U.S. patent application number 10/778432 was filed with the patent office on 2004-11-04 for novel process for making 5-substituted pyrazoles.
Invention is credited to Brown, David L., Graneto, Matthew J., Hartmann, Susan J., Metz, Suzanne, Stealey, Michael A., Talley, John J., Vazquez, Michael L., Weier, Richard M., Xu, Xiangdong.
Application Number | 20040220232 10/778432 |
Document ID | / |
Family ID | 22326224 |
Filed Date | 2004-11-04 |
United States Patent
Application |
20040220232 |
Kind Code |
A1 |
Brown, David L. ; et
al. |
November 4, 2004 |
Novel process for making 5-substituted pyrazoles
Abstract
This invention relates to a novel process of preparing selected
5-substituted pyrazoles useful as p38 kinase and COX-2
inhibitors.
Inventors: |
Brown, David L.;
(Chesterfield, MO) ; Graneto, Matthew J.;
(Chesterfield, MO) ; Hartmann, Susan J.;
(Kirkwood, MO) ; Metz, Suzanne; (Chesterfield,
MO) ; Stealey, Michael A.; (Libertyville, IL)
; Talley, John J.; (Somerville, MA) ; Vazquez,
Michael L.; (Ballwin, MO) ; Weier, Richard M.;
(Lake Bluff, IL) ; Xu, Xiangdong; (Buffalo Grove,
IL) |
Correspondence
Address: |
PHARMACIA CORPORATION
GLOBAL PATENT DEPARTMENT
POST OFFICE BOX 1027
ST. LOUIS
MO
63006
US
|
Family ID: |
22326224 |
Appl. No.: |
10/778432 |
Filed: |
February 14, 2004 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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10778432 |
Feb 14, 2004 |
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10268818 |
Oct 10, 2002 |
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6750338 |
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10268818 |
Oct 10, 2002 |
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09922819 |
Aug 6, 2001 |
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6482955 |
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09922819 |
Aug 6, 2001 |
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09772743 |
Jan 30, 2001 |
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6342608 |
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09772743 |
Jan 30, 2001 |
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09633726 |
Aug 7, 2000 |
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6242612 |
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09633726 |
Aug 7, 2000 |
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09442971 |
Nov 18, 1999 |
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6143892 |
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60109177 |
Nov 20, 1998 |
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Current U.S.
Class: |
514/341 ;
514/406; 546/275.4; 548/371.4 |
Current CPC
Class: |
C07D 409/06 20130101;
C07D 231/18 20130101; C07D 339/00 20130101; C07D 401/04 20130101;
C07D 401/14 20130101; C07D 405/14 20130101 |
Class at
Publication: |
514/341 ;
514/406; 546/275.4; 548/371.4 |
International
Class: |
C07D 231/04; A61K
031/416 |
Claims
1. A process of making a compound, wherein: the compound
corresponds in structure to Formula Ia or Ib: 115R.sub.1 is phenyl
substituted with one or more substituents selected from the group
consisting of halo, alkoxy, alkylthio, cyano, CF.sub.3, OCF.sub.3,
alkyl, SO.sub.2CH.sub.3, SO.sub.2NH.sub.2, SO.sub.2NHCOalkyl,
SO.sub.2NHCOalkyl, alkenyl, and alkynyl; R.sub.2 is selected from
the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen,
halo, alkyl, and 6-membered heterocycle, wherein the heterocycle is
substituted with one or two substituents selected from the group
consisting of halo, alkoxy, alkylthio, cyano, CF.sub.3, OCF.sub.3,
alkyl, alkylamino, dialkylamino, and phenyl substituted with one or
two substituents selected from the group consisting of halo,
alkoxy, alkylthio, cyano, CF.sub.3, OCF.sub.3, alkyl, alkylamino,
and dialkylamino; R.sub.3 is selected from the group consisting of
hydrogen, alkyl, and phenyl, wherein the alkyl and phenyl may
optionally be substituted by one or more substituents selected from
the group consisting of SO.sub.2CH.sub.3, halo, alkyl, alkoxy,
alkylthio, cyano, CF.sub.3, OCF.sub.3, and SO.sub.2NH.sub.2;
R.sub.4 and R.sub.5 taken together form piperazine substituted with
one or two alkyl; and the process comprises: reacting an
organometallic reagent of the formula R.sub.2CH.sub.2M (wherein M
is selected from the group consisting of Li, Na, K, and Mg) with an
activated form of a carboxylic acid to produce a ketone of Formula
Ic: 116treating the ketone of Formula Ic with a mixture of carbon
disulfide and dihalomethane in the presence of a base and a solvent
to produce a dithietane derivative of Formula Id: 117reacting the
dithietane derivative of Formula Id with an amine of formula
R.sub.4--NH--R.sub.5 to produce a thioamide of Formula Ie, If, or
Ig: 118condensing the thioamide of Formula Ie, If, or Ig with
hydrazine or substituted hydrazine.
2. The process of claim 1, wherein: R.sub.1 is phenyl substituted
with one or more substituents selected from the group consisting of
halo, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, cyano, CF.sub.3,
OCF.sub.3, C.sub.1-3 alkyl, SO.sub.2CH.sub.3, SO.sub.2NH.sub.2,
SO.sub.2NHCOC.sub.1-4 alkyl, SO.sub.2NHCOC.sub.1-4 alkyl, C.sub.2-4
alkenyl, and C.sub.2-4 alkynyl; R.sub.2 is selected from the group
consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo,
C.sub.1-6, alkyl, and 6-membered heterocycle substituted with 1 to
2 substituents selected from the group consisting of halo,
C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, cyano, CF.sub.3, OCF.sub.3,
C.sub.1-6 alkyl, C.sub.1-6 alkylamino, C.sub.1-6 dialkylamino,
phenyl substituted with one or two substituents selected from the
group consisting of halo, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio,
cyano, CF.sub.3, OCF.sub.3, C.sub.1-6 alkyl, C.sub.1-6 alkylamino,
and C.sub.1-6 dialkylamino; R.sub.3 is selected from the group
consisting of hydrogen, C.sub.1-6 alkyl, and phenyl, wherein the
C.sub.1-6 alkyl and phenyl may be optionally substituted by one or
more substituents selected from the group consisting of
SO.sub.2CH.sub.3, halo, C.sub.1-3 alkyl, C.sub.1-3 alkoxy,
C.sub.1-3 alkylthio, cyano, CF.sub.3, OCF.sub.3, and
SO.sub.2NH.sub.2; and R.sub.4 and R.sub.5 taken together form
piperazine substituted with one or two methyl.
3. The process of claim 1, wherein the dihalomethane is
dibromomethane.
4. The process of claim 1, wherein the dihalomethane is
iodochloromethane.
5. The process of claim 1, wherein the process comprises making a
compound selected from the group consisting of: 119120121122123
6. A process of making a compound, wherein: the compound
corresponds in structure to Formula IIa or IIb: 124R.sub.1 is
phenyl substituted with one or more substituents selected from the
group consisting of hydrogen, halo, alkoxy, alkylthio, cyano,
CF.sub.3, OCF.sub.3, alkyl, SO.sub.2CH.sub.3, SO.sub.2NH.sub.2,
SO.sub.2NHCOalkyl, SO.sub.2NHCOalkyl, alkenyl, and alkynyl; R.sub.2
is selected from the group consisting of pyridyl, pyrimidyl,
triazinyl, hydrogen, halo, alkyl, and 6-membered heterocycle,
wherein the heterocycle is substituted with one or two substituents
is selected from the group consisting of halo, alkoxy, alkylthio,
cyano, CF.sub.3, OCF.sub.3, alkyl, alkylamino, dialkylamino, and
phenyl, wherein the phenyl is substituted with one or two
substituents selected from the group consisting of halo, alkoxy,
alkylthio, cyano, CF.sub.3, OCF.sub.3, alkyl, alkylamino.sub.2 and
dialkylamino; R.sub.3 is selected from the group consisting of
hydrogen, alkyl, and phenyl wherein the alkyl and phenyl may
optionally be substituted by one or more substituents selected from
the group consisting of SO.sub.2CH.sub.3, halo, alkyl, alkoxy,
alkylthio, cyano, CF.sub.3, OCF.sub.3, and SO.sub.2NH.sub.2;
R.sub.6 is selected from the group consisting of hydrogen, alkyl,
phenyl, cycloalkyl, and heterocyclyl which may be optionally
substituted by one or more substituents selected from the group
consisting of phenyl, substituted phenyl, alkoxycarbonyl, acyl,
halo, OH, NH.sub.2, NHR.sub.3, N(R.sub.3).sub.2, and cyano,
cycloalkyl, heterocycloalkyl, and 3-7 membered heterocycle ring;
and the process comprises: reacting an organometallic reagent of
the formula R.sub.2CH.sub.2M (wherein M is selected from the group
consisting of Li, Na, K, and Mg) with an activated form of a
carboxylic acid to produce a ketone of Formula IIc: 125treating the
ketone of Formula IIc with a mixture of carbon disulfide and dihalo
methane such as dibromomethane or iodochloromethane in the presence
of a base and a solvent to produce a dithietane derivative of
Formula IId: 126reacting the dithietane derivative of Formula IId
with NaOR.sub.6 to produce a compound of Formula IIe: 127condensing
the compound of Formula IIe with hydrazine or substituted
hydrazine.
7. The process of claim 6, wherein: R.sub.1 is phenyl substituted
by one or more substituents selected from the group consisting of
halo, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, cyano, CF.sub.3,
OCF.sub.3, C.sub.1-3 alkyl, SO.sub.2CH.sub.3, SO.sub.2NH.sub.2,
SO.sub.2NHCOC.sub.1-4 alkyl, SO.sub.2NHCOC.sub.1-4 alkyl, C.sub.2-4
alkenyl, and C.sub.2-4 alkynyl; R.sub.2 is selected from the group
consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo,
C.sub.1-6 alkyl, and 6-membered heterocycle, wherein the
heterocycle is substituted with one or two substituents selected
from the group consisting of halo, C.sub.1-6 alkoxy, C.sub.1-6
alkylthio, cyano, CF.sub.3, OCF.sub.3, C.sub.1-6 alkyl, C.sub.1-6
alkylamino, C.sub.1-6 dialkylamino, and phenyl substituted with one
or two substituents selected from the group consisting of halo,
C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, cyano, CF.sub.3, OCF.sub.3,
C.sub.1-6 alkyl, C.sub.1-6 alkylamino, and C.sub.1-6 dialkylamino;
R.sub.3 is selected from the group consisting of hydrogen,
C.sub.1-6 alkyl, and phenyl, wherein the C.sub.1-6 alkyl and phenyl
may optionally be substituted by one or more substituents selected
from the group consisting of SO.sub.2CH.sub.3, halo, C.sub.1-3
alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, cyano, CF.sub.3,
OCF.sub.3, and SO.sub.2NH.sub.2; and R.sub.6 is, selected from the
group consisting of hydrogen and C.sub.1-6 alkyl which may be
optionally substituted by one or more substituents selected from
the group consisting of phenyl, substituted phenyl, halo, OH,
NH.sub.2, NHR.sub.3, N(R.sub.3).sub.2, and cyano, C.sub.3-7
cycloalkyl, C.sub.3-7 heterocycloalkyl, and 3-7 membered
heterocycle ring.
8. The process of claim 6, wherein the dihalomethane is
dibromomethane.
9. The process of claim 6, wherein the dihalomethane
isiodochloromethane.
10. The process of claim 6, wherein the dithietane is added to a
solution of sodium alkoxide.
11. The process of claim 6, the process comprises making a compound
selected from the group consisting of: 128129
12. A process of making compounds of a compound, wherein: the
compound corresponds in structure to Formula IIIa or IIIb:
130R.sub.1 is phenyl substituted with one or more substituents
selected from the group consisting of halo, alkoxy, alkylthio,
cyano, CF.sub.3, OCF.sub.3, alkyl, SO.sub.2CH.sub.3,
SO.sub.2NH.sub.2, SO.sub.2NHCOalkyl, SO.sub.2NHCOalkyl, alkenyl,
and alkynyl; R.sub.2 is selected from the group consisting of
pyridyl, pyrimidyl, triazinyl, hydrogen, halo, alkyl, 6-membered
heterocycle, wherein the heterocycle is substituted with one or two
substituents selected from the group consisting of halo, alkoxy,
alkylthio, cyano, CF.sub.3, OCF.sub.3, alkyl, alkylamino,
dialkylamino, and phenyl, wherein the phenyl is substituted
substituted with one or two substituents selected from the group
consisting of halo, alkoxy, alkylthio, cyano, CF.sub.3, OCF.sub.3,
alkyl, alkylamino, and dialkylamino; R.sub.3 is selected from the
group consisting of hydrogen, alkyl, and phenyl, wherein the alkyl
and phenyl may be optionally substituted by one or more of the
group consisting of SO.sub.2CH.sub.3, halo, alkyl, alkoxy,
alkylthio, cyano, CF.sub.3, OCF.sub.3, and SO.sub.2NH.sub.2;
R.sub.6 is selected from the group consisting of hydrogen, alkyl,
phenyl, cycloalkyl, and heterocyclyl which may be optionally
substituted by one or more substituents selected from the group
consisting of phenyl, substituted phenyl, halo, alkoxycarbonyl,
acyl, OH, NH.sub.2, NHR.sub.3, N(R.sub.3).sub.2, and cyano,
cycloalkyl, heterocycloalkyl, and 3-7 membered heterocycle ring;
and the process comprises: reacting an organometallic reagent of
the formula R.sub.2CH.sub.2M (wherein M is selected from the group
consisting of Li, Na, K, and Mg) with an activated form of a
carboxylic acid to produce a ketone of Formula IIIc: 131treating
the ketone of Formula IIIc with a mixture of carbon disulfide and
dihalomethane in the presence of a base and a solvent to produce a
dithietane derivative of Formula IIId: 132reacting the dithietane
derivative of Formula IIId with R.sub.3NHNH.sub.2 to produce a
heterocycle of the formula IIIe or IIIf and their tautomers:
133reacting the heterocycle of the formula IIIe or IIIf with an
activated form of R.sub.6 in the presence of a base and a
solvent.
13. The process of claim 12, wherein: R.sub.1 is phenyl substituted
with one or more substituents selected from the group consisting of
halo, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, cyano, CF.sub.3,
OCF.sub.3, C.sub.1-3 alkyl, SO.sub.2CH.sub.3, SO.sub.2NH.sub.2,
SO.sub.2NHCOC.sub.1-4 alkyl, SO.sub.2NHCOC.sub.1-4 alkyl, C.sub.2-4
alkenyl, and C.sub.2-4 alkynyl; R.sub.2 is selected from the group
consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo,
C.sub.1-6 alkyl, 6-membered heterocycle, wherein the heterocycle is
substituted with one or two substients selected from the group
consisting of halo, C.sub.1-6 alkoxy, C.sub.1-6alkylthio, cyano,
CF.sub.3, OCF.sub.3, C.sub.1-6 alkyl, C.sub.1-6 alkylamino,
C.sub.1-6 dialkylamino, and phenyl, wherein the phenyl is
substituted with one or two substituents selected from the group
consisting of halo, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, cyano,
CF.sub.3, OCF.sub.3, C.sub.1-6 alkyl, C.sub.1-6 alkylamino, and
C.sub.1-6 dialkylamino; R.sub.3 is selected from the group
consisting of hydrogen, C.sub.1-6 alkyl, and phenyl, wherein the
C.sub.1-6 alkyl and phenyl may be optionally substituted by one or
more substituents selected from the group consisting of
SO.sub.2CH.sub.3, halo, C.sub.1-3 alkyl, C.sub.1-3 alkoxy,
C.sub.1-3 alkylthio, cyano, CF.sub.3, OCF.sub.3, and
SO.sub.2NH.sub.2; and R.sub.6 is selected from the group consisting
of hydrogen and C.sub.1-6 alkyl which may be optionally substituted
by one or more substituents selected from the group consisting of
phenyl, substituted phenyl, halo, OH, NH.sub.2, NHR.sub.3,
N(R.sub.3).sub.2, and cyano, C.sub.1-7 cycloalkyl, C.sub.1-7
heterocycloalkyl, and 3-7 membered heterocycle ring.
14. The process of claim 12, wherein the dihalomethane is
dibromomethane.
15. The process of claim 12, wherein the dihalomethane is
iodochloromethane.
16. The process of claim 12, wherein the process comprising making
a compound selected from the group consisting of: 134135
Description
[0001] This application claims priority to U.S. Provisional
Application No. 60/109,177 filed Nov. 20, 1998.
FIELD OF THE INVENTION
[0002] This invention relates to the preparation of selected
substituted heterocycles that are useful for the treatment of
inflammatory diseases. In particular, the application discloses a
method for the preparation of a number of substituted heterocycles
that are p38 kinase and COX-2 inhibitors. The heterocycles
described herein may be useful for the treatment of other disease
states.
