U.S. patent application number 10/989745 was filed with the patent office on 2005-07-07 for amide derivatives as abl modulators.
This patent application is currently assigned to Ambit Biosciences Corporation. Invention is credited to Grotzfeld, Robert M., Lai, Andiliy G., Lockhart, David J., Mehta, Shamal A., Milanov, Zdravko V., Patel, Hitesh K..
Application Number | 20050148605 10/989745 |
Document ID | / |
Family ID | 34623983 |
Filed Date | 2005-07-07 |
United States Patent
Application |
20050148605 |
Kind Code |
A1 |
Grotzfeld, Robert M. ; et
al. |
July 7, 2005 |
Amide derivatives as ABL modulators
Abstract
The invention provides methods and compositions for treating
conditions mediated by abl wherein derivatives of amide compounds
are employed. The invention also provides methods of using the
compounds and/or compositions in the treatment of a variety of
diseases and unwanted conditions in subjects.
Inventors: |
Grotzfeld, Robert M.;
(Carlsbad, CA) ; Patel, Hitesh K.; (Encinitas,
CA) ; Mehta, Shamal A.; (San Diego, CA) ;
Milanov, Zdravko V.; (San Diego, CA) ; Lai, Andiliy
G.; (San Diego, CA) ; Lockhart, David J.; (Del
Mar, CA) |
Correspondence
Address: |
WILSON SONSINI GOODRICH & ROSATI
650 PAGE MILL ROAD
PALO ALTO
CA
943041050
|
Assignee: |
Ambit Biosciences
Corporation
|
Family ID: |
34623983 |
Appl. No.: |
10/989745 |
Filed: |
November 15, 2004 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60520273 |
Nov 13, 2003 |
|
|
|
60527094 |
Dec 3, 2003 |
|
|
|
60531243 |
Dec 18, 2003 |
|
|
|
60531082 |
Dec 18, 2003 |
|
|
|
Current U.S.
Class: |
514/263.2 ;
514/266.23 |
Current CPC
Class: |
A61K 31/42 20130101;
C07D 231/40 20130101; A61P 11/00 20180101; A61P 29/00 20180101;
A61P 11/08 20180101; C07D 413/14 20130101; Y02A 50/411 20180101;
C07D 495/04 20130101; A61P 43/00 20180101; C07D 261/18 20130101;
C07D 277/46 20130101; C07D 471/04 20130101; A61P 9/00 20180101;
Y02A 50/30 20180101; C07D 405/12 20130101; C07D 471/06 20130101;
A61P 35/00 20180101; C07D 413/12 20130101; C07D 417/14 20130101;
C07D 487/04 20130101; A61P 9/10 20180101; C07D 513/04 20130101;
C07D 277/82 20130101; C07D 261/14 20130101; C07D 413/04 20130101;
Y02A 50/401 20180101; A61P 35/02 20180101; A61P 35/04 20180101;
C07D 417/12 20130101; C07D 231/12 20130101; C07D 261/08
20130101 |
Class at
Publication: |
514/263.2 ;
514/266.23 |
International
Class: |
A61K 031/52; A61K
031/517 |
Claims
What is claimed is:
1. A method of modulating abl kinase, said method comprising
administering an effective amount of a compound corresponding to
Formula (IA): 320wherein: M is substituted or unsubstituted
heteroaryl, or substituted or unsubstituted aryl; N is a
substituted or unsubstituted aryl, or substituted or unsubstituted
hetroaryl; and K is 321Y is O or S; each R.sub.k is independently
H, halogen, substituted or unsubstituted alkyl, --OH, substituted
or unsubstituted alkoxy, --OC(O)R.sub.2, --NO.sub.2,
--N(R.sub.2).sub.2, --SR.sub.2, --C(O)R.sub.2, --C(O).sub.2R.sub.2,
--C(O)N(R.sub.2).sub.2, or --N(R.sub.2)C(O)R.sub.2, each R.sub.2 is
independently H, substituted or unsubstituted alkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl; or wherein two R.sub.2 groups are linked
together by an optionally substituted alkylene; and each n is
independently 0, 1, 2, 3 or 4; or an active metabolite, or a
pharmaceutically acceptable prodrug, isomer, pharmaceutically
acceptable salt or solvate thereof.
2. The method of claim 1, wherein said compound corresponds to
Formula (IB): 322wherein: each Z is independently C, CR.sub.3, N,
NR.sub.3, O, or S, provided that no more than two Z's are
heteroatoms and wherein no two adjacent Z's are O or S, where
R.sub.3 is H, substituted or unsubstituted alkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl,
or substituted or unsubstituted aryl; and each R.sub.1 is
independently H, halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkoxy, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sub.c --OH, --OC(O)R.sub.c, --NO.sub.2, --N(R.sub.c).sub.2,
--SR.sub.c, S(O).sub.jR.sub.c where j is 1 or 2,
--NR.sub.c(O)R.sub.c, --C(O)N(R.sub.c).sub.2, --C(O).sub.2R.sub.c,
or --C(O)R.sub.c; or two adjacent R.sub.1's, are taken together to
form a substituted or unsubstituted aryl or heteroaryl, each
R.sub.c is independently H, substituted or unsubstituted alkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl.
3. The method of claim 2, wherein said compound corresponds to
Formula (I): 323wherein K is 324each R.sub.k is independently H,
halogen, substituted or unsubstituted alkyl, or substituted or
unsubstituted alkoxy.
4. The method of claim 3, wherein said compound corresponds to
Formula (II): 325
5. The method of claim 4, wherein said compound corresponds to
Formula (III): 326wherein Z.sub.1 is CR.sub.3 or N; and Z.sub.2 is
O or S.
6. The method of claim 5, wherein said compound corresponds to
Formula (IV): 327wherein: L is a linker selected from the group
consisting of a covalent bond, substituted or unsubstituted
alkenylene, substituted or unsubstituted alkylene, --C(O)NH--,
--C(O)--, --NH--, --O--, --S--, --O(substituted or unsubstituted
alkylene)-, --N(substituted or unsubstituted alkylene)-,
--C(O)NH(substituted or unsubstituted alkylene)-,
--C(O)NH(substituted or unsubstituted alkenylene)-,
--NHC(O)(substituted or unsubstituted alkylene)-,
--NHC(O)(substituted or unsubstituted alkenylene)-,
--C(O)(substituted or unsubstituted alkenylene)-, and
--NHC(O)(substituted or unsubstituted alkylene)S(substituted or
unsubstituted alkylene)C(O)NH--; and T is a mono-, bi-, or
tricyclic, substituted or unsubstituted cycloalkyl, heterocyclyl,
aryl, or heteroaryl.
7. The method of claim 6, wherein T of said compound corresponds to
Formula (V): 328wherein A is a substituted or unsubstituted five or
six-membered heterocyclyl, aryl, or heteroaryl; and B is a
substituted or unsubstituted five or six-membered heterocyclene,
arylene, or heteroarylene, wherein A and B together form a fused
two ring moiety.
8. The method of claim 7, wherein said compound corresponds to
Formula (VI): 329
9. The method of claim 8, wherein L of said compound is
--O(substituted or unsubstituted alkylene)-, --C(O)NH--, or a
covalent bond.
10. The method of claim 8, wherein A of said compound is
substituted or unsubstituted five or six-membered aryl or
heteroaryl; and B of said compound is substituted or unsubstituted
five or six-membered arylene or heteroarylene.
11. The method of claim 10, wherein said compound corresponds to
Formula (VII): 330wherein: each X is independently C, CR, N, NR, or
O, wherein no more than three X's is a heteroatom, and no two
adjacent ring atoms are O; and each R is independently H, halogen,
substituted or unsubstituted alkyl, --OH, substituted or
unsubstituted alkoxy, --OC(O)R.sub.d, --NO.sub.2,
--N(R.sub.d).sub.2, --SR.sub.d, --S(O).sub.jR.sub.d where j is 1 or
2, --NR.sub.d C(O)R.sub.d, --C(O).sub.2R.sub.d,
--C(O)N(R.sub.d).sub.2 or --C(O)R.sub.d, or two adjacent R's are
taken together to form a substituted or unsubstituted aryl or
hetroaryl, where each R.sub.d is independently H, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl or substituted or unsubstituted
heteroaryl.
12. The method of claim 11, wherein said compound corresponds to
Formula (VIII): 331
13. The method of claim 12, wherein said compound is selected from
the group consisting of: 332
14. The method of claim 10, wherein said compound corresponds to
Formula (IX): 333wherein: each X is independently C, CR, N, NR, S
or O, wherein no more than three X's is a heteroatom, and no two
adjacent ring atoms are O or S; and each R is independently H,
halogen, substituted or unsubstituted alkyl, --OH, substituted or
unsubstituted alkoxy, --OC(O)R.sub.d, --NO.sub.2,
--N(R.sub.d).sub.2, --SR.sub.d, --S(O).sub.jR.sub.d where j is 1 or
2, --NR.sub.d C(O)R.sub.d, --C(O).sub.2R.sub.d,
--C(O)N(R.sub.d).sub.2 or --C(O)R.sub.d, or two adjacent R's are
taken together to form a substituted or unsubstituted aryl or
hetroaryl, where each R.sub.d is independently H, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl or substituted or unsubstituted
heteroaryl.
15. The method of claim 14, wherein said compound corresponds to
Formula (X): 334
16. The method of claim 15, wherein said compound corresponds to
Formula (XI): 335
17. The method of claim 16, wherein said compound is selected from
the group consisting of: 336
18. The method of claim 15, wherein said compound corresponds to
Formula (XII): 337
19. The method of claim 1, wherein said abl kinase is mutant T315I
Abl-1 kinase.
20. The method of claim 1, wherein said compound is selected from
the group consisting of: 338
21. A method of treating a disease mediated by abl kinase, said
method comprising administering a therapeutically effective amount
of a compound corresponding to Formula (IA): 339wherein: M is
substituted or unsubstituted heteroaryl, or substituted or
unsubstituted aryl; N is a substituted or unsubstituted aryl, or
substituted or unsubstituted hetroaryl; and K is 340Y is O or S;
each R.sub.k is independently H, halogen, substituted or
unsubstituted alkyl, --OH, substituted or unsubstituted alkoxy,
--OC(O)R.sub.2, --NO.sub.2, --N(R.sub.2).sub.2, --SR.sub.2,
--C(O)R.sub.2, --C(O).sub.2R.sub.2, --C(O)N(R.sub.2).sub.2, or
--N(R.sub.2)C(O)R.sub.2, each R.sub.2 is independently H,
substituted or unsubstituted alkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
or wherein two R.sub.2 groups are linked together by an optionally
substituted alkylene; and each n is independently 0, 1, 2, 3 or 4;
or an active metabolite, or a pharmaceutically acceptable prodrug,
isomer, pharmaceutically acceptable salt or solvate thereof.
Description
[0001] This application claims priority to U.S. Provisional
Application No. 60/520,273, filed Nov. 13, 2003, U.S. Provisional
Application No. 60/527,094, filed Dec. 3, 2003, U.S. Provisional
Application No. 60/531,243, filed Dec. 18, 2003, and U.S.
Provisional Application No. 60/531,082, filed Dec. 18, 2003, the
contents of which are incorporated herein by reference in their
entirety.
BACKGROUND
[0002] Protein kinases (PKs) play a role in signal transduction
pathways regulating a number of cellular functions, such as cell
growth, differentiation, and cell death. PKs are enzymes that
catalyze the phosphorylation of hydroxy groups on tyrosine, serine
and threonine residues of proteins, and can be conveniently broken
down into two classes, the protein tyrosine kinases (PTKs) and the
serine-threonine kinases (STKs). Growth factor receptors with PTK
activity are known as receptor tyrosine kinases. Protein receptor
tyrosine kinases are a family of tightly regulated enzymes, and the
aberrant activation of various members of the family is one of the
hallmarks of cancer. The protein-tyrosine kinase family, which
includes Bcr-Abl tyrosine kinase, can be divided into subgroups
that have similar structural organization and sequence similarity
within the kinase domain. The members of the type III group of
receptor tyrosine kinases include the platelet-derived growth
factor (PDGF) receptors (PDGF receptors .alpha. and .beta.),
colony-stimulating factor (CSF-1) receptor (CSF-1R, c-Fms), FLT-3,
and stem cell or steel factor receptor (c-kit). A more complete
listing of the known Protein receptor tyrosine kinases subfamilies
is described in Plowman et al., DN&P, 7(6): 334-339 (1994),
which is incorporated by reference, including any drawings, as if
fully set forth herein. Furthermore, for a more detailed discussion
of "non-receptor tyrosine kinases", see Bolen, Oncogene, 8:
2025-2031 (1993), which is incorporated by reference, including any
drawings, as if fully set forth herein.
[0003] Hematologic cancers, also known as hematologic or
hematopoietic malignancies, are cancers of the blood or bone
marrow; including leukemia and lymphoma. Acute myelogenous leukemia
(AML) is a clonal hematopoietic stem cell leukemia that represents
.about.90% of all acute leukemias in adults. See e.g., Lowenberg et
al., N. Eng. J. Med. 341: 1051-62 (1999). While chemotherapy can
result in complete remissions, the long term disease-free survival
rate for AML is about 14% with about 7,400 deaths from AML each
year in the United States. The single most commonly mutated gene in
AML is FLT3 kinase. See e.g., Abu-Duhier et al., Br. J. Haemotol.
111: 190-05 (2000); Kiyoi et al., Blood 93: 3074-80 (1999);
Kottaridis et al., Blood 98: 1752-59 (2001); Stirewalt et al.,
Blood 97: 3589-95 (2001). Such mutations also indicate a poor
prognosis for the patient.
[0004] The compounds provided by the present invention are urea
derivatives of substituted aryls and hetroaryls, e.g., isoxazoles,
pyrazoles and isothiazoles. Urea derivatives of pyrazoles have been
reported to be selective p38 kinase inhibitors by Dumas, J., et
al., Bioorg. Medic. Chem. Lett. 10: 2051-2054 (2000). Oxazoles and
isopyrazoles are suggested as blockers of cytokine production in WO
00/43384 published 27 Jul. 2000. Urea derivatives of isoxazole and
pyrazoles are described as inhibitors of RAF kinase in WO 99/32106
published 1 Jul. 1999. Such compounds are also described as p38
kinase inhibitors by Dumas, J., et al., Bioorg. Medic. Chem. Lett.
