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Kinase inhibitor scaffolds and methods for their preparationRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of Two Nitrogens And Four Carbon Atoms (e.g., Pyridazines, Etc.), 1,4-diazine As One Of The CyclosKinase inhibitor scaffolds and methods for their preparation description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070191380, Kinase inhibitor scaffolds and methods for their preparation. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This patent application claims the benefit of U.S. Provisional Patent Application No. 60/328,763, filed Oct. 12, 2001, U.S. Provisional Patent Application No. 60/331,835, filed Nov. 20, 2001, U.S. Provisional Patent Application No. 60/346,480, filed Jan. 7, 2002 and U.S. Provisional Patent Application No. 60/348,089, filed Jan. 10, 2002, the teachings of all of which are incorporated herein by reference. This patent application is related to U.S. Provisional Patent Application No. 60/328,741, filed Oct. 12, 2001, U.S. Provisional Patent Application No. 60/346,552, filed Jan. 7, 2002, U.S. Provisional Patent Application No. 60/347,037, filed Jan. 8, 2002, the teachings of all of which are incorporated herein by reference. BACKGROUND OF THE INVENTION [0002] With the large number of novel proteins being derived from genomics, proteomics, and traditional biochemical approaches there is a tremendous need to develop more efficient methods for the discovery and optimization of small molecule ligands to help determine the biological function of these proteins. Not surprisingly, many of these new targets come from protein families that have received considerable attention ((a) Dolle, R. E., Molecular Diversity, 3, 199 (1998); (b) Dolle et al., J. Comb. Chem., 1, 235 (1999); (c) Dolle, R. E., J. Comb. Chem., 2, 383 (2000) and references therein) in the past such as GPCRs, proteases, and kinases. This presents the combinatorial chemists with the opportunity to take scaffolds developed against a particular protein family member and develop generalized synthetic schemes that allow other family members to be selectively targeted. [0003] A survey of the literature (McMahon et al., Current Opinion in Drug Discovery & Development, 1, 131 (1998); Adams et al., Current Opinion in Drug Discovery & Development, 2, 96 (1999); Garcia-Echeverria et al., Med. Res. Rev, 20, 28 (2000) and references therein) reveals that the vast majority of kinase inhibitor scaffolds consist of planar heteroaryls that present both key hydrogen bond donating/accepting functionality and proper hydrophobicity (FIG. 1). [0004] The purine ring is a prime example of one of these planar heteroaryls. Guanosine and adenosine, two of the most common purines, serve as key recognition and anchoring elements in a variety of cofactors and signaling molecules (e.g., ATP, GTP, cAMP, cGMP, adoMet, adenosine and NADH). Correspondingly, an enormous number of proteins have evolved to recognize the purine motif including reductases, polymerases, G-proteins, methyltransferases, and protein kinases. Despite the abundance of protein kinases (Venter, J. C. et al., Science, 291, 1304 (2001)) (estimated to be encoded by 2 to 5% of the eukaryotic genome) and the high degree of conservation of active site residues, ATP-binding site directed inhibitors have been designed that are highly specific. For example, STI571 (Druker et al., Nat. Med., 2, 561 (1996); Zimmermann et al., Bioorg. Med. Chem. Lett., 7, 187 (1997); Schindler et al., Science, 289, 1938 (2000)) has been developed as a potent and selective Ab1 kinase inhibitor, and is in use for the treatment of chronic myelogenous leukemia (CML). Screens of purine libraries (Gray et al., Science, 281, 533 (1998) and references therein; Rosania et al., Proc. Natl. Acad. Sci. USA, 96, 4797 (1999); Chang et al., Chemistry and Biology, 6, 361 (1999)) have resulted in the identification of diverse purines that inhibit mitosis, alter cellular morphology, and induce apoptosis. By constructing new purine derivatives, we hope to develop inhibitors of different ATP-dependent proteins, which will be useful for elucidating function and potentially provide starting points for the development of new therapeutics. [0005] Previous syntheses of purine libraries have relied on nucleophilic-aromatic substitution and alkylation chemistry to derivatize the 2-, 6- and 9-positions of the purine ring. One of the primary limitations of this chemistry is the inability to access a large number of pharmacologically relevant derivatives bearing aryl, anilino or phenolic substituents. In addition, the sluggish aromatic substitution of 2-fluoro or 2-chloro substituted purine compounds precludes the introduction of sterically hindered amines or anilines (Chang et al., Chemistry and Biology, 6, 361 (1999)). [0006] Recently, there have been significant advances in methodology for performing palladium-catalyzed C--C, C--N and C--O bond formation reactions with a wide variety of substrates. For example, new phosphine ligands (Wolfe et al., J. Am. Chem. Soc., 121, 9550 (1999); Sturmer, R., Angew. Chem. Int. Ed., 38, 3307 (1999) and references therein; Wolfe et al., J. Org. Chem., 65, 1158 (2000)) have allowed palladium mediated functionalization of inexpensive chloroarenes with boronic acids and amines at room temperature. 