmol) and PtO2 (30 mg, 0.13 mmol) in glacial acetic
acid (5 mL) was stirred under 1 atmosphere of H.sub.2 for 20 hr.
The mixture was filtered, fresh PtO2 (30 mg, 0.13 mmol) was added
and the mixture was stirred under 1 atmosphere of H.sub.2 for 2.5
hr. The mixture was poured onto Na.sub.2CO.sub.3 (20 g) and
H.sub.2O (200 mL) and it was extracted with CH.sub.2Cl.sub.2
(4.times.20 mL). The combined extracts were dried over
Na.sub.2SO.sub.4 and filtered. The solvent was evaporated and the
residue was purified by flash chromatography using 1:1
CH.sub.2Cl.sub.2:EtOAc as eluent to yield yellow waxy solid (68 mg,
45%). Step C: ##STR1832##
[0561] By essentially the same procedure set forth in Example 425,
Step B only substituting the compound prepared in Example 426, Step
B, the compound shown above was prepared, MS: MH.sup.+=344.
Mp=110-112.degree. C.
Example 427
[0562] Step A: ##STR1833##
[0563] A mixture of the compound prepared in Preparative Example
194 (527 mg, 1.00 mmol), triethyl(trifluoromethyl)silane (666 mg,
3.60 mmol), potassium fluoride (210 mg, 3.60 mmol), and CuI (850
mg, 4.46 mmol) in anhydrous DMF (4 mL) was stirred in a closed
pressure vessel at 80.degree. C. for 72 hr. CH.sub.2Cl.sub.2 (80
mL) was added and the mixture was filtered through Celite. The
solvent was evaporated and the residue was purified by flash
chromatography using 2:1 CH.sub.2Cl.sub.2:EtOAc as eluent to yield
pale orange waxy solid (70 mg, 15%). LCMS: M.sup.+=470. Step B:
##STR1834##
[0564] TFA (0.70 mL) was added at 0.degree. C. under N.sub.2 to a
stirred solution of the compound prepared in Example 427, Step A
(70 mg, 0.15 mmol), in anhydrous CH.sub.2Cl.sub.2 (3 mL). The
mixture was stirred at 0.degree. C. for 10 min, then at 25.degree.
C. for 2 hr. It was poured into 10% aqueous Na.sub.2CO.sub.3 (50
mL), extracted with CH.sub.2Cl.sub.2 (3.times.15 mL), dried over
Na.sub.2SO.sub.4, and filtered. The solvent was evaporated and the
residue was purified by flash chromatography using EtOAc as eluent
to yield off-white solid (40 mg, 73%). LCMS: M.sup.+=370.
Mp=156-158.degree. C.
Example 428
[0565] Step A: ##STR1835##
[0566] A mixture of the compound prepared in Preparative Example
193 (100 mg, 0.28 mmol), tetracyclopropylltin (91 mg, 0.32 mmol),
Pd.sub.2dba.sub.3 (8.0 mg, 0.009 mmol) and Pd(Pt--Bu.sub.3).sub.2
(9.0 mg, 0.017 mmol) in anhydrous dioxane (3 mL) was refluxed under
N.sub.2 for 27 hr. The solvent was evaporated and the residue was
purified by flash chromatography using 1:1 CH.sub.2Cl.sub.2:EtOAc
as eluent to yield colorless waxy solid (38 mg, 38%). LCMS:
MH.sup.+=366. Step B: ##STR1836##
[0567] A mixture of the compound prepared in Example 428, Step A
(36 mg, 0.10 mmol) and KOH (300 mg, 5.40 mmol) in ethanol (3 mL),
1,2-dimethoxyethane (3.0 mL0 and H.sub.2O (0.8 mL) was refluxed
under N.sub.2 for 4 hr. It was poured into saturated aqueous
NaHCO.sub.3 (100 mL), extracted with CH.sub.2Cl.sub.2 (5.times.10
mL), dried over Na.sub.2SO.sub.4, and filtered. The solvent was
evaporated and the residue was purified by flash chromatography
using 30:1 EtOAc:MeOH as eluent to yield colorless waxy (18 mg,
69%). LCMS: MH.sup.+=266. Step C: ##STR1837##
[0568] N-bromosuccinimide (12 mg, 0.068 mmol) in anhydrous
CH.sub.3CN (2 mL) was added under N.sub.2 to a stirred solution of
the compound prepared in Example 428, Step B (18 mg, 0.068 mmol),
in anhydrous CH.sub.3CN (2 mL). The mixture was stirred at
25.degree. C. for 2 hr. The solvent was evaporated and the residue
was purified by flash chromatography using EtOAc as eluent to yield
5 mg (17%) of the dibromo compound (white solid, LCMS:
MH.sup.+=370, mp=150-152.degree. C.) and 8 mg (34%) of the
monobromo compound (colorless solid, LCMS: M.sup.+=344,
mp=196-198.degree. C.).
Example 429
[0569] Step A: ##STR1838##
[0570] 1,3-propanesultam (72 mg, 0.60 mmol) in anhydrous DMF (3 mL)
was added under N.sub.2 to 60% NaH in mineral oil (36 mg, 0.90
mmol). The mixture was stirred for 20 min, then the compound
prepared in Preparative Example 196 (200 mg, 0.46 mmol) was added.
The mixture was stirred at 100.degree. C. for 30 min, the solvent
was evaporated and the residue was purified by flash chromatography
using EtOAc as eluent to yield colorless solid (150 mg, 63%). LCMS:
M.sup.+=523. Step B: ##STR1839##
[0571] TFA (1.5 mL) was added at 0.degree. C. under N.sub.2 to a
stirred solution of the compound prepared in Preparative Example
196 (140 mg, 0.27 mmol), in anhydrous CH.sub.2Cl.sub.2 (5 mL). The
mixture was stirred at 0.degree. C. for 10 min, then at 25.degree.
C. for 2 hr. It was poured onto Na.sub.2CO.sub.3 (10 g), extracted
with CH.sub.2Cl.sub.2 (3.times.50 mL), and filtered. The solvent
was evaporated and the residue was purified by flash chromatography
using 40:1 EtOAc:MeOH as eluent to yield white solid (32 mg, 28%).
LCMS: M.sup.+=423. Mp=218-220.degree. C.
Example 430
[0572] ##STR1840##
[0573] 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine
(1 equivalent) (prepared as described in Preparative Example 129),
or 3-Bromo-7-chloro-5-phenylpyrazolo[1,5-a]pyrimidine (1
equivalent) (prepared as described in Preparative Example 127),
R.sub.1NH.sub.2 (1.2 equivalents) and diisopropyl ethylamine (2
equivalents) were dissolved in anhydrous 1,4-dioxane and the
mixture was heated at 75.degree. C. for the time given in Table 97.
The solution was evaporated to dryness and the residue was
chromatographed on a silica gel column as described in Table 97, to
give the title compound.
[0574] Using the appropriate reactants and essentially the same
procedure as described above, the products of Examples 431 to 438
were prepared. Variations in the reaction conditions are noted in
Table 35. TABLE-US-00035 TABLE 35 FABMS Reaction Chromatographic
Ex. Structure MW MH.sup.+ Conditions Yield Data 431 ##STR1841##
463.8 463.0 75.degree. C./ 26 h 52% 15 .times. 2.5 cm 0.5-2% (10%
Conc. ammonium hydroxide in methanol)- dichloromethane 432
##STR1842## 429.3 429.2 75.degree. C./ 26 h 25.degree. C./ 39 h 53%
15 .times. 5 cm Dichloromethane; 1.5% (10% Conc. ammonium hydroxide
in methanol)- dichloromethane 433 ##STR1843## 477.8 477.1
75.degree. C./ 26 h 48% 15 .times. 5 cm Dichloromethane; 3.5-15%
(10% Conc. ammonium hydroxide in methanol)- dichloromethane 434
##STR1844## 477.8 477.0 75.degree. C./ 26 h 50% 15 .times. 5 cm
Dichloromethane: 3.5-15% (10% Conc. ammonium hydroxide in
methanol)- dichloromethane 435 ##STR1845## 434.8 434.1 75.degree.
C./ 24 h 25.degree. C./ 65 h 53% 15 .times. 2.5 cm 3% (10% Conc.
ammonium hydroxide in methanol)- dichloromethane 436 ##STR1846##
434.8 434.2 75.degree. C./ 27 h 31% 15 .times. 2.5 cm 3% (10% Conc.
ammonium hydroxide in methanol)- dichloromethane 437 ##STR1847##
438.7 438.1 75.degree. C./ 21 h 25.degree. C./ 46 h 97% 15 .times.
2.5 cm 0.25% (10% Conc. ammonium hydroxide in methanol)-
dichloromethane 438 ##STR1848## 438.7 438.1 75.degree. C./ 28 h
-20.degree. C./ 72 h 95% 60 .times. 2.5 cm 20% Ethyl acetate in
hexane
Additional physical data for the compounds are given below:
Example 431
[0575] Reactants:
3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (110
mg, 0.318 mmoles) (prepared as described in Preparative Example
129); 3-(aminomethyl)piperidine-1-carboxamide (60 mg, 0.382 mmoles)
(prepared as described in Preparative Example 241 above);
diisopropyl ethylamine (0.111 mL, 0.636 mmoles); anhydrous
1,4-dioxane (2.5 mL). Physical properties: HRFABMS: m/z 463.0628
(MH.sup.+). Calcd. for C.sub.19H.sub.21N.sub.6OBrCl: m/z 463.0649:
.delta..sub.H (CDCl.sub.3) 1.38 (1H, m, CH.sub.2), 1.52 (1H, m,
CH.sub.2), 1.73 (1H, m, CH), 1.93 (1H, m, CH.sub.2), 2.02 (1H, m,
CH.sub.2), 2.98 (1H, m, CH.sub.2), 3.06 (1H, m, CH.sub.2), 3.37
(2H, m, CH.sub.2), 3.58 (1H, m, CH.sub.2), 3.82 (1H, m, CH.sub.2),
4.87 (2H, bm, CONH.sub.2), 6.28 (1H, s, H.sub.6), 7.02 (1H, m, NH),
7.36 (2H, m, Ar--H), 7.45 (1H, m, Ar--H), 7.68 (1H, m, Ar--H) and
8.00 ppm (1H, s, H.sub.2); .delta..sub.C (CDCl.sub.3) CH.sub.2:
23.7, 28.1, 44.6, 45.5, 47.2; CH: 35.2, 87.4, 127.2, 130.1, 130.3,
131.6, 143.9: C: 83.1, 132.1, 138.6, 145.5, 146.5, 158.0,
158.4.
Example 432
[0576] Reactants:
3-Bromo-7-chloro-5-phenylpyrazolo[1,5-a]pyrimidine (500 mg, 1.62
mmoles) (prepared as described in Preparative Example 127);
3-(aminomethyl)piperidine-1-carboxamide (306 mg, 1.944 mmoles)
(prepared as described in Preparative Example 241 above);
diisopropyl ethylamine (0.566 mL, 3.24 mmoles); anhydrous
1,4-dioxane (13 mL). Physical properties: HRFABMS: m/z 429.1031
(MH.sup.+). Calcd. for C.sub.19H.sub.22N.sub.6OBr: m/z 429.1038;
.delta..sub.H (CDCl.sub.3) 1.44 (1H, m, CH.sub.2), 1.59 (1H, m,
CH.sub.2), 1.79 (1H, m, CH), 2.01 (1H, m, CH.sub.2), 2.08 (1H, m,
CH.sub.2), 3.03 (1H, m, CH.sub.2), 3.13 (1H, m, CH.sub.2), 3.39
(1H, m, CH.sub.2), 3.47 (1H, m, CH.sub.2), 3.63 (1H, m, CH.sub.2),
3.90 (1H, m, CH.sub.2), 4.88 (2H, bm, CONH.sub.2), 6.40 (1H, s,
H.sub.6), 6.90 (1H, m, NH), 7.53 (2H, m, Ar--H), 8.02 (1H, s,
H.sub.2) and 8.12 (1H, m, Ar--H); .delta..sub.C (CDCl.sub.3)
CH.sub.2: 23.7, 28.2, 44.7, 45.5, 47.3; CH: 35.2, 82.9, 127.5,
127.5, 128.7, 128.7, 130.0, 143.9; C: 83.0, 138.5, 145.8, 147.1,
158.3, 158.5.
Example 433
[0577] Reactants:
3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (347
mg, 1.01 mmoles) (prepared as described in Preparative Example
129); 3-(aminoethyl)piperidine-1-carboxamide (208 mg, 1.21 mmoles)
(prepared as described in Preparative Example 242 above);
diisopropyl ethylamine (0.393 mL, 2.02 mmoles); anhydrous
1,4-dioxane (9 mL). Physical properties: .delta..sub.H (CDCl.sub.3)
1.24 (1H, m, CH.sub.2), 1.55 (1H, m, CH), 1.72 (4H, m, CH.sub.2),
1.93 (1H, m, CH.sub.2), 2.69 (1H, m, CH.sub.2), 2.94 (1H, m,
CH.sub.2), 3.55 (2H, m, CH.sub.2), 3.73 (1H, m, CH.sub.2), 3.98
(1H, m, CH.sub.2), 4.83 (2H, bm, CONH.sub.2), 6.55 (1H, s,
H.sub.6), 6.78 (1H, m, NH), 7.41 (2H, m, Ar--H), 7.50 (1H, m,
Ar--H), 7.75 (1H, m, Ar--H) and 8.04 ppm (1H, s, H.sub.2);
.delta..sub.C (CDCl.sub.3) CH.sub.2: 24.6, 30.7, 32.6, 39.9, 45.3,
49.3; CH: 33.3, 87.5, 127.4, 130.1, 130.2, 131.6, 143.8; C: 83.2,
132.1, 138.8, 145.7, 146.2, 158.1, 158.1.
Example 434
[0578] Reactants:
3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (275
mg, 0.803 mmoles) (prepared as described in Preparative Example
129); 4-(aminoethyl)piperidine-1-carboxamide (165 mg, 0.963 mmoles)
(prepared as described in Preparative Example 243 above);
diisopropyl ethylamine (0.311 mL, 0.963 mmoles); anhydrous
1,4-dioxane (7.2 mL). Physical properties: .delta..sub.H
(d.sub.6-DMSO) 1.00 (2H, m, CH.sub.2), 1.50 (1H, m, CH), 1.59 (2H,
m, CH.sub.2), 1.67 (2H, m, CH.sub.2), 2.60 (2H, m, CH.sub.2), 3.48
(2H, m, CH.sub.2), 3.70 (2H, m, CH.sub.2), 5.84 (2H, bs,
CONH.sub.2), 6.43 (1H, s, H.sub.6), 7.50 (2H, m, Ar--H), 7.62 (2H,
m, Ar--H), 8.30 (1H, s, H.sub.2) and 8.36 ppm (1H, m, NH);
.delta..sub.C (d.sub.6-DMSO)CH.sub.2: 31.5, 31.5, 34.8, 43.5, 43.5,
43.5; CH: 32.8, 86.8, 127.1, 129.7, 130.3, 131.0, 143.3; CH: 81.3,
131.0, 138.7, 145.1, 146.4, 157.3, 157.8.
