Jaybe. Way over my head. But this good stuff
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Publication Dates Range: 11-Oct-2012 - 11-Oct-2012
Filing Dates Range: 06-Apr-2012 - 06-Apr-2012
Assigned IPC Subclass: A61K
Abstract (English, WO 2012139027 A1)
The invention discloses methods and compositions for treating or preventing neurodegenerative disease by administering a compound of Formula I: or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the variables are defined as herein.
Patent Family Members (1; WO):
WO 2012139027 A1
application
Methods and compositions for treating neurodegenerative diseases (11-Oct-2012)
Applicants: ARIAD PHARMACEUTICALS, INC., SHAKESPEARE, William, C., HALUSKA, Frank, G.
Description (English, WO 2012139027 A1) Jump to: claims top
METHODS AND COMPOSITIONS FOR TREATING
NEURODEGENERATIVE DISEASES
RELATED APPLICATION DATA
This application claims the benefit of US Provisional Application Nos. 61 /472,961 filed April 7, 201 1 and 61 /518,427 filed May 5, 201 1 , both of which are hereby incorporated herein by reference in their entirety.
TECHNICAL FIELD
This invention relates to methods for treating or preventing neurodegenerative diseases by administering a targeted tyrosine kinase inhibitor disclosed herein or a pharmaceutically acceptable salt thereof.
BACKGROUND
While many details concerning the biological mechanisms underlying the development and progression of neurodegenerative diseases remain unclear, there have been important recent developments. For instance, both Parkinson's disease (PD) and Alzheimer's disease (AD), have been linked to protein misfolding and aggregation (see Gregersen N. J Inherit Metab Dis 29:456 (2006), and Whatley et al., Biochim Biophys Acta 1782:700 (2008)). The accumulation of misfolded proteins in these diseases appears to arise from an imbalance in the generation and clearance of misfolded proteins. Protein misfolding can occur as a result of genetic mutations, environmental insults or oxidative damage (Olzmann et al., Curr Med Chem 15 :47 (2008)). As for clearance of such misfolded proteins, the ubiquitin-proteasome system and the aggresome-autophagy pathway both appear to be important cellular defense mechanisms against toxic build-up of misfolded proteins ( opito RR. Trends Cell Biol 10:524-530 (2000); Xie et al, Nat Cell Biol 9: 1 102-1 109 (2007); and Levine et al., Cell 2008, 132:27-42(2008)). The failure of cells to cope with excess misfolded proteins is believed to be a common pathological mechanism linking these clinically distinct diseases.
Recent studies suggest that the protein, parkin, may play an important role. Parkin- mediated Lys63-linked polyubiquitination of misfolded proteins promotes their sequestration into aggresomes and subsequent clearance by autophagy (Olzmann et al., J Cell Biol 178: 1025 (2007); and Olzmann et al., Autophagy 4:85 (2008)). Furthermore, loss-of-function mutations in parkin are a major cause of recessively transmitted neurodegenerative diseases, such as early-onset PD (Kitada et al, Nature 392:605 (1998); and Hattori et al., Lancet 364:722 (2004)). Parkin has also been reported to play a role in targeting damaged mitochondria for mitophagy (Narendra et al, J Cell Biol 183 :795 (2008)), and so may be implicated in neurodegenerative diseases associated with mitochondrial dysfunction. Parkin has also been reported to protect dopamine neurons from tau-induced degeneration (Klein et al, Neurosci Lett. 401 : 130 (2006)).
Parkin is believed be a pan-neuroprotective agent against a number of different toxic insults including elevated expression of substrates for parkin ubiquitination (Lo Bianco et al., Proc. Natl. Acad. Sci. U.S.A 101 : 17510 (2004); Petrucelli et al., Neuron 36: 1007 (2002); Yamada et al., Hum. Gene Ther 16:262 (2005); and Yang et al., Neuron 37:91 1 (2003)) as well as other toxins (Darios et al., Hum. Mol. Genet 12:517 (2003); Hyun et al, J. Neurosci. Res 82:232 (2005); Manfredsson et al., Mol. Therapy l l (Suppl. 1 ):24 (2005); and Staropoli et al, Neuron 37:735 (2003)). Increasing parkin expression reduces oxidative damage (Hyun et al., J. Biol. Chem 277:28572 (2002)) while blocking parkin expression increases oxidative damage (Greene et al., Hum. Mol. Genet 14:799 (2005); and Palacino et al, J. Biol. Chem 279: 18614 (2004)), which explains the general protection from parkin against a variety of insults.
PD is a chronic, progressive motor system disorder. Approximately 50,000 Americans are diagnosed with PD each year. The primary symptoms of this neurodegenerative disease are trembling, rigidity, slowness of movement, and impaired balance. In addition, many PD patients experience a variety of other symptoms, including emotional changes, memory loss, speech problems, or difficulty sleeping. As the disease progresses, many patients find it increasingly difficult to walk, talk, swallow or carry out simple tasks.
PD is caused by specific and progressive neuronal loss of mid-brain dopamine (DA) neurons. Ordinarily, these neurons produce dopamine, a chemical messenger responsible for transmitting signals between the substantia nigra and the corpus striatum, resulting in smooth, purposeful muscle activity. However, loss of dopamine causes the nerve cells of the striatum to fire in an uncontrolled manner, leaving patients with impaired ability to direct and control their movements, an impairment that can be severe and profoundly crippling.
There is no cure for PD. Current therapy relies heavily on replenishing dopamine by giving patients oral doses of a dopaminergic agent like the dopamine precursor levodopa (alone or in the combination carbidopa/levodopa) or a dopamine agonist. Such therapy can provide relief, although with the increasing risk of serious side effects and often with diminishing therapeutic results, requiring increasing doses as treatment continues, and more serious side effects. There is a profound need for additional therapeutics for PD. c-Abl is a major regulator of parkin function and phosphorylates parkin on tyrosine 143. This phosphorylation inhibits parkin's E3 ubiquitin ligase activity leading to accumulation of AIMP2 and FBP1 and loss of parkin's cytoprotective function and cell death. One Abl inhibitor, STI-571 , has been found to maintain parkin in a catalytically active and neuroprotective state by preventing phosphorylation of parkin. As such, it is believed that inhibition of c-Abl presents a viable approach for the treatment of PD. o, et al., PNAS, 107(38), 16691 -16696 (2010). One challenge of using STI-571 to treat PD is that it has poor penetration of the blood-brain barrier as demonstrated in mice and humans. Thus, there is a need for Abl inhibitors that cross the blood-brain barrier for the treatment of PD.
Desirable therapies for Alzheimer's disease share certain characteristics with those for PD. Yet, the etiologies of PD and AD are not identical. In the case of AD, therapies are generally directed to the reduction of amyloid-ß peptides. Amyloid-ß peptides are metabolites of the amyloid precursor protein and are believed to be its major pathological determinant. The proteolytic cleavages that form the amyloid-ß N and C termini are catalyzed by ß-secretase and ?-secretase, respectively. It is postulated that reducing amyloid- ß without affecting Notch- 1 cleavage may prove useful as a basis for developing therapies for AD. Netzer, et al, PNAS, 100(21 ): 12444- 12449 (2003). That is, ?-secretase inhibitors that can reduce amyloid-ß formation without impairing cleavage of other ?-secretase substrates such as Notch are potentially useful for the treatment of AD. ?-secretase activating protein (GSAP) is a recently identified target that does not interact with Notch and its reduced concentrations in cell lines was associated with decreased amyloid-ß concentrations. He, et al , Nature., 467: 95-98 (2010). Compounds that accumulate in the brain and target GSAP represent a valid approach for development of AD therapies. Id.
In the context of testing STI-571 in their models, Netzer, et al hypothesized that Abl kinase is not believed to be required for amyloid-ß production, although it may tangentially impact certain other kinases implicated in certain neurodegenerative diseases. Id. , Hanger, et al , Trends in Mol. Med., 15(3), 1 12- 1 19 (2009). These certain other kinases potentially implicated in amyloid-ß production include ARG, PDGFR, Src, and c-kit. Netzer, et al, PNAS, 100(21 ): 12444-12449 (2003). Despite the apparent promise of STI-571 in in vitro and certain in vivo models, its clinical promise for humans is stymied by its inability to cross the blood-brain barrier, which is viewed as being necessary to improve the likelihood of therapeutic benefit despite certain contradictory views. Sutcliffe, et al, J. of Neuro. Res., 89:808-814 (201 1 ).
In the context of targeted therapies, it has been found that the microtubule-associated protein tau is integral to the pathogenesis of AD and related disorders termed tauopathies. Strategies for targeting tau in neurodegenerative disease include (i) reducing tau phosphorylation through inhibition of specific protein kinases; (ii) disaggregating tau inclusions; and (iii) tau immunotherapy with (i) being the preferred approach. Hanger, et al , Trends in Mol. Med., 15(3), 1 12-1 19 (2009). Specific protein kinases implicated in the reduction of tau phosphorylation include glycogen synthase kinase-3 (GSK-3), cyclin- dependent kinase-5 (cdk5), extracellular signal-regulated kinase-2 (ERK2), cyclic AMP- dependent protein kinase (PKA), casein kinase 1 (CK1 ), MAPK and JNK. These kinases and the kinases implicated with AD such as Fyn, Syk and c-Abl are also of interest in ability to phosphorylate tau at Y 18, Y 197 and Y394, respectively. Id.
While the etiology of these neurodegenerative diseases is not fully understood, it is believed that there is a need for inhibitors of Abl that also exhibit activity against other kinases such as src, PDGFR and/or c-kit. Such inhibitors would be attractive for development. Applicant's own WO 2007/075869, which is hereby incorporated herein by reference for all purposes, discloses certain compounds that are targeted tyrosine kinase inhibitors. One notable targeted TKI is ponatinib, which is currently the subject of a clinical trial to determine the efficacy of ponatinib in patients with chronic myeloid leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast phase (BP) or with Ph positive (Ph+) acute lymphoblastic leukemia (ALL) who either are resistant or intolerant to either dasatinib or nilotinib, or have the T315I mutation of Bcr-Abl (clinical trials.gov identifier NCTOl 207440). WO 2007/075869 does not explicitly mention using such targeted TKI's for the treatment of AD or other neurodegenerative diseases.
Applicant's own WO 201 1 /053938, which is hereby incorporated herein by reference for all purposes, discloses in the context of methods for treating cancer that these compounds have a wide range of kinase activity beyond the initial focus on Abl inhibition. For instance, these compounds demonstrate potency against PDGFR, c-SRC, and certain other kinases shown at Table 8.
SUMMARY
It has been unexpectedly discovered that certain targeted TKI's cross the blood brain barrier and are useful in the inhibition of ß-amyloid production and accordingly for the treatment of AD. In addition, such targeted TKI's are useful for targeting tau and accordingly for the treatment of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and other neurodegenerative diseases as disclosed herein.
