WO2005028488A1 - Heteroaryl phosphinyl and thiophosphinyl compounds for regulation of glucose, triglycerides, and ldl/hdl levels - Google Patents
Heteroaryl phosphinyl and thiophosphinyl compounds for regulation of glucose, triglycerides, and ldl/hdl levels Download PDFInfo
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- WO2005028488A1 WO2005028488A1 PCT/US2004/029701 US2004029701W WO2005028488A1 WO 2005028488 A1 WO2005028488 A1 WO 2005028488A1 US 2004029701 W US2004029701 W US 2004029701W WO 2005028488 A1 WO2005028488 A1 WO 2005028488A1
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- 0 C*C(*)Cc1c[s]c2cc(*)ccc12 Chemical compound C*C(*)Cc1c[s]c2cc(*)ccc12 0.000 description 2
- HGZSEVGNXRWFHY-UHFFFAOYSA-N CC1N=C(c2ccncc2)SC1Cc1nc(cc(cc2)NC(P3(NCCN3)=O)P3(NCCN3)=O)c2[nH]1 Chemical compound CC1N=C(c2ccncc2)SC1Cc1nc(cc(cc2)NC(P3(NCCN3)=O)P3(NCCN3)=O)c2[nH]1 HGZSEVGNXRWFHY-UHFFFAOYSA-N 0.000 description 1
- GRRIMVWABNHKBX-UHFFFAOYSA-N COc1cc(CN)ccc1 Chemical compound COc1cc(CN)ccc1 GRRIMVWABNHKBX-UHFFFAOYSA-N 0.000 description 1
- KGPWGADEZKRIII-UHFFFAOYSA-N Cc1c(CC(O)=O)[s]c(-c2ccncc2)n1 Chemical compound Cc1c(CC(O)=O)[s]c(-c2ccncc2)n1 KGPWGADEZKRIII-UHFFFAOYSA-N 0.000 description 1
- KWFPOWHTJFGJEL-UHFFFAOYSA-N Cc1c(Cc2nc(C=C(CC3)[N+]([O-])=O)c3[nH]2)[s]c(-c2ccncc2)n1 Chemical compound Cc1c(Cc2nc(C=C(CC3)[N+]([O-])=O)c3[nH]2)[s]c(-c2ccncc2)n1 KWFPOWHTJFGJEL-UHFFFAOYSA-N 0.000 description 1
- RAUWPNXIALNKQM-UHFFFAOYSA-N Nc(c(N)c1)ccc1[N+]([O-])=O Chemical compound Nc(c(N)c1)ccc1[N+]([O-])=O RAUWPNXIALNKQM-UHFFFAOYSA-N 0.000 description 1
- PBCQAUIPFVKGOW-UHFFFAOYSA-N O=Cc1c[s]c2c1ccc(Br)c2 Chemical compound O=Cc1c[s]c2c1ccc(Br)c2 PBCQAUIPFVKGOW-UHFFFAOYSA-N 0.000 description 1
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- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
- C07F9/6539—Five-membered rings
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4025—Esters of poly(thio)phosphonic acids
- C07F9/4028—Esters of poly(thio)phosphonic acids containing no further substituents than -PO3H2 groups in free or esterified form
- C07F9/4031—Acyclic unsaturated derivatives
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4056—Esters of arylalkanephosphonic acids
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- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
- C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
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- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
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- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
- C07F9/653—Five-membered rings
- C07F9/65306—Five-membered rings containing two nitrogen atoms
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- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
- C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
- C07F9/65848—Cyclic amide derivatives of acids of phosphorus, in which two nitrogen atoms belong to the ring
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Abstract
The invention provides phosphorus-containing compounds, pharmaceutical formulations comprising the compounds, and methods of administering the compounds to a subject, wherein the compounds are of the Formula I wherein A, B, D, L, Ar1, Ar2, Y1, Y2, Z1, Z2, E, F, G, X, U, V, R1, and R2 are as defined herein.
Description
HETEROARYL PHOSPHINYL AND THIOPHOSPHINYL COMPOUNDS FOR REGULATION OF GLUCOSE, TRIGLYCERIDES, AND LDL/HDL LEVELS
FEELD OF THE INVENTION The present invention relates to phosphoms-containing compounds, pharmaceutical formulations comprising phosphoms-containing compounds, and uses thereof. More specifically, the present invention relates to aryl and heteroaryl phosphonates, processes for their preparation, pharmaceutical formulations comprising them, and their use in methods of regulating plasma levels of glucose, triglycerides, and/or HDL/LDL.
BACKGROUND OF THE INVENTION Compounds that can bind as ligands for a variety of nuclear hormone receptors, particularly to a sub-family of nuclear hormone receptors that are activated by ligand binding and heterodimerization with retinoid X receptor (RXR) nuclear hormone receptors can be effective in regulating metabolic processes. Such receptors include peroxisome proliferator activated receptor (PPARα, PPARβ, PPARγ), farnesoid X receptor (FXR), liver X receptor (LXRα, LXRβ), vitamin D receptor (VDR), thyroid hormone receptor (TR), and retinoic acid receptor (RAR). These receptors are important regulators of metabolism, and are involved in multiple signal transduction pathways. Therefore compounds that modulate these receptors can be useful drags for treatment of a wide range of metabolic disorders, including, for example, hypercholesteremia, hypertriglyceridemia, low HDL-C atherosclerosis, hyperglycemia, syndrome X, hyperinsulinemia, and diabetes. Aralkyl phosphonates have been disclosed with biological activity in a variety of metabolic disease states. For example, some phosphonates reduce total plasma concentrations of cholesterol in many species, [Phan, et al., WO 02/26752]. This effect is
caused by major reductions in the plasma Low Density Lipoprotein (LDL-C) fraction. High total cholesterol levels have been shown to coπelate with increased morbidity and mortality in epidemiological studies [Framingham Heart Study, Canadian Journal of Cardiology 4 suppA, 5A-10A (1988)]. In this and many similar studies the increased risk was associated with the LDL-C levels, and high HDL-C levels were associated with a decreased risk of CV disease and mortality. Reductions in total cholesterol, especially through treatment with HMG CoA reductase inhibitory "statins" which lead to dramatic reductions in LDL, have been shown to be beneficial in both preventing cardiovascular disease and in decreasing overall mortality. These same phosphonate compounds have been disclosed as useful for regulating the amount of Lp(a), a LDL-like lipoprotein wherein the major lipoprotein, apo B-100, is covalently linked to an unusual glycoprotein, apoprotien(a), in blood. [Phan, et al., WO 02/26752]. The covalent association between apo(a) and apo B to fonn Lp(a) is a secondary event which is independent of the plasma concentration of apo B. Due to its structural similarity to plasminogen, apo(a) interferes with the normal physiological thrombosis-hemostasis process by preventing thrombolysis, that is clot dissolution. The structural feature of Lp(a), where the LDL lipoprotein is linked to apo(a), is thought to be responsible for its atherogenic and thrombogenic activities. Furthermore, aralkyl phosphonates have been disclosed which raise the amount of the High Density Lipoprotein in serum, [Phan et al. WO 03/070169]. Increases in HDL are strongly coπelated with decreased cardiovascular disease risk in man, although to date only niacin has been shown to raise HDL in humans by 20% or more. In the HDL intervention trial [Rubins et al., New England Journal of Medicine 34, 410-418, (1999)], even a 6% increase in plasma HDL was shown to coπelate with over a 20% decrease in cardiac morbidity and mortality.
The cardioprotective effects of HDL-C are believed to be derived from two major processes. One is the known antioxidant effects of certain HDL subtractions, and the other is the role of HDL in Reverse Cholesterol Transport (RCT), the process by which cholesterol is removed from peripheral tissues, and returned to the liver. In atherosclerosis, it is believed that the disease process involves macrophages which are involved in removing cholesterol-rich lipid deposits from the arterial intima. Normally, these macrophages ingest lipid residues on the surface of the intima, and then secrete cholesterol which is incorporated into HDL particles, where they are turned into cholesteryl esters, and then absorbed into the liver through SR-B1 scavenger receptors. Once in the liver, a major route of cholesterol disposal is conversion into bile acids and secretion in bile. In atherosclerotic lesions, this process appears to become highly disregulated, and the macrophages absorb large amounts of lipid, but do not successfully package it into HDL, with the result that they fill up with cholesterol-rich lipids and become foam cells, a major component ofthe atherosclerotic plaque. The aralkyl phosphonates described in Phan et al. WO 03/070169 and WO
03/070179 also cause macrophages to secrete large quantities of Apo E. This apolipoprotein is a minor component of HDL, and may well be involved in RCT from macrophages and the arterial intima. In ApoE -/- mice atherosclerotic disease occurs very quickly, and the disease progression can be halted by transfecting Apo E back into the mice, suggesting that Apo E is cardioprotective. Furthermore, Apo E has been shown to have strong antioxidant properties, and may be be useful in neuroprotective indications. As mentioned above, cholesterol is secreted from the liver as bile acids, which are derived from cholesterol by a series of oxidative steps. When bile acids are secreted from the liver, they also contain cholesterol itself, which can either be excreted or reabsorbed lower in the GI tract. Bile acids turn out to be ligands for the FXR receptor, one of the
RXR heterodimerizing nuclear hormone receptors. FXR controls a lot of genes involved in cholesterol homeostasis, and the bile acid/FXR interaction is undoubtedly one of the most important feedback loops in cholesterol homeostasis. Many tissues either do not rely on HDL at all, or only in part for RCT. The other major pathway of cholesterol secretion from tissues is side chain hydroxylation of cholesterol, to give the so-called oxysterols. These compounds have considerably more water solubility than cholesterol itself, and have carrier proteins in plasma. Once excreted into plasma, they are also absorbed by the liver, and then further processed, some into bile acids. The LXR heterodimeric nuclear hormone receptor is an oxysterol receptor, and controls many genes involved in cholesterol homeostasis, similar to FXR. The PPAR family of RXR-heterodimerizing nuclear hormone receptors is very important in metabolic regulation. PPARα is the target of the fibrate drugs, which can raise HDL, and marginally lower LDL, and also strongly reduce triglycerides. PPARα agonists have also been revealed to have anti-obesity effects, presumably due to their effects on lipid metabolism [Willson, US Patent 6.028,109]. PPARγ agonists, such as Rosiglitazone and Pioglitazone are marketed for lowering blood glucose in diabetics. These compounds can also show effects on semm cholesterol and triglycerides, both of which were lowered by Troglitazone, but raised by Rosiglitazone. Although PPARβ is less well characterized than the other PPARs, it also appears to be strongly involved in metabolic regulation and there are claims that using PPARβ agonists leads to lower total cholesterol levels [Shimokawa et al., US Patent 6,300,364]. Retinoids, such as Accutane, also have effects on metabolism, with raised triglyceride levels being a major side effect of Accutane treatment.
All of this data taken together suggests that the RXR-heterodimerizing nuclear hormone receptors are involved in a very complicated cross-regulation of metabolism, energy utilization and cholesterol homeostasis. Therefore ligands which modulate this system in favourable ways should be useful in the treatment of metabolic diseases such as dyslipidemiasa and diabetes. The compounds of the cuπent invention are phosphorus- based ligands for several of these receptors, and therefore are useful in treating metabolic disease conditions, and the diseases which arise from metabolic imbalances such as atherosclerosis.
SUMMARY OF THE INVENTION The present invention provides aryl and heteroaryl phosphorus-containing compounds, or pharmaceutically acceptable salts thereof, ofthe Formula (I):
E is a bond, S(0)m, NR6, C=0, C02, CONR6, O, -OC=0, NR6C=0, NR6C02, OC=ONR6, OC02, orNR6CONR6a; F is (CH2)n, (CH2)00(CH2)p, (CH2)0NR6(CH2)p, (CH2)0NR6CO(CH2)P, (CH2)0CONR6 (CH2)P, (CH2)0(CR6=CR6)q(CH2)p, (CH2)0-(C ^)q-(CH2)p; G is a bond, O, NR6, CO, C02, OCO, OC02, S(0)m, CONR6, NR6CO, NR6C02, OCONR6, NR6CONR6 , or G can optionally be attached to Ar2 at two contiguous C atoms to form a 5- to 7-membered partially saturated ring, which contains 0, 1, or 2 heteroatoms selected from the group consisting of O, N, and S; X, X1 are independently O or S Z2 is nothing, H or Ar1 optionally substituted with Y1 and Y2;
R1, R2, R3, and R4, are each independently selected from H, Ci-C6 lower alkyl,
lower alkenyl, C3-C6 lower alkynyl, C3-C6 lower cycloalkyl, C4-C6 lower cycloalkenyl, or independently R1 and R2 or R3 and R4 can be taken together to form a 5 to 8-membered ring containing 2-7 carbon atoms, the 5 to 8-membered ring optionally substituted with zero to 3 substituents selected from the group Ci- C4 lower alkyl, Cι-C4 lower alkoxy, Cj-C lower alkylamino, C C4 lower dialkylamino, amino, hydroxyl, hydroxymethyl, methoxymethyl, phenyl, substituted phenyl, benzyl, substituted benzyl; U and V are each independently a bond, O or NR ; R5 R6 and R6a are each independently -Cβ alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 cycloalkenyl, C3-C6 alkynyl, and H; R7 and R8 are each independently H, Cι-C4 lower alkyl, or are taken together to form a saturated C3-C6 carbocyclic ring; Rf is Cι-C4 straight or branched lower perfluoroalkyl; all lower alkyl, alkenyl and alkynyl groups including those linked via heteroatoms can be straight chain or branched; m is O, 1, or 2; n is 0, 1, 2, 3, 4, 5, or 6; o is O, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; and q is O, 1, 2, 3, 4, 5, or 6. The present invention also relates to pharmaceutical formulations comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, excipient, solvent, adjuvant or diluent.
The present invention further relates to methods of regulating HDL and or LDL cholesterol levels in a subject comprising administering to a subject a compound, or pharmaceutical formulation comprising a compound, of Formula (I) or pharmaceutically acceptable salt thereof. The invention relates to methods of lowering blood triglyceride and/or glucose levels in a subject comprising administering to a subject in need of such treatment an effective amount of a compound, or pharmaceutical formulation comprising a compound, of Formula (I) or pharmaceutically acceptable salt thereof. The invention also relates to methods of treating disease states related to blood levels of HDL/LDL levels, triglycerides, and or glucose in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound, or pharmaceutical formulation comprising a compound, of Formula (I), or pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION Definitions Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are hereby incorporated by reference for all purposes. A "therapeutically effective" amount is defined as an amount effective to reduce or lessen at least one symptom of the disease being treated or to reduce or delay onset of one or more clinical markers or symptoms ofthe disease. As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.
Thus, for example, reference to a composition containing "a compound" includes a mixture of two or more compounds. It should also be noted that the term "or" is generally employed in its sense including "and or" unless the content clearly dictates otherwise. By "alkyl" and "C1-G5 alkyl" in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2- hexyl, 3-hexyl, and 3-methylpentyl. It is understood that in cases where an alkyl chain of a substituent (e.g. of an alkyl, alkoxy or alkenyl group) is shorter or longer than 6 carbons, it will be so indicated in the second "C" as, for example, "Cr o indicates a maximum of 10 carbons. By the term "halogen" in the present invention is meant fluorine, bromine, chlorine, and iodine. "Alkenyl" and "C2-C6 alkenyl" means straight and branched hydrocarbon groups having from 2 to 6 carbon atoms and from one to three double bonds and includes, for example, ethenyl, propenyl, l-but-3-enyl, l-pent-3-enyl, l-hex-5-enyl and the like. As used herein, the term "cycloalkyl" refers to saturated carbocyclic groups having three to twelve carbon atoms. The cycloalkyl can be monocyclic, or a polycyclic fused system. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. For example, such cycloalkyl groups may be optionally substituted with, for example, Cι-C6 alkyl, Cι-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C]-C6)alkylamino, di(Cι-C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, Cι-C6 haloalkyl, Cι-C6 haloalkoxy, amino(Cι-C6)alkyl, mono(C1-C6)alkylamino(C1-C6)alkyl or di(C1-C6)alkylamino(Cι-C6)alkyl.
In one aspect, the present invention relates to phosphoms-containing compounds of Formula (I):
G is a bond, O, NR6, CO, C02, OCO, OC02, S(0)m, CONR6, NR6CO, NR6C02, OCONR6, NR6CONR6a, or G can optionally be attached to Ar2 at two contiguous C atoms to form a 5- to 7-membered partially saturated ring, which contains 0, 1, or 2 heteroatoms selected from the group consisting of O, N, and S; X, X1 are independently O or S
Z2 is nothing, H or Ar1 optionally substituted with Y1 and Y2;
R1, R2, R3, and R4, are each independently selected from H, -Cδ lower alkyl, C3-C6 lower alkenyl, C -C6 lower alkynyl, C3-C6 lower cycloalkyl, C4-C6 lower cycloalkenyl, or independently R1 and R2 or R3 and R4 can be taken together to form a 5 to 8-membered ring containing 2-7 carbon atoms, the 5 to 8-membered ring optionally substituted with zero to 3 substituents selected from the group Ci- C4 lower alkyl, Cι-C4 lower alkoxy, Cι-C4 lower alkylamino, Cι-C4 lower dialkylamino, amino, hydroxyl, hydroxymethyl, methoxymethyl, phenyl, substituted phenyl, benzyl, substituted benzyl; U and V are each independently a bond, O or NR ;
R5 R6 and R6a are each independently -Cδ alkyl, C3-C6 cycloalkyl, C -C6 alkenyl, C3-C6 cycloalkenyl, C3-C6 alkynyl, and H; R7 and R8 are each independently H, Cι-C4 lower alkyl, or are taken together to form a saturated C3-C6 carbocyclic ring; Rf is Cι-C4 straight or branched lower perfluoroalkyl; all lower alkyl, alkenyl and alkynyl groups including those linked via heteroatoms can be straight chain or branched; m is 0, 1, or 2; n is 0, 1, 2, 3, 4, 5, or 6; o is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; and q is 0, 1, 2, 3, 4, 5, or 6; or a pharmaceutically acceptable salt thereof. In one embodiment of this aspect, the compound is of Formula (I), wherein A is selected from a bond, O, and CH2; B is P(=0)(UR3)(VR4); D is H; and the L^C bond is a single bond. In a further embodiment of this aspect, the compound is of Formula (I), wherein A is selected from a bond, O, and CH2; B is P(=0)(UR3)(VR4); D is H; the L~C bond is a single bond; and Ar1 is phenyl. In yet a further embodiment of this aspect, the compound is of Formula (I), wherein A is selected from a bond, O, and CH2; B is P(=0)(UR3)(VR4); D is H; the L=C bond is a single bond; Ar1 is phenyl; and U and V are each O. In a prefeπed embodiment, the invention provides phosphorus-containing compounds of Formula (I):
wherein A is a bond, O, CH2, CHF, CF2, or NR6; B is H, Cι-C6 lower alkyl, or P(=X1)(UR3)(VR4); D is a) H or lower alkyl, wherein the L— C bond is a single bond; or b) OH, OCOR5, NH2, NR6R6a, or NHCOR5, wherein the L^C bond is a single bond, with the proviso that A is CH2, CHF, CF2; L is a) NR6, CR7R8, -OCR7R8-, -NR6CR7R8-, or -S(0)mCR7R8-, wherein the L^C bond is a single bond; or b) CR7, whenin the L— C bond is a double bond, with the proviso that D is absent when the L— C bond is a double bond; or c) absent, wherein C is covalently bonded by a single bond to Ar1; Ar1 and Ar2 are each independently mono- or bicyclic aromatic rings of 5-12 atoms, including, but not limited to phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyπolyl, imidazyl, pyrazolyl, oxazolyl, isoxoazolyl, thiazolyl, isothiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,3- triazolyl, 1,3,4-triazolyl, 1,2,4-triazinyl, 1,3,5-triazinyl, benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazyl, benzoxazoyl, benzoisozazolyl, benzothiazoyl, benzoisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridyl, or purinyl; Y1, Y2, and Z1 are each independently a lone electron pair, H, Cι-C6 lower alkyl, C2- C lower alkenyl, C2-C6 lower alkynyl, Cι-C6 lower alkoxy, Cι-C6 lower
alkylamino, Ci-Ce lower dialkylamino, C2-C6 lower cycloalkyl, C4-C6 lower cycloalkenyl, Ci-Cδ lower thioalkyl, Cι-C6 lower sulfinylalkyl, Cι-C6 lower sulfonylalkyl, Cι-C6 lower acyloxy, -Cδ lower acylamino with N substituted with R6, CH2OR5, CH2NR6R6a, Rf, R OH, NH2, CN, N02, F, CI, Br, I, or N3; E is a bond, S(0)m, NR6, C=0, C02, CONR6, O, -0C=0, NR6C=0, NR6C02, OC=ONR6, OC02, orNR6CONR6a; F is (CH2)π, (CH2)oO(CH2)p, (CH2)0NR6(CH2)P, (CH2)0NR6CO(CH2)p, (CH2)0CONR6 (CH2)P, (CH2)0(CR6=CR6)q(CH2)p, (CH2)0-(C ^)q-(CH2)p; G is a bond, O, NR6, CO, C02, OCO, OC02, S(0)m, CONR6, NR6CO, NR6C02, OCONR6, NR6CONR6a, or G can optionally be attached to Ar2 at two contiguous C atoms to form a 5- to 7-membered partially saturated ring, which contains 0, 1, or 2 heteroatoms selected from the group consisting of O, N, and S; X, X1 are independently O or S
Z2 is nothing, H or Ar1 optionally substituted with Y1 and Y2; R1, R2, R3, and R4, are each independently selected from H, -Cδ lower alkyl, C3-C6 lower alkenyl, C3-C6 lower alkynyl, C3-C6 lower cycloalkyl, C4-C6 lower cycloalkenyl, or independently R1 and R2 or R3 and R4 can be taken together to form a 5 to 8-membered ring containing 2-7 carbon atoms, the 5 to 8-membered ring optionally substituted with zero to 3 substituents selected from the group Ci- C lower alkyl, C C4 lower alkoxy, Ci-C4 lower alkylamino, Cι-C lower dialkylamino, amino, hydroxyl, hydroxymethyl, methoxymethyl, phenyl, substituted phenyl, benzyl, substituted benzyl; U and V are each independently a bond, O or NR6;
R5 R6 and R6a are each independently Cι-C6 alkyl, C3-C6 cycloalkyl, C3-Ce alkenyl, C3-C6 cycloalkenyl, C3-C6 alkynyl, and H;
R7 and R8 are each independently H, Cι-C4 lower alkyl, or are taken together to form a saturated C3-Cό carbocyclic ring; Rf is Cι-C straight or branched lower perfluoroalkyl; all lower alkyl, alkenyl and alkynyl groups including those linked via heteroatoms can be straight chain or branched; m is 0, 1, or 2; n is O, 1, 2, 3, 4, 5, or 6; o is O, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; and q is O, 1, 2, 3, 4, 5, or 6; with the provisos that when A is a bond or O, B is P(0)(OR3)(OR4), and D is selected from the group H, OH, OCOCH3, and NH2, and when R1 = R2 and R3 = R4, and both are selected from the group H or unsubstituted Cι-C4 lower alkyl, and E and G are bonds, and F is (CH2)n where n is 0, and both Ar1 and Ar2 are phenyl, then at least one of Y1, Y2, Z1, or Z2 must not be H; and when A is a bond or CH2, and B is P(0)(OR3)(OR4), and either D is H or Cι-C4 lower alkyl where L is CH2, or D is absent, with L— C taken together represent an ethenylidene group, and Ar1 is phenyl, and E is a bond or O, and R1 = R2 and R3 = R4, and both are drawn from the group H or Cι-C6 unsubstituted lower alkyl, then one of Y1 and Y2 must be other than H or unsubstituted Cι-C4 lower alkyl or unsubstituted Cι-C4 lower alkoxy; and when A is O, and B is H or P(0)(OR3)(OR4), and R1, R2, R3, and R4 are all selected from the group H or Cι-C6 unsubstituted lower alkyl, and D is H, and L is a bond, and Ar1 is phenyl, and E is other than a bond or O, then one of Y1 or Y2 must
be other than H, or d-C4 unsubstituted lower alkyl or d-C4 unsubstituted lower alkoxy; or a pharmaceutically acceptable salt thereof. In a more prefeπed embodiment, the compound of Formula (I) is selected from: Diethyl l-(diethoxyphosphinyloxy)-l-(4-[2-{N-methyl-N-pyrid-2-ylamino}etlιoxy]-3- fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[Ν-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N- methylaminocarbonyl]-3-fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[3 - {N-methyl-N-pyrid-2-ylamino } - 1 -oxoprop- 1 - yl]-3-fluorophenyl)methylphosphonate;
Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4- [2- {5-methyl-2-phenyloxazol-4-yl} ethoxy]-3- fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[N-(2- {5-methyl-2-phenyloxazol-4-yl}ethyl)-N- methylaminocarbonyl] -3 -fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[2- { 5 -methyl-2-phenylthiazol-4-yl} ethoxy] -3 - fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1-(4-[3-{5 -methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- l-yl]-3-fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(4-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]- 3 -fluorophenyl)methylphosphonate;
Diethyl l-(diethoxyphosphinyloxy)-l-(4-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]- 3-fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)-l -(4-[3- {5-methyl-2-pyrid-4-yloxazol-4-yl} -1 - oxoprop- 1 -yl] -3 -fiuorophenyl)methylphosphonate;
Diethyl l-(hydroxy)-l-(4-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N- methylaminocarbonyl]-3-fluorophenyl)methylphosphonate; Diethyl l-(hydroxy)-l-(4-[2-{4-(4-trifluoromethylphenyl)phenoxy}ethoxy]-3- fluorophenyl)methylphosphonate; Diethyl 1 -(hydroxy)- 1 -(4-[N-(2- {4-(4-trifluoromethylphenyl)phenoxy} ethyl)-N- methylaminocarbonyl]-3-fluorophenyl)methylphosphonate; Diethyl 1 -(hydroxy)- 1 -(4-[3 - {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl] -3 - fluorophenyl)methylphosphonate; Diethyl 1 -(hydroxy)- 1 -(4-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3 - hexylureido} ethyl]-3-fluorophenyl)methylphosphonate;
Diethyl 1 -(hydroxy)- 1 -(4-[2- { 1 -butyl-3-(5-methoxypyrid-2-yl)ureido} ethyl]-3- fluorophenyl)methylphosphonate; Diethyl l-(hydroxy)-l-(4-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3- fluorophenyl)methylphosphonate; Diethyl l-(hydroxy)-l-(4-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]-3- fluorophenyl)methylphosphonate; Diethyl l-(hydroxy)-l-(4-[3,N-phthalimidopropoxy]-3-fluorophenyl)methylphosphonate; Diethyl 1 -(hydroxy)- 1 -(4-[4,N-phthalimidobutoxy]-3 -fluorophenyl)methylphosphonate; Tetraethyl 1 -(3-[3- {N-methyl-N-pyrid-2-ylamino}propoxy]-4-fluorophenyl )methylidenebisphosphonate;
Tetraethyl 1 -(3 - [N-(3 - {N-methyl-N-pyrid-2-ylamino } propyl)-N-methylamino] -4- fluorophenyl)methylidenebisphosphonate; Tetraethyl 1 -(3-[3- {N-methyl-N-pyrid-2-ylamino} -1 -oxoprop-1 -ylamino]-4- fluorophenyl)methylidenebisphosphonate;
Tetraethyl l-(3-[3-{5-methyl-2-phenyloxazol-4-yl}propoxy]-4- fiuorophenyl)methylidenebisphosphonate; Tetraethyl l-(3-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylaminocarbonyl]-4- methoxyphenyl)methylidenebisphosρhonate; Tetraethyl l-(3-[3-{5-methyl-2-phenylthiazol-4-yl}propoxy]-4- fluorophenyl)methylidenebisphosphonate; Tetraethyl l-(3-[3-{5-methyl-2-phenylthiazol-4-yl}-l-oxoprop-l-yl]-4- fluorophenyl)methylidenebisphosphonate; Tetraethyl 1 -(3-[4- {5-methyl-2-pyrid-4-yloxazol-4-yl}butoxy]-4- fluorophenyl)methylidenebisphosphonate;
Tetraethyl l-(3-[3-{5 -methyl-2-pyrid-4-ylthiazol-4-yl }propoxy] -4- fluorophenyl)methylidenebisphosphonate; Tetraethyl 1 -(3 - [3 - {5-methyl-2-pyrid-4-yloxazol-4-yl } - 1 -oxoprop- 1 -ylthio] -4- fluorophenyl)methylidenebisphosphonate; Tetraethyl 2-(3-[N-(3-{5-methyl-2-pyrid-4-ylthiazol-4-yl}proρyl)-N-methylamino]-4- fluorophenyl)vinylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(3-[3-{4-(4-trifluoromethylphenyl)phenoxy}propoxy]-4- fluorophenyl)vinylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(3 - [N-(3 - {4-(4-trifluoromethylphenyl)phenoxy } propyl)-N-methylamino] -4- fluorophenyI)vinylidene- 1 , 1 -bisphosphonate;
Tetraethyl 2-(3-[4-{4-(4-trifluoromethylphenyl)phenoxy)-l-oxobut-l-yl]-4- fluorophenyl)vinylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(3-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]-4- fluorophenyl)vinylidene- 1 , 1 -bisphosphonate;
Tetraethyl 2-(3-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]-4- fluorophenyl)vinylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(3-[4-{4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]-4- fluorophenyl)vinylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(3 -[3 - {4H-3 -oxobenzo [ 1 ,4] oxazin-2-yl }propoxy] -4-fluorophenyl)vinylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(3-[3,N-phthalimidopropoxy]-4-fiuorophenyl)vinylidene-l,l-bisphosphonate; Tetraethyl 2-(3-[4,N-phthalimidobutoxy]-4-fluorophenyl)vinylidene-l,l-bisphosphonate; Tetraethyl 1 -(6-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]indol-2-yl)ethylidene- 1 ,2- bisphosphonate;
Tetraethyl l-(6-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]indol-2- yl)ethylidene- 1 ,2-bisphosphonate; Tetraethyl l-(6-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l-yl]indol-2-yl)ethylidene- 1 ,2-bisphosphonate; Tetraethyl l-(6-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy] indol-2-yl)ethylidene-l,2- bisphosphonate; Tetraethyl 1 -(6-[N-(2- {5-methyl-2-phenyloxazol-4-yl} ethyl)-N-methylamino] indol-2- yl)ethylidene- 1 ,2-bisphosphonate; Tetraethyl l-(6-[2-{5-methyl-2-phenylthiazoI-4-yl}ethoxy]indol-2-yl)ethylidene-l,2- bisphosphonate;
Tetraethyl 1 -(6-[3 - {5-methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl]indol-2-yl)ethylidene- 1 ,2-bisphosphonate; Tetraethyl 1 -(6-[2- {5-methyl-2-pyrid-4-yloxazol-4-yl} ethoxy]indol-2-yl)ethylidene- 1 ,2- bisphosphonate;
Tetraethyl l-(6-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]indol-2-yl)ethylidene-l,2- bisphosphonate; Tetraethyl 1 -(6-[3 - {5-methyl-2-pyrid-4-yloxazol-4-yl} - 1 -oxoprop- 1 -yl]indol-2- yl)ethylidene- 1 ,2-bisphosphonate; Tetraethyl 2-(6-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]indol-2- yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(6-[2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy] indol-2-yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(6-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]indol- 2-yl)ethylidene- 1 , 1 -bisphosphonate;
Tetraethyl 2-(6-[2- { 1 - [4-(2-trifluoromethylphenyl)phenylmethyl]-3 - hexylureido } ethyl]indol-2-yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(6-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]indol-2-yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(6-[3-{4-(4-trifluoromethylphenyl)phenoxy}-l-oxoprop-l-yl]indol-2- yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(6-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]indol-2-yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(6-[2- {4H-3 -oxobenzo[ 1 ,4]oxazin-2-yl} ethoxy]indol-2-yl)efhylidene- 1,1- bisphosphonate;
Tetraethyl 2-(6-[3,N-phthalimidopropoxy]indol-2-yl)ethylidene-l , 1 -bisphosphonate; Tetraethyl 2-(6-[4,N-phthalimidobutoxy]indol-2-yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl N-(5-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]pyrid-2- yl)aminomethylidenebisphosphonate;
Tetraethyl N-(5-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]pyrid-2- yl)aminomethylidenebisphosphonate; Tetraethyl N-(5 -[3 - {N-methyl-N-pyrid-2-ylamino } - 1 -oxoprop- 1 -yl]pyrid-2- yl)aminomethylidenebisphosphonate; Tetraethyl N-(5-[2- {5-methyl-2-phenyloxazol-4-yl}ethoxy]pyrid-2- yl)aminomethylidenebisρhosphonate Tetraethyl N-(5-[N-(2- {5-methyl-2-phenyloxazol-4-yl} ethyl)-N-methylamino]pyrid-2- yl)aminomethylidenebisphosphonate; Tetraethyl N-(5-[2- {5-methyl-2-phenylthiazol-4-yl} ethoxy]pyrid-2- yl)aminomethylidenebisphosphonate;
Tetraethyl N-(5-[3 - {5-methyl-2-pyrid-4-yloxazol-4-yl} - 1 -oxoprop- 1 -yl]pyrid-2- yl)aminomethylidenebisphosphonate; Tetraethyl N-(5-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]pyrid-2- yl)aminomethylidenebisphosphonate; Tetraethyl N-(5-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]pyrid-2- yl)aminomethylidenebisphosphonate; Tetraethyl N-(5-[2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethoxy]pyrid-2- yl)aminomethylidenebisphosphonate; 2-[l-Hydroxy-l-(5-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N- methylamino]pyrid-2-yl)methyl]- 1 ,3 ,2-dioxaphospholane-2-oxide;
2-[l-Hydroxy-l-(5-[2-{4-(4-trifluoromethylphenyl)phenoxy}ethoxy]-pyrid-2-yl)methyl]- 1 ,3 ,2-dioxaphospholane-2 -oxide; 2-[l-Hydroxy-l-(5-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N- methylamino]pyrid-2-yl)methyl]-l,3,2-dioxaphospholane-2-oxide;
- [1 -Hydroxy- 1 -(5-[3- {4-(4-trifluoromethylphenyl)ρhenoxy} - 1 -oxoprop-1 -yl]-pyrid-2- yl)methyl]-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3- hexylureido} ethyl]pyrid-2-yl)methyl]- 1 ,3 ,2-dioxaphospholane-2-oxide;-[l -Hydroxy-1 -(5-[2- { 1 -butyl-3-(5-methoxypyrid-2-yl)ureido} ethyl]pyrid-2-ylmethyl]- 1 ,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-15-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]pyrid-2-ylmethyl]- 1 ,3 ,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(5 -[2- {4H-3 -oxobenzo [ 1 ,4]oxazin-2-yl} ethoxy]pyrid-2-yl)methyl]- 1 ,3,2- dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(5 -[3 ,N-phthalimidopropoxy]pyrid-2-yl)methyl]- 1 ,3 ,2-dioxaphospholane- 2-oxide;-[l-Hydroxy-l-(5-[4,N-phthalimidobutoxy]pyrid-2-yl)methyl]-l,3,2-dioxaphospholane- 2-oxide;-[ 1 -Hydroxy- 1 -(5 -[2- {N-methyl-N-pyrid-2-ylamino } ethoxy]benzothien-2-yl)methyl] - [4R]-methyl-l,3,2-dioxaphospholane-2-oxide;- [ 1 -Hydroxy- 1 -(5 -[N-(2- {N-methyl-N-ρyrid-2-ylamino } ethyl)-N- methylamino]benzothien-2-yl)methyl]- [4R]-methyl-l,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(5 -[3 - {N-methyl-N-pyrid-2-ylamino } - 1 -oxoprop- 1 -yl]benzothien-2- yl)methyl]- [4R]-methyl-l,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(5 -[2- { 5 -methyl-2-phenyloxazol-4-yl} ethoxy]benzothien-2-yl)methyl] - [4R]-methyl-l,3,2-dioxaphospholane-2-oxide;-[l -Hydroxy-1 -(5-[N-(2- {5-methyl-2-phenyloxazol-4-yl} ethyl)-N- methylamino]benzothien-2-yl)methyl]- [4R]-methyl-l,3,2-dioxaphospholane-2-oxide;
-[ 1 -Hydroxy- 1 -(5 -[2- { 5 -methyl-2-phenylthiazol-4-yl} ethoxy]benzothien-2-yl)methyl] - [4R]-methyl- 1 ,3,2-dioxaphospholane-2-oxide;- [ 1 -Hydroxy- 1 -(5 - [3 - { 5 -methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl]benzothien-2- yl)methyl] - [4R] -methyl- 1 ,3 ,2-dioxaphospholane-2-oxide ;-[l-Hydroxy-l-(5-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]benzothien-2- yl)methyl]- [4R]-methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]benzothien-2- yl)methyl]- [4R]-methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-yl]benzothien-2- yl)methyl]- [4R] -methyl- 1, 3 ,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5- N-(2-{5-methyl-2-ρyrid-4-ylthiazol-4-yl}ethyl)-N- methylamino]benzothien-2-yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;- [ 1 -Hydroxy- 1 -(5 -[2- {4-(4-trifluoromethylphenyl)phenoxy } ethoxy]benzothien-2- yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[N-(2-{4-(4-frifluoromethylphenyl)phenoxy}ethyl)-N- methylamino]benzothien-2-yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;- [ 1 -Hydroxy- 1 -(5 -[3 - {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yfjbenzothien- 2-yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;- [ 1 -Hydroxy- l-(5-[2-{l -[4-(2-trifluoromethylphenyl)phenylmethyl] -3 - hexylureido}ethyl]benzothien-2-yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2- oxide;-[l-Hydroxy-l-(5-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]benzothien-2- yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(5 - [3 - {4-acetyl-3 -hydroxy-2-propylphenoxy)propoxy]benzothien-2- yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;
-[ 1 -Hydroxy-l-(5-[2- {4H-3 -oxobenzo [1 ,4]oxazin-2-yl} ethoxy]benzothien-2-yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[3,N-phthalimidopropoxy]benzothien-2-yl)methyl]- [4S]-methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(5-[4,N-ρhthalimidobutoxy]benzothien-2-yl)methyl]- [4S]-methyl-l ,3,2- dioxaphospholane-2 -oxide;-[l-Hydroxy-l-(4-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]thiazol-2-yl)methyl]-4,5- dimethyl-l,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(4-[N-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N-methylamino]thiazol-2- yl)methyl]-4,5 -dimethyl- 1 ,3 ,2-dioxaphospholane-2-oxide;- [ 1 -Hydroxy- 1 -(4- [3 - {N-methyl-N-pyrid-2-ylamino } - 1 -oxoprop- 1 -yl]thiazol-2- yl)methyl]-4,5-dimethyl- 1 ,3 ,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]thiazol-2-yl)methyl]-4,5- dimethyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(4-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]thiazol- 2-yl)methyl]-4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(4-[2- {5-methyl-2-phenylthiazol-4-yl} ethoxy]thiazol-2-yl)methyl] -4,5- dimethyl- 1 ,3 ,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(4-[3- {5-methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl]thiazol-2- yl)methyl]-4,5-dimethyl- 1 ,3 ,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(4-[2- {5-methyl-2-pyrid-4-yloxazol-4-yl} ethoxy]thiazol-2-yl)methyl] - 4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(4-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]thiazol-2-yl)methyl]- 4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide;