Example 435
[0579] Reactants:
3-Bromo-7-chloro-5-phenylpyrazolo[1,5-a]pyrimidine (174 mg, 0.507
mmoles) (prepared as described in Preparative Example 129) and
3-(aminomethyl)-1-methylpiperidine (65 mg, 0.507 mmoles) (prepared
as described in Preparative Example 244 above); diisopropyl
ethylamine (0.178 mL, 1.014 mmoles); anhydrous 1,4-dioxane (2.5
mL). Physical properties: HRFABMS: m/z 434.0742 (MH.sup.+). Calcd.
for C.sub.19H.sub.22N.sub.5BrCl: m/z 434.0747; .delta..sub.H
(CDCl.sub.3) 1.18 (1H, m, CH.sub.2), 1.68 (1H, m, CH.sub.2), 1.80
(1H, m, CH.sub.2), 1.87 (1H, m, CH.sub.2), 1.96 (1H, m, CH), 2.14
(2H, m, CH.sub.2), 2.32 (3H, s, NCH.sub.3), 2.75 (1H, m, CH.sub.2),
2.29 (1H, m, CH.sub.2), 3.42 (2H, m, --NHCH.sub.2CH), 6.36 (1H, s,
H.sub.6), 6.64 (1H, bm, NH), 7.41 (2H, m, Ar--H), 7.51 (1H, m,
Ar--H), 7.74 (1H, m, Ar--H) and 8.06 ppm (1H, s, H.sub.2);
.delta..sub.C (CDCl.sub.3) CH.sub.3: 46.6; CH.sub.2: 24.4, 27.9,
46.1, 56.1, 59.6; CH: 36.0, 87.4, 127.1, 130.1, 130.2, 131.6,
143.8; C: 83.2, 132.1, 138.9, 145.6, 146.4, 158.2.
Example 436
[0580] Reactants:
3-Bromo-7-chloro-5-phenylpyrazolo[1,5-a]pyrimidine (111.4 mg, 0.325
mmoles) (prepared as described in Preparative Example 129);
4-(aminomethyl)-1-methylpiperidine (50 mg, 0.39 mmoles) (prepared
as described in Preparative Example 245 above); diisopropyl
ethylamine (0.1135 mL, 0.65 mmoles); anhydrous 1,4-dioxane (1.5
mL). Physical data: HRFABMS: m/z 434.0735 (MH.sup.+). Calcd. for
C.sub.19H.sub.22N.sub.5BrCl: m/z 434.0747; .delta..sub.H
(CDCl.sub.3) 1.42 (2H, m, CH.sub.2), 1.72 (1H, m, CH), 1.82 (2H, m,
CH.sub.2), 1.93 (2H, m, CH.sub.2), 2.20 (3H, s, NCH.sub.3), 2.89
(2H, m, CH.sub.2), 3.34 (2H, m, --NHCH.sub.2CH), 6.31 (1H, s,
H.sub.6), 6.46 (1H, m, NH), 7.36 (2H, m, Ar--H), 7.46 (1H, m,
Ar--H), 7.70 (1H, m, Ar--H) and 8.00 ppm (1H, s, H.sub.2);
.delta..sub.C (CDCl.sub.3) CH.sub.3: 46.4; CH.sub.2: 30.2, 30.2,
48.0, 55.3, 55.3; CH: 35.4, 87.5, 127.2, 130.2, 130.2, 131.6,
143.8; C: 83.3, 132.2, 138.9, 145.7, 146.4, 158.1.
Example 437
[0581] Reactants:
3-Bromo-7-chloro-5-phenylpyrazolo[1,5-a]pyrimidine (191 mg, 0.557
mmoles) (prepared as described in Preparative Example 129);
3-(aminomethyl)benzonitrile (88.3 mg, 0.668 mmoles) (prepared as
described in Preparative Example 246 above); diisopropyl ethylamine
(0.192 mL, 1.114 mmoles); anhydrous 1,4-dioxane (4.5 mL). Physical
data: HRFABMS: m/z 438.0125 (MH.sup.+). Calcd. for
C.sub.19H.sub.12N.sub.5BrCl: m/z 438.0121; .delta..sub.H
(CDCl.sub.3) 4.76 (2H, d, --CH.sub.2NH--), 6.32 (1H, s, H.sub.6),
7.00 (1H, m, --CH.sub.2NH--), 7.40 (2H, m, Ar--H), 7.46 (1H, m,
Ar--H), 7.55 (1H, m, Ar--H), 7.67 (2H, m, Ar--H), 7.71 (1H, m,
Ar--H), 7.75 (1H, m Ar--H) and 8.10 ppm (1H, s, H.sub.2);
.delta..sub.C (CDCl.sub.3) CH.sub.2: 45.5; CH: 88.2, 127.2, 130.0,
130.2, 130.4, 130.6, 131.4, 131.6, 131.9, 144.1; C: 83.8, 113.4,
118.3, 132.0, 137.8, 138.3, 145.6, 145.9, 158.0.
Example 438
[0582] Reactants: 3-Bromo-7-chloro-5-phenyl
pyrazolo[1,5-a]pyrimidine (233.5 mg, 0.681 mmoles) (prepared as
described in Preparative Example 129); 4-(aminomethyl)benzonitrile
(108 mg, 0.817 mmoles) (prepared as described in Preparative
Example 247 above); diisopropyl ethylamine (0.235 mL, 1.362
mmoles); anhydrous 1,4-dioxane (5.3 mL). Physical data: HRFABMS:
m/z 438.0117 (MH.sup.+) Calcd. for C.sub.20H.sub.14N.sub.5BrCl: m/z
438.0121; .delta..sub.H (CDCl.sub.3) 4.80 (2H, d, CH.sub.2), 6.30
(1H, s, H.sub.6), 7.01 (1H, m, NH), 7.40 (2H, m, Ar--H), 7.47 (1H,
m, Ar--H), 7.70 (2H, m, Ar--H), 7.72 (2H, m, Ar--H), 7.80 (1H, m,
Ar--H) and 8.10 ppm (1H, s, H.sub.2); .delta..sub.C (CDCl.sub.3)
CH.sub.2: 45.8; CH: 88.2, 127.2, 127.7, 127.7, 130.2, 130.4, 131.6,
132.9, 132.9, 144.1; C: 83.8, 112.2, 118.4, 132.0, 138.2, 141.5,
145.5, 146.0, 158.0.
Example 439
[0583] ##STR1849##
[0584] 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine
(50 mg, 0.146 mmoles) (prepared as described in Preparative Example
129) was dissolved in anhydrous 1,4-dioxane (5 mL) in a GeneVac
Technologies carousel reaction tube. PS-diisopropyl ethylamine
resin (161 mg, 0.5828 mmoles) was added to each tube. A freshly
prepared 1M solution of the appropriate amine R.sub.1NH.sub.2 in
anhydrous 1,4-dioxane (0.2185 mL, 0.2185 mmoles) was added to each
tube and the tubes were sealed and heated at 70.degree. C. for 78 h
with magnetic stirring in the reaction block. Each tube was
filtered and the resin was washed with anhydrous 1,4-dioxane and
then dichloromethane. The combined individual filtrates from each
tube were evaporated to dryness and the residues were each
re-dissolved in anhydrous 1,4-dioxane (5 mL) and placed in GeneVac
reaction tubes. To each tube was added PS-isocyanate resin (594 mg,
0.8742 mmoles) and PS-trisamine resin (129 mg, 0.4371 mmoles) and
the tubes were stirred at 25.degree. C. for 20 h in the reaction
block. The resins were filtered off and washed with anhydrous
1,4-dioxane and dichloromethane. The filtrates from each tube were
evaporated to dryness and the residues were each chromatographed on
a silica gel column using the column size and the eluant shown in
Table 36, to give the title compounds. TABLE-US-00036 TABLE 36
FABMS Chromatographic Ex. Structure MW MH.sup.+ Yield Data 440
##STR1850## 428.7 428.0 81% 15 .times. 2.5 cm Dichloromethane; 0.5%
Methanol in dichloromethane 441 ##STR1851## 428.7 428.0 48% 20
.times. 2 cm Dichloromethane; 1.5% Methanol in dichloromethane 442
##STR1852## 428.7 428.0 24% 15 .times. 2.5 cm Dichloromethane; 1.5%
Methanol in dichloromethane 443 ##STR1853## 463.8 463.0 44% 15
.times. 2.2 cm Dichloromethane; 5% Methanol in dichloromethane 444
##STR1854## 434.8 434.1 63% 15 .times. 2.5 cm 5% Methanol in
dichloromethane 445 ##STR1855## 448.8 448.2 65% 15 .times. 2.5 cm
5% Methanol in dichloromethane 446 ##STR1856## 448.8 448.1 40% 15
.times. 2.5 cm Dichloromethane; 0.5% Methanol in dichloromethane
447 ##STR1857## 436.7 436.1 72% 15 .times. 2.5 cm 0.5% Methanol in
dichloromethane 448 ##STR1858## 450.8 450.0 53% 20 .times. 2 cm
Dichloromethane; 0.5% Methanol in dichloromethane 449 ##STR1859##
381.7 381.0 44% 20 .times. 2 cm 1.5% Methanol in
dichloromethane
Additional physical data for the compounds are given below:
Example 440
[0585] Physical properties: HRFABMS: m/z 428.0272 (MH.sup.+).
Calcd. for C.sub.19H.sub.16N.sub.5BrCl: m/z 428.0278; .delta..sub.H
(CDCl.sub.3) 3.28 (2H, dd, C.sub.5H.sub.4NCH.sub.2CH.sub.2NH--),
3.94 (2H, ddd, C.sub.5H.sub.4NCH.sub.2CH.sub.2NH--), 6.40 (1H, s,
H.sub.6), 7.22-7.29 (3H, m, Ar--H), 7.38-7.44 (2H, m, Ar--H), 7.51
(1H, m, Ar--H), 7.68 (1H, ddd, Ar--H), 7.73 (1H, Ar--H), 8.18 (1H,
s, H.sub.2) and 8.68 ppm (1H, NH); .delta..sub.C (CDCl.sub.3)
CH.sub.2: 36.4, 41.5; CH: 87.3, 122.1, 123.6, 127.1, 130.1, 130.1,
131.6, 137.0, 143.8, 149.5; C: 83.1, 132.1, 138.9, 145.7, 146.3,
158.0, 158.1.
Example 441
[0586] Physical properties: HRFABMS: m/z 428.0272 (MH.sup.+).
Calcd. for C.sub.19H.sub.16N.sub.5BrCl: m/z 428.0278; .delta..sub.H
(CDCl.sub.3) 3.12 (2H, dd, C.sub.5H.sub.4NCH2CH.sub.2NH--), 3.77
(2H, ddd, C.sub.5H.sub.4NCH.sub.2CH.sub.2NH--), 6.40 (1H, s,
H.sub.6), 6.59 (1H, m, Ar--H), 7.34 (1H, bm, Ar--H), 7.39-7.45 (2H,
m, Ar--H), 7.52 (1H, m, Ar--H), 7.62 (1H, m, Ar--H), 7.75 (1H, m,
Ar--H), 8.05 (1H, s, H.sub.2) and 8.63 ppm (1H, m, NH);
.delta..sub.C (CDCl.sub.3) CH.sub.2: 32.7, 43.1; CH: 87.5, 127.2,
130.2, 130.3, 131.6, 136.4, 142.9, 148.3, 149.8; C: 83.5, 132.0,
138.6, 145.6, 145.9, 158.1.
Example 442
[0587] Physical properties: HRFABMS: m/z 428.0275 (MH.sup.+).
Calcd. for C.sub.19H.sub.16N.sub.5BrCl: m/z 428.0278; .delta..sub.H
(CDCl.sub.3) 3.13 (2H, dd, C.sub.5H.sub.4NCH2CH.sub.2NH--), 3.80
(2H, ddd, C.sub.5H.sub.4NCH.sub.2CH.sub.2NH--), 6.42 (1H, s,
H.sub.6), 6.53 (1H, m, Ar--H), 7.23 (2H, m, Ar--H), 7.40-7.46 (2H,
m, Ar--H), 7.62 (1H, m, Ar--H), 7.76 (1H, m, Ar--H), 8.07 (1H, s,
H.sub.2) and 8.63 ppm (1H, m, NH); .delta..sub.C (CDCl.sub.3)
CH.sub.2: 34.7, 42.5; CH: 87.4, 124.5, 124.5, 127.2, 130.2, 130.3,
131.6, 144.0, 150.2, 150.2; C: 83.5, 132.0, 138.6, 145.6, 145.9,
146.6, 158.1.
Example 443
[0588] Physical properties: HRFABMS: m/z 463.1003 (MH.sup.+).
Calcd. for C.sub.20H.sub.25N.sub.6BrCl: m/z 463.1013; .delta..sub.H
(CDCl.sub.3) 1.98 (2H, m, .dbd.NCH.sub.2CH.sub.2CH.sub.2NH--), 2.43
(3H, s, NCH.sub.3), 2.67 (2H, m,
.dbd.NCH.sub.2CH.sub.2CH.sub.2NH--), 2.70 (8H, piperazine
CH.sub.2), 3.58 (2H, m, .dbd.NCH.sub.2CH.sub.2CH.sub.2NH--), 6.32
(1H, s, H.sub.6), 7.37-7.43 (2H, m, Ar--H), 7.50 (1H, m, Ar--H),
7.73 (1H, m, Ar--H), 8.06 (1H, s, H.sub.2) and 8.60 ppm (1H, m,
NH); .delta..sub.C (CDCl.sub.3) CH.sub.3: 46.1; CH.sub.2: 24.1,
42.8, 53.3, 54.6, 54.6, 57.5, 57.5; CH: 87.1, 127.0, 130.0, 130.1,
131.5, 143.4; C: 82.7, 132.1, 139.2, 145.7, 146.7, 158.0.
Example 444
[0589] Physical properties: HRFABMS: m/z 434.0742 (MH.sup.+).
