AU2006202624A1

AU2006202624A1 - Novel bisamidate phosphonate prodrugs

Info

Publication number: AU2006202624A1
Application number: AU2006202624A
Authority: AU
Inventors: Tao Jiang; Srinivas Rao Kasibhatla; K. Raja Reddy
Original assignee: Metabasis Therapeutics Inc
Current assignee: Metabasis Therapeutics Inc
Priority date: 1999-12-22
Filing date: 2006-06-20
Publication date: 2006-07-20
Anticipated expiration: 2020-12-22
Also published as: AU2006202624B2

Description

S&F Ref: 597542D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Metabasis Therapeutics, Inc., of 9390 Towne Centre Drive, San Diego, California, 92121, United States of America Tao Jiang Srinivas Rao Kasibhatla K. Raja Reddy Spruson Ferguson St Martins Tower Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Novel bisamidate phosphonate prodrugs The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c NOVEL BISAMIDATE PHOSPHONATE PRODRUGS Field of the Invention The present invention is directed towards novel prodrugs, to their preparation, to their use for the oral delivery of Fructose-1,6-bisphosphatase inhibitors (FBPase), and to their use in the treatment of diabetes and other diseases where the inhibition of gluconeogenesis, control of blood glucose levels, reduction in glycogen storage, or reduction in insulin levels is beneficial.

Background of the Invention Organic compounds that are charged at physiological pH frequently exhibit limited oral bioavailability, cell penetration, and tissue distribution CNS). These properties are attributed to the failure of ionic compounds to cross cell membranes by passive diffusion.

One strategy to circumvent this problem is to prepare lipophilic prodrugs which are capable of crossing cell membranes and subsequently undergoing a transformation to generate the charged compound. The transformation could result from either chemical instability or an enzyme-catalyzed reaction.

A large number of structurally-diverse prodrugs are described for phosphonic acids.

Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997). The most commonly used prodrug class is the acyloxyalkyl ester, which was first used as a prodrug strategy for carboxylic acids and then applied to phosphates in 1983 by Farquhar et al. J Pharm. Sci. 72: 324 (1983). Subsequently, the acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bioavailability. A close variant of the acyloxyalkyl ester strategy, the alkoxycarbonyloxyalkyl ester, is also reported to enhance oral bioavailability.

Much less success has been achieved with other classes ofphosphonate prodrugs.

Aryl esters, especially phenyl esters, are reported in a few cases to enhance oral bioavailability. DeLambert et al., J. Med. Chem. 37: 498 (1994). Phenyl esters containing a carboxylic ester ortho to the phosphate have also been described. Khamnei and Torrence, J Med. Chem. 39:4109-4115 (1996). Benzyl esters are reported to generate the parent phosphonic acid. In some cases using substituents at the ortho- orpara-position can accelerate the hydrolysis. Benzyl analogs with an acylated phenol or an alkylated phenol can generate the phenolic compound through the action of enzymes, e.g. esterases, oxidases, etc., which in turn undergoes cleavage at the benzylic C-O bond to generate the phosphoric acid and the quinone methide intermediate. Examples of this class of prodrugs are described by Mitchell et al., J Chem. Soc. Perkin Trans. 12345 (1992); Brook, et al. WO 91/19721. Still other benzylic prodrugs have been described containing a carboxylic ester-containing group attached to the benzylic methylene. Glazier et al. WO 91/19721. Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide. Desterification or reduction of the disulfide generates the free thio intermediate which subsequently breaks down to the phosphoric acid and episulfide. Puech et al., Antiviral Res., 22: 155-174 (1993); Benzaria, et al., J. Med. Chem. 39: 4958 (1996). Cyclic phosphonate esters have also been described as prodrugs of phosphorus-containing compounds.

Some phosphoramidates are also known prodrugs of phosphonates, but they have shown poor oral bioavailability. In some cases the phosphoramidates were very unstable under acidic conditions which was reported as a potential explanation for their poor oral bioavailability (J Med. Chem., 37: 1857-1864 (1994)). Similarly, poor oral bioavailability was reported for a bisamidate of a PMEA analog Med. Chem., 38: 1372-1379 (1995)).

Another PMEA prodrug consists of a mono glycine ester amidate and a phenyl ester (WO 95/07920).

Although numerous phosphoric acid prodrug strategies are reported to achieve high intracellular delivery of phosphoric acids, few are known to result in good oral bioavailability.

In some cases, the prodrugs are unstable to the gastrointestinal tract environment (low pH, esterase activity). In other cases the prodrugs are too stable and are therefore poorly transformed in vivo to the parent drug.

WO 98/39344, WO 98/39343, WO 98/139342, and WO 00/14095 describe compounds containing phosphoric acids and esters that inhibit fructose-1,6-bisphosphatase.

The entire disclosures of the publication and references referred to above and hereafter in this specification are incorporated herein by reference and are not admitted to be prior art.

Summary of the Invention The present invention is directed towards novel bisamidate phosphonates that are potent FBPase inhibitors. In one aspect these compounds possess superior oral bioavailability compared to the corresponding phosphonic acids. In another aspect, the present invention is directed to the in vitro and in vivo FBPase inhibitory activity of these compounds. Another aspect of the present invention is directed to the clinical use of these FBPase inhibitors as a method of treatment or prevention of diseases responsive to inhibition of gluconeogenesis and in diseases responsive to lowered blood glucose levels.

In another aspect, the compounds are also useful in treating or preventing excess glycogen storage diseases and diseases such as cardiovascular diseases including atherosclerosis, myocardial ischemic injury, and diseases such as metabolic disorders such as hypercholesterolemia, hyperlipidemia which are exacerbated by hyperinsulinema and hyperglycemia.

