U.S. patent application number 14/468512 was filed with the patent office on 2014-12-11 for pyrazinopyrazines and derivatives as kinase inhibitors.
The applicant listed for this patent is ARIAD Pharmaceuticals, Inc.. Invention is credited to Wei-Sheng Huang, Ranny M. Thomas.
Application Number | 20140364423 14/468512 |
Document ID | / |
Family ID | 42170207 |
Filed Date | 2014-12-11 |
United States Patent
Application |
20140364423 |
Kind Code |
A1 |
Huang; Wei-Sheng ; et
al. |
December 11, 2014 |
Pyrazinopyrazines and Derivatives as Kinase Inhibitors
Abstract
This invention relates to compounds of the general formula:
##STR00001## in which the variable groups are as defined herein,
and to their preparation and use.
Inventors: |
Huang; Wei-Sheng; (Acton,
MA) ; Thomas; Ranny M.; (Sharon, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ARIAD Pharmaceuticals, Inc. |
Cambridge |
MA |
US |
|
|
Family ID: |
42170207 |
Appl. No.: |
14/468512 |
Filed: |
August 26, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12998634 |
Aug 12, 2011 |
8846664 |
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PCT/US2009/006057 |
Nov 12, 2009 |
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14468512 |
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61198995 |
Nov 12, 2008 |
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Current U.S.
Class: |
514/221 ;
514/234.2; 514/249; 540/568; 544/117; 544/118; 544/295;
544/350 |
Current CPC
Class: |
A61K 9/2866 20130101;
A61P 43/00 20180101; A61K 47/10 20130101; A61K 9/0019 20130101;
A61P 35/04 20180101; A61K 9/4858 20130101; A61K 9/2018 20130101;
C07D 487/04 20130101; A61P 35/00 20180101; A61K 9/008 20130101;
C07D 471/04 20130101 |
Class at
Publication: |
514/221 ;
514/234.2; 514/249; 540/568; 544/117; 544/118; 544/295;
544/350 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 471/04 20060101 C07D471/04 |
Claims
1. A compound of Formula I, a tautomer, a pharmaceutically
acceptable salt and a solvate thereof: ##STR00172## wherein W.sup.1
represents an aryl, a 3- to 8-membered carbocyclyl, a 5-, 6- or
7-membered heterocyclic or heteroaryl ring comprising carbon atoms
and 1-4 heteroatoms independently selected from O, N, P(O) and
S(O).sub.r and W.sup.1 is optionally substituted with 1-5 R.sup.a
groups; W.sup.2 represents an aryl or a 5- or 6-membered heteroaryl
ring comprising carbon atoms and 1-3 heteroatoms independently
selected from O, N, P(O) and S(O).sub.r, and W.sup.2 is optionally
substituted with 1-5 R.sup.b groups; Q is N or CR.sup.c; L.sup.1
and L.sup.2 are independently selected from the group consisting of
a bond, C.sub.1-6-alkyl, O--C.sub.0-6-alkyl,
NR.sup.1--C.sub.0-6-alkyl, C(O)NR.sup.1--C.sub.0-6-alkyl,
NR.sup.1C(O)--C.sub.0-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.0-6-alkyl-S(O).sub.r,
C.sub.0-6-alkyl-S(O).sub.2NR.sup.1,
C.sub.0-6-alkyl-NR.sup.1S(O).sub.2, C(O)--C.sub.0-6-alkyl,
OC(O)NR.sup.1--C.sub.0-6-alkyl, NR.sup.1C(O)O--C.sub.0-6-alkyl,
NR.sup.1C(O)NR.sup.1--C.sub.0-6-alkyl; and the linkers L.sup.1 and
L.sup.2 can be included in either direction; R.sup.a and R.sup.b
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.3).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;
alternatively two adjacent R.sup.a or two adjacent R.sup.b can form
with the atoms to which they are attached, a 5-, 6- or 7-membered
saturated, partially saturated or unsaturated ring, which can be
optionally substituted and which contains 0-3 heteroatoms selected
from N, O, P(O) and S(O).sub.r; R.sup.c is selected from the group
consisting of halo, --R.sup.3, --OR.sup.2 and --SR.sup.2; wherein
each Y is independently a bond, --O--, --S-- or --NR.sup.1--; r is
0, 1 or 2; n is 1 or 2; each occurrence of R.sup.1 and R.sup.2 is
independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; each
occurrence of R.sup.3 is independently selected from alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,
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, P(O) and
S(O).sub.r; and each of the foregoing alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and
heterocyclic moiety is optionally substituted.
2. A compound of claim 1 in which n is 1.
3. A compound of claim 1 in which n is 2.
4. A compound of any of claims 1 to 3 in which Q is N.
5. A compound of any of claims 1 to 3 in which Q is CR.sup.c.
6. A compound of claim 5 in which R.sup.c is an alkyl.
7. A compound of claim 5 in which R.sup.c is halo.
8. A compound of any of claims 1 to 3 in which L.sup.1 is a
bond.
9. A compound of any of claims 1 to 3 in which L.sup.1 is
C(O)C.sub.0-6alkyl.
10. A compound of any of claims 1 to 3 in which L.sup.1 is
C(O)NHC.sub.0-6alkyl
11. A compound of any of claims 1 to 3 and 8 to 10 in which W.sup.1
is aryl.
12. A compound of any of claims 1 to 3 and 8 to 10 in which W.sup.1
is 5- or 6-membered heteroaryl.
13. A compound of any of claims 1 to 3 and 8 to 10 in which W.sup.1
is a 5-, 6- or 7-membered heterocyclyl.
14. A compound of any of claims 1 to 3 and 8 to 10 in which W.sup.1
is a 3- to 8-membered carbocyclyl.
15. A compound of any of claims 1 to 3 in which L.sup.2 is CH.sub.2
or CH(CH.sub.3).
16. A compound of claim 15 in which L.sup.2 is CH.sub.1.
17. A compound of claim 15 having the following formulae:
##STR00173## in which R is CH.sub.3 or H.
18. A compound of claim 15 having the following formulae:
##STR00174##
19. A compound of claim 17 having the formulae: ##STR00175##
20. A compound of claim 19 in which Q is N.
21. A compound of claim 19 in which Q is CR.sup.c.
22. A compound of claim 21 in which R.sup.c is a lower alkyl or
halo.
23. A compound of claim 19 in which n is 1.
24. A compound of claim 19 in which n is 2.
25. A compound of claim 19 in which W.sup.1 and W.sup.2 are aryl
optionally substituted with 1-5 R.sup.a and 1-5 R.sup.b
respectively; and R is H.
26. A compound of claim 19 in which W.sup.1 is a 5- or 6-membered
heteroaryl optionally substituted with 1-5 R.sup.a and W.sup.2 is
an aryl optionally substituted with 1-5 R.sup.b respectively; and R
is H.
27. A compound of any of claims 1 to 3 in which L.sup.2 is
C(O)C.sub.0-6alkyl.
28. A compound of claim 27 in which L.sup.2 is C(O).
29. A compound of claim 27 in which L.sup.2 is C(O)CH.sub.2.
30. A compound of claim 27 having the following formulae:
##STR00176##
31. A compound of claim 30 in which W.sup.1 and W.sup.2 are aryl
optionally substituted with 1-5 R.sup.a and 1-5 R.sup.b
respectively.
32. A compound of claim 30 in which W.sup.1 is a 5- or 6-membered
heteroaryl optionally substituted with 1-5 R.sup.a, W.sup.2 is an
aryl optionally substituted with 1-5 R.sup.b.
33. A compound of claim 30 in which Q is N.
34. A compound of claim 30 in which Q is CR.sup.c.
35. A compound of claim 34 in which R.sup.c is a lower alkyl or
halo.
36. A compound of claim 30 in which n is 1.
37. A compound of claim 30 in which n is 2.
38. A method for treating cancer in a mammal in need thereof,
comprising administering to the mammal a therapeutically effective
amount of a compound of any of the claims 1 to 37; or a
pharmaceutically acceptable salt, solvate or hydrate thereof.
39. A method of claim 38 in which the cancer is non-small-cell lung
cancer, gliosblastoma, neuroblastoma, esophageal carcinomas,
diffuse large B-cell lymphomas, breast cancer, rhabdomyosarcomas,
anaplastic large-cell lymphomas and inflammatory myofibroblastic
tumors.
40. A composition comprising a compound of any of claims 1 to 37;
or a pharmaceutically acceptable salt, solvate or hydrate thereof
and a pharmaceutical carrier, diluent or vehicle.
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-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, P13k, 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] This invention concerns a new family of pyrazinopyrazine
compounds and their use in treating cancers and other diseases.
DESCRIPTION OF THE INVENTION
1. General Description of Compounds of the Invention
[0004] The compounds of this invention 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:
[0006] A compound of Formula I, a tautomer, a pharmaceutically
acceptable salt and a solvate thereof:
##STR00002## [0007] wherein [0008] W.sup.1 represents an aryl, a 3-
to 8-membered carbocyclyl, a 5-, 6- or 7-membered heterocyclic or
heteroaryl ring comprising carbon atoms and 1-4 heteroatoms
independently selected from O, N, P(O) and S(O).sub.r and W.sup.1
is optionally substituted with 1-5 R.sup.a groups; [0009] W.sup.2
represents an aryl or a 5- or 6-membered heteroaryl ring comprising
carbon atoms and 1-3 heteroatoms independently selected from O, N,
P(O) and S(O).sub.r, and W.sup.2 is optionally substituted with 1-5
R.sup.b groups; [0010] Q is N or CR.sup.c; [0011] L.sup.1 and
L.sup.2 are independently selected from the group consisting of a
bond, C.sub.1-6-alkyl, O--C.sub.0-6-alkyl,
NR.sup.1--C.sub.0-6-alkyl, C(O)NR.sup.1--C.sub.0-6-alkyl,
NR.sup.1C(O)--C.sub.0-6-alkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.0-6-alkyl-S(O).sub.r,
C.sub.0-6alkyl-S(O).sub.2NR.sup.1,
C.sub.0-6alkyl-NR.sup.1S(O).sub.2, C(O)--C.sub.0-6alkyl,
OC(O)NR.sup.1--C.sub.0-6-alkyl, NR.sup.1C(O)O--C.sub.0-6-alkyl,
NR.sup.1C(O)NR.sup.1--C.sub.0-6-alkyl; and the linkers L.sup.1 and
L.sup.2 can be included in either direction; [0012] R.sup.a and
R.sup.b 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.3).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;
alternatively two adjacent R.sup.a or two adjacent R.sup.b can form
with the atoms to which they are attached, a 5-, 6- or 7-membered
saturated, partially saturated or unsaturated ring, which can be
optionally substituted and which contains 0-3 heteroatoms selected
from N, O, P(O) and S(O).sub.r; [0013] R.sup.c is selected from the
group consisting of halo, --R.sup.3, --OR.sup.2 and --SR.sup.2;
[0014] wherein each Y is independently a bond, --O--, --S-- or
--NR.sup.1--; [0015] r is 0, 1 or 2; [0016] n is 1 or 2; [0017]
each occurrence of R.sup.1 and R.sup.2 is independently selected
from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl, heterocyclic and heteroaryl; [0018] each
occurrence of R.sup.3 is independently selected from alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,
heterocyclic and heteroaryl; [0019] 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, P(O) and S(O).sub.r; and [0020] each of the foregoing
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,
aryl, heteroaryl and heterocyclic moiety is optionally
substituted.
[0021] 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
[0022] One class of compounds which is of special interest for use
in this invention are compounds of Formula I, as described above in
Part 1, in which Q is N. This class is illustrated by compounds of
formula IA:
##STR00003##
[0023] A subclass of interest include compound of formula IA in
which n is 1.
[0024] Another subclass of interest includes compounds of formula
IA in which n is 2.
[0025] Another subclass of interest includes compounds of Formula
IA in which W.sup.1 is an aryl.
[0026] Another subclass of interest includes compounds of Formula
IA in which W.sup.1 is a 5- or 6-membered heteroaryl.
[0027] Another subclass of interest includes compounds of Formula
IA in which W.sup.1 is a 5-, 6-, or 7-membered heterocyclyl.
[0028] Another subclass of interest includes compounds of Formula
IA in which W.sup.1 is a 3- to 8-membered carbocyclyl.
[0029] Another class of compounds which is of special interest for
use in this invention are compounds of Formula I, as described
above, in which Q is CR.sup.c.
[0030] This class is illustrated by compounds of Formula IB:
##STR00004##
[0031] A subclass of interest include compound of formula IB in
which n is 1.