Calcd. for C.sub.19H.sub.22N.sub.5BrCl: m/z 434.0747; .delta..sub.H
(CDCl.sub.3) 1.72 (1H, m, CH/CH.sub.2), 1.78-1.90 (2H, m,
CH/CH.sub.2), 2.02 (3H, m, CH/CH.sub.2), 2.50 (1H, m, CH/CH.sub.2),
2.45 (3H, s, NCH.sub.3), 2.51 (1H, m, CH/CH.sub.2), 3.23 (1H, m,
CH/CH.sub.2), 3.54 (1H, m, CH/CH.sub.2), 3.60 (1H, m, CH/CH.sub.2),
6.32 (1H, s, H.sub.6), 7.38-7.44 (2H, m, Ar--H), 7.51 (1H, m,
Ar--H), 7.75 (1H, m, Ar--H), 7.96 (1H, bm, NH) and 8.05 ppm (1H, s,
H.sub.2); .delta..sub.C (CDCl.sub.3) CH.sub.3: 40.7; CH.sub.2:
22.7, 29.3, 30.1, 39.4, 57.0; CH: 64.2, 87.1, 127.1, 130.0, 130.1,
131.6, 143.8; C: 82.8, 132.1, 139.1, 145.7, 146.4, 158.0.
Example 445
[0590] Physical properties: HRFABMS: m/z 448.0910 (MH.sup.+).
Calcd. for C.sub.20H.sub.24N.sub.5BrCl: m/z 448.0904; .delta..sub.H
(CDCl.sub.3) 1.90 (4H, m, CH.sub.2), 2.00 (4H, m, CH.sub.2), 2.84
(2H, m, CH.sub.2), 2.95 (4H, m, CH.sub.2), 3.51 (2H, m, CH.sub.2),
6.32 (1H, s, H.sub.6), 7.05 (1H, bm, NH), 7.37-7.43 (2H, m, Ar--H),
7.50 (1H, m, Ar--H), 7.73 (1H, m, Ar--H) and 8.04 ppm (1H, s,
H.sub.2); .delta..sub.C (CDCl.sub.3) CH.sub.2: 23.4, 23.4, 24.8,
26.4, 41.8, 53.9, 53.9, 55.2; CH: 87.3, 127.1, 130.1, 130.2, 131.6,
143.7; C: 83.0, 132.0, 138.9, 145.7, 146.3, 158.1.
Example 446
[0591] Physical properties: HRFABMS: m/z 448.0548 (MH.sup.+).
Calcd. for C.sub.19H.sub.20N.sub.5OBrCl: m/z 448.0540;
.delta..sub.H (CDCl.sub.3) 1.94 (2H, m, CH.sub.2), 2.09 (2H, m,
CH.sub.2), 2.49 (2H, m, CH.sub.2), 3.45 (2H, m, CH.sub.2), 3.51
(4H, m, CH.sub.2), 6.32 (1H, s, H.sub.6), 7.37-7.44 (3H, m,
Ar--H/NH), 7.51 (1H, m, Ar--H), 7.75 (1H, m, Ar--H) and 8.10 ppm
(1H, s, H.sub.2); .delta..sub.C (CDCl.sub.3) CH.sub.2: 18.0, 26.3,
30.8, 39.2, 39.9, 47.5; CH: 87.0, 127.1, 130.1, 130.1, 131.6,
144.1; C: 82.9, 132.1, 138.9, 145.6, 146.2, 157.9, 176.2.
Example 447
[0592] Physical properties: HRFABMS: m/z 436.0532 (MH.sup.+).
Calcd. for C.sub.18H.sub.20N.sub.5OBrCl: m/z 436.0540;
.delta..sub.H (CDCl.sub.3) 2.60 (4H, bm,
--N(CH.sub.2CH.sub.2).sub.2O), 2.83 (2H, m, .dbd.NCH2CH.sub.2NH--),
3.57 (2H, m, .dbd.NCH.sub.2CH.sub.2NH--), 3.83 (4H, m,
--N(CH.sub.2CH.sub.2).sub.2O), 6.37 (1H, s, H.sub.6), 6.99 (1H, bm,
NH), 7.38-7.45 (2H, m, Ar--H), 7.51 (1H, m, Ar--H), 7.75 (1H, m,
Ar--H) and 8.09 ppm (1H, s, H.sub.2); .delta..sub.C (CDCl.sub.3)
CH.sub.2: 38.2, 53.3, 53.3, 56.2, 66.9, 66.9; CH: 87.6, 127.1,
130.1, 130.2, 131.6, 143.9; C; 83.1, 132.1, 138.9, 145.7, 146.2,
158.1.
Example 448
[0593] Physical properties: HRFABMS: m/z 450.0688 (MH.sup.+).
Calcd. for C.sub.19H.sub.22N.sub.5OBrCl: m/z 450.0696;
.delta..sub.H (CDCl.sub.3) 1.98 (2H, m,
.dbd.NCH.sub.2CH.sub.2CH.sub.2NH--), 2.58 (4H, m,
--N(CH.sub.2CH.sub.2).sub.2O), 2.67 (2H, m,
.dbd.NCH.sub.2CH.sub.2CH.sub.2NH--), 3.59 (2H, m,
.dbd.NCH.sub.2CH.sub.2CH.sub.2NH--), 3.94 (4H, m,
--N(CH.sub.2CH.sub.2).sub.2O), 6.31 (1H, s, H.sub.6), 7.37-7.44
(2H, Ar--H), 7.51 (1H, m, Ar--H), 7.78 (1H, m, Ar--H), 8.08 (1H, s,
H.sub.2) and 8.60 ppm (1H, bm, NH); .delta..sub.C (CDCl.sub.3)
CH.sub.2: 23.7, 42.7, 52.9, 52.9, 58.0, 66.6, 66.6; CH: 87.0,
127.1, 130.0, 130.1, 131.5, 143.6; C: 82.8, 132.1, 139.1, 145.7,
146.7, 158.0.
Example 449
[0594] Physical properties: HRFABMS: m/z 381.0114 (MH.sup.+).
Calcd. for C.sub.15H.sub.15N.sub.4OBrCl: m/z 381.0118;
.delta..sub.H (CDCl.sub.3) 1.39 (3H, d, CHCH.sub.3), 2.76 (1H, bm,
--OH), 3.71 (1H, m, .dbd.CHCH.sub.2OH), 3.81 (1H, m,
.dbd.CHCH.sub.2OH), 3.88 (1H, m, .dbd.CHCH.sub.2OH), 6.38 (1H, s,
H.sub.6), 7.38 (2H, m, Ar--H), 7.48 (1H, m, Ar--H), 7.68 (1H, m,
Ar--H) and 8.02 ppm (1H, s, H.sub.2); .delta..sub.C (CDCl.sub.3)
CH.sub.3: 16.9; CH.sub.2: 65.0; CH: 50.0, 88.0, 127.1, 130.1,
130.3, 131.4, 143.8; C: 83.0, 132.0, 138.5, 145.6, 146.0,
158.2.
Example 450
[0595] ##STR1860##
[0596] 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine
(50 mg, 0.146 mmoles) (prepared as described in Preparative Example
129) was dissolved in anhydrous 1,4-dioxane (5 mL) in a GeneVac
Technologies carousel reaction tube. PS-diisopropyl ethylamine
resin (161 mg, 0.5828 mmoles) was added to each tube. A freshly
prepared solution of the appropriate amine R.sub.1NH.sub.2 (0.219
mmoles) in anhydrous 1,4-dioxane (0.3 mL) was added to each tube,
with the exception of Example 99-5 in which the amine was dissolved
in 10% MeOH in 1,4-dioxane (0.3 mL), and the tubes were sealed and
heated at 70.degree. C. for 74 h with magnetic stirring in the
reaction block. Each tube was filtered and the resin was washed
with anhydrous 1,4-dioxane and then dichloromethane. The combined
individual filtrates from each tube were evaporated to dryness and
the residues were each re-dissolved in anhydrous 1,4-dioxane (5 mL)
and placed in GeneVac reaction tubes. To each tube was added
PS-isocyanate resin (594 mg, 0.8742 mmoles) and PS-trisamine resin
(129 mg, 0.4371 mmoles) and the tubes were stirred at 25.degree. C.
for 20 h in the reaction block. The resins were filtered off and
washed with anhydrous 1,4-dioxane and dichloromethane. The
filtrates from each tube were evaporated to dryness and the
residues were each chromatographed on a silica gel column using the
column size and the eluant shown in Table 37, to give the title
compounds. TABLE-US-00037 TABLE 37 FABMS Chromatographic Ex.
Structure MW MH.sup.+ Yield Data 451 ##STR1861## 381.7 380.9 66% 15
.times. 2.5 cm; 0.5% Methanol in dichloromethane 452 ##STR1862##
381.7 380.9 60% 20 .times. 2.5 cm; 0.5% Methanol in dichloromethane
453 ##STR1863## 381.7 380.9 69% 15 .times. 2.5 cm; 0.35% Methanol
in dichloromethane 454 ##STR1864## 381.7 380.9 75% 15 .times. 2.5
cm; 0.35% Methanol in dichloromethane 455 ##STR1865## 397.7 397.2
84% 15 .times. 2.5 cm; 1.5% Methanol in dichloromethane 456
##STR1866## 397.7 457 ##STR1867## 395.7 395.0 60% 15 .times. 2.5
cm; 0.35% Methanol in dichloromethane 458 ##STR1868## 395.1 396.3
50% 15 .times. 2.5 cm; 0.35% Methanol in dichloromethane 459
##STR1869## 395.7 396.0 76% 15 .times. 2.5 cm; 0.35% Methanol in
dichloromethane
Additional physical data for the compounds are given below:
Example 451
[0597] Physical properties: HRFABMS: m/z 381.0115 (MH.sup.+).
Calcd. for C.sub.15H.sub.15N.sub.4OBrCl: m/z 381.0118;
[.alpha.].sub.D.sup.25.degree. C.+1.40.degree. (c=0.25, MeOH);
.delta..sub.H (CDCl.sub.3) 1.44 (3H, d, --CHCH.sub.3), 3.77 3.89
(1H, dd, CHCH.sub.2OH), (1H, dd, CHCH.sub.2OH), 3.94 (1H, m,
CHCH.sub.2OH), 6.41 (1H, s, H.sub.6), 6.58 (1H, d, NH), 7.41 (2H,
m, Ar--H), 7.51 (1H, m, Ar--H), 7.74 (1H, m, Ar--H) and 8.04 ppm
(1H, s, H.sub.2); .delta..sub.C (CDCl.sub.3) CH.sub.3: 17.1;
CH.sub.2: 65.5; CH: 49.9, 88.0, 127.1, 130.1, 130.2, 131.6, 143.8;
C: 83.2, 132.1, 138.7, 145.6, 145.8, 158.1.
Example 452
[0598] Physical properties: HRFABMS: m/z 381.0115 (MH.sup.+).
Calcd. for C.sub.15H.sub.15N.sub.4OBrCl: m/z 381.0118;
[.alpha.].sub.D.sup.25.degree. C.+6.50.degree. (c=0.32, MeOH);
.delta..sub.H (CDCl.sub.3) 1.44 (3H, d, --CHCH.sub.3), 3.78 (1H,
dd, CHCH.sub.2OH), 3.89 (1H, dd, CHCH.sub.2OH), 3.96 (1H, m,
CHCH.sub.2OH), 6.41 (1H, s, H.sub.6), 6.58 (1H, d, NH), 7.41 (2H,
m, Ar--H), 7.51 (1H, m, Ar--H), 7.75 (1H, m, Ar--H) and 8.04 ppm
(1H, s, H.sub.2); .delta..sub.C (CDCl.sub.3) CH.sub.3: 17.1;
CH.sub.2: 65.5; CH: 49.9, 88.0, 127.1, 130.1, 130.3, 131.6, 143.8;
C: 83.2, 132.1, 138.6, 145.6, 145.8, 158.1.
Example 453
[0599] Physical properties: HRFABMS: m/z 381.0115 (MH.sup.+).
Calcd. for C.sub.15H.sub.15N.sub.4OBrCl: m/z 381.0118;
[.alpha.].sub.D.sup.25.degree. C.+9.40.degree. (c=0.27, MeOH);
.delta..sub.H (CDCl.sub.3) 1.33 (3H, d, CH.sub.3), 2.25 (1H, bs,
OH), 3.37 (1H, dd, CH.sub.2), 3.51 (1H, m, CH.sub.2), 4.16 (1H, m,
CHOH), 6.35 (1H, s, H.sub.6), 6.93 (1H, m, NH), 7.40 (2H, m,
Ar--H), 7.50 (1H, m, Ar--H), 7.70 (1H, m, Ar--H) and 8.04 ppm (1H,
s, H.sub.2); .delta..sub.C (CDCl.sub.3) CH.sub.3: 20.8; CH.sub.2:
49.2; CH: 65.7, 87.8, 127.1, 130.1, 130.2, 131.2, 143.9; C: 83.1,
132.1, 138.5, 145.6, 146.6, 158.3.
Example 454
[0600] Physical properties: HRFABMS: m/z 381.0112 (MH.sup.+).
Calcd. for C.sub.15H.sub.15N.sub.4OBrCl: m/z 381.0118;
[.alpha.].sub.D.sup.25.degree. C.-3.20.degree. (c=0.29, MeOH);
.delta..sub.H (CDCl.sub.3) 1.32 (3H, d, CH.sub.3), 2.48 (1H, bs,
OH), 3.35 (1H, dd, CH.sub.2), 3.49 (1H, m, CH.sub.2), 4.15 (1H, m,
CHOH), 6.34 (1H, s, H.sub.6), 6.93 (1H, m, NH), 7.39 (2H, m,
Ar--H), 7.49 (1H, m, Ar--H), 7.68 (1H, m, Ar--H) and 8.03 ppm (1H,
s, H.sub.2); .delta..sub.C (CDCl.sub.3) CH.sub.3: 20.8; CH.sub.2:
49.2; CH: 65.7, 87.7, 127.1, 130.1, 130.3, 131.4, 143.9; C: 83.0,
132.0, 138.6, 145.6, 146.6, 158.3.
Example 455
[0601] Physical properties: HRFABMS: m/z 397.0054 (MH.sup.+).
Calcd. for C.sub.15H.sub.15N.sub.4O.sub.2BrCl: m/z 397.0067;
[.alpha.].sub.D.sup.25.degree. C.-9.5.degree. (c=0.28, MeOH);
.delta..sub.H (CDCl.sub.3) 3.18 (2H, bs, OH), 3.47 (1H, dd,
CH.sub.2), 3.58 (1H, dd, CH.sub.2), 3.63 (1H, dd, CH.sub.2OH), 3.70
(1H, dd, CH.sub.2OH), 3.98 (1H, m, CH), 6.35 (1H, s, H.sub.6), 7.10
(1H, m, NH), 7.37 (2H, m, Ar--H), 7.46 (1H, m, Ar--H), 7.64 (1H, m,
Ar--H) and 8.01 ppm (1H, s, H.sub.2); .delta..sub.C (CDCl.sub.3)
CH.sub.2: 44.7, 64.0; CH: 69.7, 87.7, 127.0, 130.1, 130.3, 131.3,
143.9; C: 82.9, 132.0, 138.4, 145.4, 146.7, 158.3.