The invention also comprises the novel compounds and methods of using them as specified below in formulae I, X, and XI. Also included in the scope of the present invention are standard salts and prodrugs of the compounds of formulae I, X, and XI.

0 RI 0 R 8 R N-CR

X

2

-N-(CR

2 R NRsR 1 8

NR

15 Rl E2 2 Formula I Formula X

A

3 I 0

R

18 L 3

Y

Formula XI Since these compounds may have asymmetric centers, the present invention is directed not only to racemic mixtures of these compounds, but also to individual stereoisomers. The present invention also includes pharmaceutically acceptable and/or useful salts of the compounds of formulae I, X, and XI, including acid addition salts. The present inventions also encompass standard prodrugs of compounds of formulae I, X, and XI.

DETAILED DESCRIPTION OF THE INVENTION Definitions In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.

X, X 2 and X 3 group nomenclature as used herein in formulae I and XI describes the group attached to the phosphonate and ends with the group attached to the heteroaromatic ring. For example, when X is alkylamino, the following structure is intended: (heteroaromatic ring)-NR-alk-P(O)(NR 15 RI )(NR 18 -(CR1 2 R1 3 )n-(C(O)-R14) Likewise, A, B, C, D, E, A 2

L

2

E

2

J

2

A

3

L

3

E

3 and j 3 groups and other substituents of the heteroaromatic ring are described in such a way that the term IL ends with the group attached to the heteroaromatic ring. Generally, substituents are named O 5 such that the term ends with the group at the point of attachment. A hyphen before or after a kLO term indicates a point of attachment. For example, "-alkyl-" refers to divalent alkcyl or alkylene.

SThe term "aryl" refers to aromatic groups which have 5-14 ring atoms and at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted. Suitable aryl groups include phenyl and Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds such as optionally substituted naphthyl groups.

Heterocyclic aryl or heteroaryl groups are groups having from 1 to 4 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms.

Suitable heteroatoms include oxygen, sulfur, nitrogen, and selenium. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, and the like, all optionally substituted.

The term "annulation" or "annulated" refers to the formation of an additional cyclic moiety onto an existing aryl or heteroaryl group. It is a form of optional substitution on an aryl or heteroaryl group. The newly formed ring may be carbocyclic or heterocyclic, saturated or unsaturated, and contains 2-9 new atoms of which 0-3 may be heteroatoms taken from the group of N, 0, and S. The annulation may incorporate atoms from the X group as part of the newly formed ring. For example, the phrase "together L 2 and E 2 form an annulated cyclic group", includes G oN D HN

I

SNR

15

R

16 The term "biaryl" represents aryl groups containing more than one aromatic ring including both fused ring systems and aryl groups substituted with other aryl groups. Such groups may be optionally substituted. Suitable biaryl groups include naphthyl and biphenyl.

The term "alicyclic" means compounds which combine the properties of aliphatic and cyclic compounds. Such cyclic compounds include but are not limited to, aromatic, cycloalkyl and bridged cycloalkyl compounds. The cyclic compounmd includes heterocycles.

Cyclohexenylethyl and cyclohexylethyl are suitable alicyclic groups. Such groups may be optionally substituted.

The term "optionally substituted" or "substituted" includes groups substituted by one to four substituents, independently selected from lower alkyl, lower aryl, lower aralkyl, lower alicyclic, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, heteroaryl, heterocyclic alkyl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino, guanidino, amidino, halo, lower alkylthio, oxo, acylalkyl, carboxy esters, carboxyl, -carboxamido, nitro, acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino, aralkcylamino, phosphono, sulfonyl, -carboxamidoalkylaryl, -carboxamidoaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy-, aminocarboxamidoalkyl-, cyano, lower alkoxyalkyl, lower perhaloalkyl, and arylalkyloxyalkyl. "Substituted aryl" and "substituted heteroaryl" refer to aryl and heteroaryl groups substituted with 1-2; 1-3; or 1-4 substituents. In one aspect, suitable substituents of aryl groups include lower alkyl, lower alkoxy, lower O perhaloalkyl, halo, hydroxy, and amino. "Substituted" when describing an R 5 group does not include annulation.

The term "aralkyl" refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted. The 5 term "-aralkyl-" refers to a divalent group -aryl-alkylene-. "Heteroarylalkyl" refers to an alkylene group substituted with a heteroaryl group.

IND The term "-alkylaryl-" refers to the group -alk-aryl- where "alk" is an alkylene group.

"Lower -alkylaryl-" refers to such groups where alkylene is lower alkylene.

The term "lower" referred to herein in connection with organic radicals or compounds respectively defines such as with up to and including 10, or up to and including 6, or one to four carbon atoms. Such groups may be straight chain, branched, or cyclic.

The terms "arylamino" and "aralkylamino" respectively, refer to the group -NRR' wherein respectively, R is aryl and R' is hydrogen, alkyl, aralkyl or aryl, and R is aralkyl and R' is hydrogen or aralkyl, aryl, alkyl.

The term "acyl" refers to -C(0)R where R is alkyl and aryl.

The term "carboxy esters" refers to -C(O)OR where R is alkyl, aryl, aralkyl, and alicyclic, all optionally substituted.

The term "carboxyl" refers to -C(O)OH.

The term "oxo" refers to =0 in an alkyl group.

