AU2439701A - Novel heterocycles - Google Patents

Novel heterocycles Download PDF

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Publication number
AU2439701A
AU2439701A AU24397/01A AU2439701A AU2439701A AU 2439701 A AU2439701 A AU 2439701A AU 24397/01 A AU24397/01 A AU 24397/01A AU 2439701 A AU2439701 A AU 2439701A AU 2439701 A AU2439701 A AU 2439701A
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independently
substituted
occurrence
absent
compound
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AU24397/01A
Inventor
Regine Bohacek
David C Dalgarno
Noriyuki H. Kawahata
George P Luke
Chester A. Metcalf Iii
Tomi K. Sawyer
William C. Shakespeare
Rajeswari Sundaramoorthi
Chi B Vu
Yihan Wang
Manfred Weigele
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Ariad Pharmaceuticals Inc
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Ariad Pharmaceuticals Inc
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Application filed by Ariad Pharmaceuticals Inc filed Critical Ariad Pharmaceuticals Inc
Priority claimed from US09/740,653 external-priority patent/US20020132819A1/en
Publication of AU2439701A publication Critical patent/AU2439701A/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/548—Phosphates or phosphonates, e.g. bone-seeking
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C07F9/4012—Esters of acyclic acids which can have further substituents on alkyl substituted by B, Si, P or a metal
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4025—Esters of poly(thio)phosphonic acids
    • C07F9/405—Esters of poly(thio)phosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Description

WO 01/44258 PCT/USOO/34487 5 NOVEL HETEROCYCLES Priority Information The present application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application number 60/172,5 10, filed December 17, 1999, entitled "Bone Targeting Agents", U.S. Provisional Patent Application number 60/172,161, 10 filed December 17, 1999, entitled "Proton Pump Inhibitors", and U.S. Provisional Patent Application number 60/240,788, filed October 16, 2000 entitled "Bone Targeting Agents", and the entire contents of each of these applications are hereby incorporated by reference. The application further claims priority to U.S. National Patent Application 15 number 09/741,619, entitled "Proton Pump Inhibitors", and U.S. National Patent Application number 09/740,653, entitled "Novel Purines", each of which is filed on even date herewith and is hereby incorporated by reference. Background of the Invention 20 The need to treat debilitating bone disorders, such as osteoporosis, has led to extensive research on the mechanism and regulation of continuous bone formation and resorption. In particular, an appropriate balance of osteoblasts, which function to form bone tissue, and osteoclasts, which function to resorb bone tissue, is required to maintain the structural integrity and proper functioning of the skeleton in spite of 25 continuous metabolism. Any changes in this balance of metabolism, such as an increased bone resorption (either absolute, or an increase via decreased bone formation relative to bone resorption) can lead bone diseases or disorders. One of the most common diseases resulting from this imbalance is osteoporosis, which is characterized by a decrease in bone mass and deterioration in skeletal micro 30 architecture leading to an increased fragility and susceptibility to fractures. Other diseases which result from alterations in bone resorption include, but are not limited to, Paget's Disease, primary and secondary hyperparathyroidism, humoral hypercalcemia of malignancy, various cancers where resorption is increased, and rheumatoid arthritis.
WO 01/44258 PCT/USOO/34487 5 Because of the serious disorders that may result from a metabolic imbalance, researchers have been interested in studying bone metabolism, and the mechanism by which bone resorption and formation occurs, to ultimately develop a strategy for inhibiting resorption, and/or for improving bone mass and/or bone micro-architecture by stimulating osteoblast activity. However, the action of both osteoclasts and 10 osteoblasts is controlled by a number of complex factors, and thus developing selective therapeutics has proven to be a difficult task. One approach that has been taken for the development of novel therapeutics for bone disorders is inhibition of the osteoclast proton pump. Baron and coworkers have previously demonstrated that this proton pump is a vacuolar H*-ATPase (see, 15 Blair et al., Science 1989, 245, 855-857; Finbow et al., Biochem. J. 1997, 324, 697 712; Forgac, M. Soc. Gen. Physiol. Ser. 1996, 51, 121-132). It has been shown that osteoclasts, to effect bone resorption, ultimately lower the pH in the sealed microcompartment which underlies their site of attachment to the bone surface (see, Baron et al., J. Cell. Biol. 1985, 101, 2210-2222), thus resulting in the acidic 20 envionment required to dissolve the bone mineral and to allow degradation of the bone matrix by proteases. The osteoclast uses a proton pump (an ATP-dependent transport of protons) to achieve this acidification and thus any therapeutic inhibition of the osteoclast proton pump should lead to a decrease in bone loss or turnover. As a result, many novel therapeutics developed to reduce bone resorption have focused on 25 the inhibition of the proton pump to prevent osteoclast activity and excessive bone resorption. For a discussion of the vacuolar H+-ATPase and inhibitors of vacuolar H*-ATPase see Farina et al., Exp. Opin. Ther. Patents 1999, 9, 157-168 and David, P. and Baron, R. "The Vacuolar H*-ATPase: A Potential Target for Drug Development in Bone Diseases" Exp. Opin. Invest. Drugs 1995, 4, 725-740. 30 In addition to the inhibition of the proton pump, studies have also been directed towards the control of signal transduction to ultimately affect osteoclast or osteoblast function. For example, studies have provided evidence that Src protein kinases play a cruical role in osteoclastic function, and it has been shown in different cell types that phosphorylation by Src, and related kinases, of proteins proposed to 35 participate or regulate the cytoskeletal architecture is one important requirement for their proper function (see, for example, Missbach et al., "A Novel Inhibitor of the 2 WO 01/44258 PCT/USOO/34487 5 Tyrosine Kinase Src Suppresses Phosphorylation of Its Major Cellular Substrates and Reduces Bone Resorption In Vitro and in Rodent Models In Vivo," Bone 1999, 24, 437-449). Because the cytoskeleton plays an important role in osteoclast motility, attachment, and formation of the sealing zone, it is likely that these cytoskeletal proteins may influence osteoclast function. Thus, agents which inhibit or promote 10 interactions with Src or related kinases, are likely to affect cyctoskeletal proteins and ultimately affect osteoclast function. Several compounds have been reported as inhibitors of tyrosine Src kinase and thus are useful in the inhibition of osteoclast mediated bone resorption (see, for example, Missbach et al., Bone 1999, 24, 437-449; Connolly et al., Bioorg. & Med Chem. Lett. 1997, 7, 2415-2420; Trump-Kallmeyer et 15 al., J Med Chem. 1998, 41, 1752-1763; Klutchko et al., J. Med Chem. 1998, 41, 3276-3292; Legraverend et al., Bioorg. & Med Chem. 1999, 7, 1281-1293; Chang et al., Chem. & Biol. 1999, 6, 361-375; Lev et al. Nature 1995, 376, 737-784; Palmer et al., J. Med Chem. 1997, 40, 1519-1529. As described above, many of the existing therapeutics that have been 20 developed for the treatment of bone disorders such as osteoporosis are thought to act by inhibiting osteoclast activity. For example, estrogens, bisphosphonates, calcitonin, flavonoids, and selective estrogen receptor modulators are believed to act by the inhibition of osteoclast activity. Additionally, more recently, novel therapeutics have been developed to promote a fast increase in bone mineral content by promoting 25 osteoblast activity. Such examples include peptides from the parathyroid hormone family, strontium ranelate, and growth hormone and insulin-like growth response (see, for example, Reginster et al. "Promising New Agents in Osteoporosis," Drugs R & D 1999, 3, 195-201). Unfortunately, a significant problem of many of these therapetic agents, however, is that they are not specific enough for bone tissue and 30 thus may lead to unwanted adverse side effects. Clearly, as evidenced by the number of different approaches to the available therapeutic agents, bone metabolism is controlled by a variety of factors. A common theme, however, is the desire to develop selective inhibitors or promoters of osteoclast or osteoblast activity, respectively. Although progress has been made towards 35 developing therapeutic agents for osteoporosis and other bone disorders, there remains a need to develop potent and selective agents having minimal side effects. 3 WO 01/44258 PCT/USOO/34487 5 Summary of the Invention In general, the present invention provides compounds comprising a bone targeting moiety and a payload for the treatment or prevention of bone disorders and/or other conditions. In other embodiments, certain novel bone targeting moieties 10 themselves, as described herein, also act as therapeutic agents for use in the treatment of bone disorders and/or other conditions. In certain other embodiments, the present invention provides compounds comprising a bone targeting moiety and a kinase inhibitor. Thus, the present invention provides, in certain embodiments, compounds of 15 Formula I, or pharmaceutically acceptable derivatives thereof. In certain embodiments, a subject compound has the structure of Formula (I): Hc-X-K-Cy-L-Z-Tb (I) 20 wherein L and K, independently, are absent or represent -Ma-Y-Mp-; X, Y, and Z, independently, are absent or represent NR, 0, or S; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, such as -CH 2 -, -CHF-, -CHOH-, -CH(Me)-, -C(=0)-, 25 etc., or two M taken together represent substituted or unsubstituted ethene or ethyne; R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl or alkyl. Cy represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl, including polycyclic groups; 30 p and n, independently, represent integers from 0-10, preferably from 0-5, even more preferably, from 0-3. Hc represents a heterocycle, preferably a nitrogen-containing heterocycle; and Tb represents a bone-targeting moiety preferably selected from: 4 WO 01/44258 PCT/USOO/34487 O O OR4 PX 'I
OR
4
OR
4 I
OR
4 0
OR
4 0 OR400 1 1 4N 0 ~ R 4 0 I-O- N "O R 4 0 j FO R 4
OR
4 H 4 ORj OR 4
OR
4
OR
4 iv V 0U 0 0 vi R0 jjNOR4 R40Of OR 4 R OR4 OR4 OR A O4 R OR4O OR O OR4 OR4 OR4 5vii viii ix 5 PO(OR4)2
PO(OR
4
)
2 PO(OR 4
)
2 x xi PO(OR4) 2 C0 2
R
4
R
4 0 2 C O xii C0 2
R
4
R
4 0 2 C N C0 2
R
4
R
4 0 2 C N PO(OR 4
)
2 0 N PO(OR 4
)
2 xiii xiv xv wherein R 4 independently for each occurrence represents H or lower alkyl, preferably H or CI-C 3 lower alkyl. 10 In embodiments wherein Tb is selected from i, v, vi, vii, viii, and ix, Z is preferably absent. In embodiments wherein Tb is selected from ii, iii, and iv, Z may be absent or represent 0 or NR. In embodiments wherein Tb is selected from x, xi, xii, xiii, xiv, and xv, Z may be absent or represent 0 or NR, preferably being absent. 15 In certain embodiments, R 4 represents H for all occurrences. In certain embodiments, L represents alkyl-Y-alkyl, alkyl-Y-acyl, or alkyl. 5 WO 01/44258 PCT/USOO/34487 5 In certain embodiments, the compound is free of hydrolyzable linkages. Hydrolyzable linkages, as the term is used herein, are saturated (sp 3 -hybridized) carbons bound to two heteroatoms, of which at least one is selected from S, N, or 0. 10 In certain embodiments, M represents a substituted or unsubstituted methylene group, such as -CH 2 -, -CHF-, -CHOH-, -CH(Me)-, -C(=0)-, etc. In certain embodiments, Cy represents a carbocycle or a nitrogen-bearing heterocycle. Cy is preferably uncharged. 15 In certain embodiments, Cy represents a phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system, preferably having between 8 and 11 atoms, such as a fused cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy represents a fused ring system, one substituent of L and K (or Hc or Tb) 20 may be attached to one of the two rings, and the other substituent to the other of the two rings. In certain embodiments, Cy is phenyl. In certain embodiments, K is absent. 25 In certain embodiments, K represents alkyl-Y-alkyl, alkyl-Y-acyl, or alkyl. In certain embodiments, Hc represents a bicyclic structure, preferably including heteroatoms in both rings. In certain embodiments, the ring(s) of Hc consist of C and N atoms. In certain embodiments, Hc represents a bicyclic heteroaryl 30 structure. In certain embodiments, K is directly attached to a heteroatom of He, or X represents NR. 35 In certain embodiments, He includes at least one aryl substituent. 6 WO 01/44258 PCT/USOO/34487 5 In certain embodiments, Hc-X taken together represent one of the following structures: R2 R2 R1 \ N \ N .. . - N \ N - - -\ R R 1 N N N N NHR3 N NHR 3
R
2 HN N NHR 3 xvi xvii xviii 41 R1 R, N IN R3 R3 N N N W N N NHR 2 H I H xix R2 xx wherein W represents 0 or S, and one of R 1 , R 2 , and R 3 represents a bond to K, and the others represent, independently, hydrogen, halogen, alkyl, aralkyl, aryl, 10 cycloalkyl, heteroaryl, heterocyclic, cycloalkyl, polycyclic, alkyl alkenyl, alkyl alkynyl, or alkanoyl, or taken together with the nitrogen to which it is attached, represent amidine, amide, carbamate, urea, or guanidine. In certain embodiments wherein Hc-X is represented by xix or xx, R 3 15 represents a bond to K, R 2 is selected from hydrogen, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, heteroaryl, heterocyclyl, cycloalkyl, polycyclyl, alkyl alkenyl, alkyl alkynyl, and alkanoyl; and Ri is selected from hydrogen, halogen, aryl, and heteroaryl. In certain embodiments, R 2 is selected from hydrogen, (CH 2 )nPh, where Ph is phenyl or substituted phenyl and n is 0, 1, 2, or 3; heteroaryl, cycloalkyl, CI-C 6 20 alkanoyl, CI-C 6 alkyl, C 2
-C
6 alkenyl, and C 2
-C
6 alkynyl, where the alkyl, alkenyl and alkynyl groups may be substituted by NR 5
R
6 , phenyl, thioalkyl, alkyloxy, hydroxy, carboxy, halogen, cycloalkyl, and where R 5 and R 6 are independently hydrogen, Cj
C
6 alkyl, C 2
-C
6 alkenyl, C 2
-C
6 alkynyl, (CH 2 )nPh where Ph is phenyl and n is 0, 1, 2, or 3; cycloalkyl, heteroaryl, and R 5 and R 6 taken together with the nitrogen to which 25 they are attached can complete a ring having 3 to 7 carbon atoms and optionally containing 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, 7 WO 01/44258 PCT/USOO/34487 5 substituted nitrogen, oxygen and sulfur. In certain embodiments, R, is a substituted aryl moiety selected from of monohaloaryl, dihaloaryl, monomethylaryl, and dimethylaryl. In certain embodiments, at least one of R 1 , R 2 , and R 3 , other than the bond to K, represents an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl. 10 In certain embodiments wherein Hc-X is represented by xvi or xvii, at least one of R 1 , R 2 , or R 3 represents a bond to K, R 3 , if not a bond to K, is selected from hydrogen or alkyl, R 2 , if not a bond to K, is selected from alkyl, cycloalkyl, alkyl alkenyl, alkyl alkynyl, and R 1 , if not a bond to K, is selected from hydrogen, alkyl, 15 cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroalkyl, alkyl alkenyl, alkyl alkynyl, alkyl cycloalkyl, or alkyl heterocyclyl. In certain embodiments, at least one of R 1 , R 2 , and R 3 , other than the bond to K, represents an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl. 20 In certain embodiments wherein Hc-X is represented by xviii, R 2 represents a bond to K, and R, and R 3 are selected, independently, from hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heteroalkyl, heteroaralkyl, alkyl alkenyl, alkyl alkynyl, alkyl cycloalkyl, and alkyl heterocyclyl. In certain embodiments, R, is alkyl or branched alkyl and R 3 is aryl, heteroaryl, or cycloalkyl. In 25 certain embodiments, R 3 is selected from monohaloaryl, dihaloaryl, monohaloheteroaryl, dihaloheteroaryl, monohalocycloalkyl, or dihalocycloalkyl. In certain embodiments, at least one of R 1 , R 2 , and R 3 , other than the bond to K, represents an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl. 30 In certain embodiments wherein Tb is represented by vii or viii, the compound is free of hydrolyzable linkages. In certain embodiments, L and K do not comprise nitrogen. In certain embodiments, Hc represents a heterocyclic bicycle. In certain embodiments, Hc represents a bicyclic heteroaryl structure. In certain embodiments, 35 Hc is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, R4 represents H for all occurrences. In certain embodiments, Cy represents a phenyl, pyridyl, 8 WO 01/44258 PCT/USOO/34487 5 cyclopentyl, cyclohexyl, or a fused bicyclic ring system, preferably having between 8 and 11 atoms, such as a fused cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy represents a fused ring system, one substituent of L and K (or Hc or Tb) may be attached to one of the two rings, and the other substituent to the other of the two rings. In embodiments wherein X is absent, K is preferably directly attached 10 to a heteroatom of Hc. In certain embodiments, K is absent. In certain embodiments, Tb is represented by xi, xii, xiv, or xv. In certain embodiments, K and L do not include an amide bond, or are preferably free of nitrogen atoms. In certain embodiments, Hc represents a heterocyclic bicycle. In 15 certain embodiments, Hc represents a bicyclic heteroaryl structure. In certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, the compound does not include a hydrolyzable linkage. In certain embodiments, R 4 represents H for all occurrences. In certain embodiments, Cy represents a phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system, 20 preferably having between 8 and 11 atoms, such as a fused cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy represents a fused ring system, one substituent of L and K (or Hc or Tb) may be attached to one of the two rings, and the other substituent to the other of the two rings. In embodiments wherein X is absent, K is preferably directly attached to a heteroatom of Hc. In certain embodiments, K is 25 absent. In certain embodiments wherein Tb is represented by the moiety xiii, that moiety is not present in another portion of the compound, e.g., Hc is not xiii, etc. In certain embodiments, K does not include an amide bond, or is preferably free of 30 nitrogen atoms. In certain embodiments, Hc represents a heterocyclic bicycle. In certain embodiments, Hc represents a bicyclic heteroaryl structure. In certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, the compound does not include a hydrolyzable linkage. In certain embodiments, R 4 represents H for all occurrences. In certain embodiments, Cy 35 represents a phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system, preferably having between 8 and 11 atoms, such as a fused cyclohexyl/cyclopentyl 9 WO 01/44258 PCT/USOO/34487 5 ([4.3.0]-bicyclononane) ring system. When Cy represents a fused ring system, one substituent of L and K (or He or Tb) may be attached to one of the two rings, and the other substituent to the other of the two rings In embodiments wherein X is absent, K is preferably directly attached to a heteroatom of Hc. In certain embodiments, K is absent. 10 In certain embodiments wherein Tb is represented by x, K does not include an amide bond, is free of carbonyls, is free of amine substituents, or is free of nitrogen atoms. In certain embodiments, He represents a heterocyclic bicycle. In certain embodiments, He represents a bicyclic heteroaryl structure. In certain embodiments, 15 He is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, the compound does not include a hydrolyzable linkage. In certain embodiments, R 4 represents H for all occurrences. In certain embodiments, Cy represents a phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system, preferably having between 8 and 11 atoms, such as a fused cyclohexyl/cyclopentyl ([4.3.0] 20 bicyclononane) ring system. When Cy represents a fused ring system, one substituent of L and K (or He or Tb) may be attached to one of the two rings, and the other substituent to the other of the two rings. In embodiments wherein X is absent, K is preferably directly attached to a heteroatom of Hc. In certain embodiments, K is absent. 25 In certain embodiments wherein Tb is represented by ii, iii, iv, or v, the compound does not include a hydrolyzable linkage. In certain embodiments, He represents a heterocyclic bicycle. In certain embodiments, He represents a bicyclic heteroaryl structure. In certain embodiments, He is selected from xvi, xvii, xviii, xix, 30 and xx. In certain embodiments, I 4 represents H for all occurrences. In certain embodiments, Cy represents a phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system, preferably having between 8 and 11 atoms, such as a fused cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy represents a fused ring system, one substituent of L and K (or He or Tb) may be attached to one of 35 the two rings, and the other substituent to the other of the two rings. In certain 10 WO 01/44258 PCT/USOO/34487 5 embodiments, K is directly attached to a heteroatom of He. In certain embodiments, K is absent. In certain embodiments wherein Tb is represented by ix, Cy is preferably uncharged, and/or L-Cy-K is preferably free of hydrolyzable linkages. In certain 10 embodiments, the compound is free of hydrolyzable linkages. In certain embodiments, Cy is preferably selected from aryl, carbocyclic, nitrogen-containing heterocyclic, and nitrogen-containing heteroaryl groups, and preferably does not include S or 0 atoms in the ring structure. In preferred embodiments, Cy contains 0 or 1 heteroatoms. In certain embodiments, Hc represents a heterocyclic bicycle. In 15 certain embodiments, Hc represents a bicyclic heteroaryl structure. In certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, R 4 represents H for all occurrences. In certain embodiments, Cy represents a phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system, preferably having between 8 and 11 atoms, such as a fused cyclohexyl/cyclopentyl 20 ([4.3.0]-bicyclononane) ring system. When Cy represents a fused ring system, one substituent of L and K (or He or Tb) may be attached to one of the two rings, and the other substituent to the other of the two rings. In embodiments wherein X is absent, K is preferably directly attached to a heteroatom of Hc. In certain embodiments, K is absent. 25 In certain embodiments wherein Tb is represented by i, Cy is preferably uncharged, and/or L-Cy-K is preferably free of hydrolyzable linkages. In certain embodiments, Cy is preferably selected from aryl, carbocyclic, nitrogen-containing heterocyclic, and nitrogen-containing heteroaryl groups, and preferably does not 30 include S or 0 atoms in the ring structure. In preferred embodiments, the ring system of Cy contains 0 or 1 heteroatoms. In certain embodiments, Hc represents a heterocyclic bicycle. In certain embodiments, He represents a bicyclic heteroaryl structure. In certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, R 4 represents H for all occurrences. In certain embodiments, Cy 35 represents a phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system, preferably having between 8 and 11 atoms, such as a fused cyclohexyl/cyclopentyl 11 WO 01/44258 PCT/USOO/34487 5 ([4.3.0]-bicyclononane) ring system. When Cy represents a fused ring system, one substituent of L and K (or Hc or Tb) may be attached to one of the two rings, and the other substituent to the other of the two rings. In embodiments wherein X is absent, K is preferably directly attached to a heteroatom of Hc. In certain embodiments, K is absent. 10 In certain embodiments wherein Tb is represented by i, Z and L are absent. In certain embodiments, Cy represents an aryl or heteroaryl group, such as a phenyl or pyridyl group. In certain embodiments, Cy is preferably uncharged, and/or the compound is preferably free of hydrolyzable linkages. In certain embodiments, Cy is 15 preferably selected from aryl, carbocyclic, nitrogen-containing heterocyclic, and nitrogen-containing heteroaryl groups, and preferably does not include S or 0 atoms in the ring structure. In preferred embodiments, the ring system of Cy contains 0 or 1 heteroatoms, or is preferably phenyl. In certain embodiments, He represents heterocyclic bicycle. In certain embodiments, He represents a bicyclic heteroaryl 20 structure. In certain embodiments, He is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, R 4 represents H for all occurrences. In certain embodiments, Cy represents a phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system, preferably having between 8 and 11 atoms, such as a fused cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy represents a fused ring system, one 25 substituent of L and K (or He or Tb, where L and/or K is absent) may be attached to one of the two rings, and the other substituent to the other of the two rings. In embodiments wherein X is absent, K is preferably directly attached to a heteroatom of Hc. In certain embodiments, K is absent. 30 In certain embodiments of Formula I, Tb is selected from i and ix, and K is absent or represents -Y-, such as -NH-. In certain embodiments, He is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, Cy is aryl or heteroaryl, preferably aryl. In certain embodiments, He is further substituted with an aryl group, e.g., at a position of R 1 , R 2 , and R 3 not substituted with K. In certain embodiments, 35 each of R 1 , R 2 , and R 3 represents a hydrocarbon substituent. In certain embodiments, 12 WO 01/44258 PCT/USOO/34487 5 L represents alkyl, alkyl-Y-alkyl or alkyl-Y-acyl, wherein Y is preferably NR, such as NH or NMe. In certain embodiments of Formula I, Tb is x and K is absent. In certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and xx. In certain 10 embodiments, Hc is further substituted with an aryl group, e.g., at a position of R 1 , R 2 , and R 3 not substituted with K. In certain embodiments, each of R 1 , R 2 , and R 3 represents a hydrocarbon substituent. In certain embodiments, L represents alkyl, alkyl-Y-alkyl or alkyl-Y-acyl, wherein Y is preferably NR, such as NH or NMe. 15 In certain embodiments, a subject compound has the structure of Formula (II): Hc-X-K-Z-Tb (II) 20 wherein Hc, X, K, Z, and Tb are as defined above. In certain embodiments of Formula II, Tb is selected from x, xi, xii, xiii, xiv, and xv. In embodiments wherein Tb is selected from x, xi, xii, xiii, xiv, and xv, Z may be absent or represent 0 or NR, preferably being absent. 25 In certain embodiments, R 4 represents H for all occurrences. In certain embodiments, the compound is free of hydrolyzable linkages. Hydrolyzable linkages, as the term is used herein, are saturated (sp 3 -hybridized) 30 carbons bound to two heteroatoms, of which at least one is selected from S, N, or 0. In certain embodiments, M represents a substituted or unsubstituted methylene group, such as -CH 2 -, -CHF-, -CHOH-, -CH(Me)-, -C(=0)-, etc. 35 In certain embodiments, K is absent. In certain embodiments, K represents alkyl-Y-alkyl, alkyl-Y-acyl, or alkyl. 13 WO 01/44258 PCT/USOO/34487 5 In certain embodiments, Hc represents a bicyclic structure, preferably including heteroatoms in both rings. In certain embodiments, the ring(s) of Hc consist of C and N atoms. 10 In certain embodiments, K is directly attached to a heteroatom of Hc, or X represents NR. In certain embodiments, Hc includes at least one aryl substituent. 15 In certain embodiments, Hc-X taken together represent one of the following structures: R2 R2 R1 N N N N N N N N NHR3 N NHR 3
R
2 HN N NHR 3 xixvii xviii R3
R
3 N N N W N N N NHR 2 H IH xix R2 xx wherein W represents 0 or S, and one of R 1 , R 2 , and R 3 represents a bond to K, and 20 the others represent, independently, hydrogen, halogen, amidine, amide, carbamate, urea, guanidine, alkyl, aralkyl, aryl, cycloalkyl, heteroaryl, heterocyclic, cycloalkyl, polycyclic, alkyl alkenyl, alkyl alkynyl, or alkanoyl, or taken together with the nitrogen to which it is attached, represent amidine, amide, carbamate, urea, or guanidine. 25 14 WO 01/44258 PCT/USOO/34487 5 In certain embodiments wherein Hc-X is represented by xix or xx, R 3 represents a bond to K, R 2 is selected from hydrogen, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, heteroaryl, heterocyclyl, cycloalkyl, polycyclyl, alkyl alkenyl, alkyl alkynyl, and alkanoyl; and R 1 is selected from hydrogen, halogen, aryl, and heteroaryl. In certain embodiments, R 2 is selected from hydrogen, (CH 2 )nPh, where 10 Ph is phenyl or substituted phenyl and n is 0, 1, 2, or 3; heteroaryl, cycloalkyl, CI-C 6 alkanoyl, CI-C 6 alkyl, C 2
-C
6 alkenyl, and C 2
-C
6 alkynyl, where the alkyl, alkenyl and alkynyl groups may be substituted by NR 5
R
6 , phenyl, thioalkyl, alkyloxy, hydroxy, carboxy, halogen, cycloalkyl, and where R 5 and R 6 are independently hydrogen, CI
C
6 alkyl, C 2
-C
6 alkenyl, C 2
-C
6 alkynyl, (CH 2 )nPh where Ph is phenyl and n is 0, 1, 2, 15 or 3; cycloalkyl, heteroaryl, and R 5 and R 6 taken together with the nitrogen to which they are attached can complete a ring having 3 to 7 carbon atoms and optionally containing 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen and sulfur. In certain embodiments, R, is a substituted aryl moiety selected from of monohaloaryl, dihaloaryl, monomethylaryl, and 20 dimethylaryl. In certain embodiments, at least one of R 1 , R2, and R 3 , other than the bond to K, represents an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl. In certain embodiments wherein Hc-X is represented by xviii, R 2 represents a 25 bond to K, and Ri and R3 are selected, independently, from hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heteroalkyl, heteroaralkyl, alkyl alkenyl, alkyl alkynyl, alkyl cycloalkyl, and alkyl heterocyclyl. In certain embodiments, R 1 is alkyl or branched alkyl and R 3 is aryl, heteroaryl, or cycloalkyl. In certain embodiments, R 3 is selected from monohaloaryl, dihaloaryl, 30 monohaloheteroaryl, dihaloheteroaryl, monohalocycloalkyl, or dihalocycloalkyl. In certain embodiments, at least one of R 1 , R2, and R 3 , other than the bond to K, represents an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl. 35 In certain embodiments wherein Hc-X is represented by xvi or xvii, at least one of R 1 , R 2 , or R3 represents a bond to K, R 3 , if not a bond to K, is selected from 15 WO 01/44258 PCT/USOO/34487 5 hydrogen or alkyl, R 2 , if not a bond to K, is selected from alkyl, cycloalkyl, alkyl alkenyl, alkyl alkynyl, and R 1 , if not a bond to K, is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroalkyl, alkyl alkenyl, alkyl alkynyl, alkyl cycloalkyl, or alkyl heterocyclyl. In certain embodiments, at least one of R 1 , R 2 , and R 3 , other than the bond to K, represents an aryl or heteroaryl 10 substituent, preferably a substituted or unsubstituted phenyl. In certain embodiments wherein Tb is represented by vii or viii, the compound is free of hydrolyzable linkages. In certain embodiments, K does not comprise nitrogen. In certain embodiments, Hc represents a heterocyclic bicycle. In certain 15 embodiments, Hc represents a bicyclic heteroaryl structure. In certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, R 4 represents H for all occurrences. In embodiments wherein X is absent, K is preferably directly attached to a heteroatom of Hc. In certain embodiments, K is absent. 20 In certain embodiments, Tb is represented by xi, xii, xiv, or xv. In certain embodiments, K does not include an amide bond, or are preferably free of nitrogen atoms. In certain embodiments, Hc represents a heterocyclic bicycle. In certain embodiments, Hc represents a bicyclic heteroaryl structure. In certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, the 25 compound does not include a hydrolyzable linkage. In certain embodiments, R 4 represents H for all occurrences. In embodiments wherein X is absent, K is preferably directly attached to a heteroatom of Hc. In certain embodiments, K is absent. In certain embodiments wherein Tb is represented by the moiety xiii, that 30 moiety is not present in another portion of the compound, e.g., Hc is not xiii, etc. In certain embodiments, K does not include an amide bond, or is preferably free of nitrogen atoms. In certain embodiments, Hc represents a heterocyclic bicycle. In certain embodiments, Hc represents a bicyclic heteroaryl structure. In certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and xx. In certain 35 embodiments, the compound does not include a hydrolyzable linkage. In certain embodiments, R 4 represents H for all occurrences. In embodiments wherein X is 16 WO 01/44258 PCT/USOO/34487 5 absent, K is preferably directly attached to a heteroatom of Hc. In certain embodiments, K is absent. In certain embodiments wherein Tb is represented by x, K does not include an amide bond, is free of carbonyls, is free of amine substituents, or is free of nitrogen 10 atoms. In certain embodiments, the compound does not include a hydrolyzable linkage. In certain embodiments, Hc represents a heterocyclic bicycle. In certain embodiments, Hc represents a bicyclic heteroaryl structure. In certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, R 4 represents H for all occurrences. In embodiments wherein X is absent, K is preferably directly 15 attached to a heteroatom of Hc. In certain embodiments, K is absent. In certain embodiments wherein Tb is represented by ii, iii, iv, or v, the compound does not include a hydrolyzable linkage. In certain embodiments, Hc represents a heterocyclic bicycle. In certain embodiments, Hc represents a bicyclic 20 heteroaryl structure. In certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, R4 represents H for all occurrences. In certain embodiments, K is directly attached to a heteroatom of Hc. In certain embodiments, K is absent. 25 In certain embodiments wherein Tb is represented by ix, the compound is preferably free of hydrolyzable linkages. In certain embodiments, the compound is free of hydrolyzable linkages. In certain embodiments, Hc represents a heterocyclic bicycle. In certain embodiments, Hc represents a bicyclic heteroaryl structure. In certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and xx. In certain 30 embodiments, RI 4 represents H for all occurrences. In embodiments wherein X is absent, K is preferably directly attached to a heteroatom of Hc. In certain embodiments, K is absent. In certain embodiments wherein Tb is represented by i, Hc represents a 35 heterocyclic bicycle. In certain embodiments, Hc represents a bicyclic heteroaryl structure. In certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and xx. In 17 WO 01/44258 PCT/USOO/34487 5 certain embodiments, R4 represents H for all occurrences. In embodiments wherein X is absent, K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent. In certain embodiments of Formula II, Tb is selected from i and ix, and K is 10 branched or unbranched alkyl. In certain embodiments, He is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, He is further substituted with an aryl group, e.g., at a position of R 1 , R2, and R 3 not substituted with K. In certain embodiments, each of R 1 , R2, and R 3 represents a hydrocarbon substituent. 15 In certain embodiments of Formula II, Tb is xii, and K is absent or represents Y-, such as -NH-. In certain embodiments, He is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, He is further substituted with an aryl group, e.g., at a position of R 1 , R 2 , and R 3 not substituted with K. In certain embodiments, each of R 1 ,
