JP2003532632A - New heterocycle - Google Patents

Abstract

  (57) [Summary] The present invention relates to bone targeting compounds useful for treating various disorders and conditions, such as, for example, bone tissue.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD OF THE INVENTION

This application is based on United States Patent Act Section 119 (e) under the title "Invention".
US Provisional Patent Application No. 60 / filed on Dec. 17, 1999 for "bone targeting drug"
No. 172,510, entitled "Proton Pump Inhibitor", Dec. 1, 1999
U.S. Provisional Patent Application No. 60 / 172,161, filed on October 7, and U.S. Provisional Patent Application No. 60, filed on October 16, 2000, under the title of "Bone Targeting Agent".
/ 240,788, the entire contents of each of which are hereby incorporated by reference.

The present application is further directed to US patent application Ser. No. 0 under the title “Proton Pump Inhibitor”.
9 / 741,619 and US patent application Ser. No. 0, entitled "Novel Purine"
Claiming priority to 9 / 740,653, each of these applications filed on the same date and incorporated herein by reference.

[0003]

[Prior art]

Due to the need to treat debilitating bone disorders such as osteoporosis, there has been extensive research into the mechanisms and regulation of constant bone formation and bone resorption. In particular, an appropriate balance between osteoblasts, which act to form bone tissue, and osteoclasts, which act to absorb bone tissue, shows that despite the constant metabolism, the structural integrity and appropriateness of the skeleton Need to maintain functionality. Metabolic changes such as increased bone resorption (absolutely, or due to decreased bone formation compared to bone resorption) can result in even minor changes in such balance, bone disease, That is, it will lead to bone abnormalities. One of the most common abnormalities resulting from such imbalances is osteoporosis, which leads to reduced bone mass and increased fragility and fragility of the skeletal microstructure, leading to increased fracture proneness. It is a feature. Other diseases that result from altered bone resorption include
These include, but are not limited to, Paget's disease, primary and secondary hyperparathyroidism, malignant humoral hypercalcemia, various cancers with increased absorption, and rheumatoid arthritis.

Due to the various abnormalities that can result from metabolic imbalances, researchers have become interested in studying bone metabolism and the mechanisms by which bone resorption and bone formation occur.
Ultimately, it suppresses resorption by stimulating the effects of osteoblasts, and / or
Alternatively, strategies are being developed to increase bone mass and / or improve bone microstructure. However, the action of both osteoclasts and osteoblasts has been found to be a difficult task to develop a selective treatment, as the actions of both are governed by a number of complex factors.

One strategy taken to develop new treatments for bone disorders is to inhibit the proton pump of osteoclasts. Baran and coworkers have already demonstrated that this proton pump is a vacuolar H ⁺ -ATPase (
Blair et al., Science 1989, 245, 855-857; Finb.
ow et al., Biochem. J. 1997, 324, 697-712; Forga.
c., et al. Soc. Gen. Physiol. Ser. 1996.51.121
-132). Bone resorbing osteoclasts ultimately lower the pH in enclosed microcompartments that direct their binding sites to the surface of bone (Bar.
on et al. Cell. Biol. 1985, 101, 2210-2222), and it was found that proteases degrade the bone matrix by creating the acidic atmosphere necessary to dissolve the bone mineral. Osteoclasts utilize a proton pump (proton transfer by ATP) to carry out such acidification, thus providing all therapeutic inhibition of the osteoclast proton pump to reduce bone loss, ie turnover. The rate should be lowered. As a result, many new therapies developed to reduce bone resorption focus on inhibition of the proton pump to prevent osteoclast action and excessive bone resorption. Vacuolar H ⁺ -ATPase and vacuolar H ⁺ -A
For a discussion of inhibitors of TPase, see Farina et al., Exp. Opin. T
her. Patents, 1999, 9, 157-168, and David.
P. and Baron, R.A. "Vacuolar H ⁺ -ATP-ase: potential targets for drug development in bone diseases ^{(The Vacuolar H + -ATPase: A} Potenti
al Target for Drug Development in Bone D
,), Exp. Opin. Invest. Drugs, 1995.
4, 725-740.

In addition to the inhibition of the proton pump, research has also been directed at controlling signal transduction, which ultimately affects osteoclast or osteoblast activity. For example, studies have revealed that Src protein kinases play a crucial role in osteoclast action and have been proposed to be involved in or regulate cytoskeletal structure, Src, and phosphorylation by related kinases. Oxidation has been demonstrated by different cell types to be one important requirement for proper function (eg, Missbach et al., “Suppression of phosphorylation of major cell substrates, and in vitro and in vivo”). A Novel Inhibitor of the Tyrosine Kinase Src (A Novel Inhibitor of the T
Yrosine Kinase Src Suppresses Phosphor
ylation of It's Major Cellular Substrat
es and Reductions Bone Resorption In Vitro
and Rodent Model In Vivo) ", Bone. 1999,
24, 437-449). These cytoskeletal proteins may influence osteoclast function because the cytoskeleton plays an important role in osteoclast mobility, closed zone binding and closed zone formation . Therefore, Sr
Agents that inhibit, or promote, the interaction with c and related kinases appear to affect cytoskeletal proteins and ultimately osteoclast activity. Several compounds have been reported as inhibitors of tyrosine Src kinase and are useful in inhibiting osteoclast-mediated bone resorption (eg Missbach et al., Bone 19).
99, 24, 437-449; Connolly et al., Bioorg. & Med.
Chem. Lett. 1997, 7, 2415-2420; Trump-Kal.
Lmeyer et al. Med. Chem. 1998, 41, 1752-1763
Klutchko et al., J. Med. Chem. 1998, 41, 3276-3
292; Legraverend et al., Bioorg. & Med. Chem. 19
99, 7, 1281-1293; Chang et al., Chem. & Biol. 199
9, 6, 361-375; Lev et al., Nature 1995, 376, 737-.
784; Palmer et al. Med. Chem. 1997, 40, 1519-
See 1529.

As mentioned above, many existing therapies developed for the treatment of bone abnormalities such as osteoporosis are believed to exert their efficacy by inhibiting the effect of osteoclasts.
For example, estrogens, bisphosphonates, calcitonin, flavonoids, and selective estrogen receptor modulators are believed to exert efficacy by inhibiting osteoclast action. Further, recently, new therapeutic methods have been developed to promote a rapid increase in bone mineral content by promoting the action of osteoblasts. Such examples include the parathyroid hormone lineage, strontium ranelate, and peptides from growth hormone and insulin-like growth responses (eg, Regins
Ter et al., “Promising new drug in osteoporosis (Promising N
ew Agents in Osteoporosis) ", Drugs R & D.
1999, 3, 195-201). Unfortunately, however, an important problem with many of these therapeutic agents is that they are not sufficiently specific for bone tissue and thus may lead to unwanted side effects.

[0008]

[Problems to be Solved by the Invention]

Obviously, bone metabolism is controlled by a variety of factors, as evidenced by the many different approaches to available therapeutic agents. However, a common theme is the desire to develop selective inhibitors or promoters of osteoclast or osteoblastic action, respectively. Although progress has been made towards developing therapeutic agents for osteoporosis and other bone disorders, there is still a need to develop effective therapeutic agents with minimal side effects and selective therapeutic agents.

[0009]

SUMMARY OF THE INVENTION Broadly, the present invention provides a compound comprising a bone targeting moiety and a payload for the treatment or prevention of bone abnormalities and / or other conditions. In another embodiment, as described herein, certain novel bone targeting moieties themselves also act as therapeutic agents for use in treating bone disorders and / or other conditions. In certain other embodiments, the present invention provides compounds that include a bone targeting moiety and a kinase inhibitor.

Accordingly, the present invention provides, in one embodiment, a compound of formula I, or a pharmaceutically acceptable derivative thereof.

In some embodiments, the subject compound has the structure of formula (I): —Hc-X-K-Cy-L-Z-Tb (I) where L and K are independently nonexistent or -M _n -Y-M _p - repetition is the; X, Y and Z are independently existent or NR, are repetitions of O or S; M, for each occurrence, _{independently, -CH 2 -, - CHF -} , - CHOH-,
Two M's representing a substituted or unsubstituted methylene group such as -CH (Me)-, -C (= O)-, etc., or in combination represent a substituted or unsubstituted ethene or ethyne;

R independently represents H or substituted or unsubstituted aryl, heterocyclic, heteroaryl, aralkyl, alkenyl or alkyl for each occurrence.

Cy represents cycloalkyl, including substituted or unsubstituted aryl, heterocyclic, heteroaryl, or polycyclic groups; p and n are independently 0 to 10, preferably 0 to 5, still more preferably an integer of 0 to 3.

[0014]   Hc represents a heterocycle, preferably a nitrogen-containing heterocycle; and   Tb represents a bone targeting moiety preferably selected from:

[Chemical 37] Wherein R ₄ independently represents H or lower alkyl, preferably H or C ₁ -C ₃ lower alkyl.

In the embodiment where Tb is selected from i, v, vi, vii, viii and ix, it is preferred that Z is absent. In an embodiment in which Tb is selected from ii, iii and iv, Z is absent or represents O or NR. In embodiments in which Tb is selected from x, xi, xii, xiii, xiv, and xv, Z is absent or can represent O or NR and is preferably absent.

In one embodiment, R ₄ represents H for all occurrences.

In some embodiments, L is alkyl-Y-alkyl, alkyl-Y-acyl,
Or represents alkyl.

In some embodiments, the compound does not include hydrolyzable bonds. A hydrolyzable bond, as the term is used herein, is a saturated (sp ^3-) bonded to two heteroatoms.
(Blended) carbon, at least one of the two being selected from S, N or O.

In some embodiments, M is —CH ₂ —, —CHF—, —CHOH—, —CH (
Represents a substituted or unsubstituted methylene group such as Me)-, -C (= O)-, and the like.

In one embodiment, Cy represents a carbocycle or a nitrogen-containing heterocycle. Cy is preferably an uncharged type.

In some embodiments, Cy is such as a phenyl, pyridyl, cyclopentyl, cyclohexyl, or fused bicyclic ring system, preferably a fused cyclohexyl / cyclopentyl ([4.3.0] -bicyclononane) ring system. It preferably has 8 to 11 atoms. When Cy represents a fused ring system, L and K (or Hc or T
It is possible that one substituent of b) is attached to one ring of the two rings and another substituent is attached to the other ring of the two rings. In some embodiments, Cy is phenyl.

[0022]   In some embodiments, K is absent.

In some embodiments, K represents alkyl-Y-alkyl, alkyl-Y-acyl, or phenyl.

In one embodiment, Hc represents a bicyclic structure, preferably containing heteroatoms in both rings. In one embodiment, the ring (s) of Hc consist of C and N atoms.
In one embodiment, Hc represents a bicyclic heteroaryl structure.

In some embodiments, K is directly attached to the heteroatom of Hc or X represents NR.

[0026]   In some embodiments, Hc contains at least one aryl substituent.

[0027]   In some embodiments, the combined Hc-X represents one of the following structural formulas:

[Chemical 38] In the formula, W represents O or S, R ₁ , R ₂ , and R ₃ represent a bond with K, and the others are independently hydrogen, halogen, alkyl, aralkyl, aryl, cycloalkyl, hetero. It represents aryl, heterocyclic, cycloalkyl, polycyclic, alkylalkenyl, alkylalkynyl, or alkanoyl, and when taken together with its attached nitrogen represents amidine, amide, carbamate, urea, or guanidine.

When Hc-X is represented by xix or xx, R ₃ represents a bond with K, R ₂ represents hydrogen, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, heteroaryl, heterocyclic, Selected from cycloalkyl, polycyclic, alkylalkenyl, alkylalkynyl and alkanoyl; and R ₁ is selected from hydrogen, halogen, aryl and heteroaryl. In some embodiments, R ₂ is hydrogen, (CH ₂ ) _n Ph, wherein Ph is phenyl or substituted phenyl, and n is 0, 1, 2, or 3; heteroaryl , Cycloalkyl, C ₁ -C ₆ alkanoyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, and C ₂ -C ₆ alkynyl, where the alkyl, alkenyl and alkynyl groups are NR ₅ R ₆ , phenyl, It may be substituted with thioalkyl, alkyloxy, hydroxy, carboxy, halogen, cycloalkenyl, and R ₅ and R ₆ are independently hydrogen, C ₁ -C ₆ alkyl,
C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, (CH _{2) n} Ph, where, Ph is phenyl, n is 0, 1, 2, or 3; cycloalkyl, heteroaryl, and R ₅ and R _{6 in} combination with its attached nitrogen have from 3 to 7 carbon atoms and are optionally selected from the group consisting of nitrogen, substituted nitrogen, oxygen and sulfur 1, 2 or A ring containing three heteroatoms can be completed. In some embodiments, R ₁ is a substituted aryl moiety selected from monohaloaryl, dihaloaryl, monomethylaryl and dimethylaryl. In one embodiment,
At least one of R ₁ , R ₂ and R ₃ represents an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl, except for a bond with K.

In certain embodiments where Hc-X is represented by xvi or xvii, at least one of R ₁ , R ₂ , and R ₃ represents a bond with K and is not bonded with K. R ₃ is hydrogen,
Or R ₂ selected from alkyl, not bonded to K, is selected from alkyl, cycloalkyl, alkylalkenyl, alkylalkynyl, and R ₁ not bonded to K is hydrogen, alkyl, cycloalkyl. , Aryl, heteroaryl, heterocyclic, arylalkyl, heteroalkyl, alkylalkenyl, alkylalkynyl, alkylcycloalkyl, or alkylheterocyclic. In certain embodiments, at least one of R ₁ , R ₂ , and R ₃ represents, in addition to the bond with K, an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl.

In certain embodiments where Hc-X is represented by xviii, R ₂ represents a bond with K and R ₁
And R ₃ are independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heteroalkyl, heteroaralkyl, alkylalkenyl, alkylalkynyl, alkylcycloalkyl, or alkylheterocyclic. Be done. In some embodiments, R ₁ is alkyl or branched alkyl and R ₃ is aryl, heteroaryl or cycloalkyl. In certain embodiments, R ₃ is monohaloaryl, dihaloaryl, monohaloheteroaryl,
It is selected from dihaloheteroaryl, monohalocycloalkyl, or dihalocycloalkyl. In certain embodiments, at least one of R ₁ , R ₂ , and R ₃ represents, in addition to the bond with K, an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl.

In certain embodiments in which Tb is represented by vii or viii, the compound does not contain a hydrolyzable bond. In some embodiments, L and K do not contain nitrogen. In one embodiment, Hc represents a heterocyclic bicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is selected from xvi, xvii, xviii, xix and xx. In one embodiment, R ₄ represents H for all that occurs. In some embodiments, Cy represents phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused ring system, such as 8 to 8 such as a fused cyclohexyl / cyclopentyl ([4.3.0] -bicyclononane) ring system. It preferably has 11 atoms. When Cy represents a fused ring system, one substituent of L and K (or Hc or Tb) is attached to one of the two rings, while another substituent is another ring of the two rings. Can be combined with. In embodiments where X is absent, K is preferably attached directly to the heteroatom of Hc. In some embodiments, K is absent.

In some embodiments, Tb is represented by xi, xii, xiv, or xv. In some embodiments, K and L do not contain amide bonds, or preferably do not contain nitrogen atoms. In one embodiment, Hc represents a heterocyclic bicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is xvi, xvii, xviii, xix.
And xx. In some embodiments, the compounds do not contain hydrolyzable bonds.
In one embodiment, R ₄ represents H for all that occurs. In one embodiment,
Cy represents phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused ring system, having 8 to 11 atoms, such as a fused cyclohexyl / cyclopentyl ([4.3.0] -bicyclononane) ring system Is preferred. When Cy represents a fused ring system, one substituent on L and K (or Hc or Tb) is one of two rings.
It is possible to attach one to the other, while another substituent is attached to another of the two rings. In embodiments where X is absent, K is preferably attached directly to the heteroatom of Hc. In some embodiments, K is absent.

In certain embodiments where Tb is represented by moiety xiii, this moiety is not present in another moiety of the compound, eg, Hc is not xiii, etc. In some embodiments, K and L do not contain amide bonds, or preferably do not contain nitrogen atoms. In one embodiment, Hc represents a heterocyclic bicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is selected from xvi, xvii, xviii, xix and xx. In some embodiments, the compounds do not contain hydrolyzable bonds. In one embodiment, R ₄ represents H for all that occurs. In some embodiments, Cy represents phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused ring system, such as 8 to 8 such as a fused cyclohexyl / cyclopentyl ([4.3.0] -bicyclononane) ring system. It preferably has 11 atoms. When Cy represents a fused ring system, L
And one substituent of K (or Hc or Tb) can be attached to one of the two rings, while another substituent can be attached to the other of the two rings. In embodiments where X is absent, K is preferably attached directly to the heteroatom of Hc. In some embodiments, K is absent.

In some embodiments where Tb is represented by x, K does not contain an amide bond, does not contain a carbonyl, does not contain an amine substituent, or does not contain a nitrogen atom. In one embodiment, Hc represents a heterocyclic bicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is selected from xvi, xvii, xviii, xix and xx. In some embodiments, the compounds do not contain hydrolyzable bonds. In one embodiment, R ₄ represents H for all that occurs. In some embodiments, Cy represents phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused ring system, such as 8 to 8 such as a fused cyclohexyl / cyclopentyl ([4.3.0] -bicyclononane) ring system. It preferably has 11 atoms. When Cy represents a fused ring system, one substituent of L and K (or Hc or Tb) is attached to one of the two rings, while another substituent is another ring of the two rings. Can be combined with. In embodiments where X is absent, K is preferably attached directly to the heteroatom of Hc. In some embodiments, K is absent.

In certain embodiments where Tb is represented by ii, iii, iv or v, the compound does not contain a hydrolyzable bond. In one embodiment, Hc represents a heterocyclic bicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is xvi, x
It is selected from vii, xviii, xix and xx. In one embodiment, R ₄ represents H for all that occurs. In some embodiments, Cy represents phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused ring system, such as 8 to 8 such as a fused cyclohexyl / cyclopentyl ([4.3.0] -bicyclononane) ring system. It preferably has 11 atoms. When Cy represents a fused ring system, one substituent of L and K (or Hc or Tb) is attached to one of the two rings, while another substituent is another ring of the two rings. Can be combined with. In embodiments where X is absent, K is Hc
Bond directly to the heteroatom of. In some embodiments, K is absent.

In some embodiments where Tb is represented by ix, Cy is preferably uncharged and / or L-Cy-K preferably contains no hydrolyzable bond. In one embodiment,
The compound contains no hydrolyzable bonds. In certain embodiments, Cy is preferably selected from aryl, carbocyclic, nitrogen-containing heterocyclic, and nitrogen-containing heteroaryl groups, and preferably does not contain S or O atoms in the ring structure. In some embodiments, C
y contains 0 or 1 heteroatoms. In one embodiment, Hc represents a heterocyclic bicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is selected from xvi, xvii, xviii, xix and xx. In one embodiment, R ₄ represents H for all that occurs. In some embodiments, Cy is phenyl,
It represents a pyridyl, cyclopentyl, cyclohexyl, or fused ring system, preferably having 8 to 11 atoms, such as a fused cyclohexyl / cyclopentyl ([4.3.0] -bicyclononane) ring system. When Cy represents a fused ring system, one substituent of L and K (or Hc or Tb) is attached to one of the two rings, while another substituent is another ring of the two rings. Can be combined with. In embodiments where X is absent, K is preferably attached directly to the heteroatom of Hc. In some embodiments, K is absent.

In certain embodiments where Tb is represented by i, Cy is preferably uncharged and / or L-Cy-K preferably contains no hydrolyzable bond. In one embodiment,
Cy is preferably selected from aryl, carbocyclic, nitrogen-containing heterocyclic, and nitrogen-containing heteroaryl groups, and preferably contains no S or O atom in the ring structure.
In some embodiments, the Cy ring system contains 0 or 1 heteroatoms. In one embodiment, Hc represents a heterocyclic bicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is selected from xvi, xvii, xviii, xix and xx. In one embodiment, R ₄ represents H for all that occurs. In one embodiment, Cy represents phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused ring system, fused cyclohexyl / cyclopentyl ([4.3.0]-
It preferably has 8 to 11 atoms, such as the bicyclononane) ring system. C
When y represents a fused ring system, one substituent of L and K (or Hc or Tb) is attached to one of the two rings, while another substituent is another ring of the two rings. Can be combined with. In embodiments where X is absent, K is preferably attached directly to the heteroatom of Hc. In some embodiments, K is absent.

In some embodiments where Tb is represented by i, Z and L are absent. In one embodiment, Cy represents an aryl or heteroaryl group such as a phenyl or pyridine group. In some embodiments, Cy is preferably uncharged and / or the compound preferably contains no hydrolyzable bonds. In certain embodiments, Cy is preferably selected from aryl, carbocyclic, nitrogen-containing heterocyclic, and nitrogen-containing heteroaryl groups, and preferably does not contain S or O atoms in the ring structure. In some embodiments, C
The ring system of y contains 0 or 1 heteroatoms, or is preferably phenyl. In one embodiment, Hc represents a heterocyclic bicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is xvi, xvii, xviii, xix.
And xx. In one embodiment, R ₄ represents H for all that occurs. In one embodiment, Cy represents phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused ring system, fused cyclohexyl / cyclopentyl ([4.
It is preferred to have 8 to 11 atoms such as the [3.0] -bicyclononane) ring system. When Cy represents a fused ring system, one substituent of L and K (or Hc or Tb) is attached to one of the two rings, while another substituent is another ring of the two rings. Can be combined with. In embodiments where X is absent, K is preferably attached directly to the heteroatom of Hc. In some embodiments, K is absent.

In some embodiments of Formula I, Tb is selected from i and ix and K is absent
Or represents -Y- such as -NH-. In some embodiments, Hc is xvi, xvii, xvi
selected from ii, xix and xx. In some embodiments, Cy is aryl or heteroaryl, preferably aryl. In some embodiments, Hc is further substituted with aryl groups, eg, no K at the R ₁ , R ₂ , and R ₃ positions. In some embodiments, each of R _1, R _2, and R ₃ represents a hydrocarbon substituent. In some embodiments, L represents alkyl, alkyl-Y-alkyl, alkyl-Y-acyl, where Y is preferably NR such as NH or NMe.

In some embodiments of Formula I, Tb is x and K is absent. In some embodiments, Hc is selected from xvi, xvii, xviii, xix and xx. In some embodiments, Hc
Is further substituted with aryl groups, eg, no K at the R ₁ , R ₂ , and R ₃ positions. In some embodiments, each of R _1, R _2, and R ₃ represents a hydrocarbon substituent. In some embodiments, L is alkyl, alkyl-Y-alkyl, alkyl-
Represents Y-acyl, where Y is preferably NR such as NH or NMe.

[0041]   In some embodiments, the subject compound has the structure of formula (II): Hc-X-K-Z-Tb (II) In the formula, Hc, X, K, Z and Tb are as defined above.

In some embodiments of Formula II, Tb is selected from x, xi, xii, xiii, xiv, and xv. In embodiments in which Tb is selected from x, xi, xii, xiii, xiv, and xv, Z is absent or can represent O or NR and is preferably absent.

In one embodiment, R ₄ represents H for all that occurs.

In some embodiments, the compound does not include hydrolyzable bonds. A hydrolyzable bond, as the term is used herein, is a saturated (sp ³ bonded to two heteroatoms.
-Mixed) carbon, at least one of which is selected from S, N or O.

In some embodiments, M is —CH ₂ —, —CHF—, —CHOH—, —CH (
Represents a substituted or unsubstituted methylene group such as Me)-, -C (= O)-, and the like.

[0046]   In some embodiments, K is absent.

In one embodiment K represents alkyl-Y-alkyl, alkyl-Y-acyl or alkyl.

In some embodiments, Hc represents a bicyclic structure and preferably contains heteroatoms in both rings. In one embodiment, the ring (s) of Hc consist of C and N atoms.

In some embodiments, K is directly attached to the heteroatom of Hc, or X represents NR.

[0050]   In some embodiments, Hc contains at least one aryl substituent.

[0051]   In some embodiments, the combined Hc-X represents one of the following structures:

[Chemical Formula 39] In the formula, W represents O or S, _one of R ₁ , R ₂ and R ₃ represents a bond with K, and the others independently represent hydrogen, halogen, amidine, amide, carbamate, urea. , Guanidine, alkyl, aralkyl, aryl, cycloalkyl, heteroalkyl, heterocyclic, cycloalkyl, polycyclic, alkylalkenyl, alkylalkynyl, or alkanoyl, or together with its attached nitrogen amidine, amide , Carbamate, urea or guanidine.

In certain embodiments, where Hc-X is represented by xix or xx, R ₃ represents a bond with K,
R ₂ is hydrogen, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, heteroaryl, heterocyclic, cycloalkyl, polycyclic, alkylalkenyl,
Selected from alkylalkynyl, and alkanoyl; and R ₁ is selected from hydrogen, halogen, aryl, and heteroaryl. In some embodiments, R ₂ is hydrogen, (CH ₂ ) _n Ph, wherein Ph is phenyl or substituted phenyl, and n is 0, 1, 2, or 3; heteroaryl , Cycloalkyl, C ₁ -C ₆ alkanoyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, and C ₂ -C ₆ alkynyl, where the alkyl, alkenyl and alkynyl groups are NR ₅ R ₆ , phenyl, It may be substituted with thioalkyl, alkyloxy, hydroxy, carboxy, halogen, cycloalkenyl, and R ₅ and R ₆ are independently hydrogen, C _1-.
C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, (CH _{2) n} Ph, where, Ph is phenyl, n is 0, 1, 2, or 3; cycloalkyl,
Heteroaryl, and R ₅ and R _{6 in} combination with the nitrogen to which it is attached have from 3 to 7 carbon atoms and are optionally selected from the group consisting of nitrogen, substituted nitrogen, oxygen and sulfur. Rings containing 1, 2 or 3 heteroatoms can be completed. In some embodiments, R ₁ is a substituted aryl moiety selected from monohaloaryl, dihaloaryl, monomethylaryl and dimethylaryl. In certain embodiments, at least one of R ₁ , R ₂ , and R ₃ represents, in addition to the bond with K, an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl.

In certain embodiments where Hc-X is represented by xviii, R ₂ represents a bond with K and R ₁
And R ₃ are independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, aralkyl, heteroalkyl, heteroaralkyl, alkylalkenyl, alkylalkynyl, alkylcycloalkyl and alkylheterocyclic. . In some embodiments, R ₁ is alkyl or branched alkyl,
R ₃ is aryl, heteroaryl or cycloalkyl. In some embodiments, R ₃ is mono-halo aryl, dihaloaryl, monohaloalkyl heteroaryl, dihalo heteroaryl, selected from mono-halocycloalkyl, or di-halocycloalkyl. In certain embodiments, at least one of R ₁ , R ₂ , and R ₃ represents, in addition to the bond with K, an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl.

In certain embodiments, where Hc-X is represented by xvi or xvii, at least one of R ₁ , R ₂ , and R ₃ represents a bond with K, and R when not bonded with K. ₃ is selected from hydrogen or alkyl, R ₂ when not bonded to K is selected from alkyl, cycloalkyl, alkylalkenyl, alkylalkynyl, and R ₁ when not bonded to K is hydrogen, alkyl , Cycloalkyl, aryl, heteroaryl, heterocyclic, aralkyl, heteroalkyl, alkylalkenyl, alkylalkynyl, alkylcycloalkyl, or alkylheterocyclic. In certain embodiments, at least one of R ₁ , R ₂ , and R ₃ represents, in addition to the bond with K, an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl.

In certain embodiments in which Tb is represented by vii or viii, the compound does not contain a hydrolyzable bond. In some embodiments, K does not include nitrogen. In one embodiment, Hc represents a heterocyclic bicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is selected from xvi, xvii, xviii, xix and xx. In one embodiment, R ₄ represents H for all that occurs. In embodiments where X is absent, K is preferably attached directly to the heteroatom of Hc. In some embodiments, K is absent.

In some embodiments, Tb is represented by xi, xii, xiv, or xv. In some embodiments, K does not contain an amide bond, or preferably does not contain a nitrogen atom. In one embodiment, Hc represents a heterocyclic bicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is xvi, xvii, xviii, xix and xx
Chosen from. In some embodiments, the compounds do not contain hydrolyzable bonds. In one embodiment, R ₄ represents H for all that occurs. In embodiments where X is absent, K is preferably attached directly to the heteroatom of Hc. In some embodiments, K is absent.

In certain embodiments where Tb is represented by moiety xiii, that moiety is not present in another moiety of the compound, eg, Hc is not xiii, etc. In some embodiments, K does not contain an amide bond, or preferably does not contain a nitrogen atom. In one embodiment, Hc represents a heterocyclic bicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is selected from xvi, xvii, xviii, xix and xx. In some embodiments, the compounds do not contain hydrolyzable bonds. In some embodiments, R ₄
Represents H for all that occurs. In embodiments where X is absent, K is preferably attached directly to the heteroatom of Hc. In some embodiments, K is absent.

In some embodiments where Tb is represented by x, K is free of amide bonds, free of carbonyls, free of amine substituents, or free of nitrogen atoms. In some embodiments, the compounds do not contain hydrolyzable bonds. In one embodiment, Hc represents a heterocyclic bicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is selected from xvi, xvii, xviii, xix and xx. In one embodiment, R ₄ represents H for all that occurs. In embodiments where X is absent, K is preferably attached directly to the heteroatom of Hc. In one embodiment,
K does not exist.

In some embodiments where Tb is represented by ii, iii, iv or v, the compound does not contain a hydrolyzable bond. In one embodiment, Hc represents a heterocyclic bicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is xvi, x
It is selected from vii, xviii, xix and xx. In one embodiment, R ₄ represents H for all that occurs. In some embodiments, K is directly attached to the heteroatom of Hc. In some embodiments, K is absent.

In certain embodiments where Tb is represented by ix, it is preferred that the compound contains no hydrolyzable bonds. In some embodiments, the compounds do not contain hydrolyzable bonds. In one embodiment, Hc represents a heterocyclic bicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is xvi, xvii, xviii, xix and x.
chosen from x. In one embodiment, R ₄ represents H for all that occurs. X
In the embodiment where is not present, K is preferably directly attached to the heteroatom of Hc. In some embodiments, K is absent.

In some embodiments where Tb is represented by i, Hc represents a heterocyclic bicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is
It is selected from xvi, xvii, xviii, xix and xx. In one embodiment, R ₄ represents H for all that occurs. In embodiments where X is absent, K is preferably attached directly to the heteroatom of Hc. In some embodiments, K is absent.

In some embodiments of Formula II, Tb is selected from i and ix and K is branched or unbranched alkyl. In some embodiments, Hc is selected from xvi, xvii, xviii, xix and xx. In some embodiments, Hc is further substituted with an aryl group, such as R ₁
, R ₂ and R ₃ are not substituted by K. In _one embodiment, each of R ₁ , R ₂ and R ₃ represents a hydrocarbon substituent.

In some embodiments of Formula II, Tb is xii, K is absent, or —NH—
Represents -Y-. In some embodiments, Hc is xvi, xvii, xviii, xix and x.
chosen from x. In some embodiments, Hc is further substituted with an aryl group, eg, no K at the R ₁ , R ₂ , and R ₃ positions. In some embodiments, R ₁ ,
Each of R ₂ and R ₃ represents a hydrocarbon substituent.

In certain embodiments of formula II, Tb is x and K represents alkyl or -Y-. In some embodiments, Hc is selected from xvi, xvii, xviii, xix and xx. In some embodiments, Hc is further substituted with an aryl group, such as R ₁ , R ₂ , and R ₃
Is not replaced by K at the position. In _one embodiment, each of R ₁ , R ₂ and R ₃ represents a hydrocarbon substituent. In some embodiments of Formula I or II, Tb represents the formula:

[Chemical 40]

In yet another embodiment of the invention, a pharmaceutical composition comprising any one composition of the invention, or a pharmaceutically acceptable derivative thereof, and one or more pharmaceutically acceptable excipients. A composition is provided.

