U.S. patent application number 14/671944 was filed with the patent office on 2015-07-30 for dihydropyridophthalazinone inhibitors of poly(adp-ribose)polymerase (parp) for use in treatment of diseases associated with a pten deficiency.
The applicant listed for this patent is BIOMARIN PHARMACEUTICAL INC.. Invention is credited to Daniel Chu, Ying Feng, Leonard Edwin Post, Yuqiao Shen, Bing Wang.
Application Number | 20150209363 14/671944 |
Document ID | / |
Family ID | 44342189 |
Filed Date | 2015-07-30 |
United States Patent
Application |
20150209363 |
Kind Code |
A1 |
Chu; Daniel ; et
al. |
July 30, 2015 |
DIHYDROPYRIDOPHTHALAZINONE INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE
(PARP) FOR USE IN TREATMENT OF DISEASES ASSOCIATED WITH A PTEN
DEFICIENCY
Abstract
A compound having the structure set forth in Formula (I) and
Formula (II): ##STR00001## wherein the substituents Y, Z, A, B,
R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are as defined
herein. Provided herein are inhibitors of
poly(ADP-ribose)polymerase activity. Also described herein are
pharmaceutical compositions that include at least one compound
described herein and the use of a compound or pharmaceutical
composition described herein to treat diseases, disorders and
conditions associated with a PTEN deficiency that are ameliorated
by the inhibition of PARP activity.
Inventors: |
Chu; Daniel; (Santa Clara,
CA) ; Wang; Bing; (San Jose, CA) ; Feng;
Ying; (Fremont, CA) ; Shen; Yuqiao; (Moraga,
CA) ; Post; Leonard Edwin; (Orinda, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BIOMARIN PHARMACEUTICAL INC. |
Novato |
CA |
US |
|
|
Family ID: |
44342189 |
Appl. No.: |
14/671944 |
Filed: |
March 27, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13972166 |
Aug 21, 2013 |
9018201 |
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14671944 |
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13020619 |
Feb 3, 2011 |
8541403 |
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13972166 |
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61301174 |
Feb 3, 2010 |
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Current U.S.
Class: |
514/210.21 ;
514/232.8; 514/248 |
Current CPC
Class: |
A61N 2005/1098 20130101;
A61K 45/06 20130101; A61P 11/00 20180101; A61P 17/00 20180101; A61P
1/04 20180101; A61P 35/00 20180101; A61P 13/10 20180101; A61K
31/5377 20130101; A61P 15/00 20180101; A61P 13/12 20180101; A61P
43/00 20180101; C07D 487/06 20130101; A61P 25/00 20180101; A61P
13/08 20180101; A61P 19/08 20180101; A61N 5/10 20130101; A61K
31/5025 20130101; A61P 5/00 20180101 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 45/06 20060101 A61K045/06; A61N 5/10 20060101
A61N005/10; A61K 31/5025 20060101 A61K031/5025 |
Claims
1-22. (canceled)
23. A method of treating a disease or condition associated with a
PTEN deficiency comprising administering to the subject a
therapeutically effective amount of a compound having the
structure: ##STR00041## wherein: Y is an aryl or heteroaryl group
optionally substituted with at least one R.sub.6; Z is an aryl
group optionally substituted with at least one R.sub.6; A and B are
each independently selected from hydrogen, Br, Cl, F, I, OH,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, alkoxy,
alkoxyalkyl; wherein the C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl; and wherein B is not OH; R.sub.6 is
selected from OH, NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, C.sub.2-C.sub.8heterocycloalkyl,
C.sub.2-C.sub.6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, C.sub.2-C.sub.6alkynyl, aryl, arylalkyl,
C.sub.3-C.sub.8cycloalkylalkyl, haloalkoxy, haloalkyl,
hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,
C.sub.2-C.sub.8heterocycloalkylthio, heterocyclooxy,
heterocyclothio, NR.sub.AR.sub.B,
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene;
R.sub.2 is selected from hydrogen, Br, Cl, I, or F; R.sub.A, and
R.sub.B are independently selected from the group consisting of
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, and
alkylcarbonyl; or R.sub.A and R.sub.B taken together with the atom
to which they are attached form a 3-10 membered heterocycle ring
optionally having one to three heteroatoms or hetero
functionalities selected from the group consisting of --O--, --NH,
--N(C.sub.1-C.sub.6alkyl)-, --NCO(C.sub.1-C.sub.6alkyl)-,
--NCO(C.sub.3-C.sub.8cycloalkyl)-, --N(aryl)-,
--N(aryl-C.sub.1-C.sub.6alkyl-)-,
--N(substituted-aryl-C.sub.1-C.sub.6alkyl-)-, --N(heteroaryl)-,
--N(heteroaryl-C.sub.1-C.sub.6alkyl-)-,
--N(substituted-heteroaryl-C.sub.1-C.sub.6alkyl-)-, --S--, and
S(O).sub.q--, wherein q is 1 or 2; and wherein the 3-10 membered
heterocycle ring, the substituted-aryl, and the
substituted-heteroaryl are each independently substituted with one
or more substituents selected from alkenyl, alkoxy, alkoxyalkyl,
alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio,
alkylthioalkyl, alkenyl, carboxy, cyano, formyl, haloalkoxy,
haloalkyl, halogen, hydroxyl, hydroxyalkylene, mercapto, nitro,
--NR.sub.AR.sub.B, and --(NR.sub.AR.sub.B)carbonyl; or a
pharmaceutically acceptable salt or solvate thereof.
24. The method of claim 23, wherein R.sub.2 is fluorine.
25. The method of claim 23, wherein Y is heteroaryl optionally
substituted with 1, 2, or 3 R.sub.6.
26. The method of claim 25, wherein Y is triazole substituted with
C.sub.1-C.sub.6 alkyl.
27. The method of claim 23, wherein Z is phenyl optionally
substituted with 1, 2, or 3 R.sub.6.
28. The method of claim 27, wherein Z is phenyl substituted with
halogen.
29. The method of claim 23, wherein Y is triazole substituted with
C.sub.1-C.sub.6 alkyl; and Z is phenyl substituted with fluoro.
30. The method of claim 23, wherein the compound is:
(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,-
9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
(8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-p-
yrido[4,3,2-de]phthalazin-3(7H)-one,
(8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-
-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one,
(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dih-
ydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, or
(8S,9R)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-py-
rido[4,3,2-de]phthalazin-3(7H)-one; or a pharmaceutically
acceptable salt or solvate thereof.
31. The method of claim 23, wherein the compound is:
(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,-
9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, or a
pharmaceutically acceptable salt or solvate thereof.
32. The method of claim 31, wherein the disease or condition
associated with a PTEN deficiency is cancer selected from
glioblastoma, prostate cancer, renal cancer, small cell lung
carcinoma, meningioma, head and neck cancer, colorectal cancer,
thyroid cancer, bladder cancer, breast cancer, or melanoma.
33. The method of claim 32, wherein said administration is in
combination with ionizing radiation, one or more chemotherapeutic
agents, or a combination thereof.
34. A method of treating small cell lung cancer comprising
administering to the subject a therapeutically effective amount of
a compound having the structure: ##STR00042## wherein: Y is an aryl
or heteroaryl group optionally substituted with at least one
R.sub.6; Z is an aryl group optionally substituted with at least
one R.sub.6; A and B are each independently selected from hydrogen,
Br, Cl, F, I, OH, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl,
alkoxy, alkoxyalkyl; wherein the C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl; and wherein B is not OH; R.sub.6 is
selected from OH, NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, C.sub.2-C.sub.8heterocycloalkyl,
C.sub.2-C.sub.6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, C.sub.2-C.sub.6alkynyl, aryl, arylalkyl,
C.sub.3-C.sub.8cycloalkylalkyl, haloalkoxy, haloalkyl,
hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,
C.sub.2-C.sub.8heterocycloalkylthio, heterocyclooxy,
heterocyclothio, NR.sub.AR.sub.B,
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene;
R.sub.2 is selected from hydrogen, Br, Cl, I, or F; R.sub.A, and
R.sub.B are independently selected from the group consisting of
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, and
alkylcarbonyl; or R.sub.A and R.sub.B taken together with the atom
to which they are attached form a 3-10 membered heterocycle ring
optionally having one to three heteroatoms or hetero
functionalities selected from the group consisting of --O--, --NH,
--N(C.sub.1-C.sub.6alkyl)-, --NCO(C.sub.1-C.sub.6alkyl)-,
--NCO(C.sub.3-C.sub.8cycloalkyl)-, --N(aryl)-,
--N(aryl-C.sub.1-C.sub.6alkyl-)-,
--N(substituted-aryl-C.sub.1-C.sub.6alkyl-)-, --N(heteroaryl)-,
--N(heteroaryl-C.sub.1-C.sub.6alkyl-)-,
--N(substituted-heteroaryl-C.sub.1-C.sub.6alkyl-)-, --S--, and
S(O).sub.q--, wherein q is 1 or 2; and wherein the 3-10 membered
heterocycle ring, the substituted-aryl, and the
substituted-heteroaryl are each independently substituted with one
or more substituents selected from alkenyl, alkoxy, alkoxyalkyl,
alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio,
alkylthioalkyl, alkenyl, carboxy, cyano, formyl, haloalkoxy,
haloalkyl, halogen, hydroxyl, hydroxyalkylene, mercapto, nitro,
--NR.sub.AR.sub.B, and --(NR.sub.AR.sub.B)carbonyl; or a
pharmaceutically acceptable salt or solvate thereof.
35. The method of claim 34, wherein Y is triazole substituted with
C.sub.1-C.sub.6 alkyl; and Z is phenyl substituted with
halogen.
36. A method of treating small cell lung cancer comprising
administering to the subject a therapeutically effective amount of
the compound:
(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,-
9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, or a
pharmaceutically acceptable salt or solvate thereof.
37. The method of claim 34, wherein said administration is in
combination with ionizing radiation, one or more chemotherapeutic
agents, or a combination thereof.
38. The method of claim 36, wherein said administration is in
combination with ionizing radiation, one or more chemotherapeutic
agents, or a combination thereof.
39. A method of treating head and neck cancer, meningioma,
anaplastic astrocytoma, or colorectal cancer, the method comprising
administering to the subject a therapeutically effective amount of
a compound having the structure: ##STR00043## wherein: Y is an aryl
or heteroaryl group optionally substituted with at least one
R.sub.6; Z is an aryl group optionally substituted with at least
one R.sub.6; A and B are each independently selected from hydrogen,
Br, Cl, F, I, OH, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl,
alkoxy, alkoxyalkyl; wherein the C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl; and wherein B is not OH; R.sub.6 is
selected from OH, NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, C.sub.2-C.sub.8heterocycloalkyl,
C.sub.2-C.sub.6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, C.sub.2-C.sub.6alkynyl, aryl, arylalkyl,
C.sub.3-C.sub.8cycloalkylalkyl, haloalkoxy, haloalkyl,
hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,
C.sub.2-C.sub.8heterocycloalkylthio, heterocyclooxy,
heterocyclothio, NR.sub.AR.sub.B,
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene;
R.sub.2 is selected from hydrogen, Br, Cl, I, or F; R.sub.A, and
R.sub.B are independently selected from the group consisting of
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, and
alkylcarbonyl; or R.sub.A and R.sub.B taken together with the atom
to which they are attached form a 3-10 membered heterocycle ring
optionally having one to three heteroatoms or hetero
functionalities selected from the group consisting of --O--, --NH,
--N(C.sub.1-C.sub.6alkyl)-, --NCO(C.sub.1-C.sub.6alkyl)-,
--NCO(C.sub.3-C.sub.8cycloalkyl)-, --N(aryl)-,
--N(aryl-C.sub.1-C.sub.6alkyl-)-,
--N(substituted-aryl-C.sub.1-C.sub.6alkyl-)-, --N(heteroaryl)-,
--N(heteroaryl-C.sub.1-C.sub.6alkyl-)-,
--N(substituted-heteroaryl-C.sub.1-C.sub.6alkyl-)-, --S--, and
S(O).sub.q--, wherein q is 1 or 2; and wherein the 3-10 membered
heterocycle ring, the substituted-aryl, and the
substituted-heteroaryl are each independently substituted with one
or more substituents selected from alkenyl, alkoxy, alkoxyalkyl,
alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio,
alkylthioalkyl, alkenyl, carboxy, cyano, formyl, haloalkoxy,
haloalkyl, halogen, hydroxyl, hydroxyalkylene, mercapto, nitro,
--NR.sub.AR.sub.B, and --(NR.sub.AR.sub.B)carbonyl; or a
pharmaceutically acceptable salt or solvate thereof.
40. The method of claim 39, wherein Y is triazole substituted with
C.sub.1-C.sub.6 alkyl; and Z is phenyl substituted with
halogen.
41. The method of claim 39, wherein the compound is:
(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,-
9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, or a
pharmaceutically acceptable salt or solvate thereof.
42. The method of claim 39, wherein said administration is in
combination with ionizing radiation, one or more chemotherapeutic
agents, or a combination thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/972,166, filed Aug. 21, 2013, which is a
continuation of U.S. patent application Ser. No. 13/020,619, filed
Feb. 3, 2011, now U.S. Pat. No. 8,541,403, which claims the benefit
of priority of U.S. Provisional Patent Application No. 61/301,174,
filed Feb. 3, 2010, each of which is hereby incorporated by
reference in its entirety into this application.
FIELD OF THE INVENTION
[0002] Described herein are compounds, methods of making such
compounds, pharmaceutical compositions and medicaments containing
such compounds, and methods of using such compounds to modulate the
activity of PARP to treat or prevent diseases or conditions
associated with a deficiency in the enzyme phosphatase and tensin
homolog deleted on chromosome 10 (PTEN).
BACKGROUND OF THE INVENTION
[0003] The family of poly(ADP-ribose)polymerases (PARP) includes
approximately 18 proteins, which all display a certain level of
homology in their catalytic domain but differ in their cellular
functions (Ame et al., BioEssays., 26(8), 882-893 (2004)). PARP-1
and PARP-2 are unique members of the family, in that their
catalytic activities are stimulated by the occurrence of DNA strand
breaks.
[0004] PARP has been implicated in the signaling of DNA damage
through its ability to recognize and rapidly bind to DNA single or
double strand breaks (D'Amours, et al., Biochem. J., 342, 249-268
(1999)). It participates in a variety of DNA-related functions
including gene amplification, cell division, differentiation,
apoptosis, DNA base excision repair as well as effects on telomere
length and chromosome stability (d'Adda di Fagagna, et al., Nature
Gen., 23(1), 76-80 (1999)).
[0005] Phosphatase and tensin homolog deleted on chromosome 10
(PTEN) is a lipid and protein phosphatase. PTEN functions as a
protein phosphatase by dephosphorylating protein substrates on
serine, threonine, and tyrosine residues (Myers et al., Proc Natl
Acad Sci USA 94:9052-9057 (1997)). PTEN functions as a lipid
phospatase by dephosphorylating phophoinosital 3,4,5-triphosphate
(PIP3), a key signaling component of the phosphoinositol-3-kinase
(PI3-kinase) pathway (Maehama and Dixon, J Biol Chem
273:13375-13378 (1998)).
[0006] PTEN is a known tumor suppressor that has been implicated in
cellular processes including mediation of the MAP kinase signaling
pathway, centromeric maintenance, and is implicated in DNA repair
pathways through mediation of Rad51 gene expression. (Gu et al., J
Cell Bio 143:1375-1383 (1998); Weng et al., Hum Mol Genet (2001);
and Shen et al., Cell 128:157-170 (2007)).
SUMMARY OF THE INVENTION
[0007] Provided herein are compounds, compositions and methods for
modulating the activity of PARP to treat or prevent diseases or
conditions associated with a PTEN deficiency. Among the compounds
that are provided herein, are compounds that are inhibitors of
PARP. Also described herein is the use of such compounds,
compositions and methods for the treatment of diseases, disorders
or conditions associated with a PTEN deficiency.
[0008] In one aspect is a method of inhibiting
poly(ADP-ribose)polymerase (PARP) in a subject having a disease or
disorder associated with a PTEN deficiency comprising administering
to the subject a therapeutically effective amount of a compound of
Formula (I) or Formula (II):
##STR00002##
where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, A, B, Y, and Z
are as defined in the Detailed Description of the Invention.
[0009] In still another aspect is a method of treating a disease,
disorder or condition associated with a PTEN deficiency which is
ameliorated by the inhibition of PARP comprising administering to a
subject in need of treatment a therapeutically effective amount of
a compound of Formula (I) or Formula (II).
[0010] In one aspect is a method of treating a cancer associated
with a PTEN deficiency comprising administering to a subject in
need of treatment a therapeutically effective amount of a compound
of Formula (I) or Formula (II). In certain aspects, the cancer is
endometrial carcinoma, glioblastoma (glioblastoma
multiforme/anaplastic astrocytoma), prostate cancer, renal cancer,
small cell lung carcinoma, meningioma, head and neck cancer,
thyroid cancer, bladder cancer, colorectal cancer, breast cancer or
melanoma.
[0011] In certain other aspects, provided herein are methods of
treating a cancer associated with a PTEN deficiency wherein one or
more cancer cells have an abrogated or reduced ability to control
the phosphoinositide 3-kinase signaling pathway, comprising
administering to a subject in need of treatment a therapeutically
effective amount of a compound of Formula (I) or Formula (II). In
certain embodiments, the cancer comprises one or more cancer cells
having a reduced or abrogated ability to control the
phosphoinositide 3-kinase signaling pathway for regulation of cell
growth relative to normal cells.
[0012] In yet another aspect is a method of treating a cancer
deficient in Homologous Recombination (HR) dependent DNA double
strand break (DSB) repair pathway, comprising administering to a
subject in need of treatment a therapeutically effective amount of
a compound of Formula (I) or Formula (II). In certain embodiments
the cancer comprises one or more cancer cells having a reduced or
abrogated ability to repair DNA DSB by HR relative to normal cells.
In one embodiment the cancer cells have a PTEN deficient phenotype.
In yet another embodiment the cancer cells are deficient in PTEN.
In a further embodiment the subject is heterozygous for a mutation
in a gene encoding a component of the HR dependent DNA DSB repair
pathway. In yet a further embodiment the subject is heterozygous
for a mutation in PTEN. In certain aspects, the cancer is
endometrial carcinoma, glioblastoma (glioblastoma
multiforme/anaplastic astrocytoma), prostate cancer, renal cancer,
small cell lung carcinoma, meningioma, head and neck cancer,
thyroid cancer, bladder cancer, colorectal cancer, breast cancer or
melanoma.
[0013] In another aspect is a method of treating cancer, comprising
administering to a subject in need of treatment a therapeutically
effective amount of a compound of Formula (I) or Formula (II) in
combination with ionizing radiation, one or more chemotherapeutic
agents, or a combination thereof.
[0014] In one embodiment the compound of Formula (I) or Formula
(II) is administered simultaneously with ionizing radiation, one or
more chemotherapeutic agents, or a combination thereof. In another
embodiment the compound of Formula (I) or Formula (II) is
administered sequentially with ionizing radiation, one or more
chemotherapeutic agents, or a combination thereof
[0015] In one aspect is the use of a compound of Formula (I) or
Formula (II) in the formulation of a medicament for the treatment
of a poly(ADP-ribose)polymerase mediated disease or condition
associated with a PTEN deficiency.
[0016] In another aspect is an article of manufacture, comprising
packaging material, a compound of Formula (I) or Formula (II), and
a label, wherein the compound is effective for modulating the
activity of the enzyme poly(ADP-ribose)polymerase, or for
treatment, prevention or amelioration of one or more symptoms of a
disease or condition associated with a PTEN deficiency, wherein the
compound is packaged within the packaging material, and wherein the
label indicates that the compound, or pharmaceutically acceptable
salt, pharmaceutically acceptable N-oxide, pharmaceutically active
metabolite, pharmaceutically acceptable prodrug, or
pharmaceutically acceptable solvate thereof, or a pharmaceutical
composition comprising such a compound is used for modulating the
activity of poly(ADP-ribose)polymerase, or for treatment,
prevention or amelioration of one or more symptoms of a disease or
condition associated with a PTEN deficiency.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] The novel features of the invention are set forth with
particularity in the appended claims. A better understanding of the
features and advantages of the present invention will be obtained
by reference to the following detailed description that sets forth
illustrative embodiments, in which the principles of the invention
are utilized, and the accompanying drawings of which:
[0018] FIG. 1 provides the results of the in vitro cytotoxicity
assays performed on PTEN -/- (PTEN deficient) tumor cell lines
treated with a PARP inhibitor described herein (Compound X). (- -)
LNCap tumor cell line; (-.box-solid.-) PC-3 tumor cell line; and
(-.tangle-solidup.-) MDA-MB-468 tumor cell line.
[0019] FIG. 2 provides the results of the in vitro cytotoxicity
assays performed on tumor cell lines wild type for PTEN treated
with a PARP inhibitor described herein (Compound X). (- -)
MDA-MB-231 tumor cell line; and (-.box-solid.-) LoVo tumor cell
line.
[0020] FIG. 3 provides the results of an in vivo efficacy study of
a PARP inhibitor (Compound X) in a PTEN deficient LNCap Xenograft
model.
[0021] FIG. 4 provides the results of an in vivo efficacy study of
a PARP inhibitor (Compound X) in a PTEN deficient MDA-MB-668
Xenograft model.
[0022] FIG. 5 provides the results of an in vivo efficacy study of
a PARP inhibitor (Compound X) in a PTEN deficient PC-3 Xenograft
model.
DETAILED DESCRIPTION OF THE INVENTION
[0023] Provided herein are methods for the treatment of diseases or
disorders associated with a PTEN deficiency, including certain
cancers, comprising the administration of the
poly(ADP-ribose)polymerases (PARP) inhibitors described herein. In
some embodiments, the methods presented herein comprise the
administration of a PARP inhibitor described herein to a subject in
need thereof having a disease or disorder associated with a PTEN
deficiency. In some embodiments, the disease or disorder associated
with a PTEN deficiency is cancer. In certain embodiments, the
disease or disorder associated with a PTEN deficiency is
endometrial carcinoma. In certain embodiments, the disease or
disorder associated with a PTEN deficiency is glioblastoma. In
certain embodiments, the disease or disorder associated with a PTEN
deficiency is prostate cancer. In certain embodiments, the disease
or disorder associated with a PTEN deficiency is bladder cancer. In
certain embodiments, the disease or disorder associated with a PTEN
deficiency is breast cancer. In certain embodiments, the disease or
disorder associated with PTEN deficiency is colorectal cancer. In
certain embodiments, the disease or disorder associated with a PTEN
deficiency is melanoma.
Poly(ADP-Ribose)Polymerases (PARP)
[0024] The mammalian enzyme PARP-1 is a multidomain protein. PARP-1
is implicated in the signaling of DNA damage through its ability to
recognize and rapidly bind to DNA single or double strand breaks.
D'Amours, et al., Biochem. J., 342, 249-268 (1999); and Virag et
al. Pharmacological Reviews, vol. 54, no. 3, 375-429 (2002) are
hereby incorporated by reference for such disclosure.
[0025] The family of poly(ADP-ribose)polymerases includes
approximately 18 proteins, which all display a certain level of
homology in their catalytic domain but differ in their cellular
functions. PARP-1 and PARP-2 are unique members of the family, in
that their catalytic activities are stimulated by the occurrence of
DNA strand breaks. Ame et al., BioEssays 26(8), 882-893 (2004) is
hereby incorporated by reference for such disclosure.
[0026] PARP-1 participates in a variety of DNA-related functions
including gene amplification, cell division, differentiation,
apoptosis, DNA base excision repair as well as effects on telomere
length and chromosome stability. d'Adda di Fagagna, et al., Nature
Gen., 23(1), 76-80 (1999) is hereby incorporated by reference for
such disclosure.
[0027] Studies on the mechanism by which PARP-1 modulates DNA
repair and other processes identifies its importance in the
formation of poly(ADP-ribose) chains within the cellular nucleus.
The DNA-bound, activated PARP-1 utilizes NAD+ to synthesize
poly(ADP-ribose) on a variety of nuclear target proteins, including
topoisomerases, histones and PARP itself. Althaus, F. R. and
Richter, C., ADP-Ribosylation of Proteins: Enzymology and
Biological Significance, Springer-Verlag, Berlin (1987); and Rhun,
et al., Biochem. Biophys. Res. Commun., 245, 1-10 (1998) are hereby
incorporated by reference for such disclosure.
[0028] Poly(ADP-ribosyl)ation is also associated with malignant
transformation. For example, PARP-1 activity is higher in the
isolated nuclei of SV40-transformed fibroblasts, while both
leukemic cells and colon cancer cells show higher enzyme activity
than the equivalent normal leukocytes and colon mucosa.
Furthermore, malignant prostate tumors have increased levels of
active PARP as compared to benign prostate cells, which is
associated with higher levels of genetic instability. Miwa, et al.,
Arch. Biochem. Biophys., 181, 313-321 (1977); Burzio, et al., Proc.
Soc. Exp. Biol. Med., 149, 933-938 (1975); Hirai, et al., Cancer
Res., 43, 3441-3446 (1983); and Mcnealy, et al., Anticancer Res.,
23, 1473-1478 (2003) are hereby incorporated by reference for such
disclosure.
[0029] In cells treated with alkylating agents, the inhibition of
PARP leads to a marked increase in DNA-strand breakage and cell
killing. PARP-1 inhibitors also enhance the effects of radiation
response by suppressing the repair of potentially lethal damage.
PARP inhibitors are also effective in radio-sensitizing hypoxic
tumor cells. In certain tumor cell lines, chemical inhibition of
PARP activity is also associated with marked sensitization to very
low doses of radiation.
[0030] Furthermore, PARP-1 knockout (PARP -/-) animals exhibit
genomic instability in response to alkylating agents and
.gamma.-irradiation. Data indicates that PARP-1 and PARP-2 possess
both overlapping and non-redundant functions in the maintenance of
genomic stability, making them both interesting targets. Wang, et
al., Genes Dev., 9, 509-520 (1995); Menissier de Murcia, et al.,
Proc. Natl. Acad. Sci. USA, 94, 7303-7307 (1997); and Menissier de
Murcia, et al., EMBO. J., 22(9), 2255-2263 (2003) are hereby
incorporated by reference for such disclosure.
Phosphatase and Tensin Homologue Deleted on Chromosome 10
(PTEN)
[0031] There are two major domains of PTEN, the N-terminal
phosphatase domain and the C-terminal domain (Lee et al., 1999).
While the role of PTEN in tumor suppression has been mostly
attributed to its N-terminal lipid phosphatase activity (Cantley
and Neel, Proc Natl Acad Sci USA 96:4240-4245 (1999)), more than
40% of PTEN tumorigenic mutations occur in the C-terminal domain
(Waite and Eng, Am J. Hum Gen 70:829-844 (2002)). This fact
indicates that PTEN may have additional functions through its
C-terminal domain, which is significant in tumor suppression. The
C-terminal domain contains both a C2 domain and a tail region that
may be related to PTEN stability (Georgescu et al., Proc Natil Acd
Sci USA 96:10182-10187 (1999)) and protein-protein interaction
(Fanning and Anderson, Curr Opin Cell Biol 11:432-439 (1999)). The
C2 domain is understood to play a role in PTEN stability (Georgescu
et al., Cancer Res 60:7033-7038 (2000)) and its recruitment to
phospholipid membranes (Das et al., Proc Natil Acd Sci USA
100:7491-7496 (2003)). Crystal structure analysis of this domain
revealed a .beta.-sandwich structure (Lee et al., Cell 99:323-334
(1999)), suggesting a basis for its interaction with DNA and other
proteins. Additionally, it is known that PTEN uses the C2 domain to
interact with the centromere (Shen et al., Cell 128:157-170
(2007)).
PTEN Activity
[0032] PTEN is a lipid and protein phosphatase. PTEN protein
phosphatase can dephosphorylate protein substrates on serine,
threonine and tyrosine residues. The lipid phosphatase activity of
PTEN is known to act upon the substrate phosphoinositol
3,4,5-triphosphate (PIP3), a key signaling component of the
phosphoinositol-3-kinase (PI3-kinase) pathway (Maehama and Dixon, J
Biol Chem 273:13375-13378 (1998)). The PI3-kinase/Akt pathway is
regarded as the primary physiological target of PTEN.
[0033] PTEN phosphatase also targets different proteins. Focal
adhesion kinase (FAK), a nonreceptor protein tyrosine kinase, has
been identified as a direct protein target of PTEN. Similarly, PTEN
also reduces the tyrosine phosphorylation of p130Cas, a FAK
downstream effector. By targeting and dephosphorylating FAK and
p130Cas, PTEN regulates dynamic cell surface interactions and
inhibits cell migration and invasion. Additionally, PTEN lipid
phosphatase activity is understood to be involved in the inhibition
of cell motility and phosphorylation of both Rac1 and Cdc42
(Liliental et al., Curr Biol 10:401-404 (2000)). In addition to
FAK/p130Cas, Rac1 and Cdc42, PTEN can also regulate cell motility
by directly targeting and dephosphorylating Shc kinase, thereby
inhibiting the mitogen-activated protein (MAP) kinase signaling
pathway.
[0034] As an important intracellular signaling pathway, the MAP
kinase cascade provides multiple potential targets for PTEN. PTEN
can inactivate multiple membraneproximal proteins upstream of MAP
kinase such as Ras and IRS-1 (Gu et al., J Cell Bio 143:1375-1383
(1998); Weng et al., Hum Mol Genet 10:605-616 (2001b)). The
prototypical MAP kinase, extracellular signal-regulated kinase, is
often affected by PTEN status. The protein phosphatase activity of
PTEN is known to inhibit FAK and extracellular signal-regulated
kinase and subsequently block the expression and secretion of
matrix metalloproteinase-9, which may contribute to the suppression
of glioblastoma invasion. PTEN also inhibits phosphorylation of
proteins downstream of MAP kinases. One prominent example is ETS-2,
a nuclear target of the MAP kinase pathway and a transcription
factor whose DNA-binding ability is controlled by phosphorylation.
PTEN also regulates phosphorylation of another transcription factor
Sp1, likely through its protein phosphatase activity.
[0035] In addition to intracellular signaling molecules, receptor
tyrosine kinases also can serve as direct protein targets of PTEN.
PTEN physically associates with the receptor of platelet-derived
growth factor and directly dephosphorylates the receptor, whereas
the phosphatase-deficient PTEN mutant (C124S) not only fails to
dephosphorylate the platelet-derived growth factor receptor but
also acts in a dominant-negative fashion to increase its
phosphorylation (Mahimainathan and Choudhury, J Biol Chem
279:15258-15268 (2004)).
PTEN and Disease
[0036] Genome or chromosome instability is a hallmark of cancers.
Tumor suppressors play roles in maintaining genome stability, and
loss of function of these tumor suppressors is known to result in
genomic instability. Genetic instability represents an inevitable
consequence of the loss of tumor suppressors. Indeed, the frequent
occurrence of PTEN mutation and genetic instability is found in a
large range of PTEN-deficient cancers. Likewise, it is known that
several tumor cell lines are PTEN deficient. PTEN-null embryonic
stem cells were shown to exhibit DNA repair checkpoint defects in
response to ionizing radiation, which results in the accumulation
of unrepaired chromosomes with DNA double-strand gaps and breaks.