RELATED ART
[0003] Dithietanes have previously been prepared from selected
1,3-dicarbonyl compounds. These so-called active methylene
compounds include esters of malonic acid, beta-keto esters, and
1,3-diketones. [(1) Katagiri, N.; Ise, S.; Watanabe, N.; Kaneko,
C., Chem. Pharm. Bull. 1990, 12,3242-3248. (2) Okajima, N.; Okada,
Y., J. Heterocyclic Chem. 1990,27, 567-574.] Selected dithioles
derived from esters of malonic acid have been described as
inhibitors of cancer metastasis. [Onaka, S.; Gokou, S. Japanese
Patent Application JP 10212239 1998. Certain
(1,2,4-triazolyl)ketene S,S-acetals have been previously reported
to react with hydrazine to afford pyrazolyl-1,2,4-triazoles.
[Huang, Z. N.; Li, Z. M., Synth. Commun. 1996, 26, 3115-3120.]
Condensation of selected cyclic
alpha-oxo-alpha-(1,2,4-triazol-1-yl)ketene N,S-acetals with
hydrazine afforded 5-mercaptoalkylamino- and
5-anilinoalkylthiopyrazolyl-- 1,2,4-triazoles. [(1) Huang, Z. N.;
Li, Z. M., Heterocycles 1995, 41, 1653-1658.] Historically,
3-amino-pyrazoles have been prepared by a sulfur extrusion
rearrangement from 6H-1,3,4-thiadiazine derivatives in the presence
of base. [(1) Beyer, H.; Honeck, H.; Reichelt, L., Justus Liebigs
Ann. Chem. 1970, 741, 45. (2) Schmidt, R. R.; Huth, H., Tetrahedron
Lett. 1975, 33. (3) Pfeiffer, W. D.; Dilk, E.; Bulka, E.,
Synthesis, 1977, 196-198.] This experimental protocol normally
works adequately for the preparation of simple 3-amino4-pyrazoles.
The 6H-1,3,4-thiadiazine derivatives are in turn prepared by the
condensation of alpha-chloroketones with thiosemicarbazides. This
in turn necessitates preparing both the requisite
alpha-chloroketone and thiosemicarbazide. In general, the
aforementioned methodology was not useful for the preparation of
the anti-inflammatory pyrazoles of the present invention. The known
literature methods for the preparation of pyrazoles described above
suffered from poor chemical yields and often gave mixtures of
products that necessitated a careful chromatographic separation. In
a number of instances, no desired pyrazole at all could be obtained
using the methods disclosed in the literature. The present method
has the advantage of being more direct (fewer steps) and provides
the desired pyrazoles in significantly higher yield and with higher
purity. In addition, the present method has the added advantage
that it does not rely on the preparation of unstable
alpha-chloroketones. Frequently the alpha-chloroketones suffered
de-chlorination upon treatment with thiosemicarbazides.
SUMMARY OF THE INVENTION
[0004] This invention encompasses a process for the preparation of
selected substituted pyrazole derivatives of the Formula A and B
useful for the treatment of inflammatory diseases, wherein Y is
SR.sub.6, NR.sub.4R.sub.5, or OR.sub.6. 1
DETAILED DESCRIPTION OF THE INVENTION
[0005] The invention encompasses a process for making acompound of
Formula Ia or Ib 2
[0006] wherein
[0007] R.sub.1 is selected from the group consisting of hydrogen,
alkyl, O-alkyl, O-cycloalkyl, cycloalkyl, cycloalkenyl, and a 5 or
6 membered heterocycle substituted with one or more substituents
selected from the group consisting of C.sub.1-3 alkyl, halo, OH,
O-alkyl, cyano, CF.sub.3, OCF.sub.3 and substituted phenyl wherein
the substituents are selected from the group consisting of
hydrogen, halo, alkoxy, alkylthio, cyano, CF.sub.3, OCF.sub.3,
alkyl, SO.sub.2CH.sub.3, SO.sub.2NH.sub.2, SO.sub.2NHCOalkyl,
SO.sub.2NHCOalkyl, alkenyl, and alkynyl;
[0008] R.sub.2 is selected from the group consisting of pyridyl,
pyrimidyl, triazinyl, hydrogen, halo, alkyl, and mono- or
di-substituted 6-membered heterocycle wherein the substituent is
selected from the group consisting of hydrogen, halo, O-alkyl,
S-alkyl, cyano, CF.sub.3, OCF.sub.3, alkyl, alkyl amino, dialkyl
amino, and mono or di-substituted phenyl optionally substituted
from the group selected from hydrogen, halo, alkoxy, alkylthio,
cyano, CF.sub.3, OCF.sub.3, alkyl, alkylamino, and
dialkylamino;
[0009] R.sub.3 is selected from the group selected from hydrogen,
alkyl, and phenyl, wherein all but hydrogen may optionally be
substituted by one or more of the group consisting of
SO.sub.2CH.sub.3, halo, alkyl, O-alkyl, S-alkyl, cyano, CF.sub.3,
OCF.sub.3 and SO.sub.2NH.sub.2;
[0010] R.sub.4 is selected from the group consisting of alkyl,
phenyl, cycloalkyl and heterocyclyl optionally substituted by one
or more of the group consisting of OH, NH.sub.2, SH, O-alkyl,
NHR.sub.7, N(R.sub.7).sub.2, alkoxycarbonyl, acyl and halo;
[0011] R.sub.5 is selected from the group consisting of alkyl,
phenyl, cycloalkyl and heterocyclyl optionally substituted by one
or more of the group consisting of OH, NH.sub.2, SH, S-alkyl,
O-alkyl, NHR.sub.7, N(R.sub.7).sub.2, CO.sub.2H, halo,
alkoxycarbonyl, acyl, heterocyclyl, cycloalkyl, heterocycloalkyl,
and heterocyclyl;
[0012] R.sub.4 and R.sub.5 taken together may form a ring selected
from the group consisting of morpholine, aziridine, thiomorpholine,
piperidine, piperazine, and N'-piperazine;
[0013] R.sub.7 is selected from the group consisting of alkyl and
cycloalkyl;
[0014] comprising:
[0015] reacting an organometallic reagent of the formula
R.sub.2CH.sub.2M wherein M is selected from the group consisting of
Li, Na, K, and Mg, with an activated form of a carboxylic acid to
produce a ketone of Formula Ic; 3
[0016] treating the ketone of Formula Ic with a mixture of carbon
disulfide and dihalomethane such as dibromomethane or
iodochloromethane in the presence of a base and a solvent to
produce the dithietane derivative of Formula Id; 4
[0017] reacting the dithietane derivative of Formula Id with an
amine of formula R.sub.4--NH--R.sub.5 to produce the thioamide of
Formula Ie, If, or Ig; 5
[0018] condensing the thioamide of Formula Ie, If or Ig with
hydrazine or substituted hydrazine.
[0019] In another embodiment of the invention is the process of
making compounds of Formula IIa or IIb 6
[0020] wherein:
[0021] R.sub.1 is selected from the group consisting of hydrogen,
alkyl, O-alkyl, O-cycloalkyl, cycloalkyl, cycloalkenyl, and 5 or 6
membered heterocycle substituted with one or more substituents
selected from the group consisting of C.sub.1-3 alkyl, halo, OH,
O-alkyl, cyano, CF.sub.3, OCF.sub.3, and substituted phenyl wherein
the substituents are selected from one or more of the group
consisting of hydrogen, halo, alkoxy, alkylthio, cyano, CF.sub.3,
OCF.sub.3, alkyl, SO.sub.2CH.sub.3, SO.sub.2NH.sub.2,
SO.sub.2NHCOalkyl, SO.sub.2NHCOalkyl, alkenyl, and alkynyl;
[0022] R.sub.2 is selected from the group consisting of pyridyl,
pyrimidyl, triazinyl, hydrogen, halo, alkyl, and mono- or
di-substituted 6-membered heterocycle wherein the substituent is
selected from the group consisting of hydrogen, halo, O-alkyl,
S-alkyl, cyano, CF.sub.3, OCF.sub.3, alkyl, alkylamino,
dialkylamino, and mono or di-substituted phenyl optionally
substituted from the group selected from hydrogen, halo, alkoxy,
alkylthio, cyano, CF.sub.3, OCF.sub.3, alkyl, alkylamino and
dialkylamino;
[0023] R.sub.3 is selected from the group selected from hydrogen,
alkyl, and phenyl wherein all but hydrogen may be substituted by
one or more of the group consisting of SO.sub.2CH.sub.3, halo,
alkyl, O-alkyl, S-alkyl, cyano, CF.sub.3, OCF.sub.3, and
SO.sub.2NH.sub.2;
[0024] R.sub.6 is selected from the group consisting of hydrogen,
alkyl, phenyl, cycloalkyl and heterocyclyl which may be optionally
substituted by one or more of the group consisting of phenyl,
substituted phenyl, alkoxycarbonyl, acyl, halo, OH, NH.sub.2,
NHR.sub.3, N(R.sub.3).sub.2, and cyano, cycloalkyl,
heterocycloalkyl, and 3-7 membered heterocycle ring;
[0025] comprising:
[0026] reacting an organometallic reagent of the formula
R.sub.2CH.sub.2M wherein M is selected from the group consisting of
Li, Na, K, and Mg, with an activated form of a carboxylic acid to
produce a ketone of Formula IIc; 7
[0027] treating the ketone of Formula IIc with a mixture of carbon
disulfide and dihalo methane such as dibromomethane or
iodochloromethane in the presence of a base and a solvent to
produce the dithietane derivative of Formula IId; 8
[0028] reacting the dithietane derivative of Formula IId with
NaOR.sub.6 to produce Formula IIe; 9
[0029] condensing Formula IIe with hydrazine or substituted
hydrazine.
[0030] In another embodiment of the invention is the process of
making compounds of Formula IIIa or IIIb 10
[0031] wherein:
[0032] R.sub.1 is selected from the group consisting of hydrogen,
alkyl, O-alkyl, O-cycloalkyl, cycloalkyl, cycloalkenyl, and 5 or 6
membered heterocycle substituted with one or more of the
substituents selected from the group consisting of alkyl, halo, OH,
O-alkyl, cyano, CF.sub.3, OCF.sub.3, and substituted phenyl wherein
the substituents are selected from the group consisting of
hydrogen, halo, alkoxy, alkylthio, cyano, CF.sub.3, OCF.sub.3,
alkyl, SO.sub.2CH.sub.3, SO.sub.2NH.sub.2, SO.sub.2NHCOalkyl,
SO.sub.2NHCOalkyl, alkenyl, and alkynyl;
[0033] R.sub.2 is selected from the group consisting of pyridyl,
pyrimidyl, triazinyl, hydrogen, halo, alkyl, mono- or
di-substituted 6-membered heterocycle wherein the substituent is
selected from the group consisting of one or more hydrogen, halo,
O-alkyl, S-alkyl, cyano, CF.sub.3, OCF.sub.3, alkyl, alkylamino,
dialkylamino, and mono or di-substituted phenyl substituted from
the group selected from hydrogen, halo, alkoxy, alkylthio, cyano,
CF.sub.3, OCF.sub.3, alkyl, alkylamino, and dialkylamino;
[0034] R.sub.3 is selected from the group selected from hydrogen,
alkyl, phenyl of which all but hydrogen may be optionally
substituted by one or more of the group consisting of
SO.sub.2CH.sub.3, halo, alkyl, O-alkyl, S-alkyl, cyano, CF.sub.3,
OCF.sub.3, and SO.sub.2NH.sub.2;
[0035] R.sub.6 is selected from the group consisting of hydrogen,
alkyl, phenyl, cycloalkyl, and heterocyclyl which may be optionally
substituted by one or more of the group consisting of phenyl,
substituted phenyl, halo, alkoxycarbonyl, acyl, OH, NH.sub.2,
NHR.sub.3, N(R.sub.3).sub.2, and cyano, cycloalkyl,
heterocycloalkyl, and 3-7 membered heterocycle ring;
[0036] comprising:
[0037] reacting an organometallic reagent of the formula
R.sub.2CH.sub.2M wherein M is selected from the group consisting of
Li, Na, K, and Mg, with an activated form of a carboxylic acid to
produce a ketone of Formula IIIc; 11
[0038] treating the ketone of Formula IIIc with a mixture of carbon
disulfide and dihalomethane such as iodochloromethane or
dibromomethane in the presence of a base and a solvent to produce
the dithietane derivative of Formula IIId; 12
[0039] reacting the dithietane derivative of Formula IIId with
R.sub.3NHNH.sub.2 to produce a heterocycle of the formula IIIe or
IIIf and their tautomers; 13
[0040] reacting the heterocycle of the formula IIIe or IIIf with an
activated form of R.sub.6 in the presence of a base and a
solvent.
[0041] The term "alkyl", alone or in combination, means an acyclic
alkyl radical containing from 1 to about 10, or from 1 to about 8
carbon atoms or 1 to about 6 carbon atoms. Said alkyl radicals may
be optionally substituted. Examples of such radicals include
methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl,
isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl,
pentyl, aminopentyl, iso-amyl, hexyl, octyl and the like.
[0042] The term "alkenyl" refers to an unsaturated, acyclic
hydrocarbon radical in so much as it contains at least one double
bond. Such radicals containing from about 2 to about 10 carbon
atoms, or from about 2 to about 8 carbon atoms or 2 to about 6
carbon atoms. Said alkenyl radicals may be optionally substituted.
Examples of suitable alkenyl radicals include propylenyl,
2-chloropropylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl,
2-2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl,
3-hydroxyhexen-1-yl, hepten-1-yl, and octen-1-yl, and the like.
[0043] The term "alkynyl" refers to an unsaturated, acyclic
hydrocarbon radical in so much as it contains one or more triple
bonds, such radicals containing about 2 to about 10 carbon atoms,
or about 2 to about 8 carbon atoms or 2 to about 6 carbon atoms.
Said alkynyl radicals may be optionally substituted. Examples of
suitable alkynyl radicals include ethynyl, propynyl,
hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl,
4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl,
hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.
[0044] The term "cyano" radical denotes a carbon radical having
three of four covalent bonds shared by a nitrogen atom.
[0045] The term "halo" means halogens such as fluorine, chlorine,
bromine or iodine atoms.
[0046] The term "haloalkenyl" denotes linear or branched radicals
having from 1 to about 10 carbon atoms and having one or more
double bonds wherein any one or more of the alkenyl carbon atoms is
substituted with halo as defined above. Dihaloalkenyl radicals may
have two or more of the same halo atoms or a combination of
different halo radicals and polyhaloalkenyl radicals may have more
than two of the same halo atoms or a combination of different halo
radicals.
[0047] The term "heterocyclyl" embraces saturated, partially
saturated and unsaturated heteroatom-containing ring-shaped
radicals, where the heteroatoms may be selected from nitrogen,
sulfur and oxygen. Examples of saturated heterocyclic radicals
include saturated 3 to 7-membered heteromonocylic group containing
1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl,
piperidino, piperazinyl, etc.]; saturated 3 to 7-membered
heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to 7-membered
heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3
nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of partially
saturated heterocyclyl radicals include dihydrothiophene,
dihydropyran, dihydrofuran and dihydrothiazole. Examples of
unsaturated heterocyclic radicals, also termed "heteroaryl"
radicals, include unsaturated 5 to 6 membered heteromonocyclyl
group containing 1 to 4 nitrogen atoms, for example, pyrrolyl,
pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
pyrimdyl, pyrazinyl, pyridazinyl, triazolyl [e.g.,
4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.]
tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.;
unsaturated condensed heterocyclic group containing 1 to 5 nitrogen
atoms, for example, indolyl, isoindolyl, indolizinyl,
benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,
tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl, etc.],
etc.; unsaturated 3 to 6-membered heteromonocyclic group containing
an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.;
unsaturated 5 to 6-membered heteromonocyclic group containing a
sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated
5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen
atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl,
oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,
1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic
group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms
[e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to
6-membered heteromonocyclic group containing 1 to 2 sulfur atoms
and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl
[e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl,
etc.] etc.; unsaturated condensed heterocyclic group containing 1
to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl,
benzothiadiazolyl, etc.] and the like. The term also embraces
radicals where heterocyclic radicals are fused with aryl radicals.
Examples of such fused bicyclic radicals include benzofuran,
benzothiophene, and the like. Said "heterocyclyl" group may have 1
to 3 substituents as defined below. Heterocyclic radicals include
five to ten membered fused or unfused radicals. Non-limiting
examples of heterocyclic radicals include pyrrolyl, pyridinyl,
pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl,
thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl,
2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl,
2-imidazolinyl, imidazoidinyl, 2-pyrazolinyl, pyrazolidinyl,
isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl,
1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl,
1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl,
pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl,
benzo(b)thiophenyl, benzimidazonyl, quinolinyl, tetaazolyl, and the
like.
[0048] The term "cycloalkyl" embraces radicals having three to ten
carbon atoms. Cycloalkyl radicals are "lower cycloalkyl" radicals
having three to seven carbon atoms. Examples include radicals such
as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl. The term "cycloalkylalkyl" embraces
cycloalkyl-substituted alkyl radicals. Cycloalkylalkyl radicals are
"lower cycloalkylalkyl" radicals having cycloalkyl radicals
attached to alkyl radicals having one to six carbon atoms. Examples
of such radicals include cyclohexylhexyl.
[0049] The term "cycloalkenyl" embraces radicals having three to
ten carbon atoms and one or more carbon-carbon double bonds.