In another embodiment, the compound of the present invention or the composition containing the compound is administered to a cell or an animal, preferably a mammal in need thereof, as a method for treating a bone disorder. In particular cases, it is preferred to carry out the method of the invention described above with a pharmaceutical composition comprising a bone targeting compound capable of inhibiting bone resorption. In other cases, it is preferred to carry out the method of the invention described above using a pharmaceutical composition comprising a bone targeting compound that acts specifically as a Src kinase inhibitor. In other cases, it is preferred to carry out the method with a bone targeting compound of the invention having a payload attached to the bone targeting compound that can treat bone abnormalities by other means.

In yet another embodiment, the method is practiced with a pharmaceutical composition comprising a bone targeting moiety capable of treating bone abnormalities alone by inhibiting bone resorption or by other means. It is preferable.

Definitions As mentioned above, the present invention provides a new class of bone targeting compounds useful in the treatment of bone abnormalities, preferably by inhibiting bone resorption. The compounds of the present invention include compounds of Formulas I and II described herein, in part by various classes, subdivisions and subclasses of the foregoing compounds, as well as the specification and claims. And various subsections and species disclosed elsewhere in the drawings. The compounds of the present invention can be provided in the form of individual enantiomers, diastereomers, ie geometric isomers, or in the form of a mixture of stereoisomers.

Also included are pharmaceutically acceptable derivatives of said compounds, in which case the phrase “
"Pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable salt of a compound of the invention,
An ester, or a salt of said ester, or a compound described elsewhere herein when administered to a patient, or a metabolite or a residue thereof, preferably a compound capable of suppressing bone resorption (direct or indirect). To any other addition or derivative that can be provided. Thus, pharmaceutically acceptable derivatives include especially prodrugs. Prodrugs are usually derivatives of compounds that have significantly less pharmacological activity, are more likely to be excreted, and contain an additional moiety that creates the parent molecule as the pharmacologically active species in vivo. An example of a prodrug is an ester which, when degraded in vivo, produces the compound in question. Various compounds, and prodrugs of substances, and methods of derivatizing a parent compound to produce a prodrug are well known and can be applied to the present invention. One technique for providing prodrugs of the compounds of the present invention is Niemi
J. et al. Med. Chem. 1999, 42, 5053-5058.

The terms “inhibition of bone resorption” or “inhibition of osteoclast action” or “inhibition of Src kinase action” preferably refer to specific inhibition. To treat or prevent bone abnormalities and / or other conditions, and in particular to inhibit bone resorption, and / or Src tyrosine phosphorylation, using any of various in vitro or in vitro quantification methods. The efficacy of the compounds and compositions of the present invention can be evaluated in order to suppress inflammation (e.g., useful rabbit osteoclast assay for studying effects on bone resorption, and useful Src kinase inhibition assay). Please refer to the example part given). In a particularly preferred embodiment of the invention, the observed effect on bone metabolism is that the compounds or compositions of the invention have a significant negative effect on biological processes other than bone metabolism, specifically bone resorption or Src kinase action. It is excellent in that it has no effect.
For example, particularly preferred compositions of the present invention have been shown to clearly inhibit Src kinase action as compared to the action of non-Src kinases, or kinases at sites remote from bone. In some cases, such definite inhibition may result from the definite localization of the composition of the invention at the site of the bone, so that the composition delivered in vivo is not It does not have the opportunity to suppress the process that occurs; in other cases, definite suppression may result in osteoclast activity or Sr compared to another cell or kinase.
It may be due to the definite effect of the payload of the invention on the action of c-kinase.

The term “payload” includes a therapeutic agent (eg, a small molecule, a drug, a radiotherapy atom, etc.), a detectable label (eg, fluorescent, radioactive, radiopaque, etc.), or an action Included are any other parts that are desired to be delivered to the site (eg, bone, or other site that suffers from an abnormal condition).

As used herein, the term “small molecule” refers to about 2500 mass units (amu).
Less than 1, preferably less than about 1000 amu.

“Subject” shall mean a human or animal (eg, rat, mouse, cow, pig, horse, sheep, monkey, cat, dog, goat, etc.).

“Target” shall mean the in-vivo site to which a targeting agent binds. The target is
It can refer to the molecular structure to which the targeting moiety binds, eg, a hapten, epitope, receptor, double-stranded DNA fragment, carbohydrate, or enzyme. Alternatively or additionally, the target can be some type of tissue, such as bone. The preferred target is bone. In certain preferred embodiments, target cells include osteoclasts.

The term “targeting moiety” refers to any composition that assists the compositions of the invention in localizing to a particular target region, entering a target cell (s), and / or binding to a target receptor. Refers to a molecular structure. Preferred targeting moieties according to the present invention include the bone targeting moieties described herein.

“Therapeutic agent” shall mean an agent capable of exerting a biological effect on a recipient. A preferred therapeutic agent is one of bone disorders such as metabolic bone disorders.
One or more symptoms can be prevented and / or treated. Other preferred therapeutic agents can prevent or treat other bone abnormalities or related conditions. Examples of therapeutic agents that are considered within the scope of the present invention include bone-containing compounds (eg, carboranes), chemotherapeutic nucleotides, agents (eg, antibiotics, antivirals, antifungals),
Enedyne (eg, calicheamicin, esperamicin, dynemicin, neocarzinostatin chromophore, and kedarcidin chromophore), heavy metal complexes (eg, ciplatin), hormone antagonists (eg, tamoxifen), non-specific (non-antibody) Proteins (eg sugar oligomers), oligonucleotides (eg antisense oligonucleotides that bind to target nucleic acid series (eg messenger RNA series)), peptides, photodynamic agents (eg rhodamine 123),
Radionuclides (eg, I-131, Re-186, Re-188, Y-90, B
i-212, At-211, Sr-89, Ho-166, Sm-153, Cu-
67, and Cu-64), toxins (eg, lysine), and transcription drugs. In certain preferred embodiments of the invention in which a composition for treating or preventing tumor colonization and growth is provided, the therapeutic agent is a radionuclide, a toxin, a hormone antagonist, a heavy metal complex, an oligonucleotide, a chemical agent. Therapeutic methods are nucleotides, peptides, non-specific (non-antibody) proteins, boron compounds or enene. In a preferred embodiment in which a composition for treating osteoporosis is provided, the therapeutic agent is a Src kinase inhibitor that can suppress osteoclast hyperactivity.

For the compounds of this invention, the named R group generally has a structure that is accepted in the art as corresponding to the R group bearing that name. For purposes of illustration, representative R groups listed in the specification and claims of this application are defined herein. These definitions are meant to supplement and explain the definitions well known to those of skill in the art and are not intended to interfere.

To indicate that the R groups can be the same or different, we use the term “
“Independently selected” is used.

The term “alkyl” refers to straight chain alkyl groups, branched chain alkyl groups, cycloalkyl (
Aliphatic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups, including saturated aliphatic groups. In a preferred embodiment, the straight chain or branched chain alkyl has 30 or less in the main chain (for example, C ₁ -C _{30 in} the case of a straight chain, C ₃ -C _{30 in} the case of a branched chain), and more preferably. Has up to 20 carbon atoms. Similarly, preferred cycloalkyls have from 3 to 10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbon atoms in the ring structure.

Furthermore, the term “alkyl” (or “lower alkyl”), as used throughout the specification, examples and claims, is a product that includes both “unsubstituted alkyl” and “substituted alkyl”. The latter of which refers to an alkyl moiety having a substituent replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents include, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphonate. , Phosphinates, aminos, amides, amidines, imines, cyanos, nitros, azides, sulfhydryls, alkylthios, sulfates, sulfonates, flufamoyls, flufoamides, sulfonyls, heterocycles, aralkyls, or aromatic or heteroaromatic moieties. It will be appreciated by those skilled in the art that the substituted moieties on the hydrocarbon chain may themselves be optionally substituted. For example, the substituents on a substituted alkyl include amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (sulfate,
Sulfonamide, including sulfamoyl and sulfonate), as well as silyl group, ether, alkylthio, carbonyl (including ketones, aldehydes, including carboxylates and _{esters), - CF 3 -, -} CN, substituted and the like and unsubstituted forms Can be mentioned. Exemplary substituted alkyls are shown below. Cycloalkyl further alkyl, alkenyl, alkoxy, alkylthio, amino alkyl, carbonyl - substituted alkyl, -CF ₃ -, - CN, and it is possible substituted by an.

The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group (eg, an aromatic or heteroaromatic group). Exemplary aralkyl groups include:
Include, but are not limited to, benzyl and more commonly (CH ₂ ) _n Ph,
In the formula, Ph is phenyl or substituted phenyl, and n is 1, 2 or 3.

The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic group analogs in the long chain direction, which may be substituted on said alkyl, but which are each at least one double bond or triple. Including joins.

If the number of carbons is not otherwise defined, “lower alkyl” as used herein refers to
It means an alkyl group as defined above, but has from 1 to 10 carbon atoms in its backbone structure, more preferably from 1 to 6 carbon atoms. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. A preferred alkyl group is lower alkyl. In a preferred embodiment, the substituents referred to herein as alkyl are lower alkyl.

The term “aryl” as used herein includes 5-, 6- and 7-membered monocyclic aromatics which can contain 0 to 4 heteroatoms, for example benzene, pyrrole. , Furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. These aryl groups having a heteroatom in the ring structure can also be referred to as "arylheterocycle" or "heteroaromatic". The aromatic ring is a substituent as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carnoxyl, silyl. , Ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclic, aromatic or heteroaromatic moieties, —CF ₃ —, —CN, etc. The term "aryl" may also include polycyclic ring systems having two or more cyclic rings in which two or more carbons share two adjacent rings (rings are "fused rings"), In this case, at least one ring is an aromatic ring, for example the other ring is a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl group and / or heterocyclic ring.

The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-substituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and orthodimethylbenzene are synonymous.

The term “heterocyclic” or “heterocyclic group” refers to a 3 to 10 membered ring structure, more preferably a 3 to 7 membered ring, which ring structure contains from 1 to 4 heteroatoms. Heterocycles can also be polycycles. Heterocyclic groups include, for example: thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathine, 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, phenalsazine, phenothiazine, flazan, Phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactone, a Lactams such as Chijinon and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring is a substituent as described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino,
Amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl,
It can be substituted at one or more positions with ethers, alkylthios, sulfonyls, ketones, aldehydes, esters, heterocyclics, aromatic or heteroaromatic moieties, —CF ₃ —, —CN, etc.

The term “polycyclic” or “polycyclic group” refers to two or more rings sharing two or more carbons in two adjacent rings, eg, where the ring is a “fused ring”. (Eg, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and / or heterocyclic). Rings that are joined by non-adjacent atoms are called "bridged" rings.
Each ring of the polycycle has a substituent as described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro,
Sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic, aromatic or heteroaromatic moiety, -CF _3- , -C
It can be replaced with N, etc.

The term “carbocycle” as used herein refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.

As used herein, the term “nitro” means —NO ₂ ; the term “halogen”.
Means - and the term "sulfonyl" is _{-SO 2; -F, -Cl, -Br} , or refers to -I is; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH To do.

The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines, for example, moieties that can be represented by the general formula:

[Chemical 41] Wherein R ₉ , R ₁₀ and R ′ ₁₀ each independently represent hydrogen, alkyl, alkenyl, — (CH ₂ ) _m —R ₈ or R ₉ and R _{9 in} combination with an added N atom. R ₁₀ completes a heterocycle having 4 to 8 atoms in the ring structure; R ₈ represents aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; and m is 0,
Alternatively, it is an integer of 1 to 8. In one preferred embodiment only one of R ₉ or R ₁₀ can be a carbonyl, eg R ₉ , R ₁₀ and nitrogen together do not form an imide. In a further preferred embodiment, R ₉ and R ₁₀ (and optionally R ′ ₁₀ are each independently hydrogen, alkyl, alkenyl, or — (
It represents the CH _{2) m} -R _8. Therefore, the term "alkylamine" as used herein
Means an amine group, as defined above, which is attached to a substituted or unsubstituted alkyl, ie at least one of R ₉ and R ₁₀ is an alkyl group.

The term “acylamino” is art-recognized and refers to a moiety that can be represented by the following general formula:

[Chemical 42] In the formula, R ₉ is as defined above, R ′ 11 is hydrogen, alkyl, alkenyl,
Or - (CH ₂₎ a _m -R _8, wherein, m and R ₈ are as defined above.

The term “amido” is art recognized as an amino-substituted carbonyl and includes moieties that can be represented by the general formula:

[Chemical 43] In the formula, R ₉ and R ₁₀ are as defined above. A preferred embodiment of the amide is
Does not contain imide, which can be unstable.

The term “amidine” is recognized in the art as a group that can be represented by the general formula:

[Chemical 44] In the formula, R ₉ and R ₁₀ are as defined above.

The term “guanidine” is recognized in the art as a group that can be represented by the general formula:

[Chemical formula 45] In the formula, R ₉ and R ₁₀ are as defined above.

The term “alkylthio” refers to an alkyl group with a sulfur group attached as defined above. In one preferred embodiment, the "alkylthio" moiety is -S-alkyl,
-S- alkenyl, -S- alkynyl, and -S- (CH ₂₎ represented by one of the _m -R _8), wherein, m and R ₈ are as defined above. Representative alkylthio groups include methylthio, ethylthio and the like.

The term “carbonyl” is art-recognized and includes moieties as can be represented by the general formula:

[Chemical formula 46] In the formula, X is one bond or represents oxygen or sulfur, R ₁₁ represents hydrogen, alkyl, alkenyl, — (CH ₂ ) _m —R ₈ or a pharmaceutically acceptable salt, and R ′ ₁₁
It is hydrogen, alkyl, alkenyl, or - represents a (CH _{2) m} -R _8, wherein, m and R ₈ are as defined above. When X is oxygen and R ₁₁ and R ′ ₁₁ are not hydrogen, this formula represents an “ester”. When X is oxygen and R ₁₁ is as defined above, this moiety is referred to herein as a carboxyl group, especially when R ₁₁ is hydrogen, the formula represents a “carboxylic acid”. X is oxygen when R _'11 is hydrogen, the formula "
In general, when the oxygen atom of the above formula is replaced by sulfur, the formula represents a “thiocarbonyl” group. When X is sulfur and R ₁₁ and R ′ ₁₁ are not hydrogen, This formula represents a “thiol ester.” When X is sulfur and R ₁₁ is hydrogen, this formula represents a “thiocarboxylic acid.” When X is sulfur and R ′ ₁₁ is hydrogen, this formula is a “thioformate. On the other hand, if X is one bond and R ₁₁ is not hydrogen, the above formula represents a “ketone” group. If X is one bond and R ₁₁ is hydrogen, then The formula represents an "aldehyde" group.

The term “alkoxyl” or “alkoxy” as used herein refers to an oxygenated alkyl group, as defined above. Representative alkoxyl groups include methoxy, ethoxy, propoxy, tert-butoxy and the like. "ether"
Are two hydrocarbons covalently bound by oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether, -O- alkyl, -O- alkenyl, -O- alkynyl, and _{-O- (CH 2) m -R 8} ( wherein, m and R ₈ are Alkoxyl as can be represented by one of the above),
Or an analogue.

The term “sulfonate” is art-recognized and includes moieties that can be represented by the following general formula:

[Chemical 47] Where R ₄₁ is an electron pair, hydrogen, alkyl, cycloalkyl or aryl.

The terms trifuryl, tosyl, mesyl and nonafuryl are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. The terms triflate, tosylate, mesylate, and nonaflate are art-recognized and include trifluoromethanesulfonate ester, p-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups, and each of the above. Refers to a molecule containing a group.

The abbreviations Me, Et, Ph, Tf, Nf, Ts and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A relatively comprehensive list of abbreviations used by ordinary organic chemists in the art is the Journal of
In the first issue of each volume of Organic Chemistry, this list is a standard list of abbreviations (Standard Lists of Abbreviati).
On) is commonly found in the table titled. The abbreviations included in this list, and those used by ordinary organic chemists of ordinary skill in the art, are incorporated herein by reference.

The term “sulfate” is art-recognized and includes moieties that can be represented by the general formula:

[Chemical 48] In the formula, R ₄₁ is as defined above.

The term “sulfonamide” is art-recognized and includes moieties that can be represented by the following general formula:

[Chemical 49] In the formula, R ₉ and R ′ ₁₁ are as defined above.

The term “sulfamoyl” is art recognized and includes a moiety that can be represented by the following general formula:

[Chemical 50] In the formula, R ₉ and R ′ ₁₁ are as defined above.

The term “sulfonyl,” as used herein, refers to a moiety that can be represented by the general formula:

[Chemical 51] Wherein R ₄₄ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

The term “sulfoxide” as used herein refers to a moiety that can be represented by the general formula:

[Chemical 52] Wherein R ₄₄ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aralkyl, or aryl.

[0106]   "Phosphoryl" is commonly represented by the formula:

[Chemical 53] In the formula, Q ₁ represents S or O, and R ₄₆ represents hydrogen, lower alkyl, or aryl. For example, when used to replace alkyl, the phosphoryl group of phosphorylalkyl can be represented by any of the following general formulas:

[Chemical 54] In the formula, Q ₁ represents S or O, each R ₄₆ independently represents hydrogen, lower alkyl, or aryl, and Q ₂ represents S, O or N. When Q ₁ is S, the phosphoryl moiety is "
"Phosphorothioart".

As used herein, each notation, for example definition of alkyl, m, n, etc., is:
When it appears more than once in any given structure, it means that the definition is independent elsewhere in the same structure.

“Substitution” or “substituted with” includes potential, provided that such substitution is
It is conditional that the atoms to be substituted and the valences of the substituents are consistent, and that the substitution results in the formation of stable compounds, such as transformations such as rearrangement, cyclization, elimination, etc. occurring simultaneously. Understood not to.

As used herein, the term “substituted” is considered to include all permissible substituents of organic compounds. In a broad perspective, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Exemplary substituents include, for example, the substituents previously described herein. The permissible substituents can be one or more and the same or different for compatible organic compounds. For purposes of this invention, a heteroatom such as nitrogen has a hydrogen substituent and / or any permissible substituents of organic compounds that satisfy the valences of the heteroatoms described herein. Is possible. The invention is in no way limited by the permissible substituents of organic compounds.

As used herein, the phrase "protecting group" means a temporary substituent that protects a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. A review has been published in the field of protecting group chemistry (Green, TW; Wutz, PGM,
Protective groups in organic synthesis (Protective Groups in Orga)
Nic Synthesis), Second Edition; Wiley: New York, 1991.
, Hereby incorporated by reference).

Certain compounds of the present invention may exist in specific geometric, ie stereoisomeric forms. The present invention provides cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D) -isomers, (L) -isomers, racemic mixtures thereof and other mixtures thereof. Including, all compounds as being within the scope of the invention are contemplated. Additional asymmetric carbon atoms may be included in a substituent such as an alkyl group. Not only all such isomers, but also mixtures thereof are included in the present invention.

Isomeric mixtures containing any of the various isomer ratios can be used according to the invention. For example, when combining only two types of isomers, 50:50, 60:40,
70:30, 80:20, 90:10, 95: 5, 96: 4, 97: 3, 98:
Mixtures containing isomer ratios of 2, 99: 1, or 100: 0 are all considered by the present invention. One of ordinary skill in the art will readily recognize that similar ratios are possible for more complex isomer mixtures.

For example, if a particular enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, in which case the resulting diastereomer. Separation of the mer mixture and cleavage of the auxiliary compound yields the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as an amino group or an acidic functional group such as a carboxyl group, a diastereomeric salt is formed using a suitable optically active acid or base, and then formed. The resulting diastereomers are resolved by fractional crystallization or chromatographic means well known to those skilled in the art to recover the pure enantiomers.

Expected equivalents of the foregoing compounds include compounds that otherwise correspond to the equivalents, and compounds that have generally the same properties as their equivalents (eg, bone-targeted agents), in which case , One or more simple changes to the substituents that do not adversely affect the efficacy of the compound in targeting bone. In general, the compounds of the present invention may be prepared, for example, by the methods described in the general reaction schemes below using readily available starting materials, reagents and conventional synthetic procedures, or by modifications thereof. Is possible. For these reactions, it is also possible to make use of variants which are known per se but are not mentioned here.

For the purposes of the present invention, chemical elements are represented by the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, Chapter 6.
7th Edition, on the inner cover of 1986-87.

[0116]

DETAILED DESCRIPTION OF THE INVENTION

As mentioned above, there remains a need to develop selective and potent agents for treating bone disorders, preferably metabolic bone disorders. Accordingly, generally, the present invention provides compounds comprising a bone targeting agent and a payload for use in treating bone disorders and other related disorders. In certain embodiments, the present invention provides compounds, pharmaceutical compositions and methods for selectively treating metabolic bone disorders. In certain embodiments, these compounds and compositions are used to treat diseases that result from the function of overactive osteoclasts. In certain other preferred embodiments, these compounds and compositions are used to treat osteoporosis.

Obviously, there are many factors involved in bone metabolism,
There are several approaches to developing new therapeutic agents. As mentioned above, one approach is to suppress the activity of osteoclasts by suppressing the proton pump or Src tyrosine phosphorylation. Other approaches involve the promotion of osteoblast activity. However, regardless of the approach taken, there is still a need to develop selective and potent therapeutic agents that can directly target bone tissue.

In view of this need for improved agents, the present invention provides new compounds consisting of a bone targeting agent and a payload. In certain embodiments, the present invention contemplates the use of bone targeting agents having a specific payload attached, as described in more detail. This bound specific payload inhibits osteoclast activity by inhibiting the proton pump, by inhibiting Src tyrosine kinase, or by some other mechanism that affects osteoclast or osteoblast function. Can be useful for In certain other embodiments, the bone targeting agent itself acts as a selective and potent inhibitor of osteoclast function.

In certain embodiments therefor, the present invention provides a composition comprising a compound having the structure of formula (I). Hc-X-K-Cy- L-Z-Tb (I) wherein, L and K are or absent respectively, -M _n -Y-M _p - a represents; X, Y and Z are each notation Absent, respectively, or NR, O or S
Represents;

M is -CH _2- , -CHF-, -CHOH-, -CH (Me)-, -C (=
O)-, etc., represents a substituted or unsubstituted methylene group, or two M together represent a substituted or unsubstituted ethene or ethyne; R is H or a substituted or unsubstituted, respectively for each notation. Represents an aryl group, heterocyclic group, heteroaryl group, aralkyl, alkenyl or alkyl; Cy represents cycloalkyl containing a substituted or unsubstituted aryl group, heterocyclic group, heteroaryl group or polycyclic group; p and n Each represent an integer of 0-10, preferably 0-5, more preferably 0-3; Hc represents a heterocyclic group, preferably a nitrogen-containing heterocyclic group. Tb represents a bone target that is preferably selected from the following structures:

[Chemical 55]

Here, R ₄ represents H, lower alkyl, or a pharmaceutically active small molecule or its precursor drug in each notation, preferably H or C ₁ -C ₃ lower alkyl. .

In an embodiment where Tb is selected from i, v, vi, vii and ix, Z
Is preferably absent. In an embodiment in which Tb is selected from ii, iii and iv, Z is absent or represents O or NR. Tb is x, xi,
In an embodiment selected from xii, xiii, xiv and xv, Z is absent or represents O or NR and is preferably absent.

In some embodiments, all represented R ₄ are H. In certain embodiments, the R ₄ depicted represents -CH ₂ OC (= O)-(drug)-or -CH ₂ OC (= O)-(precursor drug)-.

[0124] In one embodiment, L represents alkyl-Y-alkyl, alkyl-Y-acyl or alkyl.

In some embodiments, L-Cy-K-X-Hc contains no hydrolyzable bond. At least one of the hydrolysable bonds used herein is S
Saturated with two heteroatoms selected from N, O or N (sp ³ hybrid orbital)
It is carbon.

In one embodiment, each M is —CH ₂ —, —CHF—
, -CHOH-CH (Me)-, -C (= O)-and the like represent a substituted or unsubstituted methylene group.

In certain embodiments, Cy represents a carbocycle or a nitrogen-containing heterocycle. Cy is preferably uncharged.

In certain embodiments, Cy is optionally substituted with a second bone targeting group (Tb) via a linking group (such as -LZ-).

In some embodiments, Cy has preferably between 8 and 11 atoms, such as phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused cyclohexyl / cyclopentyl (“4.3.0” -bicyclononane) ring system. Represents a fused bicyclic ring system having. , Cy represents a fused ring system, one substituent of L and K (or Hc or Tb) may be bonded to one of the two rings and the other substituent may be bonded to the other of the two rings. . In some embodiments, Cy is phenyl.

[0130]   In some embodiments, K is absent.

In one embodiment, K represents alkyl-Y-alkyl, alkyl-Y-acyl or alkyl.

In one embodiment, Hc preferably represents a bicyclic structure containing heteroatoms in both rings. In some embodiments, the ring of Hc (or both rings)
Is composed of C and N atoms. In one embodiment, Hc represents a bicyclic heteroaryl structure.

In certain embodiments, K is directly attached to a heteroatom of Hc or X represents NR.

[0134] In some embodiments, Hc contains at least one aryl substituent.

[0135] In some embodiments, Hc-X together represent one of the following structures:

[Chemical 56]

Here, W represents O or S, _one of R ₁ , R ₂ and R ₃ represents a bond to K, and the other each represents hydrogen, halogen, alkyl, aralkyl, aryl, cycloalkyl, hetero. Represents aryl, heterocyclic, cycloalkyl, polycyclic, alkylalkenyl, alkylalkynyl or alkanoyl, or together with the nitrogen attached thereto represents amidine, amide, carbamate, urea or guanidine. .

In certain embodiments, Hc-X is represented by ix or xx, R ₃ represents a bond to K, and R ₂ is hydrogen, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, heteroaryl, hetero. Selected from cyclic, cycloalkyl, polycyclic, alkylalkenyl, alkylalkynyl and alkanoyl,
R ₁ is selected from hydrogen, halogen, aryl and heteroaryl. In certain embodiments, R ₂ is hydrogen, (CH ₂ ) _n Ph (where Ph is phenyl or substituted phenyl, n is 0, 1, 2 or 3), heteroaryl, cycloalkyl, C ₁ -C ₆ alkanoyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl, where alkyl, alkenyl and alkynyl groups are NR ₅ R ₆ , phenyl, thioalkyl, alkyl It may be substituted by oxy, hydroxy, carboxy, halogen, cycloalkyl. Where R ₅ and R ₆ are each hydrogen, C ₁ -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, R ₅ and R ₆ together with the nitrogen to which they are attached have from 3 to 7 carbon atoms, nitrogen, substituted nitrogen , A ring optionally containing 1, 2 or 3 heteroatoms selected from the group consisting of oxygen and sulfur can be completed. In certain embodiments, R ₁ is a substituted aryl moiety selected from monohaloaryl, dihaloaryl, monomethylaryl and methylaryl. In some embodiments, K
At least one of R ₁ , R ₂ and R ₃ other than a bond to R represents an aryl substituent or a heteroaryl substituent, and is preferably substituted or unsubstituted phenyl.

In certain embodiments, Hc-X is represented by xviii, R ₂ represents a bond to K, and R ₁ and R ₃ are each hydrogen, alkyl, cycloalkyl, aryl, heterocyclic, heterocycle It is selected from aryl, aralkyl, heteroalkyl, heteroaralkyl, alkylalkenyl, alkylalkynyl, alkylcycloalkyl and alkylheterocyclic. In certain embodiments, R ₁ is alkyl or branched alkyl and R ₃ is aryl, heteroaryl or cycloalkyl. In certain embodiments, R ₃ is selected from monohaloaryl, dihaloaryl, monohaloheteroaryl, dihaloheteroaryl, monohalocycloalkyl or dihalocycloalkyl. In some embodiments, K
At least one of R ₁ , R ₂ and R ₃ other than a bond to R represents an aryl substituent or a heteroaryl substituent, and is preferably substituted or unsubstituted phenyl.

In certain embodiments, where Hc-X is represented by xvi or xvii,
At least one of R ₁ , R ₂ and R ₃ represents a bond to K, R ₃ is selected from hydrogen or alkyl unless it is a bond to K, and R ₂ is alkyl or cyclo unless it is a bond to K. Selected from alkyl, alkylalkenyl, alkylalkynyl, and if not a bond to K, R ₁ is hydrogen, alkyl, cycloalkyl, aryl,
Heteroaryl, heterocyclic, aralkyl, heteroalkyl, alkylalkenyl, alkylalkynyl, alkylcycloalkyl or alkylheterocyclic. In one embodiment, at least one of R ₁ , R ₂ and R ₃ other than the bond to K represents an aryl substituent or a heteroaryl substituent, preferably substituted or unsubstituted phenyl.

In certain embodiments, where Tb is represented by vii or viii, L-
Cy-K-X-Hc does not contain hydrolyzable bonds. In some embodiments, L and K do not contain nitrogen. In some embodiments, Hc is a heterobicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is selected from xvi, xvii, xviii, xix and xx. In certain embodiments, all R ₄ depicted represent H. In one embodiment, Cy represents phenyl, pyridyl, cyclopentyl, cyclohexyl or a fused bicyclic ring system, preferably fused cyclohexyl /
It has between 8 and 11 atoms, such as the cyclopentyl (“4.3.0” -bicyclononane) ring system. When Cy represents a fused ring system, one substituent of L and K (or Hc or Tb) is attached to one of the two rings and the other substituent is attached to the other of the two rings. You can stay. In an embodiment where X is absent,
K is preferably directly attached to the heteroatom of Hc. In some embodiments, K is absent.

In some embodiments, Tb is represented by xi, xii, xiv or xv. In some embodiments, K and L do not contain an amide bond or are preferably free of nitrogen atoms. In some embodiments, Hc is a heterocyclic bicycle. In some embodiments, Hc is selected from xvi, xvii, xviii, xiv and xx. In some embodiments, L-Cy-K-X-Hc contains no hydrolytic linkage. In some embodiments, all R ₄ represented are H
Represents In certain embodiments, Cy represents phenyl, pyridyl, cyclopentyl, cyclohexyl or a fused bicyclic ring system, preferably 8 to 8 such as a fused cyclohexyl / cyclopentyl (“4.3.0” -bicyclononane) ring system. 1
Has between 1 atom. When Cy represents a fused bicyclic ring system, one substituent of L and K (or Hc or Tb) may be attached to one of the two rings,
The other substituent may be attached to the other of the two rings. In the embodiment where X is absent, K is preferably attached directly to the heteroatom of Hc. In some embodiments, K is absent.

In certain embodiments, where Tb is represented by moiety xiii, this moiety is not present elsewhere in the compound, eg, Hc is not xiii, etc. In some embodiments, K does not contain an amide bond or is preferably free of nitrogen atoms. In one embodiment, Hc represents a heterocyclic bicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is selected from xvi, xvii, xviii, xix and xx. In some embodiments, L-Cy-K-X-Hc contains no hydrolyzable linking group. In one embodiment, all R ₄ represented represent H. In certain embodiments, Cy represents phenyl, pyridyl, cyclopentyl, cyclohexyl or a fused bicyclic ring system, preferably 8 to 8 such as a fused cyclohexyl / cyclopentyl (“4.3.0” -bicyclononane) ring system. It has between 11 atoms. When Cy represents a fused bicyclic ring system, L and K (or Hc or T
One substituent of b) may be attached to one of the two rings and the other substituent may be attached to the other of the two rings. In the embodiment where X is absent, preferably K is directly attached to the heteroatom of Hc. In some embodiments, K
Does not exist.

In certain embodiments, where Tb is represented by x, K contains no amide bond, no carbonyl is present, no amine substituent is present, or no nitrogen atom is present. In one embodiment, Hc represents a heterocyclic bicycle. Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is xvi, xvi
It is selected from i, xviii, xix and xx. In some embodiments, L
-Cy-K-X-Hc contains no hydrolyzable linking group. In one embodiment, all R ₄ represented represent H. In some embodiments, Cy
Is phenyl, pyridyl, cyclopentyl, cyclohexyl or a fused bicyclic ring system, preferably fused cyclohexyl / cyclopentyl (“4.3.0”-
Bicyclononane) ring system having between 8 and 11 atoms. When Cy represents a fused ring system, one substituent of L and K (or Hc or Tb) may be attached to one of the two rings and the other substituent is attached to the other of the two rings. Can be combined. In the embodiment where X is absent, preferably K is directly attached to the heteroatom of Hc. In some embodiments, K is absent.