-[ 1 -Hydroxy- 1 -(4-[3- {5-methyl-2-pyrid-4-yloxazol-4-yl} - 1 -oxoprop- 1 -yl]thiazol-2- yl)methyl]-4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(4-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N- methylamino]thiazol-2-yl)methyl]-l,3,2-dioxaphosphinane-2-oxide;-[l-Hydroxy-l-(4-[2-{4-(4-trifϊuoromethylphenyl)phenoxy}ethoxy]thiazol-2-yl)methyl]- 1 ,3,2-dioxaphosρhinane-2-oxide;-[ 1 -Hydroxy- 1 -(4-[N-(2- {4-(4-trifluoromethylphenyl)phenoxy} ethyl)-N- methylamino]thiazol-2-yl)methyl]-l,3,2-dioxaphosphinane-2-oxide;-[ 1 -Hydroxy-1 -(4-[3 - {4-(4-trifluoromethylphenyl)phenoxy} - 1 -oxoprop- 1 -yl]thiazol-2- yl)methyl]-l ,3,2-dioxaphosphinane-2-oxide;-[l-Hydroxy-l-(4-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3- hexylureido}ethyl]thiazol-2-yl)methyl]-l,3,2-dioxaphosphinane-2-oxide;-[ 1 -Hydroxy- 1 -(4-[2- { 1 -butyl-3 -(5-methoxypyrid-2-yl)ureido} ethyl]thiazol-2- yl)methyl] - 1 ,3 ,2-dioxaphosphinane-2-oxide;-[l-Hydroxy-l-(4-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]thiazol-2- yl)methyl]-l,3,2-dioxaphosphinane-2-oxide;-[l-Hydroxy-l-(4-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]thiazol-2-yl)methyl]- 1 ,3 ,2-dioxaphosphinane-2-oxide;-[ 1 -Hydroxy- 1 -(4-[3 ,N-phthalimidopropoxy]thiazol-2-yl)methyl]- 1,3,2- dioxaphosphinane-2-oxide;-[l-Hydroxy-l-(4-[4,N-phthalimidobutoxy]thiazol-2-yl)methyl]-l,3,2- dioxaphosphinane-2 -oxide;[l-(6-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]-3-methoxyquinolin-2-yl)-l-(2-oxido- l,3,2-dioxaphospholan-2-yl)methoxy]-l,3,2-dioxaphospholane-2-oxide;
[l-(6-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]-3-methoxyquinolin- 2-yl)-l-(2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-l,3,2-dioxaphospholane-2- oxide; [ 1 -(6- [3 - {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop- 1 -yl] -3 -methoxyquinolin-2-yl)- 1 -(2- oxido- 1 ,3,2-dioxaphospholan-2-yl)methoxy]-l ,3,2-dioxaphospholane-2-oxide; [ 1 -(6-[2- { 5 -methyl-2-phenyloxazol-4-yl} ethoxy] -3 -methoxyquinolin-2-yl)- 1 -(2-oxido- l,3,2-dioxaphospholan-2-yl)methoxy]-l,3,2-dioxaphospholane-2-oxide; [ 1 -(6-[N-(2- { 5 -methyl-2-phenyloxazol-4-yl} ethyl)-N-methylamino] -3 -methoxy quinolin- 2-yl)-l-(2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-l,3,2-dioxaphospholane-2- oxide;[l-(6-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l-(2-oxido- l,3,2-dioxaphospholan-2-yl)methoxy]-l,3,2-dioxaphospholane-2-oxide;[l-(6-[3-{5-methyl-2-phenylthiazol-4-yl}-l-oxoprop-l-yl]-3-methoxyquinolin-2-yl)-l- (2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-l,3,2-dioxaphospholane-2-oxide;[l-(6-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l-(2- oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-l,3,2-dioxaphospholane-2-oxide;[l-(6-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l-(2- oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- 1 ,3 ,2-dioxaphospholane-2-oxide;[ 1 -(6- [3 - { 5 -methyl-2-pyrid-4-yloxazol-4-yl } - 1 -oxoprop- 1 -yl] -3 -methoxyquinolin-2-yl)- 1 -(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- 1 ,3 ,2-dioxaphospholane-2-oxide;[l-(6-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)- 1 -( [4R] -methyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2- ' yl)methoxy]-[4R]-methyl-l,3,2-dioxaphospholane-2-oxide;
[ 1 -(6- [2- {4-(4-trifluoromethylphenyl)ρhenoxy } ethoxy] -3 -methoxyquinolin-2-yl)- 1 - ([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-[4R]-methyl-l,3,2- dioxaρhospholane-2-oxide;[l-(6-[N-(2-{4-(4-trifIuoromethylphenyl)phenoxy}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)-l-([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2- yl)methoxy]-[4R]-methyl-l,3,2-dioxaphospholane-2-oxide; [ 1 -(6- [3 - {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl] -3 -methoxyquinolin-2- yl)-l-([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-[4R]-methyl-l,3,2- dioxaphospholane-2-oxide;[l-(6-[2-{l-[4-(2-trifluoromethylρhenyl)phenylmethyl]-3-hexylureido}ethyl]-3- methoxyquinolin-2-yl)- 1 -([4R]-methyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2- yl)methoxy]-[4R]-methyl- 1 ,3 ,2-dioxaphospholane-2-oxide; [ 1 -(6- [2- { 1 -butyl-3 -(5-methoxypyrid-2-yl)ureido } ethyl]-3 -methoxyquinolin-2-yl)- 1 - ([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-[4R]-methyl-l,3,2- dioxaphospholane-2-oxide;[ 1 -(6-[3 - {4-acetyl-3 -hydroxy-2-propylphenoxy)propoxy]-3 -methoxyquinolin-2-yl)- 1 - ([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-[4R]-methyl-l,3,2- dioxaphospholane-2-oxide;[l-(6-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]-3-methoxyquinolin-2-yl)-l-([4R]- methyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]-[4R]-methyl- 1,3,2- dioxaphospholane-2-oxide; [ 1 -(6- [3 ,N-phthalimidopropoxy] -3 -methoxy quinolin-2-yl)- 1 -([4R] -methyl-2-oxido- 1,3,2- dioxaphospholan-2-yl)methoxy]-[4R]-methyl-l,3,2-dioxaphospholane-2-oxide;[l-(6-[4,N-phthalimidobutoxy]-3-methoxyquinolin-2-yl)-l-([4R]-methyl-2-oxido-l,3,2- dioxaphospholan-2-yl)methoxy]-[4R]-methyl-l,3,2-dioxaphospholane-2-oxide;
[1 -(5-[2- {N-methyl-N-pyrid-2-ylamino}ethoxy]thien-2-yl)-l -([4S]-methyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;[l-(5-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]thien-2-yl)-l-([4S]- methyl-2-oxido-l ,3,2-dioxaphospholan-2-yl)methoxy]- [4S] -methyl- 1 ,3,2- dioxaphospholane-2-oxide;[ 1 -(5-[3 - {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop- 1 -yl]thien-2-yl)- 1 -([4S]-methyl-2- oxido-l,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l,3,2-dioxaphospholane-2- oxide;[ 1 -(5-[2- {5-methyl-2-ρhenyloxazol-4-yl} ethoxy]thien-2-yl)-l -([4S]-methyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;[l-(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]thien-2-yl)-l-([4S]- methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l,3,2- dioxaphospholane-2-oxide;[ 1 -(5-[2- {5-methyl-2-phenylthiazol-4-yl} ethoxy]thien-2-yl)-l -([4S]-methyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl- 1 ,3 ,2-dioxaphospholane-2-oxide; [ 1 -(5-[3- { 5-methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl]thien-2-yl)- 1 -([4S]-methyl-2- oxido-l,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l,3,2-dioxaphospholane-2- oxide;[l-(5-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]thien-2-yl)-l-([4S]-methyl-2-oxido- l,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;[l-(5-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]thien-2-yl)-l-([4S]-methyl-2-oxido- l,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;[l-(5-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-yl]thien-2-yl)-l-([4S]-methyl- 2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l,3,2-dioxaphospholane- 2-oxide;
[1 -(5-[N-(2- {5- ethyl-2-pyrid-4-ylthiazol-4-yl} ethyl)-N-methylamino]thien-2-yl)- 1 - (4,S-dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2- dioxaphospholane-2-oxide;[ 1 -(5-[2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy]thien-2-yl)- 1 -(4,5-dimethyl-2- oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2- oxide;[l-(5-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]thien-2-yl)-l- (4,5-dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2- dioxaphospholane-2-oxide;[ 1 -(5- [3- {4-(4-trifluoromethylphenyl)phenoxy} - 1 -oxoprop- 1 -yl]thien-2-yl)- 1 -(4,5- dimethyl-2-oxido-l ,3 ,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyl 1 ,3,2- dioxaphospholane-2-oxide;[l-(5-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]thien-2-yl)- 1 -(4,5-dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyl 1 ,3 ,2- dioxaphospholane-2-oxide;[l-(5-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]thien-2-yl)-l-(4,5-dimethyl-2- oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2- oxide;[l-(5-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]thien-2-yl)-l-(4,5-dimethyl-2- oxido-1 ,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll ,3,2-dioxaphospholane-2- oxide;[l-(5-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]thien-2-yl)-l-(4,5-dimethyl-2-oxido- l,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;[l-(5-[3,N-phthalimidopropoxy]thien-2-yl)-l-(4,5-dimethyl-2-oxido-l,3,2- dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;
[l-(5-[4,N-phthalimidobutoxy]thien-2-yl)-l-(4,5-dimethyl-2-oxido-l,3,2- dioxaphospholan-2-yl)methoxy]-4,5-dimethyl 1 ,3 ,2-dioxaphospholane-2-oxide; [l-(4-[2-{N-methyl-N-ρyrid-2-ylamino}ethoxy]-3-fluorophenyl)-l-(2-oxido-l,3,2- dioxaphosphinan-2-yl)methoxy] - 1 ,3 ,2-dioxaphosphinane-2-oxide; [l-(4-[Ν-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylaminocarbonyl]-3- fluorophenyl)-l-(2-oxido-l,3,2-dioxaphosphinan-2-yl)methoxy]-l,3,2- dioxaphosphinane-2-oxide; [ 1 -(4-[3 - {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop- 1 -yl]-3-fluorophenyl)- 1 -(2-oxido- l,3,2-dioxaphosphinan-2-yl)methoxy]-l,3,2-dioxaphosphinane-2-oxide; 2[l-(4-[2-{5-methyl-2-ρhenyloxazol-4-yl}ethoxy]-3-fluoroρhenyl)-l-(2-oxido-l,3,2- dioxaphosphinan-2-yl)methoxy]- 1 ,3 ,2-dioxaphosphinane-2-oxide; l-(4-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylaminocarbonyl]-3- fluorophenyl)- 1 , 1 -bis(2-oxido-l ,3 ,2-dioxaphospholan-2-yl)methane; l-(4-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]-3-fluorophenyl)-l,l-bis(2-oxido-l,3,2- dioxaphospholan-2-yl)methane; l-(4-[3-{5 -methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl] -3 -fluorophenyl)- 1 , 1 -bis(2- oxido-l,3,2-dioxaphospholan-2-yl)methane; 1 -(4-[2- {5-methyl-2-pyrid-4-yloxazol-4-yl} ethoxy]-3 -fluorophenyl)- 1 , 1 -bis(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; l-(4-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]-3-fluorophenyl)-l,l-bis(4,5-dimethyl- 2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; 1 -(4-[3 - { 5-methyl-2-pyrid-4-yloxazol-4-yl} - 1 -oxoprop- 1 -yl] -3 -fluorophenyl)- 1 , 1 -bis(2- oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methane; l-(4-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-Ν-methylaminocarbonyl]-3- fluorophenyl)- 1 , 1 -bis(4,5 -dimethyl-2-oxido-l ,3 ,2-dioxaphospholan-2-yl)methane;
-(4-[2- {4-(4-trifluoromethylphenyl)phenoxy } ethoxy]-3 -fluorophenyl)- 1 , 1 -bis(2-oxido- 1 ,3 ,2-dioxaphosρhinan-2-yl)methane; -(4- [N-(2- {4-(4-trifluoromethylphenyl)phenoxy } ethyl)-N-methylaminocarbonyl] -3 - fluorophenyl)-l,l-bis(4,5-dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methane; -(4-[3- {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl]-3-fluorophenyl)- 1,1- bis(2-oxido- 1 ,3 ,2-dioxaphosρhinan-2-yl)methane; -(4-[2- { 1 - [4-(2-trifluoromethylphenyl)phenylmethyl] -3 -hexylureido} ethyl] -3 - fluorophenyl)- 1 , 1 -bis(4,5-dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; -(4-[2- { 1 -butyl-3 -(5-methoxypyrid-2-yl)ureido} ethyl]-3 -fluorophenyl)- 1 , 1 -bis(2-oxido- 1 ,3,2-dioxaphosphinan-2-yl)methane;-(4-[3-{4-acetyl-3-hydroxy-2-propylρhenoxy)proρoxy]-3-fluorophenyl)-l,2-bis(2-oxido- l,3,2-dioxaphospholan-2-yl)ethane;-(4-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]-3-fluorophenyl)-l,2-bis([4R]-methyl-2- oxido-l,3,2-dioxaphospholan-2-yl)ethane;-(4-[3,N-phthalimidopropoxy]-3-fluorophenyl)-l,2-bis(2-oxido-l,3,2-dioxaphospholan- 2-yl)ethane;-(4-[4,N-phthalimidobutoxy]-3-fluorophenyl)-l,2-bis([4R]-methyl-2-oxido-l,3,2- dioxaphospholan-2-yl)ethane;-(3-[3-{N-methyl-N-pyrid-2-ylamino}propoxy]-4-fluorophenyl )-l,2-bis(2-oxido-l,3,2- dioxaphospholan-2-yl)ethane;-(3-[N-(3-{N-methyl-N-pyrid-2-ylamino}propyl)-N-methylamino]-4-fluorophenyl)-l,2- bis([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)ethane;-(3 -[3 - {N-methyl-N-pyrid-2-ylamino } - 1 -oxoprop- 1 -ylamino] -4-fluorophenyl)- 1 ,2-bis(2- oxido-l,3,2-dioxaphospholan-2-yl)ethane;
-(3-[3-{5-methyl-2-phenyloxazol-4-yl}propoxy]-4-fluorophenyl)-l,2-bis([4R]-methyl-2- oxido-l,3,2-dioxaphospholan-2-yl)ethane; -(3-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylaminocarbonyl]-4- methoxyphenyl)- 1 , 1 -bis(4,5-dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)ethane; -(3-[3-{5 -methyl-2-phenylthiazol-4-yl}propoxy] -4-fluorophenyl)- 1 , 1 -bis(2-oxido- 1,3,2- dioxaphosphinan-2-yl)ethane; -(3 -[3 - {5 -methyl-2-phenylthiazol-4-yl } - 1 -oxoprop- 1 -yl] -4-fluorophenyl)- 1 , 1 -bis(4,5 - dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)ethane; -(3-[4-{5-methyl-2-pyrid-4-yloxazol-4-yl}butoxy]-4-fluorophenyl)-l,l-bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)ethane; -(3-[3-{5-methyl-2-pyrid-4-ylthiazol-4-yl}propoxy]-4-fluorophenyl)-l,l-bis(4,5- dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)ethane; -(3-[3 - {5-methyl-2-pyrid-4-yloxazol-4-yl} - 1 -oxoprop- 1 -ylthio]-4-fluorophenyl)- 1,1- bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)ethane; -(3-[N-(3- {5-methyl-2-pyrid-4-ylthiazol-4-yl}propyl)-N-methylamino]-4-fluorophenyl)- 1 , 1 -bis(4,5-dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)ethane; -(3-[3-{4-(4-trifluoromethylphenyl)phenoxy}propoxy]-4-fluorophenyl)-l,l-bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)ethane; l-[N-(3-[N-(3-{4-(4-trifluoromethylphenyl)phenoxy}propyl)-N-methylamino]-4- fluorophenyl)amino]- 1 , 1 -bis(2-oxido-l ,3 ,2-dioxaphospholan-2-yl)methane;
1 -[N-(3 - [4- {4-(4-trifluoromethylphenyl)phenoxy)- 1 -oxobut- 1 -yl] -4-fluorophenyl)amino] - 1 , 1 -bis([4R]-methyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; 1 -[N-(3-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido} ethyl]-4- fluorophenyl)amino]-l,l-bis(2-oxido-l,3,2-dioxaphospholan-2-yl)methane;
1 -[N-(3-[2- { 1 -butyl-3 -(5-methoxypyrid-2-yl)ureido} ethyl]-4-fluorophenyl)amino]- 1 , 1 - bis([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methane; 1 -[N-(3 - [4- {4-acetyl-3 -hydroxy-2-propylphenoxy)butoxy] -4-fluorophenyl)amino] -1,1- bis(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; 1 -[N-(3 -[3 - {4H-3 -oxobenzo [ 1 ,4] oxazin-2-yl} propoxy] -4-fluorophenyl)amino] -1,1- bis([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methane; 1 -[N-(3 -[3 ,N-phthalimidopropoxy]-4-fluorophenyl)amino]- 1 , 1 -bis(2-oxido- 1,3,2- dioxaphospholan-2-yl)methane; l-[N-(3-[4,N-phthalimidobutoxy]-4-fluorophenyl)amino]-l,l-bis([4R]-methyl-2-oxido- 1,3 ,2-dioxaphospholan-2-yl)methane ;
1 -[N-(6-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]indol-2-yl)amino] -1,1 -bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methane; l-[N-(6-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]indol-2-yl)amino]- 1 , 1 -bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methane; 1 -[N-(6-[3- {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop- 1 -yl]indol-2-yl)amino]~ 1 , 1 -bis(2- oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methane; l-[N-(6-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy] indol-2-yl)amino]-l,l-bis(2-oxido- l,3,2-dioxaphosphinan-2-yl)methane; 2-[l-(Diethoxyphosphinyloxy)-l-(6-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N- methylamino] indol-2-yl)methyl]-l ,3,2-dioxaphospholane-2-oxide;
2-[ 1 -(Diethoxyphosphinyloxy)- 1 -(6-[2- {5-methyl-2-phenylthiazol-4-yl} ethoxy]indol-2- yl)methyl]-l ,3 ,2-dioxaphospholane-2-oxide; 2-[ 1 -(Diethoxyphosphinyloxy)- 1 -(6-[3 - {5-methyl-2-phenylthiazol-4-yl} - 1 -oxoprop-1 - yl]indol-2-yl)methyl]-l,3,2-dioxaphospholane-2-oxide;
-[ 1 -(Diethoxyphosphinyloxy)- 1 -(6-[2- {5-methyl-2-pyrid-4-yloxazol-4-yl} ethoxy]indol- 2-yl)methyl]-l,3,2-dioxaphospholane-2-oxide;-[l -(Diethoxyphosphinyloxy)- 1 -(6-[2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethoxy]indol- 2-yI)methyl]- 1 ,3 ,2-dioxaphosphinane-2-oxide;-[l-(Diethoxyphosphinyloxy)-l-(6-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoρrop-l- yl]indol-2-yl)methyl]-l,3,2-dioxaphosphinane-2 -oxide;-[l-(Diethoxyphosphinyloxy)-l-(6-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N- methylamino]indol-2-yl)methyl]-l,3,2-dioxaphosphinane-2-oxide;-[l-(Diethoxyphosphinyloxy)-l-(6-[2-{4-(4-trifluoromethylphenyl)phenoxy}ethoxy] indol-2-yl)methyl]- 1 ,3 ,2-dioxaphosphinane-2-oxide;[l-(6-[N-(2-{4-(4-trifluoromethylphenyI)phenoxy}ethyl)-N-methylamino]indol-2-yl)-l- (diethoxyphosphinyl)methoxy]-4[S]-methyl-l,3,2-dioxaphospholane-2-oxide; [ 1 -(6- [3 - {4-(4-trifluoromethylρhenyl)phenoxy} - 1 -oxoprop- 1 -yl]indol-2-yl)- 1 - (diethoxyphosphinyl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;[ 1 -(6-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]indol-2-yl)- 1 -(diethoxyphosphinyl)methoxy]-4[S]-mefhyl-l ,3 ,2-dioxaphospholane-2-oxide;[l-(6-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]indol-2-yl)- l-(diethoxyphosphinyl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;[1 -(6-[3- {4-acetyl-3-hydroxy-2-propylphenoxy)proρoxy]indol-2-yl)- 1 - (diethoxyphosphinyl)methoxy]-4[S]-methyl-l,3,2-dioxaphospholane-2-oxide;[l-(6-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]indol-2-yl)-l- (diethoxyphosphinyl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;[l-(6-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]indol-2-yl)-l- (diethoxyphosphinyl)methoxy]-4[S]-methyl-l,3,2-dioxaphospholane-2-oxide;
[l-(6-[3N-phthalimidopropoxy]indol-2-yl)-l-(diethoxyphosphinyl)methoxy]-4,5- dimethyl 1 ,3 ,2-dioxaphospholane-2-oxide;[1- 6-[4,N-phthalimidobutoxy]indol-2-yl)-l-(diethoxyphosphinyl)methyl]-4[R]-methyl- ,3 ,2-dioxaphospholane-2-oxide;[1- 5-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]pyrid-2-yl)-l- diethoxyphosphinyl)methyl] -4[R] -methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;[ 5-[N-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N-methylamino]pyrid-2-yl)- 1 - diethoxyphosphinyl)methyl]-4[R]-methyl-l,3,2-dioxaphospholane-2-oxide;[l-ι 5 - [3 - {N-methyl-N-pyrid-2-ylamino } - 1 -oxoprop- 1 -yl]pyrid-2-yl)- 1 - diethoxyphosphinyl)methyl]-4[R]-methyl-l,3,2-dioxaphospholane-2-oxide;[1- 5-[2- {5-methyI-2-phenyloxazol-4-yl} ethoxy ]pyrid-2-yl)- 1 - diethoxyphosphinyl)methyl]-l,3,2-dioxaphosphinane-2-oxide;[1- 5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]pyrid-2-yl)-l- diethoxyphosphinyl)methyl]-l,3,2-dioxaphosphinane-2-oxide;[L 5 -[N-(2- { 5 -methyl-2-phenyloxazol-4-yl} ethyl)-N-methylamino]pyrid-2-yl)- 1 - diethoxyphosphinyl)methyl]-l,3,2-dioxaphosphinane-2-oxide;[1 5-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]pyrid-2-yl)-l- diethoxyphosphinyl)methyl]-l,3,2-dioxaphosphinane-2-oxide;[1-' 5-[3 - {5-methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl]pyrid-2-yl)-2- diethoxyphosphinyl)eth- 1 -yl]-4,5-dimethyl 1 ,3 ,2-dioxaphospholane-2-oxide;[1- 5-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]pyrid-2-yl)-2- diethoxyphosphinyl)eth- 1 -yl] -1,3 ,2-dioxaphosphinane-2-oxide;[l-ι 5-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]pyrid-2-yl)-2- diethoxyphosphinyl)eth-l-yl]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;
[l-(5-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-yl]pyrid-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphosphinane-2-oxide;[l-(5-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]pyrid-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]-4,5-dimethyl 1 ,3 ,2-dioxaphospholane-2-oxide;[l-(5-[2-{4-(4-trifluoromethylphenyl)phenoxy}ethoxy]-pyrid-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-l,3,2-dioxaphosphinane-2-oxide;[l-(5-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]pyrid-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;[ 1 -(5-[3- {4-(4-trifiuoromethylphenyl)phenoxy} - 1 -oxoprop- 1 -yl]-pyrid-2-yl)-2- (diethoxyphosphinyrjeth- 1 -yl]- 1 ,3 ,2-dioxaphosphinane-2-oxide;[2-(5-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]pyrid-2-yl)- 2-(diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphospholane-2-oxide;[2-(5-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]pyrid-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl] -4 [R] -methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;[2-(5-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]pyrid-2-yl)-2- (diethoxyphosphinyι)eth- 1 -yl]- 1 ,3,2-dioxaphospholane-2-oxide;[2-(5-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]ρyrid-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-4[R]-methyl-l,3,2-dioxaphospholane-2-oxide;[2-(5-[3 ,N-phthalimidopropoxy]pyrid-2-yl)-2-(diethoxyphosphinyl)eth- 1 -yl]- 1,3,2- dioxaphospholane-2-oxide;[2-(5-[4,N-phthalimidobutoxy]pyrid-2-yl)-2-(diethoxyphosphinyl)eth-l-yl]-4[R]-methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;[2-(5-[2-{N-methyl-N-ρyrid-2-ylamino}ethoxy]benzothien-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-l,3,2-dioxaphospholane-2-oxide;
2[2-(5-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]benzothien-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-4[R]-methyl-l,3,2-dioxaphospholane-2-oxide; 2[2-(5 - [3 - {N-methyl-N-pyrid-2-ylamino } - 1 -oxoprop- 1 -yl]benzothien-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphosphinane-2-oxide; 2[2-(5-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]benzothien-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl] - 1 ,3 ,2-dioxaphosphinane-2-oxide; 2[2-(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]benzothien-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphosphinane-2-oxide; 2[2-(5-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]benzothien-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl] -1,3 ,2-dioxaphosphinane-2-oxide;
2[2-(5-[3- {5-methyl-2-phenylthiazol-4-yl} -1 -oxoprop- 1 -yl]benzothien-2-yl)-l - (diethoxyphosphmyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphospholane-2-oxide; 2[2-(5-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]benzothien-2-yl)-l- (diethoxyphosphinyl)eth-l -yl]-l ,3,2-dioxaphospholane-2-oxide; 2[2-(5-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]benzothien-2-yl)-l- (diethoxyphosphinyl)eth-l-yl]-l,3,2-dioxaphospholane-2-oxide; 2[2-(5-[3-{5 -methyl-2-pyrid-4-yloxazol-4-yl} - 1 -oxoprop- 1 -yl]benzothien-2-yl)- 1 - (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphospholane-2-oxide; N,N,N',N'-Tetramethyl-l (5-/N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N- methylamino]benzothien-2-yl)- 1 -hydroxymethylphosphondiamide;
N,N'-Diethyl l-(5-[2-{4-(4-trifluoromethylphenyl)phenoxy}ethoxy]benzothien-2-yl)-l- hydroxymethylphosphondiamide; 2-[ 1 -hydroxy- 1 -(5-[N-(2- {4-(4-trifluoromethylphenyl)phenoxy} ethyl)-N- methylamino]benzothien-2-yl)methyl]-[4S,5S]-dimethyl- 1 ,3 ,2-diazaphospholidine-2- oxide;
2-[ 1 -hydroxy- 1 -(5 - [3 - {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yfjbenzothien- 2-yl)methyl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2-oxide; 2-[ 1 -hydroxy- l-(5-[2-{l- [4-(2-trifluoromethylphenyl)phenylmethyl] -3 - hexylureido}ethyl]benzothien-2-yl)methyl]-[4S]-ethyl-l,3,2-oxazaphospholidine-2- oxide;
2-[l-hydroxy-l-(5-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]benzothien-2- yl)methyl]-[4R]methyl-l,3,2-oxazaphosphinane-2-oxide; N,N,N',N'-Tetramethyl-1 (5-[3- {4-acetyl-3-hydroxy-2- propylphenoxy)propoxy]benzothien-2-yl)-l-hydroxymethylphosphondiamide; N,N'-Diethyl l-(5-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]benzothien-2-yl)-l- hydroxymethylphosphondiamide; 2-[l-hydroxy-l-(5-[3,N-phthalimidopropoxy]benzothien-2-yl)methyl]-[4S,5S]-dimethyl- 1 ,3 ,2-diazaphospholidine-2 -oxide; 2-[l-hydroxy-l-(5-[4,N-phthalimidobutoxy]benzothien-2-yl)methyl]-l,3,5,5-tetramethyl- 1 ,3 ,2-diazaphosphinane-2-oxide;
2-[l-hydroxy-l-(4-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]thiazol-2-yl)methyl]-[4S]- ethyl- 1 ,3 ,2-oxazaphospholidine-2-oxide; 2-[ 1 -hydroxy- 1 -(4-[N-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N-methylamino]thiazol-2- yl)methyl]-[4R]methyl-l,3,2-oxazaphosphinane-2-oxide; NNN'.N'-Tetramethyl 1 -(4-[3- {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop- 1 -yl]thiazol-2- yl)-l-(bis[N,N-dimethylamino]phosphoryloxy)methylphosphondiamide; N,N'-Diethyl l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]thiazol-2-yl)-l-(bis[N- ethylamino]phosphoryloxy)methylphosphondiamide;
2-[l-{([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)oxy}-l-(4-[N-(2-{5- methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]thiazol-2-yl)methyl]-[4S,5S]- dimethyl- 1 ,3 ,2-diazaphospholidine-2-oxide; 2-[l-{(l,3,5,5-teframethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)oxy}-l-(4-[2-{5-methyl- 2-phenylthiazol-4-yl}ethoxy]thiazol-2-yl)methyl]-l,3,5,5-teframethyl-l,3,2- diazaphosphinane-2-oxide; 2-[l-{(4S]-ethyl-2-oxido-l,3,2-oxazaphospholidin-2-yl)oxy}-l-(4-[3-{5-methyl-2- phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl]thiazol-2-yl)methyl] - [4S] -ethyl- 1,3,2- oxazaphospholidine-2-oxide; 2-[l-{([4R]methyl-l,3,2-oxazaphosphinan-2-yl)oxy}-l-(4-[2-{5-methyl-2-pyrid-4- yloxazol-4-yl} ethoxy]thiazol-2-yl)methyl]-[4R]methyl- 1 ,3 ,2-oxazaphosphinane-2- oxide; N)N,N',N'-Tetramethyl l-(4-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]thiazol-2-yl)- l-(bis[N,N-dimethylamino]phosphoryloxy)methylphosphondiamide; N,NJ-Diethyl l-(4-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-yl]thiazol-2-yl)-l- (bis[N-ethylamino]phosphoryloxy)methylphosphondiamide; 2-[l-{([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)oxy}-l-(4-[N-(2-{5- methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]thiazol-2-yl)methyl]-[4S,5S]- dimethyl- 1 ,3 ,2-diazaphospholidine-2-oxide; 2-[l-{(l,3,5,5-tetramethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)oxy}-l-(4-[2-{4-(4- frifiuoromethylphenyl)phenoxy}ethoxy]thiazol-2-yl)methyl]-l,3,5,5-tetramethyl- 1 ,3 ,2-diazaphosphinane-2-oxide; 2-[l-{(4S]-ethyl-2-oxido-l,3,2-oxazaphospholidin-2-yl)oxy}-l-(4-[N-(2-{4-(4- trifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]thiazol-2-yl)methyl]-[4S]- ethyl- 1 ,3 ,2-oxazaphospholidine-2-oxide;
-[ 1 - {([4R]methyl- 1 ,3 ,2-oxazaphosρhinan-2-yl)oxy} -1 -(4-[3 - {4-(4- trifluoromethylphenyl)phenoxy} - 1 -oxoprop- 1 -yl]thiazol-2-yl)methyI]-[4R]methyl- 1 ,3 ,2-oxazaphosphinane-2-oxide; 1 -(4-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido} ethyl]thiazol-2-yl)- 1,1 -bis(bis[N,N-dimethylamino]phosphoryl)methane;
1 -(4-[2- { 1 -butyl-3-(5-methoxypyrid-2-yl)ureido} ethyl]thiazol-2-yl)- 1 , 1 -bis(bis[N- ethylamino]phosphoryl)methane; l-(4-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]thiazol-2-yl)-l,l-bis([4S,5S]- dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)methane; l-(4-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]thiazol-2-yl)-l,l-bis(l,3,5,5- tetramethyl-2-oxido- 1 ,3 ,2-diazaphosphinan-2-yl)methane ; 1 -(4-[3 ,N-phthalimidopropoxy]thiazol-2-yl)- 1 , 1 -bis ([4S]-ethyl-2-oxido- 1,3,2- oxazaphosρholidin-2-yl)methane; 1 -(4-[4,N-ρhthalimidobutoxy]thiazol-2-yl)- 1 , 1 -bis ([4R]methyl-2-oxido- 1 ,3,2- oxazaphosphinan-2-yl)methane;
1 -(6-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]-3-methoxyquinolin-2-yl)-l , 1 -bis(bis[N,N- dimethylamino]phosphoryl)methane; l-(6-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]-3-methoxyquinolin-2- yl)- 1 , 1 -bis(bis[N-ethylamino]phosphoryl)methane; 1 -(6-[3 - {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop- 1 -yl]-3 -methoxyquinolin-2-yl)- 1,1- bis([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)methane; l-(6-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l,l-bis(l,3,5,5- tetramethyl-2-oxido-l,3,2-diazaρhosphinan-2-yl)methane; l-(6-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]-3-methoxyquinolin-2- yl)-l,l-bis ([4S]-ethyl-2-oxido-l,3,2-oxazaphospholidin-2-yl)methane;
1 -(6-[2- {5-methyl-2-phenylthiazol-4-yl} ethoxy]-3 -methoxyquinolin-2-yl)- 1 , 1 -bis ([4R]methyl-2-oxido- 1 ,3 ,2-oxazaphosphinan-2-yl)methane; l-(6-[3-{5 -methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl] -3 -methoxyquinolin-2-yl)- 1 ,2- bis(bis[NN-dimethylamino]phosphoryl)ethane; l-(6-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l,2- bis(bis[N-ethylamino]phosphoryl)ethane; l-(6-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l,2- bis([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)ethane; l-(6-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-yl]-3-methoxyquinolin-2-yl)- l,2-bis(l,3,5,5-tetramethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)ethane; l-(6-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)-l,2-bis ([4S]-ethyl-2-oxido-l,3,2-oxazaphospholidin-2- yl)ethane; 1 -(6- [2- {4-(4-frifluoromethylphenyl)phenoxy} ethoxy] -3 -methoxyquinolin-2-yl)-l ,2-bis ([4R]methyl-2-oxido- 1 ,3 ,2-oxazaphosphinan-2-yl)ethane; l-(6-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)-l,2-bis(bis[N,N-dimethylamino]phosphoryl)ethane; 1 -(6-[3 - {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl] -3 -methoxy quinolin-2-yl)- l,2-bis(bis[N-ethylamino]phosphoryl)ethane; 1 -(6-[2- { 1 -[4-(2-frifluoromethylphenyl)phenylmethyl]-3-hexylureido} ethyl]-3- methoxyquinolin-2-yl)-l,2-bis([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2- yl)ethane; l-(6-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]-3-methoxyquinolin-2-yl)-l,2- bis(l,3,5,5-teframethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)ethane;
l-(6-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-methoxyquinolin-2-yl)-l,2-bis ([4S]-ethyl-2-oxido- 1 ,3 ,2-oxazaphospholidin-2-yl)ethane; l-(6-[3N-phthalimidopropoxy]-3-methoxyquinolin-2-yl)-l,2-bis ([4R]methyl-2-oxido- 1 ,3 ,2-oxazaphosphinan-2-yl)ethane; 2-(6-[4,N-phthalimidobutoxy]-3-methoxyquinolin-2-yl)-l,l-bis(bis[N,N- dimethylamino]phosphoryl)ethane; 2-(5-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]thien-2-yl)-l,l-bis(bis[N- ethylamino]phosphoryl)ethane; 2-(5-[N-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N-methylamino]thien-2-yl)- 1,1- bis([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)ethane;
2-(5-[3 - {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop- 1 -yl]thien-2-yl)- 1 , 1 -bis(l ,3 ,5,5- tetramethyl-2-oxido- 1 ,3 ,2-diazaphosphinan-2-yl)ethane; 2-(5-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]thien-2-yl)-l,l-bis ([4S]-ethyl-2-oxido- l,3,2-oxazaphospholidin-2-yl)ethane; 2-(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]thien-2-yl)-l,l-bis ([4R]methyl-2-oxido- 1 ,3 ,2-oxazaphosphinan-2-yl)ethane; 2-(5-[2- {5-methyl-2-phenylthiazol-4-yl} ethoxy]thien-2-yl)- 1 , 1 -bis(bis[N,N- dimethylamino]phosphoryl)ethane; 2-(5-[3 - {5-methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl]thien-2-yl)- 1 , 1 -bis(bis[N- ethylamino]phosphoryl)ethane;
2-(5-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]thien-2-yl)-l,l-bis([4S,5S]-dimethyl- 2-oxido- 1 ,3 ,2-diazaphospholidin-2-yl)ethane; 2-(5-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]thien-2-yl)-l,l-bis(l,3,5,5- tetramethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)ethane;
-(5-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoρrop-l-yl]thien-2-yl)-l,l-bis ([4S]- ethyl-2-oxido- 1 ,3 ,2-oxazaphospholidin-2-yl)ethane; -(5-[N-(2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethyl)-N-methylamino]thien-2-yl)- 1 , 1 -bis ([4R]methyl-2-oxido- 1 ,3 ,2-oxazaphosphinan-2-yl)ethane; 1 -[N-(5-[2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy]thien-2-yl)amino]-l ,1 - bis(bis[N,N-dimethylamino]phosphoryl)methane; l-[N-(5-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]thien-2- yl)amino] -1,1 -bis(bis[N-ethylamino]phosphoryl)methane ; 1 - [N-(5 -[3 - {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl] thien-2-yl)amino] -1,1- bis([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)methane;
1 - [N-(5 -[2- { 1 - [4-(2-trifluoromethylphenyl)phenylmethyl] -3 -hexylureido } ethyl] thien-2- yl)amino]- 1 , 1 -bis( 1 ,3 ,5 ,5-tetramethyl-2-oxido- 1 ,3 ,2-diazaphosphinan-2-yl)methane; 1 - [N-(5 -[2- { 1 -butyl-3 -(5 -methoxypyrid-2-yl)ureido} ethyl]thien-2-yl)amino] - 1 , 1 -bis ([4S]-ethyl-2-oxido-l,3,2-oxazaphospholidin-2-yl)methane; 1 - [N-(5 - [3 - {4-acetyl-3 -hydroxy-2-propylphenoxy)propoxy] thien-2-yl)amino]- 1 , 1 -bis ([4R]methyl-2-oxido-l,3,2-oxazaphosphinan-2-yl)methane; l-[N-(5-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]thien-2-yl)amino]-l,l-bis(bis[N,N- dimethylamino]phosphoryl)methane; 1 -[N-(5 - [3 ,N-phthalimidopropoxy]thien-2-yl)amino] - 1 , 1 -bis(bis [N- ethylamino]phosphoryl)methane; l-[N-(5-[4,N-phthalimidobutoxy]thien-2-yl)amino]-l,l-bis([4S,5S]-dimethyl-2-oxido- 1 ,3 ,2-diazaphospholidin-2-yl)methane; l-[N-(4-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]-3-fluorophenyl)amino]-l,l-bis(l,3,5,5- tetramethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)methane;
-[N-(4-[N-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N-methylaminocarbonyl]-3- fluorophenyl)amino]- 1 , 1 -bis ([4S]-ethyl-2-oxido- 1 ,3 ,2-oxazaphospholidin-2- yl)methane; -[N-(4-[3- {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop-1 -yl]-3-fluorophenyl)amino]- 1 , 1 - bis ([4R]methyl-2-oxido-l,3,2-oxazaphosphinan-2-yl)methane;-[ 1 -(Bis[N-ethylamino]phosphoryloxy)- 1 -(4-[2- { 5-methyl-2-phenyloxazol-4-yl} ethoxy]- 3-fluorophenyl)methyl]-[4S,5S]-dimethyl-l,3,2-diazaphospholidine-2-oxide;-[l -(Bis[N-ethylamino]phosphoryl)-l -(4-[N-(2- {5-methyl-2-phenyloxazol-4-yl} ethyl)-N- methylaminocarbonyl]-3-fluorophenyl)methoxy]-[4S,5S]-dimethyl-l,3,2- diazaphospholidine-2-oxide;-[l-(Bis[N-ethylamino]phosphoryl)-l-(4-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]-3- fluorophenyl)methyl]- 1 ,3 ,5 ,5-tetramethyl- 1 ,3 ,2-diazaphosphinane-2-oxide;-[l-(Bis[N-ethylamino]phosphoryl)-2-(4-[3-{5-methyl-2-phenylthiazol-4-yl}-l-oxoprop- l-yl]-3-fluorophenyl)ethen-l-yl]-[4S]-ethyl-l,3,2-oxazaphospholidine-2-oxide;- [ 1 -(Bis [N-ethylamino]phosphoryl)-2-(4- [2- { 5-methyl-2-pyrid-4-yloxazol-4-yl} ethoxy] - 3 -fluorophenyl)eth- 1 -yl] - [4R]methyl- 1 ,3 ,2-oxazaphosphinane-2-oxide ;-[2-(Bis[N-ethylamino]phosphoryl)-2-(4-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]- 3-fluorophenyl)eth-l-yl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2-oxide;-[2-(Bis[N-ethylamino]phosphoryl)-l-(4-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l- oxoprop-l-yl]-3-fluorophenyl)eth-l-yl]-[4S]-ethyl-l,3,2-oxazaphospholidine-2-oxide;-[ 1 -(Bis[N-ethylamino]phosphoryloxy)- 1 -(4-[N-(2- {5-methyl-2-pyrid-4-ylthiazol-4- yl}ethyl)-Ν-methylaminocarbonyl]-3-fluorophenyl)methyl]-[4S,5S]-dimethyl-l,3,2- diazaphospholidine-2-oxide;
-[ 1 -(Bis[N-ethylamino]phosphoryl)- 1 -(4-[2- {4-(4- trifluoromethylphenyl)phenoxy } ethoxy] -3 -fluorophenyl)methoxy] - [4S , 5 S ] -dimethyl- l,3,2-diazaphospholidine-2 -oxide;-[ 1 -(Bis[N-ethylamino]phosphoryl)- 1 -(4-[N-(2- {4-(4- frifluoromethylphenyl)phenoxy } ethyl)-N-methylaminocarbonyl] -3 - fluorophenyl)methyl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2-oxide;-[l-(Bis[N-ethylamino]phosphoryl)-2-(4-[3-{4-(4-trifluoromethylphenyl)phenoxy}-l- oxoprop-l-yl]-3-fiuorophenyl)ethen-l-yl]-[4S]-ethyl-l,3,2-oxazaphospholidine-2- oxide;-[l-(Bis[N-ethylamino]phosphoryl)-2-(4-[2-{l-[4-(2- trifiuoromethylphenyl)phenylmethyl] -3 -hexylureido } ethyl] -3 -fluorophenyl) eth- 1 -yl] - [4R]methyl- 1 ,3 ,2-oxazaphosphinane-2-oxide;-[2-(Bis[N-ethylamino]phosphoryl)-2-(4-[2-{l-butyl-3-(5-methoxypyrid-2- yl)ureido}ethyl]-3-fluorophenyl)eth-l-yl]-l,3,5,5-tetramethyl-l,3,2- diazaphosphinane-2-oxide;-[2-(Bis[N-ethylamino]phosphoryl)-l-(4-[3-{4-acetyl-3-hydroxy-2- propylphenoxy)propoxy] -3 -fluorophenyl)eth- 1 -yl] - [4S] -ethyl- 1,3,2- oxazaphospholidine-2-oxide;-[l-(Diethoxyphosphoryloxy)-l-(4-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]-3- fluorophenyl)methyl]-[4S,5S]-dimethyl-l,3,2-diazaphospholidine-2-oxide;-[l-(Diethoxyphosphoryl)-l-(4-[3,N-phthalimidopropoxy]-3-fluorophenyl)methoxy]- [4S,5S]-dimethyl-l,3,2-diazaphospholidine-2-oxide;-[l-(Diethoxyphosphoryl)-l-(4-[4,N-phthalimidobutoxy]-3-fluorophenyl)methyl]- 1 ,3,5,5-teframethyl-l ,3,2-diazaphosphinane-2-oxide;
-[l-(Diethoxyphosphoryl)-2-(3-[3-{N-methyl-N-pyrid-2-ylamino}propoxy]-4- fluorophenyl)ethen-l-yl]-[4S]-ethyl-l,3,2-oxazaphospholidine-2-oxide;-[l-(Diethoxyphosphoryl)-2-(3-[N-(3-{N-methyl-N-pyrid-2-ylamino}propyl)-N- methylamino]-4-fluorophenyl)eth-l-yl]-[4R]methyl-l,3,2-oxazaphosphinane-2-oxide;-[2-(Diethoxyphosphoryl)-2-(3-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l- ylamino]-4-fluorophenyl)eth-l-yl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2- oxide;-[2-(Diethoxyphosphoryl)-l-(3-[3-{5-methyl-2-phenyloxazol-4-yl}propoxy]-4- fluorophenyl)eth-l-yl]-[4S]-ethyl-l,3,2-oxazaphospholidine-2-oxide;-[l-(Diethoxyphosphoryloxy)-l-(3-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N- methylaminocarbonyl]-4-methoxyphenyl)methyl]-[4S,5S]-dimethyl-l,3,2- diazaphospholidine-2-oxide;-[l-(Diethoxyphosphoryl)-l-(3-[3-{5-methyl-2-phenylthiazol-4-yl}propoxy]-4- fluorophenyl)methoxy]-[4S,5S]-dimethyl-l,3,2-diazaphospholidine-2-oxide;-[l-(Diethoxyphosphoryl)-l-(3-[3-{5-methyl-2-phenylthiazol-4-yl}-l-oxoprop-l-yl]-4- fluorophenyl)methyl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2-oxide;-[l-(Diethoxyphosphoryl)-2-(3-[4-{5-methyl-2-pyrid-4-yloxazol-4-yl}butoxy]-4- fluorophenyl)ethen-l-yl]-[4S]-ethyl-l,3,2-oxazaphospholidine-2-oxide;- [ 1 -(Diethoxyphosphoryl)-2-(3 -[3 - {5 -methyl-2-pyrid-4-ylthiazol-4-yl } propoxy] -4- fluorophenyl)eth-l-yl]-[4R]methyl-l,3,2-oxazaphosphinane-2-oxide;-[2-(Diethoxyphosphoryl)-2-(3-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l- ylthio]-4-fluorophenyl)eth-l-yl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2-oxide;-[2-(Diethoxyphosphoryl)-l-(3-[N-(3-{5-methyl-2-ρyrid-4-ylthiazol-4-yl}proρyl)-N- methylamino]-4-fluorophenyl)eth-l-yl]-[4S]-ethyl-l,3,2-oxazaphospholidine-2-oxide.