R
2 , and R 3 represents a hydrocarbon substituent. 20 In certain embodiments of Formula II, Tb is x, and K represents alkyl or -Y-. In certain embodiments, He is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, He is further substituted with an aryl group, e.g., at a position of R1, R2, and R3 not substituted with K. In certain embodiments, each of R 1 , R2, and R3 25 represents a hydrocarbon substituent. In certain embodiments of Formula I or II, Tb represents CO2R4 N N
R
4
O
2 C N CO 2
R
4 xxi OR 4 xxii PO(OR 4
)
2 xxnm
OR
4 C0 2
R
4
R
4 0 2 C N xxiv N C0 2
R
4 N OH xxvi PO(OR 4
)
2 18 WO 01/44258 PCT/USOO/34487 5 In still other embodiments of the present invention, pharmaceutical compositions are provided comprising any one of the compounds of the present invention, or a pharmaceutically acceptable derivative thereof, and one or more pharmaceutically acceptable excipients. 10 In yet other embodiments, compounds of the invention, or compositions containing such compounds are administered to cells or to animals, preferably to a mammal in need therof, as a method for treating bone disorders. In particular cases, it will be advantageous to carry out such inventive methods using a pharmaceutical composition comprising a bone targeted compound which is capable of inhibiting 15 bone resorption. In other cases, it will be advantageous to carry out that method using a pharmaceutical composition comprising a bone targeted compound that specifically acts as a Src kinase inhibitor. In other cases, it will be advantageous to carry out that method using a bone targeted compound of the present invention having a payload attached thereto that is capable of treating bone disorders by other means. 20 In still other embodiments, it will be advantageous to carry out inventive methods using a pharmaceutical composition comprising a bone targeting moiety that, alone, is capable of effecting treatment of bone disorders by inhibiting bone resorption or by other means. 25 Definitions As mentioned above, this invention provides a novel class of bone targeted compounds useful for the treatment of bone disorders, preferably by inhibition of bone resorption. Compounds of this invention include those of Formula I and Formula II, set forth herein, and are illustrated in part by the various classes, 30 subgenera and subsets of compounds described above, and by the various subgenera and species disclosed elsewhere in the specification, claims and figures. It will be appreciated that inventive compounds may be provided in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers. 19 WO 01/44258 PCT/USOO/34487 5 Also included are pharmaceutically acceptable derivatives of the foregoing compounds, where the phrase "pharmaceutically acceptable derivative" denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of an inventive compound, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described 10 herein, or a metabolite or residue thereof, preferably one which is capable of inhibiting bone resorption. Pharmaceutically acceptable derivatives thus include among others pro-drugs. A pro-drug is a derivative of a compound, usually with significantly reduced pharmacological activity, which contains an additional moiety which is susceptible to removal in vivo yielding the parent molecule as the 15 pharmacologically active species. An example of a pro-drug is an ester which is cleaved in vivo to yield a compound of interest. Pro-drugs of a variety of compounds, and materials and methods for derivatizing the parent compounds to create the pro drugs, are known and may be adapted to the present invention. One technique for providing a prodrug of a compound of the present invention is described generally in 20 Niemi et al., J Med Chem. 1999, 42, 5053-5058. The terms "inhibition of bone resorption" or "inhibition of osteoclast activity" or "inhibition of Src kinase activity" preferably refer to specific inhibition. Any of a variety of in vivo or in vitro assays may be employed to assess the ability of inventive 25 compounds and compositions to treat or prevent bone disorders and/or other conditions, and in particular to inhibit bone resorption and/or to inhibit Src tyrosine phosphorylation (see, for example, the Exemplification section, which describes a useful rabbit osteoclast assay for studying effects on bone resorption, and a useful Src kinase inhibition assay). In particularly preferred embodiments of the invention, the 30 observed effects on bone metabolism are selective in that the inventive compounds or compositions do not exert significant negative effects on biological processes other than bone metabolism, or specifically bone resporption or Src kinase activity. For example, particularly preferred inventive compositions show specific inhibition of Src kinase activity as compared with the activity of non-Src kinanses, or kinases located 35 at sites away from bone. In some cases, such specific inhibition may result from specific localization of the inventive composition to bone sites, so that compositions 20 WO 01/44258 PCT/USOO/34487 5 delivered in vivo do not have the opportunity to inhibit processes that occur away from bone; in other cases, specific inhibition may be attributed to specific action of the inventive payload on the osteoclast activity or on Src kinase activity, as compared with other cells or kinases. 10 The term "payload" includes therapeutic agents (e.g., a small molecule, a drug, a radiotherapeutic atom, etc.), detectable labels (e.g., fluorescent, radioactive, radiopaque, etc.), or any other moiety desired to be delivered to a site of action (e.g., a bone or other site suffering an abnormal condition). 15 A "small molecule" as the term is used herein refers to an organic molecule of less than about 2500 amu, preferably less than about 1000 amu. "Subject" shall mean a human or animal (e.g., rat, mouse, cow, pig, horse, sheep, monkey, cat, dog, goat, etc.). 20 A "target" shall mean an in vivo site to which targeted agents bind. A target may refer to a molecular structure to which a targeting moiety binds, such as a hapten, epitope, receptor, dsDNA fragment, carbohydrate, or enzyme. Alternativelyy or additionally, a target may be a type of tissue, e.g., bone. A preferred target is bone. 25 In certain preferred embodiments, target cells include osteoclasts. The term "targeting moiety" refers to any molecular structure which assists the inventive composition in localizing to a particular target area, entering a target cell(s), and/or binding to a target receptor. Preferred targeting moieties according to the present invention include bone targeting moieties, as described herein. 30 A "therapeutic agent" shall mean an agent capable of having a biological effect on a host. Preferred therapeutic agents are capable of preventing and/or treating one or more symptoms of a bone disorder, such as a metabolic bone disorder. Other preferred therapeutic agents are capable of preventing or treating other bone disorders or related conditions. Examples of therapeutic agents considered to be within the 35 scope of the present invention include boron-containing compounds (e.g. carborane), 21 WO 01/44258 PCT/USOO/34487 5 chemotherapeutic nucleotides, drugs (e.g., antibiotics, antivirals, antifungals), enediynes (e.g., calicheamicins, esperamicins, dynemicin, neocarzinostatin chromophore, and kedarcidin chromophore), heavy metal complexes (e.g., cisplatin), hormone antagonists (e.g., tamoxifen), non-specific (non-antibody) proteins (e.g., sugar oligomers), oligonucleotides (e.g., antisense oligonucleotides that bind to a 10 target nucleic acid sequence (e.g., mRNA sequence)), peptides, photodynamic agents (e.g., rhodamine 123), radionuclides (e.g., 1-13 1, Re-186, Re-188, Y-90, Bi-212, At-21 1, Sr-89, Ho-166, Sm-153, Cu-67 and Cu-64), toxins (e.g., ricin), and transcription-based pharmaceuticals. In one preferred embodiment of the present invention in which compositions are provided for treating or preventing the 15 establishment or growth of a tumor, the therapeutic agent is a radionuclide, toxin, hormone antagonist, heavy metal complex, oligonucleotide, chemotherapeutic nucleotide, peptide, non-specific (non-antibody) protein, a boron compound or an enediyne. In a preferred embodiment in which compositions are provided for treating osteoporosis, the therapeutic agent is a Src kinase inhibitor, capable of inhibiting the 20 overactivity of osteoclasts. With respect to the compounds of the present invention, a named R group will generally have the structure which is recognized in the art as corresponding to R groups having that name. For the purposes of illustration, representative R groups as enumerated in the specification and claims of the present application are defined 25 herein. These definitions are intended to supplement and illustrate, not preclude, the definitions known to those of skill in the art. The term "independently selected" is used herein to indicate that the R groups can be identical or different. The term "alkyl" refers to the radical of saturated aliphatic groups, including 30 straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C 1
-C
3 0 for straight chain, C 3
-C
30 for branched chain), and more preferably 20 or fewer. Likewise, preferred cycloalkyls have from 22 WO 01/44258 PCT/USOO/34487 5 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure. Moreover, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having 10 substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a 15 nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms 20 of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF 3 , -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, 25 alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF 3 , -CN, and the like. The term "aralkyl", as used herein, refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group). Exemplary aralkyl groups include, but are not limited to, benzyl and more generally (CH 2 )nPh, where Ph is phenyl or substituted phenyl, and n is 1, 2, or 3. 30 The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to ten carbons, 35 more preferably from one to six carbon atoms in its backbone structure. Likewise, 23 WO 01/44258 PCT/USOO/34487 5 "lower alkenyl" and "lower alkynyl" have similar chain lengths. Preferred alkyl groups are lower alkyls. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl. The term "aryl" as used herein includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, 10 benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics." The aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, 15 alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF 3 , -CN, or the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common 20 to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls. The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho 25 dimethylbenzene are synonymous. The terms "heterocyclyl" or "heterocyclic group" refer to 3- to 10-membered ring structures, more preferably 3- to 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can also be polycycles. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, 30 xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, 35 phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, 24 WO 01/44258 PCT/USOO/34487 5 morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, 10 aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like. The terms "polycyclyl" or "polycyclic group" refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". 15 Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or 20 heteroaromatic moiety, -CF 3 , -CN, or the like. The term "carbocycle", as used herein, refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon. As used herein, the term "nitro" means -NO 2 ; the term "halogen" designates F, -Cl, -Br or -I; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; 25 and the term "sulfonyl" means -SO 2
-
The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the general formula: /R Rio 10 -N --- N- Rio R or 9 R9 30 wherein R 9 , R 10 and R'10 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)m-R8, or R 9 and R 10 taken together with the N atom to which they 25 WO 01/44258 PCT/USOO/34487 5 are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R 8 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In preferred embodiments, only one of R 9 or
R
1 0 can be a carbonyl, e.g., R 9 , R 1 0 and the nitrogen together do not form an imide. In even more preferred embodiments, R 9 and R 10 (and optionally R'10) each 10 independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2)m-R8. Thus, the term "alkylamine" as used herein means an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R 9 and R 1 0 is an alkyl group. The term "acylamino" is art-recognized and refers to a moiety that can be 15 represented by the general formula: 0 -N R'11
L\
9 wherein R 9 is as defined above, and R'l I represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-R8, where m and R 8 are as defined above. The term "amido" is art recognized as an amino-substituted carbonyl and 20 includes a moiety that can be represented by the general formula: 0 N_ R9 Rio wherein R 9 , R 10 are as defined above. Preferred embodiments of the amide will not include imides which may be unstable. The term "amidine" is art-recognized as a group that can be represented by the 25 general formula:
NR
9 N .R1 0 R 26 WO 01/44258 PCT/USOO/34487 5 wherein R 9 , R 10 are as defined above. The term "guanidine" is art-recognized as a group that can be represented by the general formula:
NR
9
R
9 wherein R 9 , R 1 0 are as defined above. 10 The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In preferred embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2)m-R8, wherein m and R 8 are defined above. Representative alkylthio groups include methylthio, ethyl thio, and the like. 15 The term "carbonyl" is art recognized and includes such moieties as can be represented by the general formula: 0 0 X-Ri Ior __X R'a wherein X is a bond or represents an oxygen or a sulfur, and RI I represents a hydrogen, an alkyl, an alkenyl, -(CH2)m-R8 or a pharmaceutically acceptable salt, 20 R' I represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-R8, where m and R 8 are as defined above. Where X is an oxygen and RI 1 or R'l I is not hydrogen, the formula represents an "ester". Where X is an oxygen, and R 1 I is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when RI I is a hydrogen, the formula represents a "carboxylic acid". Where X is an oxygen, and 25 R' I is hydrogen, the formula represents a "formate". In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiolcarbonyl" group. Where X is a sulfur and R 1 I or R'l I is not hydrogen, the formula represents a "thiolester." Where X is a sulfur and Rl 1 is hydrogen, the 27 WO 01/44258 PCT/USOO/34487 5 formula represents a "thiolcarboxylic acid." Where X is a sulfur and R 1 l' is hydrogen, the formula represents a "thiolformate." On the other hand, where X is a bond, and R 1 1 is not hydrogen, the above formula represents a "ketone" group. Where X is a bond, and R 1 1 is hydrogen, the above formula represents an "aldehyde" group. 10 The terms "alkoxyl" or "alkoxy" as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be 15 represented by one of -0-alkyl, -0-alkenyl, -0-alkynyl, -O-(CH2)m-R8, where m and
R
8 are described above. The term "sulfonate" is art recognized and includes a moiety that can be represented by the general formula: 0 I|
-S-OR
4 1 0 20 in which R41 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl. The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. The terms triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, p 25 toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively. The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of the abbreviations 30 utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in this list, 28 WO 01/44258 PCT/USOO/34487 5 and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference. The term "sulfate" is art recognized and includes a moiety that can be represented by the general formula: 0 -o -S- OR41 I I 0 10 in which R 4 1 is as defined above. The term "sulfonamido" is art recognized and includes a moiety that can be represented by the general formula: 0 I| -N-S-R' R90 in which R 9 and R'l I are as defined above. 15 The term "sulfamoyl" is art-recognized and includes a moiety that can be represented by the general formula: o R || / -- S -N o " in which R 9 and Rio0 are as defined above. The term "sulfonyl", as used herein, refers to a moiety that can be represented 20 by the general formula: 0 00 I I \R in which R 4 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. 29 WO 01/44258 PCT/USOO/34487 5 The term "sulfoxido" as used herein, refers to a moiety that can be represented by the general formula: 0 11 -S -R44 in which R 4 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl. 10 A "phosphoryl" can in general be represented by the formula: Q, 1
OR
4 6 wherein Qi represented S or 0, and R 4 6 represents hydrogen, a lower alkyl or an aryl. When used to substitute, e.g., an alkyl, the phosphoryl group of the phosphorylalkyl can be represented by the general formula: -- Q2- -0- -Q2- p- OR46 | , or I 15
OR
4 6
OR
4 6 wherein Qi represented S or 0, and each R 4 6 independently represents hydrogen, a lower alkyl or an aryl, Q2 represents 0, S or N. When Qi is an S, the phosphoryl moiety is a "phosphorothioate". As used herein, the definition of each expression, e.g. alkyl, m, n, etc., when it 20 occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure. It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable 25 compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. 30 WO 01/44258 PCT/USOO/34487 5 As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The 10 permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents 15 of organic compounds. The phrase "protecting group" as used herein means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, 20 respectively. The field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2"d ed.; Wiley: New York, 1991, incorporated herein by reference). Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, 25 including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention. 30 Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomer ratios are all contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are 35 contemplated for more complex isomer mixtures. 31 WO 01/44258 PCT/USOO/34487 5 If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional 10 group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. Contemplated equivalents of the compounds described above include 15 compounds which otherwise correspond thereto, and which have the same general properties thereof (e.g., bone targeting agents), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound in targeting bone. In general, the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, 20 described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here. For purposes of this invention, the chemical elements are identified in 25 accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. Detailed Description of Certain Preferred Embodiments of the Invention As discussed above, there remains a need to develop selective and potent 30 agents for treatment of bone disorders, preferably metabolic bone disorders. Thus, in general, the present invention provides compounds comprising a bone targeting agent and a payload for use in the treatment of bone disorders and other related disorders. In certain embodiments, the present invention provides compounds, pharmaceutical compositions and methods of selective treatment of metabolic bone disorders. In 35 certain embodiments, these compounds and compositions are used to treat disorders 32 WO 01/44258 PCT/USOO/34487 5 resulting from overactive osteoclast function. In certain other preferred embodiments, these compounds and compositions are used to treat osteoporosis. Clearly, because of the numerous factors involved in bone metabolism, there are several approaches for the development of novel therapeutics. As described above, one approach would be to inhibit the activity of osteoclasts by inhibition of a 10 proton pump, or by inhibition of Src tyrosine phosphorylation. Other approaches might involve the promotion of osteoblast activity. Irrespective of the approach taken, however, there remains a need for the development of selective and potent therapeutics capable of targeting bone tissue directly. In view of this need for improved agents, the present invention provides novel 15 compounds comprising a bone targeting moiety and a payload. Thus, in certain embodiments, the present invention contemplates the use of bone targeting agents, as described in more detail herein, having a specific payload attached thereto. The specific payload attached thereto may be useful in the inhibition of osteoclast activity via a proton pump, or via inhibition of Src tyrosine kinase, or via any other 20 mechanism that affects the functioning of osteoclast or osteoblast cells. In certain other embodiments, the bone targeting agents themselves act as selective and potent inhibitors of osteoclast function. Thus, the present invention, provides, in certain embodiments, compositions comprising a compound having the structure of Formula (I): 25 Hc-X-K-Cy-L-Z-Tb (I) wherein L and K, independently, are absent or represent -Mn-Y-Mp-; 30 X, Y, and Z, independently, are absent or represent NR, 0, or S; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, such as -CH 2 -, -CHF-, -CHOH-, -CH(Me)-, -C(=O)-, etc., or two M taken together represent substituted or unsubstituted ethene or ethyne; R represents, independently for each occurrence, H or substituted or 35 unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl or alkyl. 33 WO 01/44258 PCT/USOO/34487 5 Cy represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl, including polycyclic groups; p and n, independently, represent integers from 0-10, preferably from 0-5, even more preferably, from 0-3. Hc represents a heterocycle, preferably a nitrogen-containing heterocycle; and 10 Tb represents a bone-targeting moiety preferably selected from: O O ~I "-I 'OR,, \xSr'R \1-1 OR 4 ,
OR
4
OR
4 ROR OR4 OR4 O OR4 V N IOR 4
R
4 0 NOR R 4 0 OR 4 4
OR
4 OR 4
OR
4
OR
4
OR
4 OR OR OOOR iv V 0 00 0 Vi
R
4 0~ Ii'l"OR 4
R
4 0___ OR 4 P
OR
4 0
OR
4 0 O
OR
4
OR
4 Vii viii ix PO(OR4)2
PO(
O
R4)2
PO(OR
4
)
2 x x P0 3
(R
4
)
2 C0 2
R
4
R
4 0 2 C 0 Xii C0 2
R
4
R
4 0 2 C N CO 2
R
4
R
4 0 2 C N PO(OR 4
)
2 0 N PO(OR 4
)
2 Xiii xiv XV wherein R 1 4 , independently for each occurrence, represents H, lower alkyl, or a 15 pharmaceutically active small molecule or a prodrug form thereof, preferably H or Ci
C
3 lower alkyl. 34 WO 01/44258 PCT/USOO/34487 5 In embodiments wherein Tb is selected from i, v, vi, vii, viii, and ix, Z is preferably absent. In embodiments wherein Tb is selected from ii, iii, and iv, Z may be absent or represent 0 or NR. In embodiments wherein Tb is selected from x, xi, xii, xiii, xiv, and xv, Z may be absent or represent 0 or NR, preferably being absent. 10 In certain embodiments, R 4 represents H for all occurrences. In certain embodiments, an occurrence of R 1 4 represents -CH 2 0C(=0)-(drug) or-CH 2 OC(=0) (prodrug). In certain embodiments, L represents alkyl-Y-alkyl, alkyl-Y-acyl, or alkyl. 15 In certain embodiments, L-Cy-K-X-Hc is free of hydrolyzable linkages. Hydrolyzable linkages, as the term is used herein, are saturated (sp 3 -hybridized) carbons bound to two heteroatoms, of which at least one is selected from S, N, or 0. 20 In certain embodiments, M represents, independently for each occurrence, a substituted or unsubstituted methylene group, such as -CH 2 -, -CHF-, -CHOH-, CH(Me)-, -C(=0)-, etc. In certain embodiments, Cy represents a carbocycle or a nitrogen-bearing 25 heterocycle. Cy is preferably uncharged. In certain embodiments, Cy is substituted with a second bone-targeting group (Tb), optionally through a linking group (such as -L-Z-). 30 In certain embodiments, Cy represents a phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system, preferably having between 8 and 11 atoms, such as a fused cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy represents a fused ring system, one substituent of L and K (or Hc or Tb) may be attached to one of the two rings, and the other substituent to the other of the 35 two rings. In certain embodiments, Cy is phenyl. 35 WO 01/44258 PCT/USOO/34487 5 In certain embodiments, K is absent. In certain embodiments, K represents alkyl-Y-alkyl, alkyl-Y-acyl, or alkyl. In certain embodiments, He represents a bicyclic structure, preferably 10 including heteroatoms in both rings. In certain embodiments, the ring(s) of Hc consist of C and N atoms. In certain embodiments, Hc represents a bicyclic heteroaryl structure. In certain embodiments, K is directly attached to a heteroatom of Hc, or X 15 represents NR. In certain embodiments, Hc includes at least one aryl substituent. In certain embodiments, Hc-X taken together represent one of the following 20 structures: R2 R2 R1 N N .- -- N N N N N N N NHR3 N NHR 3
R
2 HN N NHR 3 xvi xvii xviii N R1 N R3 N N N W N N N NHR 2 H I H XiX R2 x wherein W represents 0 or S, and one of R 1 , R 2 , and R 3 represents a bond to K, and the others represent, independently, hydrogen, halogen, alkyl, aralkyl, aryl, cycloalkyl, heteroaryl, heterocyclic, cycloalkyl, polycyclic, alkyl alkenyl, alkyl 25 alkynyl, or alkanoyl, or taken together with the nitrogen to which it is attached, represent amidine, amide, carbamate, urea, or guanidine. 36 WO 01/44258 PCT/USOO/34487 5 In certain embodiments wherein Hc-X is represented by xix or xx, R 3 represents a bond to K, R 2 is selected from hydrogen, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, heteroaryl, heterocyclyl, cycloalkyl, polycyclyl, alkyl alkenyl, alkyl alkynyl, and alkanoyl; and Ri is selected from hydrogen, halogen, aryl, and 10 heteroaryl. In certain embodiments, R 2 is selected from hydrogen, (CH 2 )nPh, where Ph is phenyl or substituted phenyl and n is 0, 1, 2, or 3; heteroaryl, cycloalkyl, CI-C 6 alkanoyl, CI-C 6 alkyl, C 2
-C
6 alkenyl, and C 2
-C
6 alkynyl, where the alkyl, alkenyl and alkynyl groups may be substituted by NR 5
R
6 , phenyl, thioalkyl, alkyloxy, hydroxy, carboxy, halogen, cycloalkyl, and where R 5 and R 6 are independently hydrogen, CI 15 C 6 alkyl, C 2
-C
6 alkenyl, C 2
-C
6 alkynyl, (CH 2 )nPh where Ph is phenyl and n is 0, 1, 2, or 3; cycloalkyl, heteroaryl, and R 5 and R 6 taken together with the nitrogen to which they are attached can complete a ring having 3 to 7 carbon atoms and optionally containing 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen and sulfur. In certain embodiments, R, is a substituted 20 aryl moiety selected from of monohaloaryl, dihaloaryl, monomethylaryl, and dimethylaryl. In certain embodiments, at least one of R 1 , R 2 , and R 3 , other than the bond to K, represents an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl. 25 In certain embodiments wherein Hc-X is represented by xviii, R 2 represents a bond to K, and Ri and R 3 are selected, independently, from hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heteroalkyl, heteroaralkyl, alkyl alkenyl, alkyl alkynyl, alkyl cycloalkyl, and alkyl heterocyclyl. In certain embodiments, R, is alkyl or branched alkyl and R 3 is aryl, heteroaryl, or cycloalkyl. In 30 certain embodiments, R 3 is selected from monohaloaryl, dihaloaryl, monohaloheteroaryl, dihaloheteroaryl, monohalocycloalkyl, or dihalocycloalkyl. In certain embodiments, at least one of R 1 , R 2 , and R 3 , other than the bond to K, represents an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl. 35 37 WO 01/44258 PCT/USOO/34487 5 In certain embodiments wherein Hc-X is represented by xvi or xvii, at least one of R 1 , R 2 , or R 3 represents a bond to K, R 3 , if not a bond to K, is selected from hydrogen or alkyl, R 2 , if not a bond to K, is selected from alkyl, cycloalkyl, alkyl alkenyl, alkyl alkynyl, and R 1 , if not a bond to K, is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroalkyl, alkyl alkenyl, alkyl 10 alkynyl, alkyl cycloalkyl, or alkyl heterocyclyl. In certain embodiments, at least one of R 1 , R 2 , and R 3 , other than the bond to K, represents an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl. In certain embodiments wherein Tb is represented by vii or viii, L-Cy-K-X-Hc 15 is free of hydrolyzable linkages. In certain embodiments, L and K do not comprise nitrogen. In certain embodiments, He represents a heterocyclic bicycle. In certain embodiments, He represents a bicyclic heteroaryl structure. In certain embodiments, He is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, R 4 represents H for all occurrences. In certain embodiments, Cy represents a phenyl, pyridyl, 20 cyclopentyl, cyclohexyl, or a fused bicyclic ring system, preferably having between 8 and 11 atoms, such as a fused cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy represents a fused ring system, one substituent of L and K (or He or Tb) may be attached to one of the two rings, and the other substituent to the other of the two rings. In embodiments wherein X is absent, K is preferably directly attached 25 to a heteroatom of He. In certain embodiments, K is absent. In certain embodiments, Tb is represented by xi, xii, xiv, or xv. In certain embodiments, K and L do not include an amide bond, or are preferably free of nitrogen atoms. In certain embodiments, He represents a heterocyclic bicycle. In 30 certain embodiments, He represents a bicyclic heteroaryl structure. In certain embodiments, He is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, L-Cy-K-X-Hc does not include a hydrolyzable linkage. In certain embodiments, R 4 represents H for all occurrences. In certain embodiments, Cy represents a phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system, 35 preferably having between 8 and 11 atoms, such as a fused cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy represents a fused ring system, one 38 WO 01/44258 PCT/USOO/34487 5 substituent of L and K (or He or Tb) may be attached to one of the two rings, and the other substituent to the other of the two rings. In embodiments wherein X is absent, K is preferably directly attached to a heteroatom of Hc. In certain embodiments, K is absent. 10 In certain embodiments wherein Tb is represented by the moiety xiii, that moiety is not present in another portion of the compound, e.g., He is not xiii, etc. In certain embodiments, K does not include an amide bond, or is preferably free of nitrogen atoms. In certain embodiments, He represents a heterocyclic bicycle. In certain embodiments, He represents a bicyclic heteroaryl structure. In certain 15 embodiments, He is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, L-Cy-K-X-Hc does not include a hydrolyzable linkage. In certain embodiments, R 4 represents H for all occurrences. In certain embodiments, Cy represents a phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system, preferably having between 8 and 11 atoms, such as a fused cyclohexyl/cyclopentyl 20 ([4.3.0]-bicyclononane) ring system. When Cy represents a fused ring system, one substituent of L and K (or He or Tb) may be attached to one of the two rings, and the other substituent to the other of the two rings In embodiments wherein X is absent, K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent. 25 In certain embodiments wherein Tb is represented by x, K does not include an amide bond, is free of carbonyls, is free of amine substituents, or is free of nitrogen atoms. In certain embodiments, He represents a heterocyclic bicycle. In certain embodiments, He represents a bicyclic heteroaryl structure. In certain embodiments, 30 He is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, L-Cy-K-X He does not include a hydrolyzable linkage. In certain embodiments, R 4 represents H for all occurrences. In certain embodiments, Cy represents a phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system, preferably having between 8 and 11 atoms, such as a fused cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring 35 system. When Cy represents a fused ring system, one substituent of L and K (or He or Tb) may be attached to one of the two rings, and the other substituent to the other of 39 WO 01/44258 PCT/USOO/34487 5 the two rings. In embodiments wherein X is absent, K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent. In certain embodiments wherein Tb is represented by ii, iii, iv, or v, L-Cy-K X-Hc does not include a hydrolyzable linkage. In certain embodiments, He represents 10 a heterocyclic bicycle. In certain embodiments, He represents a bicyclic heteroaryl structure. In certain embodiments, He is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, R 4 represents H for all occurrences. In certain embodiments, Cy represents a phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system, preferably having between 8 and 11 atoms, such as a fused 15 cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy represents a fused ring system, one substituent of L and K (or He or Tb) may be attached to one of the two rings, and the other substituent to the other of the two rings. In certain embodiments, K is directly attached to a heteroatom of Hc. In certain embodiments, K is absent. 20 In certain embodiments wherein Tb is represented by ix, Cy is preferably uncharged, and/or L-Cy-K is preferably free of hydrolyzable linkages. In certain embodiments, L-Cy-K-X-Hc is free of hydrolyzable linkages. In certain embodiments, Cy is preferably selected from aryl, carbocyclic, nitrogen-containing 25 heterocyclic, and nitrogen-containing heteroaryl groups, and preferably does not include S or 0 atoms in the ring structure. In preferred embodiments, Cy contains 0 or 1 heteroatoms. In certain embodiments, He represents a heterocyclic bicycle. In certain embodiments, He represents a bicyclic heteroaryl structure. In certain embodiments, He is selected from xvi, xvii, xviii, xix, and xx. In certain 30 embodiments, R 4 represents H for all occurrences. In certain embodiments, Cy represents a phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system, preferably having between 8 and 11 atoms, such as a fused cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy represents a fused ring system, one substituent of L and K (or He or Tb) may be attached to one of the two rings, and the 35 other substituent to the other of the two rings. In embodiments wherein X is absent, K 40 WO 01/44258 PCT/USOO/34487 5 is preferably directly attached to a heteroatom of Hc. In certain embodiments, K is absent. In certain embodiments wherein Tb is represented by i, Cy is preferably uncharged, and/or L-Cy-K is preferably free of hydrolyzable linkages. In certain 10 embodiments, Cy is preferably selected from aryl, carbocyclic, nitrogen-containing heterocyclic, and nitrogen-containing heteroaryl groups, and preferably does not include S or 0 atoms in the ring structure. In preferred embodiments, the ring system of Cy contains 0 or 1 heteroatoms. In certain embodiments, He represents a heterocyclic bicycle. In certain embodiments, He represents a bicyclic heteroaryl 15 structure. In certain embodiments, He is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, R 4 represents H for all occurrences. In certain embodiments, Cy represents a phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system, preferably having between 8 and 11 atoms, such as a fused cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy represents a fused ring system, one 20 substituent of L and K (or He or Tb) may be attached to one of the two rings, and the other substituent to the other of the two rings. In embodiments wherein X is absent, K is preferably directly attached to a heteroatom of Hc. In certain embodiments, K is absent. 25 In certain embodiments wherein Tb is represented by i, Z and L are absent. In certain embodiments, Cy represents an aryl or heteroaryl group, such as a phenyl or pyridyl group. In certain embodiments, Cy is preferably uncharged, and/or L-Cy-K X-Hc is preferably free of hydrolyzable linkages. In certain embodiments, Cy is preferably selected from aryl, carbocyclic, nitrogen-containing heterocyclic, and 30 nitrogen-containing heteroaryl groups, and preferably does not include S or 0 atoms in the ring structure. In preferred embodiments, the ring system of Cy contains 0 or 1 heteroatoms, or is preferably phenyl. In certain embodiments, He represents heterocyclic bicycle. In certain embodiments, He represents a bicyclic heteroaryl structure. In certain embodiments, He is selected from xvi, xvii, xviii, xix, and xx. In 35 certain embodiments, R 4 represents H for all occurrences. In certain embodiments, Cy represents a phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring 41 WO 01/44258 PCT/USOO/34487 5 system, preferably having between 8 and 11 atoms, such as a fused cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy represents a fused ring system, one substituent of L and K (or He or Tb, where L and/or K is absent) may be attached to one of the two rings, and the other substituent to the other of the two rings. In embodiments wherein X is absent, K is preferably directly 10 attached to a heteroatom of Hc. In certain embodiments, K is absent. In certain embodiments of Formula I, Tb is selected from i and ix, and K is absent or represents -Y-, such as -NH-. In certain embodiments, He is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, Cy is aryl or heteroaryl, 15 preferably aryl. In certain embodiments, He is further substituted with an aryl group, e.g., at a position of R 1 , R 2 , and R 3 not substituted with K. In certain embodiments, each of R 1 , R 2 , and R 3 represents a hydrocarbon substituent. In certain embodiments, L represents alkyl, alkyl-Y-alkyl or alkyl-Y-acyl, wherein Y is preferably NR, such as NH or NMe. 20 In certain embodiments of Formula I, Tb is x and K is absent. In certain embodiments, He is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, He is further substituted with an aryl group, e.g., at a position of R 1 , R2, and R 3 not substituted with K. In certain embodiments, each of R 1 , R 2 , and R 3 25 represents a hydrocarbon substituent. In certain embodiments, L represents alkyl, alkyl-Y-alkyl or alkyl-Y-acyl, wherein Y is preferably NR, such as NH or NMe. In certain embodiments, a subject compound has the structure of Formula (II): 30 Hc-X-K-Z-Tb (II) wherein He, X, K, Z, and Tb are as defined above. 35 In certain embodiments of Formula II, Tb is selected from x, xi, xii, xiii, xiv, and xv. In embodiments wherein Tb is selected from x, xi, xii, xiii, xiv, and xv, Z may be absent or represent 0 or NR, preferably being absent. 42 WO 01/44258 PCT/USOO/34487 5 In embodiments wherein Tb is selected from i, v, vi, vii, viii, and ix, Z is preferably absent. In embodiments wherein Tb is selected from ii, iii, and iv, Z may be absent or represent 0 or NR. 10 In certain embodiments, R 4 represents H for all occurrences. In certain embodiments, K-X-Hc is free of hydrolyzable linkages. Hydrolyzable linkages, as the term is used herein, are saturated (sp 3 -hybridized) carbons bound to two heteroatoms, of which at least one is selected from S, N, or 0. 15 In certain embodiments, M represents a substituted or unsubstituted methylene group, such as -CH 2 -, -CHF-, -CHOH-, -CH(Me)-, -C(=0)-, etc. In certain embodiments, K is absent. 20 In certain embodiments, K represents alkyl-Y-alkyl, alkyl-Y-acyl, or alkyl. In certain embodiments, Hc represents a bicyclic structure, preferably including heteroatoms in both rings. In certain embodiments, the ring(s) of Hc consist 25 of C and N atoms. In certain embodiments, K is directly attached to a heteroatom of Hc, or X represents NR. 30 In certain embodiments, Hc includes at least one aryl substituent. In certain embodiments, Hc-X taken together represent one of the following structures: 43 WO 01/44258 PCT/USOO/34487 R2 R2 R, N N-N N R, R, N N N N NHR 3 N NHR 3
