FORMULARIO SAT 0052 PDF
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In particular, the invention relates to inhibitors of phosphatidylinositol 3-kinase PBK signaling pathways, and methods of their use. Summary of the Related Art. Accordingly, protein kinases have become a very 00052 group of drug targets. See Cohen, Nature, 1: Various protein kinase inhibitors formulatio been used clinically in the treatment of a wide variety of diseases, such as cancer and chronic inflammatory diseases, including diabetes and stroke.
Protein kinases may exert positive or negative regulatory effects, depending upon their target protein. Protein kinases are involved in specific signaling pathways which regulate cell functions such as, but not limited to, metabolism, cell cycle progression, cell adhesion, vascular function, apoptosis, and angiogenesis.
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Malfunctions of cellular signaling have been associated with many diseases, the most characterized of which include cancer and diabetes. The regulation of signal transduction by cytokines and the association of signal molecules with saf and tumor suppressor genes have been well documented. Similarly, the connection between diabetes and related conditions, and deregulated levels of protein kinases, has been demonstrated. Pharmaceutical Research, 17 Viral infections and the conditions related thereto have also been associated with the regulation of protein kinases.
Fprmulario 7 Increased copy number and expression of PIK3CA is associated with a number of malignancies such as ovarian cancer Campbell et al.
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Cancer Biol Ther3, ; Levine, et al. Science, ; Velho et al. Eur J Cancer41,endometrial cancer Oda et al. Acta Neuropathol Berl, ; Samuels et al.
These aspects and other aspects and embodiments are described more fully below. All references cited in this specification are hereby incorporated by reference in their entirety. In the event of a discrepancy between the express disclosure of this specification and the references incorporated by reference, the express disclosure of this specification shall control. This invention also provides methods of making the compound, methods of using such compounds in the treatment of hyperproliferative diseases in humans and to pharmaceutical compositions containing such compounds.
R 1 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
R 2 is hydrogen or alkyl where the alkyl is optionally substituted with 1, 2, 3, 4, or 5 R 8 groups.
R 6 is phenyl, acyl, or heteroaryl wherein the phenyl and heteroaryl are optionally substituted with 1, 2, 3, 4, or 5 R 9 groups; each R 8when present, is independently hydroxy, halo, alkoxy, haloalkoxy, amino, alkylamino, dialkylaminoalkyl, or alkoxyalkylamino; and each R 9when present, is independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, alkylamino, dialkylamino, alkoxyalkyl, carboxyalkyl, alkoxycarbonyl, aminoalkyl, cycloalkyl, aryl, arylalkyl, aryloxy, heterocycloalkyl, or heteroaryl and where the cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, each either alone or as part of another group within R 9are independently optionally substituted with 1, 2, 3, or 4 groups selected from halo, alkyl, haloalkyl, hydroxy, alkoxy, haloalkxy, ammo, alkylamino, and dialkylamino.
R 1 is hydrogen, optionally substituted alkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
R 2 is hydrogen, haloalkyl, optionally tormulario alkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkyl-aryl- or optionally substituted heteroaryl; R is optionally further substituted with one or more R groups.
R 3R 3aand R 3b are independently hydrogen, optionally substituted alkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl.
R 4 is hydrogen, halo, haloalkyl, haloalkoxy, -NR 3a – optionally substituted alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. Vormulario 5 is hydrogen, halo, haloalkyl, aat, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted aryl, optionally substituted aryl C 1 -C 6 alkyl or optionally substituted heteroaryl; and.
Abbreviations and Definitions 17] The following abbreviations and terms have the foemulario meanings throughout: For example, in the structure on the left-hand side of the schematic below there are nine hydrogens implied. The nine hydrogens are depicted in the right-hand structure. Sometimes a particular atom in a structure is described in textual formula as having a hydrogen or hydrogens as substitution expressly defined hydrogenfor example, – CH 2 CH 2.
It is understood by one of ordinary skill in the art that the aforementioned descriptive techniques are common in the chemical arts to provide brevity and simplicity to description of otherwise complex structures.
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In the example depicted, the “R” group may reside on either the 5- membered or the 6-membered ring of the fused ring system. In the formula depicted above, when y is 2 for example, then the two “R’s” may reside on any two atoms of the ring system, again assuming each replaces a depicted, implied, or expressly defined hydrogen on the ring.
A simple example is when R is a methyl group; there can exist a geminal dimethyl on a carbon of the depicted ring an “annular” carbon. In another example, two R’s on the same carbon, including that carbon, may form a ring, thus creating a spirocyclic ring a “spirocyclyl” group structure with the depicted ring as for example in the formula:. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents e.
Representative examples include methoxymethyl and the like. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. Representative examples include phenyl, naphthyl, and indanyl, and the like. Fused bicyclic hydrocarbon radical includes bridged ring systems. One or two ring carbon atoms may be replaced by a.