10: 2047-2050 (2000). These compounds are also suggested as p38
kinase inhibitors in PCT publication WO 99/32111 published 1 Jul.
1999.
[0005] There remains a need for additional compounds that are
effective in inhibiting kinase activity. Given the complexities of
signal transduction with the redundancy and crosstalk between
various pathways, the identification of specific kinase inhibitors
permits accurate targeting with limited inhibition of other
pathways, thus reducing the toxicity of such inhibitory
compounds.
SUMMARY OF THE INVENTION
[0006] The present invention provides compounds which modulate
kinase activity, and in some embodiments inhibit protein tyrosine
kinases or a specific kinase or kinase class. In some embodiments,
the compositions and methods for treating and preventing conditions
and diseases, such as cancer, hematologic malignancies,
cardiovascular disease, inflammation or multiple sclerosis. The
compounds of the invention can be delivered alone or in combination
with additional agents, and are used for the treatment and/or
prevention of conditions and diseases. Unless otherwise stated,
each of the substituents is as previously defined.
[0007] Provided herein are compositions and methods for treating a
disease comprising administering to a subject in need thereof an
effective amount of an abl kinase modulating compound having the
structure: 1
[0008] wherein:
[0009] (a) A.sub.a1 is N--R.sub.3a or C--R(.sub.3a).sub.2 and
A.sub.a2 is N--R.sub.3a or C--R(.sub.3a).sub.2, wherein one of
A.sub.a1 or A.sub.a2 is N and one is C wherein each R.sub.3a is
independently a suitable substituent selected from hydrogen, or an
alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl,
heterocycloalkyl, heteroaryl group unsubstituted or substituted
with one or more suitable substituents independently selected from
the group consisting of: halogens; --CN; and --NO.sub.2; and alkyl,
alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl,
heterocycloalkyl, heteroaryl, --(CH.sub.2).sub.zCN where z is a
whole integer, preferably from 0 to 4, .dbd.NH, --NHOH, --OH,
--C(O)H, --OC(O)H, --C(O)OH, --OC(O)OH, --OC(O)OC(O)H, --OOH,
--C(NH)NH.sub.2, --NHC(NH)NH.sub.2, --C(S)NH.sub.2,
--NHC(S)NH.sub.2, --NHC(O)NH.sub.2, --S(O.sub.2)H, --S(O)H,
--NH.sub.2, --C(O)NH.sub.2, --OC(O)NH.sub.2, --NHC(O)H, --NHC(O)OH,
--C(O)NHC(O)H, --OS(O.sub.2)H, --OS(O)H, --OSH, --SC(O)H,
--S(O)C(O)OH, --SO.sub.2C(O)OH, --NHSH, --NHS(O)H, --NHSO.sub.2H,
--C(O)SH, --C(O)S(O)H, --C(O)S(O.sub.2)H, --C(S)H, --C(S)OH,
--C(SO)OH, --C(SO.sub.2)OH, --NHC(S)H, --OC(S)H, --OC(S)OH,
--OC(SO.sub.2)H, --S(O.sub.2)NH.sub.2, --S(O)NH.sub.2, --SNH.sub.2,
--NHCS(O.sub.2)H, --NHC(SO)H, --NHC(S)H, and --SH groups
unsubstituted or substituted with one or more suitable substituents
independently selected from the group consisting of halogens,
.dbd.O, --NO.sub.2, --CN, --(CH.sub.2).sub.z--CN where z is a whole
integer, preferably from 0 to 4, --OR.sub.c, --NR.sub.cOR.sub.c,
--NR.sub.cR.sub.c, --C(O)NR.sub.c, --C(O)OR.sub.c, --C(O)R.sub.c,
--NR.sub.cC(O)NR.sub.cR.sub.c, --NR.sub.cC(O)R.sub.c,
--OC(O)OR.sub.c, --OC(O)NR.sub.cR.sub.c, --SR.sub.c, unsubstituted
alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted
aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and
unsubstituted heteroaryl, or two or more substituents cyclize to
form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl,
aryl, or heteroaryl group, where each R.sub.c is indepenently
selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl,
unsubstituted alkynyl, unsubstituted aryl, unsubstituted
cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted
heteroaryl, or two or more R.sub.c groups together cyclize to form
part of a heteroaryl or heterocycloalkyl group unsubstituted or
substituted with an unsubstituted alkyl group; or two R.sub.3a's
cyclize to form part of a heteroaryl or heterocycloalkyl group
unsubstituted or substituted with one two or three suitable
substituents selected from halogen, .dbd.O; .dbd.S; --CN;
--NO.sub.2, or an alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl,
aryl, cycloalkyl, heterocycloalkyl, heteroaryl group unsubstituted
or substituted with one or more suitable substituents independently
selected from the group consisting of: halogens; .dbd.O; .dbd.S;
--CN; and --NO.sub.2; and alkyl, alkenyl, heteroalkyl, haloalkyl,
alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,
--(CH.sub.2).sub.zCN where z is a whole integer, preferably from 0
to 4, .dbd.NH, --NHOH, --OH, --C(O)H, --OC(O)H, --C(O)OH,
--OC(O)OH, --OC(O)OC(O)H, --OOH, --C(NH)NH.sub.2,
--NHC(NH)NH.sub.2, --C(S)NH.sub.2, --NHC(S)NH.sub.2,
--NHC(O)NH.sub.2, --S(O.sub.2)H, --S(O)H, --NH.sub.2,
--C(O)NH.sub.2, --OC(O)NH.sub.2, --NHC(O)H, --NHC(O)OH,
--C(O)NHC(O)H, --OS(O.sub.2)H, --OS(O)H, --OSH, --SC(O)H,
--S(O)C(O) OH, --SO.sub.2C(O)OH, --NHSH, --NHS(O)H, --NHSO.sub.2H,
--C(O)SH, --C(O)S(O)H, --C(O)S(O.sub.2)H, --C(S)H, --C(S)OH,
--C(SO)OH, --C(SO.sub.2)OH, --NHC(S)H, --OC(S)H, --OC(S)OH,
--OC(SO.sub.2)H, --S(O.sub.2)NH.sub.2, --S(O)NH.sub.2, --SNH.sub.2,
--NHCS(O.sub.2)H, --NHC(SO)H, --NHC(S)H, and --SH groups
unsubstituted or substituted with one or more suitable substituents
independently selected from the group consisting of halogens,
.dbd.O, --NO.sub.2, --CN, --(CH.sub.2).sub.z--CN where z is a whole
integer, preferably from 0 to 4, --OR.sub.c, --NR.sub.cOR.sub.c,
--NR.sub.cR.sub.c, --C(O)NR.sub.c, --C(O)OR.sub.c, --C(O)R.sub.c,
--NR.sub.cC(O)NR.sub.cR.sub.c, --NR.sub.cC(O)R.sub.c,
--OC(O)OR.sub.c, --OC(O)NR.sub.cR.sub.c, --SR.sub.c, unsubstituted
alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted
aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and
unsubstituted heteroaryl, or two or more substituents cyclize to
form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl,
aryl, or heteroaryl group, where each R.sub.c is independently
selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl,
unsubstituted alkynyl, unsubstituted aryl, unsubstituted
cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted
heteroaryl, or two or more R.sub.c groups together cyclize to form
part of a heteroaryl or heterocycloalkyl group unsubstituted or
substituted with an unsubstituted alkyl group;
[0010] (b) Ar.sub.1, Ar.sub.2 and Ar.sub.3 are each independently
an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group
unsubstituted or substituted with one or more suitable substituents
independently selected from the group consisting of: halogens;
.dbd.O; .dbd.S; --CN; and --NO.sub.2; and alkyl, alkenyl,
heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl,
heterocycloalkyl, heteroaryl, --(CH.sub.2).sub.nCN where z is a
whole integer, preferably from 0 to 4, .dbd.NH, --NHOH, --OH,
--C(O)H, --OC(O)H, --C(O)OH, --OC(O)OH, --OC(O)OC(O)H, --OOH,
--C(NH)NH.sub.2, --NHC(NH)NH.sub.2, --C(S)NH.sub.2,
--NHC(S)NH.sub.2, --NHC(O)NH.sub.2, --S(O.sub.2)H, --S(O)H,
--NH.sub.2, --C(O)NH.sub.2, --OC(O)NH.sub.2, --NHC(O)H, --NHC(O)OH,
--C(O)NHC(O)H, --OS(O.sub.2)H, --OS(O)H, --OSH, --SC(O)H,
--S(O)C(O)OH, --SO.sub.2C(O)OH, --NHSH, --NHS(O) H, --NHSO.sub.2H,
--C(O)SH, --C(O)S(O)H, --C(O)S(O.sub.2)H, --C(S)H, --C(S)OH,
--C(SO)OH, --C(SO.sub.2)OH, --NHC(S)H, --OC(S)H, --OC(S)OH,
--OC(SO.sub.2)H, --S(O.sub.2)NH.sub.2, --S(O)NH.sub.2, --S
NH.sub.2, --NHCS(O.sub.2)H, --NHC(SO)H, --NHC(S)H, and --SH groups
unsubstituted or substituted with one or more suitable substituents
independently selected from the group consisting of halogens,
.dbd.O, --NO.sub.2, --CN, --(CH.sub.2).sub.z--CN where z is a whole
integer, preferably from 0 to 4, --OR.sub.c, --NR.sub.cOR.sub.c,
--NR.sub.cR.sub.c, --C(O)NR.sub.c, --C(O)OR.sub.c, --C(O)R.sub.c,
--NR.sub.cC(O)NR.sub.cR.sub.c, --NR.sub.cC(O)R.sub.c,
--OC(O)OR.sub.c, --OC(O)NR.sub.cR.sub.c, --SR.sub.c, unsubstituted
alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted
aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and
unsubstituted heteroaryl, or two or more substituents cyclize to
form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl,
aryl, or heteroaryl group, where each R.sub.c is independently
selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl,
unsubstituted alkynyl, unsubstituted aryl, unsubstituted
cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted
heteroaryl, or two or more R.sub.c groups together cyclize to form
part of a heteroaryl or heterocycloalkyl group unsubstituted or
substituted with an unsubstituted alkyl group;
[0011] (c) n.sub.1 is 0, 1, 2, 3 or 4;
[0012] (d) n.sub.2 is 0, 1, 2, 3 or 4;
[0013] (e) n.sub.3 is 0, 1, 2, 3 or 4;
[0014] (f) Z.sub.a is a bond or is selected from S, O, N, NR.sub.c,
C(O)NR.sub.c, NR.sub.c(O), and CR.sub.c, wherein R.sub.c is a
suitable substituent selected from hydrogen, unsubstituted alkyl,
unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl,
unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or
unsubstituted heteroaryl group; and
[0015] (g) W.sub.a is S or O;
[0016] or a pharmaceutically acceptable salt, pharmaceutically
acceptable N-oxide, isomer, derivative, pharmaceutically active
metabolite, pharmaceutically acceptable prodrug, or
pharmaceutically acceptable solvate thereof.
[0017] Provided herein are compositions and methods for treating a
disease comprising administering to a subject in need thereof an
effective amount of an abl kinase modulating compound having the
structure: 2
[0018] wherein:
[0019] (a) R.sub.2g, R.sub.3g and R.sub.4g are each independently
selected from hydrogen, unsubstituted alkyl, unsubstituted aryl,
and unsubstituted heteroaryl;
[0020] (b) n is 0, 1 or 2;
[0021] (c) n.sub.1 is 0, 1 or 2;
[0022] (d) n.sub.2 is 0, 1 or 2;
[0023] (e) Ar.sub.2 is: 3
[0024] (i) R.sub.6g and R.sub.7g cyclize to form a 5- or 6-membered
aryl, heteroaryl, heterocycloalkyl or cycloakyl group unsubstituted
or substituted with one, two or three suitable substituents
independently selected from the group consisting of: halogens;
--CN; and --NO.sub.2; and alkyl, alkenyl, heteroalkyl, haloalkyl,
alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,
--(CH.sub.2).sub.nCN where z is a whole integer from 0 to 4, NH,
--NHOH, --OH, --C(O)H, --OC(O)H, --C(O)OH, --OC(O)OH,
--OC(O)OC(O)H, --OOH, --C(NH)NH.sub.2, --NHC(NH)NH.sub.2,
--C(S)NH.sub.2, --NHC(S)NH.sub.2, --NHC(O)NH.sub.2, --S(O.sub.2)H,
--S(O)H, --NH.sub.2, --C(O)NH.sub.2, --OC(O)N H.sub.2, --NHC(O)H,
--NHC(O)OH, --C(O)NHC(O)H, --OS(O.sub.2)H, --OS(O)H, --OSH,
--SC(O)H, --S(O)C(O)OH, --SO.sub.2C(O)OH, --NHSH, NHS(O)H,
--NHSO.sub.2H, --C(O)SH, --C(O)S(O)H, --C(O)S(O.sub.2)H, --C(S)H,
--C(S)OH, --C(SO)OH, --C(SO.sub.2)OH, --NHC(S)H, --OC(S)H,
--OC(S)OH, --OC(SO.sub.2)H, --S(O.sub.2)NH.sub.2, --S(O)NH.sub.2,
--SNH.sub.2, --NHCS(O.sub.2)H, --NHC(SO)H, --NHC(S)H, and --SH
groups unsubstituted or substituted with one, two or three suitable
substituents independently selected from the group consisting of
halogens, .dbd.O, --NO.sub.2, --CN, --(CH.sub.2).sub.z--CN where z
is a whole integer from 0 to 4, --OR.sub.c, --NR.sub.cOR.sub.c,
--NR.sub.cR.sub.c, --C(O)NR.sub.c, --C(O)OR.sub.c, --C(O)R.sub.c,
--NR.sub.cC(O)NR.sub.cR.sub.c, --NR.sub.cC(O)R.sub.c,
--OC(O)OR.sub.c, --OC(O)NR.sub.cR.sub.c, --SR.sub.c, unsubstituted
alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted
aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and
unsubstituted heteroaryl, or two or more substituents cyclize to
form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl,
aryl, or heteroaryl group, where each R.sub.c is independently
selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl,
unsubstituted alkynyl, unsubstituted aryl, unsubstituted
cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted
heteroaryl, or two or more R.sub.c groups together cyclize to form
part of a heteroaryl or heterocycloalkyl group unsubstituted or
substituted with an unsubstituted alkyl group;
[0025] (ii) R.sub.10g is a suitable substituent selected from
hydrogen; halogens; --CN; and --NO.sub.2; and alkyl, alkenyl,
heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl,
heterocycloalkyl, heteroaryl, --(CH.sub.2).sub.zCN where z is a
whole integer from 0 to 4, NH, --NHOH, --OH, --C(O)H, --OC(O)H,
--C(O)OH, --OC(O)OH, --OC(O)OC(O)H, --OOH, --C(NH)NH.sub.2,
--NHC(NH)NH.sub.2, --C(S)NH.sub.2, --NHC(S)NH.sub.2,
--NHC(O)NH.sub.2, --S(O.sub.2)H, --S(O)H, --NH.sub.2,
--C(O)NH.sub.2, --OC(O)NH.sub.2, --NHC(O)H, --NHC(O)OH,
--C(O)NHC(O)H, --OS(O.sub.2)H, --OS(O)H, --OSH, --SC(O)H,
--S(O)C(O)OH, --SO.sub.2C(O)OH, --NHSH, NHS(O)H, --NHSO.sub.2H,
--C(O)SH, --C(O)S(O)H, --C(O)S(O.sub.2)H, --C(S)H, --C(S)OH,
--C(SO)OH, --C(SO.sub.2)OH, --NHC(S)H, --OC(S)H, --OC(S)OH,
--OC(SO.sub.2)H, --S(O.sub.2)NH.sub.2, --S(O)NH.sub.2, --SNH.sub.2,
--NHCS(O.sub.2)H, --NHC(SO)H, --NHC(S)H, and --SH groups
unsubstituted or substituted with one, two or three suitable
substituents independently selected from the group consisting of
halogens, .dbd.O, --NO.sub.2, --CN, --(CH.sub.2).sub.n--CN where z
is a whole integer from 0 to 4, --OR.sub.c, --NR.sub.cOR.sub.c,
--NR.sub.cR.sub.c, --C(O)NR.sub.c, --C(O)OR.sub.c, --C(O)R.sub.c,
--NR.sub.cC(O)NR.sub.cR.su- b.c, --NR.sub.cC(O)R.sub.c,
--OC(O)OR.sub.c, --OC(O)NR.sub.cR.sub.c, --SR.sub.c, unsubstituted
alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted
aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and
unsubstituted heteroaryl, or two or more substituents cyclize to
form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl,
aryl, or heteroaryl group, where each R.sub.c is independently
selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl,
unsubstituted alkynyl, unsubstituted aryl, unsubstituted
cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted
heteroaryl, or two or more R.sub.c groups together cyclize to form
part of a heteroaryl or heterocycloalkyl group unsubstituted or
substituted with an unsubstituted alkyl group; and
[0026] (iii) T.sub.1 and T.sub.2 are each independently selected
from CR.sub.w and N, where R.sub.w is a suitable substituent
selected from hydrogen; halogens; --CN; and --NO.sub.2; and
unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl,
unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted
heterocycloalkyl, and unsubstituted heteroaryl, or two or more
substituents cyclize to form a fused or spiro polycyclic
cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
[0027] or a pharmaceutically acceptable salt, pharmaceutically
acceptable N-oxide, pharmaceutically active metabolite,
pharmaceutically acceptable prodrug, or pharmaceutically acceptable
solvate thereof.