R
2 HN N NHR 3 Xvi Xvii Xviii R1 R, N NN R3
R
3 N N N W R N N N NHR 2 H I H 5 XiX R2 XX wherein W represents 0 or S, and one of R 1 , R 2 , and R 3 represents a bond to K, and the others represent, independently, hydrogen, halogen, alkyl, aralkyl, aryl, cycloalkyl, heteroaryl, heterocyclic, cycloalkyl, polycyclic, alkyl alkenyl, alkyl 10 alkynyl, or alkanoyl, or taken together with the nitrogen to which it is attached, represent amidine, amide, carbamate, urea, or guanidine. In certain embodiments wherein Hc-X is represented by xix or xx, R 3 represents a bond to K, R 2 is selected from hydrogen, alkyl, alkenyl, alkynyl, aralkyl, 15 cycloalkyl, heteroaryl, heterocyclyl, cycloalkyl, polycyclyl, alkyl alkenyl, alkyl alkynyl, and alkanoyl; and R 1 is selected from hydrogen, halogen, aryl, and heteroaryl. In certain embodiments, R 2 is selected from hydrogen, (CH 2 )nPh, where Ph is phenyl or substituted phenyl and n is 0, 1, 2, or 3; heteroaryl, cycloalkyl, CI-C 6 alkanoyl, CI-C 6 alkyl, C 2
-C
6 alkenyl, and C 2
-C
6 alkynyl, where the alkyl, alkenyl and 20 alkynyl groups may be substituted by NR 5
R
6 , phenyl, thioalkyl, alkyloxy, hydroxy, carboxy, halogen, cycloalkyl, and where R 5 and R 6 are independently hydrogen, Ci
C
6 alkyl, C 2
-C
6 alkenyl, C 2
-C
6 alkynyl, (CH 2 )nPh where Ph is phenyl and n is 0, 1, 2, or 3; cycloalkyl, heteroaryl, and R 5 and R 6 taken together with the nitrogen to which they are attached can complete a ring having 3 to 7 carbon atoms and optionally 25 containing 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen and sulfur. In certain embodiments, R, is a substituted 44 WO 01/44258 PCT/USOO/34487 5 aryl moiety selected from of monohaloaryl, dihaloaryl, monomethylaryl, and dimethylaryl. In certain embodiments, at least one of R 1 , R 2 , and R 3 , other than the bond to K, represents an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl. 10 In certain embodiments wherein Hc-X is represented by xviii, R 2 represents a bond to K, and R, and R3 are selected, independently, from hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heteroalkyl, heteroaralkyl, alkyl alkenyl, alkyl alkynyl, alkyl cycloalkyl, and alkyl heterocyclyl. In certain embodiments, R, is alkyl or branched alkyl and R 3 is aryl, heteroaryl, or cycloalkyl. In 15 certain embodiments, R3 is selected from monohaloaryl, dihaloaryl, monohaloheteroaryl, dihaloheteroaryl, monohalocycloalkyl, or dihalocycloalkyl. In certain embodiments, at least one of R1, R2, and R3, other than the bond to K, represents an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl. 20 In certain embodiments wherein Hc-X is represented by xvi or xvii, at least one of R 1 , R 2 , or R 3 represents a bond to K, R 3 , if not a bond to K, is selected from hydrogen or alkyl, R2, if not a bond to K, is selected from alkyl, cycloalkyl, alkyl alkenyl, alkyl alkynyl, and R 1 , if not a bond to K, is selected from hydrogen, alkyl, 25 cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroalkyl, alkyl alkenyl, alkyl alkynyl, alkyl cycloalkyl, or alkyl heterocyclyl. In certain embodiments, at least one of R 1 , R 2 , and R 3 , other than the bond to K, represents an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl. 30 In certain embodiments wherein Tb is represented by vii or viii, K-X-Hc is free of hydrolyzable linkages. In certain embodiments, K does not comprise nitrogen. In certain embodiments, Hc represents a heterocyclic bicycle. In certain embodiments, Hc represents a bicyclic heteroaryl structure. In certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, R 4 represents H for all 35 occurrences. In embodiments wherein X is absent, K is preferably directly attached to a heteroatom of Hc. In certain embodiments, K is absent. 45 WO 01/44258 PCT/USOO/34487 5 In certain embodiments, Tb is represented by xi, xii, xiv, or xv. In certain embodiments, K does not include an amide bond, or are preferably free of nitrogen atoms. In certain embodiments, He represents a heterocyclic bicycle. In certain embodiments, He represents a bicyclic heteroaryl structure. In certain embodiments, 10 He is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, K-X-Hc does not include a hydrolyzable linkage. In certain embodiments, R 4 represents H for all occurrences. In embodiments wherein X is absent, K is preferably directly attached to a heteroatom of Hc. In certain embodiments, K is absent. 15 In certain embodiments wherein Tb is represented by the moiety xiii, that moiety is not present in another portion of the compound, e.g., He is not xiii, etc. In certain embodiments, K does not include an amide bond, or is preferably free of nitrogen atoms. In certain embodiments, He represents a heterocyclic bicycle. In certain embodiments, He represents a bicyclic heteroaryl structure. In certain 20 embodiments, He is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, K-X-Hc does not include a hydrolyzable linkage. In certain embodiments, R 4 represents H for all occurrences. In embodiments wherein X is absent, K is preferably directly attached to a heteroatom of Hc. In certain embodiments, K is absent. 25 In certain embodiments wherein Tb is represented by x, K does not include an amide bond, is free of carbonyls, is free of amine substituents, or is free of nitrogen atoms. . In certain embodiments, K-X-Hc does not include a hydrolyzable linkage. In certain embodiments, He represents a heterocyclic bicycle. In certain embodiments, 30 He represents a bicyclic heteroaryl structure. In certain embodiments, He is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, R 1 4 represents H for all occurrences. In embodiments wherein X is absent, K is preferably directly attached to a heteroatom of Hc. In certain embodiments, K is absent. 35 In certain embodiments wherein Tb is represented by ii, iii, iv, or v, K-X-Hc does not include a hydrolyzable linkage. In certain embodiments, He represents a 46 WO 01/44258 PCT/USOO/34487 5 heterocyclic bicycle. In certain embodiments, Hc represents a bicyclic heteroaryl structure. In certain embodiments, Ho is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, R 4 represents H for all occurrences. In certain embodiments, K is directly attached to a heteroatom of Hc. In certain embodiments, K is absent. 10 In certain embodiments wherein Tb is represented by ix, K-X-Hc is preferably free of hydrolyzable linkages. In certain embodiments, the compound is free of hydrolyzable linkages. In certain embodiments, Hc represents a heterocyclic bicycle. In certain embodiments, Ho represents a bicyclic heteroaryl structure. In certain embodiments, Ho is selected from xvi, xvii, xviii, xix, and xx. In certain 15 embodiments, R4 represents H for all occurrences. In embodiments wherein X is absent, K is preferably directly attached to a heteroatom of Hc. In certain embodiments, K is absent. In certain embodiments wherein Tb is represented by i, Ho represents a 20 heterocyclic bicycle. In certain embodiments, Ho represents a bicyclic heteroaryl structure. In certain embodiments, Ho is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, R4 represents H for all occurrences. In embodiments wherein X is absent, K is preferably directly attached to a heteroatom of Hc. In certain embodiments, K is absent. 25 In certain embodiments of Formula II, Tb is selected from i and ix, and K is branched or unbranched alkyl. In certain embodiments, Ho is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, Hc is further substituted with an aryl group, e.g., at a position of R 1 , R 2 , and R 3 not substituted with K. In certain 30 embodiments, each of R 1 , R 2 , and R 3 represents a hydrocarbon substituent. In certain embodiments of Formula II, Tb is xii, and K is absent or represents Y-, such as -NH-. In certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, Ho is further substituted with an aryl group, e.g., at a 35 position of R 1 , R 2 , and R 3 not substituted with K. In certain embodiments, each of R 1 , R2, and R3 represents a hydrocarbon substituent. 47 WO 01/44258 PCT/USOO/34487 5 In certain embodiments of Formula II, Tb is x, and K represents alkyl or -Y-. In certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and xx. In certain embodiments, Hc is further substituted with an aryl group, e.g., at a position of R 1 , R 2 , and R 3 not substituted with K. In certain embodiments, each of R 1 , R 2 , and R 3 10 represents a hydrocarbon substituent. In certain embodiments, a subject compound has the structure of formula III: Tb-L-V, wherein Tb, R, and L are as defined above, and V represents OR, NR 2 , or SR. 15 In embodiments wherein Tb is selected from i, ii, iii, iv, v, vi, vii, viii, and ix, L is preferably not absent, and even more preferably represents alkyl. In certain embodiments, Tb represents i, ii, iii, or iv, preferably i. In certain embodiments, Tb represents v or vi. In certain embodiments, Tb represents vii or viii. In certain 20 embodiments, Tb represents ix. In certain embodiments, V represents NR 2 . In certain embodiments, all occurrences of R in V are H. In certain embodiments, Tb is selected from x, xi, xii, xiii, xiv, xv, xxi, xxii, xxiii, xxiv, and xxv. In certain embodiments, Tb is selected from xi, xii, xiv, or xv. In 25 certain embodiments, Tb is x. In certain embodiments, Tb is xiii. In certain embodiments, V represents NR 2 . In certain embodiments, Tb is xxi, xxii, xxiii, xxiv, or xxv. In certain embodiments, Tb is xx. In certain embodiments, all occurrences of R in V are H. In certain embodiments, L represents lower alkyl or is absent. 30 In certain embodiments, a subject compound has the structure of Formula IV: Tb-Cy-L-V, wherein Tb, Cy, L, and V are as defined above, and Tb is selected from i, ii, iii, iv, v, vi, vii, viii, and ix. In certain embodiments, Tb represents i, ii, iii, or iv, preferably i. In certain embodiments, Tb represents v or vi. In certain embodiments, Tb represents vii or viii. In certain embodiments, Tb represents ix. In certain 35 embodiments, L is absent. In certain embodiments, Cy represents a phenyl ring. In 48 WO 01/44258 PCT/USOO/34487 5 certain embodiments, V represents NR 2 . In certain embodiments, all occurrences of R in V are H. In certain embodiments, L represents lower alkyl or is absent. In certain embodiments, a subject compound has the structure of Formula V: Tb-L-U, wherein Tb, R, and L are as defined above, and 10 U represents a sulfonate ester (e.g., triflate, tosylate, mesylate, etc.), halogen (e.g., Cl, Br, I, preferably Br, I), formyl (CHO), or a suitable leaving group (e.g., a moiety whose conjugate acid, UH, has a pKa lower than 5, preferably lower than 0). In embodiments wherein Tb is selected from i, ii, iii, iv, v, vi, vii, viii, and ix, 15 L is preferably not absent, and even more preferably represents alkyl. In certain embodiments, Tb represents i, ii, iii, or iv, preferably i. In certain embodiments, Tb represents v or vi. In certain embodiments, Tb represents vii or viii. In certain embodiments, Tb represents ix. 20 In certain embodiments, Tb is selected from x, xi, xii, xiii, xiv, xv, xxi, xxii, xxiii, xxiv, and xxv. In certain embodiments, Tb is selected from xi, xii, xiv, or xv. In certain embodiments, Tb is x. In certain embodiments, Th is xiii. In certain embodiments, V represents NR 2 . In certain embodiments, Tb is xxi, xxii, xxiii, xxiv, or xxv. In certain embodiments, Tb is xx. 25 In certain embodiments, a subject compound has the structure of Formula VI: Tb-Cy-L-U, wherein Tb, Cy, L, and U are as defined above, and Tb is selected from i, ii, iii, iv, v, vi, vii, viii, and ix. In certain embodiments, Tb represents i, ii, iii, or iv, preferably i. In certain embodiments, Tb represents v or vi. In certain embodiments, 30 Tb represents vii or viii. In certain embodiments, Tb represents ix. In certain embodiments, L is absent. In certain embodiments, Cy represents a phenyl ring. In certain embodiments of Formulas I -VI, Tb represents: 35 49 WO 01/44258 PCT/USOO/34487 N C0 2
R
4
R
4 0 2 C N C0 2
R
4 xxi OR 4 xxii PO(OR 4
)
2 mi OR4 C0 2
R
4
R
4 0 2 C N- 5 N C0 2
R
4 XXv N OH XXVI
PO(OR
4
)
2 In certain embodiments of Formulas I -VI, Tb may have a structure selected from: O O
YR
4
YR
4
YR
4 O YR 4 XVil XXViii XXIX 11 0 0 0 0 0
R
4 Y MR 4 Y M YR 4
R
4 Y Mx YR 4 YR4 YR 4 YR4 0 YR 4 O O H
(R
4 Y)OCN O M YR 4
YR
4
YR
4 M xxii xxiV PO(YR 4
)
2 XXX11 10 50 WO 01/44258 PCT/USOO/34487 R6 P6 R PO(YR4)2 xxxvi PO(YR 4
)
2 PO(YR 4
)
2 xxxvi xxi
PO(YR
4
)
2
COYR
4
R
4 YOC O xxxviii MRe M
R
4 YOC N COYR 4
R
4 YOC N PO(YR 4
)
2 0 N PO(YR 4
)
2 5 xxxix xxxx xxxxi
COYR
4 RRe N COYR 4 XXXXVi PO(YR 4
)
2 xxxxvii
OR
4 COYR 4 R6 R6 xxxxv N COYR 4 N OR 4 wherein M is defined as above, x represents 1,2, 3, 4, 5, or 6; 10 each occurence of Y is independently a covalent bond, -0-, -S-, or -N(Rj)2, wherein Rj, for each occurence, is independently hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl;
R
6 represents from 0-3 substituents selected from halogen, lower alkyl, lower alkenyl, aryl, heteroaryl, carbonyl, thiocarbonyl, ketone, aldehyde, amino, acylamino, 15 amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamido, phosphoryl, phosphonate, phosphinate, -(CH2)palkyl, -(CH 2 )palkenyl, (CH2)palkynyl, -(CH2)paryl, -(CH2)paralkyl, -(CH 2 )pOH, -(CH2)pO-lower alkyl, (CH 2 )pO-lower alkenyl, -O(CH2)nR, -(CH 2 )pSH, -(CH 2 )pS-lower alkyl, -(CH2)pS lower alkenyl, -S(CH 2 )nR, -(CH 2 )pN(R) 2 , -(CH 2 )pNR-lower alkyl, -(CH 2 )pNR-lower 20 alkenyl, -NRs(CH 2 )nR, or protected forms of the above, and wherein p is 1-10; and 51 WO 01/44258 PCT/USOO/34487 5 each occurrence of R 4 is independently hydrogen or a lower alkyl. In certain embodiments, M, where it occurs in Tb is selected from CH 2 , CHJ and CJ 2 , wherein J represents a halogen, such as F, Cl, Br, or I, preferably F or Cl, even more preferably F. In certain embodiments, R6, is selected from lower alkyl, hydrophilic groups, 10 and lower alkyl substituted with hydrophilic groups. Representative hydrophilic groups include hydroxyl, sulfhydryl, amino, amido, carboxyl, sulfonate, phosphonate, and salts thereof. In certain embodiments of Formulas I -VI, Tb has the structure xxxxii: _A 15 " "" B wherein A represents a group selected from GPO 3
(R
4
)
2 , GCO 2
R
4 , and GSO 3
R
4 ; and B represents a group selected from NH 2 , OH, GPO 3
(R
4
)
2 , GCO 2 R4, and
GSO
3
R
4 ; and G is absent or represents a linkage of one or two atoms, such as CF 2 ,
CH
2 , 0, S, NR, CH 2 S, CH 2 NR, CH 2 0, etc. PO(OR4) 2 PO(OR4) 2
PO(OR
4
)
2
(R
4 0) 2 0P O (R 4 0) 2 0P (R 4 0) 2 0P cF2 PO(OR4) 2
PO(OR
4
)
2
PO(OR
4
)
2 O C
F
2 20 (R 4 0) 2 0P (R 4
)
2 OPO (R 4 0) 2 0P cF2 In certain embodiments, the phenyl ring may bear one or more additional R 6 substituents. In certain embodiments, G is absent, while in other embodiments, G is present. In certain embodiments, at least one occurrence of G is absent. In certain 25 embodiments, Tb has a structure such as: 52 WO 01/44258 PCT/USOO/34487 5 In certain embodiments of Formulas I -VI, Tb has the structure xxxxiii: xxxxiii B wherein B is defined as above. In certain embodiments, the pyridyl ring may bear one or more additional R 6 10 substituents. In certain embodiments of Formulas I -VI, Tb has the structure xxxxiv or xxxxv: B B A N C0 2
R
4
(R
4 0) 2 OP N C xxxxiv xxxxv 15 wherein C represents H, R 6 , NH 2 , OH, GPO 3
(R)
2 , GCO 2
R
4 , or GSO 3
R
4 , and in xxxxiv, any one occurrence of A or B is present, and the other occurrences may represent a bond to Z, H, or R 6 as desired. In certain embodiments, the pyridyl ring may bear one or more additional R 6 substituents. 20 In certain embodiments of Formulas I -VI, Tb represents a heteroaryl, preferably a nitrogen-containing heteroaryl, bearing one B substituent, preferably an A substituent, or two B substituents, and optionally including one or more R 6 substituents. In preferred embodiments, the heteroaryl group is selected from 25 thiazoline, oxazoline, pyrrole, pyrazole, imidazole, pyridine, pyrazine, pyridazine, and pyrimidine, preferably pyridine, pyrazole, pyrazine, and pyrimidine. Solid Phase Synthesis and Combinatorial Libraries of Bone Targeting Agents 53 WO 01/44258 PCT/USOO/34487 5 The inventive compounds may be prepared by any available method. Preferably, they are synthesized, for example using solution phase or solid phase techniques. Often, solid-phase syntheses will be modified versions of the compounds described herein that allow their attachment to a solid support. Thus, the present invention also contemplates particularly preferred because it enables the use of more 10 rapid split and pool techniques to generate larger libraries (e.g., greater than 10,000 members) more easily. It will be appreciated that solid phase parallel synthesis techniques also can be utilized, such as those described in U.S. Patents 5,712,171 and 5,736,412, incorporated herein by reference. A solid support, for the purposes of this invention, is defined as an insoluble 15 material to which compounds are attached during a synthesis sequence. The use of a solid support is advantageous for the synthesis of libraries because the isolation of support-bound reaction products can be accomplished simply by washing away reagents from the support-bound material and therefore the reaction can be driven to completion by the use of excess reagents. Additionally, the use of a solid support also 20 enables the use of specific encoding techniques to "track" the identity of the inventive compounds in the library. A solid support can be any material which is an insoluble matrix and can have a rigid or semi-rigid surface. Exemplary solid supports include, but are not limited to, pellets, disks, capillaries, hollow fibers, needles, pins, solid fibers, cellulose beads, pore-glass beads, silica gels, polystyrene beads optionally 25 cross-linked with divinylbenzene, grafted co-poly beads, poly-acrylamide beads, latex beads, dimethylacrylamide beads optionally crosslinked with N-N'-bis acryloylethylenediamine, and glass particles coated with a hydrophobic polymer. One of ordinary skill in the art will realize that the choice of particular solid support will be limited by the compatability of the support with the reaction chemistry being 30 utilized. In one particularly preferred embodiment, a Tentagel amino resin, a composite of 1) a polystyrene bead crosslinked with divinylbenzene and 2) PEG (polyethylene glycol), is employed for use in the present invention. Tentagel is a particularly useful solid support because it provides a versatile support for use in on bead or off-bead assays, and it also undergoes excellent swelling in solvents ranging 35 from toluene to water. 54 WO 01/44258 PCT/USOO/34487 5 The compounds of the present invention may be attached directly to the solid support or may be attached to the solid support through a linking reagent. Direct attachment to the solid support may be useful if it is desired not to detach the library member from the solid support. For example, for direct on-bead analysis of biological/pharmacological activitiy or analysis of the compound structure, a stronger 10 interaction between the library member and the solid support may be desirable. Alternatively, the use of a linking reagent may be useful if more facile cleavage of the inventive library members from the solid support is desired. Furthermore, any linking reagent used in the present invention may comprise a single linking molecule, or alternatively may comprise a linking molecule and one or 15 more spacer molecules. A spacer molecule is particularly useful when the particular reaction conditions require that the linking molecule be separated from the library member, or if additional distance between the solid support/linking unit and the library member is desired. In one particularly preferred embodiment, photocleavable linkers are employed to attach the solid phase resin to the component. Photocleavable 20 linkers are particularly advantageous for the presently claimed invention because of the ability to use these linkers in in vivo screening strategies. Once the inventive compound is released from the solid support via photocleavage, the compound is able to enter the cell. Exemplary photocleavable linkers include, but are not limited to ortho-Nitrobenzyl photolinkers and dithiane protected benzoin photolinkers. One of 25 ordinary skill in the art will readily appreciate that the method of the present invention is not limited to the use of photocleavable linkers; rather other linkers may be employed, preferably those that are capable of delivering the desired compounds in vivo. In one embodiment of the present invention, the synthesis of libraries of bone 30 targeting agents is performed using established combinatorial methods for solution phase, solid phase, or a combination of solution phase and solid phase synthesis techniques. The synthesis of combinatorial libraries is well known in the art and has been reviewed (see, e.g., "Combinatorial Chemistry", Chemical and Engineering News, Feb. 24, 1997, p. 43; Thompson, L.A., Ellman, J.A., Chem. Rev. 1996, 96, 555, 35 incorporated herein by reference.) One of ordinary skill in the art will realize that the choice of method will depend upon the specific number of compounds to be 55 WO 01/44258 PCT/USOO/34487 5 synthesized, the specific reaction chemistry, and the availability of specific instrumentation, such as robotic instrumentation for the preparation and analysis of the inventive libraries. In particularly preferred embodiments, the reactions to be performed on the inventive scaffolds to generate the libraries are selected for their ability to proceed in high yield, and in a stereoselective fashion, if applicable. 10 In one embodiment of the present invention, libraries are generated using a solution phase technique. Traditional advantages of solution phase techniques for the synthesis of combinatorial libraries include the availability of a much wider range of organic reactions, and the relative ease with which products can be characterized. In a preferred embodiment, for the generation of a solution phase 15 combinatorial library, a parallel synthesis technique is utilized, in which all of the products are assembled separately in their own reaction vessels. In a particularly preferred parallel synthesis procedure, a microtitre plate containing n rows and m columns of tiny wells which are capable of holding a few milliliters of the solvent in which the reaction will occur, is utilized. It is possible to then use n variants of 20 reactant A, and m variants of reactant B, to obtain n x m variants, in n x m wells. One of ordinary skill in the art will realize that this particular procedure is most useful when smaller libraries are desired, and the specific wells can provide a ready means to identify the library members in a particular well. In another embodiment of the present invention, a solid phase synthesis 25 technique is utilized, in which the desired scaffold structures are attached to the solid phase directly or though a linking unit, as discussed above. Advantages of solid phase techniques include the ability to more easily conduct multi-step reactions and the ability to drive reactions to completion because excess reagents can be utilized and the unreacted reagent washed away. Perhaps one of the most significant advantages 30 of solid phase synthesis is the ability to use a technique called "split and pool", in addition to the parallel synthesis technique, develped by Furka. (Furka et al., Abstr. 14th Int. Congr. Biochem., Prague, Czechoslovakia, 1988, 5, 47; Furka et al., Int. J. Pept. Protein Res. 1991, 37, 487; Sebestyen et al., Bioorg. Med Chem. Lett., 1993, 3, 413) In this technique, a mixture of related compounds can be made in the same 35 reaction vessel, thus substantially reducing the number of containers required for the synthesis of very large libraries, such as those containing as many as or more than one 56 WO 01/44258 PCT/USOO/34487 5 million library members. As an example, the solid support scaffolds can be divided into n vessels, where n represents the number species of reagent A to be reacted with the scaffold structures. After reaction, the contents from n vessels are combined and then split into m vessels, where m represents the number of species of reagent B to be reacted with the scaffold structures. This procedure is repeated until the desired 10 number of reagents is reacted with the scaffold structures to yield the inventive library. The use of solid phase techniques in the present invention may also include the use of a specific encoding technique. Specific encoding techniques have been reviewed by Czarnik. (Czarnik, A.W., Current Opinion in Chemical Biology, 1997, 1, 15 60) As used in the present invention, an encoding technique involves the use of a particular identifyingg agent" attached to the solid support, which enables the determination of the structure of a specific library member without reference to its spatial coordinates. One of ordinary skill in the art will also realize that if smaller solid phase libraries are generated in specific reaction wells, such as 96 well plates, or 20 on plastic pins, the reaction history of these library members may also be identified by their spatial coordinates in the particular plate, and thus are spatially encoded. It is most preferred, however for large combinatorial libraries, to use an alternative encoding technique to record the specific reaction history. Examples of alternative encoding techniques that can be utilized in the present 25 invention include, but are not limited to, spatial encoding techniques, graphical encoding techniques, including the "tea bag" method, chemical encoding methods, and spectrophotometric encoding methods. Spatial encoding refers to recording a reaction's history based on its location. Graphical encoding techniques involve the coding of each synthesis platform to permit the generation of a relational database. 30 Examples of preferred spectrophotometic encoding methods include the use of mass spectroscopy, fluorescence emission, and nuclear magnetic resonance spectroscopy. In a preferred embodiment, chemical encoding methods are utilized, which uses the structure of the reaction product to code for its identity. Decoding using this method can be performed on the solid phase or off of the solid phase. One of ordinary skill in 35 the art will realize that the particular encoding method to be used in the present 57 WO 01/44258 PCT/USOO/34487 5 invention must be selected based upon the number of library members desired, and the reaction chemistry employed. Subsequent characterization of the library members, or individual compounds, can be performed using standard analytical techniques, such as mass spectrometry, Nuclear Magnetic Resonance Spectroscopy, and gas chromatrography. 10 Once specific libraries of compounds have been prepared, specific assay techniques, such as those described herein, may be utilized to test the ability of compounds to function as Src kinase inhibitors. In certain preferred embodiments, high throughput assay techniques are utilized. 15 Uses of Compounds of the Invention As discussed above, the compounds of the present invention are useful in the selective treatment or prevention of bone disorders. These compounds or pharmaceutical compositions may effect treatment via inhibition of osteoclast activity, promotion of osteoblast activity, or promotion or inhibition of other cellular events 20 necessary for healthy bone metabolism. In certain preferred embodiments, these compounds are useful for the treatment or prevention of diseases and conditions associated with bone metabolic disorders such as osteoclast overactivity. In still other preferred embodiments, the compounds of the present invention are targeted Src kinase inhibitors and thus inhibit bone resorption by osteoclasts. 