[0032] Another subclass of interest includes compounds of formula
IB in which n is 2.
[0033] Another subclass of interest includes compounds of Formula
IB in which W.sup.1 is an aryl.
[0034] Another subclass of interest includes compounds of Formula
IB in which W.sup.1 is a 5- or 6-membered heteroaryl.
[0035] Another subclass of interest includes compounds of Formula
IB in which W.sup.1 is a 5-, 6-, or 7-membered heterocyclyl.
[0036] Another subclass of interest includes compounds of Formula
IB in which W.sup.1 is a 3- to 8-membered carbocyclyl.
[0037] Another subclass of interest includes compound of Formula IB
and all previous subclasses in which R.sup.c is halo or lower alkyl
(i.e. Methyl, Ethyl).
[0038] For the previously described classes and subclasses of
compounds described above R.sup.a, R.sup.b, L.sup.2, L.sup.1,
W.sup.2 are defined above in part 1.
[0039] One class of compounds of special interest are compounds of
Formula IA or IB in which L.sup.1 is NR.sup.1--C.sub.0-6-alkyl.
[0040] Illustrative examples of this class are compounds of the
following types in which n is 1:
##STR00005##
[0041] Other illustrative examples of this class are compounds of
the following types in which n is 2:
##STR00006##
[0042] In another embodiment, this invention relates to compounds
of Formula IA or IB as described above, in which L.sup.1 is
O--C.sub.0-6-alkyl. Of special interest are compounds of this class
in which W.sup.1 and W.sup.2 are aryl or heteroaryl.
[0043] Illustrative examples of this class are compounds of the
following types in which n is 1:
##STR00007##
[0044] Other illustrative examples of this class are compounds of
the following types in which n is 2:
##STR00008##
[0045] In another embodiment, this invention relates to compounds
of Formula IA or IB as described above, in which L.sup.1 is
S--C.sub.0-6-alkyl.
[0046] Illustrative examples of this class are compounds of the
following types in which n is 1:
##STR00009##
[0047] Other illustrative examples of this class are compounds of
the following types in which n is 2:
##STR00010##
[0048] In another embodiment, this invention relates to compounds
of Formula IA or IB as described above, in which L.sup.1 is a bond.
This is illustrated by compound of the following formula IC:
##STR00011##
[0049] Of further interest are compounds of formula IC in which Q
is N.
[0050] Of other interest are compounds of formula IC in which Q is
CR.sup.c, in which for example R.sup.c is lower alkyl or halo.
[0051] In one aspect of the above embodiment are compounds of
Formula IC in which n is 1. In another aspect of this embodiment
are compounds of formula IC in which n is 2.
[0052] Of special interest are compounds of formula IC in which
L.sup.2 is C.sub.0-6alkyl. Of further interest are compounds of
this class in which L.sup.2 is CHCH.sub.3 or CH.sub.1. Of further
interest are compounds of this class and subclass in which W.sup.1
and W.sup.2 are independently chosen from aryl and heteroaryl.
[0053] Illustrative examples of this class are compounds of formula
IC of the following types in which n is 1:
##STR00012## ##STR00013##
[0054] Other illustrative examples of this class are compounds of
formula IC of the following types in which n is 2:
##STR00014##
[0055] In some embodiment, this invention relates to compounds of
Formulae IA or IB as described above, in which L.sup.1 is
C(O)C.sub.0-6alkyl. Of further interest are compounds of this class
in which W.sup.1 is a 5- to 7-membered heterocyclyl. Illustrative
examples of this class are compounds of the following types:
##STR00015## ##STR00016##
[0056] In some embodiment, this invention relates to compounds of
Formulae IA or IB as described above, in which L.sup.1 is
C(O)NHC.sub.0-6alkyl. Illustrative examples of this class are
compounds of the following types:
##STR00017##
[0057] In some embodiment, this invention relates to compounds of
Formula IA or IB as described above, in which L.sup.1 is
C.sub.2alkynyl.
[0058] Non limiting examples of this embodiment include the
following compounds:
##STR00018##
[0059] In one embodiment are compounds of Formulae IA, IB, IC or
other classes and subclasses of this invention, in which is an aryl
optionally substituted with 1-5 R.sup.a, (i.e. optionally
substituted phenyl). Illustrative examples of Phenyl moieties
substituted with R.sup.a are:
##STR00019## ##STR00020## ##STR00021## ##STR00022## ##STR00023##
##STR00024##
[0060] In another aspect of the previous embodiment are compounds
of Formulae IA, IB, IC or other classes and subclasses of this
invention in which W.sup.1 is a 5-, 6- or 7-membered heterocyclyl
ring comprising carbon atoms and 1-4 heteroatoms independently
selected from O, N, P(O) and S(O).sub.r, and W.sup.1 is substituted
on carbon or on the heteroatom(s) with 1-5 R.sup.a groups. It is
understood that the total number of substituents R.sup.a does not
exceed the normal available valencies.
[0061] Non-limiting examples of this class are compounds of formula
IA or IB in which W.sup.1 is of the following types:
##STR00025##
[0062] Non-limiting illustrative examples are compounds of the
following formulae:
##STR00026## ##STR00027##
[0063] In another aspect of the previous embodiment are compounds
of Formulae IA, IB or IC in which W.sup.1 is a 3- to 8-membered
carbocyclyl and W.sup.1 is substituted with 1-5 R.sup.a groups.
Non-limiting examples of this class are compounds of the following
types:
##STR00028##
[0064] In another embodiment are compounds of Formulae IA, IB or IC
in which W.sup.1 is a 5-, 6-membered heteroaryl ring comprising
carbon atoms and 1-4 heteroatoms independently selected from O, N
and S(O).sub.r, and W.sup.1 is optionally substituted on carbon or
on the heteroatom(s) with 1-5 R.sup.a groups. It is understood that
the total number of substituents R.sup.a does not exceed the normal
available valencies.
[0065] In one aspect of the previous embodiment are compounds of
Formulae IA, IB, IC or other subclasses in which W.sup.1 is a
5-membered ring heteroaryl comprising carbon atoms and 1-3 Nitrogen
atoms. Non-limiting examples of this class are compounds in which
W.sup.1 is of the following types:
##STR00029##
in which R.sup.a is as previously defined and p is 0, 1 2, 3 or 4.
It is understood that the total number of substituents R.sup.a does
not exceed the normal available valencies.
[0066] In a particular aspect of this embodiment, W.sup.1 has the
following formulae:
##STR00030## [0067] R.sup.a is as defined previously in part 1. Of
additional interest is a class of compounds as described above in
which R.sup.a 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.a is H, an aryl, heteroaryl,
substituted alkyl or heterocyclyl. Non limiting examples of
substituted alkyl are H,
--(CH.sub.2).sub.yC(.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.yC(.dbd.O)OR.sup.1,
--(CH.sub.2).sub.yheterocyclyl, --(CH.sub.2).sub.yaryl,
--(CH.sub.2).sub.yheteroaryl in which y is 0, 1, 2, 3 or 4, 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.
[0068] Illustrative examples of such compounds include those in
which substituent R.sup.a is without limitation:
##STR00031##
[0069] Other illustrative examples of this class include compounds
in which W.sup.1 is of the following types:
##STR00032##
[0070] Non-limiting Illustrative examples of this class are
compounds of the following formulae:
##STR00033## ##STR00034##
[0071] In other particular aspects of the previous embodiment,
W.sup.1 is a 5-membered ring heteroaryl comprising carbon atoms and
1-4 Nitrogen atoms and the heteroaryl ring is linked to the core
moiety via a nitrogen atom.
[0072] Non-limiting examples include compounds in which the
N-linked W.sup.1 has the following formulae:
##STR00035##
in which R.sup.a and p are as previously defined. It is understood
that the total number of substituents R.sup.a does not exceed the
normal available valencies. Thus, for example, when W.sup.1 is an
N-linked pyrolle ring, it can be substituted with 1 to 4
substituents (i.e. p is 1, 2, 3 or 4), whereas when W.sup.1 is an
N-linked pyrazole or an N-linked imidazole, it can only be
substituted with a maximum of 3 substituents (i.e. p is 1, 2 or 3).
[0073] R.sup.a is as defined previously in part 1. Of additional
interest is a class of compounds as described above in which
R.sup.a 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.a is an aryl,
heteroaryl, substituted alkyl or heterocyclyl. Non limiting
examples of R.sup.a 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.
[0074] Illustrative non limiting examples of such compounds include
compounds of Formula IA or IB in which W.sup.1 is a triazole of the
following formulae:
##STR00036##
[0075] In another aspect of the previous embodiment, W.sup.1 is a
pyrazole of the following formulae:
##STR00037## ##STR00038##
[0076] In another aspect of the previous embodiment, W.sup.1 is a
tetrazole of the following formulae:
##STR00039##
[0077] Non-limiting Illustrative examples of this class are
compounds of the following formulae:
##STR00040## ##STR00041##
[0078] In another aspect of the previous embodiment, W.sup.1 is a
5-membered ring heteroaryl comprising carbon atoms and 1-4
heteroatoms selected from N and O. Non limiting examples are
compounds of formula IA, IB or IC in which W.sup.1 is of the
following type:
##STR00042##
in which p is defined previously and the total number of
substituents R.sup.a does not exceed the normal available
valencies.
[0079] In a particular aspect of this embodiment, W.sup.1 has the
following formulae:
##STR00043##
in which W.sup.1 is substituted with one or two R.sup.a
substituents. [0080] R.sup.a is as defined previously in part 1. Of
additional interest is a class of compounds as described above in
which R.sup.a 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.a 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.a
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.
[0081] Non-limiting examples of this class include compounds of
formulae IA, IB or IC in which W.sup.1 is:
##STR00044## ##STR00045##
[0082] Specific, non-limiting illustrative examples of this class
include compounds of formula IA, IB or IC in which substituted
W.sup.1 is of the following formulae:
##STR00046## ##STR00047## ##STR00048##
[0083] Non-limiting Illustrative examples of this class are
compounds of the following formulae:
##STR00049## ##STR00050##
[0084] In another specific embodiment, W.sup.1 is a 5-membered
heteroaryl comprising carbon atoms and 1-4 heteroatoms selected
from N and S.
##STR00051##
in which p is defined previously and the total number of
substituents R.sup.a does not exceed the normal available
valencies.
[0085] Of particular interest is a class of compounds as described
above in which R.sup.a is selected from the group consisting of
--R.sup.1, --P(.dbd.O)(R.sup.3).sub.2, --OR.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.a 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.a 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.
[0086] Non-limiting examples of this class include compounds of
formula IA, IB or IC in which W.sup.1 is:
##STR00052##
[0087] Specific, non-limiting illustrative examples of this class
include compounds of formula IA, IB or IC in which substituted
W.sup.1 is of the following formulae:
##STR00053## ##STR00054##
[0088] Non-limiting Illustrative examples of this class are
compounds of the following formulae:
##STR00055## ##STR00056##
[0089] Other non-limiting examples include compounds of formula IA,
IB or IC in which W.sup.1 is furan or thiofuran:
##STR00057##
in which p is defined previously and the total number of
substituents R.sup.a does not exceed the normal available
valencies.
[0090] Specific, non-limiting illustrative examples of this class
include compounds of formula IA, IB or IC in which substituted
W.sup.1 is of the following formulae:
##STR00058##
[0091] Non-limiting Illustrative examples of this class are
compounds of the following formulae:
##STR00059## ##STR00060##
[0092] In another embodiment, W.sup.1 is a 6-membered heteroaryl
ring.
[0093] In one aspect of this embodiment, W.sup.1 is a pyrimidine of
the following types:
##STR00061##
in which p is as previously described and the total number of
substituents R.sup.a does not exceed the normal available
valencies.
[0094] Of particular interest is a class of compounds as described
above in which R.sup.a 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.a 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.
[0095] Non-limiting examples of this class are compounds of formula
IA, IB or IC in which W.sup.1 is:
##STR00062## ##STR00063##
[0096] Specific, non-limiting illustrative examples of this class
include compounds of formula IA, IB or IC in which substituted
W.sup.1 is of the following formulae:
##STR00064## ##STR00065##
[0097] Non-limiting Illustrative examples of this class are
compounds of the following formulae:
##STR00066## ##STR00067##
[0098] In another embodiment, W.sup.1 is a pyridine substituted
with 1-4 R.sup.a. Of particular interest is a class of compounds as
described above in which R.sup.a 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.a is H,
NHC(O)R.sup.2, NR.sup.1R.sup.4, an aryl, heteroaryl, substituted
alkyl or heterocyclyl. Non limiting examples of R.sup.a are H,
--(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.