The term "amino" refers to -NRR 1 where R and R' are independently selected from hydrogen, alkyl, aryl, aralkyl and alicyclic, all except H are optionally substituted; and R and R' can form a cyclic ring system.

The term "carbonylamino" and "-carbonylamino-" refers to RCONR- and -CONR-, respectively, where each R is independently hydrogen or alkyl.

The term "halogen" or "halo" refers to -Cl, -Br and -I.

The term "-oxyalkylamino-" refers to -O-alk-NR-, where "alk" is an alkylene group and R is H or alkyl.

O The term "-alkylaminoalkylcarboxy-" refers to the group -alk-NR-alkc-C(O)-0 where "alk" is an alkylene group, and R is a H or lower alkyl.

The term "-alkylaminocarbonyl-" refers to the group -alk-NR-C(O)- where "alk" is an alkylene group, and R is a H or lower alkyl.

The term "-oxyalkyl-" refers to the group -O-alk- where "alk" is an alkylene group.

The term "-alkylcarboxyalkyl-" refers to the group -alk-C(O)-O-alk- where each alk is independently an alkylene group.

The term "alkyl" refers to saturated aliphatic groups including straight-chain, branched chain and cyclic groups. Alkyl groups may be optionally substituted. Suitable alkyl groups include methyl, isopropyl, and cyclopropyl.

The term "cyclic alkyl" or "cycloalkyl" refers to alkyl groups that are cyclic groups of 3 to 6; or 3 to 10 atoms. Suitable cyclic groups include norbomyl and cyclopropyl. Such groups may be substituted.

The term "heterocyclic" and "heterocyclic alkyl" refer to cyclic groups of 3 to 6; or 3 to 10 atoms, containing at least one heteroatom. In one aspect, these groups contain 1 to 3 heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic groups may be attached through a nitrogen or through a carbon atom in the ring. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl. Such groups may be substituted.

The term "phosphono" refers to -P0 3

R

2 where R is selected from the group consisting of-H, alkyl, aryl, aralkyl, and alicyclic.

The term "sulphonyl" or "sulfonyl" refers to -SO 3 R, where R is H, alkyl, aryl, aralkyl, and alicyclic.

The term "alkenyl" refers to unsaturated groups which contain at least one carboncarbon double bond and includes straight-chain, branched-chain and cyclic groups. Alkenyl groups may be optionally substituted. Suitable alkenyl groups include allyl. "1-alkenyl" refers to alkenyl groups where the double bond is between the first and second carbon atom.

If the 1-alkenyl group is attached to another group, e.g. it is a W substituent attached to the cyclic phosph(oramid)ate, it is attached at the first carbon.

The term "alkynyl" refers to unsaturated groups which contain at least one carboncarbon triple bond and includes straight-chain, branched-chain and cyclic groups. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl. "l-alkynyl" refers to alkynyl groups where the triple bond is between the first and second carbon atom. If the 1-alkynyl group is attached to another group, it is attached at the first carbon.

The term "alkylene" refers to a divalent straight chain, branched chain or cyclic saturated aliphatic group.

The term "-cycloalkylene-COOR 3 refers to a divalent cyclic alkyl group or heterocyclic group containing 4 to 6 atoms in the ring, with 0-1 heteroatoms selected from 0, N, and S. The cyclic alkyl or heterocyclic group is substituted with -COOR 3 The term "acyloxy" refers to the ester group where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or alicyclic.

The term "aminoalkyl-" refers to the group NR 2 -alk- wherein "alk" is an alkylene group and R is selected from H, alkyl, aryl, aralkyl, and alicyclic.

The term "-alkyl(hydroxy)-" refers to an -OH off the alkyl chain. When this term is an X group, the -OH is at the position a to the phosphorus atom.

The term "alkylaminoalkyl-" refers to the group alkyl-NR-alk- wherein each "alk" is an independently selected alkylene, and R is H or lower alkyl. "Lower alkylaminoalkyl-" refers to groups where each alkylene group is lower alkylene.

The term "arylaminoalkyl-" refers to the group aryl-NR-alk- wherein "alk" is an alkylene group and R is H, alkyl, aryl, aralkyl, and alicyclic. In "lower arylaminoalkyl-", the alkylene group is lower alkylene.

The term "alkylarninoaryl-" refers to the group alkyl-NR-aryl- wherein "aryl" is a divalent group and R is H, alkyl, aralkyl, and alicyclic. In "lower alkylaminoaryl-", the alkylene group is lower alkyl.

The term "alkyloxyaryl-" refers to an aryl group substituted with an alkyloxy group.

In "lower atkyloxyaryl-", the alkyl group is lower alkcyl.

The term "aryloxyalkyl-" refers to an alkcyl group substituted with an aryloxy group.

The term "aralkcyloxyalkyl-" refers to the group aryl-alk-O-alk- wherein "allc" is an alkylene group. "Lower aralkyloxyalkyl-" refers to such groups where the alkylene groups are lower alkylene.

The term "-alkoxy-" or "-alkyloxy-" refers to the group -alk-O- wherein "alkc" is an atkylene group. The teirm "ailcoxy-" refers to the group alkyl-O-.

The term "-alkoxyaLkyl-" or "-alkyloxyalkyl-" refer to the group -alk-O-alk- wherein each "alk" is an independently selected alkylene group. In "lower -alkoxyalkyl-", each alicylene is lower alkylene.

The terms "alkylthio-" and "-allkylthio-" refer to the groups alkyl-S-, and -All-S-, respectively, wherein "alk" is alkylene group.