Cycloalkenyl radicals are "lower cycloalkenyl" radicals having
three to seven carbon atoms. Examples include radicals such as
cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
[0050] The term "halocycloalkyl" embraces radicals wherein any one
or more of the cycloalkyl carbon atoms is substituted with halo as
defined above. Specifically embraced are monohalocycloalkyl,
dihalocycloalkyl and polyhalocycloalkyl radicals. A
monohalocycloalkyl radical, for one example, may have either a
bromo, chloro or a fluoro atom within the radical. Dihalo radicals
may have two or more of the same halo atoms or a combination of
different halo radicals and polyhalocycloalkyl radicals may have
more than two of the same halo atoms or a combination of different
halo radicals. Halocycloalkyl radicals are "lower halocycloalkyl"
radicals having three to about eight carbon atoms. Examples of such
halocycloalkyl radicals include fluorocyclopropyl,
difluorocyclobutyl, trifluorocyclopentyl, tetrafluorocyclohexyl,
and dichlorocyclopropyl. The term "halocycloalkenyl" embraces
radicals wherein any one or more of the cycloalkenyl carbon atoms
is substituted with halo as defined above. Specifically embraced
are monohalocycloalkenyl, dihalocycloalkenyl and
polyhalocycloalkenyl radicals. The term "halocycloalkoxy" also
embraces cycloalkoxy radicals having one or more halo radicals
attached to the cycloalkoxy radical, that is, to form
monohalocycloakoxy, dihalocycloalkoxy, and polycycloalkoxy
radicals.
[0051] The term "alkylthio" embraces radicals containing a linear
or branched alkyl radical, of one to ten carbon atoms, attached to
a divalent sulfur atom. Alkylthio radicals are "lower alkylthio"
radicals having one to six carbon atoms. An example of "lower
alkylthio" is methylthio (CH.sub.3--S--). The term "alkylsulfinyl"
embraces radicals containing a linear or branched alkyl radical, of
one to ten carbon atoms, attached to a divalent --S(.dbd.O)--
atom.
[0052] The terms "alkoxy" and "alkoxyalkyl" embrace linear or
branched oxy-containing radicals each having alkyl portions of one
to about ten carbon atoms, such as methoxy radical. The term
"alkoxyalkyl" also embraces alkyl radicals having one or more
alkoxy radicals attached to the alkyl radical, that is, to form
moncalkoxyalkyl and dialkoxyalkyl radicals. Alkoxy radicals are
"lower alkoxy" radicals having one to six carbon atoms. Examples of
such radicals include methoxy, ethoxy, propoxy, butoxy and
tert-butoxy alkyls. The "alkoxy" radicals may be further
substituted with one or more halo atoms, such as fluoro, chloro or
bromo, to provide "haloalkoxy" radicals. Examples of such radicals
include fluoromethoxy, chloromethoxy, trifluoromethoxy,
difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy,
pentafluoroethoxy, and fluoropropoxy.
[0053] The term "substituted phenyl" embraces a phenyl moiety
substituted at one or more carbons with one or more suitable
substituent. Said substituents include alkyl, alkenyl, alkynyl,
O-alkyl, S-alkyl, O-alkenyl, S-alkenyl, halo, cyano, CF.sub.3,
OCF.sub.3, SO.sub.2NH.sub.2, SO.sub.2CH.sub.3, OH, NH.sub.2, N, S,
O, and the like. 14
[0054] Scheme 1 shows a process for synthesis of selected
5-amino-pyrazoles. Treatment of 1 with a base such as sodium
bis(trimethylsilyl)amide generates the corresponding
organometallic. This organometallic reagent is then treated with an
ester 2 in a suitable solvent such as tetrahydrofuran to afford the
desired ketone 3. Treatment of ketone 3 with a mixture of carbon
disulfide, dihalomethane, and a base such as potassium carbonate in
a suitable solvent such as acetone provides the key dithietane
compound 4. The dithietane compound 4 may then be reacted with an
appropriate amine with or without heating in an acceptable solvent
such as toluene or acetonitrile to make the thioamide compound 5.
Thioamide compound 5 is treated with a mono-substituted hydrazine
(6) or hydrazine (6, R.dbd.H) in an appropriate solvent such as
tetrahydrofuran or an alcohol with or without heating to produce
pyrazoles 7 and 8. In the case of hydrazine (6, R.dbd.H) the
pyrazoles (7 and 8, R.sub.3.dbd.H) thus produced are tautomers.
15
[0055] The dithietane 4 is added to a solution of a sodium or
potassium alkoxide in THF. The alkoxide may be generated by
treating an alcohol, in THF, with a suitable base, such as sodium
hydride, NaHMDS, or KHMDS. The reaction mixture is allowed to stir
from 4 to 72 hours at room temperature. The resulting thionoester 9
is allowed to react with hydrazine, or its hydrate, in ethanol,
methanol, or THF at room temperature for 2-18 hours to generate the
pyrazole products 10. 16
[0056] To the dithietane 4 in toluene is added an amine, such as
thiomorpholine and heated from 80-110.degree. C. The resulting
thioanide 11 may be isolated or used directly in the next reaction
step. To the thioamide in THF is added a suitable base, such as
potassium t-butoxide and the resulting thiol anion alkylated with
iodomethane. The resulting intermediate 12 can be cyclized with
hydrazine, in a solvent, such as THF or ethanol, to generate the
pyrazole 13. 17
[0057] The dithietane 4 in a suitable solvent, such as THF or
ethanol, is allowed to react with hydrazine, or its hydrate, at
room temperature up to the reflux temperature of the solvent to
generate the thiopyrazole 14. The thiol group may be alkylated with
a variety of alkylating agents, such as alkyl halides or Michael
acceptors, including; methyl chloroacetate, ethyl acrylate, and
benzyl bromide, in the presence of a suitable base such as
potassium carbonate, sodium ethoxide or triethylanine in a solvent
such as DMF or ethanol to generate the desired pyrazoles 15. 18
[0058] Pyrazoles, such as 16, containing acid labile amine
protecting groups may be treated with a suitable acid catalyst,
such as TFA in dichloromethane or HCl in ethanol or dioxane. The
resulting amine 17 can then be acylated or alkylated in a
straightforward fashion using a suitable base, such as potassium
carbonate or triethylamine, with a reagent, such as for example;
acetyl chloride or methyl iodide. In addition, N-methylation can be
performed directly, using formaldehyde and formic acid in
ethanol/water at reflux to give the desired pyrazoles 18. 19
[0059] Pyrazoles containing base labile esters, such as 19, may be
treated with a suitable base, such as, NaOH to generate the free
acid 20. The resulting acid can then arninated in a straightforward
fashion using a suitable coupling reagent, such as EDC or TBTU,
with or without catalysts, such as HOBt or N-hydroxysuccinimide,
and an appropriate amine. In addition, amidation can be performed
directly, by treating the methyl ester with an appropriate amine,
for example N-methylpiperazine, in a suitable solvent such as DMF
or methanol, at a temperature from room temperature up to reflux to
generate the desired pyrazoles 21.
[0060] The following examples are provided to illustrate the
present invention and are not intended to limit the scope thereof.
Those skilled in the art will readily understand that known
variations of the conditions and processes of the following
preparative procedures can be used to prepare these compounds.
[0061] Without further elaboration, it is believed that one skilled
in the art can, using the preceding descriptions, utilize the
present invention to its fullest extent. Therefore the following
preferred specific embodiments are to be construed as merely
illustrative and not limitative of the remainder of the disclosure
in any way whatsoever. Compounds containing multiple variations of
the structural modifications illustrated in the preceding schemes
or the following Examples are also contemplated.
[0062] The starting materials which are required for the above
processes herein described are known in the literature or can be
made by known methods from known starting materials.
EXAMPLE 1
[0063] 20
1-[5-(3-Tolyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl-4-methylpiperazine
[0064] Step 1. Preparation of 1-tolyl-2-(4-pyridyl)ethanone. 21
[0065] Methyl 3-methylbenzoate (6.0 g, 40 mmol), tetrahydrofuran
(50 mL), and 4-picoline (4.1 g, 44 mmol) were stirred at
-78.degree. C. under an atmosphere of nitrogen. Sodium
bis(trimethylsilyl)amide 1.0 M in THF (88 mL, 88 mmol) was added
dropwise. The mixture was allowed to warm to room temperature and
stir for 16 h when it was poured into saturated aqueous sodium
bicarbonate solution. The mixture was then extracted with ethyl
acetate (3.times.50 mL). The combined organics were washed with
brine (2.times.50 mL), dried over magnesium sulfate, and
concentrated. The product was recrystallized from ethyl
acetate/hexane to yield a light yellow solid (5.7 g, 67%): mp
118.0-119.0.degree. C. .sup.1H NMR (acetone-d.sub.6/300 MHz) 8.50
(m, 2H), 7.90 (m, 2H), 7.44 (m, 2H), 7.29 (m, 2H), 4.45 (s, 2H),
2.41 (s, 3H). ESHRMS m/z 212.1067 (M+H, C.sub.14H.sub.13NO requires
212.1075).
[0066] Anal. Calc'd for C.sub.14H.sub.13NO: C, 79.59; H, 6.20; N,
6.63. Found: C, 79.54; H, 6.30; N, 6.56.
[0067] Step 2. Preparation of
1-(3-tolyl)-2-(1,3-dithietan-2-ylidene)-2-(4- -pyridyl)ethanone.
22
[0068] 1-Tolyl-2-(4-pyridyl)ethanone (4.22 g, 20 mmol), acetone
(100 mL), potassium carbonate (8.3 g, 60 mmol), carbon disulfide
4.56 g, 60 mmol), and dibromomethane (10.43 g, 60 mmol) were
stirred at room temperature for 16 h. Water (100 mL) was added and
the mixture was extracted with ethyl acetate (3.times.50 mL). The
combined organic extracts were washed with brine (2.times.50 mL),
dried over magnesium sulfate and concentrated. This crude material
was purified by either flash column chromatography eluting with
ethyl acetate:hexane or crystallization from ethyl acetate/hexane
to yield a yellow solid (4.8 g, 80%): mp 178.6-179.2.degree. C.
.sup.1H NMR (acetone-d.sub.6/300 MHz) 8.47 (m, 2H), 7.08 (m, 6H),
4.37 (s, 2H), 2.21 (s, 3H). ESHRMS m/z 300.0521 (M+H,
C.sub.16H.sub.14NOS.sub.2 requires 300.0517).
[0069] Anal. Calc'd for C.sub.16H.sub.13NOS.sub.2: C, 64.18; H,
4.38; N, 4.68. Found: C, 64.08; H, 4.25; N, 4.62.
[0070] Step 3. Preparation of
1-[3-(3-tolyl)-3-oxo-2-(4-pyridyl)-1-thiopro-
pyl]-4-methylpiperazine. 23
[0071]
1-(3-tolyl)-2-(1,3-dithietan-2-ylidene)-2-(4-pyridyl)ethanone (3.0
g, 10 mmol), N-methylpiperazine (5.0 g, 50 mmol), and toluene (50
mL) were heated to reflux using a Dean-Stark apparatus for 1 to 3
h. The reaction was allowed to cool to room temperature and was
concentrated to dryness under high vacuum. This thick, oily
material was crystallized from ethyl acetate/hexane (2.9 g, 82%):
mp 124.8-125.8.degree. C. .sup.1H NMR (acetone-d.sub.6/300 MHz)
8.57 (m, 2H), 7.75 (m, 2H), 7.54 (m, 2H), 7.37 (m, 2H) 6.54 (s,
1H), 4.27 (m, 2H), 4.19 (m, 1H), 3.83 (m, 1H), 2.47-2.28 (m, 6H),
2.22 (s, 3H), 2.17 (m, 1H). ESHRMS m/z 354.1669 (M+H,
C.sub.20H.sub.24N.sub.3OS requires 354.1640).
[0072] Anal. Calc'd for C.sub.20H.sub.23N.sub.3OS: C, 67.96; H,
6.56; N, 11.89. Found: C, 67.79; H, 6.66; N, 11.88.
[0073] Step 4. Preparation of
1-[5-(3-tolyl)-4-(4-pyridinyl)-1H-pyrazol-3--
yl-4-methylpiperazazine. 24
[0074]
1-[3-(3-tolyl)-3-oxo-2-(4-pyridyl)-1-thiopropyl]-4-methylpiperazine
(1.06 g, 3 mmol), tetrahydrofuran (50 mL), and hydrazine (15 mL, 15
mmol, 1.0 M in THF were stirred at room temperature for 16 h. A
white solid was collected by filtration. Purification when
necessary was by trituration or recrystallization (0.98 g, 97%): mp
261.9-262.0.degree. C. .sup.1H NMR (DMSO-d.sub.6/300 MHz) 12.6
(brs, 1H), 8.42 (m, 2H), 7.2 (m, 4H), 7.12 (s, 1H), 7.0 (m, 1H),
2.86 (m, 4H), 2.34 (m, 4H) 2.25 (s, 3H), 2.16 (s, 3H). ESHRMS m/z
334.2049 (M+H, C.sub.20H.sub.24N.sub.5 requires 334.2032).
[0075] Anal. Calc'd for C.sub.20H.sub.23N.sub.5: C, 72.04; H, 6.95;
N, 21.00. Found: C, 71.83; H, 7.06; N, 20.83.
EXAMPLE 2
[0076] 25
[0077] Step 1. 1-(4-chlorophenyl)-2-(4-pyridyl)ethanone was
prepared according to the procedure used in example 1, step 1,
Yield: 74%, yellow solid, mp 95.5-97.3.degree. C.
[0078] .sup.1H-NMR (DMSO-d.sub.6/300 MHz) 8.57 (br d, 2H), 7.92 (d,
2H), 7.46 (d, 2H), 7.20 (d, 2H), 4.28 (s, 2H). ESLRMS m/z 232
(M+H).
[0079] Step 2. To a solution of
1-(4-chlorophenyl)-2-(4-pyridyl)ethanone (70.0 g, 0.3 mol),
dibromomethane (200 mL) and carbon disulfide (25.9 g, 0.34 mol) in
acetone (800 mL) was added potassium carbonate (83.0 g, 0.6 mol).
The reaction mixture was stirred at room temperature for 24 h. An
additional two equivalents of potassium carbonate and one
equivalent of carbon disulfide was added and the stirring was
continued for another 24 h. Solvent was removed and the residue was
partitioned between dichloromethane and water. The organic layer
was washed with brine, dried over magnesium sulfate and filtered.
The filtrate was concentrated and the crude product was stirred
with 1 L of a mixture of ethyl acetate and ether (1:9) to give 78.4
g, 82% of pure product as a yellow solid, mp 185.3-185.4.degree. C.
.sup.1H NMR (acetone-d.sub.6/300 MHz) 8.49 (m, 2H), 7.31 (m, 4H),
7.09 (m, 2H), 4.39 (s, 2H). ESHRMS m/z 319.9981 (M+H,
C.sub.15H.sub.11CINOS.sub.2 requires 319.9971).
[0080] Anal. Calc'd for C.sub.15H.sub.10CINOS.sub.2: C, 56.33; H,
3.15; N, 4.38. Found: C, 56.47; H, 3.13; N, 4.44.
EXAMPLE 3
[0081] 26
[0082] Prepared by the method described in Example 1, steps 1 and
2. mp 164.0-165.0.degree. C.
[0083] .sup.1H NMR.(acetone-d.sub.6/300 MHz) 8.49 (m, 2H), 7.25 (m,
2H), 7.0 (m, 3H), 4.38 (s, 2H), 2.24(s, 3H). ESHRMS m/z 334.0130
(M+H, C.sub.16H.sub.12CINOS.sub.2 requires 334.0127).
[0084] Anal. Calc'd for C.sub.16H.sub.12CINOS.sub.2: C, 57.56; H,
3.62; N, 4.20. Found: C, 57.68; H, 3.67; N, 4.17. 27
[0085] Prepared by the method described in Example 1, steps 1 and
2. mp 126.5-126.6.degree. C.
[0086] .sup.1H NMR (acetone-d.sub.6/300 MHz) 8.40 (m, 2H), 7.17 (m,
2H), 7.0 (m, 4H), 4.39 (s, 2H), 2.85 (s, 3H). ESHRMS m/z 300.0483
(M+H, C.sub.16H.sub.14NOS.sub.2 requires 300.0517).
[0087] Anal. Calc'd for C.sub.16H.sub.13NOS.sub.2: C, 64.18; H,
4.38; N, 4.68. Found: C, 64.05; H, 4.27; N, 4.59.
EXAMPLE 5
[0088] 28
[0089] Prepared by the method described in Example 1, steps 1 and
2. mp 159.6-159.7.degree. C.
[0090] .sup.1H NMR (acetone-d.sub.6/300 MHz) 8.52 (m, 2H), 7.6 (m,
1H), 7.50 (s, 1H), 7.21 (m, 2H), 7.13 (m, 2H), 4.40 (s, 2H). ESHRMS
m/z 363.9503 (M+H, C.sub.15H.sub.11BrNOS.sub.2 requires
363.9465).
[0091] Anal. Calc'd for C.sub.15H.sub.10BrNOS.sub.2: C, 49.46; H,
2.77; N, 3.84. Found: C, 49.51; H, 2.68; N. 3.74.
EXAMPLE 6
[0092] 29
[0093] Prepared by the method described in Example 1, steps 1 and
2. mp 198.8-198.9.degree. C.