Example 456
[0602] This enantiomer may be prepared by essentially the same
manner as described above.
Example 457
[0603] Physical properties: HRFABMS: m/z 395.0260 (MH.sup.+).
Calcd. for C.sub.16H.sub.17N.sub.4OBrCl: m/z 395.0274;
[.alpha.].sub.D.sup.25.degree. C.-34.3.degree. (c=0.28, MeOH);
.delta..sub.H (CDCl.sub.3) 1.08 (3H, dd, CH.sub.3), 1.78 (1H, m,
CH.sub.2), 1.86 (1H, m, CH.sub.2), 2.35 (1H, bs, CH.sub.2OH), 3.71
(1H, m, CHNH), 3.81 (1H, dd, CH.sub.2OH), 3.90 (1H, dd,
CH.sub.2OH), 6.42 (1H, s, H.sub.6), 6.53 (1H, m, NH), 7.41 (2H, m,
Ar--H), 7.51 (1H, Ar--H), 7.75 (1H, m, Ar--H) and 8.04 ppm (1H, s,
H.sub.2); .delta..sub.C (CDCl.sub.3) CH.sub.3: 10.5; CH.sub.2:
24.5, 63.7; CH: 55.9, 88.0, 127.1, 130.1, 130.2, 131.6, 143.8; C:
83.2, 132.1, 138.6, 145.6, 146.3, 158.1.
Example 458
[0604] Physical properties: HRFABMS: m/z 395.0274 (MH.sup.+).
Calcd. for C.sub.16H.sub.17N.sub.4OBrCl: m/z 395.0274;
[.alpha.].sub.D.sup.25.degree. C. +27.50.degree. (c=0.25, MeOH);
.delta..sub.H (CDCl.sub.3) 1.05 (3H, dd, CH.sub.3), 1.76 (1H, m,
CH.sub.2), 1.85 (1H, m, CH.sub.2), 2.28 (1H, bs, CH.sub.2OH), 3.67
(1H, m, CHNH), 3.77 (1H, dd, CH.sub.2OH), 3.84 (1H, dd,
CH.sub.2OH), 6.49 (1H, s, H.sub.6), 6.66 (1H, m, NH), 7.39 (2H, m,
Ar--H), 7.49 (1H, Ar--H), 7.71 (1H, m, Ar--H) and 8.04 ppm (1H, s,
H.sub.2); .delta..sub.C (CDCl.sub.3) CH.sub.3: 10.5; CH.sub.2:
24.3, 63.3; CH: 56.1, 88.0, 127.1, 130.1, 130.3, 131.5, 143.8; C:
83.0, 132.1, 138.6, 145.6, 146.3, 158.2.
Example 459
[0605] Physical properties: HRFABMS: m/z 395.0264 (MH.sup.+).
Calcd. for C.sub.16H.sub.17N.sub.4OBrCl: m/z 395.0274;
.delta..sub.H (CDCl.sub.3) 1.77 (2H, m,
--NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2OH), 1.90 (1H, bm,
--NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2OH), 1.93 (2H, m,
--NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2OH), 3.54 (2H, m,
--NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2OH), 3.77 (2H, m,
--NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2OH), 6.37 (1H, s, H.sub.6),
6.72 (1H, m, --NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2OH), 7.41 (2H, m,
Ar--H), 7.51 (1H, m, Ar--H), 7.75 (1H, m, Ar--H) and 8.06 ppm (1H,
s, H.sub.2); .delta..sub.C (CDCl.sub.3) CH.sub.2: 25.7, 29.7, 42.2,
62.2; CH: 87.4, 127.1, 130.1, 130.2, 131.6, 143.8; C: 83.1, 132.1,
138.8, 145.6, 146.3, 158.1.
Example 460
4-{[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YLAMINO]METHYL}PI-
PERIDINE-1-CARBOXYLIC ACID AMIDE
[0606] ##STR1870##
A.
4-{[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YLAMINO]METHYL-
}PIPERIDINE-1-CARBOXYLIC ACID tert-BUTYL ESTER
[0607] ##STR1871##
[0608] 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine
(300 mg, 0.875 mmoles) (prepared as described in Preparative
Example 129) was dissolved in anhydrous 1,4-dioxane (6.8 mL).
4-(aminomethyl)piperidine-1-carboxylic acid tert-butyl ester (225
mg, 1.05 mmoles) and diisopropyl ethylamine (0.3055 mL, 1.75
mmoles) were added and the mixture was heated at 75.degree. C. for
24 h. The solution was evaporated to dryness and the residue was
chromatographed on a silica gel column (15.times.5 cm) using
dichloromethane as the eluant to give
4-{[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]methyl}p-
iperidine-1-carboxylic acid tert-butyl ester (461.2 mg, 100%):
FABMS: m/z 520.1 (MH.sup.+); HRFABMS: m/z 520.1111 (MH.sup.+).
Calcd. for C.sub.23H.sub.28N.sub.5O.sub.2BrCl: m/z 520.1115;
.delta..sub.H (CDCl.sub.3) 1.30 (2H, m, CH.sub.2), 1.51 (9H, s,
--COOC(CH.sub.3).sub.3), 1.85 (2H, d, CH.sub.2), 1.95 (1H, m, CH),
2.76 (2H, m, CH.sub.2), 3.40 (2H, m, CH.sub.2), 6.37 (1H, s,
H.sub.6), 6.55 (1H, m, NH), 7.42 (2H, m, Ar--H), 7.52 (1H, m,
Ar--H), 7.76 (1H, m, Ar--H) and 8.07 ppm (1H, s, H.sub.2);
.delta..sub.C (CDCl.sub.3) CH.sub.3: 28.5, 28.5, 28.5; CH.sub.2:
29.1, 29.1, 43.5, 43.5, 47.9; CH: 36.3, 87.5, 127.2, 130.2, 130.3,
131.6, 143.9; C: 79.7, 83.3, 132.1, 138.6, 145.4, 146.3, 154.7,
158.1.
B.
[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YL]PIPERIDIN-4-YL-
METHYLAMINE
[0609] ##STR1872##
[0610]
4-{[3-Bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]m-
ethyl}piperidine-1-carboxylic acid tert-butyl ester (441 mg, 0.847
mmoles) (prepared as described in Example 460, Step A above) was
dissolved in methanol (4.5 mL) and 10% (v/v) conc. sulfuric acid in
1,4-dioxane (11.46 mL) was added. The mixture was stirred at
25.degree. C. for 0.5 h. The product was worked up as described in
Preparative Example 241, step B and chromatographed on a silica gel
column (15.times.5 cm) using 8% (10% conc. ammonium hydroxide in
methanol)-dichloromethane as the eluant to give
[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-4-
-ylmethylamine (314.4 mg, 88%): FABMS: m/z 420.0 (MH.sup.+);
HRFABMS: m/z 420.0585 (MH.sup.+). Calcd. for
C.sub.18H.sub.20N.sub.5BrCl: m/z 420.0591; .delta..sub.H
(CDCl.sub.3) 1.34 (2H, m, CH.sub.2), 1.86 (2H, m, CH.sub.2), 1.91
(1H, m, CH), 2.10 (1H, bm, piperidine-NH), 2.67 (2H, m, CH.sub.2),
3.18 (2H, m, CH.sub.2), 3.38 (2H, m, CH.sub.2), 6.37 (1H, s,
H.sub.6), 6.53 (1H, m, NH), 7.42 (2H, m, Ar--H), 7.52 (1H, m,
Ar--H), 7.76 (1H, m, Ar--H) and 8.06 ppm (1H, s Ar--H);
.delta..sub.C (CDCl.sub.3) CH.sub.2: 31.2, 31.2, 46.2, 46.2, 48.4;
CH: 36.4, 89.5, 127.1, 130.1, 130.5, 131.6, 143.8; C: 83.2, 132.1,
138.9, 145.6, 146.4, 158.1.
C.
4-{[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YLAMINO]METHYL-
}PIPERIDINE-1-CARBOXYLIC ACID AMIDE
[0611] ##STR1873##
[0612]
[3-Bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-
-4-ylmethylamine (57 mg, 0.136 mmoles) (prepared as described in
Example 460, Step B above) was dissolved in anhydrous
dichloromethane (1.2 mL) and trimethylsilylisocyanate (0.091 mL,
0.679 mmoles) was added. The mixture was stirred at 25.degree. C.
for 2.5 h. The mixture was diluted with dichloromethane and washed
with saturated aqueous sodium bicarbonate. The organic layer was
dried (MgSO.sub.4), filtered and evaporated to dryness. The residue
was chromatographed on a silica gel column (30.times.2.5 cm) using
3% (10% conc. ammonium hydroxide in methanol)-dichloromethane as
the eluant to give
4-{[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]methyl}p-
iperidine-1-carboxylic acid amide (53.7 mg, 86%): FABMS: m/z 463.1
(MH.sup.+); HRFABMS: m/z 463.0647 (MH.sup.+). Calcd. for
C.sub.19H.sub.21N.sub.6OBrCl: m/z 463.0649; .delta..sub.H
(d.sub.6-DMSO) 1.09 (2H, m, CH.sub.2), 1.63 (2H, m, CH.sub.2), 1.87
(1H, m, CH), 2.60 (2H, m, CH.sub.2), 3.53 (2H, bm, CONH.sub.2),
3.91 (2H, d, CH.sub.2), 6.52 (1H, s, H.sub.6), 7.50 (2H, m, Ar--H),
7.62 (2H, m, Ar--H), 8.33 (1H, s, H.sub.2) and 8.52 ppm (1H, m,
NH); .delta..sub.C (d.sub.6-DMSO)CH.sub.2: 30.1, 30.1, 44.2, 44.2,
47.7; CH: 36.4, 88.2, 128.1, 130.7, 131.4, 132.1, 147.9; C: 82.1,
132.1, 139.4, 145.7, 147.9, 158.1, 158.8.
Example 461
2-{2-[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YLAMINO]ETHYL}P-
IPERIDINE-1-CARBOXYLIC ACID AMIDE
[0613] ##STR1874##
A.
2-{2-[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YLAMINO]ETHY-
L}PIPERIDINE-1-CARBOXYLIC ACID tert-BUTYL ESTER
[0614] ##STR1875##
[0615] 3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine
(400 mg, 1.166 mmoles) (prepared as described in Preparative
Example 129) was dissolved in anhydrous 1,4-dioxane (5.7 mL).
2-Aminoethylpiperidine-1-carboxylic acid tert-butyl ester (266 mg,
1.166 mmoles) and diisopropyl ethylamine (0.409 mL, 2.33 mmoles)
were added and the mixture was heated at 75.degree. C. for 48 h.
Additional diisopropyl ethylamine (0.204 mL, 1.166 mmoles) was
added and the heating was continued for a total of 58 h. The
solution was evaporated to dryness and the residue was
chromatographed on a silica gel column (15.times.5 cm) using
dichloromethane followed by 0.3% (10% conc. ammonium hydroxide in
methanol)-dichloromethane as the eluant to give
2-{[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]ethyl}pi-
peridine-1-carboxylic acid tert-butyl ester (491.1 mg, 79%): FABMS:
m/z 534.1 (MH.sup.+); HRESIMS: m/z 534.12797 (MH.sup.+). Calcd. for
C.sub.24H.sub.30N.sub.5O.sub.2BrCl: m/z 534.12714; .delta..sub.H
(CDCl.sub.3) 1.50 (1H, m, CH.sub.2), 1.51 (9H, s,
COOC(CH.sub.3).sub.3), 1.57 (2H, m, CH.sub.2), 1.68 (2H, m,
CH.sub.2), 1.76 (2H, m, CH.sub.2), 2.24 (1H, bm, CH.sub.2),
2.82/3.40/3.54/4.08/4.51 (5H, m, CH/CH.sub.2), 6.34 (1H, s,
H.sub.6), 7.41 (2H, m, Ar--H), 7.51 (1H, m, Ar--H), 7.76 (1H, m,
Ar--H) and 8.08 ppm (1H, s, H.sub.2); .delta..sub.C (CDCl.sub.3)
CH.sub.3: 28.5, 28.5, 28.5; CH.sub.2: 19.2, 25.5, 29.2, 29.2, 39.2,
67.1; CH: .about.47.4, 87.1, 127.1, 130.1, 130.1, 131.6, 143.9; C:
80.0, 83.0, 132.1, 138.9, 145.7, 146.2, 158.0.
B.
[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YL]-(2-PIPERIDIN--
2-YLETHYL)AMINE
[0616] ##STR1876##
[0617]
2-{[3-Bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]e-
thyl}piperidine-1-carboxylic acid tert-butyl ester (465 mg, 0.869
mmoles) (prepared as described in Example 461, Step A above) was
dissolved in methanol (4.5 mL) and 10% (v/v) conc. sulfuric acid in
1,4-dioxane (11.76 mL) was added. The mixture was stirred at
25.degree. C. for 1.5 h. The product was worked up as described in
Preparative Example 241, step B and chromatographed on a silica gel
column (15.times.5 cm) using 3.5% (10% conc. ammonium hydroxide in
methanol)-dichloromethane as the eluant to give
[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-
-ylethyl)amine (365.6 mg, 97%): FABMS: m/z 434.1 (MH.sup.+);
HRFABMS: m/z 434.0726 (MH.sup.+). Calcd. for
C.sub.19H.sub.22N.sub.5BrCl: m/z 434.0747; .delta..sub.H
(CDCl.sub.3) 1.24 (1H, m, CH.sub.2), 1.41 (1H, m, CH.sub.2), 1.49
(1H, m, CH.sub.2), 1.66 (1H, m, CH.sub.2), 1.73 (1H, m, CH.sub.2),
1.81 (1H, m, CH.sub.2), 1.88 (2H, m, CH.sub.2), 2.68 (1H, m,
CH.sub.2), 2.78 (1H, m, CH.sub.2), 3.20 (1H, m, CH), 3.55 (1H, m,
CH.sub.2), 3.60 (1H, m, CH.sub.2), 6.32 (1H, s, H.sub.6), 7.41 (2H,
m, Ar--H), 7.51 (1H, m, Ar--H), 7.74 (1H, m, Ar--H), 7.78 (1H, m,
NH) and 8.05 ppm (1H, s, H.sub.2); .delta..sub.C (CDCl.sub.3)
CH.sub.2: 24.7, 26.8, 33.1, 35.2, 40.3, 47.0; CH: 55.7, 87.2,
127.1, 130.0, 130.1, 131.5, 143.8; C: 82.9, 132.1, 139.0, 145.7,
146.5, 158.1.
C.