25 The present invention therefore provides a method for the treatment, prophylaxis, and/or prevention of bone and other related disorders which method comprises the administration of an effective non-toxic amount of an inventive compound, or a pharmaceutically composition thereof. As mentioned above, although the inventive compounds effect treatment via several mechanisms, (i.e. 30 inhibition of osteoclast activity, promotion of osteoblast activity, or regulation of other cellular events necessary for healthy bone metabolism), in certain preferred embodiments, these compounds are selective inhibitors of osteoclast activity. In a further aspect, the present invention provides an inhibitor of mammalian osteoclasts, for example any one of the compounds of the present invention or a 35 pharmaceutical composition thereof. In still another aspect, the present invention provides compounds or pharmaceutical compositions that are selective Src kinase 58 WO 01/44258 PCT/USOO/34487 5 inhibitors. In particular, the method of present invention comprises providing any one of the compounds of the present invention or a pharmaceutically composition thereof, for use in the treatment of and/or prophylaxis of osteoporosis and related osteopenic diseases. It will also be appreciated that, although many of the compounds and 10 compositions described herein comprise a bone targeting moiety and a payload, the present invention also contemplates the use of bone targeting agents alone for the treatment of bone disorders, preferably by the selective inhibition of osteoclast activity. It will further be appreciated that, in addition to the treatment or prevention of 15 osteoporosis, particularly osteoporosis associated with the peri and post menopausal conditions, the present invention also contemplates the treatment and prophylaxis or prevention of Paget's disease, hypercalcemia associated with bone neoplasms and other types of osteoporotic diseases and related disorders, including but not limited to involutional osteoporosis, Type I or postmenopausal osteoporosis, Type II or senile 20 osteoporosis, juvenile osteoporosis, idiopathic osteoporosis, endocrine abnormality, hyperthyroidism, hypogonadism, ovarian agensis or Turner's syndrome, hyperadrenocorticism or Cushing's syndrome, hyperparathyroidism, bone marrow abnormalities, multiple myeloma and related disorders, systemic mastocytosis, disseminated carcinoma, Gaucher's disease, connective tissue abnormalities, 25 osteogenesis imperfecta, homocystinuria, Ehlers-Danlos syndrome, Marfan's syndrome, Menke's syndrome, immobilization or weightlessness, Sudeck's atrophy, chronic obstructive pulmonary disease, chronic heparin administration, and chronic ingestion of anticonvulsant drugs In addition to providing compounds for the selective inhibition of Src tyrosine 30 kinase (and thus the inhibition of osteoclast activity), the present invention contemplates the use of alternate payloads to achieve desired therapeutic effects. The targeted constructs of the present invention may include any of a wide variety of chemical entities to be delivered to the target site or into target cells. Generally, the payloads may be categorized as therapeutic agents (such as Src kinase inhibitors) or 35 imaging agents. Imaging agents comprise those payloads which are detectable, e.g., by emitting light, radioactive emissions, or chemical signals, by absorbing radiation 59 WO 01/44258 PCT/USOO/34487 5 (e.g., x-rays), or by otherwise changing a characteristic of treated cells relative to untreated cells. Therapeutic agents include payloads which are biologically active, preferably by countering an abnormal condition of the bone targeted site (e.g., tumor or infection). A therapeutic agent useful in a targeted compound may be any of a number of 10 chemical entities, e.g., an enzyme, drug, radionuclide, enzyme inhibitor, etc. For example, moieties useful as therapeutic agents include inhibitors of osteoclast activity such as Src kinase inhibitors, cathespin inhibitors, or proton pump inhibitors, amino acids and their derivatives; analgesics such as acetaminophen, aspirin, and ibuprofen; antifungal agents including: allyamines, imidazoles, polyenes, and triazoles; antigens 15 and antibodies thereto; antihistamines such as chlorpheniramine and brompheniramine; antihypertensive agents such as clonidine, methyldopa, prazosin, verapamil, nifedipine, captopril, and enalapril; antiinflammatory agents including non-steroidal agents, such as aminoarylcarboxylic acid derivatives, arylacetic acid derivatives, arylbutyric acid derivatives, arylcarboxylic acids, arylpropionic acid 20 derivatives, pyrazoles, pyrazolones, salicylic acid derivatives thiazinecarboxamides and others, as well as steroidal agents, such as glucocorticoids; antimicrobials such as aminoglycosides, amphenicols, cinoxacin, ciprofloxacin, 2,4-diaminopyrimidines, p lactams (e.g., carbapenems, cephalosporins, cephamycins, monobactams, oxacephems and penicillins), lincosamides, macrolides, nitrofurans, norfloxacin, peptides, 25 polypeptides, and proteins (e.g., defensins, bacitracin, polymyxin, cecropins, magainin II, indolicidin, ranalexin, protegrins, gallinacins, tritrpticin, lactoferricin, drosomycin, holotricin, thanatin, dermaseptin, iturins, syringomycins, nikkomycins, polyoxins, FR-900403, echinocandins, pneumocandins, aculeacins, mulundocandins, WF 11899, aureobasidins, schizotrin A, cepacidines, zeamatin, cyclopeptides and 30 D4el), quinolones and analogs, sulfonamides, sulfones, tetracyclines; apoproteins, antivirals including: purines/pyrimidinones (e.g. acyclovir, dideoxy -cytidine, adenosine, or -inosine, interferons, amantadine, ribavirin); beta-blockers such as propranolol, metoprolol, atenolol, labetolol, timolol, penbutolol, and pindolol; cancer drugs including chemotherapeutic agents; cardiovascular agents including cardiac 35 glycosides, antianginals and vasodilators; coenzymes; enzymes; enzyme inhibitors; expectorants; glycoproteins; H-2 antagonists such as nizatidine, cimetidine, 60 WO 01/44258 PCT/USOO/34487 5 famotidine, and ranitidine; haptens and antibodies thereto; hormones, lipids, liposomes; protein analogs in which at least one non-peptide linkage replaces a peptide linkage; phospholipids; prostaglandins; radionuclides (e.g. ' 3 1, 1 6 sRe, 188Re, 90Y, 212Bi, 21At, 89 Sr, 1 66 Ho, 53 Sm, 67 Cu and "Cu); receptors and other membrane proteins; retro-inverso oligopeptides; stimulants; toxins such as aflatoxin, digoxin, 10 rubratoxin, and xanthotoxin; tranquilizers such as diazepam, chordiazepoxide, oxazepam, alprazolam, and triazolam; and vitamins and mineral and nutritional additives. For other therapeutic agents, see, e.g., the Merck Index. The present invention contemplates agents that are useful for treating or preventing the progression of a bone or other related disorder, preferably by inhibiting osteoclast 15 activity. In an exemplary embodiment, the compounds and compositions of the present invention are also inhibitors of cathepsin K, and thus can be used to treat bone disorders. In particular, it has been discovered that osteoclasts contain large quantities of cathepsin K and it has been suggested that cathepsin K thus plays an important role 20 in bone resorption (Smith et al., Exp. Opin. Ther. Patents 1999, 9, 683-694 and references cited therein). For example, it has been reported that the enzyme is active over a pH range (3.5-4.0) consistent with the pH of the local bone environment during resorption, that a cathepsin K antisense nucleotide was effective in the inhibition of osteoclast bone resorption, and that there is a link between mutations in the human 25 cathepsin K gene and the rare skeletal dysplasia, pycnodysostosis, a disease characterized by abnormal bone resorption (see, Smith et al.). Thus compounds of the present that are cathepsin K inhibitors would be useful as agents for the inhibition of bone resorption and thus could be used to treat osteoporosis or other disorders resulting from abnormal bone resorption. 30 Bone-targeted compounds can alternatively or additionally be labeled with any of a variety of imaging agents which are known in the art and which will depend to some extent on the means used to detect or monitor the compound in vivo or in vitro. Preferred imaging agents for performing positron emission tomography (PET) and single photon emission computer tomography (SPECT) include F-18, Tc-99m, and 35 1-123. Preferred imaging agents for magnetic resonance imaging (MRI) include an appropriate atom with unpaired spin electrons or a free radical. 61 WO 01/44258 PCT/USOO/34487 5 When the payload is intended to perform in an imaging capacity, the payload comprises a moiety such as a radionuclide or paramagnetic contrast agent, fluorescent or chemiluminescent label, or other type of detectable marker. The imaging agents described above may contain any label in accordance with the invention. Highly specific and sensitive labels are provided by radionuclides, which can then be 10 detected using positron emission tomography (PET) or Single Photon Emission Computed Tomography (SPECT) imaging. More preferably, the imaging agent of the invention contains a radionuclide selected from the group consisting of 1311, 12, 1231, 99mTc, 18F, 68 67 Ga, 72 As, 89 Zr, 6 4 Cu, 62 Cu, "'In, 203Pb, 1 98 Hg, "C, 97 Ru, and 201 T1 or a paramagnetic contrast agent, such as gadolinium, cobalt, nickel, manganese, and 15 iron. As will be appreciated, these atoms may be directly incorporated into the bone targeting moiety or the payload. Therapeutic/Prophylactic Administration and Pharmceutical Compositions As discussed above, the compounds of the present invention are useful in the 20 treatment of bone disorders, preferably imbalances in bone metabolism, such as overactivity of bone resorption. In certain preferred embodiments, the compounds of the present invention are useful as inhibitors of Src tyrosine phosphorylation. When the compounds of the present invention are used for therapeutic and/or prophylactic administration, they can exist in free form, or, where appropriate, in salt 25 form. Pharmceutically acceptable salts of many types of compounds and their preparation are well-known to those of skill in the art. The pharmaceutically acceptable salts of compounds of this invention include the conventional non-toxic salts or the quaternary ammonium salts of such compounds which are formed, for example, from inorganic or organic acids of bases. 30 The compounds of the invention may form hydrates or solvates. It is known to those of skill in the art that charged compounds form hydrated species when lyophilized with water, or form solvated species when concentrated in solution with an appropriate organic solvent. This invention relates to pharmaceutical compositions comprising a 35 therapeutically (or prophylactically) effective amount of the compound, and a pharmaceutically acceptable carrier or excipient. Carriers include, e.g., saline, 62 WO 01/44258 PCT/USOO/34487 5 buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof, and are discussed in greater detail below. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. The composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release forrmulation, or powder. The compsition can be formulated as a suppository, with 10 traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Formulation may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. 15 The pharmaceutical carrier may be, for example, either a solid or liquid. Illustrative solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidannts, compression aids, binders or tablet 20 disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active 25 ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. Illustrative liquid carriers include syrup, peanut oil, olive oil, water, et. Liquid 30 carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring aents, suspending agents, thickening agents, colors, viscosity 35 regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, 63 WO 01/44258 PCT/USOO/34487 5 e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carders are useful in sterile liquid form 10 compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically propellant. Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compound can also be 15 administered orally either in liquid or solid composition form. The carrier or excipient may include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate along or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like. When formulated for oral administration, 0.01% Tween 80 in PHOSAL PG-50 20 (phospholipid concentrate with 1,2-propylene glycol, A. Nattermann & Cie. GmbH) has been recognized as providing an acceptable oral formulation for other compounds, and may be adapted to formulations for various compounds of this invention. A wide variety of pharmaceutical forms can be employed. If a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or 25 pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1g. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectible solution or suspension in an ampule or vial or nonaqueous liquid suspension. 30 To obtain a stable water soluble dosage form, a pharmaceutically acceptable salt of the compound may be dissolved in an aqueous solution or an organic or inorganic acid, such as a 0.3 M solution of succinic acid or citric acid. Alternatively, acidic derivatives can be dissolved in suitable basic solutions. If a soluble salt form is not available, the compound is dissolved in a suitable cosolvent or combinations 35 thereof. Examples of such suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin, polyoxyethylated 64 WO 01/44258 PCT/USOO/34487 5 fatty acids, fatty alcohols or glycerin hydroxy fatty acids esters and the like in concentrations ranging from 0-60% of the total volume. Various delivery systems are know and can be used to administer the compound, or the various formulations thereof, including tablets, capsules, injectable solutions, encapsulation in liposomes, microparticles, microcapsules, etc. Methods of 10 introduction include but are not limited to dermal, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, pulmonary, epidural, ocular and (as is usually preferred) oral routes. The compound may be administered by any convenient or otherwise appropriate route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g. oral mucosa, rectal 15 and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. For treatment or prophylaxis of nasal, bronchial or pulmonary conditions, preferred routes are oral, nasal or via a bronchial aerosol or nebulizer. In certain embodiments, it may desirable to administer the compound locally 20 to an area in need of treatment; this may be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, by injection, by means of a catheter, by means of a suppository, or by means of a skin patch or implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. 25 In a specific embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic to ease pain 30 at the side of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantitity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile 35 pharmaceutical grade water or saline. Where the composition is administered by 65 WO 01/44258 PCT/USOO/34487 5 injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration. Administration to an individual of an effective amount of the compound can also be accomplished topically by administering the compound(s) directly to the affected area of the skin of the individual. For this purpose, the compound is 10 administered or applied in a composition including a pharmacologically acceptable carrier, such as a gel, an ointment, a lotion, or a cream, which includes, without limitation, such carriers as water, glycerol, alcohol, propylene glycol, fatty acids, triglycerides, fatty acid esters, or mineral oils. Other topical carriers include liquid petroleum, isopropyl palmitate, 15 polyethylene glycol, ethanol (95%), polyoxyethylene monolaurate (5%) in water, or sodium lauryl sulfate (5%) in water. Other materials such as anti-oxidants, humectants, viscosity stabilizers, and similar agents may be added as necessary. Percutaneous penetration enhancers such as Azone may also be included. In addition, in certain instances, it is expected that the compound may be 20 disposed witin devices placed upon, in, or under the skin. Such devices include patches, implants, and injections which release the compound into the skin, by either passive or active release mechanisms. Materials and methods for producing the various formaulations are well known in the art and may be adapted for practicing the subject invention. See e.g. US 25 Patent Nos. 5,182,293 and 4,837,311 (tablets, capsules and other formulations as well as intravenous formulations) and European Patent Application Publication Nos. 0 649 659 (published April 6, 1995; illustrative formulation for IV administration) and 0 648 494 (published April 19, 1995; illustrative formulation for oral administration). The effective dose of the compound will typically be in the range of about 30 0.01 to about 50 mg/kgs, preferably about 0.1 to about 10 mg/kg of mammalian body weight, administered in single or multiple doses. Generally, the compound may be administered to patients in need of such treatment in a daily dose range of about 1 to about 2000 mg per patient. The amount of compound which will be effective in the treatment or 35 prevention of a particular disorder or condition will depend in part on the nature and severisty of the disorder or condition, which can be determined by standard clinical 66 WO 01/44258 PCT/USOO/34487 5 techniques. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dose ranges. Effective doses may be extrapolated from dose response curves derived from in vitro or animal model test systems. The precise dosage level should be determined by the attending physician or other health care provider and will depend upon well known factors, including route of administration, 10 and the age, body weight, sex and general health of the individual; the nature, severity and clinical stage of the disease; the use (or not) of concomitant therapies. Treatment Kits In other embodiments, the present invention relates to a kit for conveniently 15 and effectively carrying out the methods in accordance with the present invention. In general, the pharmaceutical pack or kit comprises one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Such kits are especially suited for the delivery of solid oral forms such as tablets or capsules. Such a kit preferably includes a number of unit dosages, and may also 20 include a card having the dosages oriented in the order of their intended use. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered. Alternatively, placebo dosages, or calcium dietary supplements, either in a form similar to or distinct from the bone 25 targeted dosages, can be included to provide a kit in which a dosage is taken every day. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration. 30 Equivalents The representative examples which follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further 35 embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including 67 WO 01/44258 PCT/USOO/34487 5 the examples which follow and the references to the scientific and patent literature cited herein. It should further be appreciated that the contents of those cited references are incorporated herein by reference to help illustrate the state of the art. The following examples contain important additional information, exemplification and guidance which can be adapted to the practice of this invention in 10 its various embodiments and the equivalents thereof. Exemplification The described phosphorus-containing moieties can be synthesized according to the schemes outlined below: 15 A) Embodiments wherein Tb is i Example 1 [(3-Amino-propyl)-ethoxy-phosphinoylmethyll-phosphonic acid diethyl ester 20 OEt OEt [(3-Benzyloxy-propyl)-ethoxy-phosphinoylmethyl]-phosphonic acid diethyl ester: To an oven-dried flask was added 10.25 g (44.7 mmol) of (3-Bromo-propoxymethyl) benzene and 7.67 mL (44.7mmol) of triethyl phosphite. The flask was fitted with a short-path distillation head, for removal of bromoethane, and the mixture heated at 25 150 "C for 4 h. The reaction was cooled to ambient temperature, and then diluted with 120 mL of absolute ethanol and 1.8 N KOH (120mL, 216 mol). The distillation head was replaced with a reflux condenser and the solution heated at reflux for 5 h. The reaction was cooled then concentrated in vacuo. The basic aqueous layer was extracted with EtOAc (2x) and then acidified to pH 3 with conc. HCl. The aqueous 30 layer was extracted with EtOAc (3x) and the combined extracts were dried over MgSO 4 and concentrated. The resulting crude product (8.24 g) was used as is in the next reaction. "P NMR (300 MHz, DMSO-d 6 ) 8 34.113. To a solution of the crude phosphonate (8.24 g, 32.5 mmol) in 100 mL
CH
2 Cl 2 , under an atmosphere of N 2 , was added 10.8 mL (113.8 mmol) of oxalyl 35 chloride. DMF (several drops) was slowly added to initiate the reaction. After gas 68 WO 01/44258 PCT/USOO/34487 5 evolution had ceased, the reaction was stirred for 30 min at ambient temperature. Upon concentration in vacuo, the residue was titurated several times with hexane, then dissolved in 167 mL of anhydrous THF. In a separate flask, a cooled (-78 C, under N 2 ) solution of diethyl methylphosphonate (10.25 mL, 69.9 mmol) in 337 mL of anhydrous THF was added 2.5 M n-butyl lithium (27.95 mL, 69.9 mmol) dropwise. 10 The reaction mixture was stirred for 30 min at -78 *C, at which time the in situ generated acid chloride was added dropwise. The solution was stirred for an additional 2.5 h at -78 "C, quenched with 5 mL glacial acetic acid, and then warmed to ambient temperature. Water was added to the reaction mixture and the THF was removed in vacuo. The aqueous layer was extracted with EtOAc (3x) and the 15 combined organics washed with saturated NaHCO 3 , brine, then dried over MgSO 4 and concentrated. The crude product was purified by silica gel chromatography (eluted with 50:1 CH 2
CI
2 /MeOH) affording 6.15 g of a yellow oil. 3 'P NMR (300 MHz, DMSO-d 6 ) 5 51.479, 26.291. 20 [(3-Amino-propyl)-ethoxy-phosphinoylmethyl]-phosphonic acid diethyl ester: To a solution of [(3-Benzyloxy-propyl)-ethoxy-phosphinoylmethyl] phosphonic acid diethyl ester (5.7 g, 14.5 mmol) in 100 mL of EtOH was added 1.2 g of palladium on carbon. The mixture was flushed with H 2 and stirred at ambient temperature (H2 balloon) for 1 h. The reaction mixture was filtered through Celite 25 and the solvent evaporated to provide 3.5 g of a pale yellow oil. 3 'P NMR (300 MHz, DMSO-d 6 ) d 52.219, 26.317. To a cooled (0 *C, under N 2 ) solution of the crude alcohol (3.5 g, 14.5 mmol) in 53 mL of CH 2
CI
2 was added 2.4 mL (17.4 mmol) of triethylamine followed by 1.25 mL (16 mmol) of methanesulfonyl chloride. The reaction mixture was warmed to 30 ambient temperature and stirred for 1 h. The reaction mixture was then quenched with water and the layers separated. The organic layer was washed with water and brine, dried over Na 2
SO
4 , and concentrated. The crude orange-yellow oil (5.5 g) was used as is in the next reaction. 3 'P NMR (300 MHz, DMSO-d 6 ) 8 51.135, 26.614. To a solution of the crude mesylate (5.5 g, 14.4 mmol) in 17 mL DMF was 35 added 4.7 g (72.4 mmol) of sodium azide. The resulting slurry was heated at 55 C and stirred overnight. The reaction mixture was diluted with EtOAc and washed with 69 WO 01/44258 PCT/USOO/34487 5 water (2x). The combined organics were then dried over Na 2
SO
4 and concentrated. The crude azide (2.61 g) was used as is in the next reaction. "P NMR (300 MHz, DMSO-d 6 ) d 51.230, 26.183. To a solution of the crude azide (2.61 g, 8 mmol) in 100 mL of EtOH was added 0.8 g of palladium on carbon. The mixture was flushed with H 2 and stirred at 10 ambient temperature (H 2 balloon) for 16 h. The reaction mixture was filtered through Celite and the solvent evaporated to provide 2.3 g of a yellow oil: 1 H NMR (300 MHz, DMSO-d 6 ) 8 4.03 (in, 6H), 2.84-2.52 (m, 4H), 1.91-1.80 (in, 2H), 1.65-1.61 (in, 2H), 1.23 (m,9H). "P NMR (300 MHz, DMSO-d 6 ) 8 51.757, 26.344. 15 Example 2 ({3-[3-(4-Amino-3-p-tolyl-pyrazolo[3,4-dlpyrimidin-1 -yl)-benzoylaminol-propyl} hydroxy-phosphinoylmethyl)-phosphonic acid Me NH2 N/N NN N N H P0 3
H
2 OH 0 The title compound was made as for example 16 (below) using [(3-amino 20 propyl)-ethoxy-phosphinoylmethyl]-phosphonic acid diethyl ester. Example 3 Synthesis of Phenyl-i compounds 25 For the synthesis of these examples, one of two coupling procedures can be used, either the coupling of sulfone 1/2 with the aniline or the coupling of amine 3/4 with the aryl bromide. 70 WO 01/44258 PCT/USOO/34487 General Scheme for Targeted Aminopyrido[2,3-dlpyrimidin-7(8H)-ones R.
NH
2 (Aniline) N R2 HN )'N N 0 R MeO O OMe Me M e ' O l150 *CR 1R =R'= C A 2 R=R'=Me NH3 Br Pd(OAC) 2 BINAP R1 Cs 2 C0 3 N R2 H 2 N < N N (A ry l b ro m id e ) H12N N R Me 3 R = R'=CI 4 R = R'= Me R~.R' R R'HN"NN 0FHN N N 0 HNN N0 TMSI HNH Me CH 3 CN Me OEt O t -10 *C <2] rt e.g., R '= CI, or H H -- -O1 HO -- -OH 0 0 0~ 0 1I 5 A 00 H QEt
NO
2 EtO-.OEt
NO
2
NH
2 _ _. SnCl2-2H 2 0 Pd(PPh) ByJ t 3Et EtOH OEt 3 EtO.-p-- -OEt EtO --- O!Ht 0 00 0 6 Synthesis of aniline 6 10 (a) A mixture of diethyl (ethoxyphosphinyl)methylphosphonate (2.35 g, 9.62 mmol), Et 3 N (3.8 mL, 27.5 mmol), 1-iodo-4-nitrobenzene (2.28 g, 9.17 mmol) and Pd(PPh 3
)
4 (265 mg, 0.229 mmol) in CH 3 CN (14 mL) under N 2 was stirred at 80 *C for 2.5 h. After cooling to rt, the reaction mixture was poured into 50 mL of 1 N aq HCl and extracted with CH 2 Cl 2 . The extract was washed with H 2 0 (50 mL) and 15 brine (50 mL). The aqueous washes were reextracted once with CH 2 Cl 2 , and the combined extracts were dried over Na 2
SO
4 and concentrated. The crude material was purified by flash chromatography on silica gel. Elution with 30:1 CHCl 3 -MeOH 71 WO 01/44258 PCT/USOO/34487 5 followed by 20:1 CHCl 3 -MeOH and finally 15:1 CHCl 3 -MeOH afforded 3.28 g (98%) of the desired (arylphosphinylmethyl)phosphonate. (b) A mixture of the nitroarene (940 mg, 2.57 mmol) and SnCl 2 -2H 2 0 (2.9 g, 12.9 mmol) in EtOH (~10 mL) was stirred at 70 'C for 44 min and then 10 concentrated at rt. The residue was taken up in CH 2 Cl 2 and washed with half saturated aq NaHCO 3 (40 mL), H 2 0 (40 mL) and brine (40 mL). The aqueous washes were reextracted once with CH 2 Cl 2 , and the combined extracts were dried over K 2 CO3 and concentrated. The crude material was purified by flash chromatography on silica gel. Elution with 20:1 CHCl 3 -MeOH followed by 15:1 CHCl 3 -MeOH afforded 657 15 mg (76%) of aniline 6. c N OHde HO--..OH 8 8 i-A (a) A mixture of aniline 6 (1.89 g, 5.65 mmol) and sulfone 1 (866 mg, 20 2.25 mmol) in 2-methoxyethyl ether (3 mL) was stirred at 150 *C for 6 h. The reaction mixture was allowed to cool to rt. It was then diluted with a small amount of CHC1 3 and purified by flash chromatography on silica gel. Elution with 30:1 CHCl 3 MeOH, 20:1 1 CHCl 3 -MeOH, and 15:1 1 CHCl 3 -MeOH afforded material that was still very impure. The chromatography was repeated using the same eluants to 25 provide material that was still fairly impure. This material was then purified by reversed phase HPLC using water-acetonitrile (+0.1% TFA). The fractions containing product were collected and concentrated to a small volume (-20 mL). The residue was then partitioned between CH 2 Cl 2 and saturated aqueous NaHCO 3 . The layers were separated, and the aqueous layer was reextracted twice with CH 2
CI
2 . The 30 combined extracts were dried over K 2 C0 3 and concentrated to 429 mg (30%) of pure coupled product. 72 WO 01/44258 PCT/USOO/34487 5 (b) To a solution of the coupled product (420 mg, 0.657 mmol) in 10 mL of CH 3 CN at -10 'C was added TMSI (1.40 mL, 9.85 mmol). The reaction mixture was stirred at -10 *C for 15 min. and at rt for 75 min. The reaction mixture was then diluted with saturated aqueous NaHCO 3 (-13 mL), a few drops of aqueous NaHSO 3 and H 2 0 (-2 mL). The mixture was further diluted with a small amount of DMF and 10 then purified by reversed phase HPLC using water-acetonitrile (+0.1% TFA). The fractions containing product were then lyophilized to afford pure i-A. Br H oEt Br EtO ----- OEt Br Pd PPh3)4ot NMM OEt EtO.---p-OEt 11 I 0 8 0 Synthesis of aryl bromide 8 15 A mixture of diethyl (ethoxyphosphinyl)methylphosphonate (1.85 g, 7.58 mmol), 1-bromo-4-iodobenzene (1.95 g, 6.89 mmol), NMM (1.51 mL, 13.8 mmol) and Pd(PPh 3
)
4 (199 mg, 0.172 mmol) in CH 3 CN was stirred at 100 *C overnight. After cooling to rt, the reaction mixture was concentrated. The residue was then partitioned between 1 N aq HCl and CH 2 Cl 2 . The layers were separated, and the 20 organic layer was washed with H 2 0 and brine. The aqueous washes were reextracted once with CH 2 Cl 2 , and the combined extracts were dried over Na 2
SO
4 and concentrated. The crude material was purified by flash chromatography on silica gel. Elution with 30:1 CHCl 3 -MeOH followed by 20:1 CHCl 3 -MeOH and finally 15:1 CHCl 3 -MeOH afforded 1.52 g (55%) of aryl bromide 8 contaminated with a trace 25 amount of Ph 3 PO. Me HN Me OH HO--.-OH 8 8 i-B 73 WO 01/44258 PCT/USOO/34487 5 (a) Into a glass pressure tube containing sulfone 2 (235 mg, 0.684 mmol) at -78 *C was condensed NH 3 (-2 mL). The tube was capped and allowed to warm to rt. The reaction mixture was allowed to stir at rt overnight, and then the NH 3 was allowed to evaporate. The residue was purified by flash chromatography on silica gel. Elution with 40:1 CHCl 3 -MeOH afforded 193 mg (quant) of amine 4. 10 (b) A mixture of amine 4 (176 mg, 0.628 mmol), aryl bromide 8 (301 mg, 0.753 mmol), powdered Cs 2
CO
3 (368 mg, 1.13 mmol), BINAP (59 mg, 0.0942 mmol) and Pd(OAc) 2 (14 mg, 0.0.0628) in toluene (3.5 mL) was stirred at 100 *C overnight. After cooling, the reaction mixture was partitioned between CH 2 Cl 2 and 1 N aq HCL. 15 The layers were separated, and the organic layer was washed with H 2 0 and brine. The aqueous washes were reextracted once with CH 2
C
2 , and the combined extracts were dried over Na 2
SO
4 and concentrated. The crude material was purified by flash chromatography on silica gel. Elution with 30:1 CHCl 3 -MeOH followed by 20:1
CHCI
3 -MeOH and finally 15:1 CHCl 3 -MeOH afforded 231 mg (62%) of the desired 20 coupled product. (c) The coupled product was then converted to i-B in the same fashion as previously described (i-A, (b)). NHBoc EtO.-H OEt NHBoc NH 2 __ __ O0--t 0 __ 0 0 OEt o T TFA , OEt OEt Pd(PPh 3
)
4 OEt CH 2 Cl 2 25 o o 7 0 0 Synthesis of aniline 7 (a) The intermediate (arylphosphinyl)methylphosphonate was prepared from N-(t-butylcarbonyl)-3-iodoaniline in a manner analogous to that described for 30 the synthesis of aryl bromide 8. (b) The intermediate carbamate was converted to aniline 7 in a manner analogous to that described for 5 (f). 74 WO 01/44258 PCT/USOO/34487 5 Me N HN N N 0 Me Me OH P P0 3
H
2 0 i-C (a) Aniline 7 was condensed with sulfone 1 in a manner analogous to the condensation of aniline 6 with sulfone 1 (i-A, (a)). 10 (b) The coupled product was then converted to i-C in the same fashion as previously described (i-A, (b)). B) Embodiments wherein Tb is vi 15 A bone-targeting group vi was synthesized according to the following scheme: 0 0
NH
2 HN IU CF 3 HN"1CF3 (CF3) 2 0, Py, NBS, CC14, light,
CH
2 Cl 2 , 18h, rt reflux, 6h 0 3 2 THF,PO(OEt) 3 O N NaOH, 60 0
C,.
reflux, 4h O 0 - n O0 HNt 5h O Oh
H
2 J CF3 4 75 WO 01/44258 PCT/USOO/34487 0 HN CF 3 5 0 2 Diethyl (4-(N-trifluoroacetyl amino benzyl) phosphonate 2: To diethyl (4-aminobenzyl)phosphonate (10 g) in anhydrous dichloromethane (100 mL) was added pyridine (4.0 mL)followed by trifluoroacetic anhydride (7.0 mL) 10 and stirred at rt overnight (-18 hrs). Reaction mixture was washed carefully with a saturated solution of aqueous sodium bicarbonate (10 mL), brine (10 mL) and the dichloromethane was dried (Na 2
SO
4 ) to afford product 2 (93%). MS: 338 (M-1) 0 H N-ICF 3 6 Br p,0P 15 3 Diethyl (4-(N-trifuoroacetylamino)-a-bromobenzyl) phosphonate 3: To the above compound 2 (9.75 g, 41.13 mmols) in anhydrous carbon tetrachloride (100 mL) was added NBS (1.6 g , 41.13 mmols) and heated to reflux under intense visible light with stirring under which time a white precipitate formed. 20 The reaction was cooled to rt and then filtered. The filtrate was half concentrated then left in the freezer overnight to crystallize. The crystalline product 3 was seperated by filtration (7.2 g, 60%). MS : 416,418 (M-1 Br 79 Br 80 ). oJ O P-0 OsI HN
CF
3 25 4 76 WO 01/44258 PCT/USOO/34487 5 1 -(Bis-diethylphosphonomethylene-4-(N-trifluoroacetylamino)benzene 4: To compound 3 (7.2 g, 17.22 mmols) in anhydrous THF (50 mL) was added triethylphosphite (0.82 mL, 17mmol) and stirred under reflux for 4 h. Reaction mixture was cooled to rt and concentrated. Residue was taken up in boiling ethyl ether and cooled to rt. Solid was filtered off to afford 6.0 g product (73%). Pale pink solid. 10 MS: 476 (M+H), 475 (M-H).
H
2 N 1-(Bis-diethylphosphonomethylene)-4-aminobenzene 1: 15 The above N-trifluoroacetate salt 4 (1.2 g, 2.52 mmols) in NaOH solution (0.1 N, 10 mL) was heated to 60 *C for 5 h. The reaction mixture was cooled to rt, and extracted with methylene chloride. Combined organic layers were dried over sodium sulfate and concentrated to afford the product 1 (0.85 g, 97%). MS: 412 (M+23). 20 Example 4 ({4-[6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo-4a,7,8,8a-tetrahydro-pyrido[2,3 dlpyrimidin-2-ylaminol-phenyl}-phosphono-methyl)-phosphonic acid CI CI HN N O
H
2 0 3 P P0 3
H
2 25 a) (4-Bromo-benzyl)-phosphonic acid diethyl ester 77 WO 01/44258 PCT/USOO/34487 Br Br P(OEt)3 5 Br
PO
3 Et 2 A mixture of triethylphosphite (25 mL, 14.6 mmol) and 4 bromobenzylbromide (2.50 g, 10.0 mmol) was heated to 130 *C and allowed to stir for 5 h. The solution was cooled to rt and chromatographed over silica gel 10 (EtOAc:hexanes, stepwise gradient 1:1 to 100% EtOAc) to give 3.21 g (> 100%) of a yellowish oil. Electrospray Mass Spectrum (50/50 acetonitrile/water) m/z 307 (M+H). b) [(4-Bromo-phenyl)-(diethoxy-phosphoryl)-methyll-phosphonic acid diethyl ester r Br LHMDS (EtO) 2 POCI 15 PO 3 Et 2 Et 2
O
3
PO
3 Et 2 To a cooled (-50 'C) solution of (4-bromo-benzyl)-phosphonic acid diethyl ester (3.21 g, 10.4 mmol) in THF (25 mL) was added a IM solution of lithium hexamethyldisilylazide in THF (25 mL) over 3 min. Diethylchlorophosphate (2.9 20 mL, 20 mmol) was added and the mixture was allowed to stir at 50 *C. After 0.5 h, satd NH 4 Cl was added and the mixture diluted with EtOAc and H 2 0. The aqueous layer was extracted with fresh EtOAc and the combined organic extracts were washed with brine, dried over Na 2
SO
4 and concentrated. The residue was chromatographed over silica gel (CHCl 3 :MeOH, stepwise gradient 99:1 to 96:4) to give 1.35 g (29%) of 25 a colorless oil. Electrospray Mass Spectrum (50/50 acetonitrile/water) m/z 441 (M-H). c) r4-[6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo-4a,7,8,8a-tetrahydro-pyrido[2,3 dipyrimidin-2-ylaminol-phenyl}-(diethoxy-phosphoryl)-methyll-phosphonic acid diethyl ester 30 78 WO 01/44258 PCT/USOO/34487 C (S)-BINAP Br Cs 2
CO
3 N Pd(OAc) 2 CN HN-' N N O C EtO 3~ PO3E2EH2 Et 2 5 PE 3 Et 2 PE 5 ~~Et 2
O
3 F0 t (4-Bromopyridin-2-yl)-phosphonic acid diethyl ester (64 mg, 0.22 mmol), 2 amino-6-(2,6-dichlorophenyl)pyrido-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (60 mg, 0.19 mmol), palladium acetate (3.6 mg, 0.0.016 mmol), [(4-Bromo-phenyl) 10 (diethoxy-phosphoryl)-methyl]-phosphonic acid diethyl ester (100 mg, 0.23 mmol), (S)-BINAP (18 mg, 0.029 mmol) and cesium carbonate (91 mg, 0.28 mmol) were placed in toluene (1 mL), flushed with argon, sealed and heated to 100 *C. After 45 h, the reaction was allowed to cool to rt and diluted with H 2 0. The mixture was extracted twice with EtOAc and the combined organic extracts washed with brine and 15 dried over Na 2
SO
4 . The solution was concentrated and chromatographed over silica gel (CHC3: MeOH, stepwise gradient 99:1 to 95:5) to give 44 mg (41%) of a yellow solid. Electrospray Mass Spectrum (50/50 acetonitrile/water) m/z 681 (M-H). d) ({4-[6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo-4a,7,8,8a-tetrahydro-pyrido[2,3 20 dlpyrimidin-2-ylaminol-phenyl}-phosphono-methyl)-phosphonic acid C1 C / C 'N N N CIN NN HN N N I-TMS HN N N C Et 2
O
3 H203 P3H2 To a cooled solution (0 'C) [{4-[6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo 25 4a,7,8,8a-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-(diethoxy 79 WO 01/44258 PCT/USOO/34487 5 phosphoryl)-methyl]-phosphonic acid diethyl ester (44 mg, 0.77 mmol) in MeCN (1.2 mL) was added iodotrimethylsilane (0.3 mL). After 5 h, the reaction was quenched with sodium hydroxide (1 N) and satd sodium thiosulfate. The mixture was filtered and the filtrate chromatographed using reversed-phase HPLC to give 5 mg (11%) of a yellow solid after lyophilization. Electrospray Mass Spectrum (50/50 10 acetonitrile/water) m/z 571 (M+H). C) Embodiments wherein Tb is ix Example 5 15 Synthesis of analogs of 5-(3-methoxyphenyl)-7-[4-(2-hydroxyethylphenyl)-4 aminopyrrolo[2,3-dl-pyrimidine 8 and 5-(3-hydroxyphenyl)-7-[4-(2 hydroxyethylphenyl)-4-aminopyrrolo[2,3-dlpyrimidine 12: The 8-series and 12-series of compounds were synthesized according to 20 Scheme 3 &Scheme 4. Compounds 9, 10, 11 were synthesized following Scheme 3. Compounds 13 and 14 were sythesized following Scheme 4. Essentially the synthesis consists of phosphorylation of the primary alcohol 12 in Scheme 3 (described in Method A) and demethylation of the methyl ether (described in Method B) followed by phosphorylation in Scheme 4. 25 Scheme 3 R1C CI 0 N c. C 6 N 9. R1 = NH 2 , R2 0 No 10. R1 = NMe 2 , R2 = 0 (METHOD A C111. R1 = NH 2 , R2 =-NMe-CH2-CH2-O 0 0 R2 R R-, OH 8 A. R1 =NH2, R2 =OH OH OH B. RI = NMe 2 , R2 = OH C. R1 = NH2, R2 = -NMe-CH 2 -CH2-OH Scheme 4 30 80 WO 01/44258 PCT/USOO/34487 Ri Q\/R OH /\ 'l i OH N BBr3, CH2Cl2. N 0 0 N 13. R1 =NH2, R2 =O -2q-N. -~ 14. R1=NH 2 , /20P- METHD Bh N PO(OMe)3, 0 0 C, 16h R2 =Ne-CH2-CH2-0 / METHODOB / METHOD A/ R2 R2 R -AOH OH OH 8 12 A Ri = NH 2 , R2 =OH B. RI = NH2, R2 = -NMe-CH2-CH2-OH 5 C. RI =NH2, R2 -N OH Method A: To the alcohol (1 mmol ) in trimethylphosphate (1 mL) under anhydrous condition was added the bis-phosphonomethylene dichloride (4 mmol) at 0 *C and 10 stirred at this temp. for 16 h. The reaction mixture was then quenched with ammonium hydroxide and washed with ether. The aqueous layer was purified by preparative HPLC.
NH
2 KD No N 0 0 OH OH 15 9 5-(3-methoxyphenyl)-7-{ 4-r2-0-(triethylbisphosphonomethylene)ethyllphenyl)}-4 amino pyrrolo[2,3-dl-pyrimidine 9: This was prepared from 8A. Purified by HPLC as a white solid. MS: 517 (M H), 518 (M+H). 20 81 WO 01/44258 PCT/USOO/34487 0 0 Q...F&IP-OH 5 OH OH 10 5-(3-methoxyphenyl)-7- {4-[2-0-(triethylbisphosphonomethylene)ethyllpheny -4 (N,N-dimethylamino pyrrolo[2,3-dl-pyrimidine 10: This was prepared from 8B. Purified by HPLC as a white solid. MS: 545 (M 10 H), 547 (M+H).