[0028] Provided herein are compositions and methods for treating a
disease comprising administering to a subject in need thereof an
effective amount of an abl kinase modulating compound having the
structure: 4
[0029] wherein:
[0030] M is substituted or unsubstituted heteroaryl, or substituted
or unsubstituted aryl;
[0031] N is a substituted or unsubstituted aryl, or substituted or
unsubstituted hetroaryl; and
[0032] K is 5
[0033] Y is O or S;
[0034] each R.sub.k is independently H, halogen, substituted or
unsubstituted alkyl, --OH, substituted or unsubstituted alkoxy,
--OC(O)R.sub.2, --NO.sub.2, --N(R.sub.2).sub.2, --SR.sub.2,
--C(O)R.sub.2, --C(O).sub.2R.sub.2, --C(O)N(R.sub.2).sub.2, or
--N(R.sub.2)C(O)R.sub.2,
[0035] each R.sub.2 is independently H, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl; or
wherein two R.sub.2 groups are linked together by an optionally
substituted alkylene; and
[0036] each n is independently 0, 1, 2, 3 or 4;
[0037] or an active metabolite, or a pharmaceutically acceptable
prodrug, isomer, pharmaceutically acceptable salt or solvate
thereof.
[0038] Provided herein are compositions and methods for treating a
disease comprising administering to a subject in need thereof an
effective amount of an abl kinase modulating compound having the
structure: 6
[0039] wherein:
[0040] each Z is independently C, CR.sub.3, N, NR.sub.3, O, or S,
provided that no more than two Z's are heteroatoms and wherein no
two adjacent Z's are O or S, where R.sub.3 is H, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heteroaryl, or substituted or
unsubstituted aryl; and
[0041] each R.sub.1 is independently H, halogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkoxy,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sub.c--OH,
--OC(O)R.sub.c, --NO.sub.2, --N(R.sub.c).sub.2, --SR.sub.c,
S(O).sub.jR.sub.c, where j is 1 or 2, --NR.sub.cC(O)R.sub.c,
--C(O)N(R.sub.c).sub.2, --C(O).sub.2R.sub.c, or --C(O)R.sub.c; or
two adjacent R.sub.1's, are taken together to form a substituted or
unsubstituted aryl or heteroaryl,
[0042] each R.sub.c is independently H, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl, or substituted or unsubstituted
heteroaryl.
[0043] Provided herein are compositions and methods for treating a
disease comprising administering to a subject in need thereof an
effective amount of an abl kinase modulating compound having the
structure: 7
[0044] wherein K is 8
[0045] where
[0046] each R.sub.k is independently H, halogen, substituted or
unsubstituted alkyl, or substituted or unsubstituted alkoxy.
[0047] Provided herein are compositions and methods for treating a
disease comprising administering to a subject in need thereof an
effective amount of an abl kinase modulating compound having the
structure: 9
[0048] Provided herein are compositions and methods for treating a
disease comprising administering to a subject in need thereof an
effective amount of an abl kinase modulating compound having the
structure: 10
[0049] wherein Z.sub.1 is CR.sub.3 or N; and Z.sub.2 is O or S.
[0050] Provided herein are compositions and methods for treating a
disease comprising administering to a subject in need thereof an
effective amount of an abl kinase modulating compound having the
structure: 11
[0051] wherein:
[0052] L is a linker selected from the group consisting of a
covalent bond, substituted or unsubstituted alkenylene, substituted
or unsubstituted alkylene, --C(O)NH--, --C(O)--, --NH--, --O--,
--S--, --O(substituted or unsubstituted alkylene)-, --N(substituted
or unsubstituted alkylene)-, --C(O)NH(substituted or unsubstituted
alkylene)-, --C(O)NH(substituted or unsubstituted alkenylene)-,
--NHC(O)(substituted or unsubstituted alkylene)-,
--NHC(O)(substituted or unsubstituted alkenylene)-,
--C(O)(substituted or unsubstituted alkenylene)-, and
--NHC(O)(substituted or unsubstituted alkylene)S(substituted or
unsubstituted alkylene)C(O)NH--; and
[0053] T is a mono-, bi-, or tricyclic, substituted or
unsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl.
[0054] In some embodiments, T is 12
[0055] wherein A is a substituted or unsubstituted five or
six-membered heterocyclyl, aryl, or heteroaryl; and B is a
substituted or unsubstituted five or six-membered heterocyclene,
arylene, or heteroarylene, wherein A and B together form a fused
two ring moiety.
[0056] Provided herein are compositions and methods for treating a
disease comprising administering to a subject in need thereof an
effective amount of an abl kinase modulating compound having the
structure: 13
[0057] In some embodiments, L of said compound is --O(substituted
or unsubstituted alkylene)-, --C(O)NH--, or a covalent bond. In
other embodiemnts, A of said compound is substituted or
unsubstituted five or six-membered aryl or heteroaryl; and B of
said compound is substituted or unsubstituted five or six-membered
arylene or heteroarylene.
[0058] Provided herein are compositions and methods for treating a
disease comprising administering to a subject in need thereof an
effective amount of an abl kinase modulating compound having the
structure: 14
[0059] wherein:
[0060] each X is independently C, CR, N, NR, or O, wherein no more
than three X's is a heteroatom, and no two adjacent ring atoms are
0; and
[0061] each R is independently H, halogen, substituted or
unsubstituted alkyl, --OH, substituted or unsubstituted alkoxy,
--OC(O)R.sub.d, --NO.sub.2, --N(R.sub.d).sub.2, --SR.sub.d,
--S(O).sub.jR.sub.d where j is 1 or 2, --NR.sub.d, C(O)R.sub.d,
--C(O).sub.2R.sub.d, --C(O)N(R.sub.d).sub.2 or --C(O)R.sub.d, or
two adjacent R's are taken together to form a substituted or
unsubstituted aryl or hetroaryl, where
[0062] each R.sub.d is independently H, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl or substituted or unsubstituted
heteroaryl.
[0063] Provided herein are compositions and methods for treating a
disease comprising administering to a subject in need thereof an
effective amount of an abl kinase modulating compound having the
structure: 15
[0064] Provided herein are compositions and methods for treating a
disease comprising administering to a subject in need thereof an
effective amount of an abl kinase modulating compound having the
structure: 16
[0065] wherein:
[0066] each X is independently C, CR, N, NR, S or O, wherein no
more than three X's is a heteroatom, and no two adjacent ring atoms
are O or S; and
[0067] each R is independently H, halogen, substituted or
unsubstituted alkyl, --OH, substituted or unsubstituted alkoxy,
--OC(O)R.sub.d, --NO.sub.2, --N(R.sub.d).sub.2, --SR.sub.d,
--S(O).sub.jR.sub.d where j is 1 or 2, --NR.sub.d C(O)R.sub.d,
--C(O).sub.2R.sub.d, --C(O)N(R.sub.d).sub.2 or --C(O)R.sub.d, or
two adjacent R's are taken together to form a substituted or
unsubstituted aryl or hetroaryl, where
[0068] each R.sub.d is independently H, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl or substituted or unsubstituted
heteroaryl.
[0069] Provided herein are compositions and methods for treating a
disease comprising administering to a subject in need thereof an
effective amount of an abl kinase modulating compound having the
structure: 17
[0070] Provided herein are compositions and methods for treating a
disease comprising administering to a subject in need thereof an
effective amount of an abl kinase modulating compound having the
structure: 18
[0071] Provided herein are compositions and methods for treating a
disease comprising administering to a subject in need thereof an
effective amount of an abl kinase modulating compound having the
structure: 19
[0072] The present invention provides compounds which modulate the
activity, and in some embodiments, preferentially inhibit
non-receptor tyrosine kinases. In some embodiments, the
non-receptor tyrosine kinases include Frk, Btk, Csk, Abl, Zap70,
Fes, Fps, Fak, Jak and Ack, their respective subfamilies. In a
futher embodiemnt, the non-receptor tyrosine kinase is selected
from the Src subfamily, which includes Src, Yes, Fyn, Lyn, Lck,
Blk, Hck, Fgr and Yrk. In some embodiments, said abl kinase is
mutant T315I Abl-1 kinase.
[0073] The compounds and compositions disclosed herein may be used
for the prevention or treatment of cancers such as stomach,
gastric, bone, ovary, colon, lung, brain, larynx, lymphatic system,
genitourinary tract, ovarian, squamous cell carcinoma, astrocytoma,
Kaposis sarcoma, glioblastoma, lung cancer, bladder cancer, head
and neck cancer, melanoma, ovarian cancer, prostate cancer, breast
cancer, small-cell lung cancer, leukemia, glioma, colorectal
cancer, genitourinary cancer gastrointestinal cancer, or pancreatic
cancer. In particular, the cancer is acute myelogenous leukemia
(AML), B-precursor cell acute lymphoblastic leukemias,
myelodysplastic leukemias, T-cell acute lymphoblastic leukemias,
and chronic myelogenous leukemias (CMLs).
[0074] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
Bcr-Abl receptor modulating compound are provided herein. In one
embodiment, the disease is cancer. In other embodiments, the cancer
is a malignant tumor, or a hematologic malignancy such as leukemia
and lymphoma. In some embodiments, the leukemia is chronic myeloid
leukemia (CML) or acute myelogenous leukemia (AML).
[0075] These and other aspects of the present invention will become
evident upon reference to the following detailed description. In
addition, various references are set forth herein which describe in
more detail certain procedures or compositions, and are
incorporated by reference in their entirety.
DISCLOSURE OF THE INVENTION
[0076] To more readily facilitate an understanding of the invention
and its preferred embodiments, the meanings of terms used herein
will become apparent from the context of this specification in view
of common usage of various terms and the explicit definitions of
other terms provided in the glossary below or in the ensuing
description.
[0077] Glossary of Terms
[0078] Unless otherwise stated, the following terms used in this
application, including the specification and claims, have the
definitions given below. It must be noted that, as used in the
specification and the appended claims, the singular forms "a," "an"
and "the" include plural referents unless the context clearly
dictates otherwise. Definition of standard chemistry terms may be
found in reference works, including Carey and Sundberg (1992)
"ADVANCED ORGANIC CHEMISTRY 3.sup.RD ED." Vols. A and B, Plenum
Press, New York. Unless otherwise indicated, conventional methods
of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry,
recombinant DNA techniques and pharmacology, within the skill of
the art are employed.
[0079] The term "modulator" means a molecule that interacts with a
target either directly or indirectly. The interactions include, but
are not limited to, agonist, antagonist, and the like.
[0080] The term "agonist" means a molecule such as a compound, a
drug, an enzyme activator or a hormone that enhances the activity
of another molecule or the activity of a receptor site etiehr
directly or indirectly.
[0081] The term "antagonist" means a molecule such as a compound, a
drug, an enzyme inhibitor, or a hormone that diminishes or prevents
the action of another molecule or the activity of a receptor site
either directly or indirectly.