[0099] Non-limiting examples of this class are compounds of formula
IA, LB or IC in which W.sup.1 is:
##STR00068##
[0100] Specific, non-limiting illustrative examples of this class
include compounds of formula IA, LB or IC in which substituted
W.sup.1 is of the following formulae:
##STR00069## ##STR00070##
[0101] Non-limiting Illustrative examples of this class are
compounds of the following formulae:
##STR00071## ##STR00072##
[0102] In another embodiment, W.sup.1 is a pyrazine substituted
with 1-3 R.sup.a: Non-limiting examples of this class of compounds
in which W.sup.1 is:
##STR00073##
[0103] Specific, non-limiting illustrative examples of this class
include compounds of formula IA, IB or IC in which substituted
W.sup.1 is of the following formulae:
##STR00074## ##STR00075##
[0104] In another embodiment, W.sup.1 is a triazine substituted
with 1 to 2 R.sup.a groups. Examples include compounds in which
W.sup.1 has the following formulae:
##STR00076##
in which p is defined previously and the number of substituents
R.sup.a does not exceed the maximum available valencies, which in
the triazine case p is 0, 1 or 2.
[0105] In one embodiment, two R.sup.a groups form with the atoms to
which they are attached, a 5- or 6- or 7-membered saturated,
partially saturated or unsaturated ring, which contains 0-3
heteroatoms selected from N, O, P(O) and S(O).sub.r; and the
resulting fused ring system is optionally substituted. Non-Limiting
examples include compounds of Formula IA or IB or any of the
classes and subclasses of this invention in which W.sup.1 has the
following formulae:
##STR00077## ##STR00078## ##STR00079## [0106] and the depicted
fused ring systems are optionally substituted with R.sup.d, which
is 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.3).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, in
which R.sup.1, R.sup.2, R.sup.3, Y and r are previously defined.
Additionally the depicted hydrogen can also be replaced by an
R.sup.d group; or the nitrogen bearing the depicted hydrogen can be
the point of attachment to the core molecule (i.e. the nitrogen is
attached to L.sup.1 and the depicted hydrogen is therefore
absent).
[0107] Specific, non-limiting illustrative examples of this class
include compounds of formula IA, IB or IC or other classes and
subclasses of this invention, in which substituted W.sup.1 is of
the following formulae:
##STR00080## ##STR00081## ##STR00082##
[0108] For the previously described classes and subclasses of
compounds, as in all compounds of the invention, Q, L.sup.2 and
W.sup.2 are defined as in part 1.
[0109] In one embodiment of this invention are compounds of
Formulae I, IA, IB or IC in which L.sup.2 is C(O)C.sub.0-6alkyl. Of
further interest are compounds of this class in which L.sup.2 is
C(O)CH.sub.2 or C(O).
[0110] In another embodiment of this invention are compounds of
Formulae I, IA or IB in which L.sup.2 is C.sub.0-6alkyl. Of further
interest are compounds of this class in which L.sup.2 is CH.sub.2
or CH(CH.sub.3).
[0111] In some embodiment of this invention are compounds of
Formulae I, IA, IB, IC or ID or any other classes or subclasses of
this invention in which W.sup.2 is a phenyl substituted with 1-5
R.sup.b.
[0112] In some other embodiment are compounds of formulae IA, IB,
IC or ID in which W.sup.2 is a 6-membered ring heteroaryl. Examples
of this class are compounds of the above classes and subclasses in
which W.sup.2 is a pyridine, pyrazine, pyridazine, pyrimidine or
triazine optionally substituted with 1-4 R.sup.b.
[0113] In other embodiment are compounds of formulae IA, IB, IC or
ID in which W.sup.2 is a 5-membered ring heteroaryl. Examples of
this class are compounds of the above classes and subclasses in
which W.sup.2 is imidazole, pyrazole, tetrazole, oxazole, thiazole,
isoxazole, pyrolle, or the like and W.sup.2 is optionally
substituted with 1-3 R.sup.b.
[0114] Of particular interest is a class of compounds as described
above in which R.sup.b is selected from the group consisting of
halo, --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 or P.dbd.O(R.sup.3).sub.2. In another
subclass of interest, are compounds of the above embodiment in
which R.sup.b is 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 or
P(.dbd.O)(alkyl).sub.2. Non limiting examples of R.sup.b are is H,
F, Cl, Br, 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 and
--(CH.sub.2).sub.mP(.dbd.O)(Me).sub.2,
--(CH.sub.2).sub.mP(.dbd.O)(Et).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.
[0115] Of current special interest is a class of compounds of
formulae IA, IB, IC or ID and other classes and subclasses of this
invention in which R.sup.b is selected from H, halo, lower alkyl
(i.e: methyl, ethyl, cyclopropyl and the like), --CF.sub.3,
--OCF.sub.3, --CN, --NH(alkyl), alkenyl and alkynyl (i.e.:
acetylene). Of other current interest are compounds of this class
in which R.sup.b is H, halo, lower alkyl or CF.sub.3.
[0116] In a particular embodiment of the previous classes and
subclasses, one of R.sup.a is or R.sup.b contains
YP(O)(YR.sup.3).sub.2 group and more preferably a
P(O)(R.sup.3).sub.2 group. Examples of R.sup.a or R.sup.b
containing P(O)(R.sup.3).sub.2 groups are 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.
[0117] Illustrative examples of this class are compounds of Formula
IA, IB, IC or ID of the following types:
##STR00083## ##STR00084##
[0118] In some embodiment, a R.sup.a or R.sup.b containing
P(O)(R.sup.3), substituent can be of cyclic structure. In some
non-limiting cases, two R.sup.3 groups can form with the phosphine
atom to which they are attached 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.
[0119] Non limiting examples of this embodiment include compounds
in which R.sup.a or R.sup.b containing P(O)(R.sup.3).sub.2 group is
of the following formula:
##STR00085##
[0120] Illustrative examples of this class are compounds of Formula
IA or IB of the following types:
##STR00086## ##STR00087##
[0121] In other cases, R.sup.a or R.sup.b group can be 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. Non limiting examples of this embodiment
include compounds in which R.sup.a- or R.sup.b-containing
P(O)(R.sup.3).sub.2 group is of the following formulae:
##STR00088##
[0122] Illustrative examples of this class are compounds of Formula
IA, IC or ID of the following types:
##STR00089##
[0123] Of special interest for use in this invention are compounds
of formula IA or IB in which L.sup.2 is CH.sub.2 or CH(CH.sub.3).
Of further interest are compounds of this class in which L.sup.1 is
a bond NH, C(O), C(O)NH, C(O)NHC.sub.1-6alkyl, CH.sub.2NH, O or S.
Illustrative, non-limiting examples of this subclass are compounds
of the following formulae:
##STR00090##
in which R is H or CH.sub.3; and Q, W.sup.1 and W.sup.2 are
previously defined. Of further interest are compounds of these
formulae in which n is 1. Of other interest are compounds of these
formulae in which n is 2. Of particular current interest are
compounds of Formula IA, IB, IC or ID in which L.sup.2 is CH.sub.2
or CH(CH.sub.3); W.sup.1 and W.sup.2 are phenyls: non limiting
examples of this subclass are compounds of the following
formulae:
##STR00091##
[0124] Of particular interest of the previous embodiment are
compounds of Formulae IC in which L.sup.2 is C.sub.0-6alkyl. Of
further interest are compounds of this class in which L.sup.2 is
CH.sub.2 or CH(CH.sub.3). This class is represented by compound of
Formula ID:
##STR00092##
in which R is H or CH.sub.3; and W.sup.2, Q and n are as previously
defined in part 1.
[0125] In one particular aspect of this embodiment, are compounds
of formula ID in which Q is N.
[0126] In another aspect of this embodiment are compounds of
formula ID in which Q is CR.sup.c, in which R.sup.c is for example
lower alkyl or halo.
[0127] In another aspect of this embodiment are compounds of
formula ID in which n is 0.
[0128] In another aspect of this embodiment are compounds of
formula ID in which n is 1.
[0129] Of particular current interest are compounds of the above
classes and subclasses in which L.sup.2 is CH.sub.2 or
CH(CH.sub.3); W.sup.2 is phenyl and W.sup.1 is a 5-, 6- or
7-membered heterocyclyl. Illustrative, non-limiting examples of
this subclass are compounds of the following formulae:
##STR00093##
[0130] Of particular current interest are compounds of the above
classes and subclasses in which L.sup.2 is CH.sub.2 or
CH(CH.sub.3); W.sup.2 is a phenyl and W.sup.1 is a 5- or 6-membered
ring heteroaryl. Illustrative, non-limiting examples of this
subclass are compounds of the following formulae:
##STR00094##
[0131] Of special interest for use in this invention are compounds
of formula IA or IB in which L.sup.2 is C(O) or C(O)CH.sub.2. Of
further interest are compounds of this class in which L.sup.1 is a
bond NH, C(O), C(O)NH, C(O)NHC.sub.1-6alkyl, CH.sub.2NH, O or S.
Illustrative, non-limiting examples of this subclass are compounds
of the following formulae:
##STR00095##
[0132] Of further interest are compounds of these formulae in which
n is 1. Of other interest are compounds of these formulae in which
n is 2.
[0133] Of special interest for use in this invention are compounds
of formula IA or IB in which L.sup.2 is SO.sub.2. Of further
interest are compounds of this class in which L.sup.1 is a bond NH,
C(O), C(O)NH, C(O)NHC.sub.1-6alkyl, CH.sub.2NH, O or S.
Illustrative, non-limiting examples of this subclass are compounds
of the following formulae:
##STR00096##
[0134] Of further interest are compounds of these formulae in which
n is 1. Of other interest are compounds of these formulae in which
n is 2.
[0135] In one embodiment of this invention are compounds of formula
IA, IB, IC and ID and of all previously described classes and
subclasses, in which Q is N.
[0136] In another embodiment of this invention are compounds of
formula IA, IB, IC and ID and of all previously described classes
and subclasses, in which Q is CR.sup.c. Of further interest are
compound of this class in which R.sup.c is selected from small
alkyl (i.e.: methyl, ethyl and the like) and halo.
[0137] Compounds of this invention of particular interest include
those with on or more of the following characteristics: [0138] 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 [0139] 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 [0140] 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 [0141] inhibitory activity for Alk, Met,
Jak2 or B-Raf with a 1 .mu.M or better IC.sub.50 value against
each; or [0142] 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.
[0143] 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 this invention.
[0144] The cancer treatment method of this invention involves
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 this 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. [0145] 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 or residue (MW>300) thereof. 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 present invention.
[0146] 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 this invention with enhanced aqueous
solubility or active transport through the gut membrane, relative
to the parent compound. [0147] One important aspect of this
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 this
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 this
invention. [0148] 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. [0149] This
invention further comprises the preparation of a compound of any of
Formulae I, IA, IB, IC, ID or of any other classes and subclasses
of compounds of this invention. [0150] 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). The compounds of this invention are useful in the
manufacture of an anti-cancer medicament. The compounds of the
present invention are also 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, P13k, etc. [0151] This 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.
[0152] Compounds of this invention are also 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
[0153] In reading this document, the following information and
definitions apply unless otherwise indicated.
[0154] 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.
[0155] 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.
[0156] "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.
[0157] 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.
[0158] 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.
[0159] 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".
[0160] 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.
[0161] 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.
[0162] "Heterocycle", "heterocyclyl", or "heterocyclic" as used
herein refers to non-aromatic ring systems having five to fourteen
ring atoms, preferably five to ten, in which one or more ring
carbons, preferably one to four, are each replaced by a heteroatom
such as N, O, or S, 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. 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.
[0163] 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.
[0164] 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]pyiridinyl, 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". [0165] 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, --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.3).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, 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(O)R.sup.3R.sup.3, Si(R.sup.3).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). [0166] 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(O)(CH.sub.3).sub.2, Si(CH.sub.3).sub.3 and the
like. [0167] An alkyl, alkenyl, alkynyl, alkoxy, haloalkyl,
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, aryl, heteroaryl, heterocyclyl. [0168] 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. [0169] 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,
cycloalkkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and
heterocyclyl; each occurrence of R.sup.1 and R.sup.2 is
independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkkyl,
cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocyclyl.
[0170] 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.
[0171] This invention encompasses only those combinations of
substituents and variables that result in a stable or chemically
feasible compound. A stable compound or chemically feasible
compound is one that has stability sufficient to permit its
preparation and detection. Preferred compounds of this invention
are sufficiently stable that they are not substantially altered
when kept at a temperature of 40.degree. C. or less, in the absence
of moisture or other chemically reactive conditions, for at least a
week.