NH
2 O/ 0 0 IN -P _O ,,/-OH OH OH 11 5-(3-methoxyphenyl)-7-{4-N-{N'-methyl- [(N'-2'-(O-(triethylbis 15 phosphonomethylene) ethyl} aminoethylphenyl)-4-(amino -pyrrolo[2,3-dl-pyrimidine 11: This was prepared from 8C. Purified by HPLC as a white solid. MS: 574 (M-H), 576 (M+H). 20 Method B: To 1 mmol of methyl ether (8A, 8B & 8C) in methylene chloride (5 mL) was added boron tribromide in methylene chloride (1 M solution, 10 mmol) at 20 *C and after stirring at this temperature for 3 h, reaction was quenched with methanol (5 mL) and concentrated. Compounds were purified by HPLC. 25 82 WO 01/44258 PCT/USOO/34487 / \ H
NH
2 N \ N 5 OH 12A 5-(3-Hydroxyphenyl)-7-{4-[2-0- ethylphenyl)-4-aminopyrrolo[2,3-dl-pyrimidine 12A: Prepared from 8A following Method B. Off-white solid. MS: 345(M-1), 347 10 (M+H). S OH
NH
2 N NN H N 12B 5-(3-Hydroxyphenyl)-7-{4-(2-N-(N'-methyl-N'-2'-hydroxyethyl)-aminoethylphenyl) 15 4-amino-pyrrolor2,3-dl-pyrimidine 12B: Prepared from 8B using Method B. Off-white solid. MS: 402(M-H), 404 (M+H). N OH 20 12C 83 WO 01/44258 PCT/USOO/34487 5 5-(3-Hydroxyphenyl)-7-{4-(2-N-(4'-hydroxypiperidinyl) aminoethylphenyl)-4 amino-pyrrolo[2,3-dl-pyrimidine 12C: Prepared from 8C using Method B. Off-white solid. MS: 428(M-H), 430 (M+H)
NH
2 0 0 O-P,,,.A-OH 10 OH OH 13 5-(3-Hydroxyphenyl)-7-{4-[2-0-(triethylbisphosphonomethylene)ethylphenyl)-4 aminopyrrolo[2,3-dl-pyrimidine 13: Prepared from 12A using Method A. White solid. MS: 503(M-H), 505(M+H). / \ H
NH
2 N 0 0 15 OH OH 14 5-(3-Hydroxyphenyl)-7-{4-N-{N'-methyl- [(N'-2'-(0 (triethylbisphosphonomethylene) ethyl) aminoethylphenyl)-4-amino -pyrrolo[2,3-dl pyrimidine 14: 20 Prepared from 12B using Method A. White solid. MS : 560 (M-H), 562 (M+H). Scheme 5 describes the synthesis of compound 15 starting from 5 iodopyrrolo-pyrimidine (J.Med.Chem., 1990). 25 Scheme 5 84 WO 01/44258 PCT/USOO/34487 5 Q 0 IPd(Ph3P) 4 , Na 2 00 2 I OH
NH
2 - O 1. NaH, DMF N DMF ater, h 2 NH3/dioxane, N| OH N H 2. 2-odopropane 2. NaBH4 MeOH N 1200C,48h N 1C 481301in 16 17 18 0 pH C C NH 2 - OH O O N PO(OMe) 3 , 00C. N 16h1 Method A 15 CI 16 10 4-Chloro-5-iodo-7-isopropyl-pyrrolo[2,3-dl-pyrimidine 16: To a solution of 4-chloro-5-iodo-7-H-pyrrolo[2,3-d]-pyrimidine (484 mg, 1.729 mmol) in DMF (5 mL) at 0 *C was added sodium hydride (138.4 mg, 60% emulsion, 3.46 mmol). After 30 min at rt., 2-iodopropane (518 pL, 5.19 mmol)was added and the mixture was allowed to stir at rt for 3h. DMF was poured into water 15 and the aqueous later was extracted with ethyl acetate (3 X 30 mL). The organic layer was washed with water (5 mL), dried (sodium sulfate) and concentrated to give a pale yellow solid (520 mg, quantitative). MS: 301(M-H). Ci - OH N N \ N N 20 17 4-Chloro-5-(3-hydroxymethyl phenyl)-7-isopropyl-pyrrolo[2,3-dl-pyrimidine 17: A. To a solution of 4-chloro-5-iodo-7-isopropyl-pyrrolo[2,3-d]-pyrimidine (522 mg, 1.729 mmol)and 3-formylphenylboronic acid (285 mg, 1.902 mmol) in 85 WO 01/44258 PCT/USOO/34487 5 DMF (13.5mL) was added tetrakis triphenylphosphine palladium(0) (95.58 mg, 0.0865 mmol, 5%) strictly in an argon atmosphere followed by a solution of sodiumbicarbonate (2 M, 1.73 mL) and this mix was heated to 80 *C for 18 h. The reaction was monitored by HPLC. It was diluted with water and extracted with ethyl acetate (50 mL, X 3). Ethyl 10 acetate layer was washed (water), dried (sodium sulfate) and concentrated and the resulting gum was purified by column chromatography on silica gel using hexane/ ethyl acetate to give 306 mg (63%) of pale yellow gum. MS:298 (M-H), 300 (M+H). B. To a solution of the above aldehyde (300 mg, 1.008 mmol) in methanol (20 15 mL) was added sodium borohydride (45 mg, 1.296 mmol) and the reaction was monitored by HPLC. After 1 h methanol was removed in vacuo. To the residue was added water (10 mL) and the aqueous layer was extracted in ethyl acetate. Ethyl acetate was dried (sodium sulfate) and concentrated to give a white solid 17 which was used as such in the next step. MS : 300(M-H), 302(M+H). 20
NH
2 OH N 18 4-Amino-5-(3-hydroxymethyl phenyl)-7-isopropyl-pyrrolo[2,3-di-pyrimidine 18: To the above chloro compound (281 mg, 0.931 mmol) in dioxane (10 mL) was 25 added ammonium hydroxide (10 mL) and sealed and heated at 120 *C for 2 days. The solvent was concentrated to give a white solid (200 mg) which was clean enough to take it to the next step. MS : 281(M-H), 282 (M+H). O H Q(_ OH
NH
2 OH 0 N N \ N N 30 15 86 WO 01/44258 PCT/USOO/34487 5 4-Amino-5-r(3-0-bisphosphonomethylene methyl)1phenyl-7-isopropyl-pyrrolor2,3 dl-pyrimidine 15: Prepared from 18 using Method A as a white solid. MS: 439(M-H), 441 (M+H). 10 Example 6 ({2-r6-(3-Chloro-phenylamino)-9-isopropyl-9H-purin-2-ylaminol-ethoxyl-hydroxy phosphorylmethyl)-phosphonic acid HN CI N NZ N H 0 0 6-Chloro-2-fluoro-9H-purine: 15 A 0.3 M aqueous solution of NaNO 2 (200 mL, 60 mmol) was added dropwise to a cooled (-15 C ), vigorously stirred suspension of 2-amino-6-chloro-9H-purine (6.0 g, 35.4 mmol) in 120 mL HBF 4 (48 w% in H 2 0, 0.92 mol) over 75 min. The pale yellow reaction was stirred at r. t. for 20 min and then recooled to -15 C and neutralized to PH = 6.0 with aqueous NaOH (50 w/o in H 2 0). The water was removed in vacuo and 20 the resulting orange solid chromatographed on silica gel (90 : 10 CH 2
C
2 : MeOH, Rf 0.50). The final product was obtained as white solid (3.0 g, 49.1 %). 6-Chloro-2-fluoro-9-isopropyl-9H-purine: 6-Chloro-2-fluoro-9H-purine (517.7 mg, 3 mmol), 2-propanol (198.3 mg, 3.3 mmol), 25 PPh 3 (866 mg, 3.3 mmol) was mixed under N 2 in a 50 mL round-bottom flask at 0 *C. DEAD (575 mg, 3.3 mmol) was added via syringe dropwise to the mixture. The temperature was raised to r. t. and the mixture was stirred overnight. Sovent was removed in vacuo and the resulting residue was chromatographed on silica gel
(CH
2 Cl 2 /EtOAc, 4:1, Rf 0.62). The product was obtained as a white solid (411 mg, 64 30 %). (3-Chlorophenyl)-(2-fluoro-9-isopropyl-9H-purin-6-yl)amine: 87 WO 01/44258 PCT/USOO/34487 5 6-Chloro-2-fluoro-9-isopropyl-9H-purine (214 mg, 1 mmol) was mixed with 3 chloroaniline (127.6 mg, 1 mmol) in 12 mL n-BuOH. DIEA (357.6 mg, 2.8 mmol) was added and the solution was heated at 90 "C overnight. Solvent was removed in vacuo and the residue was chromatographed on silica gel (CH 2 Cl 2 /EtOAc 2:2, Rf 0.44) to get the product as a white solid (148 mg, 48 %). 10 2-(6-(3-chlorophenylamino-9-isopropyl-9H-purin-2-ylamino)ethanol: (3-Chlorophenyl)-(2-fluoro-9-isopropyl-9H-purin-6-yl)amine (92 mg, 0.3 mmol) and ethanolamine (92 mg, 1.5 mmol) was mixed in 5 mL nBuOH/DMSO (4/1 v/v) and heated at 120 "C overnight. Solvent was removed in vacuo. The residue was 15 chromatographed on silica gel (EtOAc, Rf 0.45) to get the product as a greenish solid (24 mg, 90 %). ({2-[6-(3-Chloro-phenylamino)9-isopropyl-9H-purin-2-ylamino]-ethoxy}-hydroxy phosphorylmethyl)-phosphonic acid: 20 2-(6-(3-chlorophenylamino-9-isopropyl-9H-purin-2-ylamino)ethanol (180 mg, 0.52 mmol) was dissolved in 3 mL trimethyl phosphate at 0 "C. Methylenebis(phosphonic dichloride) (514 mg, 2.1 mmol) was added in one portion and the reaction was stirred at 0 0 C for 16 hrs. The solution was neutralized with 5 N ammonia to PH 6.0. The resulting mixture was purified by RP HPLC. Lyophilization 25 left a white solid (147 mg, 56 %). Example 7 ({2-r6-(3-Chloro-phenylamino)-9-isopropyl-9H-purin-2-ylaminol-3-methyl-butoxy} hydroxy-phosphorylmethyl)-phosphonic acid 30 HNIZaCi S 2> H (a) 2-(6-(3-chlorophenylamino-9-isopropyl-9H-purin-2-ylamino)-3-methyl-butan-1-ol 88 WO 01/44258 PCT/USOO/34487 5 The title compound was synthesized in a manner similar to that described in example 6 (d). ES-MS: m/z 388 (M-H). (b) ({2-[6-(3-Chloro-phenylamino)-9-isopropyl-9H-purin-2-ylaminol-3-methyl butoxyl-hydroxy-phosphorylmethyl)-phosphonic acid 10 The title compound was synthesized in a manner similar to that described in example 6 (e). ES-MS: m/z 546 (M-H). Example 8 ({3-[6-(3-Chloro-phenylamino)-9-isopropyl-9H-purin-2-ylaminol-propoxy}-hydroxy 15 phosphorylmethyl)-phosphonic acid HN a ci H4'1_ 0 , NX HO OH H (a) 3-(6-(3-chlorophenylamino-9-isopropyl-9H-purin-2-ylamino)-propano 20 The title compound was synthesized in a manner similar to that described in example 6 (d). ES-MS: m/z 360 (M-H). (b) ({2-[6-(3-Chloro-phenylamino)-9-isopropyl-9H-purin-2-ylaminol-propoxyl hydroxy-phosphorylmethyl)-phosphonic acid 25 The title compound was synthesized in a manner similar to that described in example 6 (e). ES-MS: m/z 518 (M-H). Example 9 ({4-r6-(3-Chloro-phenylamino)-9-isopropyl-9H-purin-2-ylaminol-butoxyl-hydroxy 30 phosphorylmethyl)-phosphonic acid 89 WO 01/44258 PCT/USOO/34487 H~ Cl n H 5 0 0 (a) 4-(6-(3-chlorophenylamino-9-isopropyl-9H-purin-2-ylamino)-butanol The title compound was synthesized in a manner similar to that described in example 6 (d). ES-MS: m/z 374 (M-H). 10 (b) ({2-[6-(3-Chloro-phenylamino)-9-isopropyl-9H-purin-2-ylaminol-butoxyl hydroxy-phosphorylmethyl)-phosphonic acid The title compound was synthesized in a manner similar to that described in example 6 (e). ES-MS: m/z 532 (M-H). 15 Example 10 ( 2-r6-(3-Chloro-phenylamino)-9-isopropyl-9H-purin-2-ylaminol-3-methyl-butoxyl hydroxy-phosphorylmethyl)-phosphonic acid CI 11 r| H 20 0 0 (a) (3-Chloro-phenyl)-(2-fluoro-9-isopropyl-9H-purin-6-yl)-methyl-amine The title compound was synthesized in a manner similar to that described in example 6 (c). ES-MS: m/z 319 (M-H). 25 (b) 2-{6-r(3-chloro-phenyl)-methyl-aminol-9-isopropyl-9H-purin-2-ylamino}-3 methyl-butan-1-ol The title compound was synthesized in a manner similar to that described in example 6 (d). ES-MS: m/z 402 (M-H). 90 WO 01/44258 PCT/USOO/34487 5 (c) [(2-{6-[(3-Chloro-phenyl)-methyl-aminol-9-isopropyl-9H-purin-2-ylamino1-3 methyl-butoxy)-hydroxy-phosphorylmethyll-phosphonic acid The title compound was synthesized in a manner similar to that described in example 6 (e). ES-MS: m/z 560 (M-H). 10 Example 11 ({ 2-[6-(3-Chloro-phenylamino)-9-methyl-9H-purin-2-ylaminol-3-methyl-butoxyl hydroxy-phosphorylmethyl)-phosphonic acid HN''CI N Cl I I H 15 0 0 (a) 6-Chloro-2-fluoro-9-methyll-9H-purine The title compound was synthesized in a manner similar to that described in example 6 (b). ES-MS: m/z 186 (M-H). 20 (b) (3-Chloro-phenyl)-(2-fluoro-9-methyl-9H-purin-6-yl) -amine The title compound was synthesized in a manner similar to that described in example 6 (c). ES-MS: m/z 276 (M-H). 25 (c) 2-[6-(3 -chloro-phenylamino)-9-isopropyl-9H-purin-2-ylaminol-3-methyl-butan- 1 ol The title compound was synthesized in a manner similar to that described in example 6 (d). ES-MS: m/z 360 (M-H). 30 (d) [{2-r6-(3-Chloro-phenylamino)-9-methyl-9H-purin-2-ylaminol-3-methyl butoxyl-hydroxy-phosphorylmethyl)-phosphonic acid The title compound was synthesized in a manner similar to that described in example 6 (e). ES-MS: m/z 518 (M-H). 91 WO 01/44258 PCT/USOO/34487 5 Example 12 {[4-(4-Amino-5-p-tolyl-pyrrolor2,3-dlpyrimidin-7-yl)-tetrahydrofuran-2-ylmethoxyll hydroxy-phosphorylmethyl I phosphonic acid H2 -w/ H 10 0 0 (a) 7-Benzenesulfonyl-4-chloro-5-iodo-7H-pyrrolor2,3-djpyrimidine To 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.26 g, 4.5 mmol) in 45 mL dry THF was added NaH (217 mg, 9.0 mmol). The mixture was stirred at r. t. for 1 hr. 15 PhSO 2 C1 (875 mg, 5.0 mmol) was added via syringe dropwise. Stirring was continued for another 2 hrs. Solvent was removed in vacuo. The residue was diluted with ice
H
2 0 and then neutralized with saturated NH 4 Cl 13.5 mL. The mixture was extracted with CH 2 Cl 2 (2 X 60 mL). The combined organic layer was washed with brine and dried over MgSO 4 . Solvent was removed in vacuo and residue was chromatographed 20 on silica gel (CH 2
CI
2 , Rf 0.44 ). The product was obtained as a white solid (1.12 g, 59 (b) 7-Benzenesulfonyl-4-chloro-5-p-tolyl-7H-pyrrolo2,3-dlpyrimidine 7-Benzenesulfonyl-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.12 g, 2.67 25 mmol), 4-methylbenzeneboronic acid (373 mg, 2.74 mmol) and NaHCO 3 (693 mg, 8.25 mmol) was mixed with EtOH (6 mL ), toluene (43 mL ) and H20 (12 mL ). The mixture was bubbled with Ar for 1 hour before Pd(PPh 3
)
2 Cl 2 (189 mg, 0.27 mmol) was added. The reaction mixture was heated at 95 "C overnight. After cooling to r. t., the reaction mixture was filtered through a pad of Celite. The filtrate was partitioned 30 between EtOAc and water, organic layer was separated, dried and concentrated. 92 WO 01/44258 PCT/USOO/34487 5 Residue was chromatographed on silica gel (3/1 hexane/EtOAc, Rf 0.34) to get product as a white solid (0.74 g, 74 %). (c) 4-Chloro-5-p-tolyl-7H-pyrrolo[2,3-dpyrimidine 7-Benzenesulfonyl-4-chloro-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidine (740 mg, 10 1.93 mmol) in 50 mL THF was added TBAF 1.93 mL (1.0 M solution in THF). The reaction mixture was heated under reflux for 1.5 hrs. The solvent was removed in vacuo. The residue was partitioned between EtOAc and water. The organic layer was separated and the aqueous layer was extracted with EtOAc (2 X ). Combined organic layer was dried over Na 2
SO
4 and concentrated. The residue was chromatographed on 15 silica gel (2/1 CH 2 Cl 2 /EtOAc, Rf 0.42) to give product as a white solid (343 mg, 73%). (d) 4-Amino-5-p-tolyl-7H-pyrrolo[2,3-dlpyrimidine 4-Chloro-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidine (220 mg, 0.9 mmol) was 20 dissolved in 5 mL dioxane in a pressure tube and then concentrated ammonia 5 mL was added. The mixture was heated at 120 0 C for 4 days. Solvent was removed and the resulting residue was partitioned between EtOAc/H 2 0. Organic layer was separated and the aqueous layer was extracted with EtOAc (3 X). Combined organic layer was dried (Na 2
SO
4 ), concentrated to provide crude product as a white solid (202 25 mg, -100%). (e) Toluene-4-sulfonic acid 5-dimethoxymethyl-tetrahydro-furan-3-yl ester The title compound was synthesized according to the procedure described in Tetrahedron Lett. 1989, 30, 6259-6262. 30 (f) 7-(5-Dimethoxymethyl-tetrahydro-furan-3-yl)-5-p-tolyl-7H-pyrrolo[2,3 dlpyrimidin-4-ylamine To 4-amino-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidine (250 mg, 1.2 mmol), 18 Crown-6 (316 mg, 1.2 mmol) in 32 mL dry DMF was added K 2
CO
3 (326 mg, 2.4 35 mmol). The mixture was stirred at r.t. for 30 min. Then toluene-4-sulfonic acid 5 dimethoxymethyl-tetrahydro-furan-3-yl ester (100 mg, 1.2 mmol) in 15 mL DMF was 93 WO 01/44258 PCT/USOO/34487 5 added and the reaction was heated at 80 "C overnight. After cooling to r.t., the mixture was partitioned between EtOAc and water, organic layer was separated and the aqueous layer was extracted with EtOAc (3 X). Combined organic layer was dried (Na 2
SO
4 ), concentrated and the residue was chromatographed on silica gel (10 % MeOH in EtOAc, Rf 0.38). The product is obtained as a liquid (357 mg, 80 %). 10 (g) [4-(4-Amino-5-p-tolyl-pyrrolo[2,3-dlpyrimidin-7-yll-tetrahydrofuran-2-yll methanol 7-(5-Dimethoxymethyl-tetrahydro-furan-3-yl)-5-p-tolyl-7H-pyrrolo[2,3 d]pyrimidin-4-ylamine (357 mg, 1 mmol) was dissolved in 10 mL dioxane and 1 % 15 TFA/H 2 0 10 mL was added and the mixture was heated at 80 C overnight. The solution was added 1 N NaOH until PH = 6.0. NaBH 4 (38 mg, 1 mmol) was added and the solution was stirred at r. t. for 10 min. Solvent was removed in vacuo and the resulting residue was partitioned between EtOAc and H 2 0. Organic layer was separated and the aqueous layer was extracted with EtOAc (3 X). Combined organic 20 layer was dried (Na 2
SO
4 ), concentrated and the residue was chromatographed on silica gel (10 % MeOH in EtOAc, Rf 0.38). The product was obtained as a white solid (201 mg, 62 %). (h) {[4-(4-Amino-5-p-tolyl-pyrrolor2,3-dlpyrimidin-7-yl)-tetrahydrofuran-2 25 ylmethoxyll-hydroxy-phosphorylmethyl} phosphonic acid [4-(4-Amino-5-p-tolyl-pyrrolo[2,3-d]pyrimidin-7-yl]-tetrahydrofuran-2-yl] methanol was dissolved in 4 mL trimethyl phosphate and was cooled to -5-0 C. Methylenebis (phosphonic dichloride) (212 mg, 0.8 mmol) was added in one portion and the resulting mixture was stirred at that temperature for 2 hrs. The reaction 30 mixture was transferred via syringe to 20 mL cold 10 % NaHCO 3 . The mixture was neutralized with 1 N HCl, and then purified by RP HPLC. The final product was obtained as a white solid (31 mg, 32%). ES-MS: m/z 481 (M-H). Example 13 35 { [4-(4-Amino-3-p-tolyl-3a,7a-dihydro-pyrazolo[3,4-dlpyrimidin-1-yl)-butoxyl hydroxy-phosphorylmethyl}-phosphonic acid 94 WO 01/44258 PCT/USOO/34487
NH
2 ~ H 2 5 N PO3 H2 (a) Acetic acid 4-(4-amino-3-p-tolyl-3a,7a-dihydro-pyrazolo[3,4-dlpyrimidin-1-yl) butyl ester The title compound was made according to the procedure detailed in J. Med. 10 Chem. 1990, 33, 1980-1983. (b) 4-(4-Amino-3-p-tolyl-3a,7a-dihydro-pyrazolo[3,4-djpyrimidin-1-yl)-butan-1-ol Acetic acid 4-(4-amino-3 -p-tolyl-3 a,7a-dihydro-pyrazolo [3,4-d]pyrimidin- 1 yl)-butyl ester (0.85 g, 2.5 mmol), and LiOH-H 2 0 (0.25 g, 5.96 mmol) were dissolved 15 in THF (3 mL)/H 2 0 (10 mL) and heated to 70 "C for 2 h. After cooling, the mixture was dumped into water and extracted with EtOAc. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated to a yellow solid which was used without purification in the next reaction (0.20 g, 27%). 20 (c) Toluene-4-sulfonic acid 4-(4-amino-3-p-tolyl-3a,7a-dihydro-pyrazolo[3,4 dlpyrimidin-1-yl)-butyl ester A mixture of 4-(4-amino-3-p-tolyl-3a,7a-dihydro-pyrazolo[3,4-d]pyrimidin-1 yl)-butan-1-ol (0.19 g, 0.66 mmol), TsCl (0.28 g, 1.50 mmol), DMAP (0.19 g, 1.56 mmol) and CH 2 C1 2 (10 mL) were stirred for 24 h at rt. The mixture was dumped into 25 water and extracted with CH 2
CI
2 . The combined extracts were washed with water, dried over magnesium sulfate, and concentrated to a yellow solid which was purified over silica gel (1% MeOH/CH 2 Cl 2 ) to yield a white foam (0.25 g, 85%). MS [M + H]*452. 30 (d) {r4-(4-Amino-3-p-tolyl-3a,7a-dihydro-pyrazolo[3,4-dlpyrimidin-1-yl)-butoxyl hydroxy-phosphorylmethyl}-phosphonic acid 95 WO 01/44258 PCT/USOO/34487 5 The title compound was made following the procedure detailed in JOC 1987, 52, 1794. MS [M - H]~454. D) Embodiments wherein Tb is x Bis-3,4-(diethylphophonyl)-p-phenylethyl amine 5
NH
2 o 10 5 N-t-butoxycarbonyl-3-hydroxytyramine To a solution of 3-hydroxytyramine hydrochloride (5.0 g, 26.36 mmol) in dixane/water (50/30 mL) at 0 *C was added sodium bicarbonate (6.64g, 79.08 mmol) 15 and stirred for 10 min. To this was added Boc anhydride (7.48 g, 34.275 mmol) and stirred at rt for 18 h. After removing dioxane in vacuo, the slurry was taken up in water (-60 mL) and extracted in ethyl acetate (25 mL X 3). The organics were washed with IN HCl (10 mL X 2) followed by brine (10mL); dried (sodium sulfate) and concentrated which when cooled in the refregerator crystallized the next day 20 (3.87 g, 57%). MS: 252 (M-H). N-t-butoxycarbonyl-bis-3,4-O-triflyl-p-phenylethyl amine To a solution of N-Boc-3-hydroxytyramine (3.87 g, 15.28 mmol) in anhydrous dichloromethane (70 mL) was added triethyl amine (61.12 mmol) followed by N 25 phenyl triflamide (16.37 g, 45.84 mmol) and stirred at rt for 24 h. Reaction mixture was diluted with dichloromethane (100 mL) and washed successively with IN HCl (3X 10 mL) and brine (10 mL) and dried (sodium sulfate). After concentration of dichloromethane extract the brown oil was chromatographed on silicagel using hexane /ethyl acetate (10-100%) to give product as a viscous oil (6.32 g, 80%). MS: 30 516 (M-H). 96 WO 01/44258 PCT/USOO/34487 5 N-t-butoxycarbonyl-bis-3,4-(diethylphophonyl)-/-phenylethyl amine To the N-t-butoxycarbonyl-bis-3,4-O-triflyl-p-phenylethyl amine (6.32 g, 12.21 mmol) in acetonitrile in an atmosphere of argon was carefully added diethyl phosphite (3.46 mL, 26.87 mmol), N-methylmorpholine (3.09 mL, 30.54 mmol), tetrakistriphenylphosphine palladium(0) (1.41 g, 1.221 mmol) and after flushing the 10 solution with argon for 10 min. it was stoppered and heated to 90 *C for 2 days. Acetonitrile was concentrated, and the residue was diluted with ethyl acetate. The organic layer was washed with citric acid (10%, 10 mL X2), brine (10 mL) and dried (sodium sulfate). The yellow gum after concentration of ethyl acetate was purified by flash column chromatography on silica gel using ethyl acetate in hexane (33%-100%) 15 followed by ethyl acetate/methanol (9/1) to give a pale yellow gum (992 mg, 16.5%). MS: 492(M-H). Bis-3,4-(diethylphophonyl)-3-phenylethyl amine To the N-t-butoxycarbonyl-bis-3,4-(diethylphophonyl)-p-phenylethyl amine (0.992 g, 20 2.01 mmol) in dichloromethane (10 mL) was added TFA (25% in dichloromethane, 2.5 mL). After 1.5 h the solvents were removed in vacuo and the residue was diluted with saturated sodium bicarbonate and dichloromethane (5 mL and 50 mL). The aqueous layer was re extracted with dichloromethane (25 mL X 2). Combined organics were concentrated to give a pale brown gum (0.758 g, 96%) which was pure 25 enough for the next step. MS:392 (M-H), 416 (M+23). Example 14 [4-Aminomethyl-2-(diethoxy-phosphoryl)-phenyll-phosphonic acid diethyl ester Et 2 O3 30 Et 2
O
3
NH
2 (b) (3,4-Dihydroxy-benzyl)-carbamic acid tert-butyl ester 4-Aminomethyl-benzene-1,2-diol hydrobromide (5.6 g, 25.2 mmol) was dissolved in CH 3
CN/H
2 0 1:1 (100 mL). NaHCO 3 (4.3 g, 50.4 mmol) was added 35 followed by Boc 2 0 (5.5 g, 25.2 mmol). The mixture was stirred for 18 h, 97 WO 01/44258 PCT/USOO/34487 5 concentrated, and extracted with EtOAc. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated to a tan solid which was used without purification in the next reaction. (c) Trifluoro-methanesulfonic acid 5-(tert-butoxycarbonylamino-methyl)-2 10 trifluoromethanesulfonyloxy-phenyI ester (3,4-Dihydroxy-benzyl)-carbamic acid tert-butyl ester (5.5 g, 23.0 mmol), N phenyltrifluoromethanesulfonimide (26.9 g, 75 mmol), and Et 3 N (14.9 mL, 107 mmol) were dissolved in CH 2 Cl 2 (80 mL) and stirred for 24 h. The mixture was dumped into water and the layers seperated. The aqueous layer was extracted with 15 methylene chloride. The combined extracts were washed with water, dried over magnesium sulfate, concentrated, and purified by silica gel chromatography (hexane/EtOAc 3:1) to yield the product as a brown oil (9.0 g, 78%). (d) [4-(tert-Butoxycarbonylamino-methyl)-2-(diethoxy-phosphoryl)-phenyll 20 phosphonic acid diethyl ester Trifluoro-methanesulfonic acid 5-(tert-butoxycarbonylamino-methyl)-2 trifluoromethanesulfonyloxy-phenyl ester (5 g, 10.o mmol), diethyl phosphite (2.8 mL, 20.3 mmol), N-methylmorpholine (2.7 mL, 25.1 mmol) and tetrakis(triphenylphosphine)-palladium(O) (1.2 g) were dissolved in anhydrous 25 acetonitrile (100 mL) and heated in a sealed tube at 90 "C for 48 h. After cooling, the mixture was diluted with EtOAc (200 mL) and washed with water, 1 N HCI and brine. The organic layer was dried over magnesium sulfate, concentrated, and purified by silica gel chromatography (5% MeOH/CHCl 3 ) to yield the product as a colorless oil (2.0 g, 42%). 'H NMR (300 Mhz, CDCl 3 ) 8 1.35 (in, 12 H), 3.79 (bs, 2 30 H), 3.96 (in, 8H), 7.45 (in, 1H), 7.91 (in, 2H). (e) [4-Aminomethyl-2-(diethoxy-phosphoryl)-phenyll-phosphonic acid diethyl ester [4-(tert-Butoxycarbonylamino-methyl)-2-(diethoxy-phosphoryl)-phenyl] phosphonic acid diethyl ester (2.0 g, 4.2 mmol) was dissolved in TFA/CH 2 Cl 2 (25%, 35 20 mL) and stirred for 3 h. The mixture was evaporated under a stream of N 2 , dissolved in EtOAc and washed with sat'd NaHCO 3 . The organic layer was dried over 98 WO 01/44258 PCT/USOO/34487 5 magnesium sulfate, and concentrated to a brown oil (0.9 g, 2.3 mmol) which was used without purification in the next reaction. Example 15 10 3-(3,4-Bis-phosphono-phenyl)-propionic acid 4-(4-amino-5-p-tolyl-pyrrolo[2,3 d]pyrimidin-7-yl)-tetrahydro-furan-2-ylmethyl ester
NH
2 N""~ *I~OH N OH NN Vg/ OH 0 (a) 3-[3,4-Bis-(diethoxy-phosphoryl)-phenyll-propionic acid 4-(4-amino-5-p-tolyl 15 pyrrolo[2,3-dlpyrimidin-7-yl)-tetrahydro-furan-2-ylmethyl ester [4-(4-Amino-5-p-tolyl-pyrrolo[2,3-d]pyrimidin-7-yl]-tetrahydrofuran-2-yl] methanol (32.4 mg, 0.1 mmol), 3-[3,4-bis-(diethoxy-phosphoryl)-phenyl]-propionic acid (47 mg, 0.11 mmol), DCC (22.7 mg, 0.11 mmol) and DMAP (5 mg, 0.041 mmol) was mixed in 2 mL dry DMF under N 2 . The reaction mixture was stirred at r.t. 20 overnight. The product was purified by RP HPLC to get a liquid (17 mg, 25 %). (b) 3-(3,4-Bis-phosphono-phenyl)-propionic acid 4-(4-amino-5-p-tolyl-pyrrolo[2,3 dlpyrimidin-7-yl)-tetrahydro-furan-2-ylmethyl ester 3-[3,4-Bis-(diethoxy-phosphoryl)-phenyl]-propionic acid 4-(4-amino-5-p 25 tolyl-pyrrolo[2,3-d]pyrimidin-7-yl)-tetrahydro-furan-2-ylmethyl ester (18 mg, 0.025 mmol) was dissolved in 2 mL dry acetonitrile under N 2 . The solution was cooled to 12 C. TMSI (100 mg, 0.5 mmol) was added via syringe and the reaction was stirred at that temperature for 16 hrs. To the solution was added 10 % NaHCO 3 until pH 7.0. Then a few drops of sat. Na 2
S
2
O
3 was added just enough to make the yellow 30 color disappear. The resulting mixture was purified by RP HPLC. The final product is a white powder (6.5 mg, 42 %). ES-MS: m/z 616 (M-H). 99 WO 01/44258 PCT/USOO/34487 5 Example 16 (4-{{3-(4-Amino-3-p-tolyl-3a,7a-dihydro-pyrazolor3,4-dlpyrimidin-1-yl) benzoylaminol-methyl}-2-phosphono-phenyl)-phosphonic acid Me
NH
2 ~ N
H
2 0 3 P PO 3
H
2 ' ,N 0H N N H N:: 0 10 (a) 3-(4-Amino-3-p-tolyl-3a,7a-dihydro-pyrazolo[3,4-dlpyrimidin-1-yl)-benzoic acid The title compound was made as for example 19(b). (b) [4-{[3-(4-Amino-3-p-tolyl-pyrazolo[3,4-dlpyrimidin-1-yl)-benzoylaminol 15 methyl}-2-(diethoxy-phosphoryl)-phenyll-phosphonic acid diethyl ester 3-(4-Amino-3-p-tolyl-3a,7a-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl)-benzoic acid (0.015 g, 0.043 mmol), [4-aminomethyl-2-(diethoxy-phosphoryl)-phenyl] phosphonic acid diethyl ester (0.021 g, 0.054 mmol), HOBt (0.007 g, 0.052 mmol), and EDC-HCl (0.01 g, 0.052 mmol) were dissolved in DMF (1 mL) and stirred at rt 20 for lh. Purification by RP HPLC (CH 3
CN/H
2 0) and lyophylization yielded a white powder (0.023 g, 75%). MS [M + H]+ 708. (c) (4-{[3-(4-Amino-3-p-tolyl-3a,7a-dihydro-pyrazolo[3,4-dlpyrimidin-1-yI) benzoylaminol-methyl}-2-phosphono-phenyl)-phosphonic acid 25 [4-{[3-(4-Amino-3-p-tolyl-pyrazolo[3,4-d]pyrimidin-1-yl)-benzoylamino] methyl}-2-(diethoxy-phosphoryl)-phenyl]-phosphonic acid diethyl ester (0.023 g, 0.033 mmol) dissolved in CH 3 CN (1 mL) was treated with TMSI (0.093 mL, 0.65 mmol). The mixture was stirred for 4 h, made basic with IN NaOH, and decolorized with solid NaSHO 3 . The resulting solution was diluted with DMF (5 mL) and 100 WO 01/44258 PCT/USOO/34487 5 purified by RP HPLC (CH 3
CN/H
2 0). Lyophylization yielded a white powder (0.011 g, 75%). MS [M - H] 593. E) Embodiments wherein Tb is xii 10 General Scheme for Embodiments wherein Tb is a subsituted aryl: Error! Objects cannot be created from editing field codes. Example 17 O2tBu
CO
2 tBu CO2H (PhO)2PON3,
NH
2 NaH 1. LDA t-BuOH, A (EtO)2P(O)CI 2. BnBr, NaH P3Et2 2. TFA PO 3 Et 2 OH OPO 3 Et 2 OBn OBn 15 Synthesis of aniline 5 (a) To a suspension of NaH (220 mg of a 60% dispersion in mineral oil (5.5 mmol), washed three times with hexanes) in THF (15 mL) at rt under N 2 was added t-butyl 4-hydroxybenzoate (971 mg, 5.0 mmol) in one portion. After H 2 20 evolution ceased (-10 min.), diethyl chlorophosphate (0.79 mL, 5.5 mmol) was added. The reaction mixture was stirred at rt overnight and then poured into 1.0 N aq NaOH (20 mL) and extracted with EtOAc. The organic extract was washed with H 2 0 (20 mL) and brine (20 mL), dried over MgSO 4 and concentrated. The crude oil was purified by flash chromatography on silica gel. Elution with 2:1 hexanes-EtOAc 25 followed by 1:1 hexanes-EtOAc afforded 1.48 g (90%) of the phosphate as a colorless oil. (b) To a solution of i-Pr 2 NEt (1.2 mL, 8.48 mmol) in THF (22 mL) at 0 'C under N 2 was slowly added 1.6 Mn-BuLi in hexanes (5.3 mL, 8.48 mmol). After 10 30 min., the LDA solution was cooled to -78 *C, and a solution of the phosphate (1.40 g, 4.24 mmol) in THF (5 mL) was slowly added via cannula. A 2 mL rinse of the flask was also added. The reaction mixture was stirred at -78 *C for 2 h and at 0 'C for 1 h. The reaction mixture was then diluted with half saturated aq NH 4 Cl (20 mL). The mixture was further acidified by the addition of a small amount of 6 N aq HC1, and 35 then extracted with EtOAc. The extract was washed with H 2 0 (10 mL) and brine (10 101 WO 01/44258 PCT/USOO/34487 5 mL). The aqueous washes were reextracted once with EtOAc, and the combined extracts were dried over MgSO 4 and concentrated. The crude material was purified by flash chromatography on silica gel. Elution with 5:1 hexanes-EtOAc followed by 3:1 hexanes-EtOAc afforded 1.32 g (94%) of the desired phosphonate as a light yellow oil. 10 (c) To a solution of the phenol (1.30 g, 3.94 mmol) in CH 3 CN (10 mL) at rt under N 2 was added K 2
