EP1246829A1 - Nouveaux heterocycles - Google Patents

Nouveaux heterocycles

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Publication number
EP1246829A1
EP1246829A1 EP00988160A EP00988160A EP1246829A1 EP 1246829 A1 EP1246829 A1 EP 1246829A1 EP 00988160 A EP00988160 A EP 00988160A EP 00988160 A EP00988160 A EP 00988160A EP 1246829 A1 EP1246829 A1 EP 1246829A1
Authority
EP
European Patent Office
Prior art keywords
independently
substituted
occurrence
absent
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00988160A
Other languages
German (de)
English (en)
Inventor
Manfred Weigele
David C. Dalgarno
George P. Luke
Tomi K. Sawyer
Regine Bohacek
William C. Shakespeare
Rajeswari Sundaramoorthi
Yihan Wang
Chester A. Metcalf, Iii
Chi B. Vu
Noriyuki H. Kawahata
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ariad Pharmaceuticals Inc
Original Assignee
Ariad Pharmaceuticals Inc
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Filing date
Publication date
Application filed by Ariad Pharmaceuticals Inc filed Critical Ariad Pharmaceuticals Inc
Priority claimed from US09/740,619 external-priority patent/US6420384B2/en
Publication of EP1246829A1 publication Critical patent/EP1246829A1/fr
Withdrawn legal-status Critical Current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

Definitions

  • osteoporosis which is characterized by a decrease in bone mass and deterioration in skeletal micro- 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.
  • 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.
  • the action of both osteoclasts and osteoblasts is controlled by a number of complex factors, and thus developing selective therapeutics has proven to be a difficult task.
  • osteoclast proton pump is a vacuolar H + -ATPase (see, Blair et al., Science 1989, 245, 855-857; Finbow et al., Biochem. J. 1997, 324, 691- 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.
  • 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.
  • proton pump an ATP-dependent transport of protons
  • many novel therapeutics developed to reduce bone resorption have focused on the inhibition of the proton pump to prevent osteoclast activity and excessive bone resorption.
  • 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 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 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).
  • osteoporosis many of the existing therapeutics that have been developed for the treatment of bone disorders such as osteoporosis are thought to act by inhibiting osteoclast activity.
  • estrogens, bisphosphonates, calcitonin, flavonoids, and selective estrogen receptor modulators are believed to act by the inhibition of osteoclast activity.
  • novel therapeutics have been developed to promote a fast increase in bone mineral content by promoting 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).
  • a significant problem of many of these therapetic agents is that they are not specific enough for bone tissue and thus may lead to unwanted adverse side effects.
  • 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.
  • certain novel bone targeting moieties themselves, as described herein also act as therapeutic agents for use in the treatment of bone disorders and/or other conditions.
  • the present invention provides compounds comprising a bone targeting moiety and a kinase inhibitor.
  • the present invention provides, in certain embodiments, compounds of Formula I, or pharmaceutically acceptable derivatives thereof.
  • a subject compound has the structure of Formula (I):
  • L and K independently, are absent or represent -M n -Y-M p -;
  • X, Y, and Z independently, are absent or represent NR, O, or S;
  • 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; p and n, independently, represent integers from 0-10, preferably from 0-5, even more preferably, from 0-3.
  • He represents a heterocycle, preferably a nitrogen-containing heterocycle
  • Tb represents a bone-targeting moiety preferably selected from: Vlll
  • R 4 independently for each occurrence represents H or lower alkyl, preferably H or C C 3 lower alkyl.
  • Tb is selected from i, v, vi, vii, viii, and ix
  • Z is preferably absent.
  • Tb is selected from ii, iii, and iv
  • Z may be absent or represent O or NR.
  • Tb is selected from x, xi, xii, xiii, xiv, and xv
  • Z may be absent or represent O or NR, preferably being absent.
  • I j represents H for all occurrences.
  • L represents alkyl-Y-alkyl, alkyl-Y-acyl, or alkyl.
  • the compound is free of hydrolyzable linkages. Hydrolyzable linkages, as the term is used herein, are saturated (sp -hybridized) carbons bound to two heteroatoms, of which at least one is selected from S, N, or O.
  • Cy represents a carbocycle or a nitrogen-bearing heterocycle. Cy is preferably uncharged.
  • 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.
  • 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.
  • Cy is phenyl.
  • K is absent.
  • K represents alkyl- Y-alkyl, alkyl- Y-acyl, or alkyl.
  • He represents a bicyclic structure, preferably including heteroatoms in both rings.
  • the ring(s) of He consist of C and N atoms.
  • He represents a bicyclic heteroaryl structure.
  • K is directly attached to a heteroatom of He, or X represents NR.
  • He includes at least one aryl substituent.
  • Hc-X taken together represent one of the following structures:
  • W represents O or S
  • 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 alkynyl, or alkanoyl, or taken together with the nitrogen to which it is attached, represent amidine, amide, carbamate, urea, or guanidine.
  • 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
  • Ri is selected from hydrogen, halogen, aryl, and heteroaryl.
  • R 2 is selected from hydrogen, (CH 2 ) n Ph, where Ph is phenyl or substituted phenyl and n is 0, 1, 2, or 3; heteroaryl, cycloalkyl, C ⁇ -C 6 alkanoyl, C ⁇ -C 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, C ⁇ - C alkyl, C -C 6 alkenyl, C 2 -C alkynyl, (CH 2 ) n Ph where Ph is phenyl and n is 0, 1, 2, or 3; cycloalkyl, heteroaryl, and R 5 and Re taken together with the nitrogen to which they are attached
  • Ri is a substituted aryl moiety selected from of monohaloaryl, dihaloaryl, monomethylaryl, and dimethylaryl.
  • at least one of Ri, R 2 , and R 3 , other than the bond to K, represents an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl.
  • Hc-X is represented by xvi or xvii
  • at least one of Ri, 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?
  • a bond to K is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroalkyl, alkyl alkenyl, alkyl alkynyl, alkyl cycloalkyl, or alkyl heterocyclyl.
  • , R 2 , and R 3 , other than the bond to K represents an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl.
  • R 2 represents a bond to K
  • 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.
  • R t is alkyl or branched alkyl and R 3 is aryl, heteroaryl, or cycloalkyl.
  • R 3 is selected from monohaloaryl, dihaloaryl, monohaloheteroaryl, dihaloheteroaryl, monohalocycloalkyl, or dihalocycloalkyl.
  • Tb is represented by vii or viii
  • the compound is free of hydrolyzable linkages.
  • L and K do not comprise nitrogen.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • R 4 represents H for all occurrences.
  • 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.
  • 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.