[0094] .sup.1H NMR (acetone-d.sub.6/300 MHz) 8.45 (m, 2H), 7.05 (m,
3H), 6.95 (m, 1H), 6.82 (m, 1H), 4.29 (s, 2H), 2.14 (s, 3H), 2.08
(s, 3H). ESHRMS m/z 314.0691 (M+H, C.sub.17H.sub.16NOS.sub.2
requires 314.0673).
EXAMPLE 7
[0095] 30
[0096] Prepared by the method described in Example 1, steps 1 and
2. mp 182.6-183.0.degree. C.
[0097] .sup.1H NMR (acetone-.sub.6/300 MHz) 8.50 (m, 2H), 7.42 (d,
2H, J=8.5 Hz), 7.23 (d, 2H, J=8.5 Hz), 7.10 (m, 2H), 4.40 (s, 2H).
ESHRMS m/z 370.0173 (M+H, C.sub.16H.sub.11F.sub.3NO.sub.2S.sub.2
requires 370.0183).
EXAMPLE 8
[0098] 31
[0099] Prepared by the method described in Example 1, steps 1 and
2. mp 193.3-193.4.degree. C.
[0100] .sup.1H NMR (acetone-d.sub.6/300 MHz) 8.49 (m, 2H), 7.69 (d,
2H, J=8.2 Hz), 7.46 (d, 2H, J=8.2 Hz), 7.01 (m, 2H), 4.43 (s, 2H).
ESHRMS m/z 311.0327 (M+H, C.sub.16H.sub.11N.sub.2OS.sub.2 requires
311.0313).
EXAMPLE 9
[0101] 32
[0102] Prepared by the method described in Example 1, steps 1 and
2. mp 191.5-192.5.degree. C.
[0103] .sup.1H NMR (CDCl.sub.3/300 MHz) 8.55 (dd, 2H, J=4.6, 1.6
Hz), 7.4 (m, 1H), 7.09-7.03 (m, 3H), 6.67 (d, 1H, J=8.7 Hz), 4.17
(s, 2H), 3.86 (s, 3H). ESHRMS m/z 350.0090 (M+H,
C.sub.16H.sub.13ClNO.sub.2S.sub.2 requires 350.0076).
[0104] Anal. Calc'd. for C.sub.16H.sub.12ClNO.sub.2S.sub.2: C,
54.93; H, 3.60; N, 4.00; Cl, 10.13; S, 18.33. Found: C, 54.74; H,
3.60; N, 3.89; Cl, 10.45; S, 18.32.
EXAMPLE 10
[0105] 33
[0106] Prepared by the method described in Example 1, steps 1 and
2. mp 172.1-173.1.degree. C.
[0107] .sup.1H NMR (CDCl.sub.3/300 MHz) 8.51 (dd, 2H, J=4.4, 1.6
Hz), 7.23-7.21 (m, 4H), 7.04 (dd, 2H, J=4.6, 1.6 Hz), 4.17 (s, 2H),
1.25 (s, 9H). ESHRMS m/z 342.1004 (M+H, C.sub.19H.sub.20NOS.sub.2
requires 342.0986).
[0108] Anal. Calc'd for C.sub.19H.sub.19NOS.sub.2: C, 66.83; H,
5.61; N, 4.10; S, 18.78. Found: C, 66.97; H, 5.89; N, 4.02; S,
18.64.
EXAMPLE 11
[0109] 34
[0110] Prepared by the method described in Example 1, steps 1 and
2. mp 203.0-204.1.degree. C.
[0111] .sup.1H NMR (CDCl.sub.3/300 MHz) 8.52 (dd, 2H, J=4.4, 1.6
Hz), 7.29 (d, 1H, J=6.8 Hz), 7.28 (d, 1H, J=7.0 Hz), 7.05 (dd, 2H,
J=4.4, 1.6 Hz), 6.70 (d, 1H, J=6.8 Hz), 6.69 (d, 1H, J=6.8 Hz),
4.17 (s, 2H), 3.79 (s, 3H). ESHRMS m/z 316.0475 (M+H,
C.sub.16H.sub.14NO.sub.2S.sub.2 requires 316.0466).
[0112] Anal. Calc'd, for C.sub.16H.sub.13NO.sub.2S.sub.2: C, 60.93;
H, 4.15; N, 4.44; S, 20.33. Found: C, 60.46; H, 4.17; N, 4.37; S,
19.84.
EXAMPLE 12
[0113] 35
[0114] Prepared by the method described in Example 1, steps 1 and
2. mp 209.1-215.1.degree. C.
[0115] .sup.1H NMR (CDCl.sub.3/300 MHz) 8.50 (dd, 2H, J=4.4, 1.6
Hz), 7.20 (d, 2H, J=8.0 Hz), 7.03-6.99 (m, 4H), 4.18 (s, 2H), 2.30
(s, 3H). ESHRMS m/z 300.0517 (M+H, C.sub.16H.sub.14NOS.sub.2
requires 300.0517).
[0116] Anal. Calc'd, for C.sub.16H.sub.13NOS.sub.2: C64.18; H,
4.38; N, 4.69; S, 21.42. Found: C, 64.02; H, 4.62; N, 4.54; S,
21.24.
EXAMPLE 13
[0117] 36
[0118] Prepared by the method described in Example 1, steps 1 and
2. mp 257.6-257.7.degree. C.
[0119] .sup.1H NMR (CDCl.sub.3/300 MHz) 8.51 (dd, 2H, J=4.4, 1.6
Hz), 7.57 (d, 2H, J=8.5 Hz), 7.27-6.99 (m, 4H), 4.18 (s, 2H).
ESHRMS m/z 411.9348 (M+H, C.sub.15H.sub.11NIOS.sub.2 requires
411.9327).
[0120] Anal. Calc'd, for C.sub.15H.sub.10NIOS.sub.2: C, 43.81; H,
2.45; N, 3.41. Found: C, 43.71; H, 2.27; N, 3.41.
EXAMPLE 14
[0121] 37
[0122] Prepared by the method described in Example 1, steps 1 and
2. mp 197.3-202.2.degree. C.
[0123] .sup.1H NMR (CDCl.sub.3/300 MHz) 8.53(dd, 2H, J=4.4, 1.6
Hz), 7.26 (d, 2H, J=9.3 Hz), 7.09 (dd, 2H, J=4.4, 1.6 Hz), 6.43 (d,
2H, J=9.3 Hz), 4.14 (s, 2H), 2.97 (s, 6H). ESHRMS m/z 329.0789
(M+H, C.sub.17H.sub.17N.sub.2OS.sub.2 requires 329.0782).
[0124] Anal. Calc'd, for C.sub.17H.sub.16N.sub.2OS.sub.2: C, 62.17;
II, 4.91; N, 8.53; S, 19.53. Found: C, 61.93; H, 5.12; N, 8.46; S,
19.26.
EXAMPLE 15
[0125] 38
[0126] Prepared by the method described in Example 1, steps 1 and
2. mp 176.6-176.7.degree. C.
[0127] .sup.1H NMR (CDCl.sub.3/300 MHz) 8.51 (dd, 2H, J=4.4, 1.6
Hz), 7.29-7.22 (m, 4H), 7.03 (dd, 2H, J=4.4, 1.6 Hz), 6.64 (dd, 1H,
J=17.5, 10.9 Hz), 5.76 (d, 1H, J=17.7 Hz), 5.31 (d, 1H, J=10.9 Hz),
4.19 (s, 2H). ESHRMS 312.0513 (M+H, C.sub.17H.sub.14NOS.sub.2
requires 312.0517).
[0128] Anal. Calc'd, for C.sub.17H.sub.13NOS.sub.2: C, 65.56; H,
4.21; N, 4.50. Found: C, 65.75; H, 4.11; N, 4.46.
EXAMPLE 16
[0129] 39
[0130] Prepared by the method described in Example 1, steps 1 and
2. mp 174.8-175.0.degree. C.
[0131] .sup.1H NMR (CDCl.sub.3/300 MHz) 8.50 (dd, 2H, J=4.4, 1.6
Hz), 7.23-7.20 (m, 4H), 7.03 (dd, 2H, J=4.6, 1.6 Hz), 4.17 (s, 2H),
2.59 (q, 2H, J=7.6 Hz), 1.17 (t, 3H, J=7.7 Hz). ESHRMS m/z 314.0677
(M+H, C.sub.17H16NOS.sub.2 requires 314.0673).
[0132] Anal. Calc'd, for C.sub.17H.sub.15NOS.sub.2: C, 65.14; H,
4.82; N, 4.47. Found: C, 64.90; H, 4.62; N, 4.45.
EXAMPLE 17
[0133] 40
[0134] Prepared by the method described in Example 1, steps 1 and
2. mp 167.1-167.5.degree. C.
[0135] .sup.1H NMR (CDCl.sub.3/300 MHz) 8.52 (dd, 1H, J=4.4, 1.6
Hz), 7.33 (d, 1H, J=8.3 Hz), 7.02-7.00 (m, 3H), 6.87-6.83 (m, 1H),
4.19 (s, 2H), 2.28 (s, 3H). ESHRMS m/z 379.9577 (M+H,
C.sub.16H.sub.13BrNOS.sub.2 requires 379.9622).
[0136] Anal. Calc'd, for C.sub.16H.sub.12BrNOS.sub.2: C, 50.80; H,
3.20; N, 3.70. Found: C, 50.69; H, 3.19; N, 3.71.
EXAMPLE 18
[0137] 41
[0138] Prepared from Example 3 by the method described in Example
1, steps 3 and 4. mp 236.7-239.3.degree. C. .sup.1H NMR
(DMSO-d.sub.6/300 MHz) 12.6 (brs, 1H), 8.45 (m, 2H), 7.41 (m, 1H),
7.26 (m, 3H), 7.0 (m, 1H), 2.86 (m, 4H), 2.35 (m, 4H), 2.27 (s,
3H), 2.16 (s, 3H). ESHRMS m/z 368.4653 (M+H,
C.sub.20H.sub.23ClN.sub.5 requires 368.1642).
EXAMPLE 19
[0139] 42
[0140] Prepared from Example 4 by the method described in Example
1, steps 3 and 4. mp 244.0-244.2.degree. C. .sup.1H NMR
(acetone-d.sub.6/300 MHz) 11.6 (brs, 1H), 8.35 (m, 2H), 7.35 (m,
2H), 7.25 (m, 4H), 3.05 (m, 4H), 2.47 (m, 4H), 2.25 (s, 3H), 2.00
(s, 3H). ESHRMS m/z 334.2018 (M+H, C.sub.20H.sub.24N.sub.5 requires
334.2032).
[0141] Anal. Calc'd for C.sub.20H.sub.23N.sub.5: C, 72.04; H, 6.95;
N, 21.00. Found: C, 72.03; H, 7.00; N, 20.85.
EXAMPLE 20
[0142] 43
[0143] Prepared from Example 5 by the method described in Example
1, steps 3 and 4. mp 222.5-223.4.degree. C. .sup.1H NMR
(acetone-d.sub.6/300 MHz) 11.8 (brs, 1H), 8.51 (m, 2H), 7.55 (m,
2H), 7.34 (m, 4H), 3.0 (m, 4H), 2.41 (m, 4H), 2.22 (s, 3H). ESHRMS
m/z 398.0982 (M+H, C.sub.19H.sub.21BrN.sub.5 requires
398.0980).
EXAMPLE 21
[0144] 44
[0145] Prepared from Example 6 by the method described in Example
1, steps 3 and 4. mp 270.9-272.7.degree. C. .sup.1H NMR
(DMSO-d.sub.6/300 MHz) 12.5 (brs, 1H), 8.41 (m, 2H), 7.24 (m, 2H),
7.26 (m, 3H), 7.10 (m, 2H), 6.92 (m, 1H), 2.86 (m, 4H), 2.38 (m,
4H), 2.21 (s, 3H), 2.19 (s, 3H), 2.16 (s, 3H). ESHRMS m/z 348.2183
(M+H, C.sub.22H.sub.25N.sub.5 requires 348.2188).
EXAMPLE 22
[0146] 45
[0147] Prepared from Example 7 by the method described in Example
1, steps 3 and 4. mp 221.0-221.2.degree. C. .sup.1H NMR
(DMSO-d.sub.6/300 MHz) 12.7 (brs, 1H), 8.45 (m, 2H), 7.38 (s, 4H),
7.24 (m, 2H), 2.86 (m, 4H), 2.34 (m, 4H), 2.16 (s, 3H). ESHRMS m/z
404.1698 (M+H, C.sub.20H.sub.21F.sub.3N.sub.5O requires
404.1698).
EXAMPLE 23
[0148] 46
[0149] Prepared from Example 8 by the method described in Example
1, steps 3 and 4. mp >300.degree. C. .sup.1H NMR
(DMSO-d.sub.6/300 MHz) 12.8 (brs, 1H), 8.47 (m, 2H), 7.83 (m, 2H),
7.42 (m, 2H), 2.88 (m, 4H), 2.39 (m, 4H), 2.20 (s, 3H). ESHRMS m/z
345.1848 (M+H, C.sub.20H.sub.21N.sub.6 requires 345.1828).
EXAMPLE 24
[0150] 47
[0151] Prepared from Example 9 by the method described in Example
1, steps 3 and 4. mp 272.7-276.4.degree. C. .sup.1H NMR
(DMSO-d.sub.6/300 MHz) 8.44 (dd, 2H, J=4.6, 1.6 Hz), 7.32-7.13 (m,
5H), 3.84 (s, 3H), 2.90-2.85 (m, 4H), 2.38-2.35 (m, 4H), 2.16 (s,
3H). ESHRMS m/z 384.1580 (M+II C.sub.20H.sub.23ClN.sub.5O requires
384.1591).
EXAMPLE 25
[0152] 48
[0153] Prepared from Example 10 by the method described in Example
1, 3 and 4. mp 243.6-244.3.degree. C. .sup.1H NMR (DMSO-d.sub.6/300
MHz) 8.44 (dd, 2H, J=4.6, 1.6, Hz), 7.40 (d, 2H, J=8.3 Hz),
7.28-7.18 (m, 4H), 2.90-2.85 (m, 4=H), 2.38-2.34 (m, 4H), 2.16
(s,3H), 1.26 (s, 9H). ESHRMS m/z 376.2491 (M+H,
C.sub.23H.sub.30N.sub.5 requires 376.2501).
EXAMPLE 26
[0154] 49
[0155] Prepared from Example 11 by the method described in Example
1, steps 3 and 4. mp 259.0-260.2.degree. C. .sup.1H NMR
(DMSO-d.sub.6/300 MHz) 8.53 (dd, 2H, J=4.4, 1.6 Hz), 7.24 (dd, 2H,
J=4.4, 1.6 Hz), 7.18 (d, 2H, J=8.9 Hz), 6.94 (d, 2H, J=8.9 Hz),
3.75 (s, 3H), 2.90-2.85 (m, 4H), 2.39-2.35 (m, 4H), 2.16 (s, 3H).
ESHRMS m/z 350.1991 (M+H, C.sub.20H.sub.24N.sub.5O requires
350.1981).
[0156] Anal. Calc'd. for C.sub.20H.sub.23N.sub.5O+3.93% H.sub.2O:
C, 66.04; H, 6.81; N, 19.25. Found: C, 66.01; H, 6.62; N,
19.32.
EXAMPLE 27
[0157] 50
[0158] Prepared from Example 12 by the method described in Example
1, steps 3 and 4. mp 243.0-246.8.degree. C. .sup.1H NMR
(DMSO-d.sub.6/300 MHz) 8.41 (dd, 2H, J=4.6, 1.6 Hz), 7.24 (m, 6H),
2.91-2.86 (m, 4H), 2.40-2.35 (m, 4H), 2.29 (s, 3H), 2.16 (s, 3H).
ESHRMS m/z 334.2041 (M+H, C.sub.20H.sub.24N.sub.5 requires
334.2032).
[0159] Anal. Calc'd for C.sub.20H.sub.23N.sub.5+4.09% H.sub.2O: C,
69.10; H, 7.13; N, 20.14. Found: C, 69.10; H, 7.08; N, 20.13.
EXAMPLE 28
[0160] 51
[0161] Prepared from Example 13 by the method described in Example
1, steps 3 and 4. mp 265.2-265.8.degree. C. .sup.1H NMR
(CD.sub.3OD/300 MHz) 8.41 (dd, 2H, J=4.6, 1.6 Hz), 7.76-7.74 (m,
2H), 7.41-7.39 (m, 2H), 7.08-7.05 (m, 2H), 3.08-3.04 (m, 4H),
2.61-2.58 (m, 4H), 2.35 (s, 3H). ESHRMS m/z 446.0847 (M+H,
C.sub.19H.sub.21IN.sub.5 requires 446.084169)
[0162] Anal. Calc'd. for C.sub.19H.sub.20IN.sub.5+12.09% H.sub.2O:
C, 44.60; H, 5.39; N, 13.69. Found: C, 44.56; H, 4.56; N,
13.66.
EXAMPLE 29
[0163] 52
[0164] Prepared from Example 15 by the method described in Example
1, steps 3 and 4. mp >300.degree. C. .sup.1H NMR (CD.sub.3OD/300
MHz) 8.49 (dd, 2H, J=4.6, 1.6 Hz), 7.47-7.44 (m, 4H), 7.26 (d, 2H,
J=8.4 Hz), 6.75 (dd, J=17.7, 11.1 Hz), 5.83 (d, 1H, J=17.5 Hz),
5.28 (d, 1H, J=11.1 Hz), 3.07-3.03 (m, 4H), 2.58-2.53(m, 4H), 2.31
(s, 3H). ESHRMS m/z 346.2034 (M+H, C.sub.21H.sub.24N.sub.5 requires
346.2032).