Further mechanistic study revealed that the observed G2 checkpoint
defects may result from functional impairment of the checkpoint
protein, CHK1, due to lack of PTEN. PTEN deficiency directly
elevates AKT kinase activity, which triggers CHK1 phosphorylation.
Phosphorylated CHK1 undergoes ubiquitination, which prevents its
entry into the nucleus. Sequestering CHK1 in the cytoplasm impairs
its normal function in initiating a DNA repair checkpoint. In
addition, CHK1 inactivation in PTEN-deficient cells leads to the
accumulation of DNA double-strand breaks (Puc and Parsons, Cell
Cycle 4:927-929 (2005)). Examination of CHK1 localization in a
large panel of primary human breast carcinomas indicates an
increased cytoplasmic level of CHK1 in tumor cells with lower
expression of PTEN and elevated AKT phosphorylation. Furthermore,
aneuploidy was frequently observed in both human breast carcinomas
with low expression of PTEN and prostatic intraepithelial neoplasia
from Pten .sup.+/.sup.- mice (Puc and Parsons, Cell Cycle 4:927-929
(2005)). Such in vitro and in vivo observations indicate that PTEN
deficiencies are involved in initiation of an oncogenic signaling
process by causing dysfunction of important checkpoint
proteins.
[0037] Additionally, the role of nuclear PTEN in the maintenance of
chromosomal stability has been demonstrated in both mouse and human
systems (Shen et al., Cell 128:157-170 (2007)). First, PTEN
interacts with centromeres and maintains their stability. It is
believed that PTEN does so through its C2 domain, as mutant PTEN
without this C2 domain loses the capability to interact with
centromeres. Second, PTEN may be necessary for DNA repair because
loss of PTEN results in a high frequency of double-strand breaks.
PTEN affects double-strand breaks through regulation of Rad51, a
key component for homologous recombination repair of DNA
double-strand breaks. It has also been demonstrated that PTEN
physically associates with an integral component of centromeres in
the nucleus, disruption of which causes centromere breakage and
massive chromosomal aberrations (Shen et al., Cell
128:157-170(2007)).
[0038] The cytoplasm has been considered as the primary site for
PTEN to elicit its tumor-suppressive function, and the ability of
PTEN to block the PI3-kinase pathway through its phosphatase
activity has been regarded as the key mechanism by which PTEN
suppresses carcinogenesis. Although the cellular distribution of
PTEN varies in different tissues, endogenous PTEN in neurons,
gliomas and cells of the thyroid, pancreas and skin is found mostly
in the nuclear compartment (Yin and Shen, Oncogene 27:5443-5453
(2008)). Growing evidence indicate that malignancies may be
accompanied by translocation of PTEN from the nucleus to the
cytoplasm. The function of nuclear PTEN may deviate from its role
in regulating PIP3 at the plasma membrane, but is consistent with
an alternative role in controlling genetic stability and involving
chromatin function. In addition, high expression levels of nuclear
PTEN have recently been associated with cell cycle arrest at the
G0/G1 phase (Ginn-Pease and Eng, Cancer Res 63:282-286 (2003)),
indicating a likely role of nuclear PTEN in cell growth inhibition.
Similarly, multiple aspects of the anti-oncogenic function of PTEN,
such as regulation of cell growth and migration, are found
independent of its phosphatase activity. Indeed, somatic PTEN
mutations do occur outside the phosphatase domain, implying that
PTEN can function in tumor suppression through additional
activities besides antagonism of the PI3-kinase pathway.
[0039] Inactivation of PTEN, either by mutations, deletions, or
promoter hypermethylation, has been identified in a wide variety of
tumors. The most common way to detect PTEN deficiency is by
immunohistochemistry (IHC) staining of paraffin-embedded patient
tumor sections (Pallares et al., Modern Pathology 18:719-727
(2005)). It is also possible to utilize commercial laboratories,
such as Quest Diagnostics (Madison, N.J. USA) or Quintiles (Durham,
N.C. USA), which provide services to analyze tumor samples by IHC
for PTEN. PTEN mutations may also be identified in human tumors
samples by examining the PTEN gene by single-strand conformational
polymorphism (SSCP) analysis and DNA sequencing (Minaguchi et al.,
Cancer Lett. 210:57-62 (2004)). This method is particularly useful
for PTEN-deficient tumors that still make a mutant protein that
will show up on IHC. In addition, the expression level of PTEN can
be determined using reverse transcription coupled with PCR (RT-PCR)
(Mutter et al., J. Clin. Endocrin. & Metab. 85:2334-2338,
(2000)).
PARP Inhibitors
[0040] A PTEN deficiency in certain tumor cells results in
homologous recombination defects which sensitize tumor cells to
treatment with PARP inhibitors. The present invention is directed
to the used of a PARP inhibitor described herein for the treatment
of diseases or disorders associated with a PTEN deficiency,
including certain cancers. In some embodiments, a PARP inhibitor
described herein reduces or inhibits the activity of one or both of
PARP1 and/or PARP2. In some embodiments, a PARP inhibitor described
herein reduces or inhibits the activity of PARP1 while not
affecting the activity of PARP2. In some embodiments, a PARP
inhibitor described herein reduces or inhibits the activity of
PARP2 while not affecting the activity of PARP1. In some
embodiments, a PARP inhibitor described herein is a substantially
complete inhibitor of one or more PARPs. As used herein,
"substantially complete inhibition" means, for example, >95%
inhibition of one or more targeted PARPs. In other embodiments,
"substantially complete inhibition" means, for example, >90%
inhibition of one or more targeted PARPs. In other embodiments,
"substantially complete inhibition" means, for example, >80%
inhibition of one or more targeted PARPs. In other embodiments, a
PARP inhibitor described herein is a partial inhibitor of one or
more PARPs. As used herein, "partial inhibition" means, for
example, between about 40% and about 60% inhibition of one or more
targeted PARPs. In other embodiments, "partial inhibition" means,
for example, between about 50% and about 70% inhibition of one or
more targeted PARPs.
[0041] In some embodiments, compounds provided herein have the
structure of Formula (I) and Formula (II) and pharmaceutically
acceptable salts, solvates, esters, acids and prodrugs thereof. In
certain embodiments, provided herein are compounds having the
structure of Formula (I) and Formula (II) that are inhibitors of
the enzyme poly(ADP-ribose)polymerase (PARP).
[0042] Described herein are
8-B,Z-2-R.sub.4-4-R.sub.1-5-R.sub.2-6R.sub.3-7R.sub.5-9-A,Y-8,9-dihydro-2-
H-pyrido[4,3,2-de]phthalazin-3(7H)-ones,
8-B,Z-5-R.sub.2-9-A,Y-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one-
s, in which A, B, Z, Y, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and
R.sub.5 are further described herein. In certain embodiments,
isomers including enantiomers and diastereoisomers, and chemically
protected forms of compounds having a structure represented by
Formula (I) and Formula (II) are also provided.
[0043] Formula (I) is as follows:
##STR00003##
wherein: Y and Z are each independently selected from the group
consisting of: [0044] a) an aryl group optionally substituted with
1, 2, or 3 R.sub.6; wherein each R.sub.6 is selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, C.sub.2-C.sub.8heterocycloalkyl;
C.sub.2-C.sub.6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, C.sub.2-C.sub.6alkynyl, aryl, arylalkyl,
C.sub.3-C.sub.8cycloalkylalkyl, haloalkoxy, haloalkyl,
hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,
C.sub.2-C.sub.8heterocycloalkylthio, heterocyclooxy,
heterocyclothio, NR.sub.AR.sub.B,
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene;
[0045] b) a heteroaryl group optionally substituted with 1, 2, or 3
R.sub.6; [0046] c) a substituent independently selected from the
group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl,
cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo,
heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl,
arylcarbonyl, heteroarylcarbonyl alkylsulfonyl, arylsulfonyl,
heteroarylsulfonyl, (NR.sub.AR.sub.B)alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene;
R.sub.1, R.sub.2, and R.sub.3 are each independently selected from
the group consisting of hydrogen, halogen, alkenyl, alkoxy,
alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy,
haloalkyl, hydroxyl, hydroxyalkylene, nitro, NR.sub.AR.sub.B,
NR.sub.AR.sub.Balkylene, and (NR.sub.AR.sub.B)carbonyl; A and B are
each independently selected from hydrogen, Br, Cl, F, I, OH,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, alkoxy,
alkoxyalkyl wherein C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl, wherein B is not OH; R.sub.A, and
R.sub.B are independently selected from the group consisting of
hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or R.sub.A and
R.sub.B taken together with the atom to which they are attached
form a 3-10 membered heterocycle ring optionally having one to
three heteroatoms or hetero functionalities selected from the group
consisting of --O--, --NH, --N(C.sub.1-C.sub.6-alkyl)-,
--NCO(C.sub.1-C.sub.6-alkyl)-, --N(aryl)-,
--N(aryl-C.sub.1-C.sub.6-alkyl-)-,
--N(substituted-aryl-C.sub.1-C.sub.6-alkyl-)-, --N(heteroaryl)-,
--N(heteroaryl-C.sub.1-C.sub.6-alkyl-)-,
--N(substituted-heteroaryl-C.sub.1-C.sub.6-alkyl-)-, and --S-- or
S(O).sub.q--, wherein q is 1 or 2 and the 3-10 membered heterocycle
ring is optionally substituted with one or more substituents;
R.sub.4 and R.sub.5 are each independently selected from the group
consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl,
hydroxyalkylene, and (NR.sub.AR.sub.B)alkylene; and isomers, salts,
solvates, chemically protected forms, and prodrugs thereof.
[0047] Formula (II) is as follows:
##STR00004##
wherein: Y is an aryl or heteroaryl group optionally substituted
with at least one R.sub.6; Z is an aryl group optionally
substituted with at least one R.sub.6; A and B are each
independently selected from hydrogen, Br, Cl, F, I, OH,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, alkoxy,
alkoxyalkyl wherein C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl, wherein B is not OH; R.sub.6 is selected
from OH, NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, C.sub.2-C.sub.8heterocycloalkyl;
C.sub.2-C.sub.6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, C.sub.2-C.sub.6alkynyl, aryl, arylalkyl,
C.sub.3-C.sub.8cycloalkylalkyl, haloalkoxy, haloalkyl,
hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,
C.sub.2-C.sub.8heterocycloalkylthio, heterocyclooxy,
heterocyclothio, NR.sub.AR.sub.B,
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene;
R.sub.2 is selected from hydrogen, Br, Cl, I, or F; R.sub.A, and
R.sub.B are independently selected from the group consisting of
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, and
alkylcarbonyl; or R.sub.A and R.sub.B taken together with the atom
to which they are attached form a 3-10 membered heterocycle ring
optionally having one to three heteroatoms or hetero
functionalities selected from the group consisting of --O--, --NH,
--N(C.sub.1-C.sub.6alkyl)-, --NCO(C.sub.1-C.sub.6alkyl)-,
--NCO(C.sub.3-C.sub.8cycloalkyl)-, --N(aryl)-,
--N(aryl-C.sub.1-C.sub.6alkyl-)-,
--N(substituted-aryl-C.sub.1-C.sub.6alkyl-)-, --N(heteroaryl)-,
--N(heteroaryl-C.sub.1-C.sub.6alkyl-)-,
--N(substituted-heteroaryl-C.sub.1-C.sub.6alkyl-)-, and --S-- or
S(O).sub.q--, wherein q is 1 or 2 and the 3-10 membered heterocycle
ring is optionally substituted with one or more substituents; or a
pharmaceutically acceptable salt, solvate or prodrug thereof
[0048] In certain embodiments are provided compounds of Formula (I)
or a therapeutically acceptable salt thereof wherein R.sub.1,
R.sub.2, R.sub.3 are independently selected from a group consisting
of hydrogen, alkyl, and halogen; R.sub.4 is hydrogen and R.sub.5 is
selected from the group consisting hydrogen, alkyl, cycloalkyl,
alkoxyalkyl, haloalkyl, hydroxyalkylene, and
(NR.sub.AR.sub.B)alkylene; R.sub.A, and R.sub.B are independently
selected from the group consisting of hydrogen, alkyl, cycloalkyl,
and alkylcarbonyl; or R.sub.A and R.sub.B taken together with the
atom to which they are attached form a 3-10 membered heterocycle
ring optionally having one to three heteroatoms or hetero
functionalities selected from the group consisting of --O--, --NH,
--N(C.sub.1-C.sub.6-alkyl)-, --NCO(C.sub.1-C.sub.6-alkyl)-,
--N(aryl)-, --N(aryl-C.sub.1-C.sub.6-alkyl-)-,
--N(substituted-aryl-C.sub.1-C.sub.6-alkyl-)-, --N(heteroaryl)-,
--N(heteroaryl-C.sub.1-C.sub.6-alkyl-)-,
--N(substituted-heteroaryl-C.sub.1-C.sub.6-alkyl-)-, and --S-- or
S(O).sub.q--, wherein q is 1 or 2 and the 3-10 membered heterocycle
ring is optionally substituted with one or more substituents.
[0049] In one embodiment is a compound of Formula (I) wherein Y is
an aryl group. In another embodiment the aryl group is a phenyl
group. In yet another embodiment the phenyl group is substituted
with at least one R.sub.6 selected from Br, Cl, F, or I. In one
embodiment R.sub.6 is F. In one embodiment the phenyl group is
substituted with at least one R.sub.6 selected from
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene.
In one embodiment R.sub.6 is
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene. In another embodiment
C.sub.1-C.sub.6alkyl is selected from methylene, ethylene,
n-propylene, iso-propylene, n-butylene, iso-butylene, and
tert-butylene. In yet another embodiment C.sub.1-C.sub.6alkyl is
methylene. In yet a further embodiment R.sub.A and R.sub.B are each
independently hydrogen, C.sub.1-C.sub.6alkyl, or
C.sub.3-C.sub.8cycloalkyl. In one embodiment C.sub.1-C.sub.6alkyl
is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, and tert-butyl. In one embodiment C.sub.1-C.sub.6alkyl
is methyl. In another embodiment C.sub.1-C.sub.6alkyl is ethyl. In
yet another embodiment C.sub.3-C.sub.8cycloalkyl is cyclopropyl,
cyclobutyl, cyclopentyl, and cyclohexyl. In a further embodiment
C.sub.3-C.sub.8cycloalkyl is cyclopropyl. In yet a further
embodiment R.sub.6 is hydroxyalkylene. In one embodiment
hydroxyalkylene is selected from CH.sub.2OH, CH.sub.2CH.sub.2OH,
CH.sub.2CH.sub.2CH.sub.2OH, CH(OH)CH.sub.3, CH(OH)CH.sub.2CH.sub.3,
CH.sub.2CH(OH)CH.sub.3, and CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH. In
another embodiment R.sub.A and R.sub.B taken together with the
nitrogen to which they are attached form a 6 membered heterocycle
ring having 1 heteroatom or hetero functionality selected from the
group consisting of --O--, --NH, or --N(C.sub.1-C.sub.6alkyl). In
yet another embodiment the hetero functionality is
--N(C.sub.1-C.sub.6alkyl). In a further embodiment
C.sub.1-C.sub.6alkyl is selected from methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a further
embodiment C.sub.1-C.sub.6alkyl is methyl. In one embodiment Y is a
heteroaryl group optionally substituted with at least one R.sub.6.
In another embodiment the heteroaryl group is selected from furan,
pyridine, pyrimidine, pyrazine, imidazole, thiazole, isothiazole,
pyrazole, triazole, pyrrole, thiophene, oxazole, isoxazole,
1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-triazine, indole,
benzothiophene, benzoimidazole, benzofuran, pyridazine,
1,3,5-triazine, thienothiophene, quinoxaline, quinoline, and
isoquinoline. In yet another embodiment the heteroaryl group is
imidazole. In a further embodiment imidazole is substituted with
C.sub.1-C.sub.6alkyl selected from methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a further
embodiment C.sub.1-C.sub.6alkyl is methyl. In one embodiment the
heteroaryl group is furan. In another embodiment the heteroaryl
group is thiazole. In yet another embodiment the heteroaryl group
is 1,3,4-oxadiazole. In a further embodiment heteroaryl group is
substituted with C.sub.1-C.sub.6alkyl selected from methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a
further embodiment C.sub.1-C.sub.6alkyl is methyl. In one
embodiment Z is an aryl group. In another embodiment the aryl group
is a phenyl group. In yet another embodiment the phenyl group is
substituted with at least one R.sub.6 selected from Br, Cl, F, or
I. In a further embodiment R.sub.6 is F. In yet a further
embodiment R.sub.6 is Cl. In one embodiment the phenyl group is
substituted with at least one R.sub.6 selected from
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene.
In another embodiment R.sub.6 is
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene. In yet another embodiment
C.sub.1-C.sub.6alkyl is selected from methylene, ethylene,
n-propylene, iso-propylene, n-butylene, iso-butylene, and
tert-butylene. In yet a further embodiment C.sub.1-C.sub.6alkyl is
methylene. In a further embodiment R.sub.A and R.sub.B are each
independently hydrogen, C.sub.1-C.sub.6alkyl, or
C.sub.3-C.sub.8cycloalkyl. In one embodiment C.sub.1-C.sub.6alkyl
is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, and tert-butyl. In another embodiment
C.sub.1-C.sub.6alkyl is methyl. In yet another embodiment R.sub.A
and R.sub.B taken together with the nitrogen to which they are
attached form a 6 membered heterocycle ring having 1 heteroatom or
hetero functionality selected from the group consisting of --O--,
--NH, or --N(C.sub.1-C.sub.6alkyl). In a further embodiment the
hetero functionality is --N(C.sub.1-C.sub.6alkyl). In one
embodiment C.sub.1-C.sub.6alkyl is selected from methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a
further embodiment C.sub.1-C.sub.6alkyl is methyl. In one
embodiment Z is a heteroaryl group optionally substituted with at
least one R.sub.6. In another embodiment the heteroaryl group is
selected from furan, pyridine, pyrimidine, pyrazine, imidazole,
thiazole, isothiazole, pyrazole, triazole, pyrrole, thiophene,
oxazole, isoxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole,
1,2,4-triazine, indole, benzothiophene, benzoimidazole, benzofuran,
pyridazine, 1,3,5-triazine, thienothiophene, quinoxaline,
quinoline, and isoquinoline. In yet another embodiment the
heteroaryl group is imidazole. In a further embodiment imidazole is
substituted with C.sub.1-C.sub.6alkyl selected from methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a
further embodiment C.sub.1-C.sub.6alkyl is methyl. In one
embodiment the heteroaryl group is furan. In another embodiment the
heteroaryl group is thiazole. In yet another embodiment the
heteroaryl group is 1,3,4-oxadiazole. In a further embodiment
heteroaryl group is substituted with C.sub.1-C.sub.6alkyl selected
from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and
tert-butyl. In yet a further embodiment C.sub.1-C.sub.6alkyl is
methyl. In another embodiment R.sub.2 is hydrogen. In yet another
embodiment R.sub.2 is selected from F, Cl, Br, and I. In a further
embodiment R.sub.2 is F.
[0050] In one embodiment is a compound of Formula (I) wherein A is
hydrogen. In another embodiment A is C.sub.1-C.sub.6alkyl. In a
further embodiment, A is selected from methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl.
In yet another embodiment, methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl are
optionally substituted with OH, NO.sub.2, CN, Br, Cl, F, and I. In
a further embodiment A is methyl. In yet another embodiment, A is
selected from F, Cl, Br, and I. In another embodiment, A is
C.sub.3-C.sub.8cycloalkyl. In another embodiment, A is cyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment, A is
substituted with OH, NO.sub.2, or CN. In a further embodiment, B is
C.sub.1-C.sub.6alkyl. In a further embodiment, B is selected from
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
tert-butyl, n-pentyl, and n-hexyl. In yet another embodiment,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
tert-butyl, n-pentyl, and n-hexyl are optionally substituted with
OH, NO.sub.2, CN, Br, Cl, F, and I. In one embodiment is a compound
of Formula (I) wherein B is hydrogen. In a further embodiment B is
methyl. In yet another embodiment, B is selected from F, Cl, Br,
and I. In another embodiment, B is C.sub.3-C.sub.8cycloalkyl. In
another embodiment, B is cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl. In one embodiment, A is substituted with OH, NO.sub.2,
or CN. In a further embodiment, is a compound of Formula (I)
wherein A is hydrogen and B is selected from Br, Cl, F, I,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, alkoxy,
alkoxyalkyl wherein C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl. In another embodiment, is a compound of
Formula (I) wherein B is hydrogen and A is selected from Br, Cl, F,
I, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, alkoxy,
alkoxyalkyl wherein C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl. In yet another embodiment, both A and B
are hydrogen. In a further embodiment, both A and B are selected
from Br, Cl, F, I, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl,
alkoxy, alkoxyalkyl wherein C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl.
[0051] In one embodiment is a compound of Formula (II) wherein Y is
an aryl group. In another embodiment the aryl group is a phenyl
group. In yet another embodiment the phenyl group is substituted
with at least one R.sub.6 selected from Br, Cl, F, or I. In one
embodiment R.sub.6 is F. In one embodiment the phenyl group is
substituted with at least one R.sub.6 selected from
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene.
In one embodiment R.sub.6 is
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene. In another embodiment
C.sub.1-C.sub.6alkyl is selected from methylene, ethylene,
n-propylene, iso-propylene, n-butylene, iso-butylene, and
tert-butylene. In yet another embodiment C.sub.1-C.sub.6alkylene is
methylene. In yet a further embodiment R.sub.A and R.sub.B are each
independently hydrogen, C.sub.1-C.sub.6alkyl, or
C.sub.3-C.sub.8cycloalkyl. In one embodiment C.sub.1-C.sub.6alkyl
is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, and tert-butyl. In one embodiment C.sub.1-C.sub.6alkyl
is methyl. In another embodiment C.sub.1-C.sub.6alkyl is ethyl. In
yet another embodiment C.sub.3-C.sub.8cycloalkyl is cyclopropyl,
cyclobutyl, cyclopentyl, and cyclohexyl. In a further embodiment
C.sub.3-C.sub.8cycloalkyl is cyclopropyl. In yet a further
embodiment R.sub.6 is hydroxyalkylene. In one embodiment
hydroxyalkylene is selected from CH.sub.2OH, CH.sub.2CH.sub.2OH,
CH.sub.2CH.sub.2CH.sub.2OH, CH(OH)CH.sub.3, CH(OH)CH.sub.2CH.sub.3,
CH.sub.2CH(OH)CH.sub.3, and CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH. In
another embodiment R.sub.A and R.sub.B taken together with the
nitrogen to which they are attached form a 6 membered heterocycle
ring having 1 heteroatom or hetero functionality selected from the
group consisting of --O--, --NH, or --N(C.sub.1-C.sub.6alkyl). In
yet another embodiment the hetero functionality is
--N(C.sub.1-C.sub.6alkyl). In a further embodiment
C.sub.1-C.sub.6alkyl is selected from methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a further
embodiment C.sub.1-C.sub.6alkyl is methyl. In one embodiment Y is a
heteroaryl group optionally substituted with at least one R.sub.6.
In another embodiment the heteroaryl group is selected from furan,
pyridine, pyrimidine, pyrazine, imidazole, thiazole, isothiazole,
pyrazole, triazole, pyrrole, thiophene, oxazole, isoxazole,
1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-triazine, indole,
benzothiophene, benzoimidazole, benzofuran, pyridazine,
1,3,5-triazine, thienothiophene, quinoxaline, quinoline, and
isoquinoline. In yet another embodiment the heteroaryl group is
imidazole. In a further embodiment imidazole is substituted with
C.sub.1-C.sub.6alkyl selected from methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a further
embodiment C.sub.1-C.sub.6alkyl is methyl. In one embodiment the
heteroaryl group is furan. In another embodiment the heteroaryl
group is thiazole. In yet another embodiment the heteroaryl group
is 1,3,4-oxadiazole. In a further embodiment heteroaryl group is
substituted with C.sub.1-C.sub.6alkyl selected from methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a
further embodiment C.sub.1-C.sub.6alkyl is methyl. In one
embodiment Z is an aryl group. In another embodiment the aryl group
is a phenyl group. In yet another embodiment the phenyl group is
substituted with at least one R.sub.6 selected from Br, Cl, F, or
I. In a further embodiment R.sub.6 is F. In yet a further
embodiment R.sub.6 is Cl. In one embodiment the phenyl group is
substituted with at least one R.sub.6 selected from
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene.
In another embodiment R.sub.6 is
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene. In yet another embodiment
C.sub.1-C.sub.6alkylene is selected from methylene, ethylene,
n-propylene, iso-propylene, n-butylene, iso-butylene, and
tert-butylene. In yet a further embodiment C.sub.1-C.sub.6alkyl is
methylene. In a further embodiment R.sub.A and R.sub.B are each
independently hydrogen, C.sub.1-C.sub.6alkyl, or
C.sub.3-C.sub.8cycloalkyl. In one embodiment C.sub.1-C.sub.6alkyl
is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, and tert-butyl. In another embodiment
C.sub.1-C.sub.6alkyl is methyl. In yet another embodiment R.sub.A
and R.sub.B taken together with the nitrogen to which they are
attached form a 6 membered heterocycle ring having 1 heteroatom or
hetero functionality selected from the group consisting of --O--,
--NH, or --N(C.sub.1-C.sub.6alkyl). In a further embodiment the
hetero functionality is --N(C.sub.1-C.sub.6alkyl). In one
embodiment C.sub.1-C.sub.6alkyl is selected from methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a
further embodiment C.sub.1-C.sub.6alkyl is methyl. In another
embodiment R.sub.2 is hydrogen. In yet another embodiment R.sub.2
is selected from F, Cl, Br, and I. In a further embodiment R.sub.2
is F.
[0052] In one embodiment is a compound of Formula (II) wherein A is
hydrogen. In another embodiment A is C.sub.1-C.sub.6alkyl. In a
further embodiment, A is selected from methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl.
In yet another embodiment, methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl are
optionally substituted with OH, NO.sub.2, CN, Br, Cl, F, and I. In
a further embodiment A is methyl. In yet another embodiment, A is
selected from F, Cl, Br, and I. In another embodiment, A is
C.sub.3-C.sub.8cycloalkyl. In another embodiment, A is cyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment, A is
substituted with OH, NO.sub.2, or CN. In one embodiment is a
compound of Formula (II) wherein B is hydrogen. In a further
embodiment, B is C.sub.1-C.sub.6alkyl. In a further embodiment, B
is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, tert-butyl, n-pentyl, and n-hexyl. In yet another
embodiment, methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, tert-butyl, n-pentyl, and n-hexyl are optionally
substituted with OH, NO.sub.2, CN, Br, Cl, F, and I. In a further
embodiment B is methyl. In yet another embodiment, B is selected
from F, Cl, Br, and I. In another embodiment, B is
C.sub.3-C.sub.8cycloalkyl. In another embodiment, B is cyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment, A is
substituted with OH, NO.sub.2, or CN. In a further embodiment, is a
compound of Formula (II) wherein A is hydrogen and B is selected
from Br, Cl, F, I, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl,
alkoxy, alkoxyalkyl wherein C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl. In another embodiment, is a compound of
Formula (II) wherein B is hydrogen and A is selected from Br, Cl,
F, I, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, alkoxy,
alkoxyalkyl wherein C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl. In yet another embodiment, both A and B
are hydrogen. In a further embodiment, both A and B are selected
from Br, Cl, F, I, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl,
alkoxy, alkoxyalkyl wherein C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl.
[0053] In yet a further aspect is a compound selected from:
##STR00005## ##STR00006## ##STR00007## ##STR00008##
or a pharmaceutically acceptable salt, solvate or prodrug
thereof
[0054] In yet another aspect is a compound selected from:
##STR00009## ##STR00010## ##STR00011## ##STR00012##
or a pharmaceutically acceptable salt, solvate or prodrug
thereof
[0055] In yet another aspect is a compound selected from:
##STR00013## ##STR00014## ##STR00015## ##STR00016##
or a pharmaceutically acceptable salt, solvate or prodrug
thereof
[0056] In yet a further embodiment is a compound selected from:
##STR00017## ##STR00018##
or a pharmaceutically acceptable salt, solvate or prodrug
thereof
[0057] In yet a further embodiment is a compound selected from:
[0058]
(8S,9R)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-py-
rido[4,3,2-de]phthalazin-3(7H)-one; [0059]
(8R,9S)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-py-
rido[4,3,2-de]phthalazin-3(7H)-one; [0060]
(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dih-
ydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0061]
(8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dih-
ydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0062]
(8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-p-
yrido[4,3,2-de]phthalazin-3(7H)-one; [0063]
(8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-p-
yrido[4,3,2-de]phthalazin-3(7H)-one; [0064]
(8S,9R)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro--
2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0065]
(8R,9S)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro--
2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0066]
(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,-
9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0067]
(8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,-
9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0068]
(8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-
-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0069]
(8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-
-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0070]
(8S,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-
-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;
and [0071]
(8R,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1-
H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;
or a pharmaceutically acceptable salt, solvate or prodrug
thereof
[0072] In another aspect is a pharmaceutical composition comprising
a compound of Formula (I) or Formula (II) or a pharmaceutically
acceptable salt, pharmaceutically acceptable solvate, or
pharmaceutically acceptable prodrug and a pharmaceutically
acceptable carrier, excipient, binder or diluent thereof.
[0073] In certain embodiments are provided PARP inhibitor compounds
of Formula (I)
##STR00019##
or a therapeutically acceptable salt thereof wherein R.sub.1,
R.sub.2, and R.sub.3 are each independently selected from the group
consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl,
alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl,
hydroxyalkylene, nitro, NR.sub.AR.sub.B, NR.sub.AR.sub.Balkylene,
and (NR.sub.AR.sub.B)carbonyl; R.sub.A, and R.sub.B are
independently selected from the group consisting of hydrogen,
alkyl, cycloalkyl, and alkylcarbonyl; or R.sub.A and R.sub.B taken
together with the atom to which they are attached form a 3-10
membered heterocycle ring optionally having one to three
heteroatoms or hetero functionalities selected from the group
consisting of --O--, --NH, --N(C.sub.1-C.sub.6-alkyl)-,
--NCO(C.sub.1-C.sub.6-alkyl)-, --N(aryl)-,
--N(aryl-C.sub.1-C.sub.6-alkyl-)-,
--N(substituted-aryl-C.sub.1-C.sub.6-alkyl-)-, --N(heteroaryl)-,
--N(heteroaryl-C.sub.1-C.sub.6-alkyl-)-,
--N(substituted-heteroaryl-C.sub.1-C.sub.6-alkyl-)-, and --S-- or
S(O).sub.q--, wherein q is 1 or 2 and the 3-10 membered heterocycle
ring is optionally substituted with one or more substituents;
R.sub.4 and R.sub.5 are each independently selected from the group
consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl,
hydroxyalkylene, and (NR.sub.AR.sub.B)alkylene; A and B are each
independently selected from hydrogen, Br, Cl, F, I, OH,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, alkoxy,
alkoxyalkyl wherein C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl, wherein B is not OH; Y and Z are each
independently selected from the group consisting of: [0074] a) an
aryl group optionally substituted with 1, 2, or 3 substituents
R.sub.6; R.sub.6 is selected from OH, NO.sub.2, CN, Br, Cl, F, I,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl,
C.sub.2-C.sub.8heterocycloalkyl; C.sub.2-C.sub.6alkenyl, alkoxy,
alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,
C.sub.2-C.sub.6alkynyl, aryl, arylalkyl,
C.sub.3-C.sub.8cycloalkylalkyl, haloalkoxy, haloalkyl,
hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,
C.sub.2-C.sub.8heterocycloalkylthio, heterocyclooxy,
heterocyclothio, NR.sub.AR.sub.B,
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene;
[0075] b) a heteroaryl group optionally substituted with 1, 2, or 3
substituents R.sub.6; R.sub.6 is previously as defined; [0076] c) a
substituent independently selected from the group consisting of
hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl, cycloalkyl,
cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo, heterocycloalkyl,
heterocycloalkylalkyl, alkylcarbonyl, arylcarbonyl,
heteroarylcarbonyl alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
(NR.sub.AR.sub.B)alkylene, (NR.sub.AR.sub.B)carbonyl,
(NR.sub.AR.sub.B)carbonylalkylene, (NR.sub.AR.sub.B)sulfonyl, and
(NR.sub.AR.sub.B)sulfonylalkylene; or a pharmaceutically acceptable
salt, solvate or prodrug thereof.