  • K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • Tb is represented by xi, xii, xiv, or xv.
  • K and L do not include an amide bond, or are preferably free of nitrogen atoms.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • the compound does not include a hydrolyzable linkage.
  • R represents H for all occurrences.
  • 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.
  • 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.
  • K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • 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.
  • K does not include an amide bond, or is preferably free of nitrogen atoms.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • the compound does not include a hydrolyzable linkage.
  • i represents H for all occurrences.
  • 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.
  • 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
  • K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • K does not include an amide bond, is free of carbonyls, is free of amine substituents, or is free of nitrogen atoms.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • the compound does not include a hydrolyzable linkage.
  • R 4 represents H for all occurrences.
  • 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.
  • Cy represents a fused ring system
  • one substituent of L and K may be attached to one of the two rings, and the other substituent to the other of the two rings.
  • K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • Tb is represented by ii, iii, iv, or v
  • the compound does not include a hydrolyzable linkage.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • R 4 represents H for all occurrences.
  • 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.
  • Cy represents a fused ring system
  • one substituent of L and K may be attached to one of the two rings, and the other substituent to the other of the two rings.
  • K is directly attached to a heteroatom of He.
  • K is absent.
  • Cy is preferably uncharged, and/or L-Cy-K is preferably free of hydrolyzable linkages. In certain embodiments, the compound is free of hydrolyzable linkages.
  • Cy is preferably selected from aryl, carbocyclic, nitrogen-containing heterocyclic, and nitrogen-containing heteroaryl groups, and preferably does not include S or O atoms in the ring structure. In preferred embodiments, Cy contains 0 or 1 heteroatoms.
  • 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.
  • 1 ⁇ represents H for all occurrences.
  • 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.
  • Cy represents a fused ring system
  • one substituent of L and K may be attached to one of the two rings, and the other substituent to the other of the two rings.
  • K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • Cy is preferably uncharged, and/or L-Cy-K is preferably free of hydrolyzable linkages.
  • Cy is preferably selected from aryl, carbocyclic, nitrogen-containing heterocyclic, and nitrogen-containing heteroaryl groups, and preferably does not include S or O atoms in the ring structure.
  • the ring system of Cy contains 0 or 1 heteroatoms.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • 1 ⁇ represents H for all occurrences.
  • 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.
  • Cy represents a fused ring system
  • one substituent of L and K may be attached to one of the two rings, and the other substituent to the other of the two rings.
  • K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • Cy represents an aryl or heteroaryl group, such as a phenyl or pyridyl group.
  • Cy is preferably uncharged, and/or the compound is preferably free of hydrolyzable linkages.
  • Cy is preferably selected from aryl, carbocyclic, nitrogen-containing heterocyclic, and nitrogen-containing heteroaryl groups, and preferably does not include S or O atoms in the ring structure.
  • the ring system of Cy contains 0 or 1 heteroatoms, or is preferably phenyl.
  • He represents heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • 1 ⁇ represents H for all occurrences.
  • 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.
  • one substituent of L and K may be attached to one of the two rings, and the other substituent to the other of the two rings.
  • K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • Tb is selected from i and ix, and K is absent or represents -Y-, such as -NH-.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • Cy is aryl or heteroaryl, preferably aryl.
  • He is further substituted with an aryl group, e.g., at a position of Ri, R 2 , and R 3 not substituted with K.
  • each of Rj, R 2 , and R 3 represents a hydrocarbon substituent.
  • L represents alkyl, alkyl- Y-alkyl or alkyl- Y-acyl, wherein Y is preferably NR, such as NH or NMe.
  • Tb is x and K is absent.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • He is further substituted with an aryl group, e.g., at a position of R ⁇ , R 2 , and R 3 not substituted with K.
  • each of Ri, R 2 , and R 3 represents a hydrocarbon substituent.
  • L represents alkyl, alkyl- Y-alkyl or alkyl- Y-acyl, wherein Y is preferably NR, such as NH or NMe.
  • a subject compound has the structure of Formula (II):
  • He, X, K, Z, and Tb are as defined above.
  • Tb is selected from x, xi, xii, xiii, xiv, and xv.
  • Z may be absent or represent O or NR, preferably being absent.
  • R represents H for all occurrences.
  • the compound is free of hydrolyzable linkages.
  • Hydrolyzable linkages as the term is used herein, are saturated (sp -hybridized) carbons bound to two heteroatoms, of which at least one is selected from S, N, or O.
  • K is absent.
  • K represents alkyl- Y-alkyl, alkyl- Y-acyl, or alkyl.
  • He represents a bicyclic structure, preferably including heteroatoms in both rings.
  • the ring(s) of He consist of C and N atoms.
  • K is directly attached to a heteroatom of He, or X represents NR.
  • He includes at least one aryl substituent.
  • Hc-X taken together represent one of the following structures:
  • W represents O or S
  • one of R ⁇ , R 2 , and R 3 represents a bond to K
  • 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.
  • 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
  • R t is selected from hydrogen, halogen, aryl, and heteroaryl.
  • R 2 is selected from hydrogen, (CH 2 ) n Ph, where Ph is phenyl or substituted phenyl and n is 0, 1, 2, or 3; heteroaryl, cycloalkyl, C ⁇ -C 6 alkanoyl, C ⁇ -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 e are independently hydrogen, C ⁇ - C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (CH 2 ) n Ph where Ph is phenyl and n is 0, 1, 2, or 3; cycloalkyl, heteroaryl, and R 5 and R ⁇ taken together with the nitrogen
  • Ri is a substituted aryl moiety selected from of monohaloaryl, dihaloaryl, monomethylaryl, and dimethylaryl.
  • at least one of Ri, R 2 , and R 3 , other than the bond to K, represents an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl.
  • R 2 represents a bond to K
  • 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.
  • Ri is alkyl or branched alkyl and R 3 is aryl, heteroaryl, or cycloalkyl.
  • R 3 is selected from monohaloaryl, dihaloaryl, monohaloheteroaryl, dihaloheteroaryl, monohalocycloalkyl, or dihalocycloalkyl.
  • at least one of Ri, R 2 , and R 3 , other than the bond to K, represents an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl.
  • At least one of Ri, R 2 , or R 3 represents a bond to K
  • R 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
  • Ri 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.
  • at least one of Ri, R 2 , and R 3 other than the bond to K, represents an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl.
  • Tb is represented by vii or viii
  • the compound is free of hydrolyzable linkages.
  • K does not comprise nitrogen.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • R 4 represents H for all occurrences.
  • K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • Tb is represented by xi, xii, xiv, or xv.
