U.S. patent application number 11/839833 was filed with the patent office on 2008-02-07 for novel compounds.
This patent application is currently assigned to SmithKline Beecham Corporation. Invention is credited to Jerry L. Adams, Jeffrey C. Boehm, Ralph Hall, Qi Jin, Jiri Kasparec, Domingos J. Silva, John T. Taggart.
Application Number | 20080033170 11/839833 |
Document ID | / |
Family ID | 27399571 |
Filed Date | 2008-02-07 |
United States Patent
Application |
20080033170 |
Kind Code |
A1 |
Adams; Jerry L. ; et
al. |
February 7, 2008 |
NOVEL COMPOUNDS
Abstract
Novel substituted
2,4,8-trisubstituted-8H-pyrido[2,3-d]pyrimidin-7-one compounds and
compositions for use in therapy as CSBP/p38 kinase inhibitors.
Inventors: |
Adams; Jerry L.; (King of
Prussia, PA) ; Boehm; Jeffrey C.; (King of Prussia,
PA) ; Hall; Ralph; (King of Prussia, PA) ;
Jin; Qi; (King of Prussia, PA) ; Kasparec; Jiri;
(King of Prussia, PA) ; Silva; Domingos J.; (King
of Prussia, PA) ; Taggart; John T.; (King of Prussia,
PA) |
Correspondence
Address: |
GLAXOSMITHKLINE
Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
SmithKline Beecham
Corporation
|
Family ID: |
27399571 |
Appl. No.: |
11/839833 |
Filed: |
August 16, 2007 |
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Application
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10399614 |
Apr 18, 2003 |
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PCT/US01/50493 |
Oct 23, 2001 |
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11839833 |
Aug 16, 2007 |
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60242461 |
Oct 23, 2000 |
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60310349 |
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60326618 |
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Current U.S.
Class: |
544/58.2 ;
544/117; 544/279; 544/317; 544/58.4 |
Current CPC
Class: |
A61P 17/00 20180101;
A61P 27/02 20180101; A61P 17/06 20180101; A61P 11/00 20180101; A61P
31/04 20180101; A61P 17/02 20180101; A61P 17/04 20180101; A61P
19/02 20180101; A61P 1/18 20180101; A61P 21/00 20180101; A61P 35/00
20180101; A61P 31/00 20180101; A61P 19/06 20180101; A61P 27/16
20180101; A61P 9/10 20180101; A61P 19/10 20180101; A61P 19/08
20180101; A61P 43/00 20180101; A61P 13/12 20180101; A61P 31/12
20180101; A61P 11/06 20180101; A61P 31/16 20180101; A61P 35/04
20180101; C07D 471/04 20130101; A61P 29/00 20180101; A61P 25/00
20180101; A61P 31/14 20180101; A61P 37/06 20180101; A61P 19/00
20180101; A61P 7/00 20180101; C07D 239/47 20130101; A61P 1/04
20180101; A61P 1/00 20180101; A61P 7/02 20180101; A61P 3/10
20180101; A61P 9/00 20180101; A61P 9/04 20180101 |
Class at
Publication: |
544/058.2 ;
544/117; 544/279; 544/317; 544/058.4 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 239/47 20060101 C07D239/47; C07D 279/12 20060101
C07D279/12; C07D 413/12 20060101 C07D413/12 |
Claims
1. A process for producing a compound according to Formula (Ia)
##STR260## R.sub.1 is an optionally substituted aryl or an
optionally substituted heteroaryl ring; R.sub.2 is hydrogen,
C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylalkyl,
aryl, arylC.sub.1-10 alkyl, heteroaryl, heteroarylC.sub.1-10 alkyl,
heterocyclic, or a heterocyclylC.sub.1-10 alkyl moiety, which
moieties are all optionally substituted, or R.sub.2 is the moiety
X.sub.1(CR.sub.10R.sub.20).sub.qC(A.sub.1)(A.sub.2)(A.sub.3), or
C(A.sub.1)(A.sub.2)(A.sub.3); A.sub.1 is an optionally substituted
C.sub.1-10 alkyl; A.sub.2 is an optionally substituted C.sub.1-10
alkyl; A.sub.3 is hydrogen or is an optionally substituted
C.sub.1-10 alkyl; R.sub.3 is an C.sub.1-10 alkyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-4alkyl, aryl,
arylC.sub.1-10 alkyl, heteroaryl, heteroarylC.sub.1-10 alkyl,
heterocyclic, or a heterocyclylC.sub.1-10 alkyl moiety, which
moieties are optionally substituted; R.sub.4 and R.sub.14 are each
independently selected from hydrogen, optionally substituted
C.sub.1-4 alkyl, optionally substituted C.sub.3-7 cycloalkyl,
C.sub.3-7 cycloalkylC.sub.1-4alkyl, optionally substituted aryl, or
optionally substituted aryl-C.sub.1-4 alkyl, or R.sub.4 and
R.sub.14 together with the nitrogen which they are attached form an
optionally substituted heterocyclic ring of 4 to 7 members, which
ring optionally contains an additional heteroatom selected from
oxygen, sulfur or NR.sub.9; R.sub.6 is hydrogen, C.sub.1-10 alkyl,
C.sub.3-7 cycloalkyl, heterocyclyl, heterocyclyl C.sub.1-10alkyl,
aryl, arylC.sub.1-10 alkyl, heteroaryl or heteroarylC.sub.1-10
alkyl, wherein each of these moieties may be optionally
substituted; R.sub.9 is hydrogen, C(Z)R.sub.6 or optionally
substituted C.sub.1-10 alkyl, optionally substituted aryl or
optionally substituted aryl-C.sub.1-4 alkyl; R.sub.10 and R.sub.20
are independently selected from hydrogen or C.sub.1-4alkyl; X is
R.sub.2, OR.sub.2, S(O).sub.mR.sub.2,
(CH.sub.2).sub.nN(R.sub.10)S(O).sub.mR.sub.2,
(CH.sub.2).sub.nN(R.sub.10)C(O)R.sub.2,
(CH.sub.2).sub.nNR.sub.4R.sub.14, or
(CH.sub.2).sub.nN(R.sub.2).sub.2; X.sub.1 is N(R.sub.10), O,
S(O).sub.m, or CR.sub.10R.sub.20; n is 0 or an integer having a
value of 1 to 10; m is 0 or an integer having a value of 1 or 2; q
is 0 or an integer having a value of 1 to 10; Z is oxygen or
sulfur; or a pharmaceutically acceptable salt thereof, which
process comprises reacting a compound of the formula: ##STR261##
wherein R.sub.1 is a halogen, optionally substituted aryl or an
optionally substituted heteroaryl ring; R.sub.3 is an optionally
substituted aryl, or heteroaryl moiety; m is 0 or an integer having
a value of 0, 1 or 2; and Rg is a C1-4 alkyl; with a mixture of an
acetylating agent, and a base, and optionally with heating to yield
a compound of Formula (Ia), and thereafter if necessary, converting
a precursor of R.sub.1, R.sub.3 and X to a group R.sub.1, R.sub.3
and X as defined in Formula (Ia) above, or a pharmaceutically
acceptable salt thereof.
2. The process according to claim 1 wherein the base is pyridine,
diisopropyl ethylamine, or pyrrolidine.
3. The process according to claim 1 wherein the acetylating agent
is acetic anhydride, acetyl chloride, or ketene.
4. The process according to claim 2 wherein the acetylating agent
is acetic anhydride, acetyl chloride, or ketene.
5. The process according to claim 1 wherein in the compound of
Formula (VIa) m is 0.
6. The process according to claim 1 wherein in the resulting
compound of Formula (Ia) m is 0.
7. The process according to claim 6 wherein the compound of Formula
(Ia) when m is 0, is oxidized to a compound of Formula (Ia) wherein
m is 2.
8. The process according to claim 7 wherein the oxidation uses meta
chloroperoxybenzoic acid, OsO4 and catalytic tertiary amine N-oxide
derivatives, hydrogen peroxide and other peracids, oxygen, ozone,
organic peroxides, potassium permanganate, zinc permanganate,
potassium persulfate and sodium hypochlorite.
9. The process according to claim 7 wherein the sulfoxide of
Formula (Ia) wherein m is 2 is displaced by a primary or secondary
alkylamine.
10. The process according to claim 9 wherein the displacement is in
a polar aprotic solvent.
11. The process according to claim 1 wherein in the compound of
Formula (Ia): R.sub.1 is an optionally substituted aryl or an
optionally substituted heteroaryl ring; R.sub.2 is the moiety
X.sub.1(CR.sub.10R.sub.20).sub.qC(A1)(A2)(A3); A.sub.1 is an
optionally substituted C.sub.1-10alkyl; A.sub.2 is an optionally
substituted C.sub.1-10 alkyl; A.sub.3 is hydrogen or is an
optionally substituted C.sub.1-10 alkyl; and wherein A.sub.1,
A.sub.2, and A.sub.3,excluding hydrogen, are optionally substituted
1 to 4 times by (CR.sub.10R.sub.20).sub.nOR.sub.6; R.sub.3 is an
C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4alkyl, aryl, arylC.sub.1-10 alkyl, heteroaryl,
heteroarylC.sub.1-10 alkyl, heterocyclic, or a
heterocyclylC.sub.1-10 alkyl moiety, which moieties are optionally
substituted; R.sub.6 is hydrogen, or C.sub.1-10 alkyl; R.sub.10 and
R.sub.20 are independently selected from hydrogen or
C.sub.1-4alkyl; X is R.sub.2; X.sub.1 is N(R.sub.10), O,
S(O).sub.m, or CR.sub.10R.sub.20; n is 0 or an integer having a
value of 1 to 10; m is 0 or an integer having a value of 1 or 2;
and q is 0 or an integer having a value of 1 to 10.
12. The process according to claim 1 wherein X is
(CH.sub.2).sub.nNR.sub.4R.sub.14, or
(CH.sub.2).sub.nN(R.sub.2).sub.2.
13. The compound according to claim 11 wherein R.sub.3 is an
optionally substituted C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl,
C.sub.3-7 cycloalkylalkyl, or aryl.
14. The compound according to claim 13 wherein R.sub.3 is
optionally substituted one or more times independently with
C.sub.1-10 alkyl, halo-substituted C.sub.1-10 alkyl, C.sub.2-10
alkenyl, C.sub.2-10alkynyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-10 alkyl, C.sub.5-7cycloalkenyl,
C.sub.5-7cycloalkenylC.sub.1-10 alkyl, halogen, cyano, nitro,
(CR.sub.10R.sub.20).sub.nOR.sub.6, (CR.sub.10R.sub.20).sub.nSH,
(CR.sub.10R.sub.20).sub.nS(O).sub.mR.sub.7,
(CR.sub.10R.sub.20).sub.nNHS(O).sub.2R.sub.7,
(CR.sub.10R.sub.20).sub.nNR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nCN,
(CR.sub.10R.sub.20).sub.nS(O).sub.2NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nC(Z)R.sub.6,
(CR.sub.10R.sub.20).sub.nOC(Z)R.sub.6,
(CR.sub.10R.sub.20).sub.nC(Z)OR.sub.6,
(CR.sub.10R.sub.20).sub.nC(Z)NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nNR.sub.10C(Z)R.sub.6,
(CR.sub.10R.sub.20).sub.nNR.sub.10C(.dbd.NR.sub.10)NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nOC(Z)NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nNR.sub.10C(Z)NR.sub.4R.sub.14, or
(CR.sub.10R.sub.20).sub.nNR.sub.10C(Z)OR.sub.7; and wherein R.sub.7
is a C.sub.1-6alkyl, aryl, arylC.sub.1-6alkyl, heterocyclic,
heterocyclylC.sub.1-6 alkyl, heteroaryl, or
heteroarylC.sub.1-6alkyl and wherein each of these moieties may be
optionally substituted; R.sub.4 and R.sub.14 are each independently
selected from hydrogen, optionally substituted C.sub.1-4 alkyl,
optionally substituted C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4alkyl, optionally substituted aryl, or
optionally substituted aryl-C.sub.1-4 alkyl, or R.sub.4 and
R.sub.14 together with the nitrogen which they are attached form an
optionally substituted heterocyclic ring of 4 to 7 members, which
ring optionally contains an additional heteroatom selected from
oxygen, sulfur or NR.sub.9; R.sub.9 is hydrogen, C(Z)R.sub.6 or
optionally substituted C.sub.1-10 alkyl, optionally substituted
aryl or optionally substituted aryl-C.sub.1-4 alkyl; and Z is
oxygen or sulfur.
15. The compound according to claim 14 wherein the R.sub.3 optional
substituent is independently selected from halogen, alkyl, hydroxy,
alkoxy, amino, or halosubstituted alkyl.
16. The process according to claim 15 wherein R.sub.3 is an
optionally substituted aryl.
17. The process according to claim 16 wherein R.sub.3 is an
optionally substituted phenyl.
18. The process according to claim 11 wherein R.sub.3 is a phenyl
ring, substituted one or more times independently by halogen,
C.sub.1-4 alkyl, or halo-substituted-C.sub.1-4 alkyl.
19. The process according to claim 18 wherein the phenyl ring is
substituted in the 2, 4, or 6-position, di-substituted in the
2,4-position, or tri-substituted in the 2,4,6-position.
20. The process according to claim 11 wherein R.sub.3 is phenyl,
2-methylphenyl, 2-chlorophenyl, 2-fluorophenyl, 4-fluorophenyl,
2,4-difluorophenyl, 2,6-difluorophenyl, 2-methyl-4-fluorophenyl, or
2,4,6-trifluorophenyl.
21. The process according to claim 20 wherein R.sub.3 is
2,6-difluorophenyl.
22. The process according to claim 1 wherein R.sub.3 in Formula
(VIa) is a 2,6-difluorophenyl.
23. The process according to claim 1 wherein the R.sub.1 in Formula
(VIa) is a halogen or an optionally substituted aryl.
24. The process according to claim 24 wherein the R.sub.1 in
Formula (VIa) is a phenyl optionally substituted one or more times
independently by halogen, alkyl, hydroxy, alkoxy, amino, or
halosubstituted alkyl.
25. The process according to claim 24 wherein the R.sub.1 phenyl in
Formula (VIa) is substituted in the 2, 4, or 6-position,
di-substituted in the 2,4-position, or tri-substituted in the 2, 4,
6-position.
26. The process according to claim 1 wherein R.sub.2 is the moiety
X.sub.1 (CR.sub.10R.sub.20).sub.qC(A.sub.1)(A.sub.2)(A.sub.3), or
C(A.sub.1)(A.sub.2)(A.sub.3).
27. The process according to claim 26 wherein X.sub.1 is oxygen or
N(R.sub.10).
28. The process according to claim 27 wherein at least one of
A.sub.1, A.sub.2 or A.sub.3 is substituted by
(CR.sub.10R.sub.20).sub.nOR.sub.6.
29. The process according to claim 28 wherein q is 0, n is 0, and
R.sub.6 is hydrogen.
30. The process according to claim 11 wherein q is 0.
31. The process according to claim 30 wherein X.sub.1 is
N(R.sub.10), and R.sub.10 is hydrogen, and A.sub.1 and A.sub.2 are
independently CH.sub.2OH.
32. The process according to claim 31 wherein A.sub.3 is
hydrogen.
33. The process according to claim 29 wherein X.sub.1 is
N(R.sub.10), and R.sub.10 is hydrogen.
34. The process according to claim 11 wherein the aryl ring of
R.sub.1 is optionally substituted one or more times, independently,
by halogen, C.sub.1-4 alkyl, halo-substituted-C.sub.1-4 alkyl,
cyano, nitro, (CR.sub.10R.sub.20).sub.vNR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.vC(Z)NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.vC(Z)OR.sub.8,
(CR.sub.10R.sub.20).sub.vCOR.sub.a',
(CR.sub.10R.sub.20).sub.vC(O)H, SR.sub.5, S(O)R.sub.5,
S(O).sub.2R.sub.5, (CR.sub.10R.sub.20).sub.vOR.sub.8,
ZC(Z)R.sub.11, NR.sub.10C(Z)R.sub.11, or
NR.sub.10S(O).sub.2R.sub.7; and wherein R.sub.4 and R.sub.14 are
each independently selected from hydrogen, optionally substituted
C.sub.1-4 alkyl, optionally substituted C.sub.3-7 cycloalkyl,
C.sub.3-7 cycloalkylC.sub.1-4alkyl, optionally substituted aryl, or
optionally substituted aryl-C.sub.1-4 alkyl, or R.sub.4 and
R.sub.14 together with the nitrogen which they are attached form an
optionally substituted heterocyclic ring of 4 to 7 members, which
ring optionally contains an additional heteroatom selected from
oxygen, sulfur or NR.sub.9; R.sub.5 is hydrogen, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl or NR.sub.4R.sub.14, excluding
the moieties SR.sub.5 being SNR.sub.4R.sub.14, S(O).sub.2R.sub.5
being SO.sub.2H and S(O)R.sub.5 being SOH; R.sub.7 is a
C.sub.1-6alkyl, aryl, arylC.sub.1-6alkyl, heterocyclic,
heterocyclylC.sub.1-6 alkyl, heteroaryl, or
heteroarylC.sub.1-6alkyl; and wherein each of these moieties may be
optionally substituted; R.sub.8 is hydrogen, C.sub.1-4 alkyl,
halo-substituted C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.3-7 cycloalkyl, C.sub.5-7 cycloalkenyl, aryl,
arylC.sub.1-4 alkyl, heteroaryl, heteroarylC.sub.1-4 alkyl,
heterocyclyl, heterocyclylC.sub.1-4 alkyl,
(CR.sub.10R.sub.20).sub.tOR.sub.7,
(CR.sub.10R.sub.20).sub.tS(O).sub.mR.sub.7,
(CR.sub.10R.sub.20).sub.tNHS(O).sub.2R.sub.7, or
(CR.sub.10R.sub.20).sub.tNR.sub.4R.sub.14; and wherein the
cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaryl
alkyl, heterocyclic and heterocyclic alkyl moieties may be
optionally substituted; R.sub.9 is hydrogen, C(Z)R.sub.6 or
optionally substituted C.sub.1-10 alkyl, optionally substituted
aryl or optionally substituted aryl-C.sub.1-4 alkyl; R.sub.11 is
C.sub.1-4 alkyl, halo-substituted C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.3-7 cycloalkyl, C.sub.5-7
cycloalkenyl, aryl, arylC.sub.1-4 alkyl, heteroaryl,
heteroarylC.sub.1-4 alkyl, heterocyclyl, heterocyclylC.sub.1-4
alkyl, (CR.sub.10R.sub.20).sub.tOR.sub.7,
(CR.sub.10R.sub.20).sub.tS(O).sub.mR.sub.7,
(CR.sub.10R.sub.20).sub.tNHS(O).sub.2R.sub.7 or
(CR.sub.10R.sub.20).sub.vNR.sub.4R.sub.14; and wherein the aryl,
arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclyl, and
heterocyclylalkyl moieties may be optionally substituted; v is 0 or
an integer having a value of 1 or 2; t is an integer having a value
of 1 to 3; Z is oxygen or sulfur; R.sub.a' is C.sub.1-4 alkyl,
halo-substituted C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.3-7 cycloalkyl, C.sub.5-7 cycloalkenyl, aryl,
arylC.sub.1-4 alkyl, heteroaryl, heteroarylC.sub.1-4 alkyl,
heterocyclyl, heterocyclylC.sub.1-4 alkyl,
(CR.sub.10R.sub.20).sub.vOR.sub.7,
(CR.sub.10R.sub.20).sub.vS(O).sub.mR.sub.7,
(CR.sub.10R.sub.20).sub.vNHS(O).sub.2R.sub.7, or
(CR.sub.10R.sub.20).sub.vNR.sub.4R.sub.4, wherein the aryl,
arylalkyl, heteroaryl, and heteroaryl alkyl may be optionally
substituted.
35. The process according to claim 1 wherein R.sub.1 is an
optionally substituted phenyl.
36. The process according to claim 11 wherein R.sub.1 is an
optionally substituted phenyl.
37. The process according to claim 35 wherein the aryl is a phenyl
optionally substituted one or more times independently by halogen,
alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.
38. The process according to claim 36 wherein the aryl is a phenyl
optionally substituted one or more times independently by halogen,
alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.
39. The process according to claim 38 wherein the R.sub.1 phenyl is
substituted in the 2, 4, or 6-position, di-substituted in the
2,4-position, or tri-substituted in the 2, 4, 6-position.
40. The process according to claim 39 wherein R.sub.1 is
2,4-difluorophenyl, 2-fluorophenyl, 4-fluorophenyl,
2-methyl-4-fluorophenyl, or 2,4,6-trifluorophenyl.
41. The process according to claim 40 wherein R.sub.1 is
2-methyl-4-fluorophenyl.
41. The process according to claim 1 wherein R.sub.1 is
2-methyl-4-fluorophenyl.
42. The process according to claim 1 wherein the compound of
Formula (I) is
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hy-
droxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, or a
pharmaceutically acceptable salt thereof.
43. A process of making a compound of the formula: ##STR262##
wherein R.sub.1 is an optionally substituted aryl or an optionally
substituted heteroaryl ring; R.sub.2 is hydrogen, C.sub.1-10 alkyl,
C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylalkyl, aryl,
arylC.sub.1-10 alkyl, heteroaryl, heteroarylC.sub.1-10 alkyl,
heterocyclic, or a heterocyclylC.sub.1-10 alkyl moiety, which
moieties are all optionally substituted, or R.sub.2 is the moiety
X.sub.1(CR.sub.10R.sub.20).sub.qC(A.sub.1)(A.sub.2)(A.sub.3), or
C(A.sub.1)(A.sub.2)(A.sub.3); A.sub.1 is an optionally substituted
C.sub.1-10 alkyl; A.sub.2 is an optionally substituted C.sub.1-10
alkyl; A.sub.3 is hydrogen or is an optionally substituted
C.sub.1-10 alkyl; R.sub.3 is an C.sub.1-10 alkyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-4alkyl, aryl,
arylC.sub.1-10 alkyl, heteroaryl, heteroarylC.sub.1-10 alkyl,
heterocyclic, or a heterocyclylC.sub.1-10 alkyl moiety, which
moieties are optionally substituted; R.sub.4 and R.sub.14 are each
independently selected from hydrogen, optionally substituted
C.sub.1-4 alkyl, optionally substituted C.sub.3-7 cycloalkyl,
C.sub.3-7 cycloalkylC.sub.1-4alkyl, optionally substituted aryl, or
optionally substituted aryl-C.sub.1-4 alkyl, or R.sub.4 and
R.sub.14 together with the nitrogen which they are attached form an
optionally substituted heterocyclic ring of 4 to 7 members, which
ring optionally contains an additional heteroatom selected from
oxygen, sulfur or NR.sub.9; R.sub.6 is hydrogen, C.sub.1-10 alkyl,
C.sub.3-7 cycloalkyl, heterocyclyl, heterocyclyl C.sub.1-10alkyl,
aryl, arylC.sub.1-10 alkyl, heteroaryl or heteroarylC.sub.1-10
alkyl, wherein each of these moieties may be optionally
substituted; R.sub.9 is hydrogen, C(Z)R.sub.6 or optionally
substituted C.sub.1-10 alkyl, optionally substituted aryl or
optionally substituted aryl-C.sub.1-4 alkyl; R.sub.10 and R.sub.20
are independently selected from hydrogen or C.sub.1-4alkyl; X is
R.sub.2, OR.sub.2, S(O).sub.mR.sub.2,
(CH.sub.2).sub.nN(R.sub.10)S(O).sub.mR.sub.2,
(CH.sub.2).sub.nN(R.sub.10)C(O)R.sub.2,
(CH.sub.2).sub.nN.sub.4R.sub.14, or
(CH.sub.2).sub.nN(R.sub.2).sub.2; X.sub.1 is N(R.sub.10), O,
S(O).sub.m, or CR.sub.10R.sub.20; n is 0 or an integer having a
value of 1 to 10; m is 0 or an integer having a value of 1 or 2; q
is 0 or an integer having a value of 1 to 10; Z is oxygen or
sulfur; or a pharmaceutically acceptable salt thereof, which
process comprises reacting a compound of the formula: ##STR263##
wherein R.sub.1 is an aryl or heteroaryl ring, which ring is
optionally substituted, R.sub.3 is an C.sub.1-10 alkyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkylalkyl, aryl, arylC.sub.1-10 alkyl,
heteroaryl, heteroarylC.sub.1-10 alkyl, heterocyclic, or a
heterocyclylC.sub.1-10 alkyl moiety, which moieties are optionally
substituted; and R.sub.12 is a C.sub.1-10 alkyl, aryl, heteroaryl,
or arylalkyl; m is 0 or an integer having a value of 1 or 2; and Rg
is a C.sub.1-4 alkyl; with heating in a suitable organic solvent,
and optionally with a base.
44. The process according to claim 43 wherein the organic solvent
is an organic hydrocarbon, cresol, dioxane, DMF, pyridine, or
xylene.
45. The process according to claim 44 wherein the base is
diisopropyl ethylamine, pyridine, DBU, lithium
bis(trimethylsilyl)amide, or LDA.
45. The process according to claim 43 wherein the base is
diisopropyl ethylamine, pyridine, DBU, lithium
bis(trimethylsilyl)amide, or LDA.
46. The process according to claim 59 wherein R.sub.3 is an
optionally substituted aryl.
47. The process according to claim 43 wherein in the compound of
Formula (Va) m is 0.
48. The process according to claim 1 wherein in the resulting
compound of Formula (Ia) m is 0.
49. The process according to claim 48 wherein the compound of
Formula (Ia) when m is 0, is oxidized to a compound of Formula (Ia)
wherein m is 2.
50. The process according to claim 7 wherein the oxidation uses
meta chloroperoxybenzoic acid, OsO4 and catalytic tertiary amine
N-oxide derivatives, hydrogen peroxide and other peracids, oxygen,
ozone, organic peroxides, potassium permanganate, zinc
permanganate, potassium persulfate and sodium hypochlorite.
51. The process according to claim 43 wherein in the compound of
Formula (Ia): R.sub.1 is an optionally substituted aryl or an
optionally substituted heteroaryl ring; R.sub.2 is the moiety
X.sub.1(CR.sub.10R.sub.20).sub.qC(A1)(A2)(A.sub.3); A.sub.1 is an
optionally substituted C.sub.1-10 alkyl; A.sub.2 is an optionally
substituted C.sub.1-10 alkyl; A.sub.3 is hydrogen or is an
optionally substituted C.sub.1-10 alkyl; and wherein A.sub.1,
A.sub.2, and A.sub.3,excluding hydrogen, are optionally substituted
1 to 4 times by (CR.sub.10R.sub.20).sub.nOR.sub.6; R.sub.3 is an
C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4alkyl, aryl, arylC.sub.1-10 alkyl, heteroaryl,
heteroarylC.sub.1-10 alkyl, heterocyclic, or a
heterocyclylC.sub.1-10 alkyl moiety, which moieties are optionally
substituted; R.sub.6 is hydrogen, or C.sub.1-10 alkyl; R.sub.10 and
R.sub.20 are independently selected from hydrogen or
C.sub.1-4alkyl; X is R.sub.2; XI is N(R.sub.10), O, S(O).sub.m, or
CR.sub.10R.sub.20; n is 0 or an integer having a value of 1 to 10;
m is 0 or an integer having a value of 1 or 2; and q is 0 or an
integer having a value of 1 to 10.
52. The process according to claim 43 wherein X is
(CH.sub.2).sub.nNR.sub.4R.sub.14, or
(CH.sub.2).sub.nN(R.sub.2).sub.2.
53. The compound according to claim 51 wherein R.sub.3 is an
optionally substituted C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl,
C.sub.3-7 cycloalkylalkyl, or aryl.
54. The compound according to claim 53 wherein R.sub.3 is
optionally substituted one or more times independently with
C.sub.1-10 alkyl, halo-substituted C.sub.1-10 alkyl, C.sub.2-10
alkenyl, C.sub.2-10alkynyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-10 alkyl, C.sub.5-7cycloalkenyl,
C.sub.5-7cycloalkenylC.sub.1-10 alkyl, halogen, cyano, nitro,
(CR.sub.10R.sub.20).sub.nOR.sub.6, (CR.sub.10R.sub.20).sub.nSH,
(CR.sub.10R.sub.20).sub.nS(O).sub.mR.sub.7,
(CR.sub.10R.sub.20).sub.nNHS(O).sub.2R.sub.7,
(CR.sub.10R.sub.20).sub.nNR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nCN,
(CR.sub.10R.sub.20).sub.nS(O).sub.2NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nC(Z)R.sub.6,
(CR.sub.10R.sub.20).sub.nOC(Z)R.sub.6,
(CR.sub.10R.sub.20).sub.nC(Z)OR.sub.6,
(CR.sub.10R.sub.20).sub.nC(Z)NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nNR.sub.10C(Z)R.sub.6,
(CR.sub.10R.sub.20).sub.nNR.sub.10C(.dbd.NR.sub.10)NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nOC(Z)NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nNR.sub.10C(Z)NR.sub.4R.sub.14, or
(CR.sub.10R.sub.20).sub.nNR.sub.10C(Z)OR.sub.7; and wherein R.sub.7
is a C.sub.1-6alkyl, aryl, arylC.sub.1-6alkyl, heterocyclic,
heterocyclylC.sub.1-6 alkyl, heteroaryl, or
heteroarylC.sub.1-6alkyl and wherein each of these moieties may be
optionally substituted; R.sub.4 and R.sub.14 are each independently
selected from hydrogen, optionally substituted C.sub.1-4 alkyl,
optionally substituted C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4alkyl, optionally substituted aryl, or
optionally substituted aryl-C.sub.1-4 alkyl, or R.sub.4 and
R.sub.14 together with the nitrogen which they are attached form an
optionally substituted heterocyclic ring of 4 to 7 members, which
ring optionally contains an additional heteroatom selected from
oxygen, sulfur or NR.sub.9; R.sub.9 is hydrogen, C(Z)R.sub.6 or
optionally substituted C.sub.1-10 alkyl, optionally substituted
aryl or optionally substituted aryl-C.sub.1-4 alkyl; and Z is
oxygen or sulfur.
55. The process according to claim 54 wherein the R.sub.3 optional
substituent is independently selected from halogen, alkyl, hydroxy,
alkoxy, amino, or halosubstituted alkyl.
56. The process according to claim 55 wherein R.sub.3 is an
optionally substituted aryl.
57. The process according to claim 16 wherein R.sub.3 is an
optionally substituted phenyl.
58. The process according to claim 51 wherein R.sub.3 is a phenyl
ring, substituted one or more times independently by halogen,
C.sub.1-4 alkyl, or halo-substituted-C.sub.1-4 alkyl.
59. The process according to claim 58 wherein the phenyl ring is
substituted in the 2, 4, or 6-position, di-substituted in the
2,4-position, or tri-substituted in the 2,4,6-position.
60. The process according to claim 11 wherein R.sub.3 is phenyl,
2-methylphenyl, 2-chlorophenyl, 2-fluorophenyl, 4-fluorophenyl,
2,4-difluorophenyl, 2,6-difluorophenyl, 2-methyl-4-fluorophenyl, or
2,4,6-trifluorophenyl.
61. The process according to claim 60 wherein R.sub.3 is
2,6-difluorophenyl.
62. The process according to claim 51 wherein R.sub.3 in Formula
(Va) is a 2,6-difluorophenyl.
63. The process according to claim 51 wherein the R.sub.1 in
Formula (Va) is an optionally substituted aryl.
64. The process according to claim 63 wherein the R.sub.1 in
Formula (Va) is a phenyl optionally substituted one or more times
independently by halogen, alkyl, hydroxy, alkoxy, amino, or
halosubstituted alkyl.
65. The process according to claim 64 wherein the R.sub.1 phenyl in
Formula (Va) is substituted in the 2, 4, or 6-position,
di-substituted in the 2,4-position, or tri-substituted in the 2, 4,
6-position.
66. The process according to claim 51 wherein R.sub.2 is the moiety
X.sub.1 (CR.sub.10R.sub.20).sub.qC(A.sub.1)(A.sub.2)(A.sub.3), or
C(A.sub.1)(A.sub.2)(A.sub.3).
67. The process according to claim 66 wherein X.sub.1 is oxygen or
N(R.sub.10).
68. The process according to claim 67 wherein at least one of
A.sub.1, A.sub.2 or A.sub.3 is substituted by
(CR.sub.10R.sub.20).sub.nOR.sub.6.
69. The process according to claim 68 wherein q is 0, n is 0, and
R.sub.6 is hydrogen.
70. The process according to claim 51 wherein q is 0.
71. The process according to claim 70 wherein X.sub.1 is
N(R.sub.10), and R.sub.10 is hydrogen, and A.sub.1 and A.sub.2 are
independently CH.sub.2OH.
72. The process according to claim 71 wherein A.sub.3 is
hydrogen.
73. The process according to claim 69 wherein X.sub.1 is
N(R.sub.10), and R.sub.10 is hydrogen.
74. The process according to claim 51 wherein the aryl ring of
R.sub.1 is optionally substituted one or more times, independently,
by halogen, C.sub.1-4 alkyl, halo-substituted-C.sub.1-4 alkyl,
cyano, nitro, (CR.sub.10R.sub.20).sub.vNR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.vC(Z)NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.vC(Z)OR.sub.8,
(CR.sub.10R.sub.20).sub.vCOR.sub.a',
(CR.sub.10R.sub.20).sub.vC(O)H, SR.sub.5, S(O)R.sub.5,
S(O).sub.2R.sub.5, (CR.sub.10R.sub.20).sub.vOR.sub.8,
ZC(Z)R.sub.11, NR.sub.10C(Z)R.sub.11, or
NR.sub.10S(O).sub.2R.sub.7; and wherein R.sub.4 and R.sub.14 are
each independently selected from hydrogen, optionally substituted
C.sub.1-4 alkyl, optionally substituted C.sub.3-7 cycloalkyl,
C.sub.3-7 cycloalkylC.sub.1-4alkyl, optionally substituted aryl, or
optionally substituted aryl-C.sub.1-4 alkyl, or R.sub.4 and
R.sub.14 together with the nitrogen which they are attached form an
optionally substituted heterocyclic ring of 4 to 7 members, which
ring optionally contains an additional heteroatom selected from
oxygen, sulfur or NR.sub.9; R.sub.5 is hydrogen, C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl or NR.sub.4R.sub.14, excluding
the moieties SR.sub.5 being SNR.sub.4R.sub.14, S(O).sub.2R.sub.5
being SO.sub.2H and S(O)R.sub.5 being SOH; R.sub.7 is a
C.sub.1-6alkyl, aryl, arylC.sub.1-6alkyl, heterocyclic,
heterocyclylC.sub.1-6 alkyl, heteroaryl, or
heteroarylC.sub.1-6alkyl; and wherein each of these moieties may be
optionally substituted; R.sub.8 is hydrogen, C.sub.1-4 alkyl,
halo-substituted C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.3-7 cycloalkyl, C.sub.5-7 cycloalkenyl, aryl,
arylC.sub.1-4 alkyl, heteroaryl, heteroarylC.sub.1-4 alkyl,
heterocyclyl, heterocyclylC.sub.1-4 alkyl,
(CR.sub.10R.sub.20).sub.tOR.sub.7,
(CR.sub.10R.sub.20).sub.tS(O).sub.mR.sub.7,
(CR.sub.10R.sub.20).sub.tNHS(O).sub.2R.sub.7, or
(CR.sub.10R.sub.20).sub.tNR.sub.4R.sub.14; and wherein the
cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaryl
alkyl, heterocyclic and heterocyclic alkyl moieties may be
optionally substituted; R.sub.9 is hydrogen, C(Z)R.sub.6 or
optionally substituted C.sub.1-10 alkyl, optionally substituted
aryl or optionally substituted aryl-C.sub.1-4 alkyl; R.sub.11 is
C.sub.1-4 alkyl, halo-substituted C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.3-7 cycloalkyl, C.sub.5-7
cycloalkenyl, aryl, arylC.sub.1-4 alkyl, heteroaryl,
heteroarylC.sub.1-4 alkyl, heterocyclyl, heterocyclylC.sub.1-4
alkyl, (CR.sub.10R.sub.20).sub.tOR.sub.7,
(CR.sub.10R.sub.20).sub.tS(O).sub.mR.sub.7,
(CR.sub.10R.sub.20).sub.tNHS(O).sub.2R.sub.7 or
(CR.sub.10R.sub.20).sub.vNR.sub.4R.sub.14; and wherein the aryl,
arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclyl, and
heterocyclylalkyl moieties may be optionally substituted; v is 0 or
an integer having a value of 1 or 2; t is an integer having a value
of 1 to 3; Z is oxygen or sulfur; R.sub.a' is C.sub.1-4 alkyl,
halo-substituted C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.3-7 cycloalkyl, C.sub.5-7 cycloalkenyl, aryl,
arylC.sub.1-4 alkyl, heteroaryl, heteroarylC.sub.1-4 alkyl,
heterocyclyl, heterocyclylC.sub.1-4 alkyl,
(CR.sub.10R.sub.20).sub.vOR.sub.7,
(CR.sub.10R.sub.20).sub.vS(O).sub.mR.sub.7,
(CR.sub.10R.sub.20).sub.vNHS(O).sub.2R.sub.7, or
(CR.sub.10R.sub.20).sub.vNR.sub.4R.sub.14, wherein the aryl,
arylalkyl, heteroaryl, and heteroaryl alkyl may be optionally
substituted.
75. The process according to claim 43 wherein R.sub.1 is an
optionally substituted phenyl.
76. The process according to claim 51 wherein R.sub.1 is an
optionally substituted phenyl.
77. The process according to claim 75 wherein the aryl is a phenyl
optionally substituted one or more times independently by halogen,
alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.
78. The process according to claim 76 wherein the aryl is a phenyl
optionally substituted one or more times independently by halogen,
alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.
79. The process according to claim 78 wherein the R.sub.1 phenyl is
substituted in the 2, 4, or 6-position, di-substituted in the
2,4-position, or tri-substituted in the 2, 4, 6-position.
80. The process according to claim 79 wherein R.sub.1 is
2,4-difluorophenyl, 2-fluorophenyl, 4-fluorophenyl,
2-methyl-4-fluorophenyl, or 2,4,6-trifluorophenyl.
81. The process according to claim 80 wherein R.sub.1 is
2-methyl-4-fluorophenyl.
82. The process according to claim 43 wherein R.sub.1 is
2-methyl-4-fluorophenyl.
83. The process according to claim 43 wherein the compound of
Formula (I) is
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hy-
droxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, or a
pharmaceutically acceptable salt thereof.
Description
CROSS REFERENCE OF PRIOR APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
10/399,614 filed 18 Apr. 2003 (allowed), which is the national
stage entry of PCT/US01/50493, filed 23 Oct. 2001, which claims the
benefit of priority of U.S. Provisional Applications 60/242,461
filed 23 Oct. 2000; 60/310,349 filed 6 Aug. 2001; and 60/326,618,
filed 2 Oct. 2001.
FIELD OF THE INVENTION
[0002] This invention relates to a novel group of
2,4,8-trisubstituted-8H-pyrido[2,3-d]pyrimidin-7-one compounds,
processes for the preparation thereof, the use thereof in treating
CSBP/p38 kinase mediated diseases and pharmaceutical compositions
for use in such therapy.
BACKGROUND OF THE INVENTION
[0003] Intracellular signal transduction is the means by which
cells respond to extracellular stimuli. Regardless of the nature of
the cell surface receptor (e.g. protein tyrosine kinase or
seven-transmembrane G-protein coupled), protein kinases and
phosphatases along with phopholipases are the essential machinery
by which the signal is further transmitted within the cell
[Marshall, J. C. Cell, 80, 179-278 (1995)]. Protein kinases can be
categorized into five classes with the two major classes being,
tyrosine kinases and serine/threonine kinases depending upon
whether the enzyme phosphorylates its substrate(s) on specific
tyrosine(s) or serine/threonine(s) residues [Hunter, T., Methods in
Enzymology (Protein Kinase Classification) p. 3, Hunter, T.;
Sefton, B. M.; eds. vol. 200, Academic Press; San Diego, 1991].
[0004] For most biological responses, multiple intracellular
kinases are involved and an individual kinase can be involved in
more than one signaling event. These kinases are often cytosolic
and can translocate to the nucleus or the ribosomes where they can
affect transcriptional and translational events, respectively. The
involvement of kinases in transcriptional control is presently much
better understood than their effect on translation as illustrated
by the studies on growth factor induced signal transduction
involving MAP/ERK kinase [Marshall, C. J. Cell, 80, 179 (1995);
Herskowitz, I. Cell, 80, 187 (1995); Hunter, T. Cell, 80, 225
(1995); Seger, R., and Krebs, E. G. FASEB J., 726-735 (1995)].
[0005] While many signaling pathways are part of cell homeostasis,
numerous cytokines (e.g., IL-1 and TNF) and certain other mediators
of inflammation (e.g., COX-2, and iNOS) are produced only as a
response to stress signals such as bacterial lipopolysaccharide
(LPS). The first indications suggesting that the signal
transduction pathway leading to LPS-induced cytokine biosynthesis
involved protein kinases came from studies of Weinstein [Weinstein,
et al., J. Immunol. 151, 3829 (1993)] but the specific protein
kinases involved were not identified. Working from a similar
perspective, Han [Han, et al., Science 265, 808 (1994)] identified
murine p38 as a kinase which is tyrosine phosphorylated in response
to LPS. Definitive proof of the involvement of the p38 kinase in
LPS-stimulated signal transduction pathway leading to the
initiation of proinflammatory cytokine biosynthesis was provided by
the independent discovery of p38 kinase by Lee [Lee; et al.,
Nature, 372, 739 (1994)] as the molecular target for a novel class
of anti-inflammatory agents. The discovery of p38 (termed by Lee as
CSBP 1 and 2) provided a mechanism of action of a class of
anti-inflammatory compounds for which SK&F 86002 was the
prototypic example. These compounds inhibited IL-1 and TNF
synthesis in human monocytes at concentrations in the low uM range
[Lee, et al., Int. J. Immunopharmac. 10(7), 835 (1988)] and
exhibited activity in animal models which are refractory to
cyclooxygenase inhibitors [Lee; et al., Annals N.Y. Acad. Sci.,
696, 149 (1993)].
[0006] It is now firmly established that CSBP/p38 is a one of
several kinases involved in a stress-response signal transduction
pathway which is parallel to and largely independent of the
analogous mitogen-activated protein kinase (MAP) kinase cascade.
Stress signals, including LPS, pro-inflammatory cytokines,
oxidants, UV light and osmotic stress, activate kinases upstream
from CSBP/p38 which in turn phosphorylate CSBP/p38 at threonine 180
and tyrosine 182 resulting in CSBP/p38 activation. MAPKAP kinase-2
and MAPKAP kinase-3 have been identified as downstream substrates
of CSBP/p38 which in turn phosphorylate heat shock protein Hsp 27
(FIG. 1). Additional downstream substrates known to be
phosphorylated by p38 include kinases (Mnk1/2, MSK1/2 and PRAK) and
transcription factors (CHOP, MEF2, ATF2 and CREB). While many of
the signaling pathways required for cytokine biosynthesis remain
unknown it appears clear that many of the substrates for p38 listed
above are involved. [Cohen, P. Trends Cell Biol., 353-361 (1997)
and Lee, J. C. et al, Pharmacol. Ther. vol. 82, nos. 2-3, pp.
389-397, 1999].
[0007] What is known, however, is that in addition to inhibiting
IL-1 and TNF, CSBP/p38 kinase inhibitors (SK&F 86002 and SB
203580) also decrease the synthesis of a wide variety of
pro-inflammatory proteins including, IL-6, IL-8, GM-CSF and COX-2.