In one aspect, this disclosure provides methods for treating or preventing a neurodegenerative condition in a subject in need thereof by administering to the subject an effective amount of a targeted TKI of Formula I: [Image Omitted]
Formula I
or a tautomer, or an individual isomer or a mixture of isomers thereof wherein: Ring T is a 5-membered heteroaryl ring containing 1 or 2 nitrogens with the remaining ring atoms being carbon, substituted on at least two ring atoms with R1 groups, at least two of which being located on adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, partially saturated or unsaturated 5- or 6- membered ring (Ring E), containing 0-3 heteroatoms selected from O, N, and S and being optionally substituted with 1 -4 Re groups;
Ring A is a 5- or 6-membered aryl or heteroaryl ring and is optionally substituted with 1 -4 Ra groups; Ring B is a 5- or 6-membered aryl or heteroaryl ring;
L1 is selected from NR'C(O), C(0)NR\ NR'CiO , NR1C(0)NR1 , and OC(0)NR' ; each occurrence of Ra, Rb and R' is independently selected from the group consisting of halo, -CN, -N02, -R4, -OR2, -NR2R3, -C(0)YR2, -OC(0)YR2, -NR2C(0)YR2, -SC(0)YR2, - NR2C(=S)YR2, -OC(=S)YR2, -C(=S)YR2, -YC(=NR3)YR2, -YP(=0)(YR )(YR4), -Si(R )3, - NR2S02R2, -S(0)rR2, -S02NR2R3 and -NR2S02NR2R3, wherein each Y is independently a bond, -0-, -S- or -NR3-; Re, at each occurrence, is independently selected from the group consisting of halo, =0, -CN, -N02, -R4, -OR2, -NR2R3, -C(0)YR2, -OC(0)YR2, -NR2C(0)YR2, -SC(0)YR2, - NR2C(=S)YR2, -OC(=S)YR2, -C(-S)YR2, -YC(=NR3)YR2, -YP(=0)(YR4)(YR4), -Si(R2)3, - NR2S02R2, -S(0)rR2, -S02NR2R3 and -NR2S02NR2R3, wherein each Y is independently a bond, -0-, -S- or -NR3-; R1, R2 and R3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; alternatively, R2 and RJ, taken together with the atom to which they are attached, form a 5- or 6- membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from N, O and S(0)r; each occurrence of R4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl moieties is optionally substituted; m is 0, 1 , 2, 3 or 4;
n is 2 or 3;
p is 0, 1 , 2, 3, 4 or 5; and,
r is 0, 1 or 2; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In another aspect, this disclosure provides methods for treating or preventing Alzheimer's disease in a subject in need thereof by administering to the subject a targeted tyrosine kinase inhibitor in an amount sufficient to reduce the activity of ?-secretase in the brain of the subject, wherein the targeted tyrosine kinase inhibitor is a compound of Formula
I:
[Image Omitted]
Formula I
or a tautomer, or an individual isomer or a mixture of isomers thereof wherein: Ring T is a 5-membered heteroaryl ring containing 1 or 2 nitrogens with the remaining ring atoms being carbon, substituted on at least two ring atoms with R' groups, at least two of which being located on adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, partially saturated or unsaturated 5- or 6- membered ring (Ring E), containing 0-3 heteroatoms selected from O, N, and S and being optionally substituted with 1 -4 Re groups;
Ring A is a 5- or 6-membered aryl or heteroaryl ring and is optionally substituted with 1 -4 Ra groups;
Ring B is a 5- or 6-membered aryl or heteroaryl ring;
L' is selected from NR'C(O), C(0)NR', NR'C(0)0, NR' C(0)NR', and OC(0)NR' ; each occurrence of Ra, Rb and R1 is independently selected from the group consisting of halo, -CN, -NO,, -R4, -OR2, -NR2R3, -C(0)YR2, -OC(0)YR2, -NR2C(0)YR2, -SC(0)YR2, - NR C(=S)YR2, -OC(=S)YR2, -C(=S)YR2, -YC(=NR3)YR2, -YP(=0)(YR4)(YR4), -Si(R2)3, - NR S02R2, -S(0)rR2, -S02NR2R3 and -NR2SO,NR2R3, wherein each Y is independently a bond, -0-, -S- or -NR3-;
Re, at each occurrence, is independently selected from the group consisting of halo, =0, -CN, -N02, -R4, -OR2, -NR R3, -C(0)YR2, -OC(0)YR2, -NR2C(0)YR2, -SC(0)YR2, - NR C(=S)YR2, -OC(=S)YR2, -C(=S)YR2, -YC(=NR3)YR2, -YP(=0)(YR4)(YR4), -Si(R2)3, - NR2S02R2, -S(0)rR2, -S02NR2R3 and -NR2S02NR2R3, wherein each Y is independently a bond, -0-, -S- or -NR3-;
R1, R2 and R3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; alternatively, R2 and R3, taken together with the atom to which they are attached, form a 5- or 6- membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from N, O and S(0)r; each occurrence of R4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl moieties is optionally substituted; m is 0, 1 , 2, 3 or 4;
n is 2 or 3;
p is 0, 1 , 2, 3, 4 or 5; and,
r is 0, 1 or 2; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In another aspect, this disclosure provides pharmaceutical compositions for treating or preventing a neurodegenerative condition in a subject in need thereof comprising an effective amount of a targeted tyrosine kinase inhibitor, wherein the targeted TKI is a compound of Formula I:
[Image Omitted]
Formula I
or a tautomer, or an individual isomer or a mixture of isomers thereof wherein:
Ring T is a 5-membered heteroaryl ring containing 1 or 2 nitrogens with the remaining ring atoms being carbon, substituted on at least two ring atoms with R' groups, at least two of which being located on adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, partially saturated or unsaturated 5- or 6- membered ring (Ring E), containing 0-3 heteroatoms selected from O, N, and S and being optionally substituted with 1 -4 Re groups;
Ring A is a 5- or 6-membered aryl or heteroaryl ring and is optionally substituted with 1 -4 Ra groups;
Ring B is a 5- or 6-membered aryl or heteroaryl ring; L1 is selected from NR'C(O), NR'CCO , NR1C(0)NR1, and OC(0)NR' ; each occurrence of Ra, Rb and Rl is independently selected from the group consisting of halo, -CN, -N02, -R4, -OR2, -NR2R3, -C(0)YR2, -OC(0)YR2, -NR2C(0)YR2, -SC(0)YR2, - NR2C(=S)YR2, -OC(=S)YR2, -C(=S)YR2, -YC(=NR3)YR2, -YP(=0)(YR4)(YR4), -Si(R2)3, - NR2SO,R2, -S(0)rR2, -S02NR2R3 and -NR2SO,NR2R3, wherein each Y is independently a bond, -0-, -S- or -NR3-;
Re, at each occurrence, is independently selected from the group consisting of halo, =0, -CN, -N02, -R4, -OR2, -NR2R3, -C(0)YR2, -OC(0)YR2, -NR2C(0)YR2, -SC(0)YR2, - NR2C(=S)YR2, -OC(=S)YR2, -C(=S)YR2, -YC(=NR3)YR2, -YP(=0)(YR4)(YR4), -Si(R2)3, - NR2S02R2, -S(0)rR2, -S02NR2R3 and -NR2S02NR2R3, wherein each Y is independently a bond, -0-, -S- or -NR3-; R1, R2 and R3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; alternatively, R2 and R3, taken together with the atom to which they are attached, form a 5- or 6- membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from N, O and S(0)r; each occurrence of R4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl moieties is optionally substituted; m is 0, 1 , 2, 3 or 4;
n is 2 or 3;
p is 0, 1 , 2, 3, 4 or 5; and,
r is 0, 1 or 2; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and
a pharmaceutically acceptable carrier. In another aspect, this disclosure provides kits including: (a) a presently disclosed targeted tyrosine kinase inhibitor, and (b) instructions for administering the targeted TKI to a subject diagnosed with or at risk of developing a neurodegenerative disease. The targeted tyrosine kinase inhibitor can be formulated for administration according to any of the dosing regimens described herein. As noted at the outset, the targeted tyrosine kinase inhibitor used in the various embodiments of the invention may be in the form of its free base or a pharmaceutically acceptable salt thereof.
In certain embodiments of any of the foregoing methods or pharmaceutical compositions in the compound of Formula I, the targeted tyrosine kinase inhibitor is a compound selected from the group consisting of:
N-(3-( 1 H-imidazol- 1 -yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[ 1 ,2-a]pyrazin-3- ylethynyl)-4-methylbenzamide;
3-(Imidazo[l ,2-a]pyrazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-l - yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
N-(3-(2-((dimethylamino)methyl)- 1 H-imidazol- 1 -yl)-5-(trifluoromethyl)phenyl)-3-
(imidazo[l ,2-a]pyrazin-3-ylethynyl)-4-methylbenzamide;
3-(Imidazo[l ,2-a]pyridin-3-ylethynyl)-4-methyl-N-(3-(4-methyl-l -imidazol-l-yl)- 5-(trifluoromethyl)phenyl)benzamide;
N-(3-(l H-imidazol- l -yl)-5-(tri fluoromethyl)phenyl)-3-(imidazo[l ,2- ]pyridin-3- ylethynyl)-4-methylbenzamide;
3-(Imidazo[l ,2-a]pyridin-3-ylethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2- yl)benzamide;
N-(5-tert-butylisoxazol-3-yl)-3-(imidazo[l ,2-a]pyridin-3-ylethynyl)-4- methylbenzamide;
3-(Imidazo[l ,2-a]pyridin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-l - yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
N-(3-(2-((dimethylamino)methyl)-l ?-imidazol- l -yl)-5-(tri fluoromethy l)phenyl)-3- (imidazo[l ,2-a]pyridin-3-ylethynyl)-4-methylbenzamide;
3- ((8-Acetamidoimidazo[l ,2-a]pyridin-3-yl)ethynyl)-4-methyl-N-(4- (trifluoromethyl)pyridin-2-yl)benzamide;
N-(3-( 1 H-imidazol- 1 -yl)-5-(trifluoromethyl)phenyl)-3-((8-acetamidoimidazo[ 1 ,2- a]pyridin-3-yl)ethynyl)-4-methylbenzamide;
4- Methyl-3-((8-(4-(methylsulfonyl)phenylamino)imidazo[l ,2-a]pyridin-3- yl)ethynyl)-Af-(4-(trifluoromethyl)pyridin-2-yl)benzamidei
4-methyl-3-((8-(4-sulfamoylphenylamino)imidazo[l ,2-a]pyridin-3-yl)ethynyl)-Af-(4- (trifluoromethyl)pyridin-2-yl)benzamide; (R)-N-(4-((3-(Dimethylamino)pyrrolidin- l -yl)methyl)-3-(trifluoromethyl)pheny (imidazo[l ,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide;
N-(3-(Imidazo[l ,2-b]pyridazin-3-ylethynyl)-4-methylphenyl)-4-((4-rnethylpiperazin- l -yl)methyl)-3-(trifluoromethyl)benzamide;
3-(Imidazo[l ,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-l - yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
N-(3-Chloro-4-((4-methylpiperazin-l -yl)methyl)phenyl)-3-(irnidazo[l ,2-b]pyridazin- 3-ylethynyl)-4-methylbenzamide;
N-(3-Cyclopropyl-4-((4-methylpiperazin-l -yl)rnethyl)phenyl)-3-(imidazo[l ,2- b]pyridazin-3-ylethynyl)-4-methylbenzamide;
3-(Imidazo[l,2-b]pyridazin-3-ylethynyl)-N-(4-((4-methylpiperazin-l -yl)rnethyl)-3- (trifluoromethyl)phenyl)benzamide;
N-(4-((4-(2-Hydroxyethyl)piperazin-l -yl)methyl)-3-(trifluoromethyl)phenyl)-3- (imidazo[ l ,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide; and
3-(Imidazo[l ,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-(piperazin- l -ylrnethyl)-3- (trifluoromethyl)phenyl)benzamide,
or a pharmaceutically acceptable salt thereof.
Additional features and advantages of the methods and pharmaceutical compositions disclosed herein will be apparent from the following detailed description.
DETAILED DESCRIPTION
Definitions
In reading this document, the following information and definitions apply unless otherwise indicated.
As used herein, a "targeted tyrosine kinase inhibitor" or "targeted TKI" means a compound of Formula I as disclosed herein that is active against at least one kinase selected from the group consisting of Abl, PDGFR, ARG, fyn, syk, c-kit and src, as determined by an appropriate in vitro kinase assay. In general, a targeted TKI is said to be active against a relevant kinase if it has an IC5o less than 1 µ? in such in vitro kinase assay. A typical in vitro kinase assay used to determine the activity for Abl, PDGFR, ARG, c-kit and src is described in O'Hare et al, Cancer Cell 16:401 -412 (2009) and Supplemental Data.
As used herein, the term "ponatinib" means 3-(imidazo[l ,2-b]pyridazin-3-ylethynyl)- 4-methyl-N-(4-((4-methylpiperazin-l -yl)-methyl-3-(trifluoromethyl)phenyl)benzamide (as shown in Example 16 herein) and having the chemical structure depicted below: [Image Omitted]
The term ponatinib refers only to its free base unless a pharmaceutically acceptable salt (such as ponatinib HO) is explicitly mentioned.
As used herein, the term "mean steady state trough concentration" means the average plasma concentration of a compound disclosed herein observed for a group of subjects as part of a dosing regimen for a therapy of the invention administered over a period of time sufficient to produce steady state pharmacokinetics (i.e., a period of 23 days of daily dosing), wherein the mean trough concentration is the average circulating concentration over all of the subjects at a time just prior to (i.e., within 1 hour of) the next scheduled administration in the regimen (e.g., for a daily regimen the trough concentration is measured about 24 hours after an administration of a compound disclosed herein and just prior to the subsequent daily administration).
As used herein, the terms "administration" or "administering" mean a route of administration for a compound disclosed herein. Exemplary routes of administration include, but are not limited to, oral, intravenous, intraperitoneal, intraarterial, and intramuscular. The preferred route of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition comprising a compound disclosed herein, site of the potential or actual disease and severity of disease. While ponatinib will generally be administered per orally, other routes of administration can be useful in carrying out the methods of the invention.
As used herein, the term "unit dosage form" means a physically discrete unit containing a predetermined quantity of a compound disclosed herein that is suitable for administration. Exemplary unit dosage forms include, but are not limited to, a pill, tablet, caplet, hard capsule or soft capsule.
As used herein, the term "pharmaceutically acceptable salt" means salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates and other types of compounds, are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1 -19 ( 1977), incorporated herein by reference. The salts can be prepared in situ during the isolation and purification of the compounds of the invention, or separately by reacting the free base or free acid of a compound of the invention with a suitable base or acid, respectively. Examples of pharmaceutically acceptable, nontoxic acid addition salts of a compound disclosed herein are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methane-sulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable adjuvant" refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self emulsifying drug delivery systems (SEDDS) such as d-atocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as u-, P-, and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2and 3- hydroxypropyl-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
As used herein, the terms "treatment" or "treating" mean: ( 1 ) improving or stabilizing the subject's condition or disease or (2) preventing or relieving the development or worsening of symptoms associated with the subject's condition or disease.
As used herein, the terms "amount effective" or "effective amount" mean the amount of a compound disclosed herein that when administered to a subject for treating a disease, is sufficient to effect such treatment of the disease. Any improvement in the patient is considered sufficient to achieve treatment. An effective amount of a compound disclosed herein, used for the treatment of a neurodegenerative disease can vary depending upon the manner of administration, the age, body weight, and general health of the patient. Ultimately, the prescribers or researchers will decide the appropriate amount and dosage regimen.