The term "-alkcylthioalkyl-" refers to the group -allc-S-alk- wherein each "alk" is an independently selected alkylene group. In "lower -alkylthioalkyl each alcylene is lower alkylene.

The term "alkoxycarbonyloxy-" refers to alkyl-O-C(O)-O-.

The term "aryloxycarbonyloxy-" refers to aryl-O-C(O)-O-.

The term "alkyithiocarbonyloxy-" refers to alkyl-S-C(O)-O-.

The term "-alkoxycarbonylamino-" refers to -alk-O-C(O)-NR' -,where "allc" is alkytene and R1, includes alkyl, aryl, alicyclic, and aralkyl.

The term -alkylamninocarbonylamino" refers to -alk-NR 1-C(O)-NR 1 where "alk" is alkylene and R1 is independently selected from H, alkyl, aryl, aralkcyl, and alicyclic The terms "amnido" or "carboxamaido" refer to NR 2 and where R and R 1 include H, alkyl, aryl, aralkyl, and alicyclic. The term does not include urea,

-NR-C(O)-NR-.

The terms "carboxamidoalkylaryl" and "carboxamidoaryl" refers to an aryl-alk-NR 1 and ar-NR'-C(O)-alk-, respectively, where "ar" is aryl, and "alk" is alkylene, R 1 and R include H, alkyl, aryl, aralkyl, and alicyclic.

The term "-alkylcarboxamido-" or "-alkylcarbonylamino-" refers to the group -alk-C(O)N(R)- wherein "alk" is an alkylene group and R is H or lower alkyl.

The term "-alkylaminocarbonyl-" refers to the group -alk-NR-C(O)- wherein "alk" is an alkylene group and R is H or lower alkyl.

The term "aminocarboxamidoalkyl-" refers to the group NR 2 wherein R is an alkyl group or H and "alk" is an alkylene group. "Lower aminocarboxamidoalkyl-" refers to such groups wherein "alk" is lower alkylene.

The term "thiocarbonate" refers to either in a chain or in a cyclic group.

The term "hydroxyalkyl" refers to an alkyl group substituted with one -OH.

The term "haloalkyl" refers to an alkyl group substituted with one halo, selected from the group I, Cl, Br, F.

The term "cyano" refers to -C=N.

The term "nitro" refers to -NO 2 The term "acylalkyl" refers to an alkyl-C(O)-alk-, where "alk" is alkylene.

The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group.

The term "-1,1-dihaloalkyl-" refers to an X group where the 1 position and therefore halogens are a to the phosphorus atom.

The term "perhalo" refers to groups wherein every C-H bond has been replaced with a C-halo bond on an aliphatic or aryl group. Suitable perhaloalkyl groups include -CF 3 and -CFC1 2 The term "guanidino" refers to both -NR-C(NR)-NR 2 as well as -N=C(NR 2 2 where each R group is independently selected from the group of-H, alkyl, alkenyl, alkynyl, aryl, and alicyclic, all except -H are optionally substituted.

The term "bidentate" refers to an alkyl group that is attached by its terminal ends to the same atom to form a cyclic group. For example, propylene amine contains a bidentate propylene group.

The term "naturally occurring amino acid" refers to alpha amino acids containing at least one hydrogen at the alpha carbon and when the alpha carbon is chiral, it has S absolute configuration.

The term "amidino" refers to -C(NR)-NR 2 where each R group is independently selected from the group of-H, alkyl, alkenyl, alkynyl, aryl, and alicyclic, all except -H are optionally substituted.

The term "pharmaceutically acceptable salt" includes salts of compounds of formula IA and its prodrugs derived from the combination of a compound of this invention and an organic or inorganic acid or base. Suitable acids include hydrochloric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and maleic acid.

The term "prodrug" as used herein refers to any compound that when administered to a biological system generates the "drug" substance (a biologically active compound) as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s). Standard prodrugs are formed using groups attached to functionality, e.g. HO-, HS-, HOOC-, R 2 associated with the FBPase inhibitor, that cleave in vivo. Standard prodrugs include, but are not limited to, carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate. The groups illustrated are exemplary, not exhaustive, and one skilled in the art could prepare other known varieties of prodrugs. Such prodrugs of the compounds of formulae I, X, and XI, fall within the scope of the present invention.

Prodrugs must undergo some form of a chemical transformation to produce the compound that is biologically active or is a precursor of the biologically active compound. In some cases, the prodrug is biologically active usually less than the drug itself, and serves to improve efficacy or safety through improved oral bioavailability, pharmacodynamic half-life, etc.

Phosphoramidate derivatives have been explored as phosphate prodrugs (e.g.

McGuigan et al., J. Med. Chem., 1999, 42: 393 and references cited therein) and phosphonate prodrugs (Bischofberger, et al., U.S. 5,798,340 and references cited therein) as shown in Formulae G and H.

0 C0 2 -alkyl 1_J0& NH R' -P-0 I R'R" Hi R"

HN

R" CO 2 R R" C0 2 -alkyl R'

R'

Formula G Formula H Cyclic phosphoramidates have also been studied as phosphonate prodrugs because of their speculated higher stability compared to non-cyclic phosphoramidates Starrett et al., J. Med. Chem., 1994, 37:1857).

Another type of nucleotide prodrug was reported as the combination of S-acyl-2thioethyl ester and phosphoramidate (Egron et al., Nucleosides Nucleotides, 1999,18, 981) as shown in Formula J.

A 0 S-O Sk

R

V-COi-aky Formula J The term "enhancing" refers to increasing or improving a specific property.