2-{2-[3-BROMO-5-(2-CHLOROPHENYL)PYRAZOLO[1,5-a]PYRIMIDIN-7-YLAMINO]ETHY-
L}PIPERIDINE-1-CARBOXYLIC ACID AMIDE
[0618] ##STR1877##
[0619]
[3-Bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-
-2-ylethyl)amine (200 mg, 0.46 mmoles) (prepared as described in
Example 461, Step B above) was dissolved in anhydrous
dichloromethane (2 mL) and trimethylsilylisocyanate (0.31 mL, 2.3
mmoles) was added. The mixture was stirred at 25.degree. C. for
1.25 h. Additional trimethylsilylisocyanate (0.155 mL, 1.15 mmoles)
was added and the stirring was continued for a total of 3 h. The
mixture was diluted with dichloromethane and washed with saturated
aqueous sodium bicarbonate. The organic layer was dried
(MgSO.sub.4), filtered and evaporated to dryness. The residue was
chromatographed on a silica gel column (30.times.2.5 cm) using 2%
(10% conc. ammonium hydroxide in methanol)-dichloromethane as the
eluant to give
2-{2-[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]e-
thyl}piperidine-1-carboxylic acid amide (106.3 mg, 48%): FABMS: m/z
477.0 (MH.sup.+); HRFABMS: m/z 477.0804 (MH.sup.+). Calcd. for
C.sub.20H.sub.23N.sub.6OBrCl: m/z 477.0805; .delta..sub.H
(d.sub.6-DMSO) 1.29 (1H, m, CH.sub.2), 1.52 (5H, m, CH.sub.2), 1.72
(1H, m, CH.sub.2), 2.05 (1H, m, CH.sub.2), 2.51 (2H, s,
CONH.sub.2), 2.79 (1H, dd, CH), 3.31 (1H, m, CH.sub.2), 3.34 (1H,
m, CH.sub.2), 3.76 (1H, m, CH.sub.2), 4.30 (1H, bm, CH.sub.2), 6.42
(1H, s, H.sub.6), 7.50 (2H, m, Ar--H), 7.60 (1H, m, Ar--H), 7.63
(1H, m, Ar--H), 8.29 (1H, s, H.sub.2) and 8.38 ppm (1H, dd, NH);
.delta..sub.C (d.sub.6-DMSO)CH.sub.2: 18.6, 25.2, 28.2, 38.4, 38.6,
54.8; CH: 46.7, 86.6, 127.1, 129.7, 130.3, 131.0, 143.4; C: 81.2,
131.0, 138.7, 145.1, 146.4, 158.2.
Example 462
[0620] ##STR1878##
[0621] To a solution of the compound prepared in Example 204 (1.11
g, 2.12 mmol) in anhydrous acetonitrile (20 mL) was added TMSI
(1.70 g, 8.52 mmol), dropwise at ambient temperature. After 10
minutes the acetonitrile was removed in vacuo. The resulting yellow
foam was treated with 2 N HCl solution (7 mL) and then washed
immediately with Et.sub.2O (5.times.). The pH of the aqueous was
adjusted to 10 with 50% NaOH (aq) and the product was isolated by
saturation of the solution with NaCl (s) followed by extraction
with CH.sub.2Cl.sub.2 (5.times.) to give the crystalline product
(733 mg, 89% yield). MH.sup.+=387; m. p.=207.5.degree. C.
Examples 463-472
[0622] By essentially the same procedure set forth in Example 462
only substituting the compounds shown in Column 2 of Table 38, the
compounds shown in Column 3 of Table 38 were prepared.
TABLE-US-00038 TABLE 38 Ex. Column 2 Column 3 CMPD 463 ##STR1879##
##STR1880## MH.sup.+ = 403 .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.52 (s, 1H), 8.38 (d, 1H), 8.04 (s, 1H), 7.78 (d, 1H),
7.65 (t, 1H), 6.18 (s, 1H), 4.89 (s, 2H), 3.26-3.21 (d, 2H),
2.96-2.70 (m, 3H), 2.05-1.78 (m, 4H). 464 ##STR1881## ##STR1882##
MH.sup.+ = 454 m.p. = 175.4.degree. C. 465 ##STR1883## ##STR1884##
Yield = 87 MH.sup.+ = 470 m.p. = 200.degree. C. m. pt
(hydrochloride salt) = 164.3.degree. C. 466 ##STR1885## ##STR1886##
MH.sup.+ = 464 m.p. = 206.degree. C. 467 ##STR1887## ##STR1888##
MH.sup.+ = 411 m.p. = 169.5.degree. C. 468 ##STR1889## ##STR1890##
MH.sup.+ = 334 m.p. = 176.2.degree. C. 469 ##STR1891## ##STR1892##
MH.sup.+ = 465 m.p. = 250.4.degree. C. 470 ##STR1893## ##STR1894##
MH.sup.+ = 387 m.p. = 68.5.degree. C. 471 ##STR1895## ##STR1896##
MH.sup.+ = 387 m.p. = 59.4.degree. C. 472 ##STR1897## ##STR1898##
1. mp = 230-232 2. M + H = 396 472.10 ##STR1899## ##STR1900## 1. mp
= 157-160 2. M + H = 427
Example 473
[0623] Step A: ##STR1901##
[0624] A solution of the sulfonic acid (560 mg, 1.17 mmol) in 5 mL
of dry DMF was cooled to 0.degree. C. and SOCl.sub.2 (278 mg, 2.34
mmol) was added. The reaction mixture was brought to RT and stirred
overnight. The next day the contents were poured on ice and the pH
was carefully adjusted to 8. The product was extracted in to EtOAc
and the solvent was removed after drying (Na.sub.2SO.sub.4) to
provide 240 mg (41%) of the crude sulfonyl chloride which was used
for the next step without further purification. .sup.1H NMR
(CDCl.sub.3) .delta. 8.20-8.10 (m, 1H), 8.10-7.95 (m, 3H), 7.65 (d,
2H), 7.45-7.35 (m, 1H), 7.35-7.20 (m, 1H), 7.15-7.05 (m, 1H), 6.95
(t, 1H), 4.85 (d, 2H). Step B: ##STR1902##
[0625] A solution of compound prepared in Example 473, Step A (120
mg, 0.24 mmol) in 10 mL of THF was treated with 2 mL of 1 M
MeNH.sub.2 (2.00 mmol) in THF at RT overnight. The solvent was
removed and the residue was purified by chromatography (silica,
hexane:EtOAc (4:1.fwdarw.1:1)) to provide 56 mg (48%) of the
sulfonamide. .sup.1H NMR (DMSO-d6) .delta. 9.05 (t, J=9 Hz, 1H),
8.35 (s, 1H), 7.90 (t, J=7.5 Hz, 1H), 7.75 (d, J=9 Hz, 2H), 7.62
(d, J=9 Hz, 2H), 7.55-7.46 (m, 1H), 7.45-7.38 (m, 1H), 7.38-7.25
(m, 1H), 6.50 (s, 1H), 4.80 (d, 2H), 3.30 (s, 3H) LCMS:
MH.sup.+=492.1
Example 474
[0626] ##STR1903##
[0627] By essentially the same procedure set forth in Example 473,
only substituting dimethylamine, the above compound was prepared.
.sup.1H NMR (CDCl.sub.3) .delta. 8.14 (t, J=9 Hz, 1H), 8.00 (s,
1H), 7.76 (d, J=9 Hz, 2H), 7.54 (d, J=9 Hz, 2H), 7.34-7.44 (m, 1H),
7.26 (t, J=9 Hz, 1H), 7.14-7.04 (m, 1H), 6.93 (t, J=6 Hz, 1H), 6.45
(s, 1H), 4.75 (d, 2H), 2.70 (s, 6H).
[0628] LCMS: MH.sup.+=504.2.
Example 475
[0629] ##STR1904##
[0630] A mixture of the compound prepared in Example 129 (300 mg,
0.66 mmol), NaOH (5 g), CH.sub.3OH--H.sub.2O (100 mL, 90:10) was
stirred at 25 C for about 15 h. Progress of hydrolysis was checked
by TLC. Reaction mixture was concentrated to remove methanol. The
concentrate was diluted with 50 mL water, and extracted with ether
to remove any un-reacted ester. Aqueous solution, thus obtained,
was neutralized with 3 N HCl to pH 4 to obtain free acid, filtered
and washed repeatedly with water. The acid was dried under vacuum
(270 mg, 93%) and used without further purification.
Example 476-479
[0631] By essentially the same procedure set forth in Example 475
only substituting the compounds in Column 2 of Table 39, the
compounds in Column 3 of Table 39 were prepared. TABLE-US-00039
TABLE 39 Ex. Column 2 Column 3 CMPD 476 ##STR1905## ##STR1906##
Yield = 82% LCMS: MH.sup.+ = 365 477 ##STR1907## ##STR1908## Yield
= 82% LCMS: MH.sup.+ = 379 478 ##STR1909## ##STR1910## Yield = 72%
LCMS: MH.sup.+ = 393 479 ##STR1911## ##STR1912## Yield = 70% LCMS:
MH.sup.+ = 407
Additional data for select examples shown below:
Example 476
[0632] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (m, 2H), 8.0 (m, 1H),
7.6 (m, 1H), 7.3 (m, 2H), 6.6 (s, 1H), 4.2 (d, 2H).
Example 477
.sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H), 7.4
(m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 7.0 (t, 1H), 6.5 (s, 1H),
3.8 (dt, 2H), 2.6 (t, 2H).
Example 479
[0633] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.4 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1H), 3.5 (dt,
2H), 2.4 (t, 2H), 1.8 (m, 4H).
Example 480
[0634] ##STR1913##
[0635] A mixture of the acid from Example 475 (85 mg, 0.193 mmol)
and Et.sub.3N (20 mg, 0.193 mmol) in THF (20 mL) was stirred at 25
C for 15 min. Isobutyryl chloroformate (28 mg, 0.205 mmol) was
added to the reaction mixture and stirred for 10 min followed by
addition of NH4OH solution (0.5 mL). The reaction mixture was
stirred for 1 hr and concentrated to dryness. The dry mass was
purified by column chromatography.
Examples 481-509
[0636] By essentially the same procedure set forth in Example 480
only substituting the carboxylic acid shown in Column 2 of Table 40
and the amine shown in Column 3 of Table 40, the compounds shown in
Column 4 of Table 40 were prepared. TABLE-US-00040 TABLE 40 Ex.
Column 2 Column 3 Column 4 CMPD 481 ##STR1914## CH.sub.3NH.sub.2
##STR1915## Yield =88% LCMS: MH.sup.+ =454 482 ##STR1916##
(CH.sub.3).sub.2NH.sub.2 ##STR1917## Yield =80% LCMS MH.sup.+ =468
483 ##STR1918## CH.sub.3NH.sub.2 ##STR1919## Yield =70% LCMS
MH.sup.+ =454. 484 ##STR1920## ##STR1921## ##STR1922## Yield =75%
LCMS MH.sup.+ =482.1 485 ##STR1923## ##STR1924## ##STR1925## Yield
=71% LCMS MH.sup.+ =480.1 486 ##STR1926## ##STR1927## ##STR1928##
Yield =75% LCMS MH.sup.+ =494.1 487 ##STR1929## ##STR1930##
##STR1931## Yield =75% MH.sup.+ =494.1 488 ##STR1932## ##STR1933##
##STR1934## Yield =75% MH.sup.+ =496.1 489 ##STR1935## ##STR1936##
##STR1937## Yield =75% LCMS MH.sup.+ =508.1 490 ##STR1938##
##STR1939## ##STR1940## Yield =78% LCMS MH.sup.+ =524.1 491
##STR1941## ##STR1942## ##STR1943## Yield =73% LCMS MH.sup.+ =508.1
492 ##STR1944## ##STR1945## ##STR1946## Yield =73% LCMS MH.sup.+
=510.1 493 ##STR1947## ##STR1948## ##STR1949## Yield =76% LCMS
MH.sup.+ =526.1 494 ##STR1950## ##STR1951## ##STR1952## Yield =76%
MH.sup.+ =523.1 495 ##STR1953## ##STR1954## ##STR1955## Yield =76%
MH.sup.+ =523.1 496 ##STR1956## ##STR1957## ##STR1958## Yield =51%
LCMS MH.sup.+ =484.1 497 ##STR1959## ##STR1960## ##STR1961## Yield
=66% MH.sup.+ =537.1 498 ##STR1962## ##STR1963## ##STR1964## Yield
=76% LCMS MH.sup.+ =551.2 499 ##STR1965## ##STR1966## ##STR1967##
Yield =79% LCMS MH.sup.+ =552.1 500 ##STR1968## ##STR1969##
##STR1970## Yield =80% MH.sup.+ =549.1 501 ##STR1971## ##STR1972##
##STR1973## Yield =80% LCMS MH.sup.+ =478.1 502 ##STR1974##
##STR1975## ##STR1976## Yield =80% LCMH.sup.+ =468.1 503
##STR1977## ##STR1978## ##STR1979## Yield =80% MH.sup.+ =522.1 504
##STR1980## ##STR1981## ##STR1982## Yield =82% LCMS MH.sup.+ =528.1
505 ##STR1983## CH.sub.3NH.sub.2 ##STR1984## Yield =60% MH.sup.+
=392 506 ##STR1985## ##STR1986## ##STR1987## Yield =60% LCMH.sup.+
=448.1 507 ##STR1988## ##STR1989## ##STR1990## Yield =70% MH.sup.+
=464.1 508 ##STR1991## ##STR1992## ##STR1993## Yield =50% LCMS
MH.sup.+ =436.1 508.10 ##STR1994## CH.sub.3NH.sub.2 ##STR1995##
Yield =92% MH.sup.+ =577
Additional data for select examples given below:
Example 481
[0637] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.7 (d, 2H), 7.4 (s, 1H), 7.35 (d, 2H), 7.25 (dd, 1H), 7.1 (dd,
1H), 6.95 (t, 1H), 6.5 (s, 1H), 6.25 (bs, 1H), 4.7 (d, 2H), 3.0 (d,
3H).
Example 482
[0638] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.45-7.35 (m, 4H), 7.25 (d, 2H), 7.15 (dd, 1H), 6.7 (t, 1H), 6.5
(s, 1H), 4.7 (d, 2H), 3.1 (s, 3H), 3.0 (s, 3H).
Example 483
[0639] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.8 (bs, 1H), 7.7 (d, 1H), 7.5-7.3 (m, 3H), 7.25 (d, 1H), 7.15 (dd,
1H), 6.75 (t, 1H), 6.5 (s, 1H), 6.2 (bs, 1H), 4.7 (d, 2H), 3.0 (d,
3H).
Example 484
[0640] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.7 (d, 2H), 7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd,
1H), 6.8 (t, 1H), 6.5 (s, 1H), 6.0 bs, 1H), 4.7 (d, 2H), 4.25 (m,
1H), 1.2 (d, 6H).