[0172] Certain compounds of this invention may exist in tautomeric
forms, and this invention includes all such tautomeric forms of
those compounds unless otherwise specified.
[0173] 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, this 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.
[0174] 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.
[0175] 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.
[0176] The compounds of this 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.43F and .sup.36Cl, respectively.
Compounds of this invention which contain those radioisotopes
and/or other radioisotopes of other atoms are within the scope of
this invention. Tritiated, i.e., .sup.3H, and carbon-14, i.e.,
.sup.14C, radioisotopes are particularly preferred for their ease
of preparation and detectability.
[0177] Radiolabelled compounds of this 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
[0178] 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
the compounds of this invention, including compounds containing the
various choices for the W.sup.1, W.sup.2, R.sup.a, R.sup.b,
R.sup.c, R.sup.d, R, Q, n, L.sup.1 and L.sup.2.
[0179] 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 fauns 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.
[0180] Also, one may chose reagents enriched for a desired isotope,
e.g. deuterium in place of hydrogen, to create compounds of this
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
this 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.
[0181] The compounds of this 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.
[0182] A compound of the present invention could be prepared as
outlined in Scheme 1 to Scheme 30 and via standard methods known to
those skilled in the art.
[0183] A compound of Formula I, IA, IC or ID in which L.sup.1 is a
bond, L.sup.2 is CH.sub.2 and n is 1 can be prepared in a 5 steps
synthesis as shown in Scheme 1. A L.sup.2-W.sup.2 moiety can first
be incorporated by reacting 3,5-dibromopyrazin-2-amine with
NH.sub.2CH.sub.2W.sup.2 in a suitable solvent such as for example
butanol at high temperatures in order to generate intermediate I-1.
Intermediate I-1 is then reacted with ethyl chloro(oxo)acetate in
the presence of a base (such as for example isopropyldiethylamine)
in a suitable solvent such as dichloromethane to generate
intermediate I-2. Cyclisation of intermediate I-2 can occurs at
high temperature in a suitable solvent such as diglyme to generate
intermediate I-3. Intermediate I-3 can then be reduced using
reducing agents such as for example BH.sub.3.Me.sub.2S or DIBAL-H
in a suitable solvent (for example THF or dichloromethane) to
generate intermediate I-4. The W.sup.1 moiety is introduced onto
intermediate I-4 using Suzuki coupling conditions. The displacement
of the bromide can be accomplished by using an aryl/heteroaryl
boronic acid in the presence of a palladium catalyst (such as
Pd(PH.sub.3).sub.4 and a suitable base and solvent to generate a
compound of Formula IA.
##STR00097##
[0184] A compound of Formula I, IA, IC or ID in which L.sup.1 is a
bond, L.sup.2 is CH.sub.2 and n is 2 can be prepared in a 5 steps
synthesis as shown in Scheme 2. 2-amino-3,5-dibromopyrazine is
first treated with methyl acrylate to generate intermediate II-1. A
L.sup.2-W.sup.2 moiety is then incorporated by reacting
intermediate II-1 with NH.sub.2CH.sub.2W.sup.2 in a suitable
solvent such as for example tetrahydrofuran in the presence of a
base to generate intermediate II-2. Cyclisation of intermediate
II-2 can occurs at high temperature in a suitable solvent under
acidic conditions to generate intermediate II-3. Intermediate II-3
can then be reduced using reducing agents such as for example
BH.sub.3.Me.sub.2S or DIBAL-H in a suitable solvent (for example
THF or dichloromethane) to generate intermediate II-4. The W.sup.1
moiety is introduced onto intermediate II-4 using Suzuki coupling
conditions. The displacement of the bromide can be accomplished by
using an aryl/heteroaryl boronic acid in the presence of a
palladium catalyst (such as Pd(PH.sub.3).sub.4 and a suitable base
and solvent to generate a compound of Formula IA.
##STR00098##
[0185] A compound of Formula IB, IC or ID in which R.sup.c is
methyl, L.sup.1 is a bond, L.sup.2 is CH.sup.2 and n is 1 can be
prepared in a multiple steps synthesis as shown in Schemes 3 to 5.
5-bromo-4-methyl-3-nitropyridin-2-amine can be reacted with methyl
bromo acetate in the presence of a suitable base such as sodium
hydride in a suitable solvent such as dimethylformamide to generate
intermediate III-2. Intermediate III-2 is then reduced and cyclized
under acidic conditions to generate intermediate III-3.
Intermediate III-3 can then be reduced using reducing agents such
as for example BH.sub.3.Me.sub.2S or DIBAL-H in a suitable solvent
(for example THF or dichloromethane) to generate intermediate
III-4. An alternative route to intermediate III-2 is also described
in Scheme 3: 5-bromo-2-hydroxy-4-methyl-3-nitropyridine is reacted
with phosphorous oxychloride to generate intermediate III-1 which
is subsequently reacted with methyl glycinate to generate
intermediate III-2.
##STR00099##
[0186] Intermediate III-4 can also be prepared using an alternative
route shown in Scheme 4. 5-Bromo-4-methyl-3-nitropyridin-2-amine is
reduced using a reducing agent such as Fe/HCl to generate
intermediate IV-1. Intermediate IV-1 is reacted with glyoxal to
generate intermediate IV-2. Reduction of intermediate IV-2 with
sodium borohydride generates intermediate III-4.
##STR00100##
[0187] A compound of Formula IB, IC or ID in which R.sup.c is
methyl, L.sup.1 is a bond, L.sup.2 is CH.sub.2 and n is 1 can then
be prepared from intermediate III-4 in two additional steps as
shown is Scheme 5: Intermediate III-4 is alkylated with a
LG-CH.sub.2--W.sup.2 moiety in which LG depicts a leaving group
such as I, Br, Cl and the like in a suitable solvent such as
acetonitrile. The alkylation can be facilitated by using high
temperature and/or microwave chemistry. Separation of the two
isomers V-1a and V-1b can be performed using high pressure liquid
chromatography or other separation techniques known to those
skilled in the art. Intermediate V-1b is then submitted to Suzuki
coupling reaction with W.sup.1B(OH).sub.2 in order to introduce the
W.sup.1 moiety. W.sup.1 and W.sup.2 are as previously described in
part 1.
##STR00101##
[0188] A compound of Formula ID in which R.sup.c is methyl, L.sup.1
is a bond, L.sup.2 is CH.sup.2 and n is 2 is prepared in multiple
steps as shown in Scheme 6:
5-Bromo-2-chloro-4-methyl-3-nitropyridine is reacted with methyl
.beta.-alaninate hydrochloride in order to generate intermediate
VI-1. Reduction of the nitro group using Fe/NH.sub.4Cl; followed by
cyclization under acidic conditions generate intermediate VI-3.
Selective alkylation with a LG-CH.sub.7W.sup.2 moiety, in which LG
is a leaving group such as Br, I, Cl and the like, can be
accomplished using a suitable base such as KN(SiMe.sub.3).sub.2 to
generate intermediate VI-4. Intermediate VI-4 can then be reduced
using reducing agents such as for example BH.sub.3.Me.sub.9S or
DIBAL-H in a suitable solvent (for example THF or dichloromethane)
to generate intermediate VI-5. The W.sup.1 moiety is introduced
onto intermediate VI-5 using Suzuki coupling conditions as
previously described in Scheme 1.
##STR00102##
[0189] Compounds of Formula IA or IB in which L.sup.2 is CH.sub.2
and L.sup.1 is NH can be prepared, as shown in Scheme 7, from
intermediates I-4, II-4, V-1b or VI-5 and the like, by first
protecting the free amine with a protective group such as SEM
[2-(trimethylsilyl)ethoxymethyl], and by reacting the heteroaryl
bromide (Intermediate VII-1) with a W.sup.1NH, moiety using
Buchwald-Hartwig amination conditions. The protecting group can
then be removed using the appropriate condition such as for example
TBAF for removing SEM group.
##STR00103##
[0190] In a similar way, compounds of Formula IA or IB in which
L.sup.2 is CH.sub.2 and L.sup.1 is O can be prepared, as shown in
Scheme 8, from intermediates I-4, II-4, V-1b, VI-5 or the like, by
reacting an intermediate VIII-1 with W.sup.1--OH under
Buchwald-Hartwig etherification conditions.
[0191] A prior amine protection is also required as described in
Scheme 7 and shown in Scheme 8.
##STR00104##
[0192] The preparation of a compound of Formula IA, IB or ID in
which L.sup.2 is CH.sub.1, L.sup.1 is a bond and W.sup.1 is a
N-linked 5-, 6- or 7-membered heterocyclyl, can also be achieved
using Buchwald-hartwig amination conditions as described in Schemes
7 and 8. In scheme 9, the exemplified heterocyclyl is a piperazine
substituted with R.sup.a.
##STR00105##
[0193] The preparation of a compound of Formula IA or IB in which
L.sup.2 is CH.sub.1, L.sup.1 is C(O)NH or CH.sub.2NH is described
in Scheme 10. An intermediate I-4, II-4, V-1b, VI-5 or the like,
can be reacted with W'NH, in the presence of Mo(CO).sub.6, BINAP
and Pd(OAc).sub.2 to generate a compound of Formula IA or IB in
which L.sup.1 is C(O)NH. The amide bond formation can also be
achieved via other Pd-catalyzed CO insertion and subsequent
amination. The carbon monoxide source can also be carbon monoxide
gas or other metal carbonyl complexes such as for example
Co.sub.2(CO).sub.8, Ni(CO).sub.4, Ru.sub.3(CO).sub.12,
Mn.sub.2(CO).sub.12 and the like. Reduction of the amide
functionality with a reducing agent such as for example
BH.sub.3.Me.sub.2S generates a compound of Formula IA or IB in
which L.sup.1 is CH.sub.2NH.
##STR00106##
[0194] The preparation of a compound of Formula IA or IB in which
L.sup.2 is CH.sub.1, L.sup.1 is C.dbd.C or CH.sub.2CH.sub.2 is
described in Scheme 11. An intermediate I-4, II-4, V-1b, VI-5 or
the like is reacted with an alkene such as W.sup.1CHCH.sub.2 under
Heck coupling conditions to generate a compound of Formula IA or IB
in which L.sup.1 is C.dbd.C. hydrogenation of the double bond in
the presence of Pd--C as a catalyst generates a compound of Formula
IA or IB in which L.sup.2 is CH.sub.2CH.sub.1.
##STR00107##
[0195] Alternatively an intermediate I-4, II-4, V-1b, VI-5 can be
reacted with W.sup.1C.dbd.C--B(OH), under Suzuki coupling
conditions. A similar reaction is described in tetrahedron 64(7),
1351-1370, 2008.
[0196] The preparation of a compound of Formula IA or IB in which
L.sup.2 is CH.sub.1, L.sup.1 is C.ident.C is described in Scheme
12. An intermediate I-4, II-4, V-1b, VI-5 or the like is reacted
with an alkyne under Sonagashira coupling conditions.
##STR00108##
[0197] Alternatively, an intermediate I-4, II-4, V-1b, VI-5 or the
like can be reacted with trimethylsilanylethyne under Sonagashira
conditions to generate intermediate XIII-1. Removal of the
trimethylsilane group is followed by a second Sonagashira cross
coupling reaction with a W.sup.1-halide moiety. This 2 steps
sequence reaction is illustrated in Scheme 13. A similar reaction
sequence is described in Bioorganic & Medicinal Chemistry
(2007), 15(4), 1586-1605.
##STR00109##
[0198] The preparation of compounds of Formula IA, IB or IC in
which L.sup.1 is a bond and L.sup.2 is a bond, C(O), S(O).sub.2,
C(O)NH, or an alkyl chain can be achieved via a common intermediate
A:
##STR00110##
[0199] The preparation of intermediates of type A is described
below in Scheme 14 and 16.
[0200] Scheme 14 described the preparation of an intermediate of
type A in which Q is N and n is 1. 3,5-Dibromo-pyrazin-2-amine is
converted to intermediate XIV-4 in which W.sup.2 is p-methoxyphenyl
in a reaction sequence as the one described in Scheme 1.
p-Methoxybenzyl functionality (also known as MPM group is used as a
protecting group which can be later on selectively deprotected in
the presence of a SEM protecting group. Other protecting groups can
also be used in place of the MPM groups as long as they can be
selectively deprotected in the presence of SEM. An other example is
the DMPM protecting group which can be oxidatively cleaved using
for example DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone).
Someone skilled in the art should be able to identify other
suitable protecting groups for this synthetic scheme.