In certain embodiments, where Tb is represented by ii, iii, iv or v, L-Cy-KX-Hc contains no hydrolyzable linking group. In certain embodiments, Hc represents a heterocyclic bicyclic body. In some embodiments, H
c represents a bicyclic heteroaryl structure. In some embodiments, Hc is xvi
, Xviii, xviii, xiv and xx. In one embodiment, all R ₄ represented represent H. In some embodiments, Cy is a phenyl, pyridyl, cyclopentyl, cyclohexyl or fused bicyclic ring system, preferably 8 to 11 such as a fused cyclohexyl / cyclopentyl (“4.3.0” -bicyclononane) ring system. Having atoms between. When Cy represents a fused bicyclic ring system, one substituent of L and K (or Hc or Tb) may be attached to one of the two rings, the other substituent of the two rings. May be attached to the other. In some embodiments, K is directly attached to the heteroatom of Hc. In some embodiments, K is absent.

In certain embodiments where Tb is represented by ix, Cy is preferably uncharged and / or L-Cy-K is preferably free of hydrolyzable linking groups. In some embodiments, L-Cy-K-X-Hc has no hydrolyzable linking group. In certain embodiments, Cy is preferably selected from aryl, carbocycle, nitrogen-containing heterocycle and nitrogen-containing heteroaryl groups, and preferably does not contain S or O in the ring structure. In a preferred embodiment, Cy is 0
Or it contains 1 heteroatom. In one embodiment, Hc represents a heterobicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is xvi, xvii, xviii, xix and xx.
Selected from. In one embodiment, all R ₄ represented represent H.
In some embodiments, Cy represents phenyl, pyridyl, cyclopentyl, cyclohexyl or a fused bicyclic ring system, preferably from 8 to 11 such as a fused cyclohexyl / cyclopentyl (“4.3.0” -bicyclononane) ring system. Having atoms in between. When Cy represents a fused bicyclic ring system, one substituent of L and K (or Hc or Tb) may be attached to one of the two rings, the other substituent of the two rings. May be attached to the other. In embodiments where K is absent,
Preferably K is directly attached to the heteroatom of Hc. In some embodiments, K is absent.

In certain embodiments where Tb is represented by i, Cy is preferably uncharged and / or L-Cy-K is preferably free of hydrolyzable linking groups. In certain embodiments, Cy is preferably selected from aryl, carbocycle, nitrogen-containing heterocyclic groups and nitrogen-containing heteroaryl groups, and preferably does not contain S or O in the ring structure. In a preferred embodiment, Cy contains 0 or 1 heteroatoms. In one embodiment, Hc represents a heterocylic bicyclic form. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is selected from xvi, xvii, xviii, xix and xx. In one embodiment, all R ₄ represented represent H. In certain embodiments, Cy is phenyl, pyridyl, cyclopentyl,
A cyclohexyl or fused bicyclic ring system, preferably 8 to 11 such as a fused cyclohexyl / cyclopentyl (“4.3.0” -bicyclononane) ring system
Having atoms between. When Cy represents a fused ring system, one substituent of L and K (or Hc or Tb) may be attached to one of the two rings and the other substituent is attached to the other of the two rings. Can be combined. In certain embodiments where X is absent, preferably K is directly attached to the heteroatom of Hc. In some embodiments, K is absent.

In certain embodiments where Tb is represented by i, Z and L are absent. In one embodiment, Cy represents aryl or heteroaryl such as phenyl or pyridyl. In some embodiments, Cy is preferably uncharged and / or L-Cy-K-X-Hc is preferably free of hydrolyzable linking groups. In certain embodiments, Cy is preferably selected from aryl, carbocycle, nitrogen-containing heterocyclic groups and nitrogen-containing heteroaryl groups, and preferably does not contain S or O in the ring structure. In a preferred embodiment, the Cy ring system contains 0 or 1 heteroatoms or is preferably phenyl. In one embodiment, Hc represents a heterobicycle. In some embodiments, Hc
Represents a bicyclic heteroaryl structure. In some embodiments, Hc is xvi,
It is selected from xvii, xviii, xix and xx. In one embodiment, all R ₄ represented represent H. In one embodiment, Cy represents phenyl, pyridyl, cyclopentyl, cyclohexyl or a fused bicyclic ring system,
Preferably it has between 8 and 11 atoms such as a fused cyclohexyl / cyclopentyl (“4.3.0” -bicyclononane) ring system. When Cy represents a fused bicyclic ring system, one substituent of L and K (or Hc or Tb) may be attached to one of the two rings, the other substituent of the two rings. May be attached to the other. In the embodiment where X is absent, K is preferably directly attached to the heteroatom of Hc. In some embodiments, K is absent.

In certain embodiments of formula I, Tb is selected from i and ix, K is absent, or represents -Y-, such as -NH-. In some embodiments, Hc is x
selected from vi, xvii, xviii, xix and xx. In some embodiments, Cy is aryl or heteroaryl, preferably aryl. In certain embodiments, Hc is further substituted with an aryl group at one position of R ₁ , R ₂ and R ₃ , which is not substituted by K, for example. In one embodiment, each of R ₁ , R ₂ and R ₃ represents a hydrocarbon substituent. In one embodiment, L represents alkyl, alkyl-Y-alkyl or alkyl-Y-acyl, wherein Y is preferably N or N such as NMe.
R.

In some embodiments of Formula I, Tb is x and K is absent. In some embodiments, Hc is selected from xvi, xvii, xviii, xix and xx. In certain embodiments, Hc is further substituted with an aryl group at one position of R ₁ , R ₂ and R ₃ , which is not substituted by K, for example. In one embodiment, each of R ₁ , R ₂ and R ₃ represents a hydrocarbon substituent. In some embodiments, L represents alkyl, alkyl-Y-alkyl or alkyl-Y-acyl, where Y is preferably NR such as NH or NMe.

[0150]   In certain embodiments, the subject compounds have the structure of formula (II):           Hc-X-K-Z-Tb                   (II)

Here, Hc, X, K, and Tb are the same as defined above. In certain embodiments of formula (II), Tb is x, xi, xii, xiii, x
It is selected from iv and xv. In embodiments in which Tb is selected from x, xi, xii, xiii, xiv and xv, Z is absent or represents O or NR, but is preferably absent.

In the embodiments where Tb is selected from i, v, vi, vii, viii and ix, Z is preferably absent. In an embodiment in which Tb is selected from ii, iii and iv, Z is absent or represents O or NR.

In certain embodiments, all R ₄ represented represent H.

In some embodiments, KX-Hc has no hydrolyzable linking group. The term hydrolyzable linking group, as used herein, has at least one of S,
It is a saturated (sp ³ -hybrid orbital) carbon bonded to two heteroatoms selected from N or O.

In certain embodiments, M is -CH _2- , -CHF-, -CHOH-,-
It represents a substituted or unsubstituted methylene group such as CH (Me) -C (= O)-.

[0156]   In some embodiments, K is absent.

In one embodiment, K represents alkyl-Y-alkyl, alkyl-Y-acyl or alkyl.

In certain embodiments, Hc represents a bicyclic structure, preferably containing heteroatoms in both rings. In some embodiments, one or both rings of Hc are composed of C and N atoms.

In one embodiment, K is directly attached to the heteroatom of Hc or X represents NR.

In some embodiments, Hc contains at least one aryl substituent.

[0161] In some embodiments, Hc-X together represent one of the structures below.

[Chemical 57]

Here, W represents O or S, _one of R ₁ , R ₂ and R ₃ represents a bond to K, and the other each represents hydrogen, halogen, alkyl, aralkyl, aryl, cycloalkyl, hetero. It represents aryl, heterocyclic group, cycloalkyl, polycyclic, alkylalkenyl, alkylalkynyl or alkanoyl, or together with the nitrogen to which it is attached represents amidine, amide, carbamate, urea or guanidine.

In certain embodiments, where Hc is represented by xix or xx, R ₃ is K
R ₂ represents hydrogen, alkyl, alkenyl, alkynyl, aralkyl, aralkyl, cycloalkyl, heteroaryl, heterocyclic group, cycloalkyl, polycyclic group, alkylalkenyl, alkylalkynyl or alkanoyl, and R ₁ Is selected from hydrogen, halogen, aryl and heteroaryl. In certain embodiments, R ₂ is hydrogen, (CH ₂ ) _n Ph (where Ph is phenyl or substituted phenyl, n is 0, 1, 2 or 3), heteroaryl, cycloalkyl, C ₁ -C ₆ alkanoyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂
Selected from --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.
Where R ₅ and R ₆ are each hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, (CH ₂ ) _n Ph (where Ph is phenyl,
n is 0, 1, 2 or 3), cycloalkyl, heteroaryl, R ₅ and R ₆ together with the nitrogen to which they are attached have from 3 to 7 carbon atoms,
1, 2 or 3 selected from the group consisting of nitrogen, substituted nitrogen, oxygen and sulfur
A ring optionally containing the heteroatoms of can be completed. In certain embodiments, R ₁ is a substituted aryl moiety selected from monohaloaryl, dihaloaryl, monomethylaryl and dimethylaryl. In some embodiments, K
At least one of R ₁ , R ₂ and R ₃ other than those bonded to is one of aryl or heteroaryl substituents, preferably substituted or unsubstituted phenyl.

In certain embodiments, Hc-X is represented by xviii, R ₂ represents a bond to K, and R ₁ and R ₃ are each hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl. , Aralkyl, heteroalkyl, heteroaralkyl, alkylalkenyl, alkylalkynyl, alkylcycloalkyl and alkylheterocyclyl. In some embodiments,
R ₁ is alkyl or branched alkyl and R ₃ is aryl, heteroaryl or cycloaryl. In certain embodiments, R ₃ is selected from monohaloaryl, dihaloaryl, monohaloheteroaryl, dihaloheteroaryl, monohalocycloalkyl or dihalocycloalkyl. In certain embodiments, at least one of R ₁ , R ₂ and R ₃ other than a bond to K is an aryl or heteroaryl substituent, preferably a substituted or unsubstituted phenyl.

In certain embodiments, where Hc-X is represented by xvi or xvi, at least one of R ₁ , R ₂ and R ₃ represents a bond to K and R is otherwise a bond to K. ₃ is selected from hydrogen or alkyl, R ₂ is selected from alkyl, cycloalkyl, alkylalkenyl, alkylalkynyl if not a bond to K, R ₁ is hydrogen, alkyl, cycloalkyl, or a bond not to K Selected from aryl, heteroaryl, heterocyclyl, aralkyl, heteroalkyl, alkylalkenyl, alkylalkynyl, alkylcycloalkyl or alkylheterocyclyl. In certain embodiments, R ₁ other than a bond to K is
, R ₂ and R ₃ represent at least one aryl or heteroaryl substituent, preferably substituted or unsubstituted phenyl.

In certain embodiments, where Tb is represented by vii or viii, K-
X-Hc has no hydrolyzable linking group. In some embodiments, K does not include nitrogen. In one embodiment, Hc represents a heterobicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is selected from xvi, xvii, xviii, xix and xx.
In one embodiment, all R ₄ represented represent H. In the embodiment where X is absent, preferably K is directly attached to the heteroatom of Hc. In some embodiments, K is absent.

In some embodiments, Tb is represented by xi, xii, xiv or xv. In some embodiments, K does not contain an amide bond or is preferably free of nitrogen atoms. In one embodiment, Hc represents a heterobicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is selected from xvi, xvii, xviii, xix and xx. In some embodiments, KX-Hc has no hydrolyzable linking group. In one embodiment, all R ₄ represented represent H. X
In the embodiment where is not present, preferably K is directly attached to the heteroatom of Hc. In some embodiments, K is absent.

In some embodiments, where Tb is represented by a moiety xiii that is not present in other components of the structure, for example, Hc is not xiii. In some embodiments, K does not contain an amide bond or is preferably free of nitrogen atoms. In one embodiment, Hc represents a heterobicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc
Is selected from xvi, xvii, xviii, xix and xx. In some embodiments, K-X-Hc does not include a hydrolyzable bond. In one embodiment, all R ₄ represented represent H. In the embodiment where X is absent, preferably K is directly attached to the heteroatom of Hc. In some embodiments, K is absent.

In certain embodiments where Tb is represented by x, K does not contain an amide bond, is free of carbonyls, is free of amine substituents, or is free of nitrogen atoms. K-X-Hc contains no hydrolyzable bonds. In one embodiment, Hc represents a heterobicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is xvi, xv
It is selected from ii, xviii, xix and xx. In one embodiment, all R ₄ represented represent H. In the embodiment where X is absent, preferably K is directly attached to the heteroatom of Hc. In some embodiments, K is absent.

In certain embodiments, where Tb is represented by ii, iii, iv or v, KX-Hc has no hydrolyzable linking group. In one embodiment, Hc represents a heterobicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is xvi, xvii, xvi.
It is selected from ii, xix and xx. In one embodiment, all R ₄ represented represent H. In some embodiments, K is directly attached to the heteroatom of Hc. In some embodiments, K is absent.

In certain embodiments, where Tb is represented by ix, preferably KXH
There is no hydrolyzable linking group in c. In some embodiments, the compound is free of hydrolyzable linking groups. In one embodiment, Hc represents a heterobicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is selected from xvi, xvii, xviii, xix and xx. In one embodiment, all R ₄ represented represent H. In the embodiment where X is absent, preferably K is directly attached to the heteroatom of Hc. In some embodiments, K is absent.

In certain embodiments, where Tb is represented by i, Hc represents a heterobicycle. In one embodiment, Hc represents a bicyclic heteroaryl structure. In some embodiments, Hc is selected from xvi, xvii, xviii, xix and xx. In one embodiment, all R ₄ represented represent H. In the embodiment where X is absent, preferably K is directly attached to the heteroatom of Hc. In some embodiments, K is absent.

In certain embodiments of formula (II), Tb is selected from i and ix and K is branched or unbranched alkyl. In some embodiments, Hc is xvi, x
selected from vii, xviii, xix or xx. In certain embodiments, Hc is further substituted with an aryl group, for example at one position of R ₁ , R ₂ and R ₃ which is not substituted by K. In some embodiments, R ₁
, R ₂ and R ₃ each represent a hydrocarbon substituent. In certain embodiments of formula (II), Tb is xii and K is absent or represents -Y-, such as -NH-. In some embodiments, Hc is xv
It is selected from i, xvii, xviii, xix and xx. In certain embodiments, Hc is further substituted with an aryl group, for example at one position of R ₁ , R ₂ and R ₃ which is not substituted by K. In some embodiments,
Each of R ₁ , R ₂ and R ₃ represents a hydrocarbon substituent.

In certain embodiments of formula (II), Tb is x and K is alkyl or-
Represents Y-. In some embodiments, Hc is xvi, xvii, xviii,
It is selected from xix and xx. In certain embodiments, Hc is further substituted with an aryl group, for example at one position of R ₁ , R ₂ and R ₃ which is not substituted by K. In one embodiment, each of R ₁ , R ₂ and R ₃ represents a hydrocarbon substituent.

In certain embodiments, a subject compound has the structure of formula (II): Tb-LV. Where Tb, R and L are the same as previously defined, and V represents OR, NR ₂ or SR.

In the embodiments in which Tb is selected from i, ii, iii, iv, v, vi, vii, viii and ix, L is preferably absent and more preferably represents alkyl. In one embodiment Tb preferably represents i, ii, iii or iv. In one embodiment Tb represents v or vi. In some embodiments, Tb represents vii or viii. In one embodiment Tb represents ix. In one embodiment V represents NR ₂ . In some embodiments, every R represented in V is H.

In some embodiments, Tb is x, xi, xii, xiii, xiv, xv.
, Xxi, xxii, xxiii, xxiv and xxv. In some embodiments, Tb is selected from xi, xii, xiv or xv. In some embodiments, Tb is x. In some embodiments, Tb is xi
ii. In one embodiment V represents NR ₂ . In some embodiments, Tb is xxi, xxii, xxiii, xxiv, or xxv.
In some embodiments, Tb is xx. In some embodiments, every R represented in V is H. In some embodiments, L represents lower alkyl or is absent.

In certain embodiments, a subject compound has the structure of formula (IV): Tb-Cy-LV. Where Tb, Cy, L and V are the same as previously defined and T
b is selected from i, ii, iii, iv, v, vi, vii, viii and ix. In one embodiment, Tb represents i, ii, iii or iv, preferably i. In one embodiment Tb represents v or vi. In some embodiments, Tb represents vii or viii. In one embodiment Tb represents ix. In some embodiments, L is absent. In one embodiment, Cy represents a phenyl ring. In some embodiments, every R represented in V is H. In some embodiments, L represents lower alkyl or is absent.

In certain embodiments, a subject compound has the structure of formula (V): Tb-LU. Where Tb, R and L are as defined above, U is sulfonate ester (triflate, tosylate, mesylate, etc.), halogen, (eg Cl, Br, I, preferably Br, I), formyl (CH
O) or a compatible leaving group (eg, its conjugate acid, UH is 5 or less, preferably 0).
The following shows the part having pKa).

In the embodiments where Tb is selected from i, ii, iii, iv, v, vi, vii, viii and ix, L is preferably absent or more preferably represents alkyl. In some embodiments, Tb represents i, ii, iii or iv, but is preferably i. In one embodiment Tb represents v or vi. In some embodiments, Tb represents vii or viii. In one embodiment Tb represents ix.

In some embodiments, Tb is x, xi, xii, xiii, xiv, xv.
, Xxi, xxii, xxiii, xxiv and xxv. In some embodiments, Tb is selected from xi, xii, xiv or xv. In some embodiments, Tb is x. In some embodiments, Tb is xi
ii. In one embodiment V represents NR ₂ . In some embodiments, Tb is xxi, xxii, xxiii, xxiv or xxv. In some embodiments, Tb is xx.

In certain embodiments, a subject compound has the structure of formula (VI): Tb-Cy-LU. Where Tb, Cy, L and U are the same as previously defined,
Tb is selected from i, ii, iii, iv, v, vi, vii, viii and ix. In some embodiments, Tb represents i, ii, iii or iv, but is preferably i. In one embodiment Tb represents v or vi.
In some embodiments, Tb represents vii or viii. In one embodiment Tb represents ix. In some embodiments, L is absent. In some embodiments, Cy is a phenyl ring.

[0183]   In certain embodiments of formulas (I)-(IV), Tb represents the structure:

[Chemical 58] In certain embodiments of formula (I)-(IV), Tb has a structure selected from:

[Chemical 59]

[Chemical 60] Where M is the same as previously defined, x represents 1, 2, 3, 4, 5 or 6, and each notation of Y is a conjugate bond, -O-, -S- or -N ( R _j ) ₂ −. Each R _j − represented herein is hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl. R ₆ is halogen, lower alkyl, lower alkenyl, aryl, heteroaryl, carbonyl, thiocarbonyl, ketone, aldehyde, amino, acylamino, amide, amidino, cyano, nitro, azide, sulfonyl, sulfoxide, sulfate, sulfonate, sulfamoyl, sulfonamido, phosphoryl, phosphonate, phosphinate, - (CH _{2) p} alkyl, - (CH _{2) p} alkenyl, - (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, - (CH 2) n R} , - (CH 2) p SH, - ( CH ₂ ) _p S lower alkyl,-(CH ₂ ) _p S lower alkenyl, -S (CH ₂ ) _n R,-(CH ₂ ) _p N (R) ₂
,-(CH ₂ ) _p NR-lower alkyl,-(CH ₂ ) _p NR-lower alkenyl, -N
R ₈ (CH ₂ ) _n R or 0-3 substituents selected from these protected forms, wherein p is 1-10 and each R ₄ represented is hydrogen or lower, respectively. It is alkyl.

In certain embodiments, M present in Tb is selected from CH ₂ , CHJ and CJ ₂ , where J is selected from halogen of F, Cl, Br or I, preferably F or Cl, more preferably F.

In certain embodiments, R ₆ is selected from lower alkyl, an affinity group and a lower alkyl substituted with an affinity group. Representative affinity groups include hydroxyl, sulfhydryl, amino, amide, carboxyl, sulfonate,
Phosphonates and their salts are included. In some embodiments of Formulas (I)-(VI), Tb has the following structure xxxxxxii:
Have.

[Chemical formula 61] Where A represents a group selected from GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ and GSO ₃ R ₄ : B represents NH ₂ , OH, GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ and GSO ₃ represents a group selected from R _4:, or not G is present or _{CF 2, CH 2,, O} , S, NR, CH 2 S, CH 2 NR,
It represents a linking group of one or two atoms such as CH ₂ O.

[Chemical formula 62]

In some embodiments, the phenyl ring comprises one or more additional R ₆
It may have a substituent. In some embodiments G is absent, while in other embodiments G is present. In some embodiments, at least one of the G's represented is absent. In one embodiment, Tb has the structure: In certain embodiments of formulas (I)-(VI), Tb has the structure xxxxxxiii.

[Chemical formula 63] Here, B is defined as above. In some embodiments, the pyridyl ring contains one or more additional R ₆
It may have a substituent. In some embodiments of Formulas (I)-(VI), Tb is xxxxxx or xx
It has the structure of xxv.

[Chemical 64]

Here, C represents H, R ₆ , NH ₂ , OH, GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ or GSO ₃ R _4, and in A or B represented in xxxxxx. Exists, and the other notation represents a bond to Z, H or R ₆ as necessary.

In certain embodiments, the pyridyl ring comprises one or more additional R ₆
It may have a substituent.

In certain embodiments of formulas (I)-(VI), Tb represents heteroaryl, preferably nitrogen-containing heteroaryl, having one B substituent, preferably one A substituent, or two B substituents. It has a substituent and optionally contains one or more R ₆ substituents. In a preferred embodiment, the heteroaryl group is selected from thiazoline, oxazoline, pyrrole, pyrazole, imidazole, pyridine, pyrazine, pyridazine and pyrimidine, but is preferably pyridine, pyrazole, pyrazine and pyrimidine.

Stationary Phase Synthesis and Combinatorial Library of Bone Targeting Agents This creative compound can be made by any method possible. Preferably, for example, they are synthesized using solution phase or solid phase techniques. Solid phase synthesis is an improved version of the compounds described herein, where there are many cases that allow the attachment of compounds to solid supports. A faster "spli" for easier generation of larger libraries (10,000 or more)
The present invention is believed to be particularly preferred as it allows the use of "and pool" technology. US Pat. No. 5,712,17, incorporated herein by reference.
It will be appreciated that solid phase parallel techniques may also be utilized, as described in 1 and 5,736,412.

A solid support for the purposes of this invention is defined as an insoluble material to which the compounds are attached during the synthetic sequence. By washing off the reagents, it is easy to achieve the isolation of the support-bound reaction product from the support-bound material, and it is therefore possible to drive the reaction to completion by using excess reagent, so that the solid The use of the carrier is advantageous for library synthesis. In addition, the use of solid supports allows the "tracking" of the attributes of the compounds of the invention in the library, making use of specific coding techniques. The solid carrier may be any material as long as it is an insoluble matrix and has a rigid or semi-rigid surface. Typical solid carriers include pellets, disks, capillaries, hollow fibers, needles, pins, solid fibers, cellulose beads, microporous glass beads, silica gel, polystyrene beads optionally crosslinked with divinylbenzene, and grafted copolyesters. Includes, but not limited to, polymeric beads, polyacrylamide beads, latex beads, dimethylacrylamide beads optionally crosslinked with NN'-bis-acryloylethylenediamine, and glass particles coated with hydrophobic polymers. . One of ordinary skill in the art will recognize that the choice of a particular solid support is limited by the compatibility of the support with the reaction chemistry utilized. In one particularly preferred embodiment, Tentagel amino resin: 1
) Polystyrene beads crosslinked with divinylbenzene and 2) PEG (
A complex with polyethylene glycol) has been applied for use in the present invention. T
Entagel is a particularly useful solid support because it provides a versatile support for use in on-bead or extra-bead assays and also exhibits excellent swellability in solvents from toluene to water.

The compounds of the present invention can be directly attached to the solid support or can be attached to the solid support via a linking agent. Direct attachment to a solid support is useful if it is not desired to desorb the library member from the solid support. For example, for direct analysis on biologically / pharmacologically active beads or structural analysis of compounds, strong interactions between library members and solid supports are desirable. On the one hand, the use of ligation reagents would be useful if easier cleavage of the inventive library members from the solid support was desired.

Furthermore, the linking agent used in the present invention may be composed of a single linking molecule or, alternatively, a linking molecule and one or more spacer molecules. Spacer molecules are particularly useful if the requirements of a particular reaction require separation of the ligation reagent from the library member, or if a greater distance between the solid support / ligation unit and the library member is desired. become. In one particularly preferred embodiment, photocleavable linkers are used to attach the solid phase resin to the components. Photocleavable linkers are of particular benefit to the claimed invention, as they can be used in in vivo screening strategies. Once the compound of the invention is released from the solid support via photocleavage, the compound is able to enter the cell. Representative photocleavable linkers include, but are not limited to, ortho-nitrobenzyl photolinkers and dithiane protected benzoin photolinkers. One of ordinary skill in the art will appreciate that the method of the present invention is not limited to the use of photocleavable linkers,
It will be readily appreciated that other linkers, preferably those capable of delivering the desired compound in vivo, can also be applied.

In one embodiment of the present invention, the synthesis of a library of bone-targeting agents uses combinatorial methods established for solution phase, solid phase or combination solution phase and solid phase synthesis techniques. To implement. Synthesis of combinatorial libraries is well known in the art and has been reviewed (see, eg, “Combination Chemistry”, Chemi.
cal and Engineering News, February 24, 1997, p. 43; Thompson, L .; A. Ellman, J .; A. , Chem
． Rev. 1996, 96, 555, incorporated by reference). Those of ordinary skill in the art will appreciate that the choice of method will depend on the particular number of compounds synthesized, the particular reaction chemistry, and the particular instrument, such as a robotic instrument for the production and analysis of the inventive libraries. It will be appreciated that it will depend on availability. In a particularly preferred embodiment, the scaffold-based reaction of the invention to generate the library, if applicable, is selected for its ability to proceed stereoselectively in high yields.

In one embodiment of the current invention, solution phase technology is used to generate the library. Traditional advantages of solution phase technology for the synthesis of combinatorial libraries include a much wider range of organic reaction possibilities, and thereby the relative ease with which the products can be characterized. In a preferred embodiment, parallel synthesis techniques are utilized for the generation of solution phase combinatorial libraries, where all of the products are separately collected in each vessel of those reactions. In a particularly preferred parallel synthesis procedure, a microtiter plate is used which holds n rows and m columns of small wells capable of holding a few milliliters of solvent in which the reaction takes place. Thus, it is possible to obtain nxm variants within an nxm depression using the n number of variants of Reactant A and the number of m variants of Reactant B. Those of ordinary skill in the art will appreciate that this particular procedure is most useful when smaller libraries are desired and these unique depressions identify library members within a particular depression. We will appreciate that we can provide an easy means of doing so.

In another embodiment of the present invention, solid phase synthesis techniques are utilized in which the desired scaffold structure is attached to the solid phase, either directly or via a linking unit, as described above. It Advantages of solid phase technology include the ability to more easily carry out the multi-step reaction and the ability to drive the reaction to completion as excess reagent can be used and unreacted reagent can be washed away. Perhaps one of the most significant advantages of solid-phase synthesis is that, in addition to parallel synthesis techniques, "split and" was developed by Furka.
Performance using a technique called "pool" (Furka et al., Abstr.
． 14th International Conference, Biochemistry, Prague, Czechoslovakia, 1988, 5, 47
Furka et al., Int. J. Pept. Protein Res. 1991,
37,487; Seestyen et al., Bioorg. Med. Chem. Let
t. , 1993, 3, 413). In this technique, a mixture of related compounds can be made in the same reaction vessel, thus substantially reducing the number of containers required for the synthesis of extremely large libraries containing one million or more library members. Decrease. As an example, the solid support scaffold can be divided into n containers. Here, n represents the number of reagent type A that reacts with the scaffold structure.
After the reaction, the contents from n vessels are mixed and divided into m vessels. Here, m represents the number of reagent type B that reacts with the scaffold structure. This procedure is repeated until the desired number of reagents has reacted with the scaffold structure to yield the inventive library.

The use of solid phase technology in the present invention includes the use of special coding technology. Special coding techniques have been reviewed by Czarnik. (Czar
nik, A .; W. Recent Views in Chemistry and Biology, 1997, 1, 60) As used in the present invention, the coding technique involves a special "identifying agent" attached to a solid support.
Use of. This allows the structure of a particular library member to be determined without having to discuss its spatial coordinates. Also, those with ordinary skill in this field,
Within a specific reaction well, such as on a 96 well plate or plastic pin,
It will also be appreciated that if a smaller solid phase library is generated, the spatial coordinates within that particular plate will confirm the reaction history of such library members, and thus be spatially encoded. Ah However, for large combinatorial libraries, it is most preferable to record the history of a particular reaction using another type of coding technique.

An example of another type of coding technique available in the present invention is the spatial coding technique, “te
Includes, but is not limited to, schematic coding techniques, including a bag "methods, chemical coding techniques, and spectrophotometric coding techniques. Spatial coding techniques are reactions based on their position. A schematic coding technique involves the coding of each synthetic platform that allows the generation of a relative database. An example of a preferred spectrophotometric coding technique is a mass spectrometer. , Fluorescent emission and nuclear magnetic resonance spectroscopy.In a preferred embodiment, chemical encoding techniques are used, which method uses the structure of the reaction product to encode for its properties. Decoding using this method can be performed on or away from the solid phase. Persons of ordinary skill in the art will recognize the particular coding techniques used in the present invention. It will be appreciated that the procedure will need to be selected based on the number of library members desired and the reaction chemistry employed.

Subsequent characterization of library members or individual compounds can be performed using standard analytical techniques such as mass spectrometry, nuclear magnetic resonance spectroscopy and gas chromatography.

Once a particular library of compounds has been generated, particular assay techniques as described herein could be used to test the ability of the compounds to function as Src kinase inhibitors. In certain preferred embodiments, high throughput assay techniques are utilized.

Utilization of the Compounds of the Invention As described above, the compounds of the present invention are used for the selective treatment or prevention of bone disorders. These compounds or pharmaceutical compositions serve therapeutic purposes through the inhibition of osteoclast activity, the promotion of osteoblast activity, or the promotion or inhibition of other cellular events required for healthy bone metabolism. You can In certain preferred embodiments, these compounds are useful in the treatment and prevention of diseases and conditions associated with diseases of bone metabolism such as osteoclast hyperactivity. In a more preferred embodiment, the compounds of the present invention are targeted Src kinase inhibitors and thus inhibit bone resorption by osteoclasts.

Accordingly, the present invention provides a method for the treatment, prevention and / or prevention of bone diseases and other related diseases, which method comprises the compound of the invention or a pharmaceutical composition thereof. It consists of administering an effective, non-toxic amount. As I mentioned before,
The compounds of the invention may serve therapeutic purposes through several mechanisms (ie, inhibition of osteoclast activity, promotion of osteoblast activity, or modulation of other cellular events required for healthy bone metabolism). However, in certain preferred embodiments, these compounds are also selective inhibitors of osteoclast activity.

In a further aspect, the present invention provides an inhibitor of a mammalian osteoclast, eg the inhibitor is a compound of the invention or one of its pharmaceutical compositions. In yet another aspect, the present invention provides a compound or a pharmaceutical composition thereof that is an inhibitor of a selective Src kinase. In particular, the method of the present invention consists in providing either the compound of the present invention or its pharmaceutical composition for use in the treatment and / or prophylaxis of osteoporosis and related osteopetrotic diseases. Although many of the compounds and compositions described herein consist of a bone targeting moiety and a payload, the present invention also preferably aims at treating bone disorders by selectively inhibiting osteoclast activity. The use of a bone targeting agent alone is also contemplated.