  • K does not include an amide bond, or are preferably free of nitrogen atoms.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • the compound does not include a hydrolyzable linkage.
  • R/» represents H for all occurrences.
  • K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • 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.
  • K does not include an amide bond, or is preferably free of nitrogen atoms.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • the compound does not include a hydrolyzable linkage.
  • R represents H for all occurrences.
  • K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • K does not include an amide bond, is free of carbonyls, is free of amine substituents, or is free of nitrogen atoms.
  • the compound does not include a hydrolyzable linkage.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • I represents H for all occurrences.
  • K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • Tb is represented by ii, iii, iv, or v
  • the compound does not include a hydrolyzable linkage.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • R represents H for all occurrences.
  • K is directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • the compound is preferably free of hydrolyzable linkages. In certain embodiments, the compound is free of hydrolyzable linkages. 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, 1 ⁇ 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.
  • 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, 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.
  • Tb is selected from i and ix, and K is branched or unbranched alkyl.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • He is further substituted with an aryl group, e.g., at a position of Ri, R 2 , and R 3 not substituted with K.
  • each of Ri, R 2 , and R 3 represents a hydrocarbon substituent.
  • Tb is xii
  • K is absent or represents -
  • Y- such as -NH-.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • He is further substituted with an aryl group, e.g., at a position of Rj, R 2 , and R 3 not substituted with K.
  • each of R ⁇ , R , and R 3 represents a hydrocarbon substituent.
  • Tb is x
  • K represents alkyl or -Y-.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • He is further substituted with an aryl group, e.g., at a position of Ri, R 2 , and R 3 not substituted with K.
  • each of Ri, R 2 , and R 3 represents a hydrocarbon substituent.
  • Tb represents
  • compositions comprising any one of the compounds of the present invention, or a pharmaceutically acceptable derivative thereof, and one or more pharmaceutically acceptable excipients.
  • 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.
  • inventive methods using a pharmaceutical composition comprising a bone targeted compound which is capable of inhibiting bone resorption.
  • method using a pharmaceutical composition comprising a bone targeted compound that specifically acts as a Src kinase inhibitor.
  • a bone targeted compound of the present invention having a pay load attached thereto that is capable of treating bone disorders by other means.
  • 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.
  • 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, 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.
  • 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 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 pharmacologically active species.
  • 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 Niemi et al., J Med. Chem. 1999, 42, 5053-5058.
  • inhibitors 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 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).
  • the 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.
  • inventive compositions show specific inhibition of Src kinase activity as compared with the activity of non-Src kinanses, or kinases located at sites away from bone.
  • such specific inhibition may result from specific localization of the inventive composition to bone sites, so that compositions 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.
  • 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).
  • therapeutic agents e.g., a small molecule, a drug, a radiotherapeutic atom, etc.
  • detectable labels e.g., fluorescent, radioactive, radiopaque, etc.
  • any other moiety desired to be delivered to a site of action e.g., a bone or other site suffering an abnormal condition.
  • 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.).
  • 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.
  • a target may be a type of tissue, e.g., bone.
  • a preferred target is bone.
  • target cells include osteoclasts.
  • 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.
  • 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 scope of the present invention include boron-containing compounds (e.g.
  • 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 target nucleic acid sequence (e.g., mRNA sequence)), peptides, photodynamic agents (e.g., rhodamine 123), radionuclides (e.g., 1-131, Re-186, Re-188, Y-90, Bi-212,
  • drugs e
  • 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.
  • the therapeutic agent is a Src kinase inhibitor, capable of inhibiting the overactivity of osteoclasts.
  • R group will generally have the structure which is recognized in the art as corresponding to R groups having that name.
  • representative R groups as enumerated in the specification and claims of the present application are defined herein. These definitions are intended to supplement and illustrate, not preclude, the definitions known to those of skill in the art.
  • alkyl refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and more preferably 20 or fewer.
  • preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
  • 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 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 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.
  • a halogen such as a carboxy
  • the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include substituted and unsubstituted forms 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), -CF3, -CN and the like.
  • Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.
  • aralkyl 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 ) n Ph, where Ph is phenyl or substituted phenyl, and n is 1, 2, or 3.
  • 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.
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, “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.
  • aryl as used herein includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, fiiran, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • 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, 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, -CF3, -CN, or the like.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common 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.
  • ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively.
  • the names 1 ,2-dimethylbenzene and ortho- dimethylbenzene are synonymous.
  • 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, 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, phenoxazine, pyrrolidine, o
  • 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, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,
  • 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". 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 heteroaromatic moiety, -CF3, -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl
  • carrier refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.
  • nitro means -NO2; the term “halogen” designates - F, -CI, -Br or -I; the term “sulfhydryl” means -SH; the term “hydroxyl” means -OH; and the term “sulfonyl” means -SO2-.
  • 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:
  • R9, R ⁇ Q and R' ⁇ Q each independently represent a hydrogen, an alkyl, an alkenyl, -(CH2) m -R-8' or R9 a 10 " &10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure;
  • Rg 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.
  • RlO can be a carbonyl, e.g., RQ, RI O and the nitrogen together do not form an imide.
  • RQ and Ri Q (and optionally R' IO) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2) m -R8-
  • 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 RQ and Ri Q is an alkyl group.
  • acylamino is art-recognized and refers to a moiety that can be represented by the general formula:
  • R 9 is as defined above, and R' ⁇ ⁇ represents a hydrogen, an alkyl, an alkenyl or -(CH2)n_-R8, where m and Rg are as defined above.
  • amino is art recognized as an amino-substituted carbonyl and includes a moiety that can be represented by the general formula:
  • RQ, RJQ are as defined above.
  • Preferred embodiments of the amide will not include imides which may be unstable.
  • amidine is art-recognized as a group that can be represented by the general formula:
  • alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto.
  • the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2) m -R-8' wherein m and Rg are defined above.
  • Representative alkylthio groups include methylthio, ethyl thio, and the like.
  • carbonyl is art recognized and includes such moieties as can be represented by the general formula:
  • X is a bond or represents an oxygen or a sulfur
  • Ri ⁇ represents a hydrogen, an alkyl, an alkenyl, -(CH2) m -R.8 or a pharmaceutically acceptable salt
  • R' ⁇ ⁇ represents a hydrogen, an alkyl, an alkenyl or -(CH2) m -R8 > where m and Rg are as defined above.
  • X is an oxygen and R ⁇ ⁇ or R' ⁇ ⁇ is not hydrogen
  • the formula represents an "ester”.
  • X is an oxygen
  • R ⁇ ⁇ is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R ⁇ ⁇ is a hydrogen, the formula represents a "carboxylic acid".