As used herein, the term "tau pathology" means a neurodegenerative condition characterized by intracellular inclusions, such as flame-shaped or globular neurofibrillary tangles and/or neuropil threads (fine filamentous structures found primarily in dendrites), which include insoluble phosphorylated forms of tau. Tau pathologies include Alzheimer's disease, progressive supranuclear palsy, Pick's disease, corticobasal degeneration and fronto- temporal dementia linked to chromosome 17 with parkinsonism (FTDP-17T).
As used herein, the terms "neurodegenerative condition" and "neurodegenerative disease" are used interchangeably in this document and mean diseases of the nervous system (e.g., the central nervous system or peripheral nervous system) characterized by abnormal cell death. Examples of neurodegenerative conditions include Alzheimer disease, Down's syndrome, frontotemporal dementia, progressive supranuclear palsy, Pick's disease, Niemann-Pick disease, Parkinson's disease, Huntington's disease (HD), dentatorubropallidoluysian atrophy, Kennedy's disease (also referred to as spinobulbar muscular atrophy), and spinocerebellar ataxia (e.g., type 1 , type 2, type 3 (also referred to as Machado-Joseph disease), type 6, type 7, and type 17)), fragile X (Rett's) syndrome, fragile XE mental retardation, Friedreich's ataxia, myotonic dystrophy, spinocerebellar ataxia type 8, and spinocerebellar ataxia type 12, Alexander disease, Alper's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also referred to as Spielmeyer-Vogt-Sjogren- Batten disease), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, ischemia stroke, Krabbe disease, Lewy body dementia, multiple sclerosis, multiple system atrophy, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, Refsum's disease, Sandhoff disease, Schilder's disease, spinal cord injury, spinal muscular atrophy, Steele-Richardson-Olszewski disease, and Tabes dorsalis.
As used herein, the term "neurodegenerative conditions associated with mitochondrial dysfunction" means a neurodegenerative condition that is characterized by or implicated by mitochondrial dysfunction. Exemplary neurodegenerative conditions associated with mitochondrial dysfunction include, without limitation, Friedrich's ataxia, amyotrophic lateral sclerosis, mitochondrial myopathy, encephalopathy, lactacidosis, stroke (MELAS), myoclonic epilepsy with ragged red fibers (MERFF), epilepsy, Parkinson's disease, Alzheimer's disease, and Huntington's Disease.
The terms "subject" and "patient" are used herein interchangeably. They refer to a human or another mammal (e.g., mouse, rat, rabbit, dog, cat, cattle, swine, sheep, horse or primate) that can be afflicted with or is susceptible to a disease or disorder (e.g., AD) but may or may not have the disease or disorder. In certain embodiments, the subject is a human being.
As used herein, the term "alkyl" is intended to include linear (i.e., unbranched or acyclic), branched, cyclic, or polycyclic non aromatic hydrocarbon groups, which are optionally substituted with one or more functional groups. Unless otherwise specified, "alkyl" groups contain one to eight, and preferably one to six carbon atoms. C|_6 alkyl, is intended to include C| , C2, C3, C4, C5, and C6 alkyl groups. Lower alkyl refers to alkyl groups containing 1 to 6 carbon atoms. Examples of Alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, isopentyl tert-pentyl, cyclopentyl, hexyl, isohexyl, cyclohexyl, etc. Alkyl may be substituted or unsubstituted. Illustrative substituted alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxy ethyl, 3-hydroxypropyl, benzyl, substituted benzyl, phenethyl, substituted phenethyl, etc.
As used herein, the term "Alkoxy" means a subset of alkyl in which an alkyl group as defined above with the indicated number of carbons attached through an oxygen bridge. For example, "alkoxy" refers to groups -O-alkyl, wherein the alkyl group contains 1 to 8 carbons atoms of a linear, branched, cyclic configuration. Examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, t-butoxy, n-butoxy, s-pentoxy and the like.
As used herein, the term "Haloalkyl" is intended to include both branched and linear chain saturated hydrocarbon having one or more carbon substituted with a Halogen. Examples of haloalkyl, include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl and the like.
As used herein, the term "alkenyl" is intended to include hydrocarbon chains of linear, branched, or cyclic configuration having one or more unsaturated Carbon-carbon bonds that may occur in any stable point along the chain or cycle. Unless otherwise specified, "alkenyl" refers to groups usually having two to eight, often two to six carbon atoms. For example, "alkenyl" may refer to prop-2-enyl, but-2-enyl, but-3-enyl, 2-mefhylprop-2-enyl, hex-2-enyl, hex-5-enyl, 2,3-dimethylbut-2-enyl, and the like. Furthermore, alkenyl groups may be substituted or unsubstituted.
As used herein, the term "alkynyl" is intended to include hydrocarbon chains of either linear or branched configuration, having one or more carbon-carbon triple bond that may occur in any stable point along the chain. Unless otherwise specified, "alkynyl" groups refer refers to groups having two to eight, preferably two to six carbons. Examples of "alkynyl" include, but are not limited to prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl, 3-methylpent- 4-ynyl, hex-2-ynyl, hex-5-ynyl, etc. Furthermore, alkynyl groups may be substituted or unsubstituted.
As used herein, the term "Cycloalkyl" is a subset of alkyl and includes any stable cyclic or polycyclic hydrocarbon groups of from 3 to 13 carbon atoms, any of which is saturated. Examples of such cycloalkyl include, but are not limited to cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, and the like, which, as in the case of other alkyl moieties, may optionally be substituted. The term "cycloalkyl" may be used interchangeably with the term "carbocycle".
As used herein, the term "Cycloalkenyl" is a subset of alkenyl and includes any stable cyclic or polycyclic hydrocarbon groups of from 3 to 13 carbon atoms, preferably from 5 to 8 carbon atoms, which contains one or more unsaturated carbon-carbon double bonds that may occur in any point along the cycle. Examples of such cycloalkenyl include, but are not limited to cyclopentenyl, cyclohexenyl and the like.
As used herein, the term "Cycloalkynyl" is a subset of alkynyl and includes any stable cyclic or polycyclic hydrocarbon groups of from 5 to 13 carbon atoms, which contains one or more unsaturated carbon-carbon triple bonds that may occur in any point along the cycle. As in the case of other alkenyl and alkynyl moieties, cycloalkenyl and cycloalkynyl may optionally be substituted.
As used herein, the terms "Heterocycle", "heterocyclyl", or "heterocyclic" as used herein refers to non-aromatic ring systems having five to fourteen ring atoms, preferably five to ten, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, or S. Non-limiting examples of heterocyclic rings include 3-1 H- benzimidazol-2-one, (l -substituted)-2-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl, 3- tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholinyl, 3- morpholinyl, 4-morpholinyl, 2-thiomorpholinyl, 3-fhiomorpholinyl, 4-thiomorpholinyl, 1- pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1 -piperazinyl, 2-piperazinyl, 1 -piperidinyl, 2- piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1 -phthalimidinyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, and benzothianyl. Also included within the scope of the term "heterocyclyl" or "heterocyclic", as it is used herein, is a group in which a non-aromatic heteroatom- containing ring is fused to one or more aromatic or non-aromatic rings, such as in an indolinyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the non-aromatic heteroatom-containing ring. The term "heterocycle", "heterocyclyl", or "heterocyclic" whether saturated or partially unsaturated, also refers to rings that are optionally substituted.
As used herein, the term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxy-alkyl", refers to aromatic ring groups having six to fourteen ring atoms, such as phenyl, 1-naphthyl, 2-naphthyl, 1 -anthracyl and 2-anthracyl. An "aryl" ring may contain one or more substituents. The term "aryl" may be used interchangeably with the term "aryl ring". "Aryl" also includes fused polycyclic aromatic ring systems in which an aromatic ring is fused to one or more rings. Non-limiting examples of useful aryl ring groups include phenyl, hydroxyphenyl, halophenyl, alkoxyphenyl, dialkoxyphenyl, trialkoxyphenyl, alkylenedioxyphenyl, naphthyl, phenanthryl, anthryl, phenanthro and the like, as well as 1 - naphthyl, 2-naphthyl, 1 -anthracyl and 2-anthracyl. Also included within the scope of the term "aryl", as it is used herein, is a group in which an aromatic ring is fused to one or more non- aromatic rings, such as in a indanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring.
As used herein, the term "heteroaryl" as used herein refers to stable heterocyclic, and polyheterocyclic aromatic moieties having 5 - 14 ring atoms. Heteroaryl groups may be substituted or unsubstituted and may comprise one or more rings. Examples of typical heteroaryl rings include 5-membered monocyclic ring groups such as thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl and the like; 6- membered monocyclic groups such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like; and polycyclic heterocyclic ring groups such as benzothienyl, naphtho[2,3- b]thienyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, benzothiazole, benzimidazole, tetrahydroquinoline cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, phenoxazinyl, and the like (see e.g. atritzky, Handbook of Heterocyclic Chemistry). Further specific examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2- triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzoisoxazolyl. Heteroaryl groups further include a group in which a heteroaromatic ring is fused to one or more aromatic or nonaromatic rings where the radical or point of attachment is on the heteroaromatic ring. Examples include tetrahydroquinoline, tetrahydroisoquinoline, and pyrido[3,4-d]pyrimidinyl, imidazo[ l ,2-a]pyrimidyl, imidazo[ l ,2-a]pyrazinyl, imidazo[ l ,2- ajpyiridinyl, imidazo[ l ,2-c]pyrimidyl, pyrazolo[ l ,5-a][ l ,3,5]triazinyl, pyrazolo[ l ,5- c]pyrimidyl, imidazo[l ,2-b]pyridazinyl, imidazo[l ,5-a]pyrimidyl, pyrazolo[ l ,5- b][ l ,2,4]triazine, quinolyl, isoquinolyl, quinoxalyl, imidazotriazinyl, pyrrolo[2,3-d]pyrimidyl, triazolopyrimidyl, pyridopyrazinyl. The term "heteroaryl" also refers to rings that are optionally substituted. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".
Methods
The ability of a compound to accumulate to pharmacologically relevant levels in the brain is a function of a series of factors. A partial list of such factors includes the ability of the compound to diffuse away from any protein binding in the blood, cross the blood brain barrier to enter the brain, avoid active removal by the p-Glycoprotein efflux pump and survive metabolic or other clearance mechanisms in the brain. Those individual characteristics, let alone their net cumulative net effect, cannot yet be predicted with useful precision and confidence based on the chemical structure of a given compound and therefore depend on empirical determination. Unfavorable behavior in any one of those characteristics can rule out effective accumulation in brain.
In pharmacokinetic experiments in rodents, we have found that the potent targeted tyrosine kinase inhibitor, ponatinib, not only reaches the brain and accumulates, but actually accumulates in the brain to levels between two- and three-fold higher than in blood. This was an unexpected fortuitous finding. The very favorable accumulation of ponatinib in brain combined with its significant inhibitory potency against kinases such as Abl, PDGFR, c-kit and src permits delivery of pharmacologically relevant concentrations of drug to the brain, e.g., at levels effective to inhibit ß-amyloid production or regulate tau phosphorylation in the brain which has been associated with the development of neurodegenerative disorders including AD. For a kinase inhibition profile of ponatinib, including a partial list of kinases inhibited with inter alia an IC50 below 50 nM and of kinases inhibited with an IC50 below 10 nM, see O'Hare et al, Cancer Cell 16:401 -412 (2009)(Supplemental Data) and the examples disclosed herein. While not limiting this invention to any one mechanism of action, the ability of this potent agent to accumulate as it does in brain makes ponatinib a very attractive agent for treating neurodegenerative conditions including AD. As discussed herein, this disclosure provides a method for treating neurodegenerative disorders by administering to a patient in need thereof an effective amount of a compound of Formula I such as ponatinib or a pharmaceutically acceptable salt thereof.
In certain embodiments, this disclosure provides a method for treating or inhibiting the development of neurodegenerative disorders including Alzheimer's disease including the steps of: (a) providing a subject having, or at risk of, neurodegenerative disorders including Alzheimer's disease; and (b) administering to the subject a compound of Formula I in an amount effective to treat, or inhibit the development of, neurodegenerative disorders including Alzheimer's disease.
In certain embodiments, this disclosure provides a method for treating or inhibiting the development of Alzheimer's disease including the steps of: (a) providing a subject having or at risk of developing Alzheimer's disease; and (b) administering to the subject a compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce the activity of ?-secretase in the brain of the subject.
In any of the above methods, the neurodegenerative condition can be Parkinson's disease, Alzheimer's disease, multiple sclerosis, or any other neurodegenerative disease described herein. In particular embodiments, the neurodegenerative condition is associated with mitochondrial dysfunction (e.g., Friedrich's ataxia, amyotrophic lateral sclerosis, mitochondrial myopathy, encephalopathy, lactacidosis, stroke (MELAS), myoclonic epilepsy with ragged red fibers (MERFF), epilepsy, or Huntington's Disease). In some embodiments, the neurodegenerative condition is a tau pathology (e.g., progressive supranuclear palsy, Pick's disease, corticobasal degeneration, or fronto-temporal dementia linked to chromosome 17 with parkinsonism). Therapy
The method of this invention may be carried out at the patient's residence, the doctor's office, a clinic, a hospital's outpatient department, or elsewhere. Treatment may be initiated at a hospital so that the doctor can observe the therapy's effects directly and make any adjustments that may be needed. The duration of the therapy depends on the age and condition of the patient, the stage of the patient's a neurodegenerative condition, and how the patient responds to the treatment. Additionally, a person at greater risk of developing a neurodegenerative condition (e.g., a person who is genetically predisposed) may receive ponatinib therapy to inhibit or delay onset, progression or symptoms of the disease.