In an even more prefeπed embodiment of this aspect, the compound of Formula (I) is selected from:
Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4- [2- {N-methyl-N-pyrid-2-ylamino} ethoxy] -3 - fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4- [3 ,N-phthalimidopropoxy] -3 - fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]-3- fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(3-[3- {N-methyl-N-pyrid-2-ylamino}propoxy]-4- fluorophenyl)methylphosphonate;
Diethyl l-(diethoxyphosphinyloxy)-l-(3-[4-{N-methyl-N-pyrid-2-ylamino}butoxy]-4- fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(3-[4,N-phthalimidobutoxy]-4- fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(3-[5,N-phthalimidopentoxy]-4- fiuorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)-l -(3-[4- {5-methyl-2-pyrid-4-yloxazol-4-yl}butoxy]- 4-fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(3-[5-{5-methyl-2-pyrid-4-yloxazol-4-yl}pentoxy]- 4-fluorophenyl)methylphosphonate; l-(4-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]-3-fluorophenyl)-l,l-bis([4R,5S]- dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; l-(4-[3,N-phthalimidopropoxy]-3-fluorophenyl)-l,l-bis([4R,5S]-dimethyl-2-oxido-l,3,2- dioxaphospholan-2-yl)methane;
1 -(4-[2- {5-methyl-2-phenyloxazol-4-yl} ethoxy]-3-fluorophenyl)-l , 1 -bis([4R,5S]- dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; 1 -(3-[3- {N-methyl-N-pyrid-2-ylamino}propoxy]-4-fluorophenyl )- 1 , 1 -bis([4R,5S]- dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; l-(3-[4-{N-methyl-N-pyrid-2-ylamino}butoxy]-4-fluorophenyl)-l,l-bis([4R,5S]- dimethyl-2-oxido- 1 ,3 ,2-dioxaphosρholan-2-yl)methane; l-(3-[4,N-phthalimidobutoxy]-4-fluorophenyl)-l,l-bis([4R,5S]-dimethyl-2-oxido-l,3,2- dioxaphosρholan-2-yl)methane; 1 -(3-[5 ,N-phthalimidopentoxy]-4-fluorophenyl)- 1 , 1 -bis([4R,5 S]-dimethyl-2-oxido- 1,3,2- dioxaphospholan-2-yl)methane; l-(3-[4-{5-methyl-2-pyrid-4-yloxazol-4-yl}butoxy]-4-fluorophenyl)-l,l-bis([4R,5S]- dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methane; l-(3-[5-{5-methyl-2-pyrid-4-yloxazol-4-yl}pentoxy]-4-fluorophenyl)-l,l-bis([4R,5S]- dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; N,N,N',N'-Tetramethyl 1 -(4-[2- {N-methyl-N-ρyrid-2-ylamino}ethoxy]-3-fluorophenyl)- 1 -hydroxymethylphosphondiamide; NNN',N'-Tetramethyl l-(4-[3,N-phthalimidoproρoxy]-3-fluorophenyl)-l- hydroxymethylphosphondiamide; N,N,N'/N'-Tetramethyl l-(4-[2-{5-methyl-2-phenyloxazol-4-yI}ethoxy]-3-fluorophenyl)- 1 -hydroxymethylphosphondiamide;
2-[l-hydroxy-l-(4-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]-3-fluorophenyl)methyl]- [4S]-(1 -methylethyl)- 1 ,3 ,2-oxazaphospholidine-2-oxide; 2-[ 1 -hydroxy- 1 -(4-[3 ,N-phthalimidopropoxy]-3-fluorophenyl)methyl]-[4S]-( 1 - methylethyl)-l,3,2-oxazaphospholidine-2-oxide;
2-[l-hydroxy-l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]-3-fluorophenyl)methyl]- [4S]-(l-methylethyl)-l,3,2-oxazaphospholidine-2-oxide; 1 -[N-(4-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]-3 -fluorophenyl)amino]- 1 , 1 -bis(bis[N- ethylamino]phosphoryl)methane; 1 - [N-(4- [3 ,N-phthalimidopropoxy] -3 -fluorophenyl)amino] -1,1 -bis(bis[N- ethylamino]phosρhoryl)methane; and l-[N-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]-3-fluorophenyl)amino]-l,l- bis(bis[N-ethylamino]phosphoryl)methane. The compounds of Formula (I) may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers. All isomeric forms are included within the scope ofthe present invention. In another aspect, the invention relates to pharmaceutical formulations comprising a compound, or pharmaceutically acceptable salt thereof, of Formula (I):
Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethoxy]- 3-fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(4-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l- oxoprop-l-yl]-3-fluorophenyl)methylphosphonate; Diethyl 1 -(hydroxy)- 1 -(4-[N-(2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethyl)-Ν- methylaminocarbonyl]-3-fluorophenyl)methylphosphonate; Diethyl 1 -(hydroxy)-l -(4-[2- {4-(4-trifluoromethylphenyl)phenoxy} efhoxy]-3- fluorophenyl)methylphosphonate; Diethyl l-(hydroxy)-l-(4-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N- methylaminocarbonyl]-3-fluorophenyl)methylphosphonate;
Diethyl l-(hydroxy)-l-(4-[3-{4-(4-trifluoromethylphenyl)phenoxy}-l-oxoprop-l-yl]-3- fluorophenyl)methylphosphonate; Diethyl l-(hydroxy)-l-(4-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3- hexy lureido } ethyl] -3 -fluorophenyl)methylpho sphonate;
Diethyl l-(hydroxy)-l-(4-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]-3- fluorophenyl)methylphosphonate; Diethyl 1 -(hydroxy)- 1 -(4- [3 - {4-acetyl-3 -hydroxy-2-propylphenoxy)propoxy] -3 - fluorophenyl)methylphosphonate; Diethyl l-(hydroxy)-l-(4-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]-3- fluorophenyl)methylphosphonate; Diethyl l-(hydroxy)-l-(4-[3,N-phthalimidopropoxy]-3-fluorophenyl)methylphosphonate; Diethyl l-(hydroxy)-l-(4-[4,N-phthalimidobutoxy]-3-fluorophenyl)methylphosphonate; Tetraethyl 1 -(3-[3- {N-methyl-N-pyrid-2-ylamino}propoxy]-4-fluorophenyl )methylidenebisphosphonate;
Tetraethyl 1 -(3 - [N-(3- {N-methyl-N-pyrid-2-ylamino } propyl)-N-methylamino] -4- fluorophenyl)methylidenebisphosphonate; Tetraethyl 1 -(3 -[3 - {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop- 1 -ylamino] -4- fluorophenyl)methylidenebisphosphonate; Tetraethyl l-(3-[3-{5-methyl-2-phenyloxazol-4-yl}propoxy]-4- fluorophenyl)methylidenebisphosphonate; Tetraethyl l-(3-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylaminocarbonyl]-4- methoxyphenyl)methylidenebisphosphonate; Tetraethyl l-(3-[3-{5-methyl-2-phenylthiazol-4-yl}propoxy]-4- fluorophenyl)methylidenebisphosphonate;
Tetraethyl 1 -(3-[3- {5-methyl-2-phenylthiazol-4-yl} -1 -oxoprop-1 -yl]-4- fluorophenyl)methylidenebisphosphonate; Tetraethyl 1 -(3-[4- {5-methyl-2-pyrid-4-yloxazol-4-yl}butoxy]-4- fluorophenyl)methylidenebisphosphonate;
Tetraethyl l-(3-[3-{5-methyl-2-pyrid-4-ylthiazol-4-yl}propoxy]-4- fluorophenyl)methylidenebisphosphonate; Tetraethyl 1 -(3-[3- {5-methyl-2-pyrid-4-yloxazol-4-yl} -1 -oxoprop-1 -ylthio]-4- fluorophenyl)methylidenebisphosphonate; Tetraethyl 2-(3-[N-(3-{5-methyl-2-pyrid-4-ylthiazol-4-yl}propyl)-N-methylamino]-4- fiuorophenyl)vinylidene-l , 1 -bisphosphonate; Tetraethyl 2-(3-[3- {4-(4-trifluoromethylphenyl)phenoxy}propoxy]-4- fluorophenyl)vinylidene-l , 1 -bisphosphonate; Tetraethyl 2-(3-[N-(3-{4-(4-trifluoromethylphenyl)phenoxy}propyl)-N-methylamino]-4- fluorophenyl)vinylidene- 1 , 1 -bisphosphonate;
Tetraethyl 2-(3 -[4- {4-(4-trifluoromethylphenyl)phenoxy)- 1 -oxobut- 1 -yl]-4- fluorophenyl)vinylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(3-[2-{l- [4-(2-trifluoromethylphenyl)phenylmethyl] -3 -hexylureido } ethyl] -4- fluorophenyl)vinylidene-l , 1 -bisphosphonate; Tetraethyl 2-(3-[2- { 1 -butyl-3-(5-methoxypyrid-2-yl)ureido} ethyl]-4- fluorophenyl)vinylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(3 - [4- {4-acetyl-3 -hydroxy-2-propylphenoxy)butoxy] -4- fluorophenyl)vinylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(3-[3-{4H-3-oxobenzo[l,4]oxazin-2-yl}propoxy]-4-fluorophenyl)vinylidene- 1,1 -bisphosphonate;
Tetraethyl 2-(3-[3,N-phthalimidopropoxy]-4-fluorophenyl)vinylidene-l,l-bisphosphonate; Tetraethyl 2-(3-[4,N-phthalimidobutoxy]-4-fluorophenyl)vinylidene-l,l-bisphosphonate; Tetraethyl l-(6-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]indol-2-yl)ethylidene-l,2- bisphosphonate;
Tetraethyl 1 -(6-[N-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N-methylamino]indol-2- yl)ethylidene- 1 ,2-bisphosphonate; Tetraethyl l-(6-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l-yl]indol-2-yl)ethylidene- 1 ,2-bisphosphonate; Tetraethyl l-(6-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy] indol-2-yl)ethylidene-l,2- bisphosphonate; Tetraethyl 1 -(6-[N-(2- {5-methyl-2-phenyloxazol-4-yl} ethyl)-N-methylamino] indol-2- yl)ethylidene- 1 ,2-bisphosphonate; Tetraethyl l-(6-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]indol-2-yl)ethylidene-l,2- bisphosphonate;
Tetraethyl 1 -(6-[3- {5-methyl-2-phenylthiazol-4-yl} -1 -oxoprop-1 -yl]indol-2-yl)ethylidene- 1 ,2-bisphosphonate; Tetraethyl l-(6-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]indol-2-yl)ethylidene-l,2- bisphosphonate; Tetraethyl l-(6-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]indol-2-yl)ethylidene-l,2- bisphosphonate; Tetraethyl 1 -(6-[3- {5-methyl-2-pyrid-4-yloxazol-4-yl} -1 -oxoprop-1 -yl]indol-2- yl)ethylidene- 1 ,2-bisphosphonate; Tetraethyl 2-(6-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]indol-2- yl)ethylidene- 1 , 1 -bisphosphonate;
Tetraethyl 2-(6-[2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy] indol-2-yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(6-[N-(2- {4-(4-trifluoromethylphenyl)phenoxy} ethyl)-N-methylamino]indol- 2-yl)ethylidene- 1 , 1 -bisphosphonate;
Tetraethyl 2-(6-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3- hexylureido} ethyl]indol-2-yl)ethylidene- 1 , 1 -bisphosphonate; Tefraethyl 2-(6-[2- { 1 -butyl-3 -(5-methoxypyrid-2-yl)ureido} ethyl]indol-2-yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(6-[3- {4-(4-trifluoromethylphenyl)phenoxy} - 1 -oxoprop- 1 -yl]indol-2- yl)ethylidene-l , 1 -bisphosphonate; Tetraethyl 2-(6-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]indol-2-yl)ethylidene- 1 , 1 -bisphosphonate; Tefraethyl 2-(6-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]indol-2-yl)ethylidene-l,l- bisphosphonate;
Tetraethyl 2-(6-[3 ,N-phthalimidopropoxy]indol-2-yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(6-[4,N-phthalimidobutoxy]indol-2-yl)ethylidene-l,l -bisphosphonate; Tetraethyl N-(5-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]pyrid-2- yl)aminomethylidenebisphosphonate; Tetraethyl N-(5-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]pyrid-2- yl)aminomethylidenebisphosphonate; Tetraethyl N-(5 - [3 - {N-methyl-N-pyrid-2-ylamino } - 1 -oxoprop- 1 -yl]pyrid-2- yl)aminomethylidenebisphosphonate; Tefraethyl N-(5-[2- {5-methyl-2-phenyloxazol-4-yl} ethoxy]pyrid-2- yl)aminomethylidenebisphosphonate
Tetraethyl N-(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]pyrid-2- yl)aminomethylidenebisphosphonate; Tetraethyl N-(5-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]pyrid-2- yl)aminomethylidenebisphosphonate;
Tetraethyl N-(5-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-yl]pyrid-2- yl)aminomethylidenebisphosphonate; Tefraethyl N-(5-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]pyrid-2- yl)aminomethylidenebisphosphonate; Tetraethyl N-(5-[2- {5-methyl-2-pyrid-4-yloxazol-4-yl} ethoxy]pyrid-2- yl)aminomethylidenebisphosphonate; Tefraethyl N-(5-[2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethoxy]pyrid-2- yl)aminomethylidenebisphosphonate; 2-[l-Hydroxy-l-(5-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N- methylamino]pyrid-2-yl)methyl]-l,3,2-dioxaphospholane-2-oxide;
2-[l-Hydroxy-l-(5-[2-{4-(4-trifluoromethylphenyl)phenoxy}ethoxy]-pyrid-2-yl)methyl]- 1 ,3,2-dioxaphospholane-2-oxide; 2-[l-Hydroxy-l-(5-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N- methylamino]pyrid-2-yl)methyl]-l,3,2-dioxaphospholane-2-oxide; 2-[ 1 -Hydroxy- 1 -(5 -[3 - {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl] -pyrid-2- yl)methyl] -1,3 ,2-dioxaphospholane-2-oxide; 2-[ 1 -Hydroxy- l-(5-[2-{l- [4-(2-trifiuoromethylphenyl)phenylmethyl] -3 - hexylureido}ethyl]pyrid-2-yl)methyl]-l,3,2-dioxaphospholane-2-oxide; 2-[l-Hydroxy-l-(5-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]pyrid-2-ylmethyl]- 1 ,3 ,2-dioxaphospholane-2-oxide;
2-[l-Hydroxy-15-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]pyrid-2-ylmethyl]- 1 ,3 ,2-dioxaphospholane-2-oxide; 2-[l-Hydroxy-l-(5-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]pyrid-2-yl)methyl]-l,3,2- dioxaphospholane-2-oxide;
- [ 1 -Hydroxy- 1 -(5 -[3 ,N-phthalimidopropoxy]pyrid-2-yl)methyl] -1,3 ,2-dioxaphospholane- 2-oxide;-[l-Hydroxy-l-(5-[4,N-phthalimidobutoxy]pyrid-2-yl)methyl]-l,3,2-dioxaphospholane- 2-oxide;- [ 1 -Hydroxy- 1 -(5 -[2- {N-methyl-N-pyrid-2-ylamino } ethoxy]benzothien-2-yl)methyl] - [4R] -methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(5-[N-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N- methylamino]benzothien-2-yl)methyl]- [4R]-methyl-l,3,2-dioxaphospholane-2-oxide;- [ 1 -Hydroxy- 1 -(5 - [3 - {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop- 1 -yl]benzothien-2- yl)methyl]- [4R]-methyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]benzothien-2-yl)methyl]- [4R]-methyl-l,3,2-dioxaphospholane-2-oxide;-[l -Hydroxy- 1 -(5-[N-(2- {5-methyl-2-phenyloxazol-4-yl} ethyl)-N- methylamino]benzothien-2-yl)methyl]- [4R]-methyl-l,3,2-dioxaphospholane-2-oxide;- [ 1 -Hydroxy- 1 -(5- [2- { 5 -methyl-2-phenylthiazol-4-yl} ethoxy]benzothien-2-yl)methyl] - [4R]-methyl-l,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy-1 -(5-[3- {5-methyl-2-phenylthiazol-4-yl}- 1 -oxoprop-1 -yPjbenzothien-2- yl)methyl] - [4R] -methyl- 1 ,3 ,2-dioxaphospholane-2-oxide ;-[l-Hydroxy-l-(5-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]benzothien-2- yl)methyl]- [4R]-methyl-l,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy-1 -(5-[2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethoxy]benzothien-2- yl)methyl] - [4R]-methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-yl]benzothien-2- yl)methyl] - [4R]-methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;
-[l-Hydroxy-l-(5-/N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N- methylamino]benzothien-2-yl)methyl]- [4S]-methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(5-[2- {4-(4-trifIuoromethylphenyl)phenoxy} ethoxy]benzothien-2- yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[N-(2-{4-(4-trifluoromethylphenyl)ρhenoxy}ethyl)-N- methylamino]benzothien-2-yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(5-[3- {4-(4-trifluoromethylphenyl)phenoxy} - 1 -oxoprop-1 -yl]benzothien- 2-yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(5 -[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3 - hexylureido}ethyl]benzothien-2-yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2- oxide;-[ 1 -Hydroxy- 1 -(5-[2- { 1 -butyl-3-(5-methoxypyrid-2-yl)ureido} ethyl]benzothien~2- yl)methyl]- [4S]-methyl-l ,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]benzothien-2- yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]benzothien-2-yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[3,N-phthalimidopropoxy]benzothien-2-yl)methyl]- [4S]-methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[4,N-phthalimidobutoxy]benzothien-2-yl)methyl]- [4S]-methyl-l,3,2- dioxaphospholane-2-oxide;-[l-Hydroxy-l-(4-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]thiazol-2-yl)methyl]-4,5- dimethyl- 1 ,3 ,2-dioxaphospholane-2-oxide ;-[l-Hydroxy-l-(4-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]thiazol-2- yl)methyl]-4,5-dimethyl-l ,3,2-dioxaphospholane-2-oxide;
- [ 1 -Hydroxy- 1-(4-[3- {N-methyl-N-pyrid-2-ylamino } - 1 -oxoprop- 1 -yl]thiazol-2- yl)methyl]-4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]thiazol-2-yl)methyl]-4,5- dimethyl- 1 ,3 ,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(4-[N-(2- {5-methyl-2-phenyloxazol-4-yl} ethyl)-N-methylamino]thiazol- 2-yl)methyl]-4,5-dimethyl- 1 ,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(4-[2-{5-methyl-2-ρhenylthiazol-4-yl}ethoxy]thiazol-2-yl)methyl]-4,5- dimethyl- 1 ,3 ,2-dioxaphospholane-2-oxide;- [ 1 -Hydroxy- 1-(4-[3-{5 -methyl-2-phenylthiazol-4-yl } - 1 -oxoprop- 1 -yl]thiazol-2- yl)methyl]-4,5-dimethyl- 1 ,3 ,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(4-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]thiazol-2-yl)methyl]- 4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy-1 -(4-[2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethoxy]thiazol-2-yl)methyl]- 4,5-dimethyl- 1 ,3 ,2-dioxaphospholane-2 -oxide;-[l-Hydroxy-l-(4-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-yl]thiazol-2- yl)methyl]-4,5-dimethyl- 1 ,3 ,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(4-[N-(2- { 5-methyl-2-pyrid-4-ylthiazol-4-yl} ethyl)-N- methylamino]thiazol-2-yl)methyl]-l,3,2-dioxaphosphinane-2 -oxide;-[ 1 -Hydroxy-1 -(4-[2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy]thiazol-2-yl)methyl]- 1 ,3,2-dioxaphosphinane-2-oxide;-[ 1 -Hydroxy- 1 -(4-[N-(2- {4-(4-frifluoromethylphenyl)phenoxy } ethyl)-N- methylamino]thiazol-2-yl)methyl]-l,3,2-dioxaphosphinane-2-oxide;- [ 1 -Hydroxy- 1 -(4- [3 - {4-(4-trifluoromethylphenyl)phenoxy} - 1 -oxoprop- 1 -yl] thiazol-2- yl)methyl]-l,3,2-dioxaphosphinane-2-oxide;
-[ 1 -Hydroxy- 1 -(4-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3- hexylureido } ethyl]thiazol-2-yl)methyl] -1,3 ,2-dioxaphosphinane-2-oxide;-[ 1 -Hydroxy- 1 -(4-[2- { 1 -butyl-3-(5-methoxypyrid-2-yl)ureido} ethyl]thiazol-2- yl)methyl]-l,3,2-dioxaphosphinane-2-oxide;-[l-Hydroxy-l-(4-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]thiazol-2- yl)methyl] -1,3 ,2-dioxaphosphinane-2-oxide;-[l-Hydroxy-l-(4-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]thiazol-2-yl)methyl]- 1 ,3 ,2-dioxaphosphinane-2-oxide;-[ 1 -Hydroxy- 1 -(4-[3 ,N-phthalimidopropoxy]thiazol-2-yl)methyl]- 1 ,3 ,2- dioxaphosphinane-2-oxide;-[l-Hydroxy-l-(4-[4,N-phthalimidobutoxy]thiazol-2-yl)methyl]-l,3,2- dioxaphosphinane-2-oxide; [ 1 -(6- [2- {N-methyl-N-pyrid-2-ylamino } ethoxy] -3 -methoxyquinolin-2-yl)- 1 -(2-oxido- l,3,2-dioxaphospholan-2-yl)methoxy]-l,3,2-dioxaphospholane-2-oxide;[l-(6- [N-(2- {N-methyl-N-pyrid-2-ylamino } ethyl)-N-methylamino] -3 -methoxy quinolin- 2-yl)-l -(2-oxido-l ,3,2-dioxaphospholan-2-yl)methoxy]-l ,3,2-dioxaphospholane-2- oxide;[l-(6-[3- {N-methyl-N-pyrid-2-ylamino } - 1 -oxoprop- 1 -yl] -3 -methoxyquinolin-2-yl)- 1 -(2- oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- 1 ,3 ,2-dioxaphospholane-2-oxide;[l-(6-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l-(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- 1 ,3 ,2-dioxaphospholane-2-oxide; [ 1 -(6- [N-(2- { 5-methyl-2-phenyloxazol-4-yl } ethyl)-N-methylamino] -3 -methoxyquinolin- 2-yl)-l -(2-oxido-l ,3,2-dioxaphospholan-2-yl)methoxy]-l ,3,2-dioxaphospholane-2- oxide;
[ 1 -(6-[2- { 5 -methyl-2-phenylthiazol-4-yl} ethoxy] -3 -methoxy quinolin-2-yl)- 1 -(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- 1 ,3 ,2-dioxaphospholane-2-oxide;[l-(6-[3-{5-methyl-2-phenylthiazol-4-yl}-l-oxoprop-l-yl]-3-methoxyquinolin-2-yl)-l- (2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy] -1,3 ,2-dioxaphospholane-2-oxide;[l-(6-[2-{5-methyl-2-ρyrid-4-yloxazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l-(2- oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-l,3,2-dioxaphospholane-2-oxide;[l-(6-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l-(2- oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- 1 ,3 ,2-dioxaphospholane-2-oxide; [ 1 -(6- [3 - { 5 -methyl-2-pyrid-4-yloxazol-4-yl } - 1 -oxoprop- 1 -yl] -3 -methoxyquinolin-2-yl)- 1 -(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- 1 ,3 ,2-dioxaphospholane-2 -oxide;[l-(6-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)-l-([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2- yl)methoxy]-[4R]-methyl-l ,3,2-dioxaphospholane-2-oxide;[l-(6-[2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy] -3 -methoxyquinolin-2-yl)- 1 - ([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-[4R]-methyl-l,3,2- dioxaphospholane-2-oxide;[l-(6-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)- 1 -([4R]-methyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2- yl)methoxy]-[4R]-methyl-l,3,2-dioxaphospholane-2-oxide;[l-(6-[3- {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl] -3 -methoxyquinolin-2- yl)- 1 -([4R] -methyl-2-oxido- 1 ,3,2-dioxaphospholan-2-yl)methoxy]-[4R]-methyl- 1,3,2- dioxaphospholane-2-oxide;[1 -(6-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido} ethyl]-3- methoxyquinolin-2-yl)- 1 -([4R]-methyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2- yl)methoxy]-[4R]-methyl-l,3,2-dioxaphospholane-2-oxide;
[1 -(6-[2- { 1 -butyl-3-(5-methoxypyrid-2-yl)ureido} ethyl]-3-methoxyquinolin-2-yl)-l - ([4R] -methyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy] - [4R] -methyl- 1,3,2- dioxaphospholane-2-oxide; [ 1 -(6- [3 - {4-acetyl-3 -hydroxy-2-propylphenoxy)propoxy] -3 -methoxy quinolin-2-yl)- 1 - ([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-[4R]-methyl-l,3,2- dioxaphospholane-2-oxide;[l-(6-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]-3-methoxyquinolin-2-yl)-l-([4R]- methyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy] - [4R] -methyl- 1,3,2- dioxaphospholane-2-oxide;[l-(6-[3,N-phthalimidopropoxy]-3-methoxyquinolin-2-yl)-l-([4R]-methyl-2-oxido-l,3,2- dioxaphospholan-2-yl)methoxy]-[4R]-methyl-l,3,2-dioxaphospholane-2-oxide;[l-(6-[4,N-phthalimidobutoxy]-3-methoxyquinolin-2-yl)-l-([4R]-methyl-2-oxido-l,3,2- dioxaphospholan-2-yl)methoxy]-[4R]-methyl-l,3,2-dioxaphospholane-2-oxide;[l-(5-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]thien-2-yl)-l-([4S]-methyl-2-oxido- l,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;[l-(5-[N-(2-{N-methyl-N-ρyrid-2-ylamino}ethyl)-N-methylamino]thien-2-yl)-l-([4S]- methyl-2-oxido-l ,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l ,3,2- dioxaphospholane-2 -oxide;[l-(5-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l-yl]thien-2-yl)-l-([4S]-methyl-2- oxido-1 ,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l ,3,2-dioxaphospholane-2- oxide; [ 1 -(5-[2- {5-methyl-2-phenyloxazol-4-yl} ethoxy]thien-2-yl)- 1 -([4S] -methyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- [4S] -methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;
[l-(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]thien-2-yl)-l-([4S]- methyl-2-oxido-l ,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l ,3,2- dioxaphospholane-2-oxide;[l-(5-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]thien-2-yl)-l-([4S]-methyl-2-oxido- l,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;[1 -(5-[3- {5-methyl-2-phenylthiazol-4-yl} -1 -oxoprop-1 -yl]thien-2-yl)-l -([4S]-methyl-2- oxido-l,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l,3,2-dioxaphospholane-2- oxide;[l-(5-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]thien-2-yl)-l-([4S]-methyl-2-oxido- l,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;[l-(5-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]thien-2-yl)-l-([4S]-methyl-2-oxido- l,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;[l-(5-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-yl]thien-2-yl)-l-([4S]-methyl- 2-oxido-l ,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l ,3,2-dioxaphospholane- 2-oxide;[l-(5-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]thien-2-yl)-l- (4,5-dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2- dioxaphospholane-2-oxide;[l-(5-[2-{4-(4-trifluoromethylphenyl)phenoxy}ethoxy]thien-2-yl)-l-(4,5-dimethyl-2- oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy] -4, 5-dimethyl 1 , 3 ,2-dioxaphospholane-2- oxide;[l-(5-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]thien-2-yl)-l- (4,5-dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2- dioxaphospholane-2-oxide;
[ 1 -(5- [3 - {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl]thien-2-yl)- 1 -(4,5 - dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2- dioxaphospholane-2-oxide; [ 1 -(5 - [2- { 1 - [4-(2-trifluoromethylphenyl)phenylmethyl] -3 -hexylureido} ethyl]thien-2-yl)- l-(4,5-dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2- dioxaphospholane-2-oxide;[ 1 -(5-[2- {1 -butyl-3-(5-methoxypyrid-2-yl)ureido} ethyl]thien-2-yl)-l -(4,5-dimethyl-2- oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2- oxide;[l-(5-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]thien-2-yl)-l-(4,5-dimethyl-2- oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2- oxide;[l-(5-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]thien-2-yl)-l-(4,5-dimethyl-2-oxido- l,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;[l-(5-[3,N-phthalimidopropoxy]thien-2-yl)-l-(4,5-dimethyl-2-oxido-l,3,2- dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;[ 1 -(5-[4,N-phthalimidobutoxy]thien-2-yl)- 1 -(4,5-dimethyl-2-oxido- 1,3,2- dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;[l-(4-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]-3-fluorophenyl)-l-(2-oxido-l,3,2- dioxaphosphinan-2-yl)methoxy]-l,3,2-dioxaphosphinane-2-oxide; [ 1 -(4- [Ν-(2- {N-methyl-N-pyrid-2-ylamino } ethyl)-N-methylaminocarbonyl] -3 - fluorophenyl)- 1 -(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methoxy]- 1 ,3 ,2- dioxaphosphinane-2-oxide; [ 1 -(4- [3 - {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop- 1 -yl] -3 -fluorophenyl)- 1 -(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methoxy]- 1 ,3,2-dioxaphosphinane-2-oxide;
[l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]-3-fluorophenyl)-l-(2-oxido-l,3,2- dioxaphosphinan-2-yl)methoxy]-l,3,2-dioxaphosphinane-2-oxide; 1 -(4-[N-(2- {5-methyl-2-phenyloxazol-4-yl} ethyl)-N-methylaminocarbonyl]-3- fluorophenyl)- 1 , 1 -bis(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; l-(4-[2-{5 -methyl-2-phenylthiazol-4-yl} ethoxy] -3 -fluorophenyl)- 1 , 1 -bis(2-oxido- 1,3,2- dioxaphospholan-2-yl)methane; l-(4-[3-{5 -methyl-2-phenylthiazol-4-yl } - 1 -oxoprop- 1 -yl] -3 -fluorophenyl)- 1 , 1 -bis(2- oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; l-(4-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]-3-fluorophenyl)-l,l-bis(2-oxido- l,3,2-dioxaphospholan-2-yl)methane;
1 -(4-[2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethoxy]-3-fluorophenyl)-l , 1 -bis(4,5-dimethyl- 2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; 1 -(4-[3 - { 5-methyl-2-pyrid-4-yloxazol-4-yl} - 1 -oxoprop- 1 -yl] -3 -fluorophenyl)- 1 , 1 -bis(2- oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methane; l-(4-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-Ν-methylaminocarbonyl]-3- fluorophenyl)-l,l-bis(4,5-dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methane; 1 -(4-[2- {4-(4-frifluoromethylphenyl)phenoxy } ethoxy] -3 -fluorophenyl)- 1 , 1 -bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methane; 1 -(4- [N-(2- {4-(4-trifluoromethylphenyl)phenoxy } ethy l)-N-methylaminocarbonyι] -3 - fluorophenyl)- 1 , 1 -bis(4,5-dimetlιyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane;
1 -(4-[3 - {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl] -3 -fluorophenyl)- 1,1- bis(2-oxido- 1 ,3 ,2-dioxaphosphman-2-yl)methane; 1 -(4- [2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl] -3 -hexylureido} ethyl] -3- fluorophenyl)-l,l-bis(4,5-dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methane;
l-(4-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]-3-fluorophenyl)-l,l-bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methane; 2-(4-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-fluorophenyl)-l,2-bis(2-oxido- l,3,2-dioxaphospholan-2-yl)ethane; 2-(4-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]-3-fluorophenyl)-l,2-bis([4R]-methyl-2- oxido- 1 ,3 ,2-dioxaphospholan-2-yl)ethane; 2-(4-[3N-phthalimidopropoxy]-3-fluorophenyl)-l,2-bis(2-oxido-l,3,2-dioxaphospholan- 2-yl)ethane; 2-(4-[4N-phthalimidobutoxy]-3-fluorophenyl)-l,2-bis([4R]-methyl-2-oxido-l,3,2- dioxaphospholan-2-yl)ethane;
2-(3-[3-{N-methyl-N-pyrid-2-ylamino}propoxy]-4-fluorophenyl )-l,2-bis(2-oxido-l,3,2- dioxaphospholan-2-yl)ethane; 2-(3-[N-(3-{N-methyl-N-pyrid-2-ylamino}propyl)-N-methylamino]-4-fluorophenyl)-l,2- bis([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)ethane; 2-(3-[3- {N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l -ylamino]-4-fluorophenyl)-l ,2-bis(2- oxido- 1 ,3,2-dioxaphospholan-2-yl)ethane; 2-(3-[3-{5-methyl-2-phenyloxazol-4-yl}propoxy]-4-fluorophenyl)-l,2-bis([4R]-methyl-2- oxido-l,3,2-dioxaphospholan-2-yl)ethane; 2-(3-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylaminocarbonyl]-4- methoxyphenyl)-l,l-bis(4,5-dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)ethane;
2-(3-[3-{5-methyl-2-phenylthiazol-4-yl}propoxy]-4-fluorophenyl)-l,l-bis(2-oxido-l,3,2- dioxaphosphinan-2-yl)ethane; 2-(3-[3-{5-methyl-2-phenylthiazol-4-yl}-l-oxoprop-l-yl]-4-fluorophenyl)-l,l-bis(4,5- dimethyl-2-oxido- 1 ,3 ,2-dioxaphosρholan-2-yl)ethane;
-(3-[4- {5-methyl-2-pyrid-4-yloxazol-4-yl}butoxy]-4-fluorophenyl)- 1 , l-bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)ethane; -(3-[3-{5-methyl-2-pyrid-4-ylthiazol-4-yl}propoxy]-4-fluorophenyl)-l,l-bis(4,5- dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)ethane; -(3-[3- {5-methyl-2-pyrid-4-yloxazol-4-yl} -1 -oxoprop- 1 -ylthio]-4-fluorophenyl)-l , 1 - bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)ethane; -(3-[N-(3-{5-methyl-2-pyrid-4-ylthiazol-4-yl}propyl)-N-methylamino]-4-fluorophenyl)- 1 , 1 -bis(4,5-dimethyl-2-oxido- 1 ,3,2-dioxaphospholan-2-yl)ethane; -(3 -[3 - {4-(4-trifluoromethylphenyl)phenoxy }ρropoxy] -4-fluorophenyl)- 1 , 1 -bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)ethane; l-[N-(3-[N-(3-{4-(4-trifluoromethylphenyl)phenoxy}propyl)-N-methylamino]-4- fluorophenyl)amino]-l,l-bis(2-oxido-l,3,2-dioxaphospholan-2-yl)methane; l-[N-(3-[4-{4-(4-trifluoromethylphenyl)phenoxy)-l-oxobut-l-yl]-4-fluorophenyl)amino]- 1 , 1 -bis([4R] -methyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; l-[N-(3-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]-4- fluorophenyl)amino]-l,l-bis(2-oxido-l,3,2-dioxaphospholan-2-yl)methane; 1 -[N-(3-[2- { 1 -butyl-3-(5-methoxypyrid-2-yl)ureido} ethyl] -4-fluorophenyl)amino]-l , 1 - bis([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methane; 1 -[N-(3-[4- {4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]-4-fluorophenyl)amino]-l , 1 - bis(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane;
1 -[N-(3 - [3 - {4H-3 -oxobenzo [ 1 ,4]oxazin-2-yl} propoxy] -4-fluorophenyl)amino] -1,1- bis([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methane; 1 - [N-(3 - [3 ,N-phthalimidopropoxy] -4-fluorophenyl)amino] -1,1 -bis(2-oxido- 1,3,2- dioxaphospholan-2-yl)methane;
l-[N-(3-[4,N-phthalimidobutoxy]-4-fluorophenyl)amino]-l,l-bis([4R]-methyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; 1 -[N-(6-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]indol-2-yl)amino]- 1 , 1 -bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methane; 1 -[N-(6-[N-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N-methylamino]indol-2-yl)amino]- 1 , 1 -bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methane; l-[N-(6-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l-yl]indol-2-yl)amino]-l,l-bis(2- oxido-l,3,2-dioxaphosphinan-2-yl)methane; 1 -[N-(6-[2- {5-methyl-2-phenyloxazol-4-yl} ethoxy] indol-2-yl)amino]-l , 1 -bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methane;
2- [ 1 -(Diethoxyphosphinyloxy)- 1 -(6- [N-(2- { 5 -methyl-2-phenyloxazol-4-yl} ethyl)-N- methylamino] indol-2-yl)methyl]-l,3,2-dioxaphospholane-2-oxide; 2-[l-(Diethoxyphosphinyloxy)-l-(6-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]indol-2- yl)methyl]-l,3,2-dioxaphospholane-2-oxide; 2-[ 1 -(Diethoxyphosphinyloxy)- 1 -(6-[3 - {5-methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 - yl]indol-2-yl)methyl]- 1 ,3 ,2-dioxaphospholane-2 -oxide; 2-[ 1 -(Diethoxyphosphinyloxy)- 1 -(6-[2- {5-methyl-2-pyrid-4-yloxazol-4-yl} ethoxy]indol- 2-yl)methyl]-l,3,2-dioxaphospholane-2-oxide; 2- [ 1 -(Diethoxyphosphinyloxy)- 1 -(6- [2- { 5 -methyl-2-pyrid-4-ylthiazol-4-yl} ethoxy] indol- 2-yl)methyl]-l,3,2-dioxaphosphinane-2-oxide;
2-[l-(Diethoxyphosphinyloxy)-l-(6-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l- yl]indol-2-yl)methyl]-l,3,2-dioxaphosphinane-2-oxide; 2-[l -(Diethoxyphosphinyloxy)-l -(6-[N-(2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethyl)-N- methylamino]indol-2-yl)methyl]-l,3,2-dioxaphosphinane-2-oxide;
- [ 1 -(Diethoxyphosphinyloxy)- 1 -(6- [2- {4-(4-trifluoromethylphenyl)phenoxy } ethoxy] indol-2-yl)methyl]-l,3,2-dioxaphosphinane-2-oxide; [ 1 -(6- [N-(2- {4-(4-trifluoromethylphenyl)phenoxy} ethyl) -N-methylamino]indol-2-yl)- 1 - (diethoxyphosphinyl)methoxy] -4 [S] -methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;[l-(6-[3- {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl] indol-2-yl)- 1 - (diethoxyphosphinyl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;[ 1 -(6-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido} ethyl]indol-2-yl)- l-(diethoxyphosphinyl)methoxy]-4[S]-methyl-l,3,2-dioxaphospholane-2-oxide;[ 1 -(6-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido} ethyl]indol-2-yl)- l-(diethoxyphosphinyl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide; [ 1 -(6- [3 - {4-acetyl-3 -hydroxy-2-propylphenoxy)propoxy] indol-2-yl)- 1 - (diethoxyphosphinyl)methoxy]-4[S]-methyl-l,3,2-dioxaphospholane-2-oxide;[1 -(6-[2- {4H-3-oxobenzo[l ,4]oxazin-2-yl}ethoxy]indol-2-yl)- 1 - (diethoxyphosphinyl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;[ 1 -(6-[2- { 1 -butyl-3-(5-methoxypyrid-2-yl)ureido} ethyl]indol-2-yl)-l - (diethoxyphosphinyl)methoxy]-4[S]-methyl-l,3,2-dioxaphospholane-2-oxide; [ 1 -(6- [3 ,N-phthalimidopropoxy]indol-2-yl)- 1 -(diethoxyphosphmyl)methoxy]-4,5- dimethyl 1 ,3 ,2-dioxaphospholane-2-oxide;[l-(6-[4,N-phthalimidobutoxy]indol-2-yl)-l-(diethoxyphosphinyl)methyl]-4[R]-methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;[l-(5-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]pyrid-2-yl)-l- (diethoxyphosphinyl)methyl]-4[R]-methyl-l,3,2-dioxaphospholane-2-oxide;[l-(5-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]pyrid-2-yl)-l- (diethoxyphosphinyl)methyl]-4[R]-methyl-l,3,2-dioxaphospholane-2-oxide;
[l-(5-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l-yl]pyrid-2-yl)-l- (diethoxyphosphinyl)methyl] -4 [R] -methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;[l-(5-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]pyrid-2-yl)-l- (diethoxyphosphinyl)methyl]- 1 ,3 ,2-dioxaphosphinane-2-oxide;[l-(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]pyrid-2-yl)-l- (diethoxyphosphinyl)methyl] - 1 ,3 ,2-dioxaphosphinane-2-oxide;[l-(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]pyrid-2-yl)-l- (diethoxyphosphinyl)methyl]-l,3,2-dioxaphosphinane-2-oxide;[l-(5-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]pyrid-2-yl)-l- (diethoxyphosphinyl)methyl] - 1 ,3 ,2-dioxaphosphinane-2-oxide;[l-(5-[3-{5-methyl-2-phenylthiazol-4-yl}-l-oxoprop-l-yl]pyrid-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;[l-(5-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]pyrid-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphosphinane-2-oxide;[l-(5-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]pyrid-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;[ 1 -(5-[3 - {5-methyl-2-pyrid-4-yloxazol-4-yl} - 1 -oxoprop- 1 -yl]pyrid-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphosphinane-2 -oxide;[l-(5-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]pyrid-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide; [ 1 -(5 - [2- {4-(4-frifluoromethylphenyl)phenoxy} ethoxy] -pyrid-2-yl) -2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphosphinane-2-oxide;[l-(5-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]pyrid-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;
[ 1 -(5-[3 - {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl] -pyrid-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]-l ,3 ,2-dioxaphosphinane-2-oxide;[2-(5-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]pyrid-2-yl)- 2-(diethoxyphosphinyl)eth- 1 -yl]-l ,3,2-dioxaphospholane-2-oxide;[2-(5-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]pyrid-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-4[R]-methyl-l,3,2-dioxaphospholane-2-oxide;[2-(5-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]pyrid-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-l,3,2-dioxaphospholane-2-oxide;[2-(5-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]ρyrid-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl] -4 [R] -methyl- 1 ,3,2-dioxaphospholane-2-oxide;[2-(5-[3N-phthalimidopropoxy]pyrid-2-yl)-2-(diethoxyphosphinyl)eth-l-yl]-l,3,2- dioxaphospholane-2-oxide;[2-(5-[4,N-phthalimidobutoxy]pyrid-2-yl)-2-(diethoxyphosphinyl)eth-l-yl]-4[R]-methyl- 1 ,3,2-dioxaphospholane-2-oxide;[2-(5-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]benzothien-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphospholane-2-oxide;[2-(5-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]benzothien-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-4[R]-methyl-l,3,2-dioxaphospholane-2-oxide; [2-(5- [3 - {N-methyl-N-pyrid-2-ylamino } - 1 -oxoprop- 1 -yl]benzothien-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-l,3,2-dioxaphosphinane-2-oxide;[2-(5-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]benzothien-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-l,3,2-dioxaphosphinane-2-oxide;[2-(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]benzothien-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphosphinane-2 -oxide;
2[2-(5-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]benzothien-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl] - 1 ,3 ,2-dioxaphosphinane-2-oxide; 2[2-(5-[3-{5-methyl-2-phenylthiazol-4-yl}-l-oxoprop-l-yl]benzothien-2-yl)-l- (diethoxyphosphinyl)eth-l-yl]-l,3,2-dioxaphospholane-2-oxide; 2[2-(5-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]benzothien-2-yl)-l- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphospholane-2-oxide; 2[2-(5-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]benzothien-2-yl)-l- (diethoxyphosphinyl)eth-l-yl]-l,3,2-dioxaphospholane-2-oxide; 2[2-(5-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-yl]benzothien-2-yl)-l- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphospholane-2-oxide;
NNN',N'-Tetramethyl-1 (5-/N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N- methylamino]benzothien-2-yl)-l-hydroxymethylphosphondiamide; NN'-Diethyl 1 -(5-[2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy]benzothien-2-yl)- 1 - hydroxymethylphosphondiamide; 2- [ 1 -hydroxy- 1 -(5- [N-(2- {4-(4-trifluoromethylphenyl)phenoxy } ethyl)-N- methylamino]benzothien-2-yl)methyl]-[4S,5S]-dimethyl-l,3,2-diazaphospholidine-2- oxide; 2-[ 1 -hydroxy-1 -(5-[3- {4-(4-trifluoromethylphenyl)phenoxy} - 1 -oxoprop-1 -yl]benzothien- 2-yl)methyl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2-oxide; 2-[ 1 -hydroxy-1 -(5-[2- { 1 -[4-(2-trifluoromemylphenyl)phenylmethyl]-3- hexylureido} ethyl]benzothien-2-yl)methyl]-[4S]-ethyl- 1 ,3,2-oxazaphospholidine-2- oxide; 2-[ 1 -hydroxy-1 -(5-[2- { 1 -butyl-3-(5-methoxypyrid-2-yl)ureido} ethyl]benzothien-2- yl)methyl]-[4R]methyl-l,3,2-oxazaphosphinane-2-oxide;
N,NN',N'-Tetramethyl-1 (5-[3- {4-acetyl-3-hydroxy-2- propylphenoxy)propoxy]benzothien-2-yl)-l-hydroxymethylphosphondiamide; NN'-Diethyl l-(5-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]benzothien-2-yl)-l- hydroxymethylphosphondiamide; 2-[l-hydroxy-l-(5-[3N-phthalimidopropoxy]benzothien-2-yl)methyl]-[4S,5S]-dimethyl- l,3,2-diazaphospholidine-2-oxide; 2-[l-hydroxy-l-(5-[4,N-phthalimidobutoxy]benzothien-2-yl)methyl]-l,3,5,5-tetramethyl- 1 ,3 ,2-diazaphosphinane-2-oxide; 2-[l-hydroxy-l-(4-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]thiazol-2-yl)methyl]-[4S]- ethyl- 1 ,3 ,2-oxazaphospholidine-2-oxide;
2-[ 1 -hydroxy- 1 -(4-[N-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N-methylamino]thiazol-2- yl)methyl]-[4R]methyl-l,3,2-oxazaphosphinane-2-oxide; N,NN',N'-Tetramethyl l-(4-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l-yl]thiazol-2- yl)-l-(bis[NN-dimethylamino]phosphoryloxy)methylphosphondiamide; NN'-Diethyl l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]thiazol-2-yl)-l-(bis[N- ethylamino]phosphoryloxy)methylphosphondiamide; 2-[ 1 - {([4S,5 S]-dimethyl-2-oxido- 1 ,3 ,2-diazaphospholidin-2-yl)oxy} - 1 -(4- [N-(2- {5- methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]thiazol-2-yl)methyl]-[4S,5S]- dimethyl- 1 ,3 ,2-diazaphospholidine-2-oxide; 2-[l-{(l,3,5,5-tetramethyl-2-oxido-l,3,2-diazaphosρhinan-2-yl)oxy}-l-(4-[2-{5-methyl- 2-phenylthiazol-4-yl}ethoxy]thiazol-2-yl)methyl]-l,3,5,5-teframethyl-l,3,2- diazaphosphinane-2-oxide; 2-[ 1 - { (4S]-ethyl-2-oxido-l ,3 ,2-oxazaρhospholidin-2-yl)oxy} - 1 -(4-[3- {5-methyl-2- phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl]thiazol-2-yl)methyl]-[4S]-ethyl- 1,3,2- oxazaphospholidine-2-oxide;
2-[ 1 - {([4R]methyl- 1 ,3 ,2-oxazaphosphinan-2-yl)oxy} - 1 -(4-[2- {5-methyl-2-pyrid-4- yloxazol-4-yl}ethoxy]thiazol-2-yl)methyl]-[4R]methyl-l,3,2-oxazaphosphinane-2- oxide; NNN'N'-Teframethyl 1 -(4-[2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethoxy]thiazol-2-yl)- 1 -(bis[N,N-dimethylamino]phosphoryloxy)methylphosphondiamide;
NN'-Diethyl l-(4-[3-{5-methyl-2-ρyrid-4-yloxazol-4-yl}-l-oxoprop-l-yl]thiazol-2-yl)-l- (bis[N-ethylamino]phosphoryloxy)methylphosphondiamide; 2-[l-{([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)oxy}-l-(4-[N-(2-{5- methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]thiazol-2-yl)methyl]-[4S,5S]- dimethyl- 1 ,3 ,2-diazaphospholidine-2-oxide;
2-[l-{(l,3,5,5-tetramethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)oxy}-l-(4-[2-{4-(4- trifluoromethylphenyl)phenoxy}ethoxy]thiazol-2-yl)methyl]-l,3,5,5-tetramethyl- 1 ,3 ,2-diazaphosphinane-2-oxide; 2-[l - {(4S]-ethyl-2-oxido- 1 ,3,2-oxazaphospholidin-2-yl)oxy} -1 -(4-[N-(2- {4-(4- trifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]thiazol-2-yl)methyl]-[4S]- ethyl- 1 ,3 ,2-oxazaphospholidine-2-oxide; 2-[l-{([4R]methyl-l,3,2-oxazaphosphinan-2-yl)oxy}-l-(4-[3-{4-(4- trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl] thiazol-2-yl)methyl] - [4R]methyl- 1 ,3 ,2-oxazaphosphinane-2-oxide; 1 -(4-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido} ethyl]thiazol-2-yl)- 1 , 1 -bis(bis[NN-dimethylamino]phosphoryl)methane; 1 -(4-[2- { 1 -butyl-3-(5-methoxypyrid-2-yl)ureido} ethyl]thiazol-2-yl)-l , 1 -bis(bis[N- ethylamino]phosphoryl)methane; l-(4-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]thiazol-2-yl)-l,l-bis([4S,5S]- dimethyl-2-oxido- 1 ,3 ,2-diazaphospholidin-2-yl)methane;