Inhibitors of CSBP/p38 kinase have also been shown to suppress the
TNF-induced expression of VCAM-1 on endothelial cells, the
TNF-induced phosphorylation and activation of cytosolic PLA2 and
the IL-1-stimulated synthesis of collagenase and stromelysin. These
and additional data demonstrate that CSBP/p38 is involved not only
cytokine synthesis, but also in cytokine signaling [CSBP/P38 kinase
reviewed in Cohen, P. Trends Cell Biol., 353-361 (1997)].
[0008] Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are
biological substances produced by a variety of cells, such as
monocytes or macrophages. IL-1 has been demonstrated to mediate a
variety of biological activities thought to be important in
immunoregulation and other physiological conditions such as
inflammation [See, e.g., Dinarello et al., Rev. Infect. Disease, 6,
51 (1984)]. The myriad of known biological activities of IL-1
include the activation of T helper cells, induction of fever,
stimulation of prostaglandin or collagenase production, neutrophil
chemotaxis, induction of acute phase proteins and the suppression
of plasma iron levels.
[0009] There are many disease states in which excessive or
unregulated IL-1 production is implicated in exacerbating and/or
causing the disease. These include rheumatoid arthritis,
osteoarthritis, endotoxemia and/or toxic shock syndrome, other
acute or chronic inflammatory disease states such as the
inflammatory reaction induced by endotoxin or inflammatory bowel
disease; tuberculosis, atherosclerosis, muscle degeneration,
cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid
arthritis, gout, traumatic arthritis, rubella arthritis, and acute
synovitis. Evidence also links IL-1 activity to diabetes and
pancreatic .beta. cells [review of the biological activities which
have been attributed to IL-1 Dinarello, J. Clinical Immunology, 5
(5), 287-297 (1985)].
[0010] Excessive or unregulated TNF production has been implicated
in mediating or exacerbating a number of diseases including
rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty
arthritis and other arthritic conditions; sepsis, septic shock,
endotoxic shock, gram negative sepsis, toxic shock syndrome, adult
respiratory distress syndrome, cerebral malaria, chronic pulmonary
inflammatory disease, silicosis, pulmonary sarcoisosis, bone
resorption diseases, reperfusion injury, graft vs. host reaction,
allograft rejections, fever and myalgias due to infection, such as
influenza, cachexia secondary to infection or malignancy, cachexia,
secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC
(AIDS related complex), keloid formation, scar tissue formation,
Crohn's disease, ulcerative colitis, or pyresis.
[0011] Interleukin-8 (IL-8) is a chemotactic factor produced by
several cell types including mononuclear cells, fibroblasts,
endothelial cells, and keratinocytes. Its production from
endothelial cells is induced by IL-1, TNF, or lipopolysachharide
(LPS). IL-8 stimulates a number of functions in vitro. It has been
shown to have chemoattractant properties for neutrophils,
T-lymphocytes, and basophils. In addition it induces histamine
release from basophils from both normal and atopic individuals as
well as lysozomal enzyme release and respiratory burst from
neutrophils. IL-8 has also been shown to increase the surface
expression of Mac-1 (CD11b/CD 18) on neutrophils without de novo
protein synthesis, this may contribute to increased adhesion of the
neutrophils to vascular endothelial cells. Many diseases are
characterized by massive neutrophil infiltration. Conditions
associated with an increased in IL-8 production (which is
responsible for chemotaxis of neutrophiil into the inflammatory
site) would benefit by compounds which are suppressive of IL-8
production.
[0012] IL-1 and TNF affect a wide variety of cells and tissues and
these cytokines as well as other leukocyte derived cytokines are
important and critical inflammatory mediators of a wide variety of
disease states and conditions. The inhibition of these cytokines is
of benefit in controlling, reducing and alleviating many of these
disease states.
[0013] In addition to the involvement of CSBP/p3 8 signaling in the
production of IL-1, TNF, IL-8, IL-6, GM-CSF, COX-2, collagenase and
stromelysin, signal transduction via CSBP/p38 is required for the
action of several of these same pro-inflammatory proteins plus many
others (VEGF, PDGF, NGF) [Ono, K. and Han, J. Cellular Signalling,
12 1-13 (2000)]. The involvement of CSBP/p3 8 in multiple
stress-induced signal transduction pathways provides additional
rationale for the potential utility of CSBP/p38 in the treatment of
diseases resulting from the excessive and destructive activation of
the immune system. This expectation is supported by the potent and
diverse activities described for CSBP/p38 kinase inhibitors
[Badger, et al., J. Pharm. Exp. Thera. 279 (3): 1453-1461.(1996);
Griswold, et al, Pharmacol. Comm. 7, 323-229 (1996); Jackson, et
al, J. Pharmacol. Exp. Ther. 284, 687-692 (1998);Underwood, et al.,
J. Pharmacol. Exp. Ther. 293, 281-288 (2000); Badger, et al.,
Arthritis Rheum. 43, 175-183 (2000)].
[0014] There remains a need for treatment, in this field, for
compounds which are cytokine suppressive anti-inflammatory drugs,
i.e. compounds which are capable of inhibiting the CSBP/p38/RK
kinase.
[0015] Other pyrido[2,3-d]pyrimidine containing pharmacophores
having varying pharmaceutical, insecticidal, and herbicidal
activity may be found in the art, such as in WO 98/33798; WO
98/23613; WO 95/19774, now U.S. Pat. No. 6,265,410; WO 00/23444; WO
01/19828 (published after the filing date of this application);
U.S. Pat. No. 5,532,370; U.S. Pat. No. 5,597,776; JP 2000-38350; WO
00/43374; WO 98/08846; and WO 01/55147 (also published after the
filing date of this application).
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 demonstrates the p38 kinase cascade.
SUMMARY OF THE INVENTION
[0017] This invention relates to the novel compounds of Formula (I)
and (Ia), and Formula (II) and (IIa), and pharmaceutical
compositions comprising a compound of Formula (I) and (Ia), and
Formula (II) and (IIa), and a pharmaceutically acceptable diluent
or carrier.
[0018] This invention relates to a method of treating a CSBP/RK/p38
kinase mediated disease in a mammal in need thereof, which
comprises administering to said mammal an effective amount of a
compound of Formula (I) and (Ia), and Formula (II) and (IIa).
[0019] This invention also relates to a method of inhibiting
cytokines and the treatment of a cytokine mediated disease, in a
mammal in need thereof, which comprises administering to said
mammal an effective amount of a compound of Formula (I) and (Ia),
and Formula (II) and (IIa).
[0020] This invention more specifically relates to a method of
inhibiting the production of IL-1 in a mammal in need thereof which
comprises administering to said mammal an effective amount of a
compound of Formula (I) and (Ia), and Formula (II) and (IIa).
[0021] This invention more specifically relates to a method of
inhibiting the production of IL-6 in a mammal in need thereof which
comprises administering to said mammal an effective amount of a
compound of Formula (I) and (Ia), and Formula (II) and (IIa).
[0022] This invention more specifically relates to a method of
inhibiting the production of IL-8 in a mammal in need thereof which
comprises administering to said mammal an effective amount of a
compound of Formula (I) and (Ia), and Formula (II) and (IIa).
[0023] This invention more specifically relates to a method of
inhibiting the production of TNF in a mammal in need thereof which
comprises administering to said mammal an effective amount of a
compound of Formula (I) and (Ia), and Formula (II) and (IIa).
[0024] Accordingly, the present invention provides a compound of
Formula (I) and (Ia): ##STR1## [0025] wherein [0026] R.sub.1 is an
optionally substituted aryl or an optionally substituted heteroaryl
ring; [0027] R.sub.2 is hydrogen, C.sub.1-10 alkyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkylalkyl, aryl, arylC.sub.1-10 alkyl,
heteroaryl, heteroarylC.sub.1-10 alkyl, heterocyclic, or a
heterocyclylC.sub.1-10 alkyl moiety, which moieties are all
optionally substituted, or R.sub.2 is the moiety X.sub.1
(CR.sub.10R.sub.20).sub.qC(A1)(A.sub.2)(A.sub.3), or
C(A.sub.1)(A.sub.2)(A.sub.3); [0028] A.sub.1 is an optionally
substituted C.sub.1-10 alkyl; [0029] A.sub.2 is an optionally
substituted C.sub.1-10 alkyl; [0030] A.sub.3 is hydrogen or is an
optionally substituted C.sub.1-10 alkyl; [0031] R.sub.3 is an
C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4alkyl, aryl, arylC.sub.1-10 alkyl, heteroaryl,
heteroarylC.sub.1-10 alkyl, heterocyclic, or a
heterocyclylC.sub.1-10 alkyl moiety, which moieties are optionally
substituted; [0032] R.sub.4 and R.sub.14 are each independently
selected from hydrogen, optionally substituted C.sub.1-4 alkyl,
optionally substituted C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4alkyl, optionally substituted aryl, or
optionally substituted aryl-C.sub.1-4 alkyl, or R.sub.4 and
R.sub.14 together with the nitrogen which they are attached form an
optionally substituted heterocyclic ring of 4 to 7 members, which
ring optionally contains an additional heteroatom selected from
oxygen, sulfur or NR.sub.9; [0033] R.sub.6 is hydrogen, C.sub.1-10
alkyl, C.sub.3-7 cycloalkyl, heterocyclyl, heterocyclyl C.sub.1-10
alkyl, aryl, arylC.sub.1-10 alkyl, heteroaryl or
heteroarylC.sub.1-10 alkyl, wherein each of these moieties may be
optionally substituted; [0034] R.sub.9 is hydrogen, C(Z)R.sub.6 or
optionally substituted C.sub.1-10 alkyl, optionally substituted
aryl or optionally substituted aryl-C.sub.1-4 alkyl; [0035]
R.sub.10 and R.sub.20 are independently selected from hydrogen or
C.sub.1-4alkyl; [0036] X is R.sub.2, OR.sub.2, S(O).sub.mR.sub.2,
(CH.sub.2).sub.nN(R.sub.10)S(O).sub.mR.sub.2,
(CH.sub.2).sub.nN(R.sub.10)C(O)R.sub.2,
(CH.sub.2).sub.nNR.sub.4R.sub.14, or
(CH.sub.2).sub.nN(R.sub.2).sub.2; [0037] X.sub.1 is N(R.sub.10), O,
S(O).sub.m, or CR.sub.10R.sub.20; [0038] n is 0 or an integer
having a value of 1 to 10; [0039] m is 0 or an integer having a
value of 1 or 2; [0040] q is 0 or an integer having a value of 1 to
10; [0041] Z is oxygen or sulfur; [0042] or a pharmaceutically
acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0043] Another aspect of the present invention provides for the
compound of Formula (II) and (IIa): ##STR2## [0044] wherein [0045]
R.sub.1 is the moiety YRa; [0046] R.sub.2 is hydrogen, C.sub.1-10
alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylalkyl, aryl,
arylC.sub.1-10 alkyl, heteroaryl, heteroarylC.sub.1-10 alkyl,
heterocyclic, or a heterocyclylC.sub.1-10 alkyl moiety, which
moieties are all optionally substituted, or R.sub.2 is the moiety
X.sub.1(CR.sub.10R.sub.20).sub.q C(A.sub.1)(A.sub.2)(A.sub.3), or
C(A.sub.1)(A.sub.2)(A.sub.3); [0047] A.sub.1 is an optionally
substituted C.sub.1-10 alkyl; [0048] A.sub.2 is an optionally
substituted C.sub.1-10 alkyl; [0049] A.sub.3 is hydrogen or is an
optionally substituted C.sub.1-10 alkyl; [0050] R.sub.3 is an
C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4alkyl, aryl, arylC.sub.1-10 alkyl, heteroaryl,
heteroarylC.sub.1-10 alkyl, heterocyclic, or a
heterocyclylC.sub.1-10 alkyl moiety, which moieties are optionally
substituted; [0051] R.sub.4 and R.sub.14 are each independently
selected from hydrogen, optionally substituted C.sub.1-4 alkyl,
optionally substituted C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4alkyl, optionally substituted aryl, or
optionally substituted aryl-C.sub.1-4 alkyl, or R.sub.4 and
R.sub.14 together with the nitrogen which they are attached form an
optionally substituted heterocyclic ring of 4 to 7 members, which
ring optionally contains an additional heteroatom selected from
oxygen, sulfur or NR.sub.9; [0052] R.sub.6 is hydrogen, C.sub.1-10
allyl, C.sub.3-7 cycloalkyl, heterocyclyl, heterocyclyl
C.sub.1-10alkyl, aryl, arylC.sub.1-10 alkyl, heteroaryl or
heteroarylC.sub.1-10 alkyl, wherein each of these moieties may be
optionally substituted; [0053] R.sub.9 is hydrogen, C(Z)R.sub.6 or
optionally substituted C.sub.1-10 alkyl, optionally substituted
aryl or optionally substituted aryl-C.sub.1-4 alkyl; [0054]
R.sub.10 and R.sub.20 are independently selected from hydrogen or
C.sub.1-4alkyl; [0055] Y is C(R.sub.b)(R.sub.d), C(O), N(R.sub.d),
N(R.sub.d)C(R.sub.c)(R.sub.d), oxygen, OC(R.sub.c)(R.sub.d),
S(O).sub.m, or S(O).sub.mC(R.sub.c)(R.sub.d); [0056] R.sub.a is an
aryl or heteroaryl ring, which ring is optionally substituted;
[0057] R.sub.b is hydrogen, C.sub.1-2 alkyl, NR.sub.c, hydroxy,
thio, C.sub.1-2 alkoxy, S(O).sub.mC.sub.1-2 alkyl; [0058] R.sub.c
is hydrogen or C.sub.1-2 alkyl; [0059] R.sub.d is hydrogen or
C.sub.1-2 alkyl; [0060] X is R.sub.2, OR.sub.2, S(O).sub.mR.sub.2,
(CH.sub.2).sub.nN(R.sub.10)S(O).sub.mR.sub.2,
(CH.sub.2).sub.nN(R.sub.10)C(O)R.sub.2,
(CH.sub.2).sub.nNR.sub.4R.sub.14, or
(CH.sub.2).sub.nN(R.sub.2).sub.2; [0061] X.sub.1 is N(R.sub.10), O,
S(O).sub.m, or CR.sub.10R.sub.20; [0062] n is 0 or an integer
having a value of 1 to 10; [0063] m is 0 or an integer having a
value of 1 or 2; [0064] q is 0 or an integer having a value of 1 to
10; [0065] Z is oxygen or sulfur; [0066] or a pharmaceutically
acceptable salt thereof.
[0067] The present invention is directed to novel compounds of
Formula (I) and (Ia), and those of Formula (II) and (IIa), or a
pharmaceutically acceptable salt thereof. As will be readily
recognized, the difference between compounds of Formula (I) and
(Ia) and that of Formula (II) and (IIa) lies in the unsaturation of
the pyrido-7-one ring. The respective R.sub.1, R.sub.2, X and
R.sub.3 terms are the same for both groups within the Formula
itself, for instance I and Ia. For purposes herein, everything
applicable to Formula (I) is also applicable to Formula (Ia) unless
otherwise indicated, and everything applicable to Formula (II) is
also applicable to Formula (Ia) unless otherwise indicated.
[0068] Suitably, for compounds of Formula (I), and (Ia), R.sub.1 is
an aryl, or heteroaryl ring, which ring is optionally substituted.
The R.sub.1 aryl or heteroaryl rings may be substituted one or more
times, preferably 1 to 4 times, independently, by substituents
selected from halogen, C.sub.1-4 alkyl, halo-substituted-C.sub.1-4
alkyl, cyano, nitro, (CR.sub.10R.sub.20).sub.vNR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.vC(Z)NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.vC(Z)OR.sub.8,
(CR.sub.10R.sub.20).sub.vCOR.sub.a',
(CR.sub.10R.sub.20).sub.vC(O)H, SR.sub.5, S(O)R.sub.5,
S(O).sub.2R.sub.5, (CR.sub.10R.sub.20).sub.vOR.sub.8 ZC(Z)R.sub.11,
NR.sub.10C(Z)R.sub.11, or NR.sub.10S(O).sub.2R.sub.7.
[0069] Preferably, R.sub.1 is an aryl moiety, more preferably a
phenyl ring, optionally substituted one or more times by halogen,
C.sub.1-4 alkyl, or halo-substituted-C.sub.1-4 alkyl. More
preferably, the phenyl ring is substituted in the 2, 4, or
6-position, or di-substituted in the 2,4-position, such as
2-fluoro, 4-fluoro, 2,4-difluoro, or 2-methyl-4-fluoro; or
tri-substituted in the 2,4,6-position such as 2,4,6-trifluoro.
[0070] Preferably, when R.sub.1 is a heteroaryl moiety, the ring is
not attached to the pharmacophore via one of the heteroatoms, such
as nitrogen to form a charged ring. For instance, a pyridinyl ring
would be attached through a carbon atom to yield a 2-, 3- or
4-pyridyl moiety, which is optionally substituted.
[0071] Suitably, v is 0 or an integer having a value of 1 or 2.
[0072] Suitably, Z is oxygen or sulfur.
[0073] Suitably, R.sub.a', is C.sub.1-4 alkyl, halo-substituted
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-7
cycloalkyl, C.sub.5-7 cycloalkenyl, aryl, arylC.sub.1-4 alkyl,
heteroaryl, heteroarylC.sub.1-4 alkyl, heterocyclyl,
heterocyclylC.sub.1-4 alkyl, (CR.sub.10R.sub.20).sub.vOR.sub.7,
(CR.sub.10R.sub.20).sub.vS(O).sub.mR.sub.7,
(CR.sub.10R.sub.20).sub.vNHS(O).sub.2R.sub.7, or
(CR.sub.10R.sub.20).sub.vNR.sub.4R.sub.14; and wherein the aryl,
arylalkyl, heteroaryl, heteroaryl alkyl may be optionally
substituted.
[0074] Suitably, for compounds of Formula (II), and (Ia), R.sub.1
is Y--R.sub.a.
[0075] Suitably, Y is C(R.sub.b)(R.sub.d), C(O), N(R.sub.d),
N(R.sub.d)C(R.sub.c)(R.sub.d), oxygen, OC(R.sub.c)(R.sub.d),
S(O).sub.m, or S(O).sub.mC(R.sub.c)(R.sub.d).
[0076] Suitably, R.sub.b is hydrogen, C.sub.1-2 alkyl, NR.sub.c,
hydroxy, thio, C.sub.1-2 alkoxy, S(O).sub.mC.sub.1-2 alkyl.
[0077] Suitably, R.sub.c is hydrogen or C.sub.1-2 alkyl.
[0078] Suitably, R.sub.d is hydrogen or C.sub.1-2 alkyl.
[0079] Suitably, m is 0 or an integer having a value of 1 or 2.
[0080] Suitably R.sub.a is an optionally substituted aryl ring or
an optionally substituted heteroaryl ring. The optional
substitutents for these rings are the same as for the Formula (I)
and (Ia) R.sub.1 aryl and heteroaryl rings as noted above.
[0081] As will be appreciated the difference between compounds of
Formula (I) and (II) lies in the R.sub.1 substitution. The
remaining substituent groups are the same and for purposes herein
applicable to all four formulas unless otherwise indicated.
[0082] Suitably, R.sub.4 and R.sub.14 are each independently
selected from hydrogen, optionally substituted C.sub.1-4 alkyl,
optionally substituted C.sub.3-7cycloalkyl, optionally substituted
C.sub.3-7cycloalkylC.sub.1-4 alkyl, optionally substituted aryl or
optionally substituted aryl-C.sub.1-4 alkyl, or R.sub.4 and
R.sub.14 together with the nitrogen to which they are attached may
form an optionally substituted heterocyclic ring of 4 to 7 members
which ring optionally contains an additional heteroatom selected
from oxygen, sulfur or NR.sub.9.
[0083] The C.sub.1-4 alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-4 alkyl, aryl and aryl-C.sub.1-4 alkyl
moieties may be optionally substituted, one or more times,
preferably 1 to 4 times independently by halogen, such as fluorine,
chlorine, bromine or iodine; hydroxy; hydroxy substituted
C.sub.1-10alkyl; C.sub.1-10 alkoxy, such as methoxy or ethoxy;
halosubstituted C.sub.1-10 alkoxy; S(O).sub.m alkyl, such as methyl
thio, methylsulfinyl or methyl sulfonyl; aldehydes (--C(O)), or a
ketone, such as --C(O)R.sub.6, such as C(O)C.sub.1-10alkyl or
C(O)aryl; amides, such as C(O)NR.sub.4'R.sub.14', or
NR.sub.4'C(O)C.sub.1-10alkyl, or NR.sub.4'C(O)aryl;
NR.sub.4'R.sub.14', wherein R.sub.4' and R.sub.14', are each
independently hydrogen or C.sub.1-4 alkyl, or wherein the
R.sub.4'R.sub.14' can cyclize together with the nitrogen to which
they are attached to form a 5 to 7 membered ring which optionally
contains an additional heteroatom selected from O/N/S; cyano,
nitro, C.sub.1-10 alkyl, C.sub.3-7cycloalkyl, or
C.sub.3-7cycloalkyl C.sub.1-10 alkyl group, such as methyl, ethyl,
propyl, isopropyl, t-butyl, etc. or cyclopropyl methyl;
halosubstituted C.sub.1-10 allyl, such CF.sub.2CF.sub.2H,
CH.sub.2CF.sub.3, or CF.sub.3; an optionally substituted aryl, such
as phenyl, or an optionally substituted arylalkyl, such as benzyl
or phenethyl, wherein these aryl containing moieties may also be
substituted one to two times by halogen; hydroxy; hydroxy
substituted allyl; C.sub.1-10 alkoxy; S(O)malkyl; amino, mono &
di-substituted C.sub.1-4 alkyl amino, such as in the
NR.sub.4'R.sub.14' group; C.sub.1-4 alkyl, or CF.sub.3.
[0084] When R.sub.4 and R.sub.14 together with the nitrogen cyclize
to form a ring, suitably, such rings include, but are not limited
to pyrrolidine, piperidine, piperazine, morpholine, and
thiomorpholine (including oxidizing the sulfur). The ring may be
optional substituted, one or more times, preferably 1 to 4 times,
independently by halogen, such as fluorine, chlorine, bromine or
iodine; hydroxy; hydroxy substituted C.sub.1-10alkyl; C.sub.1-10
alkoxy, such as methoxy or ethoxy; halosubstituted C.sub.1-10
alkoxy; S(O).sub.m alkyl, such as methyl thio, methylsulfinyl or
methyl sulfonyl; a ketone on the cyclized ring (--C(O)), or a
ketone or aldehyde off the ring (--C(O)R.sub.6), such as
C(O)C.sub.1-10 alkyl or C(O) aryl; NR.sub.4',R.sub.14', wherein
R.sub.4' and R.sub.14' are each independently hydrogen or C.sub.1-4
alkyl; C.sub.1-10 alkyl, C.sub.3-7cycloalkyl, or
C.sub.3-7cycloalkyl C.sub.1-10 alkyl group, such as methyl, ethyl,
propyl, isopropyl, t-butyl, etc. or cyclopropyl methyl;
halosubstituted C.sub.1-10 alkyl, such CF.sub.2CF.sub.2H,
CH.sub.2CF.sub.3, or CF.sub.3; an optionally substituted aryl, such
as phenyl, or an optionally substituted arylalkyl, such as benzyl
or phenethyl, wherein these aryl containing moieties may also be
substituted one to two times by halogen; hydroxy; hydroxy
substituted alkyl; C.sub.1-10 alkoxy; S(O).sub.malkyl; amino, mono
& di-substituted C.sub.1-4 alkyl amino, such as in the
NR.sub.4'R.sub.14' group; C.sub.1-4 alkyl, or CF.sub.3.
[0085] Suitably, R.sub.5 is hydrogen, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl or NR.sub.4R.sub.14, excluding the
moieties SR.sub.5 being SNR.sub.4R.sub.14, S(O).sub.2R.sub.5 being
SO.sub.2H and S(O)R.sub.5 being SOH.
[0086] Suitably, R.sub.6 is hydrogen, C.sub.1-10 alkyl, C.sub.3-7
cycloalkyl, heterocyclyl, heterocyclyl C.sub.1-10alkyl, aryl,
arylC.sub.1-10 alkyl, heteroaryl or heteroarylC.sub.1-10 allyl,
wherein these moieties may be optionally substituted.
[0087] Suitably, R.sub.7 is C.sub.1-6alkyl, aryl,
arylC.sub.1-6alkyl, heterocyclic, heterocyclylC.sub.1-6 alkyl,
heteroaryl, or heteroarylC.sub.1-6alkyl; and wherein each of these
moieties may be optionally substituted.
[0088] Suitably, R.sub.8 is hydrogen, C.sub.1-4 alkyl,
halo-substituted C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.3-7 cycloalkyl, C.sub.5-7 cycloalkenyl, aryl,
arylC.sub.1-4 alkyl, heteroaryl, heteroarylC.sub.1-4 alkyl,
heterocyclyl, heterocyclylC.sub.1-4 alkyl,
(CR.sub.10R.sub.20).sub.tOR.sub.7,
(CR.sub.10R.sub.20).sub.tS(O).sub.mR.sub.7,
(CR.sub.10R.sub.20).sub.tNHS(O).sub.2R.sub.7, or
(CR.sub.10R.sub.20).sub.tNR.sub.4R.sub.14; and wherein the
cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaryl
alkyl, heterocyclic and heterocyclic alkyl moieties may be
optionally substituted.
[0089] Suitably, t is an integer having a value of 1 to 3.
[0090] Suitably, R.sub.9 is hydrogen, C(Z)R.sub.6, optionally
substituted C.sub.1-10 alkyl, optionally substituted aryl or
optionally substituted aryl-C.sub.1-4 alkyl.
[0091] Suitably, R.sub.10 and R.sub.20 are independently selected
from hydrogen or a C.sub.1-4 alkyl.
[0092] Suitably, R.sub.11 is C.sub.1-4 alkyl, halo-substituted
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-7
cycloalkyl, C.sub.5-7 cycloalkenyl, aryl, arylC.sub.1-4 alkyl,
heteroaryl, heteroarylC.sub.1-4 alkyl, heterocyclyl,
heterocyclylC.sub.1-4 alkyl, (CR.sub.10R.sub.20).sub.tOR.sub.7,
(CR.sub.10R.sub.20).sub.tS(O).sub.mR.sub.7,
(CR.sub.10R.sub.20).sub.tNHS(O).sub.2R.sub.7, or
(CR.sub.10R.sub.20).sub.vNR.sub.4R.sub.14; and wherein the aryl,
arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclyl, and
heterocyclylalkyl moieties may be optionally substituted.
[0093] Suitably m is 0 or an integer having a value of 1 or 2.
[0094] Suitably, R.sub.8 is an optionally substituted C.sub.1-10
alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-10alkyl,
aryl, arylC.sub.1-10 alkyl, heteroarylC.sub.1-10alkyl, or
heterocyclylC.sub.1-10 alkyl moiety, which moieties are optionally
substituted one or more times, preferably 1 to 4 times,
independently by C.sub.1-10 alkyl, halo-substituted C.sub.1-10
alkyl, C.sub.2-10 alkenyl, C.sub.2-10alkynyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-10 alkyl, C.sub.5-7cycloalkenyl,
C.sub.5-7cycloalkenylC.sub.1-10alkyl, halogen, cyano, nitro,
(CR.sub.10R.sub.20).sub.nOR.sub.6, (CR.sub.10R.sub.20).sub.nSH,
(CR.sub.10R.sub.20).sub.nS(O).sub.mR.sub.7,
(CR.sub.10R.sub.20).sub.nNHS(O).sub.2R.sub.7,
(CR.sub.10OR.sub.20).sub.nNR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nCN,
(CR.sub.10R.sub.20).sub.nS(O).sub.2NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nC(Z)R.sub.6,
(CR.sub.10R.sub.20).sub.nOC(Z)R.sub.6,
(CR.sub.10R.sub.20).sub.nC(Z)OR.sub.6,
(CR.sub.10R.sub.20).sub.nC(Z)NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nNR.sub.10C(Z)R.sub.6,
(CR.sub.10R.sub.20).sub.nNR.sub.10C(--NR.sub.10)NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nOC(Z)NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nNR.sub.10C(Z)NR.sub.4R.sub.14, or
(CR.sub.10R.sub.20).sub.nNR.sub.10C(Z)OR.sub.7.
[0095] Preferably the optional substituents are independently
selected from halogen, alkyl, hydroxy, alkoxy, cyano, nitro, amino,
or halosubstituted alkyl. More preferably, halogen, or alkyl.
[0096] Preferably, R.sub.3 is an optionally substituted C.sub.1-10
alkyl, C.sub.3-7cycloalkyl, C.sub.3-7cycloalkylalkyl, or aryl. More
preferably, R.sub.3 is an optionally substituted C.sub.1-10 alkyl,
or aryl.
[0097] Preferably, when R.sub.3 is an aryl moiety, it is a phenyl
ring, optionally substituted one or more times by halogen,
C.sub.1-4 alkyl, or halo-substituted-C.sub.1-4 alkyl. More
preferably, the phenyl ring is substituted in the 2, 4, or
6-position, or di-substituted in the 2,4-position, such as
2-fluoro, 4-fluoro, 2,4-difluoro, or 2-methyl-4-fluoro; or
tri-substituted in the 2,4,6-position, such as 2,4,6-trifluoro.
[0098] Suitably, n is 0, or an integer having a value of 1 to
10.
[0099] Suitably, X is R.sub.2, OR.sub.2, S(O).sub.mR.sub.2,
(CH.sub.2).sub.nN(R.sub.10)S(O)mR.sub.2,
(CH.sub.2).sub.nN(R.sub.10)C(O)R.sub.2,
(CH.sub.2).sub.nNR.sub.4R.sub.14, or
(CH.sub.2).sub.nN(R.sub.2).sub.2. Preferably X is R.sub.2,
OR.sub.2, (CH.sub.2).sub.nNR.sub.4R.sub.14, or
(CH.sub.2).sub.nN(R.sub.2).sub.2. Preferably, when X is R.sub.2,
then R.sub.2 is the moiety
X.sub.1(CR.sub.10R.sub.20).sub.qC(A.sub.1)(A.sub.2)(A.sub.3), or
C(A.sub.1)(A.sub.2)(A.sub.3).
[0100] Suitably, R.sub.2 is independently selected from hydrogen,
optionally substituted C.sub.1-10 alkyl, optionally substituted
C.sub.3-7 cycloalkyl, optionally substituted
C.sub.3-7cycloalkylalkyl, optionally substituted aryl, optionally
substituted arylC.sub.1-10alkyl, optionally substituted heteroaryl,
optionally substituted heteroarylC.sub.1-10 alkyl, optionally
substituted heterocyclic, optionally substituted
heterocyclylC.sub.1-10alkyl moiety, or R.sub.2 is the moiety
X.sub.1(CR.sub.10R.sub.20).sub.qC(A.sub.1)(A.sub.2)(A.sub.3), or
C(A.sub.1)(A.sub.2)(A.sub.3).
[0101] The R.sub.2 moieties, excluding hydrogen, may be optionally
substituted one or more times, preferably 1 to 4 times,
independently by C.sub.1-10 alkyl, halo-substituted C.sub.1-10
alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-7
cycloalkyl, C.sub.3-7cycloalkylC.sub.1-10alkyl,
C.sub.5-7cycloalkenyl, C.sub.5-7 cycloalkenyl C.sub.1-10 alkyl,
halogen, --C(O), cyano, nitro, (CR.sub.10R.sub.20).sub.nOR.sub.6,
(CR.sub.10R.sub.20).sub.nSH,
(CR.sub.10R.sub.20).sub.nS(O).sub.mR.sub.7,
(CR.sub.10R.sub.20).sub.nNR.sub.10S(O).sub.2R.sub.7,
(CR.sub.10R.sub.20).sub.nNR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nCN,
(CR.sub.10R.sub.20).sub.nS(O).sub.2NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nC(Z)R.sub.6,
(CR.sub.10R.sub.20).sub.nOC(Z)R.sub.6,
(CR.sub.10R.sub.20).sub.nC(Z)OR.sub.6,
(CR.sub.10R.sub.20).sub.nC(Z)NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nNR.sub.10C(Z)R.sub.6,
(CR.sub.10R.sub.20).sub.nNR.sub.10C(.dbd.NR.sub.10)NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nC(.dbd.NOR.sub.6)NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nOC(Z)N4R.sub.14,
(CR.sub.10R.sub.20).sub.nNR.sub.10C(Z)NR.sub.4R.sub.14, or
(CR.sub.10R.sub.20).sub.nNR.sub.10C(Z)OR.sub.7.
[0102] Suitably X.sub.1 is N(R.sub.10), O, S(O).sub.m, or
CR.sub.10R.sub.20. More preferably, X.sub.1 is N(R.sub.10), or
O.
[0103] Suitably, q is 0 or an integer having a value of 1 to
10.
[0104] Suitably, A.sub.1 is an optionally substituted C.sub.1-10
alkyl.
[0105] Suitably, A.sub.2 is an optionally substituted C.sub.1-10
alkyl.
[0106] Suitably, A.sub.3 is hydrogen or is an optionally
substituted C.sub.1-10 alkyl.
[0107] The A.sub.1, A.sub.2, and A.sub.3 C.sub.1-10 alkyl moieties
may optionally substituted one or more times, independently,
preferably from 1 to 4 times, with halogen, such as chlorine,
fluorine, bromine, or iodine; halo-substituted C.sub.1-10 alkyl,
such as CF.sub.3, or CHF.sub.2CF.sub.3; C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-7 cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-10alkyl, C.sub.5-7cycloalkenyl,
C.sub.5-7 cycloalkenylC.sub.1-10alkyl,
(CR.sub.10R.sub.20).sub.nOR.sub.6, (CR.sub.10R.sub.20).sub.nSH,
(CR.sub.10R.sub.20).sub.nS(O).sub.mR.sub.7,
(CR.sub.10R.sub.20).sub.nNHS(O).sub.2R.sub.7,
(CR.sub.10R.sub.20).sub.nNR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nCN,
(CR.sub.10R.sub.20).sub.nS(O).sub.2NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nC(Z)R.sub.6,
(CR.sub.10R.sub.20).sub.nOC(Z)R.sub.6,
(CR.sub.10R.sub.20).sub.nC(Z)OR.sub.6,
(CR.sub.10R.sub.20).sub.nC(Z)NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nNR.sub.10C(Z)R.sub.6,
(CR.sub.10R.sub.20).sub.nNR.sub.10C(.dbd.NR.sub.10)NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nOC(Z)NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nNR.sub.10C(Z)NR.sub.4R.sub.14, or
(CR.sub.10R.sub.20).sub.nNR.sub.10C(Z)OR.sub.7.
[0108] Preferably, one or more of A.sub.1 to A.sub.3 is substituted
with (CR.sub.10R.sub.20).sub.nOR.sub.6. More preferably, R.sub.6 is
hydrogen.
[0109] A preferred C(A.sub.1)(A.sub.2)(A.sub.3) grouping is
CH(CH.sub.2OH).sub.2, or C(CH.sub.3)(CH.sub.2OH).sub.2,
X.sub.1(CR.sub.10R.sub.20).sub.qCH(CH.sub.2OH).sub.2, or
X.sub.1(CR.sub.10R.sub.20).sub.qC(CH.sub.3)(CH.sub.2OH).sub.2.
X.sub.1 is preferably oxygen or nitrogen.
[0110] As used herein, "optionally substituted" unless specifically
defined shall mean such groups as halogen, such as fluorine,
chlorine, bromine or iodine; hydroxy; hydroxy substituted
C.sub.1-10 alkyl; C.sub.1-10 alkoxy, such as methoxy or ethoxy;
halosubstituted C.sub.1-10 alkoxy; S(O)m alkyl, such as methyl
thio, methylsulfinyl or methyl sulfonyl; --C(O);
NR.sub.4',R.sub.14', wherein R.sub.4' and R.sub.14', are each
independently hydrogen or C.sub.1-4 alkyl, such as amino or mono or
-disubstituted C.sub.1-4 alkyl or wherein the R.sub.4'R.sub.14' can
cyclize together with the nitrogen to which they are attached to
form a 5 to 7 membered ring which optionally contains an additional
heteroatom selected from O/N/S; C.sub.1-10 alkyl,
C.sub.3-7cycloalkyl, or C.sub.3-7cycloalkyl C.sub.1-10 alkyl group,
such as methyl, ethyl, propyl, isopropyl, t-butyl, etc. or
cyclopropyl methyl; halosubstituted C.sub.1-10 allyl, such
CF.sub.2CF.sub.2H, or CF.sub.3; an optionally substituted aryl,
such as phenyl, or an optionally substituted arylalkyl, such as
benzyl or phenethyl, wherein these aryl containing moieties may
also be substituted one to two times by halogen; hydroxy; hydroxy
substituted alkyl; C.sub.1-10 alkoxy; S(O).sub.malkyl; amino, mono
& di-substituted C.sub.1-4 alkyl amino, such as in the
NR.sub.4R.sub.14 group; C.sub.1-4 alkyl, or CF.sub.3.
[0111] Suitable pharmaceutically acceptable salts are well known to
those skilled in the art and include basic salts of inorganic and
organic acids, such as hydrochloric acid, hydrobromic acid,
sulphuric acid, phosphoric acid, methane sulphonic acid, ethane
sulphonic acid, acetic acid, malic acid, tartaric acid, citric
acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic
acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic
acid.
[0112] In addition, pharmaceutically acceptable salts of compounds
of Formula (I) may also be formed with a pharmaceutically
acceptable cation, for instance, if a substituent group comprises a
carboxy moiety. Suitable pharmaceutically acceptable cations are
well known to those skilled in the art and include alkaline,
alkaline earth, ammonium and quaternary ammonium cations.
[0113] The term "halo" or "halogens" is used herein to mean the
halogens, chloro, fluoro, bromo and iodo.
[0114] The term "C.sub.1-10alkyl" or "alkyl" or "alkyl.sub.1-10" is
used herein to mean both straight and branched chain radicals of 1
to 10 carbon atoms, unless the chain length is otherwise limited,
including, but not limited to, methyl, ethyl, n-propyl, iso-propyl,
n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the
like.
[0115] The term "cycloalkyl" is used herein to mean cyclic
radicals, preferably of 3 to 8 carbons, including but not limited
to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
[0116] The term "cycloalkenyl" is used herein to mean cyclic
radicals, preferably of 5 to 8 carbons, which have at least one
bond including but not limited to cyclopentenyl, cyclohexenyl, and
the like.
[0117] The term "alkenyl" is used herein at all occurrences to mean
straight or branched chain radical of 2-10 carbon atoms, unless the
chain length is limited thereto, including, but not limited to
ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,
2-butenyl and the like.
[0118] The term "aryl" is used herein to mean phenyl and
naphthyl.
[0119] The term "heteroaryl" (on its own or in any combination,
such as "heteroaryloxy", or "heteroaryl alkyl") is used herein to
mean a 5-10 membered aromatic ring system in which one or more
rings contain one or more heteroatoms selected from the group
consisting of N, O or S, such as, but not limited, to pyrrole,
pyrazole, furan, pyran, thiophene, quinoline, isoquinoline,
quinazolinyl, pyridine, pyrimidine, pyridazine, pyrazine, uracil,
oxadiazole, oxazole, isoxazole, oxathiadiazole, thiazole,
isothiazole, thiadiazole, tetrazole, triazole, indazole, imidazole,
or benzimidazole.
[0120] The term "heterocyclic" (on its own or in any combination,
such as "heterocyclylalkyl") is used herein to mean a saturated or
partially unsaturated 4-10 membered ring system in which one or
more rings contain one or more heteroatoms selected from the group
consisting of N, O, S, or S(O)m, and m is 0 or an integer having a
value of 1 or 2; such as, but not limited to, the saturated or
partially saturated versions of the heteroaryl moieties as defined
above, such as tetrahydropyrrole, tetrahydropyran, tetrahydrofuran,
tetrahydrothiophene (including oxidized versions of the sulfur
moiety), pyrrolidine, piperidine, piperazine, morpholine,
thiomorpholine (including oxidized versions of the sulfur moiety),
or imidazolidine.
[0121] The term "aralkyl" or "heteroarylalkyl" or
"heterocyclicalkyl" is used herein to mean C.sub.1-4 alkyl as
defined above attached to an aryl, heteroaryl or heterocyclic
moiety as also defined herein unless otherwise indicate.
[0122] The term "sulfinyl" is used herein to mean the oxide S(O) of
the corresponding sulfide, the term "thio" refers to the sulfide,
and the term "sulfonyl" refers to the fully oxidized S(O).sub.2
moiety.
[0123] The term "aroyl" is used herein to mean C(O)Ar, wherein Ar
is as phenyl, naphthyl, or aryl alkyl derivative such as defined
above, such group include but are not limited to benzyl and
phenethyl.
[0124] The term "alkanoyl" is used herein to mean C(O)C.sub.1-10
alkyl wherein the alkyl is as defined above.
[0125] It is recognized that the compounds of the present invention
may exist as stereoisomers, regioisomers, or diastereiomers. These
compounds may contain one or more asymmetric carbon atoms and may
exist in racemic and optically active forms. All of these
individual compounds, isomers, and mixtures thereof are included
within the scope of the present invention.
[0126] Exemplified compounds of the compounds of this invention
include the racemates, or optically active forms of the compounds
of the working examples herein, and pharmaceutically acceptable
salts thereof.
Methods of Manufacture
[0127] The compounds of Formula (I), (Ia), (II) and (IIa) may be
obtained by applying synthetic procedures, described herein. The
synthesis provided for is applicable to producing compounds of
Formula (I), (Ia), (II) and (IIa) having a variety of different
R.sub.1, R.sub.2, Y, X, and R.sub.3 groups which are reacted,
employing optional substituents which are suitably protected, to
achieve compatibility with the reactions outlined herein.
Subsequent deprotection, in those cases, then affords compounds of
the nature generally disclosed. While a particular formula with
particular substituent groups is shown herein, the synthesis is
applicable to all formulas and all substituent groups herein.
[0128] Once the nucleus has been established, further compounds of
Formula (I), (Ia), (II) and (IIa) may be prepared by applying
standard techniques for functional group interconversion, well
known in the art. For instance: C(O)NR.sub.4R.sub.14 from
CO.sub.2CH.sub.3 by heating with HNR.sub.4R.sub.14 in CH.sub.3OH
with or without catalytic or stoichiometric metal cyanide or
Aluminum trimethyl, e.g. NaCN; OC(O)R.sub.3 from OH with e.g.,
ClC(O)R.sub.6 in bases such as triethylamine and pyridine;
NR.sub.10--C(S)NR.sub.4R.sub.14 from NHR.sub.10 with an
alkylisothiocyanate, or thiocyanic acid and ClC(S)NR.sub.4R.sub.14;
NR.sub.10C(O)OR.sub.6 from NHR.sub.10 with an alkyl or aryl
chloroformate; NR.sub.10C(O)NR.sub.4H from NHR.sub.10 by treatment
with an isocyanate, e.g. R.sub.4N.dbd.C.dbd.O;
NR.sub.10--C(O)R.sub.6 from NHR.sub.10 by treatment with
Cl--C(O)R.sub.6 in pyridine; C(.dbd.NR.sub.10)NR.sub.4R.sub.14 from
C(NR.sub.4R.sub.14)S with H.sub.3NR.sub.10.sup.+OAc-- by heating in
alcohol; C(NR.sub.4R.sub.14)SR.sub.6 from C(S)NR.sub.4R.sub.14 with
R.sub.6--I in an inert solvent, e.g. acetone;
NR.sub.10SO.sub.2R.sub.7 from NHR.sub.10 by treatment with
ClSO.sub.2R.sub.7 by heating in bases such as pyridine;
NR.sub.10C(S)R.sub.6 from NR.sub.10C(O)R.sub.6 by treatment with
Lawesson's reagent
[2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide];
NR.sub.10SO.sub.2CF.sub.3 from NHR.sub.10 with triflic anhydride
and base wherein R.sub.3, R.sub.6, R.sub.10, R.sub.4 and R.sub.14
are as defined in Formula (I) herein.