In addition to treating or preventing osteoporosis, particularly osteoporosis associated with pre- and post-menopausal conditions, the present invention provides Paget's disease, osteoneoplastic associated hypercalcemia and other types of osteoporosis. It is also intended to treat and prevent or prevent diseases associated with. These include, but are not limited to, degenerative osteoporosis, Type I,
That is, postmenopausal osteoporosis, Type II, that is, senescent osteoporosis, juvenile osteoporosis, idiopathic osteoporosis, endocrine disorders, hyperthyroidism, hypogonadism,
Ovarian dysgenesis, Turner syndrome, hyperadrenocortical disease, Cushing's syndrome, hyperparathyroidism, myelopathy, diseases associated with multiple myeloma, systemic mastocytosis, diffuse carcinoma, Gaucher disease, connective tissue abnormality , Osteogenesis imperfecta, homocystinuria, Ehlers-Danlos syndrome, Marfan syndrome, Menke's syndrome, dyskinesia or underweight, Sdec's atrophy, chronic obstructive pulmonary disease, chronic heparin administration and Includes chronic ingestion of anticonvulsants.

In addition to providing compounds directed to the selective inhibition (and inhibition of osteoclast activity) of Src tyrosine kinase, the present invention contemplates the use of alternative payloads to achieve the desired therapeutic effect. . The targeting constructs of the present invention include any of a wide variety of chemical entities that are delivered within a target site or target cell. Generally, payloads are classified as therapeutic agents (such as Src kinase inhibitors) or imaging agents. Imaging agents alter the properties of treated cells relative to untreated cells, for example by emitting light, radioluminescence or a chemical signal, by absorbing irradiated light (eg x-rays) By including a payload that is detectable. The therapeutic agent preferably includes a payload that is biologically active by combating abnormal conditions at the bone targeting site (eg, tumor or infection).

The therapeutic agent useful for the targeting compound may be any of several chemical entities such as enzymes, drugs, radionuclides, enzyme inhibitors and the like. For example, in the class useful as therapeutic agents, inhibitors of osteoclast activity such as Src inhibitors, cathepsin inhibitors or proton pump inhibitors: amino acids and their derivatives, analgesics such as acetamide fen, aspirin and ibuprofen: Antibacterial agents containing allylamine, imidazole, polyene and triazole: Antigens and their antibodies: Antihistamines such as chlorophenylamide and bromophenylamide: Antihypertensive agents such as clonidine, methyldopa, pyrazosin, verapamil, nifedipine, captopril and enalapril: aminoaryl Carboxylic acid derivatives, aryl acetic acid derivatives, aryl butyric acid derivatives, aryl carboxylic acids, aryl propionic acid derivatives, pyrazoles, pyrazolones, salicylic acid derivatives, thiazine carboxamides, etc. Non-steroidal agents, and anti-inflammatory agents including steroids such as gluco code Tico Id: aminoglycosides, amphenicols call, cinoxacin, ciprofloxacin, 2,
4-diaminopyrimidines, β-lactams (eg, carbapenem, cephalosporins, cephamycins, monobactams, oxacephems and penicillins), lincosamides, macrolides, nitrofurans, norfloxacins, peptides, polypeptides, proteins (eg, Defensin, bacitracin, polymyxin, cecropin, magainin II, indolicidin, lanalexin, protegrin, galinacin, tritopticin, lactoferricin, drosomycin, holotricin, sanatin, dermaceptin, iturin, syringomycin, nicomycin, polyoxin, FR-900403, etincan. , Nemokanjin,
Antibacterial agents such as acreasin, mrundocaidine, WF11899, aureobasidin, cizothrin A, cepacidin, zeamatin, cyclopeptide and D4el), quinoline and analogs, sulfonamides, sulfones, tetracycline: apoprotein: purine / pyrimidinone (eg, Antiviral agents containing acyclovia, dideoxy-cytidine, -adnosine or -inosine, interferon, amantadine, ribavirin): beta blockers such as proprananolol, metaprolol, atenolol, labetrol, timolol, penbutrol and pindolol: chemotherapeutic agents Cancer drugs including: Cardiac vascular agents including cardiac glycoside, antianginal and vasodilater: Coenzyme: Enzyme: Enzyme inhibitor: Expect Runt: Glycoprotein: H-2 antagonist such as Nizatidine, Cimetidine, Famotidine and Ranitidine: Hapten and its antibody: Hormone, lipid, lysosome: Protein analogue in which at least one non-peptide bond is replaced by a peptide bond: Phospholipid: Prostaglandin: Radionuclide (
For example, ¹³¹ I, ¹⁸⁶ Re, ¹⁸⁸ Re, ⁹⁰ Y, ²¹² Bi, ²¹¹ At, ⁸⁹ Sr, ¹⁶⁶ Ho.
, ¹⁵³ Sm, ⁶⁷ Cu and ⁶⁴ Cu): Receptors and other membrane proteins: Retro-
Inverso oligopeptides: stimulants: toxins such as aflatoxin, digoxin, rubratoxin and xanthotoxin: tranquilizers such as diazepam, cordiazepoxide, oxazepam, alprazolam and triazolam: and additives such as vitamins, minerals and nutrients: Is mentioned. For other therapeutic agents, see, for example, the Merck Index. The present invention contemplates agents useful in treating or preventing the progression of bone and its related diseases, preferably by inhibiting the activity of osteoclasts.

In an exemplary embodiment, the compounds and compositions of the present invention are also inhibitors of cathepsin K and can be used to treat bone disorders. In particular, it has been discovered that osteoclasts contain large amounts of cathepsin K, suggesting that cathepsin K plays an important role in bone resorption (Smith et al., Exp. Op.
in. Ther. Patents 1999, 9, 683-694 and references incorporated therein). For example, this enzyme is active in the pH range (3.5-4.0) that is consistent with the pH of the local bone environment during resorption, and that cathepsin K antisensory nucleotides are effective in inhibiting resorption of osteoclasts. It has been reported that there is a link between mutations in the human cathepsin K gene and rare skeletal dysplasia, and that there is pycnodysosis, a disease characterized by abnormal bone resorption. (See Smith et al.). Thus, the compounds of the invention that are cathepsin K inhibitors would be useful as agents for the inhibition of bone resorption and therefore could be used to treat osteoporosis or other diseases resulting from abnormal bone resorption. It was possible. Alternatively or additionally, the bone targeting compound can be labeled with any of a wide variety of imaging agents. Imaging agents are well known in the art and are used to detect or monitor compounds in vitro or in vivo, depending to some extent on the instrument. Preferred imaging agents for performing Positron Emission Tomography (PET) and Single Photon Emission Tomography (SPECT) include F-18
, Tc-99m and I-123. Preferred imaging agents for magnetic resonance imaging include compatible atoms or free radicals with unpaired spin electrons.

When the payload is to be rendered imaging capable, it contains moieties such as radionuclides or paramagnetic contrast agents, fluorescent agents, chemiluminescent agents or other types of detectable markers. The imaging agent described above may contain a label in accordance with this invention. A highly specific and sensitive label is provided by the radionuclide, which can then be detected using Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT). More preferably, the inventive imaging agents are ¹³¹ I, ¹²⁵ I, ¹²³ I, ¹⁸ F, ⁶⁸ Ga, ⁶⁷ Ga, ^72.
A radionuclide selected from the group consisting of As, ⁸⁹ Zr, ⁶⁴ Cu, ⁶² Cu, ¹¹¹ In, ²⁰³ Pb, ¹⁹⁸ Hg, ¹¹ C, ⁹⁷ Ru and ²⁰¹ Tl, or gadolinium,
It contains paramagnetic contrast agents such as cobalt, nickel, manganese and iron. As will be appreciated, these atoms may be directly incorporated into the bone targeting moiety or payload.

Therapeutic / Prophylactic Administration and Pharmaceutical Compositions As noted above, the compounds of the present invention are useful in the treatment of bone disorders, preferably imbalances in bone metabolism, such as hyperabsorption of bone resorption. In certain preferred embodiments, the compounds of the present invention are useful as inhibitors of Src tyrosine phosphorylation.

When the compounds of the present invention are used for therapeutic and / or prophylactic administration, the compounds may exist in free form or, where appropriate, in salt form. Many types of pharmaceutically acceptable salts of many compounds and their preparation are well known to those skilled in the art. The pharmaceutically acceptable salts of the compounds of the present invention include:
Conventional non-toxic salts or quaternary ammonium salts are included, which are formed, for example, from basic inorganic or organic acids.

The compounds of the invention may form hydrates or solvates. It is known to those skilled in the art that charged compounds form hydrated species when lyophilized in water, or solvated species when concentrated in solution with a compatible organic solvent. Is well known.

This invention relates to a pharmaceutical composition comprising a therapeutically (or prophylactically) effective amount of a compound and a pharmaceutically acceptable carrier or excipient. Examples of the carrier include saline solution,
Buffered saline, dextrose, water, glycerol, ethanol and combinations thereof are included, but are discussed in more detail below. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. The composition may be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation or powder. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. Formulation involves the mixing, milling and compression of the ingredients to suit the desired formulation.

The pharmaceutical carrier may be solid or liquid, for example. Representative solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Solid carriers can contain one or more substances that also act as fragrances, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet disintegrating agents. This may be the encapsulating material. When in powder form, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain up to 99% of active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carbomethylcellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. .

Representative liquid carriers include syrup, peanut oil, olive oil, water and the like. Liquid carriers are used in formulating solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable oil or fat. Liquid carriers include other compatible agents such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, fragrances, suspensions, thickeners, colorants, viscosity modifiers, stabilizers or osmotic agents. The pharmaceutical additive may be included. Examples of liquid carriers suitable for oral and parenteral administration include water (partly containing the additives mentioned above, eg cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohol (monohydric alcohol and , Including polyhydric alcohols such as glycols) and their derivatives and oils (eg, fractionated palm oil and peanut oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. For parenteral administration, sterile liquid carders in the form of sterile liquid compositions are useful. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutical propellant. Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be used by, for example, intramuscular, intraperitoneal or subcutaneous injection.
The sterile solution can also be administered by intravenous injection. The compound can be administered orally either in liquid or solid composition form.

The carrier or excipient may include time delay materials well known in the art, including gluceryl monostearate or glyceryl distearate alone or in wax, ethyl cellulose, hydroxypropyl methyl cellulose. , And combined use with methyl methacrylate and the like. When formulated for oral administration, 0 in PHOSAL PG-50 (a concentrate of phospholipids containing 1,2-propylene glycol, A. Nattermann & Cie. GmbH).
． Although 01% Tween 80 has been accepted as providing an acceptable oral formulation of other compounds, it may be applicable to formulation of various compounds of this invention. A wide range of formulation forms may be used. If a solid carrier is used, the preparation may be tabletted, in the form of powder or pellets or in the form of a troche or lozenge.
It can be placed in a hard gelatin capsule. Although the amount of solid carrier varies widely,
It is preferably between about 25 mg and about 1 g. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial, or non-aqueous suspension.

To obtain a stable water-soluble dosage form, a pharmaceutically acceptable salt of this compound is dissolved in an aqueous solution or an organic or inorganic acid such as a 0.3M solution of succinic acid or citric acid. .. Alternatively, the acidic derivative can be dissolved in a compatible basic solution. If a soluble salt form is not possible, the compound is dissolved in a compatible cosolvent or combination thereof. Examples of such compatible cosolvents include alcohols, propylene glycol, polyethylene glycol 300, polysorbate, glycerin, polyoxyethylated fatty acids, fatty alcohols or glycerin hydroxy fatty acid esters in concentrations ranging from 0-60% of the total volume. And the like, but are not limited thereto.

Various release systems are known and can be used to administer this compound or its various formulations including tablets, capsules, injectable solutions, encapsulation in liposomes, microparticles, microcapsules and the like. It is possible. The method of intake is skin, intradermal,
Intramuscular, peritoneal, intravenous, subcutaneous, intranasal, pulmonary, epidural, ocular and oral (usually preferred methods) routes are included, but are not limited to. The compounds can be administered by any convenient or suitable route, for example, by infusion or total injection by absorption through the epithelial lining or the lining of the skin and mucous membranes (eg, oral mucosa, rectal and intestinal mucosa, etc.). And may be administered in combination with other biologically active agents. Administration can be systemic or local. For the treatment or prevention of nasal, bronchial or pulmonary conditions, the preferred route is via the oral, nasal or bronchial aerosol or nebulizer.

In some embodiments, local administration is preferred to the area in need of treatment. This is achieved by, for example, but not limited to, local injection during surgery, topical application, by injection, by means of cateteres, by means of suppositories, or by the method of skin patches or skin implants. I can do it. The implant consists of a porous, non-porous or gelatinous material containing membranes or fibers.

In a particular embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Generally, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. The composition, if desired, can also contain a solubilizer to reduce the pain on the injection side and a local anesthetic. Generally, the ingredients will be supplied separately or in admixture, but each ingredient may be, for example, a lyophilized powder, or a container such as a sealed ampoule or a plastic bag indicating the quantity of active agent. Present as a water-free concentrate in the form of a unit dose. Where the composition is to be administered by infusion, it can be dispensed by an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration. Administering an effective amount of a compound to an individual can, in principle, be accomplished by administering the compound directly to the affected area of the skin of the individual. For this purpose, the compound is administered or applied in the form of a composition containing a pharmaceutically acceptable carrier, which composition includes, but is not limited to, a gel, ointment, lotion or cream. The product comprises a carrier such as water, glycerol, alcohol, propylene glycol, fatty acid, triglyceride, fatty acid ester or mineral oil.

Other principle carriers include liquid petroleum, isopropyl palmitate,
Polyethylene glycol, ethanol (95%), polyoxyethylene in water
Monolaurate (5%) or sodium lauryl sulfate in water (5%)
Is included. Other materials such as antioxidants, wetting agents, viscosity stabilizers and similar agents are added as needed. Also included are transdermal penetration enhancers such as Azone.

In addition, in some cases, it is contemplated that the compound will be treated in a device placed on, in, or under the skin. Such devices include patches, implants, injections that release the composition into the skin by a passive or active release mechanism.

Materials and methods for making various formulations are well known in the art and are applicable to the practice of the subject invention. For example, US Patent No. 5,182,293 and N
o. 4,837,311 (tablets, capsules, other formulations, as well as intravenous formulations) and European Patent Application No. 0649659 (published April 6, 1995; representative formulation for IV administration) and No. 0648494 (published April 19, 1995; representative formulations for oral administration).

An effective dose of this compound is generally from about 0.01 to about 5 per body weight of the mammal.
0 mg / kg, preferably in the range of about 0.1 to about 10 mg / kg, is administered in single or multiple doses. Generally, one patient will be able to administer the compound at a daily dosage in the range of about 1 to about 2000 mg to the patient in need of treatment.

The amount of the compound that is effective in treating or preventing an individual disease or condition will depend, in part, on the nature and severity of the disease or condition, which can be determined by standard clinical techniques. . In addition, in vitro or in vivo assays may optionally be used to help establish optimal dosage ranges. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems. The exact dose level should be determined by the attending physician or other health care provider and may include the route of administration, the age, weight, sex and general health of the individual, the nature of the illness,
It will depend on well known factors including severity and clinical stage, the use (or no use) of concomitant therapies.

Therapeutic Kits In another embodiment, the present invention relates to kits that conveniently and effectively perform the methods in accordance with the present invention. In general, a formulation pack or kit consists of one or more containers filled with one or more of the ingredients of the pharmaceutical composition of the invention. Such kits are particularly suitable for the release of solid oral dosage forms such as tablets or capsules. Such kits will preferably contain a number of unit doses, optionally with a card directing the doses in the order of their intended use.

If desired, memory aids can be provided that, for example, in the form of numbers, letters or symbols, or by calendar inserts, dated on the treatment schedule so that the dose can be administered. Alternatively, a placebo dose or a calcium-supplemented diet can be enclosed in a form similar or differentiated to the bone-targeted medication, providing a kit in which the dose is taken daily. Optionally in association with such a container,
A notice in the form of a governmental authority that regulates the manufacture, use, or sale of pharmaceutical products may be accompanied by a notice that the manufacturer's approval for manufacture, use, or sale for administration to humans. It reflects.

Equivalents The representative examples described below are intended to help explain the present invention, and should not be construed as limiting the scope of the invention.
In fact, various modifications of the invention and many additional embodiments in addition to those shown and described herein may be found in the disclosure of the examples and scientific literature as well as references in the following which are cited herein. It will be clear to those skilled in this field. It should be understood that the content of the references cited herein is hereby incorporated by reference to aid in explaining this state of the art.

The following examples contain additional important information, explanations and guidance that can be adapted to the practice of this invention in the form of various embodiments and their equivalents. .

[0229]

【Example】

  The phosphorus-containing moieties described can be synthesized according to the scheme outlined below.   A) Embodiments when Tb is i

Example 1 “(3-Amino-propyl-) ethoxy-phosphinoylmethyl” -phosphonic acid diethyl ester

[Chemical 65] [(3-Benzyloxy-propyl) -ethoxy-phosphinoylmethyl] phosphonic acid diethyl ester: In a furnace-dried flask 10.25 g (44.7 mmol) of (3-bromo-
Propoxymethyl) -benzene and 7.67 ml (44.7 mmol) triethylphosphite were added. The flask was equipped with a short path distillation head for bromoethane removal and the mixture was heated at 150 ° C. for 4 h. Cool the reaction to ambient temperature, 1
20 ml absolute ethanol and 1.8 N KOH (120 mL, 216 mol)
Diluted with. The distillation head was replaced with a reflux condenser, and this solution was heated under reflux for 5 hours. The reaction was cooled and concentrated under vacuum. The basic aqueous layer was washed with EtOAc (2
x) and then acidified to pH 3 with concentrated HCl. The aqueous layer was washed with EtOAc (3
extracted with x), dried the combined extracts over MgSO _4, and concentrated. The resulting crude product (8.24 g) was used in the next reaction. ³¹ PNMR (300M
Hz, DMSO-d ₆ ) δ34.113

This crude phosphonate (8.24) in 100 mL CH ₂ Cl ₂ under an atmosphere of N ₂ was used.
g, 32.5 mmol) solution, 10.8 mL of oxalyl chloride (113
． 8 mmol) was added. DMF (a few drops) was slowly added to start the reaction. After the gas evolution ceased, the reaction was stirred at ambient temperature for 30 minutes. Concentrate in vacuo, wash the residue several times with hexane, then dissolve in 167 mL of anhydrous THF. In a separate flask, phosphonate (dissolved in 337 mL anhydrous THF
10.25 mL, cooled 69.9 mmol) (-78 ° C., under N ₂₎ solution,
2.5M n-Butyllithium (27.95 mL, 69.9 mmol) was added dropwise. The reaction mixture was stirred at −78 ° C. for 30 minutes. At this time, the acid chloride generated in situ was added dropwise. The solution was stirred at −78 ° C. for an additional 2.5 h, quenched with 5 mL glacial acetic acid and then warmed to ambient temperature. Water was added to the reaction mixture and THF was removed in vacuo. The aqueous layer was extracted with EtOAc (3x), combined the organics washed with saturated NaHCO _3, brine, then MgSO ₄
Dried above and concentrated. The crude product was chromatographed on silica gel (50:
Purified by 1 CH ₂ Cl ₂ / MeOH) to yield 6.15 g of a yellow oil. ³¹ PNMR (300 MHz, DMSO-d ₆ ) δ51.479
, 26.291.

“(3-Amino-propyl-) ethoxy-phosphinoylmethyl” -phosphonic acid diethyl ester: “(3-Benzyloxy-propyl) -ethoxy- in 100 mL EtOH.
Phosphinoylmethyl "-phosphonic acid diethyl ester (5.7 g, 14.5 m
mol), 1.2 g of palladium on carbon was added. H ₂ was poured into this mixture, and the mixture was stirred at room temperature for 1 h (H ₂ balloon). The reaction mixture is Cel
Filter through ite and evaporate the solvent to give 3.5 g of a pale yellow oil. ³¹ P
_{NMR (300MHz, DMSO-d 6} ) δ52.219,26.317. This crude alcohol (3.5 g, 14.5 mmo in 53 mL CH ₂ Cl ₂
To a cooled solution of l) (0 ° C. under N ₂ ) was added 2.4 mL (17.4 mmol) triethylamine, followed by 1.25 mL (16 mmol) methanesulfonyl chloride. The reaction mixture was warmed to ambient temperature and stirred for 1 h. Then the reaction of the reaction mixture was quenched with water and the layers were separated. The organic layer is washed with water and brine, N
It was dried over a ₂ SO ₄ and concentrated. This crude orange to yellow oil was used for the next reaction. ³¹ PNMR (300 MHz, DMSO-d ₆ ) δ51
． 135, 26.614.

To a solution of this crude mesylate (5.5 g, 14.4 mmol) in 17 mL DMF was added 4.7 g (72.4 mmol) sodium azide. The resulting slurry was heated to 55 ° C. and stirred overnight. The reaction mixture was diluted with EtOAc and washed with water (2x). The combined organics were dried over Na ₂ SO ₄ and concentrated. This crude azide (2.61 g) was used for the next reaction. ³¹ PN
MR (300 MHz, DMSO-d ₆ ) δ51.230, 26.183. To a solution of this crude azide (2.61 g, 8 mmol) in 100 mL EtOH was added 0.8 g palladium on carbon. H ₂ was poured into this mixture, and the mixture was stirred at room temperature for 16 h (H ₂ balloon). The reaction mixture was filtered through Celite and the solvent was evaporated to give 2.3 g of a yellow oil: ¹ HPNMR (3
00MHz, DMSO-d ₆ ) δ 4.03 (m, 6H), 2.84-2.52 (
m, 4H), 1.91-1.80 (m, 2H), 1.65-1.61 (m, 2H)
), 1.23 (m, 9H). ³¹ PNMR (300 MHz, DMSO-d ₆ ) δ5
1.757, 26.344.

Example 2 ({3- "3- (4-amino-3-p-tolyl-pyrazolo" 3,4-d "pyrimidin-1-yl) benzoylamino" -propyl} -hydroxy-phosphinoyl)- Phosphonic acid

[Chemical formula 66] The title compound was made using "(3-amino-propyl) -ethoxy-phosphinoylmethyl" -phosphonic acid diethyl ester, for example as in Example 16 (below).

Example 3 Synthesis of Phenyl-i Compounds Two syntheses were prepared for the synthesis of these examples: the sulfone 1/2 and aniline cup ring, or the amine 3/4 and aryl bromide cup ring. Any one of the procedures can be used. General Scheme for Targeted Aminopyrido "2,3-d" Pyrimidin-7 (8H) -ones

[Chemical formula 67] Synthesis of aniline 6 (a) Diethyl in N ₂ under CH ₃ CN (14mL) (diethoxyphosphinyloxytetrahydropyran) methylphosphonate _{(2.35g, 9.62mmol), Et 3} N (3.8m
L, 27.5 mmol), 1-iodo-4-nitrobenzene (2.28 g, 9.
A mixture of 17 mmol) and Pd (PPh ₃ ) ₄ (2.65 mg, 0.229 mmol) was stirred at 80 ° C. for 2.5 h. After cooling to room temperature, the reaction mixture was poured into 50 mL of 1N aqueous HCl and extracted with CH ₂ Cl ₂ . The extract was washed with H ₂ O (50 mL) and brine (50 mL). This aqueous cleaning solution is CH ₂ C
Another once re-extracted with l _2, the combined extracts were dried over Na ₂ SO _4, and concentrated. The crude material was purified by flash chromatography on silica gel. 30: 1 CHCl ₃ -MeOH, then 20: 1 CHCl ₃ -MeOH
, Finally eluted with 15: 1 CHCl ₃ -MeOH, 3.28 g (98%
) Of the desired (arylphosphinylmethyl) phosphonate.

(B) This nitroarene (940 mg, 2.mL) in EtOH (-10 mL).
57 mmol) and SnCl ₂ .2H ₂ O (2.9 g, 12.9 mmol) were stirred at 70 ° C. for 44 minutes and concentrated at room temperature. The residue was taken up in CH ₂ Cl ₂ , half saturated NaHCO ₃ (40 mL), H ₂ O (40 mL) and brine (40 mL).
) Was washed with. The aqueous wash was re-extracted with CH ₂ Cl ₂ once more and the combined extracts were dried over K ₂ CO ₃ and concentrated. The crude material was purified by flash chromatography on silica gel. Elution with 20: 1 CHCl ₃ -MeOH then 15: 1 CHCl ₃ -MeOH yielded 657 mg (76%) of aniline 6.

[Chemical 68] (A) Aniline 6 (1.89 g in 2-methoxyethyl ether (3 mL)
, 5.65 mmol) and Sulfone 1 (866 mg, 2.25 mmol) were stirred at 150 ° C. for 6 h. The reaction mixture was allowed to cool to room temperature. It was then diluted with a little CHCl ₃ and purified by flash chromatography on silica gel. Elution with 30: 1 CHCl ₃ -MeOH, 20: 1 CHCl ₃ -MeOH and 15: 1 CHCl ₃ -MeOH yielded still very impure raw material. Chromatography was repeated using the same eluent, but still provided fairly impure raw material. The material was then purified by reverse phase HPLC with water-acetonitrile (+ 0.1% TFA). Fractions containing product were collected and concentrated to a small volume (-20 mL). The residue was partitioned between CH ₂ Cl ₂ and saturated aqueous NaHCO _3. Both layers were separated and the aqueous layer was reextracted twice with CH ₂ Cl ₂ . The combined extracts were dried over K ₂ CO ₃ ,
Concentrated to 9 mg (30%) of pure coupled product.

(B) This coupled product (420 mg, 0) in 10 mL of CH ₃ CN.
． 657 mmol) at -10 ° C with TMSI (1.40 mL, 9.85 m).
mol) was added. The reaction mixture was stirred at −10 ° C. for 15 minutes and then at room temperature for 75 minutes. Next, the reaction mixture saturated aqueous NaHCO ₃ (~13mL), was diluted with NaHSO few drops ₃ and H ₂ O (~2mL). The mixture was further diluted with a small amount of DMF and then purified by reverse phase HPLC with water-acetonitrile (+ 0.1% TFA). Fractions containing product were lyophilized to yield pure IA.

[Chemical 69] Diethyl during synthesis of CH ₃ CN aryl bromide 8 (diethoxyphosphinyloxytetrahydropyran) methyl phosphonate (1.
85 g, 7.58 mmol), 1-bromo-4-iodobenzene (1.95 g,
6.89 mmol), NMM (1.51 mL, 13.8 mmol) and Pd (P
A mixture of Ph ₃ ) ₄ (199 mg, 0.172 mmol) was stirred overnight at 100 ° C. After cooling to room temperature, the reaction mixture was concentrated. The residue is then treated with 1N aqueous H
Partitioned between Cl and CH ₂ Cl ₂ . The layers were separated and the organic layer was washed with H ₂ O and brine. The aqueous wash was reextracted again with CH ₂ Cl ₂ . The combined extracts were dried over Na ₂ SO ₄ and concentrated. The crude material was purified by flash chromatography on silica gel. 30: 1 CHCl ₃ -MeOH, then 20: 1 CHCl ₃ -MeOH, finally 15: 1 CHCl ₃ and eluted with -MeOH, aryl bromide 1.52g contaminated with trace amounts of Ph ₃ PO (55%) 8 Was produced.

[Chemical 70]

(A) NH ₃ (˜2 mL) was compressed at −78 ° C. into a glass pressure tube containing Sulfone 2 (235 mg 0.684 mmol). Attach a cap to this tube,
Warmed to room temperature. The reaction mixture was mixed can overnight撹at room temperature and then evaporated to NH _3. The residue was purified by flash chromatography on silica gel. Elution with 40: 1 CHCl ₃ -MeOH yielded 193 mg (quantitative) of amine 4.

(B) Amine 4 (176 mg, 0.628 mm) in toluene (3.5 mL)
ol), aryl bromide 8 (301 mg, 0.753 mmol), powdery C
s ₂ CO ₃ (368 mg, 1.13 mmol), BINAP (59 mg, 0.0
The mixture of 942 mmol) and Pd (OAc) ₂ was stirred at 100 ° C. overnight.
After cooling, the reaction mixture was partitioned between CH ₂ Cl ₂ and 1N aqueous HCl. The layers were separated and the organic layer was washed with H ₂ O and brine. The aqueous wash was reextracted again with CH ₂ Cl ₂ . The combined extracts were dried over Na ₂ SO ₄ and concentrated. The crude material was purified by flash chromatography on silica gel. Thirty
: 1 CHCl ₃ -MeOH, then 20: 1 CHCl ₃ -MeOH, finally 1
Elution with 5: 1 CHCl ₃ -MeOH yielded 231 mg (62%) of the desired coupled product. (C) Next, the coupled product was previously described (ia, (b)
) Was converted to iB by the same method.

[Chemical 71]

Synthesis of Aniline 7 (a) The intermediate (arylphosphinyl) methylphosphonate was converted into N- (t
Prepared from -butylcarbonyl) -3-iodoaniline in a manner similar to that described for the synthesis of aryl bromide 8. (B) This intermediate carbamate was converted to aniline 7 by a method similar to that described for 5 (f).

[Chemical 72]

(A) A method for condensing aniline 7 with sulfone 1 of aniline 6 (iA, (b))
2) was condensed with Sulfone 1. (B) Next, this coupled product was previously described (ia, (b)).
Converted to iC in the same manner as.

[0242] B) Embodiments in which Tb is vi   The bone targeting group vi was synthesized according to the following scheme.

[Chemical formula 73]

[Chemical 74]

Diethyl (4- (N-trifluoroacetylaminobenzyl) phosphonate 2: Diethyl (4-aminobenzyl) phosphonate (10
g), pyridine (4.0 mL), then trifluoroacetic anhydride (7.0 mL)
Was added and stirred overnight at room temperature (-18 hrs). The reaction mixture was washed thoroughly with saturated aqueous sodium bicarbonate solution (10 mL), brine (10 mL) and dichloromethane and dried (Na ₂ SO ₄ ) to yield product 2 (93%). M
S: 338 (M-1)

[Chemical 75]

Diethyl (4- (N-trifluoroacetylamino) -α-bromobenzyl) phosphonate 3 The above compound 2 (9.75, 41.13) in anhydrous carbon tetrachloride (100 mL).
NBS (1.6 g, 41.13 mmol) was added to (mmol) and heated to reflux under strong visible light with stirring. During that time a white precipitate formed. The reaction was cooled to room temperature and filtered. The filtrate was concentrated in half and left in the freezer overnight for crystallization. Crystalline product 3 (7.2 g, 60%) was isolated by filtration. MS: 416,418 (M-1 Br 79 Br 80).

[Chemical 76]

1- (Bis-diethylphosphonomethylene-4- (N-trifluoroacetylamino) benzene 4: To compound 3 (7.2 g, 17.22 mmol) in anhydrous THF (50 mL) triethyl phosphite (0 0.82 mL, 17 mmol) was added and the mixture was stirred under reflux for 4 h.The reaction mixture was cooled to room temperature and concentrated.The residue was put in boiling ethyl ether and cooled to room temperature.The solid was filtered off. , 6.0 g (73%) of product, pale pink solid, MS: 476 (M + H), 475 (M-H).
).

[Chemical 77]

1- (Bis-diethylphosphonomethylene-4-aminobenzene 1: N-trifluoroacetate salt 4 (above in NaOH solution (0.1 N, 10 mL).
1.2 g, 2.52 mmol) was heated to 60 ° C. for 5 h. The reaction mixture was cooled to room temperature and extracted with methylene chloride. The combined organic layers were dried over sodium sulfate and concentrated to yield product 1 (0.85g, 97%). MS: 4
12 (M + 23).