[0201] Intermediate XIV-4 is then treated with
2-(Trimethylsilyl)ethoxymethyl Chloride in the presence of a
suitable base such as for example NaH to generate intermediate
XIV-5. Intermediate XIV-5 is subjected to Suzuki coupling with
W.sup.1B(OH).sub.2. Selective deprotection of the MPM group can be
achieved for example using Ce(NH.sub.4).sub.2(NO.sub.3).sub.6 to
generate intermediate XIV-7.
##STR00111## ##STR00112##
[0202] Scheme 15 described the preparation of an intermediate of
type A in which Q is N and n is 2. 3,5-Dibromo-pyrazin-2-amine is
converted to intermediate XV-3 using the same reaction sequence as
the one described in Scheme 2 in which W.sup.2 is
para-methoxyphenyl. Intermediate XV-3 is then converted to
intermediate XV-4 using the protection-deprotection reaction
sequence described in Scheme 14.
##STR00113##
[0203] Scheme 16 described the preparation of an intermediate of
type A in which Q is CR.sup.c with R.sup.c being methyl and n is 1
or 2. 5-bromo-2-chloro-4-methyl-3-nitropyridine can be reacted with
a SEM-protected methyl glycinate or a SEM-protected methyl
.beta.-alaninate to generate intermediate XVI-1 which subsequently
undergoes a Suzuki coupling reaction with W.sup.1B(OH).sub.2.
Conversion of the nitro group to the amino group can be achieved
using standard hydrogenation conditions and intermediate XVI-2 also
undergoes cyclization under these conditions. The cyclized
intermediate XVI-3 is then reduced using a reducing agent such as
for example LiAlH.sub.4 to generate intermediate XVI-4.
##STR00114##
[0204] Schemes 17 to 20 illustrate the synthesis of compound of
Formula IA, IB or IC in which L.sup.2 is a bond, C(O), S(O).sub.2,
C(O)NH or a lower alkyl.
[0205] The preparation of a compound of Formula IA or IB in which
L.sup.1 and L.sup.2 are bonds is described in Scheme 17. An
intermediate of type A, such as those described above (i.e.
Intermediates XIV-7, XV-4 and XVI-4) can be reacted with W.sup.2Br
(or another halide) under Buchwald-Hartwig amination conditions.
Removal of the SEM protecting group is done under standard
conditions such as for example using TBAF or other fluoride
source.
##STR00115##
[0206] Scheme 18 described the preparation of a compound of Formula
IA, IB or IC in which L.sup.1 is a bond and L.sup.2 is C(O). An
intermediate of type A, such as for example intermediates XIV-7,
XV-4 or XVI-4, can be reacted with an acyl chloride in the presence
of a suitable base such as for example diethylisopropylamine
Acylation is followed by SEM deprotection.
##STR00116##
[0207] Under similar conditions, a compound of Formula IA, IB or IC
in which L.sup.1 is a bond and L.sup.2 is S(O).sub.2, can be
prepared as described in Scheme 19.
##STR00117##
[0208] Scheme 20 depicts the synthesis of a compound of Formula IA,
LB or IC in which L.sup.1 is a bond and L.sup.2 is C(O)NH. An
intermediate of type A, such as for example intermediates XIV-7,
XV-4 or XVI-4, is reacted with an isocyanate followed by SEM
deprotection.
##STR00118##
[0209] Scheme 21 illustrates an example of synthesis of a compound
of Formula IA, IB or IC in which L.sup.1 is a bond and L.sup.2 is a
substituted alkyl. Reacting an intermediate of type A with an
epoxide results in the formation of a compound of Formula IA or LB
in which L.sup.2 is CH.sub.2CH(OH).
##STR00119##
[0210] In some embodiments of this invention, one of R.sup.a and
R.sup.b is or contains P(.dbd.O)(R.sup.3).sub.2.
[0211] Schemes 22 to 30 illustrate the preparation of phosphorous
containing substituents and phosphorous containing moieties of
current interest.
[0212] In a general way a P(O)(R.sup.3).sub.2 group can be
introduced onto an aryl or heteroaryl moiety by reaction of an aryl
halide or heteroaryl halide with P(O)H(R.sup.3).sub.2 in the
presence of a Palladium catalyst as described in Scheme 21.
##STR00120##
[0213] In which R is R.sup.a or R.sup.b or a functional group such
as for example, NH.sub.2, OH, halo, CH.dbd.CH.sub.2, CCH and the
like.
[0214] Scheme 23 illustrates for example the preparation of a
W.sup.1--NH.sub.2 or W.sup.2--NH.sub.2 moiety in which W.sup.2 is a
pyridine substituted with P(.dbd.O)R.sup.3R.sup.3
##STR00121##
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.3R.sup.3 substituent
onto a phenyl ring whether the ring is W.sup.1 or W.sup.2. This
scheme can be used for example for the synthesis of compounds of
this invention of Formulae IA or IB in which L.sup.1 is NH.
[0215] Of other interest are compounds in which R.sup.a or R.sup.b
substituent is phosphorous containing substituent. Scheme 24
illustrates the synthesis of an intermediate W.sup.1--NH.sub.2 or
W.sup.2--NH, in which W.sup.1 or W.sup.2 is a phenyl substituted
with P(.dbd.O)(CH.sub.3).sub.2.
##STR00122##
[0216] Scheme 25 illustrates the preparation of a W.sup.1--NH, or
W.sup.2--NH.sub.2 intermediate in which W.sup.1 or W.sup.2 is a
phenyl substituted with (CH.sub.2)P(.dbd.O)R.sup.3R.sup.3. This
scheme is particularly useful for the synthesis of compounds of
Formulae IA and IB in which L.sup.1 is NH.
##STR00123##
[0217] Scheme 26 illustrates the preparation of a W.sup.1--NH, or
W.sup.2--NH.sub.2 moiety in which W.sup.1 or W.sup.2 is a bicyclic
structure such as naphthalene substituted with
P(O)(R.sup.3).sub.2.
##STR00124##
in which X is a halogen such as for example bromo or iodo.
[0218] Scheme 27 illustrates the synthesis of
W.sup.1--(CH.sub.2)--NH.sub.2 or W.sup.2--(CH.sub.2)--NH.sub.2
intermediate in which W.sup.1 or W.sup.2 is phenyl substituted with
P(O)(R.sup.3), and n is 1. This scheme is particularly useful for
the synthesis of compounds of Formulae IA or IB in which L.sup.2 is
CH.sub.2.
##STR00125##
[0219] In some embodiment, a R.sup.a or R.sup.b containing
P(O)(R.sup.3).sub.2 substituent can be of cyclic structure. Schemes
28 and 29 illustrate the synthesis of cyclic structures of interest
containing P(O)(R.sup.3).sub.2. Scheme 28 illustrates the
preparation of cyclic substituent R.sup.a (or R.sup.b) containing
P(O)(R.sup.3).sub.2.
##STR00126##
[0220] Schemes 28A and 28B illustrate the incorporation of this
cyclic substituent onto a W.sup.1 or W.sup.2. Scheme 28A and 28B
illustrate the synthesis of a W.sup.1--NH, or W.sup.2--NH.sub.2
moiety in which W.sup.1 or W.sup.2 is a phenyl substituted with a
methoxy group and with a P(.dbd.O)R.sup.3R.sup.3 containing cyclic
substituent.
##STR00127##
[0221] Scheme 29 illustrates the synthesis of a W1-NH, or
W.sup.2--NH.sub.2 intermediate in which W.sup.1 or W.sup.2 is
phenyl substituted by methoxy and a P(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.
##STR00128##
[0222] Scheme 30 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 W.sup.1--NH.sub.2 or W.sup.2--NH.sub.2
intermediate in which W.sup.1 or W.sup.2 is a phenyl substituted
with a phosphorous containing piperazine group. It could also be
used for the synthesis of a compound of formula IA or IB in which
L.sup.1 is a bond and W.sup.1 is a piperazine ring substituted with
--CH.sub.2P(.dbd.O)(CH.sub.3).sub.2.
##STR00129##
[0223] 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.
[0224] The synthetic guidance provided in Schemes 1 through 30 is
applicable to a variety of W.sup.1 and W.sup.2 moieties of this
invention and allows the preparation of all compounds of this
invention.
5. Uses, Formulations, Administration
Pharmaceutical Uses; Indications
[0225] This invention provides 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 this 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.
[0226] 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.
[0227] 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).
[0228] 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,
neuroectodennal 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).
[0229] 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 constitutuvely 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 comprisinig 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).
[0230] 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
[0231] The method of the invention comprises administering to a
subject in need thereof a therapeutically effective amount of a
compound of the invention.
[0232] 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.
[0233] 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.
[0234] 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
present 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 this invention; and like factors
well known in the medical arts.
[0235] Furthermore, after formulation with an appropriate
pharmaceutically acceptable carrier in a desired dosage, the
compositions of this invention can be administered to humans and
other animals orally, rectally, parenterally, intracistemally,
intravaginally, intraperitoneally, topically (as by transdermal
patch, powders, ointments, or drops), sublingually, bucally, as an
oral or nasal spray, or the like.
[0236] 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.
[0237] 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.
[0238] When administered for the treatment or inhibition of a
particular disease state or disorder, the effective dosage of the
compound of this 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.
[0239] When the compound of this 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
[0240] Compounds of present invention can exist in free form for
treatment, or where appropriate, as a pharmaceutically acceptable
salt or other derivative. 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 the 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.
[0241] 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.
[0242] Furthermore, the term "pharmaceutically acceptable prodrugs"
as used herein refers to those prodrugs of the compounds of the
present invention which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and lower animals with undue toxicity, irritation, allergic
response, and the like, commensurate with a reasonable benefit/risk
ratio, and effective for their intended use, as well as the
zwitterionic forms, where possible, of the 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.
Compositions
[0243] Accordingly, compositions are provided, which comprise any
one of the compounds described herein (or a prodrug,
pharmaceutically acceptable salt or other pharmaceutically
acceptable derivative thereof), and one or more pharmaceutically
acceptable carriers or excipients. These compositions optionally
further comprise one or more additional therapeutic agents.
Alternatively, a compound of this invention may be administered to
a patient in need thereof in combination with the administration of
one or more other therapeutic regimens (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, additional therapeutic agents for conjoint administration
or inclusion in a pharmaceutical composition with a compound of
this invention may be another one or more anticancer agents.
[0244] As described herein, the compositions of the present
invention comprise a compound of the invention together with a
pharmaceutically acceptable carrier, which, as used herein,
includes any and all 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.
Except insofar as any conventional carrier medium is incompatible
with the compounds of the invention, such as by producing any
undesirable biological effect or otherwise interacting in a
deleterious manner with any other component(s) of the
pharmaceutical composition, its use is contemplated to be within
the scope of this invention. Some examples of materials which can
serve as pharmaceutically acceptable carriers 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.
[0245] Formulations
[0246] This invention also encompasses a class of compositions
comprising the active compounds of this invention in association
with one or more pharmaceutically-acceptable carriers and/or
diluents and/or adjuvants (collectively referred to herein as
"carrier" materials) and, if desired, other active ingredients. The
active compounds of the present 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. The compounds and compositions of the
present 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.
[0247] The pharmaceutically active compounds of this invention can
be processed in accordance with conventional methods of pharmacy to
produce medicinal agents for administration to patients, including
humans and other mammals.
[0248] 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.
[0249] Examples of such dosage units are tablets or capsules. For
example, these 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. A suitable daily dose for a human
or other mammal may vary depending on the condition of the patient
and other factors, but, once again, can be determined using routine
methods.
[0250] The amount of compounds which are administered and the
dosage regimen for treating a disease condition with the compounds
and/or compositions of this invention depends on a variety of
factors, including the age, weight, sex and medical condition of
the subject, the type of disease, the severity of the disease, the
route and frequency of administration, and the particular compound
employed. Thus, the dosage regimen may vary widely, but can be
determined routinely using standard methods. A typical daily dose
is 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.
[0251] For therapeutic purposes, the active compounds of this
invention are ordinarily combined with one or more adjuvants,
excipients or carriers appropriate to the indicated route of
administration. If administered per os, the compounds may be
admixed with lactose, sucrose, starch powder, cellulose esters of
alkanoic acids, cellulose alkyl esters, talc, stearic acid,
magnesium stearate, magnesium oxide, sodium and calcium salts of
phosphoric and sulfuric acids, gelatin, acacia gum, sodium
alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then
tableted or encapsulated for convenient administration. Such
capsules or tablets may contain a controlled-release formulation as
may be provided in a dispersion of active compound in hydroxypropyl
methyl cellulose.