[0129] Precursors of the groups R.sub.1, R.sub.2 and R.sub.3, can
be other R.sub.1, R.sub.2 and R.sub.3, etc. groups that may be
interconverted by applying standard techniques for functional group
interconversion. For example wherein a moiety is a halo substituted
C.sub.1-10 alkyl can be converted to the corresponding C.sub.1-10
alkylN.sub.3 derivative by reacting with a suitable azide salt, and
thereafter if desired can be reduced to the corresponding
C.sub.1-10alkylNH.sub.2 compound, which in turn can be reacted with
R.sub.7S(0).sub.2X wherein X is halo (e.g., chloro) to yield the
corresponding C.sub.1-10alkylNHS(0).sub.2R.sub.7 compound.
[0130] Alternatively wherein the moiety is a halo-substituted
C.sub.1-10-alkyl it can be reacted with an amine R.sub.4R.sub.14NH
to yield the corresponding C.sub.1-10-alkylNR.sub.4R.sub.14
compound, or can be reacted with an alkali metal salt of R.sub.7SH
to yield the corresponding C.sub.1-10alkylSR.sub.7 compound.
[0131] As noted above, it may be desirable during the synthesis of
the compounds of this invention, to derivatize reactive functional
groups in the molecule undergoing reaction so as to avoid unwanted
side reactions. Functional groups such as hydroxy, amino, an acid
groups typically are protected with suitable groups that can be
readily removed when desired. Suitable common protecting groups for
use with hydroxyl groups and nitrogen groups are well known in the
art and described in many references, for instance, Protecting
Groups in Organic Synthesis, Greene et al., John Wiley & Sons,
New York, N.Y., (2nd edition, 1991 or the earlier 1981 version).
Suitable examples of hydroxyl protecting groups include ether
forming groups such as benzyl, and aryl groups such as
tert-butoxycarbonyl (Boc), silyl ethers, such as t-butyldimethyl or
t-butyldiphenyl, and alkyl ethers, such as methyl connected by an
alkyl chain of variable link, (CR.sub.10R.sub.20).sub.n. Amino
protecting groups may include benzyl, aryl such as acetyl and
trialkylsilyl groups. Carboxylic acid groups are typically
protected by conversion to an ester that can easily be hydrolyzed,
for example, trichloethyl, tert-butyl, benzyl and the like.
[0132] Pharmaceutically acid addition salts of compounds of Formula
(I), (Ia), (II) and (IIa) may be obtained in known manner, for
example by treatment thereof with an appropriate amount of acid in
the presence of a suitable solvent.
[0133] An illustration of the preparation of compounds of the
present invention is shown in the scheme below. For purposes
herein, the compounds in Schemes I and II are shown with an
S-methyl, or S(O).sub.2-methyl group which is deemed representative
of the S(O)m-Rg group, as described in the formulas below.
[0134] The starting material 1-Scheme I may be obtained from the
commercially available 4,6-dihydroxy-2-methylmercaptopyrimidine by
known literature procedures, such as those noted in Santilli et
al., J. Heterocycl. Chem. (1971), 445-53, wherein POCl.sub.3 and
DMF are used.
[0135] The intermediate 2-Scheme I was produced by two different
routes. In the first route, coupling of dichloro aldehyde 1-Scheme
I with aryl amines in the presence of NaH in DMSO (Santilli et al.,
J. Heterocycl. Chem. (1971),445-53) afforded the desired compound
2-Scheme I along with imine 13-Scheme I. The imine was converted to
aldehyde 2-Scheme I by treatment with aqueous HCl in THF.
Conversion of 1-Scheme 1 to 2-Scheme I may also be achieved using
triethylamine and the desired amine in chloroform at room
temperature for 10 minutes. The reaction was very effective for a
range of alkyl amines (78-95% yield). For aryl amines, elevated
temperatures (reflux) and longer reaction time (24 hours) were
necessary for reaction completion. Use of the base could be omitted
when 3 or more equivalent of amine were used. Other suitable bases,
include but are not limited to pyridine, diisopropyl ethylamine or
pyrrolidine, which may also be used in an appropriate organic
solvent, including but not limited to THF, diethyl ether or
dioxane.
[0136] In the second route, the nitrile 9-Scheme I was prepared in
three steps from the aldehyde 1-Scheme I (Santilli et al., J.
Heterocycl. Chem. (1971), 445-53). Coupling of dichloro nitrile
9-Scheme I with aryl amines in the presence of NaH in DMSO afforded
the desired compound 10-Scheme I. Other suitable bases such as
pyridine, diisopropyl ethylamine, or sodium may also be used in an
appropriate organic solvent such as THF, DMF or dioxane. Production
and use of the nitrile 9-Scheme-I may also be found in
PCT/US01/06688, filed Mar. 2, 2001 whose disclosure is incorporated
herein by reference in its entirety.
[0137] The nitrile 10-Scheme I was easily reduced with DIBAL in
dichloromethane at room temperature (Boschelliat et al., J. Med.
Chem. (1998), 4365-4377) to afford desired 2-Scheme I along with
the unsubstituted imine 13-Scheme I (R.dbd.H). The latter was
hydrolyzed to 2-Scheme I in situ with HCl. Other reduction agents,
such as lithium aluminum hydride, Raney Ni, or SnCl.sub.2, may be
utilized in an appropriate organic solvent such as THF, diethyl
ether or dioxane to perform the conversion of 10-Scheme 1 to
2-Scheme I.
[0138] Aldehyde 2-Scheme I was coupled to arylboronic acids under
Suzuki coupling conditions, using a palladium catalyst, such as
tetrakis(triphenylphosphine) palladium(0), to afford good to
excellent yields of 3-Scheme I. Alternatively, the bi-aryl coupling
reaction of 2-Scheme I may be performed using aryl or heteroaryl
organozinc, organocopper, organotin, or other organometallic
reagents known to afford bi-aryl cross-coupling products such as
3-Scheme I [see for example Solberg, J.; Undheim, K. Acta Chemica
Scandinavia 1989, 62-68]. Displacement of the chlorine in 2-Scheme
I may also be achieved with nitrogen nucleophiles [for related
aminations see U.S. Pat. Nos. 3,631,045 and 3,910,913], sulphur
nucleophiles, [see Tumkevicius, S. Liebigs Ann. 1995, 1703-[705],
oxygen nucleophiles, or alkyl nucleophiles.
[0139] 3-Scheme I was then converted to pyridopyrimidinone 5-Scheme
I by one of three procedures. The first procedure used the Wittig
reaction, as modified by Horner-Emmons, converting 3-Scheme 1 to
4-Scheme I. In this reaction, the aldehyde 3-Scheme I was treated
with a suitable phosphorus ylide, such as triethyl phosphonoacetate
or methyl diethylphosphonoacetate, to give the olefin intermediate
4-Scheme I. The reaction was performed under reflux, in a suitable
base, such as sodium hydride, sodium methoxide, or sodium
hydroxide, and in a suitable organic solvent such as diethyl ether,
dioxane or ethanol. The conversion of 3-Scheme 1 to 4-Scheme I may
also be performed using the Peterson olefination reaction, or an
aldol-based olefination reaction that utilizes acetic anhydride,
malonic acid and its monoalkyl esters, or ethyl acetate.
[0140] Heating of 4-Scheme I in toluene at 220.degree. C. in a
sealed tube (Matyus et al. Heterocycles (1985), 2057-64), followed
by solvent removal, afforded the desired product 5-Scheme I. This
reaction may be run in the presence of a suitable base, such as DBU
or diisopropylethyl amine, pyridine, lithium
bi(trimethylsilyl)amide, or LDA and in an appropriate organic
solvent such as an organic hydrocarbon, cresol, dioxane, DMF,
pyridine, or xylene.
[0141] The second procedure used a Horner-Emmons reaction with
Still modification (Still et al., Tetrahedron Lett. (1983), 4405-8;
Jacobsen et al., Tetrahedron (1994), 4323-34) to produce a mixture
of desired product 5-Scheme I and trans isomer 4-Scheme I. Trans
isomer 4-Scheme I was isolated and converted to the desired product
5-Scheme I by heating to 220.degree. C. in toluene in a sealed tube
as described above.
[0142] The third procedure involved acetylation of 3-Scheme I,
followed by the intramolecular aldol condensation, promoted by an
acetylating agent (such as acetic anhydride, acetyl chloride, or a
ketene) and a suitable base (such as pyridine, diispropyl
ethylamine, or pyrrolidine), to generate 5-Scheme I in a very good
yield. The third procedure is optimal when R.sub.3 is an optionally
substituted aryl, or heteroaryl. When R.sub.3 is an arylalkyl, or
heteroarylalkyl substituent it is not clear that the reaction will
form the key intermediate of Formula (VII), as shown below
(3a-Scheme II), which may optionally be isolated, as shown in
Scheme II below. Compounds of Formula (VII) are preferably not
isolated but further reacted with a base or with heat to cyclize
into 5-Scheme-I. The first and second procedures should be utilized
for all other R.sub.3 moieties.
[0143] Oxidation of the sulfide 5-Scheme I to the sulfone 6-Scheme
I was performed using meta-chloroperoxybenzoic acid (mCPBA) in high
yield and purity. Suitable oxidation methods for use herein include
use of one or two equivalents of meta-chloroperoxybenzoic acid
(mCPBA) or Oxone.RTM. afford either the sulfoxides or sulfones.
Oxidation of the sulfides to sulfoxides or sulfones can also be
effected by OSO.sub.4 and catalytic tertiary amine N-oxide,
hydrogen peroxide, other peracids, oxygen, ozone, organic
peroxides, potassium and zinc permanganate, potassium persulfate,
and sodium hypochlorite.
[0144] Displacements of the sulfones 6-Scheme I to the final
products 7-Scheme-I were usually done with an excess of amine in
N-methylpyrrolidine (Barvian et al., J. Med. Chem. (2000),
4606-4616). A wide range of primary amines underwent this reaction
with excellent yields. In some cases (in O-displacement or
sulfonamide formation) an anion of the nucleophile was prepared
with base (usually sodium hydride) in dimethylformamide and then
added to the sulfone. Yields for these reactions were usually
lower. Similarly related sulfones and sulfoxides of the compounds
herein wherein X is SO-alkyl or SO.sub.2-alkyl have been reported
in the literature to be displaced by a wide variety of
nucleophiles. Thus the analogs of the compounds herein wherein X is
an alkyl sulfone or sulfoxide may be displaced by primary and
secondary alkylamines without additional base catalysis, preferably
in a polar aprotic solvent, such as but not limited to,
N-methylpyrrolidin-2-one (NMP), and at varying temperatures
depending upon the nucleophilicity of the amine. For instance
displacement of the sulfone of analogs of Formula (I) compounds
with ethanolamine, in NMP, occurred in 30 min. at 65.degree. C.,
while a more hindered amine such as
tris(hydroxymethyl)-aminomethane may require elevated temperatures
and extended reaction times (80.degree. C. over a 24 hour reaction
time). The sulfone may also be displaced with a substituted
arylamine, or heteroarylamine at elevated temperatures, sometimes
requiring formation of the aryl or heteroarylamine anion with
sodium hydride, or other suitable base, in DMSO. In addition, the
sulfoxide analogs of Formula (I) compounds may be readily displaced
with aluminum salts of aryl or heteroaryl amines as previously
described in the patent literature (WO 99/32121). Likewise, sulfone
and sulfoxide analogs of Formula (I) and (Ia) may be displaced with
aryl or heteroaryl or alkyl thiols or alkyl or aryl or heteroaryl
alcohols. For instance analogs of (I) containing sulfones as the X
substituents may be displaced with sodium alkoxide in the alcohol,
or alternatively reactive alkoxide or phenoxide nucleophiles may be
generated from the alcohol or phenol with a suitable base such as
sodium, NaH or sodium bistrimethylsilyl amide in a polar aprotic
solvent such as DMSO, or run as a neat reaction. Similarly sulfones
related to Formula (I) and (Ia), for instance, may be displaced
with carbon nucleophiles such as aryl or alkyl Grignard reagents or
related organometallics such as organo lithium, zinc, tin or boron.
These reactions may, in some cases, require transition metal
catalysis such as with Pd or Ni catalysts. Displacement of related
2-pyrimidine sulfones with cyanide, malonate anions, unactivated
enolates, or heterocyclic C nucleophiles such as 1-methylimidazole
anion, by the generation of the anion with NaH or other suitable
base in THF also has precedent (see for example, Chem Pharm Bull.
1987, 4972-4976.). For example, analogs of Formula (I) and (Ia)
compounds wherein X is an alkyl sulfone may be displaced with the
anion of 1-methyl imidazole, generated by treatment of 1-methyl
imidazole with n-butyl lithium in a solvent such as THF at
temperatures of about -70.degree., to afford the C-alkylated
product substituted on the imidazole C-2.
[0145] For the purposes herein, compounds of Formulas (I), (Ia),
(II) and (IIa) wherein X is R.sub.2 or NHS(O).sub.mR.sub.2 may be
obtained from compounds of 6-Scheme I by displacement of the
sulfone using the appropriate "X" functionality as defined in
Formula (I) and (Ia). To obtain compounds of Formulas (I), (Ia),
(II) and (IIa) wherein X is S(O).sub.mR.sub.2 and R.sub.2 is other
than methyl, displacement of the sulfone on the corresponding
compound 6-Scheme I by thiol (R.sub.2SH) and then followed by
oxidation, if desired, with an appropriate oxidating agent, such as
MCPBA, or KMnO.sub.4. Suitable oxidation methods for use herein
include use of an oxidant such as one or two equivalents of
ineta-chloroperoxybenzoic acid or Oxone.RTM. to afford either the
sulfoxides or sulfones. Oxidation of the sulfides to sulfones may
also be effected by OSO.sub.4 and catalytic tertiary amine N-oxide.
Other methods for sulfide oxidation include the use of hydrogen
peroxide, other peracids, oxygen, ozone, organic peroxides,
potassium and zinc permanganate, potassium persulfate, and sodium
hypochlorite.
[0146] 8-Scheme I can be also prepared by heating the trans ester
4-Scheme I in alcohol in the presence of the corresponding sodium
alkoxide. The yield of this reaction was very high for primary
alcohols, but longer reaction times were required for secondary
alcohols. Sodium alkoxides may be easily prepared from
corresponding alcohol and base, such as sodium or sodium
hydride.
[0147] Reduction of trans ester 4-Scheme I with SMI.sub.2 gives the
reduced analogue 11-Scheme I. This reduction can be also done in
the presence of other reducing agents such as hydrogen gas, lithium
in liquid ammonia, magnesium or sodium borohydride in the
appropriate organic solvent such as THF, ethanol or diethyl
ether.
[0148] Cyclization of the ester 11-Scheme I can be done utilizing
sodium methoxide in methanol to give reduced analogue 12-Scheme I.
Other organic bases, such as sodium, sodium ethoxide or TEA can be
used in an appropriate organic solvent such as methanol, ethanol or
dioxane. The product 12-Scheme I can be also obtained by heating
ester 11-Scheme 1 to 150.degree. C. in an appropriate organic
solvent, such as toluene, xylene or isopropanol. ##STR3##
##STR4##
[0149] Additional procedures for producing similar intermediates to
those herein, which the skilled artisan may find may be found in WO
99/41253, now U.S. Pat. No. 6,200,977; U.S. Pat. No. 6,153,619;
U.S. Pat. No. 6,268,310; U.S. Pat. No. 5,468,751; U.S. Pat. No.
5,474,996; and EP 1 040 831.
[0150] An illustration of an alternative preparation of compounds
of Formula (VII) the present invention is shown in Scheme II below,
and described above. ##STR5##
[0151] Another aspect of the present invention are novel
intermediates of the formula (III) ##STR6## [0152] wherein [0153]
R.sub.1 is an aryl or heteroaryl ring, which ring is optionally
substituted; [0154] R.sub.3 is an C.sub.1-10 alkyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkylalkyl, aryl, arylC.sub.1-10 alkyl,
heteroaryl, heteroarylC.sub.1-10 alkyl, heterocyclic, or a
heterocyclylC.sub.1-10 alkyl moiety, which moieties are optionally
substituted; [0155] R.sub.12 is a C.sub.1-10 alkyl, aryl,
heteroaryl, or arylalkyl; [0156] m is 0 or an integer having a
value of 1 or 2; and [0157] Rg is a C.sub.1-4 alkyl.
[0158] Preferably, Rg is a C.sub.1-4 alkyl, and more preferably
methyl.
[0159] Preferably, m is 0 or an integer having a value of 1 or 2.
More preferably m is 0 or 2.
[0160] Preferably, R.sub.1 is an aryl moiety, more preferably a
phenyl ring, optionally substituted one or more times by halogen,
C.sub.1-4 alkyl, or halo-substituted-C.sub.1-4 alkyl. More
preferably, the phenyl ring is substituted in the 2, 4, or
6-positions, or di-substituted in the 2,4-positions, such as
2-fluoro, 4-fluoro, 2,4-difluoro, 2,4,6-trifluoro, or
2-methyl-4-fluoro.
[0161] Another aspect of the present invention are novel
intermediates of the formula (IIIa) ##STR7## [0162] wherein [0163]
R.sub.1 is the moiety YRa; [0164] Y is C(R.sub.b)(R.sub.d), C(O),
N(R.sub.d), N(R.sub.d)C(R.sub.c)(R.sub.d), oxygen,
OC(R.sub.c)(R.sub.d), S(O).sub.m, or S(O).sub.mC(R.sub.c)(R.sub.d);
[0165] R.sub.a is an aryl or heteroaryl ring, which ring is
optionally substituted; [0166] R.sub.b is hydrogen, C.sub.1-2
alkyl, NRC, hydroxy, thio, C.sub.1-2 alkoxy, S(O).sub.mC.sub.1-2
alkyl; [0167] R.sub.c is hydrogen or C.sub.1-2 alkyl; [0168]
R.sub.d is hydrogen or C.sub.1-2 alkyl; [0169] m is 0 or an integer
having a value of 1 or 2; and [0170] R.sub.3 is an C.sub.1-10
alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylalkyl, aryl,
arylC.sub.1-10 alkyl, heteroaryl, heteroarylC.sub.1-10 alkyl,
heterocyclic, or a heterocyclylC.sub.1-10 alkyl moiety, which
moieties are optionally substituted; [0171] R.sub.12 is a
C.sub.1-10 alkyl, aryl, heteroaryl, or arylalkyl; [0172] m is 0 or
an integer having a value of 1 or 2; and [0173] Rg is a C.sub.1-4
alkyl.
[0174] The substituents of compounds of Formula (III) and (IIIa),
and (IV) and (IVa) below follow those preferences of the final
compounds of Formula (I) or (II) herein, respectively.
[0175] Another aspect of the present invention are novel
intermediates of the formula (IV) ##STR8## [0176] wherein R.sub.1,
R.sub.3, R.sub.12, m and R.sub.g are as defined for Formula (III)
above.
[0177] Another aspect of the present invention are novel
intermediates of the formula (IVa) ##STR9## [0178] wherein R.sub.1,
R.sub.3, R.sub.12, m and R.sub.g are as defined for Formula (IIIa)
above.
[0179] Another aspect of the present invention are novel
intermediates of the formula ##STR10## [0180] wherein R.sub.1,
R.sub.3, R.sub.12, m and R.sub.g are as defined for Formula (III)
above.
[0181] Another aspect of the present invention are novel
intermediates of the formula ##STR11## [0182] wherein R.sub.1,
R.sub.3, R.sub.12, Rg and m are as defined for Formula (IIIa)
above.
[0183] Another aspect of the present invention are novel
intermediates of the formula ##STR12## [0184] wherein [0185]
R.sub.1 is a halogen, an optionally substituted aryl or an
optionally substituted heteroaryl ring; [0186] R.sub.3 is hydrogen,
C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylalkyl,
aryl, arylC.sub.1-10 alkyl, heteroaryl, heteroarylC.sub.1-10 alkyl,
heterocyclic, or a heterocyclylC.sub.1-10 alkyl moiety, which
moieties are optionally substituted; provided that when R.sub.3 is
hydrogen, then R.sub.1 is other than chlorine; [0187] m is 0 or an
integer having a value of 1 or 2; and [0188] Rg is a C.sub.1-4
alkyl.
[0189] Preferably, R.sub.1 is a halogen, more preferably chlorine,
or an aryl moiety, more preferably a phenyl ring, optionally
substituted one or more times by halogen, C.sub.1-4 alkyl, or
halo-substituted-C.sub.1-4 alkyl. More preferably, the phenyl ring
is substituted in the 2, 4, or 6-positions, or di-substituted in
the 2,4-positions, such as 2-fluoro, 4-fluoro, 2,4-difluoro,
2,4,6-trifluoro, or 2-methyl-4-fluoro.
[0190] Preferably, R.sub.3 is an optionally substituted C.sub.1-10
alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylalkyl, or
aryl.
[0191] Preferably, the R.sub.3 optional substituents are
independently selected from C.sub.1-10 alkyl, halo-substituted
C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-7
cycloalkyl, C.sub.3-7cycloalkylC.sub.1-10 allyl, C.sub.5-7
cycloalkenyl, C.sub.5-7 cycloalkenyl C.sub.1-10 alkyl, halogen,
(CR.sub.10R.sub.20).sub.nOR.sub.6, (CR.sub.10R.sub.20).sub.nSH,
(CR.sub.10R.sub.20).sub.nS(O).sub.mR.sub.7,
(CR.sub.10R.sub.20).sub.nNHS(O).sub.2R.sub.7,
(CR.sub.10R.sub.20).sub.nNR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nCN, (CR.sub.10R.sub.20).sub.n
S(O).sub.2NR.sub.4R.sub.14, (CR.sub.10R.sub.20).sub.nC(Z)R.sub.6,
(CR.sub.10R.sub.20).sub.nOC(Z)R.sub.6,
(CR.sub.10R.sub.20).sub.nC(Z)OR.sub.6,
(CR.sub.10R.sub.20).sub.nC(Z)N.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nNR.sub.10C(Z)R.sub.6,
(CR.sub.10R.sub.20).sub.nNR.sub.10C(.dbd.NR.sub.10)NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nOC(Z)NR.sub.4R.sub.14,
(CR.sub.10R.sub.20).sub.nNR.sub.10C(Z) NR.sub.4R.sub.14, or
(CR.sub.10R.sub.20).sub.nNR.sub.10C(Z)OR.sub.7.
[0192] More preferably, the optional substituents are independently
selected from halogen, alkyl, hydroxy, alkoxy, amino, or
halosubstituted alkyl.
[0193] Exemplified compounds of Formula (VI) include, but are not
limited to: [0194]
4-Chloro-2-methylsulfanyl-6-phenylamino-pyrimidine-5-carbaldehyde;
[0195]
4-Chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-
-5-carbaldehyde; [0196]
4-Chloro-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldeh-
yde; [0197]
4-Chloro-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldeh-
yde; [0198]
4-Chloro-6-(1-ethyl-propylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehy-
de; [0199]
4-Chloro-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
[0200]
4-Chloro-6-cyclopropylamino-2-methylsulfanyl-pyrimidine-5-carbald-
ehyde; [0201]
4-Chloro-6-(cyclopropylmethyl-amino)-2-methylsulfanyl-pyrimidine-5-carbal-
dehyde; [0202]
2-Methylsulfanyl-4-phenyl-6-phenylamino-pyrimidine-5-carbaldehyde;
[0203]
4-(2-Chlorophenyl)-6-(1-ethyl-propylamino)-2-methylsulfanyl-pyrim-
idine-5-carbaldehyde; [0204]
4-(2-Chlorophenyl)-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-
-carbaldehyde; [0205]
4-(2-Fluorophenyl)-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-
-carbaldehyde; [0206]
4-(2-Fluoro-phenyl)-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbal-
dehyde; [0207]
4-Chloro-2-methylsulfanyl-6-cyclohexylaminopyrimidine-5-carboxaldehyde;
[0208]
2-Methylsulfanyl-4-(2-methyl-4-fluorophenyl)-6-cyclohexylaminopyr-
imidine-5-carbaldehyde; [0209]
4-Amino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyridine-5-carbaldehyde;
[0210]
4-Cyclopropylamino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidin-
e-5-carbaldehyde; [0211]
4-(Cyclopropylmethyl-amino)-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidi-
ne-5-carbaldehyde; [0212]
4-(2,6-Difluoro-phenylamino)-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimid-
ine-5-carbaldehyde; [0213]
4-(2-Fluorophenyl)-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-
-carbaldehyde; [0214]
4-sec-Butylamino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbal-
dehyde; [0215]
4-(4-Fluoro-2-methyl-phenyl)-6-isopropylamino-2-methylsulfanyl-pyrimidine-
-5-carbaldehyde; [0216]
4-Cyclopropylamino-6-(4-fluoro-2-methyl-phenyl)-2-methyl
sulfanyl-pyrimidine-5-carbaldehyde; [0217]
4-(Cyclopropylmethyl-amino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-
-pyrimidine-5-carbaldehyde; [0218]
4-(4-Fluoro-2-methyl-phenyl)-6-(2-fluoro-phenylamino)-2-methylsulfanyl-py-
rimidine-5-carbaldehyde; [0219]
4-sec-Butylamino-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-
-5-carbaldehyde; [0220]
4-Amino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
[0221] 4-Amino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde;
[0222]
4-sec-Butylamino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldeh-
yde; [0223]
4-(2,6-Difluoro-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfany-
l-pyrimidine-5-carbaldehyde; [0224]
4-(1-Ethylpropylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyri-
midine-5-carbaldehyde; [0225]
2-Methylsulfanyl-4-(2-methyl-4-fluorophenyl)-6-cyclohexylaminopyrimidine--
5-carbaldehyde; and [0226]
4-Chloro-2-methylsulfanyl-6-cyclohexylaminopyrimidine-5-carboxaldehyde.
[0227] Another aspect of the present invention are novel
intermediates of the formula ##STR13## [0228] wherein [0229]
R.sub.1 is YRa; [0230] Y is C(R.sub.b)(R.sub.d), C(O), N(R.sub.d),
N(R.sub.d)C(R.sub.c)(R.sub.d), oxygen, OC(R.sub.c)(R.sub.d),
S(O).sub.m, or S(O).sub.mC(R.sub.c)(R.sub.d); [0231] R.sub.a is an
aryl or heteroaryl ring, which ring is optionally substituted;
[0232] R.sub.b is hydrogen, C.sub.1-2 alkyl, NR.sub.c, hydroxy,
thio, C.sub.1-2 alkoxy, S(O).sub.mC.sub.1-2 alkyl; [0233] R.sub.c
is hydrogen or C.sub.1-2 alkyl; [0234] R.sub.d is hydrogen or
C.sub.1-2 alkyl; [0235] m is 0 or an integer having a value of 1 or
2; and [0236] R.sub.3 is hydrogen, C.sub.1-10 alkyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkylalkyl, aryl, arylC.sub.1-10 alkyl,
heteroaryl, heteroarylC.sub.1-10 alkyl, heterocyclic, or a
heterocyclylC.sub.1-10 alkyl moiety, which moieties are optionally
substituted; [0237] m is 0 or an integer having a value of 1 or 2;
and [0238] Rg is a C.sub.1-4 alkyl.
[0239] Preferably, as noted above, the substituents of compounds of
Formula (VI) and (VIa) follow those of the final compounds of
Formula (I), and (II) herein.
[0240] Exemplified compounds of Formula (VI) include, but are not
limited to,
4-(2-Chloro-phenylamino)-2-methylsulfanyl-6-phenoxy-pyrimidine-5-carb-
aldehyde.
[0241] Another aspect of this invention are novel intermediates of
Formula (VII) ##STR14## wherein
[0242] R.sub.1 is as defined above for Formula (I) compounds, and
R.sub.3, Rg, and m is an optionally substituted aryl or heteroaryl
moiety, as defined for Formula (III) compounds.
[0243] Another aspect of this invention are novel intermediates of
Formula (VIIa) ##STR15## wherein
[0244] R.sub.1 is defined above for Formula (II) compounds, and
R.sub.3, Rg, and m is an optionally substituted aryl or heteroaryl
moiety, as defined for Formula (IIIa) compounds.
[0245] Another aspect of the present invention are novel
intermediates of the formula ##STR16## [0246] wherein [0247]
R.sub.1 is a halogen; [0248] R.sub.3 is hydrogen, C.sub.1-10 alkyl,
C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylalkyl, aryl,
arylC.sub.1-10 alkyl, heteroaryl, heteroarylC.sub.1-10 alkyl,
heterocyclic, or a heterocyclylC.sub.1-10 alkyl moiety, which
moieties are optionally substituted; provided that when R.sub.3 is
hydrogen, then R.sub.1 is other than chlorine; [0249] m is 0 or an
integer having a value of 1 or 2; and [0250] Rg is a
C.sub.1-4alkyl.
[0251] Preferably R.sub.1 is a halogen, more preferably
chlorine.
[0252] Suitably, the R.sub.3 substituents are the same as those for
compounds of Formulas (I) and (II) herein.
Methods of Treatment
[0253] The compounds of Formula (I) and (Ia) or a pharmaceutically
acceptable salt thereof can be used in the manufacture of a
medicament for the prophylactic or therapeutic treatment of any
disease state in a human, or other mammal, which is exacerbated or
caused by excessive or unregulated cytokine production by such
mammal's cell, such as but not limited to monocytes and/or
macrophages.
[0254] For purposes herein, compounds of Formula (I) and (Ia) will
all be referred to as compounds of Formula (I) unless otherwise
indicated.
[0255] Compounds of Formula (I) are capable of inhibiting
proinflarimatory cytokines, such as IL-1, IL-6, IL-8, and TNF and
are therefore of use in therapy. IL-1, IL-6, IL-8 and TNF affect a
wide variety of cells and tissues and these cytokines, as well as
other leukocyte-derived cytokines, are important and critical
inflammatory mediators of a wide variety of disease states and
conditions. The inhibition of these pro-inflammatory cytokines is
of benefit in controlling, reducing and alleviating many of these
disease states.
[0256] Accordingly, the present invention provides a method of
treating a cytokine-mediated disease which comprises administering
an effective cytokine-interfering amount of a compound of Formula
(I) or a pharmaceutically acceptable salt thereof.
[0257] Compounds of Formula (I) are capable of inhibiting inducible
proinflammatory proteins, such as COX-2, also referred to by many
other names such as prostaglandin endoperoxide synthase-2 (PGHS-2)
and are therefore of use in therapy. These proinflammatory lipid
mediators of the cyclooxygenase (CO) pathway are produced by the
inducible COX-2 enzyme. Regulation, therefore of COX-2 which is
responsible for the these products derived from arachidonic acid,
such as prostaglandins affect a wide variety of cells and tissues
are important and critical inflammatory mediators of a wide variety
of disease states and conditions. Expression of COX-1 is not
effected by compounds of Formula (I). This selective inhibition of
COX-2 may alleviate or spare ulcerogenic liability associated with
inhibition of COX-1 thereby inhibiting prostoglandins essential for
cytoprotective effects. Thus inhibition of these pro-inflammatory
mediators is of benefit in controlling, reducing and alleviating
many of these disease states. Most notably these inflammatory
mediators, in particular prostaglandins, have been implicated in
pain, such as in the sensitization of pain receptors, or edema.
This aspect of pain management therefore includes treatment of
neuromuscular pain, headache, cancer pain, and arthritis pain.
Compounds of Formula (I) or a pharmaceutically acceptable salt
thereof, are of use in the prophylaxis or therapy in a human, or
other mammal, by inhibition of the synthesis of the COX-2
enzyme.
[0258] Accordingly, the present invention provides a method of
inhibiting the synthesis of COX-2 which comprises administering an
effective amount of a compound of Formula (I) or a pharmaceutically
acceptable salt thereof. The present invention also provides for a
method of prophylaxis treatment in a human, or other mammal, by
inhibition of the synthesis of the COX-2 enzyme.
[0259] In particular, compounds of Formula (I) or a
pharmaceutically acceptable salt thereof are of use in the
prophylaxis or therapy of any disease state in a human, or other
mammal, which is exacerbated by or caused by excessive or
unregulated IL-1, IL-6, IL-8 or TNF production by such mammal's
cell, such as, but not limited to, monocytes and/or
macrophages.
[0260] Accordingly, in another aspect, this invention relates to a
method of inhibiting the production of IL-1 in a mammal in need
thereof which comprises administering to said mammal an effective
amount of a compound of Formula (I) or a pharmaceutically
acceptable salt thereof.
[0261] There are many disease states in which excessive or
unregulated IL-1 production is implicated in exacerbating and/or
causing the disease. These include rheumatoid arthritis,
osteoarthritis, meningitis, ischemic and hemorrhagic stroke,
neurotrauma/closed head injury, stroke, endotoxemia and/or toxic
shock syndrome, other acute or chronic inflammatory disease states
such as the inflammatory reaction induced by endotoxin or
inflammatory bowel disease, tuberculosis, atherosclerosis, muscle
degeneration, multiple sclerosis, cachexia, bone resorption,
psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis,
rubella arthritis and acute synovitis. Recent evidence also links
IL-1 activity to diabetes, pancreatic B cell diseases and
Alzheimer's disease.
[0262] Use of a CSAID inhibitor compound for the treatment of CSBP
mediated disease states, can include, but not be limited to
neurodegenerative diseases, such as Alzheimer's disease (as noted
above), Parkinson's disease and multiple sclerosis, etc.
[0263] In a further aspect, this invention relates to a method of
inhibiting the production of TNF in a mammal in need thereof which
comprises administering to said mammal an effective amount of a
compound of Formula (I) or a pharmaceutically acceptable salt
thereof.
[0264] Excessive or unregulated TNF production has been implicated
in mediating or exacerbating a number of diseases including
rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty
arthritis and other arthritic conditions, sepsis, septic shock,
endotoxic shock, gram negative sepsis, toxic shock syndrome, adult
respiratory distress syndrome, chronic pulmonary inflammatory
disease and chronic obstructive pulmonary disease, silicosis,
pulmonary sarcoisosis, bone resorption diseases, such as
osteoporosis, cardiac, brain and renal reperfusion injury, graft
vs. host reaction, allograft rejections, fever and myalgias due to
infection, such as influenza, brain infections including
encephalitis (including HIV-induced forms), cerebral malaria,
meningitis, ischemic and hemorrhagic stroke, cachexia secondary to
infection or malignancy, cachexia secondary to acquired immune
deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex),
keloid formation, scar tissue formation, inflammatory bowel
disease, Crohn's disease, ulcerative colitis and pyresis.
[0265] Compounds of Formula (I) are also useful in the treatment of
viral infections, where such viruses are sensitive to upregulation
by TNF or will elicit TNF production in vivo. The viruses
contemplated for treatment herein are those that produce TNF as a
result of infection, or those which are sensitive to inhibition,
such as by decreased replication, directly or indirectly, by the
TNF inhibiting-compounds of Formula (I). Such viruses include, but
are not limited to HIV-1, HIV-2 and HIV-3, Cytomegalovirus (CMV),
Influenza, adenovirus and the Herpes group of viruses, such as but
not limited to, Herpes Zoster and Herpes Simplex. Accordingly, in a
further aspect, this invention relates to a method of treating a
mammal afflicted with a human immunodeficiency virus (HIV) which
comprises administering to such mammal an effective TNF inhibiting
amount of a compound of Formula (I) or a pharmaceutically
acceptable salt thereof.
[0266] It is also recognized that both IL-6 and IL-8 are produced
during rhinovirus (HRV) infections and contribute to the
pathogenesis of common cold and exacerbation of asthma associated
with HRV infection (Turner et al. (1998), Clin. Infec. Dis., Vol
26, p 840; Teren et al. (1997), Am J Respir Crit. Care Med vol 155,
p1362; Grunberg et al. (1997), Am J Respir Crit. Care Med 156:609
and Zhu et al, J Clin Invest (1996), 97:421). It has also been
demonstrated in vitro that infection of pulmonary epithelial cells
with HRV results in production of IL-6 and IL-8 (Subauste et al.,
J. Clin. Invest. 1995, 96:549.) Epithelial cells represent the
primary site of infection of HRV. Therefore another aspect of the
present invention is a method of treatment to reduce inflammation
associated with a rhinovirus infection, not necessarily a direct
effect on virus itself.
[0267] Compounds of Formula (I) may also be used in association
with the veterinary treatment of mammals, other than in humans, in
need of inhibition of TNF production. TNF mediated diseases for
treatment, therapeutically or prophylactically, in animals include
disease states such as those noted above, but in particular viral
infections. Examples of such viruses include, but are not limited
to, lentivirus infections such as, equine infectious anaemia virus,
caprine arthritis virus, visna virus, or maedi virus or retrovirus
infections, such as but not limited to feline immunodeficiency
virus (FIV), bovine immunodeficiency virus, or canine
immunodeficiency virus or other retroviral infections.
[0268] The compounds of Formula (I) may also be used topically in
the treatment or prophylaxis of topical disease states mediated by
or exacerbated by excessive cytokine production, such as by IL-1 or
TNF respectively, such as inflamed joints, eczema, psoriasis and
other inflammatory skin conditions such as sunburn; inflammatory
eye conditions including conjunctivitis; pyresis, pain and other
conditions associated with inflammation. Periodontal disease has
also been implemented in cytokine production, both topically and
systemically. Hence use of compounds of Formula (I) to control the
inflammation associated with cytokine production in such peroral
diseases such as gingivitis and periodontitis is another aspect of
the present invention.
[0269] Compounds of Formula (I) have also been shown to inhibit the
production of IL-8 (Interleukin-8, NAP). Accordingly, in a further
aspect, this invention relates to a method of inhibiting the
production of IL-8 in a mammal in need thereof which comprises
administering to said mammal an effective amount of a compound of
Formula (I) or a pharmaceutically acceptable salt thereof.
[0270] There are many disease states in which excessive or
unregulated IL-8 production is implicated in exacerbating and/or
causing the disease. These diseases are characterized by massive
neutrophil infiltration such as, psoriasis, inflammatory bowel
disease, asthma, cardiac, brain and renal reperfusion injury, adult
respiratory distress syndrome, thrombosis and glomerulonephritis.
All of these diseases are associated with increased IL-8 production
which is responsible for the chemotaxis of neutrophils into the
inflammatory site. In contrast to other inflammatory cytokines
(IL-1, TNF, and IL-6), IL-8 has the unique property of promoting
neutrophil chemotaxis and activation. Therefore, the inhibition of
IL-8 production would lead to a direct reduction in the neutrophil
infiltration.
[0271] The compounds of Formula (I) are administered in an amount
sufficient to inhibit cytokine, in particular IL-1, IL-6, IL-8 or
TNF, production such that it is regulated down to normal levels, or
in some case to subnormal levels, so as to ameliorate or prevent
the disease state. Abnormal levels of IL-1, IL-6, IL-8 or TNF, for
instance in the context of the present invention, constitute: (i)
levels of free (not cell bound) IL-1, IL-6, IL-8 or TNF greater
than or equal to 1 picogram per ml; (ii) any cell associated IL-1,
IL-6, IL-8 or TNF; or (iii) the presence of IL-1, IL-6, IL-8 or TNF
mRNA above basal levels in cells or tissues in which IL-1, IL-6,
IL-8 or TNF, respectively, is produced.
[0272] The discovery that the compounds of Formula (I) are
inhibitors of cytokines, specifically IL-1, IL-6, IL-8 and TNF is
based upon the effects of the compounds of Formulas (I) on the
production of the IL-1, IL-8 and TNF in in vitro assays which are
described herein.
[0273] As used herein, the term "inhibiting the production of IL-1
(IL-6, IL-8 or TNF)" refers to:
[0274] a) a decrease of excessive in vivo levels of the cytokine
(IL-1, IL-6, IL-8 or TNF) in a human to normal or sub-normal levels
by inhibition of the in release of the cytokine by all cells,
including but not limited to monocytes or macrophages;
[0275] b) a down regulation, at the genomic level, of excessive in
vivo levels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to
normal or sub-normal levels;
[0276] c) a down regulation, by inhibition of the direct synthesis
of the cytokine (IL-1, IL-6, IL-8 or TNF) as a posttranslational
event; or
[0277] d) a down regulation, at the translational level, of
excessive in vivo levels of the cytokine (IL-1, IL-6, IL-8 or TNF)
in a human to normal or sub-normal levels.
[0278] As used herein, the term "TNF mediated disease or disease
state" refers to any and all disease states in which TNF plays a
role, either by production of TNF itself, or by TNF causing another
monokine to be released, such as but not limited to IL-1, IL-6 or
IL-8. A disease state in which, for instance, IL-1 is a major
component, and whose production or action, is exacerbated or
secreted in response to TNF, would therefore be considered a
disease stated mediated by TNF.
[0279] As used herein, the term "cytokine" refers to any secreted
polypeptide that affects the functions of cells and is a molecule
which modulates interactions between cells in the immune,
inflammatory or hematopoietic response. A cytokine includes, but is
not limited to, monokines and lymphokines, regardless of which
cells produce them. For instance, a monokine is generally referred
to as being produced and secreted by a mononuclear cell, such as a
macrophage and/or monocyte. Many other cells however also produce
monokines, such as natural killer cells, fibroblasts, basophils,
neutrophils, endothelial cells, brain astrocytes, bone marrow
stromal cells, epideral keratinocytes and B-lymphocytes.
Lymphokines are generally referred to as being produced by
lymphocyte cells. Examples of cytokines include, but are not
limited to, Interleukin-1 (IL-1), Interleukin-6 (IL-6),
Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF-a) and Tumor
Necrosis Factor beta (TNF-.beta.).
[0280] As used herein, the term "cytokine interfering" or "cytokine
suppressive amount" refers to an effective amount of a compound of
Formula (I) which will cause a decrease in the in vivo levels of
the cytokine to normal or sub-normal levels, when given to a
patient for the prophylaxis or treatment of a disease state which
is exacerbated by, or caused by, excessive or unregulated cytokine
production.
[0281] As used herein, the cytokine referred to in the phrase
"inhibition of a cytokine, for use in the treatment of a
HIV-infected human" is a cytokine which is implicated in (a) the
initiation and/or maintenance of T cell activation and/or activated
T cell-mediated HIV gene expression and/or replication and/or (b)
any cytokine-mediated disease associated problem such as cachexia
or muscle degeneration.
[0282] As TNF-.beta. (also known as lymphotoxin) has close
structural homology with TNF-.alpha. (also known as cachectin) and
since each induces similar biologic responses and binds to the same
cellular receptor, both TNF-.alpha. and TNF-.beta. are inhibited by
the compounds of the present invention and thus are herein referred
to collectively as "TNF" unless specifically delineated
otherwise.
[0283] A member of the MAP kinase family, alternatively termed
CSBP, p38, or RK, has been identified independently by several
laboratories. Activation of this novel protein kinase via dual
phosphorylation has been observed in different cell systems upon
stimulation by a wide spectrum of stimuli, such as physicochemical
stress and treatment with lipopolysaccharide or proinflammatory
cytokines such as interleukin-1 and tumor necrosis factor. The
cytokine biosynthesis inhibitors, of the present invention,
compounds of Formula (I) have been determined to be potent and
selective inhibitors of CSBP/p38/RK kinase activity. These
inhibitors are of aid in determining the signaling pathways
involvement in inflammatory responses. In particular, for the first
time a definitive signal transduction pathway can be prescribed to
the action of lipopolysaccharide in cytokine production in
macrophages. In addition to those diseases already noted, treatment
of stroke, neurotrauma, cardiac and renal reperfusion injury,
congestive heart failure, coronary arterial bypass grafting (CABG)
surgery, chronic renal failure, angiogenesis & related
processes, such as cancer, thrombosis, glomerulonephritis, diabetes
and pancreatic .beta. cells, multiple sclerosis, muscle
degeneration, eczema, psoriasis, sunburn, and conjunctivitis are
also included.