[0077] In certain embodiments are provided PARP inhibitor compounds
of Formula (I) or a therapeutically acceptable salt thereof wherein
R.sub.1, R.sub.2, R.sub.3 are independently selected from a group
consisting of hydrogen, alkyl, and halogen; R.sub.4 is hydrogen and
R.sub.5 is selected from the group consisting hydrogen, alkyl,
cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene, and
(NR.sub.AR.sub.B)alkylene; R.sub.A, and R.sub.B are independently
selected from the group consisting of hydrogen, alkyl, cycloalkyl,
and alkylcarbonyl; or R.sub.A and R.sub.B taken together with the
atom to which they are attached form a 3-10 membered heterocycle
ring optionally having one to three heteroatoms or hetero
functionalities selected from the group consisting of --O--, --NH,
--N(C.sub.1-C.sub.6-alkyl)-, --NCO(C.sub.1-C.sub.6-alkyl)-,
--N(aryl)-, --N(aryl-C.sub.1-C.sub.6-alkyl-)-,
--N(substituted-aryl-C.sub.1-C.sub.6-alkyl-)-, --N(heteroaryl)-,
--N(heteroaryl-C.sub.1-C.sub.6-alkyl-)-,
--N(substituted-heteroaryl-C.sub.1-C.sub.6-alkyl-)-, and --S-- or
S(O).sub.q--, wherein q is 1 or 2 and the 3-10 membered heterocycle
ring is optionally substituted with one or more substituents; A and
B are each independently selected from hydrogen, Br, Cl, F, I, OH,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, alkoxy,
alkoxyalkyl wherein C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl, wherein B is not OH; Y and Z are each
independently selected from the group consisting of: [0078] a) an
aryl group optionally substituted with 1, 2, or 3 R.sub.6; wherein
each R.sub.6 is selected from OH, NO.sub.2, CN, Br, Cl, F, I,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl,
C.sub.2-C.sub.8heterocycloalkyl; C.sub.2-C.sub.6alkenyl, alkoxy,
alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,
C.sub.2-C.sub.6alkynyl, aryl, arylalkyl,
C.sub.3-C.sub.8cycloalkylalkyl, haloalkoxy, haloalkyl,
hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,
C.sub.2-C.sub.8heterocycloalkylthio, heterocyclooxy,
heterocyclothio, NR.sub.AR.sub.B,
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene;
[0079] b) a heteroaryl group optionally substituted with 1, 2, or 3
R.sub.6; [0080] c) a substituent independently selected from the
group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl,
cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo,
heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl,
arylcarbonyl, heteroarylcarbonyl alkylsulfonyl, arylsulfonyl,
heteroarylsulfonyl, (NR.sub.AR.sub.B)alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene;
or a pharmaceutically acceptable salt, solvate or prodrug
thereof.
[0081] In certain embodiments are provided PARP inhibitor compounds
of Formula (I) or a therapeutically acceptable salt thereof wherein
R.sub.1, R.sub.2, and R.sub.3 are independently selected from a
group consisting of hydrogen, alkyl, and halogen; R.sub.4 and
R.sub.5 are hydrogen; R.sub.A and R.sub.B are independently
selected from the group consisting of hydrogen, alkyl, cycloalkyl,
and alkylcarbonyl; or R.sub.A and R.sub.B taken together with the
atom to which they are attached form a 3-10 membered heterocycle
ring optionally having one to three heteroatoms or hetero
functionalities selected from the group consisting of --O--, --NH,
--N(C.sub.1-C.sub.6-alkyl)-, --NCO(C.sub.1-C.sub.6-alkyl)-,
--N(aryl)-, --N(aryl-C.sub.1-C.sub.6-alkyl-)-,
--N(substituted-aryl-C.sub.1-C.sub.6-alkyl-)-, --N(heteroaryl)-,
--N(heteroaryl-C.sub.1-C.sub.6-alkyl-)-,
--N(substituted-heteroaryl-C.sub.1-C.sub.6-alkyl-)-, and --S-- or
S(O).sub.q--, wherein q is 1 or 2 and the 3-10 membered heterocycle
ring is optionally substituted with one or more substituents; A and
B are each independently selected from hydrogen, Br, Cl, F, I,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, alkoxy,
alkoxyalkyl wherein C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl; Y and Z are each independently selected
from the group consisting of: [0082] a) an aryl group optionally
substituted with 1, 2, or 3 R.sub.6; wherein each R.sub.6 is
selected from OH, NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, C.sub.2-C.sub.8heterocycloalkyl;
C.sub.2-C.sub.6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, C.sub.2-C.sub.6alkynyl, aryl, arylalkyl,
C.sub.3-C.sub.8cycloalkylalkyl, haloalkoxy, haloalkyl,
hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,
C.sub.2-C.sub.8heterocycloalkylthio, heterocyclooxy,
heterocyclothio, NR.sub.AR.sub.B,
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene;
[0083] b) a heteroaryl group optionally substituted with 1, 2, or 3
R.sub.6; [0084] c) a substituent independently selected from the
group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl,
cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo,
heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl,
arylcarbonyl, heteroarylcarbonyl alkylsulfonyl, arylsulfonyl,
heteroarylsulfonyl, (NR.sub.AR.sub.B)alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene;
or a pharmaceutically acceptable salt, solvate or prodrug
thereof.
[0085] In certain embodiments are provided PARP inhibitor compounds
of Formula (I) or a therapeutically acceptable salt thereof wherein
R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are hydrogen;
R.sub.A, and R.sub.B are independently selected from the group
consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or
R.sub.A and R.sub.B taken together with the atom to which they are
attached form a 3-10 membered heterocycle ring optionally having
one to three heteroatoms or hetero functionalities selected from
the group consisting of --O--, --NH, --N(C.sub.1-C.sub.6-alkyl)-,
--NCO(C.sub.1-C.sub.6-alkyl)-, --N(aryl)-,
--N(aryl-C.sub.1-C.sub.6-alkyl-)-,
--N(substituted-aryl-C.sub.1-C.sub.6-alkyl-)-, --N(heteroaryl)-,
--N(heteroaryl-C.sub.1-C.sub.6-alkyl-)-,
--N(substituted-heteroaryl-C.sub.1-C.sub.6-alkyl-)-, and --S-- or
S(O).sub.q--, wherein q is 1 or 2 and the 3-10 membered heterocycle
ring is optionally substituted with one or more substituents; A and
B are each independently selected from hydrogen, Br, Cl, F, I, OH,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, alkoxy,
alkoxyalkyl wherein C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl, wherein B is not OH; Y and Z are each
independently selected from the group consisting of: [0086] a) an
aryl group optionally substituted with 1, 2, or 3 R.sub.6; wherein
each R.sub.6 is selected from OH, NO.sub.2, CN, Br, Cl, F, I,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl,
C.sub.2-C.sub.8heterocycloalkyl; C.sub.2-C.sub.6alkenyl, alkoxy,
alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,
C.sub.2-C.sub.6alkynyl, aryl, arylalkyl,
C.sub.3-C.sub.8cycloalkylalkyl, haloalkoxy, haloalkyl,
hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,
C.sub.2-C.sub.8heterocycloalkylthio, heterocyclooxy,
heterocyclothio, NR.sub.AR.sub.B,
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene;
[0087] b) a heteroaryl group optionally substituted with 1, 2, or 3
R.sub.6; [0088] c) a substituent independently selected from the
group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl,
cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo,
heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl,
arylcarbonyl, heteroarylcarbonyl alkylsulfonyl, arylsulfonyl,
heteroarylsulfonyl, (NR.sub.AR.sub.B)alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene;
or a pharmaceutically acceptable salt, solvate or prodrug
thereof.
[0089] In one embodiment is a PARP inhibitor compound of Formula
(I) wherein R.sub.1, R.sub.2, R.sub.3 are each independently
selected from a group consisting of hydrogen, alkyl, and halogen;
R.sub.4 is hydrogen and R.sub.5 is selected from the group
consisting hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl,
hydroxyalkylene, and (NR.sub.AR.sub.B)alkylene; and isomers, salts,
solvates, chemically protected forms, and prodrugs thereof
[0090] In another embodiment is a PARP inhibitor compound of
Formula (I) wherein R.sub.1, R.sub.2, R.sub.3 are each
independently selected from a group consisting of hydrogen, alkyl,
and halogen; R.sub.4 and R.sub.5 are hydrogen; and isomers, salts,
solvates, chemically protected forms, and prodrugs thereof
[0091] In a further embodiment is a compound of PARP inhibitor
Formula (I) wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 are each
hydrogen and R.sub.5 is alkyl.
[0092] In yet another embodiment is a PARP inhibitor compound of
Formula (I) wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 are each
hydrogen; and R.sub.5 is methyl.
[0093] In one embodiment is a PARP inhibitor compound of Formula
(I) wherein R.sub.1, R.sub.2, and R.sub.3 are each hydrogen.
[0094] In another embodiment is a PARP inhibitor compound of
Formula (I) wherein Y and Z are each independently selected from
the group consisting of: [0095] a) a phenyl group optionally
substituted with 1, 2, or 3 R.sub.6; [0096] b) a pyridyl group
optionally substituted with 1, 2, or 3 R.sub.6; and [0097] c) a
substituent independently selected from the group consisting of
hydrogen, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, arylalkyl,
cycloalkyl, cycloalkylalkyl, haloalkyl, oxo, heterocycloalkyl,
heterocycloalkylalkyl, alkylcarbonyl, arylcarbonyl,
heteroarylcarbonyl, (NR.sub.AR.sub.B)alkylene,
(NR.sub.AR.sub.B)carbonyl, and
(NR.sub.AR.sub.B)carbonylalkylene.
[0098] In a further embodiment is a PARP inhibitor compound of
Formula (I) wherein Y and Z are each independently selected from
the group consisting of [0099] a) a phenyl group optionally
substituted with 1, 2, or 3 R.sub.6; [0100] b) a imidazole group
optionally substituted with 1, 2, or 3 R.sub.6; and [0101] c) a
substituent independently selected from the group consisting of
hydrogen, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, arylalkyl,
cycloalkyl, cycloalkylalkyl, haloalkyl, oxo, heterocycloalkyl,
heterocycloalkylalkyl, alkylcarbonyl, arylcarbonyl,
heteroarylcarbonyl, (NR.sub.AR.sub.B)alkylene
(NR.sub.AR.sub.B)carbonyl, and
(NR.sub.AR.sub.B)carbonylalkylene.
[0102] In a further embodiment is a PARP inhibitor compound of
Formula (I) wherein Y and Z are each independently selected from
the group consisting of [0103] d) a phenyl group optionally
substituted with 1, 2, or 3 R.sub.6; [0104] e) a triazole group
optionally substituted with 1, 2, or 3 R.sub.6; and [0105] f) a
substituent independently selected from the group consisting of
hydrogen, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, arylalkyl,
cycloalkyl, cycloalkylalkyl, haloalkyl, oxo, heterocycloalkyl,
heterocycloalkylalkyl, alkylcarbonyl, arylcarbonyl,
heteroarylcarbonyl, (NR.sub.AR.sub.B)alkylene
(NR.sub.AR.sub.B)carbonyl, and
(NR.sub.AR.sub.B)carbonylalkylene.
[0106] In one embodiment is a PARP inhibitor compound of Formula
(I) wherein R.sub.5 is hydrogen or an alkyl group. In another
embodiment, R.sub.5 is hydrogen. In a further embodiment, R.sub.5
is C.sub.1-C.sub.6 alkyl. In yet a further embodiment, R.sub.5 is
CH.sub.3. In another embodiment, R.sub.5 is CH.sub.2CH.sub.3.
[0107] In another embodiment is a PARP inhibitor compound of
Formula (I) wherein R.sub.4 is hydrogen or an alkyl group. In yet
another embodiment, R.sub.4 is hydrogen.
[0108] In one embodiment, R.sub.2 is selected from the group
consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl,
alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl,
hydroxyalkylene, nitro, NR.sub.AR.sub.B, NR.sub.AR.sub.Balkylene,
and (NR.sub.AR.sub.B)carbonyl. In a further embodiment R.sub.2 is a
halogen selected from F, Cl, Br, and I. In yet a further
embodiment, R.sub.2 is fluorine. In one embodiment, R.sub.2 is
hydrogen.
[0109] In another embodiment, R.sub.3 is selected from the group
consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl,
alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl,
hydroxyalkylene, nitro, NR.sub.AR.sub.B, NR.sub.AR.sub.Balkylene,
and (NR.sub.AR.sub.B)carbonyl. In a further embodiment, R.sub.3 is
hydrogen. In some embodiments, R.sub.1 is selected from the group
consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl,
alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl,
hydroxyalkylene, nitro, NR.sub.AR.sub.B, NR.sub.AR.sub.Balkylene,
and (NR.sub.AR.sub.B)carbonyl. In a further embodiment, R.sub.1 is
hydrogen.
[0110] Also disclosed herein are PARP inhibitor compounds of
Formula (I) wherein Z is an aryl group optionally substituted with
1, 2, or 3 R.sub.6; wherein each R.sub.6 is selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, C.sub.2-C.sub.8heterocycloalkyl;
C.sub.2-C.sub.6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, C.sub.2-C.sub.6alkynyl, aryl, arylalkyl,
C.sub.3-C.sub.8cycloalkylalkyl, haloalkoxy, haloalkyl,
hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,
C.sub.2-C.sub.8heterocycloalkylthio, heterocyclooxy,
heterocyclothio, NR.sub.AR.sub.B,
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene.
In one embodiment is a compound of Formula (I) wherein Z is an
optionally substituted phenyl group. In one embodiment, Z is a
phenyl group. In another embodiment, the phenyl group is optionally
substituted with at least one R.sub.6 selected from OH, NO.sub.2,
CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl,
C.sub.2-C.sub.8heterocycloalkyl; C.sub.2-C.sub.6alkenyl, alkoxy,
alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,
C.sub.2-C.sub.6alkynyl, aryl, arylalkyl,
C.sub.3-C.sub.8cycloalkylalkyl, haloalkoxy, haloalkyl,
hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,
C.sub.2-C.sub.8heterocycloalkylthio, heterocyclooxy,
heterocyclothio, NR.sub.AR.sub.B,
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene.
In another embodiment, R.sub.6 is (NR.sub.AR.sub.B)alkylene. In a
further embodiment, R.sub.6 is CH.sub.2(NR.sub.AR.sub.B). In a
further embodiment, R.sub.6 is CH.sub.2(NR.sub.AR.sub.B) wherein
NR.sub.AR.sub.B is azetidine, pyrrolidine, piperidine or
morpholine. In yet a further embodiment, R.sub.A is H or alkyl. In
another embodiment, R.sub.A is C.sub.1-C.sub.6alkyl. In yet another
embodiment, R.sub.A is CH.sub.3. In another embodiment, R.sub.B is
H or alkyl. In one embodiment, R.sub.B is C.sub.1-C.sub.6alkyl. In
yet another embodiment, R.sub.B is CH.sub.3. In a further
embodiment, R.sub.6 is CH.sub.2NHCH.sub.3. In yet a further
embodiment, R.sub.6 is CH.sub.2NCH.sub.3CH.sub.3. In one
embodiment, R.sub.6 is (C.dbd.O)heterocycloalkyl(C.dbd.O)alkyl. In
one embodiment R.sub.6 is (C.dbd.O)heterocycloalkyl(C.dbd.O)alkyl
wherein the heterocycloalkyl group has at least one heteroatom
selected from O, N, and S. In another embodiment, the
heterocycloalkyl group has two N atoms. In a further embodiment,
R.sub.6 is (C.dbd.O)heterocycloalkyl(C.dbd.O)alkyl wherein alkyl is
selected from methyl, ethyl, n-propyl, iso-propyl, cyclopropyl,
n-butyl, iso-butyl, and t-butyl. In one embodiment, the alkyl group
is cyclopropyl. In another embodiment, the alkyl group is
iso-propyl. In one embodiment, R.sub.6 is
##STR00020##
In another embodiment, R.sub.6 is
##STR00021##
[0111] Presented herein are PARP inhibitor compounds of Formula (I)
wherein Z is an optionally substituted heteroaryl group. In one
embodiment, the heteroaryl group is selected from pyridine,
pyrimidine, pyrazine, pyrazole, oxazole, thiazole, isoxazole,
isothiazole, 1,3,4-oxadiazole, pyridazine, 1,3,5-trazine,
1,2,4-triazine, quinoxaline, benzimidazole, benzotriazole, purine,
1H-[1,2,3]triazolo[4,5-d]pyrimidine, triazole, imidazole,
thiophene, furan, isobenzofuran, pyrrole, indolizine, isoindole,
indole, indazole, isoquinoline, quinoline, phthalazine,
naphthyridine, quinazoline, cinnoline, and pteridine. In one
embodiment, Z is pyridine. In another embodiment, Z is optionally
substituted pyridine.
[0112] Also disclosed herein are PARP inhibitor compounds of
Formula (I) wherein Y is an aryl group optionally substituted with
1, 2, or 3 R.sub.6; wherein each R.sub.6 is selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, C.sub.2-C.sub.8heterocycloalkyl;
C.sub.2-C.sub.6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, C.sub.2-C.sub.6alkynyl, aryl, arylalkyl,
C.sub.3-C.sub.8cycloalkylalkyl, haloalkoxy, haloalkyl,
hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,
C.sub.2-C.sub.8heterocycloalkylthio, heterocyclooxy,
heterocyclothio, NR.sub.AR.sub.B,
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene.
In one embodiment is a compound of Formula (I) wherein Y is an
optionally substituted phenyl group. In one embodiment, Y is a
phenyl group. In another embodiment, the phenyl group is optionally
substituted with at least one R.sub.6 selected from OH, NO.sub.2,
CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl,
C.sub.2-C.sub.8heterocycloalkyl; C.sub.2-C.sub.6alkenyl, alkoxy,
alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,
C.sub.2-C.sub.6alkynyl, aryl, arylalkyl,
C.sub.3-C.sub.8cycloalkylalkyl, haloalkoxy, haloalkyl,
hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,
C.sub.2-C.sub.8heterocycloalkylthio, heterocyclooxy,
heterocyclothio, NR.sub.AR.sub.B,
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene.
In a further embodiment, R.sub.6 is CH.sub.2(NR.sub.AR.sub.B). In
yet a further embodiment, R.sub.A is H or alkyl. In another
embodiment, R.sub.A is C.sub.1-C.sub.6alkyl. In yet another
embodiment, R.sub.A is CH.sub.3. In another embodiment, R.sub.B is
H or alkyl. In one embodiment, R.sub.B is C.sub.1-C.sub.6alkyl. In
yet another embodiment, R.sub.B is CH.sub.3. In a further
embodiment, R.sub.6 is CH.sub.2NHCH.sub.3. In yet a further
embodiment, R.sub.6 is CH.sub.2NCH.sub.3CH.sub.3. In one
embodiment, R.sub.6 is (C.dbd.O)heterocycloalkyl(C.dbd.O)alkyl. In
one embodiment R.sub.6 is (C.dbd.O)heterocycloalkyl(C.dbd.O)alkyl
wherein the heterocycloalkyl group has at least one heteroatom
selected from O, N, and S. In another embodiment, the
heterocycloalkyl group has two N atoms. In a further embodiment,
R.sub.6 is (C.dbd.O)heterocycloalkyl(C.dbd.O)alkyl wherein alkyl is
selected from methyl, ethyl, n-propyl, iso-propyl, cyclopropyl,
n-butyl, iso-butyl, and t-butyl. In one embodiment, the alkyl group
is cyclopropyl. In another embodiment, the alkyl group is
iso-propyl. In one embodiment, R.sub.6 is
##STR00022##
In another embodiment, R.sub.6 is
##STR00023##
[0113] Presented herein are PARP inhibitor compounds of Formula (I)
wherein Y is an optionally substituted heteroaryl group. In one
embodiment, the heteroaryl group is selected from pyridine,
pyrimidine, pyrazine, pyrazole, oxazole, thiazole, isoxazole,
isothiazole, 1,3,4-oxadiazole, pyridazine, 1,3,5-trazine,
1,2,4-triazine, quinoxaline, benzimidazole, benzotriazole, purine,
1H-[1,2,3]triazolo[4,5-d]pyrimidine, triazole, imidazole,
thiophene, furan, isobenzofuran, pyrrole, indolizine, isoindole,
indole, indazole, isoquinoline, quinoline, phthalazine,
naphthyridine, quinazoline, cinnoline, and pteridine. In one
embodiment, Y is pyridine. In another embodiment, Y is optionally
substituted pyridine. In one embodiment, Y is imidazole. In another
embodiment, Y is optionally substituted imidazole. In one
embodiment, Y is triazole. In another embodiment, Y is optionally
substituted triazole.
[0114] In one embodiment, Y is a substituent independently selected
from the group consisting of hydrogen, alkenyl, alkoxy,
alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl,
arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene,
oxo, heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl,
arylcarbonyl, heteroarylcarbonyl alkylsulfonyl, arylsulfonyl,
heteroarylsulfonyl, (NR.sub.AR.sub.B)alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene.
In one embodiment, Y is alkyl. In another embodiment, Y is
C.sub.1-C.sub.6 alkyl. In a further embodiment, Y is selected from
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or
tert-butyl. In another embodiment, Y is iso-propyl.
[0115] Also disclosed herein are compounds of Formula (I) wherein Y
is an optionally substituted heterocycloalkyl group. In one
embodiment, the heterocycloalkyl group is selected from
pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,
tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl,
piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl,
azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl,
thiepanyl, oxazepinyl, diazepinyl, thiazepinyl,
1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl,
2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl,
dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,
dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,
3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl
and quinolizinyl. In another embodiment the heterocycloalkyl group
is selected from pyrrolidinyl, imidazolidinyl, piperidinyl,
piperazinyl, pyrazolidinyl, tetrahydrofuranyl,
tetrahydrothiophenyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl,
morpholinyl, and pyrazolinyl. In another embodiment, the
heterocycloalkyl group is piperidinyl.
[0116] In another aspect is a PARP inhibitor compound of Formula
(IA):
##STR00024##
or a therapeutically acceptable salt, solvate or prodrug thereof
wherein R.sub.1, R.sub.2, and R.sub.3 are each independently
selected from the group consisting of hydrogen, halogen, alkenyl,
alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano,
haloalkoxy, haloalkyl, hydroxyl, hydroxyalkylene, nitro,
NR.sub.AR.sub.B, NR.sub.AR.sub.Balkylene, and
(NR.sub.AR.sub.B)carbonyl; R.sub.A, and R.sub.B are independently
selected from the group consisting of hydrogen, alkyl, cycloalkyl,
and alkylcarbonyl; or R.sub.A and R.sub.B taken together with the
atom to which they are attached form a 3-10 membered heterocycle
ring optionally having one to three heteroatoms or hetero
functionalities selected from the group consisting of --O--, --NH,
--N(C.sub.1-C.sub.6-alkyl)-, --NCO(C.sub.1-C.sub.6-alkyl)-,
--N(aryl)-, --N(aryl-C.sub.1-C.sub.6-alkyl-)-,
--N(substituted-aryl-C.sub.1-C.sub.6-alkyl-)-, --N(heteroaryl)-,
--N(heteroaryl-C.sub.1-C.sub.6-alkyl-)-,
--N(substituted-heteroaryl-C.sub.1-C.sub.6-alkyl-)-, and --S-- or
S(O).sub.q--, wherein q is 1 or 2 and the 3-10 membered heterocycle
ring is optionally substituted with one or more substituents;
R.sub.4 and R.sub.5 are each independently selected from the group
consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl,
hydroxyalkylene, and (NR.sub.AR.sub.B)alkylene; A and B are each
independently selected from hydrogen, Br, Cl, F, I, OH,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, alkoxy,
alkoxyalkyl wherein C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl, wherein B is not OH; Y is selected from
the group consisting of: [0117] a) an aryl group optionally
substituted with 1, 2, or 3 substituents R.sub.6; R.sub.6 is
selected from OH, NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, C.sub.2-C.sub.8heterocycloalkyl;
C.sub.2-C.sub.6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, C.sub.2-C.sub.6alkynyl, aryl, arylalkyl,
C.sub.3-C.sub.8cycloalkylalkyl, haloalkoxy, haloalkyl,
hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,
C.sub.2-C.sub.8heterocycloalkylthio, heterocyclooxy,
heterocyclothio, NR.sub.AR.sub.B,
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene;
[0118] b) a heteroaryl group optionally substituted with 1, 2, or 3
substituents R.sub.6; R.sub.6 is selected independently from the
group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl,
cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxyl,
hydroxyalkylene, nitro, oxo, heteroaryl, heteroarylalkoxy,
heteroaryloxy, heteroarylthio, heteroarylalkylthio,
heterocycloalkyl, heterocycloalkoxy, heterocycloalkylthio,
heterocyclooxy, heterocyclothio, NR.sub.AR.sub.B,
(NR.sub.AR.sub.B)alkylene, (NR.sub.AR.sub.B)carbonyl,
(NR.sub.AR.sub.B)carbonylalkylene, (NR.sub.AR.sub.B)sulfonyl, and
(NR.sub.AR.sub.B)sulfonylalkylene; [0119] c) a substituent
independently selected from the group consisting of hydrogen,
alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,
alkyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,
hydroxyalkylene, oxo, heterocycloalkyl, heterocycloalkylalkyl,
alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, (NR.sub.AR.sub.B)alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene;
and n is an integer from 0-4; or a pharmaceutically acceptable
salt, solvate or prodrug thereof
[0120] In another embodiment is a PARP inhibitor compound of
Formula (IA) having the structure:
##STR00025##
or a pharmaceutically acceptable salt, solvate, or prodrug
thereof
[0121] In one embodiment is a PARP inhibitor compound of Formula
(IA) wherein Y is an aryl group. In another embodiment, Y is a
heteroaryl group. In a further embodiment, the aryl group is a
phenyl group. In yet a further embodiment is a compound of Formula
(IA) wherein the phenyl group is substituted with at least one
R.sub.6. In yet another embodiment the phenyl group is substituted
with at least one R.sub.6 selected from Br, Cl, F, or I. In one
embodiment R.sub.6 is F. In one embodiment is a compound of Formula
(IA) wherein the phenyl group is substituted with at least one
R.sub.6 selected from (NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene.
In one embodiment R.sub.6 is
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene. In another embodiment
C.sub.1-C.sub.6alkylene is selected from methylene, ethylene,
n-propylene, iso-propylene, n-butylene, iso-butylene, and
tert-butylene. In yet another embodiment C.sub.1-C.sub.6alkylene is
methylene. In yet a further embodiment R.sub.A and R.sub.B are each
independently hydrogen, C.sub.1-C.sub.6alkyl, or
C.sub.3-C.sub.8cycloalkyl. In one embodiment C.sub.1-C.sub.6alkyl
is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, and tert-butyl. In one embodiment C.sub.1-C.sub.6alkyl
is methyl. In another embodiment C.sub.1-C.sub.6alkyl is ethyl. In
one embodiment is a compound of Formula (IA) wherein
C.sub.3-C.sub.8cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl,
and cyclohexyl. In a further embodiment C.sub.3-C.sub.8cycloalkyl
is cyclopropyl. In one embodiment is a compound of Formula (IA)
wherein R.sub.6 is hydroxyalkylene. In one embodiment
hydroxyalkylene is selected from CH.sub.2OH, CH.sub.2CH.sub.2OH,
CH.sub.2CH.sub.2CH.sub.2OH, CH(OH)CH.sub.3, CH(OH)CH.sub.2CH.sub.3,
CH.sub.2CH(OH)CH.sub.3, and CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH. In
another embodiment R.sub.A and R.sub.B taken together with the
nitrogen to which they are attached form a 6 membered heterocycle
ring having 1 heteroatom or hetero functionality selected from the
group consisting of --O--, --NH, or --N(C.sub.1-C.sub.6alkyl). In
yet another embodiment the hetero functionality is
--N(C.sub.1-C.sub.6alkyl). In a further embodiment
C.sub.1-C.sub.6alkyl is selected from methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a further
embodiment C.sub.1-C.sub.6alkyl is methyl.
[0122] In one embodiment is a PARP inhibitor compound of Formula
(IA) wherein Y is a heteroaryl group optionally substituted with at
least one R.sub.6. In another embodiment the heteroaryl group is
selected from furan, pyridine, pyrimidine, pyrazine, imidazole,
thiazole, isothiazole, pyrazole, triazole, pyrrole, thiophene,
oxazole, isoxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole,
1,2,4-triazine, indole, benzothiophene, benzoimidazole, benzofuran,
pyridazine, 1,3,5-triazine, thienothiophene, quinoxaline,
quinoline, and isoquinoline. In yet another embodiment the
heteroaryl group is imidazole. In a further embodiment imidazole is
substituted with C.sub.1-C.sub.6alkyl selected from methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a
further embodiment C.sub.1-C.sub.6alkyl is methyl. In one
embodiment the heteroaryl group is furan. In another embodiment the
heteroaryl group is thiazole. In yet another embodiment the
heteroaryl group is 1,3,4-oxadiazole. In a further embodiment
heteroaryl group is substituted with C.sub.1-C.sub.6alkyl selected
from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and
tert-butyl. In yet a further embodiment C.sub.1-C.sub.6alkyl is
methyl.
[0123] In one embodiment is a PARP inhibitor compound of Formula
(IA) wherein A and B are each independently selected from hydrogen,
Br, Cl, F, I, OH, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl,
alkoxy, alkoxyalkyl wherein C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl and B is not OH.