Example 4 ({4- “6- (2,6-dichloro-phenyl) -8-methyl-7-oxo-4
a, 7,8,8a-Tetrahydro-pyrido "2,3-d" pyrimidin-2-lamino "-phenyl})-phosphono-methyl) -phosphonic acid

[Chemical 78] a) (4-Bromo-benzyl) -phosphonic acid diethyl ester

[Chemical 79]

A mixture of triethylphosphite (25 mL, 14.6 mmol) and 4-bromobenzyl bromide (2.50 g, 10.0 mmol) was heated to 130 ° C. and stirred for 5 h. The solution was cooled to room temperature and chromatographed on silica gel (EtOAc: Hexane 1: 1 to 100% EtOAc stepwise gradient) to give 3.21 g (> 100%) of a yellowish oil. Electrospray mass spectrum (50/50 acetonitrile / water) m / z 307 (M + H
). b) "(4-Bromo-phenyl)-(diethoxy-phosphoryl) -methyl" phosphonic acid diethyl ester

[Chemical 80] To a cooled (-50 ° C) solution of (4-bromo-benzyl) -phosphonic acid diethyl ester (3.21 g, 10.4 mmol) in THF (25 mL) was added THF.
3M of a 1M solution of lithium hexamethyldisilylazide in (25 mL)
Added over the minutes. Diethyl chlorophosphato (2.9 mL, 20 mmol) was added, and the mixture was stirred at 50 ° C. After 0.5 h add saturated NH ₄ Cl,
The mixture was diluted with EtOAc and H ₂ O. The aqueous layer was extracted with fresh EtOAc and the combined organic extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was chromatographed on silica gel (CHCl ₃ : MeOH 99: 1 to 96: 4 step gradient) to give 1.35 g (29%) of a colorless oil. Electrospray mass spectrum (50/50 acetonitrile / water)
m / z 441 (M + H). c) "{4-" 2,6-dichloro-phenyl) -8-methyl-7-oxo-4a
, 7,8,8a-Tetrahydro-pyrido- "2,3-d] pyrimidin-2-ylamino" -phenyl}-(diethoxy-phosphoryl) -methyl "-phosphonic acid diethyl ester

[Chemical 81]

(4-Bromopyrimidin-2-yl) phosphonic acid diethyl ester (64 mg,
0.22 mmol), 2-amino-6- (2,6-dichlorophenyl) pyrido-
8-Methyl-8H-pyrido- “2,3-d] pyrimidin-7-one (60 mg,
0.19 mmol), palladium acetate (3.6 mg, 0.016 mmol), "
(4-Bromo-phenyl)-(diethoxy-phosphoryl) -methyl "-phosphonic acid diethyl ester (100 mg, 0.23 mmol), (S) -BINAP (
18 mg, 0.029 mmol) and cesium carbonate (91 mg, 0.28 mmo
l) was placed in toluene (1 mL), sparged with argon, sealed and heated to 100 ° C. After 45h, the reaction was allowed to cool to room temperature and diluted with H ₂ O. The mixture was extracted twice with EtOAc, the combined organic extracts were washed with brine, Na ₂
Dehydrated over SO ₄ . The solution was concentrated and chromatographed on silica gel (CH
Cl ₃ : MeOH 99: 1 to 95: 5 stepwise gradient), 44 mg
(41%) of a yellow solid was obtained. Electrospray mass spectrum (50 /
50 acetonitrile / water) m / z 681 (M + H). d) ({4- "6- (2,6-dichloro-phenyl) -8-methyl-7-oxo-4a, 7,8,8a-tetrahydro-pyrido" 2,3-d "pyrimidin-2-
Lumino "-phenyl} -phosphono-methyl) -phosphonic acid

[Chemical formula 82] ({4- "6- (2,6-dichloro-phenyl) -8-methyl-7-oxo-4a, 7,8,8a-tetrahydro-pyrido" 2,3- "dissolved in MeCN (1.2 mL) d "pyrimidin-2-lamino" -phenyl}-(diethoxy-phosphoryl) -methyl "-phosphonic acid diethyl ester (44 mg, 0.77 mmo
To the cooled (0 ° C.) solution of l) was added iodotrimethylsilane (0.3 mL). After 5 h, the reaction was quenched with sodium hydroxide (1N) and saturated sodium thiosulfate. The mixture was filtered and the filtrate was chromatographed using reverse phase HPLC and lyophilized to give 5 mg (11%) of a yellow solid. Electrospray mass spectrum (50/50 acetonitrile / water) m / z 571 (
M + H). C) Embodiment in which Tb is ix Example 5 5- (3-Methoxyphenyl) -7- [4- (2-hydroxyethylphenyl) -4-aminopyrrolo [2,3-d] -pyrimidine 8 and 5- ( Synthesis of analogs of 3-hydroxyphenyl) -7- [4- (2-hydroxyethylphenyl) -4-aminopyrrolo [2,3-d] pyrimidine 12: 8 series and 12 series compounds are Scheme 3 and Scheme 4 Was synthesized according to. Compounds 9, 10, 11 were synthesized according to Scheme 3. Compounds 13 and 14 were synthesized according to Scheme 4. In essence, the synthesis consists of phosphorylation of the primary alcohol of Scheme 3 (described in Method A) followed by demethylation of the methyl ether of Scheme 4 (described in Method B) followed by phosphorylation.

[0250] Scheme 3:

[Chemical 83] Scheme 4:

[Chemical 84]

Method A: Alcohol (1 mm) in trimethyl phosphate (1 ml) under anhydrous conditions.
ol) at 0 ° C. with bis-phosphonomethylene dichloride (4 mmol
) Was added and stirred at this temperature for 16 hours. The reaction mixture was then quenched with ammonium hydroxide and washed with ether. The aqueous layer was purified by preparative HPLC.

[0252]

[Chemical 85]

5- (3-methoxyphenyl) -7- {4- [2-O- (triethylbisphosphonomethylene) ethyl] phenyl)}-4-aminopyrrolo [2,3-d] -pyrimidine 9: Was prepared from 8A. Purified as a white solid by HPLC. MS: 51
7 (M-H), -518 (M + H).

[0254]

[Chemical 86]

5- (3-Methoxyphenyl) -7- {4- [2-O- (triethylbisphosphonomethylene) ethyl] phenyl} -4- (N, N-dimethylaminopyrrolo [2,2]
3-d] -pyrimidine 10: This was prepared from 8B. Purified as a white solid by HPLC. MS: 54
5 (M-H), 547 (M + H).

[0256]

[Chemical 87]

5- (3-methoxyphenyl) -7- {4-N- {N′-methyl-[(N′-2
′-(O- (Triethylbisphosphonomethylene) ethyl} aminoethylphenyl) -4- (aminopyrrolo [2,3-d] -pyrimidine 11: This was prepared from 8 C. Purified by HPLC as a white solid, MS. : 57
4 (M-H), 576 (M + H).

Method B: 1 mmol of methyl ether (8A, 8B & in methylene chloride (5 ml).
To 8C) was added boron tribromide (1M solution, 10 mmol) in methylene chloride at 20 ° C. and after stirring at this temperature for 3 hours the reaction was quenched with methanol (5 ml) and concentrated. Was done. The compound was purified by HPLC.

[0259]

[Chemical 88]

5- (3-hydroxyphenyl) -7- {4- [2-O- (ethylphenyl)-
4-Aminopyrrolo [2,3-d] -pyrimidine 12A: Prepared from 8A according to Method B. Off-white solid. MS: 345 (M-I),
347 (M + H).

[0261]

[Chemical 89]

5- (3-hydroxyphenyl) -7- {4- (2-N- (N′-methyl-N ′)
-2'-hydroxyethyl) -aminoethylphenyl) -4-amino-pyrrolo [
2,3-d] -Pyrimidine 12B: Prepared from 8B using Method B. Off-white solid. MS: 402 (MH)
, 404 (M + H).

[0263]

[Chemical 90]

5- (3-Hydroxyphenyl) -7- {4- (2-N- (4'-hydroxypiperidinyl) -aminoethylphenyl) -4-amino-pyrrolo [2,3-d]-
Pyrimidine 12C: Prepared from 8C using Method B. Off-white solid. MS: 428 (MH)
430 (M + H).

[0265]

[Chemical Formula 91]

5- (3-Hydroxyphenyl) -7- {4- [2-O- (triethylbisphosphonomethylene) ethylphenyl} -4-aminopyrrolo [2,3-d] -pyrimidine 13: Method A Prepared from 12A using. White solid. MS: 503 (MH), 50
5 (M + H).

[0267]

[Chemical Formula 92]

5- (3-hydroxyphenyl) -7- {4-N- {N′-methyl-[(N′-
2 '-(O- (triethylbisphosphonomethylene) ethyl) -aminoethylphenyl) -4-amino-pyrrolo [2,3-d] -pyrimidine 14: Prepared from 12B using Method A. White solid. MS: 560 (MH), 56
2 (M + H).

Scheme 5 describes the synthesis of compound 15 starting from 5-iodopyrrolo-pyrimidine (J. Med. Chem., 1990).

[0270] Scheme 5:

[Chemical formula 93]

4-Chloro-5-iodo-7-isopropyl-pyrrolo [2,3-d] -pyrimidine 16: 4-chloro-5-iodo-7-H-pyrrolo [2,3 in DMSF (5 ml). −
To a 0 [deg.] C solution of d] -pyrimidine (484 mg, 1.729 mmol) was added sodium hydride (138.4 mg, 60% emulsion, 3.46 mmol). After 30 minutes at room temperature, 2-iodopropane (518 μL, 5.19 m
mol) was added and the mixture was stirred at room temperature for 3 hours. DMF was poured into water and the aqueous layer was extracted with ethyl acetate (3x30 mL). The organic layer was washed with water (5 ml), dried (sodium sulfate) and concentrated to give a pale yellow solid (520 mg, quant). MS: 301 (MH).

[0272]

[Chemical 94]

4-Chloro-5- (3-hydroxymethylphenyl) -7-isopropyl-pyrrolo [2,3-d] -pyrimidine 17: 4-chloro-5-iodo-7 in DMF (13.5 mL). -Isopropyl-pyrrolo [2,3-d] -pyrimidine (522 mg, 1.729 mmol) and 3
-Formylphenylboronic acid (285 mg, 1.902 mmol) in solution in a strictly argon atmosphere with tetrakistriphenylphosphine (0) (9
5.58 mg, 0.0865 mmol, 5%) followed by sodium bicarbonate (
2M, 1.73 mL) was added and the mixture was added at 80 ° C. to 18
Heated for hours. The reaction was monitored by HPLC. It was diluted with water and extracted with ethyl acetate (30 mL, x3). The ethyl acetate layer is washed (water)
The dried gum, dried (sodium sulfate) and concentrated, was purified by column chromatography on silica gel with hexane / ethyl acetate to yield 306 mg (63%) of a pale yellow gum. MS: 298 (M-H
), 300 (M + H).

B. The above aldehyde (300 mg, 1.00) in methanol (20 mL).
8 mmol) solution, sodium borohydride (45 mg, 1.296 m
mol) was added and the reaction was monitored by HPLC. After 1 hour the methanol was removed in vacuo. Water (10 mL) was added to the residue and the aqueous layer was extracted into ethyl acetate. Ethyl acetate was dried (sodium sulphate) and further concentrated to give a white solid which was used in the form in the next step. MS: 300 (M
-H), 302 (M + H).

[0275]

[Chemical 95]

4-Amino-5- (3-hydroxymethylphenyl) -7-isopropyl-pyrrolo [2,3-d] -pyrimidine 18: The above chlorine compound (281 mg, 0.931 mm) in dioxane (10 mL).
ol), ammonium hydroxide (10 mL) was added and sealed, and 120
Heated at ° C for 2 days. The solvent was concentrated to give a white solid (200 mg), which was pure enough for use in the next step. MS: 281 (M-
H), 282 (M + H).

[0277]

[Chemical 96]

4-Amino-5-[(3-bisphosphonomethylenemethyl)] phenyl) -7-isoproyl-pyrrolo [2,3-d] -pyrimidine 15: using Method A as a white solid from 18 Preparation. MS: 439 (MH),
441 (M + H).

Example 6 ({2- [6- (3-Chloro-phenylamino) -9-isopropyl-9H-purin-2-ylamino] -ethoxy} -hydroxy-phosphorylmethyl) -phosphonic acid

[0280]

[Chemical 97]

[0281] 6-chloro-2-fluoro -9H- purine: HBF ₄ (48% in water, 0.92 mol) in 120mL of the cooling (-1
5 ° C), vigorously stirred 2-amino-6-chloro-9H-purine suspension (6.0 g
, 35.4 mmol) of NaNO ₂ (200 mL, 60 mmol).
A 3M aqueous solution was added dropwise over 75 minutes. The pale yellow reaction was stirred at room temperature for 20 minutes, then recooled to −15 ° C. and neutralized to pH = 6.0 with aqueous NaOH (50% by weight in water). Water was removed in vacuo and the resulting orange solid was analyzed by chromatography on silica gel (90:10).
_{CH 2 Cl 2: MeOH, Rf0.50} ). The final product was obtained as a white solid (3.0 g, 49.1%).

6-Chloro-2-fluoro-9isopropyl-9H-purine: 6-chloro-2-fluoro-9H-purine (517.7 mg, 3 mmol),
2-Propanol (198.3 mg, 3.3 mmol), PPh ₁ (866 mg)
3.3 mmol) was mixed in a 50 mL round bottom flask at 0 ° C. under N ₂ . DEAD (575 mg, 3.3 mmol) was added dropwise to the mixture by a syringe. The temperature was raised to room temperature and the mixture was stirred overnight. The solvent was removed in vacuo, the residue resulting were analyzed by chromatography on silica gel (CH ₂ Cl ₂ /EtOAc,4:1,Rf0.62). The product was obtained as a white solid (411 mg, 64%).

(3-Chlorophenyl)-(2-fluoro-9-isopropyl-9H-purine-
6-yl) amine: 6-chloro-2-fluoro-9-isopropyl-9H-purine (214 mg,
1 mmol) 3-chloroaniline (127.6) in 12 mL n-BuOH.
mg, 1 mmol). DIEA (357.6 mg, 2.8 mmol
) Was added and the solution was heated at 90 ° C. overnight. The solvent was removed in vacuo and the residue was chromatographed on silica gel (CH ₂ Cl ₂ / EtOAc, 2: 2,
Rf 0.44) gave the product as a white solid (148 mg,
48%).

2- (6- (3-chlorophenylamino-9-isopropyl-9H-purine-2
-Ylamino) ethanol: (3-chlorophenyl)-(2-fluoro-9-isopropyl-9H-purin-6-yl) amine (92 mg, 0.3 mmol) and ethanolamine (9
2 mg, 1.5 mmol) is 5 mL of nBuOH / DMSO (4/1 v / v)
) And heated at 120 overnight. The solvent was removed in vacuum. The residue was analyzed by chromatography on silica gel (EtOAc, Rf 0.45) to give the product as a greenish solid (24 mg, 90%).

({2- [6- (3-Chloro-phenylamino) 9-isopropyl-9H-purin-2-ylamino] -ethoxy} -hydroxy-phosphorylmethyl) -phosphonic acid: 2- (6- (3 -Chlorophenylamino-9-isopropyl-9H-purine-
2-ylamino) ethanol (180 mg, 0.52 mmol) was dissolved in 3 mL trimethyl phosphate at 0 ° C. Methylenebis (phosphonic acid dichloride) (514 mg, 2.1 mmol) was added in one portion and the reaction was stirred at 0 ° C. for 16 hours. The solution is pH 6.0 using 5N ammonia.
Was neutralized. The resulting mixture was purified by RP HPLC. Lyophilization left a white solid (147 mg, 56%).

Example 7 ({2- [6- (3-Chloro-phenylamino) -9-isopropyl-9H-purin-2-ylamino] -3-methyl-butoxy} -hydroxy-phosphorylmethyl) -phosphonic acid :

[0287]

[Chemical 98]

(A) 2- (6- (3-Chlorophenylamino-9-isopropyl-9H-purin-2-ylamino) -3-methyl-butan-1-ol The title compound was obtained in Example 6 (d). Synthesized in a manner similar to that described.
ES-MS: m / z 388 (MH).

(B) ({2- [6- (3-chloro-phenylamino) 9-isopropyl-9
H-Purin-2-ylamino] -3-methyl-butoxy} -hydroxy-phosphorylmethyl) -phosphonic acid The title compound was synthesized in a similar manner as described in Example 6 (e).
ES-MS: m / z 546 (MH).

Example 8 ({3- [6- (3-chloro-phenylamino) -9-isopropyl-9H-purin-2-ylamino] -propyl} -hydroxy-phosphorylmethyl) -phosphonic acid:

[0291]

[Chemical 99]

(A) 3- (6- (3-Chlorophenylamino-9-isopropyl-9H-purin-2-ylamino) -propanol The title compound was prepared in the same manner as described in Example 6 (d). Was synthesized by.
ES-MS: m / z 360 (MH).

(B) ({2- [6- (3-chloro-phenylamino) -9-isopropyl-
9H-Purin-2-ylamino] -propoxy} -hydroxy-phosphorylmethyl) -phosphonic acid The title compound was synthesized in a similar manner as described in Example 6 (e).
ES-MS: m / z 518 (MH).

Example 9 ({4- [6- (3-Chloro-phenylamino) -9-isopropyl-9H-purin-2-ylamino] -butoxy} -hydroxy-phosphorylmethyl) -phosphonic acid:

[0295]

[Chemical 100]

(A) 4- (6- (3-Chlorophenylamino-9-isopropyl-9H-purin-2-ylamino) -butanol The title compound was prepared in the same manner as described in Example 6 (d). Was synthesized by.
ES-MS: m / z 374 (MH).

(B) ({2- [6- (3-chloro-phenylamino) -9-isopropyl-
9H-Purin-2-ylamino] -butoxy} -hydroxy-phosphorylmethyl) -phosphonic acid The title compound was synthesized in a similar manner as described in Example 6 (e).
ES-MS: m / z 532 (MH).

Example 10 ({2- [6- (3-Chloro-phenylamino) -9-isopropyl-9H-purin-2-ylamino] -3-methyl-butoxy} -hydroxy-phosphorylmethyl) -phosphonic acid :

[0299]

[Chemical 101]

(A) (3-Chlorophenyl)-(2-fluoro-9-isopropyl-9H-
Purin-2-yl) -methyl-amine The title compound was synthesized in a similar manner as described in Example 6 (c).
ES-MS: m / z 319 (MH).

(B) 2- {6-[(3-chloro-phenyl) -methyl-amino] -9-isopropyl-9H-purin-2-ylamino} -3-methyl-butan-1-ol The title compound Was synthesized in a manner similar to that described in Example 6 (d).
ES-MS: m / z 402 (MH).

(C) [(2- {6-[(3-chloro-phenyl) -methyl-amino] -9-
Isopropyl-9H-purin-2-ylamino} -3-methyl-butoxy) -hydroxy-phosphorylmethyl] -phosphonic acid The title compound was synthesized in a similar manner as described in Example 6 (e).
ES-MS: m / z 560 (MH).

Example 11 ({2- [6- (3-chloro-phenylamino) -9-methyl-9H-purine-
2-ylamino] -3-methyl-butoxy} -hydroxy-phosphorylmethyl)
-Phosphonic acid

[0304]

[Chemical 102]

(A) 6-Chloro-2-fluoro-9-methyl 1-9H-purine The title compound was synthesized in a similar manner as described in Example 6 (b).
ES-MS: m / z 186 (MH).

(B) (3-Chloro-phenyl)-(2-fluoro-9-methyl-9H-purin-6-yl] -amine The title compound is similar to that described in Example 6 (c). Was synthesized by the method.
ES-MS: m / z 276 (MH).

(C) 2- [6- (3-chloro-phenylamino) -9-isopropyl-9H-
Purin-2-ylamino] -3-methyl-butan-1-ol The title compound was synthesized in a similar manner as described in Example 6 (d).
ES-MS: m / z 360 (MH).

(D) [{2- [6- (3-chloro-phenylamino) -9-methyl-9H-
Purin-2-ylamino] -3-methyl-butoxy} -hydroxy-phosphorylmethyl) -phosphonic acid: The title compound was synthesized in a similar manner as described in Example 6 (e).
ES-MS: m / z 518 (MH).

Example 12 {[4- (4-Amino-5-p-tolyl-pyrrolo [2,3-d] -7-yl)-
Tetrahydrofuran-2-ylmethoxyl] -hydroxy-phosphorylmethyl}
Phosphonic acid

[0310]

[Chemical 103]

(A) 7-Benzenesulfonyl 4-chloro-5-iodo-7H-pyrrolo [2,2]
3-d] pyrimidine 4-chloro-5-iodo-7H-pyrrolo [2,3-d in 45 mL anhydrous THF.
] For pyrimidine (1.26 g, 4.5 mmol), NaH (217 mg, 9
． 0 mmol) was added. The mixture was stirred at room temperature for 1 hour. PhSO ₂ C
1 (875 mg, 5.0 mmol) was added dropwise via syringe. Stirring was continued for another 2 hours. The solvent was removed in vacuum. The residue is diluted with ice -H ₂ O, then was neutralized with saturated NH ₄ Cl of 13.5 mL. The mixture was extracted with CH ₂ CH ₂ (2x60mL). The combined organic layers were washed with brine and dried over MgSo ₄ . The solvent was removed in vacuo, the residue was analyzed by chromatography on silica gel (CH ₂ CH ₂ Rf0.44).
The product was obtained as a white solid (1.12 g, 59%).

(B) 7-Benzenesulfonyl 4-chloro-5-p-tolyl-7H-pyrrolo [
2,3-d] pyrimidine 7-benzenesulfonyl 4-chloro-5-iodo-7H-pyrrolo [2,3-d
] Pyrimidine (1.12g, 2.67mmol), 4- methylbenzene boronic acid (373 mg, 2.74 mmol) and NaHCO ₃ (693mg, 8.25
mmol) is EtOH (6 mL), toluene (43 mL), and H2O (1
2 mL). The mixture was Pd (PPh ₃ ) ₂ Cl ₂ (189 mg,
Bubbled with Ar for 1 h before (0.27 mmol) was added. The reaction mixture was heated at 95 ° C. overnight. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite. The filtrate was partitioned between EtOH and water, the organic layer was separated, dried and concentrated. The residue was analyzed by chromatography on silica gel (3/1 hexane / EtOAc, Rf 0.34),
The product was obtained as a white solid (0.74g, 74%).

(C) 4-chloro-5-p-tolyl-7H-pyrrolo [2,3-d] pyrimidine 7-benzenesulfonyl 4-chloro-5-p-tolyl- in 50 mL of THF.
7H-pyrrolo [2,3-d] pyrimidine (740 mg, 1.93 mmol)
1.93 mL TBAF (1.0 M solution in THF) was added. The reaction mixture was heated under reflux for 1.5 hours. The solvent was removed in vacuum. The residue is E
Partitioned between tOAc and water. The organic layer was separated and the aqueous layer was washed with EtOAc (2
x). The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue is chromatographed on silica gel (2/1 CH ₂ Cl ₂ / EtO).
Ac, Rf 0.42) and the product was obtained as a white solid (3
43 mg, 73%).

(D) 4-Amino-5-p-tolyl-7H-pyrrolo [2,3-d] pyrimidine 4-chloro-5-p-tolyl-7H-pyrrolo [2,3-d] pyrimidine (220
mg, 0.9 mmol) was dissolved in 5 mL dioxane in a pressure tube, then 5 mL concentrated ammonia was added. The mixture was heated at 120 ° C. for 4 days. The solvent was removed, residue resulting was partitioned between EtOAc / H ₂ O. The organic layer was separated and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give the crude product as a white solid (202 mg, -100%).

(E) Toluene-4-sulfonic acid 5-dimethoxymethyl-tetrahydro-furan-3-yl ester The title compound was synthesized according to the method described in Tetrahedron Lett. 1989, 30, 6259-6262.

(F) 7- (5-dimethoxymethyl-tetrahydro-furan-3-yl) -5
-P-7H-pyrrolo- [2,3-d] pyrimidin-4-ylamine 4-amino-5-p-tolyl-7H-pyrrolo [2,3 in 32 mL anhydrous DMF.
-D] pyrimidine (250 mg, 1.2 mmol), 18-crown-6 (31
To 6 mg, 1.2 mmol) was added K ₂ CO ₃ (326 mg, 2.4 mmol). The mixture was stirred at room temperature for 30 minutes. Then toluene-4-sulfonic acid 5-dimethoxymethyl-tetrahydro-furan-3 in 15 mL DMF.
-Yl ester (100 mg, 1.2 mmol) was added and the reaction was heated at 80 <0> C overnight. After cooling to room temperature, the mixture was partitioned between EtOAc and water, the organic layer was separated and the aqueous layer was extracted with EtOAC (3x). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated, and the residue was analyzed by chromatography on silica gel (10% MeOH in EtOAc, Rf 0.38). The product was obtained as a liquid (357 mg, 80%).

(G) [4- (4-Amino-5-p-tolyl-pyrrolo [2,3-d] pyrimidin-7-yl] -tetrahydrofuran-2-yl] -methanol 7- (5-dimethoxymethyl -Tetrahydro-furan-3-yl) -5-p-
7H-pyrrolo- [2,3-d] pyrimidin-4-ylamine (377 mg, 1 m
mol) was dissolved in 10 mL dioxane, 1% TFA / H ₂ O was added and the mixture was heated at 80 ° C. overnight. This solution contains 1N NaOH PH = 6
． Added to 0. NaBH4 (38 mg, 1 mmol) was added and the solution was stirred at room temperature for 10 minutes. The solvent was removed in vacuo, the residue resulting was partitioned between EtOAc and H ₂ O. The organic layer is separated and the aqueous layer is separated by E
Extracted with tOAc (3x). The combined organic layers are dried (Na ₂ SO ₄ ) and concentrated, and the residue is chromatographed on silica gel (EtOA).
10% MeOH in c, Rf 0.38). The product was obtained as a white solid (201 mg, 62%).

(H) {[4- (4-Amino-5-p-tolyl-pyrrolo [2,3-d] pyrimidin-7-yl) -tetrahydrofuran-2-ylmethoxyl] -hydroxy-
Phosphorylmethyl} phosphonic acid [4- (4-amino-5-p-tolyl-pyrrolo [2,3-d] pyrimidine-7
-Yl] -Tetrahydrofuran-2-yl] -methanol was dissolved in 4 mL of trimethyl phosphate and cooled to -5 to 0 ° C. Methylenebis (phosphonic acid dichloride) (212 mg, 0.8 mmol) was added in one portion and the reaction was stirred at that temperature for 2 hours. The reaction mixture was transferred using a syringe to 20 mL of chilled 10% NaHCO ₃ . The mixture was neutralized with 1N HCl and then purified by RP HPLC. The final product was obtained as a white solid (31 mg, 32%). ES-MS: m / z 481 (MH).

Example 13 {[4- (4-amino-3-p-tolyl-3a, 7a-dihydro-pyrazolo [3
, 4-d] Pyrimidin-1-yl) -butoxy] -hydroxy-phosphorylmethyl} -phosphonic acid

[Chemical 104] (A) Acetic acid 4- (4-amino-3-p-tolyl-3a, 7a-dihydro-pyrazolo [3,4-d] pyrimidin-1-yl) -butyl ester The title compound is described in J. Med. Chem. Produced according to the method described in 1990, 33, 1980-1983.

(B) 4- (4-amino-3-p-tolyl-3a, 7a-dihydro-pyrazolo [3,4-d] pyrimidin-1-yl) -butan-1-ol acetic acid 4- (4 -Amino-3-p-tolyl-3a, 7a-dihydro-pyrazolo [
3,4-d] Pyrimidin-1-yl) -butyl ester (0.85 g, 2.5 m
mol) and LiOH.H ₂ O (0.25 g, 5.96 mmol) are THF
Dissolved in (3 mL) / H ₂ O (10 mL) and heated at 70 ° C. for 2 hours. After cooling, the mixture was dropped into water and extracted with EtOAc. The combined extracts were washed with water, dried over magnesium sulfate, concentrated to a yellow solid and used in the next reaction without purification (0.20 g, 27%).

(C) Toluene-4-sulfonic acid-4- (4-amino-3-p-tolyl-3a
, 7a-Dihydro-pyrazolo [3,4-d] pyrimidin-1-yl) -butyl ester 4- (4-amino-3-p-tolyl-3a, 7a-dihydro-pyrazolo [3,3
4-d] pyrimidin-1-yl) -butan-1-ol (0.19 mg, 0.6
6 mmol), TsCl (0.28 g, 1.50 mmol), DMAP (0.1
A mixture of 9 g, 1.56 mmol) and CH ₂ Cl ₂ (10 mL) was stirred at room temperature for 24 hours. The mixture was dropped into water and extracted with CH ₂ Cl _2.
The combined extracts were washed with water, dried over magnesium sulfate, further concentrated to a yellow solid and purified on silica gel (1% MeOH / CH ₂ Cl ₂ ) to give a white foam (0. 25 g, 85%). MS [M + H] ⁺ 452.

(D) {[4- (4-Amino-3-p-tolyl-3a, 7a-dihydro-pyrazolo [3,4-d] pyrimidin-1-yl) -butoxy] -hydroxy-phosphorylmethyl} -Phosphonic acid The title compound was made according to the method described in JOC 1987, 52, 1794. ^{MS [M + H] - 454} .

[0323] D) Embodiment in which Tb is x Bis-3,4- (diethylphosphonyl) -β-phenylethylamine 5

[0324]

[Chemical 105]

Nt-Butoxycarbonyl-3-hydroxytyramine To 3-hydroxytyramine hydrochloride (5.0 g, 26.36 mmol) in dioxane / water (50/30 mL) at 0 ° C. was added sodium bicarbonate (6
． 64 g, 79.08 mmol) was added and stirred for 10 minutes. To this, anhydrous Boc (7.48 g, 34.275 mmol) was added and stirred at room temperature for 18 hours. After removal of dioxane in vacuum, the slurry is water (~ 60 mL).
And extracted with ethyl acetate (25 mL × 3). Organic matter is 1N HCl
Washed with (10 mL x 2) followed by brine (10 mL); dried (sodium sulfate) and concentrated, then crystallized the next day when cooled in the refrigerator (3.87).
g, 57%). MS: 252 (MH).

Nt-Butoxycarbonyl-bis-3,4-O-trifluyl-β-phenylethylamine N-Boc-3-hydroxytyramine (in anhydrous dichloromethane (70 mL).
3.87 g, 15.28 mmol) solution, triethylamine (61.12)
mmol), followed by N-phenyltrifluamide (16.37 g, 45.84 m)
mol) was added and stirred at room temperature for 24 hours. The reaction mixture was diluted with dichloromethane (100 mL), IN HCl (3 x 10 mL) and brine (1
It was washed successively with 0 mL) and dried (sodium sulfate). After concentration of the dichloromethane extract, the brown oil was washed with hexane / ethyl acetate (
Chromatography (10-100%) gave the product as a viscous oil (6.32 g, 80%). MS: 516 (MH).

Nt-butoxycarbonyl-bis-3,4- (diethylphophonyl
) -Β-Phenylethylamine Nt-butoxycarbonyl-bis-3,4-O-trifluyl-β-phenylethylamine (6.32 g, 12 in acetonitrile) in an atmosphere of argon.
． 21 mmol), diethyl phosphite (3.46 mL, 26.87 m)
mol), N-methylmorpholine (3.09 mL, 30.54 mmol), tetrakisphenylphosphine palladium (0) (1.41 g, 1.221 mmo).
1) was added carefully and after 10 minutes flushing of the solution with argon it was stopped and heated at 90 ° C. for 2 days. Acetonitrile was concentrated and the residue was diluted with ethyl acetate. The organic layer is citric acid (10%, 10 mL
x2), washed with brine (10 mL) and dried (sodium sulfate).
After concentration of ethyl acetate, the yellow gum was purified by flash column chromatography on silica gel using ethyl acetate in hexane (33-100%) followed by ethyl acetate / methanol (9/1). Gave a pale yellow gum (9
92 mg, 16.5%). MS: 492 (MH).