1 -(4-[2- {4H-3-oxobenzo[l ,4]oxazin-2-yl} ethoxy]thiazol-2-yl)- 1 ,1 -bis(l ,3,5,5- tetramethyl-2-oxido- 1 ,3 ,2-diazaphosphinan-2-yl)methane; 1 _(4_[3 ,N-phthalimidopropoxy]thiazol-2-yl)- 1 , 1 -bis ([4S]-ethyl-2-oxido- 1,3,2- oxazaphospholidin-2-yl)methane; 1 -(4-[4N-phthalimidobutoxy]thiazol-2-yl)-l , 1 -bis ([4R]methyl-2-oxido- 1,3,2- oxazaphosphinan-2-yl)methane; l-(6-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]-3-methoxyquinolin-2-yl)-l,l-bis(bis[NN- dimethylamino]phosphoryl)methane; l-(6-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]-3-methoxyquinolin-2- yl)- 1 , 1 -bis(bis[N-ethylamino]phosphoryl)methane;
1 -(6- [3 - {N-methyl-N-pyrid-2-ylamino } - 1 -oxoprop- 1 -yl] -3 -methoxyquinolin-2-yl)- 1,1- bis([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)methane; l-(6-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l,l-bis(l,3,5,5- tetramethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)methane; l-(6-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]-3-methoxyquinolin-2- yl)- 1 , 1 -bis ([4S]-ethyl-2-oxido-l,3,2-oxazaphospholidin-2-yl)methane; l-(6-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l,l-bis ([4R]methyl-2-oxido- 1 ,3 ,2-oxazaphosphinan-2-yl)methane; l-(6-[3-{5-methyl-2-phenylthiazol-4-yl}-l-oxoprop-l-yl]-3-methoxyquinolin-2-yl)-l,2- bis(bis[N,N-dimethylamino]phosphoryl)ethane; l-(6-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l,2- bis(bis[N-ethylamino]phosphoryl)ethane; l-(6-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l,2- bis([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)ethane;
1 -(6- [3 - { 5-methyl-2-pyrid-4-yloxazol-4-yl} - 1 -oxoprop- 1 -yl] -3 -methoxyquinolin-2-yl)- l,2-bis(l,3,5,5-tetramethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)ethane; l-(6-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)-l,2-bis ([4S]-efhyl-2-oxido-l,3,2-oxazaphospholidin-2- yl)ethane;
1 -(6-[2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy]-3-methoxyquinolin-2-yl)-l ,2-bis ([4R]methyl-2-oxido-l,3,2-oxazaphosphinan-2-yl)ethane; l-(6-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)-l,2-bis(bis[N,N-dimethylamino]phosphoryl)ethane; l-(6-[3- {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl] -3 -methoxy quinolin-2-yl)- l,2-bis(bis[N-ethylamino]phosphoryl)ethane; 1 -(6-[2- { 1 -[4-(2-frifluoromethylphenyl)phenylmethyl]-3-hexylureido} ethyl]-3- methoxyquinolin-2-yl)-l,2-bis([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2- yl)ethane; 1 -(6-[2- { 1 -butyl-3-(5-methoxypyrid-2-yl)ureido} ethyl]-3-methoxyquinolin-2-yl)-l ,2- bis(l,3,5,5-teframethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)ethane; l-(6-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-methoxyquinolin-2-yl)-l,2-bis ([4S]-ethyl-2-oxido-l,3,2-oxazaphospholidin-2-yl)ethane; 1 -(6- [3 ,N-phthalimidopropoxy] -3 -methoxy quinolin-2-yl)- 1 ,2-bis ([4R]methyl-2-oxido- 1 ,3 ,2-oxazaphosphinan-2-yl)ethane;
2-(6-[4,N-phthalimidobutoxy]-3-methoxyquinolin-2-yl)-l,l-bis(bis[N,N- dimethylamino]phosphoryl)ethane; 2-(5-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]thien-2-yl)-l,l-bis(bis[N- ethylamino]phosphoryl)ethane;
-(5-[N-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N-methylamino]thien-2-yl)- 1 , 1 - bis([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)ethane; -(5-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoproρ-l-yl]thien-2-yl)-l,l-bis(l,3,5,5- tetramethyl-2-oxido- 1 ,3 ,2-diazaphosphinan-2-yl)ethane; -(5-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]thien-2-yl)-l,l-bis ([4S]-ethyl-2-oxido- 1 ,3 ,2-oxazaphospholidin-2-yl)ethane; -(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]thien-2-yl)-l,l-bis ([4R]methyl-2-oxido-l,3,2-oxazaphosphinan-2-yl)ethane; -(5-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]thien-2-yl)-l,l-bis(bis[NN- dimethylamino]phosphoryl)ethane; -(5-[3-{5-methyl-2-phenylthiazol-4-yl}-l-oxoprop-l-yl]thien-2-yl)-l,l-bis(bis[N- ethylamino]phosphoryl)ethane; -(5-[2- {5-methyl-2-ρyrid-4-yloxazol-4-yl} ethoxy]thien-2-yl)-l , 1 -bis([4S,5S]-dimethyl- 2-oxido-l,3,2-diazaphospholidin-2-yl)ethane; -(5-[2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethoxy]thien-2-yl)-l , 1 -bis(l ,3,5,5- tetramethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)ethane; -(5-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-yl]thien-2-yl)-l,l-bis ([4S]- ethyl-2-oxido- 1 ,3 ,2-oxazaphospholidin-2-yl)ethane; -(5-[N-(2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethyl)-N-methylamino]thien-2-yl)- 1 , 1 -bis ([4R]methyl-2-oxido-l ,3,2-oxazaphosphinan-2-yl)ethane; l-[N-(5-[2-{4-(4-trifluoromethylphenyl)phenoxy}ethoxy]thien-2-yl)amino]-l,l- bis(bis[N,N-dimethylamino]phosphoryl)methane; 1 -[N-(5-[N-(2- {4-(4-trifluoromethylphenyl)phenoxy} ethyl)-N-methylamino]thien-2- yl)amino] -1,1 -bis(bis[N-ethylamino]phosphoryl)methane;
1 -[N-(5 - [3 - {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl]thien-2-yl)amino]- 1 , 1 - bis([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)methane; 1 -[N-(5 - [2- { 1 - [4-(2-trifluoromethylphenyl)phenylmethyl] -3 -hexylureido} ethyl]thien-2- yl)amino]-l,l-bis(l,3,5,5-teframethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)methane; 1 -[N-(5-[2- { 1 -butyl-3 -(5-methoxypyrid-2-yl)ureido} ethyl]thien-2-yl)amino]- 1 , 1 -bis ([4S]-ethyl-2-oxido-l,3,2-oxazaphospholidin-2-yl)methane; l-[N-(5-[3- {4-acetyl-3 -hydroxy-2-propylphenoxy)propoxy]thien-2-yl)amino] -1,1 -bis ([4R]methyl-2-oxido- 1 ,3 ,2-oxazaphosphinan-2-yl)methane; l-[N-(5-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]thien-2-yl)amino]-l,l-bis(bis[NN- dimethylamino]phosphoryl)methane; l-[N-(5-[3,N-phthalimidopropoxy]thien-2-yl)amino]-l,l-bis(bis[N- ethylamino]phosphoryl)methane; l-[N-(5-[4,N-phthalimidobutoxy]thien-2-yl)amino]-l,l-bis([4S,5S]-dimethyl-2-oxido- 1 ,3 ,2-diazaphospholidin-2-yl)methane; 1 -[N-(4-[2- {N-methyl-N-pyrid-2-ylamino}ethoxy]-3-fluorophenyl)amino]-l , 1 -bis(l ,3,5,5- tetramethyl-2-oxido- 1 ,3 ,2-diazaphosphinan-2-yl)methane ; l-[N-(4-[Ν-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylaminocarbonyl]-3- fluorophenyl)amino]- 1 , 1 -bis ([4S]-ethyl-2-oxido- 1 ,3 ,2-oxazaphospholidin-2- yl)methane; 1 - [N-(4-[3 - {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop- 1 -yl] -3 -fluorophenyl)amino] -1,1- bis ([4R]methyl-2-oxido- 1 ,3 ,2-oxazaphosphinan-2-yl)methane; 2-[l-(Bis[N-ethylamino]phosphoryloxy)-l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]- 3-fluorophenyl)methyl]-[4S,5S]-dimethyl-l,3,2-diazaphospholidine-2-oxide;
-[l-(Bis[N-ethylamino]phosphoryl)-l-(4-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N- methylaminocarbonyl]-3-fluorophenyl)methoxy]-[4S,5S]-dimethyl-l,3,2- diazaphospholidine-2-oxide;-[l-(Bis[N-ethylamino]phosphoryl)-l-(4-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]-3- fluorophenyl)methyl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2-oxide;-[l-(Bis[N-ethylamino]phosphoryl)-2-(4-[3-{5-methyl-2-phenylthiazol-4-yl}-l-oxoprop- l-yl]-3-fluorophenyl)ethen-l-yl]-[4S]-ethyl-l,3,2-oxazaphospholidine-2-oxide;-[l-(Bis[N-ethylamino]phosphoryl)-2-(4-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]- 3-fluorophenyl)eth-l-yl]-[4R]methyl-l,3,2-oxazaphosphinane-2-oxide;-[2-(Bis[N-ethylamino]phosphoryl)-2-(4-[2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethoxy]- 3-fluorophenyl)eth-l-yl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2-oxide;-[2-(Bis[N-ethylamino]phosphoryl)-l-(4-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l- oxoprop-l-yl]-3-fluorophenyl)eth-l-yl]-[4S]-ethyl-l,3,2-oxazaphospholidine-2-oxide;-[l-(Bis[N-ethylamino]phosphoryloxy)-l-(4-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4- yl} ethyl)-Ν-methylaminocarbonyl] -3 -fluorophenyl)methyl] - [4S , 5 S] -dimethyl- 1,3,2- diazaphospholidine-2-oxide;-[l-(Bis[N-ethylamino]phosphoryl)-l-(4-[2-{4-(4- trifluoromethylphenyl)phenoxy } ethoxy] -3 -fluorophenyl)methoxy] - [4 S,5 S] -dimethyl- l,3,2-diazaphospholidine-2-oxide;-[l-(Bis[N-ethylamino]phosphoryl)-l-(4-[N-(2-{4-(4- trifluoromethylphenyl)phenoxy}ethyl)-N-methylaminocarbonyl]-3- fluorophenyl)methyl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphmane-2-oxide;-[l-(Bis[N-ethylamino]phosphoryl)-2-(4-[3-{4-(4-trifluoromethylphenyl)phenoxy}-l- oxoprop-l-yl]-3-fluorophenyl)ethen-l-yl]-[4S]-ethyl-l,3,2-oxazaphospholidine-2- oxide;
-[ 1 -(Bis[N-ethylamino]phosphoryl)-2-(4-[2- { 1 -[4-(2- trifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]-3-fluorophenyl)eth-l-yl]- [4R]methyl-l,3,2-oxazaphosphinane-2-oxide;-[2-(Bis[N-ethylamino]phosphoryl)-2-(4-[2- { 1 -butyl-3-(5-meflioxypyrid-2- yl)ureido}ethyl]-3-fluorophenyl)eth-l-yl]-l,3,5,5-tetramethyl-l,3,2- diazaphosρhinane-2-oxide;-[2-(Bis[N-ethylamino]phosphoryl)-l-(4-[3-{4-acetyl-3-hydroxy-2- propylphenoxy)propoxy] -3 -fluorophenyl)eth- 1 -yl]-[4S]-ethyl- 1,3,2- oxazaphospholidine-2-oxide;-[l-(Diethoxyphosphoryloxy)-l-(4-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]-3- fluorophenyl)methyl]-[4S,5S]-dimethyl-l,3,2-diazaphospholidine-2-oxide;-[l-(Diethoxyphosphoryl)-l-(4-[3,N-phthalimidopropoxy]-3-fluorophenyl)methoxy]- [4S , 5 S] -dimethyl- 1 ,3 ,2-diazaphospholidine-2-oxide;-[l-(Diethoxyphosphoryl)-l-(4-[4,N-phthalimidobutoxy]-3-fluorophenyl)methyl]- 1 ,3,5,5-tetramethyl-l ,3 ,2-diazaphosphinane-2-oxide;-[ 1 -(Diethoxyphosphoryl)-2-(3-[3- {N-methyl-N-pyrid-2-ylamino}propoxy]-4- fluorophenyl)ethen-l -yl]-[4S]-ethyl- 1 ,3 ,2-oxazaphospholidine-2-oxide;-[l-(Diethoxyphosphoryl)-2-(3-[N-(3-{N-methyl-N-pyrid-2-ylamino}propyl)-N- methylamino]-4-fluorophenyl)eth-l-yl]-[4R]methyl-l,3,2-oxazaphosphinane-2-oxide;-[2-(Diethoxyphosphoryl)-2-(3-[3- {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop-1 - ylamino]-4-fluorophenyl)eth-l-yl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2- oxide;-[2-(Diethoxyphosphoryl)-l-(3-[3-{5-methyl-2-phenyloxazol-4-yl}propoxy]-4- fluorophenyl)eth-l-yl]-[4S]-ethyl-l,3,2-oxazaphospholidine-2-oxide;
-[l-(Diethoxyphosphoryloxy)-l-(3-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N- methylaminocarbonyl]-4-methoxyphenyl)methyl]-[4S,5S]-dimethyl-l,3,2- diazaphospholidine-2-oxide;-[l-(Diethoxyphosphoryl)-l-(3-[3-{5-methyl-2-phenylthiazol-4-yl}propoxy]-4- fluorophenyl)methoxy]-[4S,5S]-dimethyl-l,3,2-diazaphospholidine-2-oxide;- [ 1 -(Diethoxyphosphoryl)- 1-(3-[3-{5 -methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl]-4- fluoroρhenyl)methyl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2-oxide; -[l-(Diethoxyphosphoryl)-2-(3-[4-{5-methyl-2-pyrid-4-yloxazol-4-yl}butoxy]-4- fluorophenyl)ethen-l-yl]-[4S]-ethyl-l,3,2-oxazaphospholidine-2-oxide; -[l -(Diethoxyphosphoryl)-2-(3-[3- {5-methyl-2-pyrid-4-ylthiazol-4-yl}propoxy]-4- fluorophenyl)eth- 1 -yl]-[4R]methyl- 1 ,3 ,2-oxazaphosphinane-2-oxide; -[2-(Diethoxyphosphoryl)-2-(3-[3- {5-methyl-2-pyrid-4-yloxazol-4-yl} -1 -oxoprop-1 - ylthio]-4-fluorophenyl)eth-l-yl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2-oxide; and -[2-(Diethoxyphosphoryl)-l-(3-[N-(3-{5-methyl-2-pyrid-4-ylthiazol-4-yl}propyl)-N- methylamino]-4-fluorophenyl)eth-l-yl]-[4S]-ethyl-l,3,2-oxazaphospholidine-2-oxide. In an even more prefeπed embodiment of this aspect, the compound of Foπnula (I) is selected from:
Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]-3 - fluorophenyl)methylphosphonate;
Diethyl l-(diethoxyphosphinyloxy)-l-(4-[3,N-phthalimidopropoxy]-3- fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[2- {5-methyl-2-phenyloxazol-4-yl} ethoxy] -3 - fluorophenyl)methylphosphonate;
Diethyl l-(diethoxyphosphinyloxy)-l-(3-[3-{N-methyl-N-pyrid-2-ylamino}propoxy]-4- fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(3-[4-{N-methyl-N-pyrid-2-ylamino}butoxy]-4- fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(3 - [4,N-phthalimidobutoxy] -4- fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)-l -(3-[5,N-phthalimidopentoxy]-4- fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1-(3-[4-{5 -methyl-2-pyrid-4-yloxazol-4-yl}butoxy] - 4-fluorophenyl)methylphosphonate;
Diethyl l-(diethoxyphosphinyloxy)-l-(3-[5-{5-methyl-2-pyrid-4-yloxazol-4-yl}pentoxy]- 4-fluorophenyl)methylphosphonate; 1 -(4-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]-3-fluorophenyl)-l , 1 -bis([4R,5S]- dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; 1 -(4-[3,N-phthalimidopropoxy]-3-fluorophenyl)-l , 1 -bis([4R,5S]-dimethyl-2-oxido- 1 ,3,2- dioxaphospholan-2-yl)methane; 1 -(4-[2- {5-methyl-2-phenyloxazol-4-yl} ethoxy]-3-fluorophenyl)-l , 1 -bis([4R,5S]- dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; 1 -(3 - [3 - {N-methyl-N-pyrid-2-ylamino} propoxy] -4-fluorophenyl )- 1 , 1 -bis( [4R, 5 S] - dimethyl-2-oxido-l ,3,2-dioxaphospholan-2-yl)methane;
1 -(3-[4- {N-methyl-N-pyrid-2-ylamino}butoxy]-4-fluorophenyl)-l , 1 -bis([4R,5S]- dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methane; l-(3-[4,N-phthalimidobutoxy]-4-fluorophenyl)-l,l-bis([4R,5S]-dimethyl-2-oxido-l,3,2- dioxaphosρholan-2-yl)methane;
l-(3-[5,N-phthalimidopentoxy]-4-fluorophenyl)-l,l-bis([4R,5S]-dimethyl-2-oxido-l,3,2- dioxaphospholan-2-yl)methane; 1 -(3-[4- {5-methyl-2-ρyrid-4-yloxazol-4-yl}butoxy]-4-fluorophenyl)- 1 , 1 -bis([4R,5S]- dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methane; l-(3-[5-{5-methyl-2-pyrid-4-yloxazol-4-yl}pentoxy]-4-fluorophenyl)-l,l-bis([4R,5S]- dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; NNN'.N'-Tetramethyl 1 -(4-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]-3-fluorophenyl)- 1 -hydroxymethylphosphondiamide; NNN^N'-Tetramethyl l-(4-[3,N-phthalimidopropoxy]-3-fluorophenyl)-l- hydroxymethylphosphondiamide;
NNN'N'-Tetramethyl l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]-3-fluorophenyl)- 1 -hydroxymethylphosphondiamide; 2- [ 1 -hydroxy- 1 -(4-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy] -3 -fluorophenyl)methyl] - [4S]-(1 -methylethyl)-l ,3,2-oxazaphospholidine-2-oxide; 2- [ 1 -hydroxy- 1-(4-[3 ,N-phthalimidopropoxy] -3 -fluorophenyl)methyl] -[4S] -( 1 - methylethyl)- 1 ,3 ,2-oxazaphospholidine-2-oxide; 2-[l-hydroxy-l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]-3-fluorophenyl)methyl]- [4S]-( 1 -methylethyl)- 1 ,3 ,2-oxazaphospholidine-2-oxide; 1 -[N-(4-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy] -3 -fluorophenyl)amino]-l , 1 -bis(bis[N- ethylamino]phosphoryl)methane;
1 - [N-(4- [3 ,N-phthalimidopropoxy] -3 -fluorophenyl)amino] - 1 , 1 -bis(bis[N- ethylamino]phosphoryl)methane; and l-[N-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]-3-fluorophenyl)amino]-l,l-bis(bis[N- ethylamino]phosphoryl)methane.
In another aspect, the invention provides methods for regulating levels of HDL and/or LDL cholesterol levels in blood, comprising administering to a subject a compound ofthe invention, or pharmaceutical formulation comprising a compound ofthe invention, or a pharmaceutically acceptable salt thereof, in an amount effective to regulate HDL and/or LDL cholesterol levels. This method of regulating HDL and/or LDL levels in blood can help prevent, treat, or delay the onset or progression of disease states associated with abnormal blood levels of HDL and/or LDL. In another aspect, the invention provides methods for treating disease states related to HDL and/or LDL cholesterol levels in blood, comprising administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the invention, or pharmaceutical formulation comprising a compound ofthe invention, or a pharmaceutically acceptable salt thereof. In another embodiment of this aspect, the method can optionally comprise in combination with the compound of Formula (I), pharmaceutical formulation comprising a compound of Formula (I), or pharmaceutically acceptable salts thereof, an effective amount of a compound known to regulate HDL and/or LDL levels in blood. Such known compounds include the non-limiting classes of compounds such as statins, for example, lovastatin, simvastatin, pravastatin, atorvastatin, cerivastatin, and niacin; fibrates, for example, clofibrate, bezafibrate, and gemfibrozil; bile acid sequestrants, for example, cholestyramine; and cholesterol uptake inhibitors, for example, phytosteroids, and ezitimibe. In another aspect, the invention provides methods for lowering triglyceride levels in blood, comprising administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the invention, or pharmaceutical
formulation comprising a compound of the invention, or a pharmaceutically acceptable salt thereof. In another embodiment of this aspect, the method can optionally comprise in combination with the compound of Formula (I), pharmaceutical formulation comprising a compound of Formula (I), or pharmaceutically acceptable salts thereof, an effective amount of a compound known to lower triglyceride levels in blood. Such known compounds include the non-limiting example of fibrates, for example, clofibrate, bezafibrate, and gemfibrozil. In another aspect, the invention provides methods for lowering glucose levels in blood, comprising administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the invention, or pharmaceutical formulation comprising a compound ofthe invention, or a pharmaceutically acceptable salt thereof. In another embodiment of this aspect, the method can optionally comprise in combination with the compound of Formula (I), pharmaceutical formulation comprising a compound of Formula (I), or pharmaceutically acceptable salts thereof, an effective amount of a compound known to lower glucose levels in blood. Such known compounds include the non-limiting classes glitazones, such as rosiglitazone and pioglitazone; sulfonylureas; insulin; and metformin. In another aspect, the methods of treatment can treat an existing metabolic disease, such as hypercholesteremia, hypertriglyceridemia, low HDL-C atherosclerosis, hyperglycemia, syndrome X, hyperinsulinemia, and diabetes. In another aspect, the methods of freatment can prevent a metabolic disease, such as hypercholesteremia, hypertriglyceridemia, low HDL-C atherosclerosis, hyperglycemia, syndrome X, hyperinsulinemia, and diabetes, from developing or progressing.
In one embodiment ofthe methods ofthe invention, the subject is a mammal. In a more prefeπed embodiment, the mammal is a human. The methods of the invention employ therapeutically effective amounts: for oral, parenteral, sublingual, intranasal, infrathecal, depo, implants, topical, and rectal administration from about 0.1 mg day to about 5,000 mg/day. The therapeutically effective amounts will vary according to various parameters including, for example, the particular therapeutic use and physical characteristics of the subject/patient, and are well within the knowledge of those skilled in the art. In a prefeπed aspect, the therapeutically effective amounts for oral, parenteral, and depo administration is from about 50 mg/day to about 500 mg/day. The present invention also includes the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in treating a subject who has, or in preventing a subject from developing, a metabolic disease, condition, or disorder, such as, for example, hypercholesteremia, hypertriglyceridemia, low HDL-C atherosclerosis, hyperglycemia, syndrome X, hyperinsulinemia, and diabetes and who is in need of such treatment. In one aspect, this use of a compound of formula (I) can be employed where the disease is hypercholesteremia. In another aspect, this use of a compound of formula (I) can be employed where the disease is hypertriglycertidemia. In another aspect, this use of a compound of formula (I) can be employed where the disease is low HDL-C atherosclerosis. In another aspect, this use of a compound of foπnula (I) can be employed where the disease is hyperglycemia.
In another aspect, this use of a compound of formula (I) can be employed where the disease is syndrome X. In another aspect, this use of a compound of formula (I) can be employed where the disease is hyperinsulinemia. In another aspect, this use of a compound of formula (I) can be employed where the disease is diabetes. The present invention also includes a container kit including a plurality of containers, each container including one or more unit dose of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In an embodiment, this container kit includes each container adapted for oral delivery and includes a tablet, gel, or capsule. In an embodiment, this container kit includes each container adapted for parenteral delivery and includes a depot product, syringe, ampoule, or vial. In an embodiment, this container kit includes each container adapted for topical delivery and includes a patch, medipad, ointment, or cream. The present invention also includes an agent kit including a compound of formula (I), or a pharmaceutically acceptable salt thereof; and one or more therapeutic agents selected from the group consisting of statins, fibrates, bile acid sequestrants, cholesterol uptake inhibitors, glitazones, sulfonylureas, insulin, and metformin. The compounds of formula (I) can form salts when reacted with appropriate acids or bases. Pharmaceutically acceptable salts are generally prefeπed over the corresponding compounds of formula (I) since they frequently produce compounds that are usually more water soluble, stable and/or more crystalline. Pharmaceutically acceptable salts are any salt which retains the activity of the parent compound and does not impart any deleterious or undesirable effect on the subject to whom it is administered and in the
context in which it is administered. Pharmaceutically acceptable salts include acid addition salts of both inorganic and organic acids. Prefeπed pharmaceutically acceptable salts include salts such as those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Such salts may be formed from inorganic and organic acids. Representative examples thereof include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids. For other acceptable salts, see Int. J. Pharm., 33, 201-217 (1986). Methods of the Invention The compounds of the invention, pharmaceutical formulations comprising said compounds, and pharmaceutically acceptable salts thereof, are useful for treating mammals suffering from a disease or condition characterized by at least one pathological foπn of abnormal HDL and/or LDL levels, triglyceride levels, and/or glucose levels in blood, and are useful for helping to prevent or delay the onset of such a condition. The compounds and formulations of the invention are particularly useful for treating, preventing, or slowing the progression of metabolic disorders, including, for example, hypercholesteremia, hypertriglyceridemia, low HDL-C atherosclerosis, hyperglycemia, syndrome X, hyperinsulinemia, and diabetes. When treating or preventing these diseases, the compounds of the invention can either be used individually or in combination, as is best for the subject. With regard to these diseases, the term "treating" means that compounds of the invention can be used in subjects, preferably human subjects/patients, with existing disease. The compounds ofthe invention will not necessarily cure the subject who has the
disease but will delay or slow the progression or prevent further progression of the disease thereby giving the individual a more useful life span. The term "preventing" means that that if the compounds of the invention are administered to those who do not now have the disease but who would normally develop the disease or be at increased risk for the disease, they will not develop the disease. In addition, "preventing" also includes delaying the development of the disease in an individual who will ultimately develop the disease or would be at risk for the disease due to age, familial history, genetic or chromosomal abnormalities, and/or due to the presence of one or more biological markers for the disease. By delaying the onset of the disease, compounds ofthe invention can prevent the individual from getting the disease during the period in which the individual would normally have gotten the disease or reduce the rate of development of the disease or some of its effects but for the administration of compounds of the invention up to the time the individual ultimately gets the disease. Preventing also includes administration of the compounds of the invention to those individuals thought to have predisposition for the disease. In a prefeπed aspect, the compounds of the invention are useful for slowing the progression of disease symptoms. In another prefeπed aspect, the compounds of the invention are useful for preventing the further progression of disease symptoms. In treating or preventing the above diseases, the compounds of the invention are administered in a therapeutically effective amount. The therapeutically effective amount will vary depending on the particular compound used and the route of administration, as is known to those skilled in the art.
In treating a subject displaying any of the diagnosed above conditions a physician may administer a compound of the invention immediately and continue administration indefinitely, as needed. Dosage Forms and Amounts The compounds ofthe invention can be administered orally, parenterally, (IN, IM, depo-IM, SQ, and depo SQ), sublingually, intranasally (inhalation), intrathecally, topically, or rectally. Dosage forms known to those of skill in the art are suitable for delivery ofthe compounds ofthe invention. Compositions are provided that contain therapeutically effective amounts of the compounds of the invention. The compounds are preferably formulated into suitable pharmaceutical preparations such as tablets, capsules, or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration. Typically the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art. About 1 to 500 mg of a compound or mixture of compounds ofthe invention or a physiologically acceptable salt or ester is compounded with a physiologically acceptable vehicle, caπier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in those compositions or preparations is such that a suitable dosage in the range indicated is obtained. The compositions are preferably formulated in a unit dosage form, each dosage containing from about 2 to about 100 mg, more preferably about 10 to about 30 mg of the active ingredient. The term "unit dosage from" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
To prepare compositions, one or more compounds ofthe invention are mixed with a suitable phannaceutically acceptable carrier. Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion, or the like. Liposomal suspensions may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for lessening or ameliorating at least one symptom of the disease, disorder, or condition treated and may be empirically determined. Pharmaceutical caπiers or vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration. In addition, the active materials can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, or have another action. The compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients. Where the compounds exhibit insufficient solubility, methods for solubilizing may be used. Such methods are known and include, but are not limited to, using cosolvents such as dimethylsulfoxide (DMSO), using surfactants such as Tween®, and dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as salts or prodmgs may also be used in formulating effective pharmaceutical compositions. The concentration of the compound is effective for delivery of an amount upon administration that lessens or ameliorates at least one symptom of the disorder for which
the compound is administered. Typically, the compositions are formulated for single dosage administration. The compounds of the invention may be prepared with carriers that protect them against rapid elimination from the body, such as time-release formulations or coatings. Such carriers include controlled release formulations, such as, but not limited to, microencapsulated delivery systems. The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the subject treated. The therapeutically effective concentration may be determined empirically by testing the compounds in known in vitro and in vivo model systems for the treated disorder. The compounds and compositions of the invention can be enclosed in multiple or single dose containers. The enclosed compounds and compositions can be provided in kits, for example, including component parts that can be assembled for use. For example, a compound inhibitor in lyophilized form and a suitable diluent may be provided as separated components for combination prior to use. A kit may include a compound inhibitor and a second therapeutic agent for co-administration. The inhibitor and second therapeutic agent may be provided as separate component parts. A kit may include a plurality of containers, each container holding one or more unit dose of the compound of the invention. The containers are preferably adapted for the desired mode of administration, including, but not limited to tablets, gel capsules, sustained-release capsules, and the like for oral administration; depot products, pre-filled syringes, ampoules, vials, and the like for parenteral administration; and patches, medipads, creams, and the like for topical administration.
The concentration of active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the active compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice ofthe claimed compositions. If oral administration is desired, the compound should be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be foπnulated in combination with an antacid or other such ingredient. Oral compositions will generally include an inert diluent or an edible carrier and may be compressed into tablets or enclosed in gelatin capsules. For the purpose of oral therapeutic administration, the active compound or compounds can be incorporated with excipients and used in the form of tablets, capsules, or troches. Phannaceutically compatible binding agents and adjuvant materials can be included as part of the composition.
The tablets, pills, capsules, troches, and the like can contain any of the following ingredients or compounds of a similar nature: a binder such as, but not limited to, gum tragacanth, acacia, corn starch, or gelatin; an excipient such as microcrystalline cellulose, starch, or lactose; a disintegrating agent such as, but not limited to, alginic acid and com starch; a lubricant such as, but not limited to, magnesium stearate; a gildant, such as, but not limited to, colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; and a flavoring agent such as peppermint, methyl salicylate, or fruit flavoring. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials, which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings, and flavors. The active materials can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action. Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent such as water for injection, saline solution, fixed oil, a naturally occurring vegetable oil such as sesame oil, coconut oil, peanut oil, cottonseed oil, and the like, or a synthetic fatty vehicle such as ethyl oleate, and the like, polyethylene glycol, glycerine, propylene glycol, or other synthetic solvent; antimicrobial agents such as benzyl alcohol and methyl parabens; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates, and phosphates; and agents for the adjustment of tonicity such as sodium chloride and
dextrose. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass, plastic, or other suitable material. Buffers, preservatives, antioxidants, and the like can be incorporated as required. Where administered intravenously, suitable carriers include physiological saline, phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents such as glucose, polyethylene glycol, polypropyleneglycol, and mixtures thereof. Liposomal suspensions including tissue-targeted liposomes may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known for example, as described in U.S. Patent No. 4,522,811. The active compounds may be prepared with caπiers that protect the compound against rapid elimination from the body, such as time-release formulations or coatings. Such caπiers include controlled release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers such as collagen, ethylene vinyl acetate, polyarihydrides, polyglycolic acid, polyorthoesters, polylactic acid, and the like. Methods for preparation of such formulations are known to those skilled in the art. The compounds of the invention can be administered orally, parenterally (IV, IM, depo-IM, SQ, and depo-SQ), sublingually, intranasally (inhalation), intrathecally, topically, or rectally. Dosage forms known to those skilled in the art are suitable for delivery of the compounds of the invention. Compounds ofthe invention may be administered enterally or parenterally. When administered orally, compounds of the invention can be administered in usual dosage forms for oral adminisfration as is well known to those skilled in the art. These dosage forms include the usual solid unit dosage forms of tablets and capsules as well as liquid dosage forms such as solutions, suspensions, and elixirs. When the solid dosage forms
are used, it is prefeπed that they be ofthe sustained release type so that the compounds of the invention need to be administered only once or twice daily. The oral dosage forms are administered to the subject 1, 2, 3, or 4 times daily. It is prefeπed that the compounds of the invention be administered either three or fewer times, more preferably once or twice daily. Hence, it is prefeπed that the compounds of the invention be administered in oral dosage form. It is prefeπed that whatever oral dosage form is used, that it be designed so as to protect the compounds of the invention from the acidic environment of the stomach. Enteric coated tablets are well known to those skilled in the art. In addition, capsules filled with small spheres each coated to protect from the acidic stomach, are also well known to those skilled in the art. As noted above, depending on whether asymmetric carbon atoms are present, the compounds of the invention can be present as mixtures of isomers, especially as racemates, or in the form of pure isomers, especially optical antipodes. Salts of compounds are preferably the pharmaceutically acceptable or non-toxic salts of compounds of formula I. For isolation and purification purposes it is also possible to use pharmaceutically unacceptable salts. Synthesis of Compounds The compounds useful in the methods of the invention can be synthesized using the procedures set forth in Schemes I- VI below. Those skilled in the art will appreciate that minor modifications may be made to the specific procedures in that article to arrive at compounds useful in the invention. Compounds ofthe present invention can be made by a variety of routes. The most important involve the very well characterized additions of phosphite derivatives, [Simoni et al., Tetrahedron Letters (1998), 39(41), 7615-7618.] or silylphosphite derivatives [Afarinkiaet al., Tetrahedron (1990), 46(20), 7175-96.] across carbonyl double bonds, the
so-called Abramov reaction [Abramov, V. S.; S. M. Kirov, Doklady Akademii Nauk SSSR (1950), 73 487-9]. Variations described in the literature include additions across aldehydes, ketones, acyl chlorides, [Pohjala et al., PCT Int. Appl. (1992 WO 9211269 Al US Patent 5,393,748], acylphosphonates, [Lecouvey et al., Heteroatom Chemistry (2000), 11(7), 556-561], amides, [Failla et al., Heteroatom Chemistry (2000), 11(7), 493-504.], and imines, [Wolfsberger, W., Chemiker-Zeitung (1985), 109(10), 317-32.]. Phosphite species, most of which are known to add across carbonyls, include diesters, cyclic esters, diamides, [Evans et al., Tetrahedron Letters (1977), (29), 2495-8.] cyclic diamides, [Pudovik et al., Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1980), (5), 1183- 5.], and chiral cyclic phosphinamidoates, Sum, V.; Kee, T. P., Journal of the Chemical Society, Perkin Transactions 1 (1993), (22), 2701-11.], as well as thiophosphites [Pudovik, A. N.; Zametaeva, G. A. Bull. Acad. Sci. U.S.S.R., Classe sci. chim. (1952), 825-30.], phosphinites, [Yamagishi et al., Tetrahedron (2003), 59(6), 767-772.], silylaminophosphines, [Heilson, R. H.; Goebel, D. W. Journal of the Chemical Society, Chemical Communications (1979), (17), 769-70.], phosphine oxides and phosphine sulfides. [Goerlich, J. R.; Schmutzler, R. Phosphorus, Sulfur and Silicon and the Related Elements (1995), 101(1-4), 213-20.]. Similar transformations can be caπied out by using trialkyl phosphite esters and POCl3, [Olive, G.; Jacques, A., Phosphorus, Sulfur and Silicon and the Related Elements (2003), 178(1), 33-46.], or phosphorus (III) halides and acetic acid, [et al., Journal of he American Chemical Society, (1923), 45, 165-71.]. The α-hydrox(bis)phosphonate derivatives obtained in several of these processes may be converted to other compounds of the invention such as the 1,1-bisphosphonates and 1- phosphatophosphonates, by methods described in the literature. 1,1-bisphosphonates may also be made from anions derived from the coπesponding diphosphonylated methane derivatives, [Vepsalainen et al., Acta Chemica Scandinavica (1997), 51(9), 932-937.]
which can be alkylated [Pohjala et al., PCT Int. Appl. (1992), WO 9211269 Al US Patent 5,393,748. Hutchinson, D. W.; Semple, G., Journal of Organometalhc Chemistry (1985), 291(2), 145-51,], condensed with carbonyl compounds, [Nguyen et al., Cuπent Medicinal Chemistry: Immunology, Endocrine & Metabolic Agents (2002), 2(3), 205- 217.], or crosscoupled under transition metal catalysis [Sulsky, R.; Magnin, D. R. Synlett (1993), (12), 933-4.]. 1,2-Bisphosphonates can be made from aldehydes by Horner- Emmons reaction to produce a vinyl phosphonate, [Minami, T.; Motoyoshiya, J., Synthesis (1992), (4), 333-49. Davis et al., Tetrahedron Letters (1998), 39(35), 6263- 6266.], followed by Michael addition of a second phosphite species.
Synthetic Scheme I:
Synthetic Scheme π:
Synthetic Scheme TV:
NaH
Synthetic Scheme VI:
Claims
1. A compound of the Formula (I) :
Y1, Y2, and Z1 are each independently a lone electron pair, H, Cι-C6 lower alkyl, C2- C6 lower alkenyl, C2-C6 lower alkynyl, Cι-C6 lower alkoxy, Cι-C6 lower alkylamino, Cι-C6 lower dialkylamino, C2-C6 lower cycloalkyl, C4-C6 lower cycloalkenyl, d-C6 lower thioalkyl, Ci-Cβ lower sulfinylalkyl, Cι-C6 lower sulfonylalkyl, Cι-C6 lower acyloxy, Cι-C6 lower acylamino with N substituted with R6, CH2OR5, CH2NR6R6a, Rf, RO, OH, NH2, CN, N02, F, CI, Br, I, or N3;
E is a bond, S(0)m, NR6, C=0, C02, CONR6, O, -0C=0, NR6C=0, NR6C02, OC=ONR6, OC02, or NR6CONR6a;
F is (CH2)n, (CH2)00(CH2)p, (CH2)0NR6(CH2)p, (CH2)0NR6CO(CH2)p, (CH2)0CONR6 (CH2)P, (CH2)0(CR6=CR6)q(CH2)p, (CH2)0-(C ^)q-(CH2)p;
G is a bond, O, NR6, CO, C02, OCO, OC02, S(0)m, CONR6, NR6CO, NReC02, OCONR6, NR6CONR6a, or G can optionally be attached to Ar2 at two contiguous C atoms to form a 5- to 7-membered partially saturated ring, which contains 0, 1, or 2 heteroatoms selected from the group consisting of O, N, and S;
X, X1 are independently O or S
Z2 is nothing, H or Ar1 optionally substituted with Y1 and Y2;
R1, R2, R3, and R4, are each independently selected from H, Ci-Cδ lower alkyl, C3-C6 lower alkenyl, C3-C6 lower alkynyl, C3-C6 lower cycloalkyl, C4-C6 lower cycloalkenyl, or independently R1 and R2 or R3 and R4 can be taken together to form a 5 to 8-membered ring containing 2-7 carbon atoms, the 5 to 8-membered ring optionally substituted with zero to 3 substituents selected from the group Ci- C4 lower alkyl, Cι-C4 lower alkoxy, Cj-C4 lower alkylamino, Cι-C4 lower dialkylamino, amino, hydroxyl, hydroxymethyl, methoxymethyl, phenyl, substituted phenyl, benzyl, substituted benzyl; U and V are each independently a bond, O or NR ; R5 R6 and R6a are each independently Cι-C6 alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 cycloalkenyl, C3-C6 alkynyl, and H; R7 and R8 are each independently H, Cι-C lower alkyl, or are taken together to form a saturated C3-C6 carbocyclic ring; Rf is Cι-C straight or branched lower perfluoroalkyl; all lower alkyl, alkenyl and alkynyl groups including those linked via heteroatoms can be straight chain or branched; m is 0, 1, or 2; n is O, 1, 2, 3, 4, 5, or 6; o is O, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; and q is 0, 1, 2, 3, 4, 5, or 6; with the provisos that when A is a bond or O, B is P(0)(OR3)(OR4), and D is selected from the group H, OH, OCOCH3, and NH2, and when R1 - R2 and R3 = R4, and both are selected from the group H or unsubstituted Cι-C4 lower alkyl, and E and G are bonds, and F is (CH2)n where n is 0, and both Ar1 and Ar2 are phenyl, then at least one of Y1, Y2, Z1, or Z must not be H; and when A is a bond or CH2, and B is P(0)(OR3)(OR4), and either D is H or Cι-C lower alkyl where L is CH2, or D is absent, with L— C taken together represent an ethenylidene group, and Ar1 is phenyl, and E is a bond or O, and R1 = R2 and R3 = R4, and both are drawn from the group H or Cι-C6 unsubstituted lower alkyl, then one of Y1 and Y2 must be other than H or unsubstituted Cι-C4 lower alkyl or unsubstituted Cι-C4 lower alkoxy; and when A is O, and B is H or P(0)(OR3)(OR4), and R1, R2, R3, and R4 are all selected from the group H or d-C6 unsubstituted lower alkyl, and D is H, and L is a bond, and Ar1 is phenyl, and E is other than a bond or O, then one of Y1 or Y2 must be other than H, or Cι-C4 unsubstituted lower alkyl or Cι-C4 unsubstituted lower alkoxy.
2. The compound according to Claim 1, wherein A is selected from a bond, O, and CH2; B is P(=0)(UR3)(VR4); D is H; and the L— C bond is a single bond.