Example 485
[0641] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.7 (d, 2H), 7.4 (d, 2H), 7.35 (s, 1H), 7.25 (dd, 1H), 7.1 (dd,
1H), 6.9 (t, 1H), 6.5 (s, 1H), 6.3 (t, 1H), 4.7 (d, 2H), 2.9 (m,
1H), 0.8 (bt, 2H), 0.6 (bt, 2H).
Example 486
[0642] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.8 (d, 2H), 7.4 (d, 2H), 7.35 (d, 1H), 7.25 (dd, 1H), 7.1 (dd,
1H), 6.9 (t, 1H), 6.5 (s, 1H), 6.2 (t, 1H), 4.7 (d, 2H), 3.3 (dd,
2H), 1.05 (m, 1H), 0.5 (m, 2H), 0.25 (m, 2H).
Example 487
[0643] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.7 (d, 2H), 7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd,
1H), 6.85 (t, 1H), 6.5 (s, 1H), 6.2 (bs, 1H), 4.7 (d, 2H), 4.6 (m,
1H), 2.4 (m, 2H), 1.95 (m, 1H), 1.75 (m, 2H).
Example 488
[0644] .sup.1H NMR (CDCl.sub.3) .delta. 8.5 (t, 1H), 8.15 (dt, 1H),
8.0 (s, 1H), 7.7 (d, 2H), 7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H),
7.15 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H), 5.9 (bs, 1H), 4.7 (d, 2H),
1.4 (s, 9H).
Example 489
[0645] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.7 (d, 2H), 7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd,
1H), 6.8 (t, 1H), 6.5 (s, 1H), 6.0 bs, 1H), 4.7 (d, 2H), 4.4 (m,
1H), 2.05 (m, 2H), 1.7 (m, 4H), 1.4 (m, 2H).
Example 490
[0646] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.7 (d, 2H), 7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd,
1H), 6.8 (t, 1H), 6.5 (s, 1H), 6.5 (bs, 2H), 4.7 (d, 2H), 4.1 (m,
1H), 3.9-3.7 (m, 3H), 3.3 (m, 1H), 2.0-1.9 (m, 4H).
Example 491
[0647] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.45-7.35 (m, 5H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.8 (t, 1H), 6.5
(s, 1H), 4.7 (d, 2H), 3.7 (bs, 2H), 3.3 (bs, 2H), 1.7 (bs, 4H), 1.5
(bs, 2H).
Example 492
[0648] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.45-7.35 (m, 5H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.85 (t, 1H), 6.5
(s, 1H), 4.7 (d, 2H), 3.8-3.4 (bm, 8H).
Example 493
[0649] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.45-7.35 (m, 5H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.80 (t, 1H), 6.5
(s, 1H), 4.7 (d, 2H), 4.0 (m, 2H), 3.6 (m, 2H), 2.8-2.45 (m,
4H).
Example 494
[0650] .sup.1H NMR (CH3OD) .delta. 8.15 (s, 1H), 8.0 (dt, 1H),
7.45-7.35 (m, 5H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.80 (t, 1H), 6.5
(s, 1H), 4.7 (d, 2H), 3.7 (bs, 2H), 3.4 (bs, 2H), 2.5-2.4 (m, 4H),
2.2 (s, 3H).
Example 495
[0651] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.45-7.35 (m, 5H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.80 (t, 1H), 6.5
(s, 1H), 4.7 (d, 2H), 3.75 (bs, 2H), 3.35 (bs, 2H), 2.4 (bs, 2H),
2.3 (s, 3H), 2.2 (bs, 2H).
Example 496
[0652] .sup.1H NMR (CDCl.sub.3) .delta. 7.95 (s, 1H), 7.9 (dt, 1H),
7.8 (t, 1H), 7.7 (d, 2H), 7.15 (m, 4H), 7.05 (dd, 1H), 6.9 (dd,
1H), 6.2 (s, 1H), 4.5 (d, 2H), 3.6 (t, 2H), 3.3 (dt, 2H).
Example 497
[0653] .sup.1H NMR (CH3OD) .delta. 8.1 (s, 1H), 7.9 (dt, 1H), 7.8
(d, 2H), 7.5 (d, 2H), 7.4 (m, 1H), 7.3 (dd, 1H), 7.2 (dd, 1H), 6.4
(s, 1H), 4.7 (d, 2H), 3.5 (t, 2H), 2.7 (m, 2H), 2.6 (bs, 4H), 1.8
(bs, 4H).
Example 498
[0654] .sup.1H NMR (CDCl.sub.3) .delta. 8.5 (t, 1H), 8.15 (dt, 1H),
8.0 (s, 1H), 7.8 (d, 2H), 7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H),
7.15 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 3.7-2.5 (m,
4H), 2.35 (s, 3H), 2.2 (m, 1H), 1.9-1.6 (m, 6H).
Example 499
[0655] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.8 (d, 2H), 7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd,
1H), 6.8 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 3.7 (m, 4H), 3.5 (dt,
2H), 2.6 (t, 2H), 2.5 (m, 4H).
Example 500
[0656] .sup.1H NMR (CH3OD) .delta. 8.15 (s, 1H), 7.9 (dt, 1H), 7.8
(d, 2H), 7.45 (d, 2H), 7.4 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H),
6.4 (s, 1H), 4.75 (d, 2H), 4.2 (m, 1H), 3.4-2.8 (m, 7H), 1.9-1.6
(m, 4H).
Example 501
[0657] .sup.1H NMR (CDCl.sub.3) .delta. 8.05 (dt, 1H), 8.0 (s, 1H),
7.6 (d, 2H), 7.4 (s, 1H), 7.35 (d, 2H), 7.25 (dd, 1H), 7.1 (dd,
1H), 6.9 (t, 1H), 6.5 (s, 1H), 6.4 (t, 1H), 4.7 (d, 2H), 4.2 (d,
2H), 2.3 (bs, 1H).
Example 502
[0658] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.75 (d, 2H), 7.45 (s, 1H), 7.4 (d, 2H), 7.3 (dd, 1H), 7.1(dd, 1H),
6.8 (t, 1H), 6.5 (s, 1H), 6.1(bs, 1H), 4.7 (d, 2H), 3.5 (dq, 2H),
1.2 (t, 3H).
Example 503
[0659] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.8 (d, 2H), 7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd,
1H), 6.9 (t, 1H), 6.5 (s, 1H), 6.4 (t, 1H), 4.75 (d, 2H), 4.1 (m,
2H).
Example 504
[0660] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.8 (d, 2H), 7.45 (d, 2H), 7.4 (m, 1H), 7.25 (dd, 1H), 7.1 (dd,
1H), 6.8 (t, 1H), 6.6 (t, 1H), 6.5 (s, 1H), 4.7 (d, 1H), 3.6 (m,
2H), 2.8 (t, 2H), 2.6 (q, 2H), 1.3 (t, 3H).
Example 505
[0661] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.4 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 7.0 (t, 1H), 6.5 (s,
1H), 3.8 (m, 2H), 2.7 (t, 2H), 3.0 (d, 3H).
Example 506
[0662] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.4 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 7.0 (t, 1H), 6.5 (s,
1H), 3.8 (m, 2H), 3.6 (m, 6H), 3.4 (m, 2H), 2.7 (t, 2H).
Example 507
[0663] .sup.1H NMR (CDCl.sub.3) .delta. 8.15 (dt, 1H), 8.0 (s, 1H),
7.4 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 7.0 (t, 1H), 6.5 (s,
1H), 3.9 (t, 2H), 3.8 (dt, 2H), 3.7 (t, 2H), 2.7 (t, 2H), 2.6 (m,
4H).
Example 508
[0664] .sup.1H NMR (CH.sub.3OD) .delta. 8.1 (s, 1H), 7.95 (dt, 1H),
7.5 (m, 1H), 7.35-7.2 (m, 2H), 6.5 (s, 1H), 3.6 (m, 4H), 3.25 (m,
4H), 2.4 (t, 2H), 2.05 (dt, 2H).
Example 509
[0665] ##STR1996##
[0666] A solution of NaOH (59 mg, 1.47 mmol) in 1 mL of water was
added to a suspension of NH.sub.2OH.HCl (102 mg, 1.47 mmol) in 10
mL of methanol at 0.degree. C. After 5 min, the compound prepared
in Example 210.10 (208 mg, 0.49 mmol) was added and the reaction
mixture was refluxed overnight. The solvent was removed in vacuo
and the residue was partitioned between water and EtOAc. The EtOAc
layer was dried (Na.sub.2SO.sub.4) and the solvent was evaporated.
The resulting crude amidoxime was suspended in trimethyl
orthoformate containing catalytic amount of PTS acid and refluxed
overnight. The solvent was removed and the residue was taken up in
EtOAc. The EtOAc layer was washed with aq NaHCO.sub.3 followed by
water and brine. The solvent was evaporated and the residue was
purified by chromatography (silica, hexane:EtOAc (1:1)) to provide
80 mg (35%) of the oxadiazole. .sup.1H NMR (CDCl.sub.3) .delta.
8.75 (s, 1H), 8.20-8.10 (m, 3H), 8.03 (s, 1H), 7.53 (d, J=9 Hz,
2H), 7.45-7.36 (m, 1H), 7.30-7.22 (m, 2H), 7.16-7.08 (m, 1H), 6.80
(t, J=5 Hz, 1H), 6.56 (s, 1H).
[0667] LCMS: MH.sup.+=465.2.
Example 510
[0668] ##STR1997##
[0669] By essentially the same procedure set forth in Example 509
only substituting the compound prepared in Preparative Example 192,
the above compound was prepared. yield=75; MH.sup.+=453; m.
p.=79.3.degree. C.
Example 511
[0670] ##STR1998##
[0671] A mixture of the nitrile (235 mg, 0.56 mmol) and
Me.sub.3SnN.sub.3 (343 mg, 1.67 mmol) in 20 mL of dry toluene was
refluxed for 2 days under Ar. The solvent was removed in vacuo and
the residue was dissolved in dry methanol. HCl gas was bubbled
through the solution for 15 min and the reaction mixture allowed to
stand at overnight at RT. The next day, the solvent was removed,
the residue was taken in water and the pH was adjusted to 5. The
precipitated product was extracted into EtOAc. Evaporation of the
EtOAc layer after drying (Na.sub.2SO.sub.4) provided the residue
which was purified by chromatography (silica, DCM:MeOH
(98:2.fwdarw.95:5)) to yield 50 mg (19%) of the pure tetrazole.
.sup.1H NMR (CD.sub.3OD) .delta. 8.10 (s, 1H), 8.00 (d, J=9 Hz,
2H), 7.90 (t, J=7 Hz, 1H), 7.65 (d, J=9 Hz, 2H), 7.50-7.40 (m, 1H),
7.30-7.10 (m, 2H), 6.45 (s, 1H), 4.80 (s, 2H); LCMS:
MH.sup.+=465.0.
Example 512
[0672] ##STR1999##
[0673] By essentially the same procedure set forth in Example 511
only substituting the compound prepared in Example 192, the above
compound was prepared. Yield=64; MH.sup.+=453; m. p.=238.9.degree.
C.
Example 513
[0674] ##STR2000##
[0675] The compound prepared in Example 157 was dissolved in
dioxane (30 mL) and a HCl-dioxane solution (4 M, 30 mL) was added.
The reaction mixture was stirred at room temperature for 4 h. The
reaction mixture was evaporated under reduced pressure and ethyl
acetate (200 mL) was added. The organic solution was washed with 1
N sodium hydroxide followed by saturated brine. The organic layer
was dried over anhydrous sodium sulfate and evaporated under
reduced pressure. MH.sup.+=442.1
Example 514-526
[0676] By essentially the same procedure set forth in Example 513,
only substituting the compounds shown in Column 2 of Table 41, the
compounds shown in Column 3 of Table 41 were prepared.
TABLE-US-00041 TABLE 41 Ex. Column 2 Column 3 CMPD 514 ##STR2001##
##STR2002## MH.sup.+ = 420.1 515 ##STR2003## ##STR2004## MH.sup.+ =
442.1 516 ##STR2005## ##STR2006## MH.sup.+ = 380.1 517 ##STR2007##
##STR2008## MH.sup.+ = 406.1 518 ##STR2009## ##STR2010## MH.sup.+ =
380.1 519 ##STR2011## ##STR2012## MH.sup.+ = 394.1 520 ##STR2013##
##STR2014## MH.sup.+ = 366 521 ##STR2015## ##STR2016## MH.sup.+ =
394 522 ##STR2017## ##STR2018## MH.sup.+ = 408.1 523 ##STR2019##
##STR2020## MH.sup.+ = 420.1 524 ##STR2021## ##STR2022## 525
##STR2023## ##STR2024## MH.sup.+ = 420.1 526 ##STR2025##
##STR2026## MH.sup.+ = 428.1 526.10 ##STR2027## ##STR2028##
Examples 528-564
General Procedure for 5-piperidinyl Parallel Library Formation
[0677] To a mixture of the starting material (80 mg, 0.21 mmol)
shown in Column 2 of Table 42 in anhydrous CH.sub.2Cl.sub.2 (1.5
mL) was added DIPEA (75 .mu.L, 0.42 mmol) and the appropriate
capping reagent (1.1 equiv., 0.23 mmol). After 1 to 2 h, the
reaction mixture was applied to 1000 micron preparatory TLC plate
and was subsequently developed using a 8-10% EtOH--CH.sub.2Cl.sub.2
as eluent to afford the compounds shown in Column 3 of Table 42.
TABLE-US-00042 TABLE 42 Ex. Column 2 Column 3 CMPD 528 ##STR2029##
##STR2030## MH.sup.+ = 608 m.p. = 230.1.degree. C. 529 ##STR2031##
##STR2032## Yield = 82 MH.sup.+ = 614 m.p. = 235.4.degree. C. 530
##STR2033## ##STR2034## MH.sup.+ = 486 m.p. = 60.5.degree. C. 531
##STR2035## ##STR2036## MH.sup.+ = 500 m.p. = 113.6.degree. C. 532
##STR2037## ##STR2038## MH.sup.+ = 430 m.p. = 158.3-159.2.degree.