[0284] The CSBP inhibitors were subsequently tested in a number of
animal models for anti-inflammatory activity. Model systems were
chosen that were relatively insensitive to cyclooxygenase
inhibitors in order to reveal the unique activities of cytokine
suppressive agents. The inhibitors exhibited significant activity
in many such in vivo studies. Most notable are its effectiveness in
the collagen-induced arthritis model and inhibition of TNF
production in the endotoxic shock model. In the latter study, the
reduction in plasma level of TNF correlated with survival and
protection from endotoxic shock related mortality. Also of great
importance are the compounds effectiveness in inhibiting bone
resorption in a rat fetal long bone organ culture system. Griswold
et al., (1988) Arthritis Rheum. 31:1406-1412; Badger, et al.,
(1989) Circ. Shock 27, 51-61; Votta et al., (1994) in vitro. Bone
15, 533-538; Lee et al., (1993). B Ann. N.Y. Acad. Sci. 696,
149-170.
[0285] Chronic diseases which have an inappropriate angiogenic
component are various ocular neovasularizations, such as diabetic
retinopathy and macular degeneration. Other chronic diseases which
have an excessive or increased proliferation of vasculature are
tumor growth and metastasis, atherosclerosis, and certain arthritic
conditions. Therefore CSBP kinase inhibitors will be of utility in
the blocking of the angiogenic component of these disease
states.
[0286] The term "excessive or increased proliferation of
vasculature inappropriate angiogenesis" as used herein includes,
but is not limited to, diseases which are characterized by
hemangiomas and ocular diseases.
[0287] The term "inappropriate angiogenesis" as used herein
includes, but is not limited to, diseases which are characterized
by vesicle proliferation with accompanying tissue proliferation,
such as occurs in cancer, metastasis, arthritis and
atherosclerosis.
[0288] Accordingly, the present invention provides a method of
treating a CSBP kinase mediated disease in a mammal in need
thereof, preferably a human, which comprises administering to said
mammal, an effective amount of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof.
[0289] In order to use a compound of Formula (I) or a
pharmaceutically acceptable salt thereof in therapy, it will
normally be formulated into a pharmaceutical composition in
accordance with standard pharmaceutical practice. This invention,
therefore, also relates to a pharmaceutical composition comprising
an effective, non-toxic amount of a compound of Formula (I) and a
pharmaceutically acceptable carrier or diluent.
[0290] Compounds of Formula (I), pharmaceutically acceptable salts
thereof and pharmaceutical compositions incorporating such may
conveniently be administered by any of the routes conventionally
used for drug administration, for instance, orally, topically,
parenterally or by inhalation. The compounds of Formula (I) may be
administered in conventional dosage forms prepared by combining a
compound of Formula (I) with standard pharmaceutical carriers
according to conventional procedures. The compounds of Formula (I)
may also be administered in conventional dosages in combination
with a known, second therapeutically active compound. These
procedures may involve mixing, granulating and compressing or
dissolving the ingredients as appropriate to the desired
preparation. It will be appreciated that the form and character of
the pharmaceutically acceptable character or diluent is dictated by
the amount of active ingredient with which it is to be combined,
the route of administration and other well-known variables. The
carrier(s) must be "acceptable" in the sense of being compatible
with the other ingredients of the formulation and not deleterious
to the recipient thereof.
[0291] The pharmaceutical carrier employed may be, for example,
either a solid or liquid. Exemplary of solid carriers are lactose,
terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium
stearate, stearic acid and the like. Exemplary of liquid carriers
are syrup, peanut oil, olive oil, water and the like. Similarly,
the carrier or diluent may include time delay material well known
to the art, such as glyceryl mono-stearate or glyceryl distearate
alone or with a wax.
[0292] A wide variety of pharmaceutical forms can be employed.
Thus, if a solid carrier is used, the preparation can be tableted,
placed in a hard gelatin capsule in powder or pellet form or in the
form of a troche or lozenge. The amount of solid carrier will vary
widely but preferably will be from about 25 mg. to about 1 g. When
a liquid carrier is used, the preparation will be in the form of a
syrup, emulsion, soft gelatin capsule, sterile injectable liquid
such as an ampule or nonaqueous liquid suspension.
[0293] Compounds of Formula (I) may be administered topically, that
is by non-systemic administration. This includes the application of
a compound of Formula (I) externally to the epidermis or the buccal
cavity and the instillation of such a compound into the ear, eye
and nose, such that the compound does not significantly enter the
blood stream. In contrast, systemic administration refers to oral,
intravenous, intraperitoneal and intramuscular administration.
[0294] Formulations suitable for topical administration include
liquid or semi-liquid preparations suitable for penetration through
the skin to the site of inflammation such as liniments, lotions,
creams, ointments or pastes, and drops suitable for administration
to the eye, ear or nose. The active ingredient may comprise, for
topical administration, from 0.001% to 10% w/w, for instance from
1% to 2% by weight of the formulation. It may however comprise as
much as 10% w/w but preferably will comprise less than 5% w/w, more
preferably from 0.1% to 1% w/w of the formulation.
[0295] Lotions according to the present invention include those
suitable for application to the skin or eye. An eye lotion may
comprise a sterile aqueous solution optionally containing a
bactericide and may be prepared by methods similar to those for the
preparation of drops. Lotions or liniments for application to the
skin may also include an agent to hasten drying and to cool the
skin, such as an alcohol or acetone, and/or a moisturizer such as
glycerol or an oil such as castor oil or arachis oil.
[0296] Creams, ointments or pastes according to the present
invention are semi-solid formulations of the active ingredient for
external application. They may be made by mixing the active
ingredient in finely-divided or powdered form, alone or in solution
or suspension in an aqueous or non-aqueous fluid, with the aid of
suitable machinery, with a greasy or non-greasy base. The base may
comprise hydrocarbons such as hard, soft or liquid paraffin,
glycerol, beeswax, a metallic soap; a mucilage; an oil of natural
origin such as almond, corn, arachis, castor or olive oil; wool fat
or its derivatives or a fatty acid such as steric or oleic acid
together with an alcohol such as propylene glycol or a macrogel.
The formulation may incorporate any suitable surface active agent
such as an anionic, cationic or non-ionic surfactant such as a
sorbitan ester or a polyoxyethylene derivative thereof. Suspending
agents such as natural gums, cellulose derivatives or inorganic
materials such as silicaceous silicas, and other ingredients such
as lanolin, may also be included.
[0297] Drops according to the present invention may comprise
sterile aqueous or oily solutions or suspensions and may be
prepared by dissolving the active ingredient in a suitable aqueous
solution of a bactericidal and/or fungicidal agent and/or any other
suitable preservative, and preferably including a surface active
agent. The resulting solution may then be clarified by filtration,
transferred to a suitable container which is then sealed and
sterilized by autoclaving or maintaining at 98-100.degree. C. for
half an hour. Alternatively, the solution may be sterilized by
filtration and transferred to the container by an aseptic
technique. Examples of bactericidal and fungicidal agents suitable
for inclusion in the drops are phenylmercuric nitrate or acetate
(0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate
(0.01%). Suitable solvents for the preparation of an oily solution
include glycerol, diluted alcohol and propylene glycol.
[0298] Compounds of Formula (I) may be administered parenterally,
that is by intravenous, intramuscular, subcutaneous intranasal,
intrarectal, intravaginal or intraperitoneal administration. The
subcutaneous and intramuscular forms of parenteral administration
are generally preferred. Appropriate dosage forms for such
administration may be prepared by conventional techniques.
Compounds of Formula (I) may also be administered by inhalation,
that is by intranasal and oral inhalation administration.
Appropriate dosage forms for such administration, such as an
aerosol formulation or a metered dose inhaler, may be prepared by
conventional techniques.
[0299] For all methods of use disclosed herein for the compounds of
Formula (I), the daily oral dosage regimen will preferably be from
about 0.1 to about 80 mg/kg of total body weight, preferably from
about 0.2 to 30 mg/kg, more preferably from about 0.5 mg to 15 mg.
The daily parenteral dosage regimen about 0.1 to about 80 mg/kg of
total body weight, preferably from about 0.2 to about 30 mg/kg, and
more preferably from about 0.5 mg to 15 mg/kg. The daily topical
dosage regimen will preferably be from 0.1 mg to 150 mg,
administered one to four, preferably two or three times daily. The
daily inhalation dosage regimen will preferably be from about 0.01
mg/kg to about 1 mg/kg per day. It will also be recognized by one
of skill in the art that the optimal quantity and spacing of
individual dosages of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof will be determined by the
nature and extent of the condition being treated, the form, route
and site of administration, and the particular patient being
treated, and that such optimums can be determined by conventional
techniques. It will also be appreciated by one of skill in the art
that the optimal course of treatment, i.e., the number of doses of
a compound of Formula (I) or a pharmaceutically acceptable salt
thereof given per day for a defined number of days, can be
ascertained by those sdilled in the art using conventional course
of treatment determination tests.
[0300] The novel compounds of Formula (I) may also be used in
association with the veterinary treatment of mammals, other than
humans, in need of inhibition of CSBP/p38 or cytokine inhibition or
production. In particular, CSBP/p38 mediated diseases for
treatment, therapeutically or prophylactically, in animals include
disease states such as those noted herein in the Methods of
Treatment section, but in particular viral infections. Examples of
such viruses include, but are not limited to, lentivirus infections
such as, equine infectious anaemia virus, caprine arthritis virus,
visna virus, or maedi virus or retrovirus infections, such as but
not limited to feline immunodeficiency virus (FIV), bovine
immunodeficiency virus, or canine immunodeficiency virus or other
retroviral infections.
[0301] Another aspect of the present invention is a method of
treating the common cold or respiratory viral infection caused by
human rhinovirus (HRV), other enteroviruses, coronavirus, influenza
virus, parainfluenza virus, respiratory syncytial virus, or
adenovirus in a human in need thereof which method comprises
administering to said human an effective amount of a CBSP/p38
inhibitor.
[0302] Another aspect of the present invention is a method of
treating, including prophylaxis of influenza induced pneumonia in a
human in need thereof which method comprises administering to said
human an effective amount of a CBSP/p38 inhibitor
[0303] The present invention also relates to the use of the CSBP/p3
8 kinase inhibitor for the treatment, including prophylaxis, of
inflammation associated with a viral infection of a human
rhinovirus (HRV), other enteroviruses, coronavirus, influenza
virus, parainfluenza virus, respiratory syncytial virus, or
adenovirus.
[0304] In particular, the present invention is directed to the
treatment of a viral infection in a human, which is caused by the
human rhinovirus (HRV), other enterovirus, coronavirus, influenza
virus, parainfluenza virus, respiratory syncytial virus, or an
adenovirus. In particular the invention is directed to respiratory
viral infections that exacerbate asthma (induced by such
infections), chronic bronchitis, chronic obstructive pulmonary
disease, otitis media, and sinusitis. While inhibiting IL-8 or
other cytokines may be beneficial in treating a rhinovirus may be
known, the use of an inhibitor of the p38 kinase for treating HRV
or other respiratory viral infections causing the common cold is
believed novel.
[0305] It should be noted that the respiratory viral infection
treated herein may also be associated with a secondary bacterial
infection, such as otitis media, sinusitis, or pneumonia.
[0306] For use herein treatment may include prophylaxis for use in
a treatment group susceptible to such infections. It may also
include reducing the symptoms of, ameliorating the symptoms of,
reducing the severity of, reducing the incidence of, or any other
change in the condition of the patient, which improves the
therapeutic outcome.
[0307] It should be noted that the treatment herein is not directed
to the elimination or treatment of the viral organism itself but is
directed to treatment of the respiratory viral infection that
exacerbates other diseases or symptoms of disease, such as asthma
(induced by such infections), chronic bronchitis, chronic
obstructive pulmonary disease, otitis media, and sinusitis.
[0308] A preferred virus for treatment herein is the human
rhinovirus infection (HRV) or respiratory syncytial virus
(RSV).
[0309] The invention will now be described by reference to the
following biological examples which are merely illustrative and are
not to be construed as a limitation of the scope of the present
invention.
BIOLOGICAL EXAMPLES
[0310] The cytokine-inhibiting effects of compounds of the present
invention may be determined by the following in vitro assays:
[0311] Assays for Interleukin-1 (IL-1), Interleukin-8 (IL-8), and
Tumour Necrosis Factor (TNF) are well known in the art, and may be
found in a number of publications, and patents. Representative
suitable assays for use herein are described in Adams et al., U.S.
Pat. No. 5,593,992, whose disclosure is incorporated by reference
in its entirety.
Interleukin-1 (IL-1)
[0312] Human peripheral blood monocytes are isolated and purified
from either fresh blood preparations from volunteer donors, or from
blood bank buffy coats, according to the procedure of Colotta et
al, J Immunol, 132, 936 (1984). These monocytes (1.times.10.sup.6)
are plated in 24-well plates at a concentration of 1-2 million/ml
per well. The cells are allowed to adhere for 2 hours, after which
time non-adherent cells are removed by gentle washing. Test
compounds are then added to the cells for 1 h before the addition
of lipopolysaccharide (50 ng/ml), and the cultures are incubated at
37.degree. C. for an additional 24h. At the end of this period,
culture supernatants are removed and clarified of cells and all
debris. Culture supernatants are then immediately assayed for IL-1
biological activity, either by the method of Simon et al., J.
Immunol. Methods, 84, 85, (1985) (based on ability of IL-1 to
stimulate a Interleukin 2 producing cell line (EL-4) to secrete
IL-2, in concert with A23187 ionophore) or the method of Lee et
al., J. Immuno Therapy, 6 (1), 1-12 (1990) (ELISA assay).
In vivo TNF assay:
[0313] (1) Griswold et al., Drugs Under Exp. and Clinical Res., XIX
(6), 243-248 (1993); or
[0314] (2) Boehm, et al., Journal Of Medicinal Chemistry 39,
3929-3937 (1996) whose disclosures are incorporated by reference
herein in their entirety.
LPS-induced TNF.alpha. Production in Mice and Rats
[0315] In order to evaluate in vivo inhibition of LPS-induced
TNF.alpha. production in rodents, both mice and rats are injected
with LPS.
Mouse Method
[0316] Male Balb/c mice from Charles River Laboratories are
pretreated (30 minutes) with compound or vehicle. After the 30 min.
pretreat time, the mice are given LPS (lipopolysaccharide from
Esherichia coli Serotype 055-85, Sigma Chemical Co., St Louis, Mo.)
25 ug/mouse in 25 ul phosphate buffered saline (pH 7.0)
intraperitoneally. Two hours later the mice are killed by CO.sub.2
inhalation and blood samples are collected by exsanguination into
heparinized blood collection tubes and stored on ice. The blood
samples are centrifuged and the plasma collected and stored at
-20.degree. C. until assayed for TNF.alpha. by ELISA.
Rat Method
[0317] Male Lewis rats from Charles River Laboratories are
pretreated at various times with compound or vehicle. After a
determined pretreat time, the rats are given LPS
(lipopolysaccharide from Esherichia coli Serotype 055-85, Sigma
Chemical Co., St Louis, Mo.) 3.0 mg/kg intraperitoneally. The rats
are killed by CO.sub.2 inhalation and heparinized whole blood is
collected from each rat by cardiac puncture 90 minutes after the
LPS injection. The blood samples are centrifuged and the plasma
collected for analysis by ELISA for TNF.alpha. levels.
ELISA Method
[0318] TNF.alpha. levels were measured using a sandwich ELISA, as
described in Olivera et al., Circ. Shock, 37, 301-306, (1992),
whose disclosure is incorporated by reference in its entirety
herein, using a hamster monoclonal antimurine TNF.alpha. (Genzyme,
Boston, Mass.) as the capture antibody and a polyclonal rabbit
antimurine TNFa (Genzyme) as the second antibody. For detection, a
peroxidase-conjugated goat antirabbit antibody (Pierce, Rockford,
Ill.) was added, followed by a substrate for peroxidase (1 mg/ml
orthophenylenediamine with 1% urea peroxide). TNF.alpha. levels in
the plasma samples from each animal were calculated from a standard
curve generated with recombinant murine TNF.alpha. (Genzyme).
LPS-Stimulated Cytokine Production in Human Whole Blood
[0319] Assay: Test compound concentrations were prepared at
10.times. concentrations and LPS prepared at 1 ug/ml (final conc.
of 50 ng/ml LPS) and added in 50 uL volumes to 1.5 mL eppendorf
tubes. Heparinized human whole blood was obtained from healthy
volunteers and was dispensed into eppendorf tubes containing
compounds and LPS in 0.4 mL volumes and the tubes incubated at 37
C. Following a 4 hour incubation, the tubes were centrifuged at
5000 rpm for 5 minutes in a TOMY microfuge, plasma was withdrawn
and frozen at -80 C.
[0320] Cytokine measurement: IL-1 and/or TNF were quantified using
a standardized ELISA technology. An in-house ELISA kit was used to
detect human IL-1 and TNF. Concentrations of IL-1 or TNF were
determined from standard curves of the appropriate cytokine and
IC50 values for test compound (concentration that inhibited 50% of
LPS-stimulated cytokine production) were calculated by linear
regression analysis.
CSBP/p38 Kinase Assay:
[0321] This assay measures the CSBP/p38-catalyzed transfer of
.sup.32P from [a-.sup.32P]ATP to threonine residue in an epidermal
growth factor receptor (EGFR)-derived peptide (T669) with the
following sequence: KRELVEPLTPSGEAPNQALLR (SEQ ID No. 1) (residues
661-681). (See Gallagher et al., "Regulation of Stress Induced
Cytokine Production by Pyridinyl Imidazoles: Inhibition of CSBP
Kinase", BioOrganic & Medicinal Chemistry, 1997, 5, 49-64).
[0322] Reactions were carried in round bottom 96 well plate (from
Corning) in a 30 ml volume. Reactions contained (in final
concentration): 25 mM Hepes, pH 7.5; 8 mM MgCl.sub.2; 0.17 mM ATP
(the KM.sub.[ATP] of p38 (see Lee et al., Nature 300, n72 pg.
639-746 (December 1994)); 2.5 uCi of [g-32P]ATP; 0.2 mM sodium
orthovanadate; 1 mM DTT; 0.1% BSA; 10% glycerol; 0.67 mM T669
peptide; and 2-4 nNM of yeast-expressed, activated and purified
p38. Reactions were initiated by the addition of [gamma-32P]Mg/ATP,
and incubated for 25 min. at 37.degree. C. Inhibitors (dissolved in
DMSO) were incubated with the reaction mixture on ice for 30
minutes prior to adding the 32P-ATP. Final DMSO concentration was
0.16%. Reactions were terminated by adding 10 ul of 0.3 M
phosphoric acid, and phosphorylated peptide was isolated from the
reactions by capturing it on p81 phosphocellulose filters. Filters
were washed with 75 mM phosphoric acids, and incorporated 32P was
quantified using beta scintillation counter. Under these
conditions, the specific activity of p38 was 400-450 pmol/pmol
enzyme, and the activity was linear for up to 2 hours of
incubation. The kinase activity values were obtained after
subtracting values generated in the absence of substrate which were
10-15% of total values.
[0323] Representative final compounds of Formula (I) and (Ia) which
have been tested, Examples 29, 31 to 35, 37 to 41, 43, 45 to 47, 60
to 65, 67 to 105, 107 to 109, 112 to 186, 188 to 193, 195 to 231,
233 to 239, 241 to 243 have all demonstrated positive inhibitory
activity in this binding assay, having an IC.sub.50 of <10
uM.
[0324] Representative final compounds of Formula (II) and (IIa)
which have been tested. Example 111 has demonstrated positive
inhibitory activity in this binding assay, having an IC.sub.50 of
<10 uM.
TNF-.alpha. in Traumatic Brain Injury Assay
[0325] This assay provides for examination of the expression of
tumor necrosis factor mRNA in specific brain regions which follow
experimentally induced lateral fluid-percussion traumatic brain
injury (TBI) in rats. Since TNF-.alpha. is able to induce nerve
growth factor (NGF) and stimulate the release of other cytokines
from activated astrocytes, this post-traumatic alteration in gene
expression of TNF-.alpha. plays an important role in both the acute
and regenerative response to CNS trauma. A suitable assay may be
found in WO 97/35856 whose disclosure is incorporated herein by
reference.
CNS Injury model for IL-b mRNA
[0326] This assay characterizes the regional expression of
interleukin-1.beta. (IL-1.beta.) mRNA in specific brain regions
following experimental lateral fluid-percussion traumatic brain
injury (TBI) in rats. Results from these assays indicate that
following TBI, the temporal expression of IL-1.beta. mRNA is
regionally stimulated in specific brain regions. These regional
changes in cytokines, such as IL-1.beta. play a role in the
post-traumatic pathologic or regenerative sequelae of brain injury.
A suitable assay may be found in WO 97/35856 whose disclosure is
incorporated herein by reference.
Angiogenesis Assay:
[0327] Described in WO 97/32583, whose disclosure is incorporated
herein by reference, is an assay for determination of inflammatory
angiogenesis which may be used to show that cytokine inhibition
will stop the tissue destruction of excessive or inappropriate
proliferation of blood vessels.
Rhinovirus/Influenza Assay:
[0328] Cell lines, rhinovirus serotype 39, and influenza virus
A/PR/8/34 were purchased from American Type Culture Collection
(ATCC). BEAS-2B cells were cultured according to instructions
provided by ATCC using BEGM (bronchial epithelial growth media)
purchased from Clonetics Corp. HELA cell cultures, used for
detection and titration of virus, were maintained in Eagle's
minimum essential media containing 10% fetal calf serum, 2 mM
1-glutamine, and 10 mM HEPES buffer (MEM).
[0329] A modification of the method reported by Subauste et al.,
Supra, for in vitro infection of human bronchial epithelial cells
with rhinovirus was used in these studies. BEAS-2B cells
(2.times.10.sup.5/well) were cultured in collagen-coated wells for
24 hours prior to infection with rhinovirus. Rhinovirus serotype 39
was added to cell cultures for one hour incubation at 34.degree. C.
after which inoculum was replaced with fresh media and cultures
were incubated for an additional 72 hours at 34.degree. C.
Supernatants collected at 72 hours post-infection were assayed for
cytokine protein concentration by ELISA using commercially
available kits (R&D Systems). Virus yield was also determined
from culture supernatants using a microtitration assay in HELA cell
cultures (Subauste et al., supra 1995). In cultures treated with p3
8 kinase inhibitors, drug was added 30 minutes prior to infection.
Stocks of compounds were prepared in DMSO (10 mM drug) and stored
at -20.degree. C.
[0330] For detection of p38 kinase, cultures were incubated in
basal media without growth factors and additives to reduce
endogenous levels of activated p38 kinase. Cells were harvested at
various timepoints after addition of rhinovirus. Detection of
tyrosine phosphorylated p38 kinase by immunoblot was analyzed by a
commercially available kit and was performed according to the
manufacturer's instructions (PhosphoPlus p38 MAPK Antibody Kit: New
England BioLabs Inc.).
[0331] In some experiments, BEAS-2B cells were infected with
influenza virus (strain A/PR/8/34) in place of rhinovirus. Culture
supernatant was harvested 48 and 72 hour post-infection and tested
by ELISA for cytokine as described above.
[0332] Cells and Virus: Influenza A/PR/8/34 sub type H1N1 (VR-95
American Type Culture Collection, Rockville, Md.) was grown in the
allantoic cavity of 10 day old chicken eggs. Following incubation
at 37.degree. C., and refrigeration for 21/2 hours at 4.degree. C.,
allantoic fluid was harvested, pooled, and centrifuged (1,000 ref;
15 min; 4.degree. C.) to remove cells. Supernatent was aliquoted
and stored at -70.degree. C. The titer of the stock culture of
virus was 1.0.times.10.sup.10 Tissue Culture Infective Dose/ml
(TCID.sub.50)
[0333] Inoculation procedure: Four-six week old female
Balb/cAnNcrlBr mice were obtained from Charles River, Raleigh, N.C.
Animals were infected intranasally. Mice were anesthetized by
intraperitioneal injection of Ketamine (40 mg/kg; Fort Dodge Labs,
Fort Dodge, Iowa) and Xylazine (5 mg/kg; Miles, Shawnee Mission,
Kans.) and then inoculated with 100 TCID50 of PR8 diluted in PBS in
20 ul. Animals were observed daily for signs of infection. All
animal studies were approved by SmithKline Beecham Pharmaceuticals
Institutional Animal Care and Use Committee.
[0334] Virus titration: At various times post infection, animals
were sacrificed and lungs were aseptically harvested. Tissues were
homogenized, in vials containing 1 micron glass beads (Biospec
Products, Bartlesville, Okla.) and 1 ml. of Eagles minimal
essential medium. Cell debris was cleared by centrifugation at
1,000 rcf for 15 minutes at 4.degree. C., and supernatants were
serially diluted on Madin-Darby canine kidney (MDCK) cells. After 5
days of incubation at 37.degree. C. (5% CO.sub.2), 50 .mu.of 0.5%
chick red blood cells were added per well, and agglutination was
read after 1 hour at room temperature. The virus titer is expressed
as 50% tissue culture infective dose (TCID.sub.50) calculated by
logistic regression.
[0335] ELISA: Cytokine levels were measured by quantitative ELISA
using commercially available kits. Ear samples were homogenized
using a tissue minser in PBS. Cell debris was cleared by
centrifugation at 14,000 rpm for 5 minutes. The cytokine
concentrations and thresholds were determined as described by the
manufacturer; IL-6, IFN-.gamma., and KC (R&D Systems,
Minneapolis, Minn.).
[0336] Myeloperoxidase Assay: Myeloperoxidase (MPO) activity was
determined kinetically as described by Bradley et al. (1982).
Briefly, rabbit cornea were homogenized in Hexadecyl
Trimethyl-Ammonium Bromide (HTAB) (Sigma Chemical Co. St. Louis,
Mo.) which was dissolved in 0.5 m Potassium phosphate buffer (J. T.
Baker Scientific, Phillipsburg, N.J.). Following homogenization,
the samples were subjected to freeze-thaw-sonication (Cole-Parmer
8853, Cole-Parmer, Vernon Hills, Ill.) 3 times. Suspensions were
then cleared by centrifugation at 12,500.times.g for 15 minutes at
4.degree. C. MPO enzymatic activity was determined by colormetric
change in absorbance during a reaction of O-Dianisidine
dihydrochloride (ODI) 0.175 mg/ml (Sigma Chemical Co. St. Louis,
Mo.) with 0.0002% Hydrogen peroxide (Sigma Chemical Co. St. Louis,
Mo). Measurements were performed by using a Beckman Du 640
Spectrophotometer (Fullerton, Calif.) fitted with a temperature
control device. 50 ul of material to be assayed was added to 950 ul
of ODI and change in absorbance was measured at a wave length of
460 nm for 2 minutes at 25.degree. C.
[0337] Whole Body Plethysomography: Influenza virus infected mice
were placed into a whole body plethysomograph box with an internal
volume of approximately 350-ml. A bias airflow of one 1/min was
applied to the box and flow changes were measured and recorded with
a Buxco XA data acquisition and respiratory analysis system (Buxco
Electronics, Sharon, Conn.). Animals were allowed to acclimate to
the plethysmograph box for 2 min. before airflow data was recorded.
Airway measurements were calculated as Penh (enhanced pause). Penh
has previously been shown as an index of airway obstruction and
correlates with increased intrapleural pressure. The algorithm for
Penh calculation is as follows: Penh=[(expiratory time/relaxation
time)-1].times.(peak expiratory flow/peak inspiratory flow) where
relaxation time is the amount of time required for 70% of the tidal
volume to be expired.
[0338] Determination of arterial oxygen saturation. A Nonin
veterinary hand held pulse oximeter 8500V with lingual sensor
(Nonin Medical, Inc., Plymouth Minn.) was used to determine daily
arterial oxygen saturation % SpO2 as described (Sidwell et al. 1992
Antimicrobial Agents and Chemotherapy 36:473-476).
[0339] Additional data and assay modifications may be found in
PCT/US00/25386, (WO 01/19322) filed 15 Sep. 2000, whose disclosure
is incorporated herein by reference in its entirety.
SYNTHETIC EXAMPLES
[0340] The invention will now be described by reference to the
following examples which are merely illustrative and are not to be
construed as a limitation of the scope of the present invention.
All temperatures are given in degrees centigrade, all solvents are
highest available purity and all reactions run under anhyd
conditions in an Ar atmosphere where necessary.
[0341] Mass spectra were run on an open access LC-MS system using
electrospray ionization. LC conditions: 4.5% to 90% CH.sub.3CN
(0.02% TFA) in 3.2 min with a 0.4 min hold and 1.4 min
re-equilibration; detection by MS, UV at 214 nm, and a light
scattering detector (ELS). Column: 1.times.40 mm Aquasil (C18)
.sup.1H-NMR (hereinafter "NMR") spectra were recorded at 400 MHz
using a Bruker AM 400 spectrometer or a Bruker AVANCE 400.
Multiplicities indicated are: s=singlet, d=doublet, t=triplet,
q=quartet, m=multiplet and br indicates a broad signal. For
preparative (prep) hplc; ca 50 mg of the final products were
injected in 500 uL of DMSO onto a 50.times.20 mm I. D. YMC
CombiPrep ODS-A column at 20 mL/min with a 10 min gradient from 10%
CH.sub.3CN (0.1% TFA) to 90% CH.sub.3CN (0.1% TFA) in H.sub.2O
(0.1% TFA) and a 2 min hold (unless otherwise stated). Flash
chromatography was run over Merck Silica gel 60 (230-400 mesh) in
solvent mixtures containing varying relative concentrations of
dichloromethane and methanol, or EtOAc, and hexane, unless
otherwise stated. Chromatotron chromatography as has been
previously described (Desai, H K; Joshi, B S; Panu, A M; Pelletier,
S W J. Chromatogr. 1985 223-227.) was run on chromatotron plates
available from Analtech, Wilmington Del., USA.
[0342] satd=saturated; aq=aqueous; NMP=1-methyl-2-pyrrolidinone;
other abreviations are as described in the ACS Style Guide
(American Chemical Society, Washington, D.C., 1986).
Example 1
[0343] ##STR17##
4-Chloro-2-methylsulfanyl-6-phenylamino-pyrimidine-5-carbaldehyde
[0344] To a solution of aniline (550 microliter (hereinafter
".mu.L" or "uL"), 6 millimoles (hereinafter "mmol"), 1.2
equivalents (hereinafter "eq")) in dry DMSO (100 mL) was added NaH
as a 60% suspension in mineral oil (240 milligrams (hereinafter
"mg"), 6 mmol, 1.2 eq) and the reaction mixture was stirred for 1
hour (hereinafter "h"). To the red solution was then added
4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (1.11 grams
(hereinafter "g"), 5 mmol) [Santilli, et al., J. Heterocycl. Chem.
1971, 8, 445-45] dissolved in anhydrous DMSO (20 milliliters
(hereinafter "mL")). The reaction mixture turned yellow and was
stirred 2 h at 23.degree., H.sub.2O (250 mL) was added followed by
EtOAc (500 mL). The layers were separated; the organic layer was
washed with saturated (hereinafter sat'd) aq. NaCl, dried
(MgSO.sub.4) and filtered. The organic layer was evaporated and the
crude residue was dissolved in isopropanol (50 mL) and heated to
60.degree., H.sub.2O (50 mL) was added and the solution was cooled
slowly to 230. The product was isolated by filtration and dried in
vacuo to afford 1.06 g (76% yield) of pure
4-chloro-2-methylsulfanyl-6-phenylamino-pyrimidine-5-carbaldehyde.
.sup.1H-NMR .delta. 2.59 (s, 3H), 7.21 (m, 1H), 7.44 (m, 2H), 7.68
(m, 2H), 10.37 (s, 1H), 11.38 (br s, 1H). LC MS (m/e)=280
(MH+).
Example 2
[0345] ##STR18##
4-Chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbal-
dehyde
[0346] To a solution of
4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (11.1 g, 50
mmol) in CHCl.sub.3 (100 mL) was added 2,6-difluoroaniline (8.07
mL, 75 mmol, 1.5 eq) followed by Et.sub.3N (10.43 mL, 75 mmol, 1.5
eq). The reaction mixture turned yellow and was heated to reflux
for 24 h, H.sub.2O (50 mL) was added and the layers were separated.
The organic layer was evaporated and the crude product was
recrystallized from 200 mL of a methanol: H.sub.2O mixture (2:1) to
give 12.03 g (76%) of pure
4-chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carba-
ldehyde. .sup.1H-NMR: .delta. 2.21 (s, 3H), 6.91 (m, 2H), 7.24 (m,
1H), 10.29 (s, 1H), 10.35 (br s, 1H). LC MS (m/e)=316 (MH+).
Example 3
[0347] ##STR19##
4-Chloro-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehy-
de
[0348] Prepared as described above in Example 1 starting from
4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and
2-chloroaniline to give the title compound
4-chloro-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldeh-
yde. .sup.1H-NMR: .delta. 2.55 (s, 3H), 7.17 (m, 1H), 7.29 (m, 2H),
7.44 (m, 1H), 10.37 (s, 1H), 11.49 (br s, 1H). LC MS (m/e)=315
(MH+).
Example 4
[0349] ##STR20##
4-Chloro-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehy-
de
[0350] Prepared as described above in Example 2 starting from
4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and
2-fluoroaniline to give the title compound
4-chloro-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldeh-
yde. 1H-NMR: .delta. 2.53 (s, 3H), 7.15 (m, 3H), 8.25 (m, 1H), 7.44
(m, 1H), 10.31 (s, 1H), 11.35 (br s, 1H). LC MS (m/e)=298
(MH+).
Example 5
[0351] ##STR21##
4-Chloro-6-(1-ethyl-propylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyd-
e
[0352] Prepared as described above in Example 2 starting from
4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and
3-pentylamine to give the title compound
4-chloro-6-(1-ethyl-propylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehy-
de. 1H-NMR: .delta. 0.92 (t, 6H, J=7.3 Hz), 1.50-1.74 (m, 4H), 2.52
(s, 3H), 4.22 (m, 1H), 9.21 (br s, 1H), 10.33 (s, 1H). LC MS
(m/e)=274 (MH+).
Example 6
[0353] ##STR22##
4-Chloro-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde
[0354] Prepared as described above in Example 2 starting from
4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and
isopropylamine to give the title compound
4-chloro-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde.
1H-NMR: .delta. 1.31 (d, 6H, J=5.7 Hz), 2.60 (s, 3H), 4.47 (m, 1H),
9.16 (br s, 1H), 10.25 (s, 1H). LC MS (m/e)=246 (MH+).
Example 7
[0355] ##STR23##
4-Chloro-6-cyclopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde
[0356] Prepared as described above in Example 2 starting from
4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and
cyclopropylamine to give the title compound
4-chloro-6-cyclopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde.
.sup.1H-NMR: .delta. 0.68 (m, 2H), 0.90 (m, 2H), 2.58 (s, 3H), 3.07
(m, 1H), 9.20 (br s, 1H), 10.28 (s, 1H). LC MS (m/e)=244 (MH+).
Example 8
[0357] ##STR24##
4-sec-Butylamino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde
[0358] Prepared as described above in Example 2 starting from
4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and
2-butylamine to give the title compound
4-sec-butylamino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde.
.sup.1H-NMR: .delta. 0.87 (m, 3H), 1.18 (m, 3), 1.20 (m, 2H), 2.51
(s, 3H), 4.24 (m, 1H), 9.12 (br s, 1H), 10.18 (s, 1H). LC MS
(m/e)=260 (MH+).
Example 9
[0359] ##STR25##
4-Chloro-6-(cyclopropylmethyl-amino)-2-methylsulfanyl-pyrimidine-5-carbald-
ehyde
[0360] Prepared as described above in Example 2 starting from
4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and
(aminomethyl)cyclopropane to give the title compound
4-chloro-6-(cyclopropylmethyl-amino)-2-methylsulfanyl-pyrimidine-5-carbal-
dehyde. .sup.1H-NMR: .delta. 0.32 (m, 2H), 0.59 (m, 2H), 1.12 (m,
1H), 2.55 (s, 3H), 3.46 (m, 2H), 9.35 (br s, 1H), 10.28 (s, 1H). LC
MS (m/e)=258 (MH+).
Example 10
[0361] ##STR26##
4-Amino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde
[0362] To the solution of
4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (2 g, 7.36
mmol) in benzene (20 mL) was introduced NH.sub.3 gas for 30 minutes
(hereinafter "min"). The formed solid was then filtered and
recrystallized from EtOAc (15 mL) to give 1.18 g (80%) of pure
4-amino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde.
.sup.1H-NMR: .delta. 2.50 (s, 3H), 7.28 (t, 3H, J=45 Hz, D.sub.2O
exchangeable), 8.65 (d, 3H, J=41 Hz, D.sub.2O exchangeable), 10.11
(s, 1H).
Example 11
[0363] ##STR27##
2-Methylsulfanyl-4-phenyl-6-phenylamino-pyrimidine-5-carbaldehyde
[0364] To a solution of
4-chloro-2-methylsulfanyl-6-phenylamino-pyrimidine-5-carbaldehyde
(300 mg, 1.07 mmol) in dioxane (21 mL) and H.sub.2O (7 mL) was
added anhyd K.sub.2CO.sub.3 (443 mg, 3.21-mmol, 3 eq) followed by
phenylboronic acid (196 mg, 1.6 mmol, 1.5 eq). The reaction mixture
was degassed and tetrakis(triphenylphosphine)-palladium (61 mg,
0.053 mmol, 0.05 eq) was added. The reaction mixture was then
heated under reflux for 24 h and cooled 23.degree., the layers were
separated, EtOAc (50 mL), followed by H.sub.2O (10 mL), was added,
the organic layer was separated, washed with satd aq NaCl, dried
(MgSO.sub.4) and filtered. The yellow solution was then evaporated.
Product was purified by column chromatography or by crystallization
from 10 mL of isopropanol: H.sub.2O (2:1) to give 240 mg (70%
yield) of pure
2-methylsulfanyl-4-phenyl-6-phenylamino-pyrimidine-5-carbaldehyde.
.sup.1H-NMR 8 2.60 (s, 3H), 7.22 (m, 1H), 7.35-7.81 (m, 9H), 9.89
(s, 1H), 11.31 (br s, 1H), LC MS (m/e)=322 (MH+).
Example 12
[0365] ##STR28##
4-(2,6-Difluoro-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-
-pyrimidine-5-carbaldehyde
[0366] Prepared as described above in Example 11 starting from
4-chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carba-
ldehyde and 4-fluoro-2-methyl-phenylboronic acid to give the title
compound
4-(2,6-difluoro-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-meth-
ylsulfanyl-pyrimidine-5-carbaldehyde. .sup.1H-NMR: 3 2.21 (s, 3H),
2.25 (s, 3H), 6.95 (m, 4H), 7.18 (m, 4H), 9.54 (s, 1H), 10.29 (br
s, 1H). LC MS (m/e)=390 (MH+).
Example 13
[0367] ##STR29##
4-(1-Ethyl-propylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl
pyrimidine-5-carbaldehyde
[0368] Prepared as described above in Example 11 starting from
4-chloro-6-(1-ethyl-propylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehy-
de and 4-fluoro-2-methyl-phenylboronic acid to give the title
compound
4-(1-ethyl-propylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyr-
imidine-5-carbaldehyde. .sup.1H-NMR: .delta. 0.92 (m, 6H),
1.54-1.71 (m, 4H), 2.21 (s, 3H), 2.53 (s, 3H), 4.28 (m, 1H),
6.63-7.05 (m, 2H), 7.21 (m, 1H), 9.05 (br s, 1H), 10.50 (s, 1H). LC
MS (m/e)=348 (MH+).
Example 14
[0369] ##STR30##
4-(2-Chloro-phenyl)-6-(1-ethyl-propylamino)-2-methylsulfanyl-pyrimidine-5--
carbaldehyde
[0370] Prepared as described above in Example 11 starting from
4-chloro-6-(1-ethyl-propylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehy-
de and 2-chlorophenylboronic acid to give the title compound
4-(2-chloro-phenyl)-6-(1-ethyl-propylamino)-2-methylsulfanyl-pyrimidine-5-
-carbaldehyde. .sup.1H-NMR: .delta. 0.91 (m, 6H), 1.42-1.60 (m,
4H), 2.45 (s, 3H), 4.21 (m, 1H), 7.32 (m, 4H), 8.96 (br s, 1H),
9.44 (s, 1H). LC MS (m/e)=350 (MH+).
Example 15
[0371] ##STR31##
4-(2-Chloro-phenyl)-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-
-carbaldehyde
[0372] Prepared as described above in Example 11 starting from
4-chloro-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldeh-
yde and 2-chlorophenylboronic acid to give the title compound
4-(2-chloro-phenyl)-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine--
5-carbaldehyde. .sup.1H-NMR: .delta. 2.58 (s, 3H), 7.01-7.59 (m,
7H), 8.61 (d, 1H, J=4.7 Hz), 9.65 (s, 1H), 11.48 (br s, 1H). LC MS
(m/e)=390 (MH+).
Example 16
[0373] ##STR32##
4-(2-Fluoro-phenyl)-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-
-carbaldehyde
[0374] Prepared as described above in Example 11 starting from
4-chloro-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldeh-
yde and 2-fluorophenylboronic acid to give the title compound
4-(2-fluoro-phenyl)-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine--
5-carbaldehyde. .sup.1H-NMR: .delta. 2.60 (s, 3H), 6.99-7.68 (m,
7H), 8.47 (d, 1H, J=4.7 Hz), 9.78 (s, 1H), 11.59 (br s, 1H). LC MS
(m/e)=374 (MH+).
Example 17
[0375] ##STR33##
4-Amino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde
[0376] Prepared as described above in Example 11 starting from
4-amino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and
2-fluorophenylboronic acid to give the title compound
4-amino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde.
.sup.1H-NMR: .delta. 2.59 (s, 3H), 5.78 (br s, 1H), 7.11-7.32 (m,
2H), 7.42-7.58 (m, 2H), 8.65 (br s, 1H), 9.71 (s, 1H). LC MS
(m/e)=264 (MH+).
Example 18
[0377] ##STR34##
4-(2-Fluoro-phenyl)-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbald-
ehyde
[0378] Prepared as described above in Example 11 starting from
4-chloro-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde
and 2-fluorophenylboronic acid to give the title compound
4-(2-fluoro-phenyl)-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbal-
dehyde. .sup.1H-NMR: .delta. 1.31 (d, 6H, J=5.7 Hz), 2.56 (s, 3H),
4.51 (m, 1H), 7.05-7.31 (m, 2H), 7.41-7.55 (m, 2H), 9.02 (br s,
1H), 9.64 (s, 1H). LC MS (m/e)=306 (MH+).
Example 19
[0379] ##STR35##
4-Cyclopropylamino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carba-
ldehyde
[0380] Prepared as described above in Example 11 starting from
4-chloro-6-cyclopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde
and 2-fluorophenylboronic acid to give the title compound
4-cyclopropylamino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carb-
aldehyde. .sup.1H-NMR: .delta. 0.66 (m, 2H), 0.92 (m, 2H) 2.60 (s,
3H), 3.11 (m, 1H), 7.10-7.30 (m, 2H), 7.41-7.57 (m, 2H), 9.10 (br
s, 1H), 9.66 (s, 1H). LC MS (m/e)=304 (MH+).
Example 20
[0381] ##STR36##
4-(Cyclopropylmethyl-amino)-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidin-
e-5-carbaldehyde
[0382] Prepared as described above in Example 11 starting from
4-chloro-6-cyclopropylmethyl-amino-2-methylsulfanyl-pyrimidine-5-carbalde-
hyde and 2-fluorophenylboronic acid to give the title compound
4-(cyclopropylmethyl-amino)-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidi-
ne-5-carbaldehyde. .sup.1H-NMR: .delta. 0.34 (m, 2H), 0.61 (m, 2H),
1.19 (m, 1H), 2.56 (s, 3H), 3.51 (m, 2H), 7.11-7.27 (m, 2H),
7.31-7.52 (m, 2H), 9.22 (br s, 1H), 9.69 (s, 1H). LC MS (m/e)=318
(MH+).