3. A compound according to Claim 2, wherein Ar is phenyl.
4. A compound according to Claim 3, wherein U and V are each O.
5. A compound according to Claim 1, wherein the compound is selected from the group consisting of: Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[2- {N-methyl-N-pyrid-2-ylamino } ethoxy] -3 - fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[Ν-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)- N-methylaminocarbonyl]-3-fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[3 - {N-methyl-N-pyrid-2-ylamino } - 1 - oxoprop- 1 -yl]-3 -fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]- 3-fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[N-(2- {5-methyl-2-phenyloxazol-4- yl}ethyl)-N-methylaminocarbonyl]-3-fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(4-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]- 3-fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)-l -(4-[3- {5-methyl-2-phenylthiazol-4-yl} -1 - oxoprop- 1 -yl]-3 -fluorophenyl)methylphosphonate;
Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[2- {5-methyl-2-pyrid-4-yloxazol-4- yl}ethoxy]-3-fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[2- {5-methyl-2-pyrid-4-ylthiazol-4- yl } ethoxy] -3 -fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[3-{5 -methyl-2-pyrid-4-yloxazol-4-yl} - 1 - oxoprop-l-yl]-3-fluorophenyl)methylphosphonate; Diethyl 1 -(hydroxy)-l -(4-[N-(2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethyl)-Ν- methylaminocarbonyl]-3-fluorophenyl)methylphosphonate; Diethyl 1 -(hydroxy)- 1 -(4-[2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy]-3 - fluorophenyl)methylphosphonate;
Diethyl 1 -(hydroxy)- 1 -(4- [N-(2- {4-(4-trifluoromethylphenyl)phenoxy} ethyl)-N- methylaminocarbonyl] -3 -fluorophenyl)methylphosphonate; Diethyl 1 -(hydroxy)- 1 -(4-[3 - {4-(4-trifluoromethylphenyl)phenoxy} - 1 -oxoprop- 1 -yl] - 3-fluorophenyl)methylphosphonate; Diethyl l-(hydroxy)-l-(4-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3- hexylureido } ethyl] -3 -fluorophenyl)methylphosphonate; Diethyl l-(hydroxy)-l-(4-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]-3- fluorophenyl)methylphosphonate; Diethyl l-(hydroxy)-l-(4-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3- fluorophenyl)methylphosphonate; Diethyl l-(hydroxy)-l-(4-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]-3- fluorophenyl)methylphosphonate; Diethyl l-(hydroxy)-l-(4-[3,N-phthalimidopropoxy]-3- fluoroρhenyl)methylphosphonate;
Diethyl 1 -(hydroxy)-l -(4-[4,N-phthalimidobutoxy]-3- fluorophenyl)methylphosphonate; Tetraethyl l-(3-[3-{N-methyl-N-pyrid-2-ylamino}propoxy]-4-fluorophenyl )methylidenebisphosphonate; Tetraethyl 1 -(3-[N-(3- {N-methyl-N-pyrid-2-ylamino}propyl)-N-methylamino]-4- fluorophenyl)methylidenebisphosphonate; Tetraethyl 1 -(3 - [3 - {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop- 1 -ylamino] -4- fluorophenyl)methylidenebisphosphonate; Tetraethyl l-(3-[3-{5-methyl-2-phenyloxazol-4-yl}propoxy]-4- fluorophenyl)methylidenebisphosphonate;
Tefraethyl l-(3-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N- methylaminocarbonyl]-4-methoxyphenyl)methylidenebisphosphonate; Tefraethyl l-(3-[3-{5-methyl-2-phenylthiazol-4-yl}propoxy]-4- fluorophenyl)methylidenebisphosphonate; Tetraethyl l-(3-[3-{5-methyl-2-phenylthiazol-4-yl}-l-oxoprop-l-yl]-4- fluorophenyl)methylidenebisphosphonate; Tetraethyl l-(3-[4-{5-methyl-2-pyrid-4-yloxazol-4-yl}butoxy]-4- fluorophenyl)methylidenebisphosphonate; Tetraethyl l-(3-[3-{5-methyl-2-pyrid-4-ylthiazol-4-yl}propoxy]-4- fluorophenyl)methylidenebisρhosphonate; Tefraethyl l-(3-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-ylthio]-4- fluorophenyl)methylidenebisphosphonate; Tetraethyl 2-(3-[N-(3-{5-methyl-2-pyrid-4-ylthiazol-4-yl}propyl)-N-methyIamino]-4- fluorophenyl)vinylidene-l,l-bisphosphonate;
Tetraethyl 2-(3-[3- {4-(4-trifluoromethylphenyl)phenoxy}propoxy]-4- fluorophenyl) vinylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(3-[N-(3-{4-(4-trifluoromethylphenyl)phenoxy}propyl)-N-methylamino]- 4-fluorophenyl)vinylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(3-[4-{4-(4-trifluoromethylphenyl)phenoxy)-l-oxobut-l-yl]-4- fluorophenyl)vinylidene-l,l-bisphosphonate; Tetraethyl 2-(3-[2- { 1 -[4-(2-trifluoromethylρhenyl)phenylmethyl]-3- hexylureido} ethyl]-4-fluorophenyl)vinylidene- 1 , 1 -bisphosphonate; Tefraethyl 2-(3 -[2- { 1 -butyl-3 -(5-methoxypyrid-2-yl)ureido} ethyl]-4- fluorophenyl) vinylidene- 1 , 1 -bisphosphonate;
Tetraethyl 2-(3-[4-{4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]-4- fluorophenyl)vinylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(3 -[3 - {4H-3 -oxobenzof 1 ,4] oxazin-2-yl} propoxy] -4- fluorophenyl)vinylidene-l,l-bisphosphonate; Tetraethyl 2-(3 -[3 N-phthalimidopropoxy] -4-fluorophenyl) vinylidene- 1,1- bisphosphonate; Tetraethyl 2-(3 -[4,N-phthalimidobutoxy]-4-fluorophenyl)vinylidene- 1,1- bisphosphonate; Tetraethyl l-(6-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]indol-2-yl)ethylidene-l,2- bisphosphonate; Tetraethyl 1 -(6-[N-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N-methylamino]indol-2- yl)ethylidene- 1 ,2-bisphosphonate; Tetraethyl 1 -(6-[3 - {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop- 1 -yl]indol-2- yl)ethylidene- 1 ,2-bisphosphonate;
Tetraethyl 1 -(6-[2- {5-methyl-2-phenyloxazol-4-yl} ethoxy] indol-2 -yl)ethylidene- 1 ,2- bisphosphonate; Tetraethyl l-(6-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino] indol-2- yl)ethylidene-l,2-bisρhosphonate; Tetraethyl l-(6-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]indol-2-yl)ethylidene-l,2- bisphosphonate; Tetraethyl l-(6-[3-{5 -methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl]indol-2- yl)ethylidene- 1 ,2-bisphosphonate; Tetraethyl l-(6-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]indol-2-yl)ethylidene- 1,2-bisphosphonate;
Tetraethyl 1 -(6-[2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethoxy]indol-2-yl)ethylidene- 1 ,2-bisphosphonate; Tetraethyl l-(6-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-yl]indol-2- yl)ethylidene- 1 ,2-bisphosphonate; Tetraethyl 2-(6-[N-(2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethyl)-N- methylamino]indol-2-yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(6-[2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy] indol-2- yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(6-[N-(2- {4-(4-trifluoromethylphenyl)phenoxy} ethyl)-N- methylamino]indol-2-yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(6-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3- hexylureido} ethyl]indol-2-yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(6-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]indol-2- yl)ethylidene- 1 , 1 -bisphosphonate;
Tetraethyl 2-(6-[3- {4-(4-trifluoromethylphenyl)phenoxy} - 1 -oxoprop-1 -yl]indol-2- yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(6- [3 - {4-acetyl-3 -hydroxy-2-propylphenoxy)propoxy] indol-2- yl)ethylidene-l , 1 -bisphosphonate; Tetraethyl 2-(6-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]indol-2-yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(6-[3,N-phthalimidopropoxy]indol-2-yl)ethylidene-l,l-bisphosphonate; Tetraethyl 2-(6-[4,N-phthalimidobutoxy]indol-2-yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl N-(5-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]pyrid-2- yl)aminomethylidenebisphosphonate;
Tefraethyl N-(5-[N-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N-methylamino]pyrid-2- yl)aminomethylidenebisphosphonate; Tetraetlιyl N-(5-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l-yl]pyrid-2- yl)aminomethylidenebisphosphonate; Tetraethyl N-(5-[2- {5-methyl-2-phenyloxazol-4-yl} ethoxy]pyrid-2- yl)aminomethylidenebisphosphonate Tefraethyl N-(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]pyrid-2- yl)aminomethylidenebisphosphonate; Tetraethyl N-(5-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]pyrid-2- yl)aminomethylidenebisphosphonate; Tefraethyl N-(5 -[3 - { 5 -methyl-2-pyrid-4-yloxazol-4-yl} - 1 -oxoprop- 1 -yl]pyrid-2- yl)aminomethylidenebisphosphonate; Tefraethyl N-(5-[N-(2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethyl)-N- methylamino]pyrid-2-yl)aminomethylidenebisphosphonate;
Tetraethyl N-(5-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]pyrid-2- yl)aminomethylidenebisphosphonate; Tetraethyl N-(5-[2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethoxy]pyrid-2- yl)aminomethylidenebisphosphonate; 2-[l-Hydroxy-l-(5-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N- methylamino]pyrid-2-yl)methyl]-l,3,2-dioxaphospholane-2-oxide; 2-[ 1 -Hydroxy- 1 -(5-[2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy]-pyrid-2- yl)methyl]-l,3,2-dioxaphospholane-2-oxide; 2-[l-Hydroxy-l-(5-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N- methylamino]pyrid-2-yl)methyl] -1,3 ,2-dioxaphospholane-2-oxide;
2- [ 1 -Hydroxy- 1 -(5- [3 - {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop-1 -yl] -pyrid- 2-yl)methyl]-l,3,2-dioxaphospholane-2-oxide; 2-[l-Hydroxy-l-(5-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3- hexylureido}ethyl]pyrid-2-yl)methyl]-l,3,2-dioxaphospholane-2-oxide; -[l-Hydroxy-l-(5-[2-{l-butyl-3-(5-methoxyρyrid-2-yl)ureido}ethyl]pyrid-2- ylmethyl]-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-15-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]pyrid-2- ylmethyl]- 1 ,3 ,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]pyrid-2-yl)methyl]- 1 ,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[3N-phthalimidopropoxy]pyrid-2-yl)methyl]-l,3,2- dioxaphospholane-2-oxide ;-[l-Hydroxy-l-(5-[4,N-phthalimidobutoxy]pyrid-2-yl)methyl]-l,3,2- dioxaphospholane-2-oxide;- [ 1 -Hydroxy- 1 -(5- [2- {N-methyl-N-pyrid-2-ylamino } ethoxy]benzothien-2- yl)methyl]- [4R]-methyl-l ,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(5-[N-(2- {N-methyl-N-ρyrid-2-ylamino} ethyl)-N- methylamino]benzothien-2-yl)methyl]- [4R]-methyl-l,3,2-dioxaphospholane-2- oxide;-[ 1 -Hydroxy- 1 -(5 -[3 - {N-methyl-N-pyrid-2-ylamino } - 1 -oxoprop- 1 -yl]benzothien-2- yl)methyl]- [4R]-methyl-l ,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]benzothien-2- yl)methyl]- [4R]-methyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N- methylamino]benzothien-2-yl)methyl] - [4R] -methyl- 1 ,3 ,2-dioxaphospholane-2- oxide;-[ 1 -Hydroxy-1 -(5-[2- {5-methyl-2-phenylthiazol-4-yl} ethoxy]benzothien-2- yl)methyl]- [4R]-methyl-l ,3,2-dioxaphospholane-2-oxide; -[l-Hydroxy-l -(5-[3- {5-methyl-2-ρhenylthiazol-4-yl} -1 -oxoprop- 1 -yl]benzothien-2- yl)methyl]- [4R]-methyl-l,3,2-dioxaphospholane-2-oxide;-[l -Hydroxy- 1 -(5-[2- {5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]benzothien-2- yl)methyl]- [4R]-methyl-l,3,2-dioxaphospholane-2 -oxide;-[l-Hydroxy-l-(5-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]benzothien-2- yl)methyl]- [4R]-methyl-l,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(5-[3- {5-methyl-2-pyrid-4-yloxazol-4-yl} - 1 -oxoprop- 1 - yl]benzothien-2-yl)methyl]- [4R]-methyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5- N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyI)-N- methylamino]benzothien-2-yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2- oxide;-[ 1 -Hydroxy- 1 -(5-[2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy]benzothien-2- yl)methyl]- [4S] -methyl- 1 ,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(5 -[N-(2- {4-(4-trifluoromethylphenyl)phenoxy} ethyl)-N- methylamino]benzothien-2-yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2- oxide;-[l -Hydroxy-1 -(5-[3- {4-(4-trifluoromethylphenyl)phenoxy} -1 -oxoprop- 1 - yl]benzothien-2-yl)methyl]- [4S]-methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(5-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3- hexylureido}ethyl]benzothien-2-yl)methyl]- [4S]-methyl-l ,3,2- dioxaphospholane-2 -oxide;-[ 1 -Hydroxy- 1 -(5-[2- { 1 -butyl-3 -(5-methoxypyrid-2-yl)ureido} ethyl]benzothien-2- yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2 -oxide;- [ 1 -Hydroxy- 1 -(5 -[3 - {4-acetyl-3 -hydroxy-2-propylphenoxy)propoxy]benzothien-2- yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide; -[l -Hydroxy-1 -(5-[2- {4H-3-oxobenzo[l ,4]oxazin-2-yl} ethoxy]benzothien-2- yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[3N-phthalimidopropoxy]benzothien-2-yl)methyl]- [4S]-mefhyl- 1 ,3 ,2-dioxaphospholane-2-oxide;- [ 1 -Hydroxy- 1 -(5 - [4N-phthalimidobutoxy]benzothien-2-yl)methyl] - [4S] -methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(4-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]thiazol-2-yl)methyl]- 4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide;-[l -Hydroxy- 1 -(4-[N-(2- {N-methyl-N-pyrid-2-ylamino } ethyl)-N- methylamino]thiazol-2-yl)methyl]-4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(4-[3- {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop- 1 -yl]thiazol-2- yl)methyl]-4,5-dimethyl-l,3,2-dioxaphospholane-2 -oxide;-[ 1 -Hydroxy-1 -(4-[2- {5-methyl-2-phenyloxazol-4-yl} ethoxy]thiazol-2-yl)methyl]- 4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(4-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N- methylamino]thiazol-2-yl)methyl]-4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide;-[l -Hydroxy- 1 -(4-[2- {5-methyl-2-phenylthiazol-4-yl} ethoxy]thiazol-2-yl)methyl]- 4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide;-[l -Hydroxy-1 -(4-[3- {5-methyl-2-phenylthiazol-4-yl} -1 -oxoprop- 1 -yl]thiazol-2- yl)methyl]-4,5-dimethyl-l,3,2-dioxaphospholane-2 -oxide;-[ 1 -Hydroxy- 1 -(4-[2- {5-methyl-2-pyrid-4-yloxazol-4-yl} ethoxy]thiazol-2- yl)methyl]-4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(4-[2- { 5-methyl-2-pyrid-4-ylthiazol-4-yl} ethoxy]thiazol-2- yl)methyl]-4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide; -[ 1 -Hydroxy- 1 -(4-[3 - { 5-methyl-2-pyrid-4-yloxazol-4-yl } - 1 -oxoprop- 1 -yl]thiazol-2- yl)methyl]-4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(4-[N-(2-{5-methyl-2-ρyrid-4-ylthiazol-4-yl}ethyl)-N- methylamino]thiazol-2-yl)methyl]-l,3,2-dioxaphosphinane-2-oxide;-[ 1 -Hydroxy- 1 ~(4-[2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy]thiazol-2- yl)methyl]- 1 ,3,2-dioxaphosphinane-2 -oxide;-[ 1 -Hydroxy-1 -(4-[N-(2- {4-(4-trifluoromethylphenyl)phenoxy} ethyl)-N- methylamino]thiazol-2-yl)methyl]-l,3,2-dioxaphosphinane-2-oxide;-[ 1 -Hydroxy- 1 -(4-[3- {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl]thiazol- 2-yl)methyl]-l,3,2-dioxaphosphinane-2-oxide;-[ 1 -Hydroxy- 1 -(4-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl] -3 - hexylureido}ethyl]thiazol-2-yl)methyl]-l,3,2-dioxaphosphinane-2-oxide;-[l-Hydroxy-l-(4-[2-{l-buryl-3-(5-methoxypyrid-2-yl)ureido}ethyl]thiazol-2- yl)methyl]-l,3,2-dioxaphosphinane-2-oxide;-[ 1 -Hydroxy-1 -(4-[3- {4-acetyl-3-hydroxy-2 -propylphenoxy)propoxy]thiazol-2- yl)methyl]-l,3,2-dioxaphosphinane-2 -oxide;-[l-Hydroxy-l-(4-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]thiazol-2-yl)methyl]- 1 ,3 ,2-dioxaphosphinane-2-oxide;-[l-Hydroxy-l-(4-[3,N-phthalimidopropoxy]thiazol-2-yl)methyl]-l,3,2- dioxaphosphinane-2-oxide;-[l-Hydroxy-l-(4-[4,N-phthalimidobutoxy]thiazol-2-yl)methyl]-l,3,2- dioxaphosphinane-2-oxide;[l-(6-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]-3-methoxyquinolin-2-yl)-l-(2- oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-l,3,2-dioxaphospholane-2-oxide; [l-(6-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)- 1 -(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- 1,3,2- dioxaphospholane-2-oxide; [ 1 -(6- [3 - {N-methyl-N-pyrid-2 -ylamino } - 1 -oxoprop - 1 -yl] -3 -methoxyquinolin-2-yl) - 1 -(2-oxido-l ,3,2-dioxaphospholan-2-yl)methoxy]-l ,3,2-dioxaphospholane-2- oxide;[ 1 -(6-[2- { 5-methyl-2-phenyloxazol-4-yl} ethoxy]-3 -methoxyquinolin-2-yl)- 1 -(2- oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- 1 ,3 ,2-dioxaphospholane-2-oxide;[l-(6-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)- 1 -(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- 1,3,2- dioxaphospholane-2-oxide;[l-(6-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l-(2- oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-l,3,2-dioxaphospholane-2-oxide;[l-(6-[3-{5 -methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl] -3 -methoxyquinolin-2-yl)- 1 -(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- 1 ,3 ,2-dioxaphospholane-2- oxide;[l-(6-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l-(2- oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- 1 ,3 ,2-dioxaphospholane-2-oxide;[l-(6-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l-(2- oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-l,3,2-dioxaphospholane-2-oxide;[l-(6-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-yl]-3-methoxyquinolin-2- yl)-l-(2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-l,3,2-dioxaphospholane-2- oxide; [l-(6-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)-l-([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2- yl)methoxy]-[4R]-methyl-l,3,2-dioxaphospholane-2 -oxide; [ 1 -(6- [2- {4-(4-trifluoromethylphenyl)phenoxy } ethoxy] -3 -methoxy quinolin-2-yl)- 1 - ([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-[4R]-methyl-l,3,2- dioxaphospholane-2-oxide;[l-(6-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)-l-([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2- yl)methoxy]-[4R]-methyl-l,3,2-dioxaphospholane-2-oxide;[1 -(6-[3- {4-(4-trifluoromethylphenyl)phenoxy} - 1 -oxoprop- 1 -yl]-3 -methoxyquinolin- 2-yl)- 1 -([4R]-methyl-2-oxido- 1 ,3,2-dioxaphospholan-2-yl)methoxy]-[4R]- methyl- 1 ,3 ,2-dioxaphospholane-2 -oxide;[l-(6-[2-{l-[4-(2-frifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]-3- methoxyquinolin-2-yl)- 1 -([4R]-methyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2- yl)methoxy]-[4R]-methyl-l ,3,2-dioxaphospholane-2-oxide;[l-(6-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]-3-methoxyquinolin-2-yl)-l- ([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-[4R]-methyl-l,3,2- dioxaphospholane-2-oxide ; [ 1 -(6- [3 - {4-acetyl-3 -hydroxy-2-propylphenoxy)propoxy] -3 -methoxyquinolin-2-yl)- l-([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)metlιoxy]-[4R]-methyl- 1 ,3,2-dioxaphospholane-2-oxide;[l-(6-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]-3-methoxyquinolin-2-yl)-l- ([4R]-methyl-2-oxido-l,3,2-dioxaρhospholan-2-yl)methoxy]-[4R]-methyl-l,3,2- dioxaphospholane-2-oxide; [l-(6-[3,N-phthalimidopropoxy]-3-methoxyquinolin-2-yl)-l-([4R]-methyl-2-oxido- l,3,2-dioxaphospholan-2-yl)methoxy]-[4R]-methyl-l,3,2-dioxaphospholane-2- oxide;[l-(6-[4,N-phthalimidobutoxy]-3-methoxyquinolin-2-yl)-l-([4R]-methyl-2-oxido- l,3,2-dioxaphospholan-2-yl)methoxy]-[4R]-methyl-l,3,2-dioxaphospholane-2- oxide;[ 1 -(5-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]thien-2-yl)-l -([4S]-methyl-2-oxido- l,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l,3,2-dioxaphospholane-2- oxide;[l-(5-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]thien-2-yl)-l- ([4S]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l,3,2- dioxaphospholane-2-oxide;[ 1 -(5-[3- {N-methyl-N-pyrid-2-ylamino}-l -oxoprop-1 -yl]thien-2-yl)-l -([4S]-methyl- 2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l,3,2- dioxaphospholane-2-oxide;[l-(5-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]thien-2-yl)-l-([4S]-methyl-2-oxido- l,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l,3,2-dioxaphospholane-2- oxide;[l-(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]thien-2-yl)-l- ([4S]-methyl-2-oxido- 1 ,3 ,2-dioxaphosρholan-2-yl)methoxy]- [4S]-methyl-l ,3,2- dioxaphospholane-2-oxide;[l-(5-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]thien-2-yl)-l-([4S]-methyl-2-oxido- 1 ,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l ,3,2-dioxaphospholane-2- oxide; [l-(5-[3-{5-methyl-2-phenylthiazol-4-yl}-l-oxoprop-l-yl]thien-2-yl)-l-([4S]- methyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl- 1,3,2- dioxaphospholane-2-oxide;[l-(5-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]thien-2-yl)-l-([4S]-methyl-2- oxido-l,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l,3,2- dioxaphospholane-2-oxide;[l-(5-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]thien-2-yl)-l-([4S]-methyl-2- oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl- 1,3,2- dioxaphospholane-2-oxide;[1 -(5-[3- {5-methyl-2-pyrid-4-yloxazol-4-yl} - 1 -oxoprop- 1 -yl]thien-2-yl)- 1 -([43]- methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l,3,2- dioxaphospholane-2-oxide;[l-(5-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]thien-2-yl)-l- (4,5 -dimethyl-2-oxido- 1 , 3 ,2-dioxaphospholan-2-yl)methoxy] -4, 5 -dimethyl 1,3,2- dioxaphospholane-2-oxide;[ 1 -(5-[2- {4-(4-trifluoromethylphenyl)phenoxy}etlioxy]thien-2-yl)- 1 -(4,5-dimethyl- 2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2- dioxaphospholane-2-oxide; [ 1 -(5- [N-(2- {4-(4-trifluoromethylphenyl)phenoxy } ethyl)-N-methylamino] thien-2- yl)-l-(4,5-dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5- dimethyll,3,2-dioxaphospholane-2-oxide; [ 1 -(5 -[3 - {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl]thien-2-yl)- 1 -(4,5- dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2- dioxaphospholane-2-oxide; [l-(5-[2-{l- [4-(2-trifluoromethylphenyl)phenylmethyl]-3 -hexylureido } ethyl]thien-2- yl)- 1 -(4,5-dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]-4,5 - dimethyll,3,2-dioxaphospholane-2-oxide;[1 -(5-[2- { 1 -butyl-3-(5-methoxypyrid-2-yl)ureido} ethyl]thien-2-yl)-l -(4,5-dimethyl- 2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2- dioxaphospholane-2-oxide;[l-(5-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]thien-2-yl)-l-(4,5-dimethyl- 2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy] -4, 5 -dimethyl 1,3,2- dioxaphospholane-2-oxide;[1 -(5-[2- {4H-3-oxobenzo[ 1 ,4]oxazin-2-yl} ethoxy]thien-2-yl)- 1 -(4,5-dimethyl-2- oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy] -4,5 -dimethyl 1,3,2- dioxaphospholane-2-oxide;[l-(5-[3,N-phthalimidopropoxy]thien-2-yl)-l-(4,5-dimethyl-2-oxido-l,3,2- dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide; [ 1 -(5-[4,N-phthalimidobutoxy]thien-2-yl)- 1 -(4,5-dimethyl-2-oxido- 1,3,2- dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;[l-(4-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]-3-fluoroρhenyl)-l-(2-oxido-l,3,2- dioxaphosphinan-2-yl)methoxy]-l,3,2-dioxaphosphinane-2-oxide; [ 1 -(4- [Ν-(2- {N-methyl-N-pyrid-2-ylamino } ethyl)-N-methylaminocarbonyl] -3 - fluorophenyl)-l-(2-oxido-l,3,2-dioxaphosphinan-2-yl)methoxy]-l,3,2- dioxaphosphinane-2-oxide; [ 1 -(4-[3 - {N-methyl-N-pyrid-2-ylamino } - 1 -oxoprop-1 -yl] -3 -fluorophenyl)- 1 -(2- oxido-l,3,2-dioxaphosphinan-2-yl)methoxy]-l,3,2-dioxaphosphinane-2-oxide;[ 1 -(4- [2- { 5-methyl-2-phenyloxazol-4-yl} ethoxy] -3 -fluorophenyl)- 1 -(2-oxido- 1,3,2- dioxaphosphinan-2-yl)methoxy]-l,3,2-dioxaphosphinane-2-oxide; 1 ~(4-[N-(2- {5-methyl-2-phenyloxazol-4-yl} ethyl)-N-methylaminocarbonyl]-3- fluorophenyl)- 1 , 1 -bis(2-oxido- 1 ,3 ,2-dioxaρhospholan-2-yl)methane; 1 -(4- [2- { 5-methyl-2-phenylthiazol-4-yl } ethoxy] -3 -fluorophenyl)- 1 , 1 -bis(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; l-(4-[3-{5-methyl-2-phenylthiazol-4-yl}-l-oxoprop-l-yl]-3-fluorophenyl)-l,l-bis(2- oxido-l,3,2-dioxaphospholan-2-yl)methane; 1 -(4-[2- {5-methyl-2-pyrid-4-yloxazol-4-yl} ethoxy]-3-fluorophenyl)-l ,1 -bis(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; 1 -(4-[2- {5-methyl-2-ρyrid-4-ylthiazol-4-yl} ethoxy] -3 -fluorophenyl)- 1 , 1 -bis(4,5- dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane ; l-(4-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-yl]-3-fluorophenyl)-l,l- bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methane; l-(4-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-Ν-methylaminocarbonyl]-3- fluorophenyl)- 1 , 1 -bis(4,5-dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; l-(4-[2-{4-(4-trifluoromethylphenyl)phenoxy}ethoxy]-3-fluorophenyl)-l,l-bis(2- oxido-l,3,2-dioxaphosphinan-2-yl)methane; 1 -(4-[N-(2- {4-(4-trifluoromethylphenyl)phenoxy } ethyl)-N-methylaminocarbonyl]-3- fluorophenyl)- 1 , 1 -bis(4,5-dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; 1 -(4- [3 - {4-(4-frifluoromethylphenyl)phenoxy} - 1 -oxoprop- 1 -yl]-3 -fluorophenyl)- 1,1- bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methane; l-(4-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]-3- fluorophenyl)- 1 , 1 -bis(4, 5 -dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; l-(4-[2-{l -butyl-3 -(5 -methoxypyrid-2-yl)ureido } ethyl] -3 -fluorophenyl)- 1 , 1 -bis(2- oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methane; -(4-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-fluorophenyl)-l,2-bis(2- oxido- 1 ,3 ,2-dioxaphospholan-2-yl)ethane;-(4-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]-3-fluorophenyl)-l,2-bis([4R]- methyl-2-oxido- 1 ,3,2-dioxaphospholan-2-yl)ethane;-(4-[3,N-phthalimidopropoxy]-3-fluorophenyl)-l,2-bis(2-oxido-l,3,2- dioxaphospholan-2-yl)ethane;-(4-[4,N-phthalimidobutoxy]-3-fluorophenyl)-l,2-bis([4R]-methyl-2-oxido-l,3,2- dioxaphospholan-2-yl)ethane;-(3-[3-{N-methyl-N-pyrid-2-ylamino}propoxy]-4-fluorophenyl )-l,2-bis(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)ethane;-(3-[N-(3-{N-methyl-N-pyrid-2-ylamino}propyl)-N-methylamino]-4-fluorophenyl)- l,2-bis([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)ethane;-(3-[3- {N-methyl-N-pyrid-2-ylamino} -1 -oxoprop-1 -ylamino]-4-fluorophenyl)-l ,2- bis(2-oxido-l,3,2-dioxaphospholan-2-yl)ethane;-(3-[3-{5-methyl-2-phenyloxazol-4-yl}propoxy]-4-fluorophenyl)-l,2-bis([4R]- methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)ethane;-(3-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylaminocarbonyl]-4- methoxyphenyl)- 1 , 1 -bis(4,5-dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2- yl)ethane;-(3-[3-{ 5-methyl-2-phenylthiazol-4-yl }propoxy] -4-fluorophenyl)- 1 , 1 -bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)ethane;-(3 -[3 - { 5-methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl] -4-fluorophenyl)- 1,1- bis(4,5-dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)ethane;-(3 -[4- { 5-methyl-2-pyrid-4-yloxazol-4-yl}butoxy]-4-fluorophenyl)- 1 , 1 -bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)ethane; -(3-[3-{5-methyl-2-pyrid-4-ylthiazol-4-yl}propoxy]-4-fluorophenyl)-l,l-bis(4,5- dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)ethane; -(3-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-ylthio]-4-fluorophenyl)-l,l- bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)ethane; -(3-[N-(3-{5-methyl-2-pyrid-4-ylthiazol-4-yl}propyl)-N-methylamino]-4- fluorophenyl)-l,l-bis(4,5-dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)ethane; -(3-[3- {4-(4-trifluoromethylphenyl)phenoxy}propoxy]-4-fluorophenyl)-l , 1 -bis(2- oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)ethane; l-[N-(3-[N-(3-{4-(4-trifluoromethylphenyl)phenoxy}propyl)-N-methylamino]-4- fluorophenyl)amino] -1,1 -bis(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane;
1 -[N-(3-[4- {4-(4-trifluoromethylphenyl)phenoxy)- 1 -oxobut-1 -yl]-4- fluorophenyl)amino]- 1 , 1 -bis([4R]-methyl-2-oxido-l ,3,2-dioxaphospholan-2- yl)methane; l-[N-(3-[2-{l-[4-(2-frifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]-4- fluorophenyl)amino]- 1 , 1 -bis(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; l-[N-(3-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]-4-fluorophenyl)amino]- 1 , 1 -bis([4R]-methyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; l-[N-(3-[4-{4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]-4-fluorophenyl)amino]- 1 , 1 -bis(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; 1 - [N-(3 - [3 - {4H-3 -oxobenzo [ 1 ,4]oxazin-2 -yl}propoxy] -4-fluorophenyl)amino] -1,1- bis([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methane; l-[N-(3-[3,N-phthalhnidopropoxy]-4-fluorophenyl)amino]-l,l-bis(2-oxido-l,3,2- dioxaphospholan-2-yl)methane; l-[N-(3-[4,N-phthalimidobutoxy]-4-fluorophenyl)amino]-l,l-bis([4R]-methyI-2- oxido-l,3,2-dioxaphospholan-2-yl)methane; -[N-(6-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]indol-2-yl)amino]- 1 , 1 -bis(2-oxido- l,3,2-dioxaphosphinan-2-yl)methane; -[N-(6-[N-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N-methylamino]indol-2- yl)amino] -1,1 -bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methane; - [N-(6- [3 - {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop- 1 -yl]indol-2-yl)amino]- 1 , 1 - bis(2-oxido-l,3,2-dioxaphosphinan-2-yl)methane; -[N-(6-[2- {5-methyl-2-phenyloxazol-4-yl} ethoxy] indol-2 -yl)amino]- 1 , 1 -bis(2- oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methane;-[l-(Diethoxyphosphinyloxy)-l-(6-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N- methylamino] indol-2-yl)methyl]-l,3,2-dioxaphospholane-2-oxide;-[l-(Diethoxyphosphinyloxy)-l-(6-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]indol- 2-yl)methyl]- 1 ,3 ,2-dioxaphosρholane-2-oxide;-[ 1 -(Diethoxyphosphinyloxy)- 1 -(6-[3 - {5-methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 - yl]indol-2-yl)methyl]-l,3,2-dioxaphospholane-2-oxide;-[ 1 -(Diethoxyphosphinyloxy)- 1 -(6-[2- {5-methyl-2-pyrid-4-yloxazol-4- yl} ethoxy]indol-2-yl)methyl]- 1 ,3 ,2-dioxaphospholane-2-oxide;-[ 1 -(Diethoxyphosphinyloxy)-l -(6-[2- {5-methyl-2-pyrid-4-ylthiazol-4- yl}ethoxy]indol-2-yl)methyl]-l,3,2-dioxaphosphinane-2-oxide;-[l -(Diethoxyphosphinyloxy)- 1 -(6-[3- {5-methyl-2-pyrid-4-yloxazol-4-yl} - 1 - oxoprop-l-yl]indol-2-yl)methyl]-l,3,2-dioxaphosphinane-2-oxide;-[l-(Diethoxyphosphinyloxy)-l-(6-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)- N-methylamino]indol-2-yl)methyl]- 1 ,3 ,2-dioxaphosphinane-2-oxide;-[ 1 -(Diethoxyphosphinyloxy)- 1 -(6-[2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy] indol-2-yl)methyl]- 1 ,3 ,2-dioxaphosphinane-2-oxide; [ 1 -(6-[N-(2- {4-(4-trifluoromethylphenyl)phenoxy } ethyl)-N-methylamino]indol-2- yl)-l-(diethoxyphosphinyl)methoxy]-4[S]-methyl-l,3,2-dioxaphospholane-2- oxide; [ 1 -(6- [3 - {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl]indol-2-yl)- 1 - (diethoxyphosphinyl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;[1 -(6-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido} ethyl]indol-2- yl)-l-(diethoxyphosphinyl)methoxy]-4[S]-methyl-l,3,2-dioxaphospholane-2- oxide;[l-(6-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]indol-2- yl)- 1 -(diethoxyphosphinyl)methoxy]-4,5-dimethyl 1 ,3 ,2-dioxaphospholane-2- oxide; [ 1 -(6- [3 - {4-acetyl-3 -hydroxy-2-propylphenoxy)propoxy]indol-2-yl)- 1 - (diethoxyphosphinyl)methoxy]-4[S]-methyl-l,3,2-dioxaphospholane-2-oxide;[l-(6-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]indol-2-yl)-l- (diethoxyphosphinyl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;[ 1 -(6-[2- { 1 -butyl-3-(5-methoxypyrid-2-yl)ureido} ethyl]indol-2-yl)- 1 - (diethoxyphosphinyl)methoxy]-4[S]-methyl-l,3,2-dioxaphospholane-2-oxide;[l-(6-[3,N-phthalimidopropoxy]indol-2-yl)-l-(diethoxyphosphinyl)methoxy]-4,5- dimethyll,3,2-dioxaphospholane-2-oxide;[l-(6-[4,N-ρhthalimidobutoxy]indol-2-yl)-l-(diethoxyphosρhinyl)methyl]-4[R]- methyl- 1 ,3,2-dioxaphospholane-2-oxide;[ 1 -(5-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]pyrid-2-yl)-l - (diethoxyphosphinyl)methyl]-4[R]-methyl-l,3,2-dioxaphospholane-2-oxide;[ 1 -(5-[N-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N-methylamino]pyrid-2-yl)- 1- (diethoxyphosphinyl)methyl]-4[R]-methyl-l,3,2-dioxaphospholane-2-oxide; [ 1 -(5-[3- {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop- 1 -yl]ρyrid-2-yl)- 1 - (diethoxyphosphinyl)methyl]-4[R]-methyl-l,3,2-dioxaphospholane-2-oxide;[l-(5-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]pyrid-2-yl)-l- (diethoxyphosphinyl)methyl]-l,3,2-dioxaphosphinane-2 -oxide;[l-(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]pyrid-2-yl)-l- (diethoxyphosphinyl)methyl]-l,3,2-dioxaphosphinane-2-oxide; [ 1 -(5-[N-(2- { 5-methyl-2-phenyloxazol-4-yl} ethyl)-N-methylamino]pyrid-2-yl)- 1 - (diethoxyphosphmyl)methyl] -1,3 ,2-dioxaphosphinane-2-oxide;[1 -(5-[2- {5-methyl-2-phenylthiazol-4-yl}ethoxy]pyrid-2-yl)- 1 - (diethoxyphosphinyl)methyl]-l,3,2-dioxaphosphinane-2-oxide;[1 -(5-[3- {5-methyl-2-phenylthiazol-4-yl} - 1 -oxoprop-1 -yl]pyrid-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;[l-(5-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]pyrid-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl] - 1 ,3,2-dioxaphosphinane-2-oxide;[ 1 -(5-[2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethoxy]ρyrid-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-4,5-dimethyll,3,2-dioxaphospholane-2 -oxide;[1 -(5-[3- {5-methyl-2-pyrid-4-yloxazol-4-yl} - 1 -oxoprop-1 -yl]pyrid-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphosphinane-2-oxide;[l-(5-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]pyrid-2-yl)-2- (diethoxyphosphiιιyl)eth- 1 -yl]-4,5-dimethyl 1 ,3,2-dioxaphospholane-2 -oxide;[l-(5-[2-{4-(4-trifluoromethylphenyl)phenoxy}ethoxy]-pyrid-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl] -1,3 ,2-dioxaphosphinane-2-oxide;[l-(5-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]pyrid-2- yl)-2-(diethoxyphosphinyl)eth-l-yl]-4,5-dimethyll,3,2-dioxaphospholane-2- oxide; [ 1 -(5-[3- {4-(4-trifluoromethylphenyl)phenoxy} - 1 -oxoprop- 1 -yl]-pyrid-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphosρhinane-2-oxide;[2-(5-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]pyrid-2- yl)-2-(diethoxyphosphinyl)eth-l-yl]-l,3,2-dioxaphospholane-2-oxide;[2-(5-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]pyrid-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-4[R]-methyl-l,3,2-dioxaphospholane-2-oxide;[2-(5-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]pyrid-2-yl)-2~ (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphospholane-2-oxide;[2-(5-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]pyrid-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-4[R]-methyl-l,3,2-dioxaphospholane-2 -oxide; [2-(5- [3 ,N-phthalimidopropoxy]pyrid-2-yl)-2-(diethoxyphosphinyl)eth- 1 -yl] -1,3,2- dioxaphospholane-2-oxide;[2-(5-[4,N-phthalimidobutoxy]pyrid-2-yl)-2-(diethoxyphosphinyl)eth-l-yl]-4[R]- methyl-l,3,2-dioxaphospholane-2-oxide;[2-(5-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]benzothien-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphospholane-2-oxide;[2-(5-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]benzothien-2-yl)- 2-(diethoxyphosphinyl)eth-l-yl]-4[R]-methyl-l,3,2-dioxaphospholane-2 -oxide; [2-(5- [3 - {N-methyl-N-pyrid-2-ylamino } - 1 -oxoprop- 1 -yl]benzothien-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl] -1,3 ,2-dioxaphosphinane-2-oxide;[2-(5-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]benzothien-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphosphinane-2 -oxide;[2-(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]benzothien-2-yl)- 2-(diethoxyphosphinyl)eth-l-yl]-l,3,2-dioxaphosphinane-2-oxide; 2[2-(5-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]benzothien-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphosphinane-2-oxide; 2[2-(5-[3- {5-methyl-2-phenylthiazol-4-yl}- 1 -oxoprop-1 -yl]benzothien-2-yl)-l - (diethoxyphosphinyl)eth-l-yl]-l,3,2-dioxaphosρholane-2-oxide; 2[2-(5-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]benzothien-2-yl)-l- (diethoxyphosphinyl)eth-l-yl]-l,3,2-dioxaphosρholane-2-oxide; 2[2-(5-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]benzothien-2-yl)-l- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphospholane-2 -oxide; 2[2-(5-[3 - {5-methyl-2-pyrid-4-yloxazol-4-yl} - 1 -oxoprop- 1 -yl]benzothien-2-yl)- 1 - (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphospholane-2-oxide;
N,N,N',N'-Teframethyl- 1 (5- N-(2- {5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N- methylamino]benzothien-2-yl)-l-hydroxymethylphosphondiamide; NN'-Diethyl l-(5-[2-{4-(4-trifluoromethylphenyl)phenoxy}ethoxy]benzothien-2-yl)- 1 -hydroxymethylphosphondiamide; 2-[ 1 -hydroxy- 1 -(5-[N-(2- {4-(4-trifluoromethylphenyl)phenoxy } ethyl)-N- methylamino]benzothien-2-yl)methyl]-[4S,5S]-dimethyl-l,3,2- diazaphospholidine-2-oxide; 2- [ 1 -hydroxy- 1 -(5- [3 - {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 - yl]benzothien-2-yl)methyl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2-oxide; 2-[ 1 -hydroxy-1 -(5-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3- hexylureido}ethyl]benzothien-2-yl)methyl]-[4S]-ethyl-l,3,2-oxazaphospholidine- 2-oxide; 2-[ 1 -hydroxy- 1 -(5 -[2- { 1 -butyl-3 -(5 -methoxypyrid-2-y l)ureido } ethyl]benzothien-2- yl)methyl]-[4R]methyl-l,3,2-oxazaphosphinane-2-oxide; NNN',N'-Tetτamethyl-1 (5-[3-{4-acetyl-3-hydroxy-2- propylphenoxy)propoχy]benzothien-2-yl)-l-hydroxymethylphosphondiamide; NN'-Diethyl l-(5-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]benzothien-2-yl)-l- hydroxymethylphosphondiamide; 2-[l-hydroxy-l-(5-[3,N-phthalimidopropoxy]benzothien-2-yl)methyl]-[4S,5S]- dimethyl-l,3,2-diazaphospholidine-2 -oxide; 2-[l-hydroxy-l-(5-[4,N-phthalimidobutoxy]benzothien-2-yl)methyl]-l,3,5,5- tetramethyl- 1 ,3 ,2-diazaphosphinane-2-oxide; 2-[ 1 -hydroxy- 1 -(4-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]thiazol-2-yl)methyl]- [4S]-ethyl-l,3,2-oxazaphospholidine-2-oxide;
2-[l-hydroxy-l-(4-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N- methylamino]thiazol-2-yl)methyl]-[4R]methyl-l,3,2-oxazaphosphinane-2-oxide; NNN'N'-Tetramethyl l-(4-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l- yl]thiazol-2-yl)-l-(bis[NN- dimethylamino]phosphoryloxy)methylphosphondiamide;