C. 533 ##STR2039## ##STR2040## MH.sup.+ = 531 m.p. = 105.9.degree.
C. 534 ##STR2041## ##STR2042## MH.sup.+ = 486 535 ##STR2043##
##STR2044## MH.sup.+ = 500 536 ##STR2045## ##STR2046## MH.sup.+ =
430 537 ##STR2047## ##STR2048## MH.sup.+ = 531 538 ##STR2049##
##STR2050## MH.sup.+ = 486 m.p. = 69.6.degree. C. 539 ##STR2051##
##STR2052## MH.sup.+ = 500 m.p. = 82.3.degree. C. 540 ##STR2053##
##STR2054## MH.sup.+ = 430 m.p. = 223.6.degree. C. 541 ##STR2055##
##STR2056## MH.sup.+ = 531 m.p. = 118.1.degree. C. 542 ##STR2057##
##STR2058## MH.sup.+ = 455 m.p. = 109-110.degree. C. 543
##STR2059## ##STR2060## MH.sup.+ = 429 m.p. = 111.5.degree. C. 544
##STR2061## ##STR2062## MH.sup.+ = 455 545 ##STR2063## ##STR2064##
MH.sup.+ = 429 546 ##STR2065## ##STR2066## MH.sup.+ = 455 m.p. =
80.1.degree. C. 547 ##STR2067## ##STR2068## MH.sup.+ = 429 m.p. =
64.7.degree. C. 548 ##STR2069## ##STR2070## MH.sup.+ = 494 m.p. =
76.5.degree. C. 549 ##STR2071## ##STR2072## MH.sup.+ = 493 m.p. =
83.6.degree. C. 550 ##STR2073## ##STR2074## MH.sup.+ = 465 m.p. =
207.5.degree. C. 551 ##STR2075## ##STR2076## MH.sup.+ = 494 552
##STR2077## ##STR2078## MH.sup.+ = 493 553 ##STR2079## ##STR2080##
MH.sup.+ = 465 554 ##STR2081## ##STR2082## MH.sup.+ = 481 m.p. =
102.7.degree. C. 555 ##STR2083## ##STR2084## MH.sup.+ = 494 m.p. =
85.3.degree. C. 556 ##STR2085## ##STR2086## MH.sup.+ = 493 m.p. =
89.1.degree. C. 557 ##STR2087## ##STR2088## MH.sup.+ = 465 m.p. =
83.8.degree. C. 558 ##STR2089## ##STR2090## Yield = quant. MH.sup.+
= 443 m.p. = 98.3.degree. C. (HCl salt) 559 ##STR2091## ##STR2092##
MH.sup.+ = 454 560 ##STR2093## ##STR2094## Yield = quant. MH.sup.+
= 429 m.p. = 111.5-112.6.degree. C. 561 ##STR2095## ##STR2096##
MH.sup.+ = 460 m.p. = 122.7.degree. C. 562 ##STR2097## ##STR2098##
MH.sup.+ = 460 m.p. = 95.4.degree. C. 563 ##STR2099## ##STR2100##
MH.sup.+ = 460 564 ##STR2101## ##STR2102## MH.sup.+ = 460 m.p. =
95.4.degree. C.
Additional data for select examples given below.
Example 534
[0678] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.66-8.62 (s, 1H),
8.62-8.58 (d, 1H), 7.95 (s, 1H), 7.72-7.68 (d, 1H), 7.36-7.31 (dd,
1H), 6.66-6.62 (t, 1H), 5.93 (s, 1H), 4.65-4.62 (d, 2H), 3.86-3.82
(d, 1H), 3.65-3.58 (m, 1H), 3.26-3.12 (dd, 4H), 3.02-2.80 (m, 3H),
2.10-2.00 (m, 1H), 1.67-1.57 (m, 3H).
Example 535
[0679] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.66-8.62 (s, 1H),
8.62-8.58 (d, 1H), 7.95 (s, 1H), 7.72-7.67 (d, 1H), 7.36-7.30 (dd,
1H), 6.70-6.64 (t, 1H), 5.90 (s, 1H), 4.63-4.61 (d, 2H), 3.93-3.86
(m, 1H), 3.69-3.61 (m, 4H), 3.27-3.23 (m, 4H), 3.10-3.01 (dd, 1H),
2.93-2.84 (m, 2H), 2.08-2.03 (m, 1H), 1.90-1.57 (m, 4H).
Example 536
[0680] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.67 (s, 1H),
8.62-8.58 (d, 1H), 7.96 (s, 1H), 7.72-7.68 (d, 1H), 7.36-7.30 (dd,
1H), 6.79-6.72 (t, 1H), 5.96 (s, 1H), 4.86 (br s, 2H), 4.66-4.63
(d, 2H), 3.89-3.73 (m, 2H), 3.55-3.32 (m, 2H), 3.00-2.89 (m, 1H),
2.10-1.97 (m, 2H), 1.70-1.53 (m, 2H).
Example 537
[0681] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.66 (s, 1H),
8.62-8.58 (d, 1H), 7.98 (s, 1H), 7.77-7.76 (t, 1H), 7.72-7.69 (d,
1H), 7.63-7.59 (m, 1H), 7.56 (s, 1H), 7.36-7.29 (dd, 1H), 6.83-6.79
(t, 1H), 5.96 (s, 1H), 4.67-4.64 (d, 2H), 3.98-3.93 (dd, 1H),
3.79-3.68 (m, 2H), 3.37-3.28 (m, 1H), 3.03-2.94 (m, 1H), 2.12-1.99
(m, 1H), 1.76-1.56 (m, 3H).
Example 544
[0682] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.66-8.62 (d, 1H),
8.61-8.58 (dd, 1H), 7.95 (s, 1H), 7.72-7.67 (d, 1H), 7.36-7.30 (dd,
1H), 6.80-6.62 (br s, 1H), 5.88 (s, 1H), 4.63 (s, 2H), 3.08-2.95
(m, 2H), 2.87-2.80 (m, 2H), 2.04 (m, 1H), 1.85-1.78 (m, 4H),
1.52-1.44 (m, 1H), 0.87-0.82 (m, 2H), 0.72-0.66 (m, 2H).
Example 545
[0683] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.66 (s, 1H),
8.62-8.58 (br t, 1H), 7.97 (s, 1H), 7.73-7.68 (d, 1H), 7.36-7.30
(br t, 1H), 6.79-6.72 (br t, 1H), 5.96 (s, 1H), 4.64 (br s, 2H),
4.59-4.46 (br d, 1H), 3.95-3.74 (br m, 1H), 3.57-3.49 (dd, 1H),
3.10-3.01 (dd, 1H), 2.86-2.70 (m, 2H), 2.13 (s, 3H), 2.06-2.00 (m,
2H), 1.65-1.48 (m, 2H).
Example 551
[0684] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.67 (s, 1H),
8.63-8.59 (d, 1H), 7.96 (s, 1H), 7.74-7.69 (d, 1H), 7.36-7.30 (dd,
1H), 6.69-6.64 (t, 1H), 5.95 (s, 1H), 4.67-4.63 (d, 2H), 3.85 3.65
(m, 1H), 3.75-3.65 (m, 1H), 3.25-3.18 (dd, 1H), 3.03-2.90 (m, 2H),
2.81 (s, 6H), 2.03-1.95 (m, 1H), 1.89-1.68 (m, 3H).
Example 552
[0685] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.67 (s, 1H),
8.62-8.59 (d, 1H), 7.95 (s, 1H), 7.74-7.69 (d, 1H), 7.36-7.31 (dd,
1H), 6.67-6.60 (t, 1H), 5.98 (s, 1H), 4.67-4.63 (d, 2H), 3.92-3.86
(m, 1H), 3.85-3.75 (m, 1H), 3.40-3.30 (dd, 1H), 3.27-3.16 (m, 1H),
3.10-2.86 (m, 2H), 2.10-1.78(m, 3H), 1.40-1.30 (d, 6H).
Example 553
[0686] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.67 (s, 1H), 8.62
(br s, 1H), 7.96 (s, 1H), 7.74-7.69 (d, 1H), 7.36-7.31 (dd, 1H),
6.70-6.66 (t, 1H), 5.98 (s, 1H), 4.67-4.63 (d, 2H), 3.88-3.81 (m,
1H), 3.71-3.65 (m, 1H), 3.20-3.11 (dd, 1H), 3.02-2.91 (m, 1H),
2.90-2.80 (m, 4H), 2.01-1.80 (m, 3H).
Example 559
[0687] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.66-8.60 (d, 1H),
8.50-8.44 (dd, 1H), 8.01 (s, 1H), 7.93 (m, 1H), 7.48-7.40 (dd, 1H),
6.08 (s, 1H), 4.80-7.74 (s, 2H), 4.32-4.19 (br d, 2H), 3.10-2.86
(m, 2H), 1.95-1.68 (m, 4H).
Example 563
[0688] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.66 (s, 1H),
8.62-8.58 (d, 1H), 7.96 (s, 1H), 7.73-7.68 (d, 1H), 7.36-7.30 (dd,
1H), 6.96-6.86 (br s, 1H), 6.79-6.74 (t, 1H), 6.00 (s, 1H),
4.67-4.64 (d, 2H), 4.37-4.30 (dd, 1H), 4.22-4.13 (m, 1H), 3.97-3.86
(dd, 1H), 3.73-3.64 (m, 1H), 3.17-3.14 (d, 3H), 3.07-2.99 (m, 1H),
2.20-1.97 (m, 2H), 1.68-1.48 (m, 2H). General Procedure 1:
Procedure for the Amide Formation Parallel Synthesis:
##STR2103##
[0689] Parallel synthesis was conducted in polypropylene 96-well
reaction blocks with removable top seal and fixed bottom seal. Each
reaction well was fitted with a 20 micron polypropylene bottom frit
and the maximum volume was 3 mL. Collection block was not fitted
with bottom frit. To each reaction well was added a solution of an
amine (0.021 mmol) dissolved in a DMF-THF-MeCN mixture (4:3:3 v/v,
0.95 mL), EDC resin (P-EDC, Polymer Laboratories Ltd., 43 mg, 0.063
mmol), 1-hydroxybenzotriazole (HOBt, 5.67 mg, 0.042 mmol) and a
solution of a carboxylic acid in dimethylformamide (1 M, 0.0315 mL,
0.0315 mmol). The reaction mixture was agitated at room temperature
for 16 h. The crude product solution was filtered into a reaction
well loaded with trisamine resin (P--NH2, Argonaut Tech. Inc., 30
mg, 0.126 mmol) and isocyanate resin (P--NCO, Argonaut Tech. Inc.,
35 mg, 0.063 mmol). The reaction mixture was agitated at room
temperature for 16 h and filtered into the collection block. The
product solution was evaporated under reduced pressure to afford
the desired amide product. General Procedure 2: Procedure for the
Sulfonamide Formation Parallel Synthesis ##STR2104##
[0690] Parallel synthesis was conducted in polypropylene 96-well
reaction blocks with removable top seal and fixed bottom seal. Each
reaction well was fitted with a 20 micron polypropylene bottom frit
and the maximum volume was 3 mL. Collection block was not fitted
with bottom frit. To each reaction well was added a solution of an
amine (0.021 mmol) dissolved in a DMF-THF-MeCN mixture (3:2:2 v/v,
0.95 mL), DIEA resin (P-DIEA, Argonaut Tech. Inc., 18 mg, 0.063
mmol) and a solution of a sulfonyl chloride in dimethylformamide (1
M, 0.0315 mL, 0.0315 mmol). The reaction mixture was agitated at
room temperature for 16 h. The crude product solution was filtered
into a reaction well loaded with trisamine resin (P--NH2, Argonaut
Tech. Inc., 30 mg, 0.126 mmol) and isocyanate resin (P--NCO,
Argonaut Tech. Inc., 35 mg, 0.063 mmol). The reaction mixture was
agitated at room temperature for 16 h and filtered into the
collection block. The product solution was evaporated under reduced
pressure to afford the desired sulfonamide product. General
Procedure 3: Procedure for the Urea Formation Parallel Synthesis
##STR2105##
[0691] Parallel synthesis was conducted in polypropylene 96-well
reaction blocks with removable top seal and fixed bottom seal. Each
reaction well was fitted with a 20 micron polypropylene bottom frit
and the maximum volume was 3 mL. Collection block was not fitted
with bottom frit. To each reaction well was added a solution of an
amine (0.021 mmol) dissolved in a DMF-MeCN mixture (1:1 v/v, 0.95
mL) and a solution of an isocyanate in dichloromethane (0.33 M,
0.126 mL, 0.042 mmol). The reaction mixture was agitated at room
temperature for 16 h. The crude product solution was filtered into
a reaction well loaded with trisamine resin (P--NH2, Argonaut Tech.
Inc., 30 mg, 0.126 mmol) and isocyanate resin (P--NCO, Argonaut
Tech. Inc., 35 mg, 0.063 mmol). The reaction mixture was agitated
at room temperature for 16 h and filtered into the collection
block. The product solution was evaporated under reduced pressure
to afford the desired urea product. General Procedure 4: Procedure
for the Reductive Alkylation Parallel Synthesis ##STR2106##
[0692] Parallel synthesis was conducted in polypropylene 96-well
reaction blocks with removable top seal and fixed bottom seal. Each
reaction well was fitted with a 20 micron polypropylene bottom frit
and the maximum volume was 3 mL. Collection block was not fitted
with bottom frit. To each reaction well was added a solution of an
amine (0.021 mmol) dissolved in AcOH-DCE mixture (1:99 v/v, 0.5
mL), a solution of an aldehyde or ketone in dichloroethane (1 M,
0.147 mL, 0.147 mmol), and a solution of tetramethylammonium
triacetoxyborohydride (11 mg, 0.042 mmol) dissolved in AcOH-DCE
mixture 1:99 v/v, 0.5 mL). The reaction mixture was agitated at
room temperature for 3 days. The crude product solution was
filtered into a reaction well loaded with sulfonic acid resin
Lanterns (P--SO.sub.3H, Mimotopes Pty Ltd., 0.3 mmol). The reaction
mixture was agitated at room temperature for 2 h and decanted. The
product resin Lanterns were washed with methanol (1 mL) for three
times. A solution of ammonia in methanol (2 M, 1.2 mL) was added.
The reaction mixture was agitated at room temperature for 30 min.
and filtered into the collection block. The product solution was
evaporated under reduced pressure to afford the desired tertiary
amine product. General Procedure 5: Procedure for the Parallel
Synthesis of 7,N-substituted pyrazolo[1,5a]pyrimidines
##STR2107##
[0693] To
3-bromo-7-chloro-5-(2-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine (9.0
mg, 0.03 mmol) in tetrahydrofuran were added
di-iso-propylethylamine (12 .mu.L, 0.07), followed by
cyclopropylmethylamine (70 .mu.L, 0.07 mmol; 1M solution in DMF).
The reaction mixture was heated to 70.degree. C. for 36 h and then
cooled to rt. The mixture was treated with (P--NCO, Argonaut Tech.
Inc 70 mg, 0.12 mmol), and P--CO.sub.3.sup.- (Argonaut Tech. Inc 70
mg, 0.24 mmol) and shaken at rt for 12-18 h. The solution was
filtered and evaporated to dryness to provide the product. observed
m/z 375.21.