Example 21
[0383] ##STR37##
4-(2,6-Difluoro-phenylamino)-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidi-
ne-5-carbaldehyde
[0384] Prepared as described above in Example 11 starting from
4-chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carba-
ldehyde and 2-fluorophenylboronic acid to give the title compound
4-(2,6-difluoro-phenylamino)-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimid-
ine-5-carbaldehyde. .sup.1H-NMR: 6.31 (s, 3H), 6.98-7.20 (m, 3H),
7.26 (m, 2H), 7.38-7.42 (m, 2H), 9.79 (s, 1H), 10.39 (br s, 1H). LC
MS (m/e)=376 (MH+).
Example 22
[0385] ##STR38##
4-(2-Fluoro-phenyl)-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-
-carbaldehyde
[0386] Prepared as described above in Example 11 starting from
4-chloro-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldeh-
yde and 2-fluorophenylboronic acid to give the title compound
4-(2-fluoro-phenyl)-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine--
5-carbaldehyde. .sup.1H-NMR: 8.61 (s, 3H), 7.11-7.23 (m, 4H), 7.26
(m, 1H), 7.45-7.62 (m, 2H), 8.38 (m, 1H), 9.80 (s, 1H), 11.33 (br
s, 1H). LC MS (m/e)=358 (MH+).
Example 23
[0387] ##STR39##
4-sec-Butylamino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbald-
ehyde
[0388] Prepared as described above in Example 11 starting from
4-sec-butylamino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde
and 2-fluorophenylboronic acid to give the title compound
4-sec-butylamino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbal-
dehyde. .sup.1H-NMR: .delta. 0.96 (m, 3H), 1.30 (m, 3H), 1.67 (m,
2H), 2.58 (s, 3H), 4.38 (m, 1H), 7.11-7.31 (m, 2H), 7.42-7.58 (m,
2H), 9.07 (br s, 1H), 9.63 (s, 1H). LC MS (m/e)=306 (MH+).
Example 24
[0389] ##STR40##
4-(4-Fluoro-2-methyl-phenyl)-6-isopropylamino-2-methylsulfanyl-pyrimidine--
5-carbaldehyde
[0390] Prepared as described above in Example 11 starting from
4-chloro-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde
and 4-fluoro-2-methylphenylboronic acid to give the title compound
4-(4-fluoro-2-methyl-phenyl)-6-isopropylamino-2-methylsulfanyl-pyrimidine-
-5-carbaldehyde. .sup.1H-NMR: .delta. 1.31 (d, 6H, J=5.7 Hz), 2.21
(s, 3H), 2.59 (s, 3H), 4.52 (m, 1H), 7.90-7.15 (m, 2H), 7.18-7.25
(m, 1H), 9.06 (br s, 1H), 9.50 (s, 1H). LC MS (m/e)=320 (MH+).
Example 25
[0391] ##STR41##
4-Cyclopropylamino-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidin-
e-5-carbaldehyde
[0392] Prepared as described above in Example 11 starting from
4-chloro-6-cyclopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde
and 4-fluoro-2-methylphenylboronic acid to give the title compound
4-cyclopropylamino-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidi-
ne-5-carbaldehyde. .sup.1H-NMR: .delta. 0.69 (m, 2H), 0.94 (m, 2H),
2.23 (s, 3H), 2.62 (s, 3H), 3.14 (m, 1H), 6.98 (m, 2H), 7.20 (m,
1H), 9.09 (br s, 1H), 9.49 (s, 1H). LC MS (m/e)=318 (MH+).
Example 26
[0393] ##STR42##
4-(Cyclopropylmethyl-amino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl--
pyrimidine-5-carbaldehyde
[0394] Prepared as described above in Example 11 starting from
4-chloro-6-cyclopropylmethyl-amino-2-methylsulfanyl-pyrimidine-5-carbalde-
hyde and 4-fluoro-2-methylphenylboronic acid to give the title
compound
4-(cyclopropylmethyl-amino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-
-pyrimidine-5-carbaldehyde. .sup.1H-NMR: .delta. 0.30 (m, 2H), 0.60
(m, 2H), 1.18 (m, 1H), 2.24 (s, 3H), 2.55 (s, 3H), 3.50 (m, 2H),
6.98 (m, 2H), 7.18 (m, 1H), 9.21 (br s, 1H), 9.50 (s, 1H). LC MS
(m/e)=332 (MH+).
Example 27
[0395] ##STR43##
4-(4-Fluoro-2-methyl-phenyl)-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyr-
imidine-5-carbaldehyde
[0396] Prepared as described above in Example 11 starting from
4-chloro-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldeh-
yde and 4-fluoro-2-methylphenylboronic acid to give the title
compound
4-(4-fluoro-2-methyl-phenyl)-6-(2-fluoro-phenylamino)-2-methylsulfanyl-py-
rimidine-5-carbaldehyde. .sup.1H-NMR: .delta. 2.28 (s, 3H).59 (s,
3H), 7.01 (m, 2H), 7.18 (m, 3H), 7.24 (m, 1H), 8.42 (m, 1H), 9.63
(s, 1H), 11.30 (br s, 1H). LC MS (m/e)=372 (MH+).
Example 28
[0397] ##STR44##
4-sec-Butylamino-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine--
5-carbaldehyde
[0398] Prepared as described above in Example 11 starting from
4-sec-butylamino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde
and 4-fluoro-2-methylphenylboronic acid to give the title compound
4-sec-butylamino-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-
-5-carbaldehyde. .sup.1H-NMR: .delta. 1.02 (m, 3H), 1.30 (m, 3H),
1.70 (m, 2H), 2.28 (m, 3H), 2.59 (s, 3H), 4.37 (m, 1H), 6.98 (m,
2H), 7.20 (m, 1H), 9.04 (br s, 1H), 9.50 (s, 1H). LC MS (m/e)=334
(MH+).
Example 29
[0399] ##STR45##
2-Methylsulfanyl-4,8-diphenyl-8H-pyrido[2,3-d]pyrimidin-7-one
[0400] A solution of 18-crown-6 (422 mg, 1.6 mmol, 5 eq) and
bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (81
.mu.L, 0.38 mmol, 1.2 eq) in anhydrous THF (20 mL) was cooled to
-78.degree.. To this solution was added potassium
bis(trimethylsilyl)amide (0.96 mL, 0.48 mmol, 1.5 eq) as a 0.5 mol
solution in toluene. This solution was stirred for additional 30
min at -78.degree. and
2-methylsulfanyl-4-phenyl-6-phenylamino-pyrimidine-5-carbaldehyde
(102 mg, 0.32 mmol) in dry THF (1 mL) was added dropwise. The
reaction mixture was then stirred for 8 h at -78.degree. and warmed
to 23.degree. and stirred 16 h. Sat'd aq. NH.sub.4Cl (5 mL),
followed by diethyl ether (20 mL), was added. The layers were
separated. The organic layer was washed with satd aq NaCl, dried
(MgSO.sub.4), filtered and solvent was evaporated. The yellow
residue was then purified by flash chromatography to afford 100 mg
(91% yield) of pure
2-methylsulfanyl-4,8-diphenyl-8H-pyrido[2,3-d]pyrimidin-7-one.
.sup.1H-NMR .delta. 2.19 (s, 3H), 6.70 (d, 1H, J=9.9 Hz), 7.26 (m,
2H), 7.42-7.83 (m, 8H), 7.88 (d, 1H, J=9.9 Hz), LC MS (m/e)=346
(MH+).
Example 30
[0401] ##STR46##
(E)-3-[4-(2,6-Difluoro-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methyls-
ulfanyl-pyrimidin-5-yl]-acrylic acid ethyl ester
[0402] To a solution of triethyl phosphonoacetate (8.18 mL, 41.3
mmol, 2 eq) in 120 mL of anhyd THF was added NaH (2.05 g, 60%
dispersion in mineral oil, 51.4 mmol, 2.5 eq) and the reaction
mixture was stirred for 30 min at 23.degree.. To this solution was
added
4-(2,6-difluoro-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfany-
l-pyrimidine-5-carbaldehyde (8 g, 20.65 mmol) as a solution in 10
mL of anhyd THF and the reaction mixture was heated under reflux
for 3 h while being monitored by HPLC. After completion, 20 mL of
satd aq NH.sub.4Cl was added and the layers were separated. The aq
layer was washed with Et.sub.2O (100 mL) and the organic layers
were combined. The organic layer was washed with H.sub.2O, and satd
aq NaCl, dried (MgSO.sub.4), filtered and solvent was evaporated.
The crude product was recrystallized from 100 mL of methanol:
H.sub.2O (1:1) to afford 8.1 g (88%) of pure
(E)-3-[4-(2,6-difluoro-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methyl-
sulfanyl-pyrimidin-5-yl]-acrylic acid ethyl ester. LC MS (m/e)=460
(MH+). Rt=2.49 min
Example 31
[0403] ##STR47##
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-8H-p-
yrido[2,3-d]pyrimidin-7-one
[0404]
(E)-3-[4-(2,6-difluoro-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-
-methylsulfanyl-pyrimidin-5-yl]-acrylic acid ethyl ester (8.1 g,
17.6 mmol) was dissolved in 50 mL of anhydrous toluene. Reaction
mixture was heated in a sealed tube at 220.degree. C. for 48 h,
toluene was evaporated and the yellow residue purified by Flash
chromatography to give 7.1 g (96%) of
8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-8H--
pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR (CDCl.sub.3) .delta. 2.24
(s, 3H), 2.29 (s, 3H), 6.63 (d, 1H, J=9.6 Hz), 7.03-7.20 (m, 4H),
7.25 (m, 1H), 7.51 (m, 2H); LC MS (m/e)=414 (MH+).
Example 32
[0405] ##STR48##
4,8-Bis-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one
[0406] To a solution of
4-(2-fluoro-phenyl)-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine--
5-carbaldehyde, as described in Example 22, (400 mg, 1.1 mmol) in
pyridine (2 mL) was added Ac.sub.2O (2 mL) and the reaction mixture
was heated under reflux for 48 h, solvent was evaporated and the
residue was dissolved in EtOAc (40 mL), washed with 1 M aq
Na.sub.2CO.sub.3, and H.sub.2O and satd aq NaCl, dried
(MgSO.sub.4), filtered and solvent was evaporated. The yellow
residue was purified by Flash chromatography to afford pure
4,8-bis-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-on-
e (320 mg, 76% yield). .sup.1H-NMR (CDCl.sub.3) .delta. 2.21 (s,
3H), 6.76 (d, 1H, J=9.6 Hz), 7.22-7.42 (m, 4H), 7.45-7.67 (m, 5H).
LC MS (m/e)=382 (MH+).
Example 33
[0407] ##STR49##
8-(2-Chloro-phenyl)-4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]p-
yrimidin-7-one
[0408] Prepared as described above in Example 29 starting from
4-(2-fluoro-phenyl)-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine--
5-carbaldehyde to give the title compound
8-(2-chloro-phenyl)-4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]-
pyrimidin-7-one. .sup.1H-NMR: .delta. 2.08 (s, 3H), 6.61 (d, 1H,
J=9.7 Hz), 7.11-7.51 (m, 9H). LC MS (m/e)=399 (MH+)
Example 34
[0409] ##STR50##
4,8-Bis-(2-chloro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one
[0410] Prepared as described above in Example 29 starting from
4-(2-chloro-phenyl)-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine--
5-carbaldehyde to give the title compound
4,8-bis-(2-chloro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-on-
e. .sup.1H-NMR: .delta. 1.99 (s, 3H), 6.50 (d, 1H, J=9.7 Hz),
7.11-7.48 (m, 9H). LC MS (m/e)=414 (MH+)
Example 35
[0411] ##STR51##
8-Cyclopropylmethyl-4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]p-
yrimidin-7-one
[0412] Prepared as described above in Example 29 starting from
4-(cyclopropylmethyl-amino)-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidi-
ne-5-carbaldehyde to give the title compound
8-cyclopropylmethyl-4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]-
pyrimidin-7-one. .sup.1H-NMR: .delta. 0.56 (m, 4H), 1.48 (m, 1H),
2.65 (s, 3H), 3.79 (s, 2H), 6.62 (d, 1H, J=9.7 Hz), 7.19-7.39 (m,
3H), 7.42-7.60 (m, 2H). LC MS (m/e)=342 (MH+)
Example 36
[0413] ##STR52##
8-Cyclopropyl-4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimid-
in-7-one
[0414] Prepared as described above in Example 29 starting from
4-cyclopropylamino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carb-
aldehyde to give the title compound
8-cyclopropyl-4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimi-
din-7-one. .sup.1H-NMR: .delta. 0.98 (m, 2H), 1.35 (m, 2H) 2.69 (s,
3H), 3.02 (m, 1H), 6.55 (d, 1H, J=9.6 Hz), 7.12-7.36 (m, 2H),
7.42-7.60 (m, 3H). LC MS (m/e)=328 (MH+).
Example 37
[0415] ##STR53##
8-sec-Butyl-4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-
-7-one
[0416] Prepared as described above in Example 29 starting from
4-sec-butylamino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbal-
dehyde to give the title compound
8-sec-butyl-4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidi-
n-7-one. 1H-NMR: .delta. 0.91 (m, 3H), 1.67 (m, 3H), 2.00-2.42 (m,
2H), 2.69 (s, 3H), 5.85 (m, 1H), 6.79 (d, 1H, J=9.7 Hz), 7.24-7.44
(m, 1H), 7.50-7.75 (m, 4H). LC MS (m/e)=328 (MH+)
Example 38
[0417] ##STR54##
4-(2-Fluoro-phenyl)-8-isopropyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-
-7-one
[0418] Prepared as described above in Example 29 starting from
4-(2-fluoro-phenyl)-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbal-
dehyde to give the title compound
4-(2-fluoro-phenyl)-8-isopropyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidi-
n-7-one. .sup.1H-NMR: .delta. 1.69 (m, 6H), 2.60 (s, 3H), 5.91 (m,
1H), 6.52 (d, 1H, J=9.6 Hz), 7.16-7.49 (m, 5H). LC MS (m/e)=330
(MH+).
Example 39
[0419] ##STR55##
8-Cyclopropylmethyl-4-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-8H-pyrid-
o[2,3-d]pyrimidin-7-one
[0420] Prepared as described above in Example 29 starting from
4-(cyclopropylmethyl-amino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-
-pyrimidine-5-carbaldehyde to give the title compound
8-cyclopropylmethyl-4-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-8H-pyri-
do[2,3-d]pyrimidin-7-one. .sup.1H-NMR: .delta. 0.55 (m, 4H), 1.56
(m, 1H), 2.23 (s, 3H), 2.67 (s, 3H), 4.40 (m, 2H), 6.60 (d, 1H,
J=9.6 Hz), 7.05 (m, 2H), 7.22 (m, 1H), 7.39 (d, 1H, J=9.6 Hz). LC
MS (m/e)=356 (MH+).
Example 40
[0421] ##STR56##
8-Cyclopropyl-4-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-8H-pyrido[2,3--
d]pyrimidin-7-one
[0422] Prepared as described above in Example 29 starting from
4-cyclopropylamino-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidi-
ne-5-carbaldehyde to give the title compound
8-cyclopropyl-4-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-
-d]pyrimidin-7-one. .sup.1H-NMR: .delta. 0.99 (m, 2H), 1.40 (m,
2H), 2.21 (s, 3H), 2.71 (s, 3H), 3.06 (m, 1H), 6.61 (d, 1H, J=9.6
Hz), 7.02 (m, 2H), 7.24 (m, 1H), 7.34 (d, 1H, J=9.6 Hz), LC MS
(m/e)=342 (MH+).
Example 41
[0423] ##STR57##
8-sec-Butyl-4-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]-
pyrimidin-7-one
[0424] Prepared as described above in Example 29 starting from
4-sec-butylamino-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-
-5-carbaldehyde to give the title compound
8-sec-butyl-4-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d-
]pyrimidin-7-one. .sup.1H-NMR: .delta.0.89 (m, 3H), 1.70 (m, 3H),
2.06-2.42 (m, 2H), 2.21 (s, 3H), 2.65 (s, 3H), 5.80 (m, 1H), 6.61
(d, 1H, J=9.7 Hz), 7.03 (m, 2H), 7.24 (m, 1H), 7.39 (d, 1H, J=9.7
Hz). LC MS (m/e)=328 (MH+).
Example 42
[0425] ##STR58##
4-(4-Fluoro-2-methyl-phenyl)-8-isopropyl-2-methylsulfanyl-8H-pyrido[2,3-d]-
pyrimidin-7-one
[0426] Prepared as described above in Example 29 starting from
4-(4-fluoro-2-methylphenyl)-6-isopropylamino-2-methylsulfanyl-pyrimidine--
5-carbaldehyde to give the title compound
4-(4-fluoro-2-methyl-phenyl)-8-isopropyl-2-methylsulfanyl-8H-pyrido[2,3-d-
]pyrimidin-7-one. .sup.1H-NMR: .delta. 1.68 (m, 6H), 2.21 (s, 3H),
2.70 (s, 3H), 5.95 (m, 1H), 6.60 (d, 1H, J=9.6 Hz), 6.95-7.11 (m,
2H), 7.18-7.32 (m, 2H). LC MS (m/e)=344 (MH+).
Example 43
[0427] ##STR59##
8-(2,6-Difluoro-phenyl)-4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-
-d]pyrimidin-7-one
[0428] Prepared as described above in Example 29 starting from
4-(2,6-difluoro-phenylamino)-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimid-
ine-5-carbaldehyde to give the title compound
8-(2,6-Difluoro-phenyl)-4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,-
3-d]pyrimidin-7-one. LC MS (m/e)=400 (MH+). Rt=2.42 min.
Example 44
[0429] ##STR60##
4-(2-Chloro-phenyl)-8-(1-ethyl-propyl)-2-methylsulfanyl-8H-pyrido[2,3-d]py-
rimidin-7-one
[0430] Prepared as described above in Example 29 starting from
4-(2-chloro-phenyl)-6-(1-ethyl-propylamino)-2-methylsulfanyl-pyrimidine-5-
-carbaldehyde to give the title compound
4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-2-methylsulfanyl-8H-pyrido[2,3-d]p-
yrimidin-7-one. .sup.1H-NMR: .delta.0.85 (m, 6H), 2.01 (m, 4H),
2.26-2.44 (m, 2H), 2.63 (s, 3H), 5.39 (m, 0.5H), 5.75 (m, 0.5H),
6.62 (br d, 1H, J=9.6), 7.31-7.60 (m, 5H). LC MS (m/e)=482
(MH+).
Example 45
[0431] ##STR61##
4-(4-Fluoro-2-methyl-phenyl)-8-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrid-
o[2,3-d]pyrimidin-7-one
[0432] Prepared as described above in Example 29 starting from
4-(4-fluoro-2-methyl-phenyl)-6-(2-fluoro-phenylamino)-2-methylsulfanyl-py-
rimidine-5-carbaldehyde to give the title compound
4-(4-fluoro-2-methyl-phenyl)-8-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyri-
do[2,3-d]pyrimidin-7-one. .sup.1H-NMR (CDCl.sub.3) .delta. 2.19 (s,
3H), 2.28 (s, 3H), 6.76 (d, 1H, J=9.6 Hz), 7.05 (m, 2H), 7.24-7.40
(m, 4H), 7.51 (m, 2H); LC MS (m/e)=396 (MH+).
Example 46
[0433] ##STR62##
2-Methanesulfonyl-4,8-diphenyl-8H-pyrido[2,3-d]pyrimidin-7-one
[0434] To a solution of
2-methylsulfanyl-4,8-diphenyl-8H-pyrido[2,3-d]pyrimidin-7-one (70
mg, 0.2 mmol) in dichloromethane (5 mL) was added
3-chloroperoxybenzoic acid (109 mg, 0.6 mmol, 3 eq) and the
reaction mixture was stirred 2 h at 23.degree., solvent was
evaporated and the yellow residue purified by Flash chromatography
to afford
2-methanesulfonyl-4,8-diphenyl-8H-pyrido[2,3-d]pyrimidin-7-one (55
mg, 71% yield). .sup.1H-NMR (CDCl.sub.3) .delta. 2.96 (s, 3H), 6.89
(d, 1H, J=9.8 Hz), 7.26 (m, 2H), 7.40-7.81 (m, 8H), 8.01 (d, 1H,
J=9.8 Hz), LC MS (m/e)=378 (MH+).
Example 47
[0435] ##STR63##
4,8-Bis-(2-chloro-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-on-
e
[0436] To a solution of
4,8-bis-(2-chloro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-on-
e (414 mg, 1 mmol) in CHCl.sub.3 (15 mL) was added
3-chloro-peroxybenzoic acid (549 mg, 3 mmol, 3 eq) and the reaction
mixture was stirred 5 h at 23.degree., then 1 M aq Na.sub.2CO.sub.3
(10 mL) was added, the layers were separated, and the organic layer
was washed with H.sub.2O, dried (MgSO.sub.4) and the solvent was
evaporated to afford
4,8-bis-(2-chloro-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-o-
ne (550 mg, 89% yield). .sup.1H-NMR (CDCl.sub.3) .delta. 3.15 (s,
3H), 6.96 (d, 1H, J=9.8 Hz), 7.26 (m, 2H), 7.51-7.80 (m, 9H). LC MS
(m/e)=446 (MH+).
Example 48
[0437] ##STR64##
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8H--
pyrido[2,3-d]pyrimidin-7-one
[0438] Prepared as described above in Example 47 starting from
8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-8H--
pyrido[2,3-d]pyrimidin-7-one to give the title compound
8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methane-sulfonyl-8-
H-pyrido[2,3-d]pyrimidin-7-one. LC MS (m/e)=446 (MH+). Rt=2.13
min.
Example 49
[0439] ##STR65##
4,8-Bis-(2-fluoro-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-on-
e
[0440] Prepared as described above in Example 47 starting from
4,8-bis-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-on-
e to give the title compound
4,8-bis-(2-fluoro-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-o-
ne. LC MS (m/e)=414 (MH+). Rt=1.96 min.
Example 50
[0441] ##STR66##
8-Cyclopropylmethyl-4-(2-fluoro-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]-
pyrimidin-7-one
[0442] Prepared as described above in Example 47 starting from
8-cyclopropylmethyl-4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]-
pyrimidin-7-one to give the title compound
8-cyclopropylmethyl-4-(2-fluoro-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d-
]pyrimidin-7-one. LC MS (m/e)=374 (MH+). Rt=1.90 min
Example 51
[0443] ##STR67##
8-sec-Butyl-4-(2-fluoro-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidi-
n-7-one
[0444] Prepared as described above in Example 47 starting from
8-sec-butyl-4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidi-
n-7-one to give the title compound
8-sec-butyl-4-(2-fluoro-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimid-
in-7-one. LC MS (m/e)=376 (MH+). Rt=1.95 min.
Example 52
[0445] ##STR68##
4-(2-Fluoro-phenyl)-8-isopropyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidi-
n-7-one
[0446] Prepared as described above in Example 47 starting from
4-(2-fluoro-phenyl)-8-isopropyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidi-
n-7-one to give the title compound
4-(2-fluoro-phenyl)-8-isopropyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimid-
in-7-one. LC MS (m/e)=362 (MH+). Rt=1.85 min.
Example 53
[0447] ##STR69##
8-Cyclopropylmethyl-4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8H-pyri-
do[2,3-d]pyrimidin-7-one
[0448] Prepared as described above in Example 47 starting from
8-cyclopropylmethyl-4-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-8H-pyri-
do[2,3-d]pyrimidin-7-one to give the title compound
8-cyclopropylmethyl-4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8H-pyr-
ido[2,3-d]pyrimidin-7-one. LC MS (m/e)=388 (MH+). Rt=2.13 min.
Example 54
[0449] ##STR70##
8-Cyclopropyl-4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-
-d]pyrimidin-7-one
[0450] Prepared as described above in Example 47 starting from
8-cyclopropyl-4-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-
-d]pyrimidin-7-one to give the title compound
8-cyclopropyl-4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8H-pyrido[2,-
3-d]pyrimidin-7-one. LC MS (m/e)=374 (MH+). Rt=1.79 min.
Example 55
[0451] ##STR71##
8-sec-Butyl-4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d-
]pyrimidin-7-one
[0452] Prepared as described above in Example 47 starting from
8-sec-butyl-4-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d-
]pyrimidin-7-one to give the title compound
8-sec-butyl-4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8H-pyrido[2,3--
d]pyrimidin-7-one. LC MS (m/e)=390 (MH+). Rt=2.05 min.
Example 56
[0453] ##STR72##
4-(4-Fluoro-2-methyl-phenyl)-8-isopropyl-2-methanesulfonyl-8H-pyrido[2,3-d-
]pyrimidin-7-one
[0454] Prepared as described above in Example 47 starting from
4-(4-fluoro-2-methyl-phenyl)-8-isopropyl-2-methylsulfanyl-8H-pyrido[2,3-d-
]pyrimidin-7-one to give the title compound
4-(4-fluoro-2-methyl-phenyl)-8-isopropyl-2-methanesulfonyl-8H-pyrido[2,3--
d]pyrimidin-7-one. LC MS (m/e)=376 (MH+). Rt=2.00 min.
Example 57
[0455] ##STR73##
8-(2,6-Difluoro-phenyl)-4-(2-fluoro-phenyl)-2-methanesulfonyl-8H-pyrido[2,-
3-d]pyrimidin-7-one
[0456] Prepared as described above in Example 47 starting from
8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,-
3-d]pyrimidin-7-one to give the title compound
8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-2-methanesulfonyl-8H-pyrido[2-
,3-d]pyrimidin-7-one. LC MS (m/e)=432 (MH+). Rt=2.04 min.
Example 58
[0457] ##STR74##
4-(2-Chloro-phenyl)-8-(1-ethyl-propyl)-2-methanesulfonyl-8H-pyrido[2,3-d]p-
yrimidin-7-one
[0458] Prepared as described above in Example 47 starting from
4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-2-methylsulfanyl-8H-pyrido[2,3-d]p-
yrimidin-7-one to give the title compound
4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-2-methanesulfonyl-8H-pyrido[2,3-d]-
pyrimidin-7-one. LC MS (m/e)=406 (MH+). Rt=2.15 min.
Example 59
[0459] ##STR75##
4-(4-Fluoro-2-methyl-phenyl)-8-(2-fluoro-phenyl)-2-methanesulfonyl-8H-pyri-
do[2,3-d]pyrimidin-7-one
[0460] Prepared as described above in Example 47 starting from
4-(4-fluoro-2-methyl-phenyl)-8-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyri-
do[2,3-d]pyrimidin-7-one to give the title compound
4-(4-fluoro-2-methyl-phenyl)-8-(2-fluoro-phenyl)-2-methanesulfonyl-8H-pyr-
ido[2,3-d]pyrimidin-7-one; LC MS (m/e)=428 (MH+). Rt=2.04 min.
Example 60
[0461] ##STR76##
2-(2-Diethylamino-ethylamino)-4,8-diphenyl-8H-pyrido[2,3-d]pyrimidin-7-one
[0462] A solution of the product of Example 46 (18.8 mg, 0.05
mmol), NMP (5 mL) and N,N-diethylethylenediamine (28 mg, 0.25 mmol,
5 eq) was heated to 50.degree.. After 1 h, H.sub.2O (20 mL) was
added and then EtOAc (20 mL). The layers were separated. The
organic layer was washed with satd aq NaCl, dried (MgSO.sub.4)
filtered and the solvent was evaporated in vacuo. The yellow
residue was purified by Flash chromatography to afford
2-(2-diethylamino-ethylamino)-4,8-diphenyl-8H-pyrido[2,3-d]pyrimidin-7-on-
e (21 mg, 89% yield). .sup.1H-NMR (CDCl.sub.3) .delta. 0.74-0.98
(m, 6H), 2.28-2.56 (m, 8H), 2.98 (br s, 1H), 6.32 (d, 1H, J=9.8
Hz), 7.26 (m, 2H), 7.09-7.88 (m, 11H), LC MS (m/e)=414 (MH+).
Example 61
[0463] ##STR77##
2-(2-Diethylamino-ethylamino)-8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-
-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one
[0464] The product of Example 48, and N,N-diethylenediamine were
reacted by the procedure of Example 60 to afford the title compound
2-(2-diethylamino-ethylamino)-8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methy-
l-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR (CDCl.sub.3)
.delta. 0.96 (m, 6H), 2.24 (s, 3H), 2.50 (m, 6H), 3.14 (m, 2H),
6.02 (br s, 1H), 6.36 (d, 1H, J=9.6 Hz), 7.08 (m, 4H), 7.24 (m,
2H), 7.49 (m, 1H). LC MS (m/e)=482 (MH+).
Example 62
[0465] ##STR78##
4,8-Bis-(2-chloro-phenyl)-2-(2-diethylamino-ethylamino)-8H-pyrido[2,3-d]py-
rimidin-7-one
[0466] The product of Example 47, and N,N-diethylenediamine were
reacted by the procedure of Example 60 to afford the title compound
4,8-bis-(2-chloro-phenyl)-2-(2-diethylamino-ethylamino)-8H-pyrido[2,3-d]p-
yrimidin-7-one. .sup.1H-NMR (CDCl.sub.3) .delta. 0.97 (m, 6H), 2.49
(s, 6H), 3.12 (m, 2H), 6.00 (br s, 1H), 7.18-7.63 (m, 9H). LC MS
(m/e)=482 (MH+).
Example 63
[0467] ##STR79##
8-(2-Chloro-phenyl)-2-(2-diethylamino-ethylamino)-4-(2-fluoro-phenyl)-8H-p-
yrido[2,3-d]pyrimidin-7-one
a)
8-(2-Chlorophenyl)-4-(2-fluorophenyl)-2-methanesulfonyl-8-H-pyrido[2,3--
d]pyrimidine-7-one
[0468] Prepared as described above in Example 47 starting from the
product of Example 33 to afford the title compound.
b)
8-(2-Chloro-phenyl)-2-(2-diethylamino-ethylamino)-4-(2-fluoro-phenyl)-8-
H-pyrido[2,3-d]pyrimidin-7-one
[0469] Prepared as described above in Example 60 starting from the
product of Example 63(a) to afford the title compound
8-(2-choro-phenyl)-2-(2-diethylamino-ethylamino)-4-(2-fluoro-phenyl)-8H-p-
yrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR (CDCl.sub.3) .delta. 0.99
(m, 6H), 2.49 (s, 6H), 3.16 (m, 2H), 6.03 (br s, 1H), 7.13-7.63 (m,
9H). LC MS (m/e)=466 (MH+).
Example 64
[0470] ##STR80##
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydrox-
ymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0471] To a solution of
8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8H-
-pyrido[2,3-d]pyrimidin-7-one (800 mg, 1.8 mmol) in
1-methyl-2-pyrrolidinone (8 mL) was added serinol (819 mg, 9 mmol,
5 eq) and the reaction mixture was heated to 50.degree.. After 1 h,
H.sub.2O (20 mL) was added, followed by Et.sub.2O (20 mL) and EtOAc
(20 mL). The layers were separated. The organic layer was washed
with satd aq NaCl, dried (MgSO.sub.4), filtered and the solvent was
evaporated. The yellow residue was then purified by Flash
chromatography to afford
8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydro-
xymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (750 mg, 92%
yield). .sup.1H-NMR (CDCl.sub.3) .delta. 2.30 (s, 3H), 3.67 (m,
1H), 3.88 (m, 4H), 6.30 (br s, 1H), 6.41 (d, 1H, J=9.6 Hz), 7.08
(m, 4H), 7.24 (m, 1H), 7.31 (d, 1H, J=9.6 Hz), 7.49 (m, 1H). LC MS
(m/e)=457 (MH+).
Example 65
[0472] ##STR81##
4,8-Bis-(2-chloro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyri-
do[2,3-d]pyrimidin-7-one
[0473] The product of Example 47, and serinol were reacted by the
procedure of Example 60 to afford the title compound
4,8-bis-(2-chloro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyr-
ido[2,3-d]pyrimidin-7-one. .sup.1H-NMR (CDCl.sub.3) .delta. 3.44
(m, 1H), 3.68 (m, 4H), 6.30 (br s, 1H), 6.48 (d, 1H, J=9.7 Hz),
7.24-7.65 (m, 9H). LC MS (m/e)=457 (MH+).
Example 66
[0474] ##STR82##
4-(2-Fluoro-phenyl)-8-(1-ethyl-propyl)-2-(2-hydroxy-1-hydroxymethyl-ethyla-
mino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0475]
4-(2-Fluorophenyl)-8-(1-ethylpropyl)-2-methanesulfonyl-8H-pyrido[2-
,3-d]pyrimidin-7-one, and serinol were reacted by the procedure of
Example 60 to afford the title compound
4-(2-fluoro-phenyl)-8-(1-ethyl-propyl)-2-(2-hydroxy-1-hydroxymethyl-ethyl-
amino)-8H-pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR: .delta. 0.82
(m, 6H), 1.32 (m, 4H), 1.90 (m, 2H), 2.32 (m, 2H), 3.71 (m, 2H),
4.24 (m, 1H), 5.38 (m, 0.5H), 5.69 (m, 0.5H), 5.71 (br s, 1H), 6.30
(br d, 1H, J=9.6), 7.13 (d, 1H, J=9.6 Hz), 7.30-7.55 (m, 4H). LC MS
(m/e)=401 (MH+)
Example 67
[0476] ##STR83##
4-(2-Chloro-phenyl)-8-(1-ethyl-propyl)-2-(2-hydroxy-1-hydroxymethyl-ethyla-
mino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0477] The product of Example 58, and serinol were reacted by the
procedure of Example 60 to afford the title compound
4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-2-(2-hydroxy-1-hydroxymethyl-ethyl-
amino)-8H-pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR: .delta. 0.84
(m, 6H), 1.91 (m, 2H), 2.32 (m, 2H), 3.02 (m, 2H), 3.95 (m, 4H),
4.14 (m, 1H), 5.30 (m, 0.5H), 5.52 (m, 0.5H), 6.28 (br d, 1H,
J=9.6), 6.40 (br s, 1H), 7.12 (d, 1H, J=9.6 Hz), 7.30-7.58 (m, 4H).
LC MS (m/e)=417 (MH+).
Example 68
[0478] ##STR84##
4-(2-Fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-isopropyl-8-
H-pyrido[2,3-d]pyrimidin-7-one
[0479] The product of Example 52, and serinol were reacted by the
procedure of Example 60 to afford the title compound
4-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-isopropyl--
8H-pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR: .delta. 1.54 (m, 6H),
3.80 (m, 4H), 4.11 (m, 1H), 5.75 (m, 1H), 6.19 (d, 1H, J=9.8), 6.38
(br s, 1H), 7.01-7.21 (m, 2H), 7.30-7.49 (m, 3H). LC MS (m/e)=373
(MH+).
Example 69
[0480] ##STR85##
8-Cyclopropyl-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-et-
hylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0481] The product of Example 54, and serinol were reacted by the
procedure of Example 60 to afford the title compound
8-cyclopropyl-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-e-
thylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR: .delta.
0.85 (m, 2H), 1.28 (m, 2H), 2.11 (m, 3H), 2.79 (m, 1H), 3.89 (m,
4H), 4.16 (m, 1H), 6.18 (d, 1H, J=9.8), 6.31 (br s, 1H), 6.85-7.14
(m, 4H). LC MS (m/e)=385 (MH+).
Example 70
[0482] ##STR86##
8-Cyclopropylmethyl-4-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethyl-
amino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0483] The product of Example 50, and serinol were reacted by the
procedure of Example 60 to afford the title compound
8-cyclopropylmethyl-4-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethy-
lamino)-8H-pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR: .delta. 0.40
(m, 4H), 1.25 (m, 1H), 3.89 (m, 4H), 4.13 (m, 3H), 5.75 (m, 1H),
6.30 (d, 1H, J=9.8 Hz), 6.59 (br s, 1H), 7.08-7.48 (m, 5H). LC MS
(m/e)=385 (MH+).
Example 71
[0484] ##STR87##
8-sec-Butyl-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethy-
lamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0485] The product of Example 55, and serinol were reacted by the
procedure of Example 60 to afford the title compound
8-sec-butyl-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl
ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR: .delta.
0.80 (m, 3H), 1.37 (m, 3H), 2.21 (m, 3H), 2.73 (m, 2H), 3.96 (m,
4H), 4.20 (m, 1H), 5.52 (m, 1H), 6.29 (m, 1H), 6.59 (br s, 1H),
6.91-7.40 (m, 4H). LC MS (m/e)=401 (MH+).
Example 72
[0486] ##STR88##
4-(4-Fluoro-2-methyl-phenyl)-8-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymet-
hyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0487] The product of Example 59, and serinol were reacted by the
procedure of Example 60 to afford the title compound
4-(4-fluoro-2-methyl-phenyl)-8-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxyme-
thyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR:
.delta. 2.24 (s, 3H), 2.68 (br s, 2H), 3.42 (m, 1H), 3.61 (m, 4H),
6.30 (br s, 1H), 6.38 (d, 1H, J=9.7 Hz), 7.02 (m, 2H), 7.27 (m,
5H), 7.46 (m, 1H). LC MS (m/e)=439 (MH+).
Example 73
[0488] ##STR89##
4,8-Bis-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyri-
do[2,3-d]pyrimidin-7-one
[0489] The product of Example 49, and serinol were reacted by the
procedure of Example 60 to afford the title compound
4,8-bis-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyr-
ido[2,3-d]pyrimidin-7-one. .sup.1H-NMR: .delta. 2.91 (br s, 2H),
3.39 (m, 1H), 3.55 (m, 4H), 6.05 (br s, 1H), 6.33 (d, 1H, J=9.7
Hz), 6.21 (m, 5H), 7.39 (m, 4H). LC MS (m/e)=425 (MH+).
Example 74
[0490] ##STR90##
8-(2,6-Difluoro-phenyl)-4-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-e-
thylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0491] The product of Example 57, and serinol were reacted by the
procedure of Example 60 to afford the title compound,
8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl--
ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR: .delta.
2.52 (br s, 2H), 3.45 (m, 1H), 3.60 (m, 4H), 6.28 (br s, 1H), 6.34
(d, 1H, J=9.7 Hz), 6.98 (m, 2H), 7.19 (m, 3H), 7.42 (m, 3H). LC MS
(m/e)=443 (MH+).
Example 75
[0492] ##STR91##
8-Cyclopropylmethyl-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymet-
hyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0493] The product of Example 53, and serinol were reacted by the
procedure of Example 60 to afford the title compound
8-cyclopropylmethyl-4-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethy-
lamino)-8H-pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR: .delta. 0.46
(m, 4H), 1.32 (m, 1H), 2.18 (s, 3H), 3.31 (br s, 2H), 3.89 (m, 4H),
4.15 (m, 3H), 6.30 (d, 1H, J=9.8 Hz), 6.59 (br s, 1H), 6.97 (m,
2H), 7.19 (m, 2H). LC MS (m/e)=399 (MH+).
Example 76
[0494] ##STR92##
4-(4-Fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-is-
opropyl-8H-pyrido[2,3-d]pyrimidin-7-one
[0495] The product of Example 56, and serinol were reacted by the
procedure of Example 60 to afford the title compound
4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-i-
sopropyl-8H-pyrido[2,3-d]pyrimidin-7-one .sup.1H-NMR: .delta. 1.61
(m, 6H), 2.15 (m, 3H), 3.45 (br s, 2H), 3.85 (m, 5H), 5.74 (m, 1H),
6.21 (d, 1H, J=9.8 Hz), 6.36 (br s, 1H), 6.91-7.20 (m, 4H). LC MS
(m/e)=387 (MH+).
Example 77
[0496] ##STR93##
4,8-Bis-(2-chloro-phenyl)-2-(2-dimethylamino-ethylamino)-8H-pyrido[2,3-d]p-
yrimidin-7-one
[0497] The product of Example 47, and N,N-dimethylethylenediamine
were reacted by the procedure of Example 60 to afford the title
compound
4,8-bis-(2-chloro-phenyl)-2-(2-dimethylamino-ethylamino)-8H-pyrido[2,3-d]-
pyrimidin-7-one (396 mg, 84% yield). .sup.1H-NMR (CDCl.sub.3)
.delta. 2.02-2.34 (m, 8H), 3.05 (m, 2H), 6.02 (br s, 1H), 6.39 (d,
1H, J=9.8 Hz), 7.24-7.62 (m, 9H). LC MS (m/e)=455 (MH+).
Example 78
[0498] ##STR94##
4,8-Bis-(2-chloro-phenyl)-2-(piperidin-4-ylamino)-8H-pyrido[2,3-d]pyrimidi-
n-7-one
[0499] The product of Example 47, and piperidin-4-ylamine were
reacted by the procedure of Example 60 to afford the title compound
4,8-bis-(2-chloro-phenyl)-2-(piperidin-4-ylamino)-8H-pyrido[2,3-d]pyrimid-
in-7-one. .sup.1H-NMR (CDCl.sub.3) .delta. 1.21 (m, 2H), 1.84 (m,
2H), 2.38 (m, 2H), 3.01 (m, 21), 3.30 (m, 1H), 5.36 (s, 1H), 6.40
(d, 1H, J=9.8 Hz), 7.20-7.62 (m, 9H). LC MS (m/e)=466 (MH+).
Example 79
[0500] ##STR95##
4,8-Bis-(2-chloro-phenyl)-2-(1-methyl-piperidin-4-ylamino)-8H-pyrido[2,3-d-
]pyrimidin-7-one
[0501] The product of Example 47, and 1-methylpiperidin-4-ylamine
were reacted by the procedure of Example 60 to afford the title
compound
4,8-bis-(2-chloro-phenyl)-2-(1-methyl-piperidin-4-ylamino)-8H-pyrido[2,3--
d]pyrimidin-7-one. .sup.1H-NMR (CDCl.sub.3) .delta. 1.42 (m, 2H),
1.79 (m, 4H), 2.25 (s, 3H), 2.75 (m, 2H), 3.15 (m, 1H), 5.33 (s,
1H), 6.39 (d, 1H, J=9.8 Hz), 7.24-7.59 (m, 9H). LC MS (m/e)=480
(MH+).
Example 80
[0502] ##STR96##
4,8-Bis-(2-chloro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylamino-
)-8H-pyrido[2,3-d]pyrimidin-7-one
[0503] The product of Example 47, and 2-amino-2-methylpropane
1,3-diol were reacted by the procedure of Example 60 to afford the
title compound
4,8-bis-(2-chloro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylamin-
o)-8H-pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR (CDCl.sub.3)
.delta. 1.01 (s, 3H), 3.43 (m, 2H), 3.62 (m, 2H), 6.03 (br s, 1H),
6.41 (d, 1H, J=9.6 Hz), 7.27-7.65 (m, 9H). LC MS (m/e)=471
(MH+).
Example 81
[0504] ##STR97##
4,8-Bis-(2-chloro-phenyl)-2-(2-hydroxy-ethylamino)-8H-pyrido[2,3-d]pyrimid-
in-7-one
[0505] The product of Example 47, and 2-aminoethanol were reacted
by the procedure of Example 60 to afford the title compound
4,8-bis-(2-chloro-phenyl)-2-(2-hydroxy-ethylamino)-8H-pyrido[2,3-d]pyrimi-
din-7-one. .sup.1H-NMR (CDCl.sub.3) .delta. 3.17 (m, 2H), 3.48 (m,
2H), 6.08 (br s, 1H), 6.45 (d, 1H, J=9.6 Hz), 7.26-7.67 (m, 9H). LC
MS (m/e)=427 (MH+).