[0124] In yet another embodiment is a PARP inhibitor compound
selected from:
##STR00026## ##STR00027## ##STR00028## ##STR00029## ##STR00030##
##STR00031##
or a pharmaceutically acceptable salt, solvate or prodrug
thereof
[0125] In one embodiment is a PARP inhibitor compound of Formula
(I) wherein Y is a heteroaryl group selected from furan, pyridine,
pyrimidine, pyrazine, imidazole, thiazole, isothiazole, pyrazole,
triazole, pyrrole, thiophene, oxazole, isoxazole, 1,2,4-oxadiazole,
1,3,4-oxadiazole, 1,2,4-triazine, indole, benzothiophene,
benzoimidazole, benzofuran, pyridazine, 1,3,5-triazine,
thienothiophene, quinoxaline, quinoline, and isoquinoline. In
another embodiment, Y is an imidazole group. In yet another
embodiment, the imidazole group is substituted with a
C.sub.1-C.sub.6alkyl group. In another embodiment, the
C.sub.1-C.sub.6alkyl group is methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, and tert-butyl. In a further embodiment
C.sub.1-C.sub.6alkyl is methyl. In another embodiment is a compound
of Formula (I) wherein Y is a substituted imidazole group and Z is
selected from an aryl group or a heteroaryl group. In a further
embodiment, Z is an aryl group. In yet a further embodiment, the
aryl group is a phenyl group. In yet a further embodiment, the aryl
group is a phenyl group substituted by a halogen. In yet a further
embodiment Z is a heteroaryl group. In another embodiment, the
heteroaryl group is furan, pyridine, pyrimidine, pyrazine,
imidazole, thiazole, isothiazole, pyrazole, triazole, pyrrole,
thiophene, oxazole, isoxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole,
1,2,4-triazine, indole, benzothiophene, benzoimidazole, benzofuran,
pyridazine, 1,3,5-triazine, thienothiophene, quinoxaline,
quinoline, and isoquinoline. In a further embodiment, the
heteroaryl group is imidazole. In another embodiment, the imidazole
group is substituted with a C.sub.1-C.sub.6alkyl group. In another
embodiment, the C.sub.1-C.sub.6alkyl group is methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In a
further embodiment C.sub.1-C.sub.6alkyl is methyl.
[0126] In another embodiment is a PARP inhibitor compound of
Formula (I) wherein Y is a triazole group. In yet another
embodiment, the triazole group is substituted with a
C.sub.1-C.sub.6alkyl group. In another embodiment, the
C.sub.1-C.sub.6alkyl group is methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, and tert-butyl. In a further embodiment
C.sub.1-C.sub.6alkyl is methyl. In another embodiment is a compound
of Formula (I) wherein Y is a substituted triazole group and Z is
selected from an aryl group or a heteroaryl group. In a further
embodiment, Z is an aryl group. In yet a further embodiment, the
aryl group is a phenyl group. In yet a further embodiment, the aryl
group is a phenyl group substituted by a halogen. In yet a further
embodiment Z is a heteroaryl group. In another embodiment, the
heteroaryl group is furan, pyridine, pyrimidine, pyrazine,
imidazole, thiazole, isothiazole, pyrazole, triazole, pyrrole,
thiophene, oxazole, isoxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole,
1,2,4-triazine, indole, benzothiophene, benzoimidazole, benzofuran,
pyridazine, 1,3,5-triazine, thienothiophene, quinoxaline,
quinoline, and isoquinoline. In a further embodiment, the
heteroaryl group is triazole. In another embodiment, the triazole
group is substituted with a C.sub.1-C.sub.6alkyl group. In another
embodiment, the C.sub.1-C.sub.6alkyl group is methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In a
further embodiment C.sub.1-C.sub.6alkyl is methyl.
[0127] In another embodiment is a PARP inhibitor compound selected
from
##STR00032##
or a pharmaceutically acceptable salt, solvate or prodrug
thereof
[0128] In one aspect is a PARP inhibitor compound of Formula
(II):
##STR00033##
wherein: Y is an aryl or heteroaryl group optionally substituted
with at least one R.sub.6; Z is an aryl group optionally
substituted with at least one R.sub.6; R.sub.6 is selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, C.sub.2-C.sub.8heterocycloalkyl;
C.sub.2-C.sub.6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, C.sub.2-C.sub.6alkynyl, aryl, arylalkyl,
C.sub.3-C.sub.8cycloalkylalkyl, haloalkoxy, haloalkyl,
hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,
C.sub.2-C.sub.8heterocycloalkylthio, heterocyclooxy,
heterocyclothio, NR.sub.AR.sub.B,
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene;
R.sub.2 is selected from hydrogen, Br, Cl, I, or F; A and B are
each independently selected from hydrogen, Br, Cl, F, I, OH,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, alkoxy,
alkoxyalkyl wherein C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl, wherein B is not OH; R.sub.A, and
R.sub.B are independently selected from the group consisting of
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, and
alkylcarbonyl; or R.sub.A and R.sub.B taken together with the atom
to which they are attached form a 3-10 membered heterocycle ring
optionally having one to three heteroatoms or hetero
functionalities selected from the group consisting of --O--, --NH,
--N(C.sub.1-C.sub.6alkyl)-, --NCO(C.sub.1-C.sub.6alkyl)-,
--NCO(C.sub.3-C.sub.8cycloalkyl)-, --N(aryl)-,
--N(aryl-C.sub.1-C.sub.6alkyl-)-,
--N(substituted-aryl-C.sub.1-C.sub.6alkyl-)-, --N(heteroaryl)-,
--N(heteroaryl-C.sub.1-C.sub.6alkyl-)-,
--N(substituted-heteroaryl-C.sub.1-C.sub.6alkyl-)-, and --S-- or
S(O).sub.q--, wherein q is 1 or 2 and the 3-10 membered heterocycle
ring is optionally substituted with one or more substituents; or a
pharmaceutically acceptable salt, solvate or prodrug thereof
[0129] In one embodiment is a PARP inhibitor compound of Formula
(II) wherein Y is an aryl group. In another embodiment the aryl
group is a phenyl group. In yet another embodiment the phenyl group
is substituted with at least one R.sub.6 selected from Br, Cl, F,
or I. In one embodiment R.sub.6 is F. In one embodiment the phenyl
group is substituted with at least one R.sub.6 selected from
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene.
In one embodiment R.sub.6 is
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene. In another embodiment
C.sub.1-C.sub.6alkylene is selected from methylene, ethylene,
n-propylene, iso-propylene, n-butylene, iso-butylene, and
tert-butylene. In yet another embodiment C.sub.1-C.sub.6alkylene is
methylene. In yet a further embodiment R.sub.A and R.sub.B are each
independently hydrogen, C.sub.1-C.sub.6alkyl, or
C.sub.3-C.sub.8cycloalkyl. In one embodiment C.sub.1-C.sub.6alkyl
is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, and tert-butyl. In one embodiment C.sub.1-C.sub.6alkyl
is methyl. In another embodiment C.sub.1-C.sub.6alkyl is ethyl. In
yet another embodiment C.sub.3-C.sub.8cycloalkyl is cyclopropyl,
cyclobutyl, cyclopentyl, and cyclohexyl. In a further embodiment
C.sub.3-C.sub.8cycloalkyl is cyclopropyl. In yet a further
embodiment R.sub.6 is hydroxyalkylene. In one embodiment
hydroxyalkylene is selected from CH.sub.2OH, CH.sub.2CH.sub.2OH,
CH.sub.2CH.sub.2CH.sub.2OH, CH(OH)CH.sub.3, CH(OH)CH.sub.2CH.sub.3,
CH.sub.2CH(OH)CH.sub.3, and CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH. In
another embodiment R.sub.A and R.sub.B taken together with the
nitrogen to which they are attached form a 6 membered heterocycle
ring having 1 heteroatom or hetero functionality selected from the
group consisting of --O--, --NH, or --N(C.sub.1-C.sub.6alkyl). In
yet another embodiment the hetero functionality is
--N(C.sub.1-C.sub.6alkyl). In a further embodiment
C.sub.1-C.sub.6alkyl is selected from methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a further
embodiment C.sub.1-C.sub.6alkyl is methyl.
[0130] In one embodiment is a PARP inhibitor compound of Formula
(II) wherein Y is a heteroaryl group optionally substituted with at
least one R.sub.6. In another embodiment the heteroaryl group is
selected from furan, pyridine, pyrimidine, pyrazine, imidazole,
thiazole, isothiazole, pyrazole, triazole, pyrrole, thiophene,
oxazole, isoxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole,
1,2,4-triazine, indole, benzothiophene, benzoimidazole, benzofuran,
pyridazine, 1,3,5-triazine, thienothiophene, quinoxaline,
quinoline, and isoquinoline. In yet another embodiment the
heteroaryl group is imidazole. In a further embodiment imidazole is
substituted with C.sub.1-C.sub.6alkyl selected from methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a
further embodiment C.sub.1-C.sub.6alkyl is methyl. In one
embodiment the heteroaryl group is furan. In another embodiment the
heteroaryl group is thiazole. In yet another embodiment the
heteroaryl group is 1,3,4-oxadiazole. In a further embodiment
heteroaryl group is substituted with C.sub.1-C.sub.6alkyl selected
from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and
tert-butyl. In yet a further embodiment C.sub.1-C.sub.6alkyl is
methyl.
[0131] In one embodiment is a PARP inhibitor compound of Formula
(II) wherein Z is an aryl group. In another embodiment the aryl
group is a phenyl group. In yet another embodiment the phenyl group
is substituted with at least one R.sub.6 selected from Br, Cl, F,
or I. In a further embodiment R.sub.6 is F. In yet a further
embodiment R.sub.6 is Cl. In one embodiment the phenyl group is
substituted with at least one R.sub.6 selected from
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene.
In another embodiment R.sub.6 is
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene. In yet another embodiment
C.sub.1-C.sub.6alkylene is selected from methylene, ethylene,
n-propylene, iso-propylene, n-butylene, iso-butylene, and
tert-butylene. In yet a further embodiment C.sub.1-C.sub.6alkylene
is methylene. In a further embodiment R.sub.A and R.sub.B are each
independently hydrogen, C.sub.1-C.sub.6alkyl, or
C.sub.3-C.sub.8cycloalkyl. In one embodiment C.sub.1-C.sub.6alkyl
is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, and tert-butyl. In another embodiment
C.sub.1-C.sub.6alkyl is methyl. In yet another embodiment R.sub.A
and R.sub.B taken together with the nitrogen to which they are
attached form a 6 membered heterocycle ring having 1 heteroatom or
hetero functionality selected from the group consisting of --O--,
--NH, or --N(C.sub.1-C.sub.6alkyl). In a further embodiment the
hetero functionality is --N(C.sub.1-C.sub.6alkyl). In one
embodiment C.sub.1-C.sub.6alkyl is selected from methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a
further embodiment C.sub.1-C.sub.6alkyl is methyl. In a further
embodiment, R.sub.6 is CH.sub.2(NR.sub.AR.sub.B) wherein
NR.sub.AR.sub.B is azetidine, pyrrolidine, piperidine or
morpholine. In another embodiment R.sub.2 is hydrogen. In yet
another embodiment R.sub.2 is selected from F, Cl, Br, and I. In a
further embodiment R.sub.2 is F.
[0132] In one embodiment is a PARP inhibitor compound of Formula
(II) wherein A and B are hydrogen. In another embodiment A and B
are independently selected from hydrogen and
C.sub.1-C.sub.6alkyl.
[0133] In a further embodiment is a PARP inhibitor compound of
Formula (II) wherein Z is aryl and Y is independently selected from
the group consisting of [0134] a) phenyl group optionally
substituted with 1, 2, or 3 R.sub.6; [0135] b) a imidazole group
optionally substituted with 1, 2, or 3 R.sub.6; [0136] c) a
triazole group optionally substituted with 1, 2, or 3 R.sub.6; and
[0137] d) a substituent independently selected from the group
consisting of hydrogen, alkoxyalkyl, alkoxycarbonylalkyl, alkyl,
arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, oxo,
heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl,
arylcarbonyl, heteroarylcarbonyl, (NR.sub.AR.sub.B)alkylene
(NR.sub.AR.sub.B)carbonyl.
[0138] In a further embodiment is a PARP inhibitor compound of
Formula (II) wherein Z is phenyl and Y is independently selected
from the group consisting of [0139] e) phenyl group optionally
substituted with 1, 2, or 3 R.sub.6; [0140] f) a imidazole group
optionally substituted with 1, 2, or 3 R.sub.6; [0141] g) a
triazole group optionally substituted with 1, 2, or 3 R.sub.6; and
[0142] h) a substituent independently selected from the group
consisting of hydrogen, alkoxyalkyl, alkoxycarbonylalkyl, alkyl,
arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, oxo,
heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl,
arylcarbonyl, heteroarylcarbonyl, (NR.sub.AR.sub.B)alkylene
(NR.sub.AR.sub.B)carbonyl.
[0143] In a further embodiment is a PARP inhibitor compound of
Formula (II) wherein Z is phenyl substituted with 1, 2, or 3
R.sub.6 and Y is independently selected from the group consisting
of [0144] i) phenyl group optionally substituted with 1, 2, or 3
R.sub.6; [0145] j) a imidazole group optionally substituted with 1,
2, or 3 R.sub.6; [0146] k) a triazole group optionally substituted
with 1, 2, or 3 R.sub.6; and [0147] l) a substituent independently
selected from the group consisting of hydrogen, alkoxyalkyl,
alkoxycarbonylalkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl,
haloalkyl, oxo, heterocycloalkyl, heterocycloalkylalkyl,
alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,
(NR.sub.AR.sub.B)alkylene (NR.sub.AR.sub.B)carbonyl.
[0148] In a further embodiment, A is selected from methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, and
n-hexyl. In yet another embodiment, methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl
are optionally substituted with OH, NO.sub.2, CN, Br, Cl, F, and I.
In a further embodiment A is methyl. In yet another embodiment, A
is selected from F, Cl, Br, and I. In another embodiment, A is
C.sub.3-C.sub.8cycloalkyl. In a further embodiment, A is OH. In
another embodiment, A is cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl. In one embodiment, A is substituted with OH, NO.sub.2,
or CN. In a further embodiment, A is hydrogen. In a further
embodiment, B is hydrogen. In a further embodiment, B is
C.sub.1-C.sub.6alkyl. In a further embodiment, B is selected from
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
tert-butyl, n-pentyl, and n-hexyl. In yet another embodiment,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
tert-butyl, n-pentyl, and n-hexyl are optionally substituted with
OH, NO.sub.2, CN, Br, Cl, F, and I. In a further embodiment B is
methyl. In yet another embodiment, B is selected from F, Cl, Br,
and I. In another embodiment, B is C.sub.3-C.sub.8cycloalkyl. In
another embodiment, B is cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl. In one embodiment, A is substituted with OH, NO.sub.2,
or CN. In a further embodiment, is a compound of Formula (II)
wherein A is hydrogen and B is selected from Br, Cl, F, I,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, alkoxy,
alkoxyalkyl wherein C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl. In another embodiment, is a compound of
Formula (II) wherein B is hydrogen and A is selected from Br, Cl,
F, I, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, alkoxy,
alkoxyalkyl wherein C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl. In yet another embodiment, both A and B
are hydrogen. In a further embodiment, both A and B are selected
from Br, Cl, F, I, OH, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl wherein
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, alkoxy,
alkoxyalkyl are optionally substituted with at least one
substituent selected from OH, NO.sub.2, CN, Br, Cl, F, I,
C.sub.1-C.sub.6alkyl, and C.sub.3-C.sub.8cycloalkyl wherein B is
not OH.
[0149] Also described herein are stereoisomers of PARP inhibitor
compounds of Formula (I), (IA), or (II), such as enantiomers,
diastereomers, and mixtures of enantiomers or diastereomers. In one
embodiment is a stereoisomer of a compound of Formula (II) having
the structures:
##STR00034##
wherein: Y is an aryl or heteroaryl group optionally substituted
with at least one R.sub.6; Z is an aryl group optionally
substituted with at least one R.sub.6; A and B are each
independently selected from hydrogen, Br, Cl, F, I, OH,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, alkoxy,
alkoxyalkyl wherein C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, alkoxy, alkoxyalkyl are optionally
substituted with at least one substituent selected from OH,
NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl, wherein B is not OH; R.sub.6 is selected
from OH, NO.sub.2, CN, Br, Cl, F, I, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, C.sub.2-C.sub.8heterocycloalkyl;
C.sub.2-C.sub.6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, C.sub.2-C.sub.6alkynyl, aryl, arylalkyl,
C.sub.3-C.sub.8cycloalkylalkyl, haloalkoxy, haloalkyl,
hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy,
heteroarylthio, heteroarylalkylthio, heterocycloalkoxy,
C.sub.2-C.sub.8heterocycloalkylthio, heterocyclooxy,
heterocyclothio, NR.sub.AR.sub.B,
(NR.sub.AR.sub.B)C.sub.1-C.sub.6alkylene,
(NR.sub.AR.sub.B)carbonyl, (NR.sub.AR.sub.B)carbonylalkylene,
(NR.sub.AR.sub.B)sulfonyl, and (NR.sub.AR.sub.B)sulfonylalkylene;
R.sub.2 is selected from hydrogen, Br, Cl, I, or F; R.sub.A, and
R.sub.B are independently selected from the group consisting of
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, and
alkylcarbonyl; or R.sub.A and R.sub.B taken together with the atom
to which they are attached form a 3-10 membered heterocycle ring
optionally having one to three heteroatoms or hetero
functionalities selected from the group consisting of --O--, --NH,
--N(C.sub.1-C.sub.6alkyl)-, --NCO(C.sub.1-C.sub.6alkyl)-,
--NCO(C.sub.3-C.sub.8cycloalkyl)-, --N(aryl)-,
--N(aryl-C.sub.1-C.sub.6alkyl-)-,
--N(substituted-aryl-C.sub.1-C.sub.6alkyl-)-, --N(heteroaryl)-,
--N(heteroaryl-C.sub.1-C.sub.6alkyl-)-,
--N(substituted-heteroaryl-C.sub.1-C.sub.6alkyl-)-, and --S-- or
S(O).sub.q--, wherein q is 1 or 2 and the 3-10 membered heterocycle
ring is optionally substituted with one or more substituents; or a
pharmaceutically acceptable salt, solvate or prodrug thereof
[0150] In one embodiment is the stereoisomer of the PARP inhibitor
compound of Formula (II) shown above, having the substituents shown
above, wherein R.sub.2 is fluorine. In another embodiment is the
compound of Formula (II) shown above, having the substituents shown
above, wherein Y is an imidazole group. In another embodiment is
the compound of Formula (II) shown above, having the substituents
shown above, wherein the imidazole group of Y is substituted with a
C.sub.1-C.sub.6alkyl group. In a further embodiment, the
C.sub.1-C.sub.6alkyl is methyl. In yet another embodiment is a
compound of Formula (II), shown above, having the substituents
shown above, wherein Y is a triazole group. In another embodiment
is the compound of Formula (II) shown above, having the
substituents shown above, wherein the triazole group of Y is
substituted with a C.sub.1-C.sub.6alkyl group. In a further
embodiment, the C.sub.1-C.sub.6alkyl is methyl. In yet a further
embodiment is the compound of Formula (II) shown above, having the
substituents above, wherein the Y group is an aryl group. In a
further embodiment is the compound of Formula (II) shown above,
having the substituents shown above, wherein the aryl group of Y is
a phenyl group. In a further embodiment, the phenyl group is
substituted with a halogen. In yet a further embodiment, the
halogen is F. In yet another embodiment the halogen is selected
from Br, Cl, and I. In yet another embodiment, is the compound of
Formula (II) shown above, having the substituents shown above,
wherein Z is an aryl group. In yet another embodiment is the
compound of Formula (II) shown above, having the substituents shown
above, wherein the aryl group of Z is a phenyl group. In a further
embodiment, the phenyl group of Z is substituted with a halogen,
selected from F, Br, Cl, and I. In yet another embodiment, the
phenyl group of Z is substituted with F. In yet a further
embodiment the phenyl group of Z is substituted with
C.sub.1-C.sub.6alkylene(NR.sub.AR.sub.B). In yet a further
embodiment, the C.sub.1-C.sub.6alkylene group is methylene. In yet
another embodiment NRARB is azetidine.
[0151] In one embodiment is a PARP inhibitor compound selected
from: [0152]
(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-
-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0153]
(8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,-
9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0154]
(8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-p-
yrido[4,3,2-de]phthalazin-3(7H)-one; [0155]
(8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-p-
yrido[4,3,2-de]phthalazin-3(7H)-one; [0156]
(8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-
-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0157]
(8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-
-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0158]
(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dih-
ydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0159]
(8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dih-
ydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0160]
(8S,9R)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-py-
rido[4,3,2-de]phthalazin-3(7H)-one; [0161]
(8R,9S)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-py-
rido[4,3,2-de]phthalazin-3(7H)-one; [0162]
(8S,9R)-8-(4-(azetidin-1-ylmethyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro--
2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; and [0163]
(8R,9S)-8-(4-(azetidin-1-ylmethyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro--
2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; or a pharmaceutically
acceptable salt, solvate or prodrug thereof.
[0164] In one aspect is a compound selected from: [0165]
9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;
[0166]
8,9-bis(4-((methylamino)methyl)phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phth-
alazin-3(7H)-one; [0167]
8,9-di(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;
[0168]
8,9-di(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7-
H)-one; [0169]
8,9-di(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;
[0170]
9-isopropyl-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7-
H)-one; [0171]
9-(4-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de-
]phthalazin-3(7H)-one; [0172]
9-(4-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2--
de]phthalazin-3(7H)-one; [0173]
9-(3-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de-
]phthalazin-3(7H)-one; [0174]
8-(4-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de-
]phthalazin-3(7H)-one; [0175]
8,9-bis(3-((methylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pht-
halazin-3(7H)-one; [0176]
9-(4-(hydroxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phtha-
lazin-3(7H)-one; [0177]
9-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-p-
yrido[4,3,2-de]phthalazin-3(7H)-one; [0178]
8,9-bis(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrid-
o[4,3,2-de]phthalazin-3(7H)-one; [0179]
9-(piperidin-3-yl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthal-
azin-3(7H)-one; [0180]
9-(piperidin-4-yl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthal-
azin-3(7H)-one; [0181]
8,9-bis(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]p-
hthalazin-3(7H)-one; [0182]
9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4((methyla-
mino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;
[0183]
9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4((-
dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7-
H)-one; [0184]
8-(4-(hydroxymethyl)phenyl)-9-(4-(4-isobutyrylpiperazine-1-carbonyl)pheny-
l)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0185]
8-(4-((dimethylamino)methyl)phenyl)-9-(4-(4-isobutyrylpiperazine-1-carbon-
yl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;
[0186]
9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9--
dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0187]
9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9--
dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0188]
9-(3-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2--
de]phthalazin-3(7H)-one; [0189]
8-(3-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de-
]phthalazin-3(7H)-one; [0190]
8-(4-((dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2--
de]phthalazin-3(7H)-one; [0191]
8-(4-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]ph-
thalazin-3(7H)-one; [0192]
8-(4-(hydroxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phtha-
lazin-3(7H)-one; [0193]
9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-((dimeth-
ylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one-
; [0194]
9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4--
(hydroxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one-
; [0195]
9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-(4-((methylamin-
o)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;
[0196]
9-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-(pyridin-4-yl)-8-
,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0197]
9-(3-((dimethylamino)methyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrid-
o[4,3,2-de]phthalazin-3(7H)-one; [0198]
9-(3-((methylamino)methyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[-
4,3,2-de]phthalazin-3(7H)-one; [0199]
9-(4-((dimethylamino)methyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrid-
o[4,3,2-de]phthalazin-3(7H)-one; [0200]
9-(3-(hydroxymethyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2--
de]phthalazin-3(7H)-one; [0201]
9-(4-((methylamino)methyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[-
4,3,2-de]phthalazin-3(7H)-one; [0202]
9-(3-((dimethylamino)methyl)phenyl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrid-
o[4,3,2-de]phthalazin-3(7H)-one; [0203]
9-(3-((methylamino)methyl)phenyl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[-
4,3,2-de]phthalazin-3(7H)-one; [0204]
9-(4-((dimethylamino)methyl)phenyl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrid-
o[4,3,2-de]phthalazin-3(7H)-one; [0205]
9-(4-((methylamino)methyl)phenyl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[-
4,3,2-de]phthalazin-3(7H)-one; [0206]
9-(3-(hydroxymethyl)phenyl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2--
de]phthalazin-3(7H)-one; [0207]
9-(3-((dimethylamino)methyl)phenyl)-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrid-
o[4,3,2-de]phthalazin-3(7H)-one; [0208]
9-(3-((methylamino)methyl)phenyl)-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[-
4,3,2-de]phthalazin-3(7H)-one; [0209]
9-(3-(hydroxymethyl)phenyl)-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2--
de]phthalazin-3(7H)-one; [0210]
9-(4-((dimethylamino)methyl)phenyl)-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrid-
o[4,3,2-de]phthalazin-3(7H)-one; [0211]
9-(4-((methylamino)methyl)phenyl)-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[-
4,3,2-de]phthalazin-3(7H)-one; [0212]
9-phenyl-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-
-one; [0213]
9-phenyl-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-
-one; [0214]
9-phenyl-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-
-one; [0215]
5-fluoro-9-phenyl-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthala-
zin-3(7H)-one; [0216]
9-(3-((dimethylamino)methyl)phenyl)-5-fluoro-8-(pyridin-4-yl)-8,9-dihydro-
-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0217]
5-fluoro-9-(3-((methylamino)methyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2-
H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0218]
9-(4-((dimethylamino)methyl)phenyl)-5-fluoro-8-(pyridin-4-yl)-8,9-dihydro-
-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0219]
5-fluoro-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one-
; [0220]
9-(4-((dimethylamino)methyl)phenyl)-5-fluoro-8-phenyl-8,9-dihydro-
-2H-pyrido[4,3,2-de]phthalazin-one; [0221]
5-fluoro-9-(4-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido-
[4,3,2-de]phthalazin-one; [0222]
9-(3-((dimethylamino)methyl)phenyl)-5-fluoro-8-phenyl-8,9-dihydro-2H-pyri-
do[4,3,2-de]phthalazin-one; [0223]
8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-phenyl-8,9-dihydro-2H-pyri-
do[4,3,2-de]phthalazin-one; [0224]
5-fluoro-9-(3-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido-
[4,3,2-de]phthalazin-one; [0225]
5-fluoro-8-(4-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido-
[4,3,2-de]phthalazin-one; [0226]
7-methyl-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one-
; [0227]
7-ethyl-8,9-diphenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(-
7H)-one; [0228]
5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3-
,2-de]phthalazin-3(7H)-one; [0229]
5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H--
pyrido[4,3,2-de]phthalazin-3(7H)-one; [0230]
8-(4-((dimethylamino)methyl)phenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dih-
ydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0231]
9-(1-isopropyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]-
phthalazin-3(7H)-one; [0232]
9-(4-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]pht-
halazin-3(7H)-one; [0233]
8-phenyl-9-(thiazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-
-one; [0234]
9-(furan-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-o-
ne; [0235]
8-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydr-
o-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0236]
9-phenyl-8-(4-(piperazin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-d-
e]phthalazin-3(7H)-one; [0237]
8-(1-methyl-1H-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]pht-
halazin-3(7H)-one; [0238]
9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]pht-
halazin-3(7H)-one; [0239]
8,9-bis(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthala-
zin-3(7H)-one; [0240]
9-(1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3-
(7H)-one; [0241]
9-(1-ethyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phth-
alazin-3(7H)-one; [0242]
8-phenyl-9-(1-propyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pht-
halazin-3(7H)-one; [0243]
9-(1-methyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]pht-
halazin-3(7H)-one; [0244]
9-(3-((diethylamino)methyl)phenyl)-8-(4-((diethylamino)methyl)phenyl)-8,9-
-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0245]
9-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyri-
do[4,3,2-de]phthalazin-3(7H)-one; [0246]
8-(4-(4-(cyclopropanecarbonyl)
piperazine-1-carbonyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]pht-
halazin-3(7H)-one; [0247]
9-phenyl-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-
-one; [0248]
9-phenyl-8-(piperidin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7-
H)-one; [0249]
9-phenyl-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-
-one; [0250]
8-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyri-
do[4,3,2-de]phthalazin-3(7H)-one; [0251]
8,9-bis(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-o-
ne; [0252]
8-(4-((dimethylamino)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihy-
dro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0253]
8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,-
3,2-de]phthalazin-3(7H)-one; [0254]
8,9-bis(3-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]p-
hthalazin-3(7H)-one; [0255]
9-(3-((cyclopropylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3-
,2-de]phthalazin-3(7H)-one; [0256]
8-(3-((dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2--
de]phthalazin-3(7H)-one; [0257]
8-(3-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]ph-
thalazin-3(7H)-one; [0258]
8-(4-(azetidin-1-ylmethyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrid-
o[4,3,2-de]phthalazin-3(7H)-one; [0259]
5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydr-
o-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0260]
9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-d-
e]phthalazin-3(7H)-one; [0261]
8-(4-((dimethylamino)methyl)phenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,-
9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0262]
8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-
-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0263]
8-(4-fluorophenyl)-9-methyl-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydr-
o-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0264]
8-(4-fluorophenyl)-9-(1,4,5-trimethyl-1H-imidazol-2-yl)-8,9-dihydro-2H-py-
rido[4,3,2-de]phthalazin-3(7H)-one; [0265]
8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,3-triazol-4-yl)-8,9-dihydro-2H-pyri-
do[4,3,2-de]phthalazin-3(7H)-one; [0266]
9-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3-
,2-de]phthalazin-3(7H)-one; [0267]
9-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-8-(4-fluorophenyl)-8,9-dihydro-2H--
pyrido[4,3,2-de]phthalazin-3(7H)-one; [0268]
8-(4-chlorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,-
3,2-de]phthalazin-3(7H)-one; [0269]
9-(1-methyl-1H-imidazol-2-yl)-8-(4-(trifluoromethyl)phenyl)-8,9-dihydro-2-
H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0270]
8-(4-fluorophenyl)-9-(thiazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthal-
azin-3(7H)-one; [0271]
9-(1-ethyl-1H-imidazol-2-yl)-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3-
,2-de]phthalazin-3(7H)-one; [0272]
8-(4-((4-ethyl-3-methylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-
-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0273]
8-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydr-
o-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0274]
9-(4-fluorophenyl)-8-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-8,9-dihyd-
ro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0275]
9-(4-fluorophenyl)-8-(4-(piperazin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyri-
do[4,3,2-de]phthalazin-3(7H)-one; [0276]
9-(4-fluorophenyl)-8-(4-((3-methylpiperazin-1-yl)methyl)phenyl)-8,9-dihyd-
ro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0277]
9-(4-fluorophenyl)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyr-
ido[4,3,2-de]phthalazin-3(7H)-one; [0278]
9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;
[0279]
8-(4-Fluorophenyl)-9-(4-methyl-4H-1,2,4-triazol-3-yl)-8,9-dihydro-2H-pyri-
do[4,3,2-de]phthalazin-3(7H)-one; [0280]
8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyri-
do[4,3,2-de]phthalazin-3(7H)-one; [0281]
8-(4-fluorophenyl)-9-(1-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-8,9-dihydro-
-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0282]
5-chloro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3-
,2-de]phthalazin-3(7H)-one; [0283]
8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(4-fluorophenyl)-8,9-dihyd-
ro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0284]
8,9-bis(4-((dimethylamino)methyl)phenyl)-5-fluoro-8,9-dihydro-2H-pyrido[4-
,3,2-de]phthalazin-3(7H)-one; [0285]
8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-phenyl-8,9-dihydro-2H-pyri-
do[4,3,2-de]phthalazin-3(7H)-one; [0286]
8-(4-((3,4-dimethylpiperazin-1-yl)methyl)phenyl)-9-(4-fluorophenyl)-8,9-d-
ihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0287]
8-(4-((3,5-dimethylpiperazin-1-yl)methyl)phenyl)-9-(4-fluorophenyl)-8,9-d-
ihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0288]
9-phenyl-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2--
de]phthalazin-3(7H)-one; [0289]
9-phenyl-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2--
de]phthalazin-3(7H)-one; [0290]
9-(1-methyl-1H-imidazol-2-yl)-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-8,9-dih-
ydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0291]
9-(4-fluorophenyl)-8-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,-
3,2-de]phthalazin-3(7H)-one; [0292]
9-(4-fluorophenyl)-8-(quinolin-6-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phtha-
lazin-3(7H)-one; [0293]
8-(4-((dimethylamino)methyl)phenyl)-9-p-tolyl-8,9-dihydro-2H-pyrido[4,3,2-
-de]phthalazin-3(7H)-one; [0294]
9-(4-chlorophenyl)-8-(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyr-
ido[4,3,2-de]phthalazin-3(7H)-one; [0295]
8-(4-((dimethylamino)methyl)phenyl)-9-(4-methoxyphenyl)-8,9-dihydro-2H-py-
rido[4,3,2-de]phthalazin-3(7H)-one; [0296]
8-(4-((diethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-d-
e]phthalazin-3(7H)-one; [0297]
8-(4-((diethylamino)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyri-
do[4,3,2-de]phthalazin-3(7H)-one; [0298]
9-(4-chlorophenyl)-8-(4-((diethylamino)methyl)phenyl)-8,9-dihydro-2H-pyri-
do[4,3,2-de]phthalazin-3(7H)-one; [0299]
(E)-6-fluoro-4-((1-methyl-1H-imidazol-2-yl)methyleneamino)isobenzofuran-1-
(3H)-one; [0300]
5-fluoro-9-(4-fluorophenyl)-8-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H--
pyrido[4,3,2-de]phthalazin-3(7H)-one; [0301]
8-(4-((dimethylamino)methyl)phenyl)-9-(4-ethylphenyl)-8,9-dihydro-2H-pyri-
do[4,3,2-de]phthalazin-3(7H)-one; [0302]
8-(4-((dimethylamino)methyl)phenyl)-9-(4-isopropylphenyl)-8,9-dihydro-2H--
pyrido[4,3,2-de]phthalazin-3(7H)-one;
[0303]
8-(4-((dimethylamino)methyl)phenyl)-9-(4-(trifluoromethyl)phenyl)--
8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0304]
8-(4-((diethylamino)methyl)phenyl)-9-p-tolyl-8,9-dihydro-2H-pyrido[4,3,2--
de]phthalazin-3(7H)-one; [0305]
9-(4-fluorophenyl)-8-(4-(1-methylpyrrolidin-2-yl)phenyl)-8,9-dihydro-2H-p-
yrido[4,3,2-de]phthalazin-3(7H)-one; [0306]
9-(4-fluorophenyl)-8-(4-(pyrrolidin-2-yl)phenyl)-8,9-dihydro-2H-pyrido[4,-
3,2-de]phthalazin-3(7H)-one; [0307]
8-(4-fluorophenyl)-9-methyl-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H--
pyrido[4,3,2-de]phthalazin-3(7H)-one; [0308]
9-(4-fluorophenyl)-8-(1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]ph-
thalazin-3(7H)-one; [0309]
5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrid-
o[4,3,2-de]phthalazin-3(7H)-one; [0310]
9-(4-fluorophenyl)-9-hydroxy-8-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-
-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0311]
(8S,9R)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-py-
rido[4,3,2-de]phthalazin-3(7H)-one; [0312]
(8R,9S)-5-fluoro-9-(1-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-py-
rido[4,3,2-de]phthalazin-3(7H)-one; [0313]
(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dih-
ydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0314]
(8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dih-
ydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0315]
(8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-p-
yrido[4,3,2-de]phthalazin-3(7H)-one; [0316]
(8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-p-
yrido[4,3,2-de]phthalazin-3(7H)-one; [0317]
(8S,9R)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro--
2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0318]
(8R,9S)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8-phenyl-8,9-dihydro--
2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0319]
(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,-
9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0320]
(8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,-
9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0321]
(8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-
-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0322]
(8R,9S)-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-
-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; [0323]
(8S,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-
-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;
and [0324]
(8R,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9-(1-methyl-1-
H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one;
[0325] or a pharmaceutical acceptable salt, solvate or prodrug
therefore.
[0326] In some embodiments, provided herein is a pharmaceutical
composition comprising of a compound of Formula (I), (IA) or (II)
or stereoisomers, or a pharmaceutically acceptable salt, a
pharmaceutically acceptable solvate, pharmaceutically acceptable
prodrug thereof and a pharmaceutically acceptable carrier,
excipient, binder or diluent.
[0327] Certain embodiments provide a method of inhibiting PARP in a
subject having a disease, disorder, or condition associated with a
PTEN deficiency recognized to be in need of such treatment
comprising administering to the subject a therapeutically
acceptable amount of a compound of Formula (I), (IA) or (II) or a
therapeutically acceptable salt thereof.
[0328] In one aspect is a method of inhibiting
poly(ADP-ribose)polymerase (PARP) in a subject having a disease,
disorder, or condition associated with a PTEN deficiency comprising
administering to the subject a therapeutically effective amount of
a compound of Formula (I), (IA) or Formula (II).
[0329] In still another aspect is a method of treating a disease,
disorder or condition associated with a PTEN deficiency which is
ameliorated by the inhibition of PARP comprising administering to a
subject in need of treatment a therapeutically effective amount of
a compound of Formula (I), (IA) or Formula (II). In certain
embodiments, the disease, disorder or condition is related to
Cowden Syndrome. In other embodiments, the disease, disorder or
condition is related to Bannayan-Riley-Ruvalcaba syndrome. In still
other embodiments, the disease, disorder or condition is
Lhermitte-Duclos disease.
[0330] In certain aspects, provided herein are methods for the
treatment of a cancer associated with a PTEN deficiency, comprising
administering to a subject in need of treatment a
therapeutically-effective amount of a compound of Formula (I), (IA)
or (II). In certain embodiments, the cancer cells have a PTEN
deficient phenotype. In certain embodiments, the cancer is
endometrial carcinoma, glioblastoma (glioblastoma
multiforme/anaplastic astrocytoma), prostate cancer, renal cancer,
small cell lung carcinoma, meningioma, head and neck cancer,
thyroid cancer, bladder cancer, colorectal cancer, breast cancer or
melanoma.
[0331] In certain other aspects, provided herein are methods of
treating a cancer associated with a PTEN deficiency wherein one or
more cancer cells have an abrogated or reduced ability to control
the phosphoinositide 3-kinase signaling pathway, comprising
administering to a subject in need of treatment a therapeutically
effective amount of a compound of Formula (I), (IA) or Formula
(II). In certain embodiments, the cancer comprises one or more
cancer cells having a reduced or abrogated ability to control the
phosphoinositide 3-kinase signaling pathway for regulation of cell
growth relative to normal cells.
[0332] In yet another aspect is a method of treating a cancer
associated with a PTEN deficiency wherein one or more cancer cells
is deficient in Homologous Recombination (HR) dependent DNA double
strand break (DSB) repair pathway, comprising administering to a
subject in need of treatment a therapeutically effective amount of
a compound of Formula (I), (IA) or Formula (II). In certain
embodiments the cancer comprises one or more cancer cells having a
reduced or abrogated ability to repair DNA DSB by HR relative to
normal cells. In a further embodiment the subject is heterozygous
for a mutation in a gene encoding a component of the HR dependent
DNA DSB repair pathway. In certain embodiments, one or more cancer
cells have a RAD51 deficient phenotype. In yet another embodiment,
the cancer cells are deficient in RAD51. In yet another embodiment,
the subject is heterozygous for a mutation in RAD51. In another
embodiment, the cancer cells have a BRCA1 or BRCA2 deficient
phenotype. In yet another embodiment, the cancer cells are
deficient in BRCA1 or BRCA2. In yet another embodiment, the subject
is heterozygous for a mutation in BRCA1 and/or BRCA2. In yet a
further embodiment the subject is heterozygous for a mutation in
PTEN.
[0333] In some embodiments, the method of treatment of a cancer
includes treatment of endometrial carcinoma, glioblastoma
(glioblastoma multiforme/anaplastic astrocytoma), prostate cancer,
renal cancer, small cell lung carcinoma, meningioma, head and neck
cancer, thyroid cancer, bladder cancer, colorectal cancer, breast
cancer or melanoma. In some embodiments, the method of treatment of
a cancer further includes administration of ionizing radiation or a
chemotherapeutic agent.
[0334] In some embodiments, provided herein is a method for the
treatment of a cancer associated with a PTEN deficiency, comprising
administering to a subject in need of treatment a
therapeutically-effective amount of a compound of Formula (I), (IA)
or (II) in combination with ionizing radiation or one or more
chemotherapeutic agents. In some embodiments, the compound
described herein is administered simultaneously with ionizing
radiation or one or more chemotherapeutic agents. In other
embodiments, the compound described herein is administered
sequentially with ionizing radiation or one or more
chemotherapeutic agents.
[0335] In one embodiment the compound of Formula (I), (IA) or
Formula (II) is administered simultaneously with ionizing
radiation, one or more chemotherapeutic agents, or a combination
thereof. In another embodiment the compound of Formula (I), (IA) or
Formula (II) is administered sequentially with ionizing radiation,
one or more chemotherapeutic agents, or a combination thereof
[0336] In one aspect is the use of a compound of Formula (I), (IA)
or Formula (II) in the formulation of a medicament for the
treatment of a poly(ADP-ribose)polymerase mediated disease or
condition associated with a PTEN deficiency.
[0337] Certain embodiments provide a method of potentiation of
cytotoxic cancer therapy in a subject in recognized need of such
treatment comprising administering to the subject a therapeutically
acceptable amount of a compound of Formula (I), (IA) or (II) or a
therapeutically acceptable salt thereof.
Certain embodiments provide a method of treating endometrial
carcinoma, glioblastoma (glioblastoma multiforme/anaplastic
astrocytoma), prostate cancer, renal cancer, small cell lung
carcinoma, meningioma, head and neck cancer, thyroid cancer,
bladder cancer, colorectal cancer, breast cancer or melanoma in a
subject in recognized need of such treatment comprising
administering to the subject a therapeutically acceptable amount of
a compound of Formula (I), (IA) or (II) or therapeutically
acceptable salt thereof.
[0338] Certain embodiments provide a use of a compound of Formula
(I), (IA) or (II) or a therapeutically acceptable salt thereof, to
prepare a medicament for inhibiting the PARP enzyme in a subject
having a disease or disorder associated with a PTEN deficiency
recognized to be in need of such treatment.
[0339] Certain embodiments provide a use of a compound of Formula
(I), (IA) or (II) or a therapeutically acceptable salt thereof, to
prepare a medicament for inhibiting tumor growth in a subject
having a disease or disorder associated with a PTEN deficiency
recognized to be in need of such treatment.
[0340] Certain embodiments provide a use of a compound of Formula
(I), (IA) or (II) or a therapeutically acceptable salt thereof, to
prepare a medicament for treating cancer in a subject having a
disease or disorder associated with a PTEN deficiency recognized to
be in need of such treatment.
[0341] Certain embodiments provide a use of a compound of Formula
(I), (IA) or (II) or a therapeutically acceptable salt thereof, to
prepare a medicament for treating certain cancers including, but
not limited to, endometrial carcinoma, glioblastoma (glioblastoma
multiforme/anaplastic astrocytoma), prostate cancer, renal cancer,
small cell lung carcinoma, meningioma, head and neck cancer,
thyroid cancer, bladder cancer, colorectal cancer, breast cancer or
melanoma in a subject in recognized need of such treatment.
[0342] Certain embodiments provide a use of a compound of Formula
(I), (IA) or (II) or a therapeutically acceptable salt thereof, to
prepare a medicament for potentiation of cytotoxic cancer therapy
in a subject in recognized need of such treatment comprising
administering to the subject a therapeutically acceptable amount of
a compound of Formula (I), (IA) or (II) or a therapeutically
acceptable salt thereof
[0343] Articles of manufacture, comprising packaging material, a
compound provided herein that is effective for modulating the
activity of the enzyme poly(ADP-ribose)polymerase, or for
treatment, prevention or amelioration of one or more symptoms of a
disease or condition associated with a PTEN deficiency, wherein the
compound is packaged within the packaging material, and wherein the
label indicates that the compound, or pharmaceutically acceptable
salt, pharmaceutically acceptable N-oxide, pharmaceutically active
metabolite, pharmaceutically acceptable prodrug, or
pharmaceutically acceptable solvate thereof, or a pharmaceutical
composition comprising such a compound is used for modulating the
activity of poly(ADP-ribose)polymerase, or for treatment,
prevention or amelioration of one or more symptoms of a disease or
condition associated with a PTEN deficiency are provided.
[0344] Any combination of the groups described above for the
various variables is contemplated herein.
[0345] In one embodiment, disclosed herein is a pharmaceutical
composition comprising a compound, pharmaceutically acceptable
salt, pharmaceutically acceptable N-oxide, pharmaceutically active
metabolite, pharmaceutically acceptable prodrug, or
pharmaceutically acceptable solvate of any of the compounds
disclosed herein. In some embodiments, the pharmaceutical
compositions further comprises a pharmaceutically acceptable
diluent, excipient or binder. In certain embodiments, the
pharmaceutical composition further comprises a second
pharmaceutically active ingredient.
[0346] In one embodiment, the disease or condition associated with
a PTEN deficiency in a patient, or the PTEN-deficient dependent
disease or condition in a patient is cancer or a non-cancerous
disorder. In some embodiments, the disease or condition is
iatrogenic.
[0347] In some embodiments are methods for reducing/inhibiting the
activity of PARP in a subject having a disease or disorder
associated with a PTEN deficiency that include administering to the
subject at least once an effective amount of a compound described
herein.
[0348] Certain embodiments provided herein are methods for
modulating, including reducing and/or inhibiting the activity of
PARP, directly or indirectly, in a subject having a disease or
disorder associated with a PTEN deficiency comprising administering
to the subject at least once an effective amount of at least one
compound described herein.
[0349] In further embodiments are methods for treating diseases or
conditions associated with a PTEN deficiency, comprising
administering to the subject at least once an effective amount of
at least one compound described herein.
[0350] Some embodiments include the use of a compound described
herein in the manufacture of a medicament for treating a disease or
condition associated with a PTEN deficiency in a subject in which
the PTEN deficiency contributes to the pathology and/or symptoms of
the disease or condition.
[0351] In any of the aforementioned embodiments are further
embodiments in which administration is enteral, parenteral, or
both, and wherein:
[0352] (a) the effective amount of the compound is systemically
administered to the subject;
[0353] (b) the effective amount of the compound is administered
orally to the subject;
[0354] (c) the effective amount of the compound is intravenously
administered to the subject;
[0355] (d) the effective amount of the compound administered by
inhalation;
[0356] (e) the effective amount of the compound is administered by
nasal administration;
[0357] (f) the effective amount of the compound is administered by
injection to the subject;
[0358] (g) the effective amount of the compound is administered
topically (dermal) to the subject;
[0359] (h) the effective amount of the compound is administered by
ophthalmic administration; and/or
[0360] (i) the effective amount of the compound is administered
rectally to the subject.
[0361] In any of the aforementioned embodiments are further
embodiments that include single administrations of the effective
amount of the compound, including further embodiments in which the
compound is administered to the subject (i) once; (ii) multiple
times over the span of one day; (iii) continually; or (iv)
continuously.
[0362] In any of the aforementioned embodiments are further
embodiments that include multiple administrations of the effective
amount of the compound, including further embodiments wherein:
[0363] (i) the compound is administered in a single dose;
[0364] (ii) the time between multiple administrations is every 6
hours;
[0365] (iii) the compound is administered to the subject every 8
hours.
[0366] In further or alternative embodiments, the method includes a
drug holiday, wherein the administration of the compound is
temporarily suspended or the dose of the compound being
administered is temporarily reduced; at the end of the drug
holiday, dosing of the compound is resumed. In some embodiments,
the length of the drug holiday varies from 2 days to 1 year.
[0367] In any of the aforementioned embodiments involving the
treatment of proliferative disorders, including cancer, are further
embodiments that include administering at least one additional
agent selected from among alemtuzumab, arsenic trioxide,
asparaginase (pegylated or non-), bevacizumab, cetuximab,
trastuzumab, platinum-based compounds such as cisplatin,
cladribine, daunorubicin/doxorubicin/idarubicin, irinotecan,
fludarabine, 5-fluorouracil, gemcitabine, toptecan,
cyclophosphamide, gemtuzumab, methotrexate, paclitaxel
(Taxol.RTM.), temozolomide, thioguanine, and classes of drugs
including hormones (an antiestrogen, an antiandrogen, or
gonadotropin releasing hormone analogues, interferons such as, for
example, alpha interferon, nitrogen mustards such as, for example,
busulfan, melphalan or mechlorethamine, retinoids such as, for
example, tretinoin, topoisomerase inhibitors such as, for example,
irinotecan or topotecan, tyrosine kinase inhibitors such as, for
example, gefitinib, erlotinib or imatinib, mTOR inhibitors such as,
for example temsirolimus or everolimus and agents to treat signs or
symptoms induced by such therapy including allopurinol, filgrastim,
granisetron/ondansetron/palonosetron, and/or dronabinol.
[0368] Other objects, features and advantages of the compounds,
methods and compositions described herein will become apparent from
the following description. It should be understood, however, that
the description and the specific examples, while indicating
specific embodiments, are given by way of illustration only, since
various changes and modifications within the spirit and scope of
the present description will become apparent from this detailed
description.
[0369] Described herein are compounds, methods of making such
compounds, pharmaceutical compositions and medicaments that include
such compounds, and methods of using such compounds to treat or
prevent diseases or conditions associated with a PTEN
deficiency.
[0370] In certain embodiments, PARP inhibitors, such as those of
Formula (I), (IA) or (II), have utility in: (a) preventing or
inhibiting poly(ADP-ribose) chain formation by, e.g., inhibiting
the activity of cellular PARP (PARP-1 and/or PARP-2); (b) treating
diseases or conditions associated with PTEN deficiency including,
but not limited to, Cowden's Syndrome, Lhermitte-Duclos disease or
Bannayan-Riley-Ruvalcaby syndrome; cancer or other proliferative
disorders including, but not limited to, glioblastoma, endometrial
carcinoma, melanoma, prostate cancer, colorectal cancer, breast
cancer, and bladder cancers; (c) use as an adjunct in cancer
therapy or for potentiating tumor cells for treatment with ionizing
radiation and/or chemotherapeutic agents.
[0371] In specific embodiments, compounds provided herein, such as,
for example, Formula (I), (IA) or (II), are used in anti-cancer
combination therapies (or as adjuncts) along with alkylating
agents, such as methyl methanesulfonate (MMS), temozolomide and
dacarbazine (DTIC), also with topoisomerase-1 inhibitors like
Topotecan, Irinotecan, Rubitecan, Exatecan, Lurtotecan, Gimetecan,
Diflomotecan (homocamptothecins); as well as 7-substituted
non-silatecans; the 7-silyl camptothecins, BNP 1350; and
non-camptothecin topoisomerase-I inhibitors such as
indolocarbazoles also dual topoisomerase-I and II inhibitors like
the benzophenazines, XR 11576/MLN 576 and benzopyridoindoles. In
certain embodiments, such combinations are given, for example, as
intravenous preparations or by oral administration as dependent on
the method of administration for the particular agent.
[0372] In some embodiments, PARP inhibitors, such as, for example,
compounds of Formula (I), (IA) or (II), are used in the treatment
of disease or disorder associated with a PTEN deficiency
ameliorated by the inhibition of PARP, which includes administering
to a subject in need of treatment a therapeutically-effective
amount of a compound provided herein, and in one embodiment in the
form of a pharmaceutical composition. In certain embodiments, PARP
inhibitors, such as, for example, compounds of Formula (I), (IA) or
(II), are used in the treatment of cancer, which includes
administering to a subject in need of treatment a
therapeutically-effective amount of a compound provided herein in
combination, and in one embodiment in the form of a pharmaceutical
composition, simultaneously or sequentially with radiotherapy
(ionizing radiation) or chemotherapeutic agents.
[0373] In certain embodiments, PARP inhibitors, such as, for
example, compounds of Formula (I), (IA) or (II), are used in the
preparation of a medicament for the treatment of cancer associated
with a PTEN deficiency which is deficient in Homologous
Recombination (HR) dependent DNA double strand break (DSB) repair
activity, or in the treatment of a patient with a cancer which is
deficient in HR dependent DNA DSB repair activity, which includes
administering to said patient a therapeutically-effective amount of
the compound.
[0374] The HR dependent DNA DSB repair pathway repairs
double-strand breaks (DSBs) in DNA via homologous mechanisms to
reform a continuous DNA helix. The components of the HR dependent
DNA DSB repair pathway include, but are not limited to, ATM
(NM.sub.--000051), RAD51 (NM.sub.--002875), RAD51L1
(NM.sub.--002877), RAD51C (NM.sub.--002876), RAD51L3
(NM.sub.--002878), DMC1 (NM.sub.--007068), XRCC2 (NM.sub.--005431),
XRCC3 (NM.sub.--005432), RAD52 (NM.sub.--002879), RAD54L
(NM.sub.--003579), RAD54B (NM.sub.--012415), BRCA1
(NM.sub.--007295), BRCA2 (NM.sub.--000059), RAD50
(NM.sub.--005732), MRE11A (NM.sub.--005590) and NBS1
(NM.sub.--002485). Other proteins involved in the HR dependent DNA
DSB repair pathway include regulatory factors such as EMSY. HR
components are also described in Wood, et al., Science, 291,
1284-1289 (2001), which is hereby incorporated by reference for
such disclosure. K. K. Khanna and S. P. Jackson, Nat. Genet. 27(3):
247-254 (2001); and Hughes-Davies, et al., Cell, 115, pp 523-535
are also incorporated herein by reference for such disclosure.
[0375] In some embodiments, a cancer associated with a PTEN
deficiency which is deficient in HR dependent DNA DSB repair
includes one or more cancer cells which have a reduced or abrogated
ability to repair DNA DSBs through that pathway, relative to normal
cells, i.e. the activity of the HR dependent DNA DSB repair pathway
are reduced or abolished in the one or more cancer cells.
[0376] In certain embodiments, the activity of one or more
components of the HR dependent DNA DSB repair pathway is abolished
in the one or more cancer cells of an individual having a cancer
which is deficient in HR dependent DNA DSB repair. Components of
the HR dependent DNA DSB repair pathway include the components
listed above.
[0377] In some embodiments, the cancer cells have a PTEN deficient
phenotype, i.e., PTEN activity is reduced or abolished in the
cancer cells. In certain embodiments, cancer cells with this
phenotype are deficient in PTEN, i.e., expression and/or activity
of PTEN is reduced or abolished in the cancer cells, for example by
means of mutation or polymorphism in the encoding nucleic acid, or
by means of amplification, mutation or polymorphism in a gene
encoding a regulatory factor specific for PTEN.
[0378] In some embodiments, the cancer cells have a BRCA1 and/or a
BRCA2 deficient phenotype, i.e., BRCA1 and/or BRCA2 activity is
reduced or abolished in the cancer cells. In certain embodiments,
cancer cells with this phenotype are deficient in BRCA1 and/or
BRCA2, i.e., expression and/or activity of BRCA1 and/or BRCA2 is
reduced or abolished in the cancer cells, for example by means of
mutation or polymorphism in the encoding nucleic acid, or by means
of amplification, mutation or polymorphism in a gene encoding a
regulatory factor, for example the EMSY gene which encodes a BRCA2
regulatory factor or by an epigenetic mechanism such as gene
promoter methylation.
[0379] In certain instances, mutations and polymorphisms associated
with cancer are detected at the nucleic acid level by detecting the
presence of a variant nucleic acid sequence or at the protein level
by detecting the presence of a variant (i.e. a mutant or allelic
variant) polypeptide.
DEFINITIONS
[0380] Unless defined otherwise, all technical and scientific terms
used herein have the standard meaning pertaining to the claimed
subject matter belongs. In the event that there is a plurality of
definitions for terms herein, those in this section prevail. Where
reference is made to a URL or other such identifier or address, it
understood that such identifiers can change and particular
information on the internet can come and go, but equivalent
information can be found by searching the internet. Reference
thereto evidences the availability and public dissemination of such
information.
[0381] It is to be understood that the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of any subject matter
claimed. In this application, the use of the singular includes the
plural unless specifically stated otherwise. 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. In this application, the use of
"or" means "and/or" unless stated otherwise. Furthermore, use of
the term "including" as well as other forms, such as "include",
"includes," and "included," is not limiting.
[0382] Unless otherwise indicated, conventional methods of mass
spectroscopy, NMR, HPLC, protein chemistry, biochemistry,
recombinant DNA techniques and pharmacology are employed. Unless
specific definitions are provided, the standard nomenclature
employed in connection with, and the standard laboratory procedures
and techniques of, analytical chemistry, synthetic organic
chemistry, and medicinal and pharmaceutical chemistry are employed.
In certain instances, standard techniques are used for chemical
syntheses, chemical analyses, pharmaceutical preparation,
formulation, and delivery, and treatment of patients. In certain
embodiments, standard techniques are used for recombinant DNA,
oligonucleotide synthesis, and tissue culture and transformation
(e.g., electroporation, lipofection). In some embodiments,
reactions and purification techniques are performed e.g., using
kits of manufacturer's specifications or as commonly accomplished
or as described herein.
[0383] As used throughout this application and the appended claims,
the following terms have the following meanings:
[0384] The term "alkenyl" as used herein, means a straight,
branched chain, or cyclic (in which case, it would also be known as
a "cycloalkenyl") hydrocarbon containing from 2-10 carbons and
containing at least one carbon-carbon double bond formed by the
removal of two hydrogens. In some embodiments, depending on the
structure, an alkenyl group is a monoradical or a diradical (i.e.,
an alkenylene group). In some embodiments, alkenyl groups are
optionally substituted. Illustrative examples of alkenyl include,
but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl,
3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl,
and 3-cecenyl.
[0385] The term "alkoxy" as used herein, means an alkyl group, as
defined herein, appended to the parent molecular moiety through an
oxygen atom. Illustrative examples of alkoxy include, but are not
limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,
tert-butoxy, pentyloxy, and hexyloxy.
[0386] The term "alkyl" as used herein, means a straight, branched
chain, or cyclic (in this case, it would also be known as
"cycloalkyl") hydrocarbon containing from 1-10 carbon atoms.
Illustrative examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,
2,2-dimethylpentyl, 2,3-dimethylhexyl, n-heptyl, n-octyl, n-nonyl,
and n-decyl.
[0387] The term "C.sub.1-C.sub.6-alkyl" as used herein, means a
straight, branched chain, or cyclic (in this case, it would also be
known as "cycloalkyl") hydrocarbon containing from 1-6 carbon
atoms. Representative examples of alkyl include, but are not
limited to, methyl, ethyl, n-propyl, iso-propyl, cyclopyl, n-butyl,
sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl,
cyclopentyl, and n-hexyl.
[0388] The term "cycloalkyl" as used herein, means a monocyclic or
polycyclic radical that contains only carbon and hydrogen, and
includes those that are saturated, partially unsaturated, or fully
unsaturated. Cycloalkyl groups include groups having from 3 to 10
ring atoms. Representative examples of cyclic include but are not
limited to, the following moieties:
##STR00035##
In some embodiments, depending on the structure, a cycloalkyl group
is a monoradical or a diradical (e.g., a cycloalkylene group).
[0389] The term "cycloalkyl groups" as used herein refers to groups
which are optionally substituted with 1, 2, 3, or 4 substituents
selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl,
alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen,
hydroxyl, hydroxyalkylene, mercapto, oxo, --NR.sub.AR.sub.A, and
(NR.sub.AR.sub.B)carbonyl.
[0390] The term "cycloalkylalkyl" as used herein, means a
cycloalkyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of cycloalkylalkyl include, but are not
limited to, cyclopropylmethyl, 2-cyclobutylethyl,
cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.
[0391] The term "carbocyclic" as used herein, refers to a compound
which contains one or more covalently closed ring structures, and
that the atoms forming the backbone of the ring are all carbon
atoms
[0392] The term "carbocycle" as used herein, refers to a ring,
wherein each of the atoms forming the ring is a carbon atom.
Carbocylic rings include those formed by three, four, five, six,
seven, eight, nine, or more than nine carbon atoms. Carbocycles are
optionally substituted.
[0393] The term "alkoxyalkyl" as used herein, means at least one
alkoxy group, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Illustrative
examples of alkoxyalkyl include, but are not limited to,
2-methoxyethyl, 2-ethoxyethyl, tert-butoxyethyl and
methoxymethyl.
[0394] The term "alkoxycarbonyl" as used herein, means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Illustrative examples
of alkoxycarbonyl include, but are not limited to, methoxycarbonyl,
ethoxycarbonyl, and tert-butoxycarbonyl.
[0395] The term "alkoxycarbonylalkyl" as used herein, means an
alkoxycarbonyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
[0396] The term "alkylcarbonyl" as used herein, means an alkyl
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Illustrative examples
of alkylcarbonyl include, but are not limited to, acetyl,
1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and
1-oxopentyl.
[0397] The term "alkylcarbonyloxy" as used herein, means an
alkylcarbonyl group, as defined herein, appended to the parent
molecular moiety through an oxygen atom. Illustrative examples of
alkylcarbonyloxy include, but are not limited to, acetyloxy,
ethylcarbonyloxy, and tert-butylcarbonyloxy.
[0398] The term "alkylthio" or "thioalkoxy" as used herein, means
an alkyl group, as defined herein, appended to the parent molecular
moiety through a sulfur atom. Illustrative examples of alkylthio
include, but are not limited to, methylthio, ethylthio, butylthio,
tert-butylthio, and hexylthio.
[0399] The term "alkylthioalkyl" as used herein, means an alkylthio
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Illustrative examples of
alkylthioalkyl include, but are not limited to, methylthiomethyl,
2-(ethylthio)ethyl, butylthiomethyl, and hexylthioethyl.
[0400] The term "alkynyl" as used herein, means a straight,
branched chain hydrocarbon containing from 2-10 carbons and
containing at least one carbon-carbon triple bond. In some
embodiments, alkynyl groups are optionally substituted.
Illustrative examples of alkynyl include, but are not limited to,
acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and
1-butynyl.
[0401] The term "aromatic" as used herein, refers to a planar ring
having a delocalized .pi.-electron system containing 4n+2.pi.
electrons, where n is an integer. In some embodiments, aromatic
rings are formed by five, six, seven, eight, nine, or more than
nine atoms. In other embodiments, aromatics are optionally
substituted. The term includes monocyclic or fused-ring polycyclic
(i.e., rings which share adjacent pairs of carbon atoms)
groups.
[0402] The term "aryl" as used herein, refers to an aromatic ring
wherein each of the atoms forming the ring is a carbon atom. In
some embodiments, aryl rings are formed by five, six, seven, eight,
nine, or more than nine carbon atoms. Examples of aryl groups
include, but are not limited to phenyl, naphthalenyl,
phenanthrenyl, anthracenyl, fluorenyl, and indenyl.
[0403] In some embodiments, the term "aryl" as used herein means an
aryl group that is optionally substituted with one; two, three,
four or five substituents independently selected from the group
consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl,
alkynyl, carbonyl, cyano, formyl, haloalkoxy, haloalkyl, halogen,
hydroxyl, hydroxyalkylene, mercapto, nitro, --NR.sub.AR.sub.A, and
(NR.sub.AR.sub.B)carbonyl.
[0404] The term "arylalkyl" as used herein, means an aryl group, as
defined herein, appended to the parent molecular moiety through an
alkyl group, as defined herein. Illustrative examples of arylalkyl
include, but are not limited to benzyl, 2-phenylethyl,
-phenylpropyl, 1-methyl-3-phenylpropyl, and 2-naphth-2-ylethyl.
[0405] The term "carbonyl" as used herein, means a --C(O)--
group.
[0406] The term "carboxy" as used herein, means a --COOH group.
[0407] The term "cyano" as used herein, means a --CN group.
[0408] The term "formyl" as used herein, means a --C(O)H group.
[0409] The term "halo" or "halogen" as used herein, means a --Cl,
--Br, --I or --F.
[0410] The term "mercapto" as used herein, means a --SH group.
[0411] The term "nitro" as used herein, means a --NO.sub.2
group.
[0412] The term "hydroxy" as used herein, means a --OH group.
[0413] The term "oxo" as used herein, means a .dbd.O group.
[0414] The term "bond" or "single bond" as used herein, refers to a
chemical bond between two atoms, or two moieties when the atoms
joined by the bond are considered to be part of larger
substructure.
[0415] The terms "haloalkyl," "haloalkenyl," "haloalkynyl" and
"haloalkoxy" as used herein, include alkyl, alkenyl, alkynyl and
alkoxy structures in which at least one hydrogen is replaced with a
halogen atom. In certain embodiments in which two or more hydrogen
atoms are replaced with halogen atoms, the halogen atoms are all
the same as one another. In other embodiments in which two or more
hydrogen atoms are replaced with halogen atoms, the halogen atoms
are not all the same as one another. The terms "fluoroalkyl" and
"fluoroalkoxy" include haloalkyl and haloalkoxy groups,
respectively, in which the halo is fluorine. In certain
embodiments, haloalkyls are optionally substituted.
[0416] The term "alkylamine" refers to the --N(alkyl).sub.xH.sub.y
group, where x and y are selected from among x=1, y=1 and x=2, y=0.
In some embodiments, when x=2, the alkyl groups, taken together
with the N atom to which they are attached, optionally form a
cyclic ring system.
[0417] The term "amide" as used herein, is a chemical moiety with
the formula --C(O)NHR or --NHC(O)R, where R is selected from among
hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a
ring carbon) and heterocycloalkyl (bonded through a ring carbon).
In some embodiments, an amide moiety forms a linkage between an
amino acid or a peptide molecule and a compound described herein,
thereby forming a prodrug. In some embodiments, any amine, or
carboxyl side chain on the compounds described herein is
amidified.
[0418] The term "ester" refers to a chemical moiety with formula
--COOR, where R is selected from among alkyl, cycloalkyl, aryl,
heteroaryl (bonded through a ring carbon) and heterocycloalkyl
(bonded through a ring carbon). In some embodiments, any hydroxy,
or carboxyl side chain on the compounds described herein is
esterified.
[0419] The terms "heteroalkyl" "heteroalkenyl" and "heteroalkynyl"
as used herein, include optionally substituted alkyl, alkenyl and
alkynyl radicals in which one or more skeletal chain atoms are
selected from an atom other than carbon, e.g., oxygen, nitrogen,
sulfur, silicon, phosphorus or combinations thereof
[0420] The term "heteroatom" as used herein refers to an atom other
than carbon or hydrogen. Heteroatoms are typically independently
selected from among oxygen, sulfur, nitrogen, silicon and
phosphorus, but are not limited to these atoms. In embodiments in
which two or more heteroatoms are present, the two or more
heteroatoms are all the same as one another, or some or all of the
two or more heteroatoms are each different from the others.
[0421] The term "ring" as used herein, refers to any covalently
closed structure. Rings include, for example, carbocycles (e.g.,
aryls and cycloalkyls), heterocycles (e.g., heteroaryls and
heterocycloalkyls), aromatics (e.g. aryls and heteroaryls), and
non-aromatics (e.g., cycloalkyls and heterocycloalkyls). In some
embodiments, rings are optionally substituted. In some embodiments,
rings form part of a ring system.
[0422] As used herein, the term "ring system" refers to two or more
rings, wherein two or more of the rings are fused. The term "fused"
refers to structures in which two or more rings share one or more
bonds.
[0423] The terms "heteroaryl" or, alternatively, "heteroaromatic"
refers to an aryl group that includes one or more ring heteroatoms
selected from nitrogen, oxygen and sulfur. An N-containing
"heteroaromatic" or "heteroaryl" moiety refers to an aromatic group
in which at least one of the skeletal atoms of the ring is a
nitrogen atom. In some embodiments, the polycyclic heteroaryl group
is fused or non-fused. Illustrative of heteroaryl groups include,
but are not limited to, the following moieties:
##STR00036##
In some embodiments, depending on the structure, a heteroaryl group
is a monoradical or a diradical (i.e., a heteroarylene group).
[0424] The term "heteroaryl" means heteroaryl groups that are
substituted with 0, 1, 2, 3, or 4 substituents independently
selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alynyl,
carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyl,
hydroxyalkylene, mercapto, nitro, --NR.sub.AR.sub.B, and
--(NR.sub.AR.sub.B)carbonyl.
[0425] The term "heteroarylalkyl" as used herein, means a
heteroaryl, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Illustrative
examples of heteroarylalkyl include, but are not limited to,
pyridinylmethyl.
[0426] The term "heterocycloalkyl" or "non-aromatic heterocycle" as
used herein, refers to a non-aromatic ring wherein one or more
atoms forming the ring is a heteroatom. A "heterocycloalkyl" or
"non-aromatic heterocycle" group refers to a cycloalkyl group that
includes at least one heteroatom selected from nitrogen, oxygen and
sulfur. In some embodiments, the radicals are fused with an aryl or
heteroaryl. In some embodiments, heterocycloalkyl rings are formed
by three, four, five, six, seven, eight, nine, or more than nine
atoms. In some embodiments, heterocycloalkyl rings are optionally
substituted. In certain embodiments, heterocycloalkyls contain one
or more carbonyl or thiocarbonyl groups such as, for example, oxo-
and thio-containing groups. Examples of heterocycloalkyls include,
but are not limited to, lactams, lactones, cyclic imides, cyclic
thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran,
tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin,
1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin,
1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide,
succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine,
hydantoin, dihydrouracil, morpholine, trioxane,
hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran,
pyrroline, pyrrolidine, pyrrolidone; pyrrolidione; pyrazoline,
pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole,
1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline,
isoxazolidine, oxazoline, oxazolidine, oxazolidinone; thiazoline,
thiazolidine, and 1,3-oxathiolane. Illustrative examples of
heterocycloalkyl groups, also referred to as non-aromatic
heterocycles, include, but are not limited to
##STR00037##
The term heterocycloalkyl also includes all ring forms of the
carbohydrates, including but not limited to the monosaccharides,
the disaccharides and the oligosaccharides.
[0427] The term "heterocycle" refers to heteroaryl and
heterocycloalkyl used herein, refers to groups containing one to
four heteroatoms each selected from O, S and N, wherein each
heterocycle group has from 4 to 10 atoms in its ring system, and
with the proviso that the ring of said group does not contain two
adjacent 0 or S atoms. Herein, whenever the number of carbon atoms
in a heterocycle is indicated (e.g., C.sub.1-C.sub.6 heterocycle),
at least one other atom (the heteroatom) must be present in the
ring. Designations such as "C.sub.1-C.sub.6 heterocycle" refer only
to the number of carbon atoms in the ring and do not refer to the
total number of atoms in the ring. In some embodiments, it is
understood that the heterocycle ring has additional heteroatoms in
the ring. Designations such as "4-6 membered heterocycle" refer to
the total number of atoms that are contained in the ring (i.e., a
four, five, or six membered ring, in which at least one atom is a
carbon atom, at least one atom is a heteroatom and the remaining
two to four atoms are either carbon atoms or heteroatoms). In some
embodiments, in heterocycles that have two or more heteroatoms,
those two or more heteroatoms are the same or different from one
another. In some embodiments, heterocycles are optionally
substituted. In some embodiments, binding to a heterocycle is at a
heteroatom or via a carbon atom. Heterocycloalkyl groups include
groups having only 4 atoms in their ring system, but heteroaryl
groups must have at least 5 atoms in their ring system. The
heterocycle groups include benzo-fused ring systems. An example of
a 4-membered heterocycle group is azetidinyl (derived from
azetidine). An example of a 5-membered heterocycle group is
thiazolyl. An example of a 6-membered heterocycle group is pyridyl,
and an example of a 10-membered heterocycle group is quinolinyl.
Examples of heterocycloalkyl groups are pyrrolidinyl,
tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,
tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl,
piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl,
azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl,
thiepanyl, oxazepinyl, diazepinyl, thiazepinyl,
1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl,
2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl,
dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,
dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,
3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl
and quinolizinyl. Examples of heteroaryl groups are pyridinyl,
imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,
tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,
isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,
benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,
phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl,
purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl,
benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, and furopyridinyl. In some
embodiments, the foregoing groups, as derived from the groups
listed above, are C-attached or N-attached where such is possible.
For instance, in some embodiments, a group derived from pyrrole is
pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, in
some embodiments, a group derived from imidazole is imidazol-1-yl
or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl
or imidazol-5-yl (all C-attached). The heterocycle groups include
benzo-fused ring systems and ring systems substituted with one or
two oxo (.dbd.O) moieties such as pyrrolidin-2-one. In some
embodiments, depending on the structure, a heterocycle group is a
monoradical or a diradical (i.e., a heterocyclene group).
[0428] The heterocycles described herein are substituted with 0, 1,
2, 3, or 4 substituents independently selected from alkenyl,
alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,
alkylcarbonyloxy, alkylthio, alkylthioalkyl, alynyl, carboxy,
cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyl,
hydroxyalkylene, mercapto, nitro, --NR.sub.AR.sub.B, and
--(NR.sub.AR.sub.B)carbonyl.
[0429] The term "heterocycloalkoxy" refers to a heterocycloalkyl
group, as defined herein, appended to the parent molecular moiety
through an alkoxy group.
[0430] The term "heterocycloalkylthio" refers to a heterocycloalkyl
group, as defined herein, appended to the parent molecular moiety
through an alkylthio group.
[0431] The term "heterocyclooxy" refers to a heterocycloalkyl
group, as defined herein, appended to the parent molecular moiety
through an oxygen atom.
[0432] The term "heterocyclothio" refers to a heterocycloalkyl
group, as defined herein, appended to the parent molecular moiety
through a sulfur atom.
[0433] The term "heteroarylalkoxy" refers to a heteroaryl group, as
defined herein, appended to the parent molecular moiety through an
alkoxy group.
[0434] The term "heteroarylalkylthio" refers to a heteroaryl group,
as defined herein, appended to the parent molecular moiety through
an alkylthio group.
[0435] The term "heteroaryloxy" refers to a heteroaryl group, as
defined herein, appended to the parent molecular moiety through an
oxygen atom.
[0436] The term "heteroarylthio" refers to a heteroaryl group, as
defined herein, appended to the parent molecular moiety through a
sulfur atom.
[0437] In some embodiments, the term "membered ring" embraces any
cyclic structure. The term "membered" is meant to denote the number
of skeletal atoms that constitute the ring. Thus, for example,
cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings and
cyclopentyl, pyrrole, furan, and thiophene are 5-membered
rings.
[0438] The term "non-aromatic 5, 6, 7, 8, 9, 10, 11 or 12-bicyclic
heterocycle" as used herein, means a heterocycloalkyl, as defined
herein, consisting of two carbocyclic rings, fused together at the
same carbon atom (forming a spiro structure) or different carbon
atoms (in which two rings share one or more bonds), having 5 to 12
atoms in its overall ring system, wherein one or more atoms forming
the ring is a heteroatom. Illustrative examples of non-aromatic 5,
6, 7, 8, 9, 10, 11, or 12-bicyclic heterocycle ring include, but
are not limited to, 2-azabicyclo[2.2.1]heptanyl,
7-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[3.2.0]heptanyl,
3-azabicyclo[3.2.0]heptanyl, 4-azaspiro[2.4]heptanyl,
5-azaspiro[2.4]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl,
4-azaspiro[2.5]octanyl, 5-azaspiro[2.5]octanyl,
5-azaspiro[3.4]octanyl, 6-azaspiro[3.4]octanyl,
4-oxa-7-azaspiro[2.5]octanyl, 2-azabicyclo[2.2.2]octanyl,
1,3-diazabicyclo[2.2.2]octanyl, 5-azaspiro[3.5]nonanyl,
6-azaspiro[3.5]nonanyl, 5-oxo-8-azaspiro[3.5]nonanyl,
octahydrocyclopenta[c]pyrrolyl, octahydro-1H-quinolizinyl,
2,3,4,6,7,9a-hexahydro-1H-quinolizinyl,
decahydropyrido[1,2-a]azepinyl, decahydro-1H-pyrido[1,2-a]azocinyl,
1-azabicyclo[2.2.1]heptanyl, 1-azabicyclo[3.3.1]nonanyl,
quinuclidinyl, and 1-azabicyclo[4.4.0]decanyl.
[0439] The term hydroxyalkylene" as used herein, means at least one
hydroxyl group, as defined herein, is appended to the parent
molecular moiety through an alkylene group, as defined herein.
Illustrative examples of hydroxyalkylene include, but not limited
to hydroxymethylene, 2-hydroxy-ethylene, 3-hydroxypropylene and
4-hydroxyheptylene.
[0440] The term "NR.sub.ANR.sub.B" as used herein, means two group,
R.sub.A and R.sub.B, which are appended to the parent molecular
moiety through a nitrogen atom. R.sub.A and R.sub.B are each
independently hydrogen, alkyl, and alkylcarbonyl. Illustrative
examples of NR.sub.AR.sub.B include, but are not limited to, amino,
methylamino, acetylamino, and acetylmethylamino.
[0441] The term "(NR.sub.ANR.sub.B)carbonyl" as used herein, means
a R.sub.AR.sub.B, group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Illustrative examples of (NR.sub.AR.sub.B)carbonyl include, but are
not limited to, aminocarbonyl, (methylamino)carbonyl,
(dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.
[0442] The term "NR.sub.CNR.sub.D" as used herein, means two group,
R.sub.C and R.sub.D, which are appended to the parent molecular
moiety through a nitrogen atom. R.sub.C and R.sub.D are each
independently hydrogen, alkyl, and alkylcarbonyl. Illustrative
examples of NR.sub.CR.sub.D include, but are not limited to, amino,
methylamino, acetylamino, and acetylmethylamino.
[0443] The term "(NR.sub.CNR.sub.D)carbonyl" as used herein, means
a R.sub.CR.sub.D, group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Illustrative examples of (NR.sub.CR.sub.D)carbonyl include, but are
not limited to, aminocarbonyl, (methylamino)carbonyl,
(dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.
[0444] As used herein, the term "mercaptyl" refers to a (alkyl)S--
group.
[0445] As used herein, the term "moiety" refers to a specific
segment or functional group of a molecule. Chemical moieties are
often recognized chemical entities embedded in or appended to a
molecule.
[0446] As used herein, the term "sulfinyl" refers to a
--S(.dbd.O)--R, where R is selected from the group consisting of
alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon)
and heterocycloalkyl (bonded through a ring carbon).
[0447] As used herein, the term "sulfonyl" refers to a
--S(.dbd.O).sub.2--R, where R is selected from the group consisting
of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring
carbon) and heterocycloalkyl (bonded through a ring carbon).
[0448] As used herein, the term "0 carboxy" refers to a group of
formula RC(.dbd.O)O--.
[0449] As used herein, the term "C carboxy" refers to a group of
formula --C(.dbd.O)OR.
[0450] As used herein, the term "acetyl" refers to a group of
formula --C(.dbd.O)CH.sub.3.
[0451] As used herein, the term "trihalomethanesulfonyl" refers to
a group of formula X.sub.3CS(.dbd.O).sub.2-- where X is a
halogen.
[0452] As used herein, the term "isocyanato" refers to a group of
formula --NCO.
[0453] As used herein, the term "thiocyanato" refers to a group of
formula --CNS.
[0454] As used herein, the term "isothiocyanato" refers to a group
of formula --NCS.
[0455] As used herein, the term "S sulfonamido" refers to a group
of formula --S(.dbd.O).sub.2NR.sub.2.
[0456] As used herein, the term "N sulfonamido" refers to a group
of formula RS(.dbd.O).sub.2NH--.
[0457] As used herein, the term "trihalomethanesulfonamido" refers
to a group of formula X.sub.3CS(.dbd.O).sub.2NR--.
[0458] As used herein, the term "O carbamyl" refers to a group of
formula --OC(.dbd.O)NR.sub.2.
[0459] As used herein, the term "N carbamyl" refers to a group of
formula ROC(.dbd.O)NH--.
[0460] As used herein, the term "O thiocarbamyl" refers to a group
of formula --OC(.dbd.S)NR.sub.2.
[0461] As used herein, the term "N thiocarbamyl" refers to a group
of formula ROC(.dbd.S)NH--.
[0462] As used herein, the term "C amido" refers to a group of
formula --C(.dbd.O)NR.sub.2.
[0463] As used herein, the term "N amido" refers to a group of
formula RC(.dbd.O)NH--.
[0464] As used herein, the substituent "R" appearing by itself and
without a number designation refers to a substituent selected from
among from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a
ring carbon) and non-aromatic heterocycle (bonded through a ring
carbon).
[0465] The term "substituted" means that the referenced group is
optionally substituted (substituted or unsubstituted) with one or
more additional group(s) individually and independently selected
from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,
alkoxy, aryloxy, mercapto, alkylthio, arylthio, alkylsulfoxide,
arylsulfoxide, alkylsulfone; arylsulfone; cyano, halo, carbonyl,
thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro,
perhaloalkyl, perfluoroalkyl, silyl, and amino, including mono- and
di-substituted amino groups, and the protected derivatives thereof.
By way of example an optional substituents is L.sub.sR.sub.s,
wherein each L.sub.s is independently selected from a bond, --O--,
--C(.dbd.O)--, --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--, --NH--,
--NHC(O)--, --C(O)NH--, S(.dbd.O).sub.2NH--, --NHS(.dbd.O).sub.2,
--OC(O)NH--, --NHC(O)O--, -(substituted or unsubstituted
C.sub.1-C.sub.6 alkyl), or -(substituted or unsubstituted
C.sub.2-C.sub.6 alkenyl); and each R.sub.s is independently
selected from H, (substituted or unsubstituted lower alkyl),
(substituted or unsubstituted lower cycloalkyl), heteroaryl, or
heteroalkyl.
[0466] The term "protecting group" refers to a removable group
which modifies the reactivity of a functional group, for example, a
hydroxyl, ketone or amine, against undesirable reaction during
synthetic procedures and to be later removed. Examples of
hydroxy-protecting groups include, but not limited to,
methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl,
ethers such as methoxymethyl, and esters including acetyl, benzoyl,
and the like. Examples of ketone protecting groups include, but not
limited to, ketals, oximes, O-substituted oximes for example
O-benzyl oxime, O-phenylthiomethyl oxime, 1-isopropoxycyclohexyl
oxime, and the like. Examples of amine protecting groups include,
but are not limited to, tert-butoxycarbonyl (Boc) and
carbobenzyloxy (Cbz).
[0467] The term "optionally substituted" as defined herein, means
the referenced group is substituted with zero, one or more
substituents as defined herein.
[0468] The term "protected-hydroxy" refers to a hydroxy group
protected with a hydroxy protecting group, as defined above.
[0469] In some embodiments, compounds of the described herein exist
as stereoisomers, wherein asymmetric or chiral centers are present.
Stereoisomers are designated (R) or (S) depending on the
configuration of substituents around the chiral carbon atom. The
term (R) and (S) used herein are configurations as defined in IUPAC
1974 Recommendations for Section E, Fundamental Stereochemistry,
Pure Appl. Chem., (1976), 45:13-30, hereby incorporated by
reference. The embodiments described herein specifically include
the various stereoisomers and mixtures thereof. Stereoisomers
include enantiomers, diastereomers, and mixtures of enantiomers or
diastereomers. In some embodiments, individual stereoisomers of
compounds are prepared synthetically from commercially available
starting materials which contain asymmetric or chiral centers or by
preparation of racemic mixtures followed by resolution. These
methods of resolution are exemplified by (1) attachment of a
mixture of enantiomers to a chiral axillary, separation of the
resulting mixture of diastereomers by recrystallization or
chromatography and liberation of the optically pure product from
the auxiliary or (2) direct separation of the mixture of optical
enantiomers on chiral chromatographic column.
[0470] The methods and formulations described herein include the
use of N-oxides, crystalline forms (also known as polymorphs), or
pharmaceutically acceptable salts of compounds described herein, as
well as active metabolites of these compounds having the same type
of activity. In some situations, compounds exist as tautomers. All
tautomers are included within the scope of the compounds presented
herein. In some embodiments, the compounds described herein exist
in unsolvated as well as solvated forms with pharmaceutically
acceptable solvents such as water, ethanol, and the like. The
solvated forms of the compounds presented herein are also
considered to be disclosed herein.
[0471] Throughout the specification, groups and substituents
thereof are chosen, in certain embodiments, to provide stable
moieties and compounds.
Preparation of Compounds Described Herein
[0472] In certain embodiments, the compounds described herein are
synthesized using any synthetic techniques including standard
synthetic techniques and the synthetic processes described herein.
In specific embodiments, the following synthetic processes are
utilized.
Formation of Covalent Linkages by Reaction of an Electrophile with
a Nucleophile
[0473] 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. In certain embodiments, a functional group on
an organic substance is attached directly, or attached via any
useful spacer or linker as defined below.
TABLE-US-00001 TABLE 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
[0474] 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.
[0475] 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. Carbon nucleophiles, when used in
conjunction with carbon electrophiles, engender new carbon-carbon
bonds between the carbon nucleophile and carbon electrophile.
[0476] 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
heteroatom, e. g, oxygen or nitrogen.
Use of Protecting Groups
[0477] 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. In specific embodiments, more than one protecting group is
utilized. In more specific embodiments, each protective group is
removable by a different process. Protective groups that are
cleaved under totally disparate reaction conditions fulfill the
requirement of differential removal. In various embodiments,
protective groups are removed by acid, base, or hydrogenolysis.
Groups such as trityl, dimethoxytrityl, acetal and
t-butyldimethylsilyl are acid labile and are, in some embodiments,
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. In some embodiments, carboxylic acid and hydroxy reactive
moieties are 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.
[0478] In certain embodiments, carboxylic acid and hydroxy reactive
moieties are blocked with hydrolytically removable protective
groups such as the benzyl group, while, in some embodiments, amine
groups capable of hydrogen bonding with acids are blocked with base
labile groups such as Fmoc. In various embodiments, carboxylic acid
reactive moieties are protected by conversion to simple ester
derivatives as exemplified herein, or they are blocked with
oxidatively-removable protective groups such as
2,4-dimethoxybenzyl, while, in some embodiments, co-existing amino
groups are blocked with fluoride labile silyl carbamates.
[0479] In certain instances, allyl blocking groups are useful in
the presence of acid- and base-protecting groups since the former
are stable. In some embodiments, such groups are subsequently
removed by metal or pi-acid catalysts. For example, in some
embodiments, an allyl-blocked carboxylic acid is deprotected with a
Pd.sup.0-catalyzed reaction in the presence of acid labile t-butyl
carbamate or base-labile acetate amine protecting groups. In some
embodiments, a protecting group is a resin to which a compound or
intermediate is 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.
[0480] In some embodiments, blocking/protecting groups are selected
from, by way of non-limiting example:
##STR00038##
[0481] Other protecting groups are described in Greene and Wuts,
Protective Groups in Organic Synthesis, 3rd Ed., John Wiley &
Sons, New York, N.Y., 1999.
Compounds of Formula (I)
[0482] Preparations of compounds used in the invention are
described in WO2010/017055 which is herein incorporated by
reference in its entirety.
[0483] In certain embodiments, compounds of Formula (I), composing
of Ia to If, are prepared in various ways, as outlined in Synthetic
Schemes 1 and 2. In each scheme, the variables (e.g., R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5, Y, and Z) correspond to the
same definitions as those recited above while R is alkyl and Y' is
the same or different group defined by Y and Z' is the same or
different group defined by Z. In some embodiments, compounds are
synthesized using methodologies analogous to those described below
by the use of appropriate alternative starting materials.
[0484] In certain embodiments, compounds of Formula (Ia, and Ib)
wherein Y is identical to Z are synthesized according to Synthetic
Scheme 1. Thus, the preparation of the intermediate 3 wherein
R.sub.5 is hydrogen is achieved by condensation of
4-aminoisobenzofuran-1(3H)-one 1 with an aldehyde 2 in the presence
of a base preferably alkaline alkoxides in appropriate solvents
such as ethyl acetate or ethyl propionate at either ambient or
elevated temperature. Compounds of Formula Ia wherein R.sub.5 is
hydrogen is prepared by treating the intermediate 3 with hydrazine
hydrate at ambient or elevated temperature. Compounds of Formula Ia
wherein R.sub.5 is alkyl or substituted alkyl is prepared from
compound of Formula Ia wherein R.sub.5 is hydrogen by reductive
amination reaction with R.sub.7--CHO wherein R.sub.7 is alkyl,
substituted alkyl. In some embodiments, the preparation of the
compounds in Formula Ib is accomplished by further modification of
Ia. Through appropriate functional group transformations on the
moiety of Y and Z, one affords the compounds of Formula Ib with
different entities of Y' and Z' at 2- or 3-positions.
##STR00039##
[0485] In certain embodiments, compounds of Formula (Ic, and Id)
are synthesized according to Synthetic Scheme 2. For example, the
intermediate 5 is prepared by condensation of the reagent 1 with an
aldehyde 4 in the presence of water absorbent such sodium sulfate
or magnesium sulfate at elevated temperature. A subsequent
condensation reaction of this intermediate with another aldehyde in
the presence of a base preferably alkaline alkoxides in appropriate
solvents such as ethyl acetate or ethyl propionate at either
ambient or elevated temperature gives the intermediate 6 wherein
R.sub.5 is hydrogen. Compounds of Formula Ic wherein R.sub.5 is
hydrogen is prepared by treating the intermediate 6 with hydrazine
hydrate at ambient or elevated temperature. Compounds of Formula Ic
wherein R.sub.5 is alkyl, substituted alkyl are prepared from
compounds of Formula Ic wherein R.sub.5 is hydrogen by reductive
amination reaction with R.sub.7--CHO wherein R.sub.7 is alkyl, or
substituted alkyl. In some embodiments, the preparation of
compounds of Formula Id are accomplished by further modification of
Ic. Through appropriate functional group transformations on the
moiety of Y and Z, one could afford the compounds of Formula Ic
with different entities of Y' and Z' at 2- or 3-positions.
##STR00040##
Certain Pharmaceutical Terminology
[0486] The term "acceptable" with respect to a formulation,
composition or ingredient, as used herein, means having no
persistent detrimental effect on the general health of the subject
being treated.
[0487] As used herein, the term "selective binding compound" refers
to a compound that selectively binds to any portion of one or more
target proteins.
[0488] As used herein, the term "selectively binds" refers to the
ability of a selective binding compound to bind to a target
protein, such as, for example, PARP, with greater affinity than it
binds to a non-target protein. In certain embodiments, specific
binding refers to binding to a target with an affinity that is at
least about 10, about 50, about 100, about 250, about 500, about
1000 or more times greater than the affinity for a non-target.
[0489] As used herein, the term "target protein" refers to a
molecule or a portion of a protein capable of being bound by a
selective binding compound. In certain embodiments, a target
protein is the enzyme poly(ADP-ribose)polymerase (PARP).
[0490] As used herein, the terms "treating" or "treatment"
encompass either or both responsive and prophylaxis measures, e.g.,
designed to inhibit, slow or delay the onset of a symptom of a
disease or disorder, achieve a full or partial reduction of a
symptom or disease state, and/or to alleviate, ameliorate, lessen,
or cure a disease or disorder and/or its symptoms.
[0491] As used herein, amelioration of the symptoms of a particular
disorder by administration of a particular compound or
pharmaceutical composition refers to any lessening of severity,
delay in onset, slowing of progression, or shortening of duration,
whether permanent or temporary, lasting or transient that can be
attributed to or associated with administration of the compound or
composition.
[0492] As used herein, the term "modulator" refers to a compound
that alters an activity of a molecule. For example, a modulator
includes a compound that causes an increase or a decrease in the
magnitude of a certain activity of a molecule compared to the
magnitude of the activity in the absence of the modulator. In
certain embodiments, a modulator is an inhibitor, which decreases
the magnitude of one or more activities of a molecule. In certain
embodiments, an inhibitor completely prevents one or more
activities of a molecule. In certain embodiments, a modulator is an
activator, which increases the magnitude of at least one activity
of a molecule. In certain embodiments the presence of a modulator
results in an activity that does not occur in the absence of the
modulator.
[0493] As used herein, the term "selective modulator" refers to a
compound that selectively modulates a target activity.
[0494] As used herein, the term "PARP" refers to the family of the
enzyme poly(ADP-ribose)polymerase which includes approximately 18
proteins, particularly poly(ADP-ribose)polymerase-1 (PARP-1) and
poly(ADP-ribose)polymerase-2 (PARP-2).
[0495] As used herein, the term "selective PARP modulator" refers
to a compound that selectively modulates at least one activity
associated with the enzyme poly(ADP-ribose)polymerase (PARP). In
various embodiments, the selective modulator selectively modulates
the activity of PARP-1, PARP-2, both PARP-1 and PARP-2 or several
members of the family of the enzyme poly(ADP-ribose)polymerase
(PARP).
[0496] As used herein, the term "method of inhibiting PARP" refers
to a method of inhibiting the activity of either one or more of the
family of enzyme poly(ADP-ribose)polymerase (PARP). As used herein,
the term "inhibition of PARP" refers to inhibition of the activity
of either one or more of the family of enzyme
poly(ADP-ribose)polymerase (PARP).
[0497] As used herein, the term "modulating the activity of the
enzyme poly(ADP-ribose)polymerase" refers to a modulating the
activity of either one or more of the family of enzyme
poly(ADP-ribose)polymerase (PARP).
[0498] As used herein, the term "selectively modulates" refers to
the ability of a selective modulator to modulate a target activity
to a greater extent than it modulates a non-target activity. In
certain embodiments the target activity is selectively modulated
by, for example about 2 fold up to more that about 500 fold, in
some embodiments, about 2, 5, 10, 50, 100, 150, 200, 250, 300, 350,
400, 450 or more than 500 fold.
[0499] As used herein, the term "target activity" refers to a
biological activity capable of being modulated by a selective
modulator. Certain exemplary target activities include, but are not
limited to, binding affinity, signal transduction, enzymatic
activity, tumor growth, inflammation or inflammation-related
processes, and amelioration of one or more symptoms associated with
a disease or condition.
[0500] As used herein, the term "agonist" refers to a compound, the
presence of which results in a biological activity of a protein
that is the same as the biological activity resulting from the
presence of a naturally occurring ligand for the protein, such as,
for example, PARP.
[0501] As used herein, the term "partial agonist" refers to a
compound the presence of which results in a biological activity of
a protein that is of the same type as that resulting from the
presence of a naturally occurring ligand for the protein, but of a
lower magnitude.
[0502] As used herein, the term "antagonist" or "inhibitor" refers
to a compound, the presence of which results in a decrease in the
magnitude of a biological activity of a protein. In certain
embodiments, the presence of an antagonist results in complete
inhibition of a biological activity of a protein, such as, for
example, the enzyme poly(ADP-ribose)polymerase (PARP).
[0503] As used herein, the IC.sub.50 refers to an amount,
concentration or dosage of a particular test compound that achieves
a 50% inhibition of a maximal response, such as modulation of PARP,
in an assay that measures such response.
[0504] As used herein, EC.sub.50 refers to a dosage, concentration
or amount of a particular test compound that elicits a
dose-dependent response at 50% of maximal expression of a
particular response that is induced, provoked or potentiated by the
particular test compound.
[0505] The term "cancer", as used herein refers to an abnormal
growth of cells which tend to proliferate in an uncontrolled way
and, in some cases, to metastasize (spread). The types of cancer
include, but are not limited to, solid tumors (such as those of the
bladder, bowel, brain, breast, endometrium, heart, kidney, lung,
lymphatic tissue (lymphoma), ovary, pancreas or other endocrine
organ (thyroid), prostate, skin (melanoma) or hematological tumors
(such as the leukemias).
[0506] The terms "disease, condition or disorder associated with a
PTEN deficiency" or "disease or disorder associated with a PTEN
deficiency", as used herein refer to diseases, conditions or
disorders that are caused by, mediated by or related to pathways
that are affected (either positively or negatively) by the partial
and/or complete loss of PTEN activity (e.g., PTEN deficiency). In
some embodiments, a disease or disorder associated with a PTEN
deficiency refers to a disease or disorder involving an abnormal
ability to control the phosphoinositide 3-kinase signaling pathway.
In other embodiments, a disease or disorder associated with a PTEN
deficiency refers to a disease or disorder involving a deficiency
in Homologous Recombination (HR) dependent DNA double strand break
(DSB) repair pathway. In still other embodiments, a disease or
disorder associated with a PTEN deficiency refers to a disease or
disorder related to abnormal regulation of centromere
stability.
[0507] The term "carrier," as used herein, refers to relatively
nontoxic chemical compounds or agents that facilitate the
incorporation of a compound into cells or tissues.
[0508] The terms "co-administration" or the like, as used herein,
are meant to encompass administration of the selected therapeutic
agents to a single patient, and are intended to include treatment
regimens in which the agents are administered by the same or
different route of administration or at the same or different
time.
[0509] The term "diluent" refers to chemical compounds that are
used to dilute the compound of interest prior to delivery. Diluents
include chemicals used to stabilize compounds because they provide
a more stable environment. Salts dissolved in buffered solutions
(which also can provide pH control or maintenance) are utilized as
diluents in certain embodiments, including, but not limited to a
phosphate buffered saline solution.
[0510] The terms "radiation therapy" (radiotherapy) or "ionizing
radiation therapy", as used herein, refer to the use of ionizing
radiation as part of a cancer treatment to control the
proliferation of cancer cells. Ionizing radiation therapy may be
used for curative or adjuvant cancer treatment. Additionally, it
can be used as a palliative treatment (where cure is not possible
and the aim is for local disease control or symptomatic relief) or
as a therapeutic treatment (where the therapy has survival benefit
and it can be curative). The precise treatment intent (curative,
adjuvant, neoadjuvant, therapeutic, or palliative) will depend on
the tumour type, location, and stage, as well as the general health
of the patient.
[0511] The terms "effective amount" or "therapeutically effective
amount," as used herein, refer to a sufficient amount of an agent
or a compound being administered which will relieve to some extent
one or more of the symptoms of the disease or condition being
treated. The result includes 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 uses is the amount of the composition
comprising a compound as disclosed herein required to provide a
clinically significant decrease in disease symptoms. An appropriate
"effective" amount in any individual case is determined using any
suitable technique, such as a dose escalation study.
[0512] The terms "enhance" or "enhancing," as used herein, means to
increase or prolong either in potency or duration a desired effect.
Thus, in regard to enhancing the effect of therapeutic agents, the
term "enhancing" refers to the ability to increase or prolong,
either in potency or duration, the effect of other therapeutic
agents on a system. An "enhancing-effective amount," as used
herein, refers to an amount adequate to enhance the effect of
another therapeutic agent in a desired system.
[0513] The term "enzymatically cleavable linker," as used herein
refers to unstable or degradable linkages which are degraded by one
or more enzymes.
[0514] The term "inflammatory disorders" refers to those diseases
or conditions that are characterized by one or more of the signs of
pain (dolor, from the generation of noxious substances and the
stimulation of nerves), heat (calor, from vasodilatation), redness
(rubor, from vasodilatation and increased blood flow), swelling
(tumor, from excessive inflow or restricted outflow of fluid), and
loss of function (functio laesa, which may be partial or complete,
temporary or permanent). Inflammation takes many forms and
includes, but is not limited to, inflammation that is one or more
of the following: acute, adhesive, atrophic, catarrhal., chronic,
cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing,
focal., granulomatous, hyperplastic, hypertrophic, interstitial.,
metastatic, necrotic, obliterative, parenchymatous, plastic,
productive, proliferous, pseudomembranous, purulent, sclerosing,
seroplastic, serous, simple, specific, subacute, suppurative,
toxic, traumatic, and/or ulcerative. Inflammatory disorders further
include, without being limited to those affecting the blood vessels
(polyarteritis, temporal arteritis); joints (arthritis:
crystalline, osteo-, psoriatic, reactive, rheumatoid, Reiter's);
gastrointestinal tract (Chrohn's Disease, ulcerative colitis); skin
(dermatitis); or multiple organs and tissues (systemic lupus
erythematosus).
[0515] The terms "kit" and "article of manufacture" are used as
synonyms.
[0516] A "metabolite" of a compound disclosed herein is a
derivative of that compound that is formed when the compound is
metabolized. The term "active metabolite" refers to a biologically
active derivative of a compound that is formed when the compound is
metabolized. The term "metabolized," as used herein, refers to the
sum of the processes (including, but not limited to, hydrolysis
reactions and reactions catalyzed by enzymes) by which a particular
substance is changed by an organism. Thus, in certain instances,
enzymes produce specific structural alterations to a compound. In
some embodiments, metabolites of the compounds disclosed herein are
identified either by administration of compounds to a host and
analysis of tissue samples from the host, or by incubation of
compounds with hepatic cells in vitro and analysis of the resulting
compounds.
[0517] The term "modulate," as used herein, means to interact with
a target either directly or indirectly so as to alter the activity
of the target, including, by way of example only, to enhance the
activity of the target, to inhibit the activity of the target, to
limit the activity of the target, or to extend the activity of the
target.
[0518] By "pharmaceutically acceptable" or "therapeutically
acceptable", as used herein, refers a material, such as a carrier
or diluent, which does not abrogate the biological activity or
properties of the compound, and is relatively nontoxic. In certain
instances, nontoxic and non-abrogative materials includes materials
that when administered to an individual do not cause substantial,
undesirable biological effects and/or do not interact in a
deleterious manner with any of the components of the composition in
which it is contained.
[0519] The term "pharmaceutically acceptable salt" or
"therapeutically acceptable salt", refers to a formulation of a
compound that does not cause significant irritation to an organism
to which it is administered and does not abrogate the biological
activity and properties of the compound. In certain instances,
pharmaceutically acceptable salts are obtained by reacting a
compound described herein, with acids such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,
salicylic acid and the like. In some instances, pharmaceutically
acceptable salts are obtained by reacting a compound having acidic
group described herein with a base to form a salt such as an
ammonium salt, an alkali metal salt, such as a sodium or a
potassium salt, an alkaline earth metal salt, such as a calcium or
a magnesium salt, a salt of organic bases such as
dicyclohexylamine, N-methyl-D-glucamine,
tris(hydroxymethyl)methylamine, and salts with amino acids such as
arginine, lysine, and the like, or by other methods previously
determined.
[0520] The term "pharmaceutical combination" as used herein, means
a product that results from the mixing or combining of more than
one active ingredient and includes both fixed and non-fixed
combinations of the active ingredients. The term "fixed
combination" means that the active ingredients, e.g. a compound
described herein and a co-agent, are both administered to a patient
simultaneously in the form of a single entity or dosage. The term
"non-fixed combination" means that the active ingredients, e.g. a
compound described herein and a co-agent, are administered to a
patient as separate entities either simultaneously, concurrently or
sequentially with no specific intervening time limits, wherein such
administration provides effective levels of the two compounds in
the body of the patient. The latter also applies to cocktail
therapy, e.g. the administration of three or more active
ingredients.
[0521] The term "pharmaceutical composition" refers to a mixture of
a compound described herein with other chemical components, such as
carriers, stabilizers, diluents, dispersing agents, suspending
agents, thickening agents, and/or excipients. The pharmaceutical
composition facilitates administration of the compound to an
organism. Multiple techniques of administering a compound exist in
the art including, but not limited to: intravenous, oral, aerosol,
parenteral, ophthalmic, pulmonary and topical administration.
[0522] A "prodrug" refers to an agent that is converted into the
parent drug in vivo. Prodrugs are often useful because, in some
situations, they are easier to administer than the parent drug. In
certain instances, a prodrug is bioavailable by oral administration
whereas the parent is not. In some instances, a prodrug has
improved solubility in pharmaceutical compositions over the parent
drug. An example, without limitation, of a prodrug is a compound
described herein, which is administered as an ester (the "prodrug")
to facilitate transmittal across a cell membrane where water
solubility is detrimental to mobility but which then is
metabolically hydrolyzed to the carboxylic acid, the active entity,
once inside the cell where water-solubility is beneficial. A
further example of a prodrug might be a short peptide
(polyaminoacid) bonded to an acid or amino group where the peptide
is metabolized to reveal the active moiety. In certain embodiments,
upon in vivo administration, a prodrug is chemically converted to
the biologically, pharmaceutically or therapeutically more active
form of the compound. In certain embodiments, a prodrug is
enzymatically metabolized by one or more steps or processes to the
biologically, pharmaceutically or therapeutically active form of
the compound. To produce a prodrug, a pharmaceutically active
compound is modified such that the active compound will be
regenerated upon in vivo administration. In some embodiments, the
prodrug is designed to alter the metabolic stability or the
transport characteristics of a drug, to mask side effects or
toxicity, to improve the flavor of a drug or to alter other
characteristics or properties of a drug.
[0523] The term "subject" or "patient" 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 methods and compositions provided
herein, the mammal is a human.
[0524] The terms "treat," "treating" or "treatment," as used
herein, include alleviating, abating or ameliorating a disease or
condition symptoms, preventing additional symptoms, ameliorating or
preventing the underlying metabolic causes of symptoms, inhibiting
the disease or condition, e.g., arresting the development of the
disease or condition, relieving the disease or condition, causing
regression of the disease or condition, relieving a condition
caused by the disease or condition, or stopping the symptoms of the
disease or condition either prophylactically and/or
therapeutically.
Pharmaceutical Composition/Formulation
[0525] In certain embodiments, pharmaceutical compositions are
formulated in any manner, including using one or more
physiologically acceptable carriers comprising excipients and/or
auxiliaries which facilitate processing of the active compounds
into pharmaceutical preparations. In some embodiments, proper
formulation is dependent upon the route of administration chosen.
In various embodiments, any techniques, carriers, and excipients
are used as suitable.
[0526] Provided herein are pharmaceutical compositions that include
a compound described herein and a pharmaceutically acceptable
diluent(s), excipient(s), and/or carrier(s). In addition, in some
embodiments, the compounds described herein are administered as
pharmaceutical compositions in which compounds described herein are
mixed with other active ingredients, as in combination therapy.
[0527] A pharmaceutical composition, as used herein, refers to a
mixture of a compound described herein with other chemical
components, such as carriers, stabilizers, diluents, dispersing
agents, suspending agents, thickening agents, and/or excipients. In
certain embodiments, a pharmaceutical composition facilitates
administration of the compound to an organism. In some embodiments,
practicing the methods of treatment or use provided herein,
includes administering or using a pharmaceutical composition
comprising a therapeutically effective amount of a compound
provided herein. In specific embodiments, the methods of treatment
provided for herein include administering such a pharmaceutical
composition to a mammal having a disease or condition to be
treated. In one embodiment, the mammal is a human. In some
embodiments, the therapeutically effective amount varies widely
depending on the severity of the disease, the age and relative
health of the subject, the potency of the compound used and other
factors. In various embodiments, the compounds described herein are
used singly or in combination with one or more therapeutic agents
as components of mixtures.
[0528] In certain embodiments, the pharmaceutical compositions
provided herein are formulated for intravenous injections. In
certain aspects, the intravenous injection formulations provided
herein are formulated as aqueous solutions, and, in some
embodiments, in physiologically compatible buffers such as Hank's
solution, Ringer's solution, or physiological saline buffer. In
certain embodiments, the pharmaceutical compositions provided
herein are formulated for transmucosal administration. In some
aspects, transmucosal formulations include penetrants appropriate
to the barrier to be permeated. In certain embodiments, the
pharmaceutical compositions provided herein are formulated for
other parenteral injections, appropriate formulations include
aqueous or nonaqueous solutions, and in one embodiment, with
physiologically compatible buffers or excipients.
[0529] In certain embodiments, the pharmaceutical compositions
provided herein are formulated for oral administration. In certain
aspects, the oral formulations provided herein comprise compounds
described herein that are formulated with pharmaceutically
acceptable carriers or excipients. Such carriers enable the
compounds described herein to be formulated as tablets, powders,
pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries,
suspensions and the like, for oral ingestion by a patient to be
treated.
[0530] In some embodiments, pharmaceutical preparations for oral
use are obtained by mixing one or more solid excipient with one or
more of the compounds described herein, optionally grinding the
resulting mixture, and processing the mixture of granules, after
adding suitable auxiliaries, if desired, to obtain tablets or
dragee cores. Suitable excipients include, in particular, fillers
such as sugars, including lactose, sucrose, mannitol, or sorbitol;
cellulose preparations such as: for example, maize starch, wheat
starch, rice starch, potato starch, gelatin, gum tragacanth,
methylcellulose, microcrystalline cellulose,
hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or
others such as: polyvinylpyrrolidone (PVP or povidone) or calcium
phosphate. If desired, disintegrating agents are optionally added,
such as the cross-linked croscarmellose sodium,
polyvinylpyrrolidone; agar, or alginic acid or a salt thereof such
as sodium alginate.
[0531] In certain embodiments, provided herein is a pharmaceutical
composition formulated as dragee cores with suitable coatings. In
certain embodiments, concentrated sugar solutions are used in
forming the suitable coating, and optionally contain gum arabic,
talc, polyvinylpyrrolidone; carbopol gel, polyethylene glycol,
and/or titanium dioxide, lacquer solutions, and suitable organic
solvents or solvent mixtures. In some embodiments, dyestuffs and/or
pigments are added to tablets, dragees and/or the coatings thereof
for, e.g., identification or to characterize different combinations
of active compound doses.
[0532] In certain embodiments, pharmaceutical preparations which
are used include orally include push-fit capsules made of gelatin,
as well as soft, sealed capsules made of gelatin and a plasticizer,
such as glycerol or sorbitol. In some embodiments, the push-fit
capsules contain the active ingredients in admixture with filler
such as lactose, binders such as starches, and/or lubricants such
as talc or magnesium stearate and, optionally, stabilizers. In
certain embodiments, in soft capsules, the active compounds are
dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers are optionally added. In certain embodiments, the
formulations for oral administration are in dosages suitable for
such administration.
[0533] In certain embodiments, the pharmaceutical compositions
provided herein are formulated for buccal or sublingual
administration. In certain embodiments, buccal or sublingual
compositions take the form of tablets, lozenges, or gels formulated
in a conventional manner. In certain embodiments, parenteral
injections involve bolus injection or continuous infusion. In some
embodiments, formulations for injection are presented in unit
dosage form, e.g., in ampoules or in multi-dose containers, with an
added preservative. In some embodiments, the pharmaceutical
composition described herein is in a form suitable for parenteral
injection as a sterile suspensions, solutions or emulsions in oily
or aqueous vehicles, and optionally contains formulatory agents
such as suspending, stabilizing and/or dispersing agents.
Pharmaceutical formulations for parenteral administration include
aqueous solutions of the active compounds in water-soluble form. In
some embodiments, suspensions of the active compounds are prepared
as appropriate oily injection suspensions. Suitable lipophilic
solvents or vehicles include fatty oils such as sesame oil, or
synthetic fatty acid esters, such as ethyl oleate or triglycerides,
or liposomes. In certain embodiments, aqueous injection suspensions
contain substances which increase the viscosity of the suspension,
such as sodium carboxymethyl cellulose, sorbitol, or dextran.
Optionally, the suspensions also contain suitable stabilizers or
agents which increase the solubility of the compounds to allow for
the preparation of highly concentrated solutions. In alternative
embodiments, the active ingredient is in powder form for
constitution with a suitable vehicle, e.g., sterile pyrogen-free
water, before use.
[0534] In some embodiments, the compounds described herein are
administered topically. In specific embodiments, the compounds
described herein are formulated into a variety of topically
administrable compositions, such as solutions, suspensions,
lotions, gels, pastes, medicated sticks, balms, creams or
ointments. Such pharmaceutical compounds optionally contain
solubilizers, stabilizers, tonicity enhancing agents, buffers
and/or preservatives.
[0535] In certain embodiments, the pharmaceutical compositions
provided herein are formulated for transdermal administration of
compounds described herein. In some embodiments, administration of
such compositions employs transdermal delivery devices and
transdermal delivery patches. In certain embodiments, the
compositions are lipophilic emulsions or buffered, aqueous
solutions, dissolved and/or dispersed in a polymer or an adhesive.
Such patches include those constructed for continuous, pulsatile,
or on demand delivery of pharmaceutical agents. In some
embodiments, transdermal delivery of the compounds described herein
is accomplished by use of iontophoretic patches and the like. In
certain embodiments, transdermal patches provide controlled
delivery of the compounds provided herein, such as, for example,
compounds of Formula (I), (IA) or (II). In certain embodiments, the
rate of absorption is slowed by using rate-controlling membranes or
by trapping the compound within a polymer matrix or gel.
Conversely, absorption enhancers are optionally used to increase
absorption. Absorption enhancer and carrier include absorbable
pharmaceutically acceptable solvents that assist in passage of the
compound through the skin. For example, transdermal devices are in
the form of a bandage comprising a backing member, a reservoir
containing the compound optionally with carriers, optionally a rate
controlling barrier to deliver the compound to the skin of the host
at a controlled and predetermined rate over a prolonged period of
time, and means to secure the device to the skin.
[0536] In certain embodiments, the pharmaceutical compositions
provided herein are formulated for administration by inhalation. In
certain embodiments, in such pharmaceutical compositions formulated
for inhalation, the compounds described herein are in a form as an
aerosol, a mist or a powder. In some embodiments, pharmaceutical
compositions described herein are conveniently delivered in the
form of an aerosol spray presentation from pressurized packs or a
nebuliser, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
certain aspects of a pressurized aerosol, the dosage unit is
determined by providing a valve to deliver a metered amount. In
certain embodiments, capsules and cartridges of, such as, by way of
example only, gelatin for use in an inhaler or insufflator is
formulated containing a powder mix of the compound described herein
and a suitable powder base such as lactose or starch.
[0537] In some embodiments, the compounds described herein are
formulated in rectal compositions such as enemas, rectal gels,
rectal foams, rectal aerosols, suppositories, jelly suppositories,
or retention enemas. In certain embodiments, rectal compositions
optionally contain conventional suppository bases such as cocoa
butter or other glycerides, as well as synthetic polymers such as
polyvinylpyrrolidone; PEG, and the like. In certain 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.
[0538] In various embodiments provided herein, the pharmaceutical
compositions are formulated in a conventional manner using one or
more physiologically acceptable carriers comprising excipients and
auxiliaries which facilitate processing of the active compounds
into pharmaceutically acceptable preparations. In certain
embodiments, proper formulation is dependent upon the route of
administration chosen. In various embodiments, any of the
techniques, carriers, and excipients is used as suitable. In some
embodiments, pharmaceutical compositions comprising a compound
described herein are manufactured in a conventional manner, such
as, by way of example only, by means of conventional mixing,
dissolving, granulating, dragee-making, levigating, emulsifying,
encapsulating, entrapping or compression processes.
[0539] In certain embodiments, the pharmaceutical compositions
include at least one pharmaceutically acceptable carrier, diluent
or excipient and a compound described herein described herein as an
active ingredient in free-acid or free-base form, or in a
pharmaceutically acceptable salt form. In addition, the methods and
pharmaceutical compositions described herein include the use of
N-oxides, crystalline forms (also known as polymorphs), as well as
active metabolites of these compounds having the same type of
activity. In some situations, compounds described herein exist as
tautomers. All tautomers are included within the scope of the
compounds presented herein. Additionally, included herein are the
solvated and unsolvated forms of the compounds described herein.
Solvated compounds include those that are solvated with
pharmaceutically acceptable solvents such as water, ethanol, and
the like. The solvated forms of the compounds presented herein are
also considered to be disclosed herein. In some embodiments, the
pharmaceutical compositions described herein include other
medicinal or pharmaceutical agents, carriers, adjuvants, such as
preserving, stabilizing, wetting or emulsifying agents, solution
promoters, salts for regulating the osmotic pressure, and/or
buffers. In additional embodiments, the pharmaceutical compositions
described herein also contain other therapeutically valuable
substances.
[0540] Methods for the preparation of compositions containing the
compounds described herein include formulating the compounds with
one or more inert, pharmaceutically acceptable excipients or
carriers to form a solid, semi-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. Semi-solid compositions include, but are not limited to,
gels, suspensions and creams. In various embodiments, the
compositions are in liquid solutions or suspensions, solid forms
suitable for solution or suspension in a liquid prior to use, or as
emulsions. These compositions optionally contain minor amounts of
nontoxic, auxiliary substances, such as wetting or emulsifying
agents, pH buffering agents, and so forth.
[0541] In some embodiments, a composition comprising a compound
described herein takes the form of a liquid where the agents are
present in solution, in suspension or both. In some embodiments,
when the composition is administered as a solution or suspension a
first portion of the agent is present in solution and a second
portion of the agent is present in particulate form, in suspension
in a liquid matrix. In some embodiments, a liquid composition
includes a gel formulation. In other embodiments, the liquid
composition is aqueous.
[0542] Useful aqueous suspensions optionally contain one or more
polymers as suspending agents. Useful polymers include
water-soluble polymers such as cellulosic polymers, e.g.,
hydroxypropyl methylcellulose, and water-insoluble polymers such as
cross-linked carboxyl-containing polymers. Useful compositions
optionally comprise an mucoadhesive polymer, selected for example
from carboxymethylcellulose, carbomer (acrylic acid polymer),
poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic
acid/butyl acrylate copolymer, sodium alginate and dextran.
[0543] Useful compositions optionally include solubilizing agents
to aid in the solubility of a compound described herein. The term
"solubilizing agent" generally includes agents that result in
formation of a micellar solution or a true solution of the agent.
Solubilizing agents include certain acceptable nonionic
surfactants, for example polysorbate 80, and ophthalmically
acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and
glycol ethers.
[0544] Useful compositions optionally include one or more pH
adjusting agents or buffering agents, including acids such as
acetic, boric, citric, lactic, phosphoric and hydrochloric acids;
bases such as sodium hydroxide, sodium phosphate, sodium borate,
sodium citrate, sodium acetate, sodium lactate and
tris-hydroxymethylaminomethane; and buffers such as
citrate/dextrose, sodium bicarbonate and ammonium chloride. Such
acids, bases and buffers are included in an amount required to
maintain pH of the composition in an acceptable range.
[0545] Useful compositions optionally include one or more salts in
an amount required to bring osmolality of the composition into an
acceptable range. Such salts include those having sodium, potassium
or ammonium cations and chloride, citrate, ascorbate, borate,
phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions;
suitable salts include sodium chloride, potassium chloride, sodium
thiosulfate, sodium bisulfite and ammonium sulfate.
[0546] Certain useful compositions optionally include one or more
preservatives to inhibit microbial activity. Suitable preservatives
include mercury-containing substances such as merfen and
thiomersal; stabilized chlorine dioxide; and quaternary ammonium
compounds such as benzalkonium chloride, cetyltrimethylammonium
bromide and cetylpyridinium chloride.
[0547] Some useful compositions optionally include one or more
surfactants to enhance physical stability or for other purposes.
Suitable nonionic surfactants include polyoxyethylene fatty acid
glycerides and vegetable oils, e.g., polyoxyethylene (60)
hydrogenated castor oil; and polyoxyethylene alkylethers and
alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.
[0548] Certain useful compositions optionally one or more
antioxidants to enhance chemical stability where required. Suitable
antioxidants include, by way of example only, ascorbic acid and
sodium metabisulfite.
[0549] In some embodiments, aqueous suspension compositions are
packaged in single-dose non-reclosable containers. In alternative
embodiments, multiple-dose reclosable containers are used, in which
case it is typical to include a preservative in the
composition.
[0550] In various embodiments, any delivery system for hydrophobic
pharmaceutical compounds is employed. Liposomes and emulsions are
examples of delivery vehicles or carriers for hydrophobic drugs. In
certain embodiments, certain organic solvents such as
N-methylpyrrolidone are employed. In some embodiments, the
compounds are delivered using a sustained-release system, such as
semipermeable matrices of solid hydrophobic polymers containing the
therapeutic agent. Various sustained-release materials are utilized
in the embodiments herein. In certain embodiments,
sustained-release capsules release the compounds for a few weeks up
to over 100 days. In some embodiments, depending on the chemical
nature and the biological stability of the therapeutic reagent,
additional strategies for protein stabilization are employed.
[0551] In certain embodiments, the formulations or compositions
described herein benefit from and/or optionally comprise
antioxidants, metal chelating agents, thiol containing compounds
and other general stabilizing agents. Examples of such stabilizing
agents, include, but are not limited to: (a) about 0.5% to about 2%
w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about
0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10
mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003%
to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v.
polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k)
cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m)
divalent cations such as magnesium and zinc; or (n) combinations
thereof.
Methods of Dosing and Treatment Regimens
[0552] In certain embodiments, the compounds described herein are
used in the preparation or manufacture of medicaments for the
treatment of diseases or conditions associated with a PTEN
deficiency in which inhibition of the enzyme
poly(ADP-ribose)polymerase (PARP) ameliorates the disease or
condition. In some embodiments, a method for treating any of the
diseases or conditions described herein in a subject in need of
such treatment, involves administration of pharmaceutical
compositions containing at least one compound described herein, or
a pharmaceutically acceptable salt, pharmaceutically acceptable
N-oxide, pharmaceutically active metabolite, pharmaceutically
acceptable prodrug, or pharmaceutically acceptable solvate thereof,
in therapeutically effective amounts to said subject.
[0553] In certain embodiments, the compositions containing the
compound(s) described herein are administered for prophylactic
and/or therapeutic treatments. In certain therapeutic applications,
the compositions are administered to a patient already suffering
from a disease or condition, in an amount sufficient to cure or at
least partially arrest the symptoms of the disease or condition. In
some embodiments, amounts effective for this use will depend on the
severity and course of the disease or condition, previous therapy,
the patient's health status, weight, and response to the drugs, and
the judgment of the treating physician. In certain instances, it is
considered appropriate for the caregiver to determine such
therapeutically effective amounts by routine experimentation
(including, but not limited to, a dose escalation clinical
trial).
[0554] In certain prophylactic applications, compositions
containing the compounds described herein are administered to a
patient susceptible to or otherwise at risk of a particular
disease, disorder or condition. In some embodiments, the amount
administered is defined to be a "prophylactically effective amount
or dose." In certain embodiments of this use, the precise amounts
of compound administered depend on the patient's state of health,
weight, and the like. In some embodiments, it is considered
appropriate for the caregiver to determine such prophylactically
effective amounts by routine experimentation (e.g., a dose
escalation clinical trial). In certain embodiments, when used in a
patient, effective amounts for this use will depend on the severity
and course of the disease, disorder or condition, previous therapy,
the patient's health status and response to the drugs, and the
judgment of the treating physician.
[0555] In certain instances, a patient's condition does not improve
or does not significantly improve following administration of a
compound or composition described herein and, upon the doctor's
discretion the administration of the compounds is optionally
administered chronically, that is, for an extended period of time,
including throughout the duration of the patient's life in order to
ameliorate or otherwise control or limit the symptoms of the
patient's disease or condition.
[0556] In certain cases wherein the patient's status does improve
or does not substantially improve, upon the doctor's discretion the
administration of the compounds are optionally given continuously;
alternatively, the dose of drug being administered is optionally
temporarily reduced or temporarily suspended for a certain length
of time (i.e., a "drug holiday"). In certain embodiments, the
length of the drug holiday varies between 2 days and 1 year,
including by way of example only, 2 days, 3 days, 4 days, 5 days, 6
days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days,
50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days,
250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The
dose reduction during a drug holiday includes a reduction from
about 10% to about 100%, including, by way of example only, about
10%, about 15%, about 20%, about 25%, about 30%, about 35%, about
40%, about 45%, about 50%, about 55%, about 60%, about 65%, about
70%, about 75%, about 80%, about 85%, about 90%, about 95%, or
about 100%.
[0557] In certain embodiments, once improvement of the patient's
conditions has occurred, a maintenance dose is administered if
necessary. In some embodiments, the dosage, e.g., of the
maintenance dose, or the frequency of administration, or both, are
reduced, as a function of the symptoms, to a level at which the
improved disease, disorder or condition is retained. In certain
embodiments, however, patients are optionally given intermittent
treatment on a long-term basis upon any recurrence of symptoms.
[0558] In certain embodiments, the amount of a given agent that
corresponds to an effective amount varies depending upon factors
such as the particular compound, disease or condition and its
severity, the identity (e.g., weight) of the subject or host in
need of treatment. In some embodiments, the effective amount is,
nevertheless, determined according to the particular circumstances
surrounding the case, including, e.g., the specific agent that is
administered, the route of administration, the condition being
treated, and the subject or host being treated. In certain
embodiments, however, doses employed for adult human treatment is
in the range of about 0.02 to about 5000 mg per day, in a specific
embodiment about 1 to about 1500 mg per day. In various
embodiments, the desired dose is conveniently presented in a single
dose or as divided doses administered simultaneously (or over a
short period of time) or at appropriate intervals, for example as
two, three, four or more sub-doses per day.
[0559] In some embodiments, the pharmaceutical compositions
described herein are in a unit dosage form suitable for single
administration of precise dosages. In some instances, in unit
dosage form, the formulation is divided into unit doses containing
appropriate quantities of one or more compound. In certain
embodiments, the unit dosage is in the form of a package containing
discrete quantities of the formulation. Non-limiting examples are
packaged tablets or capsules, and powders in vials or ampoules. In
some embodiments, aqueous suspension compositions are packaged in
single-dose non-reclosable containers. In alternative embodiments,
multiple-dose reclosable containers are used, in which case it is
typical to include a preservative in the composition. By way of
example only, formulations for parenteral injection are, in some
embodiments, presented in unit dosage form, which include, but are
not limited to ampoules, or in multi-dose containers, with an added
preservative.
[0560] In certain embodiments, the daily dosages appropriate for
the compounds described herein described herein are from about 0.01
to about 2.5 mg/kg per body weight. In some embodiments, an
indicated daily dosage in the larger subject, including, but not
limited to, humans, is in the range from about 0.5 mg to about 100
mg, conveniently administered in divided doses, including, but not
limited to, up to four times a day or in extended release form. In
certain embodiments, suitable unit dosage forms for oral
administration comprise from about 1 to about 50 mg active
ingredient. 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. In certain embodiments, the dosages are altered
depending on a number of variables, not limited to the activity of
the compound used, the disease or condition to be treated, the mode
of administration, the requirements of the individual subject, the
severity of the disease or condition being treated, and the
judgment of the practitioner.
[0561] In certain embodiments, toxicity and therapeutic efficacy of
such therapeutic regimens are determined by standard pharmaceutical
procedures in cell cultures or experimental animals, including, but
not limited to, the determination of the LD.sub.50 (the dose lethal
to 50% of the population) and the ED.sub.50 (the dose
therapeutically effective in 50% of the population). The dose ratio
between the toxic and therapeutic effects is the therapeutic index
and it can be expressed as the ratio between LD.sub.50 and
ED.sub.50. In certain embodiments, compounds exhibiting high
therapeutic indices are preferred. In some embodiments, the data
obtained from cell culture assays and animal studies is used in
formulating a range of dosage for use in human. In specific
embodiments, the dosage of such compounds lies within a range of
circulating concentrations that include the ED.sub.50 with minimal
toxicity. In certain embodiments, the dosage varies within this
range depending upon the dosage form employed and the route of
administration utilized.
Combination Treatments
[0562] In certain instances, it is appropriate to administer at
least one compound described herein in combination with another
therapeutic agent. By way of example only, if one of the side
effects experienced by a patient upon receiving one of the
compounds herein is inflammation, then, in some embodiments, it is
appropriate to administer an anti-inflammatory agent in combination
with the initial therapeutic agent. In some embodiments, the
therapeutic effectiveness of one of the compounds described herein
is enhanced by administration of an adjuvant (i.e., in some
embodiments, by itself the adjuvant has minimal therapeutic
benefit, but in combination with another therapeutic agent, the
overall therapeutic benefit to the patient is enhanced). In certain
embodiments, the benefit experienced by a patient is increased by
administering one of the compounds described herein with another
therapeutic agent (which also includes a therapeutic regimen) that
also has therapeutic benefit. In some embodiments, regardless of
the disease, disorder or condition being treated, the overall
benefit experienced by the patient as a result of a combination
treatment is additive or synergistic.
[0563] In certain embodiments, therapeutically-effective dosages
vary when the drugs are used in treatment combinations. In some
embodiments, therapeutically-effective dosages of drugs and other
agents for use in combination treatment regimens is determined in
any suitable manner, e.g., through the use of metronomic dosing,
i.e., providing more frequent, lower doses in order to minimize
toxic side effects. In some embodiments, combination treatment
regimen described herein encompass treatment regimens in which
administration of a PARP inhibitor described herein is initiated
prior to, during, or after treatment with a second agent described
above, and continues until any time during treatment with the
second agent or after termination of treatment with the second
agent. It also includes treatments in which a PARP inhibitor
described herein and the second agent being used in combination are
administered simultaneously or at different times and/or at
decreasing or increasing intervals during the treatment period.
Combination treatment further includes periodic treatments that
start and stop at various times to assist with the clinical
management of the patient. For example, in some embodiments, a PARP
inhibitor described herein in the combination treatment is
administered weekly at the onset of treatment, decreasing to
biweekly, and decreasing further as appropriate.
[0564] In certain embodiments, compositions and methods for
combination therapy are provided herein. In accordance with one
aspect, the pharmaceutical compositions disclosed herein are used
to in a method of treating a disease or condition associated with a
PTEN deficiency that is ameliorated by inhibition of PARP. Thus, in
accordance with certain aspects, the pharmaceutical compositions
disclosed herein are used to treat diseases or disorders associated
with a PTEN deficiency. In a certain aspect, the pharmaceutical
compositions disclosed herein are used in combination, either
simultaneously or sequentially, with ionizing radiation or one or
more chemotherapeutic agents.
[0565] In certain embodiments, combination therapies described
herein are used as part of a specific treatment regimen intended to
provide a beneficial effect from the co-action of a PARP inhibitor
described herein and a concurrent treatment. It is understood that
the dosage regimen to treat, prevent, or ameliorate the
condition(s) for which relief is sought, is optionally modified in
accordance with a variety of factors.
[0566] In certain combination therapies described herein, dosages
of the co-administered compounds vary depending on the type of
co-drug employed, on the specific drug employed, on the disease or
condition being treated and so forth. In some embodiments, when
co-administered with one or more biologically active agents, the
compound provided herein is administered either simultaneously with
the biologically active agent(s), or sequentially. In certain
aspects wherein the agents are administered sequentially, the
attending physician will decide on the appropriate sequence of
administering protein in combination with the biologically active
agent(s).
[0567] In various embodiments, the multiple therapeutic agents (one
of which is one of the compounds described herein) are administered
in any order or even simultaneously. In certain instances,
administration is simultaneous and the multiple therapeutic agents
are, optionally, provided in a single, unified form, or in multiple
forms (by way of example only, either as a single pill or as two
separate pills). In some embodiments, one of the therapeutic agents
is given in multiple doses, or both are given as multiple doses. In
some instances, administration is not simultaneous and the timing
between the multiple doses varies, by way of non-limiting example,
from more than zero weeks to less than four weeks. In addition, the
combination methods, compositions and formulations are not to be
limited to the use of only two agents; the use of multiple
therapeutic combinations are also envisioned.
[0568] In additional embodiments, the compounds described herein
are used in combination with procedures that provide additional or
synergistic benefit to the patient. By way of example only,
patients are expected to find therapeutic and/or prophylactic
benefit in the methods described herein, wherein pharmaceutical
composition of a compound disclosed herein and/or combinations with
other therapeutics are combined with genetic testing to determine
whether that individual is a carrier of a mutant gene that is known
to be correlated with certain diseases or conditions.
[0569] In certain embodiments, the compounds described herein and
combination therapies are administered before, during or after the
occurrence of a disease or condition. In certain embodiments, the
timing of administering the composition containing a compound
varies. Thus, for example, in some embodiments, the compounds are
used as a prophylactic and are administered continuously to
subjects with a propensity to develop conditions or diseases in
order to prevent the occurrence of the disease or condition. In
some embodiments, the compounds and compositions are administered
to a subject during or as soon as possible after the onset of the
symptoms. In certain embodiments, the administration of the
compounds is initiated within the first 48 hours of the onset of
the symptoms, within the first 6 hours of the onset of the
symptoms, or within 3 hours of the onset of the symptoms. The
initial administration is achieved via any route practical, such
as, for example, an intravenous injection, a bolus injection,
infusion over 5 minutes to about 5 hours, a pill, a capsule,
transdermal patch, buccal delivery, and the like, or combination
thereof. In some embodiments, a compound is administered as soon as
is practicable after the onset of a disease or condition is
detected or suspected, and for a length of time necessary for the
treatment of the disease, such as, from about 1 month to about 3
months. In certain embodiments, the length of treatment varies for
each subject, and the length is determined using any criteria. In
exemplary embodiments, a compound or a formulation containing the
compound is administered for at least 2 weeks, for about 1 month to
about 5 years, or for about 1 month to about 3 years.
Chemotherapeutic Agents
[0570] In certain embodiments described herein, methods for
treatment of PARP mediated conditions or diseases, such as
proliferative disorders, including cancer, include administration
to a patient compounds, pharmaceutical compositions, or medicaments
described herein in combination with at least one additional
chemotherapeutic agent selected from, but not limited to,
alemtuzumab, arsenic trioxide, asparaginase (pegylated or non-),
bevacizumab, trastuxumab, cetuximab, platinum-based compounds (such
as cisplatin, carboplatin or oxaliplatin), gemcitabine,
cyclphosphamide, cladribine, daunorubicin/doxorubicin/idarubicin,
irinotecan, fludarabine, 5-fluorouracil, gemtuzumab, methotrexate,
Paclitaxel.TM., taxol, temozolomide, thioguanine, or classes of
drugs including hormones (an antiestrogen, an antiandrogen, or
gonadotropin releasing hormone analogues), interferons such as
alpha interferon, nitrogen mustards such as busulfan or melphalan
or mechlorethamine, retinoids such as tretinoin, topoisomerase
inhibitors such as irinotecan or topotecan, tyrosine kinase
inhibitors such as gefitinib, erlotinib, or imatinib, mTOR
inhibitors such as temsirolimus or everolimus, or agents to treat
signs or symptoms induced by such therapy including allopurinol,
filgrastim, granisetron/ondansetron/palonosetron, and
dronabinol.
Radiation Therapy
[0571] In other embodiments described herein, methods for treatment
of PARP mediated conditions or diseases, such as proliferative
disorders, including cancer, include administration to a patient
compounds, pharmaceutical compositions, or medicaments described
herein in combination with at least one type of radiotherapy (or
ionizing radiation). Radiotherapy is the use of ionizing radiation
as part of a cancer treatment to control the proliferation of
cancer cells. Ionizing radiation therapy may be used for curative
or adjuvant cancer treatment. Additionally, it can be used as a
palliative treatment (where cure is not possible and the aim is for
local disease control or symptomatic relief) or as a therapeutic
treatment (where the therapy has survival benefit and it can be
curative). The precise treatment intent (curative, adjuvant,
neoadjuvant, therapeutic, or palliative) will depend on the tumour
type, location, and stage, as well as the general health of the
patient.
[0572] Radiation therapy works by damaging the DNA of cells. The
damage is caused by a photon, electron, proton, neutron, or ion
beam directly or indirectly ionizing the atoms which make up the
DNA chain. Indirect ionization happens as a result of the
ionization of water, forming free radicals, notably hydroxyl
radicals, which then damage the DNA. In the most common forms of
radiation therapy, most of the radiation effect is through free
radicals. Because cells have mechanisms for repairing DNA damage,
breaking the DNA on both strands proves to be the most significant
technique in modifying cell characteristics. Because cancer cells
generally are undifferentiated and stem cell-like, they reproduce
more, and have a diminished ability to repair sub-lethal damage
compared to most healthy differentiated cells. The DNA damage is
inherited through cell division, accumulating damage to the cancer
cells, causing them to die or reproduce more slowly. Proton
radiotherapy works by sending protons with varying kinetic energy
to precisely stop at the tumor.
[0573] Gamma rays are also used to treat some types of cancer
including uterine, endometrial, and ovarian cancers. In the
procedure called gamma-knife surgery, multiple concentrated beams
of gamma rays are directed on the growth in order to kill the
cancerous cells. The beams are aimed from different angles to focus
the radiation on the growth while minimizing damage to the
surrounding tissues.
Kits/Articles of Manufacture
[0574] For use in the therapeutic applications described herein,
kits and articles of manufacture are also described herein. In
various embodiments, such kits 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 described herein. Suitable containers include, for
example, bottles, vials, syringes, and test tubes. In some
embodiments, the containers are formed from a variety of materials
such as glass or plastic.
[0575] In some embodiments, the articles of manufacture provided
herein contain packaging materials. Packaging materials for use in
packaging pharmaceutical products include, but are not limited to,
blister packs, bottles, tubes, inhalers, pumps, bags, vials,
containers, syringes, bottles, and any packaging material suitable
for a selected formulation and intended mode of administration and
treatment.
[0576] In some embodiments, the container(s) described herein
comprise one or more compounds described herein, optionally in a
composition or in combination with another agent as disclosed
herein. The container(s) optionally have a sterile access port (for
example in some embodiments the container is an intravenous
solution bag or a vial having a stopper pierceable by a hypodermic
injection needle). Such kits optionally comprise a compound with an
identifying description or label or instructions relating to its
use in the methods described herein.
[0577] In some embodiments, a kit will comprises 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 described herein. Non-limiting examples of such materials
include, but are 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 is
optionally included.
[0578] In certain embodiments, a label is on or associated with the
container. In some embodiments, a label is on a container when
letters, numbers or other characters forming the label are
attached, molded or etched into the container itself; a label is
associated with a container when it is present within a receptacle
or carrier that also holds the container, e.g., as a package
insert. In certain embodiments, a label indicates that the contents
are to be used for a specific therapeutic application. In some
embodiments, the label indicates directions for use of the
contents, such as in the methods described herein.
[0579] In certain embodiments, the pharmaceutical compositions are
presented in a pack or dispenser device which contains one or more
unit dosage forms containing a compound provided herein. In some
embodiments, the pack contains a metal or plastic foil, such as a
blister pack. The pack or dispenser device is optionally
accompanied by instructions for administration. In some
embodiments, the pack or dispenser is accompanied with a notice
associated with the container in form prescribed by a governmental
agency regulating the manufacture, use, or sale of pharmaceuticals,
which notice is reflective of approval by the agency of the form of
the drug for human or veterinary administration. In certain
embodiments, such notice is, for example, the labeling approved by
the U.S. Food and Drug Administration for prescription drugs, or
the approved product insert. In some embodiments, compositions
containing a compound provided herein are formulated in a
compatible pharmaceutical carrier and are placed in an appropriate
container labeled for treatment of an indicated condition.
EXAMPLES
[0580] The following Examples are intended as an illustration of
the various embodiments as defined in the appended claims. In some
embodiments, the compounds are prepared by a variety of synthetic
routes. All publications, patents, and patent applications cited
herein are hereby incorporated by reference for all purposes.
Example 1
Example 1a
Parenteral Composition
[0581] To prepare a parenteral pharmaceutical composition suitable
for administration by injection, 100 mg of a water-soluble salt of
a compound described herein is dissolved in DMSO and then mixed
with 10 mL of 0.9% sterile saline. The mixture is incorporated into
a dosage unit form suitable for administration by injection.
Example 1b
Oral Composition
[0582] To prepare a pharmaceutical composition for oral delivery,
100 mg of a compound described herein is mixed with 750 mg of
starch. The mixture is incorporated into an oral dosage unit for,
such as a hard gelatin capsule, which is suitable for oral
administration.
Example 1c
Sublingual (Hard Lozenge) Composition
[0583] To prepare a pharmaceutical composition for buccal delivery,
such as a hard lozenge, mix 100 mg of a compound described herein,
with 420 mg of powdered sugar mixed, with 1.6 mL of light corn
syrup, 2.4 mL distilled water, and 0.42 mL mint extract. The
mixture is gently blended and poured into a mold to form a lozenge
suitable for buccal administration.
Example 1d
Inhalation Composition
[0584] To prepare a pharmaceutical composition for inhalation
delivery, 20 mg of a compound described herein is mixed with 50 mg
of anhydrous citric acid and 100 mL of 0.9% sodium chloride
solution. The mixture is incorporated into an inhalation delivery
unit, such as a nebulizer, which is suitable for inhalation
administration.
Example 1e
Rectal Gel Composition
[0585] To prepare a pharmaceutical composition for rectal delivery,
100 mg of a compound described herein is mixed with 2.5 g of
methylcelluose (1500 mPa), 100 mg of methylparapen, 5 g of glycerin
and 100 mL of purified water. The resulting gel mixture is then
incorporated into rectal delivery units, such as syringes, which
are suitable for rectal administration.
Example 1f
Topical Gel Composition
[0586] To prepare a pharmaceutical topical gel composition, 100 mg
of a compound described herein is mixed with 1.75 g of
hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of
isopropyl myristate and 100 mL of purified alcohol USP. The
resulting gel mixture is then incorporated into containers, such as
tubes, which are suitable for topical administration.
Example 1g
Ophthalmic Solution Composition
[0587] To prepare a pharmaceutical ophthalmic solution composition,
100 mg of a compound described herein is mixed with 0.9 g of NaCl
in 100 mL of purified water and filtered using a 0.2 micron filter.
The resulting isotonic solution is then incorporated into
ophthalmic delivery units, such as eye drop containers, which are
suitable for ophthalmic administration.
Biological Studies
Example 1
PARP 1 Inhibition Assays
[0588] Inhibitory effects of test compounds against human PARP 1
enzyme was assessed using Trevigen's Universal Chemiluminescent
PARP Assay Kit (Trevigen CAT#4676-096-K) following the
manufacturer's recommended protocol.
[0589] Immediately prior to performing the assay, the following
reagents were prepared: A) 20.times.PARP Assay Buffer was diluted
to 1.times. with dH.sub.2O; B) 10.times.PARP Cocktail, which
contains a mixture of NAD and biotinylated NAD, was diluted by the
addition of 10.times. Activated DNA and 1.times.PARP Assay Buffer.
Both the PARP Cocktail and Activated DNA are 1.times. after the
dilution; C) all test compounds were initially dissolved in DMSO,
and subsequently serial diluted with 1.times. PARP Assay Buffer; D)
recombinant human PARP 1 enzyme was diluted with 1.times.PARP Assay
Buffer to generate 0.5 unit/15 .mu.l; E) 10.times. Strep-Diluent
was diluted to 1.times. with 1.times.PBS/0.1% Triton X-100; F) Just
before use, dilute Strep-HRP 500-fold with 1.times.
Strep-Diluent.
[0590] The chemiluminescent assays for PARP activity were performed
in white 96-well plates that are pre-coated with histones. Briefly,
strip wells were removed from the wrapper, 50 .mu.l/well of
1.times.PARP Buffer was added to rehydrate the histones and
incubation was allowed for 30 minutes at room temperature. Removal
of the 1.times.PARP Buffer from the wells was accomplished by
tapping the strip wells on paper towel. Serial dilutions of the
test compounds were added to duplicate wells in 10 .mu.l/well
volume. Final assay concentrations of test compounds were typically
between 1 and 0.0001 .mu.M. Subsequently, recombinant human PARP 1
enzyme was added to 0.5 unit of PARP 1 enzyme/well in 15 .mu.l/well
volume. Combined volume of enzyme and inhibitor was 25 .mu.l.
Incubate the enzyme/inhibitor mixtures for 10 minutes at room
temperature. To start the reaction, 25 .mu.l/well of the
1.times.PARP Cocktail was added to all the wells. Controls included
background wells with 1.times. Assay Buffer alone (no PARP) and
wells with no inhibitor for determining the maximum or 100% PARP
activity value. In all cases the final reaction volume was 50
.mu.l.
[0591] The reactions were allowed to proceed for 1 hour at room
temperature. The plate was then washed 4 times with 200 .mu.l/well
1.times.PBS/0.1% Triton X-100, using EL.times.50 Automated Strip
Washer (BIO-TEK). After washing, all wells were incubated for 60
minutes with 50 .mu.l/well Strep-HRP, diluted 1:500 with 1.times.
Strep-Diluent. The plate was washed 4 times with 200 .mu.l/well
1.times.PBS/0.1% Triton X-100 using EL.times.50 Automated Strip
Washer (BIO-TEK). After washing, dry the wells by tapping plate
onto paper towels. Mix equal volumes of PeroxyGlow.TM. A and B
together and add 100 .mu.l per well. The light output was
immediately determined in a plate reader (EnVision, by Perkin
Elmer) set up for measuring chemiluminescence.
[0592] The % enzyme activity for each compound is then calculated
using the following equation:
% Inhibition = Activity Ctrl - X Activity Ctrl - Negative Ctrl
.times. 100 % ##EQU00001##
[0593] IC.sub.50 values (the concentration at which 50% of the
enzyme activity is inhibited) of each test compound were calculated
using GraphPad Prism5 software.
[0594] All of the compounds tested had or were expected to have
enzymatic PARP inhibitory activity. Of the compounds tested, over
100 compounds had a PARP inhibitory activity in the enzymatic assay
of less than 50 nM, with approximately 60 of these compounds having
an inhibitory activity of less than 5 nM.
[0595] Chemosensitization assay determines the extent by which a
PARP inhibitor enhances the tumor cell-killing effect of cytotoxic
drugs expressed as PF.sub.50 (potentiation factor at GI.sub.50)].
8000 LoVo cells were seeded into each well of a flat-bottomed
96-well microtiter plate in a volume of 50 .mu.l and incubated in
F12K containing 10% (v/v) FBS (medium) overnight at 37.degree. C.
Cells were added with 50 .mu.l medium alone; medium containing 2
.mu.M PARP inhibitor, medium containing increasing concentration of
Temozolomide (0-2000 .mu.M), and medium containing 2 .mu.M PARP
inhibitor and increasing concentration of Temozolomide (0-2000
.mu.M). Final concentration range for Temozolomide was 0-1000 .mu.M
where applicable, final concentration of PARP inhibitor was 1 .mu.M
where applicable. Final concentration of DMSO was 1% in each well.
Cells were allowed to grow for 5 days before cell survival was
determined by CellTiter Glo staining (Promega, Madison, Wis., USA).
Cell growth, determined after subtraction of time 0 values, was
expressed as a percentage of the control well that contained medium
with 1% DMSO. GI.sub.50 (concentration of drug that inhibited
growth by 50%) values were calculated from the computer generated
curves (GraphPad Software, Inc. San Diego Calif.). The potentiation
factor [PF.sub.50 (potentiation factor at GI.sub.50)] was
calculated as GI.sub.50 of Temozolomide alone/GI50 of
Temozolomide+PARP inhibitor. Reference: Thomas H. D. et al. (2007).
Preclinical selection of a novel poly(ADP-ribose) polymerase
inhibitor for clinical trial. Molecular Cancer Therapy 6,
945-956.
[0596] Most of the compounds tested had a PF50 of more than
2.times..
Example 2
In Vitro Cytotoxicity Assay in PTEN -/- Cell Lines Single-Agent
Cytotoxicity Assay in PTEN-/- Tumor Cell Lines
[0597] Human prostate PC-3, LNCap tumor cells and mammary
MDA-MB-468 tumor cells (all PTEN deficient) were seeded in 96-well
tissue culture plates for overnight at a density of 500, 1000, and
1000 cells/well, respectively. Culture media for PC-3 is DMEM+10%
FBS; culture media for LNCap is RPMI-1640+10% FBS; culture media
for MDA-MB-468 is Leibovitz's L-15+10% FBS.
[0598] Tumor cell lines wild type for PTEN (MDA-MB-231 and LoVo
tumor cells) were seeded as described above at a density of 1500
(MDA-MB-231) and 1000 (LoVo) cells/well. Culture media for
MDA-MB-231 is Leibovitz's L-15+10% FBS, culture media for LoVo is
F-12K+10% FBS.
[0599] All cells were then treated with fresh media containing
Compound X, a PARP inhibitor as described herein at increasing
concentrations, and incubated for 7 consecutive days (PC-3) or 12
consecutive days (LNCap, MDA-MB-468) with media changed every 5
days to replenish inhibitors.
[0600] Cell survival was determined by CellTiter Glo assay
(Promega). Cell survival fraction was expressed as a percentage of
the non-treatment control, and IC.sub.50 values were calculated
using GraphPad Prism5.
[0601] The results of the cytotoxicity assays are set forth in FIG.
1 and FIG. 2. The results show that the PTEN -/- tumor cell lines
(i.e., PTEN deficient) (LNCap, PC-3, and MDA-MB-468) displayed high
sensitivity to treatment with Compound X described herein (FIG. 1),
whereas the cell lines wild type for PTEN (MDA-MB-231 and LoVo) did
not exhibit the same level of sensitivity to Compound X (FIG.
2).
Example 3
Antitumor Efficacy Study in PTEN -/-Xenografts
[0602] Male athymic Balb/c nude mice (7-9 week old) were used for
PTEN deficient LNCap and PC-3 in vivo xenografts. Female athymic
Balb/c nude mice were used for PTEN deficient MDA-MB-468 in vivo
xenograft studies. All mice were quarantined for at least 1 week
before experimental manipulation.
[0603] Exponentially growing cells were implanted subcutaneously at
the right flank of nude mice. Tumor-bearing mice were randomized
according to tumor size into 8 mice/group in each study (average
tumor size .about.140-180 mm.sup.3). Mice were observed daily for
survival and tumors were measured twice weekly by caliper in two
dimensions and converted to tumor mass using the formula for a
prolate ellipsoid (V=0.5 a.times.b.sup.2), where a and b are the
long and short diameters of the tumor, respectively, and assuming
unit density (1 mm.sup.3=1 mg).
[0604] PARP inhibitory compound (Compound X) was evaluated in
LNCap, PC-3 and MDA-MB-468 xenografts for single agent activity.
Compound X was dosed orally (p.o.), once daily at 0.33 mg/kg for 28
days in vehicle 10% DMAc/6% Solutal/84% PBS and the same vehicle
was used as control. Mice were continuously monitored for 10 more
days after last day of dosing.
[0605] The results of the in vivo xenograft studies are set forth
in FIG. 3 (LNCap xenograft), FIG. 4 (MDA-MB-468 xenograft) and FIG.
5 (PC-3 xenograft). The results show that treatment with a PARP
inhibitory compound described herein resulted in significant
slowing of tumor growth in all three PTEN deficient xenograft
models as compared to treatment with only the vehicle
(control).
Example 4
Phase II Clinical Trial of the Safety and Efficacy of Compounds of
Formula (I), (IA) or (II)
[0606] The purpose of this phase II trial is to study the side
effects and best dose of a compound of Formula (I), (IA) or (II)
and to determine how well it works in treating patients with
advanced or recurrent endometrial cancer (EC).
[0607] Constitutively active phosphatidylinositol-3 kinase
(PI3K)/phosphatase and tensin homolog on chromosome 10 (PTEN)
pathway signaling is common in EC and involved in the development
and/or progression of the disease. PTEN deficiency has been
frequently detected in EC patients. The compounds of Formula (I),
(IA) or (II) described herein are potent inhibitors of the family
of poly(ADP-ribose)polymerases (PARP). In addition, in vivo data
(as set forth in Example 3 above) demonstrates that administration
of compounds of Formula (I), (IA) or (II) result in significant
slowing of tumor growth in three PTEN deficient xenograft models.
Therefore, compounds of Formula (I), (IA) or (II) may have utility
in the treatment of subjects with advanced or recurrent EC.
Objectives:
[0608] Primary Outcome Measures: [0609] A. Efficacy as defined by
overall response rate and progression-free survival (PFS) at 6
months [Time Frame: every 8-10 weeks] [0610] B. Safety a compound
of Formula (I), (IA) or (II) in the EC population [Time Frame:
scheduled evaluations every 2-4 weeks]
[0611] Secondary Outcome Measures: [0612] A. Duration of response
and PFS [Time Frame: every 8-10 weeks] [0613] B. Characterize
pharmacokinetic and pharmacodynamic profiles of a compound of
Formula (I), (IA) or (II) [Time Frame: at periodic visits not less
than every 4 weeks]
[0614] Tertiary: [0615] A. To evaluate PARP expression using
quantitative western blotting immuno-assays [0616] B. To analyze
tumor biopsy samples (when possible) for PTEN deficiency mutation
status, PARP activity, and PARP expression [0617] C. To analyze
paraffin sections from original diagnostic biopsies/operative
procedures (when available) for DNA repair enzyme status using
immunohistochemical techniques
Patients:
[0618] Eligible subjects will be women 18 years and older
Criteria
[0619] Inclusion Criteria: [0620] The subject has a histologically
confirmed diagnosis of EC (endometrioid, serous, clear cell
adenocarcinoma, adenosquamous carcinoma, or mixed histology, any
grade) that is advanced or recurrent and is incurable by standard
therapies, and has received no more than two prior systemic
treatment regimens for EC. [0621] The subject is at least 18 years
old. [0622] The subject has an Eastern Cooperative Oncology Group
(ECOG) performance status of 0, 1, or 2. [0623] The subject has at
least one measurable lesion [0624] Tissue samples from archival or
fresh tissue, or a tissue block of the subject's tumor [0625] The
subject has adequate organ and marrow function [0626] The subject
is capable of understanding the informed consent and complying with
the protocol and has signed the informed consent document before
any study-specific screening procedures or evaluations are
performed. [0627] Sexually active subjects of childbearing
potential and their partners must agree to use medically accepted
methods of contraception during the course of the study and for 3
months after discontinuation of study drug. [0628] Subjects of
childbearing potential must have a negative pregnancy test at
screening.
[0629] Exclusion Criteria: [0630] The subject has uterine sarcomas
(leiomyosarcoma), mixed Mullerian tumors, squamous carcinoma of the
uterus, and/or adenosarcomas of the uterus. [0631] Certain
restrictions on prior treatments apply [0632] The subject has not
recovered from toxicity due to prior therapy to Grade .ltoreq.1 or
to pre-therapy baseline (excluding alopecia and peripheral
neuropathy). [0633] The subject has a known primary brain tumor or
brain metastasis. [0634] The subject has any other diagnosis of
malignancy or evidence of malignancy (except non-melanoma skin
cancer or in situ carcinoma of the cervix) within 2 years before
screening for this study. [0635] The subject has a diagnosis of
uncontrolled diabetes mellitus or has a fasting plasma glucose
>160 mg/dL. [0636] The subject is currently receiving
anticoagulation with therapeutic doses of warfarin (low-dose
warfarin .ltoreq.1 mg/day is permitted). [0637] The subject has
prothrombin time (PT)/international normalized ratio (INR) or
partial thromboplastin time (PTT) test results at screening that
are above 1.3.times. the laboratory upper limit of normal. [0638]
The subject has uncontrolled, significant intercurrent illness
[0639] The subject has a baseline corrected QT interval .gtoreq.470
ms. [0640] The subject is known to be positive for the human
immunodeficiency virus (HIV). (Note: Baseline HIV screening is not
required.) [0641] The subject is pregnant or breastfeeding. [0642]
The subject has a previously identified allergy or hypersensitivity
to components of the study treatment formulation.
* * * * *