General Procedure 6: Procedure for the Parallel Synthesis of
5,N-Substituted pyrazolo[1,5a]pyrimidines
General Protocols:
[0694] Parallel synthesis was performed in a 96 well polypropylene
blocks as described elsewhere. In the instance that heating was
required, reactions were conducted in 2.5 mL glass tubes
individually sealed with a polypropylene mat and heating achieved
by a 96 well heat transfer block. ##STR2108## Step A:
[0695] To the
3-bromo-5-chloro-7-N--Boc-alkylamino-pyrazolo[1,5-a]pyrimidine (17
mg, 0.04 mmol) in p-dioxane were added DIEA (9 .mu.L, 0.05),
followed by cyclopropyl-methylamine (80 .mu.L, 0.08 mmol; 1M
solution in isopropanol). The reaction mixture was heated to
90.degree. C. for 36 h and then cooled to rt. The mixture was
treated with P--NCO (Argonaut Tech. Inc. 70 mg, 0.12 mmol) and
P--CO.sub.3.sup.- (Argonaut Tech. Inc. 70 mg, 0.24 mmol) and shaken
at rt for 12-18 h. The solution was filtered and evaporated to
dryness to provide the product.
Step B (Acidic):
[0696] The product from STEP A was taken up in 35% TFA/DCM and
agitated for 4 h followed by concentration under high vacuum. The
residue was treated with 10% HCl(aq) in MeOH agitated for 2 h and
then concentrated to give the desired product. observed m/z
375.21.
Step B (Basic):
[0697] The product from step A was taken up in EtOH and treated
with Ambersep.RTM. 900-OH ion exchange resin (Acros, 100 mg),
heated at reflux for 48 h with gently stirring. The reaction
mixture was cooled to rt, filtered and concentrated to provide the
desired product.
Example 565
[0698] By utilizing the procedure set forth in General Procedure 1
and the compound from Example 462 shown below, the compounds with
the observed m/z shown in Table 43 were prepared. ##STR2109##
Example 566
[0699] By utilizing the procedure set forth in General Procedure 1
and the compound from Example 471 shown below, the compounds shown
in Table 44 with the observed m/z were prepared. ##STR2110##
Example 567
[0700] By utilizing the procedure set forth in General Procedure 1
and the compound from Example 515 shown below, the compounds shown
in Table 45 with the observed m/z were prepared. ##STR2111##
Example 568
[0701] By utilizing the procedure set forth in General Procedure 1
and the compound from Example 513 shown below, the compounds shown
in Table 46 with the observed m/z were prepared. ##STR2112##
Example 569
[0702] By utilizing the procedure set forth in General Procedure 1
and the compound from Example 526 shown below, the compounds shown
in Table 47 with the observed m/z were prepared. ##STR2113##
Example 570
[0703] By utilizing the procedure set forth in General Procedure 1
and the compound from Example 524 shown below, the compounds shown
in Table 48 with the observed m/z were prepared. ##STR2114##
Example 571
[0704] By utilizing the procedure set forth in General Procedure 1
and the compound from Example 525 shown below, the compounds shown
in Table 49 with the observed m/z were prepared. ##STR2115##
Example 572
[0705] By utilizing the procedure set forth in General Procedure 1
and the compound from Example 526.10 shown below, the compounds
shown in Table 50 with the observed m/z were prepared.
##STR2116##
Example 573
[0706] By utilizing the procedure set forth in General Procedure 1
and the compound from Example 518 shown below, the compounds shown
in Table 51 with the observed m/z were prepared. ##STR2117##
Example 574
[0707] By utilizing the procedure set forth in General Procedure 1
and the compound from Example 519 shown below, the compounds shown
in Table 52 with the observed m/z were prepared. ##STR2118##
Example 575
[0708] By utilizing the procedure set forth in General Procedure 1
and the compound from Example 520 shown below, the compounds shown
in Table 53 with the observed m/z were prepared. ##STR2119##
Example 576
[0709] By utilizing the procedure set forth in General Procedure 1
and the compound from Example 522 shown below, the compounds shown
in Table 54 with the observed m/z were prepared. ##STR2120##
Example 577
[0710] By utilizing the procedure set forth in General Procedure 1
and the compound from Example 523 shown below, the compounds shown
in Table 55 with the observed m/z were prepared. ##STR2121##
Example 578
[0711] By utilizing the procedure set forth in General Procedure 2
and the compound from Example 462 shown below, the compounds shown
in Table 56 with the observed m/z were prepared. ##STR2122##
Example 579
[0712] By utilizing the procedure set forth in General Procedure 2
and the compound from Example 471 shown below, the compounds shown
in Table 57 with the observed m/z were prepared. ##STR2123##
Example 580
[0713] By utilizing the procedure set forth in General Procedure 2
and the compound from Example 515 shown below, the compounds shown
in Table 58 with the observed m/z were prepared. ##STR2124##
Example 581
[0714] By utilizing the procedure set forth in General Procedure 2
and the compound from Example 513 shown below, the compounds shown
in Table 59 with the observed m/z were prepared. ##STR2125##
Example 582
[0715] By utilizing the procedure set forth in General Procedure 2
and the compound from Example 513 shown below, the compounds shown
in Table 60 with the observed m/z were prepared. ##STR2126##
Example 583
[0716] By utilizing the procedure set forth in General Procedure 2
and the compound from Example 524 shown below, the compounds shown
in Table 61 with the observed m/z were prepared. ##STR2127##
Example 584
[0717] By utilizing the procedure set forth in General Procedure 2
and the compound from Example 525 shown below, the compounds shown
in Table 62 with the observed m/z were prepared. ##STR2128##
Example 585
[0718] By utilizing the procedure set forth in General Procedure 2
and the compound from Example 526.10 shown below, the compounds
shown in Table 63 with the observed m/z were prepared.
##STR2129##
Example 586
[0719] By utilizing the procedure set forth in General Procedure 2
and the compound from Example 518 shown below, the compounds shown
in Table 64 with the observed m/z were prepared. ##STR2130##
Example 587
[0720] By utilizing the procedure set forth in General Procedure 2
and the compound from Example 519 shown below, the compounds shown
in Table 65 with the observed m/z were prepared. ##STR2131##
Example 588
[0721] By utilizing the procedure set forth in General Procedure 2
and the compound from Example 520 shown below, the compounds shown
in Table 67 with the observed m/z were prepared. ##STR2132##
Example 589
[0722] By utilizing the procedure set forth in General Procedure 2
and the compound from Example 521 shown below, the compounds shown
in Table 68 with the observed m/z were prepared. ##STR2133##
Example 590
[0723] By utilizing the procedure set forth in General Procedure 2
and the compound from Example 523 shown below, the compounds shown
in Table 69 with the observed m/z were prepared. ##STR2134##
Example 591
[0724] By utilizing the procedure set forth in General Procedure 3
and the compound from Example 462 shown below, the compounds shown
in Table 70 with the observed m/z were prepared. ##STR2135##
Example 592
[0725] By utilizing the procedure set forth in General Procedure 3
and the compound from Example 471 shown below, the compounds shown
in Table 71 with the observed m/z were prepared. ##STR2136##
Example 593
[0726] By utilizing the procedure set forth in General Procedure 3
and the compound from Example 513 shown below, the compounds shown
in Table 72 with the observed m/z were prepared. ##STR2137##
Example 594
[0727] By utilizing the procedure set forth in General Procedure 3
and the compound from Example 524 shown below, the compounds shown
in Table 73 with the observed m/z were prepared. ##STR2138##
Example 595
[0728] By utilizing the procedure set forth in General Procedure 3
and the compound from Example 524 shown below, the compounds shown
in Table 74 with the observed m/z were prepared. ##STR2139##
Example 596
[0729] By utilizing the procedure set forth in General Procedure 3
and the compound from Example 519 shown below, the compounds shown
in Table 75 with the observed m/z were prepared. ##STR2140##
Example 597
[0730] By utilizing the procedure set forth in General Procedure 3
and the compound from Example 520 shown below, the compounds shown
in Table 76 with the observed m/z were prepared. ##STR2141##
Example 598
[0731] By utilizing the procedure set forth in General Procedure 3
and the compound from Example 521 shown below, the compounds shown
in Table 77 with the observed m/z were prepared. ##STR2142##
Example 599
[0732] By utilizing the procedure set forth in General Procedure 3
and the compound from Example 523 shown below, the compounds shown
in Table 78 with the observed m/z were prepared. ##STR2143##
Example 600
[0733] By utilizing the procedure set forth in General Procedure 4
and the compound from Example 462 shown below, the compounds shown
in Table 79 with the observed m/z were prepared. ##STR2144##
Example 601
[0734] By utilizing the procedure set forth in General Procedure 4
and the compound from Example 471 shown below, the compounds shown
in Table 80 with the observed m/z were prepared. ##STR2145##
Example 602
[0735] By utilizing the procedure set forth in General Procedure 4
and the compound from Example 525 shown below, the compounds shown
in Table 81 with the observed m/z were prepared. ##STR2146##
Example 603
[0736] By utilizing the procedure set forth in General Procedure 4
and the compound from Example 526.10 shown below, the compounds
shown in Table 82 with the observed m/z were prepared.
##STR2147##
Example 604
[0737] By utilizing the procedure set forth in General Procedure 4
and the compound from Example 521 shown below, the compounds shown
in Table 83 with the observed m/z were prepared. ##STR2148##
Example 605
[0738] By utilizing the procedure set forth in General Procedure 4
and the compound from Example 523 shown below, the compounds shown
in Table 84 with the observed m/z were prepared. ##STR2149##
Example 606
[0739] By utilizing the procedure set forth in General Procedure 5
and the compound from Preparative Example 81 shown below, the
compounds shown in Table 85 with the observed m/z were prepared.
##STR2150##
Example 607
[0740] By utilizing the procedure set forth in General Procedure 6
and the compound from Preparative Example 196, the compounds shown
in Table 86 with the observed m/z were prepared. ##STR2151## Assay:
BACULOVIRUS CONSTRUCTIONS: Cyclins A and E were cloned into
pFASTBAC (Invitrogen) by PCR, with the addition of a GluTAG
sequence (EYMPME) at the amino-terminal end to allow purification
on anti-GluTAG affinity columns. The expressed proteins were
approximately 46 kDa (cyclin E) and 50 kDa (cyclin A) in size. CDK2
was also cloned into pFASTBAC by PCR, with the addition of a
haemaglutinin epitope tag at the carboxy-terminal end (YDVPDYAS).
The expressed protein was approximately 34 kDa in size. ENZYME
PRODUCTION: Recombinant baculoviruses expressing cyclins A, E and
CDK2 were infected into SF9 cells at a multiplicity of infection
(MOI) of 5, for 48 hrs. Cells were harvested by centrifugation at
1000 RPM for 10 minutes. Cyclin-containing (E or A) pellets were
combined with CDK2 containing cell pellets and lysed on ice for 30
minutes in five times the pellet volume of lysis buffer containing
50 mM Tris pH 8.0, 0.5% NP40, 1 mM DTT and protease/phosphatase
inhibitors (Roche Diagnostics GmbH, Mannheim, Germany). Mixtures
were stirred for 30-60 minutes to promote cyclin-CDK2 complex
formation. Mixed lysates were then spun down at 15000 RPM for 10
minutes and the supernatant retained. 5 ml of anti-GluTAG beads
(for one liter of SF9 cells) were then used to capture cyclin-CDK2
complexes. Bound beads were washed three times in lysis buffer.
Proteins were competitively eluted with lysis buffer containing
100-200 ug/mL of the GluTAG peptide. Eluate was dialyzed overnight
in 2 liters of kinase buffer containing 50 mM Tris pH 8.0, 1 mM
DTT, 10 mM MgCl2, 100 uM sodium orthovanadate and 20% glycerol.
Enzyme was stored in aliquots at -70.degree. C. IN VITRO KINASE
ASSAY: CDK2 kinase assays (either cyclin A or E-dependent) were
performed in low protein binding 96-well plates (Corning Inc,
Corning, N.Y.). Enzyme was diluted to a final concentration of 50
ug/ml in kinase buffer containing 50 mM Tris pH 8.0, 10 mM
MgCl.sub.2, 1 mM DTT, and 0.1 mM sodium orthovanadate. The
substrate used in these reactions was a biotinylated peptide
derived from Histone H1 (from Amersham, UK). The substrate was
thawed on ice and diluted to 2 uM in kinase buffer. Compounds were
diluted in 10% DMSO to desirable concentrations. For each kinase
reaction, 20 ul of the 50 ug/ml enzyme solution (1 ug of enzyme)
and 20 ul of the 1 uM substrate solution were mixed, then combined
with 10 ul of diluted compound in each well for testing. The kinase
reaction was started by addition of 50 ul of 4 uM ATP and 1 uCi of
33P-ATP (from Amersham, UK). The reaction was allowed to run for 1
hour at room temperature. The reaction was stopped by adding 200 ul
of stop buffer containing 0.1% Triton X-100, 1 mM ATP, 5 mM EDTA,
and 5 mg/ml streptavidine coated SPA beads (from Amersham, UK) for
15 minutes. The SPA beads were then captured onto a 96-well GF/B
filter plate (Packard/Perkin Elmer Life Sciences) using a
Filtermate universal harvester (Packard/Perkin Elmer Life
Sciences). Non-specific signals were eliminated by washing the
beads twice with 2M NaCl then twice with 2 M NaCl with 1%
phosphoric acid. The radioactive signal was then measured using a
TopCount 96 well liquid scintillation counter (from Packard/Perkin
Elmer Life Sciences).
[0741] IC.sub.50 DETERMINATION: Dose-response curves were plotted
from inhibition data generated, each in duplicate, from 8 point
serial dilutions of inhibitory compounds. Concentration of compound
was plotted against % kinase activity, calculated by CPM of treated
samples divided by CPM of untreated samples. To generate IC.sub.50
values, the dose-response curves were then fitted to a standard
sigmoidal curve and IC.sub.50 values were derived by nonlinear
regression analysis. The thus-obtained IC.sub.50 values for the
compounds of the invention are shown in Table 87. These kinase
activities were generated by using cyclin A or cyclin E using the
above-described assay. TABLE-US-00043 TABLE 87 CMPD Example
IC.sub.50 (.mu.M) ##STR2152## 1 0.020 0.029 ##STR2153## 3 0.032
0.024 ##STR2154## 4 0.011 ##STR2155## 5 0.021 ##STR2156## 8 0.003
##STR2157## 6 0.064 0.029 ##STR2158## 7 0.01 0.006 ##STR2159## 10
0.042 ##STR2160## 12 0.17 ##STR2161## 16 0.62 ##STR2162## 1 5.6
##STR2163## 3 0.14
[0742] As demonstrated above by the assay values, the compounds of
the present invention exhibit excellent CDK inhibitory
properties.
[0743] While the present invention has been described with in
conjunction with the specific embodiments set forth above, many
alternatives, modifications and other variations thereof will be
apparent to those of ordinary skill in the art. All such
alternatives, modifications and variations are intended to fall
within the spirit and scope of the present invention.
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References