[0082] The terms "effective amount" or "therapeutically effective
amount" refer to a sufficient amount of the agent to provide the
desired biological result. That result can be reduction and/or
alleviation of the signs, symptoms, or causes of a disease, or any
other desired alteration of a biological system. For example, an
"effective amount" for therapeutic use is the amount of the
composition comprising a compound as disclosed herein required to
provide a clinically significant decrease in a disease. An
appropriate "effective" amount in any individual case may be
determined by one of ordinary skill in the art using routine
experimentation.
[0083] As used herein, the terms "treat" or "treatment" are
synonymous with the term "prevent" and are meant to indicate a
postponement of development of diseases, preventing the development
of diseases, and/or reducing severity of such symptoms that will or
are expected to develop. Thus, these terms include ameliorating
existing disease symptoms, preventing additional symptoms,
ameliorating or preventing the underlying metabolic causes of
symptoms, inhibiting the disorder or disease, e.g., arresting the
development of the disorder or disease, relieving the disorder or
disease, causing regression of the disorder or disease, relieving a
condition caused by the disease or disorder, or stopping the
symptoms of the disease or disorder.
[0084] By "pharmaceutically acceptable" or "pharmacologically
acceptable" is meant a material which is not biologically or
otherwise undesirable, i.e., the material may be administered to an
individual without causing any undesirable biological effects or
interacting in a deleterious manner with any of the components of
the composition in which it is contained.
[0085] "Carrier materials" include any commonly used excipients in
pharmaceutics and should be selected on the basis of compatibility
and the release profile properties of the desired dosage form.
Exemplary carrier materials include, e.g., binders, suspending
agents, disintegration agents, filling agents, surfactants,
solubilizers, stabilizers, lubricants, wetting agents, diluents,
and the like. "Pharmaceutically compatible carrier materials" may
comprise, e.g., acacia, gelatin, colloidal silicon dioxide, calcium
glycerophosphate, calcium lactate, maltodextrin, glycerine,
magnesium silicate, sodium caseinate, soy lecithin, sodium
chloride, tricalcium phosphate, dipotassium phosphate, sodium
stearoyl lactylate, carrageenan, monoglyceride, diglyceride,
pregelatinized starch, and the like. See, e.g., Remington: The
Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack
Publishing Company, 1995); Hoover, John E., Remington's
Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;
Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,
Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage
Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams
& Wilkinsl999).
[0086] As used herein, the term "subject" encompasses mammals and
non-mammals. Examples of mammals include, but are not limited to,
any member of the Mammalian class: humans, non-human primates such
as chimpanzees, and other apes and monkey species; farm animals
such as cattle, horses, sheep, goats, swine; domestic animals such
as rabbits, dogs, and cats; laboratory animals including rodents,
such as rats, mice and guinea pigs, and the like. Examples of
non-mammals include, but are not limited to, birds, fish and the
like. In one embodiment of the present invention, the mammal is a
human.
[0087] The term "pharmaceutically acceptable salt" of a compound
means a salt that is pharmaceutically acceptable and that possesses
the desired pharmacological activity of the parent compound. Such
salts, for example, include: (1) acid addition salts, formed with
inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like; or
formed with organic acids such as acetic acid, propionic acid,
hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic
acid, lactic acid, malonic acid, succinic acid, malic acid, maleic
acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
2-naphthalenesulfonic acid,
4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic
acid, 4,4-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid),
3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid,
and the like; (2) salts formed when an acidic proton present in the
parent compound either is replaced by a metal ion, e.g., an alkali
metal ion, an alkaline earth ion, or an aluminum ion; or
coordinates with an organic base. Acceptable organic bases include
ethanolamine, diethanolamine, triethanolamine, tromethamine,
N-methylglucamine, and the like. Acceptable inorganic bases include
aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium
carbonate, sodium hydroxide, and the like. It should be understood
that a reference to a pharmaceutically acceptable salt includes the
solvent addition forms or crystal forms thereof, particularly
solvates or polymorphs. Solvates contain either stoichiometric or
non-stoichiometric amounts of a solvent, and are often formed
during the process of crystallization. Hydrates are formed when the
solvent is water, or alcoholates are formed when the solvent is
alcohol. Polymorphs include the different crystal packing
arrangements of the same elemental composition of a compound.
Polymorphs usually have different X-ray diffraction patterns,
infrared spectra, melting points, density, hardness, crystal shape,
optical and electrical properties, stability, and solubility.
Various factors such as the recrystallization solvent, rate of
crystallization, and storage temperature may cause a single crystal
form to dominate.
[0088] As used herein, the term "biological sample" is broadly
defined to include any cell, tissue, organ or multicellular
organism. A biological sample can be derived, for example, from
cell or tissue cultures in vitro. Alternatively, a biological
sample can be derived from a living organism or from a population
of single cell organisms.
[0089] As used herein, the term "linker" means any divalent linking
moiety used to connect, join, or attach two chemical groups. For
example, linkers may be used to join two cyclic groups, such as to
join two aryl groups (e.g., phenyl), an aryl group to a cycloalkyl
group, an aryl group to a heterocyclyl group, a cycloalkyl group to
a cycloalkyl group, a cycloalkyl group to a heterocyclyl group, and
the like. Representative linkers include, but are not limited to, a
covalent bond, -(substituted or unsubstituted alkylene)-,
-(substituted or unsubstituted alkenylene)-, -(substituted or
unsubstituted alkynylene)-, -(substituted or unsubstituted
cycloalkylene)-, -(substituted or unsubstituted heterocyclylene)-,
-(substituted or unsubstituted arylene)-, and -(substituted or
unsubstituted heteroarylene)-. Exemplary linkers also include
--O--, --S--, --S(O)--, --S(O).sub.2--, --S(O).sub.3--, --C(O)--,
--NH--, --N.dbd., --N.dbd.N--, .dbd.N--N.dbd., --C(O)NH--,
--S(O)NH--, and the like. Additional examples of linkers include
--O(substituted or unsubstituted alkylene)-, --N(substituted or
unsubstituted alkylene)-, --NHC(O)(substituted or unsubstituted
alkylene)-, --C(O)(substituted or unsubstituted alkenylene)-,
--NHC(O)(substituted or unsubstituted alkylene)S(substituted or
unsubstituted alkylene)C(O)NH--, --NHC(O)(substituted or
unsubstituted alkenylene)-, and the like. Linkers, as represented
herein, embrace divalent moieties in any chemically feasible
directionality. For example, compounds comprising a linker-C(O)NH--
which attaches two aryl groups, Ar.sub.1 to Ar.sub.2, include
Ar.sub.1--C(O)NH--Ar.sub.2 as well as
Ar.sub.1--NHC(O)--Ar.sub.2.
[0090] As used herein, the term "halogen" includes fluorine,
chlorine, bromine, and iodine.
[0091] As used herein, "alkyl" means a straight chain or branched,
saturated or unsaturated chain having from 1 to 10 carbon atoms.
Representative saturated alkyl groups include, but are not limited
to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl,
2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl,
2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl,
3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl,
3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl,
3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl,
n-pentyl, isopentyl, neopentyl, and n-hexyl, and longer alkyl
groups, such as heptyl, and octyl. An alkyl group can be
unsubstituted or substituted. Unsaturated alkyl groups include
alkenyl groups and alkynyl groups, discussed below. Alkyl groups
containing three or more carbon atoms may be straight, branched or
cyclized.
[0092] As used herein, "lower alkyl" means an alkyl having from 1
to 5 carbon atoms.
[0093] As used herein, an "alkenyl group" includes a monovalent
unbranched or branched hydrocarbon chain having one or more double
bonds therein. The double bond of an alkenyl group can be
unconjugated or conjugated to another unsaturated group. Suitable
alkenyl groups include, but are not limited to, (C.sub.2-C.sub.8)
alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl,
butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl,
2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl. An alkenyl
group can be unsubstituted or substituted.
[0094] As used herein, "alkynyl group" includes a monovalent
unbranched or branched hydrocarbon chain having one or more triple
bonds therein. The triple bond of an alkynyl group can be
unconjugated or conjugated to another unsaturated group. Suitable
alkynyl groups include, but are not limited to, (C.sub.2-C.sub.6)
alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl,
hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl,
and 4-butyl-2-hexynyl. An alkynyl group can be unsubstituted or
substituted.
[0095] The terms "trifluoromethyl," "sulfonyl," and "carboxyl"
include CF.sub.3, SO.sub.3H, and CO.sub.2H, respectively.
[0096] The term "alkoxy" as used herein includes --O-(alkyl),
wherein alkyl is defined above.
[0097] As used herein, "alkoxyalkoxy" includes
--O-(alkyl)-O-(alkyl), wherein each "alkyl" is independently an
alkyl group defined above.
[0098] As used herein, "alkoxycarbonyl" includes --C(O)O-(alkyl),
wherein alkyl is defined above.
[0099] As used herein, "alkoxycarbonylalkyl" includes
-(alkyl)-C(O)O-(alkyl), wherein alkyl is defined above.
[0100] As used herein, "alkoxyalkyl" means -(alkyl)-O-(alkyl),
wherein each "alkyl" is independently an alkyl group defined
above.
[0101] As used herein, the term "aryl" (Ar) refers to a monocyclic,
or fused or spiro polycyclic, aromatic carbocycle (ring structure
having ring atoms that are all carbon) having from 3 to 12 ring
atoms per ring. Illustrative examples of aryl groups include the
following moieties: 20
[0102] and the like
[0103] As used herein, the term heteroaryl (heteroAr) refers to a
monocyclic, or fused or spiro polycyclic, aromatic heterocycle
(ring structure having ring atoms selected from carbon atoms as
well as nitrogen, oxygen and sulfur heteroatoms) having from 3 to
12 ring atoms per ring. Illustrative examples of aryl groups
include the following moieties: 21
[0104] and the like.
[0105] As used herein, the term cycloalkyl refers to a saturated or
partially saturated monocyclic or fused or spiro polycyclic,
carbocycle having from 3 to 12 ring atoms per ring. Illustrative
examples of cycloalkyl groups include the following moieties:
22
[0106] and the like.
[0107] As used herein, the term "heterocycloalkyl" refers to a
monocyclic, or fused or spiro polycyclic, ring structure that is
saturated or partially saturated and has from 3 to 12 ring atoms
per ring selected from C atoms and N, O, and S heteroatoms.
Illustrative examples of heterocycloalkyl groups include: 23
[0108] and the like.
[0109] As used herein, "aryloxy" includes --O-aryl group, wherein
aryl is as defined above. An aryloxy group can be unsubstituted or
substituted.
[0110] As used herein, "arylalkyl" includes -(alkyl)-(aryl),
wherein alkyl and aryl are defined above.
[0111] As used herein, "arylalkyloxy" includes --O-(alkyl)-(aryl),
wherein alkyl and aryl are defined above.
[0112] As used herein, "cycloalkyl" includes a monocyclic or
polycyclic saturated ring comprising carbon and hydrogen atoms and
having no carbon-carbon multiple bonds. Examples of cycloalkyl
groups include, but are not limited to, (C.sub.3-C.sub.7)cycloalkyl
groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
and cycloheptyl, and saturated cyclic and bicyclic terpenes. A
cycloalkyl group can be unsubstituted or substituted. Preferably,
the cycloalkyl group is a monocyclic ring or bicyclic ring.
[0113] As used herein, "cycloalkyloxy" includes --O-(cycloalkyl),
wherein cycloalkyl is defined above.
[0114] As used herein, "cycloalkylalkyloxy" includes
--O-(alkyl)-(cycloalkyl), wherein cycloalkyl and alkyl are defined
above.
[0115] As used herein, the term "alkylidene" includes the divalent
radical --C.sub.nH.sub.2, --, wherein n is an integer from 1 to 8,
such as --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2C- H.sub.2--, and the like,
unsubstituted or substituted with one or more alkyl groups.
[0116] As used herein, "heteroatom-containing alkylidene" includes
an alkylidene wherein at least one carbon atom is replaced by a
heteroatom selected from nitrogen, oxygen, or sulfur, such as
--CH.sub.2CH.sub.2OCH.sub.2CH.sub.2--, and the like, unsubstituted
or substituted with one or more alkyl groups.
[0117] As used herein, "aminoalkoxy" includes --O-(alkyl)-NH.sub.2,
wherein alkyl is defined above.
[0118] As used herein, "mono-alkylamino" includes --NH(alkyl),
wherein alkyl is defined above.
[0119] As used herein, "di-alkylamino" includes --N(alkyl)(alkyl),
wherein each "alkyl" is independently an alkyl group defined
above.
[0120] As used herein, "mono-alkylaminoalkoxy" includes
--O-(alkyl)-NH(alkyl), wherein each "alkyl" is independently an
alkyl group defined above.
[0121] As used herein, "di-alkylaminoalkoxy" includes
--O-(alkyl)N(alkyl)(alkyl), wherein each "alkyl" is independently
an alkyl group defined above.
[0122] As used herein, "arylamino" includes --NH(aryl), wherein
aryl is defined above.
[0123] As used herein, "arylalkylamino" includes
--NH-(alkyl)-(aryl), wherein alkyl and aryl are defined above.
[0124] As used herein, "alkylamino" includes --NH(alkyl), wherein
alkyl is defined above.
[0125] As used herein, "cycloalkylamino" includes
--NH-(cycloalkyl), wherein cyclohexyl is defined above.
[0126] As used herein, "cycloalkylalkylamino" includes
--NH-(alkyl)-(cycloalkyl), wherein alkyl and cycloalkyl are defined
above.
[0127] As used herein, "aminoalkyl" includes -(alkyl)-NH.sub.2,
wherein alkyl is defined above.
[0128] As used herein, "mono-alkylaminoalkyl" includes
-(alkyl)-NH(alkyl), wherein each "alkyl" is independently an alkyl
group defined above.
[0129] As used herein, "di-alkylaminoalkyl" includes
-(alkyl)-N(alkyl)(alkyl), wherein each "alkyl" is independently an
alkyl group defined above.
[0130] The term "whole integer" is intended to include whole
numbers. For example, a whole integer from 0 to 4 would include 0,
1, 2, 3, and 4.
[0131] Sulfonyl refers to the presence of a sulfur atom, which is
optionally linked to another moiety such as an aliphatic group, an
aromatic group, an aryl group, an alicyclic group, or a
heterocyclic group. Aryl or alkyl sulfonyl moieties have the
formula --SO.sub.2R.sub.d, and alkoxy moieties have the formula
--O--R.sub.d, wherein R.sub.d is alkyl, as defined above, or is
aryl wherein aryl is phenyl, optionally substituted with 1-3
substituents independently selected from halo (fluoro, chloro,
bromo or iodo), lower alkyl (1-6C) and lower alkoxy (1-6C).