Example 82
[0506] ##STR98##
2-(2-Amino-ethylamino)-4,8-bis-(2-chloro-phenyl)-8H-pyrido[2,3-d]pyrimidin-
-7-one
[0507] The product of Example 47, and 1,2-diaminoethane were
reacted by the procedure of Example 60 to afford the title compound
2-(2-amino-ethylamino)-4,8-bis-(2-chloro-phenyl)-8H-pyrido[2,3-d]pyrimidi-
n-7-one. .sup.1H-NMR (CDCl.sub.3) .delta. 2.59 (m, 2H), 3.11 (m,
2H), 5.91 (br s, 1H), 6.40 (d, 1H, J=9.6 Hz), 7.25-7.61 (m, 9H). LC
MS (m/e)=426 (MH+).
Example 83
[0508] ##STR99##
[4,8-Bis-(2-chloro-phenyl)-7-oxo-7
8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-acetic acid ethyl
ester
[0509] The product of Example 47, and ethyl glycinate were reacted
by the procedure of Example 60 to afford the title compound
[4,8-bis-(2-chloro-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yla-
mino]-acetic acid ethyl ester. .sup.1H-NMR (CDCl.sub.3) .delta.
1.21 (m, 3H), 3.59 (m, 2H), 4.12 (m, 2H), 5.91 (br s, 1H), 6.41 (m,
2H), 7.25-7.62 (m, 9H). LC MS (m/e)=469 (MH+). Rt=2.12 min
Example 84
[0510] ##STR100##
[4,8-Bis-(2-chloro-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylam-
ino]-acetic acid
[0511] To a solution of the product of Example 83 (20 mg, 0.43
mmol) in THF (2 mL) was added LiOH (40 mg, 1.67 mmol) dissolved in
H.sub.2O (1 mL). The reaction mixture was stirred 1 h at 23.degree.
and then neutralized with 1 M HCl, extracted with EtOAc (5 mL) and
the layers were separated. The organic layer was washed with
H.sub.2O, satd. aq NaCl, and dried (MgSO.sub.4). The solution was
filtered and evaporated to give the title
compound[4,8-bis-(2-chloro-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]p-
yrimidin-2-ylamino]-acetic acid. LC MS (m/e)=441 (MH+). Rt=1.85
min
Example 85
[0512] ##STR101##
4-(2-Chloro-phenyl)-2-(2-diethylamino-ethylamino)-8-(1-ethyl-propyl)-8H-py-
rido[2,3-d]pyrimidin-7-one
[0513] The product of Example 44, and N,N-diethylethylenediamine
were reacted by the procedure of Example 60 to afford
4-(2-chloro-phenyl)-2-(2-diethylamino-ethylamino)-8-(1-ethyl-propyl)-8H-p-
yrido[2,3-d]pyrimidin-7-one (371 mg, 80% yield. LC MS (m/e)=442
(MH+). Rt=1.77 min
Example 86
[0514] ##STR102##
2-(2-Amino-ethylamino)-4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-8H-pyrido[2,-
3-d]pyrimidin-7-one
[0515] The product of Example 44, and 1,2-diaminoethane were
reacted by the procedure of Example 60 to afford
2-(2-amino-ethylamino)-4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-8H-pyrido[2-
,3-d]pyrimidin-7-one. LC MS (m/e)=386 (MH+). Rt=1.54 min
Example 87
[0516] ##STR103##
4-(2-Chloro-phenyl)-8-(1-ethyl-propyl)-2-(2-hydroxy-ethylamino)-8H-pyrido[-
2,3-d]pyrimidin-7-one
[0517] The product of Example 44, and 2-aminoethanol were reacted
by the procedure of Example 60 to afford the title compound
4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-2-(2-hydroxy-ethylamino)-8H-pyrido-
[2,3-d]pyrimidin-7-one. LC MS (m/e)=387 (MH+). Rt=1.94 min
Example 88
[0518] ##STR104##
4-(2-Chloro-phenyl)-8-(1-ethyl-propyl)-2-((R)-2-hydroxy-1-methyl-ethylamin-
o)-8H-pyrido[2,3-d]pyrimidin-7-one
[0519] The product of Example 44, and (R)-2-aminopropan-1-ol were
reacted by the procedure of Example 60 to afford the title compound
4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-2-((R)-2-hydroxy-1-methyl-ethylami-
no)-8H-pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR: .delta. 0.81 (m,
6H), 1.30 (m, 2H), 1.96 (m, 2H), 2.36 (m, 2H), 3.71 (m, 2H), 4.25
(m, 1H), 5.31 (m, 0.5H), 5.56 (m, 0.5H), 5.71 (br s, 1H), 6.26 (br
d, 1H, J=9.6), 7.12 (d, 1H, J=9.6 Hz), 7.30-7.54 (m, 4H). LC MS
(m/e)=401 (MH+). Rt=2.07 min
Example 89
[0520] ##STR105##
4-(2-Chloro-phenyl)-8-(1-ethyl-propyl)-2-(1-methyl-piperidin-4-ylamino)-8H-
-pyrido[2,3-d]pyrimidin-7-one
[0521] The product of Example 44, and 1-methylpiperidin-4-ylamine
were reacted by the procedure of Example 60 to afford the title
compound
4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-2-(1-methyl-piperidin-4-ylamino)-8-
H-pyrido[2,3-d]pyrimidin-7-one. LC MS (m/e)=440 (MH+). Rt=1.67
min
Example 90
[0522] ##STR106##
4-(2-Chloro-phenyl)-8-(1-ethyl-propyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyri-
midin-2-ylamino]-acetic acid ethyl ester
[0523] The product of Example 44, and ethyl glycinate were reacted
by the procedure of Example 60 to afford the title compound
[4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]py-
rimidin-2-ylamino]-acetic acid ethyl ester. LC MS (m/e)=429 (MH+).
Rt=2.49 min
Example 91
[0524] ##STR107##
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-ethylami-
no)-8H-pyrido[2,3-d]pyrimidin-7-one
[0525] The product of Example 48, and 2-aminoethanol were reacted
by the procedure of Example 60 to afford the title compound
8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-ethylam-
ino)-8H-pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR (CDCl.sub.3)
.delta. 2.26 (s, 3H), 3.18 (m, 2H), 3.53 (m, 2H), 3.70 (br s, 1H),
6.21 (br s, 1H), 6.40 (d, 1H, J=9.7 Hz), 7.09 (m, 4H), 7.21-7.65
(m, 3H). LC MS (m/e)=427 (MH+). Rt=1.96 min
Example 92
[0526] ##STR108##
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(1-methyl-piperidin-
-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0527] The product of Example 48, and 1-methylpiperidin-4-ylamine
were reacted by the procedure of Example 60 to afford the title
compound
8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(1-methyl-piperidi-
n-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR
(CDCl.sub.3) .delta.1.45 (m, 2H), 1.85 (m, 4H), 2.40 (s, 3H), 2.72
(m, 2H), 3.30 (m, 1H), 5.41 (m, 1H), 6.38 (d, 1H, J=9.7 Hz), 7.05
(m, 4H), 7.29 (m, 3H). LC MS (m/e)=480 (MH+). Rt=1.67 min
Example 93
[0528] ##STR109##
N-(7-Oxo-4,8-diphenyl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-methanesulf-
onamide
[0529] To a solution of methylsulfonamide (200 mg, 2 mmol, 4 eq) in
DMF (2 mL) was added NaH (80 mg, 2 mmol, 60% dispersion in mineral
oil, 4 eq) and the reaction mixture was stirred for 30 min at
23.degree.. To this solution was added a solution of
2-methanesulfonyl-4,8-diphenyl-8H-pyrido[2,3-d]pyrimidin-7-one (190
mg, 0.5 mmol) in DMF (1 mL) and the mixture was heated to
50.degree.. After 1 h, H.sub.2O (10 mL) was added and then
Et.sub.2O (10 mL), the layers were separated, and the organic layer
was washed with satd aq NaCl, dried (MgSO.sub.4), filtered and the
solvent was evaporated. The yellow residue was then purified by
Flash chromatography to afford
N-(7-oxo-4,8-diphenyl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-methanesul-
fonamide (101 mg, 51% yield). .sup.1H-NMR (CDCl.sub.3) .delta. 2.82
(s, 3H), 6.69 (d, 1H, J=9.8 Hz), 7.31 (m, 2H), 7.59 (m, 8H), 7.91
(d, 1H, J=9.8 Hz), LC MS (m/e)=393 (MH+).
Example 94
[0530] ##STR110##
N-[4,8-Bis-(2-fluoro-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl-
]-methanesulfonamide
[0531] The product of Example 49, was reacted by the procedure of
Example 93 to afford the title compound
N-[4,8-bis-(2-fluoro-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-]pyrimidin-2-yl-
]-methanesulfonamide. .sup.1H-NMR (CDCl.sub.3) .delta. 2.81 (s,
3H), 6.66 (d, 1H, J=9.6 Hz), 7.24 (m, 4H), 7.48 (m, 4H), 7.87 (d,
1H, J=9.8 Hz), LC MS (m/e)=429 (MH+). Rt=1.84 min
Example 95
[0532] ##STR111##
N-[4-(2-Fluoro-phenyl)-8-isopropyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidi-
n-2-yl]-methanesulfonamide
[0533] The product of Example 52, was reacted by the procedure of
Example 93 to afford the title compound
N-[4-(2-fluoro-phenyl)-8-isopropyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimid-
in-2-yl]-methanesulfonamide. .sup.1H-NMR (CDCl.sub.3) .delta.1.68
(m, 6H), 3.52 (s, 3H), 5.82 (m, 1H), 6.68 (d, 1H, J=9.6 Hz),
7.21-7.61 (m, 5H). LC MS (m/e)=377 (MH+). Rt=1.83 min
Example 96
[0534] ##STR112##
N-[8-(2,6-Difluoro-phenyl)-4-(2-fluoro-phenyl)-7-oxo-7,8-dihydro-pyrido[2,-
3-d]pyrimidin-2-yl]-methanesulfonamide
[0535] The product of Example 56, was reacted by the procedure of
Example 93 to afford the title compound
N-[8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-7-oxo-7,8-dihydro-pyrido[2-
,3-d]pyrimidin-2-yl]-methanesulfonamide. .sup.1H-NMR (CDCl.sub.3)
.delta. 3.08 (s, 3H), 6.72 (d, 1H, J=9.6 Hz), 7.20 (m, 2H), 7.39
(m, 3H), 7.74 (m, 3H), LC MS (m/e) 447 (MH+). Rt=1.84 min
Example 97
[0536] ##STR113##
N-[8-(2,6-Difluoro
phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrim-
idin-2-yl]-methanesulfonamide
[0537] The product of Example 48, was reacted by the procedure of
Example 93 to afford the title compound
N-[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-
-pyrido[2,3-d]pyrimidin-2-yl]-methanesulfonamide. .sup.1H-NMR
(CDCl.sub.3) .delta. 2.29 (s, 3H), 3.04 (s, 3H), 6.69 (d, 1H, J=9.6
Hz), 7.16 (m, 4H), 7.59 (m, 3H). LC MS (m/e)=461 (MH+). Rt=1.90
min
Example 98
[0538] ##STR114##
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methoxy-8H-pyrido[2-
,3-d]pyrimidin-7-one
[0539] To a solution of the product of Example 30 (90 mg, 0.2 mmol)
in methanol (5 mL) was added sodium methoxide (1 mL of 25% w/w
solution in methanol, excess). The reaction mixture turned yellow
and was heated under reflux for 2 h evaporated and H.sub.2O (5 mL),
then EtOAc (20 mL), was added. The layers were separated. The
organic layer was washed with satd aq NaCl, dried (MgSO.sub.4),
filtered and evaporated. The yellow residue was then purified by
Flash chromatography to afford 71 mg (83% yield) of
8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methoxy--
8H-pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR (CDCl.sub.3) .delta.
2.30 (s, 3H), 3.82 (s, 3H), 6.61 (d, 1H, J=9.7 Hz), 7.01-7.18 (m,
4H), 7.25 (m, 1H), 7.52 (m, 2H); LC MS (m/e)=398 (MH+).
Example 99
[0540] ##STR115##
8-(2,6-Difluoro-phenyl)-2-ethoxy-4-(4-fluoro-2-methyl-phenyl)-8H-pyrido[2,-
3-d]pyrimidin-7-one
[0541] Prepared by the procedure of Example 98 using sodium
ethoxide to afford the title compound
8-(2,6-difluoro-phenyl)-2-ethoxy-4-(4-fluoro-2-methyl-phenyl)-8H-pyrido[2-
,3-d]pyrimidin-7-one. .sup.1H-NMR (CDCl.sub.3) .delta. 1.26 (m,
3H), 2.30 (s, 3H), 4.22 (m, 2H), 6.60 (d, 1H, J=9.6 Hz), 6.98-7.20
(m, 4H), 7.25 (m, 1H), 7.51 (m, 2H), LC MS (m/e)=412 (MH+).
Example 100
[0542] ##STR116##
2-Butoxy-8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-8H-pyrido[2,-
3-d]pyrimidin-7-one
[0543] Prepared by the procedure of Example 98 using sodium
butoxide to afford the title compound
2-butoxy-8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-8H-pyrido[2-
,3-d]pyrimidin-7-one. .sup.1H-NMR (CDCl.sub.3) .delta. 0.87 (m,
3H), 1.31 (m, 2H), 1.65 (m, 2H), 2.27 (s, 3H), 4.16 (m, 2H), 6.58
(d, 1H, J=9.6 Hz), 6.95-7.21 (m, 4H), 7.25 (m, 1H), 7.52 (m, 2H),
LC MS (m/e)=440 (MH+).
Example 101
[0544] ##STR117##
8-(2-Chloro-phenyl)-4-(2-fluoro-phenyl)-2-methoxy-8H-pyrido[2,3-d]pyrimidi-
n-7-one
[0545] Prepared as described above in Example 98 starting from
(E)-3-[4-(2-chloro-phenylamino)-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyri-
midin-5-yl]-acrylic acid methyl ester and sodium methoxide to
afford the title compound
8-(2-chloro-phenyl)-4-(2-fluoro-phenyl)-2-methoxy-8H-pyrido[2,3-d]pyrimid-
in-7-one. .sup.1H-NMR (CDCl.sub.3) .delta. 3.70 (s, 3H), 6.59 (d,
1H, J=9.7 Hz), 7.01-7.20 (m, 3H), 7.40 (m, 2H), 7.56 (m, 4H); LC MS
(m/e)=382 (MH+). Rt=2.24 min
Example 102
[0546] ##STR118##
4,8-Bis-(2-chloro-phenyl)-2-methoxy-8H-pyrido[2,3-d]pyrimidin-7-one
[0547] Prepared as described above in Example 98 starting from
(E)-3-[4-(2-chloro-phenylamino)-6-(2-chloro-phenyl)-2-methylsulfanyl-pyri-
midin-5-yl]-acrylic acid methyl ester and sodium methoxide to
afford the title compound
4,8-bis-(2-chloro-phenyl)-2-methoxy-8H-pyrido[2,3-d]pyrimidin-7-one.
.sup.1H-NMR (CDCl.sub.3) .delta. 3.71 (s, 3H), 6.55 (d, 1H, J=9.6
Hz), 7.24-7.60 (m, 9H). LC MS (m/e)=398 (MH+). Rt=2.27 min
Example 103
[0548] ##STR119##
8-(2,6-Difluoro-phenyl)-4-(2-fluoro-phenyl)-2-methoxy-8H-pyrido[2,3-d]pyri-
midin-7-one
[0549] Prepared as described above in Example 98 starting from
(E)-3-[4-(2,6-difluoro-phenyl
amino)-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidin-5-yl]-acrylic
acid methyl ester and sodium methoxide to afford the title compound
8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-2-methoxy-8H-pyrido[2,3-d]pyr-
imidin-7-one. .sup.1H-NMR (CDCl.sub.3) .delta. 3.82 (s, 3H), 6.56
(d, 1H, J=9.6 Hz), 7.08 (m, 2H), 7.26-7.59 (m, 6H). LC MS (m/e)=384
(MH+). Rt=2.22 min.
Example 104
[0550] ##STR120##
8-(1-Ethyl-propyl)-4-(4-fluoro-2-methyl-phenyl)-2-methoxy-8H-pyrido[2,3-d]-
pyrimidin-7-one
[0551] Prepared as described above in Example 98 starting from
(E)-3-[4-(1-ethyl-propylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfa-
nyl-pyrimidin-5-yl]-acrylic acid methyl ester and sodium methoxide
to afford the title compound
8-(1-ethyl-propyl)-4-(4-fluoro-2-methyl-phenyl)-2-methoxy-8H-pyrido[2,3-d-
]pyrimidin-7-one. .sup.1H-NMR (CDCl.sub.3) .delta. 0.89 (m, 6H),
2.02 (m, 2H), 2.22 (s, 3H), 2.33 (m, 2H), 3.39 (m, 2H), 4.09 (s,
3H), 5.35 (m, 0.5H), 5.62 (m, 0.5H), 6.41 (br d, 1H, J=9.6 Hz),
7.03 (m, 2H), 7.28 (m, 2H). LC MS (m/e)=356 (MH+). Rt=2.50 min.
Example 105
[0552] ##STR121##
4,8-Bis-(2-chloro-phenyl)-2-(2-hydroxy-ethoxy)-8H-pyrido[2,3-d]pyrimidin-7-
-one
[0553] Prepared as described above in Example 98 starting from
(E)-3-[4-(2-chloro-phenylamino)-6-(2-chloro-phenyl)-2-methylsulfanyl-pyri-
midin-5-yl]-acrylic acid methyl ester and ethylene glycol sodium
salt to afford the title compound
4,8-bis-(2-chloro-phenyl)-2-(2-hydroxy-ethoxy)-8H-pyrido[2,3-d]pyrimidin--
7-one. .sup.1H-NMR (CDCl.sub.3) .delta. 3.81 (m, 2H), 4.23 (m, 2H),
5.62 (m, 0.5H), 6.65 (d, 1H, J=9.6 Hz), 7.29-7.58 (9H). LC MS
(m/e)=428 (MH+). Rt=1.85 min
Example 106
[0554] ##STR122##
4-Amino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde
[0555] To a solution of the product of Example 17 (217 mg, 1.07
mmol) in dioxane (21 mL) and H.sub.2O (7 mL) was added anhydrous
K.sub.2CO.sub.3 (443 mg, 3.21 mmol, 3 eq) followed by
2-fluorophenylboronic acid (218 mg, 1.6 mmol, 1.5 eq). The reaction
mixture was degassed and tetrakis(triphenylphosphine)palladium (61
mg, 0.053 mmol, 0.05 eq) was added, and heated under reflux 24 h,
cooled to 23.degree.. The layers were separated. EtOAc (50 mL),
followed by H.sub.2O (10 mL), was added and the organic layer was
separated, washed with satd aq NaCl, dried (MgSO.sub.4), filtered,
and the solvent was evaporated. The residue was purified by Flash
chromatography (1:20 EtOAc:hexane to afford 180 mg (72% yield) of
pure
4-amino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde.
.sup.1H-NMR .delta. 2.58 (s, 3H), 5.80 (br s, 1H), 7.16 (m, 1H),
7.28 (m, 1H), 7.59 (m, 2H), 8.68 (br s, 1H), 9.71 (s, 1H), LC MS
(m/e)=264 (MH+). Rt=1.89 min
Example 107
[0556] ##STR123##
4-(2-Fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one
[0557] A solution of 18-crown-6 (422 mg, 1.6 mmol, 5 eq) and
bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (81
uL, 0.38 mmol, 1.2 eq) in anhyd THF (20 mL) was cooled to
-78.degree., potassium bis(trimethylsilyl)amide (0.96 mL, 0.48
mmol, 1.5 eq) as a 0.5 mol solution in toluene was added. This
solution was stirred for additional 30 min at -78.degree. and
4-amino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde
(85 mg, 0.32 mmol) in dry THF (1 mL) was added dropwise. The
reaction mixture was then stirred for 8 h at -78.degree. and warmed
to 23.degree., and stirred 16 h. Saturated aq NH.sub.4Cl (5 mL),
followed by Et.sub.2O (20 mL), was added. The layers were
separated. The organic layer was washed with satd aq NaCl, dried
(MgSO.sub.4), filtered and solvent was evaporated. The yellow
residue was purified by Flash chromatography to afford 100 mg (91%
yield) of
4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one.
.sup.1H-NMR 6 2.62 (s, 3H), 6.55 (d, 1H, J=9.9 Hz), 7.26 (m, 3H),
7.52 (m, 2H), 8.99 (br s, 1H). LC MS (m/e)=288 (NH+). Rt=1.75
min.
Example 108
[0558] ##STR124##
4-(2-Fluoro-phenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyridin-7-on-
e
[0559] To a solution of
4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one
(120 mg, 0.42 mmol) in 20 mL of anhyd THF was added NaH (50 mg, 1.2
mmol, 60% dispersion in mineral oil, 3 eq) followed by iodomethane
(74 .mu.L, 1.2 mmol, 3 eq). The reaction mixture was stirred 1 h at
23.degree., quenched with saturated aq NH.sub.4Cl. (20 mL),
Et.sub.2O (100 mL) was added and the layers were separated. The
organic layer was washed with satd aq NaCl, dried (MgSO.sub.4),
filtered and evaporated. The yellow residue was then purified by
Flash chromatography to afford 100 mg (92% yield) of
4-(2-Fluoro-phenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-
-one. .sup.1H-NMR .delta. 2.68 (s, 3H), 3.81 (s, 3H), 6.61 (d, 1H,
J=9.8 Hz), 7.22 (m, 3H), 7.50 (m, 3H). LC MS (m/e)=302 (MH+).
Rt=2.17 min.
Example 109
[0560] ##STR125##
8-Ethyl-4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-o-
ne
[0561] Prepared as described above in Example 108 starting from
4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one
and iodoethane to afford the title compound
8-ethyl-4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7--
one. LC MS (m/e)=316 (MH+). Rt=2.29 min
Example 110
[0562] ##STR126##
4-(2-Chloro-phenylamino)-2-methylsulfanyl-6-phenoxy-pyrimidine-5-carbaldeh-
yde
[0563] To a solution of
4-chloro-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldeh-
yde (315 mg, 1 mmol) in 10 mL of anhyd DMSO was added NaH (50 mg,
1.2 mmol, 60% dispersion in mineral oil, 1.2 eq) followed by phenol
(112 mg, 1.2 mmol, 1.2 eq). The reaction mixture was stirred for 1
h 23.degree., quenched with H.sub.2O (20 mL), Et.sub.2O (100 mL)
was added and the layers were separated. The organic layer was
washed with satd aq NaCl, dried (MgSO.sub.4) filtered and solvent
was removed in vacuo. The yellow residue was then purified by Flash
chromatography to afford 120 mg (45% yield) of
4-(2-chloro-phenylamino)-2-methylsulfanyl-6-phenoxy-pyrimidine--
5-carbaldehyde. .sup.1H-NMR .delta. 2.32 (s, 3H), 7.01-7.49 (m,
8H), 8.51 (d, 1H, J=7.2 Hz), 10.49 (s, 1H), 11.58 (br s, 1H). LC MS
(m/e)=372 (MH+). Rt=2.94 min.
Example 111
[0564] ##STR127##
8-(2-Chloro-phenyl)-2-methylsulfanyl-4-phenoxy-8H-pyrido[2,3-d]pyrimidin-7-
-one
[0565] A solution of 18-crown-6 (422 mg, 1.6 mmol, 5 eq) and
bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (81
.mu.L, 0.38 mmol, 1.2 eq) in anhyd THF (20 mL) was cooled to
-78.degree.. To this solution was added potassium
bis(trimethylsilyl)amide (0.96 mL, 0.48 mmol, 1.5 eq) as a 0.5 mol
solution in toluene. This solution was stirred for additional 30
min at -78.degree. and
4-(2-chloro-phenylamino)-2-methylsulfanyl-6-phenoxy-pyrimidine-5-carbalde-
hyde (119 mg, 0.32 mmol) in dry TH (1 mL) was added dropwise. The
reaction mixture was then stirred for 8 h at -78.degree. and warmed
to 23.degree. and stirred 16 h. Saturated aq NH.sub.4Cl (5 mL),
followed by Et.sub.2O (20 mL), was added. The layers were
separated. The organic layer was washed with satd aq NaCl, dried
(MgSO.sub.4) filtered and solvent was removed in vacuo. The yellow
residue was then purified by Flash chromatography to give 100 mg
(91% yield) of pure
8-(2-chloro-phenyl)-2-methylsulfanyl-4-phenoxy-8H-pyrido[2,3-d]pyrimidin--
7-one. .sup.1H-NMR .delta. 1.89 (s, 3H), 6.55 (d, 1H, J=9.9 Hz),
7.18 (m, 4H), 7.28 (m, 4H), 7.44 (m, 1H), 7.98 (d, 1H, J=9.9 Hz).
LC MS (m/e)=396 (MH+). Rt=2.68 min.
Example 112
[0566] ##STR128##
2-Amino-8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-8H-pyrido[2,3-d]pyrimi-
din-7-one
[0567] To a solution of
8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-2-methanesulfonyl-8H-pyrido[2-
,3-d]pyrimidin-7-one (432 mg, 1 mmol) in 1-methyl-2-pyrrolidinone
(5 mL) was added NaNH.sub.2 (195 mg, 5 mmol, 5 eq) and the mixture
was heated to 50.degree.. After 1 h, H.sub.2O (20 mL) was added
then Et.sub.2O (20 mL). The layers were separated. The organic
layer was washed with satd aq NaCl, dried (MgSO.sub.4), filtered
and solvent was removed in vacuo. The yellow residue was then
purified by Flash chromatography to afford
2-amino-8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-8H-pyrido[2,3-d]pyrim-
idin-7-one (100 mg, 53% yield). .sup.1H-NMR (CDCl.sub.3) .delta.
5.51 (br s, 2H), 6.42 (d, 1H, J=9.8 Hz), 7.08 (m, 2H), 7.30 (m,
2H), 7.50 (m, 4H), LC MS (m/e)=369 (MH+). Rt=1.77 min
Example 113
[0568] ##STR129##
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-5,8--
dihydro-6H-pyrido[2,3-d]pyrimidin-7-one
a)
3-[4-(2,6-difluoro-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsu-
lfanyl-pyrimidin-5-yl]-propionic acid methyl ester
[0569] To a solution of SmI.sub.2 in THF (0.1M) (Aldrich) (15 mL,
1.5 mmol) and MeOH (3 mL) was added the product of Example 30 (100
mg, 0.22 mmol) and the reaction mixture maintained its blue color.
The presence of new product and the disappearance of starting
material was indicated by hplc. After 30 min, the reaction was
diluted with H.sub.2O (10 mL), then 1 M HCl (3 mL), followed by
EtOAc (20 mL), the layers were shaken together and separated. The
aq phase was washed with EtOAc (20 mL) and the combined EtOAc was
dried (MgSO.sub.4) and the solvent was evaporated in vacuo and the
residue was crystallized from i-PrOH/H.sub.2O (1:1) to afford
3-[4-(2,6-difluoro-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-met-
hylsulfanyl-pyrimidin-5-yl]-propionic acid methyl ester. LC MS
(m/e)=448.2 (MH+), Rt=2.17 min.
b)
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-5-
,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one
[0570] To a solution of
3-[4-(2,6-difluoro-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulf-
anyl-pyrimidin-5-yl]-propionic acid methyl ester (45 mg, 0.1 mmol)
in methanol (5 mL) was added a solution of sodium methoxide (0.5
mL) and the reaction mixture was heated under reflux for 1 h. The
reaction mixture was then evaporated, and EtOAc (20 mL) followed by
H.sub.2O (10 mL) were added. Layers were separated, organic washed
with satd aq NaCl, dried (MgSO.sub.4), filtered and the solvent was
evaporated. Dichloromethane (5 mL) was added followed by 0.5 mL of
oxalyl chloride and 0.1 mL of Et.sub.3N. The reaction mixture was
then stirred for 2 h at 23.degree., H.sub.2O (5 mL) was then added
followed by dichloromethane (15 mL). Layers were separated, organic
layer was washed with sat'd aq. NaCl, dried (MgSO.sub.4), filtered
and solvent was evaporated. The yellow residue was purified by
Flash chromatography to give 11.2 mg (21% yield) of pure
8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methylsulf-
anyl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR
(CDCl.sub.3): .delta. 2.20 (s, 3H), 2.29 (s, 3H), 3.85 (m, 4H),
7.02 (m, 4H), 7.21 (m, 1H), 7.42 (m, 1H). LC MS (m/e)=416.2 (MH+).
Rt=2.44 min.
Example 114
[0571] ##STR130##
2-(2-Diethylamino-ethylamino)-8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-
-phenyl)-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one
[0572] The product of Example 113(b), and N,N-diethylenediamine
were reacted by the procedure of Example 60 to afford the title
compound
2-(2-diethylamino-ethylamino)-8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methy-
l-phenyl)-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR
(CDCl.sub.3): .delta. 1.01 (m, 6H), 2.01-2.80 (m, 11H), 6.89-7.40
(m, 6H). LC MS (m/e)=484.2 (MH+). Rt=1.80 min
Example 115
[0573] ##STR131##
4-(4-Fluoro-2-methyl-phenyl)-2-(2-hydroxy-ethylamino)-8-isopropyl-8H
prido 2 3-d]pyrimidin-7-one
[0574] The product of Example 56 and 2-aminoethanol were reacted by
the procedure of Example 60 to afford the title compound
4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-ethylamino)-8-isopropyl-8H-pyri-
do[2,3-d]pyrimidin-7-one. .sup.1H-NMR (CDCl.sub.3) .delta. 1.78 (m,
6H), 2.29 (s, 3H), 3.70 (br s, 2H), 3.89 (br s, 3H), 5.81 (m 1H),
6.02 (br s, 1H), 6.23 (d, 1H, J=9.7 Hz), 7.00 (m, 2H). 7.11 (d, 1H,
J=9.7 Hz), 7.19 (m, 1H), LC MS (m/e)=357.2 (MH+). Rt=1.80 min.
Example 116
[0575] ##STR132##
N-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro--
pyrido[2,3-d]pyrimidin-2-yl]-N-methyl-methanesulfonamide
[0576] To the solution of
N-[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-
-pyrido[2,3-d]pyrimidin-2-yl]-methanesulfonamide (92 mg, 0.2 mmol)
in anhydrous DMF (2 mL) was added NaH (80 mg of 60% dispersion in
mineral oil, 2 mmol, 10 eq) and the reaction mixture was stirred
for 30 minutes at 23.degree.. Iodomethane (280 mg, 2 mmol, 10 eq)
was added and the reaction mixture was stirred 1 h at 23.degree..
Saturated aq NH.sub.4Cl (5 mL) was added and the reaction mixture
was extracted with EtOAc (2.times.20 mL). Organic layers were
combined, washed with satd aq NaCl, dried (MgSO.sub.4), filtered
and solvent was evaporated. The yellow residue was then purified by
Flash chromatography to give 80 mg of pure
N-[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-
-pyrido[2,3-d]pyrimidin-2-yl]-N-methyl-methanesulfonamide.
.sup.1H-NMR (CDCl.sub.3): .delta. 2.22 (s, 3H), 2.96 (s, 3H), 3.30
(s, 3H), 6.68 (d, 1H, J=9.8 Hz), 7.02 (m, 4H). 7.213 (m, 1H), 7.42
(m, 2H), LC MS (m/e)=475.4 (MH+). Rt=2.25 min.
Example 117
[0577] ##STR133##
N-[4-(4-Fluoro-2-methylphenyl)-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]p-
yrimidin-2-yl]-N-methylmethanesulfonamide
[0578] Prepared as described above in Example 115 starting from
N-[4-(4-fluoro-2-methyl-phenyl)-8-isopropyl-7-oxo-7,8-dihydro-pyrido[2,3--
d]pyrimidin-2-yl]-methanesulfonamide to give the title compound
N-[4-(4-fluoro-2-methyl-phenyl)-8-isopropyl-7-oxo-7,8-dihydro-pyrido[2,3--
d]pyrimidin-2-yl]-N-methyl-methanesulfonamide. .sup.1H-NMR
(CDCl.sub.3): .delta. 1.75 (d, 6H, J=6.9 Hz), 2.18 (s, 3H), 3.39
(s, 3H), 3.53 (s, 3H), 5.81 (m 1H), 6.40 (d, 1H, J=9.7 Hz), 6.96
(m, 2H), 7.11 (m, 1H), 7.21 (d, 1H, J=9.7 Hz), LC MS (m/e)=405.4
(MH+). Rt=2.20 min
Example 118
[0579] ##STR134##
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-hydroxy-8H-pyrido[2-
,3-d]pyrimidin-7-one
[0580] To a solution of
8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8H-
-pyrido[2,3-d]pyrimidin-7-one (223 mg, 0.5 mmol) in
N-methylpyrollidine (5 mL) was added Et.sub.3N (0.1 mL) followed by
2-aminoethanesulfonic acid (200 mg, 1.5 mmol, 3 eq) and the
reaction mixture was heated to 50.degree. for 12 h. 1 M aq HCl was
then added dropwise till pH 3. The reaction mixture was then
extracted with EtOAc (2.times.20 mL). Organic layers were combined,
washed with satd aq NaCl, dried (MgSO.sub.4), filtered and solvent
was evaporated. The yellow residue was then purified by flash
chromatography to give an oily product, which was then
recrystallized from methanol:H.sub.2O (3:1) to afford 51 mg of pure
8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-hydroxy-8H-pyrido[-
2,3-d]pyrimidin-7-one. .sup.1H-NMR (CDCl.sub.3): .delta. 2.24 (s,
3H), 6.31 (d, 1H, J=9.8 Hz), 7.02 (m, 5H). 7.23 (m, 1H), 7.352 (m,
1H), LC MS (m/e)=384.2 (MH+). Rt=1.65 min
Example 119
[0581] ##STR135##
4-(4-Fluoro-2-methyl-phenyl)-2-methylsulfanyl-8-ortho-tolyl-8H-pyrido[2,3--
d]pyrimidin-7-one
[0582] Prepared as described above in Example 32 starting from
4-(4-Fluoro-2-methyl-phenyl)-2-methylsulfanyl-6-ortho-tolylamino-pyrimidi-
ne-5-carbaldehyde to give the title compound
4-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-8-ortho-tolyl-8H-pyrido[2,3-
-d]pyrimidin-7-one. .sup.1H-NMR (CDCl.sub.3): .delta. 2.02 (s, 3H),
2.20 (s, 3H), 2.28 (s, 3H), 6.79 (d, 1H, J=9.7 Hz).7.02 (m, 2H),
7.17 (m, 1H), 7.22 (m, 2H), 7.40 (m, 2H). 7.53 (d, 1H, J=9.7 Hz).
LC MS (m/e)=392.2 (MH+). Rt=2.40 min
Example 120
[0583] ##STR136##
8-(2,6-Dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-8H-p-
yrido[2,3-d]pyrimidin-7-one
[0584] Prepared as described above in Example 32 starting from
4-(2,6-dimethyl-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfany-
l-pyrimidine-5-carbaldehyde to give the title compound
8-(2,6-dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-8H--
pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR (CDCl.sub.3): .delta.
2.05 (s, 6H), 2.26 (s, 3H), 2.31 (s, 3H), 6.81 (d, 1H, J=9.7 Hz),
7.02 (m, 2H), 7.17 (m, 5H), 7.51 (d, 1H, J=9.7 Hz). LC MS
(m/e)=406.4 (MH+). Rt=2.55 min.
Example 121
[0585] ##STR137##
4-(4-Fluoro-2-methyl-phenyl)-2-methanesulfonyl-8-ortho-tolyl-8H-pyrido[2,3-
-d]pyrimidin-7-one
[0586] Prepared as described above in Example 47 starting from
4-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-8-ortho-tolyl-8H-pyrido[2,3-
-d]pyrimidin-7-one to give the title compound
4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8-ortho-tolyl-8H-pyrido[2,-
3-d]pyrimidin-7-one. LC MS (m/e)=424.2 (MH+). Rt=2.02 min
Example 122
[0587] ##STR138##
8-(2,6-Dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8H--
pyrido[2,3-d]pyrimidin-7-one
[0588] Prepared as described above in Example 47 starting from
8-(2,6-dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-8H--
pyrido[2,3-d]pyrimidin-7-one to give the title compound
8-(2,6-dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8H-
-pyrido[2,3-d]pyrimidin-7-one. LC MS (m/e)=438.0 (MH+). Rt=2.07
min
Example 123
[0589] ##STR139##
8-(2,6-Dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-ethylami-
no)-8H-pyrido[2,3-d]pyrimidin-7-one
[0590] Prepared as described above in Example 60 starting from
8-(2,6-dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8H-
-pyrido[2,3-d]pyrimidin-7-one and 2-aminoethanol to give the title
compound
8-(2,6-dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydrox-
y-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR
(CDCl.sub.3): .delta. 1.92 (s, 6H), 2.12 (s, 3H), 2.95 (br s, 2H),
3.30 (br s, 2H), 3.45 (br s, 1H), 6.31 (d, 1H, J=9.7 Hz), 6.92 (m,
2H), 7.17 (m, 5H). LC MS (m/e)=419.4 (MH+). Rt=1.84 min
Example 124
[0591] ##STR140##
8-(2,6-Dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydrox-
ymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0592] The product of Example 122, and serinol were reacted by the
procedure of Example 60 to afford the title compound
8-(2,6-dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydro-
xymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR
(CDCl.sub.3): .delta. 1.91 (s, 6H), 2.14 (s, 3H), 3.45 (br s, 4H),
3.93 (br s, 1H), 6.20 (br s, 1H), 6.31 (d, 1H, J=9.7 Hz), 6.93 (m,
2H), 7.11 (m, 5H). LC MS (m/e)=449.0 (MH+). Rt=1.62 min
Example 125
[0593] ##STR141##
4-(4-Fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-or-
tho-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one
[0594] The product of Example 121, and serinol were reacted by the
procedure of Example 60 to afford the title compound
4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-o-
rtho-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one. .sup.1H-NMR
(CDCl.sub.3): .delta. 2.09 (s, 3H), 2.26 (s, 3H), 3.73 (br s, 4H),
4.02 (br s, 1H), 6.30 (br s, 1H), 6.41 (d, 1H, J=9.7 Hz), 7.05 (m,
2H), 7.24 (m, 6H). LC MS (m/e)=435.2 (MH+). Rt=1.60 min
Example 126
[0595] ##STR142##
4-(4-Fluoro-2-methyl-phenyl)-2-(2-hydroxy-ethylamino)-8-o-tolyl-8H
pyrido[2,3-d]pyrimidin-7-one
[0596] The product of Example 121 (400 mg, 0.95 mmol) and
ethanolamine (0.29 mL, 4.73 mmol) in NMP (2 mL) was stirred at
23.degree. for 1 h. The mixture was diluted with EtOAc, washed with
H.sub.2O, the organic phase was separated, EtOAc was removed in
vacuo and the residue was purified by Flash chromatography on
silica gel, eluting with EtOAc/hexane/triethylamine(50/50/2,
v/v/v), followed by evaporation of solvent to afford a gummy
residue. Trituration with H.sub.2O, gave the title compound
compound
4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-o-
rtho-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one as a white solid (340
mg, 88%). LC-MS: 405.4 (MH+, m/z), Rt=1.85 min
Example 127
[0597] ##STR143##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-(3-methylsulfanylprop-
oxy)-8H-pyrido[2,3-d]pyrimidin-7-one
[0598] NaH (12 mg, 0.5 mmol) was added to 3-(methylthio)-1-propanol
(0.5 mL) and the mixture was stirred under Ar at 23.degree. . After
5 min, gas evolution ceased, and the product of Example 48 (223 mg,
0.5 mmol) was added in a single portion. The mixture was stirred
for 30 minutes. Most of the excess 3-(methylthio)-1-propanol was
removed in vacuo, and the residue partitioned between EtOAc and
H.sub.2O. The organic phase was washed with H.sub.2O, satd aq NaCl,
dried over anhyd Na.sub.2SO.sub.4, filtered and evaporated to give
the crude product. Flash chromatography eluted with 10-30%
EtOAc/hexane, followed by recrystallization from
CH.sub.2Cl.sub.2/hexane gave the title compound as a white
crystalline solid. mp 127-1280, LC MS m/z=472 (MH+) Retention
time=2.47 min.
Example 128
[0599] ##STR144##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-(3-methanesulfonylpro-
poxy)-8H-pyrido[2,3-d]pyrimidin-7-one
[0600] To the product of Example 127 (100 mg, 0.21 mmol) in
chloroform (10 mL) was added 80% 3-chloroperoxybenzoic acid (135
mg, 0.63 mmol). The mixture was stirred under Ar at 23.degree. for
2 h, after which time the solvent was removed in vacuo, and the
residue was partitioned between EtOAc and 1 M Na.sub.2CO.sub.3. The
organic phase was washed with H.sub.2O, satd aq NaCl, dried over
anhyd Na.sub.2SO.sub.4, filtered and evaporated to give the crude
product. Flash chromatography eluted with 0-20%
EtOAc/CH.sub.2Cl.sub.2, followed by recrystallization from
CH.sub.2Cl.sub.2/hexane gave the title compound as a white
crystalline solid. mp 160-162.degree., LC MS m/z=504 (MH+)
Retention time=2.02 min.
Example 129
[0601] ##STR145##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-(2-hydroxy
1-hydroxymethylethoxy)-8H-pyrido[2,3-d]pyrimidin-7-one
[0602] 1,3-O-Benzylideneglycerol (100 mg, 0.55 mmol) was dissolved
in dry THF (5 mL) and stirred under Ar at 23.degree. C. NaH (14 mg,
0.55 mmol) was added and the mixture stirred for 15 minutes at
23.degree. C., and then cooled to -78.degree.. The product of
Example 48 (222 mg, 0.5 mmol) was added, and the mixture was
allowed to slowly warm to 23 . The solvent was removed in vacuo,
and the residue was dissolved in acetic acid (2 mL), and H2O (0.5
mL) was added. The mixture was heated in an oil bath to 60.degree.
C. for three h, and then the solvents were removed in vacuo to give
the crude product. The crude product was flash chromatographed
twice on silica gel eluted with 20-50% EtOAc/CH.sub.2Cl.sub.2 to
give the product as a white-amorphous solid. 104-107.degree. C., LC
MS m/z=458 (MH+) Retention time=1.88 min.
Example 130
[0603] ##STR146##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[2-(tert-butoxycarbon-
ylamino)ethoxy]-8H-pyrido[2,3-d]pyrimidin-7-one
[0604] The product of Example 48 (445 mg, 1 mmol) and
BOC-aminoethanol (177 mg, 1.1 mmol) was dissolved in THF (10 mL),
and cooled to -78.degree. while stirring under Ar. NaH (28 mg, 1.1
mmol) was added in a single portion. The mixture allowed to slowly
warm to 23.degree., but the reaction did not go to completion.
Additional NaH (10 mg, 0.4 mmol) was added, and the reaction went
to completion. The solvent was removed in vacuo, and the residue
was partitioned between EtOAc and H2O. The organic phase was washed
with H2O, satd aq NaCl, dried over anhyd Na.sub.2SO.sub.4, filtered
and evaporated to give the crude product. Flash chromatography
eluted with 0-10% EtOAc/hexane gave the title compound as a
white-amorphous solid. mp 103-105.degree., LC MS m/z=527 (MH+)
Retention time=2.44 min.
Example 131
[0605] ##STR147##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-(2-aminoethoxy)-8H-py-
rido[2,3-d]pyrimidin-7-one
[0606] The product of Example 130 (1 g, 1.9 mmol) was dissolved in
CH.sub.2Cl.sub.2 (8 mL) and stirred under Ar in an ice bath. A
chilled solution of 25% TFA in CH.sub.2Cl.sub.2 (40 mL) was added,
and the mixture was stirred for 45 min at 0.degree. C. The solvents
were removed in vacuo, and the residue was partitioned between
EtOAc and a saturated NaHCO.sub.3 solution. The organic phase was
washed with H.sub.2O, satd aq NaCl, dried over anhyd
Na.sub.2SO.sub.4, filtered and evaporated to give the crude
product. Flash chromatography eluted with 0-10%
MeOH/CH.sub.2Cl.sub.2 gave the title compound as a white-amorphous
solid. mp 96-99.degree., LC MS m/z=427 (MH+) Retention time=1.52
min.