Bis-3,4- (diethylphosphonyl) -β-phenylethylamine Nt-butoxycarbonyl-bis-3,4 in dichloromethane (10 mL).
-(Diethylphosphonyl) -β-phenylethylamine (0.992 g, 2.0
To 1 mmol) TFA (25% in dichloromethane, 2.5 mL) was added. After 1.5 hours the solvent was removed in vacuo and the residue diluted with saturated sodium bicarbonate and dichloromethane (5 mL and 50 mL). The aqueous layer was re-extracted with dichloromethane (25 mL, x2). The combined organics were concentrated to give a light brown gum (0.758g, 96%), which was pure enough for the next step. MS: 392 (MH), 416 (M + 23).

Example 14 [4-Aminomethyl-2- (diethoxy-phosphoryl) -phenyl] -phosphonic acid diethyl ester

[0330]

[Chemical formula 106]

(B) (3,4-Dihydroxy-benzyl) -carbamic acid t-butyl ester 4-aminomethyl-benzene-1,2-diol hydrobromide (5.6 g
, 25.2 mmol) was dissolved in CH ₃ CN / H ₂ O 1: 1 (100 mL). NaHCO ₃ (4.3 g, 50.4 mmol) was followed by Boc ₂ O (5.5 g,
25.2 mmol) was added. The mixture was stirred for 18 hours, concentrated and Et.
Extracted by OAc. The combined extracts were washed with water, dried over magnesium sulfate and concentrated to a tan solid, which was used in the next reaction without purification.

(C) Trifluoro-methanesulfonic acid 5- (t-butoxycarbonylamino-methyl) -2-trifluoromethanesulfonyloxy-phenyl ester (3,4-dihydroxy-benzyl) -carbamic acid t-butyl ester ( 5
． 5g, 23.0mmol), N- phenyltrifluoromethanesulfonimide (26.9g, 75mmol), and Et ₃ N (14.9mL, 107mmo
l) was dissolved in CH ₂ Cl ₂ (80 mL) and stirred for 24 hours. The mixture was added dropwise to water and the layers separated. The aqueous layer was extracted with methylene chloride. The combined extracts were washed with water, dried over magnesium sulfate, concentrated and further purified by chromatography on silica gel (hexane / EtOAc 3: 1) to give the product as a brown oil (9 0.0 g, 78%).

(D) [4- (t-Butoxycarbonylamino-methyl) -2- (diethoxy-phosphoryl) -phenyl] -phosphonic acid diethyl ester trifluoro-methanesulfonic acid 5- (t-butoxycarbonylamino-methyl) ) -2-Trifluoromethanesulfonyloxy-phenyl ester (5 g, 1
0.0 mmol), diethyl phosphite (2.8 mL, 20.3 mmol),
N-methylmorpholine (2.7 mL, 25.1 mmol), and tetrakis (
Triphenylphosphine) -palladium (0) (1.2g) was dissolved in anhydrous acetonitrile (100mL) and heated in a sealed tube at 90 ° C for 48 hours. After cooling, the mixture was diluted with EtOAc (200 mL), water, 1N H.
Washed with Cl, and brine. The organic layer was dried over magnesium sulfate, concentrated, and purified by chromatography on silica gel (5% MeOH / CHCl ₃ ) to give the product as a colorless oil (2.0 g, 42%). ¹ H NMR (
300 Mhz, CDCl ₃ ) δ 1.35 (m, 12H), 3.79 (bs, 2H
) 3.96 (m, 8H), 7.45 (m, 1H) 7.91 (m, 2H).

(E) [4-Aminomethyl-2- (diethoxy-phosphoryl) -phenyl]-
Phosphonic acid diethyl ester [4- (t-butoxycarbonylamino-methyl) -2- (diethoxy-phosphoryl) -phenyl] -phosphonic acid diethyl ester (2.0 g, 4.2 mmo
l) was dissolved in TFA / CH ₂ Cl ₂ (25%, 20 mL) and stirred for 3 hours. The mixture was evaporated in N2 flow down, dissolved in EtOAc, washed with saturated NaHCO _3. The organic layer was dried over magnesium sulfate and concentrated to a brown oil (0.
9 g, 2.3 mmol), used in the next reaction without purification.

Example 15 3- (3,4-Bis-phosphono-phenyl) -propionic acid 4- (4-amino-
5-p-Tolyl-pyrrolo [2,3-d] pyrimidin-7-yl) -tetrahydro-furan-2-ylmethyl ester

[0336]

[Chemical formula 107]

(A) 3- [3,4-bis- (diethoxy-phosphoryl) -phenyl] propionic acid 4- (4-amino-5-p-tolyl-pyrrolo [2,3-d] pyrimidine-
7-yl) -tetrahydro-furan-2-ylmethyl ester [4- (4-amino-5-p-tolyl-pyrrolo [2,3-d] pyrimidin-7
-Yl] -tetrahydrofuran-2-yl] methanol (32.4 mg, 0.1
mmol), 3- [3,4-bis- (diethoxy-phosphoryl) -phenyl]-
Propionic acid (47 mg, 0.11 mmol), DCC (22.7 mg, 0.1
1mmol), and DMAP (5mg, 0.041mmol) in, N ₂ 2 below
Mixed in mL anhydrous DMF. The reaction mixture was stirred at room temperature overnight.
The product was purified by RP HPLC to give a liquid (17 mg, 25%).

(B) 3- (3,4-bis-phosphono-phenyl) -propionic acid 4- (4-
Amino-5-p-tolyl-pyrrolo [2,3-d] pyrimidin-7-yl) -tetrahydro-furan-2-ylmethyl ester 3- [3,4-bis- (diethoxy-phosphoryl) -phenyl] propion Acid 4- (4-amino-5-p-tolyl-pyrrolo [2,3-d] pyrimidin-7-yl) -tetrahydro-furan-2-ylmethyl ester (18 mg, 0.025
mmol) was dissolved in 2 mL anhydrous acetonitrile under N ₂ . The solution was cooled to 12 ° C. TMSI (100 mg, 0.5 mmol) was added via syringe and the reaction was stirred at that temperature for 16 hours. 10% to this solution
NaHCO ₃ was added until pH = 7.0. Then, a few drops of NaS ₂ O ₃ were added, sufficient to remove the yellow color. The resulting mixture was purified by RP HPLC. The final product is a white powder (6.5 mg, 42%). ES-MS
: M / z 616 (MH).

Example 16 (4-{[3- (4-Amino-3-p-tolyl-3a, 7a-dihydro-pyrazolo [3,4-d] pyrimidin-1-yl) -benzoylamino] -methyl } -2
-Phosphono-phenyl) -phosphonic acid

[0340]

[Chemical 108]

(A) 3- (4-Amino-3-p-tolyl-3a, 7a-dihydro-pyrazolo [3,4-d] pyrimidin-1-yl) -benzoic acid The title compound was prepared according to Example 19 ( Created as in b).

(B) [4-{[3- (4-amino-3-p-tolyl-pyrazolo [3,4-d
] Pyrimidin-1-yl) -benzoylamino] -methyl} -2- (diethoxy-phosphoryl) -phenyl] -phosphonic acid diethyl ester 3- (4-amino-3-p-tolyl-3a, 7a-dihydro-pyrazolo [3
4-d] pyrimidin-1-yl) -benzoic acid (0.015 g, 0.043 mmo)
l), [4-aminomethyl-2- (diethoxy-phosphoryl) -phenyl] -phosphonic acid diethyl ester (0.021 g, 0.054 mmol), HOBt (
0.007 g, 0.052 mmol), and EDC.HCl (0.01 g, 0
． (052 mmol) was dissolved in DMF (1 mL) and stirred at room temperature for 1 hour. RP purification and freeze-drying by _{HPLC (CH 3 CN / H 2} O) yielded a white powder (0.023g, 75%). MS [M + H] ⁺ 708

(C) (4-{[3- (4-amino-3-p-tolyl-3a, 7a-dihydro-pyrazolo [3,4-d] pyrimidin-1-yl) -benzoylamino] -methyl } -2-Phosphono-phenyl) -phosphonic acid [4-{[3- (4-amino-3-p-dissolved in CH ₃ CN (1 mL).
Tolyl-pyrazolo [3,4-d] pyrimidin-1-yl) -benzoylamino]
-Methyl} -2- (diethoxy-phosphoryl) -phenyl] -phosphonic acid diethyl ester (0.023 g, 0.033 mmol) had TMSI (0.093 m).
L, 0.65 mmol). The mixture was stirred for 4 hours and 1N NaO
Basified with H, it was decolorized with NaSHO ₃ solid. The resulting solution was diluted with DMF (5 mL), it was purified by _{RP HPLC (CH 3 CN / H} 2 O). Lyophilization produced a white powder (0.011 g, 75%). M
^{S [M-H] - 593} .

[0344] E) Aspect in which Tb is xii General scheme for embodiments in which Tb is a substituted aryl: error! The object could not be created from the edit field code.

[0345] Example 17

[0346]

[Chemical 109]

Synthesis of aniline 5 (a) To a suspension of NaH in THF (15 mL) at room temperature under N ₂ (220 mg (5.5 mmol) 60% dispersion in mineral oil, washed 3 times with hexane). On the other hand, t
-Butyl 4-hydroxybenzoate (971 mg, 5.0 mmol) was added in one portion. After completion of H ₂ release (~ 10 minutes), diethyl chlorophosphate (
0.79 mL, 5.5 mmol) was added. The reaction mixture was stirred at room temperature overnight, then poured into 1.0 N aqueous NaOH (20 mL) and extracted with EtOAc. The organic extract was washed with H ₂ O (20 mL) and brine (20 mL), dried over MgSO ₄ and concentrated. The crude oil was purified by flash chromatography on silica gel. Hexane-EtOAc 2: 1,
Subsequent elution with hexane-EtOAc 1: 1 yielded 1.48 g (90%) of the phosphate as a colorless oil.

(B) i-Pr ₂ NEt solution in THF (22 mL) at 0 ° C. under N ₂ (
1.2 mL, 8.48 mmol) against 1.6 M n-BuLi in hexane.
(5.3 mL, 8.48 mmol) was added slowly. After 10 minutes, the LDA solution was cooled to -78 ° C and the phosphate solution (1.4 g in THS (5 mL) was added.
4.24 mmol) was added slowly via cannula. 2 mL flask wash was also added. The reaction mixture was stirred at -78 ° C for 2 hours and then at 0 ° C for 1 hour. The reaction mixture was then diluted with semisaturated aqueous NH ₄ Cl (20 mL). The mixture was further acidified by the addition of a small amount of 6N HCl water and then extracted with EtOAc. The extract was H ₂ O (10 mL) and brine (10 m
Washed with L). Washing of the aqueous was once re-extracted with EtOAc, The combined extracts were dried over MgSO _4, and concentrated. The crude material was purified by flash chromatography on silica gel. Hexane-EtOAc 5: 1,
Subsequent elution with hexane-EtOAc 3: 1 yielded 1.32 g (94%) of the desired phosphate salt as a pale yellow oil.

(C) A solution of the phenol (1) in CH ₃ CN (10 mL) at room temperature under N _2.
． 30 g, 3.94 mmol), K ₂ CO ₃ (600 mg, 4.33 mmo
l), followed by benzyl bromide (0.51 mL, 4.33 mmol).
The reaction mixture was stirred at 50 ° C. After cooling, the reaction mixture was diluted with EtOAc, and washed with H ₂ O and brine. Extracts were dried over MgSO _4, and concentrated. The crude material was purified by flash chromatography on silica gel to yield 1.86 g (quantity) of the desired benzyl ether.

(D) To t-butyl ester (from above) in CH ₂ Cl ₂ (12 mL) under N _{2 at} 0 ° C., TFA (4 mL) was added slowly. The resulting solution was stirred at 0 ° C. for 1 hour and at room temperature for 3 hours. The reaction mixture is then N2
Concentration under flow followed by high vacuum yielded the desired acid as an off-white solid.

(E) To the acid solution in toluene-t-BuOH 1: 1 (4 mL) at room temperature under N ₂ was added i-Pr ₂ NEt (0.44 mL, 2.5 mmol) followed by (P
_{hO) - 2 P (O)} N 3 (0.54mL, 2.5mmol) was added. The resulting solution was then stirred under perfusion for 5 hours. The yellow solution was cooled to room temperature then partitioned between EtOAc and water (20 mL). Layer was separated and washed with an organic extracts are then H ₂ O (20mL) and brine (20 mL). The EtOAc extract was then dried over NaS ₂ O ₃ and concentrated. The crude liquid was purified by flash chromatography on silica gel. EtOAc-hexane 1:
Elution with 1 followed by EtOAcb-hexane 2: 1 was 146 m
It produced g (34%) of the desired carbamate.

(F) The carbamate solution (8 mL) in CH ₂ Cl ₂ (8 mL) at room temperature under N _2.
To 879 mg, 2.02 mmol) TFA (2 mL) was added. The solution was stirred at room temperature for 3 hours and then concentrated under a stream of N ₂ . The residue was purified by flash chromatography on silica gel. EtOAc-hexane 3: 1
And subsequent elution with EtOAcb-hexane 15: 1 with 612 m
g of the desired aniline 5 was produced.

Concentration of aniline 5 with Sulfone 1 and subsequent deprotection for 9 (a) Aniline 5 (605 mg) in 2-methoxyethyl ester (5 mL).
The mixture of 1.80 mmol) and Sulfone 1 (347 mg, 0.902 mmol) was stirred at 150 ° C. for 2 hours. The dark solution was left overnight to slowly cool to room temperature. The precipitate was washed with Et ₂ O and dried under high vacuum, 31
Yield 0 mg (54%) of the desired cup ring product.

(B) A solution of the cup ring product (from above, 39 mg, 0.610 mmol) in AcOH (about 3-4 mL) containing a catalytic amount of 10% Pd / C was added under N ₂ atmosphere. The (double-packed balloon) was stirred for 3 hours. The reaction mixture was then filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel. Elution with EtOAc-hexane 1: 1 yielded 24 mg (72%) of phenol-9.

[0355]

[Chemical 110]

(A) Phenol 9 solution (8 mL) in CH ₂ Cl ₂ (2 mL) at 0 ° C. under N _2.
5 mg, 0.155 mmol) and _{i-Pr 2 NEt (0.03mL,} 0.1
PhNTf ₂ (72 mg, 0.201 mmol) was added to 86 mmol). The reaction mixture was stirred at room temperature for 5 days. Further i-Pr ₂ NEt and PhNTf ₂ were added and the reaction mixture was stirred for another day. The reaction mixture was then diluted with EtOAc, 1M aq. HCl (10 mL), H ₂ O (10 mL).
), And brine (10 mL). The EtOAc extract was dried over Na ₂ SO ₄ and concentrated. The crude material was purified by flash chromatography on silica gel. EtOAc-hexane 1: 1, EtOAc-hexane 3: 1:
2, and finally elution with EtOAc-hexane 2: 1 was 90 mg (86
%) Of triflate.

(B) To the triflate solution (43.8 mg, 0.0644 mmol) in CH ₃ CN (1.0 mL) at room temperature under N ₂ was added NMM (0.01 mL, 0.
0911 mmol), (EtO) ₂ POH (0.011 mL, 0.0841 mm)
ol) and a catalytic amount of Pd (PPh ₃ ) ₄ were added. Then the mixture was stirred at 70 ° C. overnight. The reaction mixture was then partitioned between EtOAc and 1.0M aqueous HCl. The layers were separated, the organic layer was washed with H ₂ O and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude material was purified by flash chromatography on silica gel to give an inseparable mixture of the desired bisphosphonate and 9 which was used in the next reaction without further purification.

(C) Mixtures of the above products are those described above (iA, (b)).
Was converted to xA in the same manner as.

[0359]

[Chemical 111]

(A) Cs ₂ CO ₃ (16 mg, 0.0489 mmol) at room temperature under N _2.
A solution of phenol 9 in CH ₃ CN containing 17.9 mg (0.0326).
mmol), t-butyl bromoacetate (0.006 mL, 0.042
4 mmol) was added. The yellow color of the reaction mixture gradually disappears over time,
After 3 hours the reaction mixture was washed with EtOAc, H ₂ O and brine.
The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude residue was used without further purification.

(B) The crude residue from above was converted to xB in the same manner as previously described (iA, (b)).

[0362]

[Chemical 112]

The crude residue (x-B, (a)) from above was as previously described (i- except that it was only warmed to 0 ° C. before the reaction mixture was quenched. A, (b)
) Was converted to xC in the same manner as in

[0364]

[Chemical 113]

Phenol 9 was treated with x- in the same manner as previously described (iA, (b)).
It was changed to D.

F) Embodiments in which Tb is xiii Example 18 4- [6- (2,6-Dichloro-phenyl) -8-methyl-7-oxo-4a,
7,8,8a-Tetrahydro-pyrido [2,3-d] pyrimidin-2-ylamino] -pyridine-2,6-dicarboxylic acid

[0367]

[Chemical 114]

A) 4- [6- (2,6-Dichloro-phenyl) -8-methyl-7-oxo-
4a, 7,8,8a-Tetrahydro-pyrido [2,3-d] pyrimidin-2-ylamino] -pyridine-2,6-dicarboxylic acid diethyl ester

[0369]

[Chemical 115]

4-Bromo-pyridine-2,6-dicarboxylic acid diethyl ester (39 mg,
0.13 mmol), 2-amino-6- (2,6-dichlorophenyl) pyrido-
8-Methyl-8H-pyrido [2,3-d] pyrimidin-7-one (50 mg, 0
． 16 mmol), 4-bromopyridine-2,6-dicarboxylic acid diethyl ester (39 mg, 0.13 mmol), palladium acetate (1.5 mg, 0.006).
7 mmol), (S) -BINAP (6.0 mg, 0.0096 mmol), and cesium carbonate (60 mg, 0.18 mmol) in toluene (0.5 mL).
Placed inside. The flask was flushed with argon, sealed and heated to 100 ° C. After 20 hours, the reaction was allowed to cool to room temperature, diluted with EtOAc and H ₂ O. The aqueous layer was extracted with fresh EtOAc, the organic layers were combined, washed with brine and dried over Na ₂ SO ₄ . The solution was concentrated and purified by chromatography on silica gel with CHCl ₃ : MeOH (99: 1) yielding 49 mg of a yellow solid (69%). Electro Spray ·
Electrospray Mass Spectrum (50/50 acetonitrile / water) m / z 540 (MH).

B) 4- [6- (2,6-dichloro-phenyl) -8-methyl-7-oxo-
4a, 7,8,8a-Tetrahydro-pyrido [2,3-d] pyrimidin-2-ylamino] -pyridine-2,6-dicarboxylic acid

[0372]

[Chemical formula 116]

4- [6- (2,6-dichloro-phenyl) -8 in MeOH (0.5 mL)
-Methyl-7-oxo-4a, 7,8,8a-tetrahydro-pyrido [2,3-
d] Pyrimidin-2-ylamino] -pyridine-2,6-dicarboxylic acid diethyl ester solution (49 mg, 0.090 mmol) was added 1N sodium hydroxide (0.36 mL), resulting in a suspension. occured. Water (0.5 mL)
A solution was obtained after addition of and heating to 80 ° C. After 3 hours, the reaction was left to cool to room temperature, diluted with MeCN / H ₂ O / DMF and reversed phase HPL.
It was analyzed by chromatography using C. Concentration and lyophilization of the purified fractions yielded 23 mg (53%) yellow solid. Electrospray mass spectrum (50/50 acetonitrile / water) m / z 486 (M + H).

Example 19 4- (4-Amino-5-p-tolyl-4a, 7a-dihydro-pyrrolo [2,3-
d] pyrimidin-7-yl) -pyridine-2,6-dicarboxylic acid

[0375]

[Chemical 117]

(A) Pyridine- (2,6-dicarboxylic acid diethyl ester) -4-boronic acid 4-Bromopyridine-2,6-dicarboxylic acid diethyl ester (0.10 g, 0. 33 mmol), bis (pinacoloto) diboron (
0.093 g, 0.36 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloride (5 mol%), potassium acetate (0.097 g, 1
． The mixture of 0 mmol) was heated at 80 ° C. for 1 hour. PR HPLC
Purification with (CH ₃ CN / H ₂ O) and lyophilization gave a white powder (0.07 g, 7
9%). MS [M + H] ⁺ 268.

(B) 4- (4-amino-5-p-tolyl-4a, 7a-dihydro-pyrrolo [
2,3-d] Pyrimidin-7-yl) -pyridine-2,6-dicarboxylic acid diethyl ester Pyridine- (2,6-dicarboxylic acid diethyl ester) -4-boronic acid (0. 093 g, 0.27 mmol), 3-p-tolyl-3a
, 7a-Dihydro-1H-pyrazolo [3,4-d] pyrimidin-4-ylamine (0.03 g, 0.13 mmol mmol), cupric acetate (0.048 g, 0)
． The mixture of 27 mmol) and pyridine (0.3 mL) was stirred for 48 hours while being open to the outside air. The mixture was filtered through celite and the filtrate was purified by _{PR HPLC (CH 3 CN / H} 2 O). Lyophilization yielded a white powder (0.02g, 34%). MS [M + H] ⁺ 447.

(C) 4- (4-amino-5-p-tolyl-4a, 7a-dihydro-pyrrolo [
2,3-d] Pyrimidin-7-yl) -pyridine-2,6-dicarboxylic acid 4- (4-amino-5-p-tolyl-4a, 7a- in THF (1 mL) and water (1 mL). Dihydro-pyrrolo [2,3-d] pyrimidin-7-yl) -pyridine-2,6-dicarboxylic acid diethyl ester (0.02 g, 0.036 mm
2 N NaOH (1 mL) was added to the suspension of The mixture was heated under perfusion for 1 hour, at which time HPLC showed completion. The mixture is TFA
Acidified with and diluted with DMF (5 mL) and further PR HPLC (C
H ₃ CN / H ₂ O). Freeze-dried white powder (0.01 g, 71%
) Was produced. ^{MS [M-H] - 389} .

[0379] G) Embodiments in which Tb is xxii

[0380]

[Chemical 118]

Example 20 Diethyl 2 (5-bromopyridyl) phosphonate 2,5-Dipromopyridine (500 mg, 2.11 mmol) in CH ₃ CN.
), NMM (0.46 mL, 4.22 mmol), (EtO) ₂ POH (0.3
5 mL, 2.53 mmol), and Pd (PPh ₃ ) ₄ (122 mg, 0.10
6 mmol) was stirred overnight at 80 ° C. After cooling, the reaction mixture was partitioned between CH ₂ Cl ₂ and water. The organic extract is then washed with brine and K ₂ C
Dried over O ₃ and concentrated. The crude material was purified by flash chromatography on silica gel to yield 130 mg (21%) of the desired phosphonate.

{5- [6- (2,6-dichloro-phenyl) -8-methyl-7-oxo-4a
, 7,8,8a-Tetrahydro-pyrido [2,3-d] pyrimidin-2-ylamino] -pyridin-2-yl} -phosphonic acid

[0383]

[Chemical formula 119]

A) {5- [6- (2,6-Dichloro-phenyl) -8-methyl-7-oxo-4a, 7,8,8a-tetrahydro-pyrido [2,3-d] pyrimidine-2 −
Ilamino] -pyridin-2-yl} -phosphonic acid diethyl ester (5-bromo-pyridin-2-yl) -phosphonic acid diethyl ester

[0385]

[Chemical 120]

B) (4-Bromopyridin-2-yl) -phosphonic acid diethyl ester (64
mg, 0.22 mmol), 2-amino-6- (2,6-dichlorophenyl) pyrid-8-methyl-8H-pyrido [2,3-d] pyrimidin-7-one (70 m
g, 0.22 mmol), palladium acetate (5.0 mg, 0.00.023 mmo)
l), (5-bromopyridin-2-yl) -phosphonic acid diethyl ester (64
mg, 0.22 mmol), (S) -BINAP (20 mg, 0.032 mmo
l), and cesium carbonate (141 mg, 0.43 mmol) are toluene (1 m
L), flushed with argon, sealed and heated to 95 ° C. After 18 hours, the reaction was allowed to cool to room temperature, diluted with H ₂ O. The mixture was extracted twice with EtOAc, the combined organic extracts were washed with brine and dried over Na ₂ SO ₄ . The solution was concentrated and analyzed by chromatography on silica gel (CHCl ₃ : MeOH, stepwise gradient 99: 1 to 97: 3), 46.
This gave mg (39%) of a yellow solid. Electrospray mass spectrum (50/50 acetonitrile / water) m / z 534 (M + H).

C) {5- [6- (2,6-Dichloro-phenyl) -8-methyl-7-oxo-4a, 7,8,8a-tetrahydro-pyrido [2,3-d] pyrimidine-2 −
Ilamino] -pyridin-2-yl} -phosphonic acid

[0388]

[Chemical 121]

Cooled (0 ° C.) {5- [6- (2,6-dichloro-phenyl) -8-methyl-7-oxo-4a, 7,8,8a in MeCN (1.2 mL). -Tetrahydro-pyrido [2,3-d] pyrimidin-2-ylamino] -pyridin-2-yl} -phosphonic acid diethyl ester (46 mg, 0.86 mmol) solution to which iodotrimethylsilane (0.3 mL) was added Was done. After 2 hours, the reaction was quenched with sodium hydroxide (1N) and saturated sodium thiosulfate.
The mixture was filtered and the filtrate was analyzed by chromatography using reverse phase HPLC yielding 14 mg (34%) of a colorless solid after lyophilization. Electrospray mass spectrum (50/50 acetonitrile / water) m / z 534 (
M + H).

Example 21 Solid Phase / Combinatorial Approach: Quest 210 Synthesizer (Argonaut Technologies (A
Example 22 below by solid phase parallel synthesis using rgonaut Technologies)).
Compounds were synthesized according to the diagram for: Solid-phase parallel synthesis diagram

[0391]

[Chemical formula 122]

Example 22 (a) [(4- {2- (2-Dimethylamino-ethylamino) -9- [2- (
3-Hydroxy-phenyl) -ethyl] -9H-purin-6-ylamino} -phenyl) -hydroxy-phosphinoylmethyl] -phosphonic acid

[0393]

[Chemical 123]

(B) 3- [2- (t-Butyl-dimethyl-silanyloxy) -ethyl] -phenol 3-Hydroxyphenylethyl alcohol (6) in 275 mL CH ₂ Cl _2.
． 0g, 43.3mmol) solution, 6.55g (43.4mmol) of T
BDMS-Cl (t-butyldimethylsilyl chloride) was added, cooled to 0 ° C., and then 7.0 mL (86.8 mmol) pyridine was added. The reaction mixture was stirred overnight at ambient temperature. Upon concentration, the crude mixture was purified by silica gel flash chromatography (eluted with hexane followed by 5% EtOAc / hexane) to give 8.9 g of a clear oil: ¹ H NMR (300M
Hz, DMSO-d ₆ ) δ9.17 (s, 1H), 7.04 (m, 1H), 6.60 (m, 3H), 3.37 (t, J = 6.9Hz, 2H), 2 .65 (t
, J = 6.9 Hz, 2H), 0.83 (s, 9H) -0.03 (s, 6H).

(C) Preparation of Ether Resin (1a) To Teflon® RV (reaction vessel) containing 0.3 g (0.96 mmol / g, 0.29 mmol) Wang resin, 1.4 mL TH
3- [2- (t-Butyl-dimethyl-silanyloxy) -ethyl] -phenol (0.73 g, 2.9 mmol) and triphenylphosphine (0.
38 g, 1.44 mmol) solution was added. The RV was cooled to 0 ° C. (Julabo chiller) and then DEA in THF under N ₂ atmosphere.
2.0 mL of 0.72 M solution of D (diethylazodicarboxylate) (1.44
mmol) was added. The resin mixture was allowed to warm to ambient temperature with shaking for 2 hours, then shaken for an additional 20 hours, the RV was drained immediately and the resin was washed with THF (5 × 5.0 mL), DMA (5 × 5.0 mL), CH ₂ Cl _{2. 2} (
_{5x5.0mL), Et 2 O (2x5.0mL} ), CH 2 Cl 2 (1x5.0mL
), Et ₂ O (1 × 5.0 mL), and CH ₂ Cl ₂ ( ₂ × 5.0 mL). Excess solvent was removed by a stream of N ₂ overnight resulting in ether resin 1a. The analytical data below is 30% TFA / CH ₂ Cl ₂ (up to 5 minutes)
Was obtained for cleavage of 1a (3-5 mg) by: HPLC purity 83%; HPLC RT (retention time, min) is consistent with commercially available 3-hydroxyfetetyl alcohol (TBS group removed in TFA cleavage). ).

(D) Preparation of Purine Resin (1b) To an ether resin 1a (0.29 mmol), 6.6 mL (6.57 mm) of a 1.0 M solution of TBAF (tetrabutylammonium fluoride) in THF was added.
ol) was added. The resin mixture was shaken for 2 hours, the RV was drained immediately, and the resin was THF (5x5.0 mL), DMA (5x5.0 mL), CH ₂ Cl ₂ (5x
5.0 mL), Et ₂ O ( ₂ x 5.0 mL), CH ₂ Cl ₂ (1 x 5.0 mL),
It was washed successively with Et ₂ O (1 × 5.0 mL), and CH ₂ Cl ₂ ( ₂ × 5.0 mL). Excess solvent was removed by a stream of N ₂ overnight resulting in a deprotected resin. Aliquots of resin (3-5 mg), in order verify the integrity of the resin-bound compound was cleaved by _{30% TFA / CH 2 Cl 2} (~5 min): HPL
C purity 80%; HPLC RT (retention time, min) is consistent with commercially available 3-hydroxyphenethyl alcohol.

2-Fluoro-6-chloropurine (0.50 g, 2.9 mmol) (2-fluoro-6- in 1.75 mL THF against dry resin (0.29 mmol).
For the preparation of chloropurine, Gray, NS; Kwon, S .; Schultz, PG Tet
rahedron Lett. 1997, 38, 1161-1164) and triphenylphosphine (see
0.38 g, 1.44 mmol) of a homogeneous suspension was added. The RV was cooled to 0 ° C. (Durabo Chiller) and then under N ₂ atmosphere 2.0 mL (1.44 mmo) of a 0.72 M solution of DEAD (diethylazodicarboxylate) in THF.
l) was added. The resin mixture was allowed to warm to ambient temperature with shaking for 1.5 hours, then shaken for another 22 hours, immediately RV drained,
The resin is THF (5 x 5.0 mL), DMA (5 x 5.0 mL), CH ₂ Cl ₂ (5
x 5.0 mL), Et ₂ O ( ₂ x 5.0 mL), CH ₂ Cl ₂ (1 x 5.0 mL)
, Et ₂ O (1 x 5.0 mL), and CH ₂ Cl ₂ ( ₂ x 5.0 mL) successively. Excess solvent was removed by N ₂ flow overnight, purine resin 1b
Occurred. The following analytical data of those obtained for cleavage of 1b (3-5 mg) with a _{30% TFA / CH 2 Cl 2} (~5 min): HPLC purity 65
%; Major / minor peak ˜5: 1 (no obvious 3-hydroxyphenethyl alcohol HPLC peak).

(E) Preparation of Purine Resin (1c) 3.0 mL of n-butanol / purine resin 1b (0.29 mmol) was added.
[(4-Amino-phenyl) -ethoxy-phosphinoylmethyl] -phosphonic acid diethyl ester (0.97 g, 2.88 mmol) and N, N-diisopropylethylamine (0.25 mL, 1: 1 in DMSO 1: 1. .44 mmol)
Solution was added. The sealed RV is heated at 110 ° C for 16 hours and immediately R
V is cooled to ambient temperature and drained, and the resin is DMA (5x5.0 m).
_{L), CH 2 Cl 2 (} 5x5.0mL), Et 2 O (2x5.0mL), CH 2 Cl 2 (1x5.0mL), Et 2 O (1x5.0mL), and CH ₂ Cl ₂ (2x5
． 0 mL) and washed successively. Excess solvent was removed by a stream of N ₂ overnight resulting in aminated purine resin 1c. The following analysis data is 30% TF
Obtained for cleavage of 1c (3-5 mg) with A / CH ₂ Cl ₂ (-5 min): m / z 592 (M + H).