The method of this invention may be used to treat neurodegenerative conditions that have been linked to mitochondrial dysfunction. Many progressive neurological diseases have been linked to destruction of neurons by mitochondrial apoptosis. Friedrich's ataxia results from a genetic defect in the frataxin gene, which is involved in mitochondrial iron transport (Babcock et al, Science 276: 1709 (1997)); human deafness dystonia results from a defect in a small component of the mitochondrial protein import machinery (Koehler et al, Proc. Natl. Acad. Sci. USA 96:2141 ( 1999)); one well-characterized cause of amyotrophic lateral sclerosis is deficiency in Cu-Zn superoxide dismutase, which is located in the mitochondrial intermembrane space as well as the cytoplasm (Deng et al., Science 261 : 1047 (1993)). The discovery that several environmental toxins cause Parkinsonism by inhibiting respiratory complex I and promoting the generation of reactive oxygen species has made this complex a focus for research on the basis of Parkinson's disease (Dawson et al., Science 302:819 (2003)). More recently, the mitochondrial protein encoded by PINK 1 has provided a direct link between mitochondria and Parkinson's disease (Valente et al., Science 304: 1 158 (2004)). Alzheimer's disease is also linked to mitochondrial toxicity through the mitochondrial protein ABAD, a target of amyloid (Lustbader et al., Science 304:448 (2004)). Huntington's Disease has been associated with defects in energy metabolism that appear to be widespread, affecting both the brain and peripheral tissues, and arising from mitochondrial dysfunction (Leegwater- Kim et al., NeuroRx 1 : 128 (2004)).
The method of this invention can be used to treat neurodegenerative conditions characterized by the accumulation of misfolded proteins including, without limitation, Parkinson's disease, Alzheimer's disease and tau pathologies. Alzheimer's Disease
AD is characterized by a progressive decline in cognitive functions. Neuropathologies of the disease include the accumulation of tangles, ß-amyloid containing plaques, dystrophic neurites, and loss of synapses and neurons (Selkoe, D. et al., Alzheimer's Disease, Ed2. Terry R. et al., eds. pg. 293-310, 1999. Philadelphia: Lippincott, Williams and Wilkins), but these pathologies are preceded by deficits in spatial and long-term memory generation (Vitolo et al., Proc Natl Acad Sci USA. 99: 13217 (2002)). AD exists as sporadic as well as heritable familial forms. While the sporadic version is more prevalent, study of familial AD may provide insight into sporadic AD since pathologies of both are similar. Familial AD results from mutations in the presenilin genes, an essential component of the ?- secretase enzyme complex; or amyloid precursor proteins, a substrate of ?-secretase and the precursor of ß-amyloid. These mutations result in the accumulation of ß-amyloid protein plaques in the brains of affected individuals.
One set of criteria for the diagnosis of AD includes: (i) dementia established by examination and objective testing; (ii) deficits in two or more cognitive areas; (iii) progressive worsening of memory and other cognitive functions; (iv) no disturbance in consciousness; and (v) Onset between ages 40 and 90. Parkinson's Disease
The presence of one or more of the following symptoms may be used as part of a Parkinson's Disease (PD) diagnosis: trembling, e.g., an involuntary, rhythmic tremor of one arm or one leg; muscular rigidity, stiffness, or discomfort; general slowness in any of the activities of daily living, e.g., akinesia or bradykinesia; difficulty with walking, balance, or posture; alteration in handwriting; emotional changes; memory loss; speech problems; and difficulty sleeping. Review of a patient's symptoms, activity, medications, concurrent medical problems, or possible toxic exposures can be useful in making a PD diagnosis. In addition, a patient may be tested for the presence or absence of genetic mutations that can indicate an increased likelihood of having or developing a neurodegenerative condition. For example, the presence of one or more specific mutations or polymorphisms in the NURR1 , alpha-synuclein, parkin, MAPT, DJ- 1 , PINK 1 , SNCA, NAT2, or LRR 2 genes may be used to diagnose a patient as having or being at risk of having a neurodegenerative condition. See, e.g., U.S. Patent Application Publication Nos. 2003-01 19026 and 2005-0186591 ; Bonifati, Minerva Med. 96: 175-186, 2005; and Cookson et al., Curr. Opin. Neurol. 18:706-71 1 , 2005, each of which is hereby incorporated by reference.
Compounds of Formula I
As discussed herein, certain targeted TKI's have been found to be suitable candidates for the treatment of neurodegenerative conditions for their ability to inhibit certain tyrosine kinases such as PDGFR, src and c-kit and cross the blood-brain barrier. One class of such targeted TKI's includes the compounds disclosed in WO 2007/075869.
Targeted TKI's suitable for the presently disclosed methods and pharmaceutical compositions are compounds of Formula I:
[Image Omitted]
Formula I
or a tautomer, or an individual isomer or a mixture of isomers thereof wherein: Ring T is a 5-membered heteroaryl ring containing 1 or 2 nitrogens with the remaining ring atoms being carbon, substituted on at least two ring atoms with R' groups, at least two of which being located on adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, partially saturated or unsaturated 5- or 6- membered ring (Ring E), containing 0-3 heteroatoms selected from O, N, and S and being optionally substituted with 1 -4 Re groups;
Ring A is a 5- or 6-membered aryl or heteroaryl ring and is optionally substituted with 1 -4 Ra groups;
Ring B is a 5- or 6-membered aryl or heteroaryl ring;
L1 is selected from NR'C(O), C(0)NR' , NR'C(0)0, NR' C(0)NR' , and OC(0)NR' ; each occurrence of Ra, Rb and R' is independently selected from the group consisting of halo, -CN, -N02, -R\ -OR2, -NR2R3, -C(0)YR2, -OC(0)YR2, -NR C(0)YR2, -SC(0)YR2, - NR C(=S)YR2, -OC(=S)YR2, -C(=S)YR2, -YC(=NR3)YR2, -YP(=0)(YR4)(YR4), -Si(R2)3, - NR2S02R2, -S(0)rR2, -S02NR2R3 and -NR2S02NR2R3, wherein each Y is independently a bond, -0-, -S- or -NR3-;
Re, at each occurrence, is independently selected from the group consisting of halo, =0, -CN, -NO2, -R4, -OR2, -NR2R3, -C(0)YR2, -OC(0)YR2, -NR2C(0)YR2, -SC(0)YR2, - NR2C(=S)YR2, -OC(=S)YR2, -C(=S)YR2, -YC(=NR3)YR2, -YP(=0)(YR4)(YR4), -Si(R2)3, - NR2S02R2, -S(0)rR2, -S02NR2R3 and -NR2S02NR2R3, wherein each Y is independently a bond, -0-, -S- or -NR3-;
R1 , R2 and R3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; alternatively, R2 and RJ, taken together with the atom to which they are attached, form a 5- or 6- membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from N, O and S(0)r; each occurrence of R4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl moieties is optionally substituted; m is 0, 1 , 2, 3 or 4;
n is 2 or 3;
p is 0, 1 , 2, 3, 4 or 5; and,
r is 0, 1 or 2; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
The following portions of this section disclose various subgenuses of compounds of Formula I. In each subgenus, any variable not explicitly mentioned has the meaning defined by the genus immediately above, unless explicitly indicated otherwise.
In certain embodiments , Ring T is:
[Image Omitted]
wherein Ring E is a 5- or 6-membered unsaturated ring comprising 0-3 heteroatoms selected from O, N, and S, and s is 0, 1 , 2, 3 or 4.
Compounds useful for methods and pharmaceutical compositions disclosed herein include those in which Ring T has the following structure:
[Image Omitted]
where Ring E is a 5- or 6-membered unsaturated ring (formed by two Rt groups together with the Ring T atoms to which they are attached, as described above) and s is 0, 1 , 2, 3 or 4. These are illustrated by the compounds of Formula I in which the fused Ring T ring system is one of the following (in which one of the optional Re substituents is depicted): [Image Omitted]
In certain embodiments in the compounds of Formula I, Ring T is a bicyclic heteroaryl ring selected from:
[Image Omitted]
and s is 0, 1 , 2, 3 or 4.
For the previously described class and subclasses of compounds, as in all compounds of this invention, Ring A and Ring B are as previously defined.
[Image Omitted]
In certain embodiments in the compounds of Formula I, Ring B is a 5 or 6-membered aryl or heteroaryl ring as defined herein.
In certain of these embodiments. Ring B is:
[Image Omitted]
[Image Omitted]
In certain embodiments in the compounds of Formula I, Rings A and B are aryl.
In certain embodiments in the compounds of Formula I, one of the Rb substituents is a 5- or 6-membered ring (Ring C), which may be heteroaryl or heterocyclic, comprising carbon atoms and 1 -3 heteroatoms independently selected from O, N and S(0)r, and Ring C being optionally substituted on carbon or heteroatom(s) with 1 to 5 substituents Rc.
In certain embodiments, the targeted TKI is a compound of the Formula II:
[Image Omitted]
Formula II
wherein:
Ring C is a 5- or 6-membered heterocyclic or heteroaryl ring, comprising carbon atoms and 1 -3 heteroatoms independently selected from O, N and S(0)r;
R°, at each occurrence, is independently selected from halo, =0, -CN, -N02, -R4, - OR2, -NR2R3, -C(0)YR2, -OC(0)YR2, -NR2C(0)YR2, -Si(R2)3, -SC(0)YR2, -NR2C(=S)YR2, -OC(=S)YR2, -C(=S)YR2, -YC(=NR3)YR2, -YP(=0)(YR4)(YR4), -NR2S02R2, -S(0)rR2, - S02NR2R3 and -NR2S02NR2R3, wherein each Y is independently a bond, -0-, -S- or -NR3-; and,
v is O, 1 , 2, 3, 4 or 5.
In certain of these embodiments, Ring C is selected from the group consisting of:
[Image Omitted] in which Rc and v are as defined above. In certain embodiments in the compounds of Formula I where Ring C is present, Rings A and B are aryl.
In certain embodiments in the compound of Formula I where Ring C is present, Ring T is:
[Image Omitted]
wherein Ring E is a 5- or 6-membered unsaturated ring comprising 0-3 heteroatoms selected from O, N, and S, and s is 0, 1 , 2, 3 or 4. Illustrative subsets of such compounds of Formula I include those having the following structures:
[Image Omitted] [Image Omitted]
as embodied by the following non-limiting illustrative examples:
[Image Omitted]
In certain embodiments in the compounds of Formula I, Ring C is imidazolyl. Compounds of interest include among others, compounds of Formula II in which Ring C is an imidazole ring, optionally substituted with one or more Rc groups. Of particular interest, are compounds of this subclass in which Ring C bears a single lower alkyl (e.g., methyl) Rc group.
In certain of these embodiments where Ring C is imidazolyl, the targeted T I is a compound selected from Formulae Ila, lib, or lie:
[Image Omitted]
Formula Ila [Image Omitted]
Formula lie.
In certain embodiments within these embodiments, s is 0; m, p and v are 1 ; Ra and Rc are methyl; and Rb is CF3.
In certain embodiments in the compounds of Formula I, the targeted TKI is a compound of the formula:
[Image Omitted]
wherein:
Ring D represents a 5-, 6-heterocyclic or heteroaryl ring comprising carbon atoms and 1 -3 heteroatoms independently selected from O, N and S(0)r; L2 is (CH2)z, 0(CH2)x, NR3(CH2)X, S(CH,)X or (CH2)xNR3C(0)(CH2)x in either direction;
RD, at each occurrence, is selected from the group consisting of H, halo, =0, -CN, - N02, -R4, -OR2, -NR2R3, -C(0)YR2, -OC(0)YR2, -NR2C(0)YR2, -SC(0)YR2, - NR2C(=S)YR2, -OC(=S)YR2, -C(=S)YR2, -YC(=NR3)YR2, -YP(=0)(YR4)(YR4), -Si(R2)3, - NR2S02R2, -S(0)RR2, -S02NR2R3 and -NR2SO,NR2R3, wherein each Y is independently a bond, -0-, -S- or -NR3-;
R1, R2 and R3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl;
alternatively, R2 and RJ, taken together with the atom to which they are attached, form a 5- or 6- membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from N, O and S(0)r; each occurrence of R4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl;
each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl moieties is optionally substituted;
p is 0, 1 , 2, 3 or 4;
w is 0, 1 , 2, 3, 4 or 5;
x is 0, 1 , 2 or 3; and,
z is 1 , 2, 3 or 4.
In certain of these embodiments where Ring D is present, Ring T has the following structure:
[Image Omitted]
wherein Ring E is a 5- or 6-membered unsaturated ring comprising 0-3 heteroatoms selected from O, N, and S, and s is 0, 1 , 2, 3 or 4.
Non-limiting examples of such compounds include those having the following structures:
[Image Omitted]
31 In certain of these embodiments where Ring D is present, Rings A and B are aryl.
In certain of these embodiments where Ring D is present, Ring T is a bicyclic
[Image Omitted]
In certain embodiments in the compounds of Formula I, compounds of interest among others, compounds of Formula III in which Ring D is a piperazine ring, substituted on nitrogen with Rd. Of particular current interest, are compounds of this subclass in which Rd is a substituted or unsubstituted lower (i.e., 1 - 6 carbon) alkyl as illustrated by N- methylpiperazine moieties in some of the following examples. In certain of these embodiments where Ring D is present, Ring D is piperazinyl and L2 is CH2. In certain of these embodiments, the targeted TKI is a compound selected from Formulae Ilia, Illb,
[Image Omitted]
Formula Ilia
[Image Omitted]
Formula Illb
[Image Omitted]
Formula IIIc.