CO
3 (600 mg, 4.33 mmol) followed by benzyl bromide (0.51 mL, 4.33 mmol). The reaction mixture was stirred at 50 *C. After cooling, the reaction mixture was diluted with EtOAc and washed with H 2 0 and brine. The 15 extract was dried over MgSO 4 and concentrated. The crude material was purified by flash chromatography on silica gel to afford 1.86 g (quant) of the desired benzyl ether. (d) To a solution of the t-butyl ester (from above) in CH 2 Cl 2 (12 mL) at 0 *C under N 2 was slowly added TFA (4 mL). The resulting solution was stirred at 0 20 *C for 1 h and at rt for 3 h. The reaction mixture was then concentrated under a stream of N 2 followed by high vacuum to afford the desired acid as an off-white solid. (e) To a solution of the acid (364 mg, 1.00 mmol) in 1:1 toluene-t-BuOH (4 mL) at rt under N 2 was added i-Pr 2 NEt (0.44 mL, 2.5 mmol) followed by (PhO) 25 2
P(O)N
3 (0.54 mL, 2.5 mmol). The resulting solution was then stirred at reflux for 5 h. The yellow solution was allowed to cool to rt and was then partitioned between EtOAc and H 2 0 (20 mL). The layers were separated, and the organic extract was then washed with H 2 0 (20 mL) and brine (20 mL). The EtOAc extract was then dried over Na 2
SO
4 and concentrated. The crude was purified by flash chromatography on 30 silica gel. Elution with 1:1 EtOAc-hexanes followed by 2:1 EtOAc-hexanes afforded 146 mg (34%) of the desired carbamate. (f) To a solution of the carbamate (879 mg, 2.02 mmol) in CH 2
C
2 (8 mL) at rt under N 2 was added TFA (2 mL). The solution was stirred at rt for 3 h and then 35 concentrated under a stream of N 2 . The residue was purified by flash chromatography 102 WO 01/44258 PCT/USOO/34487 5 on silica gel. Elution with 3:1 EtOAc-hexanes followed by 15:1 CHCl 3 -MeOH afforded 612 mg of aniline 5. Condensation of aniline 5 with sulfone 1 and subsequent deprotection to 9 (a) A mixture of aniline 5 (605 mg, 1.80 mmol) and sulfone 1 (347 mg, 10 0.902 mmol) in 2-methoxyethyl ether (5 mL) was stirred at 150 *C for 2 h. The dark solution was allowed to slowly cool to rt overnight. The precipitate that had formed was then filtered, washed with Et 2 O and dried under high vacuum to afford 310 mg (54%) of the desired coupling product. 15 (b) A solution of the coupling product (from above, 39 mg, 0.610 mmol) in AcOH (~3-4 mL) containing a catalytic amount of 10% Pd/C was stirred under an atmosphere of N 2 (double stuffed balloon) for 3 h. The reaction mixture was then filtered through a pad of Celite, and the filtrate concentrated. The residue was purified by flash chromatography on silica gel. Elution with 1:1 EtOAc-hexanes 20 afforded 24 mg (72%) of phenol 9. ci N HN"'4N IN 0 OH P.-OH HO-p o HO' x-A (a) To a solution of phenol 9 (85 mg, 0.155 mmol) and i-Pr 2 NEt (0.03 mL, 25 0.186 mmol) in CH 2 Cl 2 (2 mL) at 0 0 C under N 2 was added PhNTf 2 (72 mg, 0.201 mmol). The reaction mixture was stirred at rt for 5 days. Additional i-Pr 2 NEt and PhNTf 2 was added, and the reaction mixture stirred for an additional day. The reaction mixture was then diluted with EtOAc and washed with 1.0 M aq HCl (10 mL), H 2 0 (10 mL), and brine (10 mL). The EtOAc extract was dried over Na 2
SO
4 30 and concentrated. The crude material was purified by flash chromatography on silica gel. Elution with 1:1 EtOAc-hexanes, 3:2 EtOAc-hexanes and finally 2:1 EtOAc hexanes afforded 90 mg (86%) of the triflate. 103 WO 01/44258 PCT/USOO/34487 5 (b) To a solution of the triflate (43.8 mg, 0.0644 mmol) in CH 3 CN (1.0 mL) at rt under N 2 was added NMM (0.01 mL, 0.0911 mmol), (EtO) 2 POH (0.011 mL, 0.0841 mmol) and a catalytic amount of Pd(PPh 3
)
4 . The mixture was then stirred at 70 *C overnight. The reaction mixture was then partitioned between EtOAc and 1.0 10 M aq HCL. The layers were separated and the organic layer was washed with H 2 0 and brine. The organic layer was dried over Na 2
SO
4 and concentrated. The crude material was purified by flash chromatography on silica gel to afford an inseparable mixture of the desired bisphosphonate and 9, which was used in the next reaction without further purification. 15 (c) The mixture of products from above was converted to x-A in the same fashion as previously described (i-A, (b)). c HN HN' -N N 0 OH 0O P'-OH HOx-B 20 (a) To a solution of phenol 9 (17.9 mg, 0.0326 mmol) in CH 3 CN containing Cs 2
CO
3 (16 mg, 0.0489 mmol) at rt under N 2 was added t-butyl bromoacetate (0.006 mL, 0.0424 mmol). The yellow color of the reaction mixture slowly disappeared over time, and after 3 h, the reaction mixture was diluted with 25 EtOAc and washed with H 2 0 and brine. The EtOAc layer was dried over Na 2
SO
4 and concentrated. The crude residue was used without further purification. (b) The crude residue from above was converted to x-B in the same fashion as previously described (i-A, (b)). 30 104 WO 01/44258 PCT/USOO/34487 C N HNN N 0 OEt 5O PI-OEt X-C The crude residue from above (x-B, (a)) was converted to x-C in the same fashion as previously described (i-A, (b)) except that the reaction mixture was only allowed to warm to 0 'C before being quenched. 10 CI N OH F ~OH H 6 x-D Phenol 9 was converted to x-D in the same fashion as previously described (i A, (b)). 15 F) Embodiments wherein Tb is xiii Example 18 4-[6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo-4a,7,8,8a-tetrahydro-pyrido[2,3 20 dlpyrimidin-2-ylaminol-pyridine-2,6-dicarboxylic acid Cl Cl HN N 'N 0 HO N OH N 0 0 105 WO 01/44258 PCT/USOO/34487 5 a) 4-[6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo-4a,7,8,8a-tetrahydro-pyridof2,3 dlpyrimidin-2-ylaminol-pyridine-2,6-dicarboxylic acid diethyl ester C C Pd(OAc) 2 N N CI CI (S)-BINAP HN N 0 H2N.IN O Cs2CO3 EtOy OEt Et N Et 0 0 0 0 10 4-Bromo-pyridine-2,6-dicarboxylic acid diethyl ester (39 mg, 0.13 mmol), 2 amino-6-(2,6-dichlorophenyl)pyrido-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (50 mg, 0.16 mmol), 4-bromopyridine-2,6-dicarboxylic acid diethyl ester (39 mg, 0.13 mmol), palladium acetate (1.5 mg, 0.0067 mmol), (S)-BINAP (6.0 mg, 0.0096 mmol) and cesium carbonate (60 mg, 0.18 mmol) were placed in toluene (0.5 mL). The flask 15 was purged with argon, sealed and heated to 100 0 C. After 20 h, the reaction was allowed to cool to rt and diluted with EtOAc and H 2 0. The aqueous layer was extracted with fresh EtOAc, the organic fractions combined, washed with brine and dried over Na 2
SO
4 . The solution was concentrated and chromatographed over silica gel using CHCl 3 :MeOH (99:1) to provide 49 mg (69%) of a yellow solid. 20 Electrospray Mass Spectrum (50/50 acetonitrile/water) m/z 540 (M-H). b) 4-[6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo-4a,7,8,8a-tetrahydro-pyridor2,3 dlpyrimidin-2-ylaminol-pyridine-2,6-dicarboxylic acid C C ClN0 NaOH CI H N O H N O Et IN/ Et Et IN 14 Et 25 0 0 0 0 106 WO 01/44258 PCT/USOO/34487 5 To a solution of 4-[6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo-4a,7,8,8a tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridine-2,6-dicarboxylic acid diethyl ester (49 mg, 0.090 mmol) in MeOH (0.5 mL) was added IN sodium hydroxide (0.36 mL) resulting in a suspension. A solution was obtained after addition of water (0.5 mL) and heating to 80 *C. After 3 h, the reaction was allowed to cool to rt, diluted 10 with MeCN/H 2 0/DMF and chromatographed using reversed-phase HPLC. Concentration and lyophilization of the purified fractions gave 23 mg (53%) of a yellowish solid. Electrospray Mass Spectrum (50/50 acetonitrile/water) m/z 486 (M+H). 15 Example 19 4-(4-Amino-5-p-tolyl-4a,7a-dihydro-pyrrolo[2,3-dlpyrimidin-7-yl)-pyridine-2,6 dicarboxylic acid
NH
2 N , N H HO 0 0 20 (a) Pyridine-(2,6-dicarboxylic acid diethyl ester)-4-boronic acid A mixture of 4-bromopyridine-2,6-dicarboxylic acid diethyl ester (0.10 g, 0.33 mmol), bis(pinacoloto)diboron (0.093 g, 0.36 mmol), [1, 1' bis(diphenylphosphino)ferrocene]dichloride (5 mol%), potassium acetate (0.097 g, 1.0 mmol) in DMSO (2 mL) was heated to 80 *C for 1 h. Purification by RP HPLC 25 (CH 3
CN/H
2 0) and lyophylization yielded a white powder (0.07 g, 79%). MS [M + H]+ 268. (b) 4-(4-Amino-5-p-tolyl-4a,7a-dihydro-pyrrolo[2,3-dpyrimidin-7-yl)-pyridine-2,6 dicarboxylic acid diethyl ester 107 WO 01/44258 PCT/USOO/34487 5 A mixture of pyridine-(2,6-dicarboxylic acid diethyl ester)-4-boronic acid (0.093 g, 0.27 mmol), 3-p-Tolyl-3a,7a-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4 ylamine (0.03 g, 0.13 mmol mmol), copper(II) acetate (0.048 g, 0.27 mmol) and pyridine (0.3 mL) in DMF (5 mL) were stirred open to the air for 48 h. The mixture was filtered through Celite and the filtrate purified by RP HPLC (CH 3
CN/H
2 0). 10 Lyophylization yielded a white powder (0.02 g, 34%). MS [M + H]* 447. (c) 4-(4-Amino-5-p-tolyl-4a,7a-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridine-2,6 dicarboxylic acid To a suspension of 4-(4-amino-5-p-tolyl-4a,7a-dihydro-pyrrolo[2,3 15 d]pyrimidin-7-yl)-pyridine-2,6-dicarboxylic acid diethyl ester (0.02 g, 0.036 mmol) in THF (1 mL) and water (1 mL) was added 2N NaOH (1 mL). The mixture was heated at reflux for 1 h at which point HPLC indicated completion. The mixture was acidified with TFA, diluted with DMF (5 mL) and purified by RP HPLC
(CH
3
CN/H
2 0). Lyophylization yielded a white powder (0.01 g, 71%). MS [M - H]~ 20 389. G) Embodiments wherein Tb is xxii Br Br (EtO) 2 POH N Pd(PPh 3
)
4 N NMM Br O=P-OEt OEt 25 Example 20 Preparation of diethyl 2-(5-bromopyridylbphosphonate A mixture of 2,5-dibromopyridine (500 mg, 2.11 mmol), NMM (0.46 mL, 4.22 mmol), (EtO) 2 POH (0.35 mL, 2.53 mmol) and Pd(PPh 3
)
4 (122 mg, 0.106 mmol) 30 in CH 3 CN was stirred at 80 'C overnight. After cooling, the reaction mixture was partitioned between CH 2 C1 2 and water. The organic extract was then washed with brine, dried over K 2
CO
3 and concentrated. The crude material was purified by flash chromatography on silica gel to afford 130 mg (21%) of the desired phosphonate. 108 WO 01/44258 PCT/USOO/34487 5 {5-r6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo-4a,7,8,8a-tetrahydro-pyridor2,3 dpyrimidin-2-ylaminol-pyridin-2-yl}-phosphonic acid C1 N HN ' N OCI N '-OH OH 10 a) {5-r6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo-4a,7,8,8a-tetrahydro-pyridor2,3 dlpyrimidin-2-ylaminol-pyridin-2-yl}-phosphonic acid diethyl ester (5-Bromo-pyridin-2-yl)-phosphonic acid diethyl ester C N Pd(OAc) 2 N N
H
2 NAN Nr HN-'N N C H2NL 0 (S)-BINAP Cs 2 CO3 N O~0t OEt OEt 15 b) (4-bromopyridin-2-yl)-phosphonic acid diethyl ester (64 mg, 0.22 mmol), 2-amino-6-(2,6-dichlorophenyl)pyrido-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (70 mg, 0.22 mmol), palladium acetate (5.0 mg, 0.0.023 mmol), (5-bromopyridin-2 yl)-phosphonic acid diethyl ester (64 mg, 0.22 mmol), (S)-BINAP (20 mg, 0.032 20 mmol) and cesium carbonate (141 mg, 0.43 mmol) were placed in toluene (1 mL), flushed with argon, sealed and heated to 95 *C. After 18 h, the reaction was allowed to cool to rt and diluted with H 2 0. The mixture was extracted twice with EtOAc and the combined organic extracts washed with brine and dried over Na 2
SO
4 . The solution was concentrated and chromatographed over silica gel (CHCl 3 :MeOH, 109 WO 01/44258 PCT/USOO/34487 5 stepwise gradient 99:1 to 97:3) to give 46 mg (39%) of a yellow solid. Electrospray Mass Spectrum (50/50 acetonitrile/water) m/z 534 (M+H). c) {5-[6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo-4a,7,8,8a-tetrahydro-pyrido[2,3 dlpyrimidin-2-ylaminol-pyridin-2-yl I -phosphonic acid 10 C C N 1-TMS N HN N O H NN:I [ 0 HN< I N 0~ -OEt OH 0O~t 0 *p,%H To a cooled solution (0 *C) of {5-[6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo 4a,7,8,8a-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-2-yl} -phosphonic 15 acid diethyl ester (46 mg, 0.86 mmol) in MeCN (1.2 mL) was added iodotrimethylsilane (0.3 mL). After 2 h, the reaction was quenched with sodium hydroxide (1 N) and satd sodium thiosulfate. The mixture was filtered and the filtrate chromatographed using reversed-phase HPLC to give 14 mg (34%) of a colorless solid after lyophilization. Electrospray Mass Spectrum (50/50 acetonitrile/water) m/z 20 534 (M+H). Example 21 Solid-Phase/Combinatorial Approaches: 25 Compounds were synthesized by solid-phase parallel synthesis using a Quest 210 synthesizer (Argonaut Technologies) according to the following scheme for Example 22: Solid-Phase Parallel Synthesis Scheme 110 WO 01/44258 PCT/USOO/34487 HO OTBS Ph 3 P, DEAD,THF, TBS 1. TBAF/THF a-OH + PI1 Wang Resin 0 *C - rt, 20 h 2. 2-fluoro-6-chloropurine, a Ph 3 P, DEAD,THF, 0 0 C- rt, 22 h 0 0 Cl O. V11 0Et N Et OEt OEt CIt 00~ HN.I F N N H2(10.0 eq), N lb 0 DIEA, n-BuOH/DMSO (1:1), 2 (110 OC), E N 16 h 1 o Ic C 0 0 1. (CH 3
)
2
NCH
2
CH
2
NH
2 (10.0 eq), DIEA, n-BuOH/DMSO (1:1), 2 (110 OC), 16 h 2. TFA/DCM (2% TIS) 3. TMSI, CH 3 CN, -20 toN H 4. RP HPLC 5 1 Example-22 (a) [(4-{2-(2-Dimethylamino-ethylamino)-9--[2-(3-hydroxy-phenyl)-ethyll 9H-purin-6-ylaminol-phenyl)-hydroxy-phosphinoylmethyll -phosphonic acid 0 0 II II HON XH HN~Q N N 'N H 10 H (b) 3- [2-(tert-Butyl-dimethyl-silanyloxy)-ethylI -phenol To a solution of 3-hydroxyphenethyl alcohol (6.0 g, 43.4 mmol) in 275 mL of
CH
2 C1 2 was added 6.55 g (43.4 mmol) of TBDMS-Cl (tert-butyldimethylsilyl chloride), cooled to 0 'C, then added 7.0 mL (86.8 mmol) of pyridine. The reaction 15 mixture was stirred at ambient temperature overnight. Upon concentration, the crude mixture was purified by silica gel flash chromatography (eluted with hexane then 5% EtOAc/hexane) to provide 8.9 g of a clear oil: IH NMR (300 MHz, DMSO-d) 111 WO 01/44258 PCT/USOO/34487 5 6 9.17 (s, 1H), 7.04 (m, 1H), 6.60 (m, 3H), 3.73 (t, J = 6.9 Hz, 2H), 2.65 (t, J = 6.9 Hz, 2H), 0.83 (s, 9H), -0.03 (s, 6H). (c) Preparation of Ether Resin (la) To a Teflon* RV (reaction vessel) containing 0.3 g (0.96 mmol/g, 0.29 mmol) 10 of Wang resin was added a solution of 3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl] phenol (0.73 g, 2.9 mmol) and triphenylphosphine (0.38 g, 1.44 mmol) in 1.4 mL of THF. The RV was cooled to 0 "C (Julabo chiller) and then added, under an atmosphere of N 2 , 2.0 mL (1.44 mmol) of a 0.72 M solution of DEAD (diethyl azodicarboxylate) in THF. The resin mixture was warmed, while agitating, to 15 ambient temperature over 2 h and then agitated for an additional 20 h, upon which the RV was drained and the resin washed successively with THF (5x5.0 mL), DMA (5x5.0 mL), CH 2 Cl 2 (5x5.0 mL), Et 2 O (2x5.0 mL), CH 2 Cl 2 (1x5.0 mL), Et 2 O (1x5.0 mL), and CH 2 Cl 2 (2x5.0 mL). Excess solvent was removed via N 2 flow overnight to provide the ether resin la. The following analytical data was obtained upon cleavage 20 of la (3-5 mg) with 30% TFA/CH 2 Cl 2 (-5 min): 83% HPLC purity; HPLC RT (retention time, min) matches commercially available 3-hydroxyphenethyl alcohol (TBS group removed in TFA cleavage). (d) Preparation of Purine Resin (lb) 25 To the ether resin la (0.29 mmol) was added 6.6 mL (6.57 mmol) of a 1.0 M solution of TBAF (tetrabutylammonium fluoride) in THF. The resin mixture was agitated for 2 h, upon which the RV was drained and the resin washed successively with THF (5x5.0 mL), DMA (5x5.0 mL), CH 2
CI
2 (5x5.0 mL), Et 2 0 (2x5.0 mL),
CH
2 Cl 2 (1x5.0 mL), Et 2 O (1x5.0 mL), and CH 2 Cl 2 (2x5.0 mL). Excess solvent was 30 removed via N 2 flow overnight to provide the deprotected resin. A resin aliquot (3-5 mg) was cleaved with 30% TFA/CH 2 Cl 2 (~5 min) to verify resin bound compound integrity: 80% HPLC purity; HPLC RT (retention time, min) matches commercially available 3-hydroxyphenethyl alcohol. To the dried resin (0.29 mmol) was added a homogeneous suspension of 2 35 fluoro-6-chloropurine (0.50 g, 2.9 mmol) (for the preparation of 2-fluoro-6 chloropurine see: Gray, N. S.; Kwon, S.; Schultz, P. G. Tetrahedron Lett. 1997, 38, 112 WO 01/44258 PCT/USOO/34487 5 1161-1164) and triphenylphosphine (0.38 g, 1.44 mmol) in 1.75 mL of THF. The RV was cooled to 0 C (Julabo chiller) and then added, under an atmosphere of N 2 , 2.0 mL (1.44 mmol) of a 0.72 M solution of DEAD (diethyl azodicarboxylate) in THF. The resin mixture was warmed, while agitating, to ambient temperature over 1.5 h and then agitated for an additional 22 h, upon which the RV was drained and the resin 10 washed successively with THF (5x5.0 mL), DMA (5x5.0 mL), CH 2 Cl 2 (5x5.0 mL), Et 2 O (2x5.0 mL), CH 2 Cl 2 (1x5.0 mL), Et 2 0 (1x5.0 mL), and CH 2 Cl 2 (2x5.0 mL). Excess solvent was removed via N 2 flow overnight to provide the purine resin 1b. The following analytical data was obtained upon cleavage of lb (3-5 mg) with 30%
TFA/CH
2 Cl 2 (-5 min): 65% HPLC purity, -5:1 major/minor peaks (no apparent 3 15 hydroxyphenethyl alcohol HPLC peak). (e) Preparation of Purine Resin (lc) To the purine resin lb (0.29 mmol) was added a solution of [(4-Amino phenyl)-ethoxy-phosphinoylmethyl]-phosphonic acid diethyl ester (0.97 g, 2.88 20 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.44 mmol) in 3.0 mL of 1:1 n butanol/DMSO. The sealed RV was heated at 110 *C for 16 h, upon which the RV was cooled to ambient temperature, drained, and the resin washed successively with DMA (5x5.0 mL), CH 2 Cl 2 (5x5.0 mL), Et 2 O (2x5.0 mL), CH 2 Cl 2 (1x5.0 mL), Et 2 0 (1x5.0 mL), and CH 2 Cl 2 (2x5.0 mL). Excess solvent was removed via N 2 flow 25 overnight to provide the aminated purine resin 1c. The following analytical data was obtained upon cleavage of 1c (3-5 mg) with 30% TFA/CH 2 Cl 2 (-5 min): m/z 592 (M+H). (f) [(4-f2-(2-Dimethylamino-ethylamino)-9-[2-(3-hydroxy-phenyl)-ethyll 30 9H-purin-6-ylamino}-phenyl)-hydroxy-phosphinoylmethyll-phosphonic acid To the aminated purine resin le (0.29 mmol) was added a solution of N,N dimethylethylenediamine (0.25 g, 2.88 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.44 mmol) in 3.0 mL of 1:1 n-butanol/DMSO. The sealed RV was heated at 110 C for 16 h, upon which the heat was turned off, the RV drained immediately, and 35 the resin washed (while still hot) successively with DMA (5x5.0 mL), CH 2
C
2 (5x5.0 mL, at ambient temperature), Et 2 0 (2x5.0 mL), CH 2 Cl 2 (1x5.0 mL), Et 2 0 (1x5.0 113 WO 01/44258 PCT/USOO/34487 5 mL), and CH 2 C1 2 (2x5.0 mL). Excess solvent was removed via N 2 flow overnight to provide the bis-aminated purine resin. To the bis-aminated purine resin (0.29 mmol) was added 5.6 mL of 30% TFA/
CH
2 Cl 2 (2 % triisopropyl silane). The resin mixture was agitated for 1 h, upon which the filtrate was collected and the resin washed with CH 2 Cl 2 (3x5.0 mL). The 10 combined filtrates were concentrated (Savant speed-vac), added 3-4 mL CH 2 Cl 2 , then reconcentrated to provide a dark yellow oil. The oil was dissolved in 6.6 mL of CH 3 CN, cooled to 0 *C, then added 1.0 mL (7.2 mmol) of TMSI (iodotrimethylsilane). The resulting yellow solution (some precipitate) was stored at -20 C for 2 h (periodic swirling), then 0 *C for 1 h, upon 15 which 0.4 mL (2.81 mmol) of TMSI was added and reaction continued at 0 "C for 3 h. The excess TMSI was quenched at 0 "C with -4 mL of 20% aqueous NaHSO 3 , the pH adjusted to 11-12 with 10% NaOH, and the CH 3 CN removed by rotary evaporation. The pH was re-adjusted to 10-11 with TFA, upon which the solution was filtered (0.2 pm, PTFE filter) and purified by RP-HPLC (CH 3
CN/H
2 0). Lyophilization provided 20 a white solid isolated as its TFA salt (0.035 g): IH NMR (300 MHz, DMSO-d 6 ) 6 9.76 (s, 1H), 9.33 (br s, 1H), 8.07-7.65 (in, 5H), 7.08-6.59 (in, 5H), 4.27 (in, 2H), 3.66 (in, 2H), 3.32 (in, 2H), 3.04 (in, 2H), 2.85 (s, 6H), 2.37 (in, 2H); m/z 576 (M+H). Example 23 25 [(4-{2-(trans-4-Amino-cyclohexylamino)-9-r2-(3-hydroxy-phenyl)-ethyll-9H-purin 6-ylamino}-phenyl)-hydroxy-phosphinoylmethyll-phosphonic acid 0 0 H '- OH HN . O O
H
2 Nj N H H The title compound was synthesized in a manner similar to that described for Example 22. The white solid was isolated as a TFA salt: m/z 602 (M+H) 30 Example 24 114 WO 01/44258 PCT/USOO/34487 5 [Hydroxy-(4- {9-[2-(3-hydroxy-phenyl)-ethyll-2-[2-(3H -imidazol-4-yl)-ethylaminol 9H -purin-6-ylamino -phenyl)-phosphinoylmethyll -phosphonic acid 0 0 H N H N H H H The title compound was synthesized in a manner similar to that described for Example 22. The white solid was isolated as a TFA salt: m/z 599 (M+H) 10 Example 25 [Hydroxy-(4-{2-(2-hydroxy-ethylamino)-9-[2-(3-hydroxy-phenyl)-ethyll-9H -purin 6-ylaminol-phenyl)-phosphinoylmethyll-phosphonic acid 0 0 H0 N H H 15 The title compound was synthesized in a manner similar to that described for Example 22. The product was isolated as a white solid: m/z 549 (M+H) Example 26 (5-{2-(trans-4-Amino-cyclohexylamino)-9-r2-(3-hydroxy-phenyl)-ethyll-9H -purin 20 6-ylamino}-2-phosphono-phenyl)-phosphonic acid H O,9 H P.' HN", H2 N,,Q; H H2N OH 115 WO 01/44258 PCT/USOO/34487 5 The title compound was synthesized in a manner similar to that described for Example 22. The white solid was isolated as a TFA salt: m/z 604 (M+H) Example 27 (5-{9-[2-(3-Hydroxy-phenyl)-ethyll-2-[2-(3H -imidazol-4-yl)-ethylaminol-9H -purin 10 6-ylamino}-2-phosphono-phenyl)-phosphonic acid HO 11,O '0 01 H OH HN ~IO N NLJ H H OH The title compound was synthesized in a manner similar to that described for Example 22. The white solid was isolated as a TFA salt: m/z 601 (M+H) 15 Example 28 (5-{2-(2-Dimethylamino-ethylamino)-9-[2-(3-hydroxy-phenyl)-ethyll-9H -purin-6 ylamino I -2-phosphono-phenyl)-phosphonic acid HO O H aH H OH The title compound was synthesized in a manner similar to that described for 20 Example 22. The product was obtained as a white solid: m/z 578 (M+H) Example 29 [Hydroxy-(3-19-[2-(4-hydroxy-phenyl)-ethyll-6-phenylamino-9H -purin-2-ylamino} propyl)-phosphinoylmethyll-phosphonic acid 116 WO 01/44258 PCT/USOO/34487 H 0 0 N H O H OH 5 OH OH The title compound was synthesized in a manner similar to that described for Example 22. The product was obtained as a white solid: m/z 547 (M+H) Example 30 10 [Hydroxy-(3-{9-[2-(3-hydroxy-phenyl)-ethyll-6-phenylamino-9H -purin-2-ylamino} propyl)-phosphinoylmethyll-phosphonic acid HN"O N/N 0 0 6H 6H H H The title compound was synthesized in a manner similar to that described for Example 22. The product was obtained as a white solid: m/z 547 (M+H) 15 Example 31 (Hydroxy-{3-[9-(3-hydroxy-benzyl)-6-phenylamino-9H-purin-2-ylaminol-propyl} phosphinoylmethyl)-phosphonic acid HN'0 OO H OH OH H H 20 The title compound was synthesized in a manner similar to that described for Example 22. The product was obtained as a white solid: m/z 533 (M+H) Example 32 117 WO 01/44258 PCT/USOO/34487 5 ({3-[6-(3-Chloro-phenylamino)-9-(3-hydroxy-benzyl)-9H -purin-2-ylaminol-propyl} hydroxy-phosphinoylmethyl)-phosphonic acid HN )KCI HO 0 N 6 H 6 H H OH The title compound was synthesized in a manner similar to that described for Example 22. The product was obtained as a white solid: m/z 567 (M+H) 10 Example 33 [(3-{6-(3-Chloro-phenylamino)-9-[2-(4-hydroxy-phenyl)-ethyll-9H -purin-2 ylamino}-propyl)-hydroxy-phosphinoylmethyll-phosphonic acid H I H OH OH 15 The title compound was synthesized in a manner similar to that described for Example 22. The product was obtained as a white solid: m/z 581 (M+H) Example 34 [(3- 6-(3-Chloro-phenylamino)-9-r2-(3-hydroxy-phenyl)-ethyll-9H -purin-2 20 ylamino}-propyl)-hydroxy-phosphinoylmethyll-phosphonic acid NN H OH OH The title compound was synthesized in a manner similar to that described for Example 22. The product was obtained as a white solid: m/z 581 (M+H) 118 WO 01/44258 PCT/USOO/34487 5 Example 35 The above techniques can also be applied to typical, solution-phase combinatorial synthesis. As described below, a library of compound were rapidly prepared by coupling bone-targeting moieties with payload fragments. 10 Synthesis of bone-targeting analogs of 4-amino-5-(3-methoxyphenyl)-7-(4-carboxy phenyl)pyrrolo[2,3-dl-pyrimidine These analogs 21 A-2 1 D were synthesized according to Scheme 6 starting from the 4-amino-5-(3-methoxyphenyl)-7-(4-carboxyphenyl)pyrrolo[2,3-d] 15 pyrimidine. 119 WO 01/44258 PCT/USOO/34487 5 Scheme 6
NH
2 O HN NH 2 O NH 2 NN TMSI, CH 3 CN, N N I N HATU, DMF, DIEA, N N 0 0 C, 4h N N rt, 2 days METHOD D METHOD OH N NH 0 qOH 0O 19 20 21 20A H2N PO 3 Et 2 0 = 21 A H2N P03H 2 Et 2 0 3 P
H
2 0P = 20 B H 2 N PO3Et2= 21 B H2N P03Et2P0 3
H
2
PO
3 Et 2 2 = 20C H 2 N P Et2= 21 C H 2 N N P0 3
H
2 ~POEt 2 __ PO 3 0t 2 P0 3
H
2 0 O21 D OH HN -O= 21D H2N P -OH =200 2 0N\' OH 6 Method C: 10 Carboxylic acid (0.25 mmol) 19/22 was taken up in DMF (5 mL) and cooled in ice. HATU (0.5 mmol) was then added followed by the bone-targeting amines A-D and ethyl diisopropyl amine (0.5 mmol). The reaction mixture was stirred at ambient temp. for 2 days. DMF was removed in vacuo and the residue was taken up in ethyl acetate. Ethyl acetate layer was washed with sodium bicarbonate (10%) followed by 15 10% citric acid and then water. Organic extract was dried over sodium sulphate and concentrated and purified by chromatography using methylene chloride/methanol (5 10%). 120 WO 01/44258 PCT/USOO/34487
NH
2 0 P 5 0 H 20A 4-amino-5-(3-methoxyphenyl)-7-{4-rN-(4-bisdiethylphosphonomethyl)phenyll carboxamido)}pyrrolor2,3-dl-pyrimidine 20A: Prepared from 19 as a pale yellow gum. MS: 720 (M-H), 744 (M+23). 10 af-9N O\. ~o-0 20B 4-amino-5-(3-methoxyphenyl)-7-{4-[FN-(3,.4-bisdiethylphosphono phenyl) methyl carboxamido)}pyrrolo[2,3-d1-pyrimidine 20B: 15 Prepared from 19 as a pale yellow gum. MS: 720 (M-H).
NH
2 o N 0 -/ 20C 4-amino-5-(3-methoxyphenyl)-7-{4-[N-(2-(3,4-bisdiethylphosphonophenyl)ethl)1 20 carboxamido)}pyrrolo[r2,3-d-pyrimidine 20C: Prepared from 19 as a pale yellow gum. MS: 734 (M-H), 768(M+23) 121 WO 01/44258 PCT/USOO/34487 0 NH 2 N N NN 5 H 8 0 20D 4-amino-5-(3-methoxyphenyl)-7-{4-[N-3-triethyl bisphosphono methylenepropyllphenyl carboxamido)}pyrrolor2,3-dl-pyrimidine 20D Prepared from 19 as a pale yellow gum. MS: 642 (M-H). 10 Method D: To a cooled (-20 *C) solution of the phosphonate esters 20A-D (0.2 mmol) in acetonitrile (5 mL) was added TMSI (2 mmol) and stirred at 0 *C for 4.5h after which time it was quenched with sodium bicarbonate solution followed by a 10% solution of 15 sodium bisulphite until the color of iodine is dissipated. The aqueous layer was washed with ethyl acetate and purified by Preparative HPLC. /\ O\
NH
2 N N HOOH O H 21A 20 4-amino-5-(3-methoxyphenyl)-7-{4-[N-(4-bisphosphono methyl)phenyll carboxamido)}pyrrolof2,3-dl-pyrimidine 21A: Prepared from 20A using Method D as a white solid. MS: 608 (M-H), 610 (M+H). 122 WO 01/44258 PCT/USOO/34487 /\ 0 NH2 N - \ N -OH 5 0 21B 4-amino-5-(3-methoxyphenyl)-7-{4-[N-(3,4-bisphosphono phenyl) methyl carboxamido)}pyrrolo[2,3-d1-pyrimidine 21 B: Prepared from 20B using Method D as a white solid. MS: 608 (M-H), 610 10 (M+H).
NH
2 O N 0 / PZOH P. OH N "'H 0H O 21C 4-amino-5-(3-methoxyphenyl)-7-{4-[N-(2-(3,4-bisphosphono phenyl)ethyl)1 15 carboxamido)}pyrrolo[2,3-dl-pyrimidine 21C: Prepared from 20C using Method D as a white solid. MS: 622 (M-H), 646 (M+23). /\ 0
NH
2 N OH OH 20 21D 4-amino-5-(3 -methoxyphenyl)-7- {4- [N-3 -bisphosphonomethylene propyllphenyl carboxamido)}pyrrolo[2,3-dl-pyrimidine 21D: 123 WO 01/44258 PCT/USOO/34487 5 Prepared from 20D using Method D as a white solid. MS: 558 (M-H). Synthesis of bone-targeting analogs of 4-amino-5-(3-methoxyphenyl)-7-(3 carboxyphenyl)pyrrolo[2,3-dl-pyrimidine These analogs 24A-24D were synthesized according to Scheme 7 starting 10 from the 4-amino-5-(3-methoxyphenyl)-7-(3-carboxyphenyl)pyrrolo[2,3-d] pyrimidine. Scheme 7 0/ 0
NH
2
NH
2
NH
2
H
2 N N TMSI, CH 3 CN, N N HATU, DMF, DIEA, N 0 0 C, 4h N rt, 2 days / HN METHODD / \ HN \ OH METHOD 6 -- e 0 0 O 22 23 24
H
2 N , 23A H2N PO 3 Et 2 = 24A PO3H2 Et20 3 P H 2
O
3 P = 3B H 2 j~ PO 3 Et 2 = 24B8 2 O H
PO
3
H
2 =23B H2N POE2 4 HN 03H2
PO
3 Et 2 = 24C H 2 N PO 3
H
2 23C H 2 N PO 3 Et 2
PO
3
H
2
PO
3 Et 2 0 / =24D H2N 9 -OH = 23D H 2 N P -O_ OH O O O 15 -- = NH 0 23A 124 WO 01/44258 PCT/USOO/34487 5 4-amino-5-(3-methoxyphenyl)-7-{3-[N-(4-bisdiethylphosphonomethyl)phenyll carboxamido)}pyrrolo[2,3-dl-pyrimidine 23A: Prepared from 22 as a pale yellow gum using Method C. MS: 720 (M-H), 744 (M+23). O \
NH
2 II' 100 10 0 23B 4-amino-5-(3-methoxyphenyl)-7-{3-[N-(3,4-bisdiethylphosphono phenyl) methyl] carboxamido)}pyrrolor2,3-dl-pyrimidine 23B: Prepared from 22 as a pale yellow gum using Method C. MS: 720 (M-H). 15 O\
NH
2 N N N oo 23C 4-amino-5-(3-methoxyphenyl)-7-13-[N-(2-(3,4-bisdiethylphosphonophenyl) ethyl)] carboxamido)}pyrrolor2,3-dl-pyrimidine 23C: 20 Prepared from 22 as a pale yellow gum using Method C. MS: 734 (M-H), 768 (M+23). / \
NH
2 KN N 00 23D 125 WO 01/44258 PCT/USOO/34487 5 4-amino-5-(3-methoxyphenyl)-7-{4-[N-3-triethyl bisphosphono methylenepropyllphenyl carboxamido)}pyrrolo[2,3-dl-pyrimidine 23D Prepared from 22 as a pale yellow gum. MS: 642 (M-H).