Example 132
[0607] ##STR148##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-(2-acetylaminoethoxy)-
-8H-pyrido[2,3-d]pyrimidin-7-one
[0608] The product of Example 131 (61 mg, 0.14 mmol)was dissolved
in CH.sub.2Cl.sub.2 (2 mL) and stirred at 0.degree. C. under Ar.
Triethylamine (0.1 mL) was added followed by the addition of acetic
anhydride (0.2 g, 2 mmol). The reaction was allowed to slowly warm
to 23.degree. and stir for 18 h. The solvents were removed in
vacuo, and the residue was flash chromatographed eluted with 10-30%
EtOAc/CH.sub.2Cl.sub.2 to give the title compound as a
white-amorphous solid. mp 75-79.degree., LC MS m/z=469 (MH+)
Retention time=1.95 min.
Example 133
[0609] ##STR149##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-(3-hydroxy-2-hydroxym-
ethylpropoxy)-8H-pyrido[2,3-d]pyrimidin-7-one
[0610] NaH (15 mg, 0.6 mmol) was added to
2-(hydroxymethyl)-1,3-propanediol in THF (5 mL). The mixture was
allowed to stir at 23.degree. under Ar for 10 min and was then
cooled to -78.degree.. The product of Example 48 (224 mg, 0.5 mmol)
in THF (5 mL) was added at -78.degree. and the mixture allowed to
warm to 23.degree. and stir for 2 h. The solvents were removed in
vacuo, and the residue was partitioned between EtOAc and H.sub.2O.
The organic phase was washed with H.sub.2O, satd aq NaCl, dried
over anhyd Na.sub.2SO.sub.4, filtered and evaporated to give the
crude product. Flash chromatography eluted with 70%
EtOAc/CH.sub.2Cl.sub.2 the title compound as a white-amorphous
solid. mp 77-81.degree., LC MS m/z=472 (MH+) Retention time=1.79
min.
Example 134
[0611] ##STR150##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-(2-methanesulfonyl-am-
inoethoxy)-8H-pyrido[2,3-d]pyrimidin-7-one
[0612] The product of Example 131 (100 mg, 0.23 mmol) in
CH.sub.2Cl.sub.2 (4 mL) was stirred under Ar at 23.degree..
Triethylamine (0.1 mL) was added followed by the addition of a
solution of methanesulfonyl chloride (29 mg, 0.25 mmol) in
CH.sub.2Cl.sub.2 (1 mL). The solvents were removed in vacuo, and
the residue was partitioned between EtOAc and H.sub.2O. The organic
phase was washed with H2O, satd aq NaCl, dried over anhyd
Na.sub.2SO.sub.4, filtered and evaporated to give the crude
product. Flash chromatography eluted with 0-10%
EtOAc/CH.sub.2Cl.sub.2 gave the title compound as a white-amorphous
solid. mp 95-99.degree., LC MS m/z=505 (MH+) Retention time=2.02
min.
Example 135
[0613] ##STR151##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-(2-N-methanesulfonyl--
N-methylaminoethoxy)-8H-pyrido[2,3-d]pyrimidin-7-one
[0614] The product of Example 134 (20 mg, 0.04 mmol) was dissolved
in acetone (2 mL) and stirred under Ar at 23.degree.. Potassium
carbonate (7 mg, 0.05 mmol) was added, followed by the addition of
a solution of iodomethane (6.4 mg, 0.045 mmol) in acetone (1 mL).
The mixture was allowed to stir for 18 h, the solvents were removed
in vacuo, and the residue was partitioned between EtOAc and
H.sub.2O. The organic phase was washed with H2O, satd aq NaCl,
dried over anhyd Na.sub.2SO.sub.4, filtered and evaporated to give
the crude product. Flash chromatography eluted with 0-5%
EtOAc/CH.sub.2Cl.sub.2 gave the title compound as a white-amorphous
solid. mp 89-92.degree., LC MS m/z=519 (MH+) Retention time=2.2
min.
Example 136
[0615] ##STR152##
4-(4-fluoro-2-methylphenyl)-8-(2-fluorophenyl)-2-(2-hydroxylethylamino)-8H-
-pyrido[2,3-d]pyrimidin-7-one
[0616] The product of Example 59 (200 mg, 0.47 mmol) was dissolved
in THF (4 ml) and a solution of ethanolamine (115 mg, 1.87 mmol) in
THF (1 mL) was added. The mixture was stirred under Ar at
23.degree. for 18 h. The solvents were removed in vacuo, and the
residue was partitioned between EtOAc and H.sub.2O. The organic
phase was washed with H.sub.2O, satd aq NaCl, dried over anhyd
Na.sub.2SO.sub.4, filtered and evaporated to give the crude
product. Flash chromatography eluted with 0-15%
EtOAc/CH.sub.2Cl.sub.2 gave the title compound as a light-yellow
amorphous solid. mp 120-1240, LC MS m/z=409 (MH+) Retention
time=1.84 min.
Example 137
[0617] ##STR153##
(S)-4-(4-fluoro-2-methylphenyl)-8-(2,6-difluorophenyl)-2-[(1-hydroxyprop-2-
-yl)amino]-8H-pyrido[2,3-d]pyrimidin-7-one
[0618] The product of Example 48 (200 mg, 0.45 mmol) and
(S)-2-amino-1-propanol (75 mg, 1 mmol) were dissolved in THF (10
ml) and stirred under Ar at 23.degree. for 10 days. The solvents
were removed in vacuo, and the residue was partitioned between
EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl,
dried over anhyd Na.sub.2SO.sub.4, filtered and evaporated to give
the crude product. Flash chromatography eluted with 0-15% EtOAc
CH.sub.2Cl.sub.2 gave the title compound as an off-white amorphous
solid. mp 96-101.degree., LC MS m/z=441 (MH+) Retention time=2.04
min.
Example 138
[0619] ##STR154##
(R)-4-(4-fluoro-2-methylphenyl)-8-(2,6-difluorophenyl)-2-[(1-hydroxyprop-2-
-yl)amino]-8H-pyrido[2,3-d]pyrimidin-7-one
[0620] The product of Example 48 (200 mg, 0.45 mmol) and
(R)-2-amino-1-propanol (75 mg, 1 mmol) were dissolved in THF (10
ml) and stirred under Ar at 23.degree. for 18 h. The solvents were
removed in vacuo, and the residue was partitioned between EtOAc and
H.sub.2O. The organic phase was washed with H.sub.2O, satd aq NaCl,
dried over anhyd Na.sub.2SO.sub.4, filtered and evaporated to give
the crude product. Flash chromatography eluted with 0-15%
EtOAc/CH.sub.2Cl.sub.2 gave the title compound as a off-white
amorphous solid. mp 90-95.degree., LC MS nl/z=441 (MH+) Retention
time=2.09 min.
Example 139
[0621] ##STR155##
4-(4-fluoro-2-methylphenyl)-8-(2,6-difluorophenyl)-2-(1,1-dimethyl-2-hydro-
xyethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0622] The product of Example 48 (200 mg, 0.45 mmol) and 95%
2-amino-2-methyl-1-propanol (94 mg, 1 mmol) were dissolved in THF
(10 ml) and stirred under Ar at 50.degree. for 3 days. The solvents
were removed in vacuo, and the residue was partitioned between
EtOAc and H.sub.2O. The organic phase was washed with H.sub.2O,
satd aq NaCl, dried over anhyd Na.sub.2SO.sub.4, filtered and
evaporated to give the crude product. Flash chromatography eluted
with 0-15% EtOAc/CH.sub.2Cl.sub.2 gave the title compound as a
off-white amorphous solid. mp 99-105.degree. C., LC MS m/z=455
(MH+) Retention time=2.19 min.
Example 140
[0623] ##STR156##
2-Ethylamino-4-(4-fluoro-2-methylphenyl)-8-(2-fluorophenyl)-8H-pyrido[2,3--
d]pyrimidin-7-one
[0624] The product of Example 59 (200 mg, 0.47 mmol) was combined
and stirred with 5 mL of a 2M solution of ethylamine in THF. After
5 min the solvents were removed in vacuo, and the residue was
partitioned between EtOAc and H.sub.2O. The organic phase was
washed with H.sub.2O, satd aq NaCl, dried over anhyd
Na.sub.2SO.sub.4, filtered and evaporated to give the crude
product. Flash chromatography eluted with 0-2%
EtOAc/CH.sub.2Cl.sub.2 followed by recrystallization from
CH.sub.2Cl.sub.2/hexane gave the product as a light-yellow
crystalline solid. mp 176-177.degree., LC MS m/z=393 (MH+)
Retention time=2.38 min.
Example 141
[0625] ##STR157##
(S)-4-(4-fluoro-2-methylphenyl)-8-(2-fluorophenyl)-2-F(1-hydroxyprop-2-yl)-
amino]-8H-pyrido[2,3-d]pyrimidin-7-one
[0626] The product of Example 59 (200 mg, 0.47 mmol) and
(S)-2-amino-1-propanol (75 mg, 1 mmol) were dissolved in THF (10
ml) and stirred under Ar at 23.degree. C. for 18 h. The solvents
were removed in vacuo, and the residue was partitioned between
EtOAc and H.sub.2O. The organic phase was washed with H.sub.2O,
satd aq NaCl, dried over anhyd Na.sub.2SO.sub.4, filtered and
evaporated to give the crude product. Flash chromatography eluted
with 0-20% EtOAc/CH.sub.2Cl.sub.2 gave the title compound as an
off-white amorphous solid. mp 114-120.degree., LC MS m/z=423 (MH+)
Retention time=2.0 min.
Example 142
[0627] ##STR158##
(R)-4-(4-fluoro-2-methylphenyl)-8-(2-fluorophenyl)-2-[(1-hydroxyprop-2-yl)-
amino]-8H-pyrido[2,3-d]pyrimidin-7-one
[0628] The product of Example 59 (200 mg, 0.47 mmol) and
(R)-2-amino-1-propanol (75 mg, 1 mmol) were dissolved in THF (10
ml) and stirred under Ar at 230 for 18 h. The solvents were removed
in vacuo, and the residue was partitioned between EtOAc and
H.sub.2O. The organic phase was washed with H.sub.2O, satd aq NaCl,
dried over anhyd Na.sub.2SO.sub.4, filtered and evaporated to give
the crude product. Flash chromatography eluted with 0-20%
EtOAc/CH.sub.2Cl.sub.2 gave the title compound as a off-white
amorphous solid. mp 116-122.degree., LC MS m/z=423 (MH+) Retention
time=2.04 min.
Example 143
[0629] ##STR159##
2-(1,1-dimethyl-2-hydroxyethylamino)-4-(4-fluoro-2-methylphenyl)-8-(2
fluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one
[0630] The product of Example 59 (200 mg, 0.47 mmol) and
2-amino-2-methyl-1-propanol (94 mg, 1 mmol) were dissolved in THF
(10 ml) and stirred under Ar at 500 for 3 days. The solvents were
removed in vacuo, and the residue was partitioned between EtOAc and
H.sub.2O. The organic phase was washed with H.sub.2O, satd aq NaCl,
dried over anhyd Na.sub.2SO.sub.4, filtered and evaporated to give
the crude product. Flash chromatography eluted with 0-15%
EtOAc/CH.sub.2Cl.sub.2 gave the title compound as a light-yellow
amorphous solid. mp 106-112.degree., LC MS m/z=437 (MH+) Retention
time=1.94 min.
Example 144
[0631] ##STR160##
2-Hydroxy-4-(4-fluoro-2-methylphenyl)-8-(2-fluorophenyl)-8H-pyrido[2,3-d]p-
yrimidin-7-one
[0632] A much more polar product formed in Example 143 was eluted
from the flash column on silica gel with 5% MeOH/CH.sub.2Cl.sub.2.
This was recrystallized from EtOAc to give the title compound as a
white crystalline solid. This compound was presumably formed by
reaction of the starting material sulfone with H.sub.2O that
contaminated the amine starting material. mp>280.degree., LC MS
m/z=366 (MH+) Retention time=1.7 min
Example 145
[0633] ##STR161##
2-Cyclohexylamino-4-(4-fluoro-2-methylphenyl)-8-(2-fluorophenyl)-8H-pyrido-
[2,3-d]pyrimidin-7-one
[0634] The product of Example 59 (200 mg, 0.47 mmol) and
cyclohexylamine (100 mg, 1 mmol) were combined in THF (10 mL) and
stirred under Ar at 23.degree. for 18 h. The solvents were removed
in vacuo, and the residue was flash chromatographed on silica gel
eluted with 50-100% CH.sub.2Cl.sub.2/hexane. Recrystallization from
CH.sub.2Cl.sub.2/hexane gave the title compound as a
white-crystalline solid. mp 181-182.degree., LC MS m/z=447 (MH+)
Retention time=2.71 min.
Example 146
[0635] ##STR162##
2-(Tetrahydropyran-4-ylamino)-4-(4-fluoro-2-methylphenyl)-8-(2-fluoropheny-
l)-8H-pyrido[2,3-d]pyrimidin-7-one
[0636] The product of Example 59 (200 mg, 0.47 mmol) and
4-aminotetra-hydropyran (102 mg, 1 mmol) were combined in THF (10
mL) and stirred under Ar at 23.degree.for 18 h. The solvents were
removed in vacuo, and the residue was flash chromatographed with
0-15% EtOAc/CH.sub.2Cl.sub.2. Recrystallization from
CH.sub.2Cl.sub.2/hexane gave the title compound as a light-yellow
crystalline solid. mp 211-212.degree., LC MS m/z=449 (MH+)
Retention time=2.21 min.
Example 147
[0637] ##STR163##
2-Ethylamino-4-(4-fluoro-2-methylphenyl)-8-(2,6-difluorophenyl)-8H-pyrido[-
2,3-d]pyrimidin-7-one
[0638] The product of Example 48 (200 mg, 0.45 mmol) was combined
and stirred with 5 mL of a 2M solution of ethylamine in THF. After
5 min the solvents were removed in vacuo, and the residue was
partitioned between EtOAc and H.sub.2O. The organic phase was
washed with H.sub.2O, satd aq NaCl, dried over anhyd
Na.sub.2SO.sub.4, filtered and evaporated to give the crude
product. Flash chromatography with 0-2% EtOAc/CH.sub.2Cl.sub.2
followed by recrystallization from CH.sub.2Cl.sub.2/hexane gave the
product as a white-crystalline solid. mp 195-196.degree., LC MS
m/z=411 (MH+) Retention time=2.4 min.
Example 148
[0639] ##STR164##
2-Cyclohexylamino-4-(4-fluoro-2-methylphenyl)-8-(2,6-difluorophenyl)-8H-py-
rido[2,3-d]pyrimidin-7-one
[0640] The product of Example 48 (200 mg, 0.45 mmol) and
cyclohexylamine (100 mg, 1 mmol) were combined in THF (10 mL) and
stirred under Ar at 23.degree. for 18 h. The solvents were removed
in vacuo, and the residue was flash chromatographed with 50-100%
CH.sub.2Cl.sub.2/hexane. Recrystallization from
CH.sub.2Cl.sub.2/hexane gave the title compound as a
white-crystalline solid. mp 218-219.degree. C., LC MS m/z=465 (MH+)
Retention time=2.8 min.
Example 149
[0641] ##STR165##
2-(Tetrahydropyran-4-ylamino)-4-(4-fluoro-2-methylphenyl)-8-(2,6-difluorop-
henyl)-8H-pyrido[2,3-d]pyrimidin-7-one
[0642] The product of Example 48 (200 mg, 0.45 mmol) and
4-aminotetra-hydropyran (102 mg, 1 mmol) were combined in THF (10
mL) and stirred under Ar at 230 for 18 h. The solvents were removed
in vacuo, and the residue was flash chromatographed with 0-15%
EtOAc/CH.sub.2Cl.sub.2 Recrystallization from
CH.sub.2Cl.sub.2/hexane gave the title compound as a light-yellow
crystalline solid. mp 231-232.degree., LC MS m/z=467 (MH+)
Retention time=2.27 min.
Example 150
[0643] ##STR166##
2-(2,2,2-Trifluoroethylamino)-4-(4-fluoro-2-methylphenyl)-8-(2-fluoropheny-
l)-8H-pyrido[2,3-d]pyrimidin-7-one
[0644] The product of Example 59 (200 mg, 0.47 mmol) and
trifluoroethylamine (200 mg, 2 mmol) were dissolved in THF (7 ml)
and sealed in a vial under Ar. The mixture was heated in an oil
bath to 60.degree. for 4 days. The solvents were removed in vacuo,
and the residue was flash chromatographed with 60-90%
CH.sub.2Cl.sub.2/hexane. Recrystallization from
CH.sub.2Cl.sub.2/hexane gave the title compound as a white
crystalline solid. mp 187-188.degree., LC MS m/z=447 (MH+)
Retention time=2.27 min.
Example 151
[0645] ##STR167##
trans-2-(4-Hydroxycyclohexylamino)-4-(4-fluoro-2-methylphenyl)-8-(2-fluoro-
phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one
[0646] The product of Example 59 (200 mg, 0.47 mmol),
trans-4-aminocyclohexanol hydrochloride (151 mg, 1 mmol), and
triethylamine (0.28 mL, 2 mmol)were combined in THF (10 mL) and
stirred under Ar at 50.degree. for 2 days. The solvents were
removed in vacuo, and the residue was partitioned between EtOAc and
H.sub.2O. The organic phase was washed with H.sub.2O, satd aq NaCl,
dried over anhyd Na.sub.2SO.sub.4, filtered and evaporated to give
the crude product. Flash chromatography with 0-20%
EtOAc/CH.sub.2Cl.sub.2 followed by recrystallization from
CH.sub.2Cl.sub.2/hexane gave the product as a pale yellow
crystalline solid. mp 148-151.degree., LC MS m/z=463 (MH+)
Retention time=2.0 min.
Example 152
[0647] ##STR168##
2-(1-hydroxymethyl-1-methyl-2-hydroxyethylamino)-4-(4-fluoro-2-methylpheny-
l)-8-(2-fluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one
[0648] The product of Example 59 (200 mg, 0.47 mmol) and
2-amino-2-methyl-1,3-propanediol (105 mg, 1 mmol) were combined in
THF (10 mL) and stirred under Ar at 50.degree. for 3 days. The
solvents were removed in vacuo, and the residue was flash
chromatographed with 0-25% EtOAc/CH.sub.2Cl.sub.2 Recrystallization
from CH.sub.2Cl.sub.2/hexane gave the title compound as a
white-crystalline solid. mp 160-162.degree., LC MS m/z=453 (MH+)
Retention time=1.75 min
Example 153
[0649] ##STR169##
2-(2,2,2-Trifluoroethylamino)-4-(4-fluoro-2-methylphenyl)-8-(2,6-difluorop-
henyl)-8H-pyrido[2,3-d]pyrimidin-7-one
[0650] The product of Example 48 (300 mg, 0.67 mmol) and
trifluoroethylamine (300 mg, 3 mmol) were dissolved in THF (10 ml)
and sealed in a vial under Ar. The mixture was heated in an oil
bath to 60.degree. for 4 days. The solvents were removed in vacuo,
and the residue was flash chromatographed with 60-90%
CH.sub.2Cl.sub.2/hexane. Recrystallization from
CH.sub.2Cl.sub.2/hexane gave the title compound as a white
crystalline solid. mp 195-196.degree., LC MS m/z=465 (MH+)
Retention time=2.38 min.
Example 154
[0651] ##STR170##
2-(1-hydroxymethyl-1-methyl-2-hydroxyethylamino)-4-(4-fluoro-2-methylpheny-
l)-8-(2,6-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one
[0652] The product of Example 48 (300 mg, 0.67 mmol) and
2-amino-2-methyl-1,3-propanediol (158 mg, 1.51 mmol) were combined
in THF (10 mL) and stirred under Ar at 50.degree. for 3 days. The
solvents were removed in vacuo, and the residue was flash
chromatographed with 0-25% EtOAc/CH.sub.2Cl.sub.2.
Recrystallization from CH.sub.2Cl.sub.2/hexane gave the title
compound as a white-crystalline solid. mp 158-160.degree., LC MS
m/z=471 (MH+) Retention time=1.75 min.
Example 155
[0653] ##STR171##
trans-2-(4-Hydroxycyclohexylamino)-4-(4-fluoro-2-methylphenyl)-8-(2,6-difl-
uorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one
[0654] The product of Example 48 (300 mg, 0.67 mmol),
trans-4-aminocyclohexanol hydrochloride (226 mg, 1.5 mmol), and
triethylamine (0.42 mL, 3 mmol) were combined in THF (15 mL) and
stirred under Ar at 50.degree. for 2 days. The solvents were
removed in vacuo, and the residue was partitioned between EtOAc and
H.sub.2O. The organic phase was washed with H.sub.2O, satd aq NaCl,
dried over anhyd Na.sub.2SO.sub.4, filtered and evaporated to give
the crude product. Flash chromatography with 0-20%
EtOAc/CH.sub.2Cl.sub.2 followed by recrystallization from
CH.sub.2Cl.sub.2/hexane gave the product as a white-crystalline
solid. mp 158-160.degree., LC MS m/z=481 (MH+) Retention time=2.08
min.
Example 156
[0655] ##STR172##
2-Ethoxy-4-(4-fluoro-2-methylphenyl)-8-(2-fluorophenyl)-8H-pyrido[2
3-d]pyrimidin-7-one
[0656] The product of Example 59 (200 mg, 0.47 mmol) was placed in
EtOH (10 mL) and the mixture stirred under Ar. Approximately 2 mL
of the ethanol was distilled off to dry the mixture. When the
mixture was cooled to 23.degree., some of the starting material
sulfone crystallized out. NaH (11.5 mg, 0.46 mmol) was added. The
reaction did not go to completion, so additional NaH (4 mg, 0.16
mmol) was added. The solvent was removed in vacuo, and the residue
was flash chromatographed on silica gel eluted with 60-100%
CH.sub.2Cl.sub.2/hexane. Recrystallization from
CH.sub.2Cl.sub.2/hexane gave the title compound as a white
crystalline solid. mp 137-139.degree., LC MS m/z=394(MH+) Retention
time=2.32 min.
Example 157
[0657] ##STR173##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[(2-aminoethyl)amino]-
-8H-pyrido[2,3-d]pyrimidin-7-one
[0658] The title compound of Example 48
[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-methanesulfonyl-8H--
pyrido[2,3-d]pyrimidin-7-one] (0.89 g, 0.002 mol) in dry THF,
stirring at 23.degree., under Ar, was treated with ethylenediamine
(668 uL, 0.01 mol). The color became orange. LC MS showed no
starting material after 5 min. Reaction was stripped to dryness;
the residue taken up in EtOAc-H2O. The layers were separated and
the aq phase adjusted to pH 10.5 with 10% NaOH. Aq phase was
extracted twice with EtOAc; combined organic layers were dried
(Na.sub.2SO.sub.4), then evaporated to give 0.762 g (89%) of the
title compound as a glass. LC MS (m/e)=426 (MH+). Rt=1.52 min.
Example 158
[0659] ##STR174##
1-[2-[8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7-oxo-7,8-dihydro-
-pyrido[2,3-d]pyrimidin-2-ylamino]ethyl]-3-ethylurea
[0660] The product of Example 157 (42.5 mg., 0.0001 mol) stirring
at 23.degree. in dry THF (5 mL), under Ar, was treated with ethyl
isocyanate (9.6 mg, 0.0001 mol) in one portion. After 30 min., the
resulting red solution was stripped to dryness; taken up in
methylene chloride (5 mL) and applied to a Chromatotron.TM. Rotor
Plate (1000 u thickness); plate eluted with methylene
chloride-methanol gradient (0% to 2% MeOH), to afford 30 mg (60.4%)
of pure title compound. (m.p. 130.degree.-133.degree.). LC MS
(m/e)=497 (MH+). Rt=2.04 min.
Example 159
[0661] ##STR175##
1-[2-[8-(2,6-Difluorophenyl-4-(4-fluoro-2-methylphenyl)-7-oxo-7,8-dihydro
pyrido[2,3-d]pyrimidin-2-ylamino]ethyl]-3-phenylurea
[0662] The title compound from Example 157 (42.3 mg, 0.0001 mol)
was treated with phenylisocyanate (11.9 mg, 0.00011 mol) in the
same manner as described in Example 158. Purification afforded 43
mg (79%) of the title compound as a red solid (m.p.
142.degree.-148.degree.) LC MS (m/e)=545 (MH+). Rt=2.34 min.
Example 160
[0663] ##STR176##
1-[2-[8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7-oxo-7,8-dihydro-
-pyrido[2,3-d]pyrimidin-2-ylamino]ethyl]-3-cyclohexylurea
[0664] The title compound from Example 157 (42.3 mg, 0.0001 mol)
was treated with cyclohexylisocyanate (12.5 mg, 0.00011 mol) in the
same manner as described in Example 158. Purification afforded 43
mg (78%) of the title compound as a red solid (m.p.
178.degree.-183.degree.) LC MS (m/e)=551 (MH+). Rt=2.38 min.
Example 161
[0665] ##STR177##
1-[2-[8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7-oxo-7,8-dihydro-
-pyrido[2,3-d]pyrimidin-2-ylamino]ethyl]-3-[3-fluorophenyl]urea
[0666] The title compound from Example 157 (42.3 mg, 0.0001 mol)
was treated with 3-fluorophenylisocyanate (12 mg, 0.0001 mol) in
the same manner as described in Example 158. Purification afforded
38 mg(67.6%) of the title compound as a light yellow solid (m.p.
131.degree.-144.degree.) LC MS (m/e)=563 (MH+). Rt=2.22 min.
Example 162
[0667] ##STR178##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[1-(2-aminoethyl)-3-m-
ethylureido]-8H-pyrido[2,3-d]pyrimidin-7-one
[0668] The title compound from Example 157 (150 mg, 0.00035 mol)
was treated with methylisocyanate (22 uL, 21.6 mg, 0.00035 mol) in
the same manner as described in Example 158. Purification afforded
100.5 mg (59%) of the title compound as a light red solid (m.p.
124.degree.-133.degree.) LC MS (m/e)=452 (MH+). Rt=1.85 min.
Example 163
[0669] ##STR179##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[N-(2-aminoethyl)-3-b-
enzamido]8H-pyrido[2,3-d]pyrimidin-7-one
[0670] The title compound from Example 157 (300 mg, 0.00071 mol) in
dry THF (10 mL) was treated with stirring, under Ar, with
triethylamine (78.8 mg, 109 uL, 0.00078 mol) followed by benzoyl
chloride (119 mg, 99 uL, 0.00085 mol). The mixture was stirred for
18 h at 23.degree.; stripped to dryness, then taken up in methylene
chloride (5 mL) and applied to a Chromatotron.TM. Rotor Plate (2000
u thickness); plate eluted with methylene chloride-methanol
gradient (0% to 2% MeOH). This afforded 141 mg (37.5%) of the title
compound as a off white solid. (m.p. 246.degree.-248.degree.) LC MS
(m/e)=530 (MH+). Rt=2.25 min.
Example 164
[0671] ##STR180##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[N-(2-aminoethyl)-car-
bamic acid ethyl ester)]-8H-pyrido[2,3-d]pyrimidin-7-one
[0672] The title compound from Example 157 (300 mg, 0.00071 mol)
was treated in the same manner as described in Example 163 using
ethyl chloroformate (91.8 mg, 81.2 uL, 0.00085 mol) as the
chlorocarbonyl reagent. Purification of the crude product afforded
64 mg (18%) of the title compound as a light brown solid. (m.p.
91.degree.-109.degree.) LC MS (m/e) 4.98 (MH+). Rt=2.09 min.
Example 165
[0673] ##STR181##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenol)-2-[N-(2-aminoethyl)-pro-
panamido)]-8H-pyrido[2,3-d]pyrimidin-7-one
[0674] The title compound from Example 157 (300 mg, 0.00071 mol)
was treated in the same manner as described in Example 163 using
propanoic anhydride (110 mg, 110 uL, 0.00085 mol) as the acylating
reagent. Purification of the crude product afforded 180 mg (53%) of
the title compound as a off white solid. (m.p.
214.degree.-16.degree.) LC MS (m/e)=482 (MH+). Rt1.95 min.
Example 166
[0675] ##STR182##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[N-(2-aminoethyl)-2
2-dimethylpropanamido)]-8H-pyrido[2,3-d]pyrimidin-7-one
[0676] The title compound from Example 157 (300 mg, 0.00071 mol)
was treated in the same manner as described in Example 163 using
2,2-dimethylpropanoyl chloride (102 mg, 104 uL, 0.00085 mol) as the
acylating reagent. Purification of the crude product afforded 149
mg (41%) of the title compound as a off white solid. (m.p.
111.degree.-133.degree.) LCMS (m/e)=510 (MH+). Rt=2.14 min.
Example 167
[0677] ##STR183##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[N-(2-aminoethyl)-car-
bamic acid tert-butyl ester)]-8H-pyrido[2,3-d]pyrimidin-7-one
[0678] The title compound from Example 157 (300 mg, 0.00071 mol)
was treated in the same manner as described in Example 163 using
di-tert-butyl dicarbonate (185 mg, 0.00085 mol) as the reagent for
carbamate formation; triethylamine was omitted from this reaction.
Purification of the crude product afforded 210 mg (56%) of the
title compound as a off white solid. (m.p. 106.degree.-119.degree.)
LC MS (m/e)=526 (MH+). Rt=2.30 min.
Example 168
[0679] ##STR184##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphen
I)-2-(N-aminouracil-5-yl)-8H-pyrido[2,3-d]pyrimidin-7-one
[0680] The title compound of Example 48
[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-methanesulfonyl-8H--
pyrido[2,3-d]pyrimidin-7-one] (100 mg, 0.000225 mol) and
5-aminouracil (70 mg, 0.00055 mol) were taken up in dry DMSO (1.5
mL) and, with stirring under Ar, warmed to 65.degree. for 6.5 h.
Reaction was cooled to 23.degree., then diluted with EtOAc;
solution was washed with H.sub.2O; the aq phase was extracted with
EtOAc; combined organic layers were dried (Na.sub.2SO.sub.4) then
evaporated to an amber glass. This glass was crystallized from a
small amount of MeOH, which crystals when dried afforded 15 mg
(14%) of the title compound as a light yellow crystalline solid.
(m.p.>3000) LC MS (m/e)=493 (MH+). Rt=1.82 min.
Example 169
[0681] ##STR185##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl-2-N-(2-aminoethyl)-N'-(t-
-Butoxycarbonylglycyl-)-8H-pyrido[2,3-d]pyrimidin-7-one
[0682] The title compound of Example 157 (168 mg, 0.0004 mol) in
dry THF (2 mL) with tert-butoxycarbonylglycine (70 mg, 0.0004 mol)
was treated with dicyclohexylcarbodiimide (82.4 mg, 0.0004 mol) in
dry THF (2 mL). The solution was stirred 16h at 23.degree.;
filtered and stripped to dryness. The residue was taken up in
methylene chloride (5 mL) and applied to a Chromatotron.TM. Rotor
Plate (1000 u thickness); plate eluted with methylene
chloride-methanol gradient (0% to 3% MeOH). This afforded 122 mg
(52%) of the title compound as a light red solid. LC MS (m/e)=583
(MH+). Rt2.12 min.
Example 170
[0683] ##STR186##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[N-(2-aminoethyl)-N'--
glycyl]-8H-pyrido[2,3-d]pyrimidin-7-one
[0684] The title compound of Example 169 (80 mg, 0.000137 mol) was
taken up in methylene chloride (2 mL); TFA (2 mL) was added and the
solution stirred for 0.5 hrs at 23.degree. giving a pale amber
solution. This was evaporated to an amber residue which was
triturated with ethyl ether to give a solid. Solid was collected
and dried in vacuo to afford the title compound as the
ditrifluoroacetic acid salt, an off white solid 60 mg (62%). LC MS
(m/e)=483 (MH+). Rt=1.55 min.
Example 171
[0685] ##STR187##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[N-([2,2-dimethyl-2-h-
ydroxylethylamino)]-8H-pyrido[23-d]pyrimidin-7-one
[0686] The title compound of Example 48 (150 mg, 0.000337 mol) in
dry THF (5 mL) was treated with 2,2-dimethylethanolamine (50 mg.,
50 uL, 0.00067 mol) [Prepared by the method of Bijaya L. Rai et
al., J. Med. Chem. 1998, 41, 3347]. stirred at 23.degree.; reaction
progress monitored by LC MS. Reaction was stripped to dryness; the
residue was taken up in methylene chloride (5 mL) and applied to a
Chromatotron.TM. Rotor Plate (2000 u thickness); plate eluted with
methylene chloride-methanol gradient (0% to 1.5% MeOH). This
afforded 116 mg (69%) of pure title compound as an off white solid.
LC MS (m/e)=455 (MH+). Rt=1.99 min.
Example 172
[0687] ##STR188##
S-(+)-2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl-2-[N-(1-Amino-2-propa-
nol)]-8H-pyrido[2,3-d]pyrimidin-7-one
[0688] The title compound of Example 48 (150 mg, 0.000337 mol) in
dry THF (5 mL) was treated with S-(+)-1-amino-2-propanol (76 mg.,
79 uL, 0.00098 mol) and stirred at 23.degree.; reaction progress
monitored by LC MS. Reaction was stripped to dryness; the residue
was taken up in methylene chloride (5 mL) and applied to a
Chromatotron.TM. Rotor Plate (2000 u thickness); plate eluted with
methylene chloride-methanol gradient (0% to 1.5% MeOH). This
afforded 76 mg (51%) of pure title compound as an off white solid.
LC MS (m/e)=441 (MH+). Rt=1.94 min.
Example 173
[0689] ##STR189##
R-(-)-8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[N-(1-Amino-2-p-
ropanol)]-8H-pyrido[2,3-d]pyrimidin-7-one
[0690] The title compound of Example 48 (150 mg, 0.000337 mol) in
dry THF (5 mL) was treated with R-(-)-1-amino-2-propanol (50.5 mg.,
54 uL, 0.00067 mol) and stirred at 23.degree.; reaction progress
monitored by LC MS. Reaction was stripped to dryness; the residue
was taken up in methylene chloride (5 mL) and applied to a
Chromatotron.TM. Rotor Plate (2000 u thickness); plate eluted with
methylene chloride-methanol gradient (0% to 1.5% MeOH). This
afforded 89 mg (60%) of pure title compound as an off white solid.
LC MS (m/e)=441 (MH+). Rt=1.94 min.
Example 174
[0691] ##STR190##
(R)-8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[N-(1-amino-2-hyd-
roxy-2-phenylethyl)-8H-pyrido[2,3-d]pyrimidin-7-one
[0692] The title compound of Example 48 (150 mg, 0.000337 mol) in
dry THF (5 mL) was treated with R-2-Amino-1-phenylethanol (93 mg.,
0.00067 mol) and stirred at 23.degree.; reaction progress monitored
by LC MS. Reaction was stripped to dryness; the residue was taken
up in methylene chloride (5 mL) and applied to a Chromatotron.TM.
Rotor Plate (2000 u thickness); plate eluted with methylene
chloride-methanol gradient (0% to 1.5% MeOH). This afforded 108 mg
(64%) of pure title compound as a light orange gum. LC MS (m/e)=503
(MH+). Rt=2.20 min.
Example 175
[0693] ##STR191##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[N-trihydroxy-methyla-
minomethyl]-8H-pyrido[2,3-d]pyrimidin-7-one
[0694] The title compound of Example 48 (150 mg, 0.000337 mol) and
TRIS (trihydroxymethylaminomethane) (121 mg, 0.0001 mol) in
N-methylpyrrolidinone (1.5 mL) was microwaved at 180.degree. for 2
min (with a 3 min ramp up) at 300 watts with a MARS 5.TM. Microwave
(CEM Corporation). No starting material remained as monitored by LC
MS. The solvent was stripped off at pump vacuum and the residue was
taken up in methylene chloride (5 mL) and applied to a
Chromatotron.TM. Rotor Plate (2000 u thickness); plate eluted with
methylene chloride-methanol gradient (0% to 1.5% MeOH). This
afforded 42 mg (26%) of pure title compound as a light brown solid.
LC MS (m/e)=487 (MH+). Rt=1.55 min.
Example 176
[0695] ##STR192##
8-(2-Fluorophenyl)-4-(4-fluoro-2-methylphenyl-2-[N-([2,2-dimethyl-2-hydrox-
y]ethylamino)]-8H-pyrido[2,3-d]pyrimidin-7-one
[0696] The title compound of Example 59 (144 mg, 0.000337 mol) in
dry THF (5 mL) was treated with 2,2-dimethylethanolamine (50 mg.,
50 uL, 0.00067 mol) [Prepared by the method of Bijaya L. Rai et
al., J. Med. Chem. 1998, 41, 3347] and stirred at 23.degree.;
reaction progress monitored by LC MS. Reaction was stripped to
dryness; the residue was taken up in methylene chloride (5 mL) and
applied to a Chromatotron.TM. Rotor Plate (2000 u thickness); plate
eluted with methylene chloride-methanol gradient (0% to 1.5% MeOH).
This afforded 106 mg (72%) of pure title compound as an off white
solid. LC MS (m/e)=437 (MH+). Rt=1.92 min.
Example 177
[0697] ##STR193##
(S)-(+)-8-(2-Fluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[N-([2-methyl-2-h-
ydroxy]ethylamino)]-8H-pyrido[2,3-d]pyrimidin-7-one
[0698] The title compound of Example 59 (144 mg, 0.000337 mol) in
dry THF (5 mL) was treated with S-(+)-1-amino-2-propanol (76 mg.,
79 uL, 0.00098 mol) and stirred at 23.degree.; reaction progress
monitored by LC MS. Reaction was stripped to dryness; the residue
was taken up in methylene chloride (5 mL) and applied to a
Chromatotron.TM. Rotor Plate (2000 u thickness); plate eluted with
methylene chloride-methanol gradient (0% to 1.5% MeOH). This
afforded 132 mg (93%) of pure title compound as a pale yellow
solid. LC MS (m/e)=423 (MH+). Rt=1.82 min
Example 178
[0699] ##STR194##
(R)-(-)-8-(2-Fluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[N-([2-methyl-2-h-
ydroxy]ethylamino)]-8H-pyrido[2,3-d]pyrimidin-7-one
[0700] The title compound of Example 59 (150 mg, 0.000337 mol) in
dry THF (5 mL) was treated with R-(-)-1-amino-2-propanol (50.5 mg.,
54 uL, 0.00067 mol) and stirred at 23.degree.; reaction progress
monitored by LC MS. Reaction was stripped to dryness; the residue
was taken up in methylene chloride (5 mL) and applied to a
Chromatotron.TM. Rotor Plate (2000 u thickness); plate eluted with
methylene chloride-methanol gradient (0% to 1.5% MeOH). This
afforded 151 mg (Quant.) of pure title compound as a pale yellow
gum. LC MS (m/e)=423 (MH+). Rt=1.84 min.
Example 179
[0701] ##STR195##
4-Chloro-2-methylsulfanyl-6-cyclohexylaminopyrimidine-5-carboxaldehyde
[0702] 4,6-Dichloro-2-methylsulfanylpyrimidine-5-carboxaldehyde
(4.0 g, 0.018 mol) in acetonitrile (65 mL) was treated with rapid
stirring with cyclohexylamine (3.76 g, 4.3 mL, 0.038 mol) over 1
min. Reaction stirred 16 h then diluted with 3 volumes of H.sub.2O.
The precipitated solid was collected, washed with H.sub.2O and
dried in vacuo to afford 5.1 g. (99%) of the title compound as a
white solid. LC MS (m/e)=286 (MH+). Rt=2.85 min.
Example 180
[0703] ##STR196##
2-Methylsulfanyl-4-(2-methyl-4-fluorophenyl-6-cyclohexylaminopyrimidine-5--
carbaldehyde
[0704] A mixture of the title compound from Example 180 (5.1 g.,
0.018 mol), 2-methyl-4-fluoroboronic acid (5.54 g., 0.036 mol),
Na.sub.2CO.sub.3 (3.82 g, 0.036 mol),
tetrakis(triphenylphosphine)palladium (0), dioxane (100 mL) and
H.sub.2O (50 mL), stirring under Ar, was warmed to 65.degree. and
stirred 16h. Reaction was cooled to 23.degree.; diluted with EtOAc,
and the mixture washed in turn with H.sub.2O, aq NaHCO.sub.3, and
satd aq NaCl. Organic phase was dried (Na.sub.2SO.sub.4), then
stripped to a viscous syrup. The syrup was crystallized from a
small amount of MeOH with sonication and gentle warming. This
afforded 5.5 g (86%) of the title compound as a white solid. LC MS
(m/e)=360 (MH+). Rt=3.00 min.
Example 181
[0705] ##STR197##
8-Cyclohexyl-4-(4-fluoro-2-methylphenyl)-2-methylthio-8H-pyrido[2,3-d]pyri-
midin-7-one
[0706] Triethylphosphonoacetate (3.87 mL, 0.01953 mol) in dry THF
(56 mL) was treated with NaH (60% in mineral oil) (967.5 mg, 0.0243
mol). The mixture was stirred for 30 min giving a clear solution.
The title compound from Example 180 (4.5 g, 0.0125 mol) in dry THF
(75 mL) was added in one portion and the solution gently refluxed
for 72 h. After cooling to 23.degree., the reaction mixture was
diluted with ethyl ether, then washed in turn with satd aq
NH.sub.4Cl and H.sub.2O. Organic layer was dried
(Na.sub.2SO.sub.4), then evaporated to a viscous syrup which was
flash chromatographed in methylene chloride-hexane gradient (20% to
0% hexane) to afford first 920 mg (19%) of the title compound as a
white solid. LC MS (m/e)=384 (MH+). Rt=2.79 min.
Example 182
[0707] ##STR198##
8-Cyclohexyl-4-(4-fluoro-2-methylphenyl)-2-ethoxy-8H-pyrido[2,3-d]pyrimidi-
n-7-one
[0708] The column of Example 181 was eluted with additional
methylene chloride/hexane to afford 580 mg (12.2%) of the title
compound of the present example as a white solid. LC MS (m/e)=382
(MH+). Rt=2.67 min
Example 183
[0709] ##STR199##
8-Cyclohexyl-4-(4-fluoro-2-methylphenyl)-2-methanesulfonyl-8H-pyrido[2,3-d-
]pyrimidin-7-one
[0710] The title compound from Example 181 (850 mg, 0.0022 mol)
stirring in methylene chloride (100 mL) was treated with
m-chloroperbenzoic acid (77%)(992 mg, 0.0044 mol). Solution stirred
overnight at 23.degree.. LC MS showed about 90% conversion to the
title compound, therefore, an additional 120 mg of
m-chloroperbenzoic acid was added to the reaction. After 1 h, the
reaction was washed in turn with 5% Na.sub.2CO.sub.3, then satd aq
NaCl, dried (Na.sub.2SO.sub.4). Methyl sulfide (0.5 mL) was added
to quench any excess peroxides. Solution was stripped to give 0.96
g, (quant.) of the title compound as a white solid. LC MS (m/e) 416
(MH+). Rt=2.24 min.