In certain embodiments within these embodiments, s is 0, m is 1 , p is 1 , Ra is methyl, Rb is CF3, and Rd is methyl or -CH2CH2OH.
In certain embodiments in the compounds of Formula II and Formula III, Ring T is any 6/5 fused heteroaryl ring system, optionally substituted with up to three Re groups. Of particular interest are compounds in which s is 0. Also of interest are those in which s is 1 - 3 and at least one Re is halo, lower alkyl, alkoxy, amino, -NH-alkyl, -C(0)NH-alkyl, -NHC(O)- alkyl, -NHC(0)NH-alkyl, -NHC(NH)-alkyl, -NHC(NH)NH2, -NH(CH2)x-heteroaryl, - NH(CH2)x-heterocycle, -NH(CH2)x-aryl or -(CH2)xC(0)NH2, in which x is 0, 1 , 2 or 3 and "alkyl" includes straight (i.e., unbranched and acyclic), branched and cyclic alkyl groups and in which aryl, heteroaryl, heterocyclyl rings are optionally substituted. Illustrative, non- limiting, examples of the foregoing include compounds of Formulas II and III in which Ring T is one of the following:
[Image Omitted]
In certain embodiments in the compounds of Formula II and Formula III, Ring T is an optionally substituted imidazo[l ,2-a]pyridine, imidazo[l ,2-¾]pyridazine, imidazo[ l ,2- ajpyrazine, pyrazolo[l ,5-a]pyrimidine, pyrazolo[l ,5-a]pyridine, pyrazolo[l ,5-c]pyrimidine, and pyrazolo[l ,5-a][l ,3,5]triazine.
In certain of these embodiments in the compounds of Formula II and Formula III, Rings A and B are aryl.
Illustrative, non-limiting examples of this subclass include compounds of Formulas Ha, lib, He, Ilia, Illb and IIIc:
[Image Omitted]
Formula Ha Formula lib
[Image Omitted]
Formula Illb Formula IIIc in which the variables, e.g., Ra, Rb, R°, Rd, Re, m and p, are as previously defined and s is an integer from 0 to 4.
In certain embodiments in the compounds of Formulas Ila, lib and lie, s is 0; m, p and v are 1 ; and, Ra is CH3, Rb is CF3 and Rc is methyl.
In certain embodiments in the compounds of Formulas Ilia, Illb, IIIc, s is 0; m and p are 1 ; and, Ra is CH3, Rb is CF3 and Rd is CH3 or CH2CH2OH.
In certain embodiments, the targeted TKI is a compound selected from the group consisting of:
N-(3 -( 1 H-imidazol- 1 -yl)-5-(trifluoromethy l)phenyl)-3 -(imidazo[ 1 ,2-a]pyrazin-3 - ylethynyl)-4-methylbenzamide;
3-(Imidazo[ 1 ,2-a]pyrazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin- 1 - yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
N-(3-(2-((dimethylamino)methyl)- 1 H-imidazol- 1 -yl)-5-(trifluoromethyl)phenyl)-3- (imidazo[ l ,2-a]pyrazin-3-ylethynyl)-4-methylbenzamide;
3-(Imidazo[ l ,2-cf]pyridin-3-ylethynyl)-4-methyl-Ai-(3-(4-methyl-l //-imidazol-l -yl)- 5-(trifluoromethyl)phenyl)benzamide;
N-(3-( 1 iT-imidazol- 1 -yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[ 1 ,2-a]pyridin-3- ylethynyl)-4-methylbenzamide;
3-(Imidazo[l ,2-a]pyridin-3-ylethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2- yl)benzamide;
N-(5-tert-butylisoxazol-3-yl)-3-(imidazo[l ,2-a]pyridin-3-ylethynyl)-4- methylbenzamide;
3-(Imidazo[l ,2-a]pyridin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin- l - yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; N-(3-(2-((dimethylamino)methyl)-l H-imidazol-l -yl)-5-(trifluoromethyl)phen (imidazo[ 1 ,2-a]pyridin-3-ylethynyl)-4-methylbenzamide;
3- ((8-Acetamidoimidazo[ l ,2-a]pyridin-3-yl)ethynyl)-4-methyl-N-(4- (trifluoromethyl)pyridin-2-yl)benzamide;
N-(3-( l H-imidazol-l-yl)-5-(trifluoromethyl)phenyl)-3-((8-acetamidoirnidazo[l ,2- ]pyridin-3-yl)ethynyl)-4-methylbenzamide;
4- Methyl-3-((8-(4-(methylsulfonyl)phenylamino)imidazo[l ,2-o]pyridin-3- yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamidei
4-methyl-3-((8-(4-sulfamoylphenylamino)imidazo[l ,2-o]pyridin-3-yl)ethynyl)-N-(4- (trifluoromethyl)pyridin-2-yl)benzamide;
(R)-N-(4-((3-(Dimethylamino)pyrrolidin- l -yl)methyl)-3-(trifluoromethyl)pheny (imidazo[ 1 ,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide;
N-(3-(Imidazo[ l ,2-b]pyridazin-3-ylethynyl)-4-methylphenyl)-4-((4-methylpiperazin- l -yl)methyl)-3-(trifluoromethyl)benzamide;
3-(Imidazo[ l ,2-b]pyridazin-3-ylethynyl)-4-rnethyl-N-(4-((4-methylpiperazin- l - yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
N-(3-Chloro-4-((4-methylpiperazin-l -yl)methyl)phenyl)-3-(imidazo[ l ,2-b]pyridazin- 3-ylethynyl)-4-methylbenzamide;
N-(3-Cyclopropyl-4-((4-methylpiperazin-l -yl)methyl)phenyl)-3-(imidazo[l ,2- b]pyridazin-3-ylethynyl)-4-methylbenzamide;
3-(Imidazo[l ,2-b]pyridazin-3-ylethynyl)-N-(4-((4-methylpiperazin- l -yl)rnethyl)-3- (trifluoromethyl)phenyl)benzamide;
N-(4-((4-(2-Hydroxyethyl)piperazin-l -yl)methyl)-3-(trifluoromethyl)phenyl)-3- (imidazof 1 ,2-b]pyridazin-3-y lethynyl)-4-methylbenzamide; and
3-(Imidazo[ l ,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-(piperazin-l -ylrnethyl)-3- (trifluoromethyl)phenyl)benzamide,
or a pharmaceutically acceptable salt thereof.
A targeted TKI of particular interest that is useful for the presently disclosed methods and pharmaceutical compositions is 3-(Imidazo[ l ,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4- ((4-methylpiperazin- l -yl)methyl)-3-(trifluoromethyl)phenyl)benzamide or a pharmaceutically acceptable salt thereof. A pharmaceutically acceptable salt of particular interest for this compound (ponatinib) is its hydrochloride salt.
In certain embodiments in the compounds of Formula I, the targeted tyrosine kinase inhibitor is a compound of the formula:
[Image Omitted]
wherein:
L' is NR'CtOj or CXC NR1;
Ring D is a 5- or 6-membered heterocyclyl or heteroaryl ring comprising carbon atoms and 1 -3 heteroatoms independently selected from O, N, and S(0)r;
Ring C is a 5-or 6-membered heterocyclyl or heteroaryl ring, comprising carbon atoms and 1 -3 heteroatoms independently selected from O, N, and S(0)r;
[Image Omitted]
each occurrence of Ra is independently selected from the group consisting of halo, alkyl, and cycloalkyl;
each occurrence of Rb is independently selected from the group consisting of halo, alkyl, and cycloalkyl;
each occurrence of Rc is independently selected from the group consisting of halo, alkyl, and cycloalkyl;
each occurrence of Rd is independently selected from the group consisting of halo, alkyl, cycloalkyl, and -NR2RJ;
each occurrence of Re is independently selected from the group consisting of halo, alkyl, cycloalkyl, -NR2R3, alkoxy, amino, -NH-alkyl, -C(0)NH-alkyl, -NHC(0)-alkyl, -
NHC(0)NH-alkyl, -NHC(NH)-alkyl, -NHC(NH)NH2, -NH(CH2)x-heteroaryl, -NH(CH2)X- heterocyclyl, -NH(CH2)x-aryl, and -(CH2)xC(0)NH2, wherein x is 0, 1 , 2 or 3; each of R1, R2 and RJ is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R2 and R3, taken together with the nitrogen atom to which at least one of R2 and R3 is attached, form a 5- or 6- membered heterocyclyl or heteroaryl ring;
each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, =0, =S, =NH, =N R2R:', =NNHC(0)R2, =N HC02R2, and =N HS02R2, and each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy;
m is 0, 1 , 2, 3, or 4;
p is 0, 1 , 2, 3, or 4;
r is 0, 1 , or 2;
s is 0, 1 , 2, or 3;
v is 0, 1 , 2, 3, 4, or 5;
w is 0, 1 , 2, 3, 4, or 5; and
z is 1 , 2, 3 or 4;
or a pharmaceutically acceptable salt thereof.
Formulations, Dosage and Administration
Compounds of Formula I can be formulated into a pharmaceutical composition that comprises a compound of Formula I (as an active pharmaceutical ingredient) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Similarly, ponatinib, or a pharmaceutically acceptable salt thereof, such as the mono HCl salt, can be formulated for administration, such as oral administration, using any of the materials and methods useful for such purposes. Pharmaceutically acceptable compositions containing a compound of Formula I suitable for administration may be formulated using conventional materials and methods, a wide variety of which are well known. While the composition may be in solution, suspension or emulsion form, solid oral dosage forms such as capsules, tablets, gel caps, caplets, etc. are of particular interest for the treatment of PD. Methods well known in the art for making formulations, including the foregoing unit dosage forms, are found, for example, in "Remington: The Science and Practice of Pharmacy" (20th ed., ed. A.R. Gennaro, 2000, Lippincott Williams & Wilkins). A compound of Formula I such as ponatinib (or a pharmaceutically acceptable salt thereof) may be provided neat in capsules, or combined with one or more optional, pharmaceutically acceptable excipients such as fillers, binders, stabilizers, preservatives, glidants, disintegrants, colorants, film coating, etc., as illustrated below.
For example, white opaque capsules were prepared containing nominally 2 mg of ponatinib free base, provided as the hydrochloride salt, with no excipients. White opaque capsules were also prepared containing 5 mg, 15 mg, or 20 mg of ponatinib free base, provided as the hydrochloride salt, mixed with conventional excipients. Inactive ingredients used as excipients in an illustrative capsule blend include one or more of a filler, a flow enhancer, a lubricant, and a disintegrant. For instance, a capsule blend was prepared for the 5, 15 and 20 mg capsules, containing the ponatinib HC1 salt plus colloidal silicon dioxide (ca. 0.3% w/w, a flow enhancer), lactose anhydrous (ca. 44.6% w/w, a filler), magnesium stearate (ca. 0.5% w/w, a lubricant), microcrystalline cellulose (ca. 44.6% w/w, a filler), and sodium starch glycolate (ca. 5% w/w, a disintegrant). The capsule shell contains gelatin and titanium dioxide.
The formulation process used conventional blending and encapsulation processes and machinery. The hydrochloride salt of ponatinib and all blend excipients except magnesium stearate were mixed in a V-blender and milled through a screening mill. Magnesium stearate was added and the material was mixed again. The V-blender was sampled to determine blend uniformity. The blend was tested for bulk density, tap density, flow, and particle size distribution. The blend was then encapsulated into size "3", size "4", or size "1 " capsule shells, depending upon the strength of the unit dosage form.
Ponatinib was also formulated into tablets using conventional pharmaceutical excipients, including one or more of a filler or a mixture of fillers, a disintegrant, a glidant, a lubricant, a film coating, and a coating solvent in a blend similar to that used in the higher strength capsules. For example, tablets may be prepared using the following relative amounts and proportions (weight/weight): ponatinib (90 g provided as the HC1 salt, 15.0% w/w), colloidal silicon dioxide ( 1.2 g, 0.2% w/w), lactose monohydrate (240.9 g, 40.15% w/w), magnesium stearate (3 g, 0.5% w/w), microcrystalline cellulose (240.9 g, 40.15% w/w), and sodium starch glycolate (24 g, 4.0% w/w), with the amount of lactose monohydrate adjusted based on the amount of drug used.
Ponatinib and the excipients may be mixed using the same sort of machinery and operations as was used in the case of capsules. The resultant, uniform blend may then be compressed into tablets by conventional means, such as a rotary tablet press adjusted for target tablet weight, e.g. 300 mg for 45 mg tablets or 100 mg for 15 mg tablets; average hardness of e.g., 13 kp for 45 mg tablets and 3 kp for 15 mg tablets; and friability no more than 1 %. The tablet cores so produced may be sprayed with a conventional film coating material, e.g., an aqueous suspension of Opadry® II White, yielding for example a -2.5% weight gain relative to the tablet core weight.
After formulation with an appropriate pharmaceutically acceptable carrier in a desired dosage, the compositions of disclosed herein can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by transdermal patch, powders, ointments, or drops), sublingually, bucally, as an oral or nasal spray, or the like.
In accordance with the methods, kits, and pharmaceutical compositions of the invention, a treatment will typically consist of a plurality of doses of a compound of Formula I that is administered over a period of time. Administration may be one or multiple times daily, weekly (or at some other multiple day interval) or on an intermittent schedule, with that cycle repeated a given number of times (e.g., 2-10 cycles) or indefinitely.
Optimal dosing will depend in part on the route of administration. Effective doses may be calculated according to the body weight or body surface area. Optimization of the appropriate dosages can readily be made by one skilled in the art in light of pharmacokinetic data observed in human clinical trials. The final dosage regimen will be determined by the attending physician, considering various factors which modify the action of the drugs, e.g., the drug's specific activity, the severity of the damage and the responsiveness of the subject, the age, condition, body weight, sex and diet of the subject, and other clinical factors.
In certain embodiments, a compound of Formula I is administered at a unit dose of 5 - 80 mg (e.g., from 5 to 10 mg, 10 to 25 mg, 25 to 35 mg, 35 to 50 mg, 50 to 60 mg, or 60 to 80 mg). In certain of these embodiments, the unit dose is 5 - 45 mg or 15 - 45 mg. Preferred dosage strengths for ponatinib include, but are not limited to 15 mg, 30 mg, and 45 mg.
Oral administration is of particular interest in the practice of the various embodiments of this invention, including oral administration on a daily schedule or on an intermittent schedule as mentioned above and at the dose levels mentioned above. By way of non-limiting example, daily oral administration of 5 - 80 mg of ponatinib, and in some cases, 5 - 45mg of ponatinib, are of particular current interest. In certain embodiments, 5, 10, 15, 30 or 45 mg of ponatinib, e.g., ponatinib hydrochloride, are administered orally on a daily basis. The amount and dosing schedule for ponatinib administered in any of the embodiments of the invention may be chosen or adjusted to produce a mean steady state trough concentration for ponatinib in plasma of from 5 to 200 nM (e.g., a mean steady state trough concentration for ponatinib of 5 ± 2 nM, 8 ± 3 nM, 12 ± 3 nM, 15 ± 3 nM, 20 + 5 nM, 30 ± 5 nM, 40 ± 5 nM, 50 + 10 nM, 60 ± 10 nM, 80 + 20 nM, 100 + 20 nM, 120 + 20 nM, 150 ± 25 nM, 175 + 25 nM, or 200 ± 25 nM).
The amount and dosing schedule for ponatinib administered in any of the embodiments of the invention may be chosen or adjusted to be effective to measurably reduce the desired relevant kinase activity and/or ß-amyloid in the brain of the subject.
In certain embodiments, the compound of Formula I is administered to the subject at an average daily dose of 3 ± 1 mg, 5 + 2 mg, 8 + 2 mg, 12 ± 3 mg, 15 ± 3 mg, 20 + 4 mg, 25 + 5 mg, 30 + 6 mg, 40 + 8 mg, 45 + 9 mg, 50 ± 10 mg, or 55 + 1 1 mg.
In certain embodiments, the compound of Formula I is administered to the subject on one or more days per week, including in some cases every day, every other day, every third day as well as schedules, such as, e.g., QDx6, QDx5 QDx4 QDx3 and QDx2 (i.e., 6, 5, 4, 3 or 2 days per week, respectively). On a given day, the drug may be given in one dose or may be divided into two or three doses administered during the course of the day (i.e., qd, bid or tid).
Because compounds of Formula I are orally bioavailable, a compound of Formula I such as ponatinib may be given orally as well as parenterally (e.g., i.v.) or by other pharmaceutically acceptable routes of administration. Thus, the active compounds of the disclosure may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous), rectal administration, in a form suitable for administration by inhalation or insufflation, or the active compounds may be formulated for topical administration.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e^, sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g.. methyl or propyl p-hydroxybenzoates or sorbic acid).
For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner.
For intranasal administration or administration by inhalation, the active compounds of the disclosure are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g.. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the disclosure and a suitable powder base such as lactose or starch.
The active compounds of the disclosure may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Routes of parenteral administration also include intravenous, intramuscular and subcutaneous. Formulations for injection may be presented in unit dosage form, eg., in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
The active compounds of the disclosure may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
For topical administration, a presently disclosed compound may be formulated as an ointment or cream.
Suitable modes of administration also include, but are not limited to, transdermal, vaginal, and ophthalmic.
Synthesis of Compounds of Formula I
The synthesis of compounds of Formula I have been reported in WO 2007/075,869. For the convenience of the reader, the synthetic scheme is reproduced immediately below.
A compound of the present invention could be prepared as outlined in Scheme I to
Scheme XIX and via standard methods known to those skilled in the art. A palladium catalyzed Sonogashira coupling reaction is used to link the 'top' Ring T to the 'bottom' [Ring A]-[L']-[Ring B] moiety as illustrated in Scheme I and II. In Scheme I the Sonogashira coupling reaction is performed with an acetylenic 'top' Ring T and a 'bottom' [Ring A]-[L']-[Ring B] moiety which has been activated by the presence of a reactive group, W, which is an I, a Br or another reactive group permitting the desired coupling reaction. The variables in the W-[Ring A]-[L']-[Ring B] are as defined previously, Rings A
[Image Omitted]
Scheme I: Sonogashira Coupling Reaction
An alternative coupling reaction is described in Scheme II, in which Ring T is "activated" by the presence of a reactive group W (such as I or Br) and is coupled to the 'bottom' acetylenic [RingA]-L -[RingB] under similar Palladium catalyzed coupling conditio
[Image Omitted]
Scheme H: Alternative Sonogashira Coupling Reaction
The Sonogashira coupling conditions described in Scheme I and II are applicable to all bicyclic heteroaryl Ring T's and useful to synthesize the compounds disclosed herein.
Several illustrative overall synthetic approaches to the preparation of the acetylenic Ring T moieties, based on known transformations, are illustrated below in Schemes III to VIII: [Image Omitted]
III: Preparation of 3-Ethynylimidazo[l,2-a]pyrazine
[Image Omitted]
Scheme IV: Preparation of C-8 Substituted 3-Ethynylimidazo| l,2-a]pyrazines
[Image Omitted]
Scheme V: Preparation of 3-Ethynylimidazo|l,2-a]pyridine or
3-Ethynylimidazo|l,2-b]pyridazine
[Image Omitted]
Scheme VI: Preparation of C-8 Amino Substituted 3-Ethynylimidazo[l,2-a]pyridines
[Image Omitted]
Scheme VII: Preparation of C-8 substituted 3-Ethynylimidazo( l,2-a]pyridines
[Image Omitted]
Scheme VIII: Preparation of C-6 and C-8 Substituted 3-Ethynylimidazo |l,2-a] pyridines
For the coupling step, see Malleron, J-L., Fiaud, J-C, Legros, J-Y. Handbook of Palladium Catalyzed Organic Reactions. San Diego: academic Press, 1997. As one of ordinary skill in the art would recognize, these methods for the preparation of various substituted acetylenic Ring T groups, are widely applicable to various other fused bicyclic ring systems not shown.
Schemes IX to XIII below depict the synthesis of compounds of the formula W-[Ring A]-[L']-[Ring B] which are useful as intermediates in the coupling reaction described in Schemes I and II.
It should be apparent that intermediates of the formula:
[Image Omitted]
are of particular interest as their coupling reaction with the 'top' heteroaryl rings produces compounds of the present invention. The variable groups A, L1 and B are as previously defined and are optionally substituted as described herein, and W is I or an alternative reactive group permitting the desired coupling reaction.
Illustrative such intermediates include among others those of those following structures".
[Image Omitted]
wherein the variables, e.g., Ra, Rb, Rc and Rd, are as previously defined. For instance, Ra in some embodiments is chosen from F or alkyl, e.g., Me, among others, and Rb in some embodiments is chosen from CI, F, Me, t-butyl, -CF3 or -OCF3 among others. Those and other compounds of the formula W-[Ring A]-[L ]-[Ring B] with the various permitted substituents are useful for preparing the corresponding compounds of the invention as are defined in the various formulae, classes and subclasses disclosed herein.
Some illustrative synthetic routes for the preparation of reagents and representative intermediates are presented below:
Scheme IX describes an illustrative synthesis of W-[Ring A]-[L']-[Ring B] in which Rings A and B are phenyl and L' is NHC(O).
[Image Omitted]
Scheme X
Schemes XI and XII, below, illustrate the synthesis of W-[Ring A]-[L']-[Ring B] in which Rings A and B are phenyl and Ring C is a heteroaryl ring. These intermediates are useful for making compounds of Formula II.
More specifically, Scheme XI describes the preparation of intermediates in which Ring C is an imidazole ring.
[Image Omitted]
Scheme XI Scheme XII describes the preparation of intermediates in which Ring C is a pyrrole or an oxazole ring.
[Image Omitted]
Scheme XII
Scheme XIII illustrates the synthesis of W-[Ring A]-[L ]-[Ring B] in which Rings A and B are phenyl and an Rb substituent is -L2-[Ring D]. These intermediates are useful for making compounds of Formula III in which Ring D is a 5 or 6-membered heterocycle, containing one or two heteroatoms.
[Image Omitted]
Scheme XIII
In this scheme, non-limiting examples of substituents Rb on Ring B are halo, e.g., CI; lower alkyl groups, e.g., isopropyl; and substituted lower alkyl groups, e.g. -CF3 ; and non- limiting examples of Ring D are ?,?-dimethylpyrrolidine, N-(2-hydroxyethyl)piperazine, and N-methylpiperazine.
Intermediates W-[Ring A]-[L*]-[Ring B], such as those presented in the various synthetic schemes above, can be reacted with an acetylenic Ring T using the Sonogashira coupling conditions described in the general Scheme 1.
An example is depicted below in Scheme XIV, in which Ring T moiety can be further derivatized after the Sonogashira coupling step, to generate various interesting substituted analogs of this invention. [Image Omitted]
Scheme XIV
Alternatively, the W-[Ring A]-[L']-[Ring B] can be reacted under Sonogashira conditions with trimethylsilylacetylene, prior to the coupling with an iodo- or a bromo- activated Ring T as otherwise described in the general Scheme II.
in Scheme XV:
[Image Omitted]
In other embodiments, the steps can be carried out in a different order. For example, the Sonogashira Coupling reaction can be used to Ring T to Ring A prior to linking that portion to Ring B and/or [Ring B]-[L2]-[Ring D] and/or [Ring B]-[Ring C] as shown in Scheme XVI.
[Image Omitted]
Scheme XVI
In a non-limiting example in which Ring A and Ring B are phenyl and L is CONH, Scheme XVII describes Sonogashira Coupling of an acetylenic Ring T with 3-iodo-4- methylbenzoic acid (a Ring A moiety) to generate a [Ring T]-[Ring A] intermediate which then undergoes an amide coupling with an optionally substituted Ring B moiety:
[Image Omitted]
Scheme XVII
This approach is illustrated in Scheme XVIII which depicts the coupling of an acetylenic Ring T (i.e., 3- ethynylimidazo[l ,2-b]pyridazine) with a substituted W-[Ring A] (i.e., 3-iodo-4-methylbenzoic acid), followed by an amide coupling of the resultant [Ring T]- [Ring AJ-COOH intermediate with a H2N-[Ring B]-L2-[Ring C] moiety (i.e., 4-((4- methylpiperazin-l -yl)methyl)-3-(trifluoromethylaniline):
[Image Omitted]
Scheme XVIII
Alternatively, as another illustration of the practitioner's range of assembly options, the 3-iodo-4-methylbenzoic acid Ring A intermediate can be reacted in a Sonogashira reaction with trimethyisilylacetylene, which after silyl deprotection, can a second Sonogashira coupling reaction with an activated Ring T as illustrated in Scheme XIX. [Image Omitted]
Scheme XIX
With synthetic approaches such as the foregoing, combined with the examples which follow, additional information provided herein and conventional methods and materials, the practitioner can prepare the full range of compounds disclosed herein.
In addition to the general synthetic approaches disclosed above, the synthesis of ponatinib free base and ponatinib hydrochloride have been specifically reported in Applicant's own WO 201 1/053,938, which is incorporated here by reference. For the convenience of the reader, the synthetic scheme is reproduced immediately below.
Ponatinib Synthesis: Scheme 1
Steps 1 and 2
M [Image Omitted] ol. Wt. 198.02 .15
Steps 3 and 4 [Image Omitted]
3-lodo-4-methy benzoic Acid
¾?5?3 C8H7I02 Ci6HiiN3¾ C16H11CI2N302 Mol. Wt. 143.15 Mol. Wt. 26204 Mol. Wt. 277.28 Mol. Wt. 332.18
Ste s 5 and 6 [Image Omitted]
Ponatinib (as free base) Ponatinib HCI
CieHnCbNjOs C29H27F3N60 C 8CIF3N60 Mol. Wt. 332.18 Mol. Wt. 273.30 Mol. Wt. 532.56 Mol. Wt. 569.02
5 Ponatinib Synthesis: Scheme 2
Steps 4 and 5
[Image Omitted]
C,7H13N302 Cl3H18F3N3 C29H27F3N60 C29H28CIF3N60 Mol. Wt. 291.30 Mol. Wt. 273.30 Mol. Wt. 532.56 Mol. Wt. 569.02
5
The mono-hydrochloride salt of ponatinib has been used for carrying out clinical trials. Further identifying information for ponatinib includes:
Chemical name: 3-(Imidazo[ l ,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4- methylpiperazin-l -yl)methyl)-3-(trifluoromethyl)phenyl)benzamide,
0 hydrochloride salt;
USAN: ponatinib;
USANM: ponatinib hydrochloride;
CAS Registry No.: 1 1 14544-3 1 -8 (HCl Salt) and 943319-70-8 (free base);
CAS Index name: Benzamide,3-(2-imidazo[ l ,2-b]pyridazin-3-ylethnyl)-4-methyl-N- 5 [4-[(4-methyl- 1 -piperazinyl)methyl]-3-(trifiuoromethyl)phenyl]-hydrochloride ( 1 : 1 );
Molecular Formula: C29H28C1F3N60 (HCl salt) and C29H27F3N60 (free base) (no chiral centers); and
Molecular Weight: 569.02 g/mol (HCl salt) and 532.56 g/mol (free base). 0 Exemplary Compounds of Formula I
Some of the compounds described in the following examples have been converted into an HCl salt. The general procedure for generating HCl salts is described below:
To the final product was added just enough MeOH saturated with HCl (g) to dissolve, cooled to 0 °C for 0.5-1 h, filtered, washed solid with ice cold MeOH then Et20, and the 5 resulting solid dried in a vacuum desiccator to provide in most cases the tris HCl salt.
Example 1
N-(3-(lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[l,2-a)pyrazin-3- ylethynyl)-4-methylbenzamide [Image Omitted]
Imidazo[l,2-a]pyrazine: A solution of aminopyrazine (1 g, 10.5 mmol) and chloroacetaldehyde (50% wt in H20; 1.98 g, 12.6 mmol) in 1.6 mL of EtOH was heated at 90°C in a sealed tube for 5 h. Upon cooling to ambient temperature, the reaction mixture was concentrated and diluted with dichloromethane (DCM). The organic layer washed with saturated aqueous NaHC03 then dried over MgS04 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 10% MeOH/DCM) to provide 0.8 g of product.
3-((Trimethylsilyl)ethynyl)imidazo[l,2-a]pyrazine: A mixture of 3- bromoimidazo[l ,2-a]pyrazine (0.1 5 g, 0.76 mmol; prepared according to J. Bradac, et al. J. Org. Chem. (1977), 42, 4197 - 4201 ), 0.09 g (0.91 mmol) of ethynyltrimethylsilane, 0.044 g (0.038 mmol) of Pd(PPh3)4, 0.014 g (0.076 mmol) of Cul, and 0.26 mL (1.52 mmol) of diisopropylethylamine in 3.8 mL of DMF was heated at 50°C overnight under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 50% EtOAc/hexanes) to provide 0.15 g of product: 216 m/z (M+H).
3-Ethynylimidazo[l,2-a]pyrazine: To a solution of 3- ((Trimethylsilyl)ethynyl)imidazo[l ,2-a]pyrazine (0.15 g, 0.7 mmol) in 3.5 mL of THF was added 1.05 mL (1 .05 mmol) of tetrabutylammonium fluoride ( 1.0M in THF) at ambient temperature. The solution was stirred for 15 min, concentrated, and the crude product purified by silica gel flash chromatography (eluted with 50% EtOAc/hexanes) to provide 0.078 g of product.
3-(lH-imidazol-l-yl)-5-(trifluoromethyl)aniline: A mixture of 3-Amino-5- bromobenzotrifluoride (4.0 g, 0.0167 mol), 8-hydroxy quinoline (0.362 g, 0.0025 mol), Cul (0.476 g, 0.025 mol), imidazole ( 1 .36 g, 0.0199 mol), and potassium carbonate (2.52 g, 0.01 83 mol) in 17 mL of DMSO (degassed with argon for -10 min) was heated at 120°C under an atmosphere of argon for 15 h; the HPLC indicated no starting material. A 14% aqueous solution of ammonium hydroxide was added to the cooled mixture and this was stirred for 1 h at ambient temperature. Water (50 mL) and EtOAc (200 mL) were added and the aqueous layer was extracted with EtOAc (3x30mL). The combined organic layers were dried over Na2S04 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with EtOAc/hexanes) to provide 2.51 g of product.
N-(3-( lH-imidazol- l-yl)-5-(trifluoromethyl)ph enyl)-3-iodo-4-methylbenzamide : To 3-Iodo-4-methylbenzoic acid (3.07 g, 0.01 17 mol) was added thionyl chloride ( 10 mL) and refluxed for 2 h. The excess thionyl chloride was carefully removed and the resulting acid chloride was dried in vacuo for 2 h. The residue was then dissolved in DCM (anhydrous, 25 mL) and cooled on ice. To the cooled solution was added 3-( l H-imidazol-l -yl)-5- (trifluoromethyl)aniline 5 (3.46 g, 0.0152mol) in DCM followed by the dropwise addition of diisopropylethylamine (8.2 mL, 0.047 mol). This was stirred at ambient temperature for 21 h. The white solid that separated was filtered and washed with water and dried to provide 4.65 g of product. Additional product could be obtained from the filtrate following concentration and purification by silica gel flash chromatography in EtOAc/hexanes.
N-(3-(lH-imidazol-l-yl)-5-(trifl oromethyl)phenyl)-3-(imidazo[l,2-a]pyrazin-3 ylethynyl)-4-methylbenzamide: A mixture of 3-Ethynylimidazo[l ,2-a]pyrazine (0.075 g, 0.52 mmol), 0.245 g (0.52 mmol) of N-(3-(l H-imidazol- l-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4- methylbenzamide, 0.030 g (0.026 mmol) of Pd(PPh3)4, 0.007 g (0.039 mmol) of Cul, and 0.14 mL (0.78 mmol) of diisopropylethylamine in 3.0 mL of DMF was stirred at ambient temperature overnight under an atmosphere of N2. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 10% EtOAc/hexanes, then 100% EtOAc, then 10% MeOH/EtOAc) to provide 0.090 g of product as a solid: 487 m/z (M+H).
Alternative Synthesis of N-(3-(lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl)-3- (imidazo 11,2-a] pyrazin-3-ylethynyl)-4-methylbenzamide:
3-((Trimethylsilyl)ethynyl)imidazo[l,2-a]pyrazine can be prepared as described previously. In one variation, the reaction can also be carried out in THF instead of DMF. The crude product can also be purified by silica gel pad chromatography (eluted with ethyl acetate/hexane) and a brief treatment with activated charcoal (Darco) can be carried out to help further reduce contamination with the homo coupling product.
3-Ethynylimidazo[l,2-a]pyrazine: To a solution of 3-((trimethylsilyl)ethynyl) imidazo[l ,2-a]pyrazine (1.39 mol) in l Ox volume of Ethyl acetate and 1 .5x volume of Methanol is added two and a half equivalents of potassium carbonate at ambient temperature and the solution stirred for 1 hour. Potassium carbonate is filtered off and the organic stream is washed with water and with saturated sodium chloride solution (two or more times). Aqueous phases can be combined and re-extracted with ethyl acetate. Organic streams can then be combined and concentrated under vacuum to about 0.5L. Solids can be allowed to precipitate out upon concentration. Slurry is cooled, e.g. to about -5°C, stored overnight, filtered, and washed with about 0.3 L of cold ethyl acetate. The solids can then be dried under vacuum.
3-(imidazo[l,2-a]pyrazin-3-ylethynyl)-4-methylbenzoic acid can be prepared in a manner similar to that described above for the Sonogashira reaction. 3-Ethynylimidazo[ l ,2- a]pyrazine and 3-iodo-4-methylbenzoic acid are used as coupling partners. Alternatively, the solvent (DMF) can be replaced by ethyl acetate and the base (Hunig base) can be replaced by triethylamine. The product can be isolated by filtration of the crude reaction mixture. The filter cake is washed sequentially with a solvent such as ethyl acetate and then water, then dried in a vacuum oven. Further purification can be achieved by slurrying the solids in water adjusted to pH 3 with the addition of concentrated HC1. After filtration and water wash, the product can be dried in a vacuum oven.
N-(3-(lH midazol-l-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[l,2-a]pyrazin-3- ylethynyl)-4-methylbenzamide: 3-(imidazo[ 1 ,2-a]pyrazin-3-ylethynyl)-4-methylbenzoic acid (18 mmol) is dissolved in methylene chloride (100 mL). To this solution is added 3 equivalents of 4-methylmorpholine (NMM) followed by 1 .05 equivalents of oxalyl chloride. After stirring at ambient temperature for 30 minutes, 0.8 equivalents of 3-(lH-irnidazol- l -yl)- 5-(trifluoromethyl)aniline (prep...
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Claims (English, WO 2012139027 A1) Jump to: description top
CLAIMS
What is claimed is:
1. A method for treating or preventing a neurodegenerative condition in a subject in need thereof comprising administering to the subject an effective amount of a targeted TKI, wherein the targeted TKI is a compound of Formula I:
[Image Omitted]
Formula I
or a tautomer, or an individual isomer or a mixture of isomers thereof wherein:
Ring T is a 5-membered heteroaryl ring containing 1 or 2 nitrogens with the remaining ring atoms being carbon, substituted on at least two ring atoms with R' groups, at least two of which being located on adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, partially saturated or unsaturated 5- or 6- membered ring (Ring E), containing 0-3 heteroatoms selected from O, N, and S and being optionally substituted with 1 -4 Re groups;
Ring A is a 5- or 6-membered aryl or heteroaryl ring and is optionally substituted with 1 -4 Ra groups;
Ring B is a 5- or 6-membered aryl or heteroaryl ring;
L1 is selected from NR'C(O), C(0)NR', NR'C(0)0, NR' C(0)NR' , and OC(0)NR' ; each occurrence of Ra, Rb and R' is independently selected from the group consisting of halo, -CN, -N02, -R4, -OR2, -NR2R3, -C(0)YR2, -OC(0)YR2, -NR2C(0)YR2, -SC(0)YR2, -NR2C(=S)YR2, -OC(=S)YR2, -C(=S)YR2, -YC(=NR3)YR2, -YP(=0)(YR4)(YR4), -Si(R2)3, - NR2S02R2, -S(0)rR2, -S02NR2R3 and -NR2S02NR2R3, wherein each Y is independently a bond, -0-, -S- or -NR3-;
Re, at each occurrence, is independently selected from the group consisting of halo, =0, -CN, -N02, -R4, -OR2, -NR2R3, -C(0)YR2, -OC(0)YR2, -NR2C(0)YR2, -SC(0)YR2, - NR2C(=S)YR2, -OC(=S)YR2, -C(=S)YR2, -YC(=NR3)YR2, -YP(=0)(YR4)(YR4), -Si(R2)3, - NR S02R2, -S(0)rR2, -S02NR2R3 and -NR2S02NR2R3, wherein each Y is independently a bond, -0-, -S- or -NR3-; R1, R2 and R3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl;
alternatively, R2 and R3, taken together with the atom to which they are attached, form a 5- or 6- membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from N, O and S(0)r; each occurrence of R4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl;
each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl moieties is optionally substituted;
m is 0,1 , 2, 3 or 4;
n is 2 or 3;
p is 0, 1 , 2, 3, 4 or 5; and,
r is 0, 1 or 2;
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
A method according to claim 1 , wherein in the compound of Formula I, Ring
[Image Omitted]
wherein Ring E is a 5- or 6-membered unsaturated ring comprising 0-3 heteroatoms selected from O, N, and S, and s is 0, 1 , 2, 3 or 4.
3. A method according to claim 1 , wherein in the compound of Formula I, Ring T is a bicyclic heteroaryl ring selected from:
[Image Omitted]
4. A method according to claim 1 , wherein the targeted TKI is a compound of
Formula II:
[Image Omitted]
Formula II
wherein:
Ring C is a 5- or 6-membered heterocyclic or heteroaryl ring, comprising carbon atoms and 1 -3 heteroatoms independently selected from O, N and S(0)r;
Rc, at each occurrence, is independently selected from halo, =0, -CN, -N02, -R4, - OR2, -NR2R3, -C(0)YR2, -OC(0)YR2, -NR2C(0)YR2, -Si(R2)3, -SC(0)YR2, -NR2C(=S)YR2, -OC(=S)YR2, -C(=S)YR2, -YC(=NR3)YR2, -YP(=0)(YR4)(YR4), -NR2S02R2, -S(0)rR2, - S02NR2R3 and -NR2S02NR2R3, wherein each Y is independently a bond, -0-, -S- or -NR3-; and,
v is 0, 1 , 2, 3, 4 or 5.
5. A method accordin Ring T is:
[Image Omitted]
wherein Ring E is a 5- or 6-membered unsaturated ring comprising 0-3 heteroatoms selected from O, N, and S, and s is 0, 1 , 2, 3 or 4.
6 A method according to claim 5, wherein Rings A and B are aryl.
7. A method according to claim 5, wherein Ring C is imidazolyl.
8. A method according to claim 7, wherein the targeted TKI is a compound selected from Formulae Ila, lib, or lie: [Image Omitted]
Formula lie.
9. A method according to claim 8, wherein s is 0; m, p and v are 1 ; Ra and Rc are methyl; and Rb is CF3.
10. A method according to claim 1 , wherein the targeted TKI is a compound of Formula III:
[Image Omitted]
Formula III
wherein:
Ring D represents a 5-, 6-heterocyclic or heteroaryl ring comprising carbon atoms and
1 -3 heteroatoms independently selected from O, N and S(0)r;
L2 is (CH2)z, 0(CH2)x, NR3(CH2)X, S(CH2)X or (CH2)xNR3C(0)(CH2)x in either direction;
Rd, at each occurrence, is selected from the group consisting of H, halo, =0, -CN, - N<¾, -R4, -OR2, -NR2R3, -C(0)YR2, -OC(0)YR2, -NR2C(0)YR2, -SC(0)YR2, - NR2C(=S)YR2, -OC(=S)YR2, -C(=S)YR2, -YC(=NR3)YR2, -YP(=0)(YR4)(YR4), -Si(R2)3, - NR2S02R2, -S(0)rR2, -S02NR2R3 and -NR2S02NR2R3, wherein each Y is independently a bond, -0-, -S- or -NR3-;
R1, R2 and R3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl;
alternatively, R2 and R3, taken together with the atom to which they are attached, form a 5- or 6- membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from N, O and S(0)r; each occurrence of R4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl;
each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl moieties is optionally substituted;
p is 0, 1 , 2, 3 or 4;
w is 0, 1 , 2, 3, 4 or 5;
x is 0, 1 , 2 or 3; and,
z is 1 , 2, 3 or 4.
1 1 . A method according to claim 10, wherein Ring T has the following structure: [Image Omitted]
wherein Ring E is a 5- or 6-membered unsaturated ring comprising 0-3 heteroatoms selected from O, N, and S, and s is 0, 1 , 2, 3 or 4.
12. A method according to claim 1 1 , wherein Rings A and B are aryl.
13. A method according to claim 1 1 , wherein Ring T is a bicyclic heteroaryl ring selected fro
[Image Omitted]
and s is 0, 1 , 2, 3 or 4.
14. A method according to claim 13, wherein Ring D is piperazinyl and L2 is
CH2.
15. A method according to claim 14 wherein the targeted TKI is a compound selected from Formulae Ilia, Illb, and IIIc:
[Image Omitted]
Formula Ilia
[Image Omitted]
[Image Omitted]
Formula IIIc.
16. A method according to claim 15 wherein s is 0, m is 1 , p is 1 , Ra is methyl, Rb is CF3, and Rd is methyl or -CH2CH2OH.
17. A method according to claim 1 , wherein the targeted TKI is a compound selected from the group consisting of:
N-(3-( 1 H-imidazol- 1 -yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[ 1 ,2-a]pyrazin-3- ylethynyl)-4-methylbenzamide;
3-(Imidazo[ l ,2-a]pyrazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-l - yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
N-(3-(2-((dimethylamino)methyl)- l H-imidazol-l -yl)-5-(trifluoromethyl)phenyl)-3- (imidazo[ 1 ,2-a]pyrazin-3-ylethynyl)-4-methylbenzamide;
3-(Imidazo[ l ,2-o]pyridin-3-ylethynyl)-4-methyl-Ar-(3-(4-methyl-l /-imidazol-l -yl)- 5-(trifluoromethyl)phenyl)benzamide;
N-(3-( l H-imidazol-l -yl)-5-(trifluoromethyl)phenyl)-3-(imidazo[ l ,2-a]pyridin-3- ylethynyl)-4-methylbenzamide;
3-(Imidazo[l ,2-o]pyridin-3-ylethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2- yl)benzamide;
N-(5-tert-butylisoxazol-3-yl)-3-(imidazo[ l ,2-a]pyridin-3-ylethynyl)-4- methylbenzamide; 3-(Imidazo[ l ,2-a]pyridin-3-ylethynyl)-4-methyl-Ar-(4-((4-methylpiperazin-l^ yl)rnethyl)-3-(trifluorornethyl)phenyl)benzamide;
A^3-(2-((dimethylamino)methyl)-l H-im^
(imidazo[ 1 ,2-a]pyridin-3-ylethynyl)-4-methylbenzamide;
3- ((8-Acetamidoimidazo[ l ,2- ]pyridin-3-yl)ethynyl)-4-methyl-Air-(4- (trifluoromethyl)pyridin-2-yl)benzamide;
N-(3-(l /Wmidazol-l -yl)-5-(trifluoromethyl)ph
o]pyridin-3-yl)ethynyl)-4-methylbenzamide;
4- Methyl-3-((8-(4-(methylsulfonyl)phenylamino)imidazo[ l ,2- ]pyridin-3- yl)ethynyl)-A'r-(4-(trifluoromethyl)pyridin-2-yl)benzamidei
4-methyl-3-((8-(4-sulfamoylphenylamino)imidazo[ l ,2-a]pyridin-3-yl)ethynyl)-A^-(4- (trifluoromethyl)pyridin-2-yl)benzamide;
(R)-N-(4-((3-(Dimethylamino)pyrrolidin-l -yl)methyl)-3-(trifluoromethyl)phenyl)-3- (imidazo[ l ,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide;
N-(3-(Imidazo[ l ,2-b]pyridazin-3-ylethynyl)-4-methylphenyl)-4-((4-methylpiperazin- l -yl)methyl)-3-(trifluoromethyl)benzamide;
3-(Imidazo[ l ,2-b]pyridazin-3-ylethynyl)-4-rnethyl-N-(4-((4-methylpiperazin- l - yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
N-(3-Chloro-4-((4-methylpiperazin-l -yl)methyl)phenyl)-3-(imidazo[l ,2-b]pyridazin- 3-ylethynyl)-4-methylbenzamide;
N-(3-Cyclopropyl-4-((4-methylpiperazin-l -yl)methyl)phenyl)-3-(imidazo[l ,2- b]pyridazin-3-ylethynyl)-4-methylbenzamide;
3-(Imidazo[l ,2-b]pyridazin-3-ylethynyl)-N-(4-((4-rnethylpiperazin- l -yl)methyl)-3- (tri fl uoromethy 1 )pheny 1 )benzam i de;
N-(4-((4-(2-Hydroxyethyl)piperazin- l -yl)methyl)-3-(trifluorornethyl)phenyl)-3- (imidazo[ l ,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide; and
3-(Imidazo[ l ,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-(piperazin- l -ylmethyl)-3- (trifluoromethyl)phenyl)benzamide,
or a pharmaceutically acceptable salt thereof.
18. A method according to claim 17, wherein the targeted TKI is 3-(Imidazo[ l ,2- b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-l -yl)methyl)-3- (trifiuoromethyl)phenyl)benzamide or a pharmaceutically acceptable salt thereof.
19. A method according to any of the preceding claims, wherein the neurodegenerative condition is associated with mitochondrial dysfunction and is selected from the group consisting of Friedrich's ataxia, amyotrophic lateral sclerosis, mitochondrial myopathy, encephalopathy, lactacidosis, stroke (MELAS), myoclonic epilepsy with ragged red fibers (MERFF), epilepsy, and Huntington's Disease.
20. A method according to any of the preceding claims, wherein the neurodegenerative condition is a tau pathology and is selected from the group consisting of Alzheimer's disease, progressive supranuclear palsy, Pick's disease, corticobasal degeneration, and fronto-temporal dementia linked to chromosome 17 with parkinsonism.
21. A method accordingly to any of the preceding claims, wherein the neurodegenerative condition is multiple sclerosis.
22. A method according to any of the preceding claims, wherein the targeted TKI, or a pharmaceutically acceptable salt thereof, is administered orally or intravenously.
23. A method according to of any of the preceding claims, wherein the effective amount of the targeted TKI, or a pharmaceutically acceptable salt thereof, is about 5 mg to about 80 mg.
24. A method according to any of the preceding claims, wherein the targeted TKI, or a pharmaceutically acceptable salt thereof, is administered to the subject more than one day a week or on average 4 to 7 times every 7 day period.
25. A method according to claim 24, wherein the targeted TKI, or a pharmaceutically acceptable salt thereof, is administered to the subject daily.
26. A method according to claim 25, wherein an average daily dose of 5 ± 2 mg, 8 ± 2 mg, 12 + 3 mg, 15 ± 3 mg, 20 + 4 mg, 25 ± 5 mg, 30 + 6 mg, 40 ± 8 mg, 45 ± 9 mg, 50 ± 10 mg, or 55 + 1 1 mg of the targeted TKI, or a pharmaceutically acceptable salt thereof, is administered to the subject.
27. A method for treating or preventing Alzheimer's disease in a subject in need thereof comprising administering to the subject a targeted TKI in an amount sufficient to inhibit ?-secretase in the brain of the subject, wherein the targeted TKI is a compound of Formula I:
[Image Omitted]
Formula I
or a tautomer, or an individual isomer or a mixture of isomers thereof wherein:
Ring T is a 5-membered heteroaryl ring containing 1 or 2 nitrogens with the remaining ring atoms being carbon, substituted on at least two ring atoms with R' groups, at least two of which being located on adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, partially saturated or unsaturated 5- or 6- membered ring (Ring E), containing 0-3 heteroatoms selected from O, N, and S and being optionally substituted with 1 -4 Re groups;
Ring A is a 5- or 6-membered aryl or heteroaryl ring and is optionally substituted with 1 -4 Ra groups;
Ring B is a 5- or 6-membered aryl or heteroaryl ring;
L1 is selected from NR'C(O), C(0)NR\ NR'C(0)0, NR' C(0)NR', and OC(0)NR' ; each occurrence of Ra, Rb and R' is independently selected from the group consisting of halo, -CN, -N02, -R4, -OR2, -NR2R3, -C(0)YR2, -OC(0)YR2, -NR2C(0)YR2, -SC(0)YR2, -NR2C(=S)YR2, -OC(=S)YR2, -C(=S)YR2, -YC(=NR3)YR2, -YP(=0)(YR4)(YR4), -Si(R2)3, - NR S02R2, -S(0)rR2, -S02NR2R3 and -NR2S02NR2R3, wherein each Y is independently a bond, -0-, -S- or -NR3-;
Re, at each occurrence, is independently selected from the group consisting of halo, =0, -CN, -N02, -R4, -OR2, -NR2R3, -C(0)YR2, -OC(0)YR2, -NR2C(0)YR2, -SC(0)YR2, - NR2C(=S)YR2, -OC(=S)YR2, -C(=S)YR2, -YC(=NR3)YR2, -YP(=0)(YR4)(YR4), -Si(R2)3, - NR2S02R2, -S(0)rR2, -S02NR2R3 and -NR2S02NR2R3, wherein each Y is independently a bond, -0-, -S- or -NR3-;
R1 , R2 and R3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl;
alternatively, R2 and R3, taken together with the atom to which they are attached, form a 5- or 6- membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from N, O and S(0)r; each occurrence of R4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl;
each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl moieties is optionally substituted;
m is 0,1 , 2, 3 or 4;
n is 2 or 3;
p is 0, 1 , 2, 3, 4 or 5; and,
r is 0, 1 or 2;
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
28. A pharmaceutical composition for treating or preventing a neurodegenerative condition in a subject in need thereof comprising an effective amount of a targeted T I, wherein the targeted TKI is a compound of Formula I:
[Image Omitted]
Formula I
or a tautomer, or an individual isomer or a mixture of isomers thereof wherein:
Ring T is a 5-membered heteroaryl ring containing 1 or 2 nitrogens with the remaining ring atoms being carbon, substituted on at least two ring atoms with R* groups, at least two of which being located on adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, partially saturated or unsaturated 5- or 6- membered ring (Ring E), containing 0-3 heteroatoms selected from O, N, and S and being optionally substituted with 1 -4 Re groups;
Ring A is a 5- or 6-membered aryl or heteroaryl ring and is optionally substituted with 1 -4 Ra groups;
Ring B is a 5- or 6-membered aryl or heteroaryl ring;
L1 is selected from NR'C(O), C(0)NR', NR' C(0)0, NR' C(0)NR', and 0C(0)NR' ; each occurrence of Ra, Rb and R* is independently selected from the group consisting of halo, -CN, -N02, -R4, -OR2, -NR2R3, -C(0)YR2, -OC(0)YR2, -NR2C(0)YR2, -SC(0)YR2, -NR2C(=S)YR2, -OC(=S)YR2, -C(=S)YR2, -YC(=NR3)YR2, -YP(=0)(YR4)(YR4), -Si(R2)3, - NR2S02R2, -S(0)rR2, -S02NR2R3 and -NR2S02NR2R3, wherein each Y is independently a bond, -0-, -S- or -NR3-;
Re, at each occurrence, is independently selected from the group consisting of halo, =0, -CN, -N02, -R4, -OR2, -NR2R3, -C(0)YR2, -OC(0)YR2, -NR2C(0)YR2, -SC(0)YR2, - NR2C(=S)YR2, -OC(=S)YR2, -C(=S)YR2, -YC(=NR3)YR2, -YP(=0)(YR4)(YR4), -Si(R2)3, - NR2S02R2, -S(0)rR2, -S02NR2R3 and -NR2S02NR2R3, wherein each Y is independently a bond, -0-, -S- or -NR3-;
R1, R2 and R3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl;
alternatively, R2 and R3, taken together with the atom to which they are attached, form a 5- or 6- membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from N, O and S(0)r; each occurrence of R4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl;
each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl moieties is optionally substituted;
m is 0, 1 , 2, 3 or 4;
n is 2 or 3;
p is 0, 1 , 2, 3, 4 or 5; and,
r is 0, 1 or 2;
or a pharmaceutically acceptable salt, solvate or hydrate thereof; and
a pharmaceutically acceptable carrier.
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