[0132] As used herein, the term "substituted" means that the
specified group or moiety bears one or more suitable
substituents.
[0133] As used herein, the term "unsubstituted" means that the
specified group bears no substituents.
[0134] As used herein, the term "optionally substituted" means that
the specified group is unsubstituted or substituted by one or more
substituents.
[0135] Molecular embodiments of the present invention may possess
one or more chiral centers and each center may exist in the R or S
configuration. The present invention includes all diastereomeric,
enantiomeric, and epimeric forms as well as the appropriate
mixtures thereof. Stereoisomers may be obtained, if desired, by
methods known in the art as, for example, the separation of
stereoisomers by chiral chromatographic columns. Additionally, the
compounds of the present invention may exist as geometric isomers.
The present invention includes all cis, trans, syn, anti, entgegen
(E), and zusammen (Z) isomers as well as the appropriate mixtures
thereof.
[0136] Certain functional groups contained within the compounds of
the present invention can be substituted for bioisosteric groups,
that is, groups which have similar spatial or electronic
requirements to the parent group, but exhibit differing or improved
physicochemical or other properties. Suitable examples are well
known to those of skill in the art, and include, but are not
limited to moieties described in Patini et al., Chem, Rev, 1996,
96, 3147-3176 and references cited therein.
[0137] In addition, the compounds of the present invention can
exist in unsolvated as well as solvated forms with pharmaceutically
acceptable solvents such as water, ethanol, and the like. In
general, the solvated forms are considered equivalent to the
unsolvated forms for the purposes of the present invention.
[0138] To more readily facilitate an understanding of the invention
and its preferred embodiments, the meanings of terms used herein
will become apparent from the context of this specification in view
of common usage of various terms and the explicit definitions of
other terms provided in the glossary below or in the ensuing
description.
[0139] Compounds
[0140] In one aspect, the present invention is directed to
compounds, compositions, and methods for treating conditions
associated with abnormal kinase activity. In one embodiment,
compounds useful in the invention are derivatives of isoxazoles,
pyrazoles and isothiazoles. When the compounds of the invention
contain one or more chiral centers, the invention includes
optically pure forms as well as mixtures of stereoisomers or
enantiomers.
[0141] Thus, the invention provides methods for modulating various
kinases by providing an effective amount of a compound of the
formulas described herein.
[0142] Salts of the compounds may be used for therapeutic and
prophylactic purposes, where the salt is preferably a
pharmaceutically acceptable salt. Examples of pharmaceutically
acceptable salts include those derived from mineral acids, such as
hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and
sulphuric acids, and organic acids, such as tartaric, acetic,
trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycolic,
gluconic, succinic and methanesulphonic and arylsulphonic, for
example Q-toluenesulphonic, acids.
[0143] A "prodrug" refers to a drug or compound in which the
pharmacological action results from conversion by metabolic
processes within the body. Prodrugs are generally drug precursors
that, following administration to a subject and subsequent
absorption, are converted to an active, or a more active species
via some process, such as conversion by a metabolic pathway. Some
prodrugs have a chemical group present on the prodrug that renders
it less active and/or confers solubility or some other property to
the drug. Once the chemical group has been cleaved and/or modified
from the prodrug the active drug is generated. Prodrugs may be
designed as reversible drug derivatives, for use as modifiers to
enhance drug transport to site-specific tissues. Additionally,
prodrugs can increase the effective water solubility of the
therapeutic compound for targeting to regions where water is the
principal solvent. See, e.g., Fedorak et al., Am. J. Physiol., 269:
G210-218 (1995); McLoed et al., Gastroenterol, 106: 405-413 (1994);
Hochhaus et al., Biomed. Chrom., 6: 283-286 (1992); J. Larsen and
H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et
al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J.
Pharm. Sci., 64: 181-210 (1975); T. Higuchi and V. Stella,
Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S.
Symposium Series; and Edward B. Roche, Bioreversible Carriers in
Drug Design, American Pharmaceutical Association and Pergamon
Press, 1987. Prodrug forms of the above described compounds,
wherein the prodrug is metabolized in vivo to produce a derivative
as set forth above are included within the scope of the claims.
Indeed, some of the above-described derivatives may be a prodrug
for another derivative or active compound.
[0144] The invention further provides for the optical isomers of
the compounds disclosed herein, especially those resulting from the
chiral carbon atoms in the molecule. In additional embodiments of
the invention, mixtures of enantiomers and/or diastereoisomers,
resulting from a single preparative step, combination, or
interconversion may also be useful for the applications described
herein.
[0145] In another aspect, compositions containing the above
described analogs and derivatives are provided. Preferably, the
compositions are formulated to be suitable for pharmaceutical or
clinical use by the inclusion of appropriate carriers or
excipients.
[0146] Groups such as carbonyl, carboxyl, alkoxy, amino, and cyano
groups, etc., as shown in the formula above, need not be directly
bound to the para position; they may be included elsewhere in the
alkyl, alkenyl or alkynyl substituent. Thus, also acceptable
substituents are the following representative forms:
--CH.sub.2NHCH.sub.3; --CH.sub.2OCH.sub.3; --CH.sub.2SCH.sub.3;
--NHCH.sub.3; --CH.sub.2CH.sub.3; --OCH.sub.2CH.sub.3;
--SCH.sub.2CH.sub.2CH.sub.3; --CH.dbd.CHCH.sub.2NH.s- ub.2;
--CH.sub.2CH.sub.2OH; 24
[0147] --CH.sub.2CH.sub.2CH.sub.2SH; --CH.sub.2OC(O)CH.sub.3;
--CH.sub.2NHC(O)CH.sub.2C(O)CH.sub.3;
--NHC(O)CH.sub.2CH.sub.2CH.sub.3 each of which may further be
substituted with a cycloalkyl, heterocycloalkyl, aryl or heteroaryl
group.
[0148] It will also be evident that these substituents include, for
example, trifluoromethyl, difluoromethyl and fluoromethyl (alkyl
substituted by halo) and trifluoromethoxy, difluoromethoxy and
fluoromethoxy (alkyl where one carbon is replaced by O and is
further substituted by halo).
[0149] Compounds of the invention which contain carboxyl groups or
which contain amino groups may be supplied in the forms of their
pharmaceutically acceptable salts. Pharmaceutically acceptable
salts of carboxylic acids include inorganic salts such as salts of
sodium, potassium, calcium, magnesium and the like or salts formed
with organic bases such as caffeine. Salts of amines are acid
addition salts formed from inorganic acids such as hydrochloric,
sulfuric, phosphoric acids or may be salts of organic acids such as
acetates, maleates, propionates, and the like.
[0150] The invention also provides prodrug forms of the compounds
described herein, wherein the prodrug is metabolized in vivo to
produce a derivative as set forth above. Indeed, some of the above
described derivatives may be a prodrug for another derivative or
active compound. The invention further provides for the optical
isomers of the compounds disclosed herein, especially those
resulting from the chiral carbon atoms in the molecule. In
additional embodiments of the invention, mixtures of enantiomers
and/or diastereoisomers, resulting from a single preparative step,
combination, or interconversion are provided.
[0151] In another aspect of the invention, compositions containing
the above described analogs and derivatives are provided.
Preferably, the compositions are formulated to be suitable for
pharmaceutical or clinical use by the inclusion of appropriate
carriers or excipients.
[0152] In yet another aspect of the invention, pharmaceutical
formulations are provided comprising at least one compound
described above, or a pharmaceutically acceptable salt or solvate
thereof, together with one or more pharmaceutically acceptable
carriers, diluents or excipients.
[0153] The compounds of the invention, especially when used in the
invention methods and compositions, may be "conjugated"-that is
they may be coupled to additional moieties that do not destroy
their ability to modulate kinases. For example, the compounds might
be coupled to a label such as a radioactive label, a fluorescent
label and the like, or may be coupled to targeting agents such as
antibodies or fragments, or to fragments to aid purification such
as FLAG or a histidine tag. The compounds may also be coupled to
specific binding partners such as biotin for use in assay
procedures or to moieties that alter their biological half-lives
such as polyethylene glycol. Thus, the methods of the invention
employ the invention compounds per se as well as conjugates
thereof.
[0154] Synthesis of Compounds
[0155] Compounds of the present invention may be synthesized using
standard synthetic techniques known to those of skill in the art or
using methods known in the art in combination with methods
described herein. See, e.g., March, ADVANCED ORGANIC CHEMISTRY
4.sup.th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC
CHEMISTRY 3.sup.rd Ed., Vols. A and B (Plenum 1992), and Green and
Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 2.sup.nd Ed. (Wiley
1991). General methods for the preparation of compound as disclosed
herein may be derived from known reactions in the field, and the
reactions may be modified by the use of appropriate reagents and
conditions, as would be recognized by the skilled person, for the
introduction of the various moieties found in the formulae as
provided herein.
[0156] The compounds of the invention are synthesized by methods
well known in the art. The compounds of the invention are ureas or
cyclic forms thereof and can be synthesized using generally known
procedures for urea synthesis.
[0157] In one group of methods, an amine is reacted with an
isocyanate in an aprotic solvent. Typically, in some embodiments, a
molar excess of the amine is used in the presence of an aprotic
solvent and the reaction is conducted at room temperature. The
reaction mixture is then poured into water and precipitated with
salt to recover the crude product which is then purified according
to standard methods.
[0158] In alternative methods, the ureas are formed from two
separate amine reactants in the presence of a condensing agent such
as 1,1,carbonyldiimidazole (CDI) in the presence of an inert
nonpolar solvent such as dichloromethane. One of the amines is
first added to a solution of CDI in solvent under cooling
conditions and then stirred at room temperature with the other
amine. After removal of solvent, the crude product can be purified
using standard procedures.
[0159] In still another method, one of the amines is added in an
aprotic solvent to a solution of triphosgene and then treated with
the other amine reactant dissolved in an inert solvent in the
presence of base such as triethylamine. After reaction at room
temperature, the mixture may be diluted with, for example,
ethylacetate and washed with water and brine, dried and
purified.
[0160] In still another method, one of the amine components is
treated with 4-nitrophenylchloroformate in the presence of mild
base in a solvent such as N-methylpyrrolidone (NMP). The other
amine is then added and the reaction mixture heated, then cooled,
poured into water, extracted into chloroform and further
purified.
[0161] Alternatively, the urea may be formed by the reaction of an
amine with the counterpart halo acylamine which is formed from the
parent amine by treatment with phosgene and base in an inert
solvent such as methylene dichloride or by reacting an amine with
its counterpart amine with an acyl amine containing an alternate
leaving group formed by reaction of that amine with
4-nitrophenylchloroformate in the presence of an amine base and in
an inert solvent.
[0162] Details of these methods can be found in Matsuno et al. J.
Med. Chem. 45: 3057-66 (2002); Matsuno et al. J. Med. Chem. 45:
4513-23 (2002); and and Pandley et al., J. Med. Chem. 45: 3772-93
(2002).
[0163] Cyclized forms of the ureas may be obtained by treating the
formed urea with dibromo derivatives of the bridge, typically in
the presence of a strong base and in an inert aprotic polar
solvent.
[0164] The ureas may be converted to thioureas by treating with
Lawesson's reagent in the presence of toluene.
[0165] For compounds having the moiety Ar.sup.1-L-Ar.sup.2 is
obtained by first protecting the amino group of p-hydroxy aniline
destined to become Ar.sup.1 with a protecting agent such as Boc and
then coupling the hydroxy group of Ar.sup.1 to an aryl alkyl
halide. This coupling is conducted in the presence of strong base
and in an aprotic solvent. After deprotection, the urea is formed
by reaction with the isoxazole isocyanate. These techniques are
exemplified below.
[0166] Selected examples of covalent linkages and precursor
functional groups which yield them are given in the Table entitled
"Examples of Covalent Linkages and Precursors Thereof." Precursor
functional groups are shown as electrophilic groups and
nucleophilic groups. The functional group on the organic substance
may be attached directly, or attached via any useful spacer or
linker as defined below.
1TABLE 1 Examples of Covalent Linkages and Precursors Thereof
Covalent Linkage Product Electrophile Nucleophile Carboxamides
Activated esters amines/anilines Carboxamides acyl azides
amines/anilines Carboxamides acyl halides amines/anilines Esters
acyl halides alcohols/phenols Esters acyl nitriles alcohols/phenols
Carboxamides acyl nitriles amines/anilines Imines Aldehydes
amines/anilines Hydrazones aldehydes or ketones Hydrazines Oximes
aldehydes or ketones Hydroxylamines Alkyl amines alkyl halides
amines/anilines Esters alkyl halides carboxylic acids Thioethers
alkyl halides Thiols Ethers alkyl halides alcohols/phenols
Thioethers alkyl sulfonates Thiols Esters alkyl sulfonates
carboxylic acids Ethers alkyl sulfonates alcohols/phenols Esters
Anhydrides alcohols/phenols Carboxamides Anhydrides amines/anilines
Thiophenols aryl halides Thiols Aryl amines aryl halides Amines
Thioethers Azindines Thiols Boronate esters Boronates Glycols
Carboxamides carboxylic acids amines/anilines Esters carboxylic
acids Alcohols hydrazines Hydrazides carboxylic acids N-acylureas
or Anhydrides carbodiimides carboxylic acids Esters diazoalkanes
carboxylic acids Thioethers Epoxides Thiols Thioethers
haloacetamides Thiols Ammotriazines halotriazines amines/anilines
Triazinyl ethers halotriazines alcohols/phenols Amidines imido
esters amines/anilines Ureas Isocyanates amines/anilines Urethanes
Isocyanates alcohols/phenols Thioureas isothiocyanates
amines/anilines Thioethers Maleimides Thiols Phosphite esters
phosphoramidites Alcohols Silyl ethers silyl halides Alcohols Alkyl
amines sulfonate esters amines/anilines Thioethers sulfonate esters
Thiols Esters sulfonate esters carboxylic acids Ethers sulfonate
esters Alcohols Sulfonamides sulfonyl halides amines/anilines
Sulfonate esters sulfonyl halides phenols/alcohols
[0167] In general, carbon electrophiles are susceptible to attack
by complementary nucleophiles, including carbon nucleophiles,
wherein an attacking nucleophile brings an electron pair to the
carbon electrophile in order to form a new bond between the
nucleophile and the carbon electrophile.