The term "enhanced oral bioavailability" refers to an increase of at least 50% of the absorption of the dose of the parent drug or prodrug (not of this invention) from the gastrointestinal tract. In one aspect, this increase is at least 100%. Measurement of oral bioavailability usually refers to measurements of the prodrug, drug, or drug metabolite in blood, tissues, or urine following oral administration, compared to measurements following systemic administration.

The term "parent drug" refers to any compound which delivers the same biologically active compound. The parent drug form is M-P(O)(OH) 2 and standard prodrugs, such as 7"l 5 esters.

The term "drug metabolite" refers to any compound produced in vivo or in vitro from Sthe parent drug, which can include the biologically active drug.

The term "pharmacodynamic half-life" refers to the time after administration of the drug or prodrug to observe a diminution of one half of the measured pharmacological response. In one aspect, the half-life is enhanced when the half-life is increased by at least The term "biologically active drug or agent" refers to the chemical entity that produces a biological effect. Thus, active drugs or agents include compounds which as M-P(O)(OH) 2 are biologically active.

The term "inhibitor of fructose-1,6-bisphosphatase" refers to chemical entities M-

PO

3

H

2 that have an ICso of equal to or less than 50 p.M on human liver FBPase.

The term "therapeutically effective amount" refers to an amount that has any beneficial effect in treating a disease or condition.

Compounds Suitable alkyl groups include groups having from I to about 20 carbon atoms.

Suitable aryl groups include groups having from 1 to about 20 carbon atoms. Suitable arallcyl groups include groups having from 2 to about 21 carbon atoms. Suitable acyloxy groups include groups having from 1 to about 20 carbon atoms. Suitable alkylene groups include groups having from 1 to about 20 carbon atoms. Suitable alicyclic groups include groups having 3 to about 20 carbon atoms. Suitable heteroaryl groups include groups having from 1 to about 20 carbon atoms and from 1 to 4 heteroatoms, independently selected from nitrogen, oxygen, phosphorous, and sulfur. Suitable heteroalicyclic groups include groups having from 2 to about twenty carbon atoms and from 1 to 5 heteroatoms, independently selected from nitrogen, oxygen, phosphorous, and sulfur.

One aspect of the invention is directed to the compound of formula IA 0 R 18 II I 0 M-P-N-(CR R 3 n C O R 4

NR

1 6R 1

(IA)

,1 5 wherein compounds of formula IA are converted in vivo or in vitro to M-PO 3

H

2 which is an inhibitor of fructose -1,6-bisphosphatase and n is an integer from 1 to 3;

R

2 is selected from the group of-H and -R 3

R

3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralcyl; each R 12 and R1 3 is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R 2 and R 3 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of 0, N and S, to form a cyclic group; each R 14 is independently selected from the group consisting of -OR 17

-N(R

7 2

-NHR

17

-NR

2 OR" and -SR";

R

ts is selected from the group consisting of lower alklcyl, lower aryl, lower aralkyl, or together with R 16 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of 0, N, and S;

R

16 is selected from the group consisting of -(CR1 2

R

3 )n-C(O)-R 1 4 lower alkyl, lower aryl, lower aralkyl, or together with R1 5 is connected via 2-6 atoms, optionally including I heteroatom selected from the group consisting of 0, N, and S; each R 17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R 17 and R 17 on N is connected via 2-6 atoms, optionally including I heteroatom selected from the group consisting of O, N, and S;

R

18 is independently selected from.the group consisting of H, lower alkyl, aryl, aralkyl, or together with R 12 is connected via 1-4 carbon atoms to form a cyclic group; each R 19 is independently selected from the group consisting of-H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR 3 and pharmaceutically acceptable salts thereof.

Such compounds converted to M-PO 3

H

2 include compounds that have an ICso on isolated human liver FBPase enzyme of less than or equal to 10 iM. Alternatively, the IC 5 o is less than or equal to 1 j.M. Such compounds may also bind to the AMP site of FBPase.

In one aspect, M is R 5 wherein R 5 is selected from the group consisting of:

J

A A BG and E G,

B

D

wherein: each G is independently selected from the group consisting of C, N, 0, S, and Se, and wherein only one G may be 0, S, or Se, and at most one G is N; each G' is independently selected from the group consisting of C and N and wherein no more than two G' groups are N; A is selected from the group consisting of-H, -NR 2

-CONR

4 2 -C0 2

R

3 halo,

-S(O)R

3 -SO2R 3 alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, -CH 2 OH, -CH 2

NR

4 2

-CH

2 CN, -CN, -C(S)NH 2

-OR

2

-SR

2

-N

3

-NHC(S)NR

4 2 -NHAc, and null; each B and D are independently selected from the group consisting of-H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, -C(O)SR 3

-SO

2

R

1 -S(0)R 3 -CN, -NR 9 2

-OR

3

-SR

3 perhaloalkyl, halo, -NO 2 and null, all except -CN, perhaloalkyl,

-NO

2 and halo are optionally substituted; 0Q_ E is selected from the group consisting of-H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, -C(0)OR 3

-CONR

4 2 -CN, -NR 9 2

-NO

2

-OR

3

-SR

3 perhaloalkyl, halo, and null, all except -CN, perhaloalkyl, and halo are optionally substituted; CN J is selected from the group consisting of -H and null; I 5 X is an optionally substituted linking group that links R 5 to the phosphorus atom via 2-

O

4 atoms, including 0-1 heteroatoms selected from N, 0, and S, except that if X is urea or IND carbamate there is 2 heteroatoms, measured by the shortest path between R 5 and the 0 phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein X is selected from the group consisting of-alkyl(hydroxy)-, -alkynyl-, -heteroaryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X is not substituted with -COOR 2

-SO

3 H, or -PO 3

R

2 2

R

2 is selected from the group consisting of R 3 and -H;

R

3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R 4 is independently selected from the group consisting of and alkyl, or together R 4 and R 4 form a cyclic alkyl group; each R 9 is independently selected from the group consisting of alkyl, aryl, aralkyl, and alicyclic, or together R 9 and R 9 form a cyclic alkyl group;

R

11 is selected from the group consisting of alkyl, aryl, -NR 2, and -OR 2 and with the proviso that: 1) when G' is N, then the respective A, B, D, or E is null; 2) at least one of A and B, or A, B, D, and E is not selected from the group consisting of-H or null; 3) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom; and pharmaceutically acceptable salts thereof.