(F) [(4- {2- (2-Dimethylamino-ethylamino) -9- [2- (
3-Hydroxy-phenyl) -ethyl] -9H-purin-6-ylamino} -phenyl) -hydroxy-phosphinoylmethyl] -phosphonic acid 3.0 mL for aminated purine resin 1c (0.29 mmol). N
-N, N-dimethylethylenediamine (0 in butanol / DMSO 1: 1)
． 25 g, 2.88 mmol) and N, N-diisopropylethylamine (0
． 25 mL, 1.44 mmol) solution was added. The sealed RV is 110
Heated at 16 ° C for 16 hours, immediately stopped heating, RV drained immediately, and resin (while still hot) DMA (5x5.0 mL), CH ₂ Cl ₂ (5x5.0 mL).
mL, at ambient temperature), Et ₂ O ( ₂ x 5.0 mL), CH ₂ Cl ₂ (1 x 5.0
mL), Et ₂ O (1 × 5.0 mL), and CH ₂ Cl ₂ ( ₂ × 5.0 mL). Excess solvent was removed by a stream of N ₂ overnight resulting in a bis-aminated purine resin.

To the bis-aminated purine resin (0.29 mmol), 5.6 mL of 30% TFA / CH ₂ Cl ₂ (2% triisopropylsilane) was added. The resin mixture was shaken for 1 hour, the filtrate was immediately collected, and the resin was CH ₂ Cl ₂ (3 × 5.
Washed with 0 mL). The combined filtrate was concentrated (Savant Speed-
Savant speed-vac, 3-4 mL of CH ₂ Cl ₂ was added and then reconcentrated to give a dark yellow oil.

The oil was dissolved in 6.6 mL CH ₃ CN, cooled to 0 ° C., then 1.0 m
L (7.2 mmol) TMSI (iodotrimethylsilane) was added. The resulting yellow solution (some precipitation) was stored at −20 ° C. for 2 hours (with regular swirling), then at 0 ° C. for 1 hour and immediately added to 0.4 mL (2.81 mmol).
) TMSI was added and the reaction was continued at 0 ° C. for 3 hours. Excess TMSI is quenched with 0 ℃ with 20% NaHSO ₃ water ~4mL, pH is 10% N
is adjusted to 11-12 by NaOH, further CH ₃ CN was removed by rotary evaporator. The pH was readjusted to 10-11 with TFA, the solution immediately filtered (0.2 μm, PTFE filter) and further PR HPLC.
It purified by _{(CH 3 CN / H 2 O} ). Freeze-drying the TFA salt (0.0
This resulted in a white solid isolated as 35 g). : ¹ H NMR (300 MHz,
DMSO-d ₆ ) δ 9.76 (s, 1H), 9.33 (br s, 1H), 8.
07-7.65 (m, 5H), 7.08-6.59 (m, 5H), 4.27 (m
2H), 3.66 (m, 2H), 3.32 (m, 2H), 3.04 (m, 2H)
), 2.85 (s, 6H), 2.37 (m, 2H); m / z 576 (M + H).
.

Example 23 [(4- {2- (trans-4-amino-cyclohexylamino) -9- [2-
(3-Hydroxy-phenyl) -ethyl] -9H-purin-6-ylamino}-
Phenyl) -hydroxy-phosphinoylmethyl] -phosphonic acid

[0403]

[Chemical formula 124]

The title compound was synthesized in a similar manner as described in Example 22. T
White solid isolated as FA salt: m / z 602 (M + H).

Example 24 [Hydroxy- (4- {9- [2- (3-hydroxy-phenyl) -ethyl]-
2- [2- (3H-Imidazol-4-yl) -ethylamino] -9H-purin-6-ylamino} -phenyl) -phosphinoylmethyl] -phosphonic acid

[0406]

[Chemical 125]

The title compound was synthesized in a similar manner as described in Example 22. T
White solid isolated as FA salt: m / z 599 (M + H).

Example 25 [Hydroxy- (4- {2- (2-hydroxy-ethylamino) -9- [2- (
3-Hydroxy-phenyl) -ethyl] -9H-purin-6-ylamino} -phenyl) -phosphinoylmethyl] -phosphonic acid

[0409]

[Chemical formula 126]

The title compound was synthesized in a similar manner as described in Example 22. The product was isolated as a white solid: m / z 549 (M + H)

Example 26 (5- {2- (trans-4-amino-cyclohexylamino) -9- [2- (
3-Hydroxy-phenyl) -ethyl] -9H-purin-6-ylamino} -2
--- Phosphono-phenyl] -phosphonic acid

[0412]

[Chemical 127]

The title compound was synthesized in a similar manner as described in Example 22.
White solid was isolated as TFA salt: m / z 604 (M + H).

Example 27 (5- {9- [2- (3-hydroxy-phenyl) -ethyl] -2- [2- (3
H-imidazol-4-yl) -ethylamino] -9H-purin-6-ylamino} -2-phosphono-phenyl) -phosphonic acid

[0415]

[Chemical 128]

The title compound was synthesized in a similar manner as described in Example 22. T
White solid isolated as FA salt: m / z 601 (M + H).

Example 28 [5- {2- (2-Dimethylamino-ethylamino) -9- [2- (3-hydroxy-phenyl) -ethyl] -9H-purin-6-ylamino} -2-phosphono -Phenyl) -phosphonic acid

[0418]

[Chemical formula 129] The title compound was synthesized in a manner similar to that described in Example 22. The product was isolated as a white solid: m / z 578 (M + H).

Example 29 [Hydroxy- (3- {9- [2- (4-hydroxy-phenyl) -ethyl]-
6-Phenylamino-9H-purin-2-ylamino} -propyl) -phosphinoylmethyl] -phosphonic acid

[0420]

[Chemical 130] The title compound was synthesized in a manner similar to that described in Example 22. The product was isolated as a white solid: m / z 547 (M + H).

Example 30 [Hydroxy- (3- {9- [2- (3-hydroxy-phenyl) -ethyl]-
6-Phenylamino-9H-purin-2-ylamino} -propyl) -phosphinoylmethyl] -phosphonic acid

[0422]

[Chemical 131] The title compound was synthesized in a manner similar to that described in Example 22. The product was isolated as a white solid: m / z 547 (M + H).

Example 31 [Hydroxy- {3- [9- (3-hydroxy-benzyl) -6-phenylamino-9H-purin-2-ylamino] -propyl} -phosphinoylmethyl)-
Phosphonic acid

[0424]

[Chemical 132] The title compound was synthesized in a manner similar to that described in Example 22. The product was isolated as a white solid: m / z 533 (M + H).

Example 32 ({3- [6- (3-chloro-phenylamino) -9- (3-hydroxy-benzyl) -9H-purin-2-ylamino] -propyl} -hydroxy-phosphinoylmethyl ) -Phosphonic acid

[0426]

[Chemical 133] The title compound was synthesized in a manner similar to that described in Example 22. The product was isolated as a white solid: m / z 567 (M + H).

Example 33 [(3- {6- (3-chloro-phenylamino) -9- [2- (4-hydroxy-phenyl) -ethyl] -9H-purin-2-ylamino} -propyl)- Hydroxy-phosphinoylmethyl] -phosphonic acid

[0428]

[Chemical 134] The title compound was synthesized in a manner similar to that described in Example 22. The product was isolated as a white solid: m / z 581 (M + H).

Example 34 [(3- {6- (3-chloro-phenylamino) -9- [2- (3-hydroxy-phenyl) -ethyl] -9H-purin-2-ylamino} -propyl)- Hydroxy-phosphinoylmethyl] -phosphonic acid

[0430]

[Chemical 135] The title compound was synthesized in a manner similar to that described in Example 22. The product was isolated as a white solid: m / z 581 (M + H).

Example 35 The techniques described above can also be applied to typical solution phase combinatorial synthesis. As described below, libraries of compounds are rapidly generated by coupling bone targeting moieties with payload fragments.

Synthesis of 4-Amino-5- (3-methoxyphenyl) -7- (4-carboxyphenyl) pyrrolo [2,3-d] -pyrimidine Analogs Targeting Bone These Analogs 21A-21D Was synthesized according to Scheme 6 starting from 4-amino-5- (3-methoxyphenyl) -7- (4-carboxyphenyl) pyrrolo [2,3-d] -pyrimidine.

[0433]

[Chemical 136] Method C: Carboxylic acid (0.25 mmol) 19/22 was taken up in DMF (5 mL),
Cooled in ice. HATU (0.5 mmol) was then added followed by bone targeting amines AD and ethyldiisopropylamine (0.5 mmol). The reaction mixture was stirred at ambient temperature for 2 days. DMF was removed in vacuo and the residue was taken up in ethyl acetate. The ethyl acetate layer is sodium hydrogen carbonate (
10%), followed by 10% citric acid and then water. The organic extract was dried over sodium sulfate, concentrated and further purified by chromatography with methylene chloride / methanol (5-10%).

[0434]

[Chemical 137] 4-amino-5- (3-methoxyphenyl) -7- {4- [N- (4-bisdiethylphosphonomethyl) phenyl] carboxamide)} pyrrolo [2,3-d] -pyrimidine 20A: lighter than 19 Prepared as a yellow gum. MS: 720 (MH), 744 (M + 2)
3).

[0435]

[Chemical 138]

4-Amino-5- (3-methoxyphenyl) -7- {4- [N- (3,4-bisdiethylphosphonophenyl) methyl] carboxamide)} pyrrolo [2,3-d]
-Pyrimidine 20B: Prepared as a pale yellow gum from 19. MS: 720 (MH).

[0437]

[Chemical 139]

4-amino-5- (3-methoxyphenyl) -7- {4- [N- (2- (3,4
-Bisdiethylphosphonophenyl) ethyl] carboxamide)} pyrrolo [2,3
Prepared as a pale yellow gum from -d] -pyrimidine 20C: 19. MS: 734 (MH), 768 (M + 2)
3).

[0439]

[Chemical 140]

4-Amino-5- (3-methoxyphenyl) -7- {4- [N-3-triethylbisphosphono-methylenepropyl] phenyl} carboxamide)} pyrrolo [2
3-d] -pyrimidine 20D: Prepared as a pale yellow gum from 19. MS: 642 (MH).

Method D: To a cooled (−20 ° C.) phosphonate ester 20A-D solution (0.2 mmol) in acetonitrile (5 mL) was added TMSI (2 mmol) and at 0 ° C. for 4.5 hours. It was stirred and then quenched with sodium hydrogen carbonate solution followed by 10% sodium bisulfite solution until the iodine color disappeared. The aqueous layer was washed with ethyl acetate and purified by preparative HPLC.

[0442]

[Chemical 141]

4-Amino-5- (3-methoxyphenyl) -7- {4- [N- (4-bisphosphonomethyl) phenyl] carboxamide)} pyrrolo [2,3-d] -pyrimidine 21A: Method Prepared as a white solid from 20A using D. MS: 608 (MH), 6
10 (M + H).

[0444]

[Chemical 142]

4-Amino-5- (3-methoxyphenyl) -7- {4- [N- (3,4-bisphosphonophenyl) methyl] carboxamide)} pyrrolo [2,3-d] -pyrimidine 21B : Prepared as a white solid from 20B using Method D. MS: 608 (MH), 6
10 (M + H).

[0446]

[Chemical 143]

4-amino-5- (3-methoxyphenyl) -7- {4- [N- (2- (3,4
-Bisphosphonophenyl) ethyl)] carboxamide)} pyrrolo [2,3-d]
-Pyrimidine 21C: Prepared as a white solid from 20C using Method D. MS: 622 (M-H), 6
46 (M + H).

[0448]

[Chemical 144]

4-Amino-5- (3-methoxyphenyl) -7- {4- [N-3-bisphosphonomethylenepropyl] phenyl} carboxamide} pyrrolo [2,3-d] -pyrimidine 21D: Method D Prepared as a white solid from 20D. MS: 558 (MH).

Synthesis of 4-Amino-5- (3-methoxyphenyl) -7- (3-carboxyphenyl) pyrrolo [2,3-d] -pyrimidine Analogs Targeting the Bone These Analogs 24A- 24D was synthesized according to Scheme 7 starting from 4-amino-5- (3-methoxyphenyl) -7- (3-carboxyphenyl) pyrrolo [2,3-d] -pyrimidine. Scheme 7:

[Chemical 145]

4-Amino-5- (3-methoxyphenyl) -7- {3- [N- (4-bisdiethylphosphonomethyl) phenyl] carboxamide)} pyrrolo [2,3-d] -pyrimidine 23A: Prepared as pale yellow gum from 22 using Method C. MS: 720 (MH), 7
44 (M + 23).

[0452]

[Chemical 146]

4-Amino-5- (3-methoxyphenyl) -7- {3- [N- (3,4-bisdiethylphosphonophenyl) methyl] carboxamide)} pyrrolo [2,3-d]
-Pyrimidine 23B: Prepared as a pale yellow gum from 22 using Method C. MS: 720 (MH).

[0454]

[Chemical 147]

4-amino-5- (3-methoxyphenyl) -7- {3- [N- (2- (3,4
-Bisdiethylphosphonophenyl) ethyl] carboxamide)} pyrrolo [2,3
-D] -Pyrimidine 23C: Prepared as pale yellow gum from 22 using Method C. MS: 734 (MH), 7
68 (M + 23).

[0456]

[Chemical 148]

4-Amino-5- (3-methoxyphenyl) -7- {4- [N-3-triethylbisphosphono-methylenepropyl] phenyl} carboxamide)} pyrrolo [2
Prepared as a pale yellow gum from 3-d] -pyrimidine 23D: 22. MS: 642 (MH).

[0458]

[Chemical 149]

4-Amino-5- (3-methoxyphenyl) -7- {3- [N- (4-bisphosphonomethyl) phenyl] carboxamide)} pyrrolo [2,3-d] -pyrimidine 24A: Method Prepared as a white solid from 23A using D. MS: 608 (MH), 6
10 (M + H).

[0460]

[Chemical 150]

4-Amino-5- (3-methoxyphenyl) -7- {3- [N- (3,4-bisphosphonophenyl) methyl] carboxamide)} pyrrolo [2,3-d] -pyrimidine 24B Prepared as a white solid from 23D using Method D. MS: 608 (MH). 6
10 (M + H).

[0462]

[Chemical 151]

4-amino-5- (3-methoxyphenyl) -7- {3- [N- (2- (3,4
-Bisdiphosphonophenyl) ethyl)] carboxamide)} pyrrolo [2,3-d
] -Pyrimidine 24C: Prepared as a white solid from 23C using Method D. MS: 622 (M-H), 6
46 (M + 23).

[0464]

[Chemical 152]

4-Amino-5- (3-methoxyphenyl) -7- {3- [N-3-bisphosphonomethylenepropyl] phenyl} carboxamide)} pyrrolo [2,3-d] -pyrimidine 24D: Method Prepared as a white solid from 23D using D. MS: 558 (MH).

[0466]

[Table 1]

Analysis 1. Anti-resorptive cell analysis (rabbit osteoclasts): Femur, tibia, and scapula were analyzed for 3-4 day old New Zealand White rabbits (Millb).
rook Farms, Amherst, MA). Bone 0.55 g / L NaHCO ₃ , 10 mM HEPES (Gi
bco-BRL), 50 units / ml penicillin, and a-ME containing 0.05 mg / ml streptoma
Chopped and finely ground in M (Gibco-BRL), pH 7.1. Bone fragments were allowed to settle by gravity, the supernatant was collected, centrifuged at 400 RPM (Beckman GS-6KR) for 2 minutes, and the cell pellet was resuspended in the same medium supplemented with 10% HIFBS (Hyclone). . Pre-bind
For experimentation, 0.75 ml of cell suspension was added to the culture medium containing 2X concentration of test compound.
0.75 ml was added to wells containing pre-incubated sperm whale dentin discs for 2 hours. Also, 0.75 ml of cell suspension was added to each well containing dentin slices pre-incubated using only 0.75 ml of culture medium and the test compound was added after the adhesive phase. Sperm whale dentin was cut as 1 mm x 6 mm circular discs. The adhesive phase was carried out at 37 ° C and 5% CO _{2 for} 30 minutes,
The medium and non-adherent cells and debris were then removed by aspiration. Added to fresh culture medium containing serially diluted test compounds and cells were incubated on dentin at 37 ° C., 5% CO _{2 for} 24 hours. After the absorption phase, dentin slices were soaked in 0.5% sodium hypochlorite for 30 seconds, wiped clean of adherent cells and then stained with 1% toluidine blue for 30-45 seconds. Absorption was measured using reflected light microscopy and automated image analysis. The absorption area was measured on all 6 mm discs. The residual cells in the 24-well plate were stained with tartrate-resistant acid phosphatase (TRAP), and the generation of fibroblasts was visually evaluated. Experiments were performed with 5 untreated control samples per plate, containing 3 sets of samples for each concentration of test compound. IC ₅₀ values were calculated based on the% absorption in the presence of the compound in relation to control samples treated with vehicle alone. Data were calculated from at least 3 independent experiments each containing 3 sets of samples.

2. Src Kinase Inhibition Assay: Compounds were tested for their ability to inhibit Src kinase using the scintillation proximity assay (SPA) technique developed by Amersham. Reagents are Streptavidin SPA beads from Amercham, 2- [N-morpholino] ethanesulfonic acid from Sigma, Boerh
Ainger Mannheim ATP, NEN [ ³³ P] ATP (NEG602H), in substrate-kinase buffer, 1
Biotinylated peptide substrate 1 (PKS1) (cdc2 peptide) from Pierce prepared at 2.5 μM (5X solution), and enzyme, 135 μg / ml (1/40 diluted 1/40 in kinase buffer before use.
Stock solution) containing human recombinant c-Src (3.38 μg / ml). The buffer solution is (a) MES 30.
mM pH6.8, MgCl ₂ 10mM, Orusobanajin salt 0.25 mM, PMSF 0.1 mM, and DTT 1 m
Kinase buffer containing M; (b) MgCl ₂ 50 mM buffer (stock solution), ATP buffer containing 5 mM ATP (diluted to 100 μM (5X solution) with MES before use, 100 μCi / mL [ ^{3 3} P) ATP); and (c) PBS stop buffer containing 0.1 mM ATP, 40 mM EDTA, 0.1% Triton. Streptavidin beads are 3.3 mg / ml in stop buffer
, And stirred to mix. Sequentially in the holes on a 96-well plate, the following compounds: (a) 10
Compounds tested at different concentrations in μM kinase buffer + 10% DMSO or MES + 10% DMSO, (b) 10 μL kinase buffer, (c) 10 μL substrate 12.5 μM, (d) 10 μL enzyme 3.38
The kinase reaction was allowed to proceed by adding 100 μM of 10 μL ATP containing μg / ml and (e) 0.2 μCi [ ³³ P] ATP. After incubating at 30 ° C. for 2 hours, 150 μL stop buffer containing 500 μg streptavidin beads is added. The incubation is allowed to proceed for 30 minutes at room temperature, then centrifuged for 5 minutes at 2000 rpm and read on a Wallac microbeta scintillation counter.

3. Hydroxyapatite analysis: Hydroxyapatite is an important metal component of bone. Hydroxyapatite absorption chromatography has been used as an assay to assess the potential of bone targeting in individual bone targeting components (monomers) and the potential of drug-introduced bone targeting populations. Method: The duration of the test compound is from 10 mM sodium phosphate, 0.15 N NaCl, pH = 6.8 on TSK-Gel HA 1000 high pressure liquid chromatography column (7.5 mm x 75 mm).
Measured using a 500 mM sodium phosphate, 0.15 N NaCl, primary gradient to pH = 6.8. The duration of a compound is expressed by K = (duration-void time) / void. This K value is corrected using two reference compounds that are corrected from intercolumn and Intersystem to obtain the K value.

Reference compounds: K values were determined for known bone targeting compounds, bisphosphonates, alendronate and tetracycline. Alendronate shows a K value of 3.7,
Tetracycline showed a K value of 2.0.

Example 36 As noted above, the compounds of the invention may be provided as prodrugs. One example is a bone targeting component of the formula:

[0472]

[Chemical 153]

[0473] May be protected using the following Rz groups.

[0474]

[Chemical 154]

[0475]   Also, the bone target component has the following formula:

[0476]

[Chemical 155]

May be provided as a prodrug having To consider such prodrugs, see Krise, J., Stella, VJ.
See Advanced Drug Delivery Reviews 1996, 19: 287. This document is incorporated herein by reference.

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification Code FI Theme Coat (Reference) A61P 7/00 A61P 7/00 19/00 19/00 19/08 19/08 19/10 19/10 C07D 471/04 105 C07D 471/04 105Z 118 118 (31) Priority claim number 60/240, 788 (32) Priority date October 16, 2000 (October 16, 2000) (33) Priority claim country United States (US) (31) Priority claim number 09 / 740,619 (32) Priority date December 18, 2000 (December 18, 2000) (33) Priority claiming country United States (US) (31) Priority Claim number 09 / 740,653 (32) Priority date December 18, 2000 (December 18, 2000) (33) Priority claiming country United States (US) (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I , LU, MC, NL, PT, SE, TR), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH , GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB , GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, S , SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor David See Dalgarno United States Massachusetts 02446 Brookline Crownin Shield Road 50 (72) Inventor George P. Luke United States Connecticut 06413 Clinton Vienna Lane 17 (72) Inventor Tommy Sawyer United States Massachusetts 01772 Southborough Nathan Stone Road, 8 (72) Inventor Rizine Bohachek, USA Massachusetts 02116, Boston Commonwealth Avenue 50, # 702 (72) Inventor William Sea Shakespeare, Massachusetts, USA 01772 · Southborough · Bray Lane 2 (72) Inventor Rajeswali Sandaramorty United States Massachusetts 02472 Watertown Coolidge Avenue 151 # 202 (72) Inventor Ihan One United States Massachusetts 02460 Newton Madison Avenue 45 (72) Inventor Chester A. Metcalfe III The United States Massachusetts 02492 Needham Break Street 70 (72) Inventor Chi Bee Vue United States Massachusetts 02474 Arlington Bay・ Street Road ・ 79 (72) Inventor Noriyuki H. Kawahata USA ・ Massachusetts ・ 02155 ・ Medford Auburn Street ・ 61-AF Term (reference) 4C065 AA01 AA04 BB11 CC01 DD03 DD04 EE02 HH02 HH03 HH09 JJ01 JJ04 KK01 LL07 PP12 4C086 AA02 AA03 DA34 DA38 MA02 MA05 NA14 ZA51 ZA96 ZA97 ZB15 4H050 AA01 AA03 AB20 AB27

Claims (111)