[0168] Suitable carbon nucleophiles include, but are not limited to
alkyl, alkenyl, aryl and alkynyl Grignard, organolithium,
organozinc, alkyl-, alkenyl , aryl- and alkynyl-tin reagents
(organostannanes), alkyl-, alkenyl-, aryl- and alkynyl-borane
reagents (organoboranes and organoboronates); these carbon
nucleophiles have the advantage of being kinetically stable in
water or polar organic solvents. Other carbon nucleophiles include
phosphorus ylids, enol and enolate reagents; these carbon
nucleophiles have the advantage of being relatively easy to
generate from precursors well known to those skilled in the art of
synthetic organic chemistry. Carbon nucleophiles, when used in
conjunction with carbon electrophiles, engender new carbon-carbon
bonds between the carbon nucleophile and carbon electrophile.
[0169] Non-carbon nucleophiles suitable for coupling to carbon
electrophiles include but are not limited to primary and secondary
amines, thiols, thiolates, and thioethers, alcohols, alkoxides,
azides, semicarbazides, and the like. These non-carbon
nucleophiles, when used in conjunction with carbon electrophiles,
typically generate heteroatom linkages (C--X--C), wherein X is a
hetereoatom, e.g, oxygen or nitrogen.
[0170] The term "protecting group" refers to chemical moieties that
block some or all reactive moieties and prevent such groups from
participating in chemical reactions until the protective group is
removed. It is preferred that each protective group be removable by
a different means. Protective groups that are cleaved under totally
disparate reaction conditions fulfill the requirement of
differential removal. Protective groups can be removed by acid,
base, and hydrogenolysis. Groups such as trityl, dimethoxytrityl,
acetal and t-butyldimethylsilyl are acid labile and may be used to
protect carboxy and hydroxy reactive moieties in the presence of
amino groups protected with Cbz groups, which are removable by
hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic
acid and hydroxy reactive moieties may be blocked with base labile
groups such as, without limitation, methyl, ethyl, and acetyl in
the presence of amines blocked with acid labile groups such as
t-butyl carbamate or with carbamates that are both acid and base
stable but hydrolytically removable.
[0171] Carboxylic acid and hydroxy reactive moieties may also be
blocked with hydrolytically removable protective groups such as the
benzyl group, while amine groups capable of hydrogen bonding with
acids may be blocked with base labile groups such as Fmoc.
Carboxylic acid reactive moieties may be protected by conversion to
simple ester derivatives as exemplified herein, or they may be
blocked with oxidatively-removable protective groups such as
2,4-dimethoxybenzyl, while co-existing amino groups may be blocked
with fluoride labile silyl carbamates.
[0172] Allyl blocking groups are useful in then presence of acid-
and base-protecting groups since the former are stable and can be
subsequently removed by metal or pi-acid catalysts. For example, an
allyl-blocked carboxylic acid can be deprotected with a
Pd.sub.0-catalyzed reaction in the presence of acid labile t-butyl
carbamate or base-labile acetate amine protecting groups. Yet
another form of protecting group is a resin to which a compound or
intermediate may be attached. As long as the residue is attached to
the resin, that functional group is blocked and cannot react. Once
released from the resin, the functional group is available to
react.
[0173] Typically blocking/protecting groups may be selected from:
25
[0174] Other protecting groups are described in Greene and Wuts,
Protective Groups in Organic Synthesis, 3rd Ed., John Wiley &
Sons, New York, N.Y., 1999, which is incorporated herein by
reference in its entirety.
[0175] Biological Activity
[0176] Protein kinases (PKs) play a role in signal transduction
pathways regulating a number of cellular functions, such as cell
growth, differentiation, and cell death. PKs are enzymes that
catalyze the phosphorylation of hydroxy groups on tyrosine, serine
and threonine residues of proteins. Abnormal PK activity has been
related to disorders ranging from relatively non life threatening
diseases such as psoriasis to extremely virulent diseases such as
glioblastoma (brain cancer). In addition, a variety of tumor types
have dysfunctional growth factor receptor tyrosine kinases,
resulting in inappropriate mitogenic signaling. Protein kinases are
believed to be involved in many different cellular signal
transduction pathways. In particular, protein tyrosine kinases
(PTK) are attractive targets in the search for therapeutic agents,
not only for cancer, but also against many other diseases. Blocking
or regulating the kinase phosphorylation process in a signaling
cascade may help treat conditions such as cancer or inflammatory
processes.
[0177] Protein tyrosine kinases are a family of tightly regulated
enzymes, and the aberrant activation of various members of the
family is one of the hallmarks of cancer. The protein-tyrosine
kinase family includes Bcr-Abl tyrosine kinase, and can be divided
into subgroups that have similar structural organization and
sequence similarity within the kinase domain. The members of the
type III group of receptor tyrosine kinases include the
platelet-derived growth factor (PDGF) receptors (PDGF receptors
.alpha. and .beta.), colony-stimulating factor (CSF-1) receptor
(CSF-1 R, c-Fms), FLT-3, and stem cell or steel factor receptor
(c-kit).
[0178] The compounds, compositions, and methods provided herein are
useful to modulate the activity of kinases including, but not
limited to, ERBB2, ABL1, AURKA, CDK2, EGFR, FGFR1, LCK, MAPK14,
PDGFR, KDR, ABL1, BRAF, ERBB4, FLT3, KIT, and RAF1. In some
embodiments, the compositions and methods provided herein modulate
the activity of a mutant kinase.
[0179] Inhibition by the compounds provided herein can be
determined using any suitable assay. In one embodiment, inhibition
is determined in vitro. In a specific embodiment, inhibition is
assessed by phosphorylation assays. Any suitable phosphorylation
assay can be employed. For example, membrane autophosphorylation
assays, receptor autophosphorylation assays in intact cells, and
ELISA's can be employed. See, e.g., Gazit, et al., J. Med. Chem.
(1996) 39: 2170-2177, Chapter 18 in CURRENT PROTOCOLS IN MOLECULAR
BIOLOGY (Ausubel, et al., eds. 2001). Cells useful in such assays
include cells with wildtype or mutated forms. In one embodiment,
the wildtype is a kinase that is not constitutively active, but is
activated with upon dimerization. For example, the mutant FLT3
kinase is constitutively active via internal tandem duplication
mutations or point mutations in the activation domain. Suitable
cells include those derived through cell culture from patient
samples as well as cells derived using routine molecular biology
techniques, e.g., retroviral transduction, transfection,
mutagenesis, etc. Exemplary cells include Ba/F3 or 32Dc13 cells
transduced with, e.g., MSCV retroviral constructs FLT3-ITD (Kelly
et al., 2002); Molm-13 and Molm14 cell line (Fujisaki Cell Center,
Okayama, Japan); HL60 (AML-M3), AML193 (AML-M5), KG-1, KG-1a,
CRL-1873, CRL-9591, and THP-1 (American Tissue Culture Collection,
Bethesda, Md.); or any suitable cell line derived from a patient
with a hematopoietic malignancy.
[0180] In some embodiments, the compounds described herein
significantly inhibit receptor tyrosine kinases. A significant
inhibition of a receptor tyrosine kinase activity refers to an
IC.sub.50 of less than or equal to 100 .mu.M. Preferably, the
compound can inhibit activity with an IC.sub.50 of less than or
equal to 50 .mu.M, more preferably less than or equal to 10 .mu.M,
more preferably less than 1 .mu.M, or less than 100 nM, most
preferably less than 50 nM. Lower IC.sub.50s are preferred because
the IC.sub.50 provides an indication as to the in vivo
effectiveness of the compound. Other factors known in the art, such
as compound half-life, biodistribution, and toxicity should also be
considered for therapeutic uses. Such factors may enable a compound
with a lower IC.sub.50 to have greater in vivo efficacy than a
compound having a higher IC.sub.50. Preferably, a compound that
inhibits activity is administered at a dose where the effective
tyrosine phosphorylation, i.e., IC.sub.50, is less than its
cytotoxic effects, LD.sub.50.
[0181] In some embodiments, the compounds selectively inhibit one
or more kinases. Selective inhibition of a kinase, such as FLT3,
p38 kinase, STK10, MKNK2, Bcr-Abl, c-kit, or PDGFR, is achieved by
inhibiting activity of one kinase, while having an insignificant
effect on other members of the superfamily.
[0182] Bcr-Abl
[0183] c-Abl is a nonreceptor tyrosine kinase that contributes to
several leukogenic fusion proteins, including the deregulated
tyrosine kinase, Bcr-Abl. Chronic myeloid leukemia (CML) is a
clonal disease involving the pluripotent hematopoietic stem cell
compartment and is associated with the Philadelphia chromosome
[Nowell P. C. and Hungerford D. A., Science 132, 1497 (1960)], a
reciprocal translocation between chromosomes 9 and 22 ([(9:22)
(q34; q11)]) [Rowley J. D., Nature 243,290-293 (1973)]. The
translocation links the c-Abl tyrosine kinase oncogene on
chromosome 9 to the 5 half of the bcr (breakpoint cluster region)
gene on chromosome 22 and creates the fusion gene bcr/abl. The
fusion gene produces a chimeric 8.5 kB transcript that codes for a
210-kD fusion protein (p210.sup.bcr-abl), and this gene product is
an activated protein tyrosine kinase. Thus, the Abelson tyrosine
kinase is improperly activated by accidental fusion of the bcr gene
with the gene encoding the intracellular non-receptor tyrosine
kinase, c-Abl.
[0184] The Bcr domain interferes with the intramolecular Abl
inhibitory loop and unveils a constitutive kinase activity that is
absent in the normal Abl protein. Bcr-Abl tyrosine kinase is a
potent inhibitor of apoptosis, and it is well accepted that the
oncoprotein expresses a constitutive tyrosine kinase activity that
is necessary for its cellular transforming activity. Constitutive
activity of the fusion tyrosine kinase Bcr-Abl has been established
as the characteristic molecular abnormality present in virtually
all cases of chronic myeloid leukemia (CML) and up to 20 percent of
adult acute lymphoblastic leukemia (ALL) [Faderl S. et al., N Engl
J Med 341, 164-172 (1999); Sawyers C. L., N Engl J Med 340,
1330-1340 (1999)].
[0185] Mutations present in the kinase domain of the Bcr-Abl gene
of patients suffering from CML or Ph+ ALL account for the
biological resistance of these patients towards STI571 treatment in
that said mutations lead to resistance of the Bcr-Abl tyrosine
kinase towards inhibition by STI571. Novel therapies for CML need
to address this emerging problem of clinical resistance to STI571
(Gleevec). Because tumor progression in patients receiving STI571
seem to be mediated by amplification of or mutation in the Bcr-Abl
gene that causes the tyrosine kinase to be less efficiently
inhibited by the drug, newer tyrosine kinase inhibitors may be
susceptible to the same mechanisms of resistance. None the less,
these findings are extremely valuable in the development of new
compounds or combinations of compounds which are capable to
overcome resistance towards treatment with STI571. Furthermore, in
view of the large number of protein kinase inhibitors and the
multitude of proliferative and other PK-related diseases, there is
an ever-existing need to provide novel classes of compounds that
are useful as PK inhibitors and thus in the treatment of these PTK
related diseases.
[0186] In one embodiment, compositions and methods provided herein
are effective to modulate the activity of Bcr-Abl. In other
embodiments, compositions and methods provided herein are effective
to selectively modulate the activity of Bcr-Abl. In a further
embodiment, compositions of Formula G, e.g., compounds described in
Examples M and O, inhibit the protein tyrosine kinase associated
with mutated bcr-abl, which gives rise to observed clinical
resistance towards treatment with STI571.
[0187] Formulations
[0188] The compounds described herein can be used to prepare a
medicament, such as by formulation into pharmaceutical compositions
for administration to a subject using techniques generally known in
the art. A summary of such pharmaceutical compositions may be
found, for example, in Remington's Pharmaceutical Sciences, Mack
Publishing Co., Easton, Pa. The compounds of the invention can be
used singly or as components of mixtures. Preferred forms of the
compounds are those for systemic administration as well as those
for topical or transdermal administration. Formulations designed
for timed release are also within the scope of the invention.
Formulation in unit dosage form is also preferred for the practice
of the invention.
[0189] In unit dosage form, the formulation is divided into unit
doses containing appropriate quantities of one or more compounds.
The unit dosage may be in the form of a package containing discrete
quantities of the formulation. Non-limiting examples are packeted
tablets or capsules, and powders in vials or ampoules.
[0190] The compounds described herein may be labeled isotopically
(e.g. with a radioisotope) or by any other means, including, but
not limited to, the use of chromophores or fluorescent moieties,
bioluminescent labels, or chemiluminescent labels. The compositions
may be in conventional forms, either as liquid solutions or
suspensions, solid forms suitable for solution or suspension in a
liquid prior to use, or as emulsions. Suitable excipients or
carriers are, for example, water, saline, dextrose, glycerol,
alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils,
mineral oil, propylene glycol, PPG-2 myristyl propionate, and the
like. Of course, these compositions may also contain minor amounts
of nontoxic, auxiliary substances, such as wetting or emulsifying
agents, pH buffering agents, and so forth.
[0191] Methods for the preparation of compositions comprising the
compounds described herein include formulating the derivatives with
one or more inert, pharmaceutically acceptable carriers to form
either a solid or liquid. Solid compositions include, but are not
limited to, powders, tablets, dispersible granules, capsules,
cachets, and suppositories. Liquid compositions include solutions
in which a compound is dissolved, emulsions comprising a compound,
or a solution containing liposomes, micelles, or nanoparticles
comprising a compound as disclosed herein.
[0192] A carrier of the invention can be one or more substances
which also serve to act as a diluent, flavoring agent, solubilizer,
lubricant, suspending agent, binder, or tablet disintegrating
agent. A carrier can also be an encapsulating material.
[0193] In powder forms of the invention's compositions, the carrier
is preferably a finely divided solid in powder form which is
interdispersed as a mixture with a finely divided powder from of
one or more compound. In tablet forms of the compositions, one or
more compounds is intermixed with a carrier with appropriate
binding properties in suitable proportions followed by compaction
into the shape and size desired. Powder and tablet form
compositions preferably contain between about 5 to about 70% by
weight of one or more compound. Carriers that may be used in the
practice of the invention include, but are not limited to,
magnesium carbonate, magnesium stearate, talc, lactose, sugar,
pectin, dextrin, starch, tragacanth, methyl cellulose, sodium
carboxymethyl cellulose, a low-melting wax, cocoa butter, and the
like.