[0165] Anal. Calc'd. for C.sub.21H.sub.23N.sub.5+2.83% H.sub.2O: C,
70.95; H, 6.84; N, 19.70. Found: C, 70.97; H, 6.49; N, 19.54.
EXAMPLE 30
[0166] 53
[0167] Prepared from Example 16 by the method described in Example
1, steps 3 and 4. mp 221.6-2226.degree. C. .sup.1H NMR
(CD.sub.3OD/300 MHz) 8.38 (dd, 2H, J=4.6, 1.6 Hz), 7.44-7.40 (m,
2H), 7.26-7.19 (m, 4H), 3.06-3.02 (m, 4H), 2.66 (q, 2H, J=7.5 Hz),
2.59-2.54 (m, 4H), 2.32 (s, 3H), 1.23 (t, 3H, J=7.5 Hz). ESHRMS m/z
348.2188 (M+H, C.sub.21H.sub.26N.sub.5 requires 348.2188).
[0168] Anal. Calc'd for C.sub.21H25N.sub.5+2.59% H.sub.2O: C,
70.71; H, 7.35; N, 19.63. Found: C, 70.76; H, 7.40; N, 19.46.
EXAMPLE 31
[0169] 54
[0170] Prepared from Example 17 by the method described in Example
1, steps 3 and 4. mp 294.7.degree. C. decomp. .sup.1H NMR
(CD.sub.3OD/300 MHz) 8.41 (dd, 2H, J=4.6, 1.6 Hz), 7.55 (d, 1H,
J=8.2 Hz), 7.45-7.42 (m, 2H), 7.27-7.25 (m, 1H), 7.00-6.97 (m 2H),
3.08-3.03 (m, 4H), 2.59-2.54 (m, 4H), 2.35 (s, 3H), 2.31 (s, 3H).
ESHRMS m/z 412.1124 (M+H, C.sub.20H.sub.23BrN.sub.5 requires
412.1137).
EXAMPLE 32
[0171] 55
[0172] To N-(2-hydroxyethyl)morpholine (363 uL, 3 mmol) in
anhydrous THF (7 mL), under nitrogen, was added 1M sodium
bis(trimethylsilyl)amide (3 ml, 3 mmol) in THF at ambient
temperature. The reaction mixture was stirred for 15 minutes, then
the dithietane of Example 2 (636 mg, 2 mmol) was added as a solid.
The reaction mixture gradually became dark orange. After about 18
hours at ambient temperature, the reaction was quenched with
saturated sodium bicarbonate solution (30 mL) and extracted twice
with ethyl acetate (30 mL). The organic solutions were combined and
washed with saturated NaCl solution (20 mL), then dried
(MgSO.sub.4), filtered, and concentrated to an orange oil. The oil
was taken up in MeOH (10 mL) and reconcentrated to remove any
remaining ethyl acetate. The oil was then taken up in methanol (5
mL) and anhydrous hydrazine (69 uL) was added. The reaction mixture
was allowed to stir at ambient temperature 18 hours, then quenched
with saturated sodium bicarbonate solution (30 mL) and extracted
twice with ethyl acetate (30 mL). The organic solutions were
combined and washed with water (20 mL) and saturated NaCl solution
(20 mL), then dried (MgSO.sub.4), filtered, and concentrated to an
orange semi-solid. The solid was triturated with acetonitrile (5
mL), collected by suction filtration, washed with acetonitrile and
dried in-vacuo.
[0173] Yield; off-white solid, 114 mg ,14.8%, mp
198.9-199.9.degree. C. .sup.1H-NMR (DMSO-d.sub.6/300 MHz) 12.61 (br
s, 1H), 8.41 (d, 2H), 7.52 (d, 2H), 7.38 (d, 2H), 7.21 (d, 2H),
4.33 (t, 2H), 3.54 (m, 4H), 2.70 (t, 2H), 2.44 (m 4H). ESHRMS m/z
385.1444 (M+H, C.sub.20H.sub.22ClN.sub.4O.su- b.2 requires
385.1431).
EXAMPLE 33
[0174] 56
[0175] The product was prepared in an analogous manner to that of
Example 32, starting with 4-hydroxy-N-t-boc piperidine.
Recrystallized from acetone/methanol. Yield; white solid 263 mg
,29%, mp 230.1-231.8.degree. C. .sup.1H-NMR DMSO-d.sub.6/300 MHz)
12.61 (br s, 1H), 8.42 (d, 2H), 7.52 (d, 2H), 7.38 (d, 2H), 7.20
(d, 2H), 4.88 (m, 1H), 3.52 (m, 2H), 3.30 (m, 2H), 1.93 (m, 2H),
1.65 (m, 2H), 1.39 (s, 9H).
[0176] Anal. Calc'd for C.sub.24H.sub.27ClN.sub.4O.sub.3: C, 63.36;
H, 5.98; N, 12.31. Found: C, 63.34; H, 5.97; N, 12.22.
EXAMPLE 34
[0177] 57
[0178] The product from Example 33 (130 mg, 0.28 mmol) was treated
with conc. HCl (0.5 mL) in ethanol (5 mL) for 2 hours. The solvent
was removed in-vacuo and the resulting residue dissolved in ethanol
and reconcentrated twice. The resulting solid was triturated with
acetonitrile to afford a white solid. Yield, 119 mg ,91%,
tri-hydrochloride salt, mp 220.6-222.1.degree. C. .sup.1H-NMR
(DMSO-d.sub.6/300 MHz) 13.25 (br s, 1H), 9.10 (br s, 2H), 8.67 (d,
2H), 7.75 (d, 2H), 7.60 (d, 2H), 7.50 (d, 2H), 5.04 (m, 1H), 3.17
(br d, 4H), 2.21 (m, 2H), 2.03 (m, 2H).
[0179] Anal. Calc'd for C.sub.19H.sub.19ClN.sub.4O.3 HCl: C, 49.16;
H, 4.78; N, 12.07. Found: C, 49.24; H, 4.72; N, 12.02.
EXAMPLE 35
[0180] 58
[0181] The product was prepared in a manner analogous to Example 32
starting with (+/-)3-hydroxytetrahydrofuran. Recrystallized from
ethanol. Yield; white crystalline solid, 57 mg ,8%,
mp>300.degree. C. .sup.1H-NMR (DMSO-d.sub.6/300 MHz) 12.65 (br
s, 1H), 8.42 (d, 2H), 7.52 (d, 2H), 7.38 (d, 2H), 7.18 (d, 2H),
5.28 (m, 1H), 3.86 (m, 2H), 3.82 (m, 1H), 3.75 (m, 1H), 2.26-2.01
(br m, 2H).
[0182] Anal. Calc'd for C.sub.18H.sub.16ClN.sub.3O.sub.2: C, 63.25;
H, 4.72; N, 12.29. Found: C, 63.12; H, 4.51; N, 12.31.
EXAMPLE 36
[0183] 59
[0184] The product was prepared in a manner analogous to Example 32
starting with p-methoxybenzyl alcohol. Yield; off-white solid, 252
mg ,21%, mp=229.1-229.2.degree. C. .sup.1H-NMR (acetone-d.sub.6/300
MHz) 11.62 (br s, 1H), 8.40 (br s, 2H), 7.76 (s, 2H), 7.39 (m, 4H),
7.30 (br s, 2H), 6.87 (d, 2H), 5.27 (s, 2H), 3.77 (s, 3H).
[0185] Anal. Calc'd for C.sub.22H.sub.18ClN.sub.3O.sub.2 0.25
H.sub.2O: C, 66.67; H, 4.70; N, 10.60. Found: C, 66.79 ; H, 4.95;
N, 10.54.
EXAMPLE 37
[0186] 60
[0187] The product was prepared in a manner analogous to Example 32
starting with N-Boc-ethanolamine. Recrystallized from ethyl
acetate/methanol. Yield; white solid, 75 mg ,4%, mp>300.degree.
C. .sup.1H-NMR (DMSO-d.sub.6/300 MHz) 12.60 (br s, 1H), 8.38 (d,
2H), 7.53 (d, 2H), 7.38 (d, 2H), 7.22 (d, 2H), 7.02 (t, 1H), 4.20
(t, 2H), 3.34 (m, 2H), 1.36 (s, 9H). ESHRMS m/z 415.1551 (M+H,
C.sub.21H.sub.24ClN.sub.4O.s- ub.3 requires 415.1537).
EXAMPLE 38
[0188] 61
[0189] The example was prepared in a manner analogous to Example 32
starting with methanol. Yield; off-white solid, 119 mg ,14%,
mp=265.3-265.3.degree. C. .sup.1H-NMR (DMSO-d.sub.6/300 MHz) 12.61
(br s, 1H), 8.41 (d, 2H), 7.52 (d, 2H), 7.38 (d, 2H), 7.17 (d, 2H),
3.90 (s, 3H). ESHRMS m/z 286.0766 (M+H, C.sub.15H.sub.13ClN.sub.3O
requires 286.0747).
[0190] Anal. Calc'd for C.sub.15H.sub.12ClN.sub.3O.0.25 H.sub.2O:
C, 62.08; H. 4.34; N, 14.48. Found: C, 62.24; H, 4.11; N,
14.16.
EXAMPLE 39
[0191] 62
[0192] To the dithietane of Example 2 (638 mg, 2 mmol) in toluene
(15 mL) was added thiomorpholine (800 uL, 8 uL). The reaction
mixture was heated to reflux for 6 hours, then cooled to room
temperature and diluted with toluene (20 mL). The reaction mixture
was then extracted twice with water (20 mL) and brine (20 mL). The
organic solution was dried (MgSO.sub.4), filtered, and concentrated
to an oil. Hexane was added to the residue and heated to reflux,
then decanted. The oil became semi-solid. The semi-solid was
dissolved in tetrahydrofuran (10 mL) and potassium t-butoxide 1M in
THF (2 mL, 2 mmol) was added. This was followed by iodomethane (125
uL, 2 mmol). The reaction was stirred at room temperature for 1
hour, then quenched with water (20 mL). The reaction mixture was
extracted with ethyl acetate (2.times.30 mL). The organic layers
were pooled, washed with brine (20 mL) and dried (MgSO.sub.4).
Filtration and concentration produced an oil which was chased once
with toluene to remove any ethyl acetate. The residue was dissolved
in ethanol (10 mL) and hydrazine hydrate (97 uL, 2 mmol) was added.
The reaction mixture was stirred at room temperature for 4 hours
then partitioned between ethyl acetate and saturated sodium
bicarbonate solution (30 mL each). The layers were separated and
the aqueous layer extracted again with ethyl acetate (30 mL). The
combined organic layers were washed with brine (20 mL) and dried
(MgSO.sub.4). Filtration and concentration produced an orange
residue which was triturated with acetonitrile to generate a tan
solid. Yield: 295 mg ,43%, mp>300.degree. C. .sup.1H NMR
(DMSO-d.sub.6/300 MHz) 12.70 (br s, 1H), 8.47 (d, 2H), 7.46 (d,
2H), 7.26 (m, 4H), 3.13 (m, 4H), 2.62 (m, 4H). ESHRMS m/z 357.0942
(M+H, C.sub.18H.sub.18ClN.sub.4S requires 357.0941).
[0193] Anal. Calc'd for C.sub.18H.sub.17ClN.sub.4S: C, 60.58; H,
4.80; N, 15.70. Found: C, 60.32; H, 4.96; N, 15.60.
EXAMPLE 40
[0194] 63
[0195] The product of Example 33 (455 mg, 1.5 mmol) was combined
with 98% formic acid (6 mL) and heated to 100 C. After 3 hours, 37%
formaldehyde (1.22 mL, 15 mmol) was added and the reaction was
heated for an additional 5 hours at 100 C. The reaction mixture was
allowed to cool to room temperature and filtered. The solution was
diluted with water (15 mL) and extracted once with ethyl acetate
(30 mL). The aqueous solution was then basified with 2.5 N NaOH to
pH 8. The cloudy mixture was then extracted twice with 1:1
THF:EtOAc (30 mL). The organic layers were pooled and washed once
with brine (25 mL), dried (MgSO.sub.4), filtered and concentrated
to an oil which solidified on standing. The solid was triturated
with acetonitrile and collected by suction filtration. The solid
was suspended in ethanol:water 2:1 (15 mL) and 1 mL of conc. HCl
was added. The solution was allowed to stir at room temperature for
1 hour, then filtered and concentrated. The residue was combined
with ethanol (10 mL) and reconcentrated twice. The resulting solid
was triturated with acetonitrile (10 mL) containing a small amount
of ethanol (0.5 mL) to remove some colored impurities. The solid
was collected by suction filtration, washed with acetonitrile and
dried in-vacuo.
[0196] Yield: 490 mg ,88%, mp 255.9-256.8.degree. C. .sup.1H NMR
(D.sub.20/DMSO-d6/NaOD/300 MHz) 7.93 (d, 2H), 7.09 (s, 4H), 7.00
(d, 2H), 4.42 (m, 1H), 2.26 (br m, 2H,) 2.12 (br m, 2H), 1.92 (s,
3H), 1.68 (br m, 2 H), 1.57 (br m, 2H). ESLRMS m/z 369 (M+H).
EXAMPLE 41
[0197] 64
[0198] Step 1. A mixture of the dithietane from Example 2 (78.3 g,
0.24 mol) and 1-methylpiperazine (75.0 g, 0.73 mol) in 800 mL of
toluene was heated to reflux for 2 h. Solvent and excess
1-methylpiperazine was removed under vacuum and the residue was
triturated with a mixture was ethyl acetate and ether (1:3) to give
53.0 g of product as yellow crystals ,60%, mp 149-151.degree.
C.
[0199] Anal. Calc'd, for Cl.sub.9H.sub.20ClN.sub.3OS: C, 61.03; H,
5.39; N, 11.24. Found: C, 60.74; H, 5.35; N, 11.14.
[0200] Step 2. To a suspension of the product from Step 1 (52.0 g,
0.14 mol) in 500 mL of dry tetrahydrofuran was added anhydrous
hydrazine (8.9 g, 0.28 mol) dropwise. The reaction mixture was
stirred at room temperature for 16 h. The pale yellow precipitate
was filtered and recrystallized from hot methanol to give 30.2 g of
the title compound as a white powder, 60%, mp 267-268.degree.
C.
[0201] Anal. Calc'd. for C.sub.19H.sub.20ClN.sub.5: C, 64.49; H,
5.70; N, 19.79. Found: C, 64.89; H, 5.55; N, 19.99.
EXAMPLE 42
[0202] 65
[0203] To 1-(4-fluorophenyl)-2-4-pyridyl)ethanone (1.0 g, 4.7
mmol), in anhydrous THF (10 mL) was added a solution of 1M
potassium t-butoxide in THF (10 mL, 10 mmol). The reaction mixture
was stirred for 15 minutes at room temperature, then carbon
disulifide (0.31 mL, 5.1 mmol) was added. After several minutes,
methyl iodide (0.64 10.3 mmol) was added and the reaction allowed
to stir for 4 hours. The reaction mixture was diluted with
saturated sodium bicarbonate solution (25 mL) and extracted twice
with ethyl acetate (35 mL). The combined ethyl acetate layers were
washed with water (25 mL) and brine (25mL). The organic solution
was dried (MgSO.sub.4), filtered and concentrated to an orange oil.
The oil solidified on standing to afford 1.4 g, 94%, of the
expected product mp 80.2-82.1.degree. C. .sup.1H-NMR
(CDCl.sub.3/300 MHz) 8.59 (d, 2H), 7.96 (m, 2H), 7.38 (m, 2H), 7.14
(m, 2H), 2.33 (s, 3H), 2.23 (s, 3H).
[0204] Anal. Calc'd for C.sub.16H.sub.14FNOS.sub.2: C, 60.16; H,
4.42; N, 4.39; S, 20.08. Found: C, 59.89; H. 4.09; N, 4.31; S,
20.14.
EXAMPLE 43
[0205] 66
[0206] The product was prepared in a manner analogous to Example 42
starting from 1-(4-chlorophenyl)-2-(4-pyridyl)ethanone. Crude
yield; 100%, mp 87.6-88.2.degree. C. .sup.1H-NMR (CDCl.sub.3/300
MHz) 8.60 (d, 2H), 7.87 (d, 2H), 7.44 (d, 2H), 7.37 (m, 2H), 2.33
(s, 3H), 2.22 (s, 3H). ESHRMS m/z 336.0297 (M+H,
C16H.sub.14ClNOS.sub.2 requires 336.0283).
[0207] Anal. Calc'd for C.sub.16H.sub.14ClNOS.sub.2: C, 57.22; H,
4.20; N, 4.17. Found: C, 57.44; H, 3.97; N, 4.04.