NH
2 N NN N HO b N_ HO..' HOF HO 10 24A 4-amino-5-(3-methoxyphenyl)-7-{3-rN-(4-bisphosphono methyl)phenyll carboxamido)}pyrrolo[2,3-dl-pyrimidine 24A: Prepared from 23A using Method D as a white solid. MS 608 (M-H), 610 (M+H). 15
NH
2 O -OH H 24B 4-amino-5-(3-methoxyphenyl)-7-{3-[N-(3,4-bisphosphono phenyl)methyll carboxamido)}pyrrolor2,3-dl-pyrimidine 24B: 20 Prepared from 23B using Method D as a white solid. MS 608 (M-H), 610 (M+H). / o0
NH
2 N 0 P-OH 1( 'OH - 0O 24C 126 WO 01/44258 PCT/USOO/34487 5 4-amino-5-(3-methoxyphenyl)-7-{3-[N-(2-(3,4-bisphosphono phenyl)ethyl)J carboxamido)}pyrrolo[2,3-di-pyrimidine 24C: Prepared from 23C using Method D as a white solid. MS: 622 (M-H), 646 (M+23). / \0o
NH
2 N \OH OH ~P-OH N HNJ'O 0 10 24D 4-amino-5-(3-methoxyphenyl)-7-{ 3-[N-3-bisphosphonomethylene propyllphenyl}carboxamido)}Ipyrrolo[2,3-d1-pyrimidine 24D: Prepared from 23D using Method D as a white solid. MS: 558 (M-H). 15 BONE-TARGETED PURINE SERIES [Rb] [RclNN H [Ra] 20 Example Ra Rb Re Src Kinase Anti # Inhibition Resorption IC50 (pM) Cell Assay % Inhib (pLM) 22 9 9 1 75@20 HO', OH N OH 30 Ph 0.055 100 @ 20 OH O OH 313-CPh 0.12 50-70@4 HOH0 OH 127 WO 01/44258 PCT/USOO/34487 5 BONE-TARGETED AMINOPYRIDOPYRIMIDINONES SERIES HNANXXO [ReJ 10 Example # Rd Re Src Kinase Anti Inhibition Resorption IC50 (fpM) Cell Assay % Inhib (pLM) i-A c HO H 0.002 50 @ 4 i-B H H 0.008 75-90 @ 20 i-c 0.12 100@20 HOPP2PH 128 WO 01/44258 PCT/US00/34487 5 BONE-TARGETED PYRROLOPYRIMIDINE SERIES
NH
2 Rf] N N 9 [Rg] 10 Example # Rf Rg Src Kinase Anti Inhibition Resorption IC50 (piM) Cell Assay % Inhib 14 0.004 25-50 @ 4 OH OH 21B 0.87 50 @ 4 O PO3H2 C__ _P0 3
H
2 21D 0.13 0 N '1,OH HOH OH BONE-TARGETED PYRRAZOLOPYRIMIDINE SERIES 15 NH [RO N N [Ri] Example # Rh Ri Src Kinase Anti Inhibition Resorption IC50 (pM) Cell Assay % Inhib (IM) 13 OH 29 50 @ 3 OHOH 20 129 QI ICTITI IT= QU-T IDI II l'\ WO 01/44258 PCT/USOO/34487 5 Assays 1. Anti-Resorption Cell Assay (Rabbit Osteoclast): Femurs, tibias, and scapulas were isolated from 3-4 day old New Zealand 10 white rabbits (Millbrook Farms, Amherst, MA). Bones were chopped and minced in a-MEM (Gibco-BRL) containing 0.55 g/L NaHC0 3 , 10 mM HEPES (Gibco-BRL), 50 units/ml penicillin, and 0.05 mg/ml streptomycin, pH 7.1. Bone fragments were allowed to settle by gravitation, supernatant was collected and centrifuged at 400 RPM (Beckman GS-6KR) for two minutes, and the cell pellet was resuspended in the 15 same medium supplemented with 10% HIFBS (Hyclone). For prebinding experiments, 0.75 ml of cell suspension was added to wells containing sperm whale dentine discs preincubated for 2 hours with 0.75 ml culture medium containing a 2X concentration of test compound. Alternatively, 0.75 ml of cell suspension was added to each well containing dentine slices preincubated with 0.75 ml culture medium 20 alone and test compound was added after the adhesion phase. Sperm whale dentine was cut as 1 mm x 6 mm circular discs. The adhesion phase was carried out for 30 minutes at 37 'C and 5% CO 2 and then the medium and non-adherent cells and debris were removed by aspiration. Fresh culture medium containing serially diluted test compounds was added and cells were incubated on dentine for 24 hours at 37 *C and 25 5% CO 2 . After the resorption phase, dentine slices were soaked for 30 seconds in 0.5% sodium hypochlorite, wiped clean of adherent cells, and then stained for 30-45 seconds with 1% toluidine blue. Resorption was measured using reflective light microscopy and automated image analysis. The resorbed area was measured on the entire 6 mm disc. Remaining cells in the 24-well plates were stained for tartrate 30 resistant acid phosphatase (TRAP) and also assessed visually for the presence of fibroblasts. Experiments were carried out containing triplicate samples for each concentration of compound tested with five untreated control samples per plate. IC 50 values were calculated based on the % resorption in the presence of compound relative to vehicle alone treated control samples. Data were calculated from at least 35 three independent experiments each containing triplicate samples. 2. Src Kinase Inhibition Assay: 130 WO 01/44258 PCT/USOO/34487 5 Compounds were tested for their ability to inhibit Src kinase using the scintillation proximity assay (SPA) technology as developed by Amersham. Reagents include: Streptavidin SPA beads from Amersham, 2-[N-morpholino]ethanesulfonic acid from Sigma, ATP from Boerhinger Mannheim, [ 33 P]ATP : from NEN (NEG 602H), the substrate - biotinylated peptide substrate I (PKS 1) (cdc2 peptide) from 10 Pierce which is prepared at 12.5 ptM (5X solution) in kinase buffer, and the enzyme, human recombinant c-Src at 135 ptg/ml (stock solution) which is diluted 1/40 in kinase buffer (3.38 ig/ml) before use. Buffers include: (a) Kinase buffer which contains MES 30 mM pH 6.8, MgCl 2 10 mM, Orthovanadate 0.25 mM, PMSF 0.1 mM, and DTT 1mM; (b) ATP buffer which contains ATP 5 mM in MgCl 2 50 mM 15 buffer (stock solution). Note that before each use dilute in MES to 100 pLM (5X solution) add 100 iiCi/mL [ 33 P]ATP; and (c) PBS Stop buffer which contains ATP 0.1 mM, EDTA 40 mM, Triton 0.1%. Streptavidin beads are suspended at 3.3 mg/mi in stop buffer and mixed by shaking. The Kinase reaction proceeds by stepwise addition to wells on the 96 well-plate of the following: (a) 10 pL kinase buffer + 10% DMSO 20 or compound to be tested at different concentration in MES + 10 % DMSO, (b) 10 PL kinase buffer, (c) 10 pL substrate 12.5 pLM, (d) 10 ptL enzyme 3.38 pg/ml, and (e) 10 ptL ATP 100 pM containing 0.2 pCi [ 33 P]ATP. Incubation for 2 hours at 30 degrees C is followed by addition of 150 pL Stop buffer containing 500 pig streptavidin beads. Incubation proceeds for 30 min at room temperature, followed by centrifugation for 5 25 min at 2000 rpm, and reading on a Wallac Microbeta Scintillation counter. 3. Hydroxyapatite Assay: Hydroxyapatite is the principal mineral component of bone. Hydroxyapatite adsorption chromatography is used as an assay to evaluate the bone-targeting 30 potential of both individual bone-targeting moieties ("monomers") and of pharmaceuticals incorporating bone-targeting groups. Method: The rentention time of a test compound is measured using a linear gradient from 10 mM sodium phosphate, 0.15 N NaCl, pH = 6.8 to 500 mM sodium phosphate, 0.15 N NaCl, pH = -6.8 on a TSK-Gel HA 1000 high pressure liquid 35 chromatography column (7.5 mm x 75 mm). The rentention time of the compound is expressed in terms of K = (retention time-void time)/void. This K value is corrected 131 WO 01/44258 PCT/USOO/34487 5 using two reference compounds to correct from inter-column and inter-system variation to obtain a K' value. Reference Compounds: K' values were determined for known bone targeted compounds, the bisphosphonate, alendronate and tetracycline. Alendronate gave a K' value of 3.7 and tetracycline gave a K' value of 2.0. 10 Example 36 As described previously, the compounds of the present invention may be. provided as pro-drugs. To give but one example, bone targeting moieities of the following formula: 0 PO(ORz) 2 II_-/ 15 ORz may be protected using the following Rz groups: 0O Atack, J. R. et al. J. of Pharmacology and Experimental Therapeutics 1994, 270, 70. 0 O Arimilli, M. N., et al. Antiviral Chemistry & Chemotherapy 1997, 8, 557. R Serafinowska, H. T., et el. J. Med. Chem. 1995, 35,1372. 0 Ahimark, M., J. Med. Chem. 1999, 42, 1473. R 20 Alternatively, the bone targeting moiety may be provided as a pro-drug with the formula: 0 O 6H O Meier, C., et al. J. Med. Chem. 1998, 41, 1417. OH 132 WO 01/44258 PCT/USOO/34487 5 For a review of pro-drugs such as these, please see Krise, J. P., Stella, V. J. Advanced Drug Delivery Reviews 1996, 19:287; incorporated herein by reference. 133

Claims (111)

1. A compound having the general formula (I): 10 Hc-X-K-Cy-L-Z-Tb (I) wherein L and K, independently, are absent or represent -M,-Y-Mp-; 15 X, Y, and Z, independently, are absent or represent NR, 0, or S; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene or ethyne; R represents, independently for each occurrence, H or substituted or 20 unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently, represent integers from 0-10; Cy represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a heterocycle; 25 Tb represents a bone-targeting group selected from: 0 O OR 4 OR 4 R4 OR 4 OR 4 0 OR 4 11 11 Pi N IOR 4 R 4 0 I N IOR 4 R 4 OXI I-OR 4 4 OR 4 OR 4 OR 4 OR 4 OR 4 iv v 0 0 0 0 Vi R40 OR 4 4 OXI O R OR 4 0 0 OR 4 O O OR4 OR 4 OR 4 Vii ... Villx 134 WO 01/44258 PCT/USOO/34487 PO3(R4)2 xPO3(R4)2 P0 3 (R 4 ) 2 P0 3 (R 4 ) 2 C0 2 R 4 R 4 0 2 C 0 xii Uf" C0 2 R 4 R 4 0 2 C N C0 2 R 4 R 4 0 2 C N P0 3 (R 4 ) 2 O N P0 3 (R 4 ) 2 5 xiii xiv xv and R 4 , independently for each occurrence, represents H or lower alkyl, wherein Hc-X-K-Cy-L is free of hydrolyzable linkages.
2. A compound having the general formula (1I): Hc-X-K-Z-Tb, wherein 10 K is absent or represents -Mn-Y-Mp-; X, Y, and Z, independently, are absent or represent NR, 0, or S; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethylene or ethyne; 15 p and n, independently, represent integers from 0-10. R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl. Hc represents a heterocycle; Tb represents a bone-targeting group selected from: 135 WO 01/44258 PCT/USOO/34487 0 O OR 4 OR 4 IOR4 OR 4 OR 4 0 OR 4 O O I I , N OR 4 R 4 0 N OR 4 R 4 0 KOR 4 OR 4 OR 4 OR 4 OR 4 OR 4 OR 4 iv v 0 Vi R 4 0 IKOR 4 R 4 0 OR 4 O -OR OR 4 OR 4 OR 4 OR 4 5i viii ix 5 " PO3(R4)2 PO3(R4)2 P3R) x xi P03(R4)2 P0 3 (R 4 ) 2 C0 2 R 4 R 4 0 2 C 0 Xii C0 2 R 4 R 4 0 2 C N C0 2 R 4 R 4 0 2 C N P0 3 (R 4 ) 2 0 N xiii xiv xv and R 4 , independently for each occurrence, represents H or lower alkyl, wherein Hc-X-K is free of hydrolyzable linkages. 10
3. The compound of claim 1 or 2, wherein the compound selectively targets osteoclasts.
4. The compound of claim 1 or 2, wherein R 4 represents H for all occurrences. 15
5. The compound of claim 1, wherein Cy represents an uncharged carbocycle or nitrogen-bearing heterocycle. 136 WO 01/44258 PCT/USOO/34487 5
6. The compound of claim 1, wherein Cy represents a phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system having between 8 and 11 atoms.
7. The compound of claim 1, wherein Cy represents phenyl. 10
8. The compound of claim 1, wherein Cy represents a bicyclic ring system, whereof L is attached to a first ring and K is attached to a second ring.
9. The compound of claim 1 or 2, wherein Hc represents a bicyclic structure. 15
10. The compound of claim 9, wherein the two rings of the bicyclic structure consist of carbon and nitrogen atoms.
11. The compound of claim 1 or 2, wherein K is directly attached to a heteroatom 20 of Hc.
12. The compound of claim 1 or 2, wherein Hc is selected from: R2 R2 R1 N N--N N R, R, N N N N NHR 3 N NHR 3 R 2 HN N NHR 3 xvi xvii xviii N N 3 N N N W 3 N N N NHR 2 H H xix R2 XX wherein one of RI, R 2 , and R 3 represents a bond to K, the others represent, 25 independently, hydrogen, halogen, alkyl, aralkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, cycloalkyl, polycyclyl, alkyl alkenyl, alkyl alkynyl, or alkanoyl, or taken 137 WO 01/44258 PCT/USOO/34487 5 together with the nitrogen to which it is attached, represent amidine, amide, carbamate, urea, or guanidine; and W represents 0 or S.
13. The compound of claim 1, wherein Tb is represented by i and Z is absent. 10
14. The compound of claim 13, wherein L is absent.
15. The compound of claim 1 or 2, wherein Tb is selected from xi, xii, xiv, and xv. 15
16. The compound of claim 1 or 2, wherein Tb is selected from v, vii, and viii.
17. The compound of claim 1 or 2, wherein Tb is selected from ii, iii, or iv. 20
18. The compound of claim 1 or 2, wherein Tb is represented by x.
19. The compound of claim 1 or 2, wherein Tb is represented by ix.
20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier 25 and a compound having the general formula (I): Hc-X-K-Cy-L-Z-Tb, wherein L and K, independently, are absent or represent -Mn-Y-Mp-; X, Y, and Z, independently, are absent or represent NR, 0, or S; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or 30 unsubstituted ethene or ethyne; R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently, represent integers from 0-10; Cy represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or 35 cycloalkyl; Hc represents a heterocycle; 138 WO 01/44258 PCT/USOO/34487 5 Tb represents a bone-targeting group selected from: 0o 0 O I O" OR O OR OR 4 ' OR 4 OR4 OR 4 0 OR 4 Sil i ii i N OR 4 R OR 4 R 4 0 OR 4 lv V R _ N "OORR 4 4 W' OR 4 OR OR4 OR O O O R 4 O IOR 4 OR 4 OR 4 11 -OR, R - y 139 WO 01/44258 PCT/USOO/34487 P0 3 (R 4 ) 2 P0 3 (R4) 2 P0 3 (R 4 ) 2 P0 3 (R 4 ) 2 C0 2 R 4 R 4 0 2 C 0 Xii C0 2 R 4 R 4 0 2 C N C0 2 R 4 R 4 0 2 C N P0 3 (R 4 ) 2 0 N PO 3 (R 4 ) 2 Xiii XIV XV 5 P03(R4)2 PO 3 (R 4 ) 2 P0 3 (R 4 ) 2 P0 3 (R 4 ) 2 C0 2 R 4 R 4 0 2 C 0 xii C0 2 R 4 R 4 0 2 C N C0 2 R 4 R 4 0 2 C N P0 3 (R 4 ) 2 0 N PO 3 (R4 2 Xiii Xiv XV and R 4 , independently for each occurrence, represents H or lower alkyl, wherein Hc-X-K is free of hydrolyzable linkages. 10
21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the general formula (II): Hc-X-K-Z-Tb, wherein K is absent or represents -Mn-Y-Mp-; X, Y, and Z, independently, are absent or represent NR, 0, or S; M represents, independently for each occurrence, a substituted or 15 unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethylene or ethyne; p and n, independently, represent integers from 0-10. 140 WO 01/44258 PCT/USOO/34487 5 R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl. Hc represents a heterocycle; Tb represents a bone-targeting group selected from: 0 O \ R4 OR 4 V_ I 4 \-J OR 4 OR 4 0 OR 4 V O OI O OR O O N OR 4 R 4 0 N I OR 4 R 4 0 I"'OR 4 OR 4 OR 4 OR 4 OR 4 OR 4 OR 4 iv V 0 0 0 0 Vi 11 11 110 O R40 OR 4 R 4 0O' OR 4 OR 4 0 OR 4 O OR 4 OR 4 OR 4 Vii Viii ix P0 3 (R 4 ) 2 PO3(R4)2 PO3(R4)2 x X PO 3 (R 4 ) 2 CO 2 R 4 R 4 02C 0 xii CO 2 R 4 R402C N CO 2 R 4 R 4 0 2 C N P0 3 (R 4 ) 2 O N PO3(R 4 ) 2 xiii xiv xv 10 and R 4 , independently for each occurrence, represents H or lower alkyl, wherein Hc-X-K-Cy-L is free of hydrolyzable linkages.
22. The pharmaceutical composition of claim 20 or 21, wherein the compound selectively targets osteoclasts. 15
23. The pharmaceutical composition of claim 20 or 21, wherein R 1 4 represents H for all occurrences. 141 WO 01/44258 PCT/USOO/34487 5'
24. The pharmaceutical composition of claim 20, wherein Cy represents an uncharged carbocycle or nitrogen-bearing heterocycle.
25. The pharmaceutical composition of claim 20, wherein Cy represents a phenyl, 10 pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system having between 8 and 11 atoms.
26. The pharmaceutical composition of claim 20, wherein Cy represents phenyl. 15
27. The pharmaceutical composition of claim 20, wherein Cy represents a bicyclic ring system, whereof L is attached to a first ring and K is attached to a second ring.
28. The pharmaceutical composition of claim 20 or 21, wherein Hc represents a bicyclic structure. 20
29. The pharmaceutical composition of claim 20 or 21, wherein the two rings of the bicyclic structure consist of carbon and nitrogen atoms.
30. The pharmaceutical composition of claim 20 or 21, wherein K is directly 25 attached to a heteroatom of Hc.
31. The pharmaceutical composition of claim 20 or 21, wherein Hc is selected from: 142 WO 01/44258 PCT/USOO/34487 R2 -R2 R1 N N NN R, R, N N N N NHR 3 N NHR 3 R 2 HN N NHR 3 xvi xvii xviii N N N W 3 N N N NHR 2 H I H 5 xix R2 XX wherein one of R 1 , R 2 , and R 3 represents a bond to K, the others represent, independently, hydrogen, halogen, alkyl, aralkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, cycloalkyl, polycyclyl, alkyl alkenyl, alkyl alkynyl, or alkanoyl, or taken together with the nitrogen to which it is attached, represent amidine, amide, 10 carbamate, urea, or guanidine; and W represents 0 or S.
32. The compound of claim 20, wherein Tb is represented by i and Z is absent. 15
33. The compound of claim 32, wherein L is absent.
34. The pharmaceutical composition of claim 20 or 21, wherein Tb is selected from xi, xii, xiv, and xv. 20
35. The pharmaceutical composition of claim 20 or 21, wherein Tb is selected from v, vii, and viii.
36. The pharmaceutical composition of claim 20 or 21, wherein Tb is selected from ii, iii, or iv. 25 143 WO 01/44258 PCT/USOO/34487 5
37. The pharmaceutical composition of claim 20 or 21, wherein Tb is represented by x.
38. The pharmaceutical composition of claim 20 or 21, wherein Tb is represented by ix. 10
39. A method for the treatment or prevention of a bone disorder comprising treating a patient with a compound having the general formula (I): Hc-X-K-Cy-L-Z Tb, wherein L and K, independently, are absent or represent -M,-Y-Mp-; 15 X, Y, and Z, independently, are absent or represent NR, 0, or S; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene or ethyne; R represents, independently for each occurrence, H or substituted or 20 unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently, represent integers from 0-10; Cy represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a heterocycle; 25 Tb represents a bone-targeting group selected from: O O \-> j"--oR 4 \-P KH-OR, R OR 4 OR 4 OR4 o OR4 OR4 O OR4 \-i__N 'OR 4 R 4 0 N OR 4 R 4 0 OR 4 OR 4 OR 4 OR 4 I OR 4 OR 4 OR 4 iv V y vi RO IOR RO OR PO O OR 4 0 OR 4 O OOR4 OR 4 OR 4 vii ... Vill 144 WO 01/44258 PCT/USOO/34487 P0 3 (R 4 ) 2 P0 3 (R4) 2 P0 3 (R 4 ) 2 x X P0 3 (R 4 ) 2 C0 2 R 4 R 4 0 2 C 0 xii C02R4 R 4 0 2 C N C0 2 R 4 R 4 0 2 C N P0 3 (R 4 ) 2 0 N P0 3 (R 4 ) 2 Xiii Xiv Xv 5 and R 4 , independently for each occurrence, represents H or lower alkyl.
40. A method for the treatment or prevention of a bone disorder comprising treating a patient with a compound having the general formula (I1): Hc-X-K-Z-Tb, wherein 10 K is absent or represents -Mn-Y-Mp-; X, Y, and Z, independently, are absent or represent NR, 0, or S; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethylene or ethyne; 15 p and n, independently, represent integers from 0-10. R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl. Hc represents a heterocycle; Tb represents a bone-targeting group selected from: 20 and R 4 , independently for each occurrence, represents H or lower alkyl.
41. The method of claim 39 or 40, wherein the compound selectively targets osteoclasts. 25
42. The method of claim 39 or 40, wherein R 4 represents H for all occurrences. 145 WO 01/44258 PCT/USOO/34487 5
43. The method of claim 39, wherein Cy represents an uncharged carbocycle or nitrogen-bearing heterocycle.
44. The method of claim 39, wherein Cy represents a phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system having between 8 and 11 atoms. 10
45. The method of claim 39, wherein Cy represents phenyl.
46. The method of claim 39, wherein Cy represents a bicyclic ring system, whereof L is attached to a first ring and K is attached to a second ring. 15
47. The method of claim 39 or 40, wherein Hc represents a bicyclic structure.
48. The method of claim 39 or 40, wherein the two rings of the bicyclic structure consist of carbon and nitrogen atoms. 20
49. The method of claim 39 or 40, wherein K is directly attached to a heteroatom of Hc.
50. The method of claim 39 or 40, wherein Hc is selected from: R2 R2 R, \ \ -\N R R 1 N N N N NHR 3 N NHR 3 R 2 HN N NHR 3 xvi xvii xviii RR3 N N N W N N N NHR 2 H H 25 xix R 2 XX 146 WO 01/44258 PCT/USOO/34487 5 wherein one of RI, R 2 , and R 3 represents a bond to K, the others represent, independently, hydrogen, halogen, alkyl, aralkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, cycloalkyl, polycyclyl, alkyl alkenyl, alkyl alkynyl, or alkanoyl, or taken together with the nitrogen to which it is attached, represent amidine, amide, carbamate, urea, or guanidine; and 10 W represents 0 or S.
51. The method of claim 39, wherein Tb is represented by i and Z is absent.
52. The method of claim 51, wherein L is absent. 15
53. The method of claim 39 or 40, wherein Tb is selected from xi, xii, xiv, and xv.
54. The method of claim 39 or 40, wherein Tb is selected from v, vii, and viii. 20
55. The method of claim 39 or 40, wherein Tb is selected from ii, iii, or iv.
56. The method of claim 39 or 40, wherein Tb is represented by x.
57. The method of claim 39 or 40, wherein Tb is represented by ix. 25
58. A compound having the structure: Tb-L-V, wherein L is absent or represents -Mn-Y-Mp-; Y is absent; M represents, independently for each occurrence, a substituted or 30 unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene; R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; 147 WO 01/44258 PCT/USOO/34487 5 p and n, independently, represent integers from 0-10; Tb represents a bone-targeting group selected from: OR 4 OR 4 OR 4 OR 4 0 OR 4 OR 4 OR 4 OR 4 R 4 0 OR 4 OR 4 OR 4 OR 4 OR 4 v v 0 00 0 0vi R 4 0 'II OR 4 R 4 0-' OR 4 1!P OR 4 0O OR 4 O 0 1OR 4 OR 4 OR 4 vVii viii ix PO3(R4)2 P0 3 (R 4 ) 2 P03(R 4 )2 PO3(R4)2 C0 2 R 4 R 4 0 2 C 0 xii C0 2 R 4 R 4 0 2 C N CO2R 4 R 4 0 2 C N P0 3 (R 4 ) 2 0 N P0 3 (R 4 ) 2 - xiii xiv xv N C02R4 N N R 4 0 2 C N C0 2 R 4 xxi OR 4 XXi P0 3 (R 4 ) 2 xxn OR 4 C0 2 R 4 R 4 0 2 C N xxiv N C0 2 R 4 N OH xxVI P0 3 (R 4 ) 2 xxivv R 4 , independently for each occurrence, represents H or lower alkyl, and 148 WO 01/44258 PCT/USOO/34487 5 V represents OR, NR 2 , or SR.
59. The compound of claim 58, wherein Tb is selected from xi, xii, xiv, and xv.
60. The compound of claim 58, wherein Tb is x. 10
61. The compound of claim 58, wherein Tb is xiii.
62. The compound of claim 58, wherein V represents NR 2 . 15
63. A compound having the structure: Tb-Cy-L-V, wherein L is absent or represents -Ma-Y-Mp-; Y is absent; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or 20 unsubstituted ethene; R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently, represent integers from 0-10; Cy represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or 25 cycloalkyl; Tb represents a bone-targeting group selected from: N C02R4 N N R 4 0 2 c N cO 2 R 4 xxi OR 4 XXii P0 3 (R 4 ) 2 xxiii OR 4 cO2R4 R402C N xxiv N C0 2 R 4 N OH xxvi P0 3 (R 4 ) 2 xxv R4, independently for each occurrence, represents H or lower alkyl, and 149 WO 01/44258 PCT/USOO/34487 5 V represents OR, NR 2 , or SR.
64. The compound of claim 63, wherein Cy represents a phenyl ring.
65. The compound of claim 63, wherein V represents NR 2 . 10
66. A compound having the structure: Tb-L-U, wherein L is absent or represents -Mn-Y-Mp-; Y is absent; M represents, independently for each occurrence, a substituted or 15 unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene; R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently, represent integers from 0-10; 20 Tb represents a bone-targeting group selected from: || || O4 OR4 'y "" R OR 4 OR 4 1 OR 4 OR 4 OR 4 0 OR 4 0 OR400 \-i,-w N OR 4 R 4 O_" IN' I OR 4 R 4 OR 4 OROR 4 O OR 4 4 iv V _1 0 0 0R 4 O N 0 R i OR 0 OR 4 OR OR 4 OR 4 OR 4 OR 4 Vii viii 150 WO 01/44258 PCT/USOO/34487 P0 3 (R 4 ) 2 P0 3 (R 4 ) 2 P0 3 (R 4 )2 xx P0 3 (R 4 ) 2 C0 2 R 4 R 4 0 2 C 0 Xii C0 2 R 4 R 4 0 2 C N C0 2 R 4 R 4 0 2 C N P0 3 (R 4 ) 2 0 N PO 3 (R 4 ) 2 Xiii Xiv Xv N C02R4 N ~ N R 4 0 2 C N C0 2 R 4 XXi OR 4 XXii P0 3 (R4)2 XXIII OR 4 C0 2 R 4 R 4 0 2 C N XXiv N C0 2 R 4 N OH xxvi P0 3 (R 4 ) 2 5xx R 4 , independently for each occurrence, represents H or lower alkyl, and U represents a sulfonate ester, halogen, formyl, or a suitable leaving group.
67. The compound of claim 66, wherein Tb is selected from xi, xii, xiv, and xv. 10
68. The compound of claim 66, wherein Tb is x.
69. The compound of claim 66, wherein Tb is xiii. 15
70. A compound having the structure: Tb-Cy-L-U, wherein L is absent or represents -Mn-Y-Mp-; Y is absent; 151 WO 01/44258 PCT/USOO/34487 5 M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene; R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; 10 p and n, independently, represent integers from 0-10; Cy represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl; Tb represents a bone-targeting group selected from: O O I'- ~~OR, P S V OR 4 OR 4 1. 1 0OR 4 OR 4 OR 4 0 OR 4 j ii ii' \ , I_ N I'-OR 4 R 4 0 N OR 4 R 4 0 OR 4 OR OR 4 4 OR 4 OR 4 OR 4 I OR 4 OR 4 OR iv V O 0 Vi R 4 0 IK' OR4 R 4 O R OR4 O O OR 4 0 OR 4 ' I _R OR 4 OR 4 15Vii Viii i 15"'x P03(R4)2 PO 3 (R 4 ) 2 P0 3 (R 4 ) 2 XI X( P3(R4)2 CO 2 R 4 R 4 0 2 C 0 Xii C0 2 R 4 R 4 0 2 C N CO 2 R 4 R 4 0 2 C N P0 3 (R 4 ) 2 0 N PO 3 (R 4 ) 2 xiii xiv xv R4, independently for each occurrence, represents H or lower alkyl, and U represents a sulfonate ester, halogen, formyl, or a suitable leaving group. 152 WO 01/44258 PCT/USOO/34487 5
71. A compound of claim 70, wherein Cy represents a phenyl ring.
72. A compound having the general formula (I): Hc-X-K-Cy-L-Z-Tb, or (II): Hc X-K-Z-Tb, wherein L and K, independently, are absent or represent -M 1 -Y-Mp-; X, Y, and Z, independently, are absent or represent NR, 0, or S; 10 M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene or ethyne; R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; 15 p and n, independently, represent integers from 0-10; Cy represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a heterocycle; R 4 , independently for each occurrence, represents H or lower alkyl; and 20 Tb represents one of: N C02R4 N N R 4 0 2 C N C0 2 R 4 xxi OR 4 XXfl P0 3 (R 4 ) 2 xxW OR 4 C0 2 R 4 R 4 0 2 C N xxiv N C0 2 R 4 N OH xxvi P0 3 (R 4 ) 2 xxv
73. A compound having the general formula (I): Hc-X-K-Cy-L-Z-Tb, or (II): Hc X-K-Z-Tb, wherein L and K, independently, are absent or represent -Mn-Y-Mp-; 25 X, Y, and Z, independently, are absent or represent NR, 0, or S; 153 WO 01/44258 PCT/USOO/34487 5 M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene or ethyne; R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; 10 p and n, independently, represent integers from 0-10; Cy represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl; He represents a heterocycle; R4, independently for each occurrence, represents H or lower alkyl; and 15 Tb represents a group selected from: O O YR YR 4 M YR 4 MR YR 4 xxvi xxVI xxix 1 0 0 0 0 0 R 4 Y M~ j 'YR 4 R 4 Y ~lM "YR 4 R 4 Y M YR 4 4 YR 4 YR 4 O YR 4 Xxx XXXIxxxii (R 4 Y)OCN O M4 '.YR4 YR 4 YR 4 M xxxiv PO(Y'R 4 ) 2 xxiixviixi XXX1151 15 WO 01/44258 PCT/USOO/34487 R6 R6 xxvOYRi PO(YR4)2 PO(YR 4)2(YR 4 )4) xxvi xxxvii PO(YR4) 2 COYR 4 R 4 YOC M xxxviii R6.'Re.COYR 4 R R 4 YO N COYR 4 R 4 YOC N PO(YR4) 2 0 N PO(YR 4 ) 2 5 xxxix xxxx xxxxi R S COYR 4 R6 ~ R6 N COYR 4 XXXXVI PO(YR 4 ) 2 xxxxvii OR 4 COYR 4 FRe R6 N COYR4 N OR 4 xxxxvii xxXi x represents 1, 2, 3, 4, 5, or 6; 10 each occurrence of Y is independently a covalent bond, -0-, -S-, or -N(Rj) 2 , wherein Rj, for each occurrence, is independently hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; R 6 represents from 0-3 substituents selected from halogen, lower alkyl, lower alkenyl, aryl, heteroaryl, carbonyl, thiocarbonyl, ketone, aldehyde, amino, acylamino, 15 amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamido, phosphoryl, phosphonate, phosphinate, -(CH 2 )palkyl, -(CH2)palkenyl, (CH 2 )palkynyl, -(CH 2 )paryl, -(CH2)paralkyl, -(CH 2 )pOH, -(CH2)pO-lower alkyl, (CH 2 )pO-lower alkenyl, -O(CH 2 )nR, -(CH2)pSH, -(CH 2 )pS-lower alkyl, -(CH 2 )pS lower alkenyl, -S(CH2)nR, -(CH 2 )pN(R) 2 , -(CH 2 )pNR-lower alkyl, -(CH 2 )pNR-lower 20 alkenyl, -NR(CH 2 )nR, or protected forms of the above and wherein p is 1-10; and 155 WO 01/44258 PCT/USOO/34487 5 each occurrence of R 4 is independently hydrogen or a lower alkyl.
74. The compound of claim 73, wherein M, where it occurs in Tb, is selected from CH 2 , CHJ, CHOH, and CJ 2 , wherein J represents a halogen. 10
75. The compound of claim 73, wherein R 6 is selected from lower alkyl, hydroxyl, sulfhydryl, amino, amido, carboxyl, sulfonate, phosphonate, and salts thereof, and lower alkyl substituted with hydroxyl, sulfhydryl, amino, amido, carboxyl, sulfonate, phosphonate, and salts thereof.
76. A compound having the general formula (I): Hc-X-K-Cy-L-Z-Tb, or (11): Hc 15 X-K-Z-Tb, wherein L and K, independently, are absent or represent -M-Y-Mp-; X, Y, and Z, independently, are absent or represent NR, 0, or S; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or 20 unsubstituted ethene or ethyne; R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently, represent integers from 0-10; Cy represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or 25 cycloalkyl; Hc represents a heterocycle; R 4 , independently for each occurrence, represents H or lower alkyl; and Tb represents a group having the structure: -- A xxxxii B 30 A represents a group selected from GPO 3 (R 1 ) 2 , GCO 2 R 4 , and GSO 3 R 4 ; B represents a group selected from NH 2 , OH, GPO 3 (R 4 ) 2 , GCO 2 R 4 , and GSO 3 R 4 ; and G is absent or represents a linkage of one or two atoms. 156 WO 01/44258 PCT/USOO/34487 5
77. A compound having the general formula (I): Hc-X-K-Cy-L-Z-Tb, or (II): Hc X-K-Z-Tb, wherein L and K, independently, are absent or represent -Mn-Y-Mp-; X, Y, and Z, independently, are absent or represent NR, 0, or S; M represents, independently for each occurrence, a substituted or 10 unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene or ethyne; R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently, represent integers from 0-10; 15 Cy represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a heterocycle; R 4 , independently for each occurrence, represents H or lower alkyl; and Tb has the structure xxxxiii: 20 xxxxiii B B represents a group selected from NH 2 , OH, GPO 3 (R 4 ) 2 , GCO 2 R 4 , and GSO 3 R 4 ; and G is absent or represents a linkage of one or two atoms.