[0194] The compounds of the invention may also be encapsulated or
microencapsulated by an encapsulating material, which may thus
serve as a carrier, to provide a capsule in which the derivatives,
with or without other carriers, is surrounded by the encapsulating
material. In an analogous manner, cachets comprising one or more
compounds are also provided by the instant invention. Tablet,
powder, capsule, and cachet forms of the invention can be
formulated as single or unit dosage forms suitable for
administration, optionally conducted orally.
[0195] In suppository forms of the compositions, a low-melting wax
such as, but not limited to, a mixture of fatty acid glycerides,
optionally in combination with cocoa butter is first melted. One or
more compounds are then dispersed into the melted material by, as a
non-limiting example, stirring. The non-solid mixture is then
placed into molds as desired and allowed to cool and solidify.
[0196] Non-limiting compositions in liquid form include solutions
suitable for oral or parenteral administration, as well as
suspensions and emulsions suitable for oral administration. Sterile
aqueous based solutions of one or more compounds, optionally in the
presence of an agent to increase solubility of the derivative(s),
are also provided. Non-limiting examples of sterile solutions
include those comprising water, ethanol, and/or propylene glycol in
forms suitable for parenteral administration. A sterile solution of
the invention may be prepared by dissolving one or more compounds
in a desired solvent followed by sterilization, such as by
filtration through a sterilizing membrane filter as a non-limiting
example. In another embodiment, one or more compounds are dissolved
into a previously sterilized solvent under sterile conditions.
[0197] A water based solution suitable for oral administration can
be prepared by dissolving one or more compounds in water and adding
suitable flavoring agents, coloring agents, stabilizers, and
thickening agents as desired. Water based suspensions for oral use
can be made by dispersing one or more compounds in water together
with a viscous material such as, but not limited to, natural or
synthetic gums, resins, methyl cellulose, sodium carboxymethyl
cellulose, polyvinylpyrrolidone, and other suspending agents known
to the pharmaceutical field.
[0198] In therapeutic use, the compounds of the invention are
administered to a subject at dosage levels of from about 0.5 mg/kg
to about 8.0 mg/kg of body weight per day. For example, a human
subject of approximately 70 kg, this is a dosage of from 35 mg to
560 mg per day. Such dosages, however, may be altered depending on
a number of variables, not limited to the activity of the compound
used, the condition to be treated, the mode of administration, the
requirements of the individual subject, the severity of the
condition being treated, and the judgment of the practitioner.
[0199] The foregoing ranges are merely suggestive, as the number of
variables in regard to an individual treatment regime is large, and
considerable excursions from these recommended values are not
uncommon.
[0200] Methods of Use
[0201] By modulating kinase activity, the compounds disclosed
herein can be used to treat a variety of diseases. Suitable
conditions characterized by undesirable protein-kinase activity can
be treated by the compounds presented herein. As used herein, the
term "condition" refers to a disease, disorder, or related symptom
where inappropriate kinase activity is present. In some
embodiments, these conditions are characterized by aggressive
neovasculaturization including tumors, especially acute myelogenous
leukemia (AML), B-precursor cell acute lymphoblastic leukemias,
myelodysplastic leukemias, T-cell acute lymphoblastic leukemias,
and chronic myelogenous leukemias (CMLs).
[0202] Compounds presented herein are useful in the treatment of a
variety of biologically aberrant conditions or disorders related to
tyrosine kinase signal transduction. Such disorders pertain to
abnormal cell proliferation, differentiation, and/or metabolism.
Abnormal cell proliferation may result in a wide array of diseases,
including the development of neoplasia such as carcinoma, sarcoma,
leukemia, glioblastoma, hemangioma, psoriasis, arteriosclerosis,
arthritis and diabetic retinopathy (or other disorders related to
uncontrolled angiogenesis and/or vasculogenesis).
[0203] In various embodiments, compounds presented herein regulate,
modulate, and/or inhibit disorders associated with abnormal cell
proliferation by affecting the enzymatic activity of one or more
tyrosine kinases and interfering with the signal transduced by said
kinase. More particularly, the present invention is directed to
compounds which regulate, modulate said kinase mediated signal
transduction pathways as a therapeutic approach to cure leukemia
and many kinds of solid tumors, including but not limited to
carcinoma, sarcoma, erythroblastoma, glioblastoma, meningioma,
astrocytoma, melanoma and myoblastoma. Indications may include, but
are not limited to brain cancers, bladder cancers, ovarian cancers,
gastric cancers, pancreas cancers, colon cancers, blood cancers,
lung cancers and bone cancers.
[0204] In other embodiments, compounds herein are useful in the
treatment of cell proliferative disorders including cancers, blood
vessel proliferative disorders, fibrotic disorders, and mesangial
cell proliferative disorders. Blood vessel proliferation disorders
refer to angiogenic and vasculogenic disorders generally resulting
in abnormal proliferation of blood vessels. The formation and
spreading of blood vessels, or vasculogenesis and angiogenesis,
respectively, play important roles in a variety of physiological
processes such as embryonic development, corpus luteum formation,
wound healing and organ regeneration. They also play a pivotal role
in cancer development. Other examples of blood vessel proliferation
disorders include arthritis, where new capillary blood vessels
invade the joint and destroy cartilage, and ocular diseases, like
diabetic retinopathy, where new capillaries in the retina invade
the vitreous, bleed and cause blindness. Conversely, disorders
related to the shrinkage, contraction or closing of blood vessels,
such as restenosis, are also implicated.
[0205] Fibrotic disorders refer to the abnormal formation of
extracellular matrix. Examples of fibrotic disorders include
hepatic cirrhosis and mesangial cell proliferative disorders.
Hepatic cirrhosis is characterized by the increase in extracellular
matrix constituents resulting in the formation of a hepatic scar.
Hepatic cirrhosis can cause diseases such as cirrhosis of the
liver. An increased extracellular matrix resulting in a hepatic
scar can also be caused by viral infection such as hepatitis.
Lipocytes appear to play a major role in hepatic cirrhosis. Other
fibrotic disorders implicated include atherosclerosis (see,
below).
[0206] Mesangial cell proliferative disorders refer to disorders
brought about by abnormal proliferation of mesangial cells.
Mesangial proliferative disorders include various human renal
diseases, such as glomerulonephritis, diabetic nephropathy,
malignant nephrosclerosis, thrombotic microangiopathy syndromes,
transplant rejection, and glomerulopathies. The cell proliferative
disorders which are indications of the present invention are not
necessarily independent. For example, fibrotic disorders may be
related to, or overlap, with blood vessel proliferative disorders.
For example, atherosclerosis results, in part, in the abnormal
formation of fibrous tissue within blood vessels.
[0207] Compounds of the invention can be administered to a subject
upon determination of the subject as having a disease or unwanted
condition that would benefit by treatment with said derivative. The
determination can be made by medical or clinical personnel as part
of a diagnosis of a disease or condition in a subject. Non-limiting
examples include determination of a risk of acute myelogenous
leukemia (AML), B-precursor cell acute lymphoblastic leukemias,
myelodysplastic leukemias, T-cell acute lymphoblastic leukemias,
and chronic myelogenous leukemias (CMLs).
[0208] The methods of the invention can comprise the administration
of an effective amount of one or more compounds as disclosed
herein, optionally in combination with one or more other active
agents for the treatment of a disease or unwanted condition as
disclosed herein. The subject is preferably human, and repeated
administration over time is within the scope of the present
invention.
[0209] The present invention thus also provides compounds described
above and their salts or solvates and pharmaceutically acceptable
salts or solvates thereof for use in the prevention or treatment of
disorders mediated by aberrant protein tyrosine kinase activity
such as human malignancies and the other disorders mentioned above.
The compounds of the present invention are especially useful for
the treatment of disorders caused by aberrant kinase activity such
as breast, ovarian, gastric, pancreatic, non-small cell lung,
bladder, head and neck cancers, and psoriasis. The cancers include
hematologic cancers, for example, acute myelogenous leukemia (AML),
B-precursor cell acute lymphoblastic leukemias, myelodysplastic
leukemias, T-cell acute lymphoblastic leukemias, and chronic
myelogenous leukemias (CMLs).
[0210] A further aspect of the invention provides a method of
treatment of a human or animal subject suffering from a disorder
mediated by aberrant protein tyrosine kinase activity, including
susceptible malignancies, which comprises administering to the
subject an effective amount of a compound described above or a
pharmaceutically acceptable salt or solvate thereof.
[0211] A further aspect of the present invention provides the use
of a compound described above, or a pharmaceutically acceptable
salt or solvate thereof, in the preparation of a medicament for the
treatment of cancer and malignant tumors. The cancer can be
stomach, gastric, bone, ovary, colon, lung, brain, larynx,
lymphatic system, genitourinary tract, ovarian, squamous cell
carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma, lung
cancer, bladder cancer, head and neck cancer, melanoma, ovarian
cancer, prostate cancer, breast cancer, small-cell lung cancer,
leukemia, acute myelogenous leukemia (AML), B-precursor cell acute
lymphoblastic leukemias, myelodysplastic leukemias, T-cell acute
lymphoblastic leukemias, and chronic myelogenous leukemias (CMLs),
glioma, colorectal cancer, genitourinary cancer gastrointestinal
cancer, or pancreatic cancer.
[0212] In accordance with the present invention, compounds provided
herein are useful for preventing and treating conditions associated
with ischemic cell death, such as myocardial infarction, stroke,
glaucoma, and other neurodegenerative conditions. Various
neurodegenerative conditions which may involve apoptotic cell
death, include, but are not limited to, Alzheimer's Disease, ALS
and motor neuron degeneration, Parkinson's disease, peripheral
neuropathies, Down's Syndrome, age related macular degeneration
(ARMD), traumatic brain injury, spinal cord injury, Huntington's
Disease, spinal muscular atrophy, and HIV encephalitis. The
compounds described in detail above can be used in methods and
compositions for imparting neuroprotection and for treating
neurodegenerative diseases.
[0213] The compounds described herein, can be used in a
pharmaceutical composition for the prevention and/or the treatment
of a condition selected from the group consisting of arthritis
(including osteoarthritis, degenerative joint disease,
spondyloarthropathies, gouty arthritis, systemic lupus
erythematosus, juvenile arthritis and rheumatoid arthritis), common
cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease,
Crohn's disease, emphysema, acute respiratory distress syndrome,
asthma, bronchitis, chronic obstructive pulmonary disease,
Alzheimer's disease, organ transplant toxicity, cachexia, allergic
reactions, allergic contact hypersensitivity, cancer (such as solid
tumor cancer including colon cancer, breast cancer, lung cancer and
prostrate cancer; hematopoietic malignancies including leukemias
and lymphomas; Hodgkin's disease; aplastic anemia, skin cancer and
familiar adenomatous polyposis), tissue ulceration, peptic ulcers,
gastritis, regional enteritis, ulcerative colitis, diverticulitis,
recurrent gastrointestinal lesion, gastrointestinal bleeding,
coagulation, anemia, synovitis, gout, ankylosing spondylitis,
restenosis, periodontal disease, epidermolysis bullosa,
osteoporosis, atherosclerosis (including atherosclerotic plaque
rupture), aortic aneurysm (including abdominal aortic aneurysm and
brain aortic aneurysm), periarteritis nodosa, congestive heart
failure, myocardial infarction, stroke, cerebral ischemia, head
trauma, spinal cord injury, neuralgia, neurodegenerative disorders
(acute and chronic), autoimmune disorders, Huntington's disease,
Parkinson's disease, migraine, depression, peripheral neuropathy,
pain (including low back and neck pain, headache and toothache),
gingivitis, cerebral amyloid angiopathy, nootropic or cognition
enhancement, amyotrophic lateral sclerosis, multiple sclerosis,
ocular angiogenesis, corneal injury, macular degeneration,
conjunctivitis, abnormal wound healing, muscle or joint sprains or
strains, tendonitis, skin disorders (such as psoriasis, eczema,
scleroderma and dermatitis), myasthenia gravis, polymyositis,
myositis, bursitis, burns, diabetes (including types I and II
diabetes, diabetic retinopathy, neuropathy and nephropathy), tumor
invasion, tumor growth, tumor metastasis, corneal scarring,
scleritis, immunodeficiency diseases (such as AIDS in humans and
FLV, FIV in cats), sepsis, premature labor, hypoprothrombinemia,
hemophilia, thyroiditis, sarcoidosis, Behcet's syndrome,
hypersensitivity, kidney disease, Rickettsial infections (such as
Lyme disease, Erlichiosis), Protozoan diseases (such as malaria,
giardia, coccidia), reproductive disorders, and septic shock,
arthritis, fever, common cold, pain and cancer in a mammal,
preferably a human, cat, livestock or a dog, comprising an amount
of a compound of formula described herein or a pharmaceutically
acceptable salt thereof effective in such prevention and/or
treatment optionally with a pharmaceutically acceptable
carrier.
[0214] A further aspect of the present invention provides the use
of a compound described above, or a pharmaceutically acceptable
salt thereof, in the preparation of a medicament for the treatment
of psoriasis.
[0215] As one of skill in the art will recognize, the compounds can
be administered before, during or after the occurrence of a
condition or a disease, and the timing of administering the
composition containing a compound can vary. Thus, for example, the
compounds can be used as a prophylactic and can be administered
continuously to subjects with a propensity to conditions and
diseases in order to prevent the occurrence of the disorder. The
compounds and compositions can be administered to a subject during
or as soon as possible after the onset of the symptoms. The
administration of the compounds can be initiated within the first
48 hours of the onset of the symptoms, preferably within the first
48 hours of the onset of the symptoms, more preferably within the
first 6 hours of the onset of the symptoms, and most preferably
within 3 hours of the onset of the symptoms. The initial
administration can be via any route practical, such as, for
example, an intravenous injection, a bolus injection, infusion over
5 min. to about 5 hours, a pill, a capsule, transdermal patch,
buccal delivery, and the like, or a combination thereof. A compound
is preferably administered as soon as is practicable after the
onset of a condition or a disease is detected or suspected, and for
a length of time necessary for the treatment of the disease, such
as, for example, from about 1 month to about 3 months. As one of
skill in the art will recognize, the length of treatment can vary
for each subject, and the length can be determined using the known
criteria. For example, the compound or a formulation containing the
compound can be administered for at least 2 weeks, preferably about
1 month to about 5 years, and more preferably from about 1 month to
about 3 years.