NN'-Diethyl 1 -(4-[2- {5 -methyl-2-phenyloxazol-4-yl} ethoxy]thiazol-2-yl)- 1 -(bis[N- ethylamino]phosphoryloxy)methylphosphondiamide; 2-[l-{([4S,5S]-dimethyl-2-oxido-l,3,2-diazaρhospholidin-2-yl)oxy}-l-(4-[N-(2-{5- methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]thiazol-2-yl)methyl]-[4S,5S]- dimethyl- 1 ,3,2-diazaphospholidine-2-oxide;
2-[ 1 - {(1 ,3,5,5-tetramethyl-2-oxido-l ,3,2-diazaphosphinan-2-yl)oxy}-l -(4-[2- {5- methyl-2-phenylthiazol-4-yl}ethoxy]thiazol-2-yl)methyl]-l,3,5,5-tetramethyl- 1 ,3,2-diazaphosphinane-2-oxide; 2-[ 1 - {(4S]-ethyl-2-oxido-l ,3 ,2-oxazaphospholidin-2-yl)oxy} - 1 -(4- [3- {5-methyl-2- phenylthiazol-4-yl}-l-oxoprop-l-yl]thiazol-2-yl)methyl]-[4S]-ethyl-l,3,2- oxazaphospholidine-2-oxide; 2-[ 1 - {([4R]methyl- 1 ,3 ,2-oxazaphosphinan-2-yl)oxy} -1 -(4-[2- { 5-methyl-2-pyrid-4- yloxazol-4-yl}ethoxy]thiazol-2-yl)methyl]-[4R]methyl-l,3,2-oxazaphosphinane- 2-oxide; NNN',N'-Tetramethyl l-(4-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]thiazol-2- yl)-l-(bis[N,N-dimethylamino]phosphoryloxy)methylphosphondiamide; NN'-Diethyl 1 -(4-[3- {5-methyl-2-ρyrid-4-yloxazol-4-yl} - 1 -oxoprop-1 -yl]thiazol-2- yl)- 1 -(bis[N-ethylamino]phosphoryloxy)methylphosphondiamide;
2-[l - {([4S,5S]-dimethyl-2-oxido- 1 ,3,2-diazaphospholidin-2-yl)oxy} -1 -(4-[N-(2- {5- methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]thiazol-2-yl)methyl]- [4S,5S]-dimethyl-l,3,2-diazaphospholidine-2 -oxide; 2-[ 1 - {(1 ,3,5,5-tetramethyl-2-oxido-l ,3,2-diazaphosphinan-2-yl)oxy} -1 -(4-[2- {4-(4- frifluoromethylphenyl)phenoxy}ethoxy]thiazol-2-yl)methyl]-l,3,5,5-teframethyl- 1 ,3 ,2-diazaphosphinane-2-oxide; 2-[ 1 - {(4S]-ethyl-2-oxido- 1 ,3 ,2-oxazaphospholidin-2-yl)oxy} - 1 -(4-[N-(2- {4-(4- frifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]thiazol-2-yl)methyl]-[4S]- ethyl- 1 ,3 ,2-oxazaphospholidine-2-oxide; 2-[ 1 - {([4R]methyl- 1 ,3 ,2-oxazaphosphinan-2-yl)oxy} - 1 -(4-[3- {4-(4- frifluoromethylphenyl)phenoxy} - 1 -oxoprop-1 -yl]thiazol-2-yl)methyl]- [4R]methyl-l,3,2-oxazaphosphinane-2-oxide; l-(4-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]thiazol-2- yl)-l,l-bis(bis[N,N-dimethylamino]phosphoryl)methane; 1 -(4-[2- { 1 -butyl-3 -(5 -methoxyρyrid-2-yl)ureido } ethyl]thiazol-2-yl)- 1 , 1 -bis(bis[N- ethylamino]phosphoryl)methane; l-(4-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]thiazol-2-yl)-l,l-bis([4S,5S]- dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)methane; l-(4-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]thiazol-2-yl)-l,l-bis(l,3,5,5- tetramethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)methane; 1 -(4-[3,N-phthalimidopropoxy]thiazol-2-yl)-l , 1 -bis ([4S]-ethyl-2-oxido-l ,3 ,2- oxazaphospholidin-2-yl)methane; 1 -(4-[4,N-phthalimidobutoxy]thiazol-2-yl)- 1 , 1 -bis ([4R]methyl-2-oxido- 1,3,2- oxazaphosphinan-2-yl)methane;
1 -(6-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]-3-methoxyquinolin-2-yl)-l , 1 - bis(bis[N,N-dimethylamino]phosphoryl)methane; 1 -(6- [N-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N-methylamino] -3 - methoxyquinolin-2-yl)-l,l-bis(bis[N-ethylamino]phosphoryl)methane; 1 -(6-[3 - {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop-1 -yl]-3 -methoxyquinolin-2-yl)- l,l-bis([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)methane; l-(6-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l,l- bis(l,3,5,5-teframethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)methane; l-(6-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)- 1 , 1 -bis ([4S] -ethyl-2-oxido-l ,3 ,2-oxazaphospholidin-2- yl)methane; l-(6-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l,l-bis ([4R]methyl-2-oxido-l,3,2-oxazaphosphinan-2-yl)methane; 1 -(6-[3- { 5-methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl]-3 -methoxyquinolin-2-yl)- 1 ,2-bis(bis[N,N-dimethylamino]phosphoryl)ethane; l-(6-[2-{5-metlιyl-2-pyrid-4-yloxazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l,2- bis(bis[N-ethylamino]phosphoryl)ethane; l-(6-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l,2- bis([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)ethane; 1 -(6-[3 - { 5 -methyl-2-pyrid-4-yloxazol-4-yl} - 1 -oxoprop- 1 -yl] -3 -methoxyquinolin-2- yl)-l,2-bis(l,3,5,5-tetramethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)ethane; l-(6-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)-l,2-bis ([4S]-ethyl-2-oxido-l,3,2-oxazaphospholidin-2- yl)ethane; l-(6-[2-{4-(4-trifluoromethylphenyl)phenoxy}ethoxy]-3-methoxyquinolin-2-yl)-l,2- bis ([4R]methyl-2-oxido- 1 ,3 ,2-oxazaphosphinan-2-yl)ethane; l-(6-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)-l,2-bis(bis[NN-dimethylamino]phosphoryl)ethane; 1 -(6-[3- {4-(4-trifluoromethylphenyl)phenoxy} -1 -oxoprop-1 -yl]-3-methoxyquinolin-2- yl)-l ,2-bis(bis[N-ethylamino]phosphoryl)ethane; l-(6-[2-{l-[4-(2-frifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]-3- methoxyquinolin-2-yl)-l,2-bis([4S,5S]-dimethyl-2-oxido-l,3,2- diazaphospholidin-2-yl)ethane; 1 -(6-[2- { 1 -butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]-3-methoxyquinolin-2-yl)-l ,2- bis(l,3,5,5-tetramethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)ethane;
1 -(6-[3 - {4-acetyl-3 -hydroxy-2-propylphenoxy)propoxy] -3 -methoxyquinolin-2-yl)- 1,2-bis ([4S]-ethyl-2-oxido-l,3,2-oxazaphospholidin-2-yl)ethane; l-(6-[3,N-phthalimidopropoxy]-3-methoxyquinolin-2-yl)-l,2-bis ([4R]methyl-2- oxido- 1 ,3 ,2-oxazaphosphinan-2-yl)ethane; -(6-[4,N-phthalimidobutoxy]-3-methoxyquinolin-2-yl)-l,l-bis(bis[NN- dimethylamino]phosphoryl)ethane;-(5-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]thien-2-yl)-l,l-bis(bis[N- ethylamino]phosphoryl)ethane;-(5-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]thien-2-yl)-l,l- bis([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)ethane;-(5-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l-yl]thien-2-yl)-l,l-bis(l,3,5,5- tetramethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)ethane;-(5-[2- {5-methyl-2-phenyloxazol-4-yl} ethoxy]thien-2-yl)-l , 1 -bis ([4S]-ethyl-2- oxido-1 ,3,2-oxazaphospholidin-2-yl)ethane;-(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]thien-2-yl)-l,l-bis ([4R]methyl-2-oxido-l,3,2-oxazaphosphinan-2-yl)ethane;-(5-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]thien-2-yl)-l,l-bis(bis[NN- dimethylamino]phosphoryl)ethane;-(5-[3- {5-methyl-2-phenylthiazol-4-yl} -1 -oxoprop-1 -yl]thien-2-yl)-l , 1 -bis(bis[N- ethylamino]phosphoryl)ethane;-(5-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]thien-2-yl)-l,l-bis([4S,5S]- dimethyl-2-oxido- 1 ,3 ,2-diazaphospholidin-2-yl)ethane;-(5-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]thien-2-yl)-l , 1 -bis(l ,3,5,5- tetramethyl-2 -oxido-1 ,3,2-diazaphosphinan-2-yl)ethane;-(5-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-yl]thien-2-yl)-l,l-bis ([4S]- ethyl-2-oxido-l,3,2-oxazaphospholidin-2-yl)ethane;-(5 -[N-(2- { 5 -methyl-2-pyrid-4-ylthiazol-4-yl} ethyl)-N-methylamino]thien-2-yl)- 1,1- bis ([4R]methyl-2-oxido- 1 ,3 ,2-oxazaphosphinan-2-yl)ethane; -l-[N-(5-[2-{4-(4-trifluoromethylphenyl)ρhenoxy}ethoxy]thien-2-yl)amino]-l,l- bis(bis[N,N-dimethylamino]phosphoryl)methane; l-[N-(5-[N-(2-{4-(4-frifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]thien-2- yl)amino]-l , 1 -bis(bis[N-ethylamino]phosphoryl)methane; 1 -[N-(5-[3- {4-(4-trifluoromethylphenyl)phenoxy} - 1 -oxoprop- 1 -yl]thien-2-yl)amino]- 1 , 1 -bis([4S,5 S]-dimethyl-2-oxido- 1 ,3 ,2-diazaphospholidin-2-yl)methane; l-[N-(5-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]thien- 2-yl)amino]-l,l-bis(l,3,5,5-teframethyl-2-oxido-l,3,2-diazaphosphinan-2- yl)methane; l-[N-(5-[2- { 1 -butyl-3 -(5-methoxypyrid-2-yl)ureido} ethyl] thien-2-yl)amino]-l , 1 -bis ([4S]-ethyl-2-oxido- 1 ,3 ,2-oxazaphospholidin-2-yl)methane; 1 -[N-(5-[3- {4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]thien-2-yl)amino]-l , 1 -bis ([4R]methyl-2-oxido-l,3,2-oxazaphosphinan-2-yl)methane; 1 -[N-(5-[2- {4H-3-oxobenzo[ 1 ,4]oxazin-2-yl} ethoxy]thien-2-yl)amino]-l , 1 - bis(bis[N,N-dimethylamino]phosphoryl)methane;
1 - [N-(5- [3 ,N-phthalimidopropoxy]thien-2-yl)amino]- 1 , 1 -bis(bis [N- ethylamino]phosphoryl)methane; 1 -[N-(5-[4,N-phthalimidobutoxy]thien-2-yl)amino]- 1 , 1 -bis([4S,5S]-dimethyl-2-oxido- 1 ,3 ,2-diazaphospholidin-2-yl)methane; l-[N-(4-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]-3-fluorophenyl)amino]-l,l- bis(l,3,5,5-tetramethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)methane; l-[N-(4-[Ν-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylaminocarbonyl]-3- fluorophenyl)amino]-l,l-bis ([4S]-ethyl-2-oxido-l,3,2-oxazaphospholidin-2- yl)methane; l-[N-(4-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l-yl]-3-fluorophenyl)amino]- 1 , 1 -bis ([4R]methyl-2-oxido- 1 ,3 ,2-oxazaphosphinan-2-yl)methane; 2-[l-(Bis[N-ethylamino]phosphoryloxy)-l-(4-[2-{5-methyl-2-phenyloxazol-4- yl}ethoxy]-3-fluorophenyl)methyl]-[4S,5S]-dimethyl-l,3,2-diazaphospholidine-2- oxide;
2-[l-(Bis[N-ethylamino]phosphoryl)-l-(4-[N-(2-{5-methyl-2-phenyloxazol-4- yl}ethyl)-N-methylaminocarbonyl]-3-fluorophenyl)methoxy]-[4S,5S]-dimethyl- 1 ,3 ,2-diazaphospholidine-2-oxide; 2-[l-(Bis[N-ethylamino]phosphoryl)-l-(4-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]- 3-fluorophenyl)methyl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2 -oxide;
2-[l-(Bis[N-ethylamino]phosphoryl)-2-(4-[3-{5-methyl-2-phenylthiazol-4-yl}-l- oxoprop-l-yl]-3-fluorophenyl)ethen-l-yl]-[4S]-ethyl-l,3,2-oxazaphospholidine-2- oxide; 2-[l-(Bis[N-ethylamino]phosphoryl)-2-(4-[2-{5-methyl-2-pyrid-4-yloxazol-4- yl}ethoxy]-3-fluorophenyl)eth-l-yl]-[4R]methyl-l,3,2-oxazaphosphinane-2- oxide; 2-[2-(Bis[N-ethylamino]phosphoryl)-2-(4-[2-{5-methyl-2-pyrid-4-ylthiazol-4- yl} ethoxy] -3 -fluorophenyl)eth- 1 -yl]- 1 ,3,5,5-teframethyl- 1 ,3,2-diazaphosphinane- 2-oxide; 2-[2-(Bis[N-ethylamino]phosphoryl)-l-(4-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l- oxoprop-l-yl]-3-fluorophenyl)eth-l-yl]-[4S]-ethyl-l,3,2-oxazaphospholidine-2- oxide; 2-[l-(Bis[N-ethylamino]phosphoryloxy)-l-(4-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4- yl}ethyl)-Ν-methylaminocarbonyl]-3-fluorophenyl)methyl]-[4S,5S]-dimethyl- 1 ,3 ,2-diazaphospholidine-2-oxide; -[l-(Bis[N-ethylamino]phosphoryl)-l-(4-[2-{4-(4- trifluoromethylphenyl)phenoxy}ethoxy]-3-fluorophenyl)methoxy]-[4S,5S]- dimethyl- 1 ,3 ,2-diazaphospholidine-2-oxide;-[l-(Bis[N-ethylammo]phosphoryl)-l-(4-[N-(2-{4-(4- trifluoromethylphenyl)phenoxy } ethyl)-N-methylaminocarbonyl] -3 - fluorophenyl)methyl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2-oxide;-[ 1 -(Bis[N-ethylamino]phosphoryl)-2-(4-[3 - {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl] -3-fluorophenyl)ethen- 1 -yl]-[4S]-ethyl- 1 ,3 ,2-oxazaphospholidine- 2-oxide;-[l -(Bis[N-ethylamino]phosphoryl)-2-(4-[2- { 1 -[4-(2- trifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]-3-fluorophenyl)eth-l- yl]-[4R]methyl-l,3,2-oxazaphosphinane-2-oxide;-[2-(Bis[N-ethylamino]phosphoryl)-2-(4-[2-{l-butyl-3-(5-methoxypyrid-2- yl)ureido} ethyl] -3-fluorophenyl)eth- 1 -yl]- 1 ,3 ,5 ,5-tetramethyl- 1 ,3 ,2- diazaphosphinane-2-oxide;-[2-(Bis[N-ethylamino]phosphoryl)-l-(4-[3-{4-acetyl-3-hydroxy-2- propylphenoxy)propoxy]-3-fluorophenyl)eth-l-yl]-[4S]-ethyl-l,3,2- oxazaphospholidine-2-oxide; .-[ 1 -(Diethoxyphosphoryloxy)- 1 -(4-[2- {4H-3-oxobenzo[ 1 ,4]oxazin-2-yl}ethoxy]-3- fluorophenyl)methyl]-[4S,5S]-dimethyl-l,3,2-diazaphospholidine-2-oxide;-[l-(Diethoxyphosphoryl)-l-(4-[3,N-phthalimidopropoxy]-3-fluorophenyl)methoxy]- [4S,5S]-dimethyl-l,3,2-diazaphospholidine-2-oxide;-[l-(Diethoxyphosphoryl)-l-(4-[4N-phthalimidobutoxy]-3-fluorophenyl)methyl]- l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2-oxide; -[l-(Diethoxyphosphoryl)-2-(3-[3-{N-methyl-N-pyrid-2-ylamino}propoxy]-4- fluorophenyl)ethen- 1 -yl]-[4S]-ethyl- 1 ,3 ,2-oxazaphospholidine-2-oxide;-[l-(Diethoxyphosphoryl)-2-(3-[N-(3-{N-methyl-N-pyrid-2-ylamino}propyl)-N- methylamino]-4-fluorophenyl)eth-l-yl]-[4R]methyl-l,3,2-oxazaphosphinane-2- oxide;-[2-(Diethoxyphosphoryl)-2-(3-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l- ylamino]-4-fluorophenyl)eth-l-yl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2- oxide;-[2-(Diethoxyphosphoryl)-l-(3-[3-{5-methyl-2-phenyloxazol-4-yl}propoxy]-4- fluorophenyl)eth-l-yl]-[4S]-ethyl-l,3,2-oxazaρhospholidine-2-oxide;-[l-(Diethoxyphosphoryloxy)-l-(3-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N- methylaminocarbonyl]-4-methoxyphenyl)methyl]-[4S,5S]-dimethyl-l,3,2- diazaphospholidine-2-oxide;-[l-(Diethoxyphosphoryl)-l-(3-[3-{5-methyl-2-phenylthiazol-4-yl}propoxy]-4- fluorophenyl)methoxy]-[4S,5S]-dimethyl-l,3,2-diazaphospholidine-2-oxide;-[ 1 -(Diethoxyphosphoryl)- 1 -(3-[3- {5-methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl]- 4-fluorophenyl)methyl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2-oxide;-[l-(Diethoxyphosphoryl)-2-(3-[4-{5-methyl-2-pyrid-4-yloxazol-4-yl}butoxy]-4- fluorophenyl)ethen- 1 -yl]-[4S]-ethyl- 1 ,3,2-oxazaphospholidine-2-oxide;-[l-(Diethoxyphosphoryl)-2-(3-[3-{5-methyl-2-pyrid-4-ylthiazol-4-yl}propoxy]-4- fluorophenyl)eth-l-yl]-[4R]methyl-l,3,2-oxazaphosphinane-2 -oxide;-[2-(Diethoxyphosphoryl)-2-(3-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l- ylthio]-4-fluorophenyl)eth-l -yl]- 1 ,3 ,5 ,5-teteamethyl- 1 ,3 ,2-diazaphosphinane-2- oxide; and 2-[2-(Diethoxyphosphoryl)-l-(3-[N-(3-{5-methyl-2-pyrid-4-ylthiazol-4-yl}propyl)-N- methylamino]-4-fluorophenyl)eth-l-yl]-[4S]-ethyl-l,3,2-oxazaphospholidine-2- oxide.
6. A compound according to Claim 5, wherein the compound is selected from the group consisting of: Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]-3- fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1-(4-[3 N-phthalimidopropoxy] -3 - fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]- 3-fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(3-[3-{N-methyl-N-pyrid-2-ylamino}propoxy]- 4-fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(3-[4-{N-methyl-N-pyrid-2-ylamino}butoxy]-4- fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(3-[4,N-phthalimidobutoxy]-4- fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(3-[5,N-phthalimidopentoxy]-4- fluorophenyl)methylρhosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(3 -[4- { 5 -methyl-2-pyrid-4-yloxazol-4- yl}butoxy]-4-fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(3-[5-{5-methyl-2-pyrid-4-yloxazol-4- yl}pentoxy]-4-fluorophenyl)methylphosphonate; 1 -(4-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]-3-fluoroρhenyl)-l , 1 -bis([4R,5S dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; l-(4-[3,N-phthalimidopropoxy]-3-fluorophenyl)-l,l-bis([4R,5S]-dimethyl-2-oxido- l,3,2-dioxaphospholan-2-yl)methane; l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]-3-fluorophenyl)-l,l-bis([4R,5S]- dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methane; l-(3-[3-{N-methyl-N-pyrid-2-ylamino}propoxy]-4-fluorophenyl )-l,l-bis([4R,5S]- dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; l-(3-[4-{N-methyI-N-pyrid-2-ylamino}butoxy]-4-fluorophenyl)-l,l-bis([4R,5S]- dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; l-(3-[4,N-phthalimidobutoxy]-4-fluorophenyl)-l , 1 -bis([4R,5S]-dimethyl-2-oxido- l,3,2-dioxaphospholan-2-yl)methane; l-(3-[5N-phthalimidopentoxy]-4-fluorophenyl)-l,l-bis([4R,5S]-dimethyl-2-oxido- l,3,2-dioxaphospholan-2-yl)methane; l-(3-[4-{5-methyl-2-pyrid-4-yloxazol-4-yl}butoxy]-4-fluorophenyl)-l,l-bis([4R,5S]- dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; 1 -(3-[5- {5-metlιyl-2-pyrid-4-yloxazol-4-yl}pentoxy]-4-fluorophenyl)- 1 , 1 -bis([4R,5S]- dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; NNN'N'-Tetramethyl 1 -(4-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]-3- fluorophenyl)- 1 -hydroxymethylphosphondiamide;
NNN'N'-Tetramethyl l-(4-[3,N-phthalimidopropoxy]-3-fluorophenyl)-l- hydroxymethylphosphondiamide; NNN'N'-Tetramethyl l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]-3- fluorophenyl)- 1 -hydroxymethylphosphondiamide; 2-[l-hydroxy-l-(4-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]-3-fluorophenyl)methyl]- [4S]-(l-methylethyl)-l,3,2-oxazaphospholidine-2-oxide; 2-[ 1 -hydroxy- 1 -(4- [3 ,N-phthalimidopropoxy]-3 -fluorophenyl)methyl] -[4S] -( 1 - methylethyl)- 1 ,3 ,2-oxazaphospholidine-2 -oxide; 2-[l-hydroxy-l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]-3- fluorophenyl)methyl]-[4S]-(l-methylethyl)-l,3,2-oxazaphospholidine-2-oxide; 1 -[N-(4-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]-3 -fluorophenyl)amino]-l , 1 - bis(bis[N-ethylamino]phosphoryl)methane; l-[N-(4-[3 ,N-phthalimidopropoxy]-3-fluorophenyl)amino]- 1 , 1 -bis(bis[N- ethylamino]phosphoryl)methane; and l-[N-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]-3-fluorophenyl)amino]-l,l- bis(bis[N-ethylamino]phosphoryl)methane.
7. A pharmaceutical formulation comprising a compound ofthe formula (I):
Ar1 and Ar2 are each independently mono- or bicyclic aromatic rings of 5-12 atoms, including, but not limited to phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyπolyl, imidazyl, pyrazolyl, oxazolyl, isoxoazolyl, thiazolyl, isothiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,3- triazolyl, 1,3,4-triazolyl, 1,2,4-triazinyl, 1,3,5-triazinyl, benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazyl, benzoxazoyl, benzoisozazolyl, benzothiazoyl, benzoisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridyl, or purinyl;
Y1, Y2, and Z1 are each independently a lone electron pair, H, Cι-C6 lower alkyl, C2- C6 lower alkenyl, C2-C6 lower alkynyl, Cι-C6 lower alkoxy, Cι-C6 lower alkylamino, Cι-C6 lower dialkylamino, C2-C6 lower cycloalkyl, C4-C6 lower cycloalkenyl, Ci-Cδ lower thioalkyl, d-C6 lower sulfmylalkyl, C1-C5 lower sulfonylalkyl, Ci-C6 lower acyloxy, Ci-Cβ lower acylamino with N substituted with R6, CH2OR5, CH2NR6R6a, Rf, RfO, OH, NH2, CN, N02, F, CI, Br, I, or N3; E is a bond, S(0)m, NR6, C=0, C02, CONR6, O, -OC=0, NR6C=0, NR6C02, OC=ONR6, OC02, orNR6CONR6a;
F is (CH2)n, (CH2)0O(CH2)p, (CH2)oNR6(CH2)p, (CH2)0NR6CO(CH2)p, (CH2)0CONR6 (CH2)P, (CH2)0(CR6=CR6)q(CH2)p, (CH2)0-(C s€)q-(CH2)p; G is a bond, O, NR6, CO, C02, OCO, OC02, S(0)m, CONR6, NR6CO, NR6C02, OCONR6, NR6CONR6a, or G can optionally be attached to Ar2 at two contiguous C atoms to form a 5- to 7-membered partially saturated ring, which contains 0, 1, or 2 heteroatoms selected from the group consisting of O, N, and S;
X, X1 are independently O or S
Z2 is nothing, H or Ar1 optionally substituted with Y1 and Y2; R1, R2, R3, and R4, are each independently selected from H, d-C6 lower alkyl, C3-C6 lower alkenyl, C3-Cβ lower alkynyl, C3-C6 lower cycloalkyl, C -C6 lower cycloalkenyl, or independently R1 and R2 or R3 and R4 can be taken together to form a 5 to 8-membered ring containing 2-7 carbon atoms, the 5 to 8-membered ring optionally substituted with zero to 3 substituents selected from the group d- C4 lower alkyl, Cι-C lower alkoxy, d-C4 lower alkylamino, Cι-C4 lower dialkylamino, amino, hydroxyl, hydroxymethyl, methoxymethyl, phenyl, substituted phenyl, benzyl, substituted benzyl;
U and V are each independently a bond, O or NR ;
R5 R6 and R6a are each independently Cι-C6 alkyl, C3-C6 cycloalkyl, C3-Cό alkenyl, C3-C6 cycloalkenyl, C3-C6 alkynyl, and H;
R and R are each independently H, d-C4 lower alkyl, or are taken together to form a saturated C3-C6 carbocyclic ring;
Rf is Cι-C4 straight or branched lower perfluoroalkyl; all lower alkyl, alkenyl and alkynyl groups including those linked via heteroatoms can be straight chain or branched; m is O, 1, or 2; n is 0, 1, 2, 3, 4, 5, or 6; o is O, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; and q is 0, 1, 2, 3, 4, 5, or 6; with the provisos that when A is a bond or O, B is P(0)(OR3)(OR4), and D is selected from the group H, OH, OCOCHs, and NH2, and when R1 = R2 and R3 = R4, and both are selected from the group H or unsubstituted Cj-C4 lower alkyl, and E and G are bonds, and F is (CH2)n where n is 0, and both Ar1 and Ar2 are phenyl, then at least one of Y1, Y2, Z1, or Z2 must not be H; and when A is a bond or CH2, and B is P(0)(OR3)(OR4), and either D is H or Cι-C4 lower alkyl where L is CH2, or D is absent, with L"C taken together represent an ethenylidene group, and Ar1 is phenyl, and E is a bond or O, and R1 = R2 and R3 = R4, and both are drawn from the group H or Cι-C6 unsubstituted lower alkyl, then one of Y1 and Y2 must be other than H or unsubstituted Cι-C lower alkyl or unsubstituted Cι-C4 lower alkoxy; and when A is O, and B is H or P(0)(OR3)(OR4), and R1, R2, R3, and R4 are all selected from the group H or Cι-C6 unsubstituted lower alkyl, and D is H, and L is a bond, and Ar1 is phenyl, and E is other than a bond or O, then one of Y1 or Y2 must be other than H, or Cι-C4 unsubstituted lower alkyl or Cι-C4 unsubstituted lower alkoxy; and a pharmaceutically acceptable carrier, excipient, solvent, adjuvant or diluent.
8. The pharmaceutical composition according to Claim 7, wherein in the compound of Formula I, A is selected from a bond, O, and CH2; B is P(=0)(UR3)(VR4); D is H; and the L— C bond is a single bond.
9. The pharmaceutical formulation according to Claim 8, wherein Ar1 in Formula I is phenyl.
10. The pharmaceutical formulation according to Claim 9, wherein U and V in
Formula I are each O.
11. The pharmaceutical formulation according to Claim 7, wherein the compound of Formula I is selected from the group consisting of: Diethyl l-(diethoxyphosphinyloxy)-l-(4-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]-3- fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)-! -(4-[Ν-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)- N-methylaminocarbonyl]-3-fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[3 - {N-methyl-N-pyrid-2-ylamino } - 1 - oxoprop-l-yl]-3-fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]- 3-fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[N-(2- {5-methyl-2-phenyloxazol-4- yl}ethyl)-N-methylaminocarbonyl]-3-fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[2- {5-methyl-2-phenylthiazol-4-yl} ethoxy]- 3-fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(4-[3-{5-methyl-2-phenylthiazol-4-yl}-l- oxoprop-l-yl]-3-fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(4-[2-{5-methyl-2-pyrid-4-yloxazol-4- yl}ethoxy]-3-fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)-! -(4-[2- {5-methyl-2-pyrid-4-ylthiazol-4- yl}ethoxy]-3-fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(4-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l- oxoprop-l-yl]-3-fluorophenyl)methylphosphonate; Diethyl l-(hydroxy)-l-(4-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N- methylaminocarbonyl]-3-fluorophenyl)methylphosphonate; Diethyl 1 -(hydroxy)- 1 -(4-[2- {4-(4-trifluoromethylphenyl)phenoxy } ethoxy] -3 - fluorophenyl)methylphosphonate; Diethyl 1 -(hydroxy)-l -(4-[N-(2- {4-(4-trifluoromethylphenyl)phenoxy} ethyl)-N- methylaminocarbonyl]-3-fluorophenyl)methylphosphonate;
Diethyl 1 -(hydroxy)- 1 -(4-[3 - {4-(4-trifluoromethylphenyl)phenoxy} - 1 -oxoprop- 1 -yl]- 3-fluorophenyl)methylphosphonate; Diethyl 1 -(hydroxy)- 1 -(4-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3- hexylureido}ethyl]-3-fluorophenyl)methylphosphonate; Diethyl l-(hydroxy)-l-(4-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]-3- fluorophenyl)methylphosphonate; Diethyl l-(hydroxy)-l-(4-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3- fluorophenyl)methylphosphonate; Diethyl 1 -(hydroxy)- 1 -(4-[2- {4H-3-oxobenzo[ 1 ,4]oxazin-2-yl}ethoxy]-3- fluorophenyl)methylphosphonate;
Diethyl 1 -(hydroxy)-l -(4-[3,N-phthalimidopropoxy]-3- fluorophenyl)methylphosphonate; Diethyl l-(hydroxy)-l-(4-[4,N-phthalimidobutoxy]-3- fluorophenyl)methylphosphonate; Tetraethyl l-(3-[3-{N-methyl-N-pyrid-2-ylamino}propoxy]-4-fluorophenyl )methylidenebisphosphonate; Tetraethyl 1 -(3-[N-(3- {N-methyl-N-pyrid-2-ylamino}propyl)-N-methylamino]-4- fluorophenyl)methylidenebisphosphonate; Tetraethyl l-(3-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l-ylamino]-4- fluorophenyl)methylidenebisphosphonate; Tetraethyl 1 -(3 -[3 - {5 -methyl-2-phenyloxazol-4-yl} propoxy] -4- fluorophenyl)methylidenebisphosphonate; Tetraethyl 1 -(3-[N-(2- {5-methyl-2-phenyloxazol-4-yl} ethyl)-N- methylaminocarbonyl]-4-methoxyphenyl)methylidenebisphosphonate;
Tefraethyl l-(3-[3-{5-methyl-2-phenylthiazol-4-yl}propoxy]-4- fluorophenyl)methylidenebisphosphonate; Tetraethyl 1 -(3 -[3 - { 5-methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl] -4- fluorophenyl)methylidenebisphosphonate; Tetraethyl l-(3-[4-{5-methyl-2-pyrid-4-yloxazol-4-yl}butoxy]-4- fluorophenyl)methylidenebisphosphonate; Tefraethyl l-(3-[3-{5-methyl-2-pyrid-4-ylthiazol-4-yl}propoxy]-4- fluorophenyl)methylidenebisphosphonate; Tetraethyl l-(3-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-ylthio]-4- fluorophenyl)methylidenebisphosphonate;
Tefraethyl 2-(3-[N-(3-{5-methyl-2-pyrid-4-ylthiazol-4-yl}propyl)-N-methylamino]-4- fluorophenyl)vinylidene-l,l-bisphosphonate; Tetraethyl 2-(3-[3- {4-(4-trifluoromethylphenyl)phenoxy}propoxy]-4- fluorophenyl)vinylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(3-[N-(3-{4-(4-trifluoromethylphenyl)phenoxy}propyl)-N-methylamino]- 4-fluorophenyl)vinylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(3-[4-{4-(4-trifluoromethylphenyl)phenoxy)-l-oxobut-l-yl]-4- fluorophenyl)vinylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(3-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3- hexylureido}ethyl]-4-fluorophenyl)vinylidene-l,l-bisphosphonate; Tetraethyl 2-(3-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]-4- fluorophenyl)vinylidene-l,l-bisphosphonate; Tetraethyl 2-(3-[4-{4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]-4- fluorophenyl)vinylidene- 1 , 1 -bisphosphonate;
Tetraethyl 2-(3 - [3 - {4H-3 -oxobenzo [ 1 ,4]oxazin-2-yl}propoxy]-4- fluorophenyl)vinylidene-l , 1 -bisphosphonate; Tetraethyl 2-(3 -[3 ,N-phthalimidopropoxy] -4-fluorophenyl)vinylidene- 1,1- bisphosphonate; Tetraethyl 2-(3 -[4,N-phthalimidobutoxy]-4-fluorophenyl)vinylidene- 1,1- bisphosphonate; Tetraethyl l-(6-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]indol-2-yl)ethylidene-l,2- bisphosphonate; Tetraethyl l-(6-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]indol-2- yl)ethylidene- 1 ,2-bisphosphonate;
Tetraethyl l-(6-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l-yl]indol-2- yl)ethylidene-l,2-bisphosphonate; Tefraethyl l-(6-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy] indol-2-yl)ethylidene-l,2- bisphosphonate; Tetraethyl l-(6-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino] indol-2- yl)ethylidene- 1 ,2-bisphosphonate; Tefraethyl l-(6-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]indol-2-yl)ethylidene-l,2- bisphosphonate; Tetraethyl l-(6-[3-{5-methyl-2-phenylthiazol-4-yl}-l-oxoprop-l-yl]indol-2- yl)ethylidene-l,2-bisphosphonate; Tetraethyl 1 -(6-[2- {5-methyl-2-pyrid-4-yloxazol-4-yl} ethoxy]indol-2-yl)ethyIidene- 1 ,2-bisphosphonate; Tetraethyl l-(6-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]indol-2-yl)ethylidene- 1,2-bisphosphonate;
Tetraethyl l-(6-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-yl]indol-2- yl)ethylidene- 1 ,2-bisphosphonate; Tetraethyl 2-(6-[N-(2- { 5-methyl-2-pyrid-4-ylthiazol-4-yl} ethyl)-N- methylamino]indol-2-yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(6- [2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy] indol-2- yl)ethylidene-l , 1 -bisphosphonate; Tetraethyl 2-(6-[N-(2- {4-(4-trifluoromethylphenyl)phenoxy} ethyl)-N- methylamino]indol-2-yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(6-[2-{l-[4-(2-trifluoromethylphenyl)ρhenylmethyl]-3- hexylureido} ethyl]indol-2-yl)ethylidene- 1 , 1 -bisphosphonate;
Tetraethyl 2-(6-[2-{l-butyl-3-(5-methoxyρyrid-2-yl)ureido}ethyl]indol-2- yl)ethylidene-l , 1 -bisphosphonate; Tefraethyl 2-(6-[3-{4-(4-trifluoromethylphenyl)phenoxy}-l-oxoprop-l-yl]indol-2- yl)ethylidene-l , 1 -bisphosphonate; Tetraethyl 2-(6-[3-{4-acetyl-3-hydroxy-2-propylρhenoxy)propoxy]indol-2- yl)ethylidene-l,l-bisphosphonate; Tetraethyl 2-(6-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]indol-2-yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl 2-(6-[3,N-phthalimidopropoxy]indol-2-yl)ethylidene-l ,1 -bisphosphonate;
Tetraethyl 2-(6-[4,N-phthalimidobutoxy]indol-2-yl)ethylidene- 1 , 1 -bisphosphonate; Tetraethyl N-(5-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]pyrid-2- yl)aminomethylidenebisphosphonate; Tetraethyl N-(5-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]pyrid-2- yl)aminomethylidenebisphosphonate;
Tetraethyl N-(5-[3- {N-methyl-N-pyrid-2-ylamino} -1 -oxoprop-1 -yl]pyrid-2- yl)aminomethylidenebisphosphonate; Tetraethyl N-(5-[2- {5-methyl-2-phenyloxazol-4-yl} ethoxy]pyrid-2- yl)aminomethylidenebisphosphonate Tetraethyl N-(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]pyrid-2- yl)aminomethylidenebisphosphonate; Tetraethyl N-(5-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]pyrid-2- yl)ammomethylidenebisphosphonate; Tetraethyl N-(5- [3 - { 5-methyl-2-pyrid-4-yloxazol-4-yl } - 1 -oxoprop- 1 -yl]pyrid-2- yl)aminomethylidenebisphosphonate;
Tetraethyl N-(5-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N- methylamino]pyrid-2-yl)aminomethylidenebisphosphonate; Tetraethyl N-(5-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]pyrid-2- yl)aminomethylidenebisphosphonate; Tetraethyl N-(5-[2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethoxy]pyrid-2- yl)aminomethylidenebisphosphonate; 2-[ 1 -Hydroxy- 1 -(5-[N-(2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethyl)-N- methylamino]pyrid-2-yl)methyl]-l,3,2-dioxaphospholane-2-oxide; 2-[l-Hydroxy-l-(5-[2-{4-(4-trifluoromethylphenyl)phenoxy}ethoxy]-pyrid-2- yl)methyl]- 1 ,3,2-dioxaphospholane-2 -oxide; 2-[l-Hydroxy-l-(5-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N- methylamino]pyrid-2-yl)methyl]-l,3,2-dioxaphospholane-2-oxide; 2-[ 1 -Hydroxy- 1 -(5- [3 - {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl]-pyrid- 2-yl)methyl]- 1 ,3 ,2-dioxaphospholane-2-oxide;
2-[ 1 -Hydroxy- 1 -(5-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3 - hexylureido}ethyl]pyrid-2-yl)methyl]-l,3,2-dioxaphospholane-2-oxide; 2-[ 1 -Hydroxy- 1 -(5-[2- { 1 -butyl-3 -(5-methoxypyrid-2-yl)ureido} ethyl]ρyrid-2- ylmethyl]-l,3,2-dioxaphospholane-2-oxide; 2-[l-Hydroxy-15-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]pyrid-2- ylmethyl]-l,3,2-dioxaphospholane-2-oxide; 2- [ 1 -Hydroxy- 1 -(5 - [2- {4H-3 -oxobenzo [ 1 ,4]oxazin-2-yl} ethoxy]pyrid-2-yl)methyl] - 1 ,3 ,2-dioxaphospholane-2-oxide; 2-[l-Hydroxy-l-(5-[3,N-phthalimidopropoxy]pyrid-2-yl)methyl]-l,3,2- dioxaphospholane-2-oxide;
2-[ 1 -Hydroxy- 1 -(5-[4,N-phthalimidobutoxy]ρyrid-2-yl)methyl]- 1 ,3 ,2- dioxaphospholane-2-oxide; 2-[l-Hydroxy-l-(5-[2-{N-methyl-N-pyrid-2-ylamino}etlιoxy]benzothien-2- yl)methyl] - [4R] -methyl- 1 ,3 ,2-dioxaphospholane-2-oxide; -[l-Hydroxy-l-(5-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N- methylamino]benzothien-2-yl)methyl]- [4R]-methyl- 1 ,3 ,2-dioxaphospholane-2- oxide;- [ 1 -Hydroxy- 1 -(5- [3 - {N-methyl-N-pyrid-2-ylamino } - 1 -oxoprop- 1 -yl]benzothien-2- yl)methyl]- [4R]-methyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]benzothien-2- yl)methyl]- [4R]-methyl-l ,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy-1 -(5-[N-(2- {5-methyl-2-ρhenyloxazol-4-yl} ethyl)-N- methylamino]benzothien-2-yl)methyl]- [4R]-methyl-l,3,2-dioxaphospholane-2- oxide;-[l-Hydroxy-l-(5-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]benzothien-2- yl)methyl]- [4R]-methyl-l,3,2-dioxaphospholane-2-oxide;- [ 1 -Hydroxy- 1 -(5 -[3 - {5 -methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl]benzothien-2- yl)methyl]- [4R]-methyl-l,3,2-dioxaphospholane-2-oxide;-[ 1-Hydroxy-l -(5-[2- {5-methyl-2-pyrid-4-yloxazol-4-yl} ethoxy]benzothien-2- yl)methyl]- [4R]-methyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]benzothien-2- yl)methyl]- [4R]-methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;-[l -Hydroxy- 1 -(5-[3- {5-methyl-2-pyrid-4-yloxazol-4-yl} -1 -oxoprop-1 - yl]benzothien-2-yl)methyl]- [4R]-methyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5- N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N- methylamino]benzothien-2-yl)methyl]- [4S]-methyl-l ,3 ,2-dioxaphospholane-2- oxide;-[ 1 -Hydroxy- 1 -(5-[2- {4-(4-trifluoromethylphenyl)phenoxy } ethoxy ]benzothien-2- yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide; -[l-Hydroxy-l-(5-[N-(2-{4-(4-trifluoromethylphenyl)ρhenoxy}ethyl)-N- methylamino]benzothien-2-yl)methyl] - [4S] -methyl- 1 ,3 ,2-dioxaphospholane-2- oxide;-[ 1 -Hydroxy- 1 -(5 - [3 - {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 - yl]benzothien-2-yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3- hexylureido } ethyl]benzothien-2-yl)methyl] - [4 S] -methyl- 1,3,2- dioxaphospholane-2-oxide;-[l -Hydroxy- 1 -(5 -[2- { 1 -butyl-3 -(5-methoxypyrid-2-yl)ureido} ethyl]benzothien-2- yl)methyl]- [4S]-methyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]benzothien-2- yl)methyl]- [4S]-methyl-l ,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(5 - [2- {4H-3 -oxobenzo [ 1 ,4] oxazin-2-yl} ethoxy]benzothien-2- yl)methyl]- [4S]-methyl-l ,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(5 - [3 ,N-phthalimidopropoxy]benzothien-2-yl)methyl] - [4S] -methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(5-[4,N-phthalimidobutoxy]benzothien-2-yl)methyl]- [4S]-methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(4-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]thiazol-2-yl)methyl]- 4,5-dimethyl-l ,3,2-dioxaphospholane-2-oxide;- [ 1 -Hydroxy- 1 -(4- [N-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N- methylamino]thiazol-2-yl)methyl]-4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(4-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l-yl]thiazol-2- yl)methyl]-4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide; -[l-Hydroxy-l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]thiazol-2-yl)methyl]- 4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(4-[N-(2-{5-methyl-2-ρhenyloxazol-4-yl}ethyl)-N- methylamino]thiazol-2-yl)methyl]-4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(4-[2- {5-methyl-2-phenylthiazol-4-yl} ethoxy]thiazol-2-yl)methyl]- 4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(4-[3 - {5-methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl]thiazol-2- yl)methyl]-4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(4-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]thiazol-2- yl)methyl]-4,5-dimethyl-l ,3,2-dioxaphospholane-2-oxide;-[l-Hydroxy-l-(4-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]thiazol-2- yl)methyl]-4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide;- [ 1 -Hydroxy- 1 -(4-[3 - { 5-methyl-2-pyrid-4-yloxazol-4-yl} - 1 -oxoprop- 1 -yl]thiazol-2- yl)methyl]-4,5-dimethyl-l,3,2-dioxaphospholane-2-oxide;-[ 1 -Hydroxy- 1 -(4-[N-(2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethyl)-N- methylamino]thiazol-2-yl)methyl]- 1 ,3 ,2-dioxaphosphinane-2-oxide;-[l-Hydroxy-l-(4-[2-{4-(4-trifluoromethylphenyl)phenoxy}ethoxy]thiazol-2- yl)methyl] -1,3 ,2-dioxaphosphinane-2-oxide ;-[ 1 -Hydroxy- 1 -(4-[N-(2- {4-(4-trifluoromethylphenyl)phenoxy} ethyl)-N- methylamino]thiazol-2-yl)methyl]-l,3,2-dioxaphosphinane-2 -oxide;- [ 1 -Hydroxy- 1 -(4-[3 - {4-(4-trifluoromethylphenyl)phenoxy} - 1 -oxoprop- 1 -yl]thiazol- 2-yl)methyl]-l,3,2-dioxaphosphinane-2-oxide;-[l -Hydroxy-1 -(4-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3- hexylureido} ethyl]thiazol-2-yl)methyl] - 1 ,3 ,2-dioxaphosphinane-2-oxide; -[l-Hydroxy-l-(4-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]thiazol-2- yl)methyl]-l,3,2-dioxaphosphinane-2 -oxide;-[l-Hydroxy-l-(4-[3-{4-acetyl-3-hydroxy-2-ρropylphenoxy)propoxy]thiazol-2- yl)methyl]- 1 ,3 ,2-dioxaphosphinane-2-oxide;-[ 1 -Hydroxy- 1 -(4-[2- {4N-3 -oxobenzo [ 1 ,4] oxazin-2-yl} ethoxy]thiazol-2-yl)methyl] - 1 ,3,2-dioxaphosphinane-2-oxide;-[l-Hydroxy-l-(4-[3,N-phthalimidopropoxy]thiazol-2-yl)methyl]-l,3,2- dioxaphosphinane-2-oxide;-[l-Hydroxy-l-(4-[4,N-phthalimidobutoxy]thiazol-2-yl)methyl]-l,3,2- dioxaphosphinane-2-oxide;[l-(6-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]-3-methoxyquinolin-2-yl)-l-(2- oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-l,3,2-dioxaphospholane-2-oxide;[l-(6-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)- 1 -(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- 1 ,3 ,2- dioxaphospholane-2-oxide; [ 1 -(6-[3 - {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop- 1 -yl] -3 -methoxy quinolin-2-yl)- 1 -(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- 1 ,3 ,2-dioxaphospholane-2- oxide;[l-(6-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l-(2- oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-l,3,2-dioxaphospholane-2-oxide;[l-(6-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)-l-(2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-l,3,2- dioxaphospholane-2-oxide;[l-(6-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l-(2- oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- 1 ,3 ,2-dioxaphospholane-2-oxide; [l-(6-[3-{5-methyl-2-phenylthiazol-4-yl}-l-oxoprop-l-yl]-3-methoxyquinolin-2-yl)- 1 -(2-oxido-l ,3 ,2-dioxaphospholan-2-yl)methoxy]- 1 ,3 ,2-dioxaphospholane-2- oxide; [ 1 -(6- [2- { 5-methyl-2-pyrid-4-yloxazol-4-yl} ethoxy] -3 -methoxyquinolin-2-yl)- 1 -(2- oxido-1 ,3,2-dioxaphospholan-2-yl)methoxy]-l ,3,2-dioxaρhospholane-2-oxide;[l-(6-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l-(2- oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- 1 ,3 ,2-dioxaphospholane-2-oxide; [ 1 -(6-[3 - { 5 -methyl-2-pyrid-4-yloxazol-4-yl} - 1 -oxoprop- 1 -yl] -3 -methoxyquinolin-2- yl)-l -(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- 1 ,3 ,2-dioxaphospholane-2- oxide;[l-(6-[N-(2-{5-methyl-2-ρyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)-l-([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2- yl)methoxy]-[4R]-methyl-l,3,2-dioxaphospholane-2-oxide;[ 1 -(6-[2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy]-3 -methoxyquinolin-2-yl)- 1 - ([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-[4R]-methyl-l,3,2- dioxaphospholane-2-oxide;[l-(6-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)- 1 -([4R] -methyl-2-oxido- 1 , 3 ,2-dioxaphospholan-2- yl)methoxy] - [4R] -methyl- 1 ,3 ,2-dioxaphospholane-2-oxide ;[1 -(6-[3- {4-(4-trifluoromethylphenyl)phenoxy} - 1 -oxoprop-1 -yl] -3 -methoxyquinolin- 2-yl)-l-([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-[4R]- methyl-l,3,2-dioxaphospholane-2-oxide;[l-(6-[2-{l-[4-(2-frifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]-3- methoxyquinolin-2-yl)-l-([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2- yl)methoxy] - [4R] -methyl- 1 ,3 ,2-dioxaphospholane-2-oxide ; [l-(6-[2-{l-butyl-3-(5-methoxypyrid-2-yI)ureido}ethyl]-3-methoxyquinolin-2-yl)-l- ([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-[4R]-methyl-l,3,2- dioxaphospholane-2-oxide; [ 1 -(6-[3 - {4-acetyl-3 -hydroxy-2-propylphenoxy)propoxy] -3 -methoxyquinolin-2-yl)- l-([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-[4R]-methyl- l,3,2-dioxaphospholane-2-oxide; [ 1 -(6-[2- {4H-3 -oxobenzo [1,4] oxazin-2-yl} ethoxy] -3 -methoxyquinolin-2-yl)- 1 - ([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-[4R]-methyl-l,3,2- dioxaphospholane-2-oxide ;[l-(6-[3,N-phthalimidopropoxy]-3-methoxyquinolin-2-yl)-l-([4R]-methyl-2-oxido- l,3,2-dioxaphospholan-2-yl)methoxy]-[4R]-methyl-l,3,2-dioxaphospholane-2- oxide;[l-(6-[4,N-phthalimidobutoxy]-3-methoxyquinolin-2-yl)-l-([4R]-methyl-2-oxido- l,3,2-dioxaphospholan-2-yl)methoxy]-[4R]-methyl-l,3,2-dioxaphospholane-2- oxide;[1 -(5-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]thien-2-yl)-l -([4S]-methyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl- 1 ,3 ,2-dioxaphospholane-2- oxide;[l-(5-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]thien-2-yl)-l- ([4S]-methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l,3,2- dioxaphospholane-2-oxide;[ 1 -(5-[3- {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop- 1 -yl]thien-2-yl)- 1 -([4S]-methyl- 2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl- 1,3,2- dioxaphospholane-2-oxide; [1 -(5-[2- {5-methyl-2-phenyloxazol-4-yl} ethoxy]thien-2-yl)- 1 -([4S]-methyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl- 1 ,3 ,2-dioxaphospholane-2- oxide;[l-(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]thien-2-yl)-l- ([4S]-methyl-2-oxido-l ,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l ,3,2- dioxaphospholane-2-oxide;[l-(5-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]thien-2-yl)-l-([4S]-methyl-2-oxido- l,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyI-l,3,2-dioxaphospholane-2- oxide;[1 -(5-[3- {5-methyl-2-phenylthiazol-4-yl}- 1 -oxoprop- 1 -yl]thien-2-yl)-l -([4S]- methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l,3,2- dioxaphospholane-2-oxide;[l-(5-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]thien-2-yl)-l-([4S]-methyl-2- oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl- 1,3,2- dioxaphospholane-2-oxide;[l-(5-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]thien-2-yl)-l-([4S]-methyl-2- oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl- 1,3,2- dioxaphospholane-2-oxide;[l-(5-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-yl]thien-2-yl)-l-([4S]- methyl-2-oxido-l ,3,2-dioxaphospholan-2-yl)methoxy]- [4S]-methyl-l ,3,2- dioxaphospholane-2-oxide;[l-(5-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]thien-2-yl)-l- (4,5-dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2- dioxaphospholane-2-oxide; [1 -(5-[2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy]thien-2-yl)- 1 -(4,5-dimethyl- 2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyl 1,3,2- dioxaphospholane-2-oxide; [ 1 -(5-[N-(2- {4-(4-trifluoromethylρhenyl)phenoxy} ethyl)-N-methylamino]fhien-2- yl)-l-(4,5-dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5- dimethyll,3,2-dioxaphospholane-2-oxide;[ 1 -(5-[3 - {4-(4-trifluoromethylphenyl)phenoxy} - 1 -oxoprop- 1 -yl]thien-2-yl)- 1 -(4,5- dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2- dioxaphospholane-2-oxide ;[1 -(5-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido} ethyl]thien-2- yl)-l-(4,5-dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5- dimethyll,3,2-dioxaphospholane-2-oxide;[l-(5-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]thien-2-yl)-l-(4,5-dimethyl- 2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2- dioxaphospholane-2-oxide;[l-(5-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]thien-2-yl)-l-(4,5-dimethyl- 2-oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2- dioxaphospholane-2-oxide;[ 1 -(5-[2- {4H-3-oxobenzo[ 1 ,4]oxazin-2-yl}ethoxy]thien-2-yl)-l -(4,5-dimethyl-2- oxido-l,3,2-dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2- dioxaphospholane-2-oxide;[1 -(5-[3,N-phthalimidopropoxy]thien-2-yl)-l -(4,5-dimethyl-2-oxido-l ,3 ,2- dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;[l-(5-[4,N-phthalimidobutoxy]thien-2-yl)-l-(4,5-dimethyl-2-oxido-l,3,2- dioxaphospholan-2-yl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide; [l-(4-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]-3-fluorophenyl)-l-(2-oxido-l,3,2- dioxaphosphinan-2-yl)methoxy]-l,3,2-dioxaphosphinane-2-oxide; [ 1 -(4- [Ν-(2- {N-methyl-N-pyrid-2-ylamino } ethyl)-N-methylaminocarbonyl] -3 - fluorophenyl)-l-(2-oxido-l,3,2-dioxaphosphinan-2-yl)methoxy]-l,3,2- dioxaphosphinane-2-oxide; [l-(4-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l-yl]-3-fluorophenyl)-l-(2- oxido- 1 , ,2-dioxaphosphinan-2-yl)methoxy]- 1 ,3 ,2-dioxaphosρhinane-2-oxide; [l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]-3-fluorophenyl)-l-(2-oxido-l,3,2- dioxaphosphinan-2-yl)methoxy]- 1 ,3 ,2-dioxaphosphinane-2-oxide; 1 -(4-[N-(2- {5-methyl-2-ρhenyloxazol-4-yl} ethyl)-N-methylaminocarbonyl]-3- fluorophenyl)- 1 , 1 -bis(2-oxido- 1 ,3,2-dioxaphosρholan-2-yl)methane; l-(4-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]-3-fluorophenyl)-l,l-bis(2-oxido- l,3,2-dioxaphospholan-2-yl)methane; 1 -(4-[3 - { 5-methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl]-3-fluorophenyl)- 1 , 1 -bis(2- oxido-1 ,3 ,2-dioxaphospholan-2-yl)methane;
1 -(4-[2- {5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]-3-fluorophenyl)- 1 , 1 -bis(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; 1 -(4-[2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethoxy]-3 -fluorophenyl)- 1 , 1 -bis(4,5- dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methane; 1 -(4-[3 - {5 -methyl-2-pyrid-4-yloxazol-4-yl} - 1 -oxoprop- 1 -yl] -3 -fluorophenyl)- 1 , 1 - bis(2-oxido-l,3,2-dioxaphosphinan-2-yl)methane; l-(4-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-Ν-methylaminocarbonyl]-3- fluorophenyl)-l,l-bis(4,5-dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methane; 1 -(4- [2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy]-3 -fluorophenyl)- 1 , 1 -bis(2- oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methane; 1 -(4-[N-(2- {4-(4-trifluoromethylphenyl)phenoxy} ethyl)-N-methylaminocarbonyl]-3- fluorophenyl)- 1 , 1 -bis(4,5-dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)m ethane; 1 -(4-[3 - {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl] -3 -fluorophenyl)- 1,1- bis(2-oxido- 1 ,3,2-dioxaphosphinan-2-yl)methane; l-(4-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]-3- fluorophenyl)- 1 , 1 -bis(4,5-dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; 1 -(4-[2- { 1 -butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]-3-fluorophenyl)-l , 1 -bis(2- oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methane; 2-(4-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-fluorophenyl)-l,2-bis(2- oxido- 1 ,3 ,2-dioxaphospholan-2-yl)ethane;
2-(4-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]-3-fluorophenyl)-l,2-bis([4R]- methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)ethane; 2-(4-[3 ,N-phthalimidopropoxy]-3-fluorophenyl)- 1 ,2-bis(2-oxido- 1,3,2- dioxaphospholan-2-yl)ethane; 2-(4-[4,N-phthalimidobutoxy]-3-fluorophenyl)-l ,2-bis([4R]-methyl-2-oxido-l ,3,2- dioxaphospholan-2-yl)ethane ; 2-(3-[3-{N-methyl-N-pyrid-2-ylamino}propoxy]-4-fluorophenyl )-l,2-bis(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)ethane; 2-(3-[N-(3-{N-methyl-N-pyrid-2-ylamino}propyl)-N-methylamino]-4-fluorophenyl)- 1 ,2-bis([4R]-methyl-2-oxido-l ,3,2-dioxaphospholan-2-yl)ethane;
2-(3 -[3- {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop-1 -ylamino] -4-fluorophenyl)- 1 ,2- bis(2-oxido-l,3,2-dioxaphospholan-2-yl)ethane; 2-(3-[3-{5-methyl-2-phenyloxazol-4-yl}propoxy]-4-fluorophenyl)-l,2-bis([4R]- methyl-2-oxido-l,3,2-dioxaphospholan-2-yl)ethane; -(3-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylaminocarbonyl]-4- methoxyphenyl)-l , 1 -bis(4,5-dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2- yl)ethane; -(3-[3-{5-methyl-2-phenylthiazol-4-yl}propoxy]-4-fluorophenyl)-l , 1 -bis(2-oxido- 1 ,3,2-dioxaphosphinan-2-yl)ethane; -(3 -[3 - { 5 -methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl] -4-fluorophenyl)- 1,1- bis(4,5-dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)ethane; -(3-[4-{5-methyl-2-pyrid-4-yloxazol-4-yl}butoxy]-4-fluorophenyl)-l,l-bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)ethane; -(3-[3-{5-methyl-2-pyrid-4-ylthiazol-4-yl}propoxy]-4-fluorophenyl)-l,l-bis(4,5- dimethyl-2-oxido- 1 ,3,2-dioxaphospholan-2-yl)ethane; -(3-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-ylthio]-4-fluorophenyl)-l,l- bis(2-oxido- 1 ,3,2-dioxaphosphinan-2-yl)ethane; -(3-[N-(3-{5-methyl-2-pyrid-4-ylthiazol-4-yl}propyl)-N-methylamino]-4- fluorophenyl)-l,l-bis(4,5-dimethyl-2 -oxido-1, 3,2-dioxaphospholan-2-yl)ethane;
2-(3-[3-{4-(4-trifluoromethylphenyl)phenoxy}propoxy]-4-fluorophenyl)-l,l-bis(2- oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)ethane; l-[N-(3-[N-(3-{4-(4-trifluoromethylphenyl)phenoxy}propyl)-N-methylamino]-4- fluorophenyl)amino]- 1 , 1 -bis(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; l-[N-(3-[4-{4-(4-trifluoromethylphenyl)phenoxy)-l-oxobut-l-yl]-4- fluorophenyl)amino]-l,l-bis([4R]-methyl-2-oxido-l,3,2-dioxaphospholan-2- yl)methane; l-[N-(3-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]-4- fluorophenyl)amino]- 1 , 1 -bis(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; l-[N-(3-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]-4-fluorophenyl)amino]- 1 , 1 -bis([4R] -methyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; 1 -[N-(3 - [4- {4-acetyl-3 -hydroxy-2-propylphenoxy)butoxy] -4-fluorophenyl)amino] - 1 , 1 -bis(2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; l-[N-(3-[3-{4H-3-oxobenzo[l,4]oxazin-2-yl}propoxy]-4-fluorophenyl)amino]-l,l- bis([4R] -methyl-2-oxido- 1 ,3,2-dioxaphospholan-2-yl)methane; l-[N-(3-[3,N-phthalimidopropoxy]-4-fluorophenyl)amino]-l,l-bis(2-oxido-l,3,2- dioxaphospholan-2-yl)methane; l-[N-(3-[4,N-phthalimidobutoxy]-4-fluorophenyl)amino]-l,l-bis([4R]-methyl-2- oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane;
1 -[N-(6-[2- {N-methy l-N-pyrid-2-ylamino} ethoxy]indol-2-yl)amino]- 1 , 1 -bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methane; 1 -[N-(6-[N-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N-methylamino]indol-2- yl)amino] -1,1 -bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methane; 1 -[N-(6-[3 - {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop-1 -yl]indol-2-yl)amino]- 1 , 1 - bis(2-oxido- 1 ,3 ,2-dioxaphosphinan-2-yl)methane; l-[N-(6-[2- {5-methyl-2-phenyloxazol-4-yl} ethoxy] indol-2-yl)amino]- 1 , 1 -bis(2- oxido-l,3,2-dioxaphosphinan-2-yl)methane; 2-[l-(Diethoxyphosphinyloxy)-l-(6-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N- methylamino] indol-2-yl)methyl]-l ,3,2-dioxaphospholane-2 -oxide;
2-[l-(Diethoxyphosphinyloxy)-l-(6-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]indol- 2-yl)methyl] -1,3 ,2-dioxaphospholane-2-oxide; 2-[ 1 -(Diethoxyphosphinyloxy)- 1 -(6-[3- {5-methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 - yl]indol-2-yl)methyl]- 1 ,3 ,2-dioxaphospholane-2-oxide; -[l-(Diethoxyphosphinyloxy)-l-(6-[2-{5-methyl-2-pyrid-4-yloxazol-4- yl} ethoxy]indol-2-yl)methyl]- 1 ,3 ,2-dioxaphospholane-2-oxide;- [ 1 -(Diethoxyphosphinyloxy)- 1 -(6-[2- { 5-methyl-2-ρyrid-4-ylthiazol-4- yl}ethoxy]indol-2-yl)methyl]-l,3,2-dioxaphosphinane-2 -oxide;-[l-(Diethoxyphosphinyloxy)-l-(6-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l- oxoprop-l-yl]indol-2-yl)methyl]-l,3,2-dioxaphosphinane-2-oxide;-[l-(Diethoxyphosphinyloxy)-l-(6-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)- N-methylamino]indol-2-yl)methyl]-l,3,2-dioxaphosphinane-2 -oxide;-[ 1 -(Diethoxyphosphinyloxy)- 1 -(6-[2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy] indol-2-yl)methyl]- 1 ,3 ,2-dioxaphosphinane-2-oxide;[l-(6-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]indol-2- yl)- 1 -(diethoxyphosphinyl)methoxy]-4[S]-methyl-l ,3,2-dioxaphospholane-2- oxide;[ 1 -(6-[3- {4-(4-trifluoromethylphenyl)phenoxy} - 1 -oxoprop- 1 -yl]indol-2-yl)- 1 - (diethoxyphosphinyl)methoxy]-4,5-dimethyll,3,2-dioxaphospholane-2-oxide;[l-(6-[2-{l- [4-(2-trifluoromethylphenyl)phenylmethyl] -3 -hexylureido } ethyl]indol-2- yl)- 1 -(diethoxyphosphinyl)methoxy]-4[S]-methyl- 1 ,3 ,2-dioxaphospholane-2- oxide;[ 1 -(6-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]indol-2- yl)- 1 -(diethoxyphosphinyl)methoxy]-4,5-dimethyl 1 ,3,2-dioxaphospholane-2- oxide;[l-(6-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]indol-2-yl)-l- (diethoxyphosphinyl)methoxy]-4[S]-methyl-l,3,2-dioxaphospholane-2-oxide;[l-(6-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]indol-2-yl)-l- (diethoxyphosphinyl)methoxy]-4,5-dimethyl 1 ,3 ,2-dioxaphosphoIane-2-oxide; [ 1 -(6-[2- { 1 -butyl-3-(5-methoxypyrid-2-yl)ureido } ethyl]indol-2-yl)- 1 - (diethoxyphosphinyl)methoxy]-4[S]-methyl-l,3,2-dioxaphospholane-2-oxide;[l-(6-[3,N-phthalimidopropoxy]indol-2-yl)-l-(diethoxyphosphinyl)røethoxy]-4,5- dimethyll,3,2-dioxaphospholane-2-oxide;[l-(6-[4,N-phthalimidohutoxy]indol-2-yl)-l-(diethoxyphosphinyl)methyl]-4[R]- methyl- 1 ,3 ,2-dioxaphospholane-2-oxide;[ 1 -(5-[2- {N-methyl-N-ρyrid-2-ylamino} ethoxy]pyrid-2-yl)- 1 - (diethoxyphosphinyl)methyl]-4[R]-methyl-l,3,2-dioxaphospholane-2 -oxide;[1 -(5-[N-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N-methylamino]ρyrid-2-yl)- 1 - (diethoxyphosphinyl)methyl]-4[R]-methyl-l,3,2-dioxaphospholane-2-oxide; [ 1 -(5-[3- {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop- 1 -yl]pyrid-2-yl)- 1 - (diethoxyphosphinyl)methyl]-4[R]-methyl-l,3,2-dioxaphospholane-2-oxide;[l-(5-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]pyrid-2-yl)-l- (diethoxyphosphinyl)methyl]-l,3,2-dioxaphosphinane-2-oxide;[l-(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]ρyrid-2-yl)-l- (diethoxyphosphinyl)methyl]-l,3,2-dioxaphosphinane-2-oxide;[l-(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]pyrid-2-yl)-l- (diethoxyphosphinyl)methyl]- 1 ,3,2-dioxaphosphinane-2-oxide;[l-(5-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]pyrid-2-yl)-l- (diethoxyphosphinyl)methyl]-l ,3,2-dioxaphosphinane-2-oxide;[l-(5-[3-{5-methyl-2-phenylthiazol-4-yl}-l-oxoprop-l-yl]pyrid-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-4,5-dimethyll,3,2-dioxaphospholane-2 -oxide;[l-(5-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]ρyrid-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphosphinane-2-oxide; [l-(5-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]pyrid-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-4,5-dimethyll,3,2-dioxaphospholane-2 -oxide;[1 -(5-[3- {5-methyl-2-pyrid-4-yloxazol-4-yl} - 1 -oxoprop- 1 -yl]pyrid-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphosphinane-2 -oxide; [ 1 -(5-[N-(2- {5-methyl-2-ρyrid-4-ylthiazol-4-yl} ethyl)-N-methylamino]ρyrid-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]-4,5-dimethyl 1 ,3 ,2-dioxaphospholane-2-oxide;[l-(5-[2-{4-(4-trifluoromethylphenyl)phenoxy}ethoxy]-pyrid-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphosphinane-2-oxide; [ 1 -(5- [N-(2- {4-(4-trifluoromethylphenyl)phenoxy } ethyl)-N-methylamino]pyrid-2- yl)-2-(diethoxyphosphinyl)eth- 1 -yl]-4,5-dimethyl 1 ,3 ,2-dioxaphospholane-2- oxide;[l-(5-[3- {4-(4-trifluoromethylphenyl)phenoxy} - 1 -oxoprop- 1 -yl] -pyrid-2-yl)-2- (diethoxyphosphinyl)eth-l -yl]-l ,3,2-dioxaphosphinane-2-oxide;[2-(5-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido} ethyl]pyrid-2- yl)-2-(diethoxyphosphinyl)eth-l-yl]-l,3,2-dioxaphospholane-2-oxide;[2-(5-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]pyrid-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-4[R]-methyI-l,3,2-dioxaphospholane-2-oxide;[2-(5-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]pyrid-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3,2-dioxaphospholane-2-oxide;[2-(5-[2- {4H-3-oxobenzo[ 1 ,4]oxazin-2-yl} ethoxy]pyrid-2-yl)-2- (diethoxyphosphinyl)eth-l-yl]-4[R]-methyl-l,3,2-dioxaphospholane-2-oxide;[2-(5-[3,N-phthalimidopropoxy]pyrid-2-yl)-2-(diethoxyphosphinyl)eth-l-yl]-l,3,2- dioxaphospholane-2-oxide;[2-(5-[4,N-phthalimidobutoxy]pyrid-2-yl)-2-(diethoxyphosρhinyl)eth-l-yl]-4[R]- methyl-l,3,2-dioxaphospholane-2-oxide; 2[2-(5-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]benzothien-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphospholane-2-oxide; 2[2-(5-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]benzothien-2-yl)- 2-(diethoxyphosphinyl)eth-l-yl]-4[R]-methyl-l,3,2-dioxaphospholane-2-oxide; 2[2-(5-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l-yl]benzothien-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphosphinane-2-oxide; 2[2-(5-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]benzothien-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphosphinane-2-oxide; 2[2-(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]benzothien-2-yl)- 2-(diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphosphinane-2-oxide;
2[2-(5-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]benzothien-2-yl)-2- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphosphinane-2-oxide; 2[2-(5-[3-{5 -methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl]benzothien-2-yl)- 1 - (diethoxyphosphinyl)eth-l-yl]-l,3,2-dioxaphospholane-2-oxide; 2[2-(5-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]benzothien-2-yl)-l- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphospholane-2-oxide; 2[2-(5-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]benzothien-2-yl)-l- (diethoxyphosphinyl)eth- 1 -yl]- 1 ,3 ,2-dioxaphospholane-2-oxide; 2[2-(5-[3- { 5-methyl-2-pyrid-4-yloxazol-4-yl} - 1 -oxoprop- 1 -yl]benzothien-2-yl)- 1 - (diethoxyphosphinyl)eth-l-yl]-l,3,2-dioxaphospholane-2-oxide;
N,N,N')N'-Teframethyl-l (5- N-(2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N- methylamino]benzothien-2-yl)- 1 -hydroxymethylphosphondiamide; NN'-Diethyl 1 -(5-[2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy]benzothien-2-yl)- 1 -hydroxymethylphosphondiamide; 2-[ 1 -hydroxy- 1 -(5-[N-(2- {4-(4-trifluoromethylphenyl)phenoxy} ethyl)-N- methylamino]benzothien-2-yl)methyl]-[4S,5S]-dimethyl-l,3,2- diazaphospholidine-2-oxide; 2-[ 1 -hydroxy- 1 -(5 - [3 - {4-(4-trifluoromethylphenyl)ρhenoxy } - 1 -oxoprop- 1 - yl]benzothien-2-yl)methyl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2-oxide;
2-[l-hydroxy-l-(5-[2-{l-[4-(2-trifluoromethylphenyl)phenylmethyl]-3- hexylureido}ethyl]benzothien-2-yl)methyl]-[4S]-ethyl-l,3,2-oxazaphospholidine- 2-oxide; 2-[ 1 -hydroxy- 1 -(5-[2- { 1 -butyl-3 -(5-methoxypyrid-2-yl)ureido} ethyl]benzothien-2- yl)methyl]-[4R]methyl-l,3,2-oxazaphosphinane-2-oxide;
NN,N',N'-Teframethyl-1 (5-[3-{4-acetyl-3-hydroxy-2- propylphenoxy)propoxy]benzothien-2-yl)-l-hydroxymethylphosphondiamide; NN'-Diethyl l-(5-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]benzothien-2-yl)-l- hydroxymethylphosphondiamide; 2-[l-hydroxy-l-(5-[3,N-phthalimidopropoxy]benzothien-2-yl)methyl]-[4S,5S]- dimethyl- 1 ,3 ,2-diazaphospholidine-2-oxide; 2- [ 1 -hydroxy- 1 -(5 - [4,N-phthalimidobutoxy]benzothien-2-yl)methyl] -1,3,5,5- tetramethyl- 1 ,3 ,2-diazaphosphinane-2-oxide; 2-[l-hydroxy-l-(4-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]thiazol-2-yl)methyl]- [4S]-ethyl-l ,3,2-oxazaphospholidine-2-oxide;
2-[ 1 -hydroxy- 1 -(4-[N-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N- methylamino]thiazol-2-yl)methyl]-[4R]methyl-l,3,2-oxazaphosphinane-2-oxide; NNN'N'-Tetramethyl l-(4-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l- yl]thiazol-2-yl)-l-(bis[NN- dimethylamino]phosphoryloxy)methylphosphondiamide; NN'-Diethyl l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]thiazol-2-yl)-l-(bis[N- ethylamino]phosphoryloxy)methylphosphondiamide; 2-[ 1 - {([4S,5S]-dimethyl-2-oxido- 1 ,3 ,2-diazaρhospholidin-2-yl)oxy} - 1 -(4-[N-(2- {5- methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]thiazol-2-yl)methyl]-[4S,5S]- dimethyl-l,3,2-diazaphospholidine-2 -oxide;
2-[l-{(l,3,5,5-teframethyl-2-oxido-l,3,2-diazaphosρhinan-2-yl)oxy}-l-(4-[2-{5- methyl-2-phenylthiazol-4-yl}ethoxy]thiazol-2-yl)methyl]-l,3,5,5-tetramethyl- 1 ,3,2-diazaphosphinane-2-oxide; 2-[ 1 - {(4S]-ethyl-2-oxido- 1 ,3 ,2-oxazaphospholidin-2-yl)oxy } - 1 -(4-[3 - {5-methyl-2- phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl]thiazol-2-yl)methyl] - [4S] -ethyl- 1,3,2- oxazaphospholidine-2-oxide; 2-[l - {([4R]methyl- 1 ,3,2-oxazaphosphinan-2-yl)oxy} -1 -(4-[2- {5-methyl-2-pyrid-4- yloxazol-4-yl}ethoxy]thiazol-2-yl)methyl]-[4R]methyl-l,3,2-oxazaphosphinane- 2-oxide; NNN'N'-Tetramethyl 1 -(4-[2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethoxy]thiazol-2- yl)- 1 -(bis [N, N-dimethylamino]phosphoryloxy)methylphosphondiamide; NN'-Diethyl 1 -(4- [3- {5-methyl-2-pyrid-4-yloxazol-4-yl} -1 -oxoprop- 1 -yl]thiazol-2- yl)-l-(bis[N-ethylamino]phosphoryloxy)methylρhosphondiamide; 2-[l-{([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)oxy}-l-(4-[N-(2-{5- methyl-2-pyrid-4-ylthiazol-4-yl}ethyl)-N-methylamino]thiazol-2-yl)methyl]- [4S,5S]-dimethyl-l,3,2-diazaphospholidine-2-oxide; 2-[l-{(l,3,5,5-teframethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)oxy}-l-(4-[2-{4-(4- trifluoromethylphenyl)phenoxy}ethoxy]thiazol-2-yl)methyl]-l,3,5,5-tetramethyl- 1 ,3 ,2-diazaphosphinane-2-oxide; -[l-{(4S]-ethyl-2-oxido-l,3,2-oxazaphospholidin-2-yl)oxy}-l-(4-[N-(2-{4-(4- trifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]thiazol-2-yl)methyl]-[4S]- ethyl- 1 ,3 ,2-oxazaphospholidine-2-oxide; -[ 1 - {([4R]methyl- 1 ,3,2-oxazaphosphinan-2-yl)oxy} - 1 -(4-[3- {4-(4- trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl]thiazol-2-yl)methyl] - [4R]methyl-l,3,2-oxazaphosphinane-2-oxide; 1 -(4-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]thiazol-2- yl)-l,l-bis(bis[N,N-dimethylamino]phosphoryl)methane; 1 -(4-[2- { 1 -butyl-3 -(5 -methoxypyrid-2-yl)ureido } ethyl] thiazol-2-yl)- 1 , 1 -bis(bis [N- ethylamino]phosphoryl)methane; l-(4-[3-{4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]thiazol-2-yl)-l,l-bis([4S,5S]- dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)methane; l-(4-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]thiazol-2-yl)-l,l-bis(l,3,5,5- tetramethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)methane; 1 -(4-[3 ,N-phthalimidopropoxy]thiazol-2-yl)-l , 1 -bis ([4S]-ethyl-2-oxido- 1 ,3 ,2- oxazaphospholidin-2-yl)methane ; l-(4-[4,N-phthalimidobutoxy]thiazol-2-yl)-l,l-bis ([4R]methyl-2-oxido-l,3,2- oxazaphosphinan-2-yl)methane; 1 -(6-[2- {N-methyl-N-pyrid-2-ylamino}ethoxy]-3-methoxyquinolin-2-yl)-l , 1 - bis(bis [NN-dimethylamino]phosphoryl)methane; l-(6-[N-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)-l,l-bis(bis[N-ethylamino]phosphoryl)methane; l-(6-[3- {N-methyl-N-pyrid-2-ylamino } - 1 -oxoprop- 1 -yl] -3 -methoxyquinolin-2-yl)- l,l-bis([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)methane; 1 -(6-[2- {5-methyl-2-phenyloxazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l , 1 - bis(l,3,5,5-tetramethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)methane; l-(6-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)- 1 , 1 -bis ([4S] -ethyl-2-oxido- 1 ,3 ,2-oxazaphospholidin-2- yl)methane; l-(6-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l,l-bis ([4R]methyl-2-oxido-l,3,2-oxazaphosphinan-2-yl)methane; 1 -(6-[3- {5-methyl-2-phenylthiazol-4-yl} -1 -oxoprop-1 -yl]-3-methoxyquinolin-2-yl)- l,2-bis(bis[NN-dimethylamino]phosphoryl)ethane; l-(6-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l,2- bis(bis[N-ethylamino]phosphoryl)ethane; l-(6-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]-3-methoxyquinolin-2-yl)-l,2- bis([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)ethane; l-(6-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-yl]-3-methoxyquinolin-2- yl)- 1 ,2-bis(l ,3 ,5 ,5-tetramethyl-2-oxido- 1 ,3 ,2-diazaphosphinan-2-yl)ethane;
1 -(6-[N-(2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)-l ,2-bis ([4S]-ethyl-2-oxido-l ,3,2-oxazaphospholidin-2- yl)ethane; 1 -(6-[2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy]-3-methoxyquinolin-2-yl)-l ,2- bis ([4R]methyl-2-oxido- 1 ,3 ,2-oxazaphosphinan-2-yl)ethane; l-(6-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]-3- methoxyquinolin-2-yl)-l,2-bis(bis[NN-dimethylamino]phosphoryl)ethane; l-(6-[3- {4-(4-trifluoromethylphenyl)phenoxy } - 1 -oxoprop- 1 -yl] -3 -methoxyquinolin-2- yl)-l,2-bis(bis[N-ethylamino]phosphoryl)ethane; 1 -(6-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]-3- methoxyquinolin-2-yl)- 1 ,2-bis([4S,5S]-dimethyl-2-oxido-l ,3,2- diazaphospholidin-2-yl)ethane; 1 -(6- [2- { 1 -butyl-3 -(5-methoxypyrid-2 -yl)ureido} ethyl] -3 -methoxyquinolin-2-yl)- 1,2- bis(l,3,5,5-tetramethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)ethane; l-(6-[3-{4-acetyl-3-hydroxy-2-propylρhenoxy)propoxy]-3-methoxyquinolin-2-yl)- l,2-bis ([4S]-ethyl-2-oxido-l,3,2-oxazaphospholidin-2-yl)ethane; l-(6-[3,N-phthalimidoproρoxy]-3-methoxyquinolin-2-yl)-l,2-bis ([4R]methyl-2- oxido- 1 ,3 ,2-oxazaphosphinan-2-yl)ethane; 2-(6-[4,N-phthalimidobutoxy]-3-methoxyquinolin-2-yl)- 1 , 1 -bis(bis[NN- dimethylamino]phosphoryl)ethane; 2-(5-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]thien-2-yl)- 1 , 1 -bis(bis[N- ethylamino]phosphoryl)ethane; 2-(5-[N-(2- {N-methyl-N-pyrid-2-ylamino} ethyl)-N-methylamino]thien-2-yl)-l , 1 - bis([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)ethane;
2-(5-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l-yl]thien-2-yl)-l,l-bis(l,3,5,5- teframethyl-2-oxido-l,3,2-diazaphosphinan-2-yl)ethane; 2-(5-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]thien-2-yl)-l,l-bis ([4S]-ethyl-2- oxido- 1 ,3 ,2-oxazaphospholidin-2-yl)ethane; 2-(5-[N-(2-{5-methyl-2-phenyloxazol-4-yl}ethyl)-N-methylamino]thien-2-yl)-l,l-bis ([4R]methyl-2-oxido-l,3,2-oxazaphosphinan-2-yl)ethane; 2-(5-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]thien-2-yl)-l,l-bis(bis[NN- dimethylamino]phosphoryl)ethane; 2-(5-[3- {5-methyl-2-phenylthiazol-4-yl}-l -oxoprop- 1 -yl]thien-2-yl)- 1 , 1 -bis(bis[N- ethylamino]phosphoryl)ethane; -(5-[2-{5-methyl-2-pyrid-4-yloxazol-4-yl}ethoxy]thien-2-yl)-l,l-bis([4S,5S]- dimethyl-2-oxido- 1 ,3 ,2-diazaphospholidin-2-yl)ethane; -(5-[2-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ethoxy]thien-2-yl)-l,l-bis(l,3,5,5- tetramethyl-2-oxido- 1 ,3 ,2-diazaphosphinan-2-yl)ethane; -(5-[3-{5-methyl-2-pyrid-4-yloxazol-4-yl}-l-oxoprop-l-yl]thien-2-yl)-l,l-bis ([4S]- ethyl-2-oxido-l,3,2-oxazaphospholidin-2-yl)ethane; -(5-[N-(2- {5-methyl-2-pyrid-4-ylthiazol-4-yl} ethyl)-N-methylamino]thien-2-yl)-l , 1 - bis ([4R]methyl-2-oxido- 1 ,3 ,2-oxazaphosphinan-2-yl)ethane; 1 -[N-(5-[2- {4-(4-trifluoromethylphenyl)phenoxy} ethoxy]thien-2-yl)amino]-l , 1 - bis(bis[NN-dimethylamino]phosphoryl)methane; l-[N-(5-[N-(2-{4-(4-trifluoromethylphenyl)phenoxy}ethyl)-N-methylamino]thien-2- yl)amino]- 1 , 1 -bis(bis[N-ethylamino]phosphoryl)methane; l-[N-(5-[3-{4-(4-teifluoromethylphenyl)phenoxy}-l-oxoprop-l-yl]thien-2-yl)amino]- l,l-bis([4S,5S]-dimethyl-2-oxido-l,3,2-diazaphospholidin-2-yl)methane; 1 -[N-(5-[2- { 1 -[4-(2-trifluoromethylphenyl)phenylmethyl]-3-hexylureido} ethyl]thien- 2-yl)amino]-l,l-bis(l,3,5,5-tetramethyl-2-oxido-l,3,2-diazaphosphinan-2- yl)methane; l-[N-(5-[2-{l-butyl-3-(5-methoxypyrid-2-yl)ureido}ethyl]thien-2-yl)amino]-l,l-bis ([4S]-ethyl-2-oxido-l,3,2-oxazaphospholidin-2-yl)methane; 1 -[N-(5 - [3 - {4-acetyl-3 -hydroxy-2-propylphenoxy)propoxy]thien-2-yl)amino] - 1 , 1 -bis ([4R]methyl-2-oxido- 1 ,3 ,2-oxazaphosphinan-2-yl)methane; l-[N-(5-[2-{4H-3-oxobenzo[l,4]oxazin-2-yl}ethoxy]thien-2-yl)amino]-l,l- bis(bis[NN-dimethylamino]phosphoryl)methane; l-[N-(5-[3,N-phthalimidopropoxy]thien-2-yl)amino]-l,l-bis(bis[N- ethylamino]phosphoryl)methane; l-[N-(5-[4,N-phthalimidobutoxy]thien-2-yl)amino]-l,l-bis([4S,5S]-dimethyl-2-oxido- l,3,2-diazaphosphoIidin-2-yl)methane; 1 - [N-(4- [2- {N-methyl-N-pyrid-2-ylamino } ethoxy]-3 -fluorophenyl)amino]- 1,1- bis( 1 ,3 , 5 , 5-tetramefhyl-2-oxido- 1 ,3 ,2-diazaphosphinan-2-yl)methane; l-[N-(4-[Ν-(2-{N-methyl-N-pyrid-2-ylamino}ethyl)-N-methylaminocarbonyl]-3- fluorophenyl)amino]- 1 , 1 -bis ([4S]-ethyl-2-oxido- 1 ,3 ,2-oxazaphospholidin-2- yl)methane; 1 -[N-(4-[3 - {N-methyl-N-pyrid-2-ylamino} - 1 -oxoprop- 1 -yl]-3 -fluoroρhenyl)amino]- 1 , 1 -bis ([4R]methyl-2-oxido- 1 ,3 ,2-oxazaphosphinan-2-yl)methane; 2-[l -(Bis[N-ethylamino]phosphoryIoxy)- 1-(4-[2- {5-methyl-2-phenyloxazol-4- yl}ethoxy]-3-fluorophenyl)methyl]-[4S,5S]-dimethyl-l,3,2-diazaphospholidine-2- oxide; 2-[l-(Bis[N-ethylamino]phosphoryl)-l-(4-[N-(2-{5-methyl-2-phenyloxazol-4- yl}ethyl)-N-methylaminocarbonyl]-3-fluorophenyl)methoxy]-[4S,5S]-dimethyl- l,3,2-diazaphospholidine-2-oxide;
2-[l-(Bis[N-ethylamino]phosphoryl)-l-(4-[2-{5-methyl-2-phenylthiazol-4-yl}ethoxy]- 3 -fluorophenyl)methyl]- 1 ,3 ,5,5-tetramethyl- 1 ,3 ,2-diazaphosphinane-2-oxide; 2-[l -(Bis[N-ethylamino]phosphoryl)-2-(4-[3- {5-methyl-2-phenylthiazol-4-yl} - 1 - oxoprop- 1 -yl]-3-fluorophenyl)ethen- 1 -yl]-[4S]-efhyl- 1 ,3,2-oxazaphospholidine-2- oxide;
2-[ 1 -(Bis[N-ethylamino]phosphoryl)-2-(4-[2- {5-methyl-2-pyrid-4-yloxazol-4- yl} ethoxy] -3 -fluorophenyl)eth- 1 -yl] -[4R]methyl- 1 ,3 ,2-oxazaphosphinane-2- oxide; -[2-(Bis[N-ethylamino]phosphoryl)-2-(4-[2-{5-methyl-2-pyrid-4-ylthiazol-4- yl}ethoxy]-3-fluorophenyl)eth-l-yl]-l,3,5,5-teframethyl-l,3,2-diazaphosphinane- 2-oxide;-[2-(Bis[N-ethylamino]phosphoryl)-l -(4-[3- {5-methyl-2-pyrid-4-yloxazol-4-yl} -1 - oxoprop- 1 -yl] -3 -fluorophenyl)eth- 1 -yl] - [4S] -ethyl- 1 ,3 ,2-oxazaphospholidine-2- oxide;-[l-(Bis[N-ethylamino]phosphoryloxy)-l-(4-[N-(2-{5-methyl-2-pyrid-4-ylthiazol-4- yl}ethyl)-Ν-methylaminocarbonyl]-3-fluorophenyl)methyl]-[4S,5S]-dimethyl- l,3,2-diazaphospholidine-2-oxide;-[ 1 -(Bis[N-ethylamino]phosphoryl)- 1 -(4-[2- {4-(4- trifluoromethylphenyl)phenoxy } ethoxy] -3 -fluorophenyl)methoxy] - [4S, 5 S] - dimethyl- 1 ,3 ,2-diazaphospholidine-2-oxide;-[l-(Bis[N-ethylamino]phosphoryl)-l-(4-[N-(2-{4-(4- frifluoromethylphenyl)phenoxy}ethyl)-N-methylaminocarbonyl]-3- fluorophenyl)methyl] -1,3,5,5 -tetramethyl- 1 ,3 ,2-diazaphosphinane-2-oxide;-[l-(Bis[N-ethylamino]phosphoryl)-2-(4-[3-{4-(4-trifluoromethylphenyl)phenoxy}- l-oxoprop-l-yl]-3-fluorophenyl)ethen-l-yl]-[4S]-ethyl-l,3,2-oxazaphospholidine- 2-oxide;-[ 1 -(Bis[N-ethylamino]phosphoryl)-2-(4-[2- { 1 -[4-(2- frifluoromethylphenyl)phenylmethyl]-3-hexylureido}ethyl]-3-fluorophenyl)eth-l- yl]-[4R]methyl-l,3,2-oxazaphosphinane-2-oxide;-[2-(Bis[N-ethylamino]phosphoryl)-2-(4-[2-{l-butyl-3-(5-methoxypyrid-2- yl)ureido}ethyl]-3-fluorophenyl)eth-l-yl]-l,3,5,5-tetramethyl-l,3,2- diazaphosphinane-2-oxide; -[2-(Bis[N-ethylamino]phosphoryl)-l-(4-[3-{4-acetyl-3-hydroxy-2- propylphenoxy)propoxy]-3-fluorophenyl)eth-l-yl]-[4S]-ethyl-l,3,2- oxazaphospholidine-2 -oxide;- [ 1 -(Diethoxyphosphoryloxy)- 1 -(4-[2- {4H-3 -oxobenzo [ 1 ,4] oxazin-2-yl } ethoxy] -3 - fluorophenyl)methyl]-[4S,5S]-dimethyl-l,3,2-diazaphospholidine-2-oxide;-[l-(Diethoxyphosphoryl)-l-(4-[3,N-phthalimidopropoxy]-3-fluorophenyl)methoxy]- [4S,5S]-dimethyl-l,3,2-diazaphospholidine-2-oxide;-[l-(Diethoxyphosphoryl)-l-(4-[4,N-phthalimidobutoxy]-3-fluorophenyl)methyl]- 1 ,3 ,5 ,5-tetramethyl- 1 ,3 ,2-diazaphosphinane-2-oxide;-[l-(Diethoxyphosphoryl)-2-(3-[3-{N-methyl-N-pyrid-2-ylamino}propoxy]-4- fluorophenyl)ethen-l-yl]-[4S]-ethyl-l,3,2-oxazaphospholidine-2-oxide;-[l-(Diethoxyphosphoryl)-2-(3-[N-(3-{N-methyl-N-pyrid-2-ylamino}propyl)-N- methylamino]-4-fluorophenyl)eth-l-yl]-[4R]methyl-l,3,2-oxazaphosphinane-2- oxide;-[2-(Diethoxyphosphoryl)-2-(3-[3-{N-methyl-N-pyrid-2-ylamino}-l-oxoprop-l- ylamino]-4-fluorophenyl)eth-l-yl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2- oxide;-[2-(Diethoxyphosphoryl)-l-(3-[3-{5-methyl-2-phenyloxazol-4-yl}propoxy]-4- fluorophenyl)eth- 1 -yl]-[4S]-ethyl- 1 ,3 ,2-oxazaphospholidine-2 -oxide;-[ 1 -(Diethoxyphosphoryloxy)-l -(3-[N-(2- {5-methyl-2-phenyloxazol-4-yl} ethyl)-N- methylaminocarbonyl] -4-methoxyphenyl)methyl] -[4S, 5 S] -dimethyl- 1,3,2- diazaρhospholidine-2-oxide;-[l-(Diethoxyphosphoryl)-l-(3-[3-{5-methyl-2-phenylthiazol-4-yl}propoxy]-4- fluorophenyl)methoxy]-[4S,5S]-dimethyl-l,3,2-diazaphospholidine-2 -oxide; 2-[ 1 -(Diethoxyphosphoryl)- 1 -(3 -[3 - { 5-methyl-2-phenylthiazol-4-yl} - 1 -oxoprop- 1 -yl] - 4-fluorophenyl)methyl]-l,3,5,5-tetramethyl-l,3,2-diazaphosphinane-2-oxide; 2-[l-(Diethoxyphosphoryl)-2-(3-[4-{5-methyl-2-ρyrid-4-yloxazol-4-yl}butoxy]-4- fluorophenyl)ethen-l-yl]-[4S]-ethyl-l,3,2-oxazaphospholidine-2-oxide; 2-[l-(Diethoxyphosphoryl)-2-(3-[3-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ρropoxy]-4- fluorophenyl)eth-l-yl]-[4R]methyl-l,3,2-oxazaphosphinane-2-oxide; 2-[2-(Diethoxyphosphoryl)-2-(3-[3-{5-methyl-2-ρyrid-4-yloxazol-4-yl}-l-oxoprop-l- ylthio]-4-fluorophenyl)eth- 1 -yl]- 1 ,3 ,5 ,5-teframethyl- 1 ,3 ,2-diazaphosphinane-2- oxide; and 2-[2-(Diethoxyphosphoryl)-l-(3-[N-(3-{5-methyl-2-pyrid-4-ylthiazol-4-yl}ρroρyl)-N- methylamino]-4-fϊuorophenyl)eth-l-yl]-[4S]-ethyl-l,3,2-oxazaphospholidine-2- oxide;
12. The pharmaceutical formulation according to Claim 7, wherein the compound of Formula I is selected from the group consisting of: Diethyl l-(diethoxyphosphinyloxy)-l-(4-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]-3- fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(4-[3,N-phthalimidopropoxy]-3- fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(4-[2- {5-methyl-2-phenyloxazol-4-yl} ethoxy]- 3-fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(3-[3-{N-methyl-N-pyrid-2-ylamino}propoxy]- 4-fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(3-[4-{N-methyl-N-pyrid-2-ylamino}butoxy]-4- fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(3-[4,N-phthalimidobutoxy]-4- fluorophenyl)methylphosphonate; Diethyl l-(diethoxyphosphinyloxy)-l-(3-[5,N-phthalimidopentoxy]-4- fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1 -(3-[4- {5-methyl-2-pyrid-4-yloxazol-4- yl}butoxy]-4-fluorophenyl)methylphosphonate; Diethyl 1 -(diethoxyphosphinyloxy)- 1-(3-[5-{5 -methyl-2-pyrid-4-yloxazol-4- yl}pentoxy]-4-fluorophenyl)methylphosphonate; 1 -(4-[2- {N-methyl-N-pyrid-2-ylamino} ethoxy]-3-fluorophenyl)-l , 1 -bis([4R,5S]- dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane;
1 -(4-[3 ,N-phthalimidopropoxy]-3-fluorophenyl)- 1 , l-bis([4R,5S]-dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]-3-fluorophenyl)-l,l-bis([4R,5S]- dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methane; 1 -(3 - [3 - {N-methyl-N-pyrid-2-ylamino } propoxy] -4-fluorophenyl )- 1 , 1 -bis([4R, 5 S] - dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; 1 -(3-[4- {N-methyl-N-pyrid-2-ylamino}butoxy]-4-fluorophenyl)-l , 1 -bis([4R,5S]- dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; 1 -(3 -[4,N-phthalimidobutoxy]-4-fluorophenyl)- 1 , 1 -bis([4R,5 S]-dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; l-(3-[5,N-phthalimidopentoxy]-4-fluorophenyl)-l,l-bis([4R,5S]-dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; l-(3-[4-{5-methyl-2-pyrid-4-yloxazol-4-yl}butoxy]-4-fluorophenyl)-l,l-bis([4R,5S]- dimethyl-2-oxido-l,3,2-dioxaphospholan-2-yl)methane; l-(3-[5-{5-methyl-2-pyrid-4-yloxazol-4-yl}pentoxy]-4-fluorophenyl)-l,l-bis([4R,5S]- dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl)methane; NNN'N'-Tetramethyl l-(4-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]-3- fluorophenyl)-l-hydroxymethylphosphondiamide; NNN'N'-Tetramethyl l-(4-[3N-phthalimidopropoxy]-3-fluorophenyl)-l- hydroxymethylphosphondiamide; NNN'N'-Tetramethyl l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]-3- fluorophenyl)- 1 -hydroxymethylphosphondiamide; 2-[l-hydroxy-l-(4-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]-3-fluorophenyl)methyl]- [4S]-(l-methylethyl)-l,3,2-oxazaphospholidine-2-oxide; 2-[l -hydroxy-1 -(4-[3 ,N-phthalimidopropoxy]-3-fluorophenyl)methyl]-[4S]-(l - methylethyl)- 1 ,3 ,2-oxazaphospholidine-2-oxide; 2-[l-hydroxy-l-(4-[2-{5-methyl-2-phenyloxazol-4-yl}ethoxy]-3- fluorophenyl)methyl]-[4S]-(l-methylethyl)-l,3,2-oxazaphospholidine-2-oxide; l-[N-(4-[2-{N-methyl-N-pyrid-2-ylamino}ethoxy]-3-fluorophenyl)amino]-l,l- bis(bis[N-ethylamino]phosphoryl)methane; l-[N-(4-[3,N-phthalimidopropoxy]-3-fluorophenyl)amino]-l,l-bis(bis[N- ethylamino]phosphoryl)methane; and 1 -[N-(4-[2- {5-methyl-2-phenyloxazol-4-yl} ethoxy]-3 -fluorophenyl)amino]- 1 , 1 - bis(bis[N-ethylamino]phosphoryl)methane.