EXAMPLE 44
[0208] 67
[0209] To the product of Example 42 (1.4 g, 4.4 mmol) in ethanol
(15 mL) was added 1M hydrazine in acetic acid (5 mL, 5 mmol). The
reaction was stirred at room temperature for 18 hours. No reaction
had occurred, so additional hydrazine hydrate (1.08 mL, 22 mmol)
was added and the reaction heated to reflux for 6 hours. The
product began to precipitate from the reaction mixture. The
reaction was cooled to room temperature and water was added to
precipitate the product. The solid was collected by suction
filtration and air dried to afford the crude desired pyrazole, 675
mg, 53%. The product was recrystallized from ethanol, 494 mg, mp
249.9-249.9.degree. C. .sup.1H-NMR (DMSO-d.sub.6/300 MHz) 13.51 (br
s, 1H), 8.50 (d, 2H), 7.34 (m, 2H), 7.23 (m, 2H), 7.16 (m, 2H),
2.43 (s, 3H). ESHRMS m/z 286.0807 (M+H, C.sub.15H.sub.13FN.sub.3S
requires 286.0814).
[0210] Anal. Calc'd for C.sub.15H.sub.12FN.sub.3S: C, 63.14; H,
4.24; N, 14.73. Found: C, 63.01; H, 4.43; N, 14.81.
EXAMPLE 45
[0211] 68
[0212] The product was made in an analogous manner to Example 44
starting with the product of EXAMPLE 43. Yield; 750 mg ,33%, mp
250.2-250.2.degree. C. .sup.1H NMR (DMSO-d.sub.6/300 MHz) 13.57 (br
s, 1H), 851 (m, 2H), 7.45 (br s, 2H), 7.32 (m, 2H), 7.17 (m, 2H),
2.43 (s, 3H). ESHRMS m/z 302.0537 (M+H, C.sub.15H.sub.13ClN.sub.3S
requires 302.0518).
[0213] Anal. Calc'd for C.sub.15H.sub.12ClN.sub.3S: C, 59.70; H,
4.01; N, 13.92. Found: C, 59.56; H, 3.96; N, 13.96.
EXAMPLE 46
[0214] 69
[0215] To the product of Example 44 (150 mg, 0.52 mmol) in ethanol
(15 mL) was added ammonium persulfate (450 mg, 1.97 mmol). The
reaction mixture was stirred at ambient temperature. After several
hours an additional amount of ammonium persulfate (450 mg) was
added. The reaction mixture was monitored by TLC (silica) using 5%
methanol in dichloromethane as the eluting solvent. When the
starting material had been consumed, the reaction mixture was
quenched with saturated sodium bicarbonate (25 mL) and extracted
with ethyl acetate (2.times.25 mL). The ethyl acetate layers were
combined, washed with brine (25 mL) and dried (MgSO.sub.4).
Filtration and concentration produced a white solid. The solid was
triturated with diethyl ether, collected by suction filtration, and
air dried to provide 150 mg, 96%, mp 262.9-262.9.degree. C. of the
desired sulfoxide. .sup.1H NMR (DMSO-d6/300 MHz) 14.22 (br s, 1H),
8.56 (d, 2H), 7.42-7.23 (br m, 6H), 2.94 (s, 3H).
[0216] Anal. Calc'd for C.sub.15H.sub.12FN.sub.3OS.0.25 H.sub.2O:
C, 58.91; H, 4.12; N, 13.74. Found: C, 58.88; H, 4.17; N,
13.39.
EXAMPLE 47
[0217] 70
[0218] To the product of Example 44 (285 mg, 1 mmol) in ethanol (10
mL) was added potassium peroxymonosulfate (2.45 g, 4 mmol) and
water (5 mL). The reaction mixture was stirred at ambient
temperature. After 6 hours the reaction mixture was diluted with
water (20 mL) and extracted with ethyl acetate (2.times.30 mL). The
ethyl acetate layers were combined, washed with brine (25 mL) and
dried (MgSO.sub.4). The ethyl acetate did not efficiently extract
the product from the aqueous phase, so the aqueous layer was
saturated with sodium chloride and extracted with acetonitrile (50
mL). The acetonitrile solution was dried (MgSO.sub.4), filtered,
and combined with the filtered ethyl acetate solution. The solvents
were evaporated and the resulting solid was triturated with a small
amount of acetonitrile, collected by suction filtration, and air
dried to afford 203 mg, 64, %, mp 297. 1->300.degree. C. .sup.1H
NMR (DMSO-d.sub.6/300 MHz) 14.37 (br s, 1H), 8.54 (m, 2H), 7.29 (m,
6H), 3.26 (s, 3H).
[0219] Anal. Calc'd for C.sub.15H.sub.12FN.sub.3O.sub.2S: C, 56.77;
H, 3.81; N, 13.24. Found: C, 56.52; H, 4.03; N, 13.11.
EXAMPLE 48
[0220] 71
[0221] The product was prepared in a similar manner to Example 1
starting from methyl 4-bromobenzoate. Obtained a white solid, mp
270.2-270.7.degree. C. .sup.1H NMR (DMSO-d6/300 MHz) 12.7 (br s,
1H), 8.47 (m, 2H), 7.57 (m, 2H), 7.21 (m, 2H), 2.85 (m, 4H), 2.34
(m, 4H) 2.15 (s, 3H). ESHRMS 398.0993 (M+H,
C.sub.19H.sub.21BrN.sub.5 requires 398.0980).
EXAMPLE 49
[0222] 72
[0223] The product from Example 2 (50 g, 0.156 mol) and anhydrous
hydrazine (25 mL, 0.8 mol) were heated to reflux in ethanol for 5
hours. The contents were allowed to cool whereupon a precipitate
formed that was isolated by filtration. The solid was air dried to
afford the desired product as a yellow-orange solid (21.8 g) The
filtrate was diluted with water (200 mL) and a second crop was
obtained as a yellow-orange solid (18.0 g). The pH of the filtrate
was adjusted to pH 8 with 3N HCl and the precipitated solid
filtered to give an additional crop of the desired product as a
yellow-orange solid (2.0 g). The combined crops afforded the
desired pyrazole in 93% yield, mp 266.3-268.9.degree. C. .sup.1H
NMR (DMSO-d.sub.6) 13.80 (br, 1H); 12.20 (br s, 1H); 8.32 (s, 4H);
7.50-7.30 (m, 4H). ESHRMS m/z 288.0358 (M+H,
C.sub.14H.sub.11ClN.sub.3S requires 288.0362).
[0224] Anal. Calc'd for: C.sub.14H.sub.10ClN.sub.3S (0.4 H2O): C,
57.01; H, 3.69; N, 14.25. Found: C, 56.95; H, 3.50 N, 14.14.
EXAMPLE 50
[0225] 73
[0226] The above pyrazole was prepared by the method outlined in
Example 49 mp 261.3-263.9.degree. C. .sup.1H NMR (DMSO-d) 11.55 (br
s, 1H); 8.25-8.13 (m, 2H); 7.61-7.50 (m, 2H); 7.36-7.20 (m, 2H);
7.19-7.05 (m, 2H). ESHRMS m/z 272.0691 (M+H,
C.sub.24H.sub.11FN.sub.3S requires 272.0657).
[0227] Anal. Calc'd for: C.sub.14H.sub.10FN.sub.3S (0.25 H2O): C,
60.97; H, 3.84; N, 15.24. Found: C, 61.05; H, 3.64 N, 15.12.
EXAMPLE 51
[0228] 74
[0229] To the product from Example 49 (100 mg, 0.35 mmol) in
methanol (2 mL) was added 0.5 M sodium methoxide (0.7 mL, 0.35
mmol). Contents were stirred for 15 minutes and filtered to remove
a precipitate. The filtrate was concentrated in vacuo, dissolved in
water and concentrated in vacuo leaving the desired product as a
white solid. .sup.1H NMR (DMSO-d.sub.6) 11.60 (br s, 1H); 8.20 (d,
2H); 7.60-7.50 (m, 2H); 7.40-7.20 (m, 4H).
[0230] Anal. Calc'd for: C.sub.14H.sub.9ClN.sub.3NaS (2.5 H2O): C,
47.40; H, 3.98; N, 11.84. Found: C, 47.39; H, 3.33; N, 11.50.
EXAMPLE 52
[0231] 75
[0232] To the material prepared in Example 49 (584 mg, 2.0 mmol)
and bromoacetonitrile (140 ul, 2.0 mmol) in DMF (5 mL) was added
anhydrous potassium carbonate (276 mg, 2.0 mmol). Contents were
stirred overnight, then partitioned between EtOAc and H.sub.2O: The
EtOAc layer was dried over MgSO.sub.4 and concentrated in vacuo
leaving a tan solid. The solid was triturated with MeOH and
filtered to give the desired product as a off-white solid, 369 mg,
56%, mp 230.0-230.5.degree. C. .sup.1H NMR (DMSO-d.sub.6) 13.90 (br
s, 1H); 8.58 (d, 2H); 7.60-7.13 (m, 6H); 4.10 (s, 2H). ESHRMS m/z
327.0482 (M+H, C.sub.16H.sub.12ClN.sub.4S requires 327.0471).
[0233] Anal. Calc'd for: C.sub.16H.sub.11ClN.sub.4S(0.3 H2O): C,
57.85, H. 3.52; N, 16.87. Found: C, 57.88; H, 3.31; N, 16.77.
EXAMPLE 53
[0234] 76
[0235] Prepared by the method described in Example 52, using methyl
chloroacetate. When the contents were partitioned between EtOAc and
H.sub.2O, an insoluble solid was filtered to give the desired
product as a white solid 2.16 g. A second crop, 1.68 g, of the
desired product gave a total yield of 61%, mp 192.8-195.2.degree.
C. .sup.1H NMR (DMSO-d.sub.6+approx. 10% TFA) 9.80 (d, 2H); 7.80
(d, 2H); 7.52-7.34 (m, 4H); 3.92 (s, 2H); 3.57 (s, 3H). ESHRMS m/z
360.05735 (M+H, C.sub.17H.sub.15ClN.sub.3O.sub.2 requires
360.05732).
[0236] Anal. Calc'd for: C.sub.17H.sub.14ClN.sub.3O.sub.2 (0.25
H.sub.2O): C, 56.05, H, 4.01; N, 11.53. Found: C, 56.10; H, 3.72;
N, 11.51.
EXAMPLE 54
[0237] 77
[0238] The above compound was prepared by heating the product of
Example 49 (1.2 g, 4.2 mmol), potassium carbonate (630 mg, 4.6
mmol), N-boc4bromopiperidine (1.2 g, 4.5 mmol) were heated in DMF
(15 mL) at 105 C for 3 hours. Contents were allowed to cool and
partitioned between EtOAc and water. The EtOAc layer was dried over
MgSO.sub.4 and concentrated in vacuo. The residue was triturated
with EtOAc and filtered to give the desired as a white solid 1.20
g, 61%, mp 220.9-221.0.degree. C. .sup.1H NMR (DMSO-d.sub.6) 13.70
(br, 1H); 8.60-8.50 (m, 2H); 7.58-7.10 (m, 6H); 3.80-3.60 (m, 2H);
3.40-3.20 (m, 1H); 3.00-2.63 (m, 2H); 2.00-1.53 (m, 2H); 1.50-1.05
(m, 2H); 1.40 (s, 9H). FABHRMS m/z 471.1605 (M+H,
C.sub.24H.sub.28ClN.sub.4OS requires 471.1622).
[0239] Anal. Calc'd for: C.sub.24H.sub.27ClN.sub.4OS (0.5
H.sub.2O): C, 60.05; H, 5.88; N, 11.67. Found: C, 60.04; H, 5.57;
N, 11.31.
EXAMPLE 55
[0240] 78
[0241] The product from Example 54 (5.0 g, 11 mmol), and TFA (30
mL) were mixed in CH.sub.2Cl.sub.2 (50 mL) and stirred overnight.
Contents were concentrated in vacuo leaving a pale yellow oil which
was dissolved in water. The pH was adjusted with 2.5 N NaOH to pH
9, causing a white solid to form that was isolated by filtration to
provide the desired product as a white solid, 3.7 g, 93%, mp
211.1-211.2.degree. C. .sup.1H NMR (DMSO-.sub.6) 13.80 (br, 1H);
8.55 (d, 2H); 8.40 (br, 1H); 7.50-7.15 (m, 6H); 3.50-3.00 (m, 3H);
3.00-2.80 (m, 2H); 2.05-1.80 (m, 2H); 1.65-1.42 (m, 2H). ESHRMS m/z
371.1103 (M+H, C.sub.19H.sub.20ClN.sub.4S requires 371.1097).
[0242] Anal. Calc'd for: C.sub.19H.sub.19ClN.sub.4S (H.sub.2O): C,
58.68; H, 5.44; N, 14.41. Found: C, 58.86; H, 5.28; N, 14.25.
EXAMPLE 56
[0243] 79
[0244] To 1-(2-chloroethyl)pyrrolidine hydrochloride (306 mg, 1.8
mmol) in methanol (10 mL) was added 0.5 M sodium methoxide (7.0 mL,
3.6 mmol). Contents were stirred 10 minutes and then the material
from Example 49 (500 mg, 1.8 mmol) were added. Contents were heated
to reflux 1 hour, allowed to cool and partitioned between EtOAc and
H.sub.2O. The EtOAc layer was dried over MgSO.sub.4 and
concentrated in vacuo leaving a light amber solid. The solid was
recrystallized from MeOH (15 mL) to give the desired product as a
white solid (213 mg, 33% yield). mp 189.9-190.1.degree. C. .sup.1H
NMR (DMSO-d.sub.6) 13.65 (br, 1H); 8.52 (d, 2H); 7.42 (d, 2H);
7.38-7.10 (m, 4H); 3.10-2.93 (m, 2H); 2.63-2.51 (m, 2H); 2.38 (d,
2H); 4H); 1.701.52 (m, 4H). ESHRMS m/z 385.1262 (M+H,
C.sub.20H.sub.22ClN.sub.4 requires 385.1254).
[0245] Anal. Calc'd for: C.sub.20H.sub.21ClN.sub.4: C, 62.41, H,
5.50; N, 14.56. Found C, 62.22; H, 5.62; N, 14.48.
EXAMPLE 57
[0246] 80
[0247] Method A. The material prepared in Example 53 (1.3 g, 3.6
mmol) in methanol (10 mL), 2.5N sodium hydroxide (4 mL) and water
(10 mL) were stirred overnight. The contents were concentrated in
vacuo to remove the methanol and the aqueous solution left was made
acidic to pH 6 with 3N HCl, precipitating a solid. The solid was
extracted into EtOAc, dried over MgSO.sub.4 and concentrated in
vacuo leaving light tan crystals, 205 mg. Brine was added to the
aqueous layer precipitating additional solid that was filtered to
give more desired product as a light tan powder, 529 mg, the total
yield was 61%. .sup.1H NMR (DMSO-d6+10%/ TFA) 8.80 (d, 2H); 7.83
(d, 2H); 7.55-7.35 (m, 4H); 3.87 (s, 2H).
[0248] Method B. The product from Example 53 (3.8 g, 11 mmol) and
3N HCl (30 mL) were heated to reflux for 3 hours. Contents were
allowed to cool and concentrated in vacuo. The residue was mixed
with CH.sub.3CN (50 mL). Upon standing overnight, pale yellow
crystals grew that were isolated by filtration to afford the
desired product as the HCl salt 2.9 g, 69%. .sup.1H NMR
(DMSO-d.sub.6) 8.79 (d, 2H); 7.75 (d, 2H); 7.51-7.38 (m, 4H); 3.88
(s, 2H). ESHRMS m/z 346.0435 (M+H, C.sub.17H.sub.13ClN.sub.4OS
requires 346.0417).
[0249] Anal. Calc'd for: C.sub.17H.sub.12ClN.sub.4OS (HCl, 0.5
H.sub.2O): C, 49.12; H, 3.61; N, 10.74. Found: C, 49.36; H, 3.48;
N, 10.72.
EXAMPLE 58
[0250] 81
[0251] The material prepared in Example 53 (400 mg, 11 mmol) and a
2M solution of methylamine in THF (25 mL) were heated to reflux for
3 hours. The reaction was stirred overnight at room temperature and
then filtered to afford the desired product as a light amber solid,
335 mg, 85%, mp 284.0-288.4.degree. C. .sup.1H NMR (DMSO-d6) 13.58
(br, 1H); 8.60-8.45 (m, 2H); 7.98 (br s, 1H); 7.55-7.12 (m, 6H);
3.60 (s, 2H); 2.46 (s, 3H). ESHRMS m/z 359.0733 (M+H,
C.sub.17H.sub.16ClN.sub.4OS requires 359.0745).
[0252] Anal. Calc'd for: C.sub.17H.sub.15ClN.sub.4OS: C, 56.90; H,
4.21; N, 15.61. Found: C, 56.74; H, 4.11; N, 15.17.
EXAMPLE 59
[0253] 82
[0254] The material prepared in Example 53 (415 mg, 12 mmol) and N,
N-dimethylaminopropylamine were heated to reflux in methanol (25
mL) for 3 hours. The contents were stirred overnight at room
temperature and then concentrated in vacuo to afford a solid. The
solid was triturated with EtOAc and filtered to give the desired
product as a white solid. 256 mg, 50%, mp 168.8-169.5.degree. C.
.sup.1H NMR (DMSO-d.sub.6) 13.80 (br, 1H); 8.55-8.50 (m 2H); 8.02
(t, 1H); 7.50-7.40 (m, 6H); 3.61 (s, 2H); 3.30-2.98 (m, 2H);
2.14-2.10 (m, 2H); 2.04 (s, 6H); 1.50-1.40 (m, 2H). FABHRMS m/z
430.1472 (M+H, C.sub.21H.sub.25ClN.sub.5OS requires 430.1468).