  • 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.
  • the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(CH2) -Rg, where m and
  • R41 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
  • triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, -toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively.
  • triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, p- toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
  • Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, /.-toluenesulfonyl and methanesulfonyl, respectively.
  • a more comprehensive list of the abbreviations 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, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
  • R41 is as defined above.
  • sulfonyl refers to a moiety that can be represented by the general formula:
  • R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • sulfoxido refers to a moiety that can be represented by the general formula:
  • R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.
  • a "phosphoryl” can in general be represented by the formula:
  • OR 46 wherein Q represented S or O, and R46 represents hydrogen, a lower alkyl or an aryl.
  • R46 represents hydrogen, a lower alkyl or an aryl.
  • each expression e.g. alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • 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 compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • 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 permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • 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 of organic compounds .
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2 nd 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, including cis- and tr ⁇ s-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. Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention.
  • 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 contemplated for more complex isomer mixtures.
  • 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.
  • 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 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.
  • the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, 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.
  • 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.
  • the present invention provides compounds, pharmaceutical compositions and methods of selective treatment of metabolic bone disorders.
  • these compounds and compositions are used to treat disorders resulting from overactive osteoclast function.
  • these compounds and compositions are used to treat osteoporosis.
  • the present invention provides novel compounds comprising a bone targeting moiety and a payload.
  • 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 mechanism that affects the functioning of osteoclast or osteoblast cells.
  • the bone targeting agents themselves act as selective and potent inhibitors of osteoclast function.
  • compositions comprising a compound having the structure of Formula (I):
  • L and K independently, are absent or represent -M n -Y-M p -;
  • X, Y, and Z, independently, are absent or represent NR, O, or S;
  • 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; p and n, independently, represent integers from 0-10, preferably from 0-5, even more preferably, from 0-3.
  • He represents a heterocycle, preferably a nitrogen-containing heterocycle
  • Tb represents a bone-targeting moiety preferably selected from:
  • R 4 independently for each occurrence, represents H, lower alkyl, or a pharmaceutically active small molecule or a prodrug form thereof, preferably H or d- C 3 lower alkyl.
  • Tb is selected from i, v, vi, vii, viii, and ix
  • Z is preferably absent.
  • Tb is selected from ii, iii, and iv, Z may be absent or represent O or NR.
  • Tb is selected from x, xi, xii, xiii, xiv, and xv
  • Z may be absent or represent O or NR, preferably being absent.
  • R represents H for all occurrences.
  • L represents alkyl- Y-alkyl, alkyl-Y-acyl, or alkyl.
  • L-Cy-K-X-Hc is free of hydrolyzable linkages.
  • Hydrolyzable linkages are saturated (sp -hybridized) carbons bound to two heteroatoms, of which at least one is selected from S, N, or O.
  • Cy represents a carbocycle or a nitrogen-bearing heterocycle. Cy is preferably uncharged.
  • Cy is substituted with a second bone-targeting group (Tb), optionally through a linking group (such as -L-Z-).
  • Cy represents a phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system, preferably having between 8 and 1 1 atoms, such as a fused cyclohexyl/cyclopentyl ([4.3.0] -bicyclononane) ring system.
  • 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.
  • Cy is phenyl.
  • K is absent.
  • K represents alkyl-Y-alkyl, alkyl-Y-acyl, or alkyl.
  • He represents a bicyclic structure, preferably including heteroatoms in both rings.
  • the ring(s) of He consist of C and N atoms.
  • He represents a bicyclic heteroaryl structure.
  • K is directly attached to a heteroatom of He, or X represents NR.
  • He includes at least one aryl substituent.
  • Hc-X taken together represent one of the following structures:
  • W represents O or S
  • one of Rj, R , and R 3 represents a bond to K
  • the others represent, independently, hydrogen, halogen, 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.
  • 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
  • Ri is selected from hydrogen, halogen, aryl, and heteroaryl.
  • R 2 is selected from hydrogen, (CH 2 ) n Ph, where Ph is phenyl or substituted phenyl and n is 0, 1, 2, or 3; heteroaryl, cycloalkyl, CpC .
  • alkanoyl, Cj-C ⁇ 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 , phenyl, thioalkyl, alkyloxy, hydroxy, carboxy, halogen, cycloalkyl, and where R 5 and R ⁇ s are independently hydrogen, Cj- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (CH 2 ) n Ph where Ph is phenyl and n is 0, 1 , 2, or 3; cycloalkyl, heteroaryl, and R 5 and Re 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.
  • R ⁇ is a substituted aryl moiety selected from of monohaloaryl, dihaloaryl, monomethylaryl, and dimethylaryl.
  • R 2 represents a bond to K
  • 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.
  • Ri is alkyl or branched alkyl and R 3 is aryl, heteroaryl, or cycloalkyl.
  • R 3 is selected from monohaloaryl, dihaloaryl, monohaloheteroaryl, dihaloheteroaryl, monohalocycloalkyl, or dihalocycloalkyl.
  • 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.
  • At least one of Ri, 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
  • Ri 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.
  • at least one of Ri, R 2 , and R 3 other than the bond to K, represents an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl.
  • L-Cy-K-X-Hc is free of hydrolyzable linkages.
  • L and K do not comprise nitrogen.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • R represents H for all occurrences.
  • 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.
  • 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.
  • K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • Tb is represented by xi, xii, xiv, or xv.
  • K and L do not include an amide bond, or are preferably free of nitrogen atoms.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • L-Cy-K-X-Hc does not include a hydrolyzable linkage.
  • R represents H for all occurrences.
  • 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.
  • 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.
  • K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • 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.
  • K does not include an amide bond, or is preferably free of nitrogen atoms.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • L-Cy-K-X-Hc does not include a hydrolyzable linkage.
  • 1 ⁇ represents H for all occurrences.
  • 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.
  • 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
  • K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • K does not include an amide bond, is free of carbonyls, is free of amine substituents, or is free of nitrogen atoms.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • L-Cy-K-X- Hc does not include a hydrolyzable linkage.
  • 1 ⁇ represents H for all occurrences.
  • 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.
  • 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.
  • K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • L-Cy-K- X-Hc does not include a hydrolyzable linkage.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • 1 ⁇ represents H for all occurrences.
  • 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.
  • Cy represents a fused ring system
  • one substituent of L and K may be attached to one of the two rings, and the other substituent to the other of the two rings.
  • K is directly attached to a heteroatom of He.
  • K is absent.
  • 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.
  • Cy is preferably selected from aryl, carbocyclic, nitrogen-containing heterocyclic, and nitrogen-containing heteroaryl groups, and preferably does not include S or O atoms in the ring structure. In preferred embodiments, Cy contains 0 or 1 heteroatoms.