Example 184
[0711] ##STR200##
8-Cyclohexyl-4-(4-fluoro-2-methylphenyl)-2-[N-2,2-dimethylethanolamino]-8H-
-pyrido[2,3-d]pyrimidin-7-one
[0712] The title compound of Example 183 (150 mg, 0.00036 mol) in
dry THF (2.5 mL) was treated with 2,2-dimethylethanolamine (64 mg.,
64 uL, 0.00072 mol). [Prepared by the method of Bijaya L. Rai et
al., J. Med. Chem. 1998, 41, 3347] and stirred at 23.degree., 16h;
reaction progress monitored by LC MS. Reaction was stripped to
dryness; the residue was taken up in methylene chloride (5 mL) and
applied to a Chromatotron.TM. Rotor Plate (2000 u thickness); plate
eluted with methylene chloride-methanol gradient (0% to 2% MeOH to
afford 107 mg (70%) of pure title compound as a colorless glass. LC
MS (m/e)=425 (MH+). Rt=2.22 min
Example 185
[0713] ##STR201##
(S)-(+)-8-Cyclohexyl-4-(4-fluoro-2-methylphenyl)-2-[N-1-amino-2-hydroxypro-
panyl]-8H-pyrido[2,3-d]pyrimidin-7-one
[0714] The title compound of Example 183 (150 mg, 0.00036 mol) in
dry THF (2.5 mL) was treated with S-(+)-1-amino-2-propanol (76 mg.,
79 uL, 0.00098 mol) and stirred at room temperature; reaction
progress monitored by LC MS. Reaction warmed 15h at 90.degree.
Reaction was stripped to dryness; the residue was taken up in
methylene chloride (5 mL) and applied to a Chromatotron.TM. Rotor
Plate (2000 u thickness); plate eluted with methylene
chloride-methanol gradient (0% to 2% MeOH). This afforded 118 mg
(80%) of pure title compound as a colorless gum. LC MS (m/e)=411
(MH+). Rt=2.10 min.
Example 186
[0715] ##STR202##
(R)-(-)-8-Cyclohexyl-4-(4-fluoro-2-methylphenyl)-2-[N-1-amino-2-hydroxypro-
panyl]-8H-pyrido[2,3-d]pyrimidin-7-one
[0716] The title compound of Example 183 (150 mg, 0.00036 mol) in
dry THF (2.5 mL) was treated with R-(-)-1-amino-2-propanol (54 mg.,
58 uL, 0.00072 mol) and stirred at 23.degree. 16h; reaction
progress monitored by LC MS. Reaction was stripped to dryness; the
residue was taken up in methylene chloride (5 mL) and applied to a
Chromatotron.TM. Rotor Plate (2000 u thickness); plate eluted with
methylene chloride-methanol gradient (0% to 2% MeOH) to afford 158
mg (Quant.) of pure title compound as a colorless gum. LC MS
(m/e)=411 (MH+). Rt=2.12 min
Example 187
[0717] ##STR203##
8-Cyclohexyl-4-(4-fluoro-2-methylphenyl)-2-[N-dihydroxymethylmethylamino]--
8H-pyrido[2,3-d]pyrimidin-7-one
[0718] The title compound of Example 183 (150 mg, 0.00036 mol) in
dry THF (2.5 mL) was treated with serinol (62 mg., 0.000674 mol)
and warmed at 90.degree. 16h; reaction progress monitored by LC MS.
Reaction was stripped to dryness; the residue was taken up in
methylene chloride (5 mL) and applied to a Chromatotron.TM. Rotor
Plate (2000 u thickness); plate eluted with methylene
chloride-methanol gradient (0% to 2% MeOH). This afforded 163 mg
(Quant.) of pure title compound as a colorless gum. LC MS (m/e)=427
(MH+). Rt=1.75 min
Example 188
[0719] ##STR204##
8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[N-(2-chloroethylamin-
o)]-8H-pyrido[2,3-d]pyrimidin-7-one
[0720] The title compound from Example 48 (890 mg, 0.002 mol) in
dry DMF (18 mL) was treated with stirring 2-chloroethylamine (345
mg, 0.003 mol) and K.sub.2CO.sub.3 (207 mg, 0.0015 mol). The
mixture was stirred 16h at 23'. The reaction was stripped to a
residue; taken up in EtOAc; washed with H.sub.2O (2.times.);
organic extract dried (Na.sub.2SO.sub.4), then evaporated to a
brown gum. This residue was taken up in methylene chloride (5 mL)
and applied to a Chromatotron.TM. Rotor Plate (2000 u thickness);
plate eluted with methylene chloride. This afforded 510 mg of the
title compound with improved purity. This compound was then taken
up in acetonitrile (2 mL) and sonicated to give a white crystalline
solid. Solid was collected and dried to give 280 mg(31.5%) of pure
title compound. LC MS (m/e)=445 (MH+). Rt=2.44 min.
Example 189
[0721] ##STR205##
N-[2-[[8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7,8-dihydro-7-ox-
opyrido[2,3-d]pyrimidin-2-yl]amino]ethyl]methanesulfonamide
[0722] A solution of the product of Example 157 (250 mg, 0.58
mmol), di-isopropylethylamine (111 uL, 0.64 mmol) and
CH.sub.2Cl.sub.2 (10 mL) was cooled to -5.degree. and
methanesulfonyl chloride (50 uL, 0.64 mmol) was added and the
resulting soln was warmed to 23.degree., stirred 15 min, diluted
with CH.sub.2Cl.sub.2 (75 mL) and washed with 10% aq NaOH
(2.times.20 mL) and satd aq NaCl, dried (Na.sub.2SO.sub.4), and
concentrated to afford a brown solid. Chromatotron chromatography
(CH.sub.2Cl.sub.2/CH.sub.3OH) and crystallization from Et.sub.2O
afforded a pink solid. mp=105-115.degree. (dec); LC MS (m/e)=504.2
(MH+). Rt=1.94 min
Example 190
[0723] ##STR206##
Methyl
N-[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7,8-dihydro-7-
-oxopyrido[2,3-d]pyrimidin-2-yl]glycinate
[0724] The product of Example 48 (2.25 g mg, 5.0 mmol), methyl
glycinate hydrochloride (3.13 g, 25.0 mmol), anhyd K.sub.2CO.sub.3
(3.45 g, 25.0 mmol) and NMP (25 mL) were stirred for 1 h at
60.degree.. The reaction was diluted with EtOAc (200 mL), washed
with 10% aq citric acid (2.times.25 mL), H.sub.2O (25 mL) and satd
aq NaCl (40 mL) dried (Na.sub.2SO.sub.4) and concentrated. The
resulting brown residue was filtered through a plug of silica (350
mL) (dichloromethane/methanol) to afford a brown foam. Trituration
with Et.sub.2O afforded the title compound, methyl
N-[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7,8-dihydro-7-oxopy-
rido[2,3-d]pyrimidin-2-yl]glycinate as a white solid.
mp=212-213.degree..
Example 191
[0725] ##STR207##
N-[8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7,8-dihydro-7-oxopyr-
ido[2,3-d]pyrimidin-2-yl]glycine
[0726] The product of reaction 190 was reacted by the procedure of
Example 84 to afford the title compound
N-[8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7,8-dihydro-7-oxopy-
rido[2,3-d]pyrimidin-2-yl]glycine as a white solid. mp=260-261.
Example 192
[0727] ##STR208##
2-[[8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7,8-dihydro-7-oxopy-
rido[2,3-d]pyrimidin-2-yl]amino]-N-ethylacetamide
[0728] The product of Example 191 (50 mg, 0.11 mmol),
n-hydroxybenzotriazole (21 mg, 0.34 mmol), 1-methylmorpholine (19
uL, 0.172 mmol), N-methylpyrrolidinone (2.5 mmol) were dissolved
together, then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (66 mg, 0.34 mmol) was added, stirred 1 h, and then
ethylamine (2 M in THF) (1.0 mL, 2.0 mmol) was added and the
reaction was stirred at 23.degree. for 16 h, diluted with EtOAc (50
mL), and washed with 10% aq citric acid (2.times.20 mL), H.sub.2O
(20 mL), and satd aq NaCl (20 mL), dried (MgSO.sub.4) concentrated
and purified by chromatotron chromatography
(CH.sub.2Cl.sub.2/CH.sub.3OH) to afford 35 mg of the title compound
2-[[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7,8-dihydro-7-oxop-
yrido[2,3-d]pyrimidin-2-yl]amino]- N-ethylacetamide as a white
powder. mp=250-253 (dec). LC MS (m/e)=468.2 (MH+). Rt=1.87 min.
Example 193
[0729] ##STR209##
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-morpholin-4-yl-2-
-oxo-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0730] Under Ar, a soln of morpholine (58 mg, 0.66 mmol) and
trimethylaluminum (2M in toluene) (0.33 mL, 0.66 mmol) in
dichloromethane was stirred for 10 min. A soln of the product of
Example 190 (100 mg, 0.22 mmol) in dichloromethane (2 mL) was
added. The resulting mixture was stirred for 16 h, diluted with
EtOAc and washed with H.sub.2O to give the crude material.
Purification by Flash chromatography on silica gel, eluting with
EtOAc/hexane/triethylamine(70/30/2, v/v/v), followed by
recrystallization from dichloromethane and hexane, gave the desired
product (35 mg, 31%). LC-MS: 510.10 (MH+, m/z), 1.96 (Rt, min).
Example 194
[0731] ##STR210##
4-(4-Fluoro-2-methyl-phenyl)-2-((R)-2-hydroxy-1-methyl-ethylamino)-o-tolyl-
-8H-pyrido[2,3-d]pyrimidin-7-one
[0732] Following the general procedure outlined in Example 126, the
product of Example 121 (200 mg, 0.47 mmol) and
(R)-(-)-2-amino-1-propanol (0.18 mL, 2.36 mmol) afforded the title
compound as a white solid. 170 mg (86%). LC-MS: 419.2 (MH+, m/z),
2.00 (Rt, min).
Example 195
[0733] ##STR211##
4-(4-Fluoro-2-methyl-phenyl)-2-(4-hydroxyl-cylclohexylamino)-8-o-tolyl-8H--
pyrido[2,3-d]pyrimidin-7-one
[0734] trans-4-Aminocyclohexanol hydrochloride (270 mg, 2.35 mmol),
NMP (1 mL) and triethylamine (0.33 mL, 2.35 mmol) were stirred at
23.degree. for 10 min. The product of Example 121 (200 mg, 0.47
mmol) was added and the mixture was stirred 2 h, diluted with EtOAc
and washed with H.sub.2O, Separation of the organic phase and
evaporation of solvent afforded the crude material, which was
purified as described in Example 126 to give the desired product 98
mg (46%). LC-MS: 459.4 (MH+, m/z), 2.12 (Rt, min).
Example 196
[0735] ##STR212##
4-(4-Fluoro-2-methyl-phenyl)-2-((S)-2-hydroxy-1-methyl-ethylamino)-8-o-tol-
yl-8H-pyrido[2,3-d]pyrimidin-7-one
[0736] Following the general procedure outlined in Example 126, the
product of Example 121 (200 mg, 0.47 mmol) and
(S)-(+)-2-amino-1-propanol (0.18 mL, 2.36 mmol) afforded the
desired product 185 mg (94%). LC-MS: 419.2 (MH+, m/z), 1.96 (Rt,
min).
Example 197
[0737] ##STR213##
4-(4-Fluoro-2-methyl-phenyl)-2-(2-hydroxy-1,1-dimethyl-ethylamino)-8-o-tol-
yl-8H-pyrido[2,3-d]pyrimidin-7-one
[0738] Following the general procedure outlined in Example 126, the
product of Example 121 (222 mg, 0.52 mmol) and
2-amino-2-methyl-1-propanol (0.25 mL, 2.62 mmol) were reacted to
give the crude material. Purification by Flash chromatography
eluting with dichloromethane/ethanol/triethylamine(100/1/2, v/v/v),
followed by preparative HPLC, eluting with acetonitrile/H.sub.2O
(10/90, v/v to 90/10, v/v, over 10 min), gave the desired product
25 mg (11%). LC-MS: 433.4 (MH+, m/z), 2.10 (Rt, min).
Example 198
[0739] ##STR214##
2-Ethylamino-4-(4-fluoro-2-methyl-phenyl)-8-o-tolyl-8H-pyrido[2,3-d]pyrimi-
din-7-one
[0740] Following the general procedure outlined in Example 126, the
product of Example 121 (200 mg, 0.47 mmol), and ethylamine (1.18
mL, 2.36 mmol) were reacted to give the crude material.
Purification by flash chromatography eluting with
EtOAc/hexane/triethylamine(30/70/2, v/v/v), followed by
recrystallization from dichloromethane and hexane, gave the desired
product 150 mg (82%). LC-MS: 389.2 (MH+, m/z), 2.39 (Rt, min).
Example 199
[0741] ##STR215##
2-Cyclohexylamino-4-(4-fluoro-2-methyl-phenyl)-8-o-tolyl-8H-pyrido[2,3-d]p-
yrimidin-7-one
[0742] Following the general procedure outlined in Example 126, the
product of Example 121 (200 mg, 0.47 mmol), and cyclohexylamine
(0.27 mL, 2.36 mmol) were reacted to give the crude material, which
was purified as described in Example 198 to give the desired
product 100 mg (48%). LC-MS: 443.4 (MH+, m/z), 2.79 (Rt, min).
Example 200
[0743] ##STR216##
4-(4-Fluoro-2-methyl-phenyl)-2(tetrahydro-pyran-4-ylamino)-8-o-tolyl-8H-py-
rido[2,3-d]pyrimidin-7-one
[0744] Following the general procedure outlined in Example 126, the
product of Example 121(150 mg, 0.35 mmol), and
4-aminotetrahydropyran (179 mg, 1.77 mmol) were reacted to give the
crude material, which was purified as described in Example 198 to
give the desired product 140 mg (90%). LC-MS: 445.4 (MH+, m/z),
2.27 (Rt, min).
Example 201
[0745] ##STR217##
4-(4-Fluoro-2-methyl-phenyl)-8-o-tolyl-2-(2,2,2-trifluoro-ethylamino)-8H-p-
yrido[2,3-d]pyrimidin-7-one
[0746] Following the general procedure outlined in Example 126, the
product of Example 121 (150 mg, 0.35 mmol),
2,2,2-trifluoro-ethylamine (176 mg, 1.77 mmol) were reacted to give
the crude material, which was purified as described in Example 198
to give the desired product 130 mg (84%). LC-MS: 443.0 (MH+, m/z),
2.27 (Rt, min).
Example 202
[0747] ##STR218##
4-(4-Fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylam-
ino)-8-o-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one
[0748] Following the general procedure outlined in Example 60, the
product of Example 121 (200 mg, 0.47 mmol) and
2-amino-2-methyl-1,3-propanediol (494 mg, 4.7 mmol) were reacted to
give the crude material, which was purified as described in Example
126 to give the desired product 130 mg (62%). LC-MS: 449.0 (MH+,
m/z), 1.67 (Rt, min).
Example 203
[0749] ##STR219##
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro--
pyrido[2,3-d]pyrimidine-2-ylamino]-N,N-dimethyl-acetamide
[0750] Following the general procedure outlined in Example 193,
dimethylamine (1.1 mL, 2.2 mmol), trimethylaluminum (1.1 mL, 2.2
mmol) and the product of Example 190 (100 mg, 0.22 mmol) were
reacted to give the desired product 56 mg (54%). LC-MS: 468.2 (MH+,
m/z), 2.00 (Rt, min).
Example 204
[0751] ##STR220##
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-oxo-2-pyrroli-
din-1-yl ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0752] Following the general procedure outlined in Example 193,
pyrrolidine (0.18 mL, 2.2 mmol), trimethylaluminum (1.1 mL, 2.2
mmol) and the product of Example 190 (100 mg, 0.22 mmol) were
reacted to give the desired product 52 mg (48%). LC-MS: 494.4 (MH+,
m/z), 2.10 (Rt, min).
Example 205
[0753] ##STR221##
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro--
pyrido[2,3-d]pyrimidin-2-ylamino]-N-(2-methoxy-ethyl)-acetamide
[0754] Following the general procedure outlined in Example 193,
2-methoxy-ethylamine (0.17 mL, 2.2 mmol), trimethylaluminum (1.1
mL, 2.2 mmol) and the product of Example 190 (200 mg, 0.44 mmol)
were reacted to give the desired product 145 mg (66%). LC-MS: 498.2
(MH+, m/z), 1.90 (Rt, min).
Example 206
[0755] ##STR222##
3-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro--
pyrido[2,3-d]pyrimidin-2-ylamino]-propionitrile
[0756] Following the general procedure outlined in Example 126, the
product of Example 48 (500 mg, 1.12 mmol) and 3-aminopropionitrile
(0.41 mL, 5.6 mmol) were reacted to give the desired product 270 mg
(55%). LC-MS: 436.0 (MH+, m/z), 2.17 (Rt, min).
Example 207
[0757] ##STR223##
4-(4-Fluoro-2-methyl-phenyl)-2-morpholin-4-yl-8-o-tolyl-8H-pyrido[2,3-d]py-
rimidin-7-one
[0758] Following the general procedure outlined in Example 193, the
product of Example 121 (100 mg, 0.22 mmol), morpholine (58 mg, 0.66
mmol) and trimethylaluminum (0.33 mL, 0.66 mmol) were reacted to
give the desired product, 61 mg (64%). LC-MS: 431.2 (MH+, m/z),
2.46 (Rt, min).
Example 208
[0759] ##STR224##
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(1SR,2SR)-2-hydroxy-
-cyclohexylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0760] Following the general procedure outlined in Example 195, the
product of Example 48 (200 mg, 0.45 mmol),
trans-2-hydroxy-1-cyclohexylamine hydrochloride (341 mg, 2.25 mmol)
and triethylamine (0.31 mL, 2.25 mmol) were reacted to give the
crude material, which was purified as described in Example 193 to
give the desired product 100 mg (46%). LC-MS: 481.2 (MH+, m/z),
2.25 (Rt, min).
Example 209
[0761] ##STR225##
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro--
pyrido[2,3-d]pyrimidin-2-ylamino]-N-(2-hydroxy-ethyl)-acetamide
[0762] To a soln of the product of Example 205 (50 mg, 0.1 mmol),
in dichloromethane (2 mL) was added 1 M boron tribromide in
dichloromethane (0.5 mL, 0.5 mmol). The mixture was stirred at
23.degree. for 2 h, H.sub.2O was added, extracted with EtOAc. The
organic layer was dried (Na.sub.2SO.sub.4) and concentrated to give
the crude material. Recrystallization from dichloromethane and
hexane afforded the title product (30 mg, 62%). LC-MS: 484.2 (MH+,
m/z), 1.59 (Rt, min).
Example 210
[0763] ##STR226##
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-[2-(1H-tetrazol-5-y-
l)-ethylamino]-8H-pyrido[2,3-d]pyrimidin-7-one
[0764] A suspension of the product of Example 206 (200 mg, 0.46
mmol), triethylamine hydrochloride (630 mg, 4.6 mmol) and NaN.sub.3
(299 mg, 4.6 mmol) in toluene (20 mL) was heated to toluene reflux
for 60 h. Preparative HPLC afforded the title compound 100 mg
(45%). LC-MS: 479.0 (1 MH+, m/z), 1.82 (Rt, min).
Example 211
[0765] ##STR227##
N-Cyclopropyl-2-[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-ox-
o-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-acetamide
[0766] Following the procedure outlined in Example 193,
cyclopropylamine (0.23 mL, 3.3 mmol), trimethylaluminum (1.7 mL,
3.3 mmol) and the product of Example 190 (150 mg, 0.33 mmol) were
reacted to give the desired product, 20 mg (13%). LC-MS: 480.0
(MH+, m/z), 1.89 (Rt, min).
Example 212
[0767] ##STR228##
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-((1H-tetrazol-5--
ylmethyl)amino)-8H-pyrido[2,3-d]pyrimidin-7-one
a)
[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-
-pyrido[2,3-d]pyrimidin-2-ylamino]-acetonitrile
[0768] Following the general procedure outlined in Example 195, the
product of Example 48 (500 mg, 1.12 mmol), aminoacetonitrile
hydrogen sulfate (1.16 g, 5.6 mmol) and triethylamine (0.78 mL, 5.6
mmol) were reacted at 65.degree. for 2 h to give the crude material
460 mg. LC-MS: 421.8 (MH+, m/z), 2.08 (Rt, min).
b)
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-((1H-tetrazol-
-5-ylmethyl)amino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0769] Following the procedure outlined in Example 210, the crude
product of Example 212(a),
[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-p-
yrido[2,3-d]pyrimidin-2-ylamino]-acetonitrile (460 mg),
triethylaminehydrochloride (1.54 g, 11.2 mmol) and NaN.sub.3 (728
mg, 11.2 mmol) were reacted to give the desired product 50 mg
(9.6%). LC-MS: 465.2 (MH+, m/z), 1.79 (Rt, min).
Example 213
[0770] ##STR229##
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(1
SR,2SR)-2-hydroxy-cyclopentylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
a) trans-2-azido-cyclopentanol
[0771] To a soln of cyclopenteneoxide (2.0 g, 23.8 mmol) in
CH.sub.3OH and H.sub.2O (40 mL) (4/1, v/v), were added NaN.sub.3
(7.73 g, 119 mmol) and NH.sub.4Cl (3.17 g, 59.2 mmol). The
resulting mixture was heated to solvent reflux for 18 h then cooled
to 23.degree.. The mixture was concentrated and the residue was
diluted with EtOAc, washed with H.sub.2O, the organic layer was
dried over Na.sub.2SO.sub.4, concentrated to give the desired
product (2.8 g, 93%). .sup.1H NMR (CDCl.sub.3): .delta. 4.10 (m,
1H), 3.72 (m, 1H), 2.10 (m, 2H), 1.72-1.60 (m, 4H).
b) trans-2-amino-cyclopentanol hydrochloride
[0772] To a solution of trans-2-azido-cyclopentanol (1.0 g, 7.87
mmol) in EtOAc, was added 10% Pd/C (0.5 g). The mixture was flushed
with Ar, and then stirred on Parr apparatus at 40 psi for 2 h at
23.degree.. The mixture was filtered through celite and the celite
was washed with EtOAc. The filtrate was acidified with 3 mL of 4N
HCl in 1,4-dioxane, and a white solid was precipitated. The mixture
was filtered and the solid was collected to give the desired
product (0.76 g, 99%). .sup.1H NMR (MeOD-d.sub.4): .delta.
4.09-4.04 (m, 1H), 3.29-3.25 (m, 1H), 2.18 (m, 1H), 2.03 (m, 1H),
1.83-1.80 (m, 2H), 1.65-1.58 (m, 2H).
c)
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(1SR,2SR)-2-h-
ydroxy-cyclopentylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0773] Following the general procedure outlined in Example 195, the
product of Example 48 (200 mg, 0.45 mmol),
trans-2-amino-cyclopentanol hydrochloride (227 mg, 2.25 mmol) and
triethylamine (0.3 mL, 2.25 mmol) were reacted for 2 h to give the
desired product 63 mg (30%). LC-MS: 467.0 (MH+, m/z), 2.09 (Rt,
min).
Example 214
[0774] ##STR230##
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(3-methylsulfany-
l-propylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0775] Following the general procedure outlined in Example 126, the
product of Example 48 (200 mg, 0.44 mmol) and
3-(methylthio)propylamine (23 1 mg, 2.2 mmol) were reacted to
afford the title compound 108 mg (52%). LC-MS: 471.2 (MH+, m/z),
2.37 (Rt, min).
Example 215
[0776] ##STR231##
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(3-methanesulfon-
yl-propylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0777] To a soln of the product of Example 214 (120 mg, 0.26 mmol)
in dichloromethane (5 mL), was added m-chloroperbenzoic acid (130
mg, 0.52 mmol). The mixture was stirred for 1.5 h at 23.degree..
The mixture was diluted with EtOAc and washed with H.sub.2O to give
the crude material. Purification by column chromatography eluting
with EtOAc/triethylamine(100/2, v/v), followed by recrystallization
from dichloromethane and hexane, gave the desired product (80 mg,
61%). LC-MS: 503.2 (MH+, m/z), 1.94 (Rt, min).
Example 216
[0778] ##STR232##
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-oxo-2-(3-oxo--
piperazin-1-yl)-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0779] Following the general procedure outlined in Example 193,
piperazine-2-one (165 mg, 1.65 mmol), trimethylaluminum (0.83 mL,
1.65 mmol) and the product of Example 190 (150 mg, 0.33 mmol) were
reacted to give the crude material. Preparative HPLC, eluting with
acetonitrile/H.sub.2O (10/90, v/v to 90/10, v/v, over 10 min),
followed by recrystallization from dichloromethane and hexane, gave
the desired product 50 mg (29%). LC-MS: 523.2 (MH+, m/z), 1.68 (Rt,
min).
Example 217
[0780] ##STR233##
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-[(5-methyl-4H-1,-
2,4]triazol-3-ylmethyl)-amino]-8H-pyrido[2,3-d]pyrimidin-7-one
[0781] A solution of the product of Example 48 (150 mg, 0.34 mmol)
and (5-methyl-4H-[1,2,4]triazol-3-yl)-methylamine (190 mg, 1.7
mmol) in NMP (2 mL) was stirred at 100.degree. for 16 h to give the
crude material. Preparative HPLC, eluting with
acetonitrile/H.sub.2O (10/90, v/v to 90/10, v/v, over 10 min), gave
the desired product 23 mg (14%). LC-MS: 478.2 (MH+, m/z), 1.70 (Rt,
min).
[0782] Alternatively, the desired product can be purified by flash
chromatography eluting with EtOAc/triethylamine(100/2, v/v),
followed by recrystallization as hydrochloride salt from EtOAc and
methanol.
Example 218
[0783] ##STR234##
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-((1,1-dioxo-tetr-
ahydro-1-thiophen-3-ylmethyl)-amino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0784] Following the general procedure outlined in Example 217, the
product of Example 48 (100 mg, 0.22 mmol) and
3-aminomethylsulfolane (328 mg, 2.2 mmol) were reacted to give the
crude material. Purification by Flash chromatography eluting with
EtOAc/hexane/triethylamine(65/35/2, v/v/v), gave the desired
product 25 mg (22%). LC-MS: 515.4 (MH+, m/z), 1.97 (Rt, min).
Example 219
[0785] ##STR235##
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-((3-methyl-isoxa-
zol-5-ylmethyl)amino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0786] Following the general procedure outlined in Example 217, the
product of Example 48 (100 mg, 0.22 mmol) and
(3-methyl-isoxazol-5-yl)-methylamine (125 mg, 1.12 mmol) were
reacted to give the desired product 50 mg (44%). LC-MS: 478.2 (MH+,
m/z), 2.20 (Rt, min).
Example 220
[0787] ##STR236##
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-((3S,4S)-4-hydro-
xy-1,1-dioxo-tetrahydro-1-amino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0788] Following the general procedure outlined in Example 217, the
product of Example 48 (100 mg, 0.22 mmol) and
3(S)-amino-4(S)-hydroxysulfolane (169 mg, 1.12 mmol) were reacted
to give the desired product 50 mg (44%). LC-MS: 517.0 (MH+, m/z),
1.87 (Rt, min).
Example 221
[0789] ##STR237##
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-oxo-2,3-dyhyd-
ro-pyrimidin-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0790] Following the general procedure outlined in Example 217, the
product of Example 48 (100 mg, 0.22 mmol) and cytosine (124 mg,
1.12 mmol) were reacted to give the crude material. Preparative
HPLC afforded the title compound, 27 mg (20%). LC-MS: 477.2 (MH+,
m/z), 1.77 (Rt, min).
Example 222
[0791] ##STR238##
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-((1H-imidazol-2--
ylmethyl)amino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0792] (1H-Imidazol-2-yl)-methylamine dihydrochloride (184 mg, 1.1
mmol), NMP (1 mL), and triethylamine (0.31 mL, 2.2 mmol) were
stirred at 23.degree. 10 min. The product of Example 48 (100 mg,
0.22 mmol) was added and the mixture was reacted at 1000 for 16 h
to give the crude material. Preparative hplc afforded the title
compound, 36 mg (29%). LC-MS: 463.2 (MH+, m/z), 1.42 (Rt, min).
Example 223
[0793] ##STR239##
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(1H-[1,
2,4]triazol-3-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0794] Following the general procedure outlined in Example 217, the
product of Example 48 (150 mg, 0.33 mmol) and
3-amino-1,2,4-triazole (141 mg, 1.68 mmol) were reacted to give the
crude material. Preparative hplc afforded the title compound 28 mg
(15%). LC-MS: 450.2 (MH+, m/z), 1.79 (Rt, min).
Example 224
[0795] ##STR240##
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(1H-tetrazol-5-y-
lamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0796] Following the general procedure outlined in Example 217, the
product of Example 48 (10 mg, 0.33 mmol) and 5-amino-1H-tetrazole
(143 mg, 1.68 mmol) were reacted to give the crude material, which
was purified preparative hplc to afford the title compound, 17 mg
(9%). LC-MS: 451.0 (MH+, m/z), 2.04 (Rt, min).
Example 225
[0797] ##STR241##
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl-2-(2-methoxy-ethyla-
mino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0798] A solution of the product of Example 48 (150 mg, 0.34 mmol)
and 2-methoxy-ethylamine (0.09 mL, 1.01 mmol) in DMF (2 mL) was
stirred 23.degree. for 16 h. The mixture was diluted with EtOAc and
washed with H.sub.2O to give the crude material, which was purified
as described in Example 198 to give the desired product 70 mg
(47%). LC-MS: 441.2 (MH+, m/z), 2.10 (Rt, min).
Example 226
[0799] ##STR242##
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(tetrahydro-furan-3-
-ylamino) 8H-pyrido[2,3-d]pyrimidin-7-one
a) (Tetrahydro-furan-3-yl)-carbamic acid tert-butyl ester
[0800] Under Ar, to a soln of (+/-)-tetrahydro-3-furoic acid (500
mg, 4.30 mmol) in DMF (2 mL) was added triethylamine (0.66 mL, 4.74
mmol), followed by diphenylphosphoryl azide (1.02 mL, 4.74 mmol).
The mixture was heated to 80.degree. for 3 h and cooled to
23.degree., tert-butanol (3 mL) was then added and the resulting
mixture was stirred at 23.degree. for 16 h. The mixture was diluted
with EtOAc and washed with H.sub.2O. The organic layer was dried
over Na.sub.2SO.sub.4, and concentrated to give the crude
intermediate 670 mg.
b) Tetrahydro-furan-3-ylamine hydrochloride
[0801] To a soln of the crude (tetrahydro-furan-3-yl)-carbamic acid
tert-butyl ester (460 mg) in EtOAc (10 mL) was added 2 mL of 4N HCl
in 1,4-dioxane. The mixture was stirred at 23.degree. for 16 h,
then concentrated to give crude material 240 mg.
c)
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(tetrahydro-fura-
n-3-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0802] Following the general procedure outlined in Example 195, the
product of Example 48 (125 mg, 0.28 mmol), the crude
tetrahydro-furan-3-ylamine hydrochloride (240 mg) and triethylamine
(0.27 mL, 1.9 mmol) were reacted to give the crude material.
Purification by flash chromatography, eluting with
EtOAc/hexane/triethylamine(50/50/2, v/v/v), gave the desired
product (38 mg, 30%). LC-MS: 453.2 (MH+, m/z), 2.20 (Rt, min).
Example 227
[0803] ##STR243##
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-[(2-hydroxy-ethyl)--
methyl-amino]-8H-pyrido[2,3-d]pyrimidin-7-one
[0804] Following the general procedure outlined in Example 126, the
product of Example 48 (100 mg, 0.22 mmol), N-methylethanolamine
(0.05 mL, 0.66 mmol) were reacted for 2 h to give the crude
material, which was purified by preparative hplc to affored the
title compound, 26 mg (27%). LC-MS: 441.2 (MH+, m/z), 2.19 (Rt,
min).
Example 228
[0805] ##STR244##
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-[2-(1H-imidazol-4-y-
l-ethylamino]-8H-pyrido[2,3-d]pyrimidin-7-one
[0806] Following the general procedure outlined in Example 217, the
product of Example 48 (150 mg, 0.34 mmol) and histamine (187 mg,
1.68 mmol) were reacted to give the desired product 50 mg (31%).
LC-MS: 477.0 (MH+, m/z), 1.59 (Rt, min).
Example 229
[0807] ##STR245##
[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-py-
rido[2,3-d]pyrimidine-2-ylamino]-acetamide
[0808] To a soln of trimethylaluminum (3.3 mL, 6.6 mmol) in
dichloromethane was bubbled NH.sub.3 gas for 30 min, the product of
Example 190 (500 mg, 1.1 mmol) was then added. The resulting
mixture was stirred for 16 h. The mixture was diluted with EtOAc
and washed with H.sub.2O to give the crude material. Purification
by flash chromatography, eluting with EtOAc/triethylamine(100/2,
v/v), gave the desired product (263 mg, 54%). LC-MS: 440.0 (MH+,
m/z), 1.75 (Rt, min).
Example 230
[0809] ##STR246##
Cyclopropanecarboxylic acid
[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-p-
yrido[2,3-d]pyrimidine-2-yl]-amide
a)
2-Amino-8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-8H-pyrido[-
2,3-d]pyrimidin-7-one
[0810] To a solution of the product of Example 48 (1.0 g, 2.2 mmol)
and triethylamine (1 mL) in 2 mL of NMP was bubbled NH.sub.3 gas at
23.degree. for 30 min. The mixture was diluted with EtOAc and
washed with H.sub.2O to give the crude material. Purification by
flash chromatography eluting with
EtOAc/hexane/triethylamine(50/50/2, v/v/v), followed by
recrystallization from dichloromethane and hexane, gave the title
compound, (360 mg, 43%). LC-MS: 383.0 (MH+, m/z), 1.95 (Rt,
min).
b) Cyclopropanecarboxylic acid
[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-p-
yrido[2,3-d]pyridine-2-yl]-amide
[0811] To a solution of the product of Example 230(a),
2-amino-8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-8H-pyrido[2,-
3-d]pyrimidin-7-one (100 mg, 0.26 mmol) in 3 mL of tetrahydrofuran
was added NaH (19 mg, 0.78 mmol). The mixture was stirred for 20
min at 23.degree., a soln of cyclopropanecarbonyl chloride (27 mg,
0.26 mmol) in tetrahydrofuran (1 mL) was added. The resulting
mixture was heated to solvent reflux for 16 h to give the crude
material, which was purified by preparative hplc to afford 25 mg
(21%). LC-MS: 451.2 (MH+, m/z), 2.14 (Rt, min).
Example 231
[0812] ##STR247##
Cyclopropanecarboxylic acid
(1-cyclopropyl-methanoyl)-[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-p-
henyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl]-amide
[0813] A second compound from the reaction of Example 230 after
hplc purification was the purified tile compound, 33 mg (24%).
LC-MS: 519.0 (MH+, m/z), 2.37 (Rt, min).
Example 232
[0814] ##STR248##
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-oxo-2-thiomorpho-
lin-4-yl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0815] Following the general procedure outlined in Example 193,
thiomorpholine (0.22 mL, 2.2 mmol), trimethylaluminum (1.1 mL, 2.2
mmol) and the product of Example 190 (200 mg, 0.44 mmol) were
reacted to give the desired product 200 mg (86%). LC-MS: 526.0
(MH+, m/z), 2.07 (Rt, min).
Example 233
[0816] ##STR249##
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-[(tetrahydro-furan--
2-ylmethyl)-amino]-8H-pyrido[2,3-d]pyrimidin-7-one
[0817] Following the general procedure outlined in Example 225, the
product of Example 48 (100 mg, 0.22 mmol) and
tetrahydrofurfurylamine (0.07 mL, 0.66 mmol) afforded the title
compound, 50 mg (49%). LC-MS: 467.0 (MH+, m/z), 2.22 (Rt, min).
Example 234
[0818] ##STR250##
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-[2-(3-hydroxy-azeti-
din-1-yl)-2-oxo-ethylamino]-8H-pyrido[2,3-d]pyrimidin-7-one
a) Azetidin-3-ol hydrochloride
[0819] To a soln of 1-benzhydrylazetan-3-ol (1.0 g, 4.16 mmol) in
methanol (20 mL) were added 10% Pd/C (1.0 g) and 4N HCl in
1,4-dioxane (2 mL). The mixture was flushed with Ar, and then
stirred on Parr apparatus at 40 psi H.sub.2 for 6 h at 60.degree..
The mixture was cooled to room temperature and filtered through
celite. The filtrate was concentrated and the resulting solid was
washed with diethyl ether to give the desired product 0.31 g (68%).
.sup.1H NMR (MeOD-d.sub.4): .delta. 4.17 (m, 1H), 4.22 (m, 2H),
3.91 (m, 2H).
b)
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-[2-(3-hydroxy-az-
etidin-1-yl)-2-oxo-ethylamino]-8H-pyrido[2,3-d]pyrimidin-7-one
[0820] A mixture of
[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-p-
yrido[2,3-d]pyrimidin-2-ylamino]-acetic acid (10 mg, 0.23 mmol),
azetidin-3-ol hydrochloride (37 mg, 0.34),
o-benzotriazol-1-yl-N,N,N'N'-tetramethyluronium hexafluorophosphate
(129 mg, 0.34 mmol) and N-methyl-morpholine (0.12 mL, 1.13 mmol) in
DMF (2 mL) was stirred at 23.degree. for 16 h to give the crude
material, which was purified by preparative hplc to afford the
title compound 56 mg (49%). LC-MS: 496.2 (MH+, m/z), 1.69 (Rt,
min).
Example 235
[0821] ##STR251##
4-(4-Fluoro-2-methyl-phenyl)-2-((R)-2-hydroxy-propylamino)-8-o-tolyl-8H-py-
rido[2,3-d]pyrimidin-7-one
[0822] Following the general procedure outlined in Example 225, the
product of 121 (120 mg, 0.28 mmol) and R(-)-1-amino-2-propanol
(0.064 mL, 0.85 mmol) were reacted to give the crude material.
Purification by flash chromatography eluting with
EtOAc/hexane/triethylamine(50/50/2, v/v/v), followed by
recrystallization from dichloromethane and hexane, afforded the
desired product 110 mg (94%). LC-MS: 419.0 (MH+, m/z), 1.83 (Rt,
min).
Example 236
[0823] ##STR252##
4-(4-Fluoro-2-methyl-phenyl)-2-(2-hydroxy-2-methyl-propylamino)-8-o-tolyl--
8H-pyrido[2,3-d]pyrimidin-7-one
[0824] Following the general procedure outlined in Example 225, the
product of Example 121 (120 mg, 0.28 mmol) and
1-amino-2-methyl-2-propanol (76 mg, 0.85 mmol) were reacted to give
the crude material. Purification by flash chromatography eluting
with EtOAc/hexane/triethylamine(50/50/2, v/v/v), followed by
recrystallization from dichloromethane and hexane, afforded the
desired product 96 mg (79%). LC-MS: 433.4 (MH+, m/z), 1.87 (Rt,
min).
Example 237
[0825] ##STR253##
(1SR,2RS)-2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,-
8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-cyclopentanecarboxylic
acid amide
[0826] Following the general procedure outlined in Example 225, the
product of Example 48 (120 mg, 0.34 mmol) and
cis-2-amino-2-cyclopentanecarboxamide (1390 g, 1.02 mmol) were
reacted to give the crude material. Purification by flash
chromatography eluting with EtOAc/hexane/triethylamine(50/50/2,
v/v/v), followed by recrystallization from dichloromethane and
hexane, afforded the desired product, 87 mg (52%). LC-MS: 494.0
(MH+, m/z), 2.00 (Rt, min).
Example 238
[0827] ##STR254##
4-(4-Fluoro-2-methyl-phenyl)-2-((S)-2-hydroxy-propylamino)-8-o-tolyl-8H-py-
rido[2,3-d]pyrimidin-7-one
[0828] Following the general procedure outlined in Example 225, the
product of 121 (220 mg, 0.52 mmol) and (S)-(+)-1-amino-2-propanol
(0.12 mL, 1.56 mmol) were reacted to give the crude material.
Purification by Flash chromatography eluting with
EtOAc/hexane/triethylamine(50/50/2, v/v/v), followed by
recrystallization from dichloromethane and hexane, afforded the
desired product, the desired product 135 mg (62%). LC-MS: 419.2
(MH+, m/z), 1.79 (Rt, min).
Example 239
[0829] ##STR255##
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methylamino-8H-p-
yrido[2,3-d]pyrimidin-7-one
[0830] Following the general procedure outlined in Example 225, the
product of Example 48 (1.0 g, 2.24 mmol) and methylamine (5.6 mL,
11.2 mmol) were reacted to give the crude material. Purification by
flash chromatography eluting with
EtOAc/hexane/triethylamine(30/70/2, v/v/v), followed by
recrystallization from dichloromethane and hexane, gave the desired
product 430 mg (48%). LC-MS: 397.2 (MH+, m/z), 2.14 (Rt, min).
Example 240
[0831] ##STR256##
8-(2,6-Difluoro-phenyl)-2-[2-(1,1-dioxo-1l.sup.6-thiomorpholin-4-yl)-2-oxo-
-ethylamino]-4-(4-fluoro-2-methyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one
[0832] Following the procedure outlined in Example 215, the product
of Example 232,
8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-oxo-2-thiomorph-
olin-4-yl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (164 mg, 0.3
1 mmol) and m-chloroperbenzoic acid (156 mg, 0.62 mmol) were
reacted to give the desired product 165 mg (95%). LC-MS: 558.2
(MH+, m/z), 1.77 (Rt, min).
Example 241
[0833] ##STR257##
2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(3-(2-oxo-pyrrol-
idin-1-yl)-propylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0834] Following the general procedure outlined in Example 225, the
product of Example 48 (100 mg, 0.22 mmol) and
N-(3'-aminopropyl)-2-pyrrolidinone (96 mg, 0.67 mmol) were reacted
to give the crude material. Purification by flash chromatography
eluting with EtOAc/hexane/triethylamine(70/30/2, v/v/v), followed
by recrystallization from ethanol and hexane, gave the desired
product 95 mg (85%). LC-MS: 508.2 (MH+, m/z), 2.02 (Rt, min).
Example 242
[0835] ##STR258##
3-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro--
pyrido[2,3-d]pyrimidin-2-ylamino]-N-hydroxy-propionamidine
[0836] Under Ar, a soln of hydroxylamine hydrochloride (119 mg,
1.72 mmol) and triethylamine (0.26 mL, 1.89 mmol) in 5 mL of DMSO
was stirred at room temperature for 5 min, the product of Example
206,
3-[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-
-pyrido[2,3-d]pyrimidin-2-ylamino]-propionitrile (150 mg, 0.34
mmol) was added. The resulting mixture was heated to 80.degree. for
16 h. Preparative hplc, followed by recrystallization from ethanol
and hexane, gave the desired product 80 mg (45%). LC-MS: 469.2
(MH+, m/z), 1.52 (Rt, min).
Example 243
[0837] ##STR259##
8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-[2-(5-oxo-4,5-dihyd-
ro-[1,2,4]-oxadiazol-3-yl)-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one
[0838] Under Ar, to a soln of the product of Example 242,
3-[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-
-pyrido[2,3-d]pyrimidin-2-ylamino]-N-hydroxy-propionamidine (100
mg, 0.20 mmol), and pyridine (0.048 mL, 0.6 mmol), was added
2-ethylhexyl chloroformate (0.039 mL, 0.2 mmol). The mixture was
stirred at room temperature for 2 h, then diluted with H.sub.2O and
extracted with EtOAc. The organic layer was dried over sodium
sulfate, filtered and concentrated. The resulting residue was
diluted with xylene (10 mL) and heated to reflux for 18 h to give
the crude material, which was purified by preparative hplc to give
the desired product 28 mg (28%). LC-MS: 495.0 (MH+, m/z), 1.96 (Rt,
min).
[0839] All publications, including but not limited to patents and
patent applications, cited in this specification are herein
incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
[0840] The above description fully discloses the invention
including preferred embodiments thereof. Modifications and
improvements of the embodiments specifically disclosed herein are
within the scope of the following claims. Without further
elaboration, it is believed that one skilled in the are can, using
the preceding description, utilize the present invention to its
fullest extent. Therefore, the Examples herein are to be construed
as merely illustrative and not a limitation of the scope of the
present invention in any way. The embodiments of the invention in
which an exclusive property or privilege is claimed are defined as
follows.
* * * * *