[0255] Anal. Calc'd for: C.sub.21H.sub.24ClN.sub.5OS (0.5
H.sub.2O): C, 57.46; H, 5.74; N, 15.95. Found: C, 57.71; H, 5.56;
N, 16.12.
EXAMPLE 60
[0256] 83
[0257] To the material prepared in Example 54 (1.0 g, 2.1 mmol) in
CH.sub.2Ca.sub.2 (25 mL) was added 3-chloroperbenzoic acid (425 mg,
2.1 mmol). The reaction was stirred 15 minutes and then
chromatographed on silica gel (20 g) eluting with EtOAc. The
desired product crystallized from the collected fractions and the
product was isolated by filtration and air dried to give 958 mg,
93% mp 215.8-215.9.degree. C. .sup.1H NMR (DMSO-d.sub.6) 14.34 (br
s, 1H); 8.57-8.54 (m, 2H); 7.51-7.25 (m, 6H); 4.00-3.82 (m, 2H);
3.60-3.40 (m, 1H); 2.85-2.70 (m, 2H); 2.10-1.95 (m, 1H); 1.56-1.10
(m, 3H); 1.36 (s, 9H). ESHRMS m/z 487.1580 (M+H,
C.sub.24H.sub.28ClN.sub.4O.sub.3S requires 487.1571).
[0258] Anal. Calc'd for: C.sub.24H.sub.27ClN.sub.4O.sub.3S: C,
59.19; H, 5.59; N, 11.50. Found: C, 59.00; H, 5.76; N, 11.46.
Example 61
[0259] 84
[0260] To the material prepared in Example 60 (320 mg, 0.68 mmol)
in EtOH (5 mL) was added an aqueous solution of potassium
peroxymonosulfate (420 mg, 0.68 mmol). Contents were stirred for 2
hours and extracted into EtOAc. The extracts were dried over
MgSO.sub.4 and concentrated in vacuo leaving a white solid. The
solid was triturated with methanol and filtered to give the desired
as a white solid, 90 mg, 26%, mp 228.0-230.8.degree. C. .sup.1H NMR
(DMSO-d.sub.6) 8.61 (d, 2H); 7.48 (d, 2H); 7.31-7.20 (m, 4H);
4.05-3.90 (m, 2H); 3.54-3.35 (m, 1H); 2.85-2.60 (m, 2H); 1.92-1.80
(m, 21); 1.48-1.25 (m, 2H); 1.32 (s, 9H). ESHRMS m/z 503.1541 (M+H,
C.sub.24H.sub.28ClN.sub.4O.sub.4S requires 503.1520).
[0261] Anal. Calc'd for: C.sub.24H.sub.27ClN.sub.4O.sub.4S
(H.sub.2O): C, 56.30; H, 5.51; N, 10.94. Found: C, 56.11; H, 5.78;
N, 10.54.
EXAMPLE 62
[0262] 85
[0263] The product from Example 48 was converted to the
corresponding sulfoxide by the procedure described Example 60. The
crude product was purified by flash chromatography, the solid thus
obtained was recrystallized from acetonitrile to give the desired
product as white crystals, 64 mg, 33%, mp 189.5-189.5.degree. C.
.sup.1H NMR (DMSO-46) 14.28 (br s, 1H); 8.50 (d, 2H); 7.40-7.20 (m,
4H); 7.207.05 (m, 4H); 6.85 (d, 2H); 4.41 (s, 2H); 3.70 (s, 3H).
ESHRMS m/z 408.1168 (M+H, C.sub.22H.sub.19FN.sub.3O.sub.2S requires
408.1182).
[0264] Anal. Calc'd for: C.sub.22H.sub.18FN.sub.3O.sub.2S: C,
64.85; H, 4.45; N, 10.31. Found: C, 64.44; H, 4.34; N, 10.70
EXAMPLE 63
[0265] 86
[0266] To the material prepared in Example 62 (1.2 g, 2.5 mmol) in
CH.sub.2Cl.sub.2 (50 mL) was added 3chloroperbenzoic acid (1.0 g,
5.0 mmol). Contents were stirred 1.5 hours and then filtered to
remove a white solid (620 mg). The filtrate was concentrated and
the residue chromatographed on silica gel (20 g) eluting with EtOAc
to give the desired product as a white solid, 98 mg, 9%, mp
241.9-242.0.degree. C. .sup.1H NMR (DMSO-d.sub.6) 8.48-8.40 (m,
2H); 7.33-6.80 (m, 10H); 4.55 (s, 2H); 3.72 (s, 3H). ESHRMS m/z
424.1143 (M+H, C.sub.22H.sub.19FN.sub.3- O.sub.3S requires
424.1131).
[0267] Anal. Calc'd for: C.sub.22H.sub.18FN.sub.3O.sub.3S: C,
62.40; H, 4.28; N, 9.92. Found: C, 62.14; H, 4.42; N, 9.68.
EXAMPLE 64
[0268] 87
[0269] The product from Example 54 (5.0 g, 0.01 mol) and formic
acid (96%, 7 mL) were heated at 100.degree. C. for 1 hour. Contents
were allowed to cool to about 50.degree. C. and added formaldehyde
(37%, 13 mL). The reaction was heated at 80.degree. C. for an
additional 2 hours, and then allowed to cool, diluted with water
(200 mL) and made basic to pH 11 with 2.5N NaOH whereupon a
precipitate formed. The solid was isolated by filtration and
recrystallized from methanol to give the desired product as a white
solid, 174 mg, 33%, mp 227.7-227.7.degree. C. .sup.1H NMR
(DMSO-d.sub.6) 13.70 (br s, 1H); 856-8.48 (m, 2H); 7.50-7.15 (m,
6H); 3.10-2.92 (m, 1H); 2.63-2.50 (m, 2H); 2.05 (s, 3H); 1.95-1.65
(m, 4H); 1.50-1.30 (m, 2H). ESHRMS m/z 385.1233 (M+H,
C.sub.20H.sub.22ClN.sub.4S requires 385.1254).
[0270] Anal. Calc'd for. C.sub.20H.sub.21ClN.sub.4S: C, 62.41; H.
550; N, 14.56. Found: C, 62.40; H. 5.80S N, 14.61.
EXAMPLE 65
[0271] 88
[0272] The above compound was prepared from Example 49 according to
the procedure described in Example 54 using bromoethyl methyl ether
except that the contents were heated at 70.degree. C. for 1 hour
before partitioning between EtOAc and H2O. The crude was
recrystallized from MeOH/EtOAc to give the desired product as a
white solid, 210 mg, 35%, mp 189.2-190.2.degree. C. .sup.1H NMR
(DMSO-d.sub.6) 8.60-8.45 (m, 2H); 7.60-7.10 (m, 6H); 3.60-2.85 (m,
7H). ESHRMS m/z 346.0799) M+H, C.sub.17H.sub.17ClN.sub.3OS requires
346.0781).
[0273] Anal. Calc'd for: C.sub.17H.sub.16ClN.sub.3OS (H.sub.2O): C,
58.73; H, 4.70; N, 12.09. Found: C, 58.67; H, 4.86; N, 12.03.
EXAMPLE 66
[0274] 89
[0275] The above compound was prepared from Example 49 according to
the procedure described in Example 54 using
2-chloromethylbenzimidazole except that the contents were heated at
70.degree. C. for 1 hour before partitioning between EtOAc and H2O.
An insoluble solid was filtered from the two layers and triturated
with MeOH to give the desired product as a light amber solid, 292
mg, 40%, mp 257.7-257.7.degree. C. .sup.1H NMR (DMSO-d.sub.6) 13.75
(br s, 1H); 12.30 (br s, 1H); 8.55-8.30 (m, 2H); 7.65-6.90 (m,
10H); 4.40 (br s, 2H). FABHRMS m/z 418.0895 (M+H,
C.sub.22H.sub.17ClN.sub.5 requires 418.0893).
[0276] Anal. Calc'd for: C.sub.22H.sub.16ClN.sub.5 (0.75 H.sub.2O):
C, 61.25; H, 4.09; N, 16.23. Found: C, 61.27; H, 3.90; N,
15.92.
EXAMPLE 67
[0277] 90
[0278] The above compound was prepared from Example 49 according to
the procedure described in Example 54 using
D,L-alpha-bromo-beta-(4-imidazoly- l)propionic acid except that the
contents were heated at 70.degree. C. for 1 hour. The contents
contained an insoluble solid which was diluted with water and the
pH was adjusted with 3N HCl to pH 7. Contents were filtered and
triturated with MeOH to give the desired product as a white solid,
1.5 g, 81%, mp 163.0165.5.degree. C. .sup.1H NMR
(DMSO-d.sub.6+approx. 10% TFA) 8.92 (d, 1H); 8.83-8.75 (m, 2H);
7.80 (d, 2H); 7.55-7.30 (m, 5H); 4.20-4.05 (m, 1H); 3.25-3.00 (m,
2H). ESHRMS m/z 426.0799 (M+H, C.sub.20H.sub.17ClN.sub.5O.sub.2S
requires 426.0791).
[0279] Anal. Calc'd for: C.sub.20H.sub.16ClN.sub.5O.sub.2S (1.8
H.sub.2O): C, 52.41 H, 4.31; N, 15.28. Found: C: 52.68; H, 458; N,
15.37.
EXAMPLE 68
[0280] 91
[0281] The above compound was prepared from Example 49 (264 mg, 0.9
mmol) according to the procedure described in Example 54 and
alpha-methylenebutyrolactone (0.08 mL, 0.9 mmol) in EtOH was added
a drop of triethylamine. Contents were stirred overnight and the
resulting solid was filtered and triturated with MeOH to give the
desired product as a pale yellow solid, 181 mg, 51%, mp
224.2-225.9.degree. C. .sup.1H NMR (DMSO-d.sub.6+approx. 10% TFA)
8.80 (d, 2H); 7.80 (d, 2H); 7.53-7.33 (m, 4H); 4.30-4.05 (m, 2H);
3.50-3.40 (m, 1H); 3.15-2.90 (m, 2H); 2.32-2.20 (m, 1H) 2.10-1.90
(m, 1H). ESHRMS m/z 386.0760 (M+H,
C.sub.19H.sub.17ClN.sub.3O.sub.2S requires 386.0730).
[0282] Anal. Calc'd for: C.sub.19H.sub.16ClN.sub.3O.sub.2S: C,
59.14 H, 4.18; N, 10.89. Found: C, 58.97; H, 4.21; N, 10.96.
EXAMPLE 69
[0283] 92
[0284] The above compound was prepared from Example 49 according to
the procedure described in Example 54 using
2-bromomethyl-1,3-dioxolane except that the contents were heated at
80.degree. C. for 2 hours. The reaction was diluted with water and
filtered to give a white solid, 502 mg. The solid was
recrystallized from EtOH to give the desired product as off-white
crystals, 280 mg, 43%, mp 197.0-198.2.degree. C. .sup.1H NMR
(DMSO-d.sub.6) 13.60 (br s, 1H); 8.60-8.45 (m, 2H); 7.60-7.10 (m,
6H); 5.15-4.85 (m, 1H); 3.95-3.62 (m, 4H); 3.40-2.95 (m, 2H).
ESHRMS m/z 374.0741 (M+H, C.sub.18H.sub.17ClN.sub.3O.sub.2S
requires 374.0730).
[0285] Anal. Calc'd for: C.sub.18H.sub.16ClN.sub.3O.sub.2S: C,
57.83 H, 4.31; N, 11.24. Found: C, 57.69; H, 4.41; N, 11.15.
EXAMPLE 70
[0286] 93
[0287] The above compound was prepared from Example 53 according to
the procedure described in Example 54 using
2-(2-bromoethoxy)tetrahydro-2H-py- ran except that the contents
were heated at 80.degree. C. for 4 hours. Contents were allowed to
cool and partitioned between EtOAc and water. The EtOAc layer was
dried over MgSO.sub.4 and concentrated in vacuo leaving a solid,
737 mg. The solid was recrystallized from EtOH to give the desired
product as pale yellow crystals, 281 mg, 39%, mp
163.2-163.5.degree. C. .sup.1H NMR (DMSO-d.sub.6) 13.80-13.70 (m,
1H), 8.60-8.42 (br s, 1H); 7.60-7.10 (m, 6H); 4.60-4.30 (m, 1H);
3.90-2.90 (m, 6H); 1.70-1.20 (m, 6H). ESHRMS m/z 416.1200 (M+H,
C.sub.21H.sub.23 ClN.sub.3O.sub.2S requires 416.1198).
[0288] Anal. Calc'd for: C.sub.21H.sub.22ClN.sub.3O.sub.2S: C,
60.64 H, 5.33; N, 10.10. Found: C, 60.49; H, 5.71; N, 9.96.
EXAMPLE 71
[0289] 94
[0290] The above compound was prepared from Example 49 according to
the procedure described in Example 54 using 4-bromobutyronitrile
except that the contents were heated at 55.degree. C. for 1 hour.
Contents were diluted with water (75 mL) and filtered to give a
white solid, 567 mg. The solid was recrystallized from MeOH to give
the desired product as white crystals, 333 mg, 54%, mp
216.7-216.9.degree. C. .sup.1H NMR (DMSO-d.sub.6+approx. 10% TFA)
8.80-8.75 (m, 2H); 7.83-7.75 (m, 2H); 7.50-7.35 (m, 4H); 3.10-3.00
(m, 2H); 2.60-2.45 (m, 2H); 1.95-1.80 (m, 2H). ESHRMS m/z 355.0818
(M+H, C.sub.18H.sub.16ClN.sub.4S C.sub.18H.sub.16ClN.sub.4S
requires 355.0784).
[0291] Anal. Calc'd for: C.sub.18H.sub.15ClN.sub.4S(0.5 H.sub.2O):
C, 59.42 H, 4.43; N, 15.40. Found: C, 59.64; H, 4.11; N, 15.44.
EXAMPLE 72
[0292] 95
[0293] The product from Example 57 (416 mg, 1.1 mmol), morpholine
(4 mL), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
tetrafluoroborate (481 mg, 1.5 mmol) and DMF (10 mL) were stirred
at room temperature overnight. The reaction mixture was diluted
with water (75 mL) and the resulting solid isolated by filtration,
363 mg. The crude product was recrystallized from EtOH to give the
desired product as a white solid, 219 mg, 48%, mp
215.4-215.5.degree. C. .sup.1H NMR (DMSO-.sub.6) 13.70-13.60 (m,
1H); 8.60-8.50 (m, 2H); 7.50-7.10 (m, 6H); 3.93-3.80 (m, 2H);
3.60-3.20 (m, 8M). ESHRMS m/z 415.0995 (M+H,
C.sub.20H.sub.20ClN.sub- .4O.sub.2S requires 415.1001).
[0294] Anal. Calc'd for: C.sub.20H.sub.19ClN.sub.4O.sub.2S: C,
57.90 H, 4.62; N, 13.50. Found: C, 57.87; H, 4.86; N, 13.53.
EXAMPLE 73
[0295] 96
[0296] The above compound was prepared from Example 49 according to
the procedure described in Example 54 using 2-bromopropionitrile
except that the reaction was heated at 70.degree. C. for 1 hour.
The reaction solution was diluted with water (75 mL) and filtered
to give an off-white solid, 662 mg. The crude product was
recrystallized from MeOH to give the desired product as a white
solid, 220 mg, 37%, mp 211.1-212.8.degree. C. .sup.1H NMR
(DMSO-d.sub.6+approx. 10% TFA) 8.87-8.80 (m, 2H); 7.90-7.80 (m,
2H); 7.55-7.45 (m, 6H); 4.42 (q, 1H); 1.50 (d, 3H). ESHRMS m/z
341.0628 (M+H, C.sub.18H.sub.14ClN.sub.4S requires 341.0628).
[0297] Anal. Calc'd for: C.sub.18H.sub.13ClN.sub.4S: C, 59.91 H,
3.84; N, 16.44. Found: C, 59.64; H, 4.01; N, 16.18.
EXAMPLE 74
[0298] 97
[0299] The above compound was prepared from Example 49 according to
the procedure described in Example 54 using propargyl bromide. The
reaction mixture was diluted with water (75 mL) and filtered to
give a pale yellow solid, 577 mg. The solid was triturated with
MeOH to give the desired product as a white solid, 388 mg, 68%, mp
212.7-213.2.degree. C. .sup.1H NMR (DMSO-d.sub.6+approx. 10% TFA)
8.80 (d, J=6.8 Hz, 2H); 7.82 (d, J=6.8 Hz, 2H); 7.50-7.35 (m, 4H);
3.81 (d, J=2.6 Hz, 2H); 3.05 (t, J=2.6 Hz, 1H). ESHRMS m/z 326.0533
(M+H, C.sub.17H.sub.13ClN.sub.3S requires 326.0519).
[0300] Anal. Calc'd for: C.sub.17H.sub.12ClN.sub.3S (0.2 H.sub.2O):
C, 61.98 H, 3.79; N, 12.76. Found: C, 61.89; H, 3.45; N, 12.67.