  • He represents a heterocyclic bicycle. In certain embodiments, He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • R 4 represents H for all occurrences.
  • 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.
  • 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.
  • K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • Cy is preferably uncharged, and/or L-Cy-K is preferably free of hydrolyzable linkages.
  • Cy is preferably selected from aryl, carbocyclic, nitrogen-containing heterocyclic, and nitrogen-containing heteroaryl groups, and preferably does not include S or O atoms in the ring structure.
  • the ring system of Cy contains 0 or 1 heteroatoms.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • R 4 represents H for all occurrences.
  • 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.
  • Cy represents a fused ring system
  • one substituent of L and K may be attached to one of the two rings, and the other substituent to the other of the two rings.
  • K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • Cy represents an aryl or heteroaryl group, such as a phenyl or pyridyl group.
  • Cy is preferably uncharged, and/or L-Cy-K- X-Hc is preferably free of hydrolyzable linkages.
  • Cy is preferably selected from aryl, carbocyclic, nitrogen-containing heterocyclic, and nitrogen-containing heteroaryl groups, and preferably does not include S or O atoms in the ring structure.
  • the ring system of Cy contains 0 or 1 heteroatoms, or is preferably phenyl.
  • He represents heterocyclic bicycle.
  • 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 cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system.
  • one substituent of L and K may be attached to one of the two rings, and the other substituent to the other of the two rings.
  • K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • Tb is selected from i and ix, and K is absent or represents -Y-, such as -NH-.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • Cy is aryl or heteroaryl, preferably aryl.
  • He is further substituted with an aryl group, e.g., at a position of R ls R 2 , and R 3 not substituted with K.
  • each of Ri, R 2 , and R 3 represents a hydrocarbon substituent.
  • L represents alkyl, alkyl-Y-alkyl or alkyl- Y-acyl, wherein Y is preferably NR, such as NH or NMe.
  • Tb is x and K is absent.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • He is further substituted with an aryl group, e.g., at a position of Rj, R 2 , and R 3 not substituted with K.
  • each of Ri, R 2 , and R 3 represents a hydrocarbon substituent.
  • L represents alkyl, alkyl-Y-alkyl or alkyl- Y-acyl, wherein Y is preferably NR, such as NH or NMe.
  • a subject compound has the structure of Formula (II):
  • He, X, K, Z, and Tb are as defined above.
  • Tb is selected from x, xi, xii, xiii, xiv, and xv.
  • Z may be absent or represent O or NR, preferably being absent.
  • Tb is selected from i, v, vi, vii, viii, and ix, Z is preferably absent.
  • Tb is selected from ii, iii, and iv, Z may be absent or represent O or NR.
  • R 4 represents H for all occurrences.
  • K-X-Hc is free of hydrolyzable linkages.
  • Hydrolyzable linkages as the term is used herein, are saturated (sp -hybridized) carbons bound to two heteroatoms, of which at least one is selected from S, N, or O.
  • K is absent.
  • K represents alkyl-Y-alkyl, alkyl- Y-acyl, or alkyl.
  • He represents a bicyclic structure, preferably including heteroatoms in both rings.
  • the ring(s) of He consist of C and N atoms.
  • K is directly attached to a heteroatom of He, or X represents NR.
  • He includes at least one aryl substituent.
  • Hc-X taken together represent one of the following structures:
  • W represents O or S
  • one of Ri, R 2 , and R 3 represents a bond to K
  • the others represent, independently, hydrogen, halogen, 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.
  • 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
  • Ri is selected from hydrogen, halogen, aryl, and heteroaryl.
  • R 2 is selected from hydrogen, (CH 2 ) n Ph, where Ph is phenyl or substituted phenyl and n is 0, 1, 2, or 3; heteroaryl, cycloalkyl, C ⁇ -C 6 alkanoyl, C ⁇ -C alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, where the alkyl, alkenyl and alkynyl groups may be substituted by NR R ⁇ , phenyl, thioalkyl, alkyloxy, hydroxy, carboxy, halogen, cycloalkyl, and where R 5 and R ⁇ are independently hydrogen, C ⁇ - C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (CH 2 ) n Ph where Ph is phenyl and n is 0, 1, 2, or 3; cycloalkyl, heteroaryl, and R 5 and R ⁇ taken together with the
  • R] is a substituted aryl moiety selected from of monohaloaryl, dihaloaryl, monomethylaryl, and dimethylaryl.
  • at least one of Ri, R 2 , and R , other than the bond to K, represents an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl.
  • R 2 represents a bond to K
  • 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.
  • Ri is alkyl or branched alkyl and R 3 is aryl, heteroaryl, or cycloalkyl.
  • R 3 is selected from monohaloaryl, dihaloaryl, monohaloheteroaryl, dihaloheteroaryl, monohalocycloalkyl, or dihalocycloalkyl.
  • At least one of Ri, 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
  • R l5 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.
  • at least one of Ri, R 2 , and R 3 other than the bond to K, represents an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl.
  • Tb is represented by vii or viii
  • K-X-Hc is free of hydrolyzable linkages.
  • K does not comprise nitrogen.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • R represents H for all occurrences.
  • K is preferably directly attached to a heteroatom of He.
  • K is absent.
  • Tb is represented by xi, xii, xiv, or xv.
  • K does not include an amide bond, or are preferably free of nitrogen atoms.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • K-X-Hc does not include a hydrolyzable linkage.
  • ILj represents H for all occurrences.
  • K is preferably directly attached to a heteroatom of He.
  • K is absent.
  • 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.
  • K does not include an amide bond, or is preferably free of nitrogen atoms.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • K-X-Hc does not include a hydrolyzable linkage.
  • R 4 represents H for all occurrences.
  • K is preferably directly attached to a heteroatom of He.
  • K is absent.
  • K does not include an amide bond, is free of carbonyls, is free of amine substituents, or is free of nitrogen atoms. .
  • K-X-Hc does not include a hydrolyzable linkage.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • R 4 represents H for all occurrences.
  • K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • K-X-Hc does not include a hydrolyzable linkage.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • 1 ⁇ represents H for all occurrences.
  • K is directly attached to a heteroatom of He.
  • K is absent.
  • K-X-Hc is preferably free of hydrolyzable linkages.
  • the compound is free of hydrolyzable linkages.
  • He represents a heterocyclic bicycle.
  • He represents a bicyclic heteroaryl structure.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • R 4 represents H for all occurrences.
  • K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • 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 embodiments wherein X is absent, K is preferably directly attached to a heteroatom of He. In certain embodiments, K is absent.