In one aspect, the following additional provisos may apply: 4) when R 5 is a six-membered ring, then X is not any 2 atom linker, an optionally substituted-alkyloxy-, or an optionally substituted-alkylthio-; when X is not a -heteroaryl- group, then R 5 is not substituted with two or more aryl groups.

In one aspect of the present invention, compounds of formula IA have an ICso of 50 uM on glucose production in isolated rat hepatocytes.

In one aspect, compounds of formula IA can be selected from those compounds where M is attached to 0 CH3 P- NH---COOR 2

CH

3 or 0 CH 3 P- NH--*COOR17 114 2

H

wherein R 1 7 is selected from the group consisting of ethyl, i-propyl, n-propyl and neopentyl and wherein C* has S stereochemistry.

In thiazoles where A" is -NH 2 X is furan-2,5-diyl, B" is -S(CH2) 2 CH3; or where A" is

-NH

2 D is furan-2,5-diyl, B" is -CH 2

-CH(CH

3 2 then M may be attached to 0 CH3 P- NH--COOR 17

CH

3 or wherein R 1 7 is selected from the group consisting of ethyl, i-propyl, n-propyl and neopentyl and wherein has S stereochemistry.

In one aspect, the compounds of formula IA can be selected from: 0 R 18 0 0R 18 11 11 12 13

RS-C--NH-CH

2 -P-N-(CR R 4 INR111 R 16,and 0 0R 1 8 5 1 1 12 13 1

R

5

-C-O-CH

2 -P-N-(CR R 1 15 16 NR R Within such a group, compounds of formula IA may be compounds of formulae II or 0 R 18 f-'-N-(CR 1 2 1 3

-C(O)-R

4

NR

15

R

1 0 OR 18 R 5-C-O-0H 2 -P-N-(CR 12R 1)r-C(O)-R" In one aspect, compounds are of Formula IA wherein M is wherein: G" is selected from the group consisting of and Ais selected from the group consisting of -NR 4 2 -NHAC, -SR

-C(O)NR

4 2 halo, -COR", -CN, perhaloalcyl, C1-C6 alkcyl, C2-C6 alkenyl, and C2-C6 alkynyl; L 2 E 2 and j 2 are selected from the group consisting of -NR 4 2 -NHAc, -NO 2

-H,

-OR

2

-SR

2

-G(O)NR

2 halo, -COR", -S0 2

R

3 guanidinyl, amidinyl, aryl, aralkyl, allcyloxyalkyl, -SCN, -NHSO 2

R

3 -S0 2

WR

2 -CN, -S(O)R perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C6 alkyl(OH), C1-C6 alkyl(SH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, and lower alicyclic, or together L 2 and E 2 or E 2 and J 2 form an annulated cyclic group;

X

2 is selected from the group consisting of -CR 2 2

-CF

2

-CR

2 2 -CR 2-S-,

-CH

2 and -CR 2 2

-NR

20 and wherein in the atom attached to the phosphorus is a carbon atom; with the proviso that X 2 is not substituted with

-COOR

2

-SO

3 H, or -P0 3

R

2 2

R

2 is selected from the group consisting of R 3 and -H;

R

3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R 4 is independently selected from the group consisting of-H, and alkyl, or together R 4 and R 4 form a cyclic alkyl group; R" is selected from the group consisting of alkyl, aryl, -NR 2 2 and -OR 2

R

20 is selected from the group consisting of lower alkyl, and -COR 2 and pharmaceutically acceptable salts thereof.

In one aspect, the bisphosphoramidate portion of the compounds of the invention, 0 R18 R1 2 0

-P-N-C-C-R

14 1 5 16 1 13 NR'sR R may be selected from the group consisting of O

CH

3 P- NH-- COOR 17

CH

3 and wherein R 17 is selected from the group consisting of ethyl, i-prop yl, n-propyl, n-butyl and neopentyl. In another aspect, C* has S stereochemistry.

Alternatively, such compounds maybe of the formula: 0R 2 In one aspect of the invention, M is A 3 L 3

N

E 3

N

J

3

Y

wherein:

A

3 3 and L 3 are selected from the group consisting of -NB.