[0252] In the case of skin conditions, it may be preferable to
apply a topical preparation of compounds of this invention to the
affected area two to four times a day.
[0253] 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.
[0254] 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.
[0255] The compounds of this 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.
[0256] The oily phase of the emulsions of this invention may be
constituted from known ingredients in a known manner.
[0257] 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 so-called 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
present 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.
[0258] 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.
[0259] Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils can be
used.
[0260] 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.
[0261] 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.
[0262] 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.
[0263] 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).
[0264] 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.
[0265] For pulmonary administration, the pharmaceutical composition
may be administered in the form of an aerosol or with an inhaler
including dry powder aerosol.
[0266] 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.
[0267] 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.
[0268] Pharmaceutical compositions of this invention comprise a
compound of the formulas described herein or a pharmaceutically
acceptable salt thereof; an additional agent selected from a kinase
inhibitory agent (small molecule, polypeptide, antibody, etc.), an
immunosuppressant, an anticancer agent, an anti-viral agent,
antiinflammatory agent, antifungal agent, antibiotic, or an
anti-vascular hyperproliferation compound; and any pharmaceutically
acceptable carrier, adjuvant or vehicle.
[0269] Alternate compositions of this invention comprise a compound
of the formulae described herein or a pharmaceutically acceptable
salt thereof; and a pharmaceutically acceptable carrier, adjuvant
or vehicle. Such compositions may optionally comprise one or more
additional therapeutic agents, including, for example, kinase
inhibitory agents (small molecule, polypeptide, antibody, etc),
immunosuppressants, anti-cancer agents, anti-viral agents,
antiinflammatory agents, antifungal agents, antibiotics, or
anti-vascular hyperproliferation compounds.
[0270] The term "pharmaceutically acceptable carrier or adjuvant"
refers to a carrier or adjuvant that may be administered to a
patient, together with a compound of this invention, and which does
not destroy the pharmacological activity thereof and is nontoxic
when administered in doses sufficient to deliver a therapeutic
amount of the compound.
[0271] Pharmaceutically acceptable carriers, adjuvants and vehicles
that may be used in the pharmaceutical compositions of this
invention include, but are not limited to, ion exchangers, alumina,
aluminum stearate, lecithin, selfemulsifying drug delivery systems
(SEDDS) such as d-atocopherol polyethyleneglycol 1000 succinate,
surfactants used in pharmaceutical dosage forms such as Tweens or
other similar polymeric delivery matrices, serum proteins, such as
human serum albumin, buffer substances such as phosphates, glycine,
sorbic acid, potassium sorbate, partial glyceride mixtures of
saturated vegetable fatty acids, water, salts or electrolytes, such
as protamine sulfate, disodium hydrogen phosphate, potassium
hydrogen phosphate, sodium chloride, zinc salts, colloidal silica,
magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based
substances, polyethylene glycol, sodium carboxymethylcellulose,
polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,
polyethylene glycol and wool fat. Cyclodextrins such as u-, P-, and
y-cyclodextrin, or chemically modified derivatives such as
hydroxyalkylcyclodextrins, including 2 and
3-hydroxypropyl-cyclodextrins, or other solubilized derivatives may
also be advantageously used to enhance delivery of compounds of the
formulae described herein.
[0272] The pharmaceutical compositions of this invention may be
orally administered in any orally acceptable dosage form including,
but not limited to, capsules, tablets, emulsions and aqueous
suspensions, dispersions and solutions. In the case of tablets for
oral use, carriers which are commonly used include lactose and corn
starch. Lubricating agents, such as magnesium stearate, are also
typically added. For oral administration in a capsule form, useful
diluents include lactose and dried corn starch. When aqueous
suspensions and/or emulsions are administered orally, the active
ingredient may be suspended or dissolved in an oily phase is
combined with emulsifying and/or suspending agents.
[0273] If desired, certain sweetening and/or flavoring and/or
coloring agents may be added.
[0274] The pharmaceutical compositions of this invention may
comprise formulations utilizing liposome or microencapsulation
techniques, various examples of which are known in the art.
[0275] The pharmaceutical compositions of this invention may be
administered by nasal aerosol or inhalation. Such compositions are
prepared according to techniques well known in the art of
pharmaceutical formulation and may be prepared as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, fluorocarbons,
and/or other solubilizing or dispersing agents, examples of which
are also well known in the art.
Combinations
[0276] While the compounds of the invention can be administered as
the sole active pharmaceutical agent, they can also be used in
combination with one or more other compounds of the invention or
with one or more other agents. When administered as a combination,
the therapeutic agents can be formulated as separate compositions
that are administered at the same time or sequentially at different
times, or the therapeutic agents can be given as a single
composition.
[0277] The phrase "combination therapy", in referring to the use of
a compound of this invention together with another pharmaceutical
agent, means the coadministration of each agent in a substantially
simultaneous manner as well as the administration of each agent in
a sequential manner, in either case, in a regimen that will provide
beneficial effects of the drug combination. Coadministration
includes inter alia the simultaneous delivery, e.g., in a single
tablet, capsule, injection or other dosage form having a fixed
ratio of these active agents, as well as the simultaneous delivery
in multiple, separate dosage forms for each agent respectively.
[0278] Thus, the administration of compounds of the present
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.
[0279] If formulated as a fixed dose, such combination products
employ the compounds of this invention within the accepted dosage
ranges. Compounds of this 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 this
invention may be administered prior to, simultaneously with, or
after administration of the other anticancer or cytotoxic
agent.
[0280] 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.
[0281] 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.
[0282] A first family of antineoplastic agents which may be used in
combination with compounds of the present 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.
[0283] EX-015, fazarabine, floxuridine, fludarabine phosphate,
5-fluorouracil, 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.
[0284] A second family of antineoplastic agents which may be used
in combination with compounds of the present 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).sub.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.
[0285] A third family of antineoplastic agents which may be used in
combination with compounds of the present 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-Al, Kyowa Hakko DC92-B,
ditrisarubicin B, Shionogi DOB-41, doxorubicin,
doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin,
esorubicin, esperamicin-Al, esperamicin-Alb, 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-I,
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.
[0286] A fourth family of antineoplastic agents which may be used
in combination with compounds of the present 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, antineoplaston
A10, antineoplaston A2, antineoplaston A3, antineoplaston A5.
antineoplaston AS2-1F Henkel APD, aphidicolin glycinate,
asparaginase, Avarol, baccharin, batracylin, benfluoron,
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, homohaffingtonine, 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, NCl (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, with anolides 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 alfaconl, 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 (Aetema), ambamustine, antisense
oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), cetuximab,
decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800
(Endorecherche), eniluracil, etanidazole, fenretinideI filgrastim
SDO1 (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
[0287] In other embodiments, the present invention relates to a kit
for conveniently and effectively carrying out the methods in
accordance with the present 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. 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.
[0288] The following representative examples contain important
additional information, exemplification and guidance which can be
adapted to the practice of this 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 this
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
1-(2-chloro-3,6-difluorobenzyl)-7-[3-(morpholin-4-yl)phenyl]-1,2,3,4-tetra-
hydropyrazino[2,3-b]pyrazine
##STR00130##
[0289]
5-bromo-N.sup.3-(2-chloro-3,6-difluorobenzyl)pyrazine-2,3-diamine
[0290] A solution of 2-amino-3,5-dibromopyrazine (29 mmol, 7.35 g),
2-chloro-3,6-difluorobenzylamine (29 mmol, 5.16 g), and
N,N-diethylisopropylamine (32 mmol, 5.6 mL) in n-BuOH (20 mL) was
refluxed for 72 hrs. After volatile components were removed on
rotavap, EtOAc and water were added to the residue to facilitate
the extraction. The combined organic layers were combined, dried,
concentrated, and then subjected to a silica gel column
chromatography by using hexanes/EtOAc (4:1) as eluents, furnishing
5-bromo-N.sup.3-(2-chloro-3,6-difluorobenzyl)pyrazine-2,3-diamine
in 70% yield (7.14 g).
Ethyl({5-bromo-3-[(2-chloro-3,6-difluorobenzyl)amino]pyrazin-2-yl}amino)(o-
xo)acetate
[0291] To a stirred solution of
5-bromo-N.sup.3-(2-chloro-3,6-difluorobenzyl)pyrazine-2,3-diamine
(5.15 mmol, 1.8 g) and N,N-diethylisopropylamine (9.30 mmol, 2 mL)
in CH2Cl2 (20 mL) was added ethyl glyoxylate (5.41 mmol, 0.74 g) at
0.degree. C. The suspension was warmed up naturally and stirred
overnight. Water was added to dissolve the precipitation. The
combined organic layers from extraction were combined, dried,
concentrated, and then subjected to a silica gel column
chromatography by using CH2Cl2/MeOH (9:1) as eluents, furnishing
ethyl({5-bromo-3-[(2-chloro-3,6-difluorobenzyl)amino]pyrazin-2-yl}amino)(-
oxo)acetate in 52% yield (1.20 g).
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,4-dihydropyrazino[2,3-b]pyrazine-
-2,3-dione
[0292] A solution of
ethyl({5-bromo-3-[(2-chloro-3,6-difluorobenzyl)amino]pyrazin-2-yl}amino)(-
oxo)acetate (1.20 g) in diglyme was heated at 165.degree. C. for 16
hrs. The volatile components were removed on rotavap and then under
vacuum. The residue was subjected to a silica gel column
chromatography by using CH2Cl2/MeOH (9:1) as eluents, furnishing
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,4-dihydropyrazino[2,3-b]pyrazin-
e-2,3-dione in 43% yield (0.46 g).
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]p-
yrazine
[0293] To a solution of
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,4-dihydropyrazino[2,3-b]pyrazin-
e-2,3-dione (2.5 mmol, 1.0 g) in THF (5 mL) was added BH3.Me2S (7.5
mmol, 3.75 mL, 2.0 M in THF). The resulting solution was refluxed
for 2 hrs under N2. Excessive BH3 was quenched by addition of MeOH
at rt then heating the reaction mixture for 10 min. After volatile
components were removed on rotavap, the residue was subjected to a
silica gel column chromatography by using 4:1 ratio of CH2Cl2/MeOH
(pre-saturated with ammonia gas) as eluents, furnishing
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine in 20% yield (0.19 g).
1-(2-chloro-3,6-difluorobenzyl)-7-[3-(morpholin-4-yl)phenyl]-1,2,3,4-tetra-
hydropyrazino[2,3-b]pyrazine
[0294] A mixture of
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine (0.14 mmol, 51 mg), 3-morpholinophenylboronic acid pinacol
ester (0.16 mmol, 46 mg), and Pd(PPh3)4 (0.015 mmol, 17 mg) was
placed in a Schlenk tube. This tube was degassed via 3 cycles of
vacuum--refill with N2. THF (3 mL, from sureseal bottle) and
aqueous K2CO3 (2.0 M, 1 mL, degassed by bubbling with N2 for 10
min) was then added to the solid mixture in the Schlenk tube. The
reaction was stopped after heating at 90.degree. C. for 16 hrs.
Extraction and concentration of combined organic layers gave a
residue, which was purified on a silica gel column by using 6:1
ratio of CH2Cl2/MeOH (pre-saturated with ammonia gas) as eluents,
furnishing
1-(2-chloro-3,6-difluorobenzyl)-7-[3-(morpholin-4-yl)phenyl]-1,2,3,4-tetr-
ahydropyrazino[2,3-b]pyrazine in 61% yield (38 mg).
Example 2
3-[8-(2-chloro-3,6-difluorobenzyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazi-
n-2-yl]-N-[3-(dimethylamino)propyl]benzamide
##STR00131##
[0296] The entitled compound was prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine and N-[3-(N',N'-Dimethylamino)propyl]benzamide-3-boronic
acid, pinacol ester using Suzuki coupling conditions as described
in Example 1.
Example 3
1-(2-chloro-3,6-difluorobenzyl)-7-{3-[(4-methylpiperazin-1-yl)methyl]pheny-
l}-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine
##STR00132##
[0298] The entitled compound was prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine and 3-(4-Methyl-1-piperazinemethyl)benzeneboronic acid
pinacol ester using Suzuki coupling as described in Example 1.