[0216] Kits/Articles of Manufacture
[0217] For use in the therapeutic applications described herein,
kits and articles of manufacture are also within the scope of the
invention. Such kits can comprise a carrier, package, or container
that is compartmentalized to receive one or more containers such as
vials, tubes, and the like, each of the container(s) comprising one
of the separate elements to be used in a method of the invention.
Suitable containers include, for example, bottles, vials, syringes,
and test tubes. The containers can be formed from a variety of
materials such as glass or plastic.
[0218] For example, the container(s) can comprise one or more
compounds of the invention, optionally in a composition or in
combination with another agent as disclosed herein. The
container(s) optionally have a sterile access port (for example the
container can be an intravenous solution bag or a vial having a
stopper pierceable by a hypodermic injection needle). Such kits
optionally comprising a compound with an identifying description or
label or instructions relating to its use in the methods of the
present invention.
[0219] A kit of the invention will typically may comprise one or
more additional containers, each with one or more of various
materials (such as reagents, optionally in concentrated form,
and/or devices) desirable from a commercial and user standpoint for
use of a compound of the invention. Non-limiting examples of such
materials include, but not limited to, buffers, diluents, filters,
needles, syringes; carrier, package, container, vial and/or tube
labels listing contents and/or instructions for use, and package
inserts with instructions for use. A set of instructions will also
typically be included.
[0220] A label can be on or associated with the container. A label
can be on a container when letters, numbers or other characters
forming the label are attached, molded or etched into the container
itself; a label can be associated with a container when it is
present within a receptacle or carrier that also holds the
container, e.g., as a package insert. A label can be used to
indicate that the contents are to be used for a specific
therapeutic application. The label can also indicate directions for
use of the contents, such as in the methods described herein.
[0221] The terms "kit" and "article of manufacture" may be used as
synonyms.
EXAMPLES
[0222] The present invention is further illustrated by the
following examples, which should not be construed as limiting in
any way. The experimental procedures to generate the data shown are
discussed in more detail below. For all formulations herein,
multiple doses may be proportionally compounded as is known in the
art.
[0223] The invention has been described in an illustrative manner,
and it is to be understood that the terminology used is intended to
be in the nature of description rather than of limitation. Thus, it
will be appreciated by those of skill in the art that conditions
such as choice of solvent, temperature of reaction, volumes,
reaction time may vary while still producing the desired compounds.
In addition, one of skill in the art will also appreciate that many
of the reagents provided in the following examples may be
substituted with other suitable reagents. See, e.g., Smith &
March, Advanced Organic Chemistry, 5.sup.th ed. (2001).
Example A
Synthesis of Isoxazole-Amides
[0224] Compounds A1 through A240 are synthesized by methods known
in the art or described herein. The structures are shown below in
Table A:
2TABLE A NO. STRUCTURE A1 26 A2 27 A3 28 A4 29 A5 30 A6 31 A7 32 A8
33 A9 34 A10 35 A11 36 A12 37 A13 38 A14 39 A15 40 A16 41 A17 42
A18 43 A19 44 A20 45 A21 46 A22 47 A23 48 A24 49 A25 50 A26 51 A27
52 A28 53 A29 54 A30 55 A31 56 A32 57 A33 58 A34 59 A35 60 A36 61
A37 62 A38 63 A39 64 A40 65 A41 66 A42 67 A43 68 A44 69 A45 70 A46
71 A47 72 A48 73 A49 74 A50 75 A51 76 A52 77 A53 78 A54 79 A55 80
A56 81 A57 82 A58 83 A59 84 A60 85 A61 86 A62 87 A63 88 A64 89 A65
90 A66 91 A67 92 A68 93 A69 94 A70 95 A71 96 A72 97 A73 98 A74 99
A75 100 A76 101 A77 102 A78 103 A79 104 A80 105 A81 106 A82 107 A83
108 A84 109 A85 110 A86 111 A87 112 A89 113 A90 114 A91 115 A92 116
A93 117 A94 118 A95 119 A96 120 A97 121 A98 122 A99 123 A100 124
A101 125 A102 126 A103 127 A104 128 A105 129 A106 130 A107 131 A108
132 A109 133 A110 134 A111 135 A112 136 A113 137 A114 138 A115 139
A116 140 A117 141 A118 142 A119 143 A120 144 A121 145 A122 146 A123
147 A124 148 A125 149 A126 150 A127 151 A128 152 A129 153 A130 154
A131 155 A132 156 A133 157 A134 158 A135 159 A136 160 A137 161 A138
162 A139 163 A140 164 A141 165 A142 166 A143 167 A144 168 A145 169
A146 170 A147 171 A148 172 A149 173 A150 174 A151 175 A152 176 A153
177 A154 178 A155 179 A156 180 A157 181 A158 182 A159 183 A160 184
A161 185 A162 186 A163 187 A164 188 A165 189 A166 190 A167 191 A168
192 A169 193 A170 194 A171 195 A172 196 A173 197 A174 198 A175 199
A176 200 A177 201 A178 202 A179 203 A180 204 A181 205 A182 206 A183
207 A184 208 A185 209 A186 210 A187 211 A188 212 A189 213 A190 214
A191 215 A192 216 A193 217 A194 218 A195 219 A196 220 A197 221 A198
222 A199 223 A200 224 A201 225 A202 226 A203 227 A204 228 A205 229
A206 230 A207 231 A208 232 A209 233 A210 234 A211 235 A212 236 A213
237 A214 238 A215 239 A216 240 A217 241 A218 242 A219 243 A220 244
A221 245 A222 246 A223 247 A224 248 A225 249 A226 250 A227 251 A228
252 A229 253 A230 254 A231 255 A232 256 A233 257 A234 258 A235 259
A236 260 A237 261 A238 262 A239 263 A240 264
Example B
Exemplary Synthesis of Isoxazole-Amides
[0225] 265
[0226] In a 40 mL vial, 1 mL of thionyl chloride was added to 0.2
mmol para-substituted phenylacetic acid. The vial was capped and
stirred at 80.degree. C. for approximately three hours. The
completion of the reaction was checked by TLC. The excess thionyl
chloride was removed in vacuo. The residue was dissolved in
dichloromethane and added to a mixture of
3-tert-butyl-isoxazol-5-ylamine (0.2 mmol) and DIEA (0.2 mmol). The
reaction was stirred overnight at 45.degree. C. The solvent was
removed under vacuum and the product was purified by HPLC.
Synthesis of Compound B1:
N-(3-tert-butylisoxazol-5-yl)-2-(4-(benzyloxy)ph-
enyl)acetamide
[0227] 266
[0228] (4-Benzyloxy-phenyl)-acetic acid (50 mg, 0.2 mmol, 1 eq) was
stirred with 1 mL of thionyl chloride at 80.degree. C. for
approximately three hours. The completion of the reaction was
checked by TLC. Excess thionyl chloride was removed in vacuo, the
residue was dissolved in dichloromethane and added to a mixture of
3-tert-butyl-isoxazol-5-ylamine (28 mg, 0.2 mmol, 1 eq) and DIEA
(35 .mu.L, 0.2 mmol, 1 eq). The reaction was stirred overnight at
45.degree. C. The solvent was removed and the product purified by
HPLC. Yield: 42 mg (57%), LC/MS [MH.sup.+] 365.
[0229] Compounds B2 through B16 were synthesized in a manner
analogous to Compound B1 using similar starting materials and
reagents. The structures are shown below in Table B:
3TABLE B NO. CHEMICAL STRUCTURE B1 267 B2 268 B3 269 B4 270 B5 271
B6 272 B7 273 B8 274 B9 275 B10 276 B11 277 B12 278 B13 279 B14 280
B15 281 B16 282
Example C: Synthesis of thiazole-amides
Synthesis of Compound C1:
2-(4-(benzyloxy)phenyl)-N-(5-methylthiazol-2-yl)- acetamide
[0230] 283
[0231] Compound C1 was prepared in strict analogy to compound B1
using 2-amino-5-methylthiazole as starting material instead of
3-tert-butyl-isoxazol-5-ylamine.
[0232] Compounds C2 through C6 were synthesized in a manner
analogous to Compound C1 using similar starting materials and
reagents. The structures are shown below in Table C:
4TABLE C NO. CHEMICAL STRUCTURE C1 284 C2 285 C3 286 C4 287 C5 288
C6 289
Example E
Synthesis of Di-Phenyl Ureas
Synthesis of Compound E1:
2-(4-Fluoro-phenyl)-N-(5-methyl-2-phenyl-2H-pyra-
zol-3-yl)-acetamide
[0233] 290
[0234] Compound E1 was prepared in strict analogy to compound B1
using 5-methyl-2-phenyl-2H-pyrazol-3-ylamine and
4-fluorophenylacetic acid as starting materials.
[0235] Compounds E2 through E20 were synthesized in a manner
analogous to Compound E1 using similar starting materials and
reagents. The structures are shown below in Table E:
5TABLE E NO. CHEMICAL STRUCTURE E1 291 E2 292 E3 293 E4 294 E5 295
E6 296 E7 297 E8 298 E9 299 E10 300 E11 301 E12 302 E13 303 E14 304
E15 305 E16 306 E17 307 E18 308 E19 309 E20 310
Example F
Synthesis of Isoxazole-Bis-Amides
[0236] 311
[0237] In a vial thionyl chloride was added to a para-substituted
phenylacetic acid. The vial was capped and stirred at 80.degree. C.
for approximately three hours. The completion of the reaction was
checked by TLC, and the excess thionyl chloride removed in vacuo.
The residue was dissolved in dichloromethane and added to a mixture
5-tert-butyl-isoxazol-3-ylamine and DIEA. The reaction was stirred
overnight at 45.degree. C. The solvent was removed under vacuum and
the product was purified by HPLC. 312
[0238] For the case of R.dbd.NO.sub.2, reduction to the amine was
carried out prior to reaction with an activated carboxylic acid.
1.5 gm of 1-(5-tert-butyl-isoxazol-3-yl)-3-(4-nitro-phenyl)-amide
was dissolved in 50 ml THF and 0.1 g of 10% Pd/C is added. The
solution was stirred under hydrogen at 50 psi. for 24 hours then
filtered through a Celite pad. The organic solvent was evaporated
under vacuum and the resulting residue was triturated with ethyl
acetate. 313
[0239] 1 equivalent of the carboxylic acid and 1.1 equivalent of
CDI were dissolved in dry DMF and stirred at 40.degree. C. for 2 h,
then 1 equivalent of the substituted aniline was added. The
reaction mixture was stirred at 40.degree. C. overnight and the
final product was purified by preparative HPLC. 314
[0240] Alternatively, 1 equivalent of the carboxylic acid and 1.1
equivalent of thionyl chloride were heated in a sealed tube at 50 C
for 3 h. The excess thionyl chloride was evaporated, 1 equivalent
of aniline in DMF was added, and the solution stirred at room
temperature for 8 h. The final product was purified by preparative
HPLC.
[0241] Compounds F1 through F5 are synthesized in a manner
analogous to those shown above using similar starting materials and
reagents. The structures are shown below in Table F:
6TABLE F NO. CHEMICAL STRUCTURE F1 315 F2 316 F3 317 F4 318 F5
319
[0242] Binding Constant (K.sub.d) Measurements for
Small-Molecule-Kinase Interactions
[0243] Methods for measuring binding affinities for interactions
between small molecules and kinases including FLT3, c-KIT,
ABL(T334I) [a.k.a. ABL(T315I)], VEGFR2 (a.k.a. KDR), and EGFR are
described in detail in U.S. application Ser. No. 10/873,835, which
is incorporated by reference herein in its entirety. The components
of the assays include human kinases expressed as fusions to T7
bacteriophage particles and immobilized ligands that bind to the
ATP site of the kinases. For the assay, phage-displayed kinases and
immobilized ATP site ligands are combined with the compound to be
tested. If the test compound binds the kinase it competes with the
immobilized ligand and prevents binding to the solid support. If
the compound does not bind the kinase, phage-displayed proteins are
free to bind to the solid support through the interaction between
the kinase and the immobilized ligand. The results are read out by
quantitating the amount of fusion protein bound to the solid
support, which is accomplished by either traditional phage plaque
assays or by quantitative PCR (qPCR) using the phage genome as a
template. To determine the affinity of the interactions between a
test molecule and a kinase, the amount of phage-displayed kinase
bound to the solid support is quantitated as a function of test
compound concentration. The concentration of test molecule that
reduces the number of phage bound to the solid support by 50% is
equal to the K.sub.d for the interaction between the kinase and the
test molecule. Typically, data are collected for twelve
concentrations of test compound and, the resultant binding curve is
fit to a non-cooperative binding isotherm to calculate K.sub.d.
[0244] Described in the exemplary assays below is data from binding
with varying kinases. Binding values are reported as follows "+"
for representative compounds exhibiting a binding dissociation
constant (Kd) of 10,000 nM or higher; "++" for representative
compounds exhibiting a Kd of 1,000 nM to 10,000 nM; "+++" for
representative compounds exhibiting a Kd of 100 nM to 1,000 nM; and
"++++" for representative compounds exhibiting a Kd of less than
100 nM. The term "ND" represents non-determined values.
[0245] Compound E7 and E15 were tested against abl using the
results are outlined below:
7 Binding Binding Compound Assay: AB Assay: AB No. L1(DKIN):
L1(E274K): E7 + ND B15 ND +
[0246] All references cited herein, including patents, patent
applications, and publications, are herby incorporated by reference
in their entireties, whether previously specifically incorporated
or not.
[0247] Having now fully described this invention, it will be
appreciated by those skilled in the art that the same can be
performed within a wide range of equivalent parameters,
concentrations, and conditions without departing from the spirit
and scope of the invention and without undue experimentation.
[0248] While this invention has been described in connection with
specific embodiments thereof, it will be understood that it is
capable of further modifications. This application is intended to
cover any variations, uses, or adaptations of the invention
following, in general, the principles of the invention and
including such departures from the present disclosure as come
within known or customary practice within the art to which the
invention pertains and as may be applied to the essential features
hereinbefore set forth.
* * * * *