8 2

-NO

2

-OR,-S

7

-C(O)NR

4 2 halo, -C0R 11 -S0 2

R

3 guarlidine, arnidine, -NHSO 2

R

3 -S0 2

NR

4 2

-CN,

sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C l.-C5 alkyl, C2-C5 alkenyl, alkynyl, and lower alicyclic, or together A3 and L 3 form a cyclic group, or together L 3 and E 3 form a cyclic group, or together E 3 and j 3 form a cyclic group including aryl, cyclic alkyl, and heterocyclic-, j 3 is selected from the group) consisting of -NR a 2

-NO

2 -OR7, -SR, -C(O)NR 4 2 halo, -C(O)Rl 1 -CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloallcoxy, alkyl, 0 haloalkyl, aminoalkyl, alkenyl, alkynyl; alicyclic, aryl, and aralkyl, or together with y 3 forms a cyclic group including aryl, cyclic alkyl and heterocyclic alcyl;

X

3 is selected from the group consisting of-alkyl(hydroxy)-, -alkyl-, -alkynyl-, -aryl-, C -carbonylalkyl-, -1,1-dihaloallcyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -ailcylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and IND -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X 3 is not 0 substituted with -COOR 2

-SO

3 H, or -P0 3

R

2 2 y 3 is selected from the group consisting of-H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C(O)R 3

-S(O)

2

R

3

-CONHR

3 -NR22, and

-OR

3 all except H are optionally substituted;

R

2 is selected from the group consisting of R 3 and -H;

R

3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R 4 is independently selected from the group consisting of and alkyl, or together R 4 and R 4 form a cyclic alkyl group;

R

7 is independently selected from the group consisting of lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and -C(O)Ri 0

R

8 is independently selected from the group consisting of-H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, -C(O)R 1 or together they form a bidentate alkyl; each R 9 is independently selected from the group consisting of-H, -alkyl, aralkyl, and alicyclic, or together R 9 and R 9 form a cyclic alkyl group;

R

1 0 is selected from the group consisting of-H, lower alkyl, -NH 2 lower aryl, and lower perhaloalkyl;

R'

1 is selected from the group consisting of alkyl, aryl, -NR 2 2 and -OR 2 and pharmaceutically acceptable salts thereof.

In one aspect, the following provisos may apply: a) when X 3 is alkyl or alkene, then A 3 is -N(R 8 2 b) X 3 is not alkylamine and alcylaminoalkyl substituted with phosphonic esters and acids; and c) A 3 L 3

E

3 j 3 and y 3 together may only form 0-2 cyclic groups.

In the following table, the inventors contemplate any combination of the following Maricush groups and those described above for the various variables.

Table A. Table of Markush Groups by Variable Markush Markush Markush Markush Group A Group B Group C Group D R' R' and -H lower alkyl, CL-C4 alkyl, lower aryl, lower C2-C7 alicyclic, alicyclic and C4-C6 aryl, and lower aralkcyl C5-C7 aralkyl, wherein said alicyclic, aryl, aralkyl may be optionally substituted 1-2 heteroatoms P2 alkyl, aryl, lower ailcyl, Cl-C4 alkyl, alicyclic, and lower aryl, lower C2-C7 alicyclic, aralkyl alicyclic and C4-C6 aryl, and lower aralkyl C5-C7 aralkyl, wherein said alicyclic, aryl, aralkyl may be optionally substituted with t-2 heteroatoms

R

4 and and CI-C4 alkyl, ClI-C2 alkyl R' and W 4 are connected by atoms to form a cyclic group Markush Markush Markush Markush Group A Group B Group C Group D

R

5 pyrrolyl, pyrrolyl,

NN

imidazolyl, imidazolyl, A IDoxazolyl, isothiazolyl, a ~~K1thiazolyl, 1,2,4- B isothiazolyl, thiadiazolyl,N (71 1,2,4- pyrazolyl, A IDthiadiazolyl, isoxazolyl, 1,2,3pyrazolyl, oxadiazolyl, B isoxazolyl, 1,2,3- 1,2,4oxadiazolyl, oxadiazolyl, t,2,4- 1,2,5- A A oxadiazolyl, oxadiazolyl, E" N B" 1,2,5- 1,3,4- E" B.

oxadiazolyl, oxadiazolyl, A" N~ 1,3,4- 1,2,4- 1D oxadiazolyl, thiadiazolyl, E"B. A" N 1,2,4- 1,3,4-E'B thiadiazolyl, thiadiazolyl, D" E" N) B 1,3,4- pyridinyl,E' N B thiadiazolyi, pyrirnidinyl, A"T N pyridinyl, pyrazinyl,IA" N. pyrimidinyl, pyridazinyl,N B pyrazinyl, 1,3,5-triazinyl, NY B.

pyridaziny], 1 ,2,4-triazinyl, D.

1,3,5-triazinyl, and 1,3- 1,2,4-triazinyl, selenazolyl, all and 1,3- of which contain selenazolyl, all at least one of which contain substituent at least one substituent Markush Markush Markush Markush Group A Group B Group C Group D thiazolyl, All G NNZr oxazolyl, and selenazolylE G GS lG B N R 7 lower alkyl, C(O)R 10 Cllower alicyrclic, C4 alkcyl, C2-C7 lower aralkyl, alicyclic, C4-C6 lower aryl, and aryl, and G5-C7

C(O)R

10 aralkyl, wherein said alicyclic, aryl, aralkyl may be optionally substituted with 1-2 heteroatoms

R

8 lower alkyl, H, C(O)R' 0 Cllower alicyclic, C4 alkyl, G2-C7 lower araikyl, alicyclic, C4-C6 lower aryl, and aryl, and C5-C7 C()1;or arailcyl, wherein said alicyclic, aryl, aralkyl may be optionally substituted with 1-2 heteroatoms; r to ether R 8 and to gether R 8 and R form a R 8 form bidentate ailkyl bidentate alkyl Markush Markush Markush Markush Group A Group B Group C Group D