  • Tb is selected from i and ix, and K is branched or unbranched alkyl.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • He is further substituted with an aryl group, e.g., at a position of Ri, R 2 , and R 3 not substituted with K.
  • each of R 1 ; R 2 , and R 3 represents a hydrocarbon substituent.
  • Tb is xii, and K is absent or represents - Y-, such as -NH-.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • He is further substituted with an aryl group, e.g., at a position of Rj, R 2 , and R 3 not substituted with K.
  • each of Ri, R 2 , and R 3 represents a hydrocarbon substituent.
  • Tb is x, and K represents alkyl or -Y-.
  • He is selected from xvi, xvii, xviii, xix, and xx.
  • He is further substituted with an aryl group, e.g., at a position of Ri, R 2 , and R 3 not substituted with K.
  • each of Ri, R 2 , and R 3 represents a hydrocarbon substituent.
  • 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.
  • 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.
  • Tb represents i, ii, iii, or iv, preferably i.
  • Tb represents v or vi.
  • Tb represents vii or viii.
  • Tb represents ix.
  • V represents NR 2 . In certain embodiments, all occurrences of R in V are H.
  • Tb is selected from x, xi, xii, xiii, xiv, xv, xxi, xxii, xxiiv, and xxv. In certain embodiments, Tb is selected from xi, xii, xiv, or xv. In 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.
  • 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.
  • Tb represents i, ii, iii, or iv, preferably i.
  • Tb represents v or vi.
  • Tb represents vii or viii.
  • Tb represents ix.
  • L is absent.
  • Cy represents a phenyl ring.
  • V represents NR 2 .
  • all occurrences of R in V are H.
  • L represents lower alkyl or is absent.
  • a subject compound has the structure of Formula V: Tb-L-U, wherein Tb, R, and L are as defined above, and U represents a sulfonate ester (e.g., triflate, tosylate, mesylate, etc.), halogen
  • a suitable leaving group e.g., a moiety whose conjugate acid, UH, has a pKa lower than 5, preferably lower than 0.
  • 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.
  • Tb represents i, ii, iii, or iv, preferably i.
  • Tb represents v or vi.
  • Tb represents vii or viii.
  • Tb represents ix.
  • Tb is selected from x, xi, xii, xiii, xiv, xv, xxi, xxii, xxiiv, and xxv. In certain embodiments, Tb is selected from xi, xii, xiv, or xv. In 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.
  • 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.
  • Tb represents i, ii, iii, or iv, preferably i.
  • Tb represents v or vi.
  • Tb represents vii or viii.
  • Tb represents ix.
  • L is absent.
  • Cy represents a phenyl ring.
  • Tb represents:
  • Tb may have a structure selected from:
  • each occurence of Y is independently a covalent bond, -O-, -S-, or -N(Rj) 2 , wherein Rj, for each occurence, is independently hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl;
  • Re 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, -(CH 2 )palkyl, -(CH 2 )palkenyl, - (CH 2 ) p alkynyl, -(CH 2 ) p aryl, -(CH 2 ) p aralkyl, -(CH 2 ) p OH, -(CH 2 ) p O-lower alkyl, - (CH 2 ) p O-lower alkenyl
  • M, where it occurs in Tb is selected from CH 2 , CHJ and CJ 2 , wherein J represents a halogen, such as F, CI, Br, or I, preferably F or CI, even more preferably F.
  • J represents a halogen, such as F, CI, Br, or I, preferably F or CI, even more preferably F.
  • Re is selected from lower alkyl, hydrophilic groups, and lower alkyl substituted with hydrophilic groups.
  • Representative hydrophilic groups include hydroxyl, sulfhydryl, amino, amido, carboxyl, sulfonate, phosphonate, and salts thereof.
  • Tb has the structure xxxxii:
  • A represents a group selected from GPO 3 (R 4 ) 2 , GCO 2 R , and GSO ⁇ ;
  • B represents a group selected from NH 2 , OH, GPO 3 (P M ) 2 , GCO 2 R J , and GSO ⁇ ; and G is absent or represents a linkage of one or two atoms, such as CF 2 , CH 2 , O, S, NR, CH 2 S, CH 2 NR, CH 2 O, etc.
  • the phenyl ring may bear one or more additional R$ substituents.
  • G is absent, while in other embodiments, G is present. In certain embodiments, at least one occurrence of G is absent.
  • Tb has a structure such as: In certain embodiments of Formulas I -VI, Tb has the structure xxxxiii:
  • the pyridyl ring may bear one or more additional R ⁇ substituents.
  • Tb has the structure xxxxiv or xxxxv:
  • C represents H, R ⁇ , NH 2 , OH, GPO 3 (R 4 ) 2 , G ⁇ I ⁇ , or GSO ⁇ , 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.
  • the pyridyl ring may bear one or more additional e substituents.
  • 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 substituents.
  • the heteroaryl group is selected from thiazoline, oxazoline, pyrrole, pyrazole, imidazole, pyridine, pyrazine, pyridazine, and pyrimidine, preferably pyridine, pyrazole, pyrazine, and pyrimidine.
  • inventive compounds may be prepared by any available method.
  • solid-phase syntheses will be modified versions of the compounds described herein that allow their attachment to a solid support.
  • the present invention also contemplates particularly preferred because it enables the use of more rapid split and pool techniques to generate larger libraries (e.g., greater than 10,000 members) more easily.
  • 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 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 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 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.
  • 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 from toluene to water.
  • 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 interaction between the library member and the solid support may be desirable.
  • linking reagent may be useful if more facile cleavage of the inventive library members from the solid support is desired.
  • any linking reagent used in the present invention may comprise a single linking molecule, or alternatively may comprise a linking molecule and one or 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.
  • photocleavable linkers are employed to attach the solid phase resin to the component. Photocleavable linkers are particularly advantageous for the presently claimed invention because of the ability to use these linkers in in vivo screening strategies.
  • Exemplary photocleavable linkers include, but are not limited to ortho-Nitrobenzyl photolinkers and dithiane protected benzoin photolinkers.
  • One of 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.
  • the synthesis of libraries of bone 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, 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 synthesized, the specific reaction chemistry, and the availability of specific instrumentation, such as robotic instrumentation for the preparation and analysis of the inventive libraries.
  • 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.
  • 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.
  • a parallel synthesis technique is utilized, in which all of the products are assembled separately in their own reaction vessels.
  • 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 reactant A, and m variants of reactant B, to obtain n x m variants, in n x m wells.
  • reactant A and m variants of reactant B, to obtain n x m variants, in n x m wells.
  • a solid phase synthesis technique 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.