13. A pharmaceutical formulation according to Claim 7, wherein the pharmaceutically acceptable caπier, excipient, solvent, adjuvant or diluent is selected from the group consisting of edible carriers, gelatin, gum fragacanth, acacia, com starch, gelatin, microcrystalline cellulose, starch, lactose, alginic acid, magnesium stearate, colloidal silicon dioxide, sucrose, saccharin, peppermint, methyl salicylate, fruit flavoring, a fatty oil, a syrup, a preservative, a dye, coloring, a sterile diluent such as water for injection, saline solution, fixed oil, a naturally occurring vegetable oil, sesame oil, coconut oil, peanut oil, cottonseed oil, a synthetic fatty oil, ethyl oleate, polyethylene glycol, glycerine, propylene glycol, a synthetic solvent, an antimicrobial agent, benzyl alcohol, methyl parabens, an antioxidantm, ascorbic acid, sodium bisulfite, a chelating agent, ethylenediaminetefraacetic acid (EDTA), a buffers, an acetates, a citratee, a phosphate, an agent for the adjustment of tonicity, sodium chloride, dextrose, pysiological saline, phosphate buffered saline (PBS), a thickener, a solubilizer, glucose, polyethylene glycol, polypropyleneglycol and iposomal suspensions including tissue-targeted liposomes.
14. A method of regulating HDL and LDL cholesterol levels in a mammal comprising administering to a mammal an effective amount of a compound of the formula (I):
wherein A is a bond, O, CH2, CHF, CF2, or NR6; B is H, Cι-C6 lower alkyl, or P(=X1)(UR3)(VR4); D is a) H or lower alkyl, wherein the L~ C bond is a single bond; or b) OH, OCOR5, NH2, NR6R6a, or NHCOR5, wherein the L^C bond is a single bond, with the proviso that A is CH2, CHF, CF2; L is a) NR6, CR7R8, -OCR7R8-, -NR6CR7R8-, or -S(0)mCR7R8-, wherein the L— C bond is a single bond; or b) CR7, whenin the L— C bond is a double bond, with the proviso that D is absent when the L— C bond is a double bond; or c) absent, wherein C is covalently bonded by a single bond to Ar ;
Ar1 and Ar2 are each independently mono- or bicyclic aromatic rings of 5-12 atoms, including, but not limited to phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyπolyl, imidazyl, pyrazolyl, oxazolyl, isoxoazolyl, thiazolyl, isothiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,3- triazolyl, 1,3,4-triazolyl, 1,2,4-triazinyl, 1,3,5-triazinyl, benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazyl, benzoxazoyl, benzoisozazolyl, benzothiazoyl, benzoisothiazolyl, quinolinyl, isoqumolinyl, quinazolinyl, quinoxalinyl, naphthyridyl, or purinyl;
Y1, Y2, and Z1 are each independently a lone electron pair, H, Cι-C6 lower alkyl, C2- C6 lower alkenyl, C2-C6 lower alkynyl, Cι-C6 lower alkoxy, Cι-C6 lower alkylamino, Cι-C6 lower dialkylamino, C2-C6 lower cycloalkyl, C4-C6 lower cycloalkenyl, Cι-C6 lower thioalkyl, d-C6 lower sulfinylalkyl, d-C6 lower sulfonylalkyl, Cι-C6 lower acyloxy, d-C6 lower acylamino with N substituted with R6, CH2OR5, CH2NR6R6a, Rf, RA OH, NH2, CN, N02, F, CI, Br, I, or N3; E is a bond, S(0)m, NR6, C=0, C02, CONR6, O, -OC=0, NR6C=0, NR6C02, OC=ONR6, OC02, orNR6CONR6a;
F is (CH2)n, (CH2)00(CH2)p, (CH2)0NR6(CH2)P, (CH2)0NR6CO(CH2)p, (CH2)0CONR6 (CH2)p, (CH2)0(CR6=CR6)q(CH2)p, (CH2)0-(C ^)q-(CH2)p; G is a bond, O, NR6, CO, C02, OCO, OC02, S(0)m, CONR6, NR6CO, NR6C02, OCONR6, NR6CONR6a, or G can optionally be attached to Ar2 at two contiguous C atoms to form a 5- to 7-membered partially saturated ring, which contains 0, 1, or 2 heteroatoms selected from the group consisting of O, N, and S;
X, X1 are independently O or S
Z2 is nothing, H or Ar1 optionally substituted with Y1 and Y2; R1, R2, R3, and R4, are each independently selected from H, Cι-C6 lower alkyl, C3-C6 lower alkenyl, C3-C6 lower alkynyl, C3-C6 lower cycloalkyl, C4-C6 lower cycloalkenyl, or independently R1 and R2 or R3 and R4 can be taken together to form a 5 to 8-membered ring containing 2-7 carbon atoms, the 5 to 8-membered ring optionally substituted with zero to 3 substituents selected from the group d- C4 lower alkyl, d-C4 lower alkoxy, Cι-C4 lower alkylamino, CpC4 lower dialkylamino, amino, hydroxyl, hydroxymethyl, methoxymethyl, phenyl, substituted phenyl, benzyl, substituted benzyl;
U and V are each independently a bond, O or NR6;
R5 R6 and R6a are each independently Cι-C6 alkyl, C3-Cβ cycloalkyl, C3-C6 alkenyl, C3-C6 cycloalkenyl, C3-C6 alkynyl, and H;
R and R are each independently H, Cι-C4 lower alkyl, or are taken together to form a saturated C3-C6 carbocyclic ring;
Rf is Cι-C4 straight or branched lower perfluoroalkyl; all lower alkyl, alkenyl and alkynyl groups including those linked via heteroatoms can be straight chain or branched; m is 0, 1, or 2; n is O, 1, 2, 3, 4, 5, or 6; o is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; and q is O, 1, 2, 3, 4, 5, or 6; with the provisos that when A is a bond or O, B is P(0)(OR3)(OR4), and D is selected from the group H, OH, OCOCH3, and NH2, and when R1 = R2 and R3 = R4, and both are selected from the group H or unsubstituted d-C4 lower alkyl, and E and G are bonds, and F is (CH2)n where n is 0, and both Ar1 and Ar2 are phenyl, then at least one of Y1, Y2, Z1, or Z2 must not be H; and when A is a bond or CH2, and B is P(0)(OR3)(OR4), and either D is H or C C4 lower alkyl where L is CH2, or D is absent, with L— C taken together represent an ethenylidene group, and Ar1 is phenyl, and E is a bond or O, and R1 = R2 and R3 = R4, and both are drawn from the group H or d-C6 unsubstituted lower alkyl, then one of Y and Y must be other than H or unsubstituted Cι-C4 lower alkyl or unsubstituted Cι-C4 lower alkoxy; and when A is O, and B is H or P(0)(OR3)(OR4), and R1, R2, R3, and R4 are all selected from the group H or d-C6 unsubstituted lower alkyl, and D is H, and L is a bond, and Ar1 is phenyl, and E is other than a bond or O, then one of Y1 or Y2 must be other than H, or Cι-C4 unsubstituted lower alkyl or Cι-C4 unsubstituted lower alkoxy; or a pharmaceutically acceptable salt thereof.
15. A method according to claim 14, wherein the mammal is a human.
16. A method according to claim 14, wherein the effective amount is administered in a dosage of between about 0.1 mg to about 5000 mg per day.
17. A method according to claim 14, wherein the effective amount is administered in a dosage of between about 50 mg to about 500 mg per day.
18. A method according to claim 14, wherein the effective amount of the pharmaceutical formulation is administered orally.
19. A method according to claim 14, wherein the effective amount of the pharmaceutical formulation is administered by depot injection.
20. A method of regulating HDL or LDL cholesterol levels in a mammal comprising administering to a mammal an effective amount of a pharmaceutical formulation comprising a compound ofthe formula (I):
21. A method according to claim 20, wherein the mammal is a human.
22. A method according to claim 20, wherein the effective amount is administered in a dosage of between about 0.1 mg to about 5000 mg per day.
23. A method according to claim 22, wherein the effective amount comprises a dosage of between about 50 mg to about 500 mg per day.
24. A method according to claim 20, wherein the effective amount of the pharmaceutical formulation is administered orally.
25. A method according to claim 20, wherein the effective amount of the pharmaceutical formulation is administered depot injection.
26. A method according to claim 20, wherein the pharmaceutically acceptable carrier, excipient, solvent, adjuvant or diluent is selected from the group consisting of edible carriers, gelatin, gum fragacanth, acacia, corn starch, gelatin, microcrystalline cellulose, starch, lactose, alginic acid, magnesium stearate, colloidal silicon dioxide, sucrose, saccharin, peppermint, methyl salicylate, fruit flavoring, a fatty oil, a syrup, a preservative, a dye, coloring, a sterile diluent such as water for injection, saline solution, fixed oil, a naturally occurring vegetable oil, sesame oil, coconut oil, peanut oil, cottonseed oil, a synthetic fatty oil, ethyl oleate, polyethylene glycol, glycerine, propylene glycol, a synthetic solvent, an antimicrobial agent, benzyl alcohol, methyl parabens, an antioxidantm, ascorbic acid, sodium bisulfite, a chelating agent, ethylenediammetefraacetic acid (EDTA), a buffers, an acetates, a cifratee, a phosphate, an agent for the adjustment of tonicity, sodium chloride, dextrose, pysiological saline, phosphate buffered saline (PBS), a thickener, a solubilizer, glucose, polyethylene glycol, polypropyleneglycol and iposomal suspensions including tissue-targeted liposomes.
27. A method of treating disease states related to HDL or LDL cholesterol levels comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound ofthe formula (I):
Y1, Y2, and Z1 are each independently a lone electron pair, H, Cι-C6 lower alkyl, C2- C6 lower alkenyl, C2-C6 lower alkynyl, d-Cβ lower alkoxy, Cι-C6 lower alkylamino, d-C6 lower dialkylamino, C2-C6 lower cycloalkyl, C4-C6 lower cycloalkenyl, d-C6 lower thioalkyl, Cι-C6 lower sulfmylalkyl, d-C6 lower sulfonylalkyl, d-Cδ lower acyloxy, d-C6 lower acylamino with N substituted with R6, CH2ORs, CH2NR6R6a, Rf, RfO, OH, NH2, CN, N02, F, CI, Br, I, or N3;
E is a bond, S(0)m, NR6, C=0, C02, CONR6, O, -OC=0, NR6C=0, NR6C02, OC=ONR6, OC02, or NR6CONR6a;
F is (CH2)„, (CH2)00(CH2)p, (CH2)0NR6(CH2)p, (CH2)0NR6CO(CH2)p, (CH2)0CONR6 (CH2)P, (CH2)0(CR6=CR6)q(CH2)p, (CH2)0-(C =C)q-(CH2)p;
G is a bond, O, NR6, CO, C02, OCO, OC02, S(0)m, CONR6, NR6CO, NR6C02, OCONR6, NR6CONR6a, or G can optionally be attached to Ar2 at two contiguous C atoms to form a 5- to 7-membered partially saturated ring, which contains 0, 1, or 2 heteroatoms selected from the group consisting of O, N, and S;
X, X1 are independently O or S
Z2 is nothing, H or Ar1 optionally substituted with Y1 and Y2;
R1, R2, R3, and R , are each independently selected from H, d-C6 lower alkyl, C3-C6 lower alkenyl, C3-C6 lower alkynyl, C3-C6 lower cycloalkyl, C4-C6 lower cycloalkenyl, or independently R1 and R or R3 and R can be taken together to form a 5 to 8-membered ring containing 2-7 carbon atoms, the 5 to 8-membered ring optionally substituted with zero to 3 substituents selected from the group Ci- C4 lower alkyl, d-C4 lower alkoxy, Cι-C4 lower alkylamino, d-C4 lower dialkylamino, amino, hydroxyl, hydroxymethyl, methoxymethyl, phenyl, substituted phenyl, benzyl, substituted benzyl; U and V are each independently a bond, O or NR6; R5 R6 and R6a are each independently d-C6 alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 cycloalkenyl, C3-C6 alkynyl, and H; R7 and R8 are each independently H, d-C4 lower alkyl, or are taken together to form a saturated C3-C6 carbocyclic ring; Rf is Cι-C4 straight or branched lower perfluoroalkyl; all lower alkyl, alkenyl and alkynyl groups including those linked via heteroatoms can be straight chain or branched; m is 0, 1, or 2; n is O, 1, 2, 3, 4, 5, or 6; o is O, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; and q is 0, 1, 2, 3, 4, 5, or 6; with the provisos that when A is a bond or O, B is P(0)(OR3)(OR4), and D is selected from the group H, OH, OCOCHs, and NH2, and when R1 = R2 and R3 = R4, and both are selected from the group H or unsubstituted Cι-C4 lower alkyl, and E and G are bonds, and F is (CH2)n where n is 0, and both Ar1 and Ar2 are phenyl, then at least one of Y1, Y2, Z1, or Z must not be H; and when A is a bond or CH2, and B is P(0)(OR3)(OR4), and either D is H or Cι-C lower alkyl where L is CH2, or D is absent, with L— C taken together represent an ethenylidene group, and Ar1 is phenyl, and E is a bond or O, and R1 = R2 and R3 = R4, and both are drawn from the group H or Cι-C6 unsubstituted lower alkyl, then one of Y1 and Y2 must be other than H or unsubstituted d-C4 lower alkyl or unsubstituted d-C4 lower alkoxy; and when A is O, and B is H or P(0)(OR3)(OR4), and R1, R2, R3, and R4 are all selected from the group H or d-C6 unsubstituted lower alkyl, and D is H, and L is a bond, and Ar1 is phenyl, and E is other than a bond or O, then one of Y1 or Y2 must be other than H, or C1-C4 unsubstituted lower alkyl or d-C4 unsubstituted lower alkoxy; or a pharmaceutically acceptable salt thereof.
28. A method of treating disease states related to HDL or LDL cholesterol levels comprising administering to a mammal in need of such treatment a combination of a therapeutically effective amount of a compound ofthe formula (I):
wherein A is a bond, O, CH2, CHF, CF2, or NR6; B is H, Cι-C6 lower alkyl, or P(=X1)(UR3)(VR4); D is a) H or lower alkyl, wherein the L— C bond is a single bond; or b) OH, OCOR5, NH2, NR6R6a, or NHCOR5, wherein the L-C bond is a single bond, with the proviso that A is CH2, CHF, CF2; L is a) NR6, CR7R8, -OCR7R8-, -NR6CR7R8-, or -S(0)mCR7R8-, wherein the L^C bond is a single bond; or b) CR7, whenin the L— C bond is a double bond, with the proviso that D is absent when the L" C bond is a double bond; or c) absent, wherein C is covalently bonded by a single bond to Ar ; Ar1 and Ar2 are each independently mono- or bicyclic aromatic rings of 5-12 atoms, including, but not limited to phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyπolyl, imidazyl, pyrazolyl, oxazolyl, isoxoazolyl, thiazolyl, isothiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,3- triazolyl, 1,3,4-triazolyl, 1,2,4-triazinyl, 1,3,5-triazinyl, benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazyl, benzoxazoyl, benzoisozazolyl, benzothiazoyl, benzoisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridyl, or purinyl; Y1, Y2, and Z1 are each independently a lone electron pair, H, d-Cδ lower alkyl, C2- C6 lower alkenyl, C2-C6 lower alkynyl, Cι-C6 lower alkoxy, Cι-C6 lower alkylamino, Cι-C6 lower dialkylamino, C2-C6 lower cycloalkyl, C4-C6 lower cycloalkenyl, d-Cδ lower thioalkyl, d-Cβ lower sulfinylalkyl, Cι-C6 lower sulfonylalkyl, d-C6 lower acyloxy, d-C6 lower acylamino with N substituted with R6, CH2OR5, CH2NR6R6a, Rf, RfO, OH, NH2, CN, N02, F, CI, Br, I, or N3; E is a bond, S(0)m, NR6, C=0, C02, CONR6, O, -OC=0, NR6C=0, NR6C02, OC=ONR6, OC02, orNR6CONR6a; F is (CH2)n, (CH2)0O(CH2)p, (CH2)0NR6(CH2)P, (CH2)0NR6CO(CH2)p, (CH2)0CONR6 (CH2)P, (CH2)0(CR6=CR6)q(CH2)p, (CH2)0-(C SC)q-(CH2)p; G is a bond, O, NR6, CO, C02, OCO, OC02, S(0)m, CONR6, NR6CO, NR6C02, OCONR6, NR6CONR6a, or G can optionally be attached to Ar2 at two contiguous C atoms to form a 5- to 7-membered partially saturated ring, which contains 0, 1, or 2 heteroatoms selected from the group consisting of O, N, and S; X, X1 are independently O or S Z is nothing, H or Ar optionally substituted with Y and Y ; R1, R2, R3, and R4, are each independently selected from H, Cι-C6 lower alkyl, C3-C6 lower alkenyl, C3-Ce lower alkynyl, C3-C6 lower cycloalkyl, C4-C6 lower cycloalkenyl, or independently R1 and R2 or R3 and R can be taken together to form a 5 to 8-membered ring containing 2-7 carbon atoms, the 5 to 8-membered ring optionally substituted with zero to 3 substituents selected from the group Ci- C4 lower alkyl, d-C4 lower alkoxy, d-C4 lower alkylamino, d-C4 lower dialkylamino, amino, hydroxyl, hydroxymethyl, methoxymethyl, phenyl, substituted phenyl, benzyl, substituted benzyl; U and V are each independently a bond, O or NR6; R5 R6 and R6a are each independently Cι-C6 alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 cycloalkenyl, C3-C6 alkynyl, and H; R7 and R8 are each independently H, d-C4 lower alkyl, or are taken together to form a saturated C3-C6 carbocyclic ring; Rf is d-C4 straight or branched lower perfluoroalkyl; all lower alkyl, alkenyl and alkynyl groups including those linked via heteroatoms can be straight chain or branched; m is 0, 1, or 2; n is 0, 1, 2, 3, 4, 5, or 6; o is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; and q is O, 1, 2, 3, 4, 5, or 6; with the provisos that when A is a bond or O, B is P(0)(OR3)(OR4), and D is selected from the group H, OH, OCOCHs, and NH2, and when R1 = R2 and R3 = R4, and both are selected from the group H or unsubstituted Cι-C lower alkyl, and E and G are bonds, and F is (CH2)n where n is 0, and both Ar1 and Ar2 are phenyl, then at least one of Y1, Y2, Z1, or Z2 must not be H; and when A is a bond or CH2, and B is P(0)(OR3)(OR4), and either D is H or d-C4 lower alkyl where L is CH2, or D is absent, with L— C taken together represent an ethenylidene group, and Ar1 is phenyl, and E is a bond or O, and R1 = R2 and R3 = R4, and both are drawn from the group H or Cι-C6 unsubstituted lower alkyl, then one of Y1 and Y2 must be other than H or unsubstituted d-C lower alkyl or unsubstituted Cι-C4 lower alkoxy; and when A is O, and B is H or P(0)(OR3)(OR4), and R1, R2, R3, and R4 are all selected from the group H or Cι-C6 unsubstituted lower alkyl, and D is H, and L is a bond, and Ar1 is phenyl, and E is other than a bond or O, then one of Y1 or Y2 must be other than H, or d-C4 unsubstituted lower alkyl or d-C4 unsubstituted lower alkoxy; or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a compound known to be effective for regulating HDL or LDL levels.
29. A method of treating disease states related to HDL or LDL cholesterol levels comprising administering to a mammal in need of such freatment a therapeutically effective amount of a pharmaceutical formulation comprising a compound of the formula (I): 
wherein A is a bond, O, CH2, CHF, CF , or NR6; B is H, d-C6 lower alkyl, or P(=X1)(UR3)(VR4); D is a) H or lower alkyl, wherein the L~C bond is a single bond; or b) OH, OCOR5, NH2, NR6R6a, or NHCOR5, wherein the L^C bond is a single bond, with the proviso that A is CH2, CHF, CF2; L is a) NR6, CR7R8, -OCR7R8-, -NR6CR7R8-, or -S(0)mCR7R8-, wherein the L^C bond is a single bond; or b) CR7, whenin the L— C bond is a double bond, with the proviso that D is absent when the L— C bond is a double bond; or c) absent, wherein C is covalently bonded by a single bond to Ar ; Ar1 and Ar2 are each independently mono- or bicyclic aromatic rings of 5-12 atoms, including, but not limited to phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyπolyl, imidazyl, pyrazolyl, oxazolyl, isoxoazolyl, thiazolyl, isothiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,3- triazolyl, 1,3,4-triazolyl, 1,2,4-triazinyl, 1,3,5-triazinyl, benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazyl, benzoxazoyl, benzoisozazolyl, benzothiazoyl, benzoisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridyl, or purinyl; Y1, Y2, and Z1 are each independently a lone electron pair, H, d-Cβ lower alkyl, C2- C6 lower alkenyl, C2-C6 lower alkynyl, Cι-C6 lower alkoxy, Cι-C6 lower alkylamino, Ci-Cβ lower dialkylamino, C2-C6 lower cycloalkyl, C4-C6 lower cycloalkenyl, d-Gs lower thioalkyl, Cι-C6 lower sulfmylalkyl, d-Cβ lower sulfonylalkyl, d-Cό lower acyloxy, Ci-Cβ lower acylamino with N substituted with R6, CH2OR5, CH2NR6R6a, Rf, R OH, NH2, CN, N02, F, CI, Br, I, or N3; E is a bond, S(0)m, NR6, CO, C02, CONR6, O, -OCO, NR6C=0, NR6C02, OC=ONR6, OC02, orNR6CONR6a;
F is (CH2)n, (CH2)00(CH2)p, (CH2)0NR6(CH2)P, (CH2)0NR6CO(CH2)p, (CH2)0CONR6 (CH2)P, (CH2)0(CR6=CR6)q(CH2)p, (CH2)0-(C ^€)q-(CH2)p;
G is a bond, O, NR6, CO, C02, OCO, OC02, S(0)m, CONR6, NR6CO, NR6C02, OCONR6, NR6CONR6a, or G can optionally be attached to Ar2 at two contiguous C atoms to form a 5- to 7-membered partially saturated ring, which contains 0, 1, or 2 heteroatoms selected from the group consisting of O, N, and S;
X, X1 are independently O or S
Z2 is nothing, H or Ar1 optionally substituted with Y1 and Y2; R1, R2, R3, and R4, are each independently selected from H, Cι-C6 lower alkyl, C3-C6 lower alkenyl, C3-C6 lower alkynyl, C3-C6 lower cycloalkyl, C4-C6 lower cycloalkenyl, or independently R1 and R2 or R3 and R4 can be taken together to form a 5 to 8-membered ring containing 2-7 carbon atoms, the 5 to 8-membered ring optionally substituted with zero to 3 substituents selected from the group d- C4 lower alkyl, d-C4 lower alkoxy, d-C4 lower alkylamino, d-C4 lower dialkylamino, amino, hydroxyl, hydroxymethyl, methoxymethyl, phenyl, substituted phenyl, benzyl, substituted benzyl;
U and V are each independently a bond, O or NR ;
R5 R6 and R6a are each independently d-Cδ alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 cycloalkenyl, C3-C6 alkynyl, and H; R7 and R8 are each independently H, Cι-C4 lower alkyl, or are taken together to form a saturated C3-C6 carbocyclic ring; Rf is Cι-C4 straight or branched lower perfluoroalkyl; all lower alkyl, alkenyl and alkynyl groups including those linked via heteroatoms can be straight chain or branched; m is O, 1, or 2; n is O, 1, 2, 3, 4, 5, or 6; o is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; and q is 0, 1, 2, 3, 4, 5, or 6; with the provisos that when A is a bond or O, B is P(0)(OR3)(OR4), and D is selected from the group H, OH, OCOCHj, and NH2, and when R1 = R2 and R3 = R4, and both are selected from the group H or unsubstituted d-C4 lower alkyl, and E and G are bonds, and F is (CH2)n where n is 0, and both Ar1 and Ar2 are phenyl, then at least one of Y1, Y2, Z1, or Z must not be H; and when A is a bond or CH2, and B is P(0)(OR3)(OR4), and either D is H or d-C4 lower alkyl where L is CH2, or D is absent, with L— C taken together represent an ethenylidene group, and Ar1 is phenyl, and E is a bond or O, and R1 = R2 and R3 = R4, and both are drawn from the group H or d-C6 unsubstituted lower alkyl, then one of Y1 and Y2 must be other than H or unsubstituted d-C4 lower alkyl or unsubstituted d-d lower alkoxy; and when A is O, and B is H or P(0)(OR3)(OR4), and R1, R2, R3, and R4 are all selected from the group H or Cι-C6 unsubstituted lower alkyl, and D is H, and L is a bond, and Ar1 is phenyl, and E is other than a bond or O, then one of Y1 or Y2 must be other than H, or d-C4 unsubstituted lower alkyl or d-C4 unsubstituted lower alkoxy; or pharmaceutically acceptable salt thereof; a pharmaceutically acceptable carrier, excipient, solvent, adjuvant or diluent; and optionally, a therapeutically effective amount of a compound known to be effective for regulating HDL or LDL levels.
30. The method according to any of Claims 27-29, wherein the mammal is a human.
31. The method according to any of Claims 27-29, wherein the effective amount is administered in a dosage of between about 0.1 mg to about 5000 mg per day.
32. The method according to any of Claims 27-29, wherein the effective amount comprises a dosage of between about 50 mg to about 500 mg per day.
33. The method according to any of Claims 27-29, wherein the effective amount ofthe pharmaceutical formulation is administered orally.
34. The method according to any of Claims 27-29, wherein the effective amount ofthe pharmaceutical formulation is administered depot injection.
35. The method according to Claim 28, wherein the compound known to be effective for regulating HDL or LDL levels is selected from the group consisting of statins, fibrates, bile acid sequestrants, and cholesterol uptake inhibitors.
36. The method according to Claim 35, wherein the compound known to be effective for regulating HDL or LDL levels is selected from lovastatin, simvastatin, pravastatin, atorvastatin, cerivastatin, niacin, clofibrate, bezafibrate, gemfibrozil, cholestyramine, phytosteroids, and ezitimibe
37. A method of lowering blood triglyceride levels comprising administering to a mammal in need of such freatment a therapeutically effective amount of a phannaceutical formulation comprising a compound ofthe formula (I):
Y1, Y2, and Z1 are each independently a lone electron pair, H, Cι-C6 lower alkyl, C2- C6 lower alkenyl, C2-C6 lower alkynyl, Cι-C6 lower alkoxy, Cι-C6 lower alkylamino, Cι-C6 lower dialkylamino, C2-C6 lower cycloalkyl, C4-C6 lower cycloalkenyl, d-C6 lower thioalkyl, Ci-C6 lower sulfinylalkyl, Cι-C6 lower sulfonylalkyl, d-C6 lower acyloxy, Cι-C6 lower acylamino with N substituted with R6, CH2OR5, CH2NR6R6a, Rf, RfO, OH, NH2, CN, N02, F, CI, Br, I, or N3; E is a bond, S(0)m, NR6, C=0, C02, CONR6, O, -OCO, NR6C=0, NR6C02, OC=ONR6, OC02, orNR6CONR6a;
F is (CH2)n, (CH2)oO(CH2)p, (CH2)oNR6(CH2)p, (CH2)0NR6CO(CH2)p, (CH2)0CONR6 (CH2)P, (CH2)0(CR6=CR6)q(CH2)p, (CH2)0-(C ^)q-(CH2)p; G is a bond, O, NR6, CO, C02, OCO, OC02, S(0)m, CONR6, NR6CO, NR6C02, OCONR6, NR6CONR6a, or G can optionally be attached to Ar2 at two contiguous C atoms to form a 5- to 7-membered partially saturated ring, which contains 0, 1, or 2 heteroatoms selected from the group consisting of O, N, and S; X, X1 are independently O or S Z2 is nothing, H or Ar1 optionally substituted with Y1 and Y2; R1, R2, R3, and R4, are each independently selected from H, d-C6 lower alkyl, C3-C6 lower alkenyl, C3-Cδ lower alkynyl, C3-C6 lower cycloalkyl, C4-C6 lower cycloalkenyl, or independently R1 and R2 or R3 and R4 can be taken together to form a 5 to 8-membered ring containing 2-7 carbon atoms, the 5 to 8-membered ring optionally substituted with zero to 3 substituents selected from the group Ci- C4 lower alkyl, d-C4 lower alkoxy, d-C4 lower alkylamino, d-C4 lower dialkylamino, amino, hydroxyl, hydroxymethyl, methoxymethyl, phenyl, substituted phenyl, benzyl, substituted benzyl; U and V are each independently a bond, O or NR6; R5 R6 and R6a are each independently d-C6 alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 cycloalkenyl, C3-C6 alkynyl, and H; R7 and R8 are each independently H, Cι-C4 lower alkyl, or are taken together to form a saturated C3-C6 carbocyclic ring; Rf is d-C4 straight or branched lower perfluoroalkyl; all lower alkyl, alkenyl and alkynyl groups including those linked via heteroatoms can be straight chain or branched; m is 0, 1, or 2; n is 0, 1, 2, 3, 4, 5, or 6; o is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; and q is 0, 1, 2, 3, 4, 5, or 6; with the provisos that when A is a bond or O, B is P(0)(OR3)(OR4), and D is selected from the group H, OH, OCOCH3, and NH2, and when R1 = R2 and R3 = R4, and both are selected from the group H or unsubstituted d-C4 lower alkyl, and E and G are bonds, and F is (CH2)n where n is 0, and both Ar1 and Ar2 are phenyl, then at least one of Y1, Y2, Z1, or Z2 must not be H; and when A is a bond or CH2, and B is P(0)(OR3)(OR4), and either D is H or Cι-C4 lower alkyl where L is CH2, or D is absent, with L— C taken together represent an ethenylidene group, and Ar1 is phenyl, and E is a bond or O, and R1 = R2 and R3 = R4, and both are drawn from the group H or Ci-Ce unsubstituted lower alkyl, then one of Y1 and Y2 must be other than H or unsubstituted Cι-C4 lower alkyl or unsubstituted Cι-C4 lower alkoxy; and when A is O, and B is H or P(0)(OR3)(OR4), and R1, R2, R3, and R4 are all selected from the group H or d-C6 unsubstituted lower alkyl, and D is H, and L is a bond, and Ar1 is phenyl, and E is other than a bond or O, then one of Y1 or Y2 must be other than H, or Cι-C4 unsubstituted lower alkyl or Cι-C4 unsubstituted lower alkoxy; or pharmaceutically acceptable salt thereof; a pharmaceutically acceptable caπier, excipient, solvent, adjuvant or diluent; and optionally, a therapeutically effective amount of a compound known to be effective for regulating triglyceride levels.
38. The method of Claim 37, wherein the compound known to be effective for regulating triglyceride levels comprises a fibrate.
39. A method of lowering blood glucose levels comprising administering to a mammal in need of such freatment a therapeutically effective amount of a pharmaceutical formulation comprising a compound ofthe formula (I): 
wherein A is a bond, O, CH2, CHF, CF2, or NR6; B is H, Ci-Cβ lower alkyl, or P(=XJ)(UR3)(VR4); D is a) H or lower alkyl, wherein the L— C bond is a single bond; or b) OH, OCOR5, NH2, NR6R6a, or NHCOR5, wherein the L^C bond is a single bond, with the proviso that A is CH2, CHF, CF2; L is a) NR6, CR7R8, -OCR7R8-, -NR6CR7R8-, or -S(0)mCR7R8-, wherein the L^C bond is a single bond; or b) CR7, whenin the L— C bond is a double bond, with the proviso that D is absent when the L— C bond is a double bond; or c) absent, wherein C is covalently bonded by a single bond to Ar1; Ar1 and Ar2 are each independently mono- or bicyclic aromatic rings of 5-12 atoms, including, but not limited to phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyπolyl, imidazyl, pyrazolyl, oxazolyl, isoxoazolyl, thiazolyl, isothiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,3- friazolyl, 1,3,4-triazolyl, 1,2,4-triazinyl, 1,3,5-triazinyl, benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazyl, benzoxazoyl, benzoisozazolyl, benzothiazoyl, benzoisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridyl, or purinyl; Y1, Y2, and Z1 are each independently a lone electron pair, H, d-C6 lower alkyl, C2- C6 lower alkenyl, C2-C6 lower alkynyl, Cι-C6 lower alkoxy, Cι-C6 lower alkylamino, Cι-C6 lower dialkylamino, C2-C6 lower cycloalkyl, C4-C6 lower cycloalkenyl, Cι-C6 lower thioalkyl, Cι-C6 lower sulfinylalkyl, Cι-C6 lower sulfonylalkyl, Cι-C6 lower acyloxy, Cι-C6 lower acylamino with N substituted with R6, CH2OR5, CH2NR6R6a, Rf, R OH, NH2, CN, N02, F, CI, Br, I, or N3; E is a bond, S(0)m, NR6, C=0, C02, CONR6, O, -OCO, NR6CO, NR6C02, OCONR6, OC02, orNR6CONR6a;
F is (CH2)n, (CH2)00(CH2)p, (CH2)0NR6(CH2)P, (CH2)0NR6CO(CH2)p, (CH2)0CONR6 (CH2)P, (CH2)0(CR6=CR6)q(CH2)p, (CH2)0-(C ^)q-(CH2)p;
G is a bond, O, NR6, CO, C02, OCO, OC02, S(0)m, CONR6, NR6CO, NR6C02, OCONR6, NR6CONR6a, or G can optionally be attached to Ar2 at two contiguous C atoms to form a 5- to 7-membered partially saturated ring, which contains 0, 1, or 2 heteroatoms selected from the group consisting of O, N, and S;
X, X1 are independently O or S
Z 9 is nothing, H or Ar 1 optionally substituted with Y 1 and Y9 ; R1, R2, R3, and R , are each independently selected from H, Cι-C6 lower alkyl, C3-C6 lower alkenyl, C3-C6 lower alkynyl, C3-C6 lower cycloalkyl, C4-C6 lower cycloalkenyl, or independently R and R or R and R can be taken together to form a 5 to 8-membered ring containing 2-7 carbon atoms, the 5 to 8-membered ring optionally substituted with zero to 3 substituents selected from the group d- C4 lower alkyl, d-C4 lower alkoxy, d-C4 lower alkylamino, d-C4 lower dialkylamino, amino, hydroxyl, hydroxymethyl, methoxymethyl, phenyl, substituted phenyl, benzyl, substituted benzyl; U and V are each independently a bond, O or NR ;
R5 R6 and R6a are each independently Cι-C6 alkyl, C3-C6 cycloalkyl, C3-C6 alkenyl, C3-C6 cycloalkenyl, C3-C6 alkynyl, and H; R7 and R8 are each independently H, d-C4 lower alkyl, or are taken together to form a saturated C3-C6 carbocyclic ring; Rf is d-C straight or branched lower perfluoroalkyl; all lower alkyl, alkenyl and alkynyl groups including those linked via heteroatoms can be straight chain or branched; m is 0, 1, or 2; n is O, 1, 2, 3, 4, 5, or 6; o is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; and q is 0, 1, 2, 3, 4, 5, or 6; with the provisos that when A is a bond or O, B is P(0)(OR3)(OR4), and D is selected from the group H, OH, OCOCH3, and NH2, and when R1 = R2 and R3 = R4, and both are selected from the group H or unsubstituted d-C4 lower alkyl, and E and G are bonds, and F is (CH2)n where n is 0, and both Ar1 and Ar2 are phenyl, then at least one of Y1, Y2, Z1, or Z2 must not be H; and when A is a bond or CH2, and B is P(0)(OR3)(OR4), and either D is H or CrC lower alkyl where L is CH2, or D is absent, with L" C taken together represent an ethenylidene group, and Ar1 is phenyl, and E is a bond or O, and R1 = R2 and R3 = R4, and both are drawn from the group H or Cι-C6 unsubstituted lower alkyl, then one of Y 1 and Y 9 must be other than H or unsubstituted d-C4 lower alkyl or unsubstituted Cι-C4 lower alkoxy; and when A is O, and B is H or P(0)(OR3)(OR4), and R1, R2, R3, and R4 are all selected from the group H or Cι-C6 unsubstituted lower alkyl, and D is H, and L is a bond, and Ar1 is phenyl, and E is other than a bond or O, then one of Y1 or Y2 must be other than H, or d-C4 unsubstituted lower alkyl or Cι-C4 unsubstituted lower alkoxy; or pharmaceutically acceptable salt thereof; a pharmaceutically acceptable carrier, excipient, solvent, adjuvant or diluent; and optionally, a therapeutically effective amount of a compound known to be effective for regulating glucose levels.
40. The method of Claim 39, wherein the compound known to be effective for regulating glucose levels is selected from rosiglitazone, pioglitazone, insulin, and metformin.
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| Application Number | Priority Date | Filing Date | Title |
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| US50242003P | 2003-09-12 | 2003-09-12 | |
| US60/502,420 | 2003-09-12 |
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| WO2005028488A1 true WO2005028488A1 (en) | 2005-03-31 |
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| PCT/US2004/029701 WO2005028488A1 (en) | 2003-09-12 | 2004-09-10 | Heteroaryl phosphinyl and thiophosphinyl compounds for regulation of glucose, triglycerides, and ldl/hdl levels |
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| WO2014011926A1 (en) | 2012-07-11 | 2014-01-16 | Elcelyx Therapeutics, Inc. | Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk |
| US9663486B2 (en) | 2013-10-14 | 2017-05-30 | Eisai R&D Management Co., Ltd. | Selectively substituted quinoline compounds |
| US10087174B2 (en) | 2013-10-14 | 2018-10-02 | Eisai R&D Management Co., Ltd. | Selectively substituted quinoline compounds |
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| US11202789B2 (en) | 2016-11-21 | 2021-12-21 | Viking Therapeutics, Inc. | Method of treating glycogen storage disease |
| US11707472B2 (en) | 2017-06-05 | 2023-07-25 | Viking Therapeutics, Inc. | Compositions for the treatment of fibrosis |
| US11787828B2 (en) | 2018-03-22 | 2023-10-17 | Viking Therapeutics, Inc. | Crystalline forms and methods of producing crystalline forms of a compound |
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| US7829552B2 (en) | 2003-11-19 | 2010-11-09 | Metabasis Therapeutics, Inc. | Phosphorus-containing thyromimetics |
| US10130643B2 (en) | 2005-05-26 | 2018-11-20 | Metabasis Therapeutics, Inc. | Thyromimetics for the treatment of fatty liver diseases |
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| US9663486B2 (en) | 2013-10-14 | 2017-05-30 | Eisai R&D Management Co., Ltd. | Selectively substituted quinoline compounds |
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| US10087174B2 (en) | 2013-10-14 | 2018-10-02 | Eisai R&D Management Co., Ltd. | Selectively substituted quinoline compounds |
| US11202789B2 (en) | 2016-11-21 | 2021-12-21 | Viking Therapeutics, Inc. | Method of treating glycogen storage disease |
| US11707472B2 (en) | 2017-06-05 | 2023-07-25 | Viking Therapeutics, Inc. | Compositions for the treatment of fibrosis |
| US11787828B2 (en) | 2018-03-22 | 2023-10-17 | Viking Therapeutics, Inc. | Crystalline forms and methods of producing crystalline forms of a compound |
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