Example 4
1-(2-chloro-3,6-difluorobenzyl)-7-[2-(piperazin-1-yl)pyrimidin-5-yl]-1,2,3-
,4-tetrahydropyrazino[2,3-b]pyrazine
##STR00133##
[0300] The entitled compound was prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine and 2-(4-Boc-piperazin-1-yl)pyrimidine-5-boronic acid
pinacol ester using Suzuki coupling conditions as described in
Example 1. The Suzuki coupling yielded the desired compound in its
BOC protected form. The BOC protected intermediate was then treated
with TFA in CH.sub.2Cl.sub.2 and purified by Silica gel column
chromatography.
Example 5
{4-[8-(2-chloro-3,6-difluorobenzyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyraz-
in-2-yl]phenyl}(4-methylpiperazin-1-yl)methanone
##STR00134##
[0302] The entitled compound was prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine and 4-(4-Methylpiperazine-1-carbonyl)phenylboronic acid
pinacol ester using Suzuki coupling conditions as described in
Example 1.
Example 6
1-(2-chloro-3,6-difluorobenzyl)-7-[3-(morpholin-4-ylmethyl)phenyl]-1,2,3,4-
-tetrahydropyrazino[2,3-b]pyrazine
##STR00135##
[0304] The entitled compound was prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine and 3-(Methylmorpholino)phenylboronic acid pinacol ester
using Suzuki coupling conditions as described in Example 1.
Example 7
1-(2-chloro-3,6-difluorobenzyl)-7-[4-(morpholin-4-ylmethyl)phenyl]-1,2,3,4-
-tetrahydropyrazino[2,3-b]pyrazine
##STR00136##
[0306] The entitled compound was prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine and 4-(Methylmorpholino)phenylboronic acid pinacol ester
using Suzuki coupling conditions as described in Example 1.
Example 8
1-(2-chloro-3,6-difluorobenzyl)-7-[3-(morpholin-4-yl)phenyl]-1,2,3,4-tetra-
hydropyrazino[2,3-b]pyrazine
##STR00137##
[0308] The entitled compound was prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine and 3-(Morpholino)phenylboronic acid pinacol ester using
Suzuki coupling conditions as described in Example 1.
Example 9
1-(2-chloro-3,6-difluorobenzyl)-7-{1-[2-(morpholin-4-yl)ethyl]-1H-pyrazol--
4-yl}-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine
##STR00138##
[0310] The entitled compound was prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine and 1-(2-Morpholinoethyl)-1H-pyrazole-4-boronic acid,
pinacol ester using Suzuki coupling conditions as described in
Example 1.
Example 10
3-{4-[8-(2-chloro-3,6-difluorobenzyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyr-
azin-2-yl]phenyl}propanehydrazide
##STR00139##
[0312] The entitled compound was prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine and 4-(3-Hydrazino-3-oxopropyl)benzeneboronic acid using
Suzuki coupling conditions as described in Example 1.
Example 11
1-(2,5-dichlorobenzyl)-7-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4--
tetrahydropyrazino[2,3-b]pyrazine
##STR00140##
[0314] The entitled compound was prepared from
7-bromo-1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine
and 2-(4-Methylpiperazin-1-yl)pyridine-5-boronic acid pinacol ester
using Suzuki coupling conditions as described in Example 1.
[0315]
7-bromo-1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyr-
azine was prepared from 2-amino-3,5-dibromopyrazine as described in
Example 1 by replacing 2-chloro-3,6-difluorobenzylamine in step 1
with 2,5-dichlorobenzylamine
Example 12
{3-[8-(2-chloro-3,6-difluorobenzyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyraz-
in-2-yl]phenyl}(4-methylpiperazin-1-yl)methanone
##STR00141##
[0317] The entitled compound was prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine and 3-(4-Methylpiperazine-1-carbonyl)phenylboronicacid,
pinacol ester using Suzuki coupling conditions as described in
Example 1.
Example 13
4-[8-(2-chloro-3,6-difluorobenzyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazi-
n-2-yl]-N-[2-(morpholin-4-yl)ethyl]benzamide
##STR00142##
[0319] The entitled compound was prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine and
4-{2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl}-mo-
rpholine using Suzuki coupling conditions as described in Example
1.
Example 14
{4-[8-(2-chloro-3,6-difluorobenzyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyraz-
in-2-yl]phenyl}[4-(pyrrolidin-1-yl)piperidin-1-yl]methanone
##STR00143##
[0321] The entitled compound was prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine and
[4-(pyrrolidin-1-yl)piperidin-1-yl][4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-
olan-2-yl)phenyl]methanone using Suzuki coupling conditions as
described in Example 1.
[4-(pyrrolidin-1-yl)piperidin-1-yl][4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl]methanone
[0322] A solution of
4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoic acid (9.80
mmol, 2.43 g), 4-(1-pyrrolidinyl)piperidine (10.77 mol, 1.66 g),
1-hydroxybenzotriazole (16.67 mmol, 2.25 g), and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (19.57
mmol, 3.75 g) in DMF (30 mL) was stirred overnight at 60.degree. C.
Upon removal of DMF on rotavap, the residue was taken into mixture
of EtOAc and H2O. The combined organic layers from extraction were
stirred with aq. 2N HCl for 20 min and the aqueous layer was
purified by reverse phase prep-HPLC to furnish the desired boronic
acid (1.24 g. 42%).
Example 15
2-{3-[8-(2-chloro-3,6-difluorobenzyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyr-
azin-2-yl]phenyl}acetamide
##STR00144##
[0324] The entitled compound was prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine and 3-(2-Acetamidyl)phenylboronic acid pinacol ester using
Suzuki coupling conditions as described in Example 1.
Example 16
1-(2-chloro-3,6-difluorobenzyl)-7-[2-(4-methylpiperazin-1-yl)pyridine-4-yl-
]-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine
##STR00145##
[0326] The entitled compound was prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine and 2-(4-Methylpiperazin-1-yl)pyridine-5-boronic acid
pinacol ester using Suzuki coupling conditions as described in
Scheme 1.
Example 17
1-(2-chloro-3,6-difluorobenzyl)-7-[1-(piperidin-4-yl)-1H-pyrazol-3-yl]-1,2-
,3,4-tetrahydropyrazino[2,3-b]pyrazine
##STR00146##
[0328] To a solution of
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine (prepared as in Example 1: 0.17 g, 0.45 mmol) and
4-(-pyrazol-1-yl)-N-Boc piperidine boronic acid pinacol ester
(prepared as described in WO 2007066185: 0.17 g, 0.45 mmol) in
dioxane (2 ml) was added Pd(PPh3).sub.4 (0.026 g, 0.022 mmol) and
aq. K2CO3 (2M, 1 mL). The resulting solution was subjected to
microwave irradiation at 140.degree. C. for 14 min. The solvent was
evaporated and the residue was then chromatographed, eluting with
MeOH-DCM (1:9) to yield the desired compound in its BOC protected
form; the BOC protected intermediate was then treated with TFA in
CH.sub.2Cl.sub.2. Silica gel column chromatography purification
gave the title compound.
Example 18
3-[8-(2-chloro-3,6-difluorobenzyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazi-
n-2-yl]-N-[2-(dimethylamino)ethyl]benzamide
##STR00147##
[0330] The entitled compound was prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine and N-[2-(N',N'-Dimethylamino)ethyl]benzamide-3-boronic
acid pinacol ester using Suzuki coupling conditions as described in
Example 1.
Example 19
4-[8-(2-chloro-3,6-difluorobenzyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazi-
n-2-yl]-N-[3-(dimethylamino)propyl]benzamide
##STR00148##
[0332] The entitled compound was prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine and N-[3-(N',N'-Dimethylamino)propyl]benzamide-4-boronic
acid, pinacol ester using Suzuki coupling conditions as described
in Example 1.
Example 20
4-[8-(2-chloro-3,6-difluorobenzyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazi-
n-2-yl]-N-[2-(diethylamino)ethyl]benzamide
##STR00149##
[0334] The entitled compound was prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine and 4-{[2-(Diethylamino)ethyl]carbamoyl}benzeneboronic
acid hydrochloride using Suzuki coupling conditions as described in
Scheme 1.
Example 21
{4-[8-(2-chloro-3,6-difluorobenzyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyraz-
in-2-yl]phenyl}[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]methanone
##STR00150##
[0336] The entitled compound was prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]-
pyrazine and
[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl][4-(4,4,5,5-tetramethyl-1,-
3,2-dioxaborolan-2-yl)phenyl]methanone using Suzuki coupling
conditions as described in Scheme 1.
[0337]
[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl][4-(4,4,5,5-tetramet-
hyl-1,3,2-dioxaborolan-2-yl)phenyl]methanone was prepared as
described in Example 14 from
4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoic acid and
(R)-(-)-1-(2-pyrrolidinylmethyl)pyrrolidine.
Example 22
1-(2,6-dichlorobenzyl)-7-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-1,2,3,4--
tetrahydropyrazino[2,3-b]pyrazine
##STR00151##
[0339] The entitled compound was prepared from
7-bromo-1-(2,6-dichlorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine
and 2-(4-Methylpiperazin-1-yl)pyridine-5-boronic acid pinacol ester
using Suzuki coupling conditions as described in Example 1.
[0340]
7-bromo-1-(2,6-dichlorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyr-
azine was prepared from 2-amino-3,5-dibromopyrazine as described in
Example 1 by replacing 2-chloro-3,6-difluorobenzylamine in step 1
with 2,6-dichlorobenzylamine.
Example 23
1-(2,5-difluorobenzyl)-7-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-1,2,3,4--
tetrahydropyrazino[2,3-b]pyrazine
##STR00152##
[0342] The entitled compound was prepared from
7-bromo-1-(2,5-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine
and 2-(4-Methylpiperazin-1-yl)pyridine-5-boronic acid pinacol ester
using Suzuki coupling conditions as described in Example 1.
[0343]
7-bromo-1-(2,5-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyr-
azine was prepared as described in Example 1, from
2-amino-3,5-dibromopyrazine as described in Example 1 by replacing
2-chloro-3,6-difluorobenzylamine in step 1 with
2,5-difluorobenzylamine.
Example 24
1-[5-chloro-2-(trifluoromethyl)benzyl]-7-[2-(4-methylpiperazin-1-yl)pyridi-
n-4-yl]-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine
##STR00153##
[0345] The entitled compound was prepared from
7-bromo-1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrazino-
[2,3-b]pyrazine and 2-(4-Methylpiperazin-1-yl)pyridine-5-boronic
acid pinacol ester using Suzuki coupling conditions as described in
Example 1.
[0346]
7-bromo-1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropy-
razino[2,3-b]pyrazine was prepared as described in Example 1 from
2-amino-3,5-dibromopyrazine as described in Example 1 by replacing
2-chloro-3,6-difluorobenzylamine in step 1 with
5-chloro-2-trifluoromethyl-benzylamine.
Example 25
1-(2-chloro-3,6-difluorobenzyl)-8-methyl-7-[3-(morpholin-4-yl)phenyl]-1,2,-
3,4-tetrahydropyrido[2,3-b]pyrazine
##STR00154##
[0347] 5-bromo-4-methylpyridine-2,3-diamine
[0348] 2-Amino-5-bromo-4-methyl-3-nitropyridine (5 g) was dissolved
in 6M HCl (50 mL) and iron powder was slowly added. The reaction
was then heated to reflux until no starting material was seen via
HPLC. The reaction was then cooled to room temperature and
filtered. The bis-HCl salt was dried to a cream solid which was
then taken up in EtOAc, neutralized with 50% NaOH solution to yield
5-bromo-4-methylpyridine-2,3-diamine as a free base.
7-bromo-8-methylpyrido[2,3-b]pyrazine
[0349] 5-bromo-4-methylpyridine-2,3-diamine (0.21 g, 1 mmol) was
dissolved in a mixture of EtOH--H2O; to this was added aqueous
glyoxal 40% (0.2 ml, 4 mmol) and the resulting mixture was refluxed
for 1 h. Upon cooling to room temperature, water was then added.
The product was separated, filtered and washed with excess water
yielded 7-bromo-8-methylpyrido[2,3-b]pyrazine as a sufficiently
enough pure material (0.21 g) for the next step.
7-bromo-8-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine
[0350] 7-bromo-8-methylpyrido[2,3-b]pyrazine (0.21 g) and NaBH4
(0.21 g) in THF (1.4 ml) was treated with trifluoroacetic acid (1.4
ml) at room temperature over a period of 15 min. Stirring continued
for additional 45 min then water was added followed by 50% sodium
hydroxide. The residue was extracted into CH2Cl2, filtered, dried,
and concentrated to furnish the desired product (0.12 g).