  • One of the most significant advantages 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.
  • 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 number of reagents is reacted with the scaffold structures to yield the inventive library.
  • 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, 60)
  • an encoding technique involves the use of a particular "identifiying agent" attached to the solid support, which enables the determination of the structure of a specific library member without reference to its spatial coordinates.
  • an encoding technique involves the use of a particular "identifiying agent" attached to the solid support, which enables the determination of the structure of a specific library member without reference to its spatial coordinates.
  • an encoding technique involves the use of a particular "identifiying agent" attached to the solid support, which enables the determination of the structure of a specific library member without reference to its spatial coordinates.
  • an encoding technique involves the use of a particular "identifiying agent" attached to the solid support, which enables the determination of the structure of a specific library member without reference to its spatial coordinates.
  • Examples of alternative encoding techniques that can be utilized in the present 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.
  • Examples of preferred spectrophotometic encoding methods include the use of mass spectroscopy, fluorescence emission, and nuclear magnetic resonance spectroscopy.
  • 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 the art will realize that the particular encoding method to be used in the present 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.
  • 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.
  • 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 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.
  • 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.
  • inventive compounds effect treatment via several mechanisms, (i.e. 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.
  • the present invention provides an inhibitor of mammalian osteoclasts, for example any one of the compounds of the present invention or a pharmaceutical composition thereof.
  • the present invention provides compounds or pharmaceutical compositions that are selective Src kinase inhibitors.
  • 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.
  • 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.
  • 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 osteoporosis, juvenile osteoporosis, idiopathic osteoporosis, endocrine abnormality, hyperthyroidism, hypogonadism, ovarian agensis or Turner's syndrome, hyperadrenocortogni or Cushing's syndrome, hyperparathyroidism, bone marrow abnormalities, multiple myeloma and related disorders, systemic mastocytosis, disseminated carcinoma, Gaucher's disease, connective tissue abnormalities, osteogenesis imperfect
  • 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.
  • the payloads may be categorized as therapeutic agents (such as Src kinase inhibitors) or imaging agents. Imaging agents comprise those payloads which are detectable, e.g., by emitting light, radioactive emissions, or chemical signals, by absorbing radiation (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 chemical entities, e.g., an enzyme, drug, radionuclide, enzyme inhibitor, etc.
  • 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 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 derivative
  • 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 glycosides, antianginals and vasodilators; coenzymes; enzymes; enzyme inhibitors; expectorants; glycoproteins; H-2 antagonists such as nizatidine, cimetidine, 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.
  • toxins such as aflatoxin, digoxin, rubratoxin, and xanthotoxin
  • tranquilizers such as diazepam, chordiazepoxide, oxazepam, alprazolam, and triazolam
  • 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
  • the compounds and compositions of the present invention are also inhibitors of cathepsin K, and thus can be used to treat bone disorders.
  • cathepsin K 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 in bone resorption (Smith et al., Exp. Opin. Ther. Patents 1999, 9, 683-694 and references cited therein).
  • 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 cathepsin K gene and the rare skeletal dysplasia, pycnodysostosis, a disease characterized by abnormal bone resorption (see, Smith et al.).
  • 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.
  • 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 1-123.
  • Preferred imaging agents for magnetic resonance imaging (MRI) include an appropriate atom with unpaired spin electrons or a free radical.
  • 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 detected using positron emission tomography (PET) or Single Photon Emission
  • the imaging agent of the invention contains a radionuclide selected from the group consisting of I, I, I , 99m Tc, 18 F, 68 Ga, 67 Ga, 72 As, 89 Zr, 64 Cu, 62 Cu, u l In, 203 Pb, I98 Hg, ⁇ C, 97 Ru, and 201 T1 or a paramagnetic contrast agent, such as gadolinium, cobalt, nickel, manganese, and iron.
  • SPECT Computed Tomography
  • the compounds of the present invention are useful in the treatment of bone disorders, preferably imbalances in bone metabolism, such as overactivity of bone resorption.
  • the compounds of the present invention are useful as inhibitors of Src tyrosine phosphorylation.
  • the compounds of the present invention When used for therapeutic and/or prophylactic administration, they can exist in free form, or, where appropriate, in salt 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.
  • 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.
  • compositions comprising a therapeutically (or prophylactically) effective amount of the compound, and a pharmaceutically acceptable carrier or excipient.
  • Carriers include, e.g., saline, 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 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.
  • 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- disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • 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 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 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 regulators, stabilizers or osmo-regulators.
  • suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, 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).
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carders are useful in sterile liquid form 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 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.
  • time delay material such as glyceryl monostearate or glyceryl distearate along or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.
  • Tween 80 in PHOSAL PG-50 phospholipid concentrate with 1 ,2-propylene glycol, A. Nattermann & Cie. GmbH
  • PHOSAL PG-50 phospholipid concentrate with 1 ,2-propylene glycol, A. Nattermann & Cie. GmbH
  • a solid carrier the preparation can be tableted, placed in a hard gelatin capsule in powder or 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 lg.
  • a liquid carrier 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.
  • 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.
  • 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 thereof.
  • suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin, polyoxyethylated 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 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 abso ⁇ tion through epithelial or mucocutaneous linings (e.g. oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local.
  • preferred routes are oral, nasal or via a bronchial aerosol or nebulizer.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the composition may also include a solubilizing agent and a local anesthetic to ease pain at the side of the injection.
  • 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.
  • a hermetically sealed container such as an ampoule or sachette indicating the quantitity of active agent.
  • the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • 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.
  • the compound is 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.
  • Topical carriers include liquid petroleum, isopropyl palmitate, 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.
  • the compound may be 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.
  • the effective dose of the compound will typically be in the range of about 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 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 techniques.
  • 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, 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.
  • the present invention relates to a kit for conveniently and effectively carrying out the methods in accordance with the present invention.
  • 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.
  • 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 include a card having the dosages oriented in the order of their intended use.
  • 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.
  • placebo dosages, or calcium dietary supplements 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.
  • 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 cone. HCl.
  • the aqueous layer was extracted with EtOAc (3x) and the combined extracts were dried over
  • the title compound was made as for example 16 (below) using [(3-amino- propyl)-ethoxy-phosphinoylmethyl]-phosphonic acid diethyl ester.
  • 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 O ( ⁇ 2 mL).
  • the mixture was further diluted with a small amount of DMF and then purified by reversed phase HPLC using water-acetonitrile (+0.1 % TFA). The fractions containing product were then lyophilized to afford pure /-A.
  • R1 NH2
  • R2 -NMe-CH2-CH_-OH
  • R1 NH2
  • R2 -NMe-CH_-CH_-OH
  • Scheme 5 describes the synthesis of compound 15 starting from 5- iodopyrrolo-pyrimidine (J.Med.Chem., 1990).