More specifically, the term cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, or cyclohex enyl, and the like.
Representative examples include 2- iV,iV-diethylammo -ethyloxy, and the like. In this application, fused-polycyclics and fused ring systems are not necessarily all aromatic ring systems. Typically, but not necessarily, fused-polycyclics share a vicinal set of atoms, for example naphthalene or 1,2,3,4-tetrahydro-naphthalene.
A spiro ring system is not a fused-polycyclic by eat definition, but fused polycyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic. In some examples, as appreciated by one of ordinary skill in the art, two adjacent groups on an aromatic system formularjo be fused together formulafio form a ring structure. The fused ring structure may contain heteroatoms and may be optionally substituted with one or more groups.
It should additionally be noted that saturated carbons of such fused groups i. R x is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl. Fused bicyclic radical includes bridged ring systems. Unless stated otherwise, the valency may be located on formjlario atom of any ring of formulaeio heteroaryl group, valency rules permitting. When the point of valency is located on the nitrogen, R x is absent.
Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. When the point of valency is located on a nitrogen atom, R y is absent. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure but may have aromatic substitution thereon. For example, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-lH-indene, 7-aza-bicyclo[2.
For example, as depicted below, a ring atom of a saturated bridged ring system rings B and B’but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spirocyclyl ring A attached thereto. A spirocyclyl can be carbocyclic or heteroalicyclic. So, for example, in the 002 “optionally substituted arylC alkyl,” optional substitution may occur on both formuario “C alkyl” portion and the “aryl” portion of the molecule may or may not be substituted.
A list of exemplary optional substitutions is presented below in the definition of “substituted. For example, “optionally substituted amino” includes diethylamino, methylsulfonylamino, and furanyl-oxy-sulfonamino. Within the optional substituents on “aryl”, the alkyl and alkenyl, either alone or as part of another group including, for example, the alkyl in alkoxycarbonylare independently optionally substituted with one, two, three, four, or five halo.
Within the above optional substitutents on “cycloalkyl”, the alkyl and alkenyl, either alone rormulario as part of another substituent on the cycloalkyl ring, are independently optionally substituted with one, two, three, four, or five halo, e. Within the optional substituents on “heteroaryl”, the alkyl and alkenyl, either alone or as part of another group including, for example, the alkyl in alkoxycarbonylare independently optionally substituted with one, two, three, four, or five halo.
Within the optional substituents on “heterocycloalkyl”, the alkyl and alkenyl, either alone or as part of another group including, for example, the alkyl in alkoxycarbonylare independently optionally substituted with one, two, three, four, or five halo.
Thus the methods are applicable to both human therapy and veterinary applications. In a preferred embodiment the patient is a mammal, and in a most preferred embodiment the patient is human.
Kinases either directly or indirectly participate in the signal transduction pathways of a variety of cellular activities including proliferation, adhesion, migration, differentiation and invasion. Diseases associated with kinase activities include tumor growth, the pathologic neovascularization that supports solid tumor growth, and associated with other diseases where excessive local vascularization is involved such as ocular diseases diabetic retinopathy, age-related macular degeneration, and the like and inflammation psoriasis, rheumatoid arthritis, and the like.
Therefore compounds of the invention, while forrmulario kinase activity as described herein, may also modulate, either directly or indirectly, phosphatase activity. This additional modulation, if present, may be synergistic or not saf activity of compounds of the invention toward a related or otherwise interdependent kinase or kinase family.
Rormulario any case, as stated previously, the compounds of the invention are useful for treating diseases characterized in part by abnormal levels of cell proliferation i. The amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and to this disclosure.
Thus, the term “cancerous cell” as provided herein, includes gormulario cell afflicted by any one of the above-identified conditions. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington ‘s Pharmaceutical Sciences, 17 th ed. Preferable salts are the ammonium, potassium, sodium, calcium, and saf salts.
Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Examples of organic bases szt isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resins, and the like.
Exemplary organic bases saat isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
Common examples include, but are not limited to, ester and amide forms of a compound having an active form bearing formularoo carboxylic acid moiety. Formularrio of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters for example with between about one and about six carbons the alkyl group is a straight or branched chain.
Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl. Examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides, and secondary and tertiary alkyl amides for example with between about one and about six carbons. Amides and fodmulario of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T.
Roche, American Pharmaceutical Association and Pergamon Press,both of which are incorporated herein by reference for all purposes. As used herein, the metabolite of a compound of the invention or its salt may be the biologically active form of the compound formularoo the body.
In one example, a prodrug may be used such that the biologically active form, a metabolite, is released in vivo. In another example, a biologically saat metabolite is discovered serendipitously, that is, no prodrug design tormulario se was undertaken.
An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by 0025 of ordinary skill in the art.
Specifically, R 1 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, or optionally substituted heterocycloalkylalkyl.