[Claims] 1. A general formula (I): in Hc-X-K-Cy- L-Z-Tb (I) ( wherein, L and K are independently present or not or -M _n -Y-Mp- X, Y, and Z are independently absent or represent NR, O, or S; M is independently a substituted or unsubstituted methylene group for each occurrence, or two M are combined with each other. Represents a substituted or unsubstituted ethene or ethyne; R independently represents H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl for each occurrence; p and n Independently represent an integer of 0 to 10; Cy represents a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, or cycloalkyl; Hc represents a heterocycle; Tb represents Represents a bone targeting group selected from and R ₄ independently represents H or lower alkyl for each occurrence, wherein Hc-X-K-Cy-L contains no hydrolyzable bond. ). Wherein formula (II): in Hc-X-K-Z- Tb ( wherein, K is absent or -M _n -Y-Mp- indicates, X, Y, and Z are independently , Is absent, or is NR, O, or S; M independently represents for each occurrence a substituted or unsubstituted methylene group, or two M's in combination with each other are substituted or unsubstituted ethylene or ethyne. Where p and n independently represent an integer from 0 to 10; R is independently for each occurrence H or a substituted or unsubstituted aryl, heterocyclic group,
Represents heteroaryl, aralkyl, alkenyl, or alkyl; Hc represents a heterocycle; Tb represents Represents a bone targeting group selected from; and R ₄ independently represents H or lower alkyl for each occurrence, wherein Hc-XK does not contain a hydrolyzable bond. ). 3. The compound according to claim 1, wherein the compound selectively targets osteoclasts. 4. The compound according to claim 1 or 2, wherein R ₄ represents H for all generated. 5. Cy represents an uncharged carbocyclic group or a nitrogen-containing heterocyclic group,
The compound according to claim 1. 6. The compound of claim 1, wherein Cy represents phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic system having 8 to 11 atoms. 7. The compound according to claim 1, wherein Cy represents phenyl. 8. The compound of claim 1, wherein Cy represents a bicyclic system, L is attached to the first ring and K is attached to the second ring. 9. The compound according to claim 1, wherein Hc represents a bicyclic structure. 10. The compound according to claim 9, wherein the two rings of the bicyclic structure consist of carbon atoms and nitrogen atoms. 11. The compound according to claim 1 or 2, wherein K is directly bonded to the heteroatom of Hc. 12. Hc is represented by: (Wherein _one of R ₁ , R ₂ and R ₃ represents a bond to K, the other independently hydrogen, halogen, alkyl, aralkyl, aryl, cycloalkyl, heteroaryl, heteroaryl Cyclic group, cycloalkyl, polycyclic group, alkylalkenyl,
Alkylalkynyl, or alkanoyl, or in combination with its attached nitrogen represents amidine, amide, carbamate, urea, or guanidine; and W represents O or S. 3.) A compound according to claim 1 or 2 selected from 13. The compound of claim 1, wherein Tb is represented by i and Z is absent. 14. The compound of claim 13, wherein L is absent. 15. Tb is selected from xi, xii, xiv, and xv.
Or the compound described in 2. 16. The compound according to claim 1 or 2, wherein Tb is selected from v, vii, and viii. 17. The compound according to claim 1 or 2, wherein Tb is selected from ii, iii, or iv. 18. The compound according to claim 1, wherein Tb is represented by x. 19. The compound according to claim 1, wherein Tb is represented by ix. 20. A pharmaceutically acceptable carrier and general formula (I): Hc-X-K-Cy-L-Z-Tb, wherein L and K are independently absent or -M. _n- Y-Mp-; X, Y, and Z independently are absent or represent NR, O, or S; M is independently for each occurrence a substituted or unsubstituted methylene group, Or two M in combination with each other to represent a substituted or unsubstituted ethene or ethyne; R is independently for each occurrence H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl And p and n independently represent an integer of 0 to 10; Cy represents a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, or cycloalkyl; Hc represents a heterocycle Tb is, [of 4] Shows the bone targeted group selected from; and, R ₄ is independently for each occurrence, represents H or lower alkyl, wherein, Hc-X-K does not contain hydrolyzable bonds. ) A pharmaceutical composition comprising a compound having: 21. Pharmaceutically acceptable carriers and general formula (II): in Hc-X-K-Z- Tb ( wherein, K is absent or -M _n indicates -Y-mp-; X, Y, and Z independently are absent or represent NR, O, or S; M is independently for each occurrence a substituted or unsubstituted methylene group, or two M's in combination with each other, Represents substituted or unsubstituted ethylene or ethyne; p and n independently represent an integer of 0 to 10; R represents H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl independently for each occurrence. , Alkenyl, or alkyl; Hc represents a heterocycle; Tb represents Represents a bone targeting group selected from; and R ₄ independently for each occurrence represents H or lower alkyl, wherein Hc-X-K-Cy-L does not contain a hydrolyzable bond. ) A pharmaceutical composition comprising a compound having: 22. The compound of claim 20, wherein the compound selectively targets osteoclasts.
Or the pharmaceutical composition according to 21. 23. The pharmaceutical composition according to claim 20 or 21, wherein R ₄ represents H for all that occurs. 24. The pharmaceutical composition according to claim 20, wherein Cy represents an uncharged carbocycle or a nitrogen-containing heterocycle. 25. The pharmaceutical composition according to claim 20, wherein Cy represents phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic system having 8 to 11 atoms. 26. The pharmaceutical composition according to claim 20, wherein Cy represents phenyl. 27. The pharmaceutical composition of claim 20, wherein Cy represents a bicyclic system, L is attached to the first ring and K is attached to the second ring. 28. The pharmaceutical composition according to claim 20 or 21, wherein Hc represents a bicyclic structure. 29. The pharmaceutical composition according to claim 20 or 21, wherein the two rings of the bicyclic structure consist of carbon and nitrogen atoms. 30. K is directly attached to a heteroatom of Hc.
Or the pharmaceutical composition according to 21. 31. Hc is (Wherein _one of R ₁ , R ₂ and R ₃ represents a bond to K, the other independently hydrogen, halogen, alkyl, aralkyl, aryl, cycloalkyl, heteroaryl, heteroaryl Cyclic group, cycloalkyl, polycyclic group, alkylalkenyl,
Alkylalkynyl, or alkanoyl, or in combination with the nitrogen to which it is attached, represents an amidine, amide, carbamate, urea, or guanidine; and W represents O or S. 22. A pharmaceutical composition according to claim 20 or 21, selected from 32. The compound of claim 20, wherein Tb is i and Z is absent. 33. The compound of claim 32, wherein L is absent. 34. Tb is selected from xi, xii, xiv, and xv.
The pharmaceutical composition according to 0 or 21. 35. The pharmaceutical composition according to claim 20 or 21, wherein Tb is selected from v, vii, and viii. 36. The pharmaceutical composition according to claim 20 or 21, wherein Tb is selected from ii, iii, or iv. 37. The pharmaceutical composition according to claim 20 or 21, wherein Tb is represented by x. 38. The pharmaceutical composition according to claim 20 or 21, wherein Tb is represented by ix. 39. Patients general formula (I): Hc-X- K-Cy-L-Z-Tb ( wherein, L and K are independently absent or -M _n -Y-M _p - X, Y, and Z are independently absent or represent NR, O, or S; M is independently for each occurrence a substituted or unsubstituted methylene group, or two M's are In combination, represents substituted or unsubstituted ethene or ethyne; R is independently for each occurrence H or substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl; p and n independently represents an integer of 0 to 10; Cy represents a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, or cycloalkyl; Hc represents a heterocycle; Tb represents Represents a bone targeting group selected from and R ₄ independently represents H or lower alkyl for each occurrence. ). A method of treating or preventing a bone disorder, comprising treating with a compound having 40. A patient general formula (II): in Hc-X-K-Z- Tb ( wherein, K is absent or -M _n -Y-Mp- indicates, X, Y, and Z Are independently absent or represent NR, O, or S; M is independently for each occurrence a substituted or unsubstituted methylene group, or two M's in combination with each other are substituted or unsubstituted ethylene. Or ethyne; p and n independently represent an integer from 0 to 10; R is independently for each occurrence H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl. Hc represents a heterocycle; Tb represents a bone targeting group selected from: and R ₄ independently represents H or lower alkyl for each occurrence.) A method of treating or preventing a bone disorder comprising. 41. The compound of claim 39, wherein the compound selectively targets osteoclasts.
Or the method described in 40. 42. The method according to claim 39 or 40, wherein R ₄ represents H for all that occurs. 43. The method of claim 39, wherein Cy represents an uncharged carbocyclic group or a nitrogen-containing heterocyclic group. 44. The method of claim 39, wherein Cy represents phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic system having 8-11 atoms. 45. The method of claim 39, wherein Cy represents phenyl. 46. The method of claim 39, wherein Cy represents a bicyclic system, L is attached to the first ring, and K is attached to the second ring. 47. The method of claim 39 or 40, wherein Hc represents a bicyclic structure. 48. The method of claim 39 or 40, wherein the two rings of the bicyclic structure consist of carbon and nitrogen atoms. 49. K is directly attached to a heteroatom of Hc.
Or the method described in 40. 50. Hc is (Wherein _one of R ₁ , R ₂ and R ₃ represents a bond to K, the other independently hydrogen, halogen, alkyl, aralkyl, aryl, cycloalkyl, heteroaryl, heteroaryl Cyclic group, cycloalkyl, polycyclic group, alkylalkenyl,
Alkylalkynyl, or alkanoyl, or in combination with its attached nitrogen represents amidine, amide, carbamate, urea, or guanidine; and W represents O or S. 41.) The method of claim 39 or 40, selected from 51. The method of claim 39, wherein Tb is designated by i and Z is absent. 52. The method of claim 51, wherein L is absent. 53. Tb is selected from xi, xii, xiv, and xv.
The method according to 9 or 40. 54. The method of claim 39 or 40, wherein Tb is selected from v, vii, and viii. 55. The method of claim 39 or 40, wherein Tb is selected from ii, iii, or iv. 56. The method according to claim 39 or 40, wherein Tb is indicated by x. 57. The method of claim 39 or 40, wherein Tb is designated ix. 58. Structure formula: Tb-L-V (wherein, L is absent or -M _n -Y-M _p - indicates; Y is absent; M is independently for each occurrence, A substituted or unsubstituted methylene group, or two M in combination with each other to represent a substituted or unsubstituted ethene; R is independently for each occurrence H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl , Aralkyl, alkenyl, or alkyl; and p and n independently represent an integer of 0 to 10; and Tb is R ₄ independently represents H or lower alkyl for each occurrence; and V represents OR, NR ₂ or SR. ). 59. Tb is selected from xi, xii, xiv, and xv.
8. The compound according to 8. 60. The compound of claim 58, wherein Tb is x. 61. The compound of claim 58, wherein Tb is xiii. 62. The compound of claim 58, wherein V represents NR ₂ . 63. Structure formula: Tb-Cy-L-V (wherein, L is absent or -M _n -Y-M _p - indicates; Y is absent; M is independently for each occurrence , A substituted or unsubstituted methylene group, or two M in combination with each other to represent a substituted or unsubstituted ethene; R is independently for each occurrence H or a substituted or unsubstituted aryl, heterocyclic group, Tb represents heteroaryl, aralkyl, alkenyl, or alkyl; p and n independently represent an integer of 0 to 10; Cy represents a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, or cycloalkyl; Is [Chemical 10] R ₄ independently represents H or lower alkyl for each occurrence; and V represents OR, NR ₂ or SR. ). 64. The compound according to claim 63, wherein Cy represents a phenyl ring. 65. The compound of claim 63, wherein V represents NR ₂ . 66. Structure formula: Tb-L-U (wherein, L is absent or -M _n -Y-M _p - indicates; Y is absent; M is independently for each occurrence, A substituted or unsubstituted methylene group, or two M in combination with each other to represent a substituted or unsubstituted ethene; R is independently for each occurrence H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl , Aralkyl, alkenyl, or alkyl; p and n each independently represent an integer of 0 to 10; and Tb represents R ₄ independently represents H or lower alkyl for each occurrence; and U represents a sulfonate ester, halogen, formyl, or a suitable leaving group. ). 67. Tb is selected from xi, xii, xiv, and xv.
6. The compound according to 6. 68. The compound of claim 66, wherein Tb is x. 69. The compound of claim 66, wherein Tb is xiii. Wherein 70] structural formula: Tb-Cy-L-U (wherein, L is absent or -M _n -Y-M _p - indicates; Y is absent; M is independently for each occurrence , A substituted or unsubstituted methylene group, or two M in combination with each other to represent a substituted or unsubstituted ethene; R is independently for each occurrence H or a substituted or unsubstituted aryl, heterocyclic group, Tb represents heteroaryl, aralkyl, alkenyl, or alkyl; p and n independently represent an integer of 0 to 10; Cy represents a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, or cycloalkyl; Is [Chemical 12] R ₄ independently represents H or lower alkyl for each occurrence; and U represents a sulfonate ester, halogen, formyl, or a suitable leaving group. ). 71. The compound according to claim 70, wherein Cy represents a phenyl ring. 72. A compound represented by the general formula (I): Hc-X-K-Cy-L-Z-Tb, or (II): Hc-X-K-Z-Tb (wherein L and K are independently, absent or -M _n indicates -Y-mp-; X, Y, and Z are independently absent, or NR, O or indicates S,; M is independently for each occurrence, a substituted or Represents an unsubstituted methylene group, or two M in combination with each other represents a substituted or unsubstituted ethene or ethyne; R is independently for each occurrence H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl , Aralkyl, alkenyl, or alkyl; p and n independently represent an integer of 0 to 10; Cy represents a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, or cycloalkyl; Represents a ring; R ₄ independently represents H or lower alkyl for each occurrence, and Tb represents One of the ). 73. A compound represented by the general formula (I): Hc-X-K-Cy-L-Z-Tb, or (II): Hc-X-K-Z-Tb (wherein L and K are independently, absent or -M _n indicates -Y-mp-; X, Y, and Z are independently absent, or NR, O or indicates S,; M is independently for each occurrence, a substituted or Represents an unsubstituted methylene group, or two M in combination with each other represents a substituted or unsubstituted ethene or ethyne; R is independently for each occurrence H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl , Aralkyl, alkenyl, or alkyl; p and n independently represent an integer of 0 to 10; Cy represents a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, or cycloalkyl; Represents a ring; R ₄ independently represents H or lower alkyl for each occurrence, and Tb represents X represents 1, 2, 3, 4, 5, or 6 and each occurrence of Y is independently a covalent bond, -O-, -S-, or -N (R _j ) ₂ wherein R _j is independently for each occurrence hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; R ₆ is halogen, lower alkyl, Lower alkenyl, aryl, heteroaryl, carbonyl, thiocarbonyl, ketone, aldehyde, amino, acylamino, amide, amidino, cyano, nitro, azide, sulfonyl, sulfoxide, sulfate, sulfonate, sulfamoyl, sulfonamide, phosphoryl, phosphonate, phosphinate, - (CH _{2) p} alkyl, - (CH _{2) p} alkenyl, - (CH _{2) p} Arukini , - (CH _{2) p} aryl, - (CH _{2) p} aralkyl,
_{- (CH 2) p OH,} - (CH 2) p O- lower alkyl, - (CH _{2) p} O- lower _{alkenyl, -O (CH 2) n R} , - (CH 2) p SH, - (CH _{2) p} S- lower alkyl, - (CH _{2) p} S- lower _{alkenyl, -S (CH 2) n R} , - (CH 2) p n (R) 2, - (CH 2) p NR- lower alkyl , - (CH _{2) p} NR- lower alkenyl, -
NR (CH ₂ ) _n R, or 0-3 substituents selected from the above protected forms (where p is 1-10), and each occurrence of R ₄ is independently hydrogen or lower. It is alkyl. ). 74. M generated in Tb is CH ₂ , CHJ, CHOH,
And it is selected from CJ _2, wherein, J is a halogen, 73. The compound according. 75. R ₆ is lower alkyl, hydroxyl, sulfhydryl, amino, amide, carboxyl, sulfonate, phosphonate, and salts thereof, and hydroxyl, sulfhydryl, amino, amide, carboxyl, sulfonate, phosphonate, and their salts. 74. The compound of claim 73 selected from lower alkyl substituted with a salt. 76. A compound represented by the general formula (I): Hc-X-K-Cy-L-Z-Tb, or (II): Hc-X-K-Z-Tb (wherein L and K are independently, absent or -M _n indicates -Y-mp-; X, Y, and Z are independently absent, or NR, O or indicates S,; M is independently for each occurrence, a substituted or Represents an unsubstituted methylene group, or two M in combination with each other represents a substituted or unsubstituted ethene or ethyne; R is independently for each occurrence H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl , Aralkyl, alkenyl, or alkyl; p and n independently represent an integer of 0 to 10; Cy represents a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, or cycloalkyl; Represents a ring; R ₄ independently represents H or lower alkyl for each occurrence, and Tb represents a structural formula: A represents a group selected from GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ , and GSO ₃ R ₄ ; B represents NH ₂ , OH, GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ and a group selected from GSO ₃ R ₄ and G is absent or represents a bond of 1 or 2 atoms. ). 77. A compound represented by the general formula (I): Hc-X-K-Cy-L-Z-Tb, or (II): Hc-X-K-Z-Tb (wherein L and K are independently, absent or -M _n indicates -Y-mp-; X, Y, and Z are independently absent, or NR, O or indicates S,; M is independently for each occurrence, a substituted or Represents an unsubstituted methylene group, or two M in combination with each other represents a substituted or unsubstituted ethene or ethyne; R is independently for each occurrence H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl , Aralkyl, alkenyl, or alkyl; p and n independently represent an integer of 0 to 10; Cy represents a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, or cycloalkyl; Represents a ring; R ₄ independently represents H or lower alkyl for each occurrence, and Tb represents a structural formula xxxxiii: And B is a group selected from NH ₂ , OH, GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ , and GSO ₃ R ₄ , and G is absent, or 1 or 2 Represents a bond of atoms of. ). 78. A compound represented by the general formula (I): Hc-X-K-Cy-L-Z-Tb, or (II): Hc-X-K-Z-Tb (wherein L and K are independently, absent or -M _n indicates -Y-mp-; X, Y, and Z are independently absent, or NR, O or indicates S,; M is independently for each occurrence, a substituted or Represents an unsubstituted methylene group, or two M in combination with each other represents a substituted or unsubstituted ethene or ethyne; R is independently for each occurrence H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl , Aralkyl, alkenyl, or alkyl; p and n independently represent an integer of 0 to 10; Cy represents a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, or cycloalkyl; Represents a ring; R ₄ independently represents H or lower alkyl for each occurrence, and Tb represents a structural formula xxxxiv or xxxxv: Has, A is _{GPO 3 (R 4) 2,} GCO 2 R 4, and represents a group selected from the GSO ₃ R _4,; B is _{NH 2, OH, GPO 3 (} R 4) 2, GCO 2 R ₄ and GSO ₃ represent a group selected from R ₄ , G represents the absence or bond of 1 or 2 atoms; C represents H, R ₆ , NH ₂ , OH, GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ , or GSO ₃ R ₄ , wherein the occurrence of either A or B is present in xxxxiv, other occurrences are optionally bound to Z, H, or R ₆ . May be shown. ). 79. A compound represented by the general formula (I): Hc-X-K-Cy-L-Z-Tb, or (II): Hc-X-K-Z-Tb (wherein L and K are independently, absent or -M _n indicates -Y-mp-; X, Y, and Z are independently absent, or NR, O or indicates S,; M is independently for each occurrence, a substituted or Represents an unsubstituted methylene group, or two M in combination with each other represents a substituted or unsubstituted ethene or ethyne; R is independently for each occurrence H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl , Aralkyl, alkenyl, or alkyl; p and n independently represent an integer of 0 to 10; Cy represents a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, or cycloalkyl; Represents a ring; R ₄ independently represents H or lower alkyl for each occurrence, and Tb represents a heteroaryl carrying 1 or 2 substituents B and 0 to 4 substituents R ₆ . A represents a group selected from GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ , and GSO ₃ R ₄ ; B represents NH ₂ , OH, GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ , and A group selected from GSO ₃ R ₄ and G is absent or represents a bond of 1 or 2 atoms). 80. Hc is 80. A compound according to any one of claims 72 to 79 selected from 81. The compound of any of claims 72-79, wherein, except in Tb, the compound does not contain a hydrolyzable bond. 82. A general formula: V-L-Cy-Tb, V-L-Tb, U-L-C.
During y-Tb or U-L-Tb (wherein,, U is sulfonate ester, halogen, indicates formyl or a suitable leaving group,; V is OR, NR _2, or indicates SR; or L is absent, Alternatively -M _n -Y-M _p - indicates; Y is absent; M is independently for each occurrence, a substituted or unsubstituted methylene group, or I two M are combined with each other, a substituted or unsubstituted Ethene; R independently for each occurrence H or substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl; p and n independently represent an integer from 0 to 10 R ₄ is, independently for each occurrence, H or lower alkyl, and Tb is Is shown. ). 83. A general formula: V-L-Cy-Tb, V-L-Tb, U-L-C.
During y-Tb or U-L-Tb (wherein,, U is sulfonate ester, halogen, indicates formyl or a suitable leaving group,; V is OR, NR _2, or indicates SR; or L is absent, Alternatively -M _n indicates -Y-mp-; Y is absent; M is independently for each occurrence, a substituted or indicates unsubstituted methylene group, or I two M are combined with each other, a substituted or unsubstituted ethene R is independently for each occurrence H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl; p and n are independently an integer from 0 to 10 R ₄ independently represents H or lower alkyl for each occurrence, and Tb is Represents a group selected from: x represents 1 or 2, and R ₆ represents halogen, lower alkyl, lower alkenyl, aryl, heteroaryl, carbonyl, thiocarbonyl, ketone, aldehyde, amino, acylamino,
Amide, amidino, cyano, nitro, azido, sulfonyl, sulfoxide, sulfate, sulfonate, sulfamoyl, sulfonamido, phosphoryl, phosphonate, phosphinate, - (CH _{2) p} alkyl, - (CH _{2) p} alkenyl,
- (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, -O (CH 2) n R} , - (CH 2) p SH, - (CH 2 ) _P S-lower alkyl,
- (CH _{2) p} S- lower _{alkenyl, -S (CH 2) n R} , - (CH 2) p N (R) 2
, - (CH _{2) p} NR- lower alkyl, - (CH _{2) p} NR- lower alkenyl, -N
R (CH ₂ ) _n R or a 0 to 3 substituent selected from the above protected form is shown. )
A compound having: 84. M is CH ₂ , CHJ, CH when it is generated during Tb.
OH, and it is selected from CJ _2, wherein, J is a halogen, according to claim 83 A compound according. 85. R ₆ is lower alkyl, hydroxyl, sulfhydryl, amino, amide, carboxyl, sulfonate, phosphonate, and salts thereof, and hydroxyl, sulfhydryl, amino, amide, carboxyl, sulfonate, phosphonate, and their 84. The compound of claim 83, selected from lower alkyl substituted with a salt. 86. A general formula: V-L-Cy-Tb, V-L-Tb, U-L-C.
During y-Tb or U-L-Tb (wherein,, U is sulfonate ester, halogen, indicates formyl or a suitable leaving group,; V is OR, NR _2, or indicates SR; or L is absent, Alternatively -M _n indicates -Y-mp-; Y is absent; M is independently for each occurrence, a substituted or indicates unsubstituted methylene group, or I two M are combined with each other, a substituted or unsubstituted ethene R is independently for each occurrence H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl; p and n are independently an integer from 0 to 10 R ₄ independently represents H or lower alkyl for each occurrence, and Tb is of the structural formula: A represents a group selected from GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ , and GSO ₃ R ₄ ; B represents NH ₂ , OH, GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ and a group selected from GSO ₃ R ₄ and G is absent or represents a bond of 1 or 2 atoms. ). 87. The general formula: V-L-Cy-Tb, V-L-Tb, U-L-C.
During y-Tb or U-L-Tb (wherein,, U is sulfonate ester, halogen, indicates formyl or a suitable leaving group,; V is OR, NR _2, or indicates SR; or L is absent, Alternatively -M _n indicates -Y-mp-; Y is absent; M is independently for each occurrence, a substituted or indicates unsubstituted methylene group, or I two M are combined with each other, a substituted or unsubstituted ethene R is independently for each occurrence H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl; p and n are independently an integer from 0 to 10 R ₄ independently represents H or lower alkyl for each occurrence; and Tb is of structural formula xxxxiii: B is a group selected from NH ₂ , OH, GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ , and GSO ₃ R ₄ , and G is absent or 1 or 2 Represents a bond of atoms of. ). 88. A general formula: V-L-Cy-Tb, V-L-Tb, U-L-C.
During y-Tb or U-L-Tb (wherein,, U is sulfonate ester, halogen, indicates formyl or a suitable leaving group,; V is OR, NR _2, or indicates SR; or L is absent, Alternatively -M _n indicates -Y-mp-; Y is absent; M is independently for each occurrence, a substituted or indicates unsubstituted methylene group, or I two M are combined with each other, a substituted or unsubstituted ethene R is independently for each occurrence H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl; p and n are independently an integer from 0 to 10 R ₄ independently represents H or lower alkyl for each occurrence; and Tb is of structural formula xxxxiv or xxxxv: A represents a group selected from GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ , and GSO ₃ R ₄ ; B represents NH ₂ , OH, GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ and a group selected from GSO ₃ R ₄ ; G is absent or represents a bond of 1 or 2 atoms; C is in xxxxiv the occurrence of either A or B is present. However, other occurrences may optionally indicate binding to Z, H, or R ₆ , such as H, R ₆ , NH ₂ , OH, GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ , or GSO ₃ R. _{Shows 4} . ). 89. A general formula: V-L-Cy-Tb, V-L-Tb, U-L-C.
During y-Tb or U-L-Tb (wherein,, U is sulfonate ester, halogen, indicates formyl or a suitable leaving group,; V is OR, NR _2, or indicates SR; or L is absent, Alternatively -M _n indicates -Y-mp-; Y is absent; M is independently for each occurrence, a substituted or indicates unsubstituted methylene group, or I two M are combined with each other, a substituted or unsubstituted ethene R is independently for each occurrence H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl; p and n are independently an integer from 0 to 10 R ₄ independently represents H or lower alkyl for each occurrence; and Tb represents heteroaryl having 1 or 2 substituents B, and 0 to 4 substituents R _6. A represents a group selected from GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ , and GSO ₃ R ₄ ; B represents NH ₂ , OH, GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ , and A group selected from GSO ₃ R ₄ ; and G is absent or represents a bond of 1 or 2 atoms). 90. Hc is 90. A compound according to any one of claims 82 to 89 selected from 91. The compound according to any one of claims 82-89, wherein L represents alkyl. 92. A pharmaceutically acceptable excipient and a compound of general formula (I): Hc-X.
-K-Cy-L-Z- Tb or, (II): in Hc-X-K-Z- Tb ( wherein, L and K are independently absent or -M _n -Y-M _p - a X, Y, and Z are independently absent or represent NR, O, or S; M is independently for each occurrence a substituted or unsubstituted methylene group, or two M are combined with each other. Represents a substituted or unsubstituted ethene or ethyne; R independently represents H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl for each occurrence; p and n independently represents an integer of 0; Cy is a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, or cycloalkyl,; Hc represents a heterocycle; R ₄ is independently for each occurrence It represents H or lower alkyl, and, Tb is embedded image One of the A method for treating or preventing a bone disorder, comprising: 93. A pharmaceutically acceptable excipient and a compound of general formula (I): Hc-X.
-K-Cy-L-Z- Tb or, (II): in Hc-X-K-Z- Tb ( wherein, L and K are independently absent or -M _n -Y-M _p - a X, Y, and Z are independently absent or represent NR, O, or S; M is independently for each occurrence a substituted or unsubstituted methylene group, or two M are combined with each other. Represents a substituted or unsubstituted ethene or ethyne; R independently represents H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl for each occurrence; p and n independently represents an integer of 0; Cy is a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, or cycloalkyl,; Hc represents a heterocycle; R ₄ is independently for each occurrence It represents H or lower alkyl, and, Tb is embedded image X represents 1 or 2, and R ₆ represents halogen, lower alkyl, lower alkenyl, aryl, heteroaryl, carbonyl, thiocarbonyl, ketone, aldehyde, amino, acylamino, amide, amidino, cyano, nitro, azido, sulfonyl, sulfoxide, sulfate, sulfonate, sulfamoyl, sulfonamido, phosphoryl, phosphonate, phosphinate, - (CH _{2) p} alkyl, - (CH _{2) p} alkenyl, - (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, -O (CH 2) n R} , - (CH 2) p SH, - (CH _{2) p} S- lower alkyl, - (CH _{2) p} S- lower _{alkenyl, -S (CH 2) n R} , - (CH 2) p n (R) 2, - (CH 2) p NR- lower alkyl , - (CH _{2) p} NR- lower alkenyl, -
NR (CH ₂ ) _n R or a 0 to 3 substituent selected from the above protected form is shown.
A method for treating or preventing a bone disorder, comprising: 94. When M occurs at Tb, CH ₂ , CHJ, C
93. Selected from HOH, and CJ ₂ , wherein J represents halogen.
The described compound. 95. R ₆ is lower alkyl, hydroxyl, sulfhydryl, amino, amide, carboxyl, sulfonate, phosphonate, and salts thereof, and hydroxyl, sulfhydryl, amino, amide, carboxyl, sulfonate, phosphonate, and these 93. The compound of claim 92 selected from lower alkyl substituted with a salt. 96. A pharmaceutically acceptable excipient and a compound of general formula (I): Hc-X.
-K-Cy-L-Z- Tb or, (II): in Hc-X-K-Z- Tb ( wherein, L and K are independently absent or -M _n -Y-M _p - a X, Y, and Z are independently absent or represent NR, O, or S; M is independently for each occurrence a substituted or unsubstituted methylene group, or two M are combined with each other. Represents a substituted or unsubstituted ethene or ethyne; R independently represents H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl for each occurrence; p and n independently represents an integer of 0; Cy is a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, or cycloalkyl,; Hc represents a heterocycle; R ₄ is independently for each occurrence It represents H or lower alkyl, and, Tb is embedded image A represents a group selected from GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ , and GSO ₃ R ₄ ; B represents NH ₂ , OH, GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ and a group selected from GSO ₃ R ₄ ; and G is absent or represents a bond of 1 or 2 atoms. A method for treating or preventing a bone disorder, comprising: 97. A pharmaceutically acceptable excipient and a compound of general formula (I): Hc-X.
-K-Cy-L-Z- Tb or, (II): in Hc-X-K-Z- Tb ( wherein, L and K are independently absent or -M _n -Y-M _p - a X, Y, and Z are independently absent or represent NR, O, or S; M is independently for each occurrence a substituted or unsubstituted methylene group, or two M are combined with each other. Represents a substituted or unsubstituted ethene or ethyne; R independently represents H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl for each occurrence; p and n independently represents an integer of 0; Cy is a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, or cycloalkyl,; Hc represents a heterocycle; R ₄ is independently for each occurrence It represents H or lower alkyl, and, Tb is the structural formula XXXXIII: embedded image B represents a group selected from NH ₂ , OH, GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ , and GSO ₃ R ₄ ; and G is absent or 1 or 2 Represents a bond of atoms of. A method for treating or preventing a bone disorder comprising a compound having: 98. A pharmaceutically acceptable excipient and a compound of general formula (I): Hc-X.
-K-Cy-L-Z- Tb or, (II): in Hc-X-K-Z- Tb ( wherein, L and K are independently absent or -M _n -Y-M _p - a X, Y, and Z are independently absent or represent NR, O, or S; M is independently for each occurrence a substituted or unsubstituted methylene group, or two M are combined with each other. Represents a substituted or unsubstituted ethene or ethyne; R independently represents H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl for each occurrence; p and n independently represents an integer of 0; Cy is a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, or cycloalkyl,; Hc represents a heterocycle; R ₄ is independently for each occurrence Represents H or lower alkyl, and, Tb is the structural formula: XXXXIV or XXXXV: [Formula 29] A represents a group selected from GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ , and GSO ₃ R ₄ ; B represents NH ₂ , OH, GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ and a group selected from GSO ₃ R ₄ ; G is absent or represents a bond of 1 or 2 atoms; C is in xxxxiv the occurrence of either A or B is present. However, other occurrences, such as H, R ₆ , NH ₂ , OH, GP, may be used to indicate binding to Z, H, or R ₆ .
Indicates O ₃ (R ₄ ) ₂ , GCO ₂ R ₄ , or GSO ₃ R ₄ . A method for treating or preventing a bone disorder, comprising: 99. A pharmaceutically acceptable excipient and a compound of general formula (I): Hc-X.
-K-Cy-L-Z- Tb or, (II): in Hc-X-K-Z- Tb ( wherein, L and K are independently absent or -M _n -Y-M _p - a X, Y, and Z are independently absent or represent NR, O, or S; M is independently for each occurrence a substituted or unsubstituted methylene group, or two M are combined with each other. Represents a substituted or unsubstituted ethene or ethyne; R independently represents H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl for each occurrence; p and n independently represents an integer of 0; Cy is a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, or cycloalkyl,; Hc represents a heterocycle; R ₄ is independently for each occurrence It represents H or lower alkyl, and, Tb represents a heteroaryl having one or two substituents B and 0-4 substituents R _6,; A is _{GPO 3 (R 4) 2,} GCO 2 R ₄ and a group selected from GSO ₃ R ₄ ; B represents a group selected from NH ₂ , OH, GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ , and GSO ₃ R ₄ ; and , G is absent or represents a bond of 1 or 2 atoms.) The method for treating or preventing a bone disorder. 100. Hc is 100. The method according to any one of claims 92 to 99, selected from 101. The method of any of claims 92-99, wherein, except in Tb, the compound does not contain hydrolyzable bonds. 102. A pharmaceutically acceptable excipient and the general formula: V-L-Cy.
-Tb, VL-Tb, UL-Cy-Tb, or UL-Tb, where U represents a sulfonate ester, halogen, formyl, or a suitable leaving group; V is OR, NR ₂ or indicates SR,, L is absent or -M _n -Y-M _p - indicates; Y is absent; M is independently for each occurrence, a substituted or unsubstituted methylene group or 2, Two M's in combination with each other represent a substituted or unsubstituted ethene; R independently for each occurrence is H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl; p and n independently represent an integer from 0 to 10; R ₄ independently represents H or lower alkyl for each occurrence, and Tb represents One of the A method for treating or preventing a bone disorder, comprising: 103. A pharmaceutically acceptable excipient and a general formula: V-L-Cy.
-Tb, VL-Tb, UL-Cy-Tb, or UL-Tb, where U represents a sulfonate ester, halogen, formyl, or a suitable leaving group; V is OR, NR ₂ or indicates SR,, L is absent or -M _n -Y-M _p - indicates; Y is absent; M is independently for each occurrence, a substituted or unsubstituted methylene group or 2, Two M's in combination with each other represent a substituted or unsubstituted ethene; R independently for each occurrence is H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl; p and n independently represent an integer from 0 to 10; R ₄ independently represents H or lower alkyl for each occurrence, and Tb represents X represents 1, 2, 3, 4, 5, or 6; each occurrence of Y is independently a covalent bond, -O-, -S-, or -N (R _j ) ₂ wherein R _j, at each occurrence, is independently hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; R ₆ is halogen, lower Alkyl, lower alkenyl, aryl, heteroaryl, carbonyl, thiocarbonyl, ketone, aldehyde, amino, acylamino, amide, amidino, cyano, nitro, azide, sulfonyl, sulfoxide, sulfate, sulfonate, sulfamoyl, sulfonamide, phosphoryl, phosphonate, phosphinate, - (CH _{2) p} alkyl, - (CH _{2) p} alkenyl, - (CH _{2) p} Al Cycloalkenyl, - (CH _{2) p} aryl, - (CH _{2) p} aralkyl,
_{- (CH 2) p OH,} - (CH 2) p O- lower alkyl, - (CH _{2) p} O- lower _{alkenyl, -O (CH 2) n R} , - (CH 2) p SH, - (CH _{2) p} S- lower alkyl, - (CH _{2) p} S- lower _{alkenyl, -S (CH 2) n R} , - (CH 2) p n (R) 2, - (CH 2) p NR- lower alkyl , - (CH _{2) p} NR- lower alkenyl, -
Shows the NR (CH _{2) n} R or 0-3 substituents selected from the above protected forms; and each occurrence of R ₄ is independently hydrogen or lower alkyl. A method for treating or preventing a bone disorder comprising a compound having: 104. M is CH ₂ , CHJ, when generated in Tb,
2. CHOH, and CJ ₂ , wherein J represents halogen.
The method described in 03. 105. R ₆ is lower alkyl, hydroxyl, sulfhydryl,
104. An amino, amido, carboxyl, sulphonate, phosphonate, and salts thereof, and lower alkyl substituted with hydroxyl, sulfhydryl, amino, amido, carboxyl, sulphonates, phosphonates, and salts thereof. Method. 106. A pharmaceutically acceptable excipient and a compound of the general formula: V-L-Cy.
-Tb, VL-Tb, UL-Cy-Tb, or UL-Tb, where U represents a sulfonate ester, halogen, formyl, or a suitable leaving group; V is OR, NR ₂ or indicates SR,, L is absent or -M _n -Y-M _p - indicates; Y is absent; M is independently for each occurrence, a substituted or unsubstituted methylene group or 2, Two M's in combination with each other represent a substituted or unsubstituted ethene; R independently for each occurrence is H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl; p and n independently represent an integer from 0 to 10; R ₄ independently represents H or lower alkyl for each occurrence, and Tb represents a structural formula: A represents a group selected from GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ , and GSO ₃ R ₄ ; B represents NH ₂ , OH, GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ and a group selected from GSO ₃ R ₄ ; and G is absent or represents a bond of 1 or 2 atoms. A method for treating or preventing a bone disorder, comprising: 107. A pharmaceutically acceptable excipient and a compound of the general formula: V-L-Cy.
-Tb, VL-Tb, UL-Cy-Tb, or UL-Tb, where U represents a sulfonate ester, halogen, formyl, or a suitable leaving group; V is OR, NR ₂ or indicates SR,, L is absent or -M _n -Y-M _p - indicates; Y is absent; M is independently for each occurrence, a substituted or unsubstituted methylene group or 2, Two M's in combination with each other represent a substituted or unsubstituted ethene; R independently for each occurrence is H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl; p and n independently represent an integer from 0 to 10; R ₄ independently represents H or lower alkyl for each occurrence, and Tb represents structural formula xxxxiii: B represents a group selected from NH ₂ , OH, GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ , and GSO ₃ R ₄ ; and G is absent or 1 or 2 Represents a bond of atoms of. A method for treating or preventing a bone disorder, comprising: 108. A pharmaceutically acceptable excipient and a general formula: V-L-Cy.
-Tb, VL-Tb, UL-Cy-Tb, or UL-Tb, where U represents a sulfonate ester, halogen, formyl, or a suitable leaving group; V is OR, NR ₂ or indicates SR,, L is absent or -M _n -Y-M _p - indicates; Y is absent; M is independently for each occurrence, a substituted or unsubstituted methylene group or 2, Two M's in combination with each other represent a substituted or unsubstituted ethene; R independently for each occurrence is H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl; p and n independently represent an integer from 0 to 10; R ₄ independently represents H or lower alkyl for each occurrence, and Tb represents structural formula xxxxiv or xxxxv: A represents a group selected from GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ , and GSO ₃ R ₄ ; B represents NH ₂ , OH, GPO ₃ (R ₄ ) ₂ , GCO ₂ R ₄ and a group selected from GSO ₃ R ₄ ; G is absent or represents a bond of 1 or 2 atoms; C is in xxxxiv the occurrence of either A or B is present. However, other occurrences, such as H, R ₆ , NH ₂ , OH, GP, may be used to indicate binding to Z, H, or R ₆ .
Indicates O ₃ (R ₄ ) ₂ , GCO ₂ R ₄ , or GSO ₃ R ₄ . A method for treating or preventing a bone disorder, comprising: 109. A pharmaceutically acceptable excipient and the general formula: V-L-Cy.
-Tb, VL-Tb, UL-Cy-Tb, or UL-Tb, where U represents a sulfonate ester, halogen, formyl, or a suitable leaving group; V is OR, NR ₂ or indicates SR,, L is absent or -M _n -Y-M _p - indicates; Y is absent; M is independently for each occurrence, a substituted or unsubstituted methylene group or 2, Two M's in combination with each other represent a substituted or unsubstituted ethene; R independently for each occurrence is H or a substituted or unsubstituted aryl, heterocyclic group, heteroaryl, aralkyl, alkenyl, or alkyl; p and n independently represent an integer of 0 to 10; R ₄ independently represents H or lower alkyl for each occurrence, and Tb represents one or two substituents B and 0 to 4 Set of pieces Shows a heteroaryl having a group R _6; A is _{GPO 3 (R 4) 2,} GCO 2 R 4, and GSO ₃ represents a group selected from R _4; B is _{NH 2, OH, GPO 3 (} R 4 ) ₂ , GCO ₂ R ₄ , and GSO ₃ R ₄ ; and G is absent or represents a bond of 1 or 2 atoms). How to treat or prevent. 110. Hc is 110. The method of any of claims 102-109, selected from: 111. The method of any one of claims 102-109 wherein L represents alkyl.