  • 6-Chloro-2-fluoro-9H-purine (517.7 mg, 3 mmol), 2-propanol (198.3 mg, 3.3 mmol), 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 (C ⁇ 2 Cl 2 /EtOAc, 4:1, Rf 0.62). The product was obtained as a white solid (411 mg, 64 %).
  • pyrimidin- 1 - yl)-butyl ester (0.85 g, 2.5 mmol), and LiOH » H 2 O (0.25 g, 5.96 mmol) were dissolved in THF (3 mL)/H 2 O ( 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%).
  • Trifluoro-methanesulfonic acid 5-(tert-butoxycarbonylamino-methyl)-2- trifluoromethanesulfonyloxy-phenyl ester (5 g, lO.o mmol), diethyl phosphite (2.8 mL, 20.3 mmol), N-methylmorpholine (2.7 mL, 25.1 mmol) and tetrakis(triphenylphosphine)-palladium(0) (1.2 g) were dissolved in anhydrous acetonitrile (100 mL) and heated in a sealed tube at 90 °C for 48 h.
  • the reaction mixture was then diluted with half saturated aq NH 4 C1 (20 mL).
  • the mixture was further acidified by the addition of a small amount of 6 Naq HCl, and then extracted with EtOAc.
  • the extract was washed with H 2 O (10 mL) and brine (10 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.
  • Phenol 9 was converted to x-D in the same fashion as previously described ( -
  • 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 2 h and then agitated for an additional 20 h, upon which the
  • 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 washed successively with THF (5x5.0 mL), DMA (5x5.0 mL), CH 2 C1 2 (5x5.0 mL), Et 2 O (2x5.0 mL), CH 2 C1 2 (1 5.0 mL), Et 2 O (1x5.0 mL), and CH 2 C1 2 (2x5.0 mL).
  • 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 C1 (5x5.0 mL), Et 2 O (2x5.0 mL), CH 2 C1 2 (1x5.0 mL), Et 2 O (1x5.0 mL), and CH 2 CI 2 (2x5.0 mL). Excess solvent was removed via N2 flow overnight to provide the aminated purine resin lc. The following analytical data was obtained upon cleavage of lc (3-5 mg) with 30% TFA/CH 2 C1 2 ( ⁇ 5 min): m/z 592 (M+H).
  • the sealed RV was heated at 110 °C for 16 h, upon which the heat was turned off, the RV drained immediately, and the resin washed (while still hot) successively with DMA (5x5.0 mL), C ⁇ 2CI2 (5x5.0 mL, at ambient temperature), Et 2 O (2x5.0 mL), CH 2 C1 2 (1x5.0 mL), Et 2 O (1x5.0 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.
  • Example 22 The white solid was isolated as a TFA salt: m/z 602 (M+ ⁇ )
  • Example 22 The product was isolated as a white solid: m/z 549 (M+H)
  • Example 22 The white solid was isolated as a TFA salt: m/z 604 (M+H)
  • Example 22 The product was obtained as a white solid: m/z 533 (M+ ⁇ )
  • Example 22 The product was obtained as a white solid: m/z 581 (M+ ⁇ )
  • Method C 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 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%).
  • Femurs, tibias, and scapulas were isolated from 3-4 day old New Zealand white rabbits (Millbrook Farms, Amherst, MA). Bones were chopped and minced in a-MEM (Gibco-BRL) containing 0.55 g/L NaHCO 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 same medium supplemented with 10% HIFBS (Hyclone).
  • Fresh culture medium containing serially diluted test compounds was added and cells were incubated on dentine for 24 hours at 37 °C and 5% CO . 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 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 three independent experiments each containing triplicate samples.
  • TRIP tartrate resistant acid phosphatase
  • Src Kinase Inhibition Assay 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 1 (PKS1) (cdc2 peptide) from Pierce which is prepared at 12.5 ⁇ M (5X solution) in kinase buffer, and the enzyme, human recombinant c-Src at 135 ⁇ g/ml (stock solution) which is diluted 1/40 in kinase buffer (3.38 ⁇ g/ml) before use.
  • PPS1 substrate - biotinylated peptide substrate 1
  • 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 ImM; (b) ATP buffer which contains ATP 5 mM in MgCl 2 50 mM buffer (stock solution). Note that before each use dilute in MES to 100 ⁇ M (5X solution) add 100 ⁇ Ci/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/ml 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 ⁇ L kinase buffer + 10% DMSO or compound to be tested at different concentration in MES + 10 % DMSO, (b) 10 ⁇ L kinase buffer, (c) 10 ⁇ L substrate 12.5 ⁇ M, (d) 10 ⁇ L enzyme 3.38 ⁇ g/ml, and (e) 10 ⁇ L ATP 100 ⁇ M containing 0.2 ⁇ Ci [ 33 P]ATP. Incubation for 2 hours at 30 degrees C is followed by addition of 150 ⁇ L Stop buffer containing 500 ⁇ g streptavidin beads. Incubation proceeds for 30 min at room temperature, followed by centrifugation for 5 min at 2000 rpm, and reading on a Wallac Microbeta Scintillation counter.
  • Hydroxyapatite is the principal mineral component of bone. Hydroxyapatite adsorption chromatography is used as an assay to evaluate the bone-targeting potential of both individual bone-targeting moieties ("monomers”) and of pharmaceuticals inco ⁇ orating bone-targeting groups.
  • 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.
  • the compounds of the present invention may be provided as pro-drugs.
  • Rz groups may be protected using the following Rz groups:
  • the bone targeting moiety may be provided as a pro-drug with the formula:

Abstract

La présente invention concerne des composés de ciblage du système osseux, utilisés dans le traitement de troubles et d'états pathologiques divers, par exemble des tissus osseux.
EP00988160A 1999-12-17 2000-12-18 Nouveaux heterocycles Withdrawn EP1246829A1 (fr)

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US741619 1996-10-30
US17216199P 1999-12-17 1999-12-17
US17251099P 1999-12-17 1999-12-17
US172161P 1999-12-17
US172510P 1999-12-17
US24078800P 2000-10-16 2000-10-16
US240788P 2000-10-16
PCT/US2000/034487 WO2001044258A1 (fr) 1999-12-17 2000-12-18 Nouveaux heterocycles
US09/740,619 US6420384B2 (en) 1999-12-17 2000-12-18 Proton pump inhibitors
US09/740,653 US20020132819A1 (en) 1999-12-17 2000-12-18 Novel purinse
US740653 2000-12-18

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