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-8-methyl-1,2,3,4-tetrahydropyrido[-
2,3-b]pyrazine
[0351] 1,2,3,4-Tetrahydro-6-methyl-7-bromo pyrido[2,3-b]pyrazine
(0.15 g, 1 mmol), 2-chloro 3,6-difluoro-benzyl bromide (0.16 g,
1.05 mmol), KI (0.016 mmol, 0.01 g) in acetonitrile was subjected
to microwave irradiation at 130.degree. C. for 20 min. The solvent
was stripped off and the crude residue was re-dissolved in CH2Cl2,
washed with aqueous NaHCO3 solution. Upon drying, the residue was
chromatographed, eluting with a mixture of hexanes-EtOAc (7:3) to
furnish pure desired product (0.086 g 23%). The undesired
N-alkylation product was also obtained and the structural
differentiation was based on NOE NMR experiment.
1-(2-chloro-3,6-difluorobenzyl)-8-methyl-7-[3-(morpholin-4-yl)phenyl]-1,2,-
3,4-tetrahydropyrido[2,3-b]pyrazine
[0352] To a solution of
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-8-methyl-1,2,3,4-tetrahydropyrido-
[2,3-b]pyrazine (0.048 g, 0.124 mmol) and 3-morpholinophenylboronic
acid pinacol ester (0.035 g, 0.124 mmol) in DMF-H2O (9:1, 2 mL) was
added PdCl2(PPh3)2 (0.0087 g, 0.0124 mmol) and K2CO3 (0.043 mg,
0.31 mmol). The resulting solution was subjected to microwave
irradiation at 125.degree. C. for 20 min. The solvent was filtered
using a PTFE fit and then directly purified by prep HPLC using a
gradient mixture of ACN--H2O-0.1% TFA to yield the desired product
(0.023 g 40%).
Example 26
1-(2-chloro-3,6-difluorobenzyl)-8-methyl-7-[1-(piperidin-4-yl)-1H-pyrazol--
4-yl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine
##STR00155##
[0354] To a solution of
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-8-methyl-1,2,3,4-tetrahydropyrido-
[2,3-b]pyrazine (prepared as in Example 25: 0.17 g, 0.45 mmol) and
4-(-pyrazol-1-yl)-N-Boc piperidine boronic acid pinacol ester
(prepared as described in WO 2007066185: 0.17 g, 0.45 mmol) in
dioxane (2 ml) was added Pd(PPh.sub.3).sub.4 (0.026 g, 0.022 mmol)
and aq. K.sub.2CO.sub.3 (2M, 1 mL). The resulting solution was
subjected to microwave irradiation at 140.degree. C. for 14 min.
The solvent was evaporated and the residue was then
chromatographed, eluting with MeOH-DCM (1:9) to yield the desired
compound in its BOC protected form. The BOC protected intermediate
was then treated with TFA in CH.sub.2Cl.sub.2. Silica gel column
chromatography purification gave the title compound.
Example 27
1-(2-chloro-3,6-difluorobenzyl)-8-methyl-7-{1-[2-(morpholin-4-yl)ethyl]-1H-
-pyrazol-4-yl}-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine
##STR00156##
[0356] The entitled compound can be prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-8-methyl-1,2,3,4-tetrahydropyrido-
[2,3-b]pyrazine and 1-(2-morpholinoethyl)-1H-pyrazole-4-boronic
acid pinacol ester as described in Example 25.
Example 28
5-[1-(2-chloro-3,6-difluorobenzyl)-8-methyl-1,2,3,4-tetrahydropyrido[2,3-b-
]pyrazin-7-yl]-N-[2-(morpholin-4-yl)ethyl]pyridin-2-amine
##STR00157##
[0358] The entitled compound can be prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-8-methyl-1,2,3,4-tetrahydropyrido-
[2,3-b]pyrazine and 2-(2-morpholinoethylamino)pyridine-5-boronic
acid pinacol ester as described in example 25.
Example 29
1-(2-chloro-3,6-difluorobenzyl)-8-methyl-7-{4-[2-(4-methylpiperazin-1-yl)e-
thoxy]phenyl}-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine
##STR00158##
[0360] The entitled compound can be prepared from
7-bromo-1-(2-chloro-3,6-difluorobenzyl)-8-methyl-1,2,3,4-tetrahydropyrido-
[2,3-b]pyrazine and
1-methyl-4-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenoxy]-
-ethyl}-piperazine as described in example 25.
Example 30
9-(2-chloro-3,6-difluorobenzyl)-2-[3-(morpholin-4-yl)phenyl]-6,7,8,9-tetra-
hydro-5H-pyrazino[2,3-b][1,4]diazepine
##STR00159##
[0361] Methyl N-(3,5-dibromopyrazin-2-yl)-.beta.-alaninate
[0362] A solution of 2-amino-3,5-dibromopyrazine (40 mmol, 10 g)
and methyl acrylate (56 mmol, 4.82 g) in pyridine (60 mL) was
heated at 100.degree. C. overnight. Upon cooling, volatile
components were removed on rotavap and the residue was directly
used in the next step.
[0363] Methyl
N-{5-bromo-3-[(2-chloro-3,6-difluorobenzyl)amino]pyrazin-2-yl}-.beta.-ala-
ninate was prepared from methyl
N-(3,5-dibromopyrazin-2-yl)-.beta.-alaninate and
2-chloro-3,6-difluorobenzylamine in the presence of
N,N-diethylisopropylamine as described in Example 1.
3-Bromo-5-(2-chloro-3,6-difluorobenzyl)-5,7,8,9-tetrahydro-6H-pyrazino[2,3-
-b][1,4]diazepin-6-one
[0364] A solution of methyl
N-{5-bromo-3-[(2-chloro-3,6-difluorobenzyl)amino]pyrazin-2-yl}-.beta.-ala-
ninate in HOAc was heated at reflux for 4 hrs. After volatile
components were removed on rotavap, the residue was taken in to a
mixture of EtOAc and aq. NaHCO.sub.3. The combined organic layers
from extraction was dried, concentrated, and then purified by
silica gel column chromatography (EtOAc/Hexanes 4:1) to furnish
3-bromo-5-(2-chloro-3,6-difluorobenzyl)-5,7,8,9-tetrahydro-6H-pyrazino[2,-
3-b][1,4]diazepin-6-one.
[0365]
2-Bromo-9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyraz-
ino[2,3-b][1,4]diazepine was prepared from
3-bromo-5-(2-chloro-3,6-difluorobenzyl)-5,7,8,9-tetrahydro-6H-pyrazino[2,-
3-b][1,4]diazepin-6-one by reducing the amide functionality using
BH.sub.3.Me.sub.2S as described in Example 1.
[0366]
9-(2-chloro-3,6-difluorobenzyl)-2-[3-(morpholin-4-yl)phenyl]-6,7,8,-
9-tetrahydro-5H-pyrazino[2,3-b][1,4]diazepine was prepared from
2-bromo-9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,-
3-b][1,4]diazepine and 3-morpholinophenylboronic acid pinacol ester
using standard Suzuki conditions as described in Example 1 or
2.
Example 31
3-[9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b][1-
,4]diazepin-2-yl]-N-[2-(morpholin-4-yl)ethyl]benzamide
##STR00160##
[0368] The entitled compound can be prepared from
2-Bromo-9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,-
3-b][1,4]diazepine and 3-(2-morpholinoethylcarbamoyl)phenyl boronic
acid as described in example 1 or 30.
Example 32
{3-[9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b][-
1,4]diazepin-2-yl]phenyl}[4-(2-hydroxyethyl)piperazin-1-yl]methasone
##STR00161##
[0370] The entitled compound can be prepared from
2-Bromo-9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,-
3-b][1,4]diazepine and
3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)phenylboronic acid as
described in example 1 or 30.
Example 33
9-(2-chloro-3,6-difluorobenzyl)-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin--
6-yl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b][1,4]diazepine
##STR00162##
[0372] The entitled compound can be prepared from
2-Bromo-9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,-
3-b][1,4]diazepine and
2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahyd-
roquinoline as described in example 1 or 30.
Example 34
6-[9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b][1-
,4]diazepin-2-yl]-N-methylquinazolin-2-amine
##STR00163##
[0374] The entitled compound can be prepared from
2-Bromo-9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,-
3-b][1,4]diazepine and
N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-quinazolin-2-ami-
ne as described in example 1 or 30.
Example 35
9-(2-chloro-3,6-difluorobenzyl)-2-{4-[2-(1H-imidazol-1-0)ethoxy]phenyl}-6,-
7,8,9-tetrahydro-5H-pyrazino[2,3-b][1,4]diazepine
##STR00164##
[0376] The entitled compound can be prepared from
2-Bromo-9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,-
3-b][1,4]diazepine and 4-(2-(1H-imidazol-1-yl)ethoxy)phenyl boronic
acid as described in example 1 or 30.
Example 36
Biological Evaluation of Compounds
[0377] Compounds of this invention are evaluated in a variety of
assays to determine their biological activities. For example, the
compounds of the invention are tested for their ability to inhibit
various protein kinases of interest. Some of the compounds tested
displayed potent nanomolar activity against the kinase Alk.
Furthermore some of these compounds were screened for
antiporliferative activity in the human Karpas-299 and in the human
SU-DHL-1 lymphoma cell lines. 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.
[0378] Some representative compounds of this invention are depicted
below:
##STR00165## ##STR00166## ##STR00167## ##STR00168## ##STR00169##
##STR00170## ##STR00171##
Kinase Inhibition
[0379] 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.
[0380] 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.
[0381] 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.
[0382] 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.
[0383] 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.
[0384] 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).
[0385] 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 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).
[0386] 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.
[0387] 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.
[0388] IC.sub.50 values in the low nanomolar range have been
observed for compounds of this invention against various kinases,
including ALK and Met.
Cell-Based Assays
[0389] Certain compounds of this 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 this invention, the terms "anti-tumor"
and "anti-cancer" activity are used interchangeably.
[0390] Cell-based methods for measuring antiproliferative activity
are well known and can be used for comparative characterization of
compounds of this 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).
[0391] 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).
[0392] 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.).
[0393] 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).
[0394] 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.
[0395] 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.
[0396] 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.
[0397] 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.
[0398] The antiproliferative action of the compounds of this
invention can also be determined in the human KARPAS-299 lymphoma
cell line by means of an immunoblot as described in WG Dirks et al.
Int. J. Cancer 2002, 100, 49-56., using the methodology described
above for the BaF3-NPM-ALK cell line.
[0399] In another example, antiproliferative activity can be
determined using KARPAS-299 lumphoma 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.
[0400] Several compounds of Formula I exhibit inhibitory activity
with an IC.sub.50 in the range of 10 nM to 200 nM.
[0401] 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).
[0402] 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).
Example 37
Pharmaceutical Compositions
[0403] Representative pharmaceutical dosage forms of the compounds
of this 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
TABLE-US-00002 (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
TABLE-US-00003 (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
TABLE-US-00004 (d) Capsule mg/capsule Compound 10 Lactose Ph. Eur
488.5 Magnesium 1.5
TABLE-US-00005 (e) Injection I (50 mg/ml) Compound 5.0% w/v 1M
Sodium hydroxide solution 15.0% v/v.sup. 0. IM Hydrochloric acid
(to adjust pH to 7.6) Polyethylene glycol 400 4.5% w/v Water for
injection to 100%
TABLE-US-00006 (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.sup. Water for injection to 100%
TABLE-US-00007 (g) Injection III (1 mg/ml, buffered to pH 6)
Compound .sup. 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%
TABLE-US-00008 (h) Aerosol I mg/ml Compound 10.0 Sorbitan trioleate
13.5 Trichlorofluoromethane 910.0 Dichlorodifluoromethane 490.0
TABLE-US-00009 (i) Aerosol II mg/ml Compound 0.2 Sorbitan trioleate
0.27 Trichlorofluoromethane 70.0 Dichlorodifluoromethane 280.0
Dichlorotetrafluoroethane 1094.0
TABLE-US-00010 (j) Aerosol III mg/ml Compound 2.5 Sorbitan
trioleate 3.38 Trichlorofluoromethane 67.5 Dichlorodifluoromethane
1086.0 Dichlorotetrafluoroethane 191.6
TABLE-US-00011 (k) Aerosol IV mg/ml Compound 2.5 Soya lecithin 2.7
Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0
Dichlorotetrafluoroethane 191.6
TABLE-US-00012 (l) Ointment ml Compound 40 mg Ethanol 300 .mu.l
Water 300 .mu.l 1-Dodecylazacycloheptanone 50 .mu.l Propylene
glycol to 1 ml
Note: 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.
* * * * *
References