EXAMPLE 75
[0301] 98
[0302] The above compound was prepared from Example 49 according to
the procedure described in Example 54 using allyl bromide. The
reaction mixture was diluted with water (75 mL) and filtered to
give a pale yellow solid, 509 mg. The solid was recrystallized from
MeOH to give the desired product as a pale yellow solid, 187 mg,
33%, mp 207.3-208.1.degree. C. .sup.1H NMR (DMSO-d.sub.6+approx.
10% TFA) 8.80 (d, 2H); 7.80 (d, 2H); 7.50-7.30 (m, 4H); 5.90-5.70
(m, 1H); 5.10-4.95 (m, 2H); 3.62 (d, 2H). ESHRMS m/z 328.0693 (M+H,
C.sub.17H.sub.15ClN.sub.3S requires 328.0675).
[0303] Anal. Calc'd for: C.sub.17H.sub.14ClN.sub.3S (0.1 H.sub.2O):
C, 61.94 H, 4.34; N, 12.75. Found: C, 61.83; H, 4.21; N, 12.76.
EXAMPLE 76
[0304] 99
[0305] The above compound was prepared from Example 49 according to
the procedure described in Example 54 using 2-bromoethylamine
hydrochloride except that two equivalents of potassium carbonate
were used. The reaction mixture was diluted with water (75 mL) and
filtered to give a pale yellow solid, 509 mg. The solid was
recrystallized from MeOH to give the desired product as a pale
yellow solid, 262 mg, 45%, mp 186.8-187.8.degree. C. .sup.1H NMR
(DMSO-d.sub.6+approx. 10% TFA) 8.85-8.75 (m, 2H); 8.90 (br s, 2H);
8.85-8.75 (m, 2H); 7.55-7.35 (m, 4H); 3.30-3.00 (m, 4H). ESHRMS m/z
331.0779 (M+H, C.sub.16H.sub.16ClN.sub.4S requires 331.0784).
[0306] Anal. Calc'd for: C.sub.16H.sub.15ClN.sub.4S (0.5 H.sub.2O):
C, 56.55; H, 4.75; N, 16.49. Found: C, 56.28; H, 4.38; N,
16.20.
EXAMPLE 77
[0307] 100
[0308] The above compound was prepared from Example 49 according to
the procedure described in Example-54 using 3-(2-bromoethyl)indole.
The reaction mixture was diluted with water (75 mL) and filtered to
give a pale yellow solid, 752 mg. The solid was triturated with
MeOH to give the desired product as a white solid, 682 mg, 91%, mp
211.9-213.2.degree. C. .sup.1H NMR (DMSO-d.sub.6+approx. 10% TFA)
10.80 (s, 1H); 8.72 (d, 214); 7.71 (d, 2H); 7.55-7.35 (m, 5H); 7.29
(d, 1H); 7.12-6.88 (m, 3H); 3.40-3.30 (m, 2H); 3.05-2.95 (m, 2H).
ESHRMS m/z 431.1095 (M+H, C.sub.24H.sub.20ClN.sub.4S requires
431.1097).
[0309] Anal. Calc'd for: C.sub.24H.sub.19ClN.sub.4S(0.15 H.sub.2O):
C, 66.47 H. 4.49; N, 12.92. Found: C, 66.44; H, 4.51; N, 12.84.
EXAMPLE 78
[0310] 101
[0311] The product from Example 60 (464 mg, 0.95 mmol) and TFA (8
mL) were mixed in CH.sub.2Cl.sub.2 (10 mL) and stirred overnight
The reaction mixture was concentrated in vacuo and the residue was
partitioned between ether and water. The aqueous layer was made
basic to pH 10 with 2.5N NaOH and extracted with EtOAc (2.times.100
mL). Upon standing overnight, a solid precipitated from the aqueous
layer and was filtered to give the desired product as a white
solid, 183 mg, 50%, mp 189.1-190.8.degree. C. .sup.1H NMR
(DMSO-d.sub.6+approx. 10% TFA) 8.85 (d, 2H); 8.80-8.60 (m 1H);
8.45-8.25 (m, 1H); 7.90 (d, 2H); 7.55-7.30 (m, 4H); 3.65-3.20 (m
3H); 3.10-2.80 (m 2H); 2.20-2.00 (m, 1H); 1.90-1.50 (m, 3H). ESHRMS
m/z 387.1032 (M+H, C.sub.19H.sub.20ClN.sub.4OS requires
387.1046).
[0312] Anal. Calc'd for: C.sub.19H.sub.19ClN.sub.4OS.(2 H.sub.2O):
C, 53.96 H, 5.48; N, 13.25. Found: C, 53.75; H, 4.99; N, 13.21.
EXAMPLE 79
[0313] 102
[0314] The above compound was prepared from Example 49 according to
the procedure described in Example 54 using 3-bromopropionitrile.
The reaction mixture was diluted with water (75 mL) and extracted
into EtOAc, which was dried over MgSO.sub.4 and concentrated in
vacuo leaving an orange waxy solid, 523 mg. The solid was dissolved
in acetonitrile, filtered through a pad of silica gel and eluted
with EtOAc to give a white solid. The solid was triturated with
EtOAc and filtered to give the desired product as a white solid, 76
mg, 13%, mp 205.7-206.5.degree. C. .sup.1H NMR
(DMSO-d.sub.6+approx. 10% TFA) 8.80 (d, 2H); 7.80 (d, 2H);
7.55-7.35 (m, 4H); 3.30-3.20 (m, 2H); 2.90-2.80 (m, 2H). ESHRMS m/z
341.0639 (M+H, C.sub.14H.sub.20ClN.sub.4S requires 341.0628).
[0315] Anal. Calc'd for: C.sub.14H.sub.13ClN.sub.4S (0.25
H.sub.2O): C, 59.13 H, 3.94; N, 16.22. Found: C, 59.03; H, 3.93; N,
15.90.
EXAMPLE 80
[0316] 103
[0317] Prepared by the method described in Example 1, steps 1 and
2. mp 168.6-168.7.degree. C.
[0318] .sup.1H NMR (CDCl.sub.3/300 MHz) 8.54 (dd, 2H, J=4.6, 1.8
Hz), 7.68-7.62 (m 2H), 7.43-7.39 (m, 1H), 7.33-7.28 (m, 1H), 6.99
(dd, 2H, J=4.4, 1.6 Hz), 4.22 (s, 2H). ESHRMS m/z 311.0330 (M+H
C.sub.16H.sub.10N.sub.2OS.sub.2 requires.311.0313).
[0319] Anal. Calc'd. for C.sub.16H.sub.10N.sub.2OS.sub.2: C, 61.91;
H, 3.25; N, 9.02. Found: C, 61.45; H, 3.18; N, 8.91.
EXAMPLE 81
[0320] 104
[0321] 2-(4-flourophenyl)-4-methythiophenylethanone (1.26 g, 4.84
mmol), potassium carbonate (2.04 g 14.5 mmol), carbon disulfide
(1.10 g, 14.5 mmol) and dibromomethane (1.10 g, 15.4 mmol) were
mixed together in acetone (50 ml) for 12 days. The solution was
poured into ethyl acetate (100 mL) and washed with 1N hydrochloric
acid. Hexanes (25 mL) were added and the solution was washed with
brine (2.times.100 mL). The organic solution was collected, dried
over sodium sulfate and solvent removed at reduced pressure. The
product 1 was isolated by crystallization from ethyl acetate and
hexanes. 831 mg of yellow crystals were obtained. (49% yield) mp
145.7-145.7.degree. C. .sup.1H NMR (CDCl.sub.3/300 MHz) 7.19-7.24
(m, 2H), 7.06-7.11 (m, 2H), 6.60-7.30 (m, 4H), 4.11 (s, 2H), 2.42
(s, 3H). HRMS 349.0201 (M+H calcd for C.sub.17H.sub.14FOS.sub.3
349.0191). 105
[0322] The dithiatane (613 mg, 1.76 mmol) and anhydrous hydrazine
(300 uL) were refluxed in ethanol (10 mL) for 16 hours. The
solution was cooled to room temperature and poured into ethyl
acetate (50 mL). The solution was extracted with 1 N hydrochloric
acid (2.times.25 mL). Hexanes (10 mL) were added and the solution
was extracted with brine (2.times.25 mL), dried over sodium
sulfate, and solvent removed at reduced pressure. The product 2 was
isolated by crystallization from dichloromethane and hexanes. 186
mg of yellow crystals were obtained. (32% yield) mp
142.4-143.4.degree. C. .sup.1H NMR (CD.sub.3OD/400 MHz) 7.18-7.27
(m, 6H), 7.06-7.10 (m, 3H), 2.43 (s, 3H). HRMS 317.0586 (M+H, calcd
for C.sub.16H.sub.14FN.sub.2S.sub.2 317.0582) 106
[0323] The pyrazole 2 (140 mg, 0.44 mmol), potassium carbonate (150
mg, 106 mmol) and iodomethane (71 mg, .50 mmol) were stirred in
dimethylformamide (5 mL) at room temperature for 16 h. The solution
as poured into ethyl acetate (40 mL) and washed with IN
hydrochloric acid (2.times.40 mL). Hexanes (25 mL) were added and
the solution was washed with brine (2.times.50 mL). The organic
solution was collected, dried over sodium sulfate and solvent
removed at reduced pressure. The product (22 mg) was isolated as a
semi solid by preparative thin layer chromatography. (13%
yield).sup.1H NMR (CDCl.sub.3/400 MHz) 7.23-7.27 (m, 21), 7.14-7.22
(m, 2H), 2.46 (s, 3H), 2.41 (s, 3H). HRMS 331.0735 (M+H
C.sub.17H.sub.16FN.sub.2S.sub.2 calcd for 331.0739).
EXAMPLE 82
[0324] 107
[0325] Step 1. Preparation of
1-(4-chlorophenyl)-2-(4-pyrimidyl)ethanone. 108
[0326] Lithium bis(trimethylsilyl)amide 1.0 M in THF (4.25 L, 4.25
mol) was cooled to -70.degree. C. with stirring under nitrogen.
4-methylpyrimidine (250 g, 2.66 mol) was added followed by Methyl
4-chlorobenzoate (453.2 g, 2.66 mol). The cooling bath was removed
and the mixture was allowed to warm to room temperature and stir
for 16 h. Water (3 L) and ethyl acetate (3 L) were added followed
by acetic acid (200 mL). The layers were separated and the organic
layer was washed with brine and dried over magnesium sulfate. The
mixture was then concentrated to 800 mL and hexanes (250 ML) were
added. The product was filtered, washed with hexanes, and air dried
to provide a yellow solid. (388.1 g, 64%): mp 110.4-110.5.degree.
C. .sup.1H NMR (acetone-d.sub.6/300 MHz) 14.9 (bs, 1H), 8.8 (s,
1H), 8.4 (m, 1H), 7.7 (d, 2H, J=8.7 Hz), 7.3 (d, 2H,=8.7 Hz), 6.9
(m, 1H), 5.9 (s, 1H).
[0327] Step 2. Preparation of Dithietane Compound. 109
[0328] To a solution of 1-(4-chlorophenyl)-2-(4-pyrimidyl)ethanone
(7.0 g, 0.03 mol) in a mixture of acetone (200 mL) and
dibromomethane (75 mL) was added potassium carbonate (8.3 g, 0.06
mol), followed by the slow addition of carbon disulfide (2.6 g,
0.033 mol) over 15 minutes. The reaction mixture was stirred at
room temperature for 20 h. Solvent was removed and the residue was
partitioned between water and methylene chloride. The organic layer
was washed with brine, dried over magnesium sulfate and filtered.
The filtrate was concentrated and triturated with a mixture of
ethyl acetate/ether/hexane (1:5:5) to give 7.14 g of product as a
yellow solid which was used without further purification in the
next step.
[0329] Step 3. Preparation of
1-[5-(4-chlorophenyl)-4-(4-pyrimidinyl)-1H-p-
yrazol-3-yl-3,4-dimethylpiperazine. 110
[0330] To a suspension of the crude material from Step 2 (4.0 go
0.013 mol) in 30 mL of toluene was added a solution of
2,6-dimethylpiperazine (4.65 g,-0.04 mol) in 3 mL of acetonitrile.
The reaction mixture was stirred at 85.degree. C. for 4 h. After
the removal of solvent, the crude material was dissolved in 100 mL
of dry THF and hydrazine (0.83 g, 0.026 mol) was added. The mixture
was then stirred at room temperature overnight. The solvent was
removed under vacuum and the residue was purified by chromatography
in silica gel (ethyl acetate/methanol, 3:1 to 1:1) to afford 0.75 g
of the product as a white solid (13% overall yield), mp:
212-214.degree. C.; Anal. Calcd. for C.sub.19H.sub.21ClN.sub.- 6:
C, 61.87; H, 5.74; N, 22.78. Found: C, 61.59; H, 5.28; N,
22.28.
EXAMPLE 83
[0331] 111
[0332] A mixture of the dithietane compound from example 2 (6.4 g,
0.02 mol) and 2,6-dimethylpiperazine (6.86 g, 0.06 mol) in 100 mL
of toluene was heated at reflux for 2 h. Solvent and excess
2,6-dimethylpiperazine was removed under vacuum and the crude was
used without purification. A solutoin of the above crude and
anhydrous hydrazine (1.3 g, 0.04 mol) in 100 mL of dry THF was
stirred at room temperature overnight. After the removal of THF,
the residue was stirred with a mixture of ethyl acetate (100 mL)
and ammonia hydroxide (20 mL) for 1 h. The precipitate was filtered
and air-dried to give 3.4 g of product as a white solid (46%
overall yield), mp: 236-238.degree. C.; Anal. Calcd. for
C.sub.20H.sub.22ClN.sub.5+0.25 H.sub.2O: C, 64.51; H, 6.09; N,
18.81; Cl, 952. Found: C, 64.28; H, 5.85; N, 18.70; Cl, 9.67.
EXAMPLE 84
[0333] 112
[0334] Prepared by the method described in Example 1, step 1, using
4-methylpyrimidine in place of 4-picoline. .sup.1H NMR
(CDCl.sub.3+TFA/300 MHz) 8.96 (s, 1H), 8.10 (d, 1H), 7.88 (d, 2H),
7.36 (d, 2H), 7.09 (d, 1H), 6.43 (s, 1H), 2.48 (s, 3H). ESHRMS m/z
213.1003 (M+H, C.sub.13H.sub.12N.sub.2O requires 213.1027).
[0335] Anal. Calc'd. for C1.sub.3H.sub.12N.sub.20: C, 73.56; H,
5.70; N, 13.20. Found: C, 73.41; H, 6.04; N, 13.17.
EXAMPLE 85
[0336] 113
[0337] Prepared by the method described in Example 1, step 2.
[0338] .sup.1H NMR (CDCl.sub.3/300 MHz) 9.02 (s, 1H), 8.40 (d, 1H),
7.37 (d, 2H), 7.23 (d, 2H), 6.67 (d, 1H), 4.24 (s, 2H), 2.33 (s,
3H). ESHRMS m/z 301.0488 (M+H, C.sub.15H.sub.12N.sub.2OS.sub.2
requires 301.0469).
[0339] Anal. Calc'd. for C.sub.15H.sub.12N.sub.2OS.sub.2: C, 59.97;
H, 4.03; N, 9.33. Found: C, 59.43; H. 3.86; N, 9.14.
EXAMPLE 86
[0340] 114
[0341] The product was prepared in an analogous manner to that of
Example 32, starting with 4-hydroxy-N-t-boc piperidine and the
product of Example B.
[0342] .sup.1H NMR (DMSO-d.sub.6/300 MHz) 8.85 (s, 1H), 8.66 (d,
1H), 7.68 (d, 1H), 7.37 (d, 2H), 7.22 (d, 2H), 4.94 (m, 1H), 3.58
(m, 2H), 2.34 (s, 3H), 1.97 (m, 2H), 1.69 (m 2H), 1.40 (s, 9H).
ESHRMS m/z 436.2364 (M+H, C.sub.24H.sub.29N.sub.5O.sub.3 requires
436.2348).
[0343] Anal. Calc'd, for C.sub.24H.sub.29N.sub.5O.sub.3 . 0.7
H.sub.2O: C, 64.33; H, 6.84; N, 15.63. Found: C, 64.40; H, 6.79; N,
15.63.
[0344] The following abbreviations have the indicated meanings:
1 Ac = acetyl Boc = tertiary-butyloxycarbonyl CDCl.sub.3 =
Chloroform-d DMAP = 4-(dimethylamino)pyridine DMF =
N,N-dimethylformamide DMSO = dimethylsulfoxide EDC =
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EtOAc =
ethyl acetate EtOH = ethanol ESHRMS = electro-spray high resolution
mass spectrum ESLRMS = electro-spray low resolution mass spectrum
FABHRMS = fast atom bombardment high resolution mass spectrum HCl =
Hydrochloric Acid H.sub.2O = water HOBt = 1-hydroxybenzotriazole
KHMDS = Postassium bis(trimethylsilyl)amide MeOH = methanol
MgSO.sub.4 = magnesium sulfate NaCl = Sodium Chloride NaHMDS =
Sodium bis(trimethylsilyl)amide NaOH = Sodium Hydroxide NMR =
nuclear magnetic resonance spectroscopy TBTU =
O-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium terafluoroborate
TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = Thin Layer
Chromatography
[0345] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention,
and without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *