U.S. patent application number 15/489593 was filed with the patent office on 2017-08-03 for phosphorous derivatives as kinase inhibitors.
The applicant listed for this patent is ARIAD Pharmaceuticals, Inc.. Invention is credited to David C. Dalgarno, Wei-Sheng Huang, Anna Kohlmann, Feng Li, Shuangying Liu, Jiwei Qi, Jan Antoinette C. Romero, William C. Shakespeare, R. Mathew Thomas, Yihan Wang, Xiaotian Zhu, Dong Zou.
Application Number | 20170218000 15/489593 |
Document ID | / |
Family ID | 41340562 |
Filed Date | 2017-08-03 |
United States Patent
Application |
20170218000 |
Kind Code |
A1 |
Wang; Yihan ; et
al. |
August 3, 2017 |
PHOSPHOROUS DERIVATIVES AS KINASE INHIBITORS
Abstract
The invention features compounds of the general formula (I) in
which the variable groups are as defined herein, and to their
preparation and use. ##STR00001##
Inventors: |
Wang; Yihan; (Newton,
MA) ; Huang; Wei-Sheng; (Acton, MA) ; Liu;
Shuangying; (Wellesley, MA) ; Shakespeare; William
C.; (Southborough, MA) ; Thomas; R. Mathew;
(Sharon, MA) ; Qi; Jiwei; (West Roxbury, MA)
; Li; Feng; (Winchester, MA) ; Zhu; Xiaotian;
(Newton, MA) ; Kohlmann; Anna; (Winchester,
MA) ; Dalgarno; David C.; (Brookline, MA) ;
Romero; Jan Antoinette C.; (Arlington, MA) ; Zou;
Dong; (Concord, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ARIAD Pharmaceuticals, Inc. |
Cambridge |
MA |
US |
|
|
Family ID: |
41340562 |
Appl. No.: |
15/489593 |
Filed: |
April 17, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14690916 |
Apr 20, 2015 |
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15489593 |
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12736910 |
Jan 17, 2012 |
9012462 |
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PCT/US2009/044918 |
May 21, 2009 |
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14690916 |
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61192938 |
Sep 23, 2008 |
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61192964 |
Sep 23, 2008 |
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61188796 |
Aug 13, 2008 |
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61137490 |
Jul 31, 2008 |
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61128317 |
May 21, 2008 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 11/00 20180101;
A61P 1/04 20180101; C07F 9/65218 20130101; A61P 15/00 20180101;
A61P 35/02 20180101; A61P 25/00 20180101; C07F 9/65846 20130101;
C07F 9/6521 20130101; A61P 21/00 20180101; C07F 9/6561 20130101;
C07F 9/65583 20130101; C07F 9/6512 20130101; C07F 9/65586 20130101;
C07F 9/6533 20130101; C07F 9/657172 20130101; A61P 43/00 20180101;
A61P 35/00 20180101; C07D 239/48 20130101; C07F 9/58 20130101; C07F
9/65685 20130101; C07F 9/65616 20130101; C07F 9/650905
20130101 |
International
Class: |
C07F 9/6533 20060101
C07F009/6533; C07F 9/58 20060101 C07F009/58; C07F 9/6521 20060101
C07F009/6521; C07D 239/48 20060101 C07D239/48; C07F 9/6561 20060101
C07F009/6561; C07F 9/6509 20060101 C07F009/6509; C07F 9/6571
20060101 C07F009/6571; C07F 9/6512 20060101 C07F009/6512; C07F
9/6558 20060101 C07F009/6558; C07F 9/6584 20060101 C07F009/6584;
C07F 9/6568 20060101 C07F009/6568 |
Claims
1. A compound of the formula VIa: ##STR00495## wherein X.sup.1 is
NR.sup.b1 or CR.sup.b; X.sup.3 is NR.sup.d1 or CR.sup.d; X.sup.4 is
NR.sup.e1 or CR.sup.e; Ring A and Ring E are each an independently
selected aryl or heteroaryl ring, the heteroaryl ring being a 5- or
6-membered ring containing 1 to 4 heteroatoms selected from N, O
and S(O).sub.r; each occurrence of R.sup.a, R.sup.b, R.sup.d,
R.sup.e, and R.sup.g is independently selected from the group
consisting of halo, --CN, --NO.sub.2, --R.sup.1, --OR.sup.2,
--O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2,
--NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2,
--OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2,
--NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2,
--C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2,
--YC(.dbd.N--OR.sup.1)YR.sup.2,
--YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2,
--YP(.dbd.O)(YR.sup.3)(YR.sup.3), --Si(R.sup.3a).sub.3,
--NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2,
--SO.sub.2NR.sup.1R.sup.2 and --NR.sup.1SO.sub.2NR.sup.1R.sup.2; or
alternatively, each R.sup.a and R.sup.g may also be an
independently selected moiety, --P(.dbd.O)(R.sup.3).sub.2 or a ring
system containing the moiety --P(.dbd.O)(R.sup.3)-- as a ring
member; R.sup.b1, R.sup.d1 and R.sup.e1 are absent; or
alternatively two adjacent substituents selected from R.sup.d,
R.sup.d1, R.sup.e, and R.sup.e1, or two adjacent R.sup.a moieties,
can form, with the atoms to which they are attached, a fused, 5-,
6- or 7-membered saturated, partially saturated or unsaturated
ring, which contains 0-4 heteroatoms selected from N, O and S(O),
and which may bear up to four substituents; at least one of R.sup.a
and R.sup.g is or contains a moiety, --P(.dbd.O)(R.sup.3).sub.2 or
a ring system containing the moiety --P(.dbd.O)(R.sup.3)-- as a
ring member; L is O or NH; r is 0, 1 or 2; s is 1, 2, 3, 4 or 5; p
is 1, 2, 3 or 4; each occurrence of Y is independently a bond,
--O--, --S-- or --NR.sup.1--; each occurrence of R.sup.1 and
R.sup.2 is independently H or an alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,
heterocyclic or heteroaryl moiety; each occurrence of R.sup.3 is
independently an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl moiety,
or two adjacent R.sup.3 moieties combine to form a ring system
including a phosphorous atom; each occurrence of R.sup.3a is
independently selected from alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic, and
heteroaryl; alternatively, each NR.sup.1R.sup.2 moiety may be a 5-,
6- or 7-membered saturated, partially saturated or unsaturated
ring, which can be optionally substituted and which contains 0-2
additional heteroatoms selected from N, O and S(O).sub.r; and each
of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl, heteroaryl and heterocyclic moieties is
optionally substituted.
2. The compound of claim 1 in which X.sup.1 is N.
3. The compound of claim 2 in which X.sup.3 is N and X.sup.4 is
CR.sup.e.
4. The compound of claim 2 in which X.sup.3 is CR.sup.d and X.sup.4
is CR.sup.e.
5. The compound of claim 1 in which X.sup.1 is CR.sup.b.
6. The compound of claim 5 in which X.sup.3 is N and X.sup.4 is
CR.sup.e.
7. The compound of claim 5 in which X.sup.3 is CR.sup.d and X.sup.4
is CR.sup.e.
8. The compound of any of claims 1, 2, 4, 5 or 7 in which R.sup.d
is selected from Cl, F, C1-C4 alkyl, trihaloalkyl, cycloalkyl,
C2-C4 alkenyl, and alkynyl.
9. The compound of claim 1 in which X.sup.3 is CR.sup.d and X.sup.4
is CR.sup.e wherein R.sup.d and R.sup.e, together with the atoms to
which they are attached, form a fused, 5-, 6- or 7-membered
saturated, partially saturated or unsaturated ring, which contains
0-4 heteroatoms selected from N, O and S(O).sub.r and which may
bear up to four substituents.
10. The compound of any of claims 1-9 in which s is 1, 2, 3 or 4,
and each of the substituents R.sup.a is independently selected from
halo, --R.sup.1, --OR.sup.2, --NR.sup.1R.sup.2 and
--P(.dbd.O)(R.sup.3).sub.2, wherein each R.sup.1 and R.sup.2 moiety
may be further substituted or unsubstituted.
11. The compound of claim 10 in which at least one substituent
R.sup.a is --OR.sup.2 and R.sup.2 is selected from C1-C6 alkyl,
C2-C6 alkenyl, and C2-C6 alkynyl.
12. The compound of claim 10 or 11 in which at least one
substituent R.sup.a is a 5-, 6- or 7-membered heterocyclic or 5- or
6-membered heteroaryl moiety, linked to Ring A either directly or
by an ether bond, and which may be further substituted with 1-3
substituents independently selected from halo, --CN, --NO.sub.2,
--R.sup.1, --OR.sup.2, --O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2,
--NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2,
--OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2,
--NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2,
--C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2,
--YC(.dbd.N--OR.sup.1)YR.sup.2,
--YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2,
YP(.dbd.O)(YR.sup.3)(YR.sup.3), --Si(R.sup.3a).sub.3,
--NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2,
--SO.sub.2NR.sup.1R.sup.2 and --NR.sup.1SO.sub.2NR.sup.1R.sup.2;
wherein each Y is independently a bond, --O--, --S-- or
--NR.sup.1--.
13. The compound of claim 12 in which the heterocyclic or
heteroaryl substituent R.sup.a is selected from the following:
##STR00496## ##STR00497## ##STR00498## ##STR00499##
14. The compound of any of claims 10-13 in which at least one
substituent R.sup.a is --P(.dbd.O)(R.sup.3).sub.2 in which each
R.sup.3 is, independently, a C1-C4 alkyl moiety.
15. The compound of any of claims 1-14 in which L is NH, Ring E is
aryl, and each R.sup.g is independently selected from halo,
--R.sup.1, --OR.sup.2, --S(O).sub.rR.sup.2 and
--P(.dbd.O)(R.sup.3).sub.2.
16. The compound of claim 15 in which Ring E contains at least one
moiety R.sup.g in the ortho position, relative to the ring atom
attached to L.
17. The compound of claim 15 in which Ring E contains at least one
moiety R.sup.g in the meta position, relative to the ring atom
attached to L.
18. The compound of claim 15 in which Ring E contains at least one
moiety R.sup.g in the para position, relative to the ring atom
attached to L.
19. The compound of any of claims 15-18 in which at least one
moiety R.sup.g is --P(.dbd.O)(R.sup.3).sub.2 and is
--P(.dbd.O)(R.sup.3).sub.2 is --P(.dbd.O)(CH.sub.3).sub.2 or
--P(.dbd.O)(CH.sub.2CH.sub.3).sub.2.
20. The compound of claim 13 in which L is NH; X.sup.1 is N;
X.sup.3 is CR.sup.d; X.sup.4 is CR.sup.e; Ring A is aryl and
optionally contains up to two additional R.sup.a moieties; and Ring
E is aryl and contains 1-3 R.sup.g moieties, one of which being an
ortho, meta or para --P(.dbd.O)(R.sup.3).sub.2 moiety.
21. A pharmaceutical composition containing a compound of any of
claims 1-20 or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable vehicle.
22. A method for inhibiting cellular proliferation in a subject,
said method comprising administering to said subject a compound of
any of claims 1-20 in an amount effective to inhibit said cellular
proliferation.
Description
BACKGROUND OF THE INVENTION
[0001] The protein kinases represent a large family of proteins
which play a central role in the regulation of a wide variety of
cellular processes and maintain control over cellular function. A
partial, non limiting, list of such kinases includes ALK, abl, Akt,
bcr-abl, Blk, Brk, c-kit, c-met, c-src, CDK1, CDK2, CDK3, CDK4,
CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, bRaf, cRaf1, CSK, EGFR, ErbB2,
ErbB3, ErbB4, Erk, Pak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5,
Fgr, flt-1, flt-3, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak1, Jak2,
Jak3, KDR, Lck, Lyn, FAK, MEK, p38, PDGFR, PIK, PKC, PYK2, ros,
tie, tie2, Pim-1, PI3k, TRK and Zap70. Abnormal protein kinase
activity has been related to several disorders, ranging from
non-life threatening diseases such as psoriasis to extremely
serious diseases such as cancers.
[0002] In view of this large number of protein kinases and the
multitude of protein kinase-related diseases, there is an
ever-existing need to provide new classes of compounds with
increased selectivity that are useful as protein kinase inhibitors
and therefore useful in the treatment of protein tyrosine-kinase
related diseases.
[0003] The invention concerns a new family of phosphorous compounds
and their use in treating cancers and other diseases.
DESCRIPTION OF THE INVENTION
1. General Description of Compounds of the Invention
[0004] Compounds of the invention can have a broad range of useful
biological and pharmacological activities, permitting their use in
pharmaceutical compositions and methods for treating cancer
(including lymphoma, solid tumors and leukemia among other
cancers), including, also among others, advanced cases and cases
which are resistant or refractory to one or more other
treatments.
[0005] Included are compounds of Formula I, and tautomers and
pharmaceutically acceptable salts and solvate thereof:
##STR00002##
[0006] wherein
[0007] X.sup.1 is NR.sup.b1 or CR.sup.b;
[0008] X.sup.2 is NR.sup.c1 or CR.sup.c;
[0009] X.sup.3 is NR.sup.d1 or CR.sup.d;
[0010] X.sup.4 is NR.sup.e1 or CR.sup.e;
[0011] Ring A is an aryl, a 5- or a 6-membered heteroaryl ring
which contains 1 to 4 heteroatoms selected from N, O and
S(O).sub.r;
[0012] at each occurrence R.sup.a, R.sup.b, R.sup.c, R.sup.d and
R.sup.e are independently selected from the group consisting of
halo, --CN, --NO.sub.2, --R.sup.1, --OR.sup.2,
--O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2,
--NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2,
--OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2,
--NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2,
--C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2,
--YC(.dbd.N--OR.sup.1)YR.sup.2,
--YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2,
--YP(.dbd.O)(YR.sup.3)(YR.sup.3), --Si(R.sup.3a).sub.3,
[0013] --NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2,
--SO.sub.2NR.sup.1R.sup.2 and --NR.sup.1SO.sub.2NR.sup.1R.sup.2,
and R.sup.b1, R.sup.c1, R.sup.d1 and R.sup.e1 are absent; wherein
each Y is independently a bond, --O--, --S-- or --NR.sup.1--;
or
[0014] alternatively two adjacent substituents selected from
R.sup.b, R.sup.b1, R.sup.c, R.sup.c1, R.sup.d, R.sup.d1, R.sup.e
and R.sup.e1; or two adjacent R.sup.a moieties, can form with the
atoms to which they are attached a 5-, 6- or 7-membered saturated,
partially saturated or unsaturated ring, which contains 0-4
heteroatoms selected from N, O and S(O).sub.r and which is
substituted with one to four R.sup.f moities wherein;
[0015] each R.sup.f moiety is independently selected from the group
consisting of halo, .dbd.O, .dbd.S, --CN, --NO.sub.2, --R.sup.1,
--OR.sup.2, --O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2,
--NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2,
--OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2,
--NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2,
--C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2,
--YC(.dbd.N--OR.sup.1)YR.sup.2,
--YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2,
--YP(.dbd.O)(YR.sup.3)(YR.sup.3), --Si(R.sup.3a).sub.3,
--NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2,
--SO.sub.2NR.sup.1R.sup.2 and --NR.sup.1SO.sub.2NR.sup.1R.sup.2; or
alternatively two adjacent R.sup.f moieties can form with the atoms
to which they are attached a 5-, 6- or 7-membered saturated,
partially saturated or unsaturated ring, optionally substituted;
and which contains 0-4 heteroatoms selected from N, O and
S(O).sub.r;
[0016] at least one of R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e,
R.sup.f, R.sup.b1, R.sup.c1, R.sup.d1 and R.sup.e1, when present,
is or contains --P(.dbd.O)(R.sup.3).sub.2 or a ring system
containing the moiety --P(.dbd.O)(R.sup.3)-- as a ring member.
[0017] r is 0, 1 or 2;
[0018] s is 1, 2, 3, 4 or 5
[0019] n is 0 or 1;
[0020] each occurrence of Y is independently a bond, --O--, --S--
or --NR.sup.1--;
[0021] each occurrence of R.sup.1 and R.sup.2 is independently
selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl;
[0022] each occurrence of R.sup.3 is independently selected from
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,
aryl, heteroalkyl, heterocyclic and heteroaryl, or two adjacent
R.sup.3 moieties combine to form a ring system including a
phosphorous atom;
[0023] each occurrence of R.sup.3a is independently selected from
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,
aryl, heteroalkyl, heterocyclic, and heteroaryl;
[0024] alternatively, each NR.sup.1R.sup.2 moiety may be a 5-, 6-
or 7-membered saturated, partially saturated or unsaturated ring,
which can be optionally substituted and which contains 0-2
additional heteroatoms selected from N, O and S(O).sub.r; and
[0025] each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocyclic
moiety is optionally substituted.
[0026] The foregoing definitions are further elaborated upon and
exemplified below and apply to all subsequent occurrences except to
the extent otherwise specified.
2. Featured Classes of Compounds and their Use, Generally
[0027] One class of compounds which is of special interest for use
in the invention are compounds of Formula I, as described above in
Part 1, in which X.sup.2 is CR.sup.c, X.sup.3 is CR.sup.d and
X.sup.4 is CR.sup.e. This class is illustrated by compounds of
Formula IA:
##STR00003##
[0028] wherein
[0029] X.sup.1 is N or CR.sup.b; and Ring A, R.sup.a, R.sup.b,
R.sup.c, R.sup.d, R.sup.e, n, and s are as defined in Formula
I.
[0030] One class of interest includes compounds in which Ring A is
a phenyl.
[0031] Another class of interest includes compounds in which Ring A
is a 5- or 6-membered heteroaryl.
[0032] Another class of compounds which is of special interest for
use in the invention are compounds of Formula Ia, as described
above, in which X.sup.1 is CR.sup.b.
This class is illustrated by compounds of Formula IB:
##STR00004##
[0033] A subclass of interest include compound of Formula IB in
which n is 0.
[0034] Another subclass of interest includes compounds of Formula
IB in which n is 1.
[0035] Another subclass of interest includes compounds of Formula
IB in which Ring A is phenyl.
[0036] Of special interest is another class of compounds of Formula
IA as described above in Part 1 in which X.sup.1 is N. This class
is illustrated by compounds of Formula IC:
##STR00005##
[0037] A subclass of interest include compound of Formula IC in
which n is 0.
[0038] Another subclass of interest includes compounds of Formula
IC in which n is 1.
[0039] Another subclass of interest includes compounds of Formula
IC in which Ring A is phenyl.
[0040] In Formulas IB and IC, s, R.sup.a, R.sup.b, R.sup.c, R.sup.d
and R.sup.e are as defined above in Formula I. In a particular
embodiment of the previous classes and subclasses, one of R.sup.a
is or contains a --P(.dbd.O)(R.sup.3).sub.2 group. Examples of
R.sup.a containing a --P(.dbd.O)(R.sup.3).sub.2 group include,
without limitation, --(CH.sub.2).sub.m--P(.dbd.O)(R.sup.3).sub.2,
--(CH.sub.2).sub.m--NR.sup.1--P(.dbd.O)(R.sup.3).sub.2,
--(CH.sub.2).sub.m--O--P(.dbd.O)(R.sup.3).sub.2,
--(CH.sub.2).sub.m--NR.sup.1--(CH.sub.2).sub.m--P(.dbd.O)(R.sup.3).sub.2,
--(CH.sub.2).sub.m--NR.sup.1C(O)O--(CH.sub.2).sub.m--P(.dbd.O)(R.sup.3).s-
ub.2,
--(CH.sub.2).sub.m--C(O)--(CH.sub.2).sub.m--P(.dbd.O)(R.sup.3).sub.2-
,
--(CH.sub.2).sub.m--C(O)NR.sup.1--(CH.sub.2).sub.m--P(.dbd.O)(R.sup.3).s-
ub.2 in which m is 0, 1, 2, 3 or 4.
[0041] Illustrative examples of this class are the following
compounds of Formula IA:
##STR00006##
[0042] In certain embodiments, R.sup.a contains a
--P(.dbd.O)(R.sup.3).sub.2 substituent as part of a cyclic
structure. For example, two R.sup.3 groups can combine to form a
ring system including a phosphorous atom, wherein the ring system
is a 5-, 6- or 7-membered saturated ring, optionally substituted;
and which can optionally contain one heteroatom selected from N, O
and S(O).sub.r. In certain embodiments, R.sup.a is or contains a
group described by one of the following formulas:
##STR00007##
[0043] Illustrative examples of this class are compounds of Formula
Ia include:
##STR00008##
[0044] In other cases, R.sup.a is a ring system containing the
moiety --P(.dbd.O)(R.sup.3)-- as a ring member, such as a 5-, 6- or
7-membered saturated ring, optionally substituted; which contains a
phosphorous atom and can optionally contains 1 heteroatom selected
from N, O and S(O).sub.r. In certain embodiments, R.sup.a is or
contains a group described by one of the following formulas:
##STR00009##
[0045] Illustrative examples of this class are compounds of Formula
IA include:
##STR00010##
[0046] In one subclass of interest, one of R.sup.a is
--(CH.sub.2).sub.m--P(.dbd.O)(R.sup.3).sub.2. This class is
illustrated by compounds of Formula II.
##STR00011##
in which variables R.sup.3, R.sup.a, n, Ring A, X.sup.1, X.sup.2,
X.sup.3 and X.sup.4 are as defined above in Formula I and m is 0,
1, 2, 3 or 4.
[0047] One class of compounds which is of special interest for use
in the invention are compounds of Formula II, as described above,
in which X.sup.2 is CR.sup.c, X.sup.3 is CR.sup.d and X.sup.4 is
CR.sup.e. This class is illustrated by compounds of Formula
IIA:
##STR00012##
in which variables R.sup.3, R.sup.a, Ring A, n, X.sup.1, R.sup.c,
R.sup.d, and R.sup.e are as defined above in Formula I and m is 0,
1, 2, 3 or 4.
[0048] In one subclass of interest are compounds of Formula II or
IIA in which m is 0. In another subclass m is 1.
[0049] In another subclass of interest are compounds of Formula II
or Formula IIA in which X is N.
[0050] In another subclass of interest are compounds of Formula II
or Formula IIA in which X is CR.sup.b.
[0051] In another subclass of interest are compounds of the above
classes and subclasses in which n is 0. In another subclass n is
1.
[0052] One class of compounds of special interest are compounds of
Formula IIA in which Ring A is a phenyl.
[0053] Non limiting examples of this embodiment include the
following compounds of Formula IIA:
##STR00013## ##STR00014##
[0054] In one embodiment, two adjacent substituents selected from
R.sup.c1, R.sup.d1, R.sup.c and R.sup.d, form with the atoms to
which they are attached a 5-, 6- or 7-membered saturated, partially
saturated or unsaturated Ring B, which is substituted with 1 to 4
R.sup.f; and which contains 0-4 heteroatoms selected from N, O and
S(O).sub.r. This class is illustrated by compounds of Formula
III:
##STR00015##
in which variables R.sup.a, R.sup.f, Ring A, n, s, X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 are as described in Formula I; and t
is 1, 2, 3 or 4.
[0055] One class of compounds which is of special interest for use
in the invention are compounds of Formula III, as described above,
in which X.sup.2 is CR.sup.c, X.sup.3 is CR.sup.d and X.sup.4 is
CR.sup.c and R.sup.c and R.sup.d moieties form with the atoms to
which they are attached a 5-, 6- or 7-membered saturated, partially
saturated or unsaturated Ring B. This class is illustrated by
compounds of Formula IIIA:
##STR00016##
in which variables R.sup.a, X.sup.1, Ring A, n, s, t, X.sup.1,
R.sup.e and R.sup.f are as described in Formula III.
[0056] In one particular embodiment, one R.sup.a is or contains
--P(.dbd.O)(R.sup.3).sub.2 or a ring system containing the moiety
--P(.dbd.O)(R.sup.3)-- as a ring member (i.e.
(CH.sub.2).sub.mP(.dbd.O)(alkyl).sub.2, in which m is 0, 1, 2, 3 or
4 and other examples of phosphorous containing substituents,
including cyclic ones as listed above). In another particular
embodiment, R.sup.f is or contains --P(.dbd.O)(R.sup.3).sub.2 or a
ring system containing the moiety --P(.dbd.O)(R.sup.3)-- as a ring
member (i.e. (CH.sub.2).sub.mP(.dbd.O)(alkyl).sub.2, in which m is
0, 1, 2, 3 or 4 and other examples of phosphorous containing
substituents, including cyclic ones as listed above).
[0057] One class of compounds of special interest are compounds of
Formula III or IIIA in which Ring A is a phenyl.
[0058] Illustrative examples of this class are the following
compounds of Formula IIIA:
##STR00017## ##STR00018## ##STR00019##
[0059] Other Illustrative examples of this class are the following
compounds of Formula III:
##STR00020## ##STR00021##
[0060] In another embodiment, two adjacent substituents selected
from R.sup.d1, R.sup.e1, R.sup.d and R.sup.e form with the atoms to
which they are attached a 5-, 6- or 7-membered saturated, partially
saturated or unsaturated Ring C, which is substituted with 1 to 4
R.sup.f; and which contains 0-4 heteroatoms selected from N, O and
S(O).sub.r. This class is illustrated by compounds of Formula
IV:
##STR00022##
in which Ring A, R.sup.a, R.sup.f, s, n, X.sup.1, X.sup.2, X.sup.3
and X.sup.4 are as defined in Formula I; and t is 1, 2, 3 or 4.
[0061] Illustrative examples of this class are the following
compounds of Formula IV:
##STR00023## ##STR00024##
[0062] One class of compounds which is of special interest for use
in the invention are compounds of Formula IV, as described above,
in which X.sup.1 is CR.sup.b, X.sup.2 is CR.sup.c, X.sup.3 is
CR.sup.d and X.sup.4 is CR.sup.c and R.sup.d and R.sup.e moieties
form with the atoms to which they are attached a 5-, 6- or
7-membered saturated, partially saturated or unsaturated Ring C.
This class is illustrated by compounds of Formula IVA:
##STR00025##
in which Ring A, Ring C, R.sup.a, s, n, R.sup.b, R.sup.c, R.sup.f
and t are as defined above in Formula IV.
[0063] In one particular aspect of this embodiment, one R.sup.a is
or contains --P(.dbd.O)(R.sup.3).sub.2 or a ring system containing
the moiety --P(.dbd.O)(R.sup.3)-- as a ring member.
[0064] In another aspect of this embodiment, one of R.sup.f is or
contains --P(.dbd.O)(R.sup.3).sub.2 or a ring system containing the
moiety --P(.dbd.O)(R.sup.3)-- as a ring member.
[0065] In another aspect of this embodiment, R.sup.c is or contains
--P(.dbd.O)(R.sup.3).sub.2 or a ring system containing the moiety
--P(.dbd.O)(R.sup.3)-- as a ring member.
[0066] One class of compounds of special interest are compounds of
Formula IV or IVA in which Ring A is a phenyl.
[0067] Illustrative examples of this class are the following
compounds of Formula IVA:
##STR00026## ##STR00027## ##STR00028##
[0068] In another embodiment, two adjacent substituents selected
from R.sup.b, R.sup.c, R.sup.b1 and R.sup.c1 form with the atoms to
which they are attached a 5-, 6- or 7-membered saturated, partially
saturated or unsaturated Ring D, which is substituted with 1 to 4
R.sup.f groups; and which contains 0-4 heteroatoms selected from N,
O and S(O).sub.r. This class is illustrated by compounds of Formula
V:
##STR00029##
in which R.sup.a, s, n, X.sup.1, X.sup.2, X.sup.3, X.sup.4 and
R.sup.f are as defined above in Formula I; and t is 1, 2, 3 or
4.
[0069] Illustrative examples of this class are the following
compounds of Formula V:
##STR00030##
[0070] One class of compounds which is of special interest for use
in the invention are compounds of Formula V, as described above, in
which X.sup.1 is CR.sup.b, X.sup.2 is CR.sup.c, X.sup.3 is CR.sup.d
and X.sup.4 is CR.sup.e and R.sup.b and R.sup.c form with the atoms
to which they are attached a 5-, 6- or 7-membered saturated,
partially saturated or unsaturated Ring D. This class is
illustrated by compounds of Formula VA:
##STR00031##
in which R.sup.a, s, n, t, Ring A, Ring D, R.sup.d, R.sup.e and
R.sup.f are as defined above in Formula V.
[0071] In one particular aspect of this embodiment, one R.sup.a is
or contains --P(.dbd.O)(R.sup.3).sub.2 or a ring system containing
the moiety --P(.dbd.O)(R.sup.3)-- as a ring member.
[0072] In another aspect of this embodiment, one of R.sup.f is or
contains --P(.dbd.O)(R.sup.3).sub.2 or a ring system containing the
moiety --P(.dbd.O)(R.sup.3)-- as a ring member.
[0073] One class of compounds of special interest are compounds of
Formula V or VA in which Ring A is a phenyl.
[0074] Illustrative examples of this class are the following
compounds of Formula VA:
##STR00032##
[0075] The invention also features compounds of Formula VI:
##STR00033##
[0076] wherein
[0077] X.sup.1 is NR.sup.b1 or CR.sup.b;
[0078] X.sup.3 is NR.sup.d1 or CR.sup.d;
[0079] X.sup.4 is NR.sup.e1 or CR.sup.e;
[0080] Ring A is an aryl, a 5- or a 6-membered heteroaryl ring
which contains 1 to 4 heteroatoms selected from N, O and
S(O).sub.r;
[0081] Ring E represents an aryl, a carbocyclyl or a 5-, 6- or
7-membered heterocyclic or heteroaryl ring comprising carbon atoms
and 1-4 heteroatoms independently selected from O, N and
S(O).sub.r; Ring E is optionally fused with a 5-, 6- or 7-membered
saturated, partially saturated or unsaturated ring and Ring E is
substituted on carbon or on the heteroatom(s) with 1-7 R.sup.g
groups.
[0082] L is a bond, O(CH.sub.2).sub.y, NR.sup.4(CH.sub.2).sub.y,
S(O).sub.r(CH.sub.2).sub.y, (CH.sub.2).sub.y,
(CH.sub.2).sub.ySO.sub.2NR.sup.4, (CH.sub.2).sub.yNR.sup.4SO.sub.2,
(CH.sub.2).sub.yCH.dbd.CH, (CH.sub.2).sub.yC.ident.C,
(CH.sub.2).sub.y-, (CH.sub.2).sub.yC(O)NR.sup.4,
(CH.sub.2).sub.yNR.sup.4C(O); y is 0, 1, 2, 3 or 4; p is 1, 2, 3,
4, 5, 6 or 7; r is 0, 1 or 2, R.sup.4 is H or alkyl; and the linker
L can be included in either direction.
[0083] at each occurrence R.sup.a, R.sup.b, R.sup.d and R.sup.e are
independently selected from the group consisting of halo, --CN,
--NO.sub.2, --R.sup.1, --OR.sup.2, --O--NR.sup.1R.sup.2,
--NR.sup.1R.sup.2, --NR.sup.1--NR.sup.1R.sup.2,
--NR.sup.1--OR.sup.2, --C(O)YR.sup.2, --OC(O)YR.sup.2,
--NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2,
--NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2,
--C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2,
--YC(.dbd.N--OR.sup.1)YR.sup.2,
--YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2,
--YP(.dbd.O)(YR.sup.3)(YR.sup.3), --Si(R.sup.3a).sub.3,
[0084] --NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2,
--SO.sub.2NR.sup.1R.sup.2 and --NR.sup.1SO.sub.2NR.sup.1R.sup.2,
and R.sup.b1, R.sup.d1 and R.sup.e1 are absent; wherein each Y is
independently a bond, --O--, --S-- or --NR.sup.1--; or
[0085] alternatively two adjacent substituents selected from
R.sup.b, R.sup.b1, R.sup.d, R.sup.d1, R.sup.e and R.sup.e1; or two
adjacent R.sup.a moieties, can form with the atoms to which they
are attached a 5-, 6- or 7-membered saturated, partially saturated
or unsaturated ring, which contains 0-4 heteroatoms selected from
N, O and S(O).sub.r and which is substituted with one to four
R.sup.f moities wherein;
[0086] each R.sup.f moiety is independently selected from the group
consisting of halo, .dbd.O, .dbd.S, --CN, --NO.sub.2, --R.sup.1,
--OR.sup.2, --O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2,
--NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2,
--OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2,
--NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2,
--C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2,
--YC(.dbd.N--OR.sup.1)YR.sup.2,
--YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2,
--YP(.dbd.O)(YR.sup.3)(YR.sup.3), --Si(R.sup.3a).sub.3,
--NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2,
--SO.sub.2NR.sup.1R.sup.2 and --NR.sup.1SO.sub.2NR.sup.1R.sup.2; or
alternatively two adjacent R.sup.f moieties can form with the atoms
to which they are attached a 5-, 6- or 7-membered saturated,
partially saturated or unsaturated ring, optionally substituted;
and which contains 0-4 heteroatoms selected from N, O and
S(O).sub.r;
[0087] each R.sup.g moiety is independently selected from the group
consisting of halo, .dbd.O, .dbd.S, --CN, --NO.sub.2, --R.sup.1,
--OR.sup.2, --O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2,
--NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2,
--OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2,
--NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2,
--C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2,
--YC(.dbd.N--OR.sup.1)YR.sup.2,
--YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2,
--YP(.dbd.O)(YR.sup.3)(YR.sup.3), --Si(R.sup.3a).sub.3,
--NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2,
--SO.sub.2NR.sup.1R.sup.2 and --NR.sup.1SO.sub.2NR.sup.1R.sup.2;
wherein each Y is independently a bond, --O--, --S-- or
--NR.sup.1--; and
at least one of R.sup.a, R.sup.b, R.sup.d, R.sup.e or R.sup.g, when
present, is or contains --P(.dbd.O)(R.sup.3).sub.2 or a ring system
containing the moiety --P(.dbd.O)(R.sup.3)-- as a ring member;
[0088] r is 0, 1 or 2;
[0089] s is 1, 2, 3, 4 or 5
[0090] n is 0 or 1;
[0091] p is 1, 2, 3 or 4;
[0092] each occurrence of Y is independently a bond, --O--, --S--
or --NR.sup.1--;
[0093] each occurrence of R.sup.1 and R.sup.2 is independently
selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl;
[0094] each occurrence of R.sup.3 is independently selected from
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,
aryl, heteroalkyl, heterocyclic and heteroaryl, or two adjacent
R.sup.3 moieties combine to form a ring system including a
phosphorous atom;
[0095] each occurrence of R.sup.3a is independently selected from
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,
aryl, heteroalkyl, heterocyclic, and heteroaryl;
[0096] alternatively, each NR.sup.1R.sup.2 moiety may be a 5-, 6-
or 7-membered saturated, partially saturated or unsaturated ring,
which can be optionally substituted and which contains 0-2
additional heteroatoms selected from N, O and S(O).sub.r; and
[0097] each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocyclic
moiety is optionally substituted.
[0098] In one embodiment are compounds of Formula VI in which one
of R.sup.a is or contains --P(.dbd.O)(R.sup.3).sub.2.
[0099] In another embodiment are compounds of Formula VI in which
one of R.sup.g is or contains --P(.dbd.O)(R.sup.3).sub.2.
[0100] In one embodiment are compounds of formula VI in which L is
a bond. Non-limiting examples of this class include the following
compounds:
##STR00034## ##STR00035##
[0101] In another embodiment are compounds of formula VI in which L
is NR.sup.4(CH.sub.2).sub.y. In a particular aspect, L is NR.sup.4.
In another particular aspect, L is NR.sup.4(CH.sub.2).sub.1-3.
Non-limiting examples of L linker are NHCH.sub.2CH.sub.2,
NHCH.sub.2, NH and NCH.sub.3. Non limiting examples of this class
include the following compounds:
##STR00036## ##STR00037##
[0102] In another embodiment are compounds of formula VI in which L
is O(CH.sub.2).sub.y. Non limiting examples of this class include
the following compounds:
##STR00038##
[0103] In another embodiment are compounds of formula VI in which L
is (CH.sub.2).sub.yC(O)NR.sup.4 or (CH.sub.2).sub.yNR.sup.4C(O).
Non limiting examples of this class include the following
compounds:
##STR00039##
[0104] In another embodiment are compounds of formula VI in which L
is S(CH.sub.2).sub.y. Non limiting examples of this class include
the following compounds:
##STR00040##
[0105] In still another embodiment are compounds of Formula VI in
which Ring E is an aryl, substituted with 1 to 5 R.sup.g groups.
Non-limiting examples of this class are compounds of the following
types:
##STR00041##
[0106] In another embodiment are compounds of Formula VI in which
Ring E is a 5-, 6- or 7-membered heterocyclyl ring comprising
carbon atoms and 1-3 heteroatoms independently selected from O, N
and S(O).sub.r, and Ring E is substituted on carbon or on the
heteroatom(s) with 1-7 R.sup.g groups. It is understood that the
total number of substituents R.sup.g does not exceed the normal
available valencies. Non-limiting examples of this class are
compounds of formula VI in which Ring E is of the following
types:
##STR00042##
[0107] Non-limiting illustrative examples are compounds of the
following formulae:
##STR00043##
[0108] In another embodiment are compounds of Formula VI in which
Ring E is a carbocyclyl ring and Ring E is substituted with 1-7
R.sup.g groups. Non-limiting examples of this class are compounds
of the following types:
##STR00044##
[0109] In another aspect of the previous embodiment, Ring E is a
5-, 6- or 7-membered heteroaryl ring comprising carbon atoms and
1-3 heteroatoms independently selected from O, N and S(O).sub.r.
For example, Ring E can be a 5-membered ring heteroaryl comprising
carbon atoms and 1-3 Nitrogen atoms. Non-limiting examples of this
class are compounds in which Ring E is of the following types:
##STR00045##
[0110] In certain embodiments, Ring E has the following
formulae:
##STR00046##
[0111] Of additional interest is a class of compounds as described
above in which R.sup.g is selected from the group consisting of
--R.sup.1 and --C(O)YR.sup.2. In another subclass of interest, are
compounds of the above embodiment in which R.sup.g is an aryl,
heteroaryl, substituted alkyl or heterocyclyl. Non limiting
examples of substituted alkyl are
--(CH.sub.2).sub.zC(.dbd.O)NR.sup.1R.sup.2,
--(CH.sub.2).sub.zNHC(.dbd.O)R.sup.2,
--(CH.sub.2).sub.zNR.sup.1R.sup.2,
--(CH.sub.2).sub.zC(.dbd.O)OR.sup.1,
--(CH.sub.2).sub.zheterocyclyl, --(CH.sub.2).sub.zaryl,
--(CH.sub.2).sub.zheteroaryl in which z is 1, 2, 3 or 4 and alkyl
include straight (i.e. unbranched or acyclic), branched and cyclic
alkyl groups and alkyl, aryl, heteroaryl, heterocyclyl groups are
optionally substituted.
[0112] Illustrative examples of such Ring E groups including
substituent R.sup.g include, without limitation:
##STR00047##
[0113] Non-limiting Illustrative examples of this class are
compounds of the following formulae:
##STR00048##
[0114] In another embodiment, Ring E is a 5-membered ring
heteroaryl comprising carbon atoms and 1-3 Nitrogen atoms and the
heteroaryl ring is linked to the core moiety via a nitrogen atom.
In one preferred aspect of this embodiment L is a bond or
(CH.sub.2).sub.y.
[0115] Of additional interest is a class of compounds as described
above in which R.sup.g is selected from the group consisting of
--R.sup.1, --OR.sup.2, --P(.dbd.O)(R.sup.3).sub.2,
--NR.sup.1R.sup.2, --C(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2,
--NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2,
--SO.sub.2NR.sup.1R.sup.2 and --NR.sup.1SO.sub.2NR.sup.1R.sup.2. In
another subclass of interest, are compounds of the above embodiment
in which R.sup.g is an aryl, heteroaryl, substituted alkyl or
heterocyclyl. Non limiting examples of R.sup.g are
--(CH.sub.2).sub.yC(.dbd.O)NR.sup.1R.sup.2,
--(CH.sub.2).sub.yNHC(.dbd.O)R.sup.2,
--(CH.sub.2).sub.yNR.sup.1R.sup.2, --(CH.sub.2).sub.yheterocyclyl,
--(CH.sub.2).sub.yaryl, --(CH.sub.2).sub.yheteroaryl, NH-aryl,
NH-heteroaryl and NH-heterocyclyl; in which y is 0, 1, 2, 3 or 4
and alkyl include straight (i.e. unbranched or acyclic), branched
and cyclic alkyl groups and alkyl, aryl, heteroaryl, heterocyclyl
groups are optionally substituted.
[0116] Illustrative non limiting examples of such compounds include
compounds of Formula VI in which Ring E is a triazole of the
following formulae:
##STR00049##
[0117] In another embodiment, Ring E is a pyrazole of the following
formulae:
##STR00050## ##STR00051##
[0118] In another aspect of the previous embodiment, Ring E is a
tetrazole of the following formulae:
##STR00052##
[0119] In another embodiment, Ring E is a 5-membered ring
heteroaryl comprising carbon atoms and 1-3 heteroatoms selected
from N and O. Non limiting examples are compounds of formula VI in
which Ring E is of the following type:
##STR00053##
in which p is defined previously and the total number of
substituents R.sup.g does not exceed the normal available
valencies.
[0120] In certain particular embodiments, Ring E has the following
formulae:
##STR00054##
[0121] in which Ring E is substituted with one or two R.sup.g
substituents.
[0122] Of additional interest is a class of compounds as described
above in which R.sup.g is selected from the group consisting of
--R.sup.1, --P(.dbd.O)(R.sup.3).sub.2, --OR.sup.2,
--NR.sup.1R.sup.2, --C(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2,
--NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2,
--SO.sub.2NR.sup.1R.sup.2 and --NR.sup.1SO.sub.2NR.sup.1R.sup.2. In
another subclass of interest, are compounds of the above embodiment
in which R.sup.g is NHC(O)R.sup.1, NHC(O)NR.sup.1R.sup.2,
C(O)NHR.sup.1, C(O)NR.sup.1R.sup.2, NR.sup.1R.sup.2, an aryl,
heteroaryl, substituted alkyl or heterocyclyl. Non limiting
examples of R.sup.g are --(CH.sub.2).sub.yC(.dbd.O)NR.sup.1R.sup.2,
--(CH.sub.2).sub.yNHC(.dbd.O)R.sup.2,
--(CH.sub.2).sub.yNR.sup.1R.sup.2, --(CH.sub.2).sub.yOR.sup.2,
--(CH.sub.2).sub.yheterocyclyl, --(CH.sub.2).sub.yaryl,
--(CH.sub.2).sub.yheteroaryl, NH-aryl, NH-heteroaryl and
NH-heterocyclyl, --(CH.sub.2).sub.mP(.dbd.O)(alkyl).sub.2; in which
y and m are independently selected from 0, 1, 2, 3 and 4 and alkyl
include straight (i.e. unbranched or acyclic), branched and cyclic
alkyl groups and alkyl, aryl, heteroaryl, heterocyclyl groups are
optionally substituted.
[0123] Non-limiting examples of this class include compounds of
formula VI in which Ring E is:
##STR00055## ##STR00056##
[0124] Specific, non-limiting illustrative examples of this class
include compounds of formula VI in which substituted Ring E is of
the following formulae:
##STR00057## ##STR00058## ##STR00059## ##STR00060##
[0125] In another specific embodiment, Ring E is a 5-membered
heteroaryl comprising carbon atoms and 1-3 heteroatoms selected
from N and S.
##STR00061##
in which p is defined previously and the total number of
substituents R.sup.g does not exceed the normal available
valencies.
[0126] Of particular interest is a class of compounds as described
above in which R.sup.g is selected from the group consisting of
--R.sup.1, --P(.dbd.O)(R.sup.3).sub.2, --OR.sup.2,
--NR.sup.1R.sup.2, --C(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2,
NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2,
--SO.sub.2NR.sup.1R.sup.2 and --NR.sup.1SO.sub.2NR.sup.1R.sup.2. In
another subclass of interest, are compounds of the above embodiment
in which R.sup.g is NHC(O)R.sup.1, C(O)NHR.sup.1,
C(O)NR.sup.1R.sup.2, NHC(O)NHR.sup.1, NR.sup.1R.sup.2, an aryl,
heteroaryl, substituted alkyl or heterocyclyl. Non limiting
examples of R.sup.g are --(CH.sub.2).sub.yC(.dbd.O)NR.sup.1R.sup.2,
--(CH.sub.2).sub.yNHC(.dbd.O)R.sup.2,
--(CH.sub.2).sub.yNR.sup.1R.sup.2, --(CH.sub.2).sub.yOR.sup.2,
--SO.sub.2NR.sup.1R.sup.2, --(CH.sub.2).sub.ySR.sup.2,
--(CH.sub.2).sub.yheterocyclyl, --(CH.sub.2).sub.yaryl,
--(CH.sub.2).sub.yheteroaryl, --NH-aryl, --NH-heteroaryl,
NH-heterocyclyl and --(CH.sub.2).sub.mP(.dbd.O)(alkyl).sub.2; in
which y and m are independently selected from 0, 1, 2, 3 and 4 and
alkyl include straight (i.e. unbranched or acyclic), branched and
cyclic alkyl groups and alkyl, aryl, heteroaryl, heterocyclyl
groups are optionally substituted.
[0127] Non-limiting examples of this class include compounds of
formula VI in which Ring E is:
##STR00062## ##STR00063##
[0128] Specific, non-limiting illustrative examples of this class
include compounds of formula VI in which substituted Ring E is of
the following formulae:
##STR00064## ##STR00065##
[0129] Other non-limiting examples include compounds of formula VI
in which Ring E is furan or thiofuran:
##STR00066##
in which p is defined previously and the total number of
substituents R.sup.g does not exceed the normal available
valencies.
[0130] Specific, non-limiting illustrative examples of this class
include compounds of formula VI in which substituted Ring E is of
the following formulae:
##STR00067## ##STR00068##
[0131] In another embodiment, Ring E is a 6-membered heteroaryl
ring. For example, Ring E can be a pyrimidine of the following
types:
##STR00069##
in which p is as previously described and the total number of
substituents R.sup.g does not exceed the normal available
valencies.
[0132] Of particular interest is a class of compounds as described
above in which R.sup.g is selected from the group consisting of
--R.sup.1, --P(.dbd.O)(R.sup.3).sub.2, --OR.sup.2,
--NR.sup.1R.sup.2, --C(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2,
--NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2,
--SO.sub.2NR.sup.1R.sup.2 and --NR.sup.1SO.sub.2NR.sup.1R.sup.2. In
another subclass of interest, are compounds of the above embodiment
in which R.sup.g is NHC(O)R.sup.1, NHC(O)NHR.sup.1, C(O)NHR.sup.1,
C(O)NR.sup.1R.sup.2, NR.sup.1R.sup.2, an aryl, heteroaryl,
substituted alkyl or heterocyclyl. Non limiting examples of R.sup.a
are --OCH.sub.2CH.sub.2NR.sup.1R.sup.2,
--OCH.sub.2C(O)NR.sup.1R.sup.2, --NR.sup.1C(O)NR.sup.1R.sup.2,
--(CH.sub.2).sub.yC(.dbd.O)NR.sup.1R.sup.2,
--(CH.sub.2).sub.yNHC(.dbd.O)R.sup.2,
--(CH.sub.2).sub.yNR.sup.1R.sup.2, --(CH.sub.2).sub.yOR.sup.2,
--SO.sub.2NR.sup.1R.sup.2, --(CH.sub.2).sub.ySR.sup.2,
--(CH.sub.2).sub.yheterocyclyl, --(CH.sub.2).sub.yaryl,
--(CH.sub.2).sub.yheteroaryl, NH-aryl, NH-heteroaryl,
NH-heterocyclyl and --(CH.sub.2).sub.mP(.dbd.O)(alkyl).sub.2; in
which y and m are independently selected from 0, 1, 2, 3 and 4 and
alkyl include straight (i.e. unbranched or acyclic), branched and
cyclic alkyl groups and alkyl, aryl, heteroaryl, heterocyclyl
groups are optionally substituted.
[0133] Non-limiting examples of this class are compounds of formula
VI in which Ring E is:
##STR00070## ##STR00071##
[0134] Specific, non-limiting illustrative examples of this class
include compounds of formula VI in which substituted Ring E is of
the following formulae:
##STR00072## ##STR00073##
[0135] In another embodiment, Ring E is a pyridine substituted with
1-4 R.sup.g. Of particular interest is a class of compounds as
described above in which R.sup.g is selected from the group
consisting of --R.sup.1, --P(.dbd.O)(R.sup.3).sub.2, --OR.sup.2,
--NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2,
--NR.sup.1SO.sub.2R.sup.2. In another subclass of interest, are
compounds of the above embodiment in which R.sup.g is
NHC(O)R.sup.2, NR.sup.1R.sup.4, an aryl, heteroaryl, substituted
alkyl or heterocyclyl. Non limiting examples of R.sup.g are
--(CH.sub.2).sub.yC(.dbd.O)NR.sup.1R.sup.2,
--(CH.sub.2).sub.yC(.dbd.O)aryl,
--(CH.sub.2).sub.yC(.dbd.O)heteroaryl,
--(CH.sub.2).sub.yC(.dbd.O)heterocyclyl,
--(CH.sub.2).sub.yNHC(.dbd.O)R.sup.2,
--(CH.sub.2).sub.yNR.sup.1R.sup.2, --(CH.sub.2).sub.yOR.sup.2,
--(CH.sub.2).sub.ySR.sup.2, --(CH.sub.2).sub.yheterocyclyl,
--(CH.sub.2).sub.yaryl, --(CH.sub.2).sub.yheteroaryl, --NH-aryl,
NH-heteroaryl, NH-heterocyclyl and
--(CH.sub.2).sub.mP(.dbd.O)(alkyl).sub.2; in which y and m are
independently selected from 0, 1, 2, 3 and 4; and alkyl include
straight (i.e. unbranched or acyclic), branched and cyclic alkyl
groups and alkyl, aryl, heteroaryl, heterocyclyl groups are
optionally substituted.
[0136] Non-limiting examples of this class are compounds of formula
VI in which Ring E is:
##STR00074## ##STR00075##
[0137] Specific, non-limiting illustrative examples of this class
include compounds of formula VI in which substituted Ring E is of
the following formulae:
##STR00076## ##STR00077##
[0138] In another embodiment, Ring E is a pyrazine substituted with
1-3 R.sup.g groups. Non-limiting examples of this class of
compounds in which Ring E is:
##STR00078##
[0139] Specific, non-limiting illustrative examples of this class
include compounds of formula VI in which substituted Ring E is of
the following formulae:
##STR00079## ##STR00080##
[0140] In another embodiment, Ring E is a triazine substituted with
1 to 2 R.sup.g groups. Examples include compounds in which Ring E
has the following formulae:
##STR00081##
in which p is defined previously and the number of substituents
R.sup.g does not exceed the maximum available valencies, which in
the triazine case p is 0, 1 or 2.
[0141] In one embodiment, Ring E is an aryl, a carbocyclyl or a 5-,
6- or 7-membered heterocyclic or heteroaryl ring which is fused
with a 5- or 6- or 7-membered saturated, partially saturated or
unsaturated ring, and Ring E is optionally substituted with 1-5
R.sup.g groups.
[0142] In certain embodiments, Ring E is a 5,6- or 5,5-bicyclic
fused system. Non-limiting examples include compounds of formula VI
in which Ring E has the following formulae:
##STR00082## ##STR00083## ##STR00084##
and the depicted fused ring systems can be substituted with
additional R.sup.g groups.
[0143] In some other embodiments of interest, Ring E is a 6,6- or
6,5-bicyclic fused system. Non limiting examples of this class
include compounds of formula VI in which Ring E has the following
formulae:
##STR00085## ##STR00086## ##STR00087##
and the depicted fused ring systems can be substituted with
additional R.sup.g groups.
[0144] Specific, non-limiting illustrative examples of this class
include compounds of formula VI in which substituted Ring E is of
the following formulae:
##STR00088## ##STR00089##
[0145] In some other embodiments of interest, Ring E is an aryl
fused with a 5-, 6- or 7-membered saturated, partially saturated or
unsaturated ring, and Ring E is substituted with 1-5 R.sup.g
groups. Non limiting examples of this class include compounds of
formula VI in which Ring E has the following formulae:
##STR00090## ##STR00091##
[0146] Specific, non-limiting illustrative examples of this class
include compounds of formula VI in which substituted Ring E is of
the following formulae:
##STR00092##
[0147] In embodiments of the compounds of formula VI, Ring A is a
6-membered ring heteroaryl. Examples of this class are compounds of
the above classes and subclasses in which Ring A is a pyridine,
pyrazine, pyridazine, pyrimidine or triazine.
[0148] In still other embodiments, Ring A is a 5-membered ring
heteroaryl. Examples of this class are compounds of the above
classes and subclasses in which Ring A is imidazole, pyrazole,
tetrazole, oxazole, thiazole, isoxazole, pyrrole, and the like.
[0149] Of particular interest is a class of compounds as described
above in which R.sup.a is selected from the group consisting of
halo, --P.dbd.O(R.sup.3).sub.2, --R.sup.1, --OR.sup.2,
--NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2, --NR.sup.1C(O)NR.sup.2,
--C(O)NR.sup.1R.sup.2, C(O)OR.sup.1, --SO.sub.2NR.sup.1R.sup.2,
--SO.sub.2R.sup.1, --NR.sup.1SO.sub.2R.sup.2. In another subclass
of interest, are compounds of the above embodiment in which R.sup.a
is --P(.dbd.O)(alkyl).sub.2, alkyl, alkynyl, halo, aryl,
heteroaryl, heterocyclyl, O-alkyl (i.e: OMe and the like), --CN,
--C(O)NH-alkyl, --C(O)NH-aryl, C(O)NH-heterocyclyl, OH,
--NR.sup.1R.sup.2, NHS(O).sub.2-alkyl, NHS(O).sub.2-aryl. Non
limiting examples of R.sup.a are is
--(CH.sub.2).sub.mP(.dbd.O)(Me).sub.2,
--(CH.sub.2).sub.mP(.dbd.O)(Et).sub.2, F, Cl, CF.sub.3, OCF.sub.3,
--(CH.sub.2).sub.yC(.dbd.O)NR.sup.1R.sup.2,
--(CH.sub.2).sub.yC(.dbd.O)aryl, --SO.sub.2NR.sup.1R.sup.2,
NHSO.sub.2R.sup.1, lower alkyl,
--(CH.sub.2).sub.yC(.dbd.O)heteroaryl,
--(CH.sub.2).sub.yC(.dbd.O)heterocyclyl,
--(CH.sub.2).sub.yNHC(.dbd.O)R.sup.2,
--(CH.sub.2).sub.yNR.sup.1R.sup.2, --(CH.sub.2).sub.yOR.sup.2,
--(CH.sub.2).sub.ySR.sup.2, --(CH.sub.2).sub.yheterocyclyl,
--(CH.sub.2).sub.yaryl, --(CH.sub.2).sub.yheteroaryl, NH-aryl,
NH-heteroaryl, NH-heterocyclyl, in which y and m are independently
selected from 0, 1, 2, 3 and 4; and alkyl include straight (i.e.
unbranched or acyclic), branched and cyclic alkyl groups and alkyl,
aryl, heteroaryl, heterocyclyl groups are optionally
substituted.
[0150] The invention also features compounds of Formula VIa:
##STR00093##
[0151] wherein
[0152] X.sup.1 is NR.sup.b1 or CR.sup.b;
[0153] X.sup.3 is NR.sup.d1 or CR.sup.d;
[0154] X.sup.4 is NR.sup.e1 or CR.sup.e;
[0155] Ring A and Ring E are each an independently selected aryl or
heteroaryl ring, the heteroaryl ring being a 5- or 6-membered ring
containing 1 to 4 heteroatoms selected from N, O and
S(O).sub.r;
[0156] each occurrence of R.sup.a, R.sup.b, R.sup.d, R.sup.e, and
R.sup.g is independently selected from the group consisting of
halo, --CN, --NO.sub.2, --R.sup.1, --OR.sup.2,
--O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2,
--NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2,
--OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2,
--NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2,
--C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2,
--YC(.dbd.N--OR)YR.sup.2, --YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2,
--YP(.dbd.O)(YR.sup.3)(YR.sup.3), --Si(R.sup.3a).sub.3,
--NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2,
--SO.sub.2NR.sup.1R.sup.2 and --NR.sup.1SO.sub.2NR.sup.1R.sup.2; or
alternatively, each R.sup.a and R.sup.g may also be or include an
independently selected moiety, --P(.dbd.O)(R.sup.3).sub.2 or a ring
system containing the moiety --P(.dbd.O)(R.sup.3)-- as a ring
member;
[0157] R.sup.b1, R.sup.d1 and R.sup.e1 are absent;
[0158] or alternatively two adjacent substituents selected from
R.sup.d, R.sup.d1, R.sup.e, and R.sup.e1, or two adjacent R.sup.a
moieties, can form, with the atoms to which they are attached, a
fused, 5-, 6- or 7-membered saturated, partially saturated or
unsaturated ring, which contains 0-4 heteroatoms selected from N, O
and S(O).sub.r and which may bear up to four substituents suitable
for heterocycles (see infra), a variety of which are illustrated in
exemplary compounds disclosed herein;
[0159] at least one of R.sup.a and R.sup.g is or contains a moiety,
--P(.dbd.O)(R.sup.3).sub.2 or a ring system containing the moiety
--P(.dbd.O)(R.sup.3)-- as a ring member;
[0160] L is O or NH;
[0161] r is 0, 1 or 2;
[0162] s is 1, 2, 3, 4 or 5;
[0163] p is 1, 2, 3 or 4;
[0164] each occurrence of Y is independently a bond, --O--, --S--
or --NR.sup.1--;
[0165] each occurrence of R.sup.1 and R.sup.2 is independently H or
an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,
aryl, heteroalkyl, heterocyclic or heteroaryl moiety;
[0166] each occurrence of R.sup.3 is independently an alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,
heteroalkyl, heterocyclic or heteroaryl moiety, or two adjacent
R.sup.3 moieties combine to form a ring system including a
phosphorous atom;
[0167] each occurrence of R.sup.3a is independently selected from
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,
aryl, heteroalkyl, heterocyclic, and heteroaryl;
[0168] alternatively, each NR.sup.1R.sup.2 moiety may be a 5-, 6-
or 7-membered saturated, partially saturated or unsaturated ring,
which can be optionally substituted and which contains 0-2
additional heteroatoms selected from N, O and S(O).sub.r; and
[0169] each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocyclic
moieties is optionally substituted.
[0170] In certain embodiments of the compounds of Formula VIA are
further defined as follows (1) X.sup.1 is N; (2) X.sup.3 is N and
X.sup.4 is CR.sup.e; (3) X.sup.3 is CR.sup.d and X.sup.4 is
CR.sup.e; (4) X.sup.1 is CR.sup.b; (5) X.sup.3 is N and X.sup.4 is
CR.sup.e; or (6) X.sup.3 is CR.sup.d and X.sup.4 is CR.sup.e.
[0171] In certain specific embodiments of the compounds of Formula
VIA, when X.sup.3 is CR.sup.d, R.sup.d is selected from Cl, F,
C1-C4 alkyl, trihaloalkyl, cycloalkyl, C2-C4 alkenyl, and alkynyl.
In such embodiments, Cl, F, Me and cyclopropyl are of particular
interest.
[0172] In another embodiment of the compounds of Formula VIA,
X.sup.3 is CR.sup.d and X.sup.4 is CR.sup.e wherein R.sup.d and
R.sup.e, together with the atoms to which they are attached, form a
fused, 5-, 6- or 7-membered saturated, partially saturated or
unsaturated ring, which contains 0-4 heteroatoms selected from N, O
and S(O), and which may bear up to four substituents.
[0173] Compounds of Formula VIA of particular interest, generally
and including the individual embodiments described above, include
those in which s is 1, 2, 3 or 4, and each of the substituents
R.sup.a is independently selected from halo, --R.sup.1, --OR.sup.2,
--NR.sup.1R.sup.2 and --P(.dbd.O)(R.sup.3).sub.2, wherein each
R.sup.1 and R.sup.2 moiety may be further substituted or
unsubstituted. In certain embodiments, the compounds include at
least one substituent R.sup.a that is --OR.sup.2 and R.sup.2 is
selected from C1-C6 alkyl, C2-C6, and C2-C6 alkynyl. In such cases,
as illustrated in compounds shown herein, MeO--, EtO-- and iPrO--
are often chosen as an R.sup.a moiety.
[0174] Compounds of Formula VIA, generally and including the
individual embodiments described thus far, also include compounds
having at least one substituent R.sup.a which is a 4-, 5-, 6- or
7-membered heterocyclic or 5- or 6-membered heteroaryl moiety,
linked to Ring A either directly or by an ether bond, and which may
be further substituted with 1-3 substituents independently selected
from halo, --CN, --NO.sub.2, --R.sup.1, --OR.sup.2,
--O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2,
--NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2,
--OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2,
--NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2,
--C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2,
--YC(.dbd.N--OR.sup.1)YR.sup.2,
--YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2,
--YP(.dbd.O)(YR.sup.3)(YR.sup.3), --Si(R.sup.3a).sub.3,
--NR.sup.1SO.sub.2R.sup.2, --S(O).sub.rR.sup.2,
--SO.sub.2NR.sup.1R.sup.2 and --NR.sup.1SO.sub.2NR.sup.1R.sup.2;
wherein each Y is independently a bond, --O--, --S-- or
--NR.sup.1--.
[0175] For example, compounds of Formula VIA include those having a
heterocyclic or heteroaryl substituent R.sup.a is selected from the
following:
##STR00094## ##STR00095## ##STR00096## ##STR00097##
[0176] Compounds of Formula VIA, generally and, again, including
the individual embodiments described thus far, also include
compounds of Formula VIA in which at least one substituent R.sup.a
is or bears a moiety, --P(.dbd.O)(R.sup.3).sub.2, in which R.sup.3
is a C1-C4 alkyl.
[0177] Compounds of Formula VIA, generally and, again, including
the embodiments described thus far, also include embodiments of
Formula VIA in which L is NH, Ring E is aryl, and each R.sup.g is
independently selected from halo, --R.sup.1, --OR.sup.2,
--S(O).sub.rR.sup.2 and --P(.dbd.O)(R.sup.3).sub.2. In certain
embodiments, Ring E contains at least one such R.sup.g moiety in
the ortho position relative to the ring atom attached to L. In
other embodiments, that R.sup.g moiety is in the meta position
relative to the ring atom attached to L, and in still other
embodiments, that R.sup.g moiety is in the para position relative
to the ring atom attached to L.
[0178] Embodiment of the compounds of formulas VI and VIA,
generally and, again, including the individual embodiments
described thus far, also include those compounds in which the group
--P(.dbd.O)(R.sup.3).sub.2 is selected from
--P(.dbd.O)(CH.sub.3).sub.2 and
--P(.dbd.O)(CH.sub.2CH.sub.3).sub.2.
[0179] In another embodiment of compounds of Formula I, two
adjacent R.sup.a form a 5-, 6- or 7-membered saturated, partially
saturated or unsaturated Ring F which is substituted with 1-4
R.sup.1 groups. This class of compounds is represented by compounds
of formula VII:
##STR00098##
in which Ring A, R.sup.a, R.sup.f, n, X.sup.1, X.sup.2, X.sup.3 and
X.sup.4 are as defined in Formula I; t is 1, 2, 3 or 4; and Ring F
is an aryl, a carbocyclyl, a 5- or 6- or 7-membered heteroaryl or
heterocyclyl ring substituted with 1-4 R.sup.f groups.
[0180] One class of compounds which is of special interest for use
in the invention are compounds of Formula VII are those in which
X.sup.2 is CR.sup.c, X.sup.3 is CR.sup.d and X.sup.4 is CR.sup.e.
This class is illustrated by compounds of formula VIIA:
##STR00099##
in which Ring A, Ring F, R.sup.a, R.sup.f, t, n, X.sup.1, R.sup.c,
R.sup.d and R.sup.e are as defined previously in Formula VII.
[0181] One class of compounds of further interest are compounds of
Formula VIIA in which Ring A is a phenyl. This is represented by
compounds of Formula VIIB:
##STR00100##
in which Ring F, R.sup.a, R.sup.f, t, n, X.sup.1, R.sup.c, R.sup.d
and R.sup.e are as described in Formula VII.
[0182] In Formulas VII, VIIA, and VIIB, Ring A and Ring F together
form a fused ring system. Fused ring systems that can be utilized
in compounds of formulas VII, VIIA, and VIIB include, without
limitation, those depicted for Ring E of Formula VI (see below) and
the following fused ring systems:
##STR00101## ##STR00102##
[0183] The fused ring systems are optionally substituted with
additional R.sup.a or R.sup.f groups. Of special interest are
compounds of formula VII or VIIA or VIIB in which R.sup.f is or
contains --P(.dbd.O)(R.sup.3).sub.2. Examples of R.sup.f containing
--P(.dbd.O)(R.sup.3).sub.2 include, without limitation,
--(CH.sub.2).sub.m--P(.dbd.O)(R.sup.3).sub.2,
--(CH.sub.2).sub.m--NR.sup.1--P(.dbd.O)(R.sup.3).sub.2,
--(CH.sub.2).sub.m--O--P(.dbd.O)(R.sup.3).sub.2,
--(CH.sub.2).sub.m--NR.sup.1--(CH.sub.2).sub.m--P(.dbd.O)(R.sup.3).sub.2,
--(CH.sub.2).sub.m--NR.sup.1C(O)O--(CH.sub.2).sub.m--P(.dbd.O)(R.sup.3).s-
ub.2, and
--(CH.sub.2).sub.m--C(O)NR.sup.1--(CH.sub.2).sub.m--P(.dbd.O)(R.-
sup.3).sub.2, in which m is 0, 1, 2, 3 or 4 and ring systems
containing the moiety --P(.dbd.O)(R3)- as a ring member.
[0184] Of other special interest are compounds of Formula VII or
VIIA or VIIB in which R.sup.e is or contains
--P(.dbd.O)(R.sup.3).sub.2.
[0185] In one embodiment of any of the above classes and subclasses
of compounds, Ring A is a phenyl group substituted with 1-5 R.sup.a
moieties. In certain embodiments of any of the above classes and
subclasses of compounds, Ring A is a 6-membered ring heteroaryl
(eg., a pyridine, pyrazine, pyridazine, pyrimidine or triazine
ring). In still other embodiments of any of the above classes and
subclasses of compounds, Ring A is a 5-membered ring heteroaryl
(e.g., an imidazole, pyrazole, tetrazole, oxazole, thiazole,
isoxazole, or pyrrole ring).
[0186] In another embodiment of any of the above classes and
subclasses of compounds, R.sup.a is selected from halo,
--P.dbd.O(R.sup.3).sub.2, --R.sup.1, --OR.sup.2, --NR.sup.1R.sup.2,
--NR.sup.1C(O)R.sup.2, --NR.sup.1C(O)NR.sup.2,
--C(O)NR.sup.1R.sup.2, C(O)OR.sup.1, --SO.sub.2NR.sup.1R.sup.2,
--SO.sub.2R.sup.1, and --NR.sup.1SO.sub.2R.sup.2.
[0187] Another subclass of interest are compounds of the above
embodiment in which R.sup.a is --P(.dbd.O)(alkyl).sub.2, alkyl,
alkynyl, halo, aryl, heteroaryl, heterocyclyl, --O-alkyl (i.e: OMe
and the like), --CN, --C(O)NH-alkyl, --C(O)NH-aryl,
--C(O)NH-heterocyclyl, --OH, --NR.sup.1R.sup.2, NHS(O).sub.2-alkyl,
--NHS(O).sub.2-aryl. Non limiting examples of R.sup.a include
--(CH.sub.2).sub.mP(.dbd.O)(Me).sub.2,
--(CH.sub.2).sub.mP(.dbd.O)(Et).sub.2, --F, --Cl, --CF.sub.3,
--OCF.sub.3, --(CH.sub.2).sub.yC(.dbd.O)NR.sup.1R.sup.2,
--(CH.sub.2).sub.yC(.dbd.O)aryl, --SO.sub.2NR.sup.1R.sup.2,
--NHSO.sub.2R.sup.1, lower alkyl,
--(CH.sub.2).sub.yC(.dbd.O)heteroaryl,
--(CH.sub.2).sub.yC(.dbd.O)heterocyclyl,
--(CH.sub.2).sub.yNHC(.dbd.O)R.sup.2,
--(CH.sub.2).sub.yNR.sup.1R.sup.2, --(CH.sub.2).sub.yOR.sup.2,
--(CH.sub.2).sub.ySR.sup.2, --(CH.sub.2).sub.yheterocyclyl,
--(CH.sub.2).sub.yaryl, --(CH.sub.2).sub.yheteroaryl, --NH-aryl,
--NH-heteroaryl, --NH-heterocyclyl, wherein y and m are
independently selected from 0, 1, 2, 3 and 4.
[0188] In still another embodiment of any of the above classes and
subclasses of compounds, R.sup.a is selected from
--P(.dbd.O)(alkyl).sub.2,
--(CH.sub.2).sub.1-2P(.dbd.O)(alkyl).sub.2, --O-lower alkyl (i.e
OMe and the like), lower alkyl (i.e: methyl, ethyl, cyclopropyl and
the like), halo, --CF.sub.3, --OCF.sub.3, --CN, --NH(alkyl),
alkenyl, and alkynyl (i.e: acetylene).
[0189] Illustrative examples of Phenyl moieties substituted with
R.sup.a include, without limitation, the following moieties:
##STR00103## ##STR00104## ##STR00105## ##STR00106## ##STR00107##
##STR00108##
[0190] In any of the above classes and subclasses of compounds,
R.sup.a is selected from
--(CH.sub.2).sub.m--P(.dbd.O)(R.sup.3).sub.2,
--(CH.sub.2).sub.m--NR.sup.1--P(.dbd.O)(R.sup.3).sub.2,
--(CH.sub.2).sub.m--O--P(.dbd.O)(R.sup.3).sub.2,
--(CH.sub.2).sub.m--NR.sup.1--(CH.sub.2).sub.m--P(.dbd.O)(R.sup.3).sub.2,
--(CH.sub.2).sub.m--NR.sup.1C(O)O--(CH.sub.2).sub.m--P(.dbd.O)(R.sup.3).s-
ub.2, and
--(CH.sub.2).sub.m--C(O)NR.sup.1--(CH.sub.2).sub.m--P(.dbd.O)(R.-
sup.3).sub.2, in which m is 0, 1, 2, 3 or 4. Alternatively, R.sup.a
is a moiety of one of the following formulas:
##STR00109##
[0191] For these classes and other classes and subclasses of the
invention, compounds of interest include among others compounds in
which one of R.sup.a is or contains --P(.dbd.O)(R.sup.3).sub.2.
Examples of R.sup.a containing --P(.dbd.O)(R.sup.3).sub.2 include,
without limitation, --(CH.sub.2).sub.m--P(.dbd.O)(R.sup.3).sub.2,
--(CH.sub.2).sub.m--NR.sup.1--P(.dbd.O)(R.sup.3).sub.2,
--(CH.sub.2).sub.m--O--P(.dbd.O)(R.sup.3).sub.2,
--(CH.sub.2).sub.m--NR.sup.1--(CH.sub.2).sub.m--P(.dbd.O)(R.sup.3).sub.2,
--(CH.sub.2).sub.m--NR.sup.1C(O)O--(CH.sub.2).sub.m--P(.dbd.O)(R.sup.3).s-
ub.2,
--(CH.sub.2).sub.m--C(O)NR.sup.1--(CH.sub.2).sub.m--P(.dbd.O)(R.sup.-
3).sub.2 in which m is 0, 1, 2, 3 or 4 and cyclic structures
containing --P(.dbd.O) as depicted above. Of particular current
interest are compounds of Formula Ia or Via in which Ring A is
phenyl, X.sup.1 is N, n is 0, s is 2, p is 1, R.sup.e is H and
R.sup.d is halo (i.e, F, Cl), lower alkyl (i.e. methyl, ethyl,
isopropyl and the like), cyano, nitro, alkoxy (i.e. methoxy and the
like) or CF.sub.3; one of R.sup.a is or contains
--P(.dbd.O)(R.sup.3).sub.2 and the other R.sup.a is selected from
lower alkyl, halo, cyano and alkoxy (i.e. methoxy); and R.sup.g is
S(O).sub.2alkyl.
[0192] Of other special interest for use in the invention are
compounds of formula IIIA in which Ring A is phenyl. Illustrative,
non-limiting examples of this subclass are compounds of the
formulae:
##STR00110##
[0193] Of special interest for use in the invention are compounds
of formula IIIA in which one of R.sup.a is or contains
--P(.dbd.O)(R.sup.3).sub.2 (i.e CH.sub.2P(.dbd.O)Me.sub.2,
--P(.dbd.O)Me.sub.2, --P(.dbd.O)Et.sub.2, --OP(.dbd.O)Me.sub.2,
--NHP(.dbd.O)Me.sub.2, --NHCH.sub.2P(.dbd.O)Et.sub.2 and the like).
Of particular current interest are compounds of this subclass in
which X.sup.1 is N, n is 0, R.sup.e is H and R.sup.f is selected
from alkyl, H, aryl, heteroaryl, heterocyclyl, halo (i.e, F, Cl),
NHR.sup.1, OR.sub.2, CF.sub.3, SO.sub.2-lower alkyl (i.e.
SO.sub.2-iPr and the like), --SO.sub.2NR.sup.1R.sup.2 and
C(O)NR.sup.1R.sup.2.
[0194] Other compounds of interest include among others, compounds
of formula IIIA in which R.sup.f is
--(CH.sub.2).sub.mP(.dbd.O)(alkyl).sub.2 (i.e
--CH.sub.2P(.dbd.O)Me.sub.2, --P(.dbd.O)Me.sub.2,
--P(.dbd.O)Et.sub.2, etc.). Of particular current interest are
compounds of this subclass in which X.sup.1 is N, n is 0, R.sup.a
is methoxy, and R.sup.e is H.
[0195] Other compounds of interest include among others, compounds
of the previous classes and subclasses in which R.sup.d is selected
from H, halo (i.e Chloro, Fluoro, Bromo), --CF.sub.3, optionally
substituted lower alkyl group (i.e Methyl, Ethyl, Isopropyl,
Cyclopropyl and the like), --CN, optionally substituted acetylene,
--NO.sub.2, --O-alkyl, --S-alkyl, --C(.dbd.O)alkyl, --NH-alkyl and
--C(.dbd.O)N(alkyl).sub.2. Of further interest are compounds of
this class in which R.sup.d is halo or CF.sup.3.
[0196] Other compounds of interest include among others, compounds
of the Formula I and IA and of all previous classes and subclasses
in which R.sup.e is selected from halo, --CN, --NO.sub.2,
--R.sup.1, --OR.sup.2, --O--NR.sup.1R.sup.2, --C(O)YR.sup.2,
--OC(O)YR.sup.2, --SC(O)YR.sup.2, --NR.sup.1C(.dbd.S)YR.sup.2,
--OC(.dbd.S)YR.sup.2, --C(.dbd.S)YR.sup.2,
--YC(.dbd.NR.sup.1)YR.sup.2, --YC(.dbd.N--OR.sup.1)YR.sup.2,
--YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2. Of further interest are
compounds of this class in which R.sup.e is H, CN, NO.sub.2, lower
alkyl or halo, wherein R.sup.1, R.sup.2, and Y are as defined in
Formula I. Of further interest, R.sup.e is selected from H, lower
alkyl and halo.
[0197] Compounds of the invention of particular interest include
those with on or more of the following characteristics: [0198] a
molecular weight of less than 1000, preferably less than 750 and
more preferably less than 600 mass units (not including the weight
of any solvating or co-crystallizing species, of any counter-ion in
the case of a salt); or [0199] inhibitory activity against a wild
type or mutant (especially a clinically relevant mutant) kinase,
especially a kinase such as ALK, Met, Jak2, bRaf, EGFR, Tie-2, FLT3
or another kinase of interest with an IC.sub.50 value of 1 .mu.M or
less (as determined using any scientifically acceptable kinase
inhibition assay), preferably with an IC.sub.50 of 500 nM or
better, and optimally with an IC.sub.50 value of 250 nM or better;
or [0200] inhibitory activity against a given kinase with an IC50
value at least 100-fold lower than their IC.sub.50 values for other
kinases of interest; or [0201] inhibitory activity for ALK, Met,
Jak2 or B-Raf with a 1 .mu.M or better IC.sub.50 value against
each; or [0202] a cytotoxic or growth inhibitory effect on cancer
cell lines maintained in vitro, or in animal studies using a
scientifically acceptable cancer cell xenograft model, (especially
preferred are compounds of the invention which inhibit
proliferation of Ba/F3 NMP-ALK, Ba/F3 EML4-ALK, Karpas 299 and/or
SU-DHL-1 cells with a potency at least as great as the potency of
known ALK inhibitors such as NVP-TAE684 and PF2341066 among others,
preferably with a potency at least twice that of known ALK
inhibitors, and more preferably with a potency at least 10 times
that of known ALK inhibitors as determined by comparative
studies.
[0203] Also provided is a composition comprising at least one
compound of the invention or a salt, hydrate or other solvate
thereof, and at least one pharmaceutically acceptable excipient or
additive. Such compositions can be administered to a subject in
need thereof to inhibit the growth, development and/or metastasis
of cancers, including solid tumors (e.g., prostate cancer, colon
cancer, pancreatic and ovarian cancers, breast cancer, non small
cell lung cancer (NSCLS), neural tumors such as glioblastomas and
neuroblastomas; esophaegeal carcinomas, soft tissue cancers such as
rhabdomyosarcomas; among others); various forms of lymphoma such as
a non-Hodgkin's lymphoma (NHL) known as anaplastic large-cell
lymphoma (ALCL), various forms of leukemia; and including cancers
which are resistant to other treatment, including those which are
resistant to treatment with another kinase inhibitor, and generally
for the treatment and prophylaxis of diseases or undesirable
conditions mediated by one or more kinases which are inhibited by a
compound of the invention.
[0204] The invention features a method for treating cancer. The
method includes administering (as a monotherapy or in combination
with one or more other anti-cancer agents, one or more agents for
ameliorating side effects, radiation, etc) a therapeutically
effective amount of a compound of the invention to a human or
animal in need of it in order to inhibit, slow or reverse the
growth, development or spread of cancer, including solid tumors or
other forms of cancer such as leukemias, in the recipient. Such
administration constitutes a method for the treatment or
prophylaxis of diseases mediated by one or more kinases inhibited
by one of the disclosed compounds or a pharmaceutically acceptable
derivative thereof. "Administration" of a compound of the invention
encompasses the delivery to a recipient of a compound of the sort
described herein, or a prodrug or other pharmaceutically acceptable
derivative thereof, using any suitable formulation or route of
administration, as discussed herein. Typically the compound is
administered one or more times per month, often one or more times
per week, e.g. daily, every other day, 5 days/week, etc. Oral and
intravenous administrations are of particular current interest.
[0205] The phrase, "pharmaceutically acceptable derivative", as
used herein, denotes any pharmaceutically acceptable salt, ester,
or salt of such ester, of such compound, or any other adduct or
derivative which, upon administration to a patient, is capable of
providing (directly or indirectly) a compound as otherwise
described herein, or a metabolite (MW>300) thereof which is
pharmacologically active as a kinase inhibitor. Pharmaceutically
acceptable derivatives thus include among others pro-drugs. A
pro-drug is a derivative of a compound, usually with significantly
reduced pharmacological activity, which contains an additional
moiety which is susceptible to removal in vivo yielding the parent
molecule as the pharmacologically active species. An example of a
pro-drug is an ester which is cleaved in vivo to yield a compound
of interest. Pro-drugs of a variety of compounds, and materials and
methods for derivatizing the parent compounds to create the
pro-drugs, are known and may be adapted to the invention.
[0206] Particularly favored derivatives and prodrugs of a parent
compound are those derivatives and prodrugs that increase the
bioavailability of the compound when administered to a mammal
(e.g., by permitting enhanced absorption into the blood following
oral administration) or which enhance delivery to a biological
compartment of interest (e.g., the brain or lymphatic system)
relative to the parent compound. Preferred prodrugs include
derivatives of a compound of the invention with enhanced aqueous
solubility or active transport through the gut membrane, relative
to the parent compound.
[0207] One important aspect of the invention is a method for
treating cancer in a subject in need thereof, which comprises
administering to the subject a treatment effective amount of a
composition containing a compound of the invention. Treatment may
be provided in combination with one or more other cancer therapies,
include surgery, radiotherapy (e.g., gamma-radiation, neutron beam
radiotherapy, electron beam radiotherapy, proton therapy,
brachytherapy, and systemic radioactive isotopes, etc.), endocrine
therapy, biologic response modifiers (e.g., interferons,
interleukins, and tumor necrosis factor (TNF) to name a few),
hyperthermia, cryotherapy, agents to attenuate any adverse effects
(e.g., antiemetics), and other cancer chemotherapeutic drugs. The
other agent(s) may be administered using a formulation, route of
administration and dosing schedule the same or different from that
used with the compound of the invention.
[0208] Such other drugs include but not limited to one or more of
the following: an anti-cancer alkylating or intercalating agent
(e.g., mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan,
and Ifosfamide); antimetabolite (e.g., Methotrexate); purine
antagonist or pyrimidine antagonist (e.g., 6-Mercaptopurine,
5-Fluorouracil, Cytarabile, and Gemcitabine); spindle poison (e.g.,
Vinblastine, Vincristine, Vinorelbine and Paclitaxel);
podophyllotoxin (e.g., Etoposide, Irinotecan, Topotecan);
antibiotic (e.g., Doxorubicin, Bleomycin and Mitomycin);
nitrosourea (e.g., Carmustine, Lomustine); inorganic ion (e.g.,
Cisplatin, Carboplatin, Oxaliplatin or oxiplatin); enzyme (e.g.,
Asparaginase); hormone (e.g., Tamoxifen, Leuprolide, Flutamide and
Megestrol); mTOR inhibitor (e.g., Sirolimus (rapamycin),
Temsirolimus (CCI779), Everolimus (RAD001), AP23573 or other
compounds disclosed in U.S. Pat. No. 7,091,213); proteasome
inhibitor (such as Velcade, another proteasome inhibitor (see e.g.,
WO 02/096933) or another NF-kB inhibitor, including, e.g., an IkK
inhibitor); other kinase inhibitors (e.g., an inhibitor of Src,
BRC/Abl, kdr, flt3, aurora-2, glycogen synthase kinase 3 ("GSK-3"),
EGF-R kinase (e.g., Iressa, Tarceva, etc.), VEGF-R kinase, PDGF-R
kinase, etc); an antibody, soluble receptor or other receptor
antagonist against a receptor or hormone implicated in a cancer
(including receptors such as EGFR, ErbB2, VEGFR, PDGFR, and IGF-R;
and agents such as Herceptin, Avastin, Erbitux, etc.); etc. For a
more comprehensive discussion of updated cancer therapies see,
http://www.nci.nih.gov/, a list of the FDA approved oncology drugs
at http://www.fda.gov/cder/cancer/druglistframe.htm, and The Merck
Manual, Seventeenth Ed. 1999, the entire contents of which are
hereby incorporated by reference. Examples of other therapeutic
agents are noted elsewhere herein and include among others,
Zyloprim, alemtuzmab, altretamine, amifostine, nastrozole,
antibodies against prostate-specific membrane antigen (such as
MLN-591, MLN591RL and MLN2704), arsenic trioxide, bexarotene,
bleomycin, busulfan, capecitabine, Gliadel Wafer, celecoxib,
chlorambucil, cisplatin-epinephrine gel, cladribine, cytarabine
liposomal, daunorubicin liposomal, daunorubicin, daunomycin,
dexrazoxane, docetaxel, doxorubicin, Elliott's B Solution,
epirubicin, estramustine, etoposide phosphate, etoposide,
exemestane, fludarabine, 5-FU, fulvestrant, gemcitabine,
gemtuzumab-ozogamicin, goserelin acetate, hydroxyurea, idarubicin,
idarubicin, Idamycin, ifosfamide, imatinib mesylate, irinotecan (or
other topoisomerase inhibitor, including antibodies such as MLN576
(XR11576)), letrozole, leucovorin, leucovorin levamisole, liposomal
daunorubicin, melphalan, L-PAM, mesna, methotrexate, methoxsalen,
mitomycin C, mitoxantrone, MLN518 or MLN608 (or other inhibitors of
the flt-3 receptor tyrosine kinase, PDFG-R or c-kit), itoxantrone,
paclitaxel, Pegademase, pentostatin, porfimer sodium, Rituximab
(RITUXAN.RTM.), talc, tamoxifen, temozolamide, teniposide, VM-26,
topotecan, toremifene, 2C4 (or other antibody which interferes with
HER2-mediated signaling), tretinoin, ATRA, valrubicin, vinorelbine,
or pamidronate, zoledronate or another bisphosphonate.
[0209] The invention further comprises the preparation of a
compound of any of Formulae I, Ia, II, IIa, III, IIIa, IV, IVa, V,
Va, VI, VIa VII, VIIa and VIIb or of any other of compounds of the
invention using a method described herein.
[0210] The invention also comprises the use of a compound of the
invention, or a pharmaceutically acceptable derivative thereof, in
the manufacture of a medicament for the treatment either acutely or
chronically of cancer (including lymphoma and solid tumors, primary
or metastatic, including cancers such as noted elsewhere herein and
including cancers which are resistant or refractory to one or more
other therapies). Compounds of the invention can be useful in the
manufacture of an anti-cancer medicaments. Compounds of the
invention can also be useful in the manufacture of a medicament to
attenuate or prevent disorders through inhibition of one or more
kinases such as ALK, jak2, b-raf, met, Tie-2, EGFR, FLT3, FAK,
Pim-1, PI3k, etc. . . . .
[0211] The invention further encompasses a composition comprising a
compound of the invention, including a compound of any of the
described classes or subclasses, including those of any of the
formulas noted above, among others, preferably in a
therapeutically-effective amount, in association with a least one
pharmaceutically acceptable carrier, adjuvant or diluent.
[0212] Compounds of the invention can also be useful as standards
and reagents for characterizing various kinases, especially but not
limited to ALK, Met, Jak2, b-Raf, Tie-2, EGFR, FLT3 among others as
well as for studying the role of such kinases in biological and
pathological phenomena; for studying intracellular signal
transduction pathways mediated by such kinases, for the comparative
evaluation of new kinase inhibitors; and for studying various
cancers in cell lines and animal models.
3. Definitions
[0213] In reading this document, the following information and
definitions apply unless otherwise indicated.
[0214] The term "alkyl" is intended to include linear (i.e.,
unbranched or acyclic), branched, cyclic, or polycyclic non
aromatic hydrocarbon groups, which are optionally substituted with
one or more functional groups. Unless otherwise specified, "alkyl"
groups contain one to eight, and preferably one to six carbon
atoms. C.sub.1-6 alkyl is intended to include C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, and C.sub.6 alkyl groups. Lower alkyl
refers to alkyl groups containing 1 to 6 carbon atoms. Examples of
alkyl include, but are not limited to, methyl, ethyl, n-propyl,
isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
cyclobutyl, pentyl, isopentyl tert-pentyl, cyclopentyl, hexyl,
isohexyl, cyclohexyl, etc. Alkyl may be substituted or
unsubstituted. Illustrative substituted alkyl groups include, but
are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl,
2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl,
3-hydroxypropyl, benzyl, substituted benzyl, phenethyl, substituted
phenethyl, etc.
[0215] The term "alkoxy" represents a subset of alkyl in which an
alkyl group as defined above with the indicated number of carbons
attached through an oxygen bridge. For example, "alkoxy" refers to
groups --O-alkyl, wherein the alkyl group contains 1 to 8 carbons
atoms of a linear, branched, cyclic configuration. Examples
of"alkoxy" include, but are not limited to, methoxy, ethoxy,
n-propoxy, i-propoxy, t-butoxy, n-butoxy, s-pentoxy and the
like.
[0216] "Haloalkyl" is intended to include both branched and linear
chain saturated hydrocarbon having one or more carbon substituted
with a Halogen. Examples of haloalkyl, include, but are not limited
to, trifluoromethyl, trichloromethyl, pentafluoroethyl and the
like.
[0217] The term "alkenyl" is intended to include hydrocarbon chains
of linear, branched, or cyclic configuration having one or more
unsaturated Carbon-carbon bonds that may occur in any stable point
along the chain or cycle. Unless otherwise specified, "alkenyl"
refers to groups usually having two to eight, often two to six
carbon atoms. For example, "alkenyl" may refer to prop-2-enyl,
but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl,
hex-5-enyl, 2,3-dimethylbut-2-enyl, and the like. Furthermore,
alkenyl groups may be substituted or unsubstituted.
[0218] The term "alkynyl" is intended to include hydrocarbon chains
of either linear or branched configuration, having one or more
carbon-carbon triple bond that may occur in any stable point along
the chain. Unless otherwise specified, "alkynyl" groups refer
refers to groups having two to eight, preferably two to six
carbons. Examples of"alkynyl" include, but are not limited to
prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl,
3-methylpent-4-ynyl, hex-2-ynyl, hex-5-ynyl, etc. Furthermore,
alkynyl groups may be substituted or unsubstituted.
[0219] Cycloalkyl is a subset of alkyl and includes any stable
cyclic or polycyclic hydrocarbon groups of from 3 to 13 carbon
atoms, any of which is saturated. Examples of such cycloalkyl
include, but are not limited to cyclopropyl, norbornyl,
[2.2.2]bicyclooctane, [4.4.0]bicyclodecane, and the like, which, as
in the case of other alkyl moieties, may optionally be substituted.
The term "cycloalkyl" may be used interchangeably with the term
"carbocycle".
[0220] Cycloalkenyl is a subset of alkenyl and includes any stable
cyclic or polycyclic hydrocarbon groups of from 3 to 13 carbon
atoms, preferably from 5 to 8 carbon atoms, which contains one or
more unsaturated carbon-carbon double bonds that may occur in any
point along the cycle. Examples of such cycloalkenyl include, but
are not limited to cyclopentenyl, cyclohexenyl and the like.
[0221] Cycloalkynyl is a subset of alkynyl and includes any stable
cyclic or polycyclic hydrocarbon groups of from 5 to 13 carbon
atoms, which contains one or more unsaturated carbon-carbon triple
bonds that may occur in any point along the cycle. As in the case
of other alkenyl and alkynyl moieties, cycloalkenyl and
cycloalkynyl may optionally be substituted.
[0222] The term "heteroalkyl" is meant a branched or unbranched
alkyl, alkenyl, or alkynyl group having from 1 to 7 carbon atoms in
addition to 1, 2, 3 or 4 heteroatoms independently selected from
the group consisting of N, O, S, and P. Heteroalkyls include,
without limitation, tertiary amines, secondary amines, ethers,
thioethers, amides, thioamides, carbamates, thiocarbamates,
hydrazones, imines, phosphodiesters, phosphoramidates,
sulfonamides, and disulfides. A heteroalkyl may optionally include
monocyclic, bicyclic, or tricyclic rings, in which each ring
desirably has three to six members. The heteroalkyl group may be
substituted or unsubstituted. Examples of heteroalkyls include,
without limitation, polyethers, such as methoxymethyl and
ethoxyethyl.
[0223] "Heterocycle", "heterocyclyl", or "heterocyclic" as used
herein refers to non-aromatic ring systems having five to fourteen
ring atoms in which one or more ring carbons, preferably one to
four, are each replaced by a heteroatom such as N, O, or S.
Heterocyclic groups may be substituted or unsubstituted and may
include one, two, or three fused or unfused ring systems.
Non-limiting examples of heterocyclic rings include
3-1H-benzimidazol-2-one, (1-substituted)-2-oxo-benzimidazol-3-yl,
2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl,
3-tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl,
4-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl,
4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,
1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl,
3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl,
N-substituted diazolonyl, 1-phthalimidinyl, benzoxanyl,
benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl,
and benzothianyl. A heterocylic group can include two or more of
the ring systems listed above. Also included within the scope of
the term "heterocyclyl" or "heterocyclic", as it is used herein, is
a group in which a non-aromatic heteroatom-containing ring is fused
to one or more aromatic or non-aromatic rings, such as in an
indolinyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl,
where the radical or point of attachment is on the non-aromatic
heteroatom-containing ring. The term "heterocycle", "heterocyclyl",
or "heterocyclic" whether saturated or partially unsaturated, also
refers to rings that are optionally substituted.
[0224] The term "aryl" used alone or as part of a larger moiety as
in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to aromatic
ring groups having six to fourteen ring atoms, such as phenyl,
1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. An "aryl" ring
may contain one or more substituents. The term "aryl" may be used
interchangeably with the term "aryl ring". "Aryl" also includes
fused polycyclic aromatic ring systems in which an aromatic ring is
fused to one or more rings. Non-limiting examples of useful aryl
ring groups include phenyl, hydroxyphenyl, halophenyl,
alkoxyphenyl, dialkoxyphenyl, trialkoxyphenyl, alkylenedioxyphenyl,
naphthyl, phenanthryl, anthryl, phenanthro and the like, as well as
1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. Also included
within the scope of the term "aryl", as it is used herein, is a
group in which an aromatic ring is fused to one or more
non-aromatic rings, such as in a indanyl, phenanthridinyl, or
tetrahydronaphthyl, where the radical or point of attachment is on
the aromatic ring.
[0225] The term "heteroaryl" as used herein refers to stable
heterocyclic, and polyheterocyclic aromatic moieties having 5-14
ring atoms. Heteroaryl groups may be substituted or unsubstituted
and may comprise one or more rings. Examples of typical heteroaryl
rings include 5-membered monocyclic ring groups such as thienyl,
pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl,
isoxazolyl, thiazolyl and the like; 6-membered monocyclic groups
such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and
the like; and polycyclic heterocyclic ring groups such as
benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl,
isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl,
isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl,
phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl,
benzothiazole, benzimidazole, tetrahydroquinoline cinnolinyl,
pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl,
acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl,
phenothiazinyl, phenoxazinyl, and the like (see e.g. Katritzky,
Handbook of Heterocyclic Chemistry). Further specific examples of
heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl,
2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl,
4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl,
2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl,
3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,
4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl,
5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl,
3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl,
indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl,
benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or
benzoisoxazolyl. Heteroaryl groups further include a group in which
a heteroaromatic ring is fused to one or more aromatic or
nonaromatic rings where the radical or point of attachment is on
the heteroaromatic ring. Examples include tetrahydroquinoline,
tetrahydroisoquinoline, and pyrido[3,4-d]pyrimidinyl,
imidazo[1,2-a]pyrimidyl, imidazo[1,2-a]pyrazinyl,
imidazo[1,2-a]pyridinyl, imidazo[1,2-c]pyrimidyl,
pyrazolo[1,5-a][1,3,5]triazinyl, pyrazolo[1,5-c]pyrimidyl,
imidazo[1,2-b]pyridazinyl, imidazo[1,5-a]pyrimidyl,
pyrazolo[1,5-b][1,2,4]triazine, quinolyl, isoquinolyl, quinoxalyl,
imidazotriazinyl, pyrrolo[2,3-d]pyrimidyl, triazolopyrimidyl,
pyridopyrazinyl. The term "heteroaryl" also refers to rings that
are optionally substituted. The term "heteroaryl" may be used
interchangeably with the term "heteroaryl ring" or the term
"heteroaromatic".
[0226] An aryl group (including the aryl portion of an aralkyl,
aralkoxy, or aryloxyalkyl moiety and the like) or heteroaryl group
(including the heteroaryl portion of a heteroaralkyl or
heteroarylalkoxy moiety and the like) may contain one or more
substituents. Examples of suitable substituents on the unsaturated
carbon atom of an aryl or heteroaryl group include halogen (F, Cl,
Br or I), alkyl, alkenyl, alkynyl, heteroalkyl, --CN, --R.sup.1,
--OR.sup.2, --S(O).sub.rR.sup.2, (wherein r is an integer of 0, 1
or 2), --SO.sub.2NR.sup.1R.sup.2, --NR.sup.1R.sup.2,
--O--NR.sup.1R.sup.2, --NR.sup.1--NR.sup.1R.sup.2, --(CO)YR.sup.2,
--O(CO)YR.sup.2, --NR.sup.1(CO)YR.sup.2, --S(CO)YR.sup.2,
--NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2,
--C(.dbd.S)YR.sup.2, wherein each occurrence of Y is independently
--O--, --S--, --NR.sup.1--, or a chemical bond; --(CO)YR.sup.2 thus
encompasses --C(.dbd.O)R.sup.2, --C(.dbd.O)OR.sup.2, and
--C(.dbd.O)NR.sup.1R.sup.2. Additional substituents include
--YC(.dbd.NR.sup.1)YR.sup.2, --YC(.dbd.N--OR.sup.1)YR.sup.2,
--YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --COCOR.sup.2,
--COMCOR.sup.2 (where M is a 1-6 carbon alkyl group),
--YP(.dbd.O)(YR.sup.3)(YR.sup.3) (including among others
--P(.dbd.O)(R.sup.3).sub.2), --Si(R.sup.3a).sub.3, --NO.sub.2,
--NR.sup.1SO.sub.2R.sup.2 and --NR.sup.1SO.sub.2NR.sup.1R.sup.2. To
illustrate further, substituents in which Y is --NR.sup.1 thus
include among others, --NR.sup.1C(.dbd.O)R.sup.2,
--NR.sup.1C(.dbd.O)NR.sup.1R.sup.2, --NR.sup.1C(.dbd.O)OR.sup.2,
and --NR.sup.1C(.dbd.NH)NR.sup.1R.sup.2. R.sup.3 substituent is
selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl, heteroaryl, heterocyclyl; R.sup.1 and R.sup.2
substituents at each occurrence are independently selected from
hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl, heteroaryl, heterocyclyl, and R.sup.1, R.sup.2
and R.sup.3 substituents may themselves be substituted or
unsubstituted. Examples of substituents allowed on R.sup.1, R.sup.2
and R.sup.3 include, among others amino, alkylamino, dialkylamino,
aminocarbonyl, halogen, alkyl, aryl, heteroalkyl, heteroaryl,
carbocycle, heterocycle, alkylaminocarbonyl, dialkylaminocarbonyl,
alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano,
carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, haloalkoxy
groups. Additional illustrative examples include protected OH (such
as acyloxy), phenyl, substituted phenyl, --O-phenyl,
--O-(substituted) phenyl, -benzyl, substituted benzyl,
--O-phenethyl (i.e., --OCH.sub.2CH.sub.2C.sub.6H.sub.5),
--O-(substituted)phenethyl. Non-limiting illustrations of a
substituted R.sup.1, R.sup.2 or R.sup.3 moiety include haloalkyl
and trihaloalkyl, alkoxyalkyl, halophenyl, -M-heteroaryl,
-M-heterocycle, -M-aryl, -M-OR.sup.2, -M-SR.sup.2,
-M-NR.sup.1R.sup.2, -M-OC(O)NR.sup.1R.sup.2,
-M-C(.dbd.NR.sup.2)NR.sup.1R.sup.2, -M-C(.dbd.NR.sup.1)OR.sup.2,
-M-P(.dbd.O)(R.sup.3).sub.2, Si(R.sup.3a).sub.3,
-M-NR.sup.1C(O)R.sup.2, -M-NR.sup.1C(O)OR.sup.2, -M-C(O)R.sup.2,
-M-C(.dbd.S)R.sup.2, -M-C(.dbd.S)NR.sup.1R.sup.2,
-M-C(O)NR.sup.1R.sup.2, -M-C(O)NR.sup.2-M-NR.sup.1R.sup.2,
-M-NR.sup.2C(NR.sup.1)NR.sup.1R.sup.2,
-M-NR.sup.1C(S)NR.sup.1R.sup.2, -M-S(O).sub.2R.sup.1,
-M-C(O)R.sup.1, -M-OC(O)R.sup.1, -MC(O)SR.sup.2,
-M-S(O).sub.2NR.sup.1R.sup.2, --C(O)-M-C(O)R.sup.2,
-MCO.sub.2R.sup.2, -MC(.dbd.O)NR.sup.1R.sup.2,
-M-C(.dbd.NH)NR.sup.1R.sup.2, and -M-OC(.dbd.NH)NR.sup.1R.sup.2
(wherein M is a 1-6 carbon alkyl group).
[0227] Some more specific examples include but are not limited to
chloromethyl, trichloromethyl, trifluoromethyl, methoxyethyl,
alkoxyphenyl, halophenyl, --CH.sub.2-aryl, --CH.sub.2-heterocycle,
--CH.sub.2C(O)NH.sub.2, --C(O)CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2OH, --CH.sub.2OC(O)NH.sub.2,
--CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2CH.sub.2NEt.sub.2,
--CH.sub.2OCH.sub.3, --C(O)NH.sub.2,
--CH.sub.2CH.sub.2-heterocycle, --C(.dbd.S)CH.sub.3,
--C(.dbd.S)NH.sub.2, --C(.dbd.NH)NH.sub.2, --C(.dbd.NH)OEt,
--C(O)NH-cyclopropyl, C(O)NHCH.sub.2CH.sub.2-heterocycle,
--C(O)NHCH.sub.2CH.sub.2OCH.sub.3,
--C(O)CH.sub.2CH.sub.2NHCH.sub.3, --CH.sub.2CH.sub.2F,
--C(O)CH.sub.2-heterocycle, --CH.sub.2C(O)NHCH.sub.3,
--CH.sub.2CH.sub.2P(.dbd.O)(CH.sub.3).sub.2, Si(CH.sub.3).sub.3 and
the like.
[0228] When a ring system (e.g., cycloalkyl, heterocyclyl, aryl, or
heteroaryl) is substituted with a number of substituents varying
within an expressly defined range, it is understood that the total
number of substituents does not exceed the normal available
valencies under the existing conditions. Thus, for example, a
phenyl ring substituted with "n" substituents (where "n" ranges
from 1 to 5) can have 1 to 5 substituents, whereas it is understood
that a pyridinyl ring substituted with "n" substituents has a
number of substituents ranging from 1 to 4. The maximum number of
substituents that a group in the compounds of the invention may
have can be easily determined.
[0229] An alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, heteroalkyl,
cycloalkyl, cycloalkenyl, cycloalkynyl or non-aromatic heterocyclic
group may thus also contain one or more substituents. Examples of
suitable substituents on such groups include, but are not limited
to those listed above for the carbon atoms of an aryl or heteroaryl
group and in addition include the following substituents for a
saturated carbon atom: .dbd.O, .dbd.S, .dbd.NH,
.dbd.NNR.sup.2R.sup.3, .dbd.NNHC(O)R.sup.2,
.dbd.NNHCO.sub.2R.sup.2, or .dbd.NNHSO.sub.2R.sup.2, wherein
R.sup.2 and R.sup.3 at each occurrence are independently hydrogen,
alkyl, alkenyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
cycloalkynyl, heteroalkyl, aryl, heteroaryl, heterocyclyl.
[0230] Illustrative examples of substituents on an aliphatic,
heteroaliphatic or heterocyclic group include amino, alkylamino,
dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylaminocarbonyloxy,
dialkylaminocarbonyloxy, alkoxy, nitro, --CN, carboxy,
alkoxycarbonyl, alkylcarbonyl, --OH, haloalkoxy, or haloalkyl
groups. Illustrative substituents on a nitrogen, e.g., in an
heteroaryl or non-aromatic heterocyclic ring include R.sup.1,
--NR.sup.1R.sup.2, --C(.dbd.O)R.sup.2, --C(.dbd.O)OR.sup.2,
--C(.dbd.O)SR.sup.2, --C(.dbd.O)NR.sup.1R.sup.2,
--C(.dbd.NR.sup.2)NR.sup.1R.sup.2, --C(.dbd.NR.sup.2)OR.sup.2,
--C(.dbd.NR.sup.1)R.sup.3, --COCOR.sup.2, --COMCOR.sup.2, --CN,
--SO.sub.2R.sup.2, S(O)R.sup.2, --P(.dbd.O)(YR.sup.3)(YR.sup.3),
--NR.sup.1SO.sub.2R.sup.2 and --NR.sup.1SO.sub.2NR.sup.1R.sup.2,
wherein each occurrence of R.sup.3 is alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and
heterocyclyl; each occurrence of R.sup.1 and R.sup.2 is
independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocyclyl.
[0231] When a ring system (e.g., cycloalkyl, heterocyclyl, aryl, or
heteroaryl) is substituted with a number of substituents varying
within an expressly defined range, it is understood that the total
number of substituents does not exceed the normal available
valencies under the existing conditions. Thus, for example, a
phenyl ring substituted with "m" substituents (where "m" ranges
from 0 to 5) can have 0 to 5 substituents, whereas it is understood
that a pyridinyl ring substituted with "m" substituents has a
number of substituents ranging from 0 to 4. The maximum number of
substituents that a group in the compounds of the invention may
have can be easily determined.
[0232] Certain compounds of the invention may exist in tautomeric
forms, and the invention includes all such tautomeric forms of
those compounds unless otherwise specified.
[0233] Unless otherwise stated, structures depicted herein are also
meant to include all stereochemical forms of the structure; i.e.,
the R and S configurations for each asymmetric center. Thus, single
stereochemical isomers as well as enantiomeric and diastereomeric
mixtures of the present compounds are within the scope of the
invention. Thus, the invention encompasses each diasteriomer or
enantiomer substantially free of other isomers (>90%, and
preferably >95%, free from other stereoisomers on a molar basis)
as well as a mixture of such isomers.
[0234] Particular optical isomers can be obtained by resolution of
the racemic mixtures according to conventional processes, e.g., by
formation of diastereoisomeric salts, by treatment with an
optically active acid or base. Examples of appropriate acids are
tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric,
and camphorsulfonic acid and then separation of the mixture of
diastereoisomers by crystallization followed by liberation of the
optically active bases from these salts. A different process for
separation of optical isomers involves the use of a chiral
chromatography column optimally chosen to maximize the separation
of the enantiomers. Still another method involves synthesis of
covalent diastereoisomeric molecules by reacting compounds of the
invention with an optically pure acid in an activated form or an
optically pure isocyanate. The synthesized diastereoisomers can be
separated by conventional means such as chromatography,
distillation, crystallization or sublimation, and then hydrolyzed
to deliver the enantiomerically pure compound.
[0235] Optically active compounds of the invention can be obtained
by using active starting materials. These isomers may be in the
form of a free acid, a free base, an ester or a salt.
[0236] Compounds of the invention can exist in radiolabelled form,
i.e., said compounds may contain one or more atoms containing an
atomic mass or mass number different from the atomic mass or mass
number: ordinarily found in nature. Radioisotopes of hydrogen,
carbon, phosphorous, fluorine and chlorine include .sup.3H,
.sup.14C, .sup.32P, .sup.35S, .sup.18F and .sup.36Cl, respectively.
Compounds of the invention which contain those radioisotopes and/or
other radioisotopes of other atoms are within the scope of the
invention. Tritiated, i.e., .sup.3H, and carbon-14, i. e.,
.sup.14C, radioisotopes are particularly preferred for their ease
of preparation and detectability.
[0237] Radiolabelled compounds of the invention can generally be
prepared by methods well known to those skilled in the art.
Conveniently, such radiolabelled compounds can be prepared by
carrying out the procedures disclosed herein except substituting a
readily available radiolabelled reagent for a non-radiolabelled
reagent.
4. Synthetic Overview
[0238] The practitioner has a well-established literature of
heterocyclic and other relevant chemical transformations, recovery
and purification technologies to draw upon, in combination with the
information contained in the examples which follow, for guidance on
synthetic strategies, protecting groups, and other materials and
methods useful for the synthesis, recovery and characterization of
compounds of the invention, including compounds containing the
various choices for the R.sup.a, R.sup.b, R.sup.c, R.sup.d,
R.sup.e, R.sup.b1, R.sup.c1, R.sup.d1, R.sup.e1, R.sup.f, R.sup.g,
and Rings A, B, C, D, E and F.
[0239] Various synthetic approaches may be used to produce the
compounds described herein, including those approaches depicted
schematically below. The practitioner will appreciate that
protecting groups may be used in these approaches. "Protecting
groups", are moieties that are used to temporarily block chemical
reaction at a potentially reactive site (e.g., an amine, hydroxy,
thiol, aldehyde, etc.) so that a reaction can be carried out
selectively at another site in a multifunctional compound. In
preferred embodiments, a protecting group reacts selectively in
good yield to give a protected substrate that is suitable for the
planned reactions; the protecting group should be selectively
removable in good yield by readily available, preferably nontoxic
reagents that do not unduly attack the other functional groups
present; the protecting group preferably forms an readily separable
derivative (more preferably without the generation of new
stereogenic centers); and the protecting group preferably has a
minimum of additional functionality to avoid the complication of
further sites of reaction. A wide variety of protecting groups and
strategies, reagents and conditions for deploying and removing them
are known in the art. See, e.g., "Protective Groups in Organic
Synthesis" Third Ed. Greene, T. W. and Wuts, P. G., Eds., John
Wiley & Sons, New York: 1999. For additional background
information on protecting group methodologies (materials, methods
and strategies for protection and deprotection) and other synthetic
chemistry transformations useful in producing the compounds
described herein, see in R. Larock, Comprehensive organic
Transformations, VCH Publishers (1989); T. W. Greene and P. G. M.
Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., John Wiley
and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's
Reagents for Organic Synthesis, John Wiley and Sons (1994); and L.
Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John
Wiley and Sons (1995). The entire contents of these references are
hereby incorporated by reference.
[0240] Also, one may chose reagents enriched for a desired isotope,
e.g. deuterium in place of hydrogen, to create compounds of the
invention containing such isotope(s). Compounds containing
deuterium in place of hydrogen in one or more locations, or
containing various isotopes of C, N, P and O, are encompassed by
the invention and may be used, for instance, for studying
metabolism and/or tissue distribution of the compounds or to alter
the rate or path of metabolism or other aspects of biological
functioning.
[0241] Compounds of the invention can be synthesized using the
methods described below, together with synthetic methods known in
the art of synthetic organic chemistry, or by a variation thereon
as appreciated by those skilled in the art. Preferred methods
include, but are not limited to those described below. The
reactions are preformed in a solvent appropriate to the reagents
and materials employed and suitable for the transformation being
effected. It will be understood by those skilled in the art of
organic synthesis that the functionality present on the molecule
should be consistent the transformations proposed. This will
sometimes required some judgment to modify the order of the
synthetic steps or to select one particular process scheme over
another in order to obtain a desired compound of the invention.
[0242] A compound of the invention could be prepared as outlined
from Scheme 1 to Scheme 57a and via standard methods known to those
skilled in the art. For certain compounds of the invention,
microwave-assisted synthesis may be carried out using conventional
procedures and the conditions noted in the examples which follow.
Reactions may be carried out using commercially available microwave
reactors such as the Biotage Initiator 2.0.TM. (Biotage AB,
Kungsgatan 76, SE-753 18 Uppsala, Sweden or 1725 Discovery Drive
Charlottesville, Va. 22911) or the CEM Discover.TM. System (CEM
Corporation, Matthews, N.C.) which were used in the examples
below.
[0243] A compound of Formula Ia or VIA in which n is 0 and X is N
can be prepared in a 2 steps synthesis as shown in Scheme 1. A
[Ring A] moiety can first be incorporated to the central pyrimidine
moiety by reacting [Ring A]-NH.sub.2 with
2,4-dichloro-5-(trifluoromethyl)pyrimidine in the presence of a
base such as di-isopropylethyl amine at high temperature generating
intermediate 1. The [Ring E]-L- moiety can then be incorporated
onto intermediate 1 using various conditions depending on the
nature of the L linker. The variables in the intermediate [Ring
E]-[L]- and [Ring A] are as defined previously, Rings A and E being
substituted with permitted R.sup.a and R.sup.g groups
respectively.
##STR00111##
[0244] An approach to the preparation of an intermediate 1 is
illustrated below in Scheme 1A in which Ring A is a phenyl:
##STR00112##
[0245] A compound of Formula VIA in which L is O can be prepared
using microwave chemistry, by reacting an intermediate 1 with [Ring
E]-OH in a solvent such as dimethylformamide and high temperatures
as shown in Scheme 2.
##STR00113##
[0246] An approach to the preparation of a compound of Formula VIA
in which L is O, is illustrated below in Scheme 2A in which Ring A
and Ring E are phenyls:
##STR00114##
[0247] A compound of Formula VIA in which L is NH can be prepared
using microwave chemistry, by reaction an intermediate 1 with [Ring
E]-NH.sub.2, in a polar solvent such as Ethanol, and using high
temperatures, as shown in Scheme 3. A base (i.e. di-isopropylethyl
amine, triethylamine or the like) or an acid may be added to
facilitate the displacement reaction.
##STR00115##
[0248] An approach to the preparation of a few compounds of Formula
VIA in which L is NH, is illustrated below in Scheme 3A and 3B in
which E is a phenyl or adamantanamine:
##STR00116##
##STR00117##
[0249] A compound of Formula VIA in which L is NH(CH.sub.2).sub.1-4
can be prepared using microwave chemistry, by reaction an
intermediate 1 with [Ring E]-(CH.sub.2).sub.1-4NH.sub.2, in the
presence of a base such as triethylamine, in a polar solvent such
as Ethanol, and using high temperatures, as shown in Scheme 4:
##STR00118##
[0250] An approach to the preparation of a few compounds of Formula
VIA in which L is NH(CH.sub.2).sub.1-4, is illustrated below in
Schemes 4A and 4B. Scheme 4A illustrates the synthesis of a
compound of Formula Via in which E is a phenyl and L is NHCH.sub.2
and Scheme 4B illustrates the synthesis of a compound of Formula
VIA in which E is 3-1H-indole and L is NH(CH.sub.2).sub.2:
##STR00119##
##STR00120##
[0251] A compound of Formula VIA in which L is SH(CH.sub.2)y can be
prepared using microwave chemistry, by reaction an intermediate 1
with [Ring E]-(CH.sub.2).sub.ySH, in the presence of a base such as
Cesium carbonate, and in a solvent such as dimethylformamide at
high temperatures, as shown in Scheme 5. The variable y is defined
above.
##STR00121##
[0252] An approach to the preparation of a compound of Formula Via
in which L is S(CH.sub.2).sub.y, is illustrated below in Scheme
5A:
##STR00122##
[0253] A compound of Formula VIA in which L is bond and [Ring E] is
an aryl or heteroaryl, can be prepared using Suzuki coupling
conditions. Scheme 6 illustrates the Suzuki coupling reaction.
##STR00123##
[0254] In a non limiting example, Scheme 6A illustrates the
preparation of a compound of Formula VIA in which L is a bond and
[Ring E] is a phenyl.
##STR00124##
[0255] A compound of Formula VIA in which L is bond and [Ring E] is
a N-linked heterocyclyl, can be prepared using microwave chemistry,
by reaction an intermediate 1 with the heterocyclyl, in the
presence of a base such as triethylamine, in a polar solvent such
as Ethanol, and using high temperatures, as shown in Scheme 7:
##STR00125##
[0256] In a non limiting example, Scheme 7A illustrates the
preparation of a compound of Formula VIA in which L is a bond and
[Ring E] is N-phenyl-piperazine.
##STR00126##
[0257] An alternative reaction sequence can be used for the
preparation of compounds of Formula VIa in which L is NH. [Ring
E]-NH moiety can be first incorporated to the central pyrimidine
moiety prior to the incorporation of [Ring A]-NH moiety. Scheme 8
illustrates the reaction of 2,4,5-trichloropyrimidine with a
[Ring-E]-NH.sub.2 moiety in the presence of a base (i.e. potassium
carbonate or sodium hydride or the like) in a solvent such as
dimethylformamide or Ethanol in order to generate intermediate 2.
The reaction can be perform at room temperature or may require
higher temperature.
##STR00127##
[0258] Another example of this reaction is shown below in Scheme 9
in which intermediate 3 is prepared by reacting
2,4-dichloro-5-(trifluoromethyl)pyrimidine with a [Ring E]-NH.sub.2
moiety in the presence of sodium hydride in dimethylformamide at
lower temperatures.
##STR00128##
[0259] Intermediate 2 or 3 can then be reacted with a
[Ring-A]-(CH.sub.2).sub.nNH.sub.2 moiety using regular displacement
conditions as shown below in Scheme 10.
##STR00129##
[0260] In a non limiting example, Schemes 10A and 10B illustrate
the preparation of compounds of Formula VIA in which L is NH and
Ring A and Ring E are substituted phenyl:
##STR00130##
[0261] The synthetic guidance provided in Schemes 1 through 10 is
applicable to a variety of Ring A and Ring E of the invention and
allows the preparation of all compounds of the invention.
[0262] Scheme 11 illustrates the preparation of a compound of
Formula IA and VIA in which n is 0, L is NH and X.sup.1 is CH.
[0263] In Scheme 11, [Ring E]-NH moiety is incorporated onto the
pyridine central scaffold by reacting
2-chloro-4-iodo-5-(trifluoromethyl)pyridine with [Ring E]-NH.sub.2
using Palladium coupling reaction conditions. [Ring A]-NH moiety is
then incorporated by displacement chemistry as previously described
in the above Schemes. Microwaves and heat can also be used to
accelerate or drive the displacement reaction to completion.
##STR00131##
[0264] In a non limiting example, Scheme 11A illustrates the
preparation of compounds of Formula VIA in which L is NH, X.sup.1
is CH, and Ring A and Ring E are substituted phenyl.
##STR00132##
[0265] Scheme 12 illustrates the synthesis of a compound of Formula
IVA in which X.sup.1 is CH and R.sup.d and R.sup.e form a phenyl
ring.
##STR00133##
[0266] In a non limiting example, Scheme 12A illustrates the
preparation of compounds of Formula IVA in which X.sup.1 is CH and
R.sup.d and R.sup.e form a phenyl ring, Ring A and Ring E are
substituted phenyl.
##STR00134##
[0267] Scheme 13 illustrates the synthesis of a compound of Formula
IIIA in which X.sup.1 is CH and R.sup.b and R.sup.c form a phenyl
ring which is further substituted with a phenyl ring.
##STR00135##
[0268] In a non limiting example, Scheme 13A illustrates the
preparation of compounds of Formula VA in which X.sup.1 is CH and
R.sup.b and R.sup.c form a phenyl ring, Ring A is substituted
phenyl and R.sup.f is a substituted phenyl.
##STR00136##
[0269] Scheme 14 illustrates the synthesis of a compound of Formula
IIIA in which X.sup.1 is N and R.sup.c and R.sup.d form a
pyrrole.
##STR00137##
in which Ring A and R.sup.a are as defined in part 1 and in R--X, R
is alkyl, heteroaryl, aryl, aryl alkyl, heteroaryl alkyl,
heterocyclyl and other groups selected from the R.sup.f list of
substituents; and X is a halide or other leaving groups.
[0270] Another example of preparation of a compound of Formula IIIA
is illustrated below in Scheme 15 in which substituent R depicted
in scheme 14 is a phenyl.
##STR00138##
in which R' is a substituent selected from R.sup.f list and Ring A
and R.sup.a are defined in part 1.
[0271] In a non limiting example, Scheme 15A illustrates the
preparation of compounds of Formula IIIA in which X.sup.1 is N,
R.sup.c and R.sup.d form a pyrrole, Ring A is a substituted phenyl
and R.sup.f is a substituted phenyl:
##STR00139##
[0272] In a non limiting example, Scheme 16 illustrates the
preparation of compounds of Formula IIIA in which X.sup.1 is N and
R.sup.c and R.sup.d form an imidazole ring which is substituted
with a phenyl.
##STR00140##
in which R' is a substituent selected from R.sup.f list and Ring A
and R.sup.a are defined in part 1.
[0273] For the compounds of the invention, one of R.sup.a, R.sup.b,
R.sup.b1, R.sup.c, R.sup.c1, R.sup.d, R.sup.d1, R.sup.e, R.sup.e1,
R.sup.f or R.sup.g when present, is or contains
--P(.dbd.O)(R.sup.3).sub.2.
[0274] Schemes 17 to 24 illustrate the preparation of phosphorous
containing substituents and phosphorous containing moieties of
current interest.
[0275] Scheme 17 illustrates the preparation of a [Ring A]-NH.sub.2
moiety in which Ring A is a pyridine substituted with
--P(.dbd.O)(R.sup.3).sub.2.
##STR00141##
in which R.sup.3 is defined in part 1. A similar synthetic route
could be used to introduce a --P(.dbd.O)(R.sup.3).sub.2 substituent
onto a phenyl or heteroaryl ring whether the ring is Ring A or Ring
E. This synthetic scheme also illustrates the preparation of a
[Ring E]-L moiety in which L is NH and Ring E is aryl or
heteroaryl. This scheme can be used for the synthesis of compounds
of the invention of Formulae I to VI.
[0276] Of other interest are compounds in which R.sup.a substituent
is phosphorous containing substituent. Scheme 18 illustrates the
synthesis of an intermediate [Ring A]-NH.sub.2 in which Ring A is a
phenyl substituted with --P(.dbd.O)(CH.sub.3).sub.2.
##STR00142##
[0277] Scheme 19 illustrates the preparation of a [Ring A]-NH.sub.2
intermediate in which Ring A is a phenyl substituted with
(CH.sub.2).sub.m--P(.dbd.O)(R.sup.3).sub.2 and m is 1. This scheme
is useful for the synthesis of compounds of Formulae II and
IIA.
##STR00143##
[0278] Scheme 20 illustrates the preparation of a [Ring A]-NH.sub.2
moiety in which Ring A is a bicyclic structure such as naphthalene
substituted with R.sup.f being --P(.dbd.O)(R.sup.3).sub.2.
[0279] This scheme could also be used to prepare a [Ring E]-L
moiety in which Ring E is naphthalene, L is NH and R.sup.g is
--P(.dbd.O)(R.sup.3).sub.2. This scheme can also be used for the
synthesis of compounds of the invention of Formulae VIIA.
##STR00144##
[0280] Scheme 21 illustrates the synthesis of [Ring
A]-(CH.sub.2).sub.n--NH.sub.2 intermediate in which Ring A is
phenyl substituted with --P(.dbd.O)(R.sup.3).sub.2 and n is 1.
##STR00145##
[0281] Scheme 21 can also be used for the synthesis of a [Ring E]-L
moiety in which L is CH.sub.2NH and Ring E is a phenyl substituted
with --P(.dbd.O)(R.sup.3).sub.2.
[0282] In some embodiment, a R.sup.a, R.sup.f or R.sup.g containing
--P(.dbd.O)(R.sup.3).sub.2 substituent can be of cyclic
structure.
[0283] Schemes 22 to 23 illustrate the synthesis of cyclic
structures of interest containing --P(.dbd.O)(R.sup.3).sub.2.
[0284] Scheme 22 illustrates the preparation of cyclic substituent
R.sup.a (or R.sup.f or R.sup.g) containing
--P(.dbd.O)(R.sup.3).sub.2.
##STR00146##
[0285] Schemes 22A and 22B illustrate the incorporation of this
cyclic substituent onto a Ring A or Ring E.
[0286] Scheme 22A illustrates the synthesis of a [Ring A]-NH.sub.2
moiety in which Ring A is a phenyl substituted with a methoxy group
and with a --P(.dbd.O)(R.sup.3).sub.2 containing cyclic
substituent. This scheme could also be used for the synthesis of a
[Ring E]-L moiety in which L is NH and Ring E is a phenyl
substituted with a methoxy group and with a
--P(.dbd.O)(R.sup.3).sub.2 containing cyclic substituent.
##STR00147##
##STR00148##
[0287] Scheme 23 illustrates the synthesis of a [Ring A]-NH.sub.2
intermediate in which Ring A is phenyl substituted by methoxy and a
--P(.dbd.O)(R.sub.3).sub.2 group in which the two R.sup.3 groups
form with the phosphorous atom to which they are attached
6-membered saturated ring.
##STR00149##
[0288] Scheme 24 illustrates the synthesis of a piperazine
substituent which is further substituted with
--CH.sub.2P(.dbd.O)(CH.sub.3).sub.2. This scheme can be used for
the synthesis of [Ring A]-NH.sub.2 intermediate in which Ring A is
a phenyl substituted with a phosphorous containing piperazine
group. It could also be used for the synthesis of a compound of any
of the Formulae of the invention in which one of the substituents
(R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e, R.sup.f or R.sup.g)
is NR.sup.1R.sup.2 and NR.sup.1R.sup.2 form a piperazine ring
substituted with --CH.sub.2P(.dbd.O)(CH.sub.3).sub.2.
##STR00150##
[0289] A compound of Formula IB or VI can be prepared in a 2 steps
synthesis as shown in Scheme 1. A [Ring A] moiety can first be
incorporated to the central pyrimidine moiety by reacting [Ring
A]-NH.sub.2 with a substituted or unsubstituted
4,6-dichloropyrimidine in the presence of a base such as
di-isopropylethyl amine at high temperature generating intermediate
1a. The [Ring E]-L- moiety can then be incorporated onto
intermediate 1a using various conditions depending on the nature of
the L linker. The variables in the intermediate [Ring E]-[L]- and
[Ring A] are as defined previously, Rings A and E being substituted
with permitted R.sup.a and R.sup.g groups respectively.
##STR00151##
[0290] An approach to the preparation of an intermediate 1a is
illustrated below in Scheme 1A in which Ring A is a phenyl:
##STR00152##
[0291] A compound of Formula IB or VII in which L is NH can be
prepared using microwave chemistry, by reacting an intermediate 1a
with [Ring E]-NH.sub.2 in a solvent such as n-Butanol under acidic
conditions as shown in Scheme 26.
##STR00153##
[0292] An approach to the preparation of a compound of Formula VI
in which L is NH, is illustrated below in Scheme 26A in which Ring
A and Ring E are phenyls:
##STR00154##
[0293] A compound of Formula IB or VII in which L is bond and [Ring
E] is a N-linked heterocyclyl, can be prepared by reacting an
intermediate 1a with the heterocyclyl, in the presence of a base
such as di-isopropyldiethylamine, in a polar solvent such as
iso-propanol, and using high temperatures, as shown in Scheme
27:
##STR00155##
[0294] In a non limiting example, Scheme 27A illustrates the
preparation of a compound of Formula VII or IB in which R.sup.c is
[L]-[Ring E] in which L is a bond and [Ring E] is
N-phenyl-piperazine.
##STR00156##
[0295] A compound of Formula IB or VII in which R.sup.c is
[L]-[Ring E] with L being O can be prepared by reacting
4,6-dichloropyrimidine with an optionally substituted phenol; in
the presence of sodium hydride in a solvent such as
dimethylformamide as shown in Scheme 28. A [Ring A] moiety can then
be incorporated to the central pyrimidine moiety by reacting [Ring
A]-(CH.sub.2).sub.nNH.sub.2 in the presence of a base (i.e.
di-isopropylethyl amine, triethylamine or the like) or an acid in
order to facilitate the displacement reaction.
##STR00157##
[0296] An approach to the preparation of a few compounds of Formula
IB or VII in which L is NH, is illustrated below in Scheme 28A in
which Ring A and Ring E are phenyls:
##STR00158##
[0297] A compound of Formula IB or VII in which L is
NH(CH.sub.2).sub.1-4 can be prepared using microwave chemistry, by
reaction an intermediate 1a with [Ring
E]-(CH.sub.2).sub.1-4NH.sub.2, in the presence of a base such as
triethylamine, in a polar solvent such as Ethanol, and using high
temperatures, as shown in Scheme 29:
##STR00159##
[0298] An approach to the preparation of a few compounds of Formula
VII in which L is NH(CH.sub.2).sub.1-4, is illustrated below in
Schemes 29A and 29B. Scheme 29A illustrates the synthesis of a
compound of Formula VII in which Ring E is a phenyl and L is
NHCH.sub.2 and Scheme 29B illustrates the synthesis of a compound
of Formula VII in which Ring E is 3-1H-indole and L is
NH(CH.sub.2).sub.2:
##STR00160##
##STR00161##
[0299] A compound of Formula IB and VII in which L is SH(CH.sub.2)y
can be prepared using microwave chemistry, by reaction an
intermediate 1a with [Ring E]-(CH.sub.2).sub.ySH, in the presence
of a base such as Cesium carbonate, and in a solvent such as
dimethylformamide at high temperatures, as shown in Scheme 30. The
variable y is defined above.
##STR00162##
[0300] An approach to the preparation of a compound of Formula VII
in which X.sup.3 is CH, X.sup.2 is N, L is S(CH.sub.2).sub.y and
Rings A and E are substituted phenyls, is illustrated below in
Scheme 30A:
##STR00163##
[0301] A compound of Formula IB or VII in which L is bond and [Ring
E] is an aryl or heteroaryl, can be prepared using Suzuki coupling
conditions. Scheme 31 illustrates the Suzuki coupling reaction.
##STR00164##
[0302] In a non limiting example, Scheme 31A illustrates the
preparation of a compound of Formula VII in which X.sup.3 is CH,
X.sup.2 is N, L is a bond and [Ring E] and [Ring A] are phenyl.
##STR00165##
[0303] A compound of Formula IC or VI in which R.sup.c is [L]-[Ring
E] with L being O, can be prepared in a 2 steps synthesis as shown
in Scheme 32. A [Ring E]-L- moiety can first be incorporated to the
central pyridazine moiety by reacting [Ring E]-OH with a
substituted or unsubstituted 3,5-dichloropyridazine in the presence
of a base such as sodium hydride generating intermediate 2a. The
[Ring A]-(CH.sub.2).sub.nNH.sub.2 moiety can then be reacted with
intermediate 2a in the presence of a base (i.e. di-isopropylethyl
amine, triethylamine or the like) or an acid in order to facilitate
the displacement reaction.
##STR00166##
[0304] In a non limiting example, Scheme 32A illustrates the
preparation of a compound of Formula VII in which L is O, X.sup.3
is N, X.sup.2 is CH and [Ring E] and [Ring A] are substituted
phenyl.
##STR00167##
[0305] A compound of Formula IC in which R.sup.c is [L]-[Ring E]
with L being NH(CH.sub.2).sub.y, can be prepared in 4 steps as
shown in Scheme 33. A [Ring E]-(CH.sub.2).sub.y--NH.sub.2 moiety
can first be incorporated to the central pyridazine moiety by
reacting [Ring E]-(CH.sub.2).sub.y--NH.sub.2 with
4,5-dichloropyridazin-3(2H)-one in the presence of triethylamine in
a solvent such as Ethanol generating intermediate 3a. Intermediate
3a is then hydrogenated and reduced with phosphoric trichloride
generating intermediate 4a. The [Ring A]-(CH.sub.2).sub.nNH.sub.2
moiety can then be reacted with intermediate 4a in the presence of
a base (i.e. di-isopropylethyl amine, triethylamine or the like) or
an acid in order to facilitate the displacement reaction.
##STR00168##
[0306] In a non limiting example, Scheme 33A illustrates the
preparation of a compound of Formula VII in which L is NH, X.sup.3
is N, X.sup.2 is CH and [Ring E] and [Ring A] are substituted
phenyl.
##STR00169##
[0307] In a similar way, a compound of Formula IC or VI in which
R.sup.c is [L]-[Ring E] with L being O, can be prepared by reacting
[Ring E]-OH with 4,5-dichloropyridazin-3(2H)-one in the presence of
potassium carbonate; followed by the same sequence of steps as
described in Scheme 33. This alternative synthesis is illustrated
in Scheme 34:
##STR00170##
[0308] In a similar way, a compound of Formula IC in which R.sup.c
is a N-linked heterocyclyl can be prepared by reacting a
heterocyclyl such as a substituted piperidine with
4,5-dichloropyridazin-3(2H)-one followed by the same sequence of
steps as described in Scheme 9. This synthesis is illustrated in
Scheme 35:
##STR00171##
[0309] Scheme 36 illustrates the synthesis of a compound of Formula
IIIA in which R.sup.e and R.sup.b are H and R.sup.c and R.sup.d
form an imidazole substituted with a phenyl group.
##STR00172##
in which R is a substituent selected from R.sup.f and Ring A, Ra
and n are defined above.
[0310] In a non limiting example, Scheme 36A illustrates the
preparation of compounds of Formula IIIA in which R.sup.c and
R.sup.d form an imidazole, Ring A is a substituted phenyl and
R.sup.f is a substituted phenyl:
##STR00173##
[0311] A compound of Formula I, IB, IIB or VIA in which n is 0 can
be prepared in a 2 steps synthesis as shown in Scheme 37. A [Ring
A] moiety can first be incorporated to the central triazine moiety
by reacting [Ring A]-Br with
5-chloro-6-substituted-1,2,4-triazin-3-amine under Buchwald Hartwig
cross coupling conditions to generate intermediate 1 (I-1). The
[Ring E]-L- moiety can then be incorporated onto I-1 using various
conditions depending on the nature of the L linker. The variables
in the intermediate [Ring E]-[L]- and [Ring A] are as defined
previously, Rings A and E being substituted with permitted R.sup.a
and R.sup.g groups respectively.
##STR00174##
[0312] An approach to the preparation of an intermediate 1c is
illustrated below in Scheme 37A in which Ring A is a phenyl:
##STR00175##
[0313] Intermediate I-1a is then reacted with a substituted
aniline, as illustrated in Scheme 37B, to generate compound of
Formula VIA in which L is NH, Ring A and Ring E are phenyl, n is 0,
and R.sup.d is methyl.
##STR00176##
[0314] Intermediate I-1a can also be reacted with a substituted
phenol or thiophenol, as illustrated in Scheme 37C, to generate
compound of Formula VIA in which L is O or S, Ring A and Ring E are
phenyl, n is 0, and R.sup.d is methyl.
##STR00177##
[0315] An alternative synthesis to compounds of Formula I, IB, IIB
or VIA is illustrated in Scheme 38. [Ring E]-LH moiety, in which L
is O, S or NH, can be first incorporated to the central triazine
moiety prior to the incorporation of [Ring A]-NH moiety. Schemes 38
and 39 illustrates the reaction of
3,5-dichloro-6-substituted-1,2,4-triazine with a [Ring-E]-LH moiety
in the presence of a base (for example triethylamine, potassium
carbonate, sodium carbonate or sodium hydride or the like) in a
suitable solvent such as for example dimethylformamide, methylene
chloride or tetrahydrofuran in order to generate intermediate I-2
and I-3. The reaction can be performed at room temperature or may
require higher temperature. Intermediates I-2 and I-3 are then
reacted with a [Ring A]-NH.sub.2 moiety under acidic conditions
(i.e Camphor sulfonic acid) in the presence of a suitable solvent
such as for example tetrahydrofuran at high temperature. This
sequence of reactions is described in PCT application WO
2006/015985.
##STR00178##
##STR00179##
[0316] When R.sup.d is chloro, 3,5,6-trichloro-1,2,4-triazine, can
be prepared according to methods described in PCT patent
application WO 2004/074266, by reacting 1,2,4-triazine-3,5(2H,
4H)dione with bromine in a presence of a suitable solvent, such as
for example water, to generate an intermediate of Formula I-4a.
Synthesis of 3,5,6-trichloro-1,2,4-triazine is illustrated in
Scheme 40. Intermediate I-4a is then reacted with POCl.sub.3 and
PCl.sub.5 in the presence of a base such as for example
N,N-diethylaniline.
##STR00180##
[0317] When R.sup.d is Methyl, 3,5-dichloro-6-methyl-1,2,4-triazine
can be prepared according to methods described in PCT patent
application WO 2005/054199.
[0318] When R.sup.d is H; 3,5-dichloro-1,2,4-triazine can be
prepared according to methods described in Journal of Organic
Chemistry, 23, 1522-4; 1958 in which 1,2,4-triazine-3,5(2H,
4H)dione is reacted with POCl.sub.3. The synthesis of
3,5-dichloro-1,2,4-triazine is illustrated in Scheme 41.
##STR00181##
[0319] A compound of Formula I, IA, IC, IIC or VIB can be prepared
in a 2 steps synthesis as shown in Scheme 42. A [Ring
A]-(CH.sub.2).sub.n NH-- moiety can first be incorporated to the
central triazine moiety by reacting [Ring
A]-(CH.sub.2).sub.nNH.sub.2 with
2,4-dichloro-6-substituted-1,3,5-triazine in the presence of a base
as for example di-isopropylethylamine in a suitable solvent. The
[Ring E]-L-moiety can then be incorporated onto I-6 using various
conditions depending on the nature of the L linker. The variables
in the intermediate [Ring E]-[L]- and [Ring A] are as defined
previously, Rings A and E being substituted with permitted R.sup.a
and R.sup.g groups respectively.
##STR00182##
[0320] When R.sup.e is methyl, 2,4-dichloro-6-methyl-1,3,5-triazine
can be prepared according to methods described in Bioorganic
Medicinal Chemistry letters 16(21), 5664-5667, 2006.
2,4,6-trichloro-1,3,5-triazine is reacted with methyl magnesium
bromide to generate 2,4-dichloro-6-methyl-1,3,5-triazine as
illustrated in Scheme 42A.
##STR00183##
[0321] In a non limiting example, an intermediate of formula I-6 in
which R.sup.e is H, n is 0 and Ring A is phenyl is illustrated in
Scheme 42B:
##STR00184##
[0322] A compound of Formula VIB in which L is O can be prepared
using microwave chemistry, by reacting an intermediate I-6 with
[Ring E]-OH in a solvent such as dimethylformamide and high
temperatures as shown in Scheme 43.
##STR00185##
[0323] An approach to the preparation of a compound of Formula VIB
in which L is O, is illustrated below in Scheme 43A in which Ring A
and Ring E are phenyls:
##STR00186##
[0324] A compound of Formula VIB in which L is NH can be prepared
using microwave chemistry, by reaction an intermediate I-6 with
[Ring E]-NH.sub.2, in a polar solvent such as Ethanol, and using
high temperatures, as shown in Scheme 44. A base (i.e.
di-isopropylethyl amine, triethylamine, or the like) or an acid may
be added to facilitate the displacement reaction. A similar
displacement reaction is described in PCT patent application WO
2005/047279.
##STR00187##
[0325] An approach to the preparation of a few compounds of Formula
VIB in which L is NH, is illustrated below in Scheme 44A and 44B in
which Ring E is a phenyl or adamantane respectively:
##STR00188##
##STR00189##
[0326] A compound of Formula VIB in which L is NH(CH.sub.2).sub.1-4
can be prepared using microwave chemistry, by reaction an
intermediate I-6 with [Ring E]-(CH.sub.2).sub.1-4NH.sub.2, in the
presence of a base such as triethylamine, in a polar solvent such
as Ethanol, and using high temperatures, as shown in Scheme 45:
##STR00190##
[0327] An approach to the preparation of a few compounds of Formula
VIB in which L is NH(CH.sub.2).sub.1-4, is illustrated below in
Schemes 45A and 45B. Scheme 45A illustrates the synthesis of a
compound of Formula VIB in which R.sup.e is Cl, Ring E is a phenyl
and L is NHCH.sub.2 and Scheme 45B illustrates the synthesis of a
compound of Formula VIB in which R.sup.e is Cl, Ring E is
3-1H-indole and L is NH(CH.sub.2).sub.2:
##STR00191##
##STR00192##
[0328] A compound of Formula VIB in which L is SH(CH.sub.2).sub.y
can be prepared using microwave chemistry, by reaction an
intermediate I-6 with [Ring E]-(CH.sub.2).sub.ySH, in the presence
of a base such as Cesium carbonate, and in a solvent such as
dimethylformamide at high temperatures, as shown in Scheme 46. The
variable y is defined above.
##STR00193##
[0329] An approach to the preparation of a compound of Formula VIB
in which L is S(CH.sub.2).sub.y, is illustrated below in Scheme
46A:
##STR00194##
[0330] A compound of Formula VIB in which L is bond and [Ring E] is
an aryl or heteroaryl, can be prepared using Suzuki coupling
conditions. Scheme 11 illustrates the Suzuki coupling reaction. The
displacement of one of the chlorine by and aryl Grignard or and
aryl boronic acid is described in PCT patent application WO
01/25220 and Helv. Chim. Acta, 33, 1365 (1950). The displacement of
one of the chlorines by a heteroaryl ring is described in WO
01/25220, J. Het. Chem., 11, 417 (1974); and Tetrahedron 31, 1879
(1975). These reactions can be facilitated by using Microwave
chemistry. Microwave assisted Suzuki coupling reaction is also
described in Journal of Medicinal Chemistry, 2007, 50(17),
3497.
##STR00195##
[0331] When R.sup.e is chloro, the Suzuki reaction is also
described in PCT patent application WO 2002/22605.
[0332] In a non limiting example, Scheme 47A illustrates the
preparation of a compound of Formula VIB in which L is a bond and
[Ring E] is a substituted phenyl.
##STR00196##
[0333] A compound of Formula I, IB or VIA in which L is a bond and
Ring E is an aryl or heteroaryl ring, can also be prepared in a
similar way using Suzuki coupling conditions. A similar sequence of
reaction is described in PCT patent application WO 2005/054199 and
is illustrated below in Scheme 48:
##STR00197##
[0334] A compound of Formula VIA in which L is bond and [Ring E] is
a N-linked heterocyclyl, can be prepared using microwave chemistry,
by reaction an intermediate I-6 with the heterocyclyl, in the
presence of a base such as triethylamine, in a polar solvent such
as Ethanol, and using high temperatures, as shown in Scheme 49. A
similar displacement is described in PCT patent application WO
2005/059668.
##STR00198##
[0335] In a non limiting example, Scheme 49A illustrates the
preparation of a compound of Formula VIA in which L is a bond,
R.sup.e is Cl and [Ring E] is N-phenyl-piperazine.
##STR00199##
[0336] Scheme 50 illustrates the preparation of a compound of
Formula IVA in which R.sup.c is L-[Ring E]; L is NH, X.sup.3 is N,
X.sup.4 is C and Ring C is a triazole. A similar sequence of
reaction is described in Bioorganic & Medicinal Chemistry
Letters, 16(5), 1353-1357; 2006. Microwave chemistry can also be
used to accelerate the displacement reaction.
##STR00200##
[0337] In a non limiting example, Scheme 50A illustrates the
preparation of compounds of Formula IVA in which L is NH, X.sup.3
is N, X.sup.4 is C, Ring C is a triazole, and Ring A and Ring E are
substituted phenyl.
##STR00201##
[0338] An alternative route to compounds of Formula IVA in which
Ring C is a triazole is illustrated in Scheme 51. A compound of
Formula I-15 can be reacted with an aryl halide (such as aryl
bromide) or heteroaryl halide in the presence of a base, such as
for example Cesium carbonate, and in the presence of a palladium
acetate and a phosphorous ligand (i.e. xanphos); which generates
intermediate I-15a. Intermediate I-15a is then subjected to m-CPBA
and the oxidized sulfur is displaced with a Ring A-NH.sub.2 moiety.
The synthesis of intermediate I-15 is described in Journal of
heterocyclic chemistry, 37(6), 1587-1590, 2000.
##STR00202##
[0339] In a non limiting example, Scheme 51A illustrates the
preparation of compounds of Formula IVA in which R.sup.c is L-[Ring
E], and L is NH, X.sup.3 is N, X.sup.4 is C, Ring C is a triazole,
R.sup.f is Me and Ring A and Ring E are substituted phenyl.
##STR00203##
[0340] Scheme 52 illustrates the synthesis of a compound of Formula
IVA in which X.sup.3 is N, X.sup.4 is C and Ring C is a pyrazole.
The pyrazolo[1,5-a][1,3,5]triazine ring system can be prepared from
the starting amino pyrazole as shown in Scheme 52. Synthesis of
various amino pyrazoles and cyclization conditions are described in
US patent application US 2008/187219 and Bioorganic & Medicinal
Chemistry letters, 17(15), 4191-4195, 2007.
##STR00204##
[0341] In a non limiting example, Scheme 52A illustrates the
preparation of compounds of Formula IVA in which X.sup.3 is N,
X.sup.4 is C, Ring C is a pyrazole, Ring A and Ring E are
substituted phenyl.
##STR00205##
[0342] Scheme 53 illustrates the synthesis of a compound of Formula
IVA in which X.sup.4 is N and X.sup.3 is C, R.sup.c is L-[Ring E],
L is NH and [Ring C] is a pyrrole. This synthesis is described in
PCT application WO 2008/057994.
##STR00206##
[0343] In a non limiting example, Scheme 53A illustrates the
preparation of compounds of Formula IVA in which X.sup.4 is N and
X.sup.3 is C, R.sup.c is L-[Ring E], L is NH and [Ring C] is a
pyrrole; and Ring A and Ring E are substituted phenyl.
##STR00207##
[0344] Scheme 54 illustrates the synthesis of a compound of Formula
IIIA in which Ring B is a pyrrole.
3,6-Dichloro-N-substituted-1,2-4-triazin-5-amine is reacted with a
substituted alkyne under Sonogashira conditions to generate
3-chloro-5-substituted-pyrrolo[2,3-e][1,2,4]triazine. A similar
synthetic route using Sonogashira reaction is described in
Tetrahedron Letters, 48(29), 5069-5072; 2007.
##STR00208##
in which Ring A and R.sup.a, n and s are as defined in part 1 and R
and R' are alkyl, heteroaryl, aryl, aryl alkyl, heteroaryl alkyl,
heterocyclyl and other groups selected from the R.sup.f list of
substituents. Examples of R.sup.1 are methyl, ethyl, methyl
dialkylamino, phenyl and the like. Examples of R are substituted
phenyl, substituted benzyl, substituted pyridine and the like.
[0345] In a non limiting example, Scheme 54A illustrates the
preparation of compounds of Formula IIIA in which Ring B is a
pyrrole; R' is a methyl group, R is a substituted phenyl and Ring A
is a substituted phenyl.
##STR00209##
[0346] Another example of preparation of a compound of Formula IIIA
is illustrated below in Scheme 55 in which Ring B is an imidazole.
An intermediate I-19 can be reacted with an amine to generate
intermediate I-19a and the cyclization occurs in the presence of
SOCl.sub.2 and trimethoxymethane and generates intermediate I-19b.
The cyclization step is described in Liebigs Annalen der Chemie, 7,
631-40, 1990. The methyl thioether in intermediate I-19b can then
be oxidized with m-CPBA and displaced with a [Ring
A]-(CH.sub.2).sub.nNH.sub.2 moiety as previously described in
Scheme 52.
##STR00210##
in which R is alkyl, heteroaryl, aryl, aryl alkyl, heteroaryl
alkyl, heterocyclyl and other groups selected from the R.sup.f list
of substituents. Examples of R are methyl, ethyl, methyl
dialkylamino, phenyl and the like. Examples of R are substituted
phenyl, substituted benzyl, substituted pyridine and the like. Ring
A and R.sup.a are defined in part 1.
[0347] In a non limiting example, Scheme 55A illustrates the
preparation of compounds of Formula IIIA in which Ring B is an
imidazole, Ring A is a substituted phenyl and R is a substituted
phenyl:
##STR00211##
[0348] Another example of preparation of a compound of Formula IIIA
is illustrated below in Scheme 56 in which Ring B is a pyrazole. An
intermediate I-20 can be reacted with hydrazinecarbothioamide and
the cyclization occurs in the presence of potassium carbonate which
generates intermediate I-20a. The cyclization step is described in
Journal of Heterocyclic Chemistry, 21(3), 923-6, 1984. Intermediate
I-20a is then reacted with a [Ring]A-(CH.sub.2).sub.nNH.sub.2
moiety. A similar displacement is described in Journal fuer
Praktische Chemie (Leipzig), 326(6), 994-8, 1984.
##STR00212##
in which R'' is a substituent selected from R.sup.f list and Ring A
and R.sup.a are defined in part 1.
[0349] In a non limiting example, Scheme 56A illustrates the
preparation of compounds of Formula IIIA in which Ring B is a
pyrazole, Ring A is a substituted phenyl and R'' is a methoxy
group.
##STR00213##
[0350] Another example of preparation of a compound of Formula IIIA
is illustrated below in Scheme 57 in which Ring B is a phenyl. A
substituted 2-nitroaniline can undergo cyclization in the presence
of Raney Nickel as described in Bioorganic & Medicinal
Chemistry Letters, 17(21), 5818, 2007. When 2-nitroaniline is
substituted with a bromide or halide, a Suzuki coupling reaction
can be used to introduce an aryl or heteroaryl onto the fused
phenyl ring B. The Ring A-NH.sub.2 moiety can be introduced using
Buchwald-Hartwig cross-coupling reaction.
##STR00214##
[0351] In a non limiting example, Scheme 57A illustrates the
preparation of compounds of Formula IIIA in which Ring B and Ring A
are substituted phenyl:
##STR00215##
[0352] With synthetic approaches such as the foregoing, combined
with the examples which follow, additional information provided
herein and conventional methods and materials, the practitioner
should be able to prepare the full range of compounds disclosed
herein.
5. Uses, Formulations, Administration
Pharmaceutical Uses, Indications
[0353] The invention features compounds having biological
properties which make them of interest for treating or modulating
disease in which kinases may be involved, symptoms of such disease,
or the effect of other physiological events mediated by kinases.
For instance, a number of compounds of the invention have been
shown to inhibit tyrosine kinase activity of ALK, fak and c-met,
among other tyrosine kinases which are believed to mediate the
growth, development and/or metastasis of cancer. A number of
compounds of the invention have also been found to possess potent
in vitro activity against cancer cell lines, including among others
karpas 299 cells. Such compounds are thus of interest for the
treatment of cancers, including solid tumors as well as lymphomas
and including cancers which are resistant to other therapies.
[0354] Such cancers include, among others, cancers of the breast,
non small cell lung cancer (NSCLS), neural tumors such as
glioblastomas and neuroblastomas; esophaegeal carcinomas, soft
tissue cancers such as rhabdomyosarcomas, among others); various
forms of lymphoma such as a non-Hodgkin's lymphoma (NHL) known as
anaplastic large-cell lymphoma (ALCL), various forms of leukemia;
and including cancers which are ALK or c-met mediated.
[0355] Anaplastic Lymphoma Kinase (ALK) is a cell membrane-spanning
receptor tyrosine kinase, which belong to the insulin receptor
subfamily. ALK receptor tyrosine kinase (RTK) was initially
identified due to its involvement in the human non-Hodgkin lymphoma
subtype known as anaplastic large-cell lymphoma (ALCL). ALK
normally has a restricted distribution in mammalian cells, being
found at significant levels only in nervous system during embryonic
development, suggesting a possible role for ALK in brain
development (Duyster, J. Et al., Oncogene, 2001, 20,
5623-5637).
[0356] In addition to its role in normal development, expression of
the full-length normal ALK has also been detected in cell lines
derived from a variety of tumors such as neuroblastomas,
neuroectodermal tumors (Lamant L. Et al., Am. J. Pathol., 2000,
156, 1711-1721; Osajima-Hakomori Y., et al., Am. J. Pathol. 2005,
167, 213-222) and glioblastoma (Powers C. et al., J. Biol. Chem.
2002, 277, 14153-14158; Grzelinski M. et al., Int. J. Cancer, 2005,
117, 942-951; Mentlein, R. Et al., J. Neurochem., 2002, 83,
747-753) as well as breast cancer and melanoma lines (Dirk W G. Et
al., Int. J. Cancer, 2002, 100, 49-56).
[0357] In common with other RTKs, translocations affect the ALK
gene, resulting in expression of oncogenic fusion kinases--the most
common of which is NPM-ALK. For example, approximately sixty
percent of anaplastic large cell lymphomas (ALCL) are associated
with a chromosome mutation that generates a fusion protein
consisting of nucleophosmin (NMP) and the intracellular domain of
ALK. (Armitage, J. O. et al., Cancer: principle and practice of
oncology, 6.sup.th Edition, 2001, 2256-2316; kutok, J. L. &
Aster J. C., J. Clin. Oncol., 2002, 20, 3691-3702; Wan, W. et al.,
Blood, 2006, 107, 1617-1623. This mutant protein, NMP-ALK,
possesses a constitutively active tyrosine kinase domain that is
responsible for its oncogenic property through activation of
downstream effectors (Falini, B and al., Blood, 1999, 94,
3509-3515; Morris, S. W. et al., Brit. J. Haematol., 2001, 113,
275-295). Experimental data have demonstrated that the aberrant
expression of constitutively active ALK is directly implicated in
the pathogenesis of ALCL and that inhibition of ALK can markedly
impair the growth of ALK positive lymphoma cells (Kuefer, Mu et
al., Blood, 1997, 90, 2901-2910; Bai, R. Y. et al., Exp. Hematol.,
2001, 29, 1082-1090; Slupianek, A. et al., Cancer Res., 2001, 61,
2194-2199; Turturro, F. et al., Clin. Cancer. Res., 2002, 8,
240-245). The constitutively activated chimeric ALK has also been
demonstrated in about 60% of inflammatory myofibroblastic tumors
(IMTs), a slow growing sarcoma that mainly affects children and
young adults (Lawrence, B. et al., Am. J. Pathol., 2000, 157,
377-384). Furthermore, recent reports have also described the
occurrence of a variant ALK fusion, TPM4-ALK, in cases of squamous
cell carcinoma (SCC) of the esophagus (Jazzi fr., et al., World J.
Gastroenterol., 2006, 12, 7104-7112; Du X., et al., J. Mol. Med.,
2007, 85, 863-875; Aklilu M., Semin. Radiat. Oncol., 2007, 17,
62-69). Thus, ALK is one of the few examples of an RTK implicated
in oncogenesis in both non-hematopoietic and hematopoietic
malignancies. More recently it has been shown that a small
inversion within chromosome 2p results in the formation of a fusion
gene comprising portions of the echinoderm microtubule-associated
protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK)
gene in non-small-cell lung cancer (NSCLC) cells (Soda M., et al.,
Nature, 2007, 448, 561-567).
[0358] We therefore envision that an ALK inhibitor would either
permit durable cures when used as a single therapeutic agent or
combined with current chemotherapy for ALCL, IMT, proliferative
disorders, glioblastoma and other possible solid tumors cited
herein, or, as a single therapeutic agent, could be used in a
maintenance role to prevent recurrence in patients in need of such
a treatment.
Pharmaceutical Methods
[0359] The invention features methods for treating a subject having
or at risk of contracting cancer by administering to the subject a
therapeutically effective amount of a compound of the
invention.
[0360] A "therapeutically effective amount" is that amount
effective for detectable killing or inhibition of the growth or
spread of cancer cells; the size or number of tumors; or other
measure of the level, stage, progression or severity of the cancer.
The exact amount required will vary from subject to subject,
depending on the species, age, and general condition of the
subject, the severity of the disease, the particular anticancer
agent, its mode of administration, combination treatment with other
therapies, and the like.
[0361] The compound, or a composition containing the compound, may
be administered using any amount and any route of administration
effective for killing or inhibiting the growth of tumors or other
forms of cancer.
[0362] The anticancer compounds of the invention are preferably
formulated in dosage unit form for ease of administration and
uniformity of dosage. The expression "dosage unit form" as used
herein refers to a physically discrete unit of anticancer agent
appropriate for the patient to be treated. As is normally the case,
the total daily usage of the compounds and compositions of the
invention will be decided by the attending physician using routine
reliance upon sound medical judgment. The specific therapeutically
effective dose level for any particular patient or organism will
depend upon a variety of factors including the disorder being
treated; the severity of the disorder; the potency of the specific
compound employed; the specific composition employed; the age, body
weight, general health, sex and diet of the patient; the route and
schedule of administration; the rate of metabolism and/or excretion
of the compound; the duration of the treatment; drugs used in
combination or coincident with administration of the compound of
the invention; and like factors well known in the medical arts.
[0363] Furthermore, after formulation with an appropriate
pharmaceutically acceptable carrier in a desired dosage, the
compositions of the invention can be administered to humans and
other animals orally, rectally, parenterally, intracisternally,
intravaginally, intraperitoneally, topically (as by transdermal
patch, powders, ointments, or drops), sublingually, bucally, as an
oral or nasal spray, or the like.
[0364] The effective systemic dose of the compound will typically
be in the range of 0.01 to 500 mg of compound per kg of patient
body weight, preferably 0.1 to 125 mg/kg, and in some cases 1 to 25
mg/kg, administered in single or multiple doses. Generally, the
compound may be administered to patients in need of such treatment
in a daily dose range of about 50 to about 2000 mg per patient.
Administration may be once or multiple times daily, weekly (or at
some other multiple-day interval) or on an intermittent schedule.
For example, the compound may be administered one or more times per
day on a weekly basis (e.g. every Monday) indefinitely or for a
period of weeks, e.g. 4-10 weeks. Alternatively, it may be
administered daily for a period of days (e.g. 2-10 days) followed
by a period of days (e.g. 1-30 days) without administration of the
compound, with that cycle repeated indefinitely or for a given
number of repititions, e.g. 4-10 cycles. As an example, a compound
of the invention may be administered daily for 5 days, then
discontinued for 9 days, then administered daily for another 5 day
period, then discontinued for 9 days, and so on, repeating the
cycle indefinitely, or for a total of 4-10 times.
[0365] The amount of compound which will be effective in the
treatment or prevention of a particular disorder or condition will
depend in part on well known factors affecting drug dosage. In
addition, in vitro or in vivo assays may optionally be employed to
help identify optimal dosage ranges. A rough guide to effective
doses may be extrapolated from dose-response curves derived from in
vitro or animal model test systems. The precise dosage level should
be determined by the attending physician or other health care
provider and will depend upon well known factors, including route
of administration, and the age, body weight, sex and general health
of the individual; the nature, severity and clinical stage of the
disease; the use (or not) of concomitant therapies; and the nature
and extent of genetic engineering of cells in the patient.
[0366] When administered for the treatment or inhibition of a
particular disease state or disorder, the effective dosage of the
compound of the invention may vary depending upon the particular
compound utilized, the mode of administration, the condition, and
severity thereof, of the condition being treated, as well as the
various physical factors related to the individual being treated.
In many cases, satisfactory results may be obtained when the
compound is administered in a daily dosage of from about 0.01
mg/kg-500 mg/kg, preferably between 0.1 and 125 mg/kg, and more
preferably between 1 and 25 mg/kg. The projected daily dosages are
expected to vary with route of administration. Thus, parenteral
dosing will often be at levels of roughly 10% to 20% of oral dosing
levels.
[0367] When the compound of the invention is used as part of a
combination regimen, dosages of each of the components of the
combination are administered during a desired treatment period. The
components of the combination may administered at the same time;
either as a unitary dosage form containing both components, or as
separate dosage units; the components of the combination can also
be administered at different times during a treatment period, or
one may be administered as a pretreatment for the other.
Regarding the Compounds
[0368] Compounds of present invention can exist in free form for
treatment, or where appropriate, as a pharmaceutically acceptable
salt, ester, or prodrug. As used herein, the term "pharmaceutically
acceptable salt" refers to those salts which are, within the scope
of sound medical judgment, suitable for use in contact with the
tissues of humans and lower animals without undue toxicity,
irritation, allergic response and the like, and are commensurate
with a reasonable benefit/risk ratio. Pharmaceutically acceptable
salts of amines, carboxylic acids, phosphonates and other types of
compounds, are well known in the art. For example, S. M. Berge, et
al. describe pharmaceutically acceptable salts in detail in J.
Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by
reference. The salts can be prepared in situ during the isolation
and purification of compounds of the invention, or separately by
reacting the free base or free acid of a compound of the invention
with a suitable base or acid, respectively. Examples of
pharmaceutically acceptable, nontoxic acid addition salts are salts
of an amino group formed with inorganic acids such as hydrochloric
acid, hydrobromic acid, phosphoric acid, sulfuric acid and
perchloric acid or with organic acids such as acetic acid, oxalic
acid, maleic acid, tartaric acid, citric acid, succinic acid or
malonic acid or by using other methods used in the art such as ion
exchange. Other pharmaceutically acceptable salts include adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like. Further
pharmaceutically acceptable salts include, when appropriate,
nontoxic ammonium, quaternary ammonium, and amine cations formed
using counterions such as halide, hydroxide, carboxylate, sulfate,
phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
[0369] Additionally, as used herein, the term "pharmaceutically
acceptable ester" refers preferably to esters which hydrolyze in
vivo and include those that break down readily in the human body to
leave the parent compound or a salt thereof. Suitable ester groups
include, for example, those derived from pharmaceutically
acceptable aliphatic carboxylic acids, particularly alkanoic,
alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl
or alkenyl moiety advantageously has not more than 6 carbon atoms.
Examples of particular esters include formates, acetates,
propionates, butyrates, acrylates and ethylsuccinates. Obviously,
esters can be formed with a hydroxyl or carboxylic acid group of
the compound of the invention.
[0370] Furthermore, the term "pharmaceutically acceptable prodrugs"
as used herein refers to those prodrugs of compounds of the
invention. The term "prodrug" refers to compounds that are
transformed in vivo to yield the parent compound of the above
formula, for example by hydrolysis in blood. See, e.g., T. Higuchi
and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the
A.C.S. Symposium Series, and Edward B. Roche, ed., Bioreversible
Carriers in Drug Design, American Pharmaceutical Association and
Pergamon Press, 1987, both of which are incorporated herein by
reference.
Pharmaceutical Compositions
[0371] The invention also features pharmaceutical compositions
including a compound of the invention, or a prodrug,
pharmaceutically acceptable salt or other pharmaceutically
acceptable ester thereof, and one or more pharmaceutically
acceptable carriers or excipients. The pharmaceutical compositions
optionally further comprise one or more additional therapeutic
agents. In certain instances a compound of the invention may be
administered to a subject undergoing one or more other therapeutic
interventions (e.g. Gleevec or other kinase inhibitors, interferon,
bone marrow transplant, farnesyl transferase inhibitors,
bisphosphonates, thalidomide, cancer vaccines, hormonal therapy,
antibodies, radiation, etc). For example, the compound of the
invention can be used as one component of a combination therapy in
which one or more additional therapeutic agents (e.g., an
anticancer agent), the agents being either formulated together or
separately, is administered to the subject.
[0372] The pharmaceutical compositions of the invention include a
pharmaceutically acceptable carrier or excipient. Pharmaceutically
acceptable carriers and excipient that can be used in the
pharmaceutical compositions of the invention include, without
limitation, solvents, diluents, or other vehicle, dispersion or
suspension aids, surface active agents, isotonic agents, thickening
or emulsifying agents, preservatives, solid binders, lubricants and
the like, as suited to the particular dosage form desired.
Remington's Pharmaceutical Sciences, Fifteenth Edition, E. W.
Martin (Mack Publishing Co., Easton, Pa., 1975) discloses various
carriers used in formulating pharmaceutical compositions and known
techniques for the preparation thereof. Some examples of materials
which can serve as pharmaceutically acceptable carriers or
excipients include, but are not limited to, sugars such as lactose,
glucose and sucrose; starches such as corn starch and potato
starch; cellulose and its derivatives such as sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered
tragacanth; malt; gelatin; talc; excipients such as cocoa butter
and suppository waxes; oils such as peanut oil, cottonseed oil;
safflower oil; sesame oil; olive oil; corn oil and soybean oil;
glycols; such a propylene glycol; esters such as ethyl oleate and
ethyl laurate; agar; buffering agents such as magnesium hydroxide
and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic
saline; Ringer's solution; ethyl alcohol, and phosphate buffer
solutions, as well as other non-toxic compatible lubricants such as
sodium lauryl sulfate and magnesium stearate, as well as coloring
agents, releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be
present in the composition.
[0373] Compounds of the invention may be administered by any
suitable route, preferably in the form of a pharmaceutical
composition adapted to such a route, and in a dose effective for
the treatment intended. Compounds of the invention may, for
example, be administered orally, mucosally, topically, rectally,
pulmonarily such as by inhalation spray, or parentally including
intravascularly, intravenously, intraperitoneally, subcutaneously,
intramuscularly, intrasternally and infusion techniques, in dosage
unit formulations containing conventional pharmaceutically
acceptable carriers, adjuvants, and vehicles.
[0374] For oral administration, the pharmaceutical composition may
be in the form of, for example, a tablet, capsule, suspension or
liquid. The pharmaceutical composition is preferably made in the
form of a dosage unit containing a particular amount of the active
ingredient. Each unit dosage may contain an amount of active
ingredient from about 1 to 2000 mg, preferably from about 1 to 500
mg, more commonly from about 5 to 200 mg. The amount of a compound
of the invention to be administered will typically be in the range
of 0.01 to 500 mg of compound per kg body weight, preferably
between 0.1 and 125 mg/kg body weight and in some cases between 1
and 25 mg/kg body weight. As mentioned previously, the daily dose
can be given in one administration or may be divided between 2, 3,
4 or more administrations.
[0375] In the case of skin conditions, it may be preferable to
apply a topical preparation of compounds of the invention to the
affected area two to four times a day. Formulations suitable for
topical administration include liquid or semi-liquid preparations
suitable for penetration through the skin (e.g., liniments,
lotions, ointments, creams, or pastes) and drops suitable for
administration to the eye, ear, or nose. A suitable topical dose of
active ingredient of a compound of the invention is 0.1 mg to 150
mg administered one to four, preferably one or two times daily. For
topical administration, the active ingredient may comprise from
0.001% to 10% w/w, e.g., from 1% to 2% by weight of the
formulation, although it may comprise as much as 10% w/w, but
preferably not more than 5% w/w, and more preferably from 0.1% to
1% of the formulation.
[0376] When formulated in an ointment, the active ingredients may
be employed with either paraffinic or a water-miscible ointment
base. Alternatively, the active ingredients may be formulated in a
cream with an oil-in-water cream base. If desired, the aqueous
phase of the cream base may include, for example at Least 30% w/w
of a polyhydric alcohol such as propylene glycol, butane-1,3-diol,
mannitol, sorbitol, glycerol, polyethylene glycol and mixtures
thereof. The topical formulation may desirably include a compound
which enhances absorption or penetration of the active ingredient
through the skin or other affected areas. Examples of such dermal
penetration enhancers include dimethylsulfoxide and related
analogs.
[0377] Compounds of the invention can also be administered by a
transdermal device. Preferably transdermal administration will be
accomplished using a patch either of the reservoir and porous
membrane type or of a solid matrix variety. In either case, the
active agent is delivered--continuously from the reservoir or
microcapsules through a membrane into the active agent permeable
adhesive, which is in contact with the skin or mucosa of the
recipient. If the active agent is absorbed through the skin, a
controlled and predetermined flow of the active agent is
administered to the recipient. In the case of microcapsules, the
encapsulating agent may also function as the membrane.
[0378] The oily phase of the emulsions of the invention may be
constituted from known ingredients in a known manner.
[0379] While the phase may comprise merely an emulsifier, it may
comprise a mixture of at least one emulsifier with a fat or an oil
or with both a fat and an oil. Preferably, a hydrophilic emulsifier
is included together with a lipophilic emulsifier which acts as a
stabilizer. It is also preferred to include both an oil and a fat.
Together, the emulsifier(s) with or without stabilizer(s) make-up
the socalled emulsifying wax, and the wax together with the oil and
fat make up the so-called emulsifying ointment base which forms the
oily dispersed phase of the cream formulations. Emulsifiers and
emulsion stabilizers suitable for use in the formulation of the
invention include Tween 60, Span 80, cetostearyl alcohol, myristyl
alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl
distearate alone or with a wax, or other materials well known in
the art.
[0380] The choice of suitable oils or fats for the formulation is
based on achieving the desired cosmetic properties, since the
solubility of the active compound in most oils likely to be used in
pharmaceutical emulsion formulations is very low. Thus, the cream
should preferably be a non-greasy, non-staining and washable
product with suitable consistency to avoid leakage from tubes or
other containers. Straight or branched chain, mono- or dibasic
alkyl esters such as di-isoadipate, isocetyl stearate, propylene
glycol diester of coconut fatty acids, isopropyl myristate, decyl
oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate
or a blend of branched chain esters may be used. These may be used
alone or in combination depending on the properties required.
[0381] Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils can be
used.
[0382] Formulations suitable for topical administration to the eye
also include eye drops wherein the active ingredients are dissolved
or suspended in suitable carrier, especially an aqueous solvent for
the active ingredients.
[0383] The active ingredients are preferably present in such
formulations in a concentration of 0.5 to 20%, advantageously 0.5
to 10% and particularly about 1.5% w/w.
[0384] Formulations for parenteral administration may be in the
form of aqueous or non-aqueous isotonic sterile injection solutions
or suspensions. These solutions and suspensions may be prepared
from sterile powders or granules using one or more of the carriers
or diluents mentioned for use in the formulations for oral
administration or by using other suitable dispersing or wetting
agents and suspending agents. The compounds may be dissolved in
water, polyethylene glycol, propylene glycol, ethanol, corn oil,
cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, tragacanth gum, and/or various buffers.
[0385] Other adjuvants and modes of administration are well and
widely known in the pharmaceutical art. The active ingredient may
also be administered by injection as a composition with suitable
carriers including saline, dextrose, or water, or with cyclodextrin
(i.e. Captisol), cosolvent solubilization (i.e. propylene glycol)
or micellar solubilization (i.e. Tween 80).
[0386] The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, for example as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution, and isotonic sodium
chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed, including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
find use in the preparation of injectables.
[0387] For pulmonary administration, the pharmaceutical composition
may be administered in the form of an aerosol or with an inhaler
including dry powder aerosol.
[0388] Suppositories for rectal administration of the drug can be
prepared by mixing the drug with a suitable nonirritating excipient
such as cocoa butter and polyethylene glycols that are solid at
ordinary temperatures but liquid at the rectal temperature and will
therefore melt in the rectum and release the drug.
[0389] The pharmaceutical compositions may be subjected to
conventional pharmaceutical operations such as sterilization and/or
may contain conventional adjuvants, such as preservatives,
stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and
pills can additionally be prepared with enteric coatings. Such
compositions may also comprise adjuvants, such as wetting,
sweetening, flavoring, and perfuming agents.
Combination Therapy
[0390] Compounds of the invention can be administered as part of a
treatment regimen in which the compound is the sole active
pharmaceutical agent, or used in combination with one or more other
therapeutic agents as part of a combination therapy. When
administered as one component of a combination therapy, the
therapeutic agents being administered can be formulated as separate
compositions that are administered at the same time or sequentially
at different times (e.g., within 72 hours, 48 hours, or 24 hours of
one another), or the therapeutic agents can be formulated together
in a single pharmaceutical composition and administered
simultaneously.
[0391] Thus, the administration of compounds of the invention may
be in conjunction with additional therapies known to those skilled
in the art in the prevention or treatment of cancer, such as
radiation therapy or cytostatic agents, cytotoxic agents, other
anti-cancer agents and other drugs to ameliorate symptoms of the
cancer or side effects of any of the drugs.
[0392] If formulated as a fixed dose, such combination products
employ compounds of the invention within the accepted dosage
ranges. Compounds of the invention may also be administered
sequentially with other anticancer or cytotoxic agents when a
combination formulation is inappropriate. The invention is not
limited in the sequence of administration; compounds of the
invention may be administered prior to, simultaneously with, or
after administration of the other anticancer or cytotoxic
agent.
[0393] Currently, standard treatment of primary tumors consists of
surgical excision, when appropriate, followed by either radiation
or chemotherapy, and typically administered intravenously (IV). The
typical chemotherapy regime consists of either DNA alkylating
agents, DNA intercalating agents, CDK inhibitors, or microtubule
poisons. The chemotherapy doses used are just below the maximal
tolerated dose and therefore dose limiting toxicities typically
include, nausea, vomiting, diarrhea, hair loss, neutropenia and the
like.
[0394] There are large numbers of antineoplastic agents available
in commercial use, in clinical evaluation and in pre-clinical
development, which would be selected for treatment of cancer by
combination drug chemotherapy. And there are several major
categories of such antineoplastic agents, namely, antibiotic-type
agents, alkylating agents, antimetabolite agents, hormonal agents,
immunological agents, interferon-type agents and a category of
miscellaneous agents.
[0395] A first family of antineoplastic agents which may be used in
combination with compounds of the invention includes
antimetabolite-type/thymidilate synthase inhibitor antineoplastic
agents. Suitable antimetabolite antineoplastic agents may be
selected from but not limited to the group consisting of
5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar
sodium, carmofur, CibaGeigy CGP-30694, cyclopentyl cytosine,
cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF,
Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine,
didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck &
Co.
[0396] EX-015, fazarabine, floxuridine, fludarabine phosphate,
5fluorouracil, N-(21-furanidyl) fluorouracil, Daiichi Seiyaku
FO-152, isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618,
methobenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCI
NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567,
Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi
Chemical PL-AC, Takeda TAC788, thioguanine, tiazofurin, Erbamont
TIF, trimetrexate, tyrosine kinase inhibitors, Taiho UFT and
uricytin.
[0397] A second family of antineoplastic agents which may be used
in combination with compounds of the invention consists of
alkylating-type antineoplastic agents. Suitable alkylating-type
antineoplastic agents may be selected from but not limited to the
group consisting of Shionogi 254-S, aldo-phosphamide analogues,
altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil,
budotitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139,
Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American
Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D 384,
Sumimoto DACHP(Myr)2, diphenylspiromustine, diplatinum cytostatic,
Erba distamycin derivatives, Chugai DWA-2114R, ITI E09, elmustine,
Erbamont FCE-24517, estramustine phosphate sodium, fotemustine,
Unimed G M, Chinoin GYKI-17230, hepsulfam, ifosfamide, iproplatin,
lomustine, mafosfamide, mitolactolf Nippon Kayaku NK-121, NCI
NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU,
prednimustine, Proter PTT-119, ranimustine, semustine, SmithKline
SK&F-101772, Yakult Honsha SN-22, spiromus-tine, Tanabe Seiyaku
TA-077, tauromustine, temozolomide, teroxirone, tetraplatin and
trimelamol.
[0398] A third family of antineoplastic agents which may be used in
combination with compounds of the invention consists of
antibiotic-type antineoplastic agents. Suitable antibiotic-type
antineoplastic agents may be selected from but not limited to the
group consisting of Taiho 4181-A, aclarubicin, actinomycin D,
actinoplanone, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto
AN II, Ajinomoto AN3, Nippon Soda anisomycins, anthracycline,
azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers
BMY-25067, Bristol-Myers BNY-25551, Bristol-Myers BNY-26605
IBristolMyers BNY-27557, Bristol-Myers BMY-28438, bleomycin
sulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin,
dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79,
Kyowa Hakko DC-88A, Kyowa Hakko, DC89-A1, Kyowa Hakko DC92-B,
ditrisarubicin B, Shionogi DOB-41, doxorubicin,
doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin,
esorubicin, esperamicin-A1, esperamicin-A1b, Erbamont FCE21954,
Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin,
gregatin-A, grincamycin, herbimycin, idarubicin, illudins,
kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery
KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko
KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303,
menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, neoenactin,
Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International
NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin,
pirarubicin, porothramycin, pyrindanycin A, Tobishi RA-1,
rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo
SM5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A,
sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical
SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2,
talisomycin, Takeda TAN-868A, terpentecin, thrazine, tricrozarin A,
Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi
Y-25024 and zorubicin.
[0399] A fourth family of antineoplastic agents which may be used
in combination with compounds of the invention consists of a
miscellaneous family of antineoplastic agents, including tubulin
interacting agents, topoisomerase II inhibitors, topoisomerase I
inhibitors and hormonal agents, selected from but not limited to
the group consisting of (xcarotene, (X-difluoromethyl-arginine,
acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide,
amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston
A10, antineoplaston A2, antineoplaston A3, antineoplaston A5,
antineoplaston AS2-1F Henkel APD, aphidicolin glycinate,
asparaginase, Avarol, baccharin, batracylin, benfluron, benzotript,
Ipsen-Beaufour BIM-23015, bisantrene, BristoMyers BNY-40481, Vestar
boron-10, bromofosfamide, Wellcome BW-502, Wellcome BW-773,
caracemide, carmethizole hydrochloride, Ajinomoto CDAF,
chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100,
Warner-Lambert CI-921, WarnerLambert CI-937, Warner-Lambert CI-941,
Warner-Lambert CI958, clanfenur, claviridenone, ICN compound 1259,
ICN compound 4711, Contracan, Yakult Honsha CPT-11, crisnatol,
curaderm, cytochalasin B. cytarabine, cytocytin, Merz D-609, DABIS
maleate, dacarbazine, datelliptinium, didemnin-B,
dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin,
Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693,
docetaxel elliprabin, elliptinium acetate, Tsumura EPMTC, the
epothilones, ergotamine, etoposide, etretinate, fenretinide,
Fujisawa FR-57704t gallium nitrate, genkwadaphnin, Chugai GLA-43,
Glaxo GR-63178, grifolan NMF5N, hexadecylphosphocholine, Green
Cross HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187,
ilmofosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477,
Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American
Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU 1121 Lilly
LY-186641, NCI (US) MAP, marycin, Merrel Dow MDL-27048, Medco
MEDR-340, merbarone, merocyanlne derivatives,
methylanilinoacridine, Molecular Genetics MGI136, minactivin,
mitonafide, mitoquidone mopidamol, motretinide, Zenyaku Kogyo
MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021,
N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazole
derivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI
NSC-604782, NCI NSC-95580, ocreotide, Ono ONO-112, oquizanocine,
Akzo Org-10172, paclitaxel, pancratistatin, pazelliptine,
WarnerLambert PD-111707, Warner-Lambert PD-115934, Warner-Lambert
PD-131141, Pierre Fabre PE-1001, ICRT peptide D, piroxantrone,
polyhaematoporphyrin, polypreic acid, Efamol porphyrin, probimane,
procarbazine, proglumide, Invitron protease nexin I, Tobishi
RA-700, razoxane, Sapporo Breweries RBS, restrictin-P,
retelliptine, retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc
RP-56976, SmithKline SK&F-104864, Sumitomo SM-108, Kuraray
SMANCS, SeaPharm SP10094, spatol, spirocyclopropane derivatives,
spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone,
Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide
dismutase, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303,
teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol,
topotecan, Topostin, Teijin TT82, Kyowa Hakko UCN-01, Kyowa Hakko
UCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate,
vincristine, vindesine, vinestramide, vinorelbine, vintriptol,
vinzolidine, withanolides and Yamanouchi YM Alternatively, the
present compounds may also be used in co-therapies with other
anti-neoplastic agents, such as acemannan, aclarubicin,
aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine,
aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole,
ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos),
bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin,
cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030
(Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane,
dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine,
doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil,
HIT diclofenac, interferon alfa, daunorubicin, doxorubicin,
tretinoin, edelfosine, edrecolomab eflornithine, emitefur,
epirubicin, epoetin beta, etoposide phosphate, exemestane,
exisulind, fadrozole, filgrastim, finasteride, fludarabine
phosphate, formestane, fotemustine, gallium nitrate, gemcitabine,
gemtuzumab zogamicin, gimeracil/oteracil/tegafur combination,
glycopine, goserelin, heptaplatin, human chorionic gonadotropin,
human fetal alpha fetoprotein, ibandronic acid, idarubicin,
(imiquimod, interferon alfa, interferon alfa, natural, interferon
alfa-2, interferon alfa-2a, interferon alfa-2b, interferon alfa-NI,
interferon alfa-n3, interferon alfacon1, interferon alpha, natural,
interferon beta, interferon beta-1a, interferon beta-1b, interferon
gamma, natural interferon gamma-1a, interferon gamma-1b,
interleukin-I beta, iobenguane, irinotecan, irsogladine,
lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan
sulfate, letrozole, leukocyte alpha interferon, leuprorelin,
levamisole+fluorouracil, liarozole, lobaplatin, lonidamine,
lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone,
miltefosine, mirimostim, mismatched double stranded RNA,
mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin,
naloxone+pentazocine, nartograstim, nedaplatin, nilutamide,
noscapine, novel erythropoiesis stimulating protein, NSC 631570
octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel,
pamidronic acid, pegaspargase, peginterferon alfa-2b, pentosan
polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit
antithymocyte polyclonal antibody, polyethylene glycol interferon
alfa-2a, porfimer sodium, raloxifene, raltitrexed, rasburicase,
rhenium Re 186 etidronate, RII retinamide, rituximab, romurtide,
samarium (153 Sm) lexidronam, sargramostim, sizofiran, sobuzoxane,
sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene,
tegafur, temoporfin, temozolomide, teniposide,
tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa,
topotecan, toremifene, tositumomab-iodine 131, trastuzumab,
treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor
necrosis factor alpha, natural, ubenimex, bladder cancer vaccine,
Maruyama. vaccine, melanoma lysate vaccine, valrubicin,
verteporfin, vinorelbine, VIRULIZIN, zinostatin stimalamer, or
zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense
oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), cetuximab,
decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800
(Endorecherche), eniluracil, etanidazole, fenretinidel filgrastim
SDOI (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen,
HLA-B7 gene therapy (Vical), granulocyte macrophage colony
stimulating factor, histamine dihydrochloride, ibritumomab
tiuxetan, ilomastat, IM 862 (Cytran), interleukin iproxifene, LDI
200 (Milkhaus), leridistim, lintuzumab, CA 125 MAb (Biomira),
cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb
(Medarex), idiotypic 105AD7 MAb (CRC Technology), idiotypic CEA MAb
(Trilex), LYM iodine 131 MAb (Techniclone), polymorphic epithelial
mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab,
motexafin, gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P
30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL
0903 (Shire), rubitecan, satraplatin, sodium phenylacetate,
sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN)y SU 6668
(SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine,
thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer
vaccine (Biomira), melanoma vaccine (New York University), melanoma
vaccine (Sloan Kettering Institute), melanoma oncolysate vaccine
(New York Medical College), viral melanoma cell lysates vaccine
(Royal Newcastle Hospital), or valspodar.
Treatment Kits
[0400] In other embodiments, the invention relates to a kit for
conveniently and effectively carrying out the methods in accordance
with the invention. In general, the pharmaceutical pack or kit
comprises one or more containers filled with one or more of the
ingredients of the pharmaceutical compositions of the invention and
instructions for administering the pharmaceutical composition
(e.g., a label or package insert) as part of a method described
herein. Such kits are especially suited for the delivery of solid
oral forms such as tablets or capsules. Such a kit preferably
includes a number of unit dosages, and may also include a card
having the dosages oriented in the order of their intended use. If
desired, a memory aid can be provided, for example in the form of
numbers, letters, or other markings or with a calendar insert,
designating the days in the treatment schedule in which the dosages
can be administered. Optionally associated with such container(s)
can be a notice in the form prescribed by a governmental agency
regulating the manufacture, use or sale of pharmaceutical products,
which notice reflects approval by the agency of manufacture, use or
sale for human administration.
[0401] The following representative examples contain important
additional information, exemplification and guidance which can be
adapted to the practice of the invention in its various embodiments
and the equivalents thereof. These examples are intended to help
illustrate the invention, and are not intended to, nor should they
be construed to, limit its scope. Indeed, various modifications of
the invention, and many further embodiments thereof, in addition to
those shown and described herein, will become apparent to those
skilled in the art upon review of this document, including the
examples which follow and the references to the scientific and
patent literature cited herein. The contents of those cited
references are incorporated herein by reference to help illustrate
the state of the art. In addition, for purposes of the invention,
the chemical elements are identified in accordance with the
Periodic Table of the Elements, CAS version, Handbook of Chemistry
and Physics, 75.sup.th Ed., inside cover. Additionally, general
principles of organic chemistry, as well as specific functional
moieties and reactivity, are described in "Organic Chemistry",
Thomas Sorrell, University Science Books, Sausalito: 1999, and
"Organic Chemistry", Morrison & Boyd (3d Ed), the entire
contents of both of which are incorporated herein by reference.
EXAMPLES
Example 1
N-[4-(dimethylphosphoryl)phenyl]-4-(4-methylpiperazin-1-yl)-5-(trifluorome-
thyl)pyrimidin-2-amine
##STR00216##
[0402]
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimi-
din-2-amine
[0403] A suspension of 4-amino-dimethylphenylphosphine oxide (3.7
g, 2.2 mmol) in 15 mL of N, N-Dimethylacetamide and 3.6 mL of
Diisopropylethylamine, was allowed to stirred at room temperature
for 15 minutes until a clear solution was obtained.
2,4-Dichloro-5-(trifluoromethyl) pyrimidine (5.7 g, 2.6 mmol) was
added in four portions over 5 minutes. The reaction mixture was
stirred at 60 degrees for 1 hour. The reaction mixture was cooled
to room temperature and filtered to obtain a white solid. The white
solid was washed with 50 mL of water three times and followed by 50
mL of Ethyl ether three times. The white solid was dried under
vacuum to yield desired product (3.8 g, 49% yield). MS ES+:
m/z=350.
N-[4-(dimethylphosphoryl)phenyl]-4-(4-methylpiperazin-1-yl)-5-(trifluorome-
thyl)pyrimidin-2-amine
[0404] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2--
amine (25 mg, 0.072 mmol) in 1.5 mL of ethanol was added 10 .mu.L
of triethylamine and 1-Methyl piperazine (7.2 mg, 0.072 mmol). The
mixture was microwave at 120 degrees for 20 minutes. The reaction
mixture was filtered through a syringe filter and purified by
prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases)
to yield a white solid as product (24 mg, 79% yield.) MS/ES+:
m/z=414.
Example 2
N.sup.2-[4-(dimethylphosphoryl)phenyl]-N.sup.4-(tricyclo[3.3.1.1.sup.3,7]d-
ec-1-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine
##STR00217##
[0406] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2--
amine (prepared as in Example 1:27 mg, 0.078 mmol) in 1.5 mL of
ethanol was added 10 .mu.L of triethylamine and 1-Adamantanamine
(12 mg, 0.078 mmol). The mixture was microwave at 120 degrees for
20 minutes. The reaction mixture was filtered through a syringe
filter and purified by prep-HPLC (Waters Sunfire C18 column with
ACN/water mobile phases) to yield a white solid as product (3 mg,
8% yield.) MS/ES+: m/z=465.
Example 4
N.sup.2-[4-(dimethylphosphoryl)phenyl]-N.sup.4-(morpholin-4-ylmethyl)-5-(t-
rifluoromethyl) pyrimidine-2,4-diamine
##STR00218##
[0408] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2--
amine (prepared as in Example 1:40 mg, 0.12 mmol) in 2 mL of
ethanol was added 50 .mu.L of triethylamine and 4-(2-aminoethyl)
morpholine (15 mg, 0.12 mmol). The mixture was microwave at 120
degrees for 20 minutes. The reaction mixture was filtered through a
syringe filter and purified by prep-HPLC (Waters Sunfire C18 column
with ACN/water mobile phases) to yield a white solid as product (42
mg, 81% yield.) MS/ES+: m/z=430.
Example 5
4-(2-{[2-{[4-(dimethylphosphoryl)phenyl]amino}-5-(trifluoromethyl)pyrimidi-
n-4-yl]amino}ethyl)benzenesulfonamide
##STR00219##
[0410] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2--
amine (prepared as in Example 1:40 mg, 0.12 mmol) in 2 mL of
ethanol was added 50 .mu.L of triethylamine and
4-(2-aminoethyl)benzene-sulfonamide (23 mg, 0.12 mmol). The mixture
was microwave at 120 degrees for 20 minutes. The reaction mixture
was filtered through a syringe filter and purified by prep-HPLC
(Waters Sunfire C18 column with ACN/water mobile phases) to yield a
white solid as product (30 mg, 49% yield.) MS/ES+: m/z=514.
Example 6
N.sup.2-[4-(dimethylphosphoryl)phenyl]-N.sup.4-(tetrahydrofuran-2-yl)-5-(t-
rifluoromethyl) pyrimidine-2,4-diamine
##STR00220##
[0412] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2--
amine (prepared as in Example 1:40 mg, 0.12 mmol) in 2 mL of
ethanol was added 50 .mu.L of triethylamine and
(s)-3-aminotetrahydrofuran hydrochloride salt (14 mg, 0.12 mmol).
The mixture was microwave at 120 degrees for 20 minutes. The
reaction mixture was filtered through a syringe filter and purified
by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile
phases) to yield a white solid as product (27 mg, 59% yield.)
MS/ES+: m/z=401.
Example 7
N.sup.2-[4-(dimethylphosphoryl)phenyl]-N.sup.4-(hexahydrocyclopenta[c]pyrr-
ol-2(1H)-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine
##STR00221##
[0414] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2--
amine (prepared as in Example 1:40 mg, 0.12 mmol) in 2 mL of
ethanol was added 50 .mu.L of triethylamine and
3-Amino-3-azabicyclo-[3,3,0] octane hydrochloride salt (19 mg, 0.12
mmol). The mixture was microwave at 120 degrees for 20 minutes. The
reaction mixture was filtered through a syringe filter and purified
by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile
phases) to yield a white solid as product (34 mg, 67% yield.)
MS/ES+: m/z=440.
Example 8
N.sup.2-[4-(dimethylphosphoryl)phenyl]-N.sup.4-(morpholin-4-yl)-5-(trifluo-
romethyl)pyrimidine-2,4-diamine
##STR00222##
[0416] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2--
amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of
ethanol was added 50 .mu.L of triethylamine and 4-Aminomorpholine
(12 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20
minutes. The reaction mixture was filtered through a syringe filter
and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water
mobile phases) to yield a white solid as product (6 mg, 12% yield.)
MS/ES+: m/z=416.
Example 9
N-[4-(dimethylphosphoryl)phenyl]-4-(4-phenylpiperazin-1-yl)-5-(trifluorome-
thyl) pyrimidin-2-amine
##STR00223##
[0418] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2--
amine (prepared as in Example 1:40 mg, 0.12 mmol) in 2 mL of
ethanol was added 50 .mu.L of triethylamine and 1-Phenylpiperazine
(19 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20
minutes. The reaction mixture was filtered through a syringe filter
and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water
mobile phases) to yield a white solid as product (40 mg, 73%
yield.) MS/ES+: m/z=476.
Example 10
N.sup.2-[4-(dimethylphosphoryl)phenyl]-N.sup.4-[2-(1H-indol-3-yl)ethyl]-5--
(trifluoromethyl) pyrimidine-2,4-diamine
##STR00224##
[0420] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2--
amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of
ethanol was added 50 .mu.L of triethylamine and Tryptamine (18 mg,
0.12 mmol). The mixture was microwave at 120 degrees for 20
minutes. The reaction mixture was filtered through a syringe filter
and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water
mobile phases) to yield a white solid as product (44 mg, 81%
yield.) MS/ES+: m/z=474.
Example 11
N.sup.2-[4-(dimethylphosphoryl)phenyl]-N.sup.4-(4-methylpiperazin-1-yl)-5--
(trifluoromethyl) pyrimidine-2,4-diamine
##STR00225##
[0422] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2--
amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of
ethanol was added 50 .mu.L of triethylamine and
1-Amino-4-methyl-piperazine (13 mg, 0.12 mmol). The mixture was
microwave at 120 degrees for 20 minutes. The reaction mixture was
filtered through a syringe filter and purified by prep-HPLC (Waters
Sunfire C18 column with ACN/water mobile phases) to yield a white
solid as product (17 mg, 34% yield.) MS/ES+: m/z=429.
Example 12
N.sup.2-[4-(dimethylphosphoryl)phenyl]-N.sup.4-(tricyclo[3.3.1.1.sup.3,7]d-
ec-1-ylmethyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine
##STR00226##
[0424] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2--
amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of
ethanol was added 50 .mu.L of triethylamine and
1-Adamantanemethylamine (19 mg, 0.12 mmol). The mixture was
microwave at 120 degrees for 20 minutes. The reaction mixture was
filtered through a syringe filter and purified by prep-HPLC (Waters
Sunfire C18 column with ACN/water mobile phases) to yield a white
solid as product (40 mg, 73% yield.) MS/ES+: m/z=479
Example 13
N.sup.2-[4-(dimethylphosphoryl)phenyl]-N.sup.4-[4-(4-methylpiperazin-1-yl)-
benzyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
##STR00227##
[0426] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2--
amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of
ethanol was added 50 .mu.L of triethylamine and
4-(4-methylpiperazine)-benzylamine (24 mg, 0.12 mmol). The mixture
was microwave at 120 degrees for 20 minutes. The reaction mixture
was filtered through a syringe filter and purified by prep-HPLC
(Waters Sunfire C18 column with ACN/water mobile phases) to yield a
white solid as product (21 mg, 73% yield.) MS/ES+: m/z=519
Example 14
N.sup.4-(3,5-dimethylphenyl)-N.sup.2-[4-(dimethylphosphoryl)phenyl]-5-(tri-
fluoromethyl) pyrimidine-2,4-diamine
##STR00228##
[0428] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2--
amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of
ethanol was added 10 .mu.L of Hydrochloric acid in Methanol (2M)
and 3,5-Dimethyl aniline (14 mg, 0.12 mmol). The mixture was
microwave at 120 degrees for 20 minutes. The reaction mixture was
filtered through a syringe filter and purified by prep-HPLC (Waters
Sunfire C18 column with ACN/water mobile phases) to yield a white
solid as product (32 mg, 65% yield.) MS/ES+: m/z=435
Example 15
5-chloro-N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-phenylpy-
rimidine-2,4-diamine
##STR00229##
[0429] 2,5-dichloro-N-phenylpyrimidin-4-amine
[0430] To a solution of Aniline (205 mg, 2.2 mmol) and
2,4,5-Trichloropyrimidine (500 mg, 2.7 mmol) in 5 mL of Ethanol,
was added 500 mg of Potassium carbonate. The reaction mixture was
stirred at room temperature for 2 hours. Solvent was removed under
reduced pressure. The residue was purified by silica gel flash
chromatography with 10% Ethyl Acetate in Heptane to yield the
desired product as an oil (370 mg, 70% yield).
(3-methoxy-4-nitrophenyl)(dimethyl)phosphane oxide
[0431] To a solution of 5-Chloro-2-nitroanisole (0.5 g, 2.67 mmol)
in 5 mL of DMF was added dimethylphosphine oxide (0.229 g, 2.93
mmol), palladium acetate (30 mg, 0.13 mmol), XANPHOS (0.092 g, 0.16
mmol) and potassium phosphate (0.623 g, 2.93 mmol). The mixture was
purged with argon, and heated at 120.degree. C. for 18 h. The
reaction mixture was basified with saturated sodium bicarbonate
solution, and extracted with ethyl acetate. The organic layer was
concentrated and purified by prep-HPLC to give the final product
(0.16 g, 30% yield). MS/ES+: m/z=229.
4-(dimethylphosphoryl)-2-methoxyaniline
[0432] To a solution of
(3-methoxy-4-nitrophenyl)(dimethyl)phosphane oxide (0.1 g, 0.44
mmol) in 5 mL of EtOH was added 10% weight of palladium on carbon
(0.2 g). The mixture was purged with argon, and hydrogenated under
30 psi for 2 h. The mixture was passed through Celite to a flask
containing HCl in ethanol. Concentration of the filtrate gave the
final product (0.088 g, 86% yield). MS/ES+: m/z=199.
5-chloro-N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-phenylpy-
rimidine-2,4-diamine
[0433] To a solution of 2,5-dichloro-N-phenylpyrimidin-4-amine (84
mg, 0.35 mmol) and 4-(dimethylphosphoryl)-2-methoxyaniline (60 mg,
0.30 mmol) in 1 mL of DMF, was added 0.36 mL of 2.5M HCl in
Ethanol. The reaction mixture was heated in a sealed tube at 140
degrees over night. The reaction mixture was filtered through a
syringe filter and purified by Prep-HPLC (Waters Sunfire C18 column
with ACN/water mobile phases) to yield the desired product as a
white solid. (23 mg, 16% yield). MS/ES+: m/z=403
Example 16
N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-ylsu-
lfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
##STR00230##
[0434]
2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrim-
idin-4-amine
[0435] To a solution of 1-Amino-2-(isopropylsulphonyl)benzene (350
mg, 1.6 mmol) in 4 mL of N,N-Dimethyl formamide at 0 degree, was
added Sodium hydride (100 mg) and the reaction mixture was allowed
to stirred at 0 degree for 20 minutes.
2,4-Dichloro-5-(trifluoromethyl) pyrimidine (350 mg, 1.6 mmol) was
added in one portion and the reaction mixture was warmed to room
temperature. The reaction mixture was stirred at room temperature
overnight. The reaction mixture was quenched with water and
extracted with Ethyl acetate. The combined Ethyl acetate layers
were dried over Sodium Sulfate and solvent was removed under
reduced pressure. The residue was purified by Prep-HPLC to yield
the desired product as a white solid (10 mg, 2% yield).
N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-ylsu-
lfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
[0436] To a solution of
2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidin-4-
-amine (7.5 mg, 0.02 mmol) and
4-(dimethylphosphoryl)-2-methoxyaniline (prepared as in Example 15:
15 mg, 0.7 mmol) in 1 mL of 2-Methoxy ethanol, was added 1 mL of
2.5M HCl in Ethanol. The reaction mixture was heated in a sealed
tube at 140 degree over night. The reaction mixture was filtered
through a syringe filter and purified by Prep-HPLC (Waters Sunfire
C18 column with ACN/water mobile phases) to yield the desired
product as a white solid. (0.9 mg, 8% yield). MS/ES+: m/z=543
Example 17
5-chloro-N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(prop-
an-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
##STR00231##
[0437]
2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine
[0438] To a solution of 1-Amino-2-(isopropylsulphonyl)benzene
(0.955 g, 4.80 mmol) in 2 mL of DMF at 0.degree. C. was added NaH
(60% in oil, 0.349 g, 8.72 mmol) in one portion. After stirring for
20 min, 2,4,5-trichloropyrimidine was added. The mixture was
stirred at 0.degree. C. for 30 minutes, and then at room
temperature for 2 h. After quenching with saturated ammonium
chloride solution, the mixture was poured in water and ethyl
acetate mixture. Yellow suspension was filtered as final product
(0.3 g, 20% yield). MS/ES+: m/z=346.
5-chloro-N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(prop-
an-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
[0439] To a solution of
2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine
(0.050 g, 0.14 mmol) in 1 mL of 2-methoxyethanol was added
4-(dimethylphosphoryl)-2-methoxyaniline (prepared as in Example 15:
0.029 g, 0.14 mmol) and 0.12 ml of 2.5M HCl in EtOH. The mixture
was heated in a sealed tube at 140.degree. C. for 1 h. The mixture
was basified with saturated sodium bicarbonate solution, and
extracted with ethyl acetate. The organic layer was purified by
prep-HPLC to give the final product (20 mg, 24% yield). MS/ES+:
m/z=508.
Example 18
5-chloro-N.sup.2-[4-(dimethylphosphoryl)phenyl]-N.sup.4-[2-(propan-2-ylsul-
fonyl)phenyl]pyrimidine-2,4-diamine
##STR00232##
[0441] To a solution of
2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine
(prepared as in Example 17: 50 mg, 0.14 mmol) in 1 mL of
2-methoxyethanol was added 4-(dimethylphosphoryl)-2-methoxyaniline
(prepared as in Example 15: 0.025 g, 0.14 mmol) and 0.12 ml of 2.5M
HCl in EtOH. The mixture was heated in a sealed tube at 140.degree.
C. for 1 h. The mixture was basified with saturated sodium
bicarbonate solution, and extracted with ethyl acetate. The organic
layer was purified by prep-HPLC to give the final product (0.100 g,
15% yield). MS/ES+: m/z=478.
Example 19
5-chloro-N.sup.4-[4-(dimethylphosphoryl)phenyl]-N.sup.2-{2-methoxy-4-[4-(4-
-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine
##STR00233##
[0442]
2,5-dichloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine
[0443] To a solution of 2,4,5-trichloropyrimidine (0.15 ml, 1.31
mmol) in 1 mL of DMF was added 4-(dimethylphosphoryl)aniline (0.221
g, 1.31 mmol) and potassium carbonate (0.217 g, 1.57 mmol). The
mixture was heated at 110.degree. C. for 4 h. It was basified with
saturated sodium bicarbonate solution. The suspension was filtered
and washed with ethyl acetate to give the final product (0.15 g,
36% yield). MS/ES+: m/z=316.
1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine
[0444] To a solution of 5-fluoro-2-nitroanisole (0.5 g, 2.92 mmol)
in 3 mL of DMF was added 1-methyl-4-(piperidin)piperazine (0.536 g,
2.92 mmol) and potassium carbonate (0.808, 5.84 mmol). The mixture
was heated at 120.degree. C. for 18 h. The mixture was basified
with saturated sodium bicarbonate solution and extracted with ethyl
acetate. The organic layer was purified by chromatography to give
final product as yellow solid (0.95 g, 95% yield). MS/ES+:
m/z=334.
2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline
[0445] The a solution of
1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine
(0.3 g, 0.90 mmol) in 10 mL of ethanol purged with argon was added
10% Palladium on carbon (0.060 g). The hydrogenation was finished
under 30 psi after 4 h. The mixture was passed through Celite to a
flask containing HCl in ethanol. Concentration of the filtrate gave
the final product (0.15 g, 88% yield). MS/ES+: m/z=334.
5-chloro-N.sup.4-[4-(dimethylphosphoryl)phenyl]-N.sup.2-{2-methoxy-4-[4-(4-
-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine
[0446] To the compound
2,5-dichloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine
(0.005 g, 0.16 mmol) in 1 mL of 2-methoxyethanol was added
2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (0.71
g, 0.16 mmol). The mixture was stirred at 110.degree. C. for 18 h.
The mixture was basified with saturated sodium bicarbonate solution
and extracted with limited amount of ethyl acetate. The aqueous
layer was purified by chromatography to give the final product
(0.015 g, 20% yield). MS/ES+: m/z=583.
Example 20
N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-ylsu-
lfonyl)phenyl]pyrimidine-2,4-diamine
##STR00234##
[0447]
2-Chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine
[0448] To a suspension of NaH (60% dispersion in mineral oil, 40
mg, 1.0 mmol) in 2.0 mL of DMF at room temperature was added
1-amino-2-(isopropylsulphonyl)benzene (0.20 g, 1.0 mmol) as a solid
in 3 portions. After 30 minutes of stirring at room temperature,
2,4-dichloropyrimidine (0.15 g, 1.0 mmol) was added as a solution
in 1.0 mL DMF. The reaction mixture stirred for 3 h at room
temperature. The reaction was quenched with saturated sodium
bicarbonate solution and the solution extracted ethyl acetate. The
organic layers were combined, washed with saturated sodium chloride
solution, dried with sodium sulfate, filtered and concentrated. The
crude residue was purified by silica gel chromatography (0-30%
ethyl acetate:heptane) to afford the desired compound as an
off-white solid (53 mg, 17% yield). MS/ES+: m/z=312.
N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-ylsu-
lfonyl)phenyl]pyrimidine-2,4-diamine
[0449] To a solution of
2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine (0.017
g, 0.054 mmol) in 0.5 mL of 2-methoxyethanol in a vial was added
4-(dimethylphosphoryl)-2-methoxyaniline (0.010 g, 0.044 mmol) as
the HCl salt. The vial was sealed and the reaction was heated at
90.degree. C. for 16 h. The reaction was quenched with 1N NaOH
solution and the solution extracted ethyl acetate. The organic
layers were combined, washed with saturated sodium chloride
solution, dried with sodium sulfate, filtered and concentrated. The
crude residue was purified by silica gel chromatography (0-10% 7N
ammonia in methanol:dichloromethane) to afford the desired compound
(15 mg, 72% yield). MS/ES+: m/z=475.
Example 21
N.sup.2-[4-(Dimethylphosphoryl)-2-methoxyphenyl]-5-methyl-N.sup.4-[2-(prop-
an-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
##STR00235##
[0450]
2-Chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-ami-
ne
[0451] To a suspension of NaH (60% dispersion in mineral oil, 40.0
mg, 1.00 mmol) in 2 mL of DMF at room temperature was added
1-amino-2-(isopropylsulphonyl)benzene (0.20 g, 1.0 mmol) as a solid
in 3 portions. After 30 minutes of stirring at room temperature,
2,4-dichloro-5-methylpyrimidine (0.17 g, 1.0 mmol) was added as a
solution in 1 mL DMF. The reaction mixture stirred for 3 h at room
temperature. The reaction was quenched with saturated sodium
bicarbonate solution and the solution extracted ethyl acetate. The
organic layers were combined, washed with saturated sodium chloride
solution, dried with sodium sulfate, filtered and concentrated. The
crude residue was purified by silica gel chromatography (0-30%
ethyl acetate:heptane) to afford the desired compound as an
off-white solid (78 mg, 24% yield). MS/ES+: m/z=326.
N.sup.2-[4-(Dimethylphosphoryl)-2-methoxyphenyl]-5-methyl-N.sup.4-[2-(prop-
an-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
[0452] To a solution of
2-chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine
(0.035 g, 0.11 mmol) in 1 mL of 2-methoxyethanol in a vial was
added 4-(dimethylphosphoryl)-2-methoxyaniline (0.020 g, 0.085 mmol)
as the HCl salt. The vial was sealed and the reaction was heated at
90.degree. C. for 16 h. The reaction was quenched with 1N NaOH
solution and the solution extracted ethyl acetate. The organic
layers were combined, washed with saturated sodium chloride
solution, dried with sodium sulfate, filtered and concentrated. The
crude residue was purified by silica gel chromatography (0-10% 7N
ammonia in methanol:dichloromethane) to afford the desired compound
(12 mg, 29% yield). MS/ES+: m/z=489.
Example 22
5-Chloro-N.sup.2-[5-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(prop-
an-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
##STR00236##
[0453] 5-(Dimethylphosphoryl)-2-methoxyaniline
[0454] To a solution of 5-bromo-2-methoxyaniline (0.404 g, 2.00
mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20
mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg,
0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The
mixture was purged with nitrogen, and subjected to microwaves at
150.degree. C. for 20 minutes. The reaction mixture was
concentrated and purified by silica gel chromatography (0-20% 7N
ammonia in methanol:dichloromethane) to afford the desired product
(0.365 g, 85% yield).
5-Chloro-N.sup.2-[5-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(prop-
an-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
[0455] To a solution of
2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (as
prepared in Example 17: 0.077 g, 0.22 mmol) in 1.5 mL of
2-methoxyethanol was added 5-(dimethylphosphoryl)-2-methoxyaniline
(0.050 g, 0.21 mmol) as its hydrochloride salt. The mixture was
heated in a sealed tube at 90.degree. C. for 16 h. The mixture was
basified with 1N NaOH solution, and extracted with ethyl acetate.
The organic layers were combined, washed with saturated sodium
chloride solution, dried with sodium sulfate, filtered and
concentrated. The crude residue was purified by prep-HPLC to afford
the final compound (52 mg, 48% yield). MS/ES+: m/z=509.
Example 23
5-Chloro-N.sup.2-[4-(dimethylphosphoryl)-2-methylphenyl]-N.sup.4-[2-(propa-
n-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
##STR00237##
[0456] 4-(Dimethylphosphoryl)-2-methylaniline
[0457] To a solution of 4-bromo-2-methylaniline (0.372 g, 2.00
mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20
mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg,
0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The
mixture was purged with nitrogen, and subjected to microwaves at
150.degree. C. for 20 minutes. The reaction mixture was
concentrated and purified by silica gel chromatography (0-20% 7N
ammonia in methanol:dichloromethane) to afford the desired product
(0.313 g, 85% yield).
5-Chloro-N.sup.2-[4-(dimethylphosphoryl)-2-methylphenyl]-N.sup.4-[2-(propa-
n-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
[0458] To a solution of
2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (as
prepared in Example 17: 0.083 g, 0.24 mmol) in 1.5 mL of
2-methoxyethanol was added 4-(dimethylphosphoryl)-2-methylaniline
(0.050 g, 0.23 mmol) as its hydrochloride salt. The mixture was
heated in a sealed tube at 90.degree. C. for 16 h. The mixture was
basified with 1N NaOH solution, and extracted with ethyl acetate.
The organic layers were combined, washed with saturated sodium
chloride solution, dried with sodium sulfate, filtered and
concentrated. The crude residue was purified by prep-HPLC to afford
the final compound (20 mg, 18% yield). MS/ES+: m/z=493.
Example 24
5-Chloro-N.sup.2-[4-(dimethylphosphoryl)-2-ethylphenyl]-N.sup.4-[2-(propan-
-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
##STR00238##
[0459] 4-(Dimethylphosphoryl)-2-ethylaniline
[0460] To a solution of 4-bromo-2-ethylaniline (0.400 g, 2.00 mmol)
in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol),
palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120
mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture
was purged with nitrogen, and subjected to microwaves at
150.degree. C. for 20 minutes. The reaction mixture was
concentrated and purified by silica gel chromatography (0-20% 7N
ammonia in methanol:dichloromethane) to afford the desired product
(0.308 g, 78% yield).
5-Chloro-N.sup.2-[4-(dimethylphosphoryl)-2-ethylphenyl]-N.sup.4-[2-(propan-
-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
[0461] To a solution of
2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (as
prepared in Example 17: 0.079 g, 0.22 mmol) in 1.5 mL of
2-methoxyethanol was added 4-(dimethylphosphoryl)-2-ethylaniline
(0.050 g, 0.21 mmol) as its hydrochloride salt. The mixture was
heated in a sealed tube at 90.degree. C. for 16 h. The mixture was
basified with 1N NaOH solution, and extracted with ethyl acetate.
The organic layers were combined, washed with saturated sodium
chloride solution, dried with sodium sulfate, filtered and
concentrated. The crude residue was purified by prep-HPLC to afford
the final compound (43 mg, 40% yield). MS/ES+: m/z=507.
Example 25
5-Chloro-N.sup.2-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N.sup-
.4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
##STR00239##
[0462] 4-(Dimethylphosphoryl)-2-(trifluoromethoxy)aniline
[0463] To a solution of 4-iodo-2-(trifluoromethoxy)aniline (0.606
g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171
g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS
(69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20
mmol). The mixture was purged with nitrogen, and subjected to
microwaves at 150.degree. C. for 20 minutes. The reaction mixture
was concentrated and purified by silica gel chromatography (0-20%
7N ammonia in methanol:dichloromethane) and acidified with HCl in
methanol to afford the desired product as its hydrochloride salt
(0.573 g, 98% yield).
5-Chloro-N.sup.2-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N.sup-
.4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
[0464] To a solution of
2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (as
prepared in Example 17: 0.040 g, 0.12 mmol) in 1 mL of
2-methoxyethanol was added
4-(dimethylphosphoryl)-2-(trifluoromethoxy)aniline (0.035 g, 0.12
mmol) as its hydrochloride salt. The mixture was heated in a sealed
tube at 90.degree. C. for 16 h. The mixture was basified with 1N
NaOH solution, and extracted with ethyl acetate. The organic layers
were combined, washed with saturated sodium chloride solution,
dried with sodium sulfate, filtered and concentrated. The crude
residue was purified by prep-HPLC to afford the final compound (5.8
mg, 9% yield). MS/ES+: m/z=563.
Example 26
5-Chloro-N.sup.2-[2-chloro-4-(dimethylphosphoryl)phenyl]-N.sup.4-[2-(propa-
n-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
##STR00240##
[0465] 2-Chloro-4-(dimethylphosphoryl)aniline
[0466] To a solution of 2-chloro-4-iodoaniline (0.507 g, 2.00 mmol)
in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol),
palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120
mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture
was purged with nitrogen, and subjected to microwaves at
150.degree. C. for 20 minutes. The reaction mixture was
concentrated and purified by silica gel chromatography (0-20% 7N
ammonia in methanol:dichloromethane) to afford the desired product
(0.340 g, 83% yield).
5-Chloro-N.sup.2-[2-chloro-4-(dimethylphosphoryl)phenyl]-N.sup.4-[2-(propa-
n-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
[0467] To a solution of
2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine
(0.040 g, 0.12 mmol) in 1 mL of 2-methoxyethanol was added
2-chloro-4-(dimethylphosphoryl)aniline (as prepared in Example 17:
0.025 g, 0.12 mmol) and 49 .mu.L of 2.5 M HCl in ethanol. The
mixture was heated in a sealed tube at 90.degree. C. for 16 h. The
mixture was basified with 1N NaOH solution, and extracted with
ethyl acetate. The organic layers were combined, washed with
saturated sodium chloride solution, dried with sodium sulfate,
filtered and concentrated. The crude residue was purified by
prep-HPLC to afford the final compound (5.9 mg, 10% yield). MS/ES+:
m/z=513.
Example 27
5-Chloro-N.sup.2-[4-(dimethylphosphoryl)-2-fluorophenyl]-N.sup.4-[2-(propa-
n-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
##STR00241##
[0468] 4-(Dimethylphosphoryl)-2-fluoroaniline
[0469] To a solution of 4-bromo-2-fluoroaniline (0.380 g, 2.00
mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20
mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg,
0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The
mixture was purged with nitrogen, and subjected to microwaves at
150.degree. C. for 20 minutes. The reaction mixture was
concentrated and purified by silica gel chromatography (0-20% 7N
ammonia in methanol:dichloromethane) to afford the desired product
(73.5 mg, 20% yield).
5-Chloro-N.sup.2-[4-(dimethylphosphoryl)-2-fluorophenyl]-N.sup.4-[2-(propa-
n-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
[0470] To a solution of
2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (as
prepared in Example 17: 0.040 g, 0.12 mmol) in 1 mL of
2-methoxyethanol was added 4-(dimethylphosphoryl)-2-fluoroaniline
(0.023 g, 0.12 mmol) and 49 .mu.L of 2.5 M HCl in ethanol. The
mixture was heated in a sealed tube at 90.degree. C. for 16 h. The
mixture was basified with 1N NaOH solution, and extracted with
ethyl acetate. The organic layers were combined, washed with
saturated sodium chloride solution, dried with sodium sulfate,
filtered and concentrated. The crude residue was purified by
prep-HPLC to afford the final compound (9.0 mg, 22% yield). MS/ES+:
m/z=497.
Example 28
N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-ylsu-
lfonyl)phenyl]pyrimidine-2,4,5-triamine
##STR00242##
[0472] A suspension of
N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-nitro-N.sup.4-[2-(prop-
an-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine (461 mg, 0.89 mmol)
in Ethanol was added 184 mg of 10% Pd on carbon. The reaction
mixture was stirred at room temperature overnight and filtered
through celite. The filtrate was concentrated under reduced
pressure to yield the crude product. The crude product was purified
by silica gel chromatography with 10% Methanol in DCM to yield
N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-yls-
ulfonyl)phenyl]pyrimidine-2,4,5-triamine as a solid. MS ES+:
m/z=490.
Example 29
2-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}-9-[2-(propan-2-ylsulfony-
l)phenyl]-7,9-dihydro-8H-purin-8-one
##STR00243##
[0474] To a solution of
N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-yls-
ulfonyl)phenyl]pyrimidine-2,4,5-triamine (as prepared in Example
28: 40 mg, 0.082 mmol) in THF was added N,N'-Carbonyldiimidazole
(40 mg, 0.25 mmol). The solution was stirred at room temperature
overnight. The solution was concentrated under reduced pressure and
diluted with water and extracted with Ethyl Acetate. The combined
organic layer was washed with brine and dried over Magnesium
Sulfate. The organic layer was concentrated under reduced pressure
and the residue was purified by RP Prep-HPLC to obtain the desired
product as an off white solid. MS/ES+: m/z=516
Example 30
N.sup.2-[2-methoxy-4-(4-oxido-1,4-azaphosphinan-4-yl)phenyl]-N.sup.4-[2-(p-
ropan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
##STR00244##
[0475] (3-methoxy-4-nitrophenyl) (dimethyl)phosphane oxide
[0476] To a solution of 5-chloro-2-nitroanisole (1.00 g, 5.33 mmol)
in 20 mL DMF was added diethyl phosphite (0.809 g, 5.86 mmol),
palladium acetate (0.060 g, 0.27 mmol), XantPHOS (0.185 g, 0.320
mmol), and potassium phosphate (1.24 g, 5.86 mmol). The mixture was
purged with nitrogen, and subjected to microwaves at 150.degree. C.
for 20 minutes. The reaction mixture was concentrated and purified
by silica gel chromatography (0-45% ethyl acetate:heptane) to
afford the desired product (0.504 g, 33% yield).
(3-methoxy-4-nitrophenyl)phosphonic dichloride
[0477] To a solution of
(3-methoxy-4-nitrophenyl)(dimethyl)phosphane oxide (4.54 g, 15.7
mmol) in 1.2 mL DMF was added thionyl chloride (5.7 mL, 78.5 mmol).
The reaction flask was equipped with a reflux condenser and the
mixture was heated to reflux. After 2 h at reflux, the reaction was
cooled to rt and concentrated in vacuo. The crude oil was
redissolved in CH.sub.2Cl.sub.2 and heptane was added to
precipitate the desired compound. The clear solution was decanted
and the precipitate was collected and dried to afford the desired
compound as a white solid (1.39 g, 33% yield).
Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide
[0478] To a solution of (3-methoxy-4-nitrophenyl)phosphonic
dichloride (1.39 g, 5.15 mmol) in 15 mL THF at -78.degree. C. under
nitrogen was slowly added vinylmagnesium bromide (10.3 mL, 1.0 M in
THF). After the addition was complete, the reaction stirred at
-78.degree. C. for an additional hour. The cold reaction mixture
was quenched by the addition of saturated NH.sub.4Cl (20 mL) and
the mixture was extracted with CH.sub.2Cl.sub.2. The combined
organic layers were washed with 1 M NaOH, brine, and dried over
MgSO.sub.4. The organic extracts were filtered and concentrated to
provide the desired compound (0.982 g, 75%).
1-benzyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane 4-oxide
[0479] diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.480 g,
1.90 mmol) and benzylamine (0.23 mL, 2.08 mmol) were dissolved in
50% aqueous THF (6 mL) and heated to 105.degree. C. under nitrogen.
After one hour, another portion of benzylamine was added to the
reaction mixture. The reaction mixture was refluxed for an
additional 2 h, and then cooled to rt. The reaction mixture was
partitioned between saturated aqueous NaHCO.sub.3 and
CH.sub.2Cl.sub.2. The aqueous phase was washed once with
CH.sub.2Cl.sub.2 and the organic layers were combined. The organic
extracts were washed with brine, dried over MgSO.sub.4, filtered,
and concentrated. The residue was purified by silica gel
chromatography (0-5% 7N ammonia in methanol:dichloromethane) to
afford the desired product (0.449 g, 66% yield).
4-(1-benzyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline
[0480] To a solution of
1-benzyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane 4-oxide
(0.224 g, 0.622 mmol) in 0.6 mL 4:1 ethanol:water was added iron
powder (0.348 g, 6.22 mmol) and 0.30 mL ethanolic HCl (2.5 M). The
reaction vessel was sealed and was heated to 95.degree. C. for 1 h.
The reaction mixture was cooled to rt, filtered, and concentrated.
The crude residue was purified by silica gel chromatography (0-5%
7N ammonia in methanol:dichloromethane) to afford the desired
product (86.1 mg, 42% yield).
N.sup.2-[4-(1-benzyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]-5-ch-
loro-N.sup.4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
[0481] To a solution of
2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine
(47.3 mg, 0.137 mmol) in 1.5 mL of 2-methoxyethanol was added
4-(1-benzyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline (43.0
mg, 0.13 mmol) and ethanolic HCl (0.10 mL, 2.5 M). The mixture was
heated in a sealed vial at 90.degree. C. for 16 h. The reaction was
then heated at 100.degree. C. for an additional 2 h. The mixture
was basified with 1N NaOH solution, and extracted with ethyl
acetate. The organic layers were combined, washed with saturated
sodium chloride solution, dried with sodium sulfate, filtered and
concentrated. The crude residue was purified by silica gel
chromatography (0-12% 7N ammonia in methanol:dichloromethane) to
afford the desired product (43.0 mg, 52% yield).
N.sup.2-[2-methoxy-4-(4-oxido-1,4-azaphosphinan-4-yl)phenyl]-N.sup.4-[2-(p-
ropan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
[0482] A flask was charged with
N.sup.2-[4-(1-benzyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]-5-c-
hloro-N.sup.4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
(40.0 mg, 0.0625 mmol) and 10% Pd--C (40.0 mg). The flask was
evacuated and filled with nitrogen. Anhydrous methanol (2 mL) was
added to the flask and the flask was equipped with a reflux
condenser with a nitrogen inlet. Ammonium formate (31.5 mg, 0.500
mmol) was added in one portion at room temperature. The resulting
mixture was stirred at reflux for 3 h. The reaction was filtered
through a Celite pad and the Celite was washed with 2.times.5 mL
methanol. The combined filtrate and washing was evaporated in
vacuo. The crude residue was purified by prep-HPLC to afford the
final compound (13.6 mg, 42% yield). MS/ES+: m/z=516.
Example 31
N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-ylsu-
lfonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine
##STR00245##
[0483]
2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]-
pyrimidine
[0484] To a suspension of NaH (119 mg, 60% in oil, 2.98 mmol) in
DMF (5 mL) was added 2, 4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (400
mg, 2.13 mmol) at 0.degree. C. The resulting mixture was stirred
for 30 min before 2-(trimethylsilyl)ethoxymethyl chloride (0.42 mL,
1.1 eq) was added. The mixture was then warmed up to room
temperature and stirred for 1 hr. Water was added to quench the
reaction. Extraction with CH2Cl2 followed by drying combined
organic layers, evaporation, and chromatography on silica gel (20%
EtOAc in heptane as eleunt) gave the desired product in 84% yield
(570 mg).
2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-7-{[2-(trimethylsilyl)ethoxy]me-
thyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine
[0485] To a solution of 1-amino-2-(isopropylsulphonyl)benzene (199
mg, 1 mmol) in 2 mL of DMF was added NaH (60% in oil, 44 mg, 1.1
mmol) in one portion at 0.degree. C. After the reaction mixture was
stirred for 20 min,
2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]p-
yrimidine (317 mg, 1 mmol) was added at 0.degree. C. The reaction
mixture was then warmed up to room temperature and stirred for
additional 2 h. The reaction was quenched with water. Extraction
with EtOAc followed by silica gel column chromatography (20% EtOAc
in heptane) gave the desired product (202 mg, 42% yield). MS/ES+:
m/z=481.
N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-ylsu-
lfonyl)phenyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrim-
idine-2,4-diamine
[0486] To a microwave reaction tube was charged with
2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-7-{[2-(trimethylsilyl)ethoxy]m-
ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (180 mg, 0.374 mmol),
4-(dimethylphosphonyl)-2-methoxyaniline hydrochloride (105 mg, 0.45
mmol), Pd2(dba)3 (34 mg, 0.0374 mmol), Xanthphos (26 mg, 0.045
mmol), and t-BuONa (129 mg, 1.346 mmol). This mixture was degassed
via 3-cycle of vacuum and re-fill with N2. Anhydrous 1, 4-dioxane
(2 mL from sure-seal bottle) was added and the reaction was then
run under microwave irradiation at 140.degree. C. for 20 min. Water
and EtOAc was added to facilitate extraction. Chromatography on
silica gel (10% MeOH in CH2Cl2 as eleunt) gave the desired product
in 54% yield (130 mg). MS/ES+: m/z=644.
N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-ylsu-
lfonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine
[0487] To a solution of compound
N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-yls-
ulfonyl)phenyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyri-
midine-2,4-diamine in THF (1 mL) was added tetrabutylammonium
fluoride (TBAF) in THF (1.0 M, 3 mL) and ethylenediamine (0.1 mL).
The solution was heated at 60.degree. C. for 24 hrs. About 40%
conversion was observed by HPLC monitoring. Volatile components
were removed on rotavap and the residue was subjected to prep-HPLC
purification. The desired product was determined by NMR to be
contaminated with TBAF, which was removed by water wash (4 times).
Evaporation of EtOAc gave the pure compound (14 mg). MS/ES+:
m/z=514.
Example 32
5-chloro-N.sup.2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N.sup.4-[2-
-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
##STR00246##
[0488] 6-(Dimethylphosphoryl)-2-methoxypyridin-3-ylamine
[0489] To a solution of 6-bromo-2-methoxypyridin-3-ylamine (0.203
g, 1.00 mmol) in 4 mL DMF was added dimethylphosphine oxide (0.171
g, 1.10 mmol), palladium acetate (11.0 mg, 0.0490 mmol), XANTPHOS
(35.0 mg, 0.0600 mmol), and potassium phosphate (0.233 g, 1.10
mmol). The mixture was purged with nitrogen, and subjected to
microwaves at 150.degree. C. for 20 minutes. The reaction mixture
was concentrated and purified by silica gel chromatography (0-10%
7N ammonia in methanol:dichloromethane) to afford the desired
product (77.2 mg, 39% yield).
2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine
[0490] To a solution of 1-Amino-2-(isopropylsulphonyl)benzene
(0.955 g, 4.80 mmol) in 2 mL of DMF at 0.degree. C. was added NaH
(60% in oil, 0.349 g, 8.72 mmol) in one portion. After stirring for
20 min, 2,4,5-trichloropyrimidine was added. The mixture was
stirred at 0.degree. C. for 30 minutes, and then at room
temperature for 2 h. After quenching with saturated ammonium
chloride solution, the mixture was poured in water and ethyl
acetate mixture. Yellow suspension was filtered as final product
(0.3 g, 20% yield). MS/ES+: m/z=346.
5-chloro-N.sup.2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N.sup.4-[2-
-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
[0491] To a solution of
2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine
(86.0 mg, 0.250 mmol) in 1 mL of 2-methoxyethanol was added
6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (50.0 mg, 0.250
mmol) and 0.15 mL of 2.5 M HCl in ethanol. The mixture was heated
in a sealed tube at 90.degree. C. for 16 h. The mixture was
basified with 1N NaOH solution, and extracted with ethyl acetate.
The organic layers were combined, washed with saturated sodium
chloride solution, dried with sodium sulfate, filtered and
concentrated. The crude residue was purified by silica gel
chromatography (0-10% 7N ammonia in methanol:dichloromethane) to
afford the desired product (16.7 mg, 22% yield). MS/ES+:
m/z=510.
Example 33
5-chloro-N.sup.2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N.sup.4-[2-
-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
##STR00247##
[0492] 5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine
[0493] To a solution of 5-bromo-3-methoxypyrazin-3-ylamine (0.204
g, 1.00 mmol) in 4 mL DMF was added dimethylphosphine oxide (0.171
g, 1.10 mmol), palladium acetate (11.0 mg, 0.0490 mmol), XANTPHOS
(35.0 mg, 0.0600 mmol), and potassium phosphate (0.233 g, 1.10
mmol). The mixture was purged with nitrogen, and subjected to
microwaves at 150.degree. C. for 20 minutes. The reaction mixture
was concentrated and purified by silica gel chromatography (0-10%
7N ammonia in methanol:dichloromethane) to afford the desired
product (126 mg, 63% yield).
5-chloro-N.sup.2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N.sup.4-[2-
-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
[0494] To a mixture of
2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine
(prepared in Example 32: 0.120 g, 0.348 mmol) and
5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (70.0 mg, 0.348
mmol) was added tris(dibenzylideneacetone)dipalladium(0)-chloroform
adduct (17.6 mg, 0.017 mmol), XANTPHOS (23.3 mg, 0.040 mmol), and
cesium carbonate (0.228 g, 0.700 mmol), and dioxane (3.5 mL). The
mixture was sealed and heated at 120.degree. C. After 16 h, the
reaction mixture was cooled to rt and concentrated. The crude
residue was purified by silica gel chromatography (0-10% 7N ammonia
in methanol:dichloromethane) to afford the desired product (11.4
mg, 6% yield). MS/ES+: m/z=511.
Example 34
5-chloro-N.sup.2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N.sup.4-ph-
enylpyrimidine-2,4-diamine
##STR00248##
[0496] This compound can be prepared as in Example 32 by reacting
2,5-dichloro-N-phenylpyrimidin-4-amine with
6-(Dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in
Example 32)
2,5-dichloro-N-phenylpyrimidin-4-amine
[0497] To a solution of Aniline (205 mg, 2.2 mmol) and
2,4,5-Trichloropyrimidine (500 mg, 2.7 mmol) in 5 mL of Ethanol,
was added 500 mg of Potassium carbonate. The reaction mixture was
stirred at room temperature for 2 hours. Solvent was removed under
reduced pressure. The residue was purified by silica gel flash
chromatography with 10% Ethyl Acetate in Heptane to yield the
desired product as an oil (370 mg, 70% yield).
Example 35
N.sup.2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N.sup.4-[2-(propan--
2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
##STR00249##
[0498]
4-chloro-2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-(triflu-
oromethyl) pyrimidine
[0499] A suspension of
6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in
Example 32: 2.2 mmol) in 15 mL of N, N-Dimethylacetamide and 3.6 mL
of Diisopropylethylamine, is allowed to stirred at room temperature
for 15 minutes until a clear solution is obtained.
2,4-Dichloro-5-(trifluoromethyl) pyrimidine (5.7 g, 2.6 mmol) is
added in four portions over 5 minutes. The reaction mixture is
stirred at 60 degrees for 1 hour. The reaction mixture is cooled to
room temperature and filtered to obtain a white solid. The white
solid is washed with 50 mL of water three times and followed by 50
mL of Ethyl ether three times. The white solid is dried under
vacuum to yield
4-chloro-2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-(trifluoromet-
hyl)pyrimidine.
N.sup.2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N.sup.4-[2-(propan--
2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
[0500] To a solution of
4-chloro-2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-(trifluoromet-
hyl) pyrimidine (0.072 mmol) in 1.5 mL of ethanol is added 10 .mu.L
of triethylamine and 1-Amino-2-(isopropylsulphonyl)benzene (0.072
mmol). The mixture is microwave at 120 degrees for 20 minutes. The
reaction mixture is filtered through a syringe filter and purified
by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile
phases) to generate the desired compound.
Example 36
N.sup.2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N.sup.4-[2-(propan--
2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
##STR00250##
[0501]
4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(triflu-
oromethyl)pyrimidine
[0502] A suspension of
5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (prepared in
Example 33: 2.2 mmol) in 15 mL of N, N-Dimethylacetamide and 3.6 mL
of Diisopropylethylamine, is allowed to stirred at room temperature
for 15 minutes until a clear solution is obtained.
2,4-Dichloro-5-(trifluoromethyl) pyrimidine (5.7 g, 2.6 mmol) is
added in four portions over 5 minutes. The reaction mixture is
stirred at 60 degrees for 1 hour. The reaction mixture is cooled to
room temperature and filtered to obtain a white solid. The white
solid is washed with 50 mL of water three times and followed by 50
mL of Ethyl ether three times. The white solid is dried under
vacuum to yield
4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromet-
hyl)pyrimidine.
N.sup.2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N.sup.4-[2-(propan--
2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
[0503] To a solution of
4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromet-
hyl)pyrimidine (0.072 mmol) in 1.5 mL of ethanol is added 10 .mu.L
of triethylamine and 1-Amino-2-(isopropylsulphonyl)benzene (0.072
mmol). The mixture is microwave at 120 degrees for 20 minutes. The
reaction mixture is filtered through a syringe filter and purified
by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile
phases) to generate the desired compound.
Example 37
5-chloro-N.sup.2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N.sup.4-[4-
-(dimethylphosphoryl)phenyl]pyrimidine-2,4-diamine
##STR00251##
[0505] This compound can be prepared as in Example 32 by reacting
2,5-dichloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine with
2,6-Dimethoxypyridin-3-amine.
2,5-dichloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine
[0506] To a solution of 2,4,5-trichloropyrimidine (0.15 ml, 1.31
mmol) in 1 mL of DMF was added 4-(dimethylphosphoryl)aniline (0.221
g, 1.31 mmol) and potassium carbonate (0.217 g, 1.57 mmol). The
mixture was heated at 110.degree. C. for 4 h. It was basified with
saturated sodium bicarbonate solution. The suspension was filtered
and washed with ethyl acetate to give the final product (0.15 g,
36% yield). MS/ES+: m/z=316.
Example 38
5-chloro-N.sup.2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N.sup.4-{2-
-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-
-diamine
##STR00252##
[0508] This compound can be prepared as in Example 32 by reacting
2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline with
2,4,5-trichloropyrimidine to generate
2,5-dichloro-N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phe-
nyl}pyrimidin-4-amine.
2,5-dichloro-N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phe-
nyl}pyrimidin-4-amine is then reacted with
5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (prepared in
Example 33) according to the procedure described in Example 32.
1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine
[0509] To a solution of 5-fluoro-2-nitroanisole (0.5 g, 2.92 mmol)
in 3 mL of DMF was added 1-methyl-4-(piperidin)piperazine (0.536 g,
2.92 mmol) and potassium carbonate (0.808, 5.84 mmol). The mixture
was heated at 120.degree. C. for 18 h. The mixture was basified
with saturated sodium bicarbonate solution and extracted with ethyl
acetate. The organic layer was purified by chromatography to give
final product as yellow solid (0.95 g, 95% yield). MS/ES+:
m/z=334.
2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline
[0510] The a solution of
1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine
(0.3 g, 0.90 mmol) in 10 mL of ethanol purged with argon was added
10% Palladium on carbon (0.060 g). The hydrogenation was finished
under 30 psi after 4 h. The mixture was passed through Celite to a
flask containing HCl in ethanol. Concentration of the filtrate gave
the final product (0.15 g, 88% yield). MS/ES+: m/z=334.
Example 39
5-chloro-N-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-4-(4-methylpiper-
azin-1-yl)pyrimidin-2-amine
##STR00253##
[0512] This compound can be prepared by reacting
2,4,5-trichloropyrimidine with 1-Methyl piperazine as described in
Example 32 to generate
2,5-dichloro-4-(4-methylpiperazin-1-yl)pyrimidine.
2,5-dichloro-4-(4-methylpiperazin-1-yl)pyrimidine is then reacted
with 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in
Example 32) as described in Example 32.
Example 40
N.sup.2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N.sup.4-(morpholin--
4-ylmethyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine
##STR00254##
[0514] This compound can be prepared by reacting
1-(morpholin-4-yl)methaneamine with
4-chloro-2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-(trifluoromet-
hyl) pyrimidine as described in Example 35.
Example 41
4-(2-{[2-{[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]amino}-5-(trifluor-
omethyl) pyrimidin-4-yl]amino}ethyl)benzenesulfonamide
##STR00255##
[0516] This compound can be prepared by reacting
4-(2-aminoethyl)benzene-sulfonamide with
4-chloro-2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-(trifluoromet-
hyl) pyrimidine as described in Example 35.
Example 42
2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-4-(4-phenylpiperazin-1-yl-
)-5-(trifluoromethyl)pyrimidine
##STR00256##
[0518] This compound can be prepared by reacting 1-Phenylpiperazine
with
4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromet-
hyl)pyrimidine as described in Example 36.
Example 43
2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N-[2-(1H-indol-3-yl)ethyl-
]-5-(trifluoromethyl)pyrimidin-4-amine
##STR00257##
[0520] This compound can be prepared by reacting tryptamine with
4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromet-
hyl)pyrimidine as described in Example 36.
Example 44
N.sup.2-[4-(dimethylphosphoryl)phenyl]-N.sup.4-[4-(4-methylpiperazin-1-yl)-
benzyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
##STR00258##
[0522] This compound can be prepared by reacting
4-(4-methylpiperazine)-benzylamine with
4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromet-
hyl)pyrimidine as described in Example 36.
Example 45
N.sup.2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N.sup.4-[2-(propan--
2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
##STR00259##
[0524] This compound can be prepared as in Example 32 by reacting
2-Chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine with
6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in
Example 32).
2-Chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine
[0525] To a suspension of NaH (60% dispersion in mineral oil, 40
mg, 1.0 mmol) in 2.0 mL of DMF at room temperature was added
1-amino-2-(isopropylsulphonyl)benzene (0.20 g, 1.0 mmol) as a solid
in 3 portions. After 30 minutes of stirring at room temperature,
2,4-dichloropyrimidine (0.15 g, 1.0 mmol) was added as a solution
in 1.0 mL DMF. The reaction mixture stirred for 3 h at room
temperature. The reaction was quenched with saturated sodium
bicarbonate solution and the solution extracted ethyl acetate. The
organic layers were combined, washed with saturated sodium chloride
solution, dried with sodium sulfate, filtered and concentrated. The
crude residue was purified by silica gel chromatography (0-30%
ethyl acetate:heptane) to afford the desired compound as an
off-white solid (53 mg, 17% yield). MS/ES+: m/z=312.
Example 46
N.sup.2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-methyl-N.sup.4-[2-
-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
##STR00260##
[0527] This compound can be prepared as in Example 32 by reacting
2-Chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine
with 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in
Example 32).
2-Chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine
[0528] To a suspension of NaH (60% dispersion in mineral oil, 40.0
mg, 1.00 mmol) in 2 mL of DMF at room temperature was added
1-amino-2-(isopropylsulphonyl)benzene (0.20 g, 1.0 mmol) as a solid
in 3 portions. After 30 minutes of stirring at room temperature,
2,4-dichloro-5-methylpyrimidine (0.17 g, 1.0 mmol) was added as a
solution in 1 mL DMF. The reaction mixture stirred for 3 h at room
temperature. The reaction was quenched with saturated sodium
bicarbonate solution and the solution extracted ethyl acetate. The
organic layers were combined, washed with saturated sodium chloride
solution, dried with sodium sulfate, filtered and concentrated. The
crude residue was purified by silica gel chromatography (0-30%
ethyl acetate:heptane) to afford the desired compound as an
off-white solid (78 mg, 24% yield). MS/ES+: m/z=326.
Example 47
5-chloro-N.sup.4-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phe-
nyl]-N.sup.2-(thiophen-2-ylmethyl)pyrimidine-2,4-diamine
##STR00261##
[0530] The compound can be prepared as in Example 32 by reacting
2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline with
2,4,5-trichloropyrimidine generating
2,5-dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phen-
yl]pyrimidin-4-amine.
2,5-dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phen-
yl]pyrimidin-4-amine is then reacted with
1-(thiophen-2-yl)methanamine as described in Example 32.
2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline
##STR00262##
[0531] 1-benzyl-4-methyl-1,4-azaphosphinane 4-oxide
[0532] To a solution of methylphosphonic dichloride (10.0 g, 75.2
mmol) in CH.sub.2Cl.sub.2 at -78.degree. C., was added
vinylmagnesium bromide (175 mL, 1.0 M in THF) via addition funnel
over 4 h. The solution was warmed to 0.degree. C. and quenched with
a minimum amount of saturated NH.sub.4Cl. The mixture was filtered
through a pad of silica gel and silica was extracted with 10% 7N
ammonia in methanol:dichloromethane. The solution was concentrated
under reduced pressure to afford methyl divinyl phosphine oxide as
a viscous, yellow oil that was used without purification.
[0533] A solution of methyl divinyl phosphine oxide (1.16 g, 10.0
mmol) and benzylamine (1.20 mL, 11.0 mmol) in 1:1 THF/water (25 mL)
was heated at reflux for 16 h. The reaction mixture was
concentrated in vacuo and the residue was purified by silica gel
chromatography (0-10% 7N ammonia in methanol:dichloromethane) to
afford 1-benzyl-4-methyl-[1,4]azaphosphinane-4-oxide as a white
solid (1.57 g, 70% yield).
4-methyl-[1,4]azaphosphinane-4-oxide
[0534] A flask was charged with
1-benzyl-4-methyl-[1,4]azaphosphinane-4-oxide (1.00 g, 4.47 mmol)
and 10% Pd/C (100 mg). The flask was evacuated and filled with
nitrogen. Anhydrous methanol (18 mL) was added to the flask and the
flask was equipped with a reflux condenser with a nitrogen inlet.
Ammonium formate (2.25 g, 35.8 mmol) was added in one portion at
room temperature. The resulting mixture was stirred at reflux for 2
h. The reaction was filtered through a Celite pad and the Celite
was washed with 2.times.5 mL methanol. The combined filtrate and
washing was evaporated in vacuo. The crude residue was purified by
silica gel chromatography (0-10% 7N ammonia in
methanol:dichloromethane) to afford
4-methyl-[1,4]azaphosphinane-4-oxide as a yellow gel (0.589 g, 99%
yield).
1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide
[0535] A mixture of 4-methyl-[1,4]azaphosphinane-4-oxide (133 mg,
1.00 mmol), 5-fluoro-2-nitroanisole (340 mg, 2.00 mmol),
K.sub.2CO.sub.3 (345 mg, 2.50 mmol), and DMF (5 mL) was heated to
50.degree. C. After 2 h, the reaction mixture was concentrated and
purified by silica gel chromatography (0-5% 7N ammonia in
methanol:dichloromethane) to afford
1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide as
a bright yellow solid (272 mg, 96% yield).
2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline
[0536] To a pressure vessel was added
1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide
(272 mg, 0.960 mmol), ethanol (5 mL), and 10% Pd/C (50 mg). The
vessel was connected to a Parr apparatus, evacuated, and refilled
with nitrogen. The vessel was then evacuated and filled with
hydrogen gas to a pressure of 50 psi. The reaction mixture was
shaken under 50 psi for 4 h. The mixture was filtered through
Celite to a flask containing HCl in ethanol. Concentration of the
filtrate afforded
2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline as a
gray solid (211 mg, 87% yield).
Example 48
5-chloro-N.sup.4-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phe-
nyl]-N.sup.2-[5-(propan-2-yl)-1,3-oxazol-2-yl]pyrimidine-2,4-diamine
##STR00263##
[0538] The compound can be prepared as in Example 32 by reacting
2,5-dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phen-
yl]pyrimidin-4-amine (as described in Example 47) with
5-(propan-2-yl)-1,3-oxazol-2-amine.
Example 49
5-chloro-N.sup.2-[1-(4-fluorobenzyl)-1H-pyrrol-3-yl]-N.sup.4-[2-methoxy-4--
(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidine-2,4-diamine
##STR00264##
[0540] The compound can be prepared as in Example 32 by reacting
2,5-dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phen-
yl]pyrimidin-4-amine (as described in Example 47) with
1-(4-fluorobenzyl)-1H-pyrrol-3-amine.
Example 50
2-{[(5-chloro-4-{[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phe-
nyl]amino}pyrimidin-2-yl)amino]methyl}-N,N-diethylthiophene-3-sulfonamide
##STR00265##
[0542] The compound can be prepared as in Example 32 by reacting
2,5-dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phen-
yl]pyrimidin-4-amine (as described in Example 47) with
2-(aminomethyl)-N,N-diethylthiophene-3-sulfonamide.
Example 51
N.sup.2-[5-(1,4'-bipiperidin-1'-yl)-1,3,4-thiadiazol-2-yl]-5-chloro-N.sup.-
4-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidine-2,4-diamine
##STR00266##
[0544] This compound can be prepared as in Example 32 by reacting
5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (prepared In
example 33) with 2,4,5-trichloropyrimidine to generate
2,5-dichloro-N-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidin-4--
amine.
2,5-dichloro-N-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimi-
din-4-amine is then reacted with
5-(1,4'-bipiperidin-1'-yl)-1,3,4-thiadiazol-2-amine according to
the procedure described in Example 321.
Example 52
5-chloro-N.sup.4-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N.sup.2-{[-
5-(4-methylpiperazin-1-yl)-1,3,4-oxadiazol-2-yl]methyl}pyrimidine-2,4-diam-
ine
##STR00267##
[0546] This compound can be prepared as in Example 32 by reacting
2,5-dichloro-N-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidin-4--
amine (as described in Example 51) with
1-[5-(4-methylpiperazin-1-yl)-1,3,4-oxadiazol-2-yl]methanamine.
Example 53
5-chloro-N.sup.4-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N.-
sup.2-{5-[4-(pyridin-2-yl)piperazin-1-yl]-1,3,4-oxadiazol-2-yl}pyrimidine--
2,4-diamine
##STR00268##
[0548] This compound can be prepared as in Example 32 by reacting
4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline with
2,4,5-trichloropyrimidine to generate
2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyri-
midin-4-amine.
2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyri-
midin-4-amine is then reacted with
5-[4-(pyridin-2-yl)piperazin-1-yl]-1,3,4-oxadiazol-2-amine
according to the procedure described in Example 32.
4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline
##STR00269##
[0549] 4-bromo-1-nitro-2-(propan-2-ylsulfanyl) benzene
[0550] At 0 degree, to a stirring solution of
4-Bromo-2-Floronitroaniline (2.0 g, 9.1 mmol) in DCM was added
Sodium Isopropoxide (2.0 g, 20 mmol) in two portions. The reaction
mixture was warmed to room temperature and stirred overnight. The
reaction mixture was filtered through a syringe filter. The product
was isolated by prep-HPLC (water/Acetonitrile) as a bright yellow
solid (0.8 g, 2.9 mmol, 32% yield).
4-bromo-1-nitro-2-(propan-2-ylsulfonyl)benzene
[0551] To a stirring solution of
4-bromo-1-nitro-2-(propan-2-ylsulfanyl)benzene (0.8 g, 2.9 mmol) in
Acetic Acid (10 ml) was added Hydrogen Peroxide (30% aqueous
solution, 0.6 mL, 5.8 mmol). The reaction mixture was heated to 110
degrees C. for 2 hours in oil bath. The reaction mixture was
treated with saturated Sodium Sulfide aqueous solution and basified
with saturated sodium bicarbonate solution. The mixture was
extracted with Ethyl Acetate and the combined organic layers were
dried over sodium sulfate. The organic solvent was removed under
reduced pressure and the residue was used for the next step
reaction without further purification.
Dimethyl[4-nitro-3-(propan-2-ylsulfonyl)phenyl]phosphane oxide
[0552] To a stirring solution of
4-bromo-1-nitro-2-(propan-2-ylsulfonyl)benzene (0.44 g, 1.6 mmol)
and Dimethyl Phosphine oxide (0.15 g, 1.9 mmol) in 1 mL of DMF, was
added Potassium Phosphate (0.37 g, 1.8 mmol), Pd(OAc).sub.2 (18 mg,
0.08 mmol), Xanphos (55 mg, 0.10 mmol). The reaction mixture was
stirred at 110 degrees C. overnight. The reaction mixture was
cooled to room temperature and filtered through celite. The desired
product was isolated through prep-HPLC to yield a brownish yellow
solid (0.24 g, 55% yield)
4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline
[0553] To a solution of
dimethyl[4-nitro-3-(propan-2-ylsulfonyl)phenyl]phosphane oxide
(0.24 g, 0.88 mmol) in Ethanol was added Pd on carbon (10% w/w, 24
mg) and stirred under hydrogen overnight. The reaction mixture was
filtered and the organic solvent was removed under reduced
pressure. The residue was purified by prep-HPLC to yield 100 mg of
desired product (50% yield).
Example 54
5-chloro-N.sup.4-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N.-
sup.2-{[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methyl}pyrimidine-2,4-diamine
##STR00270##
[0555] This compound can be prepared as in Example 32 by reacting
2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyri-
midin-4-amine (as described in Example 53) with
1-[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methanamine.
Example 55
N.sup.2-benzyl-5-chloro-N.sup.4-[4-(dimethylphosphoryl)-2-(propan-2-ylsulf-
onyl)phenyl]pyrimidine-2,4-diamine
##STR00271##
[0557] This compound can be prepared as in Example 32 by reacting
2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyri-
midin-4-amine (as described in Example 53) with benzylamine.
Example 56
5-chloro-N.sup.2-(5-cyclopropyl-1,3-oxazol-2-yl)-N.sup.4-{2-methoxy-4-[4-(-
4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}pyrimidine-2-
,4-diamine
##STR00272##
[0559] This compound can be prepared as in Example 32 by reacting
2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]an-
iline with 2,4,5-trichloropyrimidine to generate
2,5-dichloro-N-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)p-
iperidin-1-yl]phenyl}pyrimidin-4-amine.
2,5-dichloro-N-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)p-
iperidin-1-yl]phenyl}pyrimidin-4-amine is then reacted with
5-cyclopropyl-1,3-oxazol-2-amine according to the procedure
described in Example 32.
2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]ani-
line
##STR00273##
[0560] tert-butyl
4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidine-1-carboxylate
[0561] A solution of methyl divinyl phosphine oxide (140 mg, 1.21
mmol) and 1-Boc-4-aminopiperidine (265 mg, 1.33 mmol) in 1:1
THF/water (3 mL) was heated at reflux for 16 h. The reaction
mixture was concentrated in vacuo and the residue was purified by
silica gel chromatography (0-10% 7N ammonia in
methanol:dichloromethane) to afford the desired compound as a white
solid (178 mg, 38% yield).
1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methyl-1,4-azaphosphinane
4-oxide
[0562] To a stirring solution of tert-butyl
4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidine-1-carboxylate
(178 mg, 0.563 mmol) in CH.sub.2Cl.sub.2 (2 mL) was added
trifluoroacetic acid (0.5 mL). After 20 min, the solution was
concentrated and the resulting residue was redissolved in DMF (2
mL). Potassium carbonate (160 mg, 1.16 mmol) was added portionwise
to the stirring solution followed by 5-fluoro-2-nitroanisole (158
mg, 0.930 mmol). The reaction mixture was heated to 50.degree. C.
After 2 h, the reaction mixture was concentrated and the residue
was purified by silica gel chromatography (0-10% 7N ammonia in
methanol:dichloromethane) to afford the compound as a bright yellow
solid (176 mg, 86% yield).
2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]ani-
line
[0563] To a pressure vessel was added
1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methyl-1,4-azaphosphinane
4-oxide (176 mg, 0.485 mmol), ethanol (5 mL), and 10% Pd/C (50 mg).
The vessel was connected to a Parr apparatus, evacuated, and
refilled with nitrogen. The vessel was then evacuated and filled
with hydrogen gas to a pressure of 50 psi. The reaction mixture was
shaken under 50 psi for 4 h. The mixture was filtered through
Celite to a flask containing HCl in ethanol. Concentration of the
filtrate afforded the compound as a gray solid (178 mg, 98%
yield).
Example 57
5-chloro-N.sup.2-(5-cyclopropyl-1,3-oxazol-2-yl)-N.sup.4-[4-(1-ethyl-4-oxi-
do-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]pyrimidine-2,4-diamine
##STR00274##
[0565] This compound can be prepared as in Example 32 by reacting
4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline with
2,4,5-trichloropyrimidine to generate
2,5-dichloro-N-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxypheny-
l]pyrimidin-4-amine.
2,5-dichloro-N-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxypheny-
l]pyrimidin-4-amine is then reacted with
5-cyclopropyl-1,3-oxazol-2-amine according to the procedure
described in Example 32.
4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline
##STR00275##
[0566] Diethyl (3-methoxy-4-nitrophenyl)phosphonate
[0567] To a solution of 5-chloro-2-nitroanisole (1.00 g, 5.33 mmol)
in 20 mL DMF was added diethyl phosphite (0.809 g, 5.86 mmol),
palladium acetate (0.060 g, 0.27 mmol), XantPHOS (0.185 g, 0.320
mmol), and potassium phosphate (1.24 g, 5.86 mmol). The mixture was
purged with nitrogen, and subjected to microwaves at 150.degree. C.
for 20 minutes. The reaction mixture was concentrated and purified
by silica gel chromatography (0-45% ethyl acetate:heptane) to
afford the desired product (0.504 g, 33% yield).
(3-methoxy-4-nitrophenyl)phosphonic dichloride
[0568] To a solution of diethyl
(3-methoxy-4-nitrophenyl)phosphonate (4.54 g, 15.7 mmol) in 1.2 mL
DMF was added thionyl chloride (5.7 mL, 78.5 mmol). The reaction
flask was equipped with a reflux condenser and the mixture was
heated to reflux. After 2 h at reflux, the reaction was cooled to
rt and concentrated in vacuo. The crude oil was redissolved in
CH.sub.2Cl.sub.2 and heptane was added to precipitate the desired
compound. The clear solution was decanted and the precipitate was
collected and dried to afford the desired compound as a white solid
(1.39 g, 33% yield).
Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide
[0569] To a solution of (3-methoxy-4-nitrophenyl)phosphonic
dichloride (1.39 g, 5.15 mmol) in 15 mL THF at -78.degree. C. under
nitrogen was slowly added vinylmagnesium bromide (10.3 mL, 1.0 M in
THF). After the addition was complete, the reaction stirred at
-78.degree. C. for an additional hour. The cold reaction mixture
was quenched by the addition of saturated NH.sub.4Cl (20 mL) and
the mixture was extracted with CH.sub.2Cl.sub.2. The combined
organic layers were washed with 1 M NaOH, brine, and dried over
MgSO.sub.4. The organic extracts were filtered and concentrated to
provide Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.982 g,
75%).
1-ethyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane 4-oxide
[0570] Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.480 g,
1.94 mmol), ethylamine hydrochoride (0.174 g, 2.12 mmol), and 1 N
NaOH (2 mL) were dissolved in 50% aqueous THF (5 mL) and heated to
105.degree. C. under nitrogen. After one hour, another portion of
benzylamine was added to the reaction mixture. The reaction mixture
was refluxed for an additional 2 h, and then cooled to rt. The
reaction mixture was partitioned between saturated aqueous
NaHCO.sub.3 and CH.sub.2Cl.sub.2. The aqueous phase was washed once
with CH.sub.2Cl.sub.2 and the organic layers were combined. The
organic extracts were washed with brine, dried over MgSO.sub.4,
filtered, and concentrated. The residue was purified by silica gel
chromatography (0-10% 7N ammonia in methanol:dichloromethane) to
afford the compound (0.267 g, 46% yield).
4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline
[0571] To a solution of
1-ethyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane 4-oxide
(0.267 g, 0.895 mmol) in 5 mL ethanol was added 10% Pd/C (27 mg)
and 2.5 M HCl in ethanol (1.43 mL). The flask was equipped with a
septum, evacuated, and refilled with hydrogen. The flask was
equipped with a hydrogen balloon and the reaction stirred for 3 h.
The flask was then evacuated and refilled with nitrogen. The
reaction mixture was filtered through Celite and concentrated to
provide the crude compound as the hydrochloride salt, which was
used without purification.
Example 58
5-chloro-N.sup.2-(2-cyclopropyl-1,3-oxazol-5-yl)-N.sup.4-[4-(diethylphosph-
oryl)-2-methoxyphenyl]pyrimidine-2,4-diamine
##STR00276##
[0573] This compound can be prepared as in Example 32 by reacting
4-(diethylphosphoryl)-2-methoxyaniline with
2,4,5-trichloropyrimidine to
2,5-dichloro-N-[4-(diethylphosphoryl)-2-methoxyphenyl]pyrimidin-4-amine.
2,5-dichloro-N-[4-(diethylphosphoryl)-2-methoxyphenyl]pyrimidin-4-amine
is then reacted with 5-cyclopropyl-1,3-oxazol-2-amine according to
the procedure described in Example 32.
4-(Dipropylphosphoryl)-2-methoxyaniline
##STR00277##
[0575] To a solution of 4-bromo-2-methoxyaniline (0.100 g, 0.495
mmol) in 2 mL DMF was added dipropylphosphine oxide (0.0730 g,
0.544 mmol), palladium acetate (5.6 mg, 0.025 mmol), XANTPHOS (17.2
mg, 0.030 mmol), and potassium phosphate (0.116 g, 0.544 mmol). The
mixture was purged with nitrogen, and subjected to microwaves at
150.degree. C. for 20 minutes. The reaction mixture was
concentrated and purified by silica gel chromatography (0-12% 7N
ammonia in methanol:dichloromethane) and the fractions were
concentrated. The residue was acidified with 2.5 M HCl in ethanol
and the solution was concentrated to provide
4-(dipropylphosphoryl)-2-methoxyaniline as the hydrochloride salt
(0.132 g, 91% yield).
Example 59
N-[4-(dimethylphosphoryl)phenyl]-6-(4-methylpiperazin-1-yl)pyrimidin-4-ami-
ne
##STR00278##
[0576]
6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine
[0577] A suspension of 4-amino-dimethylphenylphosphine oxide (2.2
mmol) in 15 mL of N, N-Dimethylformamide and 3.6 mL of
Diisopropylethylamine, is stirred at room temperature until a clear
solution is obtained. 4,6-Dichloropyrimidine (2.6 mmol) is added in
four portions over 5 minutes. The reaction mixture is stirred at
high temperature until formation of the desired compound.
N-[4-(dimethylphosphoryl)phenyl]-6-(4-methylpiperazin-1-yl)pyrimidin-4-ami-
ne
[0578] To a solution of
6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (0.072
mmol) in 1.5 mL of ethanol is added 10 .mu.L of triethylamine and
1-Methyl piperazine (0.072 mmol). The mixture can be microwaved at
120 degrees. The reaction mixture can then be filtered through a
syringe filter and can be purified by prep-HPLC.
Example 60
N-[4-(dimethylphosphoryl)phenyl]-N'-(tricyclo[3.3.1.1.sup.3,7]dec-1-yl)pyr-
imidine-4,6-diamine
##STR00279##
[0580] To a solution of
6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine
(prepared as in Example 59: 0.078 mmol) in 1.5 mL of ethanol is
added 10 .mu.L of triethylamine and 1-Adamantanamine (12 mg, 0.078
mmol). The mixture can be microwaved at 120 degrees until formation
of the desired compound. The reaction mixture can then be filtered
through a syringe filter and purified by prep-HPLC.
Example 61
N-[4-(dimethylphosphoryl)phenyl]-N'-(morpholin-4-ylmethyl)pyrimidine-4,6-d-
iamine
##STR00280##
[0582] To a solution of
6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine
(prepared as in Example 59: 0.12 mmol) in 2 mL of ethanol is added
50 .mu.L of triethylamine and 4-(2-aminoethyl) morpholine (15 mg,
0.12 mmol). The mixture can be microwaved at 120 degrees until
formation of the desired compound. The reaction mixture can be
filtered through a syringe filter and purified by prep-HPLC.
Example 62
4-{2-[(6-{[4-(dimethylphosphoryl)phenyl]amino}pyrimidin-4-yl)amino]ethyl}b-
enzene sulfonamide
##STR00281##
[0584] To a solution of
6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine
(prepared as in Example 59: 0.12 mmol) in 2 mL of ethanol is added
50 .mu.L of triethylamine and 4-(2-aminoethyl)benzene-sulfonamide
(23 mg, 0.12 mmol). The mixture can be microwaved at 120 degrees
until formation of the desired compound. The reaction mixture can
be filtered through a syringe filter and purified by prep-HPLC.
Example 63
N-[4-(dimethylphosphoryl)phenyl]-N'-(tetrahydrofuran-2-yl)pyrimidine-4,6-d-
iamine
##STR00282##
[0586] To a solution of
6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine
(prepared as in Example 59: 0.12 mmol) in 2 mL of ethanol is added
50 .mu.L of triethylamine and (s)-3-aminotetrahydrofuran
hydrochloride salt (14 mg, 0.12 mmol). The mixture is microwaved at
120 degrees until formation of the desired compound. The reaction
mixture can then be filtered through a syringe filter and purified
by prep-HPLC.
Example 64
N-[4-(dimethylphosphoryl)phenyl]-N'-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl-
)pyrimidine-4,6-diamine
##STR00283##
[0588] To a solution of
6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine
(prepared as in Example 59: 0.12 mmol) in 2 mL of ethanol is added
50 .mu.L of triethylamine and 3-Amino-3-azabicyclo-[3,3,0] octane
hydrochloride salt (19 mg, 0.12 mmol). The mixture is microwaved at
120 degrees until formation of the desired compound. The reaction
mixture can then be filtered through a syringe filter and purified
by prep-HPLC.
Example 65
N-[4-(dimethylphosphoryl)phenyl]-N'-(morpholin-4-yl)pyrimidine-4,6-diamine
##STR00284##
[0590] To a solution of
6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine
(prepared as in Example 59: 0.12 mmol) in 2 mL of ethanol is added
50 .mu.L of triethylamine and 4-Aminomorpholine (12 mg, 0.12 mmol).
The mixture is microwaved at 120 degrees until formation of the
desired compound. The reaction mixture can then be filtered through
a syringe filter and purified by prep-HPLC.
Example 66
N-[4-(dimethylphosphoryl)phenyl]-6-(4-phenylpiperazin-1-yl)pyrimidin-4-ami-
ne
##STR00285##
[0592] To a solution of
6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine
(prepared as in Example 59: 0.12 mmol) in 2 mL of ethanol is added
50 .mu.L of triethylamine and 1-Phenylpiperazine (19 mg, 0.12
mmol). The mixture is microwaved at 120 degrees until formation of
the desired compound. The reaction mixture can then be filtered
through a syringe filter and purified by prep-HPLC.
Example 67
N-[4-(dimethylphosphoryl)phenyl]-N'-[2-(1H-indol-3-yl)ethyl]pyrimidine-4,6-
-diamine
##STR00286##
[0594] The compound is prepared as in Example 59 by reacting
6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine with
Tryptamine.
Example 68
N-[4-(dimethylphosphoryl)phenyl]-N'-(4-methylpiperazin-1-yl)pyrimidine-4,6-
-diamine
##STR00287##
[0596] The compound is prepared as in Example 59 by reacting
6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine with
1-Amino-4-methyl-piperazine.
Example 69
N-[4-(dimethylphosphoryl)phenyl]-N'-(tricyclo[3.3.1.1.sup.3,7]dec-1-ylmeth-
yl)pyrimidine-4,6-diamine
##STR00288##
[0598] The compound is prepared as in Example 59 by reacting
6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine with
1-adamantanemethylamine.
Example 70
N-[4-(dimethylphosphoryl)phenyl]-N'-[4-(4-methylpiperazin-1-yl)benzyl]pyri-
midine-4,6-diamine
##STR00289##
[0600] The compound is prepared as in Example 59 by reacting
6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine with
4-(4-methylpiperazine)-benzylamine.
Example 71
N-(3,5-dimethylphenyl)-N'-[4-(dimethylphosphoryl)phenyl]pyrimidine-4,6-dia-
mine
##STR00290##
[0602] The compound is prepared as in Example 59 by reacting
6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine with
3,5-dimethylaniline.
Example 72
N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-2-methyl-N'-phenylpyrimidine-4,-
6-diamine
##STR00291##
[0603] 6-chloro-2-methyl-N-phenylpyrimidin-4-amine
[0604] To a solution of Aniline (205 mg, 2.2 mmol) and
4,6-dichloro-2-methylpyrimidine (2.7 mmol) in 5 mL of Ethanol, is
added 500 mg of Potassium carbonate. The reaction mixture is
stirred at room temperature until formation of the desired
compound. Solvent is removed under reduced pressure. The residue
can be purified by silica gel flash chromatography.
(3-methoxy-4-nitrophenyl)(dimethyl)phosphane oxide
[0605] To a solution of 5-Chloro-2-nitroanisole (0.5 g, 2.67 mmol)
in 5 mL of DMF was added dimethylphosphine oxide (0.229 g, 2.93
mmol), palladium acetate (30 mg, 0.13 mmol), XANPHOS (0.092 g, 0.16
mmol) and potassium phosphate (0.623 g, 2.93 mmol). The mixture was
purged with argon, and heated at 120.degree. C. for 18 h. The
reaction mixture was basified with saturated sodium bicarbonate
solution, and extracted with ethyl acetate. The organic layer was
concentrated and purified by prep-HPLC to give the final product
(0.16 g, 30% yield). MS/ES+: m/z=229.
4-(dimethylphosphoryl)-2-methoxyaniline
[0606] To a solution of
(3-methoxy-4-nitrophenyl)(dimethyl)phosphane oxide (0.1 g, 0.44
mmol) in 5 mL of EtOH was added 10% weight of palladium on carbon
(0.2 g). The mixture was purged with argon, and hydrogenated under
30 psi for 2 h. The mixture was passed through Celite to a flask
containing HCl in ethanol. Concentration of the filtrate gave the
final product (0.088 g, 86% yield). MS/ES+: m/z=199.
N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-2-methyl-N'-phenylpyrimidine-4,-
6-diamine
[0607] To a solution of 6-chloro-2-methyl-N-phenylpyrimidin-4-amine
(0.35 mmol) and 4-(dimethylphosphoryl)-2-methoxyaniline (60 mg,
0.30 mmol) in 1 mL of DMF, is added 0.36 mL of 2.5M HCl in Ethanol.
The reaction mixture can be heated in a sealed tube at 140 degrees
until formation of the desired compound. The reaction mixture is
filtered through a syringe filter and can be purified by
Prep-HPLC.
Example 73
N.sup.3-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.5-[2-(propan-2-ylsu-
lfonyl)phenyl]pyridazine-3,5-diamine
##STR00292##
[0608]
6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine
[0609] To a solution of 1-Amino-2-(isopropylsulphonyl)benzene (350
mg, 1.6 mmol) in 4 mL of N,N-Dimethyl formamide at 0 degree, is
added Sodium hydride (100 mg) and the reaction mixture is allowed
to stirred at 0 degree for 20 minutes. 3,5-dichloropyridazine (1.6
mmol) is added and the reaction mixture is warmed to room
temperature. The reaction mixture is stirred at room temperature
until formation of the desired compound. The reaction mixture is
quenched with water and extracted with Ethyl acetate. The combined
Ethyl acetate layers are dried over Sodium Sulfate and solvent is
removed under reduced pressure. The residue can be purified by
Prep-HPLC.
N.sup.3-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.5-[2-(propan-2-ylsu-
lfonyl)phenyl]pyridazine-3,5-diamine
[0610] To a solution of
6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine (0.02
mmol) and 4-(dimethylphosphoryl)-2-methoxyaniline (prepared as in
Example 72:15 mg, 0.7 mmol) in 1 mL of 2-Methoxy ethanol, is added
1 mL of 2.5M HCl in Ethanol. The reaction mixture is heated in a
sealed tube at 140 degree until formation of the desired compound.
The reaction mixture is filtered through a syringe filter and can
be purified by Prep-HPLC.
Example 74
N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-[3-fluoro-5-(trifluoromethyl)-
phenoxy]pyridazin-3-amine
##STR00293##
[0611]
3-chloro-5-[3-fluoro-5-(trifluoromethyl)phenoxy]pyridazine
[0612] To a solution of 3-fluoro-5-(trifluoromethyl)phenol (1.6
mmol) in 4 mL of N,N-Dimethyl formamide at 0 degree, is added
Sodium hydride (100 mg) and the reaction mixture is allowed to
stirred at 0 degree for 20 minutes. 3,5-dichloropyridazine (1.6
mmol) is added and the reaction mixture is warmed to room
temperature. The reaction mixture is stirred at room temperature
until formation of the desired compound. The reaction mixture is
quenched with water and extracted with Ethyl acetate. The combined
Ethyl acetate layers are dried over Sodium Sulfate and solvent is
removed under reduced pressure. The residue can be purified by
Prep-HPLC.
N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-[3-fluoro-5-(trifluoromethyl)
phenoxy]pyridazin-3-amine
[0613] To a solution of
3-chloro-5-[3-fluoro-5-(trifluoromethyl)phenoxy]pyridazine (0.02
mmol) and 4-(dimethylphosphoryl)-2-methoxyaniline (prepared as in
Example 72:15 mg, 0.7 mmol) in 1 mL of 2-Methoxy ethanol, is added
1 mL of 2.5M HCl in Ethanol. The reaction mixture is heated in a
sealed tube at 140 degree until formation of the desired compound.
The reaction mixture is filtered through a syringe filter and can
be purified by Prep-HPLC.
Example 75
N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-2-methyl--
N'-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-4,6-diamine
##STR00294##
[0614]
6-chloro-N-[4-(dimethylphosphoryl)phenyl]-2-methylpyrimidin-4-amine
[0615] To a solution of 4,6-dichloro-2-methylpyrimidine (1.31 mmol)
in 1 mL of DMF is added 4-(dimethylphosphoryl) aniline (0.221 g,
1.31 mmol) and potassium carbonate (0.217 g, 1.57 mmol). The
mixture is heated at 110.degree. C. until formation of the desired
compound. The reaction mixture is basified with saturated sodium
bicarbonate solution. The suspension is filtered and washed with
ethyl acetate.
1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine
[0616] To a solution of 5-fluoro-2-nitroanisole (0.5 g, 2.92 mmol)
in 3 mL of DMF was added 1-methyl-4-(piperidin)piperazine (0.536 g,
2.92 mmol) and potassium carbonate (0.808, 5.84 mmol). The mixture
was heated at 120.degree. C. for 18 h. The mixture was basified
with saturated sodium bicarbonate solution and extracted with ethyl
acetate. The organic layer was purified by chromatography to give
final product as yellow solid (0.95 g, 95% yield). MS/ES+:
m/z=334.
2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline
[0617] The a solution of
1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine
(0.3 g, 0.90 mmol) in 10 mL of ethanol purged with argon was added
10% Palladium on carbon (0.060 g). The hydrogenation was finished
under 30 psi after 4 h. The mixture was passed through Celite to a
flask containing HCl in ethanol. Concentration of the filtrate gave
the final product (0.15 g, 88% yield). MS/ES+: m/z=334.
N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-2-methyl--
N'-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-4,6-diamine
[0618] To the compound
6-chloro-2-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine
(0.16 mmol) in 1 mL of 2-methoxyethanol is added
2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (0.71
g, 0.16 mmol). The mixture is stirred at 110.degree. C. until
formation of the desired compound. The mixture is basified with
saturated sodium bicarbonate solution and extracted with limited
amount of ethyl acetate. The compound can be purified by
chromatography.
Example 76
N-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N'-[2-(propan-2-ylsulfony-
l)phenyl]pyrimidine-4,6-diamine
##STR00295##
[0619] 6-(Dimethylphosphoryl)-2-methoxypyridin-3-ylamine
[0620] To a solution of 6-bromo-2-methoxypyridin-3-ylamine (0.203
g, 1.00 mmol) in 4 mL DMF was added dimethylphosphine oxide (0.171
g, 1.10 mmol), palladium acetate (11.0 mg, 0.0490 mmol), XANTPHOS
(35.0 mg, 0.0600 mmol), and potassium phosphate (0.233 g, 1.10
mmol). The mixture was purged with nitrogen, and subjected to
microwaves at 150.degree. C. for 20 minutes. The reaction mixture
was concentrated and purified by silica gel chromatography (0-10%
7N ammonia in methanol:dichloromethane) to afford the desired
product (77.2 mg, 39% yield).
6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine
[0621] To a solution of 1-Amino-2-(isopropylsulphonyl)benzene
(0.955 g, 4.80 mmol) in 2 mL of DMF at 0.degree. C. is added NaH
(60% in oil, 0.349 g, 8.72 mmol) in one portion. After stirring for
20 min, 4,6-dichloropyrimidine can be added. The mixture is stirred
at 0.degree. C. for 30 minutes, and then at room temperature until
formation of the desired compound. After quenching with saturated
ammonium chloride solution, the mixture is poured in water and
ethyl acetate mixture. The compound can be purified by HPLC.
N-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N'-[2-(propan-2-ylsulfony-
l)phenyl]pyrimidine-4,6-diamine
[0622] To a solution of
6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (0.250
mmol) in 1 mL of 2-methoxyethanol is added
6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (50.0 mg, 0.250
mmol) and 0.15 mL of 2.5 M HCl in ethanol. The mixture is heated in
a sealed tube at 90.degree. C. until formation of the desired
compound. The mixture is basified with 1N NaOH solution, and
extracted with ethyl acetate. The organic layers can be combined,
washed with saturated sodium chloride solution, dried with sodium
sulfate, filtered and concentrated. The crude residue can be
purified by silica gel chromatography.
Example 77
N-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N'-[2-(propan-2-ylsulfony-
l)phenyl]pyrimidine-4,6-diamine
##STR00296##
[0623] 5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine
[0624] To a solution of 5-bromo-3-methoxypyrazin-3-ylamine (0.204
g, 1.00 mmol) in 4 mL DMF was added dimethylphosphine oxide (0.171
g, 1.10 mmol), palladium acetate (11.0 mg, 0.0490 mmol), XANTPHOS
(35.0 mg, 0.0600 mmol), and potassium phosphate (0.233 g, 1.10
mmol). The mixture was purged with nitrogen, and subjected to
microwaves at 150.degree. C. for 20 minutes. The reaction mixture
was concentrated and purified by silica gel chromatography (0-10%
7N ammonia in methanol:dichloromethane) to afford the desired
product (126 mg, 63% yield).
5-chloro-N.sup.2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N.sup.4-[2-
-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
[0625] To a mixture of
6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine
(prepared in Example 76:0.348 mmol) and
5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (70.0 mg, 0.348
mmol) is added tris(dibenzylideneacetone)dipalladium(0)-chloroform
adduct (17.6 mg, 0.017 mmol), XANTPHOS (23.3 mg, 0.040 mmol), and
cesium carbonate (0.228 g, 0.700 mmol), and dioxane (3.5 mL). The
tube is sealed and heated at 120.degree. C. until formation of the
desired compound. The reaction mixture is then cooled to room
temperature and concentrated. The crude residue can be purified by
silica gel chromatography.
Example 77
N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N'-[2-(propan-2-ylsulfonyl)phen-
yl]pyrimidine-4,6-diamine
##STR00297##
[0626]
N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-
-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine
[0627] To a solution of
6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine
(prepared in Example 76:0.054 mmol) in 0.5 mL of 2-methoxyethanol
in a vial is added 4-(dimethylphosphoryl)-2-methyoxyaniline
(prepared in Example 73: 0.044 mmol) as the HCl salt. The vial is
sealed and the reaction is heated at 90.degree. C. until formation
of the desired compound. The reaction is quenched with 1N NaOH
solution and the solution extracted ethyl acetate. The organic
layers are combined, washed with saturated sodium chloride
solution, dried with sodium sulfate, filtered and concentrated. The
crude residue can be purified by silica gel chromatography.
Example 79
N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-ylsu-
lfonyl)phenyl]pyridine-2,4-diamine
##STR00298##
[0628]
2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridin-4-amine
[0629] To a solution of 2-chloro-4-iodo-5-methylpyridine (2.00
mmol) in 8 mL toluene is added
1-amino-2-(isopropylsulphonyl)benzene (2.20 mmol), palladium
acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and
cesium carbonate (2.20 mmol). The mixture is purged with nitrogen,
and can be subjected to microwaves at 100.degree. C. until
formation of
2-chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]pyridin-4-amine.
The reaction mixture can then be concentrated and purified by
silica gel chromatography.
N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-ylsu-
lfonyl)phenyl]pyridine-2,4-diamine
[0630] To a solution of
2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridin-4-amine (0.12
mmol) in 1 mL of 2-methoxyethanol is added
4-(dimethylphosphoryl)-2-methoxyaniline (prepared as in Example 72:
0.12 mmol) and 49 .mu.L of 2.5 M HCl in ethanol. The mixture is
heated in a sealed tube at 90.degree. C. until formation of the
desired compound. The mixture is then basified with 1N NaOH
solution, and extracted with ethyl acetate. The organic layers can
be combined, washed with saturated sodium chloride solution, dried
with sodium sulfate, filtered and concentrated. The crude residue
can be purified by prep-HPLC to afford the final compound.
Example 80
N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-ylsu-
lfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine
##STR00299##
[0631]
2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrid-
in-4-amine
[0632] To a solution of 2-chloro-4-iodo-5-(trifluoromethyl)pyridine
(2.00 mmol) in 8 mL toluene is added
1-amino-2-(isopropylsulphonyl)benzene (2.20 mmol), palladium
acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and
cesium carbonate (2.20 mmol). The mixture is purged with nitrogen,
and can be subjected to microwaves at 100.degree. C. until
formation of
2-chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]pyridin-4-amine.
The reaction mixture can then be concentrated and purified by
silica gel chromatography.
N.sup.2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-methyl-N.sup.4-[2-(prop-
an-2-ylsulfonyl)phenyl]pyridine-2,4-diamine
[0633] To a solution of
2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-a-
mine (0.12 mmol) in 1 mL of 2-methoxyethanol is added
4-(dimethylphosphoryl)-2-methoxyaniline (prepared as in Example 72:
0.12 mmol) and 49 .mu.L of 2.5 M HCl in ethanol. The mixture is
heated in a sealed tube at 90.degree. C. until formation of the
desired compound. The mixture is then basified with 1N NaOH
solution, and extracted with ethyl acetate. The organic layers can
be combined, washed with saturated sodium chloride solution, dried
with sodium sulfate, filtered and concentrated. The crude residue
can be purified by prep-HPLC to afford the final compound.
Example 81
N.sup.2-[5-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.4-[2-(propan-2-ylsu-
lfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine
##STR00300##
[0635] This compound can be prepared as described in Example 80 by
reacting
2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)py-
ridin-4-amine with 5-(Dimethylphosphoryl)-2-methoxyaniline.
5-(Dimethylphosphoryl)-2-methoxyaniline
[0636] To a solution of 5-bromo-2-methoxyaniline (0.404 g, 2.00
mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20
mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg,
0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The
mixture was purged with nitrogen, and subjected to microwaves at
150.degree. C. for 20 minutes. The reaction mixture was
concentrated and purified by silica gel chromatography (0-20% 7N
ammonia in methanol:dichloromethane) to afford the desired product
(0.365 g, 85% yield).
Example 82
N.sup.2-[4-(dimethylphosphoryl)-2-methylphenyl]-N.sup.4-[2-(propan-2-ylsul-
fonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine
##STR00301##
[0638] This compound can be prepared as described in Example 80 by
reacting
2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)py-
ridin-4-amine with 4-(Dimethylphosphoryl)-2-methylaniline.
4-(Dimethylphosphoryl)-2-methylaniline
[0639] To a solution of 4-bromo-2-methylaniline (0.372 g, 2.00
mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20
mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg,
0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The
mixture was purged with nitrogen, and subjected to microwaves at
150.degree. C. for 20 minutes. The reaction mixture was
concentrated and purified by silica gel chromatography (0-20% 7N
ammonia in methanol:dichloromethane) to afford the desired product
(0.313 g, 85% yield).
Example 83
N.sup.2-[4-(dimethylphosphoryl)-2-ethylphenyl]-N.sup.4-[2-(propan-2-ylsulf-
onyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine
##STR00302##
[0641] This compound can be prepared as described in Example 80 by
reacting
2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)py-
ridin-4-amine with 4-(Dimethylphosphoryl)-2-ethylaniline.
4-(Dimethylphosphoryl)-2-ethylaniline
[0642] To a solution of 4-bromo-2-ethylaniline (0.400 g, 2.00 mmol)
in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol),
palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120
mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture
was purged with nitrogen, and subjected to microwaves at
150.degree. C. for 20 minutes. The reaction mixture was
concentrated and purified by silica gel chromatography (0-20% 7N
ammonia in methanol:dichloromethane) to afford the desired product
(0.308 g, 78% yield).
Example 84
N.sup.2-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N.sup.4-[2-(pr-
opan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine
##STR00303##
[0644] This compound can be prepared as described in Example 80 by
reacting
2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)py-
ridin-4-amine with
4-(Dimethylphosphoryl)-2-(trifluoromethoxy)aniline.
4-(Dimethylphosphoryl)-2-(trifluoromethoxy)aniline
[0645] To a solution of 4-iodo-2-(trifluoromethoxy)aniline (0.606
g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171
g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS
(69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20
mmol). The mixture was purged with nitrogen, and subjected to
microwaves at 150.degree. C. for 20 minutes. The reaction mixture
was concentrated and purified by silica gel chromatography (0-20%
7N ammonia in methanol:dichloromethane) and acidified with HCl in
methanol to afford the desired product as its hydrochloride salt
(0.573 g, 98% yield).
Example 85
N.sup.2-[2-chloro-4-(dimethylphosphoryl)phenyl]-N.sup.4-[2-(propan-2-ylsul-
fonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine
##STR00304##
[0647] This compound can be prepared as described in Example 80 by
reacting
2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)py-
ridin-4-amine with 2-chloro-4-(dimethylphosphoryl)-aniline.
2-Chloro-4-(dimethylphosphoryl)aniline
[0648] To a solution of 2-chloro-4-iodoaniline (0.507 g, 2.00 mmol)
in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol),
palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120
mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture
was purged with nitrogen, and subjected to microwaves at
150.degree. C. for 20 minutes. The reaction mixture was
concentrated and purified by silica gel chromatography (0-20% 7N
ammonia in methanol:dichloromethane) to afford the desired product
(0.340 g, 83% yield).
Example 86
N.sup.2-[4-(dimethylphosphoryl)-2-fluorophenyl]-N.sup.4-[2-(propan-2-ylsul-
fonyl)phenyl]-5-(trifluoromethyl)pyridine-2,4-diamine
##STR00305##
[0650] This compound can be prepared as described in Example 80 by
reacting
2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)py-
ridin-4-amine with 4-(dimethylphosphoryl)-2-fluoroaniline.
4-(Dimethylphosphoryl)-2-fluoroaniline
[0651] To a solution of 4-bromo-2-fluoroaniline (0.380 g, 2.00
mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20
mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg,
0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The
mixture was purged with nitrogen, and subjected to microwaves at
150.degree. C. for 20 minutes. The reaction mixture was
concentrated and purified by silica gel chromatography (0-20% 7N
ammonia in methanol:dichloromethane) to afford the desired product
(73.5 mg, 20% yield).
Example 87
N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N'-{2-methoxy-4-[-
4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-4,6-diamine
##STR00306##
[0652] 4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline
##STR00307##
[0653] 4-bromo-1-nitro-2-(propan-2-ylsulfanyl)benzene
[0654] At 0 degree, to a stirring solution of
4-Bromo-2-Floronitrobenzene (2.0 g, 9.1 mmol) in DCM was added
Sodium 2-propane thiolate (2.0 g, 20 mmol) in two portions. The
reaction mixture was warmed to room temperature and stirred
overnight. The reaction mixture was filtered through a syringe
filter. The product was isolated by prep-HPLC (water/Acetonitrile)
as a bright yellow solid (0.8 g, 2.9 mmol, 32% yield).
4-bromo-1-nitro-2-(propan-2-ylsulfonyl)benzene
[0655] To a stirring solution of
4-bromo-1-nitro-2-(propan-2-ylsulfanyl)benzene (0.8 g, 2.9 mmol) in
Acetic Acid (10 ml) was added Hydrogen Peroxide (30% aqueous
solution, 0.6 mL, 5.8 mmol). The reaction mixture was heated to 110
degrees C. for 2 hours in oil bath. The reaction mixture was
treated with saturated Sodium Sulfide aqueous solution and basified
with saturated sodium bicarbonate solution. The mixture was
extracted with Ethyl Acetate and the combined organic layers were
dried over sodium sulfate. The organic solvent was removed under
reduced pressure and the residue was used for the next step
reaction without further purification.
Dimethyl[4-nitro-3-(propan-2-ylsulfonyl)phenyl]phosphane oxide
[0656] To a stirring solution of
4-bromo-1-nitro-2-(propan-2-ylsulfonyl)benzene (0.44 g, 1.6 mmol)
and Dimethyl Phosphine oxide (0.15 g, 1.9 mmol) in 1 mL of DMF, was
added Potassium Phosphate (0.37 g, 1.8 mmol), Pd(OAc).sub.2 (18 mg,
0.08 mmol), Xanphos (55 mg, 0.10 mmol). The reaction mixture was
stirred at 110 degrees C. overnight. The reaction mixture was
cooled to room temperature and filtered through celite. The desired
product was isolated through prep-HPLC to yield a brownish yellow
solid (0.24 g, 55% yield)
4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline
[0657] To a solution of
dimethyl[4-nitro-3-(propan-2-ylsulfonyl)phenyl]phosphane oxide
(0.24 g, 0.88 mmol) in Ethanol was added Pd on carbon (10% w/w, 24
mg) and stirred under hydrogen overnight. The reaction mixture was
filtered and the organic solvent was removed under reduced
pressure. The residue was purified by prep-HPLC to yield 100 mg of
desired product (50% yield).
6-chloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-
-4-amine
[0658] To a solution of 4,6-dichloropyrimidine (1.3 mmol) in 1 mL
of DMF is added
4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline: (1.31 mmol)
and potassium carbonate (0.217 g, 1.57 mmol). The mixture is heated
at 110.degree. C. until formation of the desired compound. The
reaction mixture is basified with saturated sodium bicarbonate
solution. The suspension is filtered and washed with ethyl
acetate.
N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N'-{2-methoxy-4-[-
4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-4,6-diamine
[0659] To the compound
6-chloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidi-
n-4-amine (0.16 mmol) in 1 mL of 2-methoxyethanol is added
2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline
(prepared in Example 75: 0.71 g, 0.16 mmol). The mixture is stirred
at 110.degree. C. until formation of the desired compound. The
mixture is basified with saturated sodium bicarbonate solution and
extracted with limited amount of ethyl acetate. The compound can be
purified by chromatography.
Example 88
N.sup.3-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]-N.sup-
.5-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine
##STR00308##
[0660]
4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline
##STR00309##
[0661] Diethyl (3-methoxy-4-nitrophenyl)phosphonate
[0662] To a solution of 5-chloro-2-nitroanisole (1.00 g, 5.33 mmol)
in 20 mL DMF was added diethyl phosphite (0.809 g, 5.86 mmol),
palladium acetate (0.060 g, 0.27 mmol), XANTPHOS (0.185 g, 0.320
mmol), and potassium phosphate (1.24 g, 5.86 mmol). The mixture was
purged with nitrogen, and subjected to microwaves at 150.degree. C.
for 20 minutes. The reaction mixture was concentrated and purified
by silica gel chromatography (0-45% ethyl acetate:heptane) to
afford the desired product (0.504 g, 33% yield).
(3-methoxy-4-nitrophenyl)phosphonic dichloride
[0663] To a solution of diethyl
(3-methoxy-4-nitrophenyl)phosphonate (4.54 g, 15.7 mmol) in 1.2 mL
DMF was added thionyl chloride (5.7 mL, 78.5 mmol). The reaction
flask was equipped with a reflux condenser and the mixture was
heated to reflux. After 2 h at reflux, the reaction was cooled to
rt and concentrated in vacuo. The crude oil was redissolved in
CH.sub.2Cl.sub.2 and heptane was added to precipitate the desired
compound. The clear solution was decanted and the precipitate was
collected and dried to afford the desired compound as a white solid
(1.39 g, 33% yield).
Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide
[0664] To a solution of (3-methoxy-4-nitrophenyl)phosphonic
dichloride (1.39 g, 5.15 mmol) in 15 mL THF at -78.degree. C. under
nitrogen was slowly added vinylmagnesium bromide (10.3 mL, 1.0 M in
THF). After the addition was complete, the reaction stirred at
-78.degree. C. for an additional hour. The cold reaction mixture
was quenched by the addition of saturated NH.sub.4Cl (20 mL) and
the mixture was extracted with CH.sub.2Cl.sub.2. The combined
organic layers were washed with 1 M NaOH, brine, and dried over
MgSO.sub.4. The organic extracts were filtered and concentrated to
provide Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.982 g,
75%).
1-ethyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane 4-oxide
[0665] Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.480 g,
1.94 mmol), ethylamine hydrochoride (0.174 g, 2.12 mmol), and 1 N
NaOH (2 mL) were dissolved in 50% aqueous THF (5 mL) and heated to
105.degree. C. under nitrogen. After one hour, another portion of
benzylamine was added to the reaction mixture. The reaction mixture
was refluxed for an additional 2 h, and then cooled to rt. The
reaction mixture was partitioned between saturated aqueous
NaHCO.sub.3 and CH.sub.2Cl.sub.2. The aqueous phase was washed once
with CH.sub.2Cl.sub.2 and the organic layers were combined. The
organic extracts were washed with brine, dried over MgSO.sub.4,
filtered, and concentrated. The residue was purified by silica gel
chromatography (0-10% 7N ammonia in methanol:dichloromethane) to
afford the compound (0.267 g, 46% yield).
4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline
[0666] To a solution of
1-ethyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane 4-oxide
(0.267 g, 0.895 mmol) in 5 mL ethanol was added 10% Pd/C (27 mg)
and 2.5 M HCl in ethanol (1.43 mL). The flask was equipped with a
septum, evacuated, and refilled with hydrogen. The flask was
equipped with a hydrogen balloon and the reaction stirred for 3 h.
The flask was then evacuated and refilled with nitrogen. The
reaction mixture was filtered through Celite and concentrated to
provide the crude compound as the hydrochloride salt, which was
used without purification.
N.sup.3-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]-N.sup-
.5-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine
[0667] To a solution of
6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine
(prepared in Example 73: 0.02 mmol) and
4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline (0.7
mmol) in 1 mL of 2-Methoxy ethanol, is added 1 mL of 2.5M HCl in
Ethanol. The reaction mixture is heated in a sealed tube at 140
degree until formation of the desired compound. The reaction
mixture is filtered through a syringe filter and can be purified by
Prep-HPLC.
Example 89
N.sup.3-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]-N.su-
p.5-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine
##STR00310##
[0668]
2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline
##STR00311##
[0669] 1-benzyl-4-methyl-1,4-azaphosphinane 4-oxide
[0670] To a solution of methylphosphonic dichloride (10.0 g, 75.2
mmol) in CH.sub.2Cl.sub.2 at -78.degree. C., was added
vinylmagnesium bromide (175 mL, 1.0 M in THF) via addition funnel
over 4 h. The solution was warmed to 0.degree. C. and quenched with
a minimum amount of saturated NH.sub.4Cl. The mixture was filtered
through a pad of silica gel and silica was extracted with 10% 7N
ammonia in methanol:dichloromethane. The solution was concentrated
under reduced pressure to afford methyl divinyl phosphine oxide as
a viscous, yellow oil that was used without purification.
[0671] A solution of methyl divinyl phosphine oxide (1.16 g, 10.0
mmol) and benzylamine (1.20 mL, 11.0 mmol) in 1:1 THF/water (25 mL)
was heated at reflux for 16 h. The reaction mixture was
concentrated in vacuo and the residue was purified by silica gel
chromatography (0-10% 7N ammonia in methanol: dichloromethane) to
afford 1-benzyl-4-methyl-[1,4]azaphosphinane-4-oxide as a white
solid (1.57 g, 70% yield).
4-methyl-[1,4]azaphosphinane-4-oxide
[0672] A flask was charged with
1-benzyl-4-methyl-[1,4]azaphosphinane-4-oxide (1.00 g, 4.47 mmol)
and 10% Pd/C (100 mg). The flask was evacuated and filled with
nitrogen. Anhydrous methanol (18 mL) was added to the flask and the
flask was equipped with a reflux condenser with a nitrogen inlet.
Ammonium formate (2.25 g, 35.8 mmol) was added in one portion at
room temperature. The resulting mixture was stirred at reflux for 2
h. The reaction was filtered through a Celite pad and the Celite
was washed with 2.times.5 mL methanol. The combined filtrate and
washing was evaporated in vacuo. The crude residue was purified by
silica gel chromatography (0-10% 7N ammonia in
methanol:dichloromethane) to afford
4-methyl-[1,4]azaphosphinane-4-oxide as a yellow gel (0.589 g, 99%
yield).
1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide
[0673] A mixture of 4-methyl-[1,4]azaphosphinane-4-oxide (133 mg,
1.00 mmol), 5-fluoro-2-nitroanisole (340 mg, 2.00 mmol),
K.sub.2CO.sub.3 (345 mg, 2.50 mmol), and DMF (5 mL) was heated to
50.degree. C. After 2 h, the reaction mixture was concentrated and
purified by silica gel chromatography (0-5% 7N ammonia in
methanol:dichloromethane) to afford
1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide as
a bright yellow solid (272 mg, 96% yield).
2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline
[0674] To a pressure vessel was added
1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide
(272 mg, 0.960 mmol), ethanol (5 mL), and 10% Pd/C (50 mg). The
vessel was connected to a Parr apparatus, evacuated, and refilled
with nitrogen. The vessel was then evacuated and filled with
hydrogen gas to a pressure of 50 psi. The reaction mixture was
shaken under 50 psi for 4 h. The mixture was filtered through
Celite to a flask containing HCl in ethanol. Concentration of the
filtrate afforded
2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline as a
gray solid (211 mg, 87% yield).
N.sup.3-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]-N.su-
p.5-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamine
[0675] To a solution of
6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine
(prepared in Example 73:0.02 mmol) and
2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline (0.7
mmol) in 1 mL of 2-Methoxy ethanol, is added 1 mL of 2.5M HCl in
Ethanol. The reaction mixture is heated in a sealed tube at 140
degree until formation of the desired compound. The reaction
mixture is filtered through a syringe filter and can be purified by
Prep-HPLC.
Example 90
N.sup.3-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-
-1-yl]phenyl}-N.sup.5-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamin-
e
##STR00312##
[0676]
2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-
-yl]aniline
##STR00313##
[0677] tert-butyl
4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidine-1-carboxylate
[0678] A solution of methyl divinyl phosphine oxide (140 mg, 1.21
mmol) and 1-Boc-4-aminopiperidine (265 mg, 1.33 mmol) in 1:1
THF/water (3 mL) was heated at reflux for 16 h. The reaction
mixture was concentrated in vacuo and the residue was purified by
silica gel chromatography (0-10% 7N ammonia in
methanol:dichloromethane) to afford the desired compound as a white
solid (178 mg, 38% yield).
1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methyl-1,4-azaphosphinane
4-oxide
[0679] To a stirring solution of tert-butyl
4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidine-1-carboxylate
(178 mg, 0.563 mmol) in CH.sub.2Cl.sub.2 (2 mL) was added
trifluoroacetic acid (0.5 mL). After 20 min, the solution was
concentrated and the resulting residue was redissolved in DMF (2
mL). Potassium carbonate (160 mg, 1.16 mmol) was added portionwise
to the stirring solution followed by 5-fluoro-2-nitroanisole (158
mg, 0.930 mmol). The reaction mixture was heated to 50.degree. C.
After 2 h, the reaction mixture was concentrated and the residue
was purified by silica gel chromatography (0-10% 7N ammonia in
methanol:dichloromethane) to afford the compound as a bright yellow
solid (176 mg, 86% yield).
2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]ani-
line
[0680] To a pressure vessel was added
1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methyl-1,4-azaphosphinane
4-oxide (176 mg, 0.485 mmol), ethanol (5 mL), and 10% Pd/C (50 mg).
The vessel was connected to a Parr apparatus, evacuated, and
refilled with nitrogen. The vessel was then evacuated and filled
with hydrogen gas to a pressure of 50 psi. The reaction mixture was
shaken under 50 psi for 4 h. The mixture was filtered through
Celite to a flask containing HCl in ethanol. Concentration of the
filtrate afforded the compound as a gray solid (178 mg, 98%
yield).
N.sup.3-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-
-1-yl]phenyl}-N.sup.5-[2-(propan-2-ylsulfonyl)phenyl]pyridazine-3,5-diamin-
e
[0681] To a solution of
6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine
(prepared in Example 73:0.02 mmol) and
2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]an-
iline (0.7 mmol) in 1 mL of 2-Methoxy ethanol, is added 1 mL of
2.5M HCl in Ethanol. The reaction mixture is heated in a sealed
tube at 140 degree until formation of the desired compound. The
reaction mixture is filtered through a syringe filter and can be
purified by Prep-HPLC.
Example 91
N.sup.3-[4-(diethylphosphoryl)-2-methoxyphenyl]-N.sup.5-[2-(propan-2-ylsul-
fonyl)phenyl]pyridazine-3,5-diamine
##STR00314##
[0682] 4-(Dipropylphosphoryl)-2-methoxyaniline
##STR00315##
[0684] To a solution of 4-bromo-2-methoxyaniline (0.100 g, 0.495
mmol) in 2 mL DMF was added dipropylphosphine oxide (0.0730 g,
0.544 mmol), palladium acetate (5.6 mg, 0.025 mmol), XANTPHOS (17.2
mg, 0.030 mmol), and potassium phosphate (0.116 g, 0.544 mmol). The
mixture was purged with nitrogen, and subjected to microwaves at
150.degree. C. for 20 minutes. The reaction mixture was
concentrated and purified by silica gel chromatography (0-12% 7N
ammonia in methanol:dichloromethane) and the fractions were
concentrated. The residue was acidified with 2.5 M HCl in ethanol
and the solution was concentrated to provide
4-(dipropylphosphoryl)-2-methoxyaniline as the hydrochloride salt
(0.132 g, 91% yield).
N.sup.3-[4-(diethylphosphoryl)-2-methoxyphenyl]-N.sup.5-[2-(propan-2-ylsul-
fonyl)phenyl]pyridazine-3,5-diamine
[0685] To a solution of
6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine
(prepared in Example 73:0.02 mmol) and
4-(Dipropylphosphoryl)-2-methoxyaniline (0.7 mmol) in 1 mL of
2-Methoxy ethanol, is added 1 mL of 2.5M HCl in Ethanol. The
reaction mixture is heated in a sealed tube at 140 degree until
formation of the desired compound. The reaction mixture is filtered
through a syringe filter and can be purified by Prep-HPLC.
Example 92
N-[4-(dimethylphosphoryl)phenyl]-4-(4-methylpiperazin-1-yl)-1,3,5-triazin--
2-amine
##STR00316##
[0686]
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine
[0687] A suspension of 4-amino-dimethylphenylphosphine oxide (3.7
g, 2.2 mmol) in 15 mL of N, N-Dimethylacetamide and 3.6 mL of
Diisopropylethylamine, can be stirred at room temperature for 15
minutes until a clear solution is obtained.
2,4-Dichloro-1,3,5-triazine (2.6 mmol) is added in four portions
over 5 minutes. The reaction mixture is stirred at 60 degrees for 1
hour. The reaction mixture is cooled to room temperature, filtered
and purified by prep-HPLC.
N-[4-(dimethylphosphoryl)phenyl]-4-(4-methylpiperazin-1-yl)-1,3,5-triazin--
2-amine
[0688] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine
(0.072 mmol) in 1.5 mL of ethanol is added 10 .mu.L of
triethylamine and 1-Methyl piperazine (7.2 mg, 0.072 mmol). The
mixture can be microwaved at 120 degrees until formation of the
desired compound. The reaction mixture is filtered through a
syringe filter and purified by prep-HPLC.
Example 93
N-[4-(dimethylphosphoryl)phenyl]-N'-(tricyclo[3.3.1.1.sup.3,7]dec-1-yl)-1,-
3,5-triazine-2,4-diamine
##STR00317##
[0690] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine
(prepared as in Example 92: 0.078 mmol) in 1.5 mL of ethanol is
added 10 .mu.L of triethylamine and 1-Adamantanamine (12 mg, 0.078
mmol). The mixture can be microwaved at 120 degrees until formation
of the desired compound. The reaction mixture is filtered through a
syringe filter and purified by prep-HPLC.
Example 94
N-[4-(dimethylphosphoryl)phenyl]-N'-(morpholin-4-ylmethyl)-1,3,5-triazine--
2,4-diamine
##STR00318##
[0692] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine
(prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added
50 .mu.L of triethylamine and 4-(2-aminoethyl) morpholine (15 mg,
0.12 mmol). The mixture can be microwaved at 120 degrees until
formation of the desired compound. The reaction mixture is filtered
through a syringe filter and purified by prep-HPLC.
Example 95
4-{2-[(4-{[4-(dimethylphosphoryl)phenyl]amino}-1,3,5-triazin-2-yl)amino]et-
hyl}benzene sulfonamide
##STR00319##
[0694] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine
(prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added
50 .mu.L of triethylamine and 4-(2-aminoethyl)benzene-sulfonamide
(23 mg, 0.12 mmol). The mixture can be microwaved at 120 degrees
until formation of the desired compound. The reaction mixture is
filtered through a syringe filter and purified by prep-HPLC.
Example 96
N-[4-(dimethylphosphoryl)phenyl]-N'-(tetrahydrofuran-2-yl)-1,3,5-triazine--
2,4-diamine
##STR00320##
[0696] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine
(prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added
50 .mu.L of triethylamine and (s)-3-aminotetrahydrofuran
hydrochloride salt (14 mg, 0.12 mmol). The mixture can be
microwaved at 120 degrees until formation of the desired compound.
The reaction mixture is filtered through a syringe filter and
purified by prep-HPLC.
Example 97
N-[4-(dimethylphosphoryl)phenyl]-N'-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl-
)-1,3,5-triazine-2,4-diamine
##STR00321##
[0698] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine
(prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added
50 .mu.L of triethylamine and 3-Amino-3-azabicyclo-[3,3,0] octane
hydrochloride salt (19 mg, 0.12 mmol). The mixture is microwaved at
120 degrees until formation of the desired compound. The reaction
mixture is filtered through a syringe filter and purified by
prep-HPLC.
Example 98
N-[4-(dimethylphosphoryl)phenyl]-N'-(morpholin-4-yl)-1,3,5-triazine-2,4-di-
amine
##STR00322##
[0700] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine
(prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added
50 .mu.L of triethylamine and 4-Aminomorpholine (12 mg, 0.12 mmol).
The mixture is microwave at 120 degrees until formation of the
desired compound. The reaction mixture is filtered through a
syringe filter and purified by prep-HPLC.
Example 99
N-[4-(dimethylphosphoryl)phenyl]-4-(4-phenylpiperazin-1-yl)-1,3,5-triazin--
2-amine
##STR00323##
[0702] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine
(prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added
50 .mu.L of triethylamine and 1-Phenylpiperazine (19 mg, 0.12
mmol). The mixture is microwaved at 120 degrees until formation of
the desired compound. The reaction mixture is filtered through a
syringe filter and purified by prep-HPLC.
Example 100
N-[4-(dimethylphosphoryl)phenyl]-N'-[2-(1H-indol-3-yl)ethyl]-1,3,5-triazin-
e-2,4-diamine
##STR00324##
[0704] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine
(prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added
50 .mu.L of triethylamine and Tryptamine (18 mg, 0.12 mmol). The
mixture is microwaved at 120 degrees until formation of the desired
compound. The reaction mixture is filtered through a syringe filter
and purified by prep-HPLC.
Example 101
N-[4-(dimethylphosphoryl)phenyl]-N'-(4-methylpiperazin-1-yl)-1,3,5-triazin-
e-2,4-diamine
##STR00325##
[0706] To a solution of
4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine
(prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added
50 .mu.L of triethylamine and 1-Amino-4-methyl-piperazine (13 mg,
0.12 mmol). The mixture is microwaved at 120 degrees until
formation of the desired compound. The reaction mixture is filtered
through a syringe filter and purified by prep-HPLC.
Example 102
6-chloro-N-[4-(dimethylphosphoryl)phenyl]-N'-(tricyclo[3.3.1.1.sup.3,7]dec-
-1-ylmethyl)-1,3,5-triazine-2,4-diamine
##STR00326##
[0707]
4,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine
[0708] A suspension of 4-amino-dimethylphenylphosphine oxide (3.7
g, 2.2 mmol) in 15 mL of N, N-Dimethylformamide and 3.6 mL of
Diisopropylethylamine is cooled to 0.degree. C.
2,4,6-trichloro-1,3,5-triazine (2.6 mmol) is added in four portions
over 5 minutes. The reaction mixture is warmed up to room
temperature and stirred until formation of the desired compound.
The reaction mixture is filtered and purified by prep-HPLC.
6-chloro-N-[4-(dimethylphosphoryl)phenyl]-N'-(tricyclo[3.3.1.1.sup.3,7]dec-
-1-ylmethyl)-1,3,5-triazine-2,4-diamine
[0709] To a solution of
4,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine
(0.072 mmol) in 1.5 mL of ethanol is added 10 .mu.L of
triethylamine and 1-(1-adamantyl)-methanamine (7.2 mg, 0.072 mmol).
The mixture can be microwaved at 120 degrees for 20 minutes. The
reaction mixture is filtered through a syringe filter and purified
by prep-HPLC.
Example 103
6-chloro-N-[4-(dimethylphosphoryl)phenyl]-N'-[4-(4-methylpiperazin-1-yl)be-
nzyl]-1,3,5-triazine-2,4-diamine
##STR00327##
[0711] To a solution of
4,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine
(prepared as in Example 102: 0.12 mmol) in 2 mL of ethanol is added
50 .mu.L of triethylamine and 4-(4-methylpiperazine)-benzylamine
(24 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until
formation of the desired compound. The reaction mixture is filtered
through a syringe filter and purified by prep-HPLC.
Example 104
6-chloro-N-(3,5-dimethylphenyl)-N'-[4-(dimethylphosphoryl)phenyl]-1,3,5-tr-
iazine-2,4-diamine
##STR00328##
[0713] To a solution of
4,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine
(prepared as in Example 102: 0.12 mmol) in 2 mL of ethanol is added
50 .mu.L of triethylamine and 3,5-dimethylaniline (24 mg, 0.12
mmol). The mixture is microwaved at 120 degrees until formation of
the desired compound. The reaction mixture is filtered through a
syringe filter and purified by prep-HPLC.
Example 105
6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.5-phenyl-1-
,2,4-triazine-3,5-diamine
##STR00329##
[0714] 3,6-dichloro-N-phenyl-1,2,4-triazin-5-amine
[0715] To a solution of Aniline (205 mg, 2.2 mmol) and
3,5,6-trichloro-1,2,4-triazine (2.7 mmol) in CH.sub.2Cl.sub.2, is
added triethylamine (3 mmol). The reaction mixture is stirred at
room temperature until formation of the desired product. Solvent is
removed under reduced pressure. The residue can be purified by
silica gel flash chromatography.
(3-methoxy-4-nitrophenyl)(dimethyl)phosphane oxide
[0716] To a solution of 5-Chloro-2-nitroanisole (0.5 g, 2.67 mmol)
in 5 mL of DMF was added dimethylphosphine oxide (0.229 g, 2.93
mmol), palladium acetate (30 mg, 0.13 mmol), XANTPHOS (0.092 g,
0.16 mmol) and potassium phosphate (0.623 g, 2.93 mmol). The
mixture was purged with argon, and heated at 120.degree. C. for 18
h. The reaction mixture was basified with saturated sodium
bicarbonate solution, and extracted with ethyl acetate. The organic
layer was concentrated and purified by prep-HPLC to give the final
product (0.16 g, 30% yield). MS/ES+: m/z=229.
4-(dimethylphosphoryl)-2-methoxyaniline
[0717] To a solution of
(3-methoxy-4-nitrophenyl)(dimethyl)phosphane oxide (0.1 g, 0.44
mmol) in 5 mL of EtOH was added 10% weight of palladium on carbon
(0.2 g). The mixture was purged with argon, and hydrogenated under
30 psi for 2 h. The mixture was passed through Celite to a flask
containing HCl in ethanol. Concentration of the filtrate gave the
final product (0.088 g, 86% yield). MS/ES+: m/z=199.
6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.5-phenyl-1-
,2,4-triazine-3,5-diamine
[0718] A mixture of 3,6-dichloro-N-phenyl-1,2,4-triazin-5-amine (1
mmol), 4-(dimethylphosphoryl)-2-methoxyaniline (1 mmol) and
camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 h in
2-propanol. The reaction mixture is allowed to cool to room
temperature, dissolved in dichloromethane and washed with an
aqueous solution of Na.sub.2CO.sub.3. The dichloromethane extract
is dried over MgSO.sub.4 and evaporated. The crude product is
purified by Prep-HPLC.
Example 106
6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.5-[2-(prop-
an-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
##STR00330##
[0719]
3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amin-
e
[0720] To a solution of 1-Amino-2-(isopropylsulphonyl)benzene (350
mg, 1.6 mmol) and 3,5,6-trichloro-1,2,4-triazine (1.6 mmol) in
CH.sub.2Cl.sub.2, is added triethylamine (2 mmol). The reaction
mixture is allowed to cool to room temperature, dissolved in
dichloromethane and washed with an aqueous solution of
Na.sub.2CO.sub.3. The dichloromethane extract is dried over
MgSO.sub.4 and evaporated. The crude product is purified by
Prep-HPLC.
6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.5-[2-(prop-
an-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
[0721] A mixture of
3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine
(1 mmol), 4-(dimethylphosphoryl)-2-methoxyaniline (prepared as in
Example 105: 1 mmol) and camphorsulfonic acid (0.7 equiv.), is
refluxed for 20-48 hours in 2-propanol. The reaction mixture is
allowed to cool to room temperature, dissolved in dichloromethane
and washed with an aqueous solution of Na.sub.2CO.sub.3. The
dichloromethane extract is dried over MgSO.sub.4 and evaporated.
The crude product is purified by Prep-HPLC.
Example 107
6-chloro-N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-{[3-fluoro-5-(triflu-
oromethyl)phenyl]sulfanyl}-1,2,4-triazin-3-amine
##STR00331##
[0722]
3,6-dichloro-5-{[3-fluoro-5-(trifluoromethyl)phenyl]sulfanyl}-1,2,4-
-triazine
[0723] To a solution of 3,5,6-trichloro-1,2,4-triazine (3 mmol) in
dry THF (30 mL) at -78.degree. C. under nitrogen atmosphere is
added 3-fluoro-5-(trifluoromethyl)benzenethiol (3 mmol) and sodium
carbonate (3 mmol). The reaction is allowed to reach room
temperature and is stirred at room temperature until formation of
the desired compound. The solvent is evaporated. The residue is
suspended in water and extracted with CH.sub.2Cl.sub.2. The
dichloromethane solution is dried over MgSO.sub.4 and evaporated.
The residue is chromatographed on a silica gel column.
6-chloro-N-[4-(dimethylphosphoryl)-2-methoxyphenyl]-5-{[3-fluoro-5-(triflu-
oromethyl)phenyl]sulfanyl}-1,2,4-triazin-3-amine
[0724] A mixture of
3,6-dichloro-5-{[3-fluoro-5-(trifluoromethyl)phenyl]sulfanyl}-1,2,4-triaz-
ine (0.7 mmol), 4-(dimethylphosphoryl)-2-methoxyaniline (prepared
as in Example 105: 15 mg, 0.7 mmol) and camphorsulfonic acid (0.7
equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction
mixture is allowed to cool to room temperature, dissolved in
dichloromethane and washed with an aqueous solution of
Na.sub.2CO.sub.3. The dichloromethane extract is dried over
MgSO.sub.4 and evaporated. The crude product is purified by
Prep-HPLC.
Example 108
6-chloro-N.sup.5-[4-(dimethylphosphoryl)phenyl]-N.sup.3-{2-methoxy-4-[4-(4-
-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-1,2,4-triazine-3,5-diamine
##STR00332##
[0725]
3,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,2,4-triazin-5-amine
[0726] To a solution of 4-amino-dimethylphenylphosphine oxide (1.6
mmol) and 3,5,6-trichloro-1,2,4-triazine (1.6 mmol) in
CH.sub.2Cl.sub.2, is added triethylamine (2 mmol). The reaction
mixture is allowed to cool to room temperature, dissolved in
dichloromethane and washed with an aqueous solution of
Na.sub.2CO.sub.3. The dichloromethane extract is dried over
MgSO.sub.4 and evaporated. The crude product is purified by
Prep-HPLC.
1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine
[0727] To a solution of 5-fluoro-2-nitroanisole (0.5 g, 2.92 mmol)
in 3 mL of DMF was added 1-methyl-4-(piperidin)piperazine (0.536 g,
2.92 mmol) and potassium carbonate (0.808, 5.84 mmol). The mixture
was heated at 120.degree. C. for 18 h. The mixture was basified
with saturated sodium bicarbonate solution and extracted with ethyl
acetate. The organic layer was purified by chromatography to give
final product as yellow solid (0.95 g, 95% yield). MS/ES+:
m/z=334.
2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline
[0728] The a solution of
1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine
(0.3 g, 0.90 mmol) in 10 mL of ethanol purged with argon was added
10% Palladium on carbon (0.060 g). The hydrogenation was finished
under 30 psi after 4 h. The mixture was passed through Celite to a
flask containing HCl in ethanol. Concentration of the filtrate gave
the final product (0.15 g, 88% yield). MS/ES+: m/z=334.
6-chloro-N.sup.5-[4-(dimethylphosphoryl)phenyl]-N.sup.3-{2-methoxy-4-[4-(4-
-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-1,2,4-triazine-3,5-diamine
[0729] A mixture of
3,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,2,4-triazin-5-amine
(0.7 mmol),
2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (0.7
mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48
hours in 2-propanol. The reaction mixture is allowed to cool to
room temperature, dissolved in dichloromethane and washed with an
aqueous solution of Na.sub.2CO.sub.3. The dichloromethane extract
is dried over MgSO.sub.4 and evaporated. The crude product is
purified by Prep-HPLC.
Example 109
6-chloro-N.sup.3-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N.sup.5-[2-
-(propan-2-ylsulfonyl) phenyl]-1,2,4-triazine-3,5-diamine
##STR00333##
[0730] 6-(Dimethylphosphoryl)-2-methoxypyridin-3-ylamine
[0731] To a solution of 6-bromo-2-methoxypyridin-3-ylamine (0.203
g, 1.00 mmol) in 4 mL DMF was added dimethylphosphine oxide (0.171
g, 1.10 mmol), palladium acetate (11.0 mg, 0.0490 mmol), XANTPHOS
(35.0 mg, 0.0600 mmol), and potassium phosphate (0.233 g, 1.10
mmol). The mixture was purged with nitrogen, and subjected to
microwaves at 150.degree. C. for 20 minutes. The reaction mixture
was concentrated and purified by silica gel chromatography (0-10%
7N ammonia in methanol:dichloromethane) to afford the desired
product (77.2 mg, 39% yield).
6-chloro-N.sup.3-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-N.sup.5-[2-
-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
[0732] A mixture of
3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine
(prepared as in Example 106: 0.7 mmol),
6-(Dimethylphosphoryl)-2-methoxypyridin-3-ylamine (0.7 mmol) and
camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in
2-propanol. The reaction mixture is allowed to cool to room
temperature, dissolved in dichloromethane and washed with an
aqueous solution of Na.sub.2CO.sub.3. The dichloromethane extract
is dried over MgSO.sub.4 and evaporated. The crude product is
purified by Prep-HPLC.
Example 110
6-chloro-N.sup.3-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N.sup.5-[2-
-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
##STR00334##
[0733] 5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine
[0734] To a solution of 5-bromo-3-methoxypyrazin-3-ylamine (0.204
g, 1.00 mmol) in 4 mL DMF was added dimethylphosphine oxide (0.171
g, 1.10 mmol), palladium acetate (11.0 mg, 0.0490 mmol), XANTPHOS
(35.0 mg, 0.0600 mmol), and potassium phosphate (0.233 g, 1.10
mmol). The mixture was purged with nitrogen, and subjected to
microwaves at 150.degree. C. for 20 minutes. The reaction mixture
was concentrated and purified by silica gel chromatography (0-10%
7N ammonia in methanol:dichloromethane) to afford the desired
product (126 mg, 63% yield).
6-chloro-N.sup.3-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-N.sup.5-[2-
-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
[0735] A mixture of
3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine
(prepared as in Example 106: 0.7 mmol),
5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (0.7 mmol) and
camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in
2-propanol. The reaction mixture is allowed to cool to room
temperature, dissolved in dichloromethane and washed with an
aqueous solution of Na.sub.2CO.sub.3. The dichloromethane extract
is dried over MgSO.sub.4 and evaporated. The crude product is
purified by Prep-HPLC.
Example 111
N.sup.5-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N.sup.3-{2--
methoxy-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-6-methyl-1,2,4-triazin-
e-3,5-diamine
##STR00335##
[0736] 4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline
##STR00336##
[0737] 4-bromo-1-nitro-2-(propan-2-ylsulfanyl) benzene
[0738] At 0 degree, to a stirring solution of
4-Bromo-2-Floronitrobenzene (2.0 g, 9.1 mmol) in DCM was added
Sodium propane-2-thiolate (2.0 g, 20 mmol) in two portions. The
reaction mixture was warmed to room temperature and stirred
overnight. The reaction mixture was filtered through a syringe
filter. The product was isolated by prep-HPLC (water/Acetonitrile)
as a bright yellow solid (0.8 g, 2.9 mmol, 32% yield).
4-bromo-1-nitro-2-(propan-2-ylsulfonyl)benzene
[0739] To a stirring solution of
4-bromo-1-nitro-2-(propan-2-ylsulfanyl) benzene (0.8 g, 2.9 mmol)
in Acetic Acid (10 ml) was added Hydrogen Peroxide (30% aqueous
solution, 0.6 mL, 5.8 mmol). The reaction mixture was heated to 110
degrees C. for 2 hours in oil bath. The reaction mixture was
treated with saturated Sodium Sulfide aqueous solution and basified
with saturated sodium bicarbonate solution. The mixture was
extracted with Ethyl Acetate and the combined organic layers were
dried over sodium sulfate. The organic solvent was removed under
reduced pressure and the residue was used for the next step
reaction without further purification.
Dimethyl[4-nitro-3-(propan-2-ylsulfonyl)phenyl]phosphane oxide
[0740] To a stirring solution of
4-bromo-1-nitro-2-(propan-2-ylsulfonyl)benzene (0.44 g, 1.6 mmol)
and Dimethyl Phosphine oxide (0.15 g, 1.9 mmol) in 1 mL of DMF, was
added Potassium Phosphate (0.37 g, 1.8 mmol), Pd(OAc).sub.2 (18 mg,
0.08 mmol), Xantphos (55 mg, 0.10 mmol). The reaction mixture was
stirred at 110 degrees C. overnight. The reaction mixture was
cooled to room temperature and filtered through celite. The desired
product was isolated through prep-HPLC to yield a brownish yellow
solid (0.24 g, 55% yield).
4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline
[0741] To a solution of
dimethyl[4-nitro-3-(propan-2-ylsulfonyl)phenyl]phosphane oxide
(0.24 g, 0.88 mmol) in Ethanol was added Pd on carbon (10% w/w, 24
mg) and stirred under hydrogen overnight. The reaction mixture was
filtered and the organic solvent was removed under reduced
pressure. The residue was purified by prep-HPLC to yield 100 mg of
desired product (50% yield).
5-chloro-N-{2-methoxy-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-6-methyl-
-1,2,4-triazin-3-amine
[0742] To a solution of 5-chloro-6-methyl-1,2,4-triazin-3-amine
(2.00 mmol) in 8 mL toluene is added
4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)aniline (2.20 mmol),
palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120
mmol), and cesium carbonate (2.20 mmol). The mixture is purged with
nitrogen, and can be subjected to microwaves at 100.degree. C.
until formation of the desired product. The reaction mixture can
then be concentrated and purified by silica gel chromatography.
N.sup.5-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]-N.sup.3-{2--
methoxy-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-6-methyl-1,2,4-triazin-
e-3,5-diamine
[0743] To a solution of
5-chloro-N-{2-methoxy-4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-6-methy-
l-1,2,4-triazin-3-amine (0.035 g, 0.11 mmol) in 1 mL of
2-methoxyethanol in a vial is added
2-methoxy-4-[(4-methylpiperazin-1-yl)sulfonyl]aniline (0.020 g,
0.085 mmol). The vial is sealed and the reaction is heated at
90.degree. C. until formation of the desired compound. The reaction
is then quenched with 1N NaOH solution and the solution extracted
ethyl acetate. The organic layers are combined, washed with
saturated sodium chloride solution, dried with sodium sulfate,
filtered and concentrated. The crude residue is purified by silica
gel chromatography.
Example 112
6-chloro-N.sup.3-[5-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.5-[2-(prop-
an-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
##STR00337##
[0744] 5-(Dimethylphosphoryl)-2-methoxyaniline
[0745] To a solution of 5-bromo-2-methoxyaniline (0.404 g, 2.00
mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20
mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg,
0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The
mixture was purged with nitrogen, and subjected to microwaves at
150.degree. C. for 20 minutes. The reaction mixture was
concentrated and purified by silica gel chromatography (0-20% 7N
ammonia in methanol:dichloromethane) to afford the desired product
(0.365 g, 85% yield).
6-chloro-N.sup.3-[5-(dimethylphosphoryl)-2-methoxyphenyl]-N.sup.5-[2-(prop-
an-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
[0746] A mixture of
3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine
(prepared as in Example 104: 0.7 mmol),
5-(Dimethylphosphoryl)-2-methoxyaniline (0.7 mmol) and
camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in
2-propanol. The reaction mixture is allowed to cool to room
temperature, dissolved in dichloromethane and washed with an
aqueous solution of Na.sub.2CO.sub.3. The dichloromethane extract
is dried over MgSO.sub.4 and evaporated. The crude product is
purified by Prep-HPLC.
Example 113
6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-methylphenyl]-N.sup.5-[2-(propa-
n-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
##STR00338##
[0747] 4-(Dimethylphosphoryl)-2-methylaniline
[0748] To a solution of 4-bromo-2-methylaniline (0.372 g, 2.00
mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20
mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg,
0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The
mixture was purged with nitrogen, and subjected to microwaves at
150.degree. C. for 20 minutes. The reaction mixture was
concentrated and purified by silica gel chromatography (0-20% 7N
ammonia in methanol:dichloromethane) to afford the desired product
(0.313 g, 85% yield).
6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-methylphenyl]-N.sup.5-[2-(propa-
n-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
[0749] A mixture of
3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine
(prepared as in Example 106: 0.7 mmol),
4-(Dimethylphosphoryl)-2-methylaniline (0.7 mmol) and
camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in
2-propanol. The reaction mixture is allowed to cool to room
temperature, dissolved in dichloromethane and washed with an
aqueous solution of Na.sub.2CO.sub.3. The dichloromethane extract
is dried over MgSO.sub.4 and evaporated. The crude product is
purified by Prep-HPLC.
Example 114
6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-ethylphenyl]-N.sup.5-[2-(propan-
-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
##STR00339##
[0750] 4-(Dimethylphosphoryl)-2-ethylaniline
[0751] To a solution of 4-bromo-2-ethylaniline (0.400 g, 2.00 mmol)
in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol),
palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120
mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture
was purged with nitrogen, and subjected to microwaves at
150.degree. C. for 20 minutes. The reaction mixture was
concentrated and purified by silica gel chromatography (0-20% 7N
ammonia in methanol:dichloromethane) to afford the desired product
(0.308 g, 78% yield).
6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-ethylphenyl]-N.sup.5-[2-(propan-
-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
[0752] A mixture of
3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine
(prepared as in Example 106: 0.7 mmol),
4-(Dimethylphosphoryl)-2-ethylaniline (0.7 mmol) and
camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in
2-propanol. The reaction mixture is allowed to cool to room
temperature, dissolved in dichloromethane and washed with an
aqueous solution of Na.sub.2CO.sub.3. The dichloromethane extract
is dried over MgSO.sub.4 and evaporated. The crude product is
purified by Prep-HPLC.
Example 115
6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N.sup-
.5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
##STR00340##
[0753] 4-(Dimethylphosphoryl)-2-(trifluoromethoxy)aniline
[0754] To a solution of 4-iodo-2-(trifluoromethoxy)aniline (0.606
g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171
g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS
(69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20
mmol). The mixture was purged with nitrogen, and subjected to
microwaves at 150.degree. C. for 20 minutes. The reaction mixture
was concentrated and purified by silica gel chromatography (0-20%
7N ammonia in methanol:dichloromethane) and acidified with HCl in
methanol to afford the desired product as its hydrochloride salt
(0.573 g, 98% yield).
6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-N.sup-
.5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
[0755] A mixture of
3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine
(prepared as in Example 106: 0.7 mmol),
4-(Dimethylphosphoryl)-2-(trifluoroethoxy)aniline (0.7 mmol) and
camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in
2-propanol. The reaction mixture is allowed to cool to room
temperature, dissolved in dichloromethane and washed with an
aqueous solution of Na.sub.2CO.sub.3. The dichloromethane extract
is dried over MgSO.sub.4 and evaporated. The crude product is
purified by Prep-HPLC.
Example 116
6-chloro-N.sup.3-[2-chloro-4-(dimethylphosphoryl)phenyl]-N.sup.5-[2-(propa-
n-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
##STR00341##
[0756] 2-Chloro-4-(dimethylphosphoryl)aniline
[0757] To a solution of 2-chloro-4-iodoaniline (0.507 g, 2.00 mmol)
in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol),
palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120
mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture
was purged with nitrogen, and subjected to microwaves at
150.degree. C. for 20 minutes. The reaction mixture was
concentrated and purified by silica gel chromatography (0-20% 7N
ammonia in methanol:dichloromethane) to afford the desired product
(0.340 g, 83% yield).
6-chloro-N.sup.3-[2-chloro-4-(dimethylphosphoryl)phenyl]-N.sup.5-[2-(propa-
n-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
[0758] A mixture of
3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine
(prepared as in Example 106: 0.7 mmol),
2-Chloro-4-(dimethylphosphoryl)aniline (0.7 mmol) and
camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in
2-propanol. The reaction mixture is allowed to cool to room
temperature, dissolved in dichloromethane and washed with an
aqueous solution of Na.sub.2CO.sub.3. The dichloromethane extract
is dried over MgSO.sub.4 and evaporated. The crude product is
purified by Prep-HPLC.
Example 117
6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-fluorophenyl]-V-[2-(propan-2-yl-
sulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
##STR00342##
[0759] 4-(Dimethylphosphoryl)-2-fluoroaniline
[0760] To a solution of 4-bromo-2-fluoroaniline (0.380 g, 2.00
mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20
mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg,
0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The
mixture was purged with nitrogen, and subjected to microwaves at
150.degree. C. for 20 minutes. The reaction mixture was
concentrated and purified by silica gel chromatography (0-20% 7N
ammonia in methanol:dichloromethane) to afford the desired product
(73.5 mg, 20% yield).
6-chloro-N.sup.3-[4-(dimethylphosphoryl)-2-fluorophenyl]-N.sup.5-[2-(propa-
n-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
[0761] A mixture of
3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine
(prepared as in Example 106: 0.7 mmol),
4-(Dimethylphosphoryl)-2-fluoroaniline (0.7 mmol) and
camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in
2-propanol. The reaction mixture is allowed to cool to room
temperature, dissolved in dichloromethane and washed with an
aqueous solution of Na.sub.2CO.sub.3. The dichloromethane extract
is dried over MgSO.sub.4 and evaporated. The crude product is
purified by Prep-HPLC.
Example 118
6-chloro-N.sup.3-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphen-
yl]-N.sup.5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
##STR00343##
[0762]
4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline
##STR00344##
[0763] Diethyl (3-methoxy-4-nitrophenyl)phosphonate
[0764] To a solution of 5-chloro-2-nitroanisole (1.00 g, 5.33 mmol)
in 20 mL DMF was added diethyl phosphite (0.809 g, 5.86 mmol),
palladium acetate (0.060 g, 0.27 mmol), XANTPHOS (0.185 g, 0.320
mmol), and potassium phosphate (1.24 g, 5.86 mmol). The mixture was
purged with nitrogen, and subjected to microwaves at 150.degree. C.
for 20 minutes. The reaction mixture was concentrated and purified
by silica gel chromatography (0-45% ethyl acetate:heptane) to
afford the desired product (0.504 g, 33% yield).
(3-methoxy-4-nitrophenyl)phosphonic dichloride
[0765] To a solution of diethyl
(3-methoxy-4-nitrophenyl)phosphonate (4.54 g, 15.7 mmol) in 1.2 mL
DMF was added thionyl chloride (5.7 mL, 78.5 mmol). The reaction
flask was equipped with a reflux condenser and the mixture was
heated to reflux. After 2 h at reflux, the reaction was cooled to
room temperature and concentrated in vacuo. The crude oil was
redissolved in CH.sub.2Cl.sub.2 and heptane was added to
precipitate the desired compound. The clear solution was decanted
and the precipitate was collected and dried to afford the desired
compound as a white solid (1.39 g, 33% yield).
Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide
[0766] To a solution of (3-methoxy-4-nitrophenyl)phosphonic
dichloride (1.39 g, 5.15 mmol) in 15 mL THF at -78.degree. C. under
nitrogen was slowly added vinylmagnesium bromide (10.3 mL, 1.0 M in
THF). After the addition was complete, the reaction stirred at
-78.degree. C. for an additional hour. The cold reaction mixture
was quenched by the addition of saturated NH.sub.4Cl (20 mL) and
the mixture was extracted with CH.sub.2Cl.sub.2. The combined
organic layers were washed with 1 M NaOH, brine, and dried over
MgSO.sub.4. The organic extracts were filtered and concentrated to
provide Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.982 g,
75%).
1-ethyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane 4-oxide
[0767] Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.480 g,
1.94 mmol), ethylamine hydrochoride (0.174 g, 2.12 mmol), and 1 N
NaOH (2 mL) were dissolved in 50% aqueous THF (5 mL) and heated to
105.degree. C. under nitrogen. After one hour, another portion of
benzylamine was added to the reaction mixture. The reaction mixture
was refluxed for an additional 2 h, and then cooled to room
temperature. The reaction mixture was partitioned between saturated
aqueous NaHCO.sub.3 and CH.sub.2Cl.sub.2. The aqueous phase was
washed once with CH.sub.2Cl.sub.2 and the organic layers were
combined. The organic extracts were washed with brine, dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified by
silica gel chromatography (0-10% 7N ammonia in
methanol:dichloromethane) to afford the compound (0.267 g, 46%
yield).
4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline
[0768] To a solution of
1-ethyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane 4-oxide
(0.267 g, 0.895 mmol) in 5 mL ethanol was added 10% Pd/C (27 mg)
and 2.5 M HCl in ethanol (1.43 mL). The flask was equipped with a
septum, evacuated, and refilled with hydrogen. The flask was
equipped with a hydrogen balloon and the reaction stirred for 3 h.
The flask was then evacuated and refilled with nitrogen. The
reaction mixture was filtered through Celite and concentrated to
provide the crude compound as the hydrochloride salt, which was
used without purification.
6-chloro-N.sup.3-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphen-
yl]-N.sup.5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
[0769] A mixture of
3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine
(prepared as in Example 106: 0.7 mmol),
4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline (0.7
mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48
hours in 2-propanol. The reaction mixture is allowed to cool to
room temperature, dissolved in dichloromethane and washed with an
aqueous solution of Na.sub.2CO.sub.3. The dichloromethane extract
is dried over MgSO.sub.4 and evaporated. The crude product is
purified by Prep-HPLC.
Example 119
6-chloro-N.sup.3-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phe-
nyl]-N.sup.5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
##STR00345##
[0770]
2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline
##STR00346##
[0771] 1-benzyl-4-methyl-1,4-azaphosphinane 4-oxide
[0772] To a solution of methylphosphonic dichloride (10.0 g, 75.2
mmol) in CH.sub.2Cl.sub.2 at -78.degree. C., was added
vinylmagnesium bromide (175 mL, 1.0 M in THF) via addition funnel
over 4 h. The solution was warmed to 0.degree. C. and quenched with
a minimum amount of saturated NH.sub.4Cl. The mixture was filtered
through a pad of silica gel and silica was extracted with 10% 7N
ammonia in methanol:dichloromethane. The solution was concentrated
under reduced pressure to afford methyl divinyl phosphine oxide as
a viscous, yellow oil that was used without purification.
[0773] A solution of methyl divinyl phosphine oxide (1.16 g, 10.0
mmol) and benzylamine (1.20 mL, 11.0 mmol) in 1:1 THF/water (25 mL)
was heated at reflux for 16 h. The reaction mixture was
concentrated in vacuo and the residue was purified by silica gel
chromatography (0-10% 7N ammonia in methanol:dichloromethane) to
afford 1-benzyl-4-methyl-[1,4]azaphosphinane-4-oxide as a white
solid (1.57 g, 70% yield).
4-methyl-[1,4]azaphosphinane-4-oxide
[0774] A flask was charged with
1-benzyl-4-methyl-[1,4]azaphosphinane-4-oxide (1.00 g, 4.47 mmol)
and 10% Pd/C (100 mg). The flask was evacuated and filled with
nitrogen. Anhydrous methanol (18 mL) was added to the flask and the
flask was equipped with a reflux condenser with a nitrogen inlet.
Ammonium formate (2.25 g, 35.8 mmol) was added in one portion at
room temperature. The resulting mixture was stirred at reflux for 2
h. The reaction was filtered through a Celite pad and the Celite
was washed with 2.times.5 mL methanol. The combined filtrate and
washing was evaporated in vacuo. The crude residue was purified by
silica gel chromatography (0-10% 7N ammonia in
methanol:dichloromethane) to afford
4-methyl-[1,4]azaphosphinane-4-oxide as a yellow gel (0.589 g, 99%
yield).
1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide
[0775] A mixture of 4-methyl-[1,4]azaphosphinane-4-oxide (133 mg,
1.00 mmol), 5-fluoro-2-nitroanisole (340 mg, 2.00 mmol),
K.sub.2CO.sub.3 (345 mg, 2.50 mmol), and DMF (5 mL) was heated to
50.degree. C. After 2 h, the reaction mixture was concentrated and
purified by silica gel chromatography (0-5% 7N ammonia in
methanol:dichloromethane) to afford
1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide as
a bright yellow solid (272 mg, 96% yield).
2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline
[0776] To a pressure vessel was added
1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide
(272 mg, 0.960 mmol), ethanol (5 mL), and 10% Pd/C (50 mg). The
vessel was connected to a Parr apparatus, evacuated, and refilled
with nitrogen. The vessel was then evacuated and filled with
hydrogen gas to a pressure of 50 psi. The reaction mixture was
shaken under 50 psi for 4 h. The mixture was filtered through
Celite to a flask containing HCl in ethanol. Concentration of the
filtrate afforded
2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline as a
gray solid (211 mg, 87% yield).
6-chloro-N.sup.3-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phe-
nyl]-N.sup.5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
[0777] A mixture of
3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine
(prepared as in Example 106: 0.7 mmol),
2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline (0.7
mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48
hours in 2-propanol. The reaction mixture is allowed to cool to
room temperature, dissolved in dichloromethane and washed with an
aqueous solution of Na.sub.2CO.sub.3. The dichloromethane extract
is dried over MgSO.sub.4 and evaporated. The crude product is
purified by Prep-HPLC.
Example 120
6-chloro-N.sup.3-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)-
piperidin-1-yl]phenyl}-N.sup.5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triaz-
ine-3,5-diamine
##STR00347##
[0778]
2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-
-yl]aniline
##STR00348##
[0779] tert-butyl
4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidine-1-carboxylate
[0780] A solution of methyl divinyl phosphine oxide (140 mg, 1.21
mmol) and 1-Boc-4-aminopiperidine (265 mg, 1.33 mmol) in 1:1
THF/water (3 mL) was heated at reflux for 16 h. The reaction
mixture was concentrated in vacuo and the residue was purified by
silica gel chromatography (0-10% 7N ammonia in
methanol:dichloromethane) to afford the desired compound as a white
solid (178 mg, 38% yield).
1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methyl-1,4-azaphosphinane
4-oxide
[0781] To a stirring solution of tert-butyl
4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidine-1-carboxylate
(178 mg, 0.563 mmol) in CH.sub.2Cl.sub.2 (2 mL) was added
trifluoroacetic acid (0.5 mL). After 20 min, the solution was
concentrated and the resulting residue was redissolved in DMF (2
mL). Potassium carbonate (160 mg, 1.16 mmol) was added portionwise
to the stirring solution followed by 5-fluoro-2-nitroanisole (158
mg, 0.930 mmol). The reaction mixture was heated to 50.degree. C.
After 2 h, the reaction mixture was concentrated and the residue
was purified by silica gel chromatography (0-10% 7N ammonia in
methanol:dichloromethane) to afford the compound as a bright yellow
solid (176 mg, 86% yield).
2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]ani-
line
[0782] To a pressure vessel was added
1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methyl-1,4-azaphosphinane
4-oxide (176 mg, 0.485 mmol), ethanol (5 mL), and 10% Pd/C (50 mg).
The vessel was connected to a Parr apparatus, evacuated, and
refilled with nitrogen. The vessel was then evacuated and filled
with hydrogen gas to a pressure of 50 psi. The reaction mixture was
shaken under 50 psi for 4 h. The mixture was filtered through
Celite to a flask containing HCl in ethanol. Concentration of the
filtrate afforded the compound as a gray solid (178 mg, 98%
yield).
6-chloro-N.sup.3-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)-
piperidin-1-yl]phenyl}-N.sup.5-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triaz-
ine-3,5-diamine
[0783] A mixture of
3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine
(prepared as in Example 106: 0.7 mmol),
2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]an-
iline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed
for 20-48 hours in 2-propanol. The reaction mixture is allowed to
cool to room temperature, dissolved in dichloromethane and washed
with an aqueous solution of Na.sub.2CO.sub.3. The dichloromethane
extract is dried over MgSO.sub.4 and evaporated. The crude product
is purified by Prep-HPLC.
Example 121
6-chloro-N.sup.3-[4-(diethylphosphoryl)-2-methoxyphenyl]-N.sup.5-[2-(propa-
n-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
##STR00349##
[0784] 4-(Diethylphosphoryl)-2-methoxyaniline
##STR00350##
[0786] To a solution of 4-bromo-2-methoxyaniline (0.100 g, 0.495
mmol) in 2 mL DMF was added diethylphosphine oxide (0.0730 g, 0.544
mmol), palladium acetate (5.6 mg, 0.025 mmol), XANTPHOS (17.2 mg,
0.030 mmol), and potassium phosphate (0.116 g, 0.544 mmol). The
mixture was purged with nitrogen, and subjected to microwaves at
150.degree. C. for 20 minutes. The reaction mixture was
concentrated and purified by silica gel chromatography (0-12% 7N
ammonia in methanol:dichloromethane) and the fractions were
concentrated. The residue was acidified with 2.5 M HCl in ethanol
and the solution was concentrated to provide
4-(diethylphosphoryl)-2-methoxyaniline as the hydrochloride salt
(0.132 g, 91% yield).
6-chloro-N.sup.3-[4-(diethylphosphoryl)-2-methoxyphenyl]-N.sup.5-[2-(propa-
n-2-ylsulfonyl)phenyl]-1,2,4-triazine-3,5-diamine
[0787] A mixture of
3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine
(prepared as in Example 106: 0.7 mmol),
4-(Diethylphosphoryl)-2-methoxyaniline (0.7 mmol) and
camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in
2-propanol. The reaction mixture is allowed to cool to room
temperature, dissolved in dichloromethane and washed with an
aqueous solution of Na.sub.2CO.sub.3. The dichloromethane extract
is dried over MgSO.sub.4 and evaporated. The crude product is
purified by Prep-HPLC.
Example 122
Synthesis of Compound 5
[0788] Compound 5 can be synthesized as outlined in Scheme 122
(below).
##STR00351##
Synthesis of 1
##STR00352##
[0790] To a solution of 2-iodoaniline (1.0 eq) and
dimethylphosphine oxide (1.1 eq) in DMF were added potassium
phosphate (1.1 eq), palladium acetate/Xantphos (catalytic). The
reaction was stirred at 150.degree. C. for 3 hours and cooled to
room temperature. The solvent was evaporated and the residue was
worked up with DCM/water. The crude product was purified with a
column (EtOAc/MeOH 10:1) to give 1 as a brown solid (80%
yield).
Synthesis of 2
##STR00353##
[0792] 2,4,5-Trichloropyrimidine (1.57 eq), 1 (1.0 eq), and
potassium carbonate (3.14 eq) in DMF were stirred at 60.degree. C.
for 5 hours and then cooled to r.t. The mixture was filtered and
the filtrate was concentrated. The residue was purified with ISCO
(DCM/MeOH 20:1) to give 2 as a yellow solid (61% yield).
Synthesis of 3
##STR00354##
[0794] 5-Fluoro-2-nitroanisole (1.0 eq),
1-methyl-4-(piperidin-4-yl)piperazine (1.0 eq), and potassium
carbonate (2.0 eq) in DMF were stirred at 120.degree. C. for 6
hours and then cooled to r.t. The mixture was filtered and
evaporated. The crude product was crystallized from ethanol to give
3 as a yellow solid (72% yield).
Synthesis of 4
##STR00355##
[0796] Palladium on activated carbon was added to a solution of 3
in ethanol under nitrogen. The suspension was then shaken under
hydrogen (50 psi) for 3 hours. The mixture was filtered and the
filtration was evaporated to give 4 as a purple solid in a
quantitative yield.
Synthesis of 5
##STR00356##
[0798] A solution of 2 (1.0 eq), 4 (1.4 eq), and 2.5 M HCl in
ethanol (excess) in 2-methoxyethanol was sealed and heated at
120.degree. C. with stirring for 5.5 hours and then cooled to r.t.
The reaction was repeated 5 times and combined. The mixture was
filtered and evaporated. Saturated Na.sub.2CO.sub.3 was added,
followed by DCM with stirring strongly. The layers were separated
and the aqueous layer was extracted with DCM. The organics were
dried, evaporated and chromatographed [EtOAc/MeOH (7M ammonia)
20:1] to give a yellow solid. EtOAc was added and the suspension
was refluxed for 30 minutes. After cooled to r.t., filtration gave
a solid, which was dissolved in DCM, filtered, and evaporated to
afford 5 as an off-white solid (66% yield).
Example 123: Biological Evaluation of Compounds
[0799] Compounds of the invention are evaluated in a variety of
assays to determine their biological activities. For example,
compounds of the invention can be tested for their ability to
inhibit various protein kinases of interest. Some of the compounds
tested displayed potent nanomolar activity against the following
kinases: ALK and c-Met. Furthermore, some of these compounds were
screened for antiproliferative activity in the human Karpas-299 and
in the human SU-DHL-1 lymphoma cell lines and demonstrated activity
on the range of 1-100 nM. The compounds can also be evaluated for
their cytotoxic or growth inhibitory effects on tumor cells of
interest, e.g., as described in more detail below and as shown
above for some representative compounds. See e.g., WO 03/000188,
pages 115-136, the full contents of which are incorporated herein
by reference.
[0800] Some representative compounds of the invention are depicted
below:
##STR00357## ##STR00358## ##STR00359## ##STR00360## ##STR00361##
##STR00362## ##STR00363## ##STR00364## ##STR00365## ##STR00366##
##STR00367## ##STR00368## ##STR00369## ##STR00370## ##STR00371##
##STR00372## ##STR00373## ##STR00374## ##STR00375## ##STR00376##
##STR00377## ##STR00378## ##STR00379## ##STR00380## ##STR00381##
##STR00382## ##STR00383##
[0801] The following representative compounds were synthesized and
tested for kinase inhibition against a panel of kinases and some
also tested in various cell lines. Many of the compounds were found
to be active in in vitro assays.
##STR00384## ##STR00385## ##STR00386## ##STR00387## ##STR00388##
##STR00389## ##STR00390## ##STR00391## ##STR00392## ##STR00393##
##STR00394## ##STR00395## ##STR00396## ##STR00397## ##STR00398##
##STR00399## ##STR00400## ##STR00401## ##STR00402## ##STR00403##
##STR00404## ##STR00405## ##STR00406## ##STR00407## ##STR00408##
##STR00409## ##STR00410## ##STR00411## ##STR00412## ##STR00413##
##STR00414## ##STR00415## ##STR00416## ##STR00417## ##STR00418##
##STR00419## ##STR00420## ##STR00421## ##STR00422## ##STR00423##
##STR00424## ##STR00425## ##STR00426## ##STR00427## ##STR00428##
##STR00429## ##STR00430## ##STR00431## ##STR00432## ##STR00433##
##STR00434## ##STR00435## ##STR00436## ##STR00437## ##STR00438##
##STR00439## ##STR00440## ##STR00441## ##STR00442## ##STR00443##
##STR00444## ##STR00445## ##STR00446## ##STR00447## ##STR00448##
##STR00449## ##STR00450## ##STR00451## ##STR00452## ##STR00453##
##STR00454## ##STR00455## ##STR00456## ##STR00457## ##STR00458##
##STR00459## ##STR00460## ##STR00461## ##STR00462## ##STR00463##
##STR00464## ##STR00465## ##STR00466## ##STR00467## ##STR00468##
##STR00469## ##STR00470## ##STR00471## ##STR00472## ##STR00473##
##STR00474## ##STR00475## ##STR00476## ##STR00477## ##STR00478##
##STR00479## ##STR00480## ##STR00481## ##STR00482## ##STR00483##
##STR00484## ##STR00485## ##STR00486## ##STR00487## ##STR00488##
##STR00489## ##STR00490## ##STR00491##
Kinase Inhibition
[0802] More specifically, the compounds described herein are
screened for kinase inhibition activity as follows. Kinases
suitable for use in the following protocol include, but are not
limited to: ALK, Jak2, b-Raf, c-Met, Tie-2, FLT3, Abl, Lck, Lyn,
Src, Fyn, Syk, Zap-70, Itk, Tec, Btk, EGFR, ErbB2, Kdr, FLT1, Tek,
InsR, and AKT.
[0803] Kinases are expressed as either kinase domains or full
length constructs fused to glutathione S-transferase (GST) or
polyHistidine tagged fusion proteins in either E. coli or
Baculovirus-High Five expression systems. They are purified to near
homogeneity by affinity chromatography as previously described
(Lehr et al., 1996; Gish et al., 1995). In some instances, kinases
are co-expressed or mixed with purified or partially purified
regulatory polypeptides prior to measurement of activity.
[0804] Kinase activity and inhibition can be measured by
established protocols (see e.g., Braunwalder et al., 1996). In such
cases, the transfer of .sup.33PO.sub.4 from ATP to the synthetic
substrates poly(Glu, Tyr) 4:1 or poly(Arg, Ser) 3:1 attached to the
bioactive surface of microtiter plates is taken as a measure of
enzyme activity. After an incubation period, the amount of
phosphate transferred is measured by first washing the plate with
0.5% phosphoric acid, adding liquid scintillant, and then counting
in a liquid scintillation detector. The IC.sub.50 is determined by
the concentration of compound that causes a 50% reduction in the
amount of .sup.33P incorporated onto the substrate bound to the
plate.
[0805] Other methods relying upon the transfer of phosphate to
peptide or polypeptide substrate containing tyrosine, serine,
threonine or histidine, alone, in combination with each other, or
in combination with other amino acids, in solution or immobilized
(i.e., solid phase) are also useful.
[0806] For example, transfer of phosphate to a peptide or
polypeptide can also be detected using scintillation proximity,
Fluorescence Polarization and homogeneous time-resolved
fluorescence. Alternatively, kinase activity can be measured using
antibody-based methods in which an antibody or polypeptide is used
as a reagent to detect phosphorylated target polypeptide.
[0807] For additional background information on such assay
methodologies, see e.g., Braunwalder et al., 1996, Anal. Biochem.
234(1):23; Cleaveland et al., 1990, Anal Biochem. 190(2):249 Gish
et al. (1995). Protein Eng. 8(6):609 Kolb et al. (1998). Drug
Discov. Toda V. 3:333 Lehr et al. (1996). Gene 169(2):27527-87
Seethala et al. (1998). Anal Biochem. 255(2):257 Wu et al.
(2000).
[0808] The inhibition of ALK tyrosine kinase activity can be
demonstrated using known methods. For example, in one method,
compounds can be tested for their ability to inhibit kinase
activity of baculovirus-expressed ALK using a modification of the
ELISA protocol reported for trkA in Angeles, T. S. et al., Anal.
Biochem. 1996, 236, 49-55, which is incorporated herein by
reference. Phosphorylation of the substrate, phopholipase C-gamma
(PLC-.gamma.) generated as a fusion protein with
glutathione-S-transferase (GST) as reported in rotin, D. et al.,
EMBO J. 1992, 11, 559-567, which is incorporated by reference, can
be detected with europium-labeled anti-phosphotyrosine antibody and
measured by time-resolved fluorescence (TRF). In this assay,
96-well plate is coated with 100 .mu.L/well of 10 .mu.g/mL
substrate (phospholipase C-.gamma. in tris-buffered saline (TBS).
The assay mixture (total volume=100 .mu.L/well) consisting of 20 nM
HEPES (pH 7.2, 1 .mu.MATP (K.sub.m level), 5 nM MnCl.sub.2, 0.1%
BSA, 2.5% DMSO, and various concentrations of test compound is then
added to the assay plate. The reaction is initiated by adding the
enzyme (30 ng/mL ALK) and is allowed to proceed at 37 degrees C.
for 15 minutes. Detection of the phosphorylated product can be
performed by adding 100 .mu.L/well of Eu-N1 labeled PT66 antibody
(Perkim Elmer #AD0041). Incubation at 37 degrees C. then proceeds
for one hour, followed by addition of 100 .quadrature.L enhancement
solution (for example Wallac #1244-105). The plate is gently
agitated and after thirty minutes, the fluorescence of the
resulting solution can be measured (for example using EnVision 2100
(or 2102) multilabel plate reader from Perkin Elmer).
[0809] Data analysis can then be performed. IC.sub.50 values can be
calculated by plotting percent inhibition versus log.sub.10 of
concentration of compound.
[0810] The inhibition of ALK tyrosine kinase activity can also be
measured using the recombinant kinase domain of the ALK in analogy
to VEDG-R kinase assay described in J. Wood et al., Cancer Res
2000, 60, 2178-2189. In vitro enzyme assays using GST-ALK protein
tyrosine kinase can be performed in 96-well plate as a filter
binding assay in 20 mMTris.HCl, pH 7.5, 3 mM MgCl.sub.2, 10 mM
MnCl.sub.2, 1 nM DTT, 0.1 .mu.Ci/assay (=30 .mu.L)
[.gamma.-.sup.33P]-ATP, 2 .mu.M ATP, 3 .mu.g/mL poly (Glu, tyr 4:1)
Poly-EY (sigma P-0275), 1% DMSO, 25 ng ALK enzyme. Assays can be
incubated for 10 min, at ambient temperature. Reactions can be
terminated by adding 50 .mu.L of 125 mM EDTA, and the reaction
mixture can be transferred onto a MAIP Multiscreen plate
(Millipore, Bedford, Mass.) previously wet with methanol, and
rehydrated for 5 minutes with water. Following washing (0.5%
H.sub.3PO.sub.4), plates can be counted in a liquid scintillation
counter. IC.sub.50 values are calculated by linear regression
analysis of the percentage inhibition.
Cell-Based Assays
[0811] Certain compounds of the invention have also been
demonstrated cytotoxic or growth inhibitory effects on tumor and
other cancer cell lines and thus may be useful in the treatment of
cancer and other cell proliferative diseases. Compounds are assayed
for anti-tumor activity using in vivo and in vitro assays which are
well known to those skilled in the art. Generally, initial screens
of compounds to identify candidate anti-cancer drugs are performed
in cellular assays. Compounds identified as having
anti-proliferative activity in such cell-based assays can then be
subsequently assayed in whole organisms for anti-tumor activity and
toxicity. Generally speaking, cell-based screens can be performed
more rapidly and cost-effectively relative to assays that use whole
organisms. For purposes of the invention, the terms "anti-tumor"
and "anti-cancer" activity are used interchangeably.
[0812] Cell-based methods for measuring antiproliferative activity
are well known and can be used for comparative characterization of
compounds of the invention. In general, cell proliferation and cell
viability assays are designed to provide a detectable signal when
cells are metabolically active. Compounds may be tested for
antiproliferative activity by measuring any observed decrease in
metabolic activity of the cells after exposure of the cells to
compound. Commonly used methods include, for example, measurement
of membrane integrity (as a measure of cell viability)(e.g. using
trypan blue exclusion) or measurement of DNA synthesis (e.g. by
measuring incorporation of BrdU or 3H-thymidine).
[0813] Some methods for assaying cell proliferation use a reagent
that is converted into a detectable compound during cell
proliferation. Particularly preferred compounds are tetrazolium
salts and include without limitation MTT (3-(4,
5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide;
Sigma-Aldrich, St. Louis, Mo.), MTS
(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl-
)-2H-tetrazolium), XTT
(2,3-bis(2-Methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide)-
, INT, NBT, and NTV (Bernas et al. Biochim Biophys Acta
1451(1):73-81, 1999). More commonly used assays utilizing
tetrazolium salts detect cell proliferation by detecting the
product of the enzymatic conversion of the tetrazolium salts into
blue formazan derivatives, which are readily detected by
spectroscopic methods (Mosman. J. Immunol. Methods. 65:55-63,
1983).
[0814] Other methods for assaying cell proliferation involve
incubating cells in a desired growth medium with and without the
compounds to be tested. Growth conditions for various prokaryotic
and eukaryotic cells are well-known to those of ordinary skill in
the art (Ausubel et al. Current Protocols in Molecular Biology.
Wiley and Sons. 1999; Bonifacino et al. Current Protocols in Cell
Biology. Wiley and Sons. 1999 both incorporated herein by
reference). To detect cell proliferation, the tetrazolium salts are
added to the incubated cultured cells to allow enzymatic conversion
to the detectable product by active cells. Cells are processed, and
the optical density of the cells is determined to measure the
amount of formazan derivatives. Furthermore, commercially available
kits, including reagents and protocols, are available for examples,
from Promega Corporation (Madison, Wis.), Sigma-Aldrich (St. Louis,
Mo.), and Trevigen (Gaithersburg, Md.).
[0815] In addition, a wide variety of cell types may be used to
screen compounds for antiproliferative activity, including the
following cell lines, among others: COLO 205 (colon cancer), DLD-1
(colon cancer), HCT-15 (colon cancer), HT29 (colon cancer), HEP G2
(Hepatoma), K-562 (Leukemia), A549 (Lung), NCI-H249 (Lung), MCF7
(Mammary), MDA-MB-231 (Mammary), SAOS-2 (Osteosarcoma), OVCAR-3
(Ovarian), PANC-1 (Pancreas), DU-145 (Prostate), PC-3 (Prostate),
ACHN (Renal), CAKI-1 (Renal), MG-63 (Sarcoma).
[0816] While the cell line is preferably mammalian, lower order
eukaryotic cells such as yeast may also be used to screen
compounds. Preferred mammalian cell lines are derived from humans,
rats, mice, rabbits, monkeys, hamsters, and guinea pigs since cells
lines from these organisms are well-studied and characterized.
However, others may be used as well.
[0817] Suitable mammalian cell lines are often derived from tumors.
For example, the following tumor cell-types may be sources of cells
for culturing cells: melanoma, myeloid leukemia, carcinomas of the
lung, breast, ovaries, colon, kidney, prostate, pancreas and
testes), cardiomyocytes, endothelial cells, epithelial cells,
lymphocytes (T-cell and B cell), mast cells, eosinophils, vascular
intimal cells, hepatocytes, leukocytes including mononuclear
leukocytes, stem cells such as haemopoetic, neural, skin, lung,
kidney, liver and myocyte stem cells (for use in screening for
differentiation and de-differentiation factors), osteoclasts,
chondrocytes and other connective tissue cells, keratinocytes,
melanocytes, liver cells, kidney cells, and adipocytes.
Non-limiting examples of mammalian cells lines that have been
widely used by researchers include HeLa, NIH/3T3, HT1080, CHO,
COS-1, 293T, WI-38 and CV1/EBNA-1.
[0818] Other cellular assays may be used which rely upon a reporter
gene to detect metabolically active cells. Non-limiting examples of
reporter gene expression systems include green fluorescent protein
(GFP), and luciferase. As an example of the use of GFP to screen
for potential antitumor drugs, Sandman et al. (Chem Biol. 6:541-51;
incorporated herein by reference) used HeLa cells containing an
inducible variant of GFP to detect compounds that inhibited
expression of the GFP, and thus inhibited cell proliferation.
[0819] An example of cell-based assay is shown as below. The cell
lines that can be used in the assay are Ba/F3, a murine pro-B cell
line, which has been stably transfected with an expression vector
pClneo.TM. (Promega Corp., Madison Wis.) coding for NPM-ALK and
subsequent selection of G418 resistant cells. Non-transfected Ba/F3
cells depend on IL-3 for cell survival. In contrast NPM-ALK
expressing Ba/F3 cells (named Ba/F3-NPM-ALK) can proliferate in the
absence of IL-3 because they obtain proliferative signal through
NMP-ALK kinase. Putative inhibitors of NPM-ALK kinase therefore
abolish the growth signal and result in antiproliferative activity.
The antiproliferative activity of inhibitors of the NPM-ALK kinase
can however be overcome by addition of IL-3 which provides growth
signals through an NPM-ALK independent mechanism. For an analogous
cell system using FLT3 kinase see E. Weisberg et al. Cancer cell,
2002, 1, 433-443. The inhibitory activity of the compounds of
formula I can be determined as follows: BaF3-NPM-ALK cells
(15,000/microtitre plate well) can be transferred to a 96-well
microtitre plates. The test compound (dissolved in DMSO) is then
added in a series of concentrations (dilution series) in such a
manner that the final concentration of DMSO is not greater than 1%
(v/v). After the addition, the plates can be incubated for two days
during which the control cultures without test compound are able to
undergo two cell-division cycles. The growth of BaF3-NPM-ALK cells
can be measured by means of Yopro.TM. staining (T Idziorek et al.,
J. Immunol. Methods 1995, 185, 249-258). 25 .mu.L of lysis buffer
consisting of 20 mM sodium citrate, pH 4.0, 26.8 nM sodium
chloride, 0.4% NP40, 20 mM EDTA and 20 mM is added into each well.
Cell lysis is completed within 60 minutes at room temperature and
total amount of Yopro bound to DNA is determined by measurement
using for example a CytoFluor II 96-well reader (PerSeptive
Biosystems). The IC.sub.50 can be determined by a computer aided
system using the formula:
IC.sub.50=[(ABS.sub.test-ABS.sub.start)/(ABS.sub.control-ABS.sub.start)]-
.times.100
in which ABS is absorption. The IC.sub.50 value in such an
experiment is given as that concentration of the test compound in
question that results in a cell count that is 50% lower than that
obtained using the control without inhibitor.
[0820] The antiproliferative action of compounds of the invention
can also be determined in the human KARPAS-299 lymphoma cell line
by means of an immunoblot as described in W G Dirks et al. Int. J.
Cancer 2002, 100, 49-56, using the methodology described above for
the BaF3-NPM-ALK cell line.
[0821] In another example, antiproliferative activity can be
determined using KARPAS-299 lymphoma cell line in the following
procedure: Compounds of the invention were incubated with the cells
for 3 days, and the number of viable cells in each well was
measured indirectly using an MTS tetrazolium assay (Promega). This
assay is a colorimetric method for determining the number of viable
cells through measurement of their metabolic activity. For example
the detection of the product of the enzymatic conversion of
tetrazolium salts into blue formazan derivatives is achieved by
measuring absorbance at 490 nm using a plate reader. 40 .mu.L of
the MTS reagent was added to all wells except the edge wells and
then the plates were returned to the incubator at 37.degree. C. for
2 hours. The absorbance in each well was then measured at 490 nm
using a Wallac Victor.sup.2V plate reader. The IC.sub.50 was
calculated by determining the concentration of compound required to
decrease the MTS signal by 50% in best-fit curves using Microsoft
XLfit software, by comparing with baseline, the DMSO control, as 0%
inhibition.
[0822] Compounds identified by such cellular assays as having
anti-cell proliferation activity are then tested for anti-tumor
activity in whole organisms. Preferably, the organisms are
mammalian. Well-characterized mammalians systems for studying
cancer include rodents such as rats and mice. Typically, a tumor of
interest is transplanted into a mouse having a reduced ability to
mount an immune response to the tumor to reduce the likelihood of
rejection. Such mice include for example, nude mice (athymic) and
SCID (severe combined immunodeficiency) mice. Other transgenic mice
such as oncogene containing mice may be used in the present assays
(see for example U.S. Pat. No. 4,736,866 and U.S. Pat. No.
5,175,383). For a review and discussion on the use of rodent models
for antitumor drug testing see Kerbel (Cancer Metastasis Rev.
17:301-304, 1998-99).
[0823] In general, the tumors of interest are implanted in a test
organism preferably subcutaneously. The organism containing the
tumor is treated with doses of candidate anti-tumor compounds. The
size of the tumor is periodically measured to determine the effects
of the test compound on the tumor. Some tumor types are implanted
at sites other than subcutaneous sites (e.g. intraperitoneal sites)
and survival is measured as the endpoint. Parameters to be assayed
with routine screening include different tumor models, various
tumor and drug routes, and dose amounts and schedule. For a review
of the use of mice in detecting antitumor compounds see Corbett et
al. (Invest New Drugs. 15:207-218, 1997; incorporated herein by
reference).
Results
[0824] A wide variety of compounds of this invention were found to
potently inhibit a number of important kinase targets. Many
exhibited IC50's under 100 nM, and in many cases under 10 nM and in
some cases under 1 nM when tested as inhibitors of the kinase, ALK,
for instance. Those included compounds containing the phosphine
oxide moiety as an R.sup.a or R.sup.e substituent as well as
compounds in which positions X.sup.3 and X.sup.4 were the base of a
substituted or unsubstituted fused ring which is present in a
number of embodiments. Some compounds were single digit nanomolar
inhibitors of a panel of kinases including kinases like ALK, FER,
FLT3, FES/FPS, FAK/PTK2, BRK and others. Compounds of the invention
of various structures were found to exhibit preferences for
inhibiting some kinases over others as well as variations in
pharmacokinetic profiles, confirming that this class of compounds
is of great interest as a source of potential pharmaceutical
agents.
[0825] To illustrate the foregoing, a varied group of compounds
(shown below) were tested and found to have IC50 values under nM
when tested against the kinase ALK.
##STR00492## ##STR00493## ##STR00494##
Example 21: Pharmaceutical Compositions
[0826] Representative pharmaceutical dosage forms of compounds of
the invention (the active ingredient being referred to as
"Compound"), are provided for therapeutic or prophylactic use in
humans:
TABLE-US-00001 (a) Tablet I mg/tablet Compound 100 Lactose Ph. Eur
182.75 Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste)
2.25 Magnesium stearate 3.0 (b) Tablet II mg/tablet Compound 50
Lactose Ph. Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0
Polyvinylpyffolidone (5% w/v paste) 2.25 Magnesium stearate 3.0 (c)
Tablet III mg/tablet Compound 1.0 Lactose Ph. Eur 93.25
Croscarmellose sodium 4.0 Maize starch paste (5% w/v paste) 0.75
Magnesium stearate 1.0-76 (d) Capsule mg/capsule Compound 10
Lactose Ph. Eur 488.5 Magnesium 1.5 (e) Injection I (50 mg/ml)
Compound 5.0% w/v 1M Sodium hydroxide solution 15.0% v/v 0.IM
Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400
4.5% w/v Water for injection to 100% (f) Injection II (10 mg/ml)
Compound 1.0% W/v Sodium phosphate BP 3.6% w/v O.1M Sodium
hydroxide solution 15.0% v/v Water for injection to 100% (g)
Injection III (1 mg/ml, buffered to pH 6) Compound 0.I % w/v Sodium
phosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol
400 3.5% w/v Water for injection to 100% (h) Aerosol I mg/ml
Compound 10.0 Sorbitan trioleate 13.5 Trichlorofluoromethane 910.0
Dichlorodifluoromethane 490.0 (i) Aerosol II mg/ml Compound 0.2
Sorbitan trioleate 0.27 Trichlorofluoromethane 70.0
Dichlorodifluoromethane 280.0 Dichlorotetrafluoroethane 1094.0 (j)
Aerosol III mg/ml Compound 2.5 Sorbitan trioleate 3.38
Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0
Dichlorotetrafluoroethane 191.6 (k) Aerosol IV mg/ml Compound 2.5
Soya lecithin 2.7 Trichlorofluoromethane 67.5
Dichlorodifluoromethane 1086.0 Dichlorotetrafluoroethane 191.6 (l)
Ointment /ml Compound 40 mg Ethanol 300 .mu.l Water 300 .mu.l
1-Dodecylazacycloheptan one 50 .mu.l Propylene glycol to 1 ml
[0827] These formulations may be prepared using conventional
procedures well known in the pharmaceutical art. The tablets
(a)-(c) may be enteric coated by conventional means, if desired to
provide a coating of cellulose acetate phthalate, for example. The
aerosol formulations (h)-(k) may be used in conjunction with
standard, metered dose aerosol dispensers, and the suspending
agents sorbitan trioleate and soya lecithin may be replaced by an
alternative suspending agent such as sorbitan monooleate, sorbitan
sesquioleate, polysorbate 80, polyglycerol oleate or oleic
acid.
OTHER EMBODIMENTS
[0828] All publications, patents, and patent applications mentioned
in this specification are incorporated herein by reference to the
same extent as if each independent publication or patent
application was specifically and individually indicated to be
incorporated by reference.
[0829] While the invention has been described in connection with
specific embodiments thereof, it will be understood that it is
capable of further modifications and this application is intended
to cover any variations, uses, or adaptations of the invention
following, in general, the principles of the invention and
including such departures from the present disclosure that come
within known or customary practice within the art to which the
invention pertains and may be applied to the essential features
hereinbefore set forth, and follows in the scope of the claims.
[0830] Other embodiments are within the claims.
* * * * *
References