1,3-Dimesityl-imidazolin-2-ylidene and its saturated analog, originally developed by Grubbs as carbene ligands for ruthenium-based olefin metathesis catalysts (Scholl et al., Tetrahedron Lett., 40, 2247 (1999); Scholl et al., Org. Lett., 1, 953 12 (1999)), have also been found to be highly effective ligands. [0007] In view of the above, a method using transition metal-catalyzed coupling reaction for the preparation of substituted purines, as well as other planar heteroaryls, would provide access to a greater diversity of substituted planar heteroaryls. Application of this method for the preparation of libraries of planar heteroaryls, which is based on a combinatorial scaffold approach, would represent a significant advance in the art. Surprisingly, the present invention provides such a method and compounds produced by the method. BRIEF SUMMARY OF THE INVENTION [0008] The present invention provides, inter alia, methods for the preparation of heteroaryls using both solution phase and solid phase chemistry. The methods of the present invention are useful for the preparation of a wide array of kinase inhibitor scaffolds and kinase inhibitors. Both the solution and solid phase synthesis methodologies of the present method provides scaffolds and inhibitors, which are synthesized rapidly and which are substantially free of side products. In particular, the methods of the present invention are useful for preparing kinase-directed heteroaryl libraries using a combinatorial scaffold approach. [0009] In addition to the method for preparing kinase inhibitor scaffolds and kinase inhibitors and, in particular, combinatorial libraries of such kinase inhibitors, the present invention provides kinase inhibitor scaffolds and kinase inhibitors and, in particular, arrays or libraries of kinase inhibitors that are based on diverse planar heteroarylalkyl and heteroaryl core molecules having pendant substituents. Representative core molecules include, but are not limited to, both substituted and unsubstituted purines, pyrimidines, quinazolines, pyrazines, pyridazines, quinoxalines, phthalazines and thiadiazoles. Other appropriate planar heteroaryl scaffold components will be both apparent, and readily accessible to those of skill in the art. [0010] The scaffolds and inhibitors of the invention are prepared by an unexpectedly efficient process for adding elements of diversity to a scaffold element using solution phase as well as solid phase synthetic methodologies. [0011] Other objects and advantages of the present invention will be apparent from the detailed description and examples that follow. BRIEF DESCRIPTION OF THE DRAWINGS [0012] FIG. 1 displays diverse kinase inhibitor scaffolds. [0013] FIG. 2 displays examples of diverse heteroaryls constructed by combinatorial scaffold approach of the invention. DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS Definitions [0014] Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures for organic and analytical chemistry are those well known and commonly employed in the art. [0015] As used herein, the term "leaving group" refers to a portion of a substrate that is cleaved from the substrate in a reaction. [0016] "Protecting group," as used herein refers to a portion of a substrate that is substantially stable under a particular reaction condition, but which is cleaved from the substrate under a different reaction condition. A protecting group can also be selected such that it participates in the direct oxidation of the aromatic ring component of the compounds of the invention. For examples of useful protecting groups, see, for example, Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, New York (1991). [0017] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C.sub.1-C.sub.10 means one to ten carbons). Examples of saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The term "alkyl," unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below as "heteroalkyl." Alkyl groups which are limited to hydrocarbon groups are termed "homoalkyl". [0018] The terms "alkoxy," "alkylamino" and "alkylthio" (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. Continue reading about Kinase inhibitor scaffolds and methods for their preparation... Full patent description for Kinase inhibitor scaffolds and methods for their preparation Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Kinase inhibitor scaffolds and methods for their preparation patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. 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