78. A compound having the general formula (I): Hc-X-K-Cy-L-Z-Tb, or (II): Hc X-K-Z-Tb, wherein 25 L and K, independently, are absent or represent -Mn-Y-Mp-; X, Y, and Z, independently, are absent or represent NR, 0, or S; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene or ethyne; 30 R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently, represent integers from 0-10; 157 WO 01/44258 PCT/USOO/34487 5 Cy represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a heterocycle; R 4 , independently for each occurrence, represents H or lower alkyl; and Tb has the structure xxxxiv or xxxxv: B B A N C0 2 R 4 (R4)20 3 P N C 10 xxxxiv xxxxv A represents a group selected from GPO 3 (R 4 ) 2 , GCO 2 R4, and GSO 3 R 4 ; B represents a group selected from NH 2 , OH, GPO 3 (R 4 ) 2 , GCO 2 R 4 , and GSO 3 R 4 ; G is absent or represents a linkage of one or two atoms; C represents H, R 6 , NH 2 , OH, GPO 3 (R 4 ) 2 , GCO 2 R 4 , or GSO 3 R4, such that in 15 xxxxiv, any one occurrence of A or B is present, and the other occurrences may represent a bond to Z, H, or R 6 as desired.
79. A compound having the general formula (I): Hc-X-K-Cy-L-Z-Tb, or (11): Hc X-K-Z-Tb, wherein L and K, independently, are absent or represent -M,-Y-Mp-; 20 X, Y, and Z, independently, are absent or represent NR, 0, or S; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene or ethyne; R represents, independently for each occurrence, H or substituted or 25 unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently, represent integers from 0-10; Cy represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a heterocycle; 30 R 4 , independently for each occurrence, represents H or lower alkyl; and Tb represents a heteroaryl bearing one or two B substituents, and 0-4 R 6 substituents; 158 WO 01/44258 PCT/USOO/34487 5 A represents a group selected from GPO 3 (R 4 ) 2 , GCO 2 R 4 , and GSO 3 R 4 ; B represents a group selected from NH 2 , OH, GPO 3 (R 4 ) 2 , GCO 2 R 4 , and GSO 3 R4; and G is absent or represents a linkage of one or two atoms.
80. The compound of any of claims 72-79, wherein Hc is selected from: R2 R2 R1 N N.-.-N N R, R, N N N N NHR3 N NHR 3 R 2 HN N NHR 3 Xvi Xvii Xviii R3N N N W R N N NHR 2 H I H 10 XiX R2 XX
81. The compound of any of claims 72-79, wherein, except in Tb, the compound is free of hydrolyzable linkages.
82. A compound having the formula: V-L-Cy-Tb, V-L-Tb, U-L-Cy-Tb, or U-L 15 Tb, wherein U represents a sulfonate ester, halogen, formyl, or a suitable leaving group; V represents OR, NR 2 , or SR; L is absent or represents -Mn-Y-Mp-; Y is absent; 20 M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene; R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; 25 p and n, independently, represent integers from 0-10; 159 WO 01/44258 PCT/USOO/34487 5 R 4 , independently for each occurrence, represents H or lower alkyl; and Tb represents one of: N C02R4 | \N N R 4 O 2 C N CO 2 R 4 xxi OR 4 xxii P0 3 (R 4 ) 2 xxi OR 4 CO 2 R 4 R 4 0 2 C N xxiv C0 2 R 4 N OH xxvi P0 3 (R 4 ) 2 XXv
83. A compound having the formula: V-L-Cy-Tb, V-L-Tb, U-L-Cy-Tb, or U-L Tb, wherein 10 U represents a sulfonate ester, halogen, formyl, or a suitable leaving group; V represents OR, NR 2 , or SR; L is absent or represents -Mn-Y-Mp-; Y is absent; M represents, independently for each occurrence, a substituted or 15 unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene; R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently, represent integers from 0-10; 20 R 4 , independently for each occurrence, represents H or lower alkyl; and Tb represents a group selected from: 160 WO 01/44258 PCT/USOO/34487 YR YR YR 4 xxvii xxviii xxix 0 0 0s R 4 Y I * Mx"-I N' YR 4 R 4 ~KMx-IINYR 4 R I x YR YR 4 YR 4 YR 4 I0 YR 4 I xxx xxxi xxxii 11 H (RY)OC,. N YR YR 4 Y R 4 x x x ii eR 4x x x iv m x P O (Y R 4 ) Pe P6N P6 xxi PO(YR 4 ) 2 xxvi PO(YR 4 ) 2 PO(YR 4 ) 2 PO(YR4) 2 COYR 4 R 4 YOC' 0O xxxviii -Ra Re COR R6 R 4 YOC N~t COYR 4 R 4 YOC N PO(YR 4 ) 2 0 N 0PO(YR 4 ) 2 xxxix xxxx xxxxi R6 -k 00 2 R 4 I R6 N 6 N 00 2 R 4 XXX'P0 3 (R 4 ) 2 x vi OR 4 C0 2 R 4 IR.i R 6 xxxiiN C0 2 R 4 xxxxix N OR 4 x represents 1 or 2, and 161 WO 01/44258 PCT/USOO/34487 5 R 6 represents from 0-3 substituents selected from halogen, lower alkyl, lower alkenyl, aryl, heteroaryl, carbonyl, thiocarbonyl, ketone, aldehyde, amino, acylamino, amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamido, phosphoryl, phosphonate, phosphinate, -(CH2)palkyl, -(CH 2 )palkenyl, (CH 2 )palkynyl, -(CH2)paryl, -(CH2)paralkyl, -(CH2)pOH, -(CH2)pO-lower alkyl, 10 (CH 2 )pO-lower alkenyl, -O(CH2)nR, -(CH 2 )pSH, -(CH 2 )pS-lower alkyl, -(CH2)pS lower alkenyl, -S(CH 2 )nR, -(CH2)pN(R) 2 , -(CH 2 )pNR-lower alkyl, -(CH 2 )pNR-lower alkenyl, -NR(CH 2 )nR, or protected forms of the above.
84. The compound of claim 83, wherein M, where it occurs in Tb, is selected from 15 CH 2 , CHJ, CHOH, and CJ 2 , wherein J represents a halogen.
85. The compound of claim 83, wherein R 6 is selected from lower alkyl, hydroxyl, sulfhydryl, amino, amido, carboxyl, sulfonate, phosphonate, and salts thereof, and lower alkyl substituted with hydroxyl, sulfhydryl, amino, amido, carboxyl, sulfonate, 20 phosphonate, and salts thereof.
86. A compound having the formula: V-L-Cy-Tb, V-L-Tb, U-L-Cy-Tb, or U-L Tb, wherein U represents a sulfonate ester, halogen, formyl, or a suitable leaving group; V represents OR, NR 2 , or SR; 25 L is absent or represents -Mn-Y-Mp-; Y is absent; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene; 30 R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently, represent integers from 0-10; R 4 , independently for each occurrence, represents H or lower alkyl; and Tb represents a group having the structure: 162 WO 01/44258 PCT/USOO/34487 -A 5 XXXXI B A represents a group selected from GPO 3 (R4) 2 , GCO 2 R 4 , and GSO 3 R 4 ; B represents a group selected from NH 2 , OH, GPO 3 (R 4 ) 2 , GCO 2 R 4 , and GSO 3 R4; and G is absent or represents a linkage of one or two atoms.
87. A compound having the formula: V-L-Cy-Tb, V-L-Tb, U-L-Cy-Tb, or U-L 10 Tb, wherein U represents a sulfonate ester, halogen, formyl, or a suitable leaving group; V represents OR, NR 2 , or SR; L is absent or represents -Mn-Y-Mp-; Y is absent; 15 M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene; R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; 20 p and n, independently, represent integers from 0-10; R 4 , independently for each occurrence, represents H or lower alkyl; and Tb has the structure xxxxiii: N xxxxiii B B represents a group selected from NH 2 , OH, GPO 3 (R 4 ) 2 , GCO 2 R 4 , and 25 GSO 3 R 4 ; and G is absent or represents a linkage of one or two atoms.
88. A compound having the formula: V-L-Cy-Tb, V-L-Tb, U-L-Cy-Tb, or U-L Tb, wherein U represents a sulfonate ester, halogen, formyl, or a suitable leaving group; V represents OR, NR 2 , or SR; 30 L is absent or represents -Mn-Y-Mp-; 163 WO 01/44258 PCT/USOO/34487 5 Y is absent; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene; R represents, independently for each occurrence, H or substituted or 10 unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently, represent integers from 0-10; R 4 , independently for each occurrence, represents H or lower alkyl; and Tb has the structure xxxxiv or xxxxv: B B A N C0 2 R 4 (R4)20 3 P N C xxxxiv xxxxv 15 A represents a group selected from GPO 3 (R 4 ) 2 , GCO 2 R 4 , and GSO 3 R4; B represents a group selected from NH 2 , OH, GPO 3 (R 4 ) 2 , GCO 2 R 4 , and GSO 3 R4; G is absent or represents a linkage of one or two atoms; C represents H, R 6 , NH 2 , OH, GPO 3 (R 4 ) 2 , GCO 2 R 4 , or GSO 3 R 4 , such that in xxxxiv, any one occurrence of A or B is present, and the other occurrences may 20 represent a bond to Z, H, or R 6 as desired.
89. A compound having the formula: V-L-Cy-Tb, V-L-Tb, U-L-Cy-Tb, or U-L Tb, wherein U represents a sulfonate ester, halogen, formyl, or a suitable leaving group; V represents OR, NR 2 , or SR; 25 L is absent or represents -Mn-Y-Mp-; Y is absent; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene; 30 R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently, represent integers from 0-10; 164 WO 01/44258 PCT/USOO/34487 5 R 1 4, independently for each occurrence, represents H or lower alkyl; and Tb represents a heteroaryl bearing one or two B substituents, and 0-4 R 6 substituents; A represents a group selected from GPO 3 (R 4 ) 2 , GCO 2 R 1 4, and GS0 3 R 4 ; B represents a group selected from NH 2 , OH, GPO 3 (R 4 ) 2 , GCO 2 R 1 4, and 10 GSO 3 R 4 ; and G is absent or represents a linkage of one or two atoms.
90. The compound of any of claims 82-89, wherein He is selected from: R2 R2 R1 N N-N N R, R, N N N N NHR 3 N NHR 3 R 2 HN N NHR 3 XVi xVil XVIII R3 R 3 R N N N W ~ N N N NHR 2 H H xix R2 xx 15
91. The compound of any of claims 82-89, wherein L represents alkyl.
92. A method for treating or preventing a bone disorder comprising a pharmaceutically acceptable excipient and a compound having the general formula (I): Hc-X-K-Cy-L-Z-Tb, or (11): Hc-X-K-Z-Tb, wherein L and K, independently, are absent or represent -M,-Y-Mp-; 20 X, Y, and Z, independently, are absent or represent NR, 0, or S; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene or ethyne; R represents, independently for each occurrence, H or substituted or 25 unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; 165 WO 01/44258 PCT/USOO/34487 5 p and n, independently, represent integers from 0-10; Cy represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl; He represents a heterocycle; R 4 , independently for each occurrence, represents H or lower alkyl; and 10 Tb represents one of: N C02R4 \N N R 4 0 2 C N C0 2 R 4 xxi OR 4 XXi P0 3 (R 4 ) 2 xxiii OR 4 C0 2 R 4 R 4 0 2 C N XXiv N C0 2 R 4 N OH xxvi P0 3 (R4)2 XXXXV xxv
93. A method for treating or preventing a bone disorder comprising a pharmaceutically acceptable excipient and a compound having the general formula (I): Hc-X-K-Cy-L-Z-Tb, or (11): Hc-X-K-Z-Tb, wherein 15 L and K, independently, are absent or represent -M,-Y-Mp-; X, Y, and Z, independently, are absent or represent NR, 0, or S; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene or ethyne; 20 R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently, represent integers from 0-10; Cy represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl; 25 Hc represents a heterocycle; R 4 , independently for each occurrence, represents H or lower alkyl; and Tb represents a group selected from: 166 WO 01/44258 PCT/USOO/34487 4R OR 4 m OR 4 OR 4 0OR xxvii xxviii xi 0t 00 0 R 4 0- Kl M " OR 4 R 4 0--Pl- I"M --- OS 4 R 4 0~ KM O 4 OR 4 OR 0R1 x OR 4 ORM IOR 4 I OR 4 OR 4 R 5xxxiiiixxi 0xv~ 1PMx IR 4 ) 2 P0 3 (OR 4 ) Mx 2 ~~0 xxvi 5xxxi x xx x xxxxl ,rC0 2 R 4 R6 xxxviP03(4)2 xx N C03R4 2 R 4 (4 XXIP0 3 (R 4 ) 2 XXXXR42C0VIIii P6R 4 C0 2 R 4 R N6 C0 2 R 4 OR 1 6 WO 01/44258 PCT/USOO/34487 5 R 6 represents from 0-3 substituents selected from halogen, lower alkyl, lower alkenyl, aryl, heteroaryl, carbonyl, thiocarbonyl, ketone, aldehyde, amino, acylamino, amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamido, phosphoryl, phosphonate, phosphinate, -(CH2)palkyl, -(CH 2 )palkenyl, (CH 2 )palkynyl, -(CH2)paryl, -(CH 2 )paralkyl, -(CH2)pOH, -(CH2)pO-lower alkyl, 10 (CH 2 )pO-lower alkenyl, -O(CH2)nR, -(CH2)pSH, -(CH 2 )pS-lower alkyl, -(CH2)pS lower alkenyl, -S(CH 2 )nR, -(CH2)pN(R) 2 , -(CH 2 )pNR-lower alkyl, -(CH 2 )pNR-lower alkenyl, -NR(CH 2 )nR, or protected forms of the above.
94. The compound of claim 92, wherein M, where it occurs in Tb, is selected from 15 CH 2 , CHJ, CHOH, and CJ 2 , wherein J represents a halogen.
95. The compound of claim 92, wherein R 6 is selected from lower alkyl, hydroxyl, sulfhydryl, amino, amido, carboxyl, sulfonate, phosphonate, and salts thereof, and lower alkyl substituted with hydroxyl, sulfhydryl, amino, amido, carboxyl, sulfonate, 20 phosphonate, and salts thereof.
96. A method for treating or preventing a bone disorder comprising a pharmaceutically acceptable excipient and a compound having the general formula (I): Hc-X-K-Cy-L-Z-Tb, or (II): Hc-X-K-Z-Tb, wherein L and K, independently, are absent or represent -Ma-Y-Mp-; 25 X, Y, and Z, independently, are absent or represent NR, 0, or S; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene or ethyne; R represents, independently for each occurrence, H or substituted or 30 unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently, represent integers from 0-10; Cy represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a heterocycle; 35 R4, independently for each occurrence, represents H or lower alkyl; and 168 WO 01/44258 PCT/USOO/34487 5 Tb represents a group having the structure: _A xxxxii B A represents a group selected from GPO 3 (R 4 ) 2 , GCO 2 R 4 , and GSO 3 R4; B represents a group selected from NH 2 , OH, GPO 3 (R 4 ) 2 , GCO 2 R 4 , and GSO 3 R4; and G is absent or represents a linkage of one or two atoms. 10
97. A method for treating or preventing a bone disorder comprising a pharmaceutically acceptable excipient and a compound having the general formula (I): Hc-X-K-Cy-L-Z-Tb, or (11): Hc-X-K-Z-Tb, wherein L and K, independently, are absent or represent -Mn-Y-Mp-; X, Y, and Z, independently, are absent or represent NR, 0, or S; 15 M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene or ethyne; R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; 20 p and n, independently, represent integers from 0-10; Cy represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl,, or cycloalkyl; Hc represents a heterocycle; R4, independently for each occurrence, represents H or lower alkyl; and 25 Tb has the structure xxxxiii: N xxxxiii B B represents a group selected from NH 2 , OH, GPO 3 (R 4 ) 2 , GCO 2 R4, and GSO 3 R 4 ; and G is absent or represents a linkage of one or two atoms. 169 WO 01/44258 PCT/USOO/34487 5
98. A method for treating or preventing a bone disorder comprising a pharmaceutically acceptable excipient and a compound having the general formula (I): Hc-X-K-Cy-L-Z-Tb, or (II): Hc-X-K-Z-Tb, wherein L and K, independently, are absent or represent -Mn-Y-Mp-; X, Y, and Z, independently, are absent or represent NR, 0, or S; 10 M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene or ethyne; R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; 15 p and n, independently, represent integers from 0-10; Cy represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a heterocycle; R4, independently for each occurrence, represents H or lower alkyl; and 20 Tb has the structure xxxxiv or xxxxv: B B K K A N C0 2 R 4 (R 4 ) 2 0 3 P N C xxxxiv xxxxv A represents a group selected from GPO 3 (R 4 ) 2 , GCO 2 R 4 , and GSO 3 R 4 ; B represents a group selected from NH 2 , OH, GPO 3 (R4) 2 , GCO 2 R 4 , and GSO 3 R 4 ; G is absent or represents a linkage of one or two atoms; 25 C represents H, R 6 , NH 2 , OH, GPO 3 (R 4 ) 2 , GCO 2 R 4 , or GSO 3 R 4 , such that in xxxxiv, any one occurrence of A or B is present, and the other occurrences may represent a bond to Z, H, or R 6 as desired.
99. A method for treating or preventing a bone disorder comprising a pharmaceutically acceptable excipient and a compound having the general formula 30 (I): Hc-X-K-Cy-L-Z-Tb, or (II): Hc-X-K-Z-Tb, wherein L and K, independently, are absent or represent -Mn-Y-Mp-; X, Y, and Z, independently, are absent or represent NR, 0, or S; 170 WO 01/44258 PCT/USOO/34487 5 M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene or ethyne; R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; 10 p and n, independently, represent integers from 0-10; Cy represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a heterocycle; R4, independently for each occurrence, represents H or lower alkyl; and 15 Tb represents a heteroaryl bearing one or two B substituents, and 0-4 16 substituents; A represents a group selected from GPO 3 (R 4 ) 2 , GCO 2 R 4 , and GSO 3 R 1 4; B represents a group selected from NH 2 , OH, GPO 3 (R 1 ) 2 , GCO 2 R 1 4, and GSO 3 R 4 ; and G is absent or represents a linkage of one or two atoms. 20
100. The method of any of claims 92-99, wherein Hc is selected from: R2 R2 R1 \N \N-..- N \N - I N N N N NHR3 N NHR 3 R 2 HN N NHR 3 XVI XVii XViii R3 R3 N N N W N N N NHR 2 H I H xix R2 xx
101. The method of any of claims 92-99, wherein, except in Tb, the compound is 25 free of hydrolyzable linkages. 171 WO 01/44258 PCT/USOO/34487 5
102. A method for treating or preventing a bone disorder comprising a pharmaceutically acceptable excipient and a compound having the formula: V-L-Cy Tb, V-L-Tb, U-L-Cy-Tb, or U-L-Tb, wherein U represents a sulfonate ester, halogen, formyl, or a suitable leaving group; V represents OR, NR 2 , or SR; 10 L is absent or represents -Mn-Y-Mp-; Y is absent; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene; 15 R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently, represent integers from 0-10; R4, independently for each occurrence, represents H or lower alkyl; and Tb represents one of: N C02R4 N N R 4 0 2 C N CO 2 R 4 xxi OR 4 XXII PO 3 (R 4 ) 2 xxiii OR 4 C0 2 R 4 R 4 0 2 C N N C0 2 R 4 N OH xxVI P0 3 (R 4 ) 2 20 Xxiv mX
103. A method for treating or preventing a bone disorder comprising a pharmaceutically acceptable excipient and a compound having the formula: V-L-Cy Tb, V-L-Tb, U-L-Cy-Tb, or U-L-Tb, wherein U represents a sulfonate ester, halogen, formyl, or a suitable leaving group; 25 V represents OR, NR 2 , or SR; L is absent or represents -M 1 -Y-Mp-; Y is absent; 172 WO 01/44258 PCT/USOO/34487 5 M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene; R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; 10 p and n, independently, represent integers from 0-10; R 1 4, independently for each occurrence, represents H or lower alkyl; and Tb represents a group selected from: O O 11 0 0 0 0 0 R YR4 RYR 4 YR 4 YR 4 YR 4 YR 4 0 YR 4 YR4 YR 4 0 YR 4 xxx xxxi i xxx 0 0 H XXX11 | | P(4 CO YR4 R4Y M xxvi R4 OYR 4 R4O N P 4) xxxi 173XXI 11 (YR1 COYR 4 OC N 4 O ~ ~ X VI YR4 COY 4 R 4 O O(YR 4 YOC PO(YR 4 ) 2 0 N PO(YR 4 ) 2 15 xxxi xxxx xxx ,x173 WO 01/44258 PCT/USOO/34487 R6iR COYR 4 R6 N R N COYR 4 Xxxxvi PO(OR4) 2 OR 4 COYR 4 R6 R 6 j 5 xxxxviii N COYR 4 N OR 4 x represents 1, 2, 3, 4, 5, or 6; each occurrence of Y is independently a covalent bond, -0-, -S-, or -N(Rj)2, wherein Rj, for each occurrence, is independently hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; 10 R 6 represents from 0-3 substituents selected from halogen, lower alkyl, lower alkenyl, aryl, heteroaryl, carbonyl, thiocarbonyl, ketone, aldehyde, amino, acylamino, amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamido, phosphoryl, phosphonate, phosphinate, -(CH2)palkyl, -(CH 2 )palkenyl, (CH 2 )palkynyl, -(CH2)paryl, -(CH2)paralkyl, -(CH 2 )pOH, -(CH 2 )pO-lower alkyl, 15 (CH 2 )pO-lower alkenyl, -O(CH 2 )nR, -(CH 2 )pSH, -(CH 2 )pS-lower alkyl, -(CH 2 )pS lower alkenyl, -S(CH 2 )nR, -(CH 2 )pN(R) 2 , -(CH 2 )pNR-lower alkyl, -(CH 2 )pNR-lower alkenyl, -NR(CH 2 )nR, or protected forms of the above; and each occurrence of R 4 is independently hydrogen or a lower alkyl. 20
104. The method of claim 103, wherein M, where it occurs in Tb, is selected from CH 2 , CHJ, CHOH, and CJ 2 , wherein J represents a halogen.
105. The method of claim 103, wherein R 6 is selected from lower alkyl, hydroxyl, sulfhydryl, amino, amido, carboxyl, sulfonate, phosphonate, and salts thereof, and 25 lower alkyl substituted with hydroxyl, sulfhydryl, amino, amido, carboxyl, sulfonate, phosphonate, and salts thereof. 174 WO 01/44258 PCT/USOO/34487 5
106. A method for treating or preventing a bone disorder comprising a pharmaceutically acceptable excipient and a compound having the formula: V-L-Cy Tb, V-L-Tb, U-L-Cy-Tb, or U-L-Tb, wherein U represents a sulfonate ester, halogen, formyl, or a suitable leaving group; V represents OR, NR 2 , or SR; 10 L is absent or represents -Ma-Y-Mp-; Y is absent; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene; 15 R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently, represent integers from 0-10; R 4 , independently for each occurrence, represents H or lower alkyl; and Tb represents a group having the structure: -A 20 "" B A represents a group selected from GPO 3 (R 4 ) 2 , GCO 2 R4, and GSO 3 R 4 ; B represents a group selected from NH 2 , OH, GPO 3 (R 4 ) 2 , GCO 2 R 4 , and GSO 3 R 4 ; and G is absent or represents a linkage of one or two atoms.
107. A method for treating or preventing a bone disorder comprising a 25 pharmaceutically acceptable excipient and a compound having the formula: V-L-Cy Tb, V-L-Tb, U-L-Cy-Tb, or U-L-Tb, wherein U represents a sulfonate ester, halogen, formyl, or a suitable leaving group; V represents OR, NR 2 , or SR; L is absent or represents -M,-Y-Mp-; 30 Y is absent; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene; 175 WO 01/44258 PCT/USOO/34487 5 R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently, represent integers from 0-10; R4, independently for each occurrence, represents H or lower alkyl; and Tb has the structure xxxxiii: N 10 xxxxiii B B represents a group selected from NH 2 , OH, GPO 3 (R 4 ) 2 , GCO 2 R4, and GSO 3 R4; and G is absent or represents a linkage of one or two atoms.
108. A method for treating or preventing a bone disorder comprising a pharmaceutically acceptable excipient and a compound having the formula: V-L-Cy 15 Tb, V-L-Tb, U-L-Cy-Tb, or U-L-Tb, wherein U represents a sulfonate ester, halogen, formyl, or a suitable leaving group; V represents OR, NR 2 , or SR; L is absent or represents -M,-Y-Mp-; Y is absent; 20 M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene; R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; 25 p and n, independently, represent integers from 0-10; R 4 , independently for each occurrence, represents H or lower alkyl; and Tb has the structure xxxxiv or xxxxv: B B A N C0 2 R 4 (R 4 ) 2 0 3 P N C xxxxiv xxxxv A represents a group selected from GPO 3 (R 4 ) 2 , GCO 2 R 4 , and GSO 3 R4; 176 WO 01/44258 PCT/USOO/34487 5 B represents a group selected from NH 2 , OH, GPO 3 (14) 2 , GCO 2 R4, and GSO 3 R4; G is absent or represents a linkage of one or two atoms; C represents H, R 6 , NH 2 , OH, GPO 3 (R4) 2 , GCO 2 R 4 , or GSO 3 R 4 , such that in xxxxiv, any one occurrence of A or B is present, and the other occurrences may represent a bond to Z, H, or R 6 as desired. 10
109. A method for treating or preventing a bone disorder comprising a pharmaceutically acceptable excipient and a compound having the formula: V-L-Cy Tb, V-L-Tb, U-L-Cy-Tb, or U-L-Tb, wherein U represents a sulfonate ester, halogen, formyl, or a suitable leaving group; V represents OR, NR 2 , or SR; 15 L is absent or represents -Mn-Y-Mp-; Y is absent; M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene; 20 R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently, represent integers from 0-10; R 4 , independently for each occurrence, represents H or lower alkyl; and Tb represents a heteroaryl bearing one or two B substituents, and 0-4 R 6 25 substituents; A represents a group selected from GPO 3 (R4) 2 , GCO 2 R4, and GSO 3 R 4 ; B represents a group selected from NH 2 , OH, GPO 3 (R4) 2 , GCO 2 R 4 , and GSO 3 R 4 ; and G is absent or represents a linkage of one or two atoms. 30
110. The method of any of claims 102-109, wherein Hc is selected from: 177 WO 01/44258 PCT/USOO/34487 R2 R2 R1 N N--N N N N N N NHR 3 N NHR 3 R 2 HN N NHR 3 xvi xvii xviii R3 NR3 NHR N N N W NN NR H I H 5 xix R2 XX
111. The method of any of claims 102-109, wherein L represents alkyl. 178
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Families Citing this family (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK1417207T3 (en) 2000-08-04 2005-12-27 Warner Lambert Co Process for Preparation of 2- (4-Pyridyl) Amino-6-Dialkyloxyphenyl-Pyrido [2,3-d] Pyrimidin-7-One
AU2002315389A1 (en) * 2001-06-21 2003-01-08 Ariad Pharmaceuticals, Inc. Novel pyrazolo-and pyrrolo-pyrimidines and uses thereof
WO2003000011A2 (en) * 2001-06-21 2003-01-03 Ariad Pharmaceuticals, Inc. Novel pyridopyrimidines and uses thereof
EP1408985A4 (en) * 2001-06-21 2006-03-22 Ariad Pharma Inc Novel pyridopyrimidones and uses thereof
TW200413381A (en) 2002-11-04 2004-08-01 Hoffmann La Roche Novel amino-substituted dihydropyrimido [4,5-d]pyrimidinone derivatives, their manufacture and use as pharmaceutical agents
US7384937B2 (en) 2002-11-06 2008-06-10 Bristol-Myers Squibb Co. Fused heterocyclic compounds and use thereof
WO2004063195A1 (en) * 2003-01-03 2004-07-29 Sloan-Kettering Institute For Cancer Research Pyridopyrimidine kinase inhibitors
CA2564994A1 (en) 2004-04-30 2005-11-10 Warner-Lambert Company Llc Substituted morpholine compounds for the treatment of central nervous system disorders
BRPI0613146B8 (en) * 2005-06-17 2021-05-25 Univ Texas therapeutic use of src kinase inhibitors
CN101421269A (en) 2006-01-13 2009-04-29 环状药物公司 Inhibitors of tyrosine kinases and uses thereof
SI2526934T1 (en) 2006-09-22 2016-04-29 Pharmacyclics Llc Inhibitors of bruton's tyrosine kinase
WO2008054827A2 (en) 2006-11-03 2008-05-08 Pharmacyclics, Inc. Bruton's tyrosine kinase activity probe and method of using
US8809273B2 (en) 2007-03-28 2014-08-19 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
AU2009270856B2 (en) 2008-07-16 2013-07-25 Pharmacyclics Llc Inhibitors of Bruton's tyrosine kinase for the treatment of solid tumors
WO2010019511A2 (en) 2008-08-13 2010-02-18 Targanta Therapeutics Corp. Phosphonated rifamycins and uses thereof for the prevention and treatment of bone and joint infections
JP5590040B2 (en) 2008-11-12 2014-09-17 アリアド・ファーマシューティカルズ・インコーポレイテッド Pyrazinopyrazine and derivatives as kinase inhibitors
US8674095B2 (en) 2008-12-19 2014-03-18 Afraxis Holdings, Inc. Compounds for treating neuropsychiatric conditions
WO2011044535A2 (en) 2009-10-09 2011-04-14 Afraxis, Inc. 8-ethyl-6-(aryl)pyrido[2,3-d]pyrimidin-7(8h)-ones for the treatment of cns disorders
MX342405B (en) 2010-06-03 2016-09-28 Pharmacyclics Inc The use of inhibitors of bruton's tyrosine kinase (btk).
WO2011156646A2 (en) * 2010-06-09 2011-12-15 Afraxis, Inc. 6-(sulfonylaryl)pyrido[2,3-d]pyrimidin-7(8h)-ones for the treatment of cns disorders
WO2012031228A2 (en) 2010-09-02 2012-03-08 The Regents Of The University Of California Llp2a-bisphosphonate conjugates for osteoporosis treatment
WO2013032527A1 (en) 2011-09-02 2013-03-07 The Regents Of The University Of California Llp2a-bisphosphonate conjugates for osteoporosis treatment
BR112014000653A2 (en) 2011-07-13 2017-02-14 Pharmacyclics Inc bruton tyrosine kinase inhibitors
JP6113185B2 (en) 2011-12-22 2017-04-12 ジェロン・コーポレーションＧｅｒｏｎ Ｃｏｒｐｏｒａｔｉｏｎ Guanine analogs as telomerase substrates and telomere length acting factors
US8377946B1 (en) 2011-12-30 2013-02-19 Pharmacyclics, Inc. Pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine compounds as kinase inhibitors
KR20150015021A (en) 2012-06-04 2015-02-09 파마시클릭스, 인코포레이티드 Crystalline forms of a bruton's tyrosine kinase inhibitor
AU2013293087B2 (en) 2012-07-24 2017-08-31 Pharmacyclics Llc Mutations associated with resistance to inhibitors of Bruton's tyrosine kinase (BTK)
PE20151495A1 (en) 2012-11-15 2015-10-23 Pharmacyclics Inc PYRROLOPYRIMIDINE COMPOUNDS AS KINASE INHIBITORS
EP3027192A4 (en) 2013-08-02 2017-03-22 Pharmacyclics, LLC Methods for the treatment of solid tumors
ES2709509T3 (en) 2013-08-12 2019-04-16 Pharmacyclics Llc Procedures for the treatment of cancer amplified by HER2
MA38961A1 (en) 2013-09-30 2018-05-31 Pharmacyclics Llc 3-phenyl-1h-pyrazolo [3,4-d] pyrimidin-4-ylamine compounds substituted for the crude tyrosine kinase inhibitors used to treat, for example, autoimmune, respiratory and inflammatory diseases, cancer, mastocytosis and osteoporosis
EP4115886A1 (en) 2013-10-25 2023-01-11 Pharmacyclics LLC Methods of treating and preventing graft versus host disease
WO2015143400A1 (en) 2014-03-20 2015-09-24 Pharmacyclics, Inc. Phospholipase c gamma 2 and resistance associated mutations
CA2959602A1 (en) 2014-08-01 2016-02-04 Pharmacyclics Llc Inhibitors of bruton's tyrosine kinase
WO2016022942A1 (en) 2014-08-07 2016-02-11 Pharmacyclics Llc Novel formulations of a bruton's tyrosine kinase inhibitor
RU2017133990A (en) 2015-03-03 2019-04-05 Фармасайкликс Элэлси PHARMACEUTICAL MEDICINAL FORMS OF BRUTON TYROSINKINASE INHIBITOR
CN104829620A (en) * 2015-04-08 2015-08-12 重庆华邦胜凯制药有限公司 Method for preparing aminopyrrolo[2,3-d]pyrimidine derivatives
US10899884B2 (en) 2018-11-29 2021-01-26 International Business Machines Corporation Flame-retardant polyetheretherketone-based compounds

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0085321B1 (en) * 1982-01-27 1986-08-27 Schering Aktiengesellschaft Diphosphonic acid derivatives and pharmaceutical preparations containing them
EP0084822B1 (en) * 1982-01-27 1986-01-08 Schering Aktiengesellschaft Diphosphonic acid derivatives and pharmaceutical preparations containing them
DE3428524A1 (en) * 1984-08-02 1986-02-13 Boehringer Mannheim Gmbh, 6800 Mannheim NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
US4687768A (en) * 1984-12-21 1987-08-18 The Procter & Gamble Company Certain hexahydroindan-2,2-diphosphonic acids useful in treating diseases associated with abnormal calcium and phosphate metabolism
IL77243A (en) * 1984-12-21 1996-11-14 Procter & Gamble Pharmaceutical compositions containing geminal diphosphonic acid compounds and certain such novel compounds
AU4859493A (en) * 1992-10-09 1994-05-09 Upjohn Company, The Pyrimidine bisphosphonate esters and (alkoxymethylphosphinyl)alkyl phosphonic acids as anti-inflammatories
SE9402001D0 (en) * 1994-06-09 1994-06-09 Leiras Oy Pyridyl bisphosphonates for use as a therapeutic agent

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