R

9 lower alkcyl, ClI -C4 alkyl, lower aralkcyl, C5-C7 aralkcyl, and lower and C2-C7 alicyclic; or aficyclic, wherein said alicyclic, and aralkyl may be optionally substituted with 1-2 heteroatomns; r togther R 9 and togther R' and R form a cyclic R form a C2-G6 alkyl group cyclic alkyl R1 0

-NH

2 lower -NH 2 CI-C4 alkyl, lower aryl, alkyl, C4-C6 and lower aryl, and C1-C4 perhaloalkyl perhaloallcyl, wherein said aryl, may be optionally substituted with 1-2 heteroatoms R" -W 2 -OR 2 -NRp 2 2 -OR 2 Cllower alkyl, and C4 alkyl, and lower aryl C4-C6 aryl, wherein said aryl may be optionally substituted with 1-2 hetero atoms Markush Markush Markush Markush Group A Group B Group C Grou D R1 2 lower ailkyl, Cl-C6 alkyl, lower Cl-C4 -H and lower -lower C1-C4 alkyl, lower alkyl, methyl, perhaloalkyl, alkoxyalcyl, alkcyl, perhaloalcyl -CH 2

-O-

lower aralkyl, lower phenyl, and lower C(CH 3 3 lower aryl, alkyltfiioalkcyl, and aryl, phenyl, optionally phenyl, and benzyl; optionally and substituted with benzyl, or or substituted benzyl; or mty

NR

2

R

3 ao -C0 2 R 3-indolyl, NR R, 4-iinidazolyl, or halogen, guandinyl; or -C0 2

R

2

H

3-indolyl, 4limidazolyl, or guanidinyl; or together R't 2 and R 1 2 and R" 3 are R 1 2 and R1 3 are R" 2 and R'1 2 and R1 3 are connected via 2- connected via 2-5 R 3arc R'1 3 are connected via 2- 5 carbon atoms carbon atoms to form connectd connectcarbon atoms to form a a cycloaLkyl group via 2 or 4 ed via 4 to formi a cycloalkyl group carbon carbon cycloalkcyl group atoms to atoms to form a form.

cyclopro- cyclopyl or pentyl cyclopent- group Y, group Markush Markush Markush Markush Group A Group B GroupC Grou D R 13 lower alicyl, CI-C6 alkyl, lower Cl-C4 -H, lower -lower C1.-C4 alkyl, lower alkyl, methyl, perhaloalkyl, alcoxyall, ailkyl, perhaloalkyl -CH 2 i-propyl, lower aralkcyl, lower phenyl, and lower C(CH 3 3 and lower aryl, alkyltb-ioalkyl, and aryl, option- phenyl, benzyl, optionally phenyl, and benzyl; ally substi- and substituted with benzyl, or or tuted with benzyl; or

-OR

9

-NR'

9 2 -OR R 9

-SR'

9 N 92 R9

NRR

3 halogen, C(O)NRR 3 -C0 2 halogen, 3-indolyl, -C0 2

R

2 3- 4-imaidazolyl, or indolyl, 4guandinyl; or imidazolyl, or guanitogether R'1 2 and R 1 2 and R' 3 are R" 2 and R' 3 arc R 1 2 and R" 2 and R1 3 are connected via 2- connected via 2-5 R 1 3 are R 1 3 are connected via 2- 5 carbon atoms carbon atoms to form connected connectcarbon atoms to form a a cycloalcyl group via 2 or 4 ed via 4 to form a cycloalkyl group carbon carbon cycloalicyl group atoms to atoms to form a form cyclo- cyclopropyl or pentyl cyclo- group pentyl group) R'1 4 -SR'1 7 and -OR" 7 lower alkyl, and C I-C6 -H and C I-C3 ailkyl methyl, ethyl, lower aryl, and alkyl, or and propyl ___lower arailcyl, or Markush Markush Markush Markush Group A Group B Group C Group D together R is and together R 15 and -NR' 5

R

16 is a cyclic NR1 5

R

1 6 is R" are R" are amine morpholinyl and connected via 2- connected via 2- pyrrolidinyl 6 atoms, 6 atoms, optionally optionally including 1 including 1 heteroatom heteroatom selected from the selected from the group consisting group consisting of O, N, and S of, O, N, and S

R

16 lower alkyl, and C1-C6 -H and C1-C3 alkyl -(CR' 2 R1 3 )n-C(O)-R 14 lower aryl, and alkyl, or lower aralkyl, together R 15 and together R is and -NRsR 16 is a cyclic NRR 1 6 is

R

1 6 are R 1 are amine morpholinyl and connected via 2- connected via 2- pyrrolidinyl 6 atoms, 6 atoms, CI-C6 alkyl and optionally optionally -(CR2R3)n-C(O)-RI4 including 1 including 1 or heteroatom heteroatom selected from the selected from the together R 15 and R 16 group consisting group consisting are connected via 2-6 of O, N, and S of, 0, N, and S atoms, optionally including 1 heteroatom selected from the group consisting of, 0, N, and S Markush Markush Markush Markush Group A Group B Group C Group D

R"

7 CI-C7 alkyl, methyl, ethyl, methyl, ethyl, ethyl, n-propyt, iphenyl, indolyl, i-propyl i-propyl, n-propyl, propyl, and neopentyl.

sesimol and n-propyl, t-butyl, t-butyl, cyclopentyl, benzyl, wherein isobuityl neo- neopentyl, phenyl and said pheny], pentyl, cyclo- benzyl ethyl, i-propyl, nindolyl, sesimol. pentyl. and propyl, n-butyl, and and benzyl. may unsubstituted neopentyl be optionally beazyl.

substituted with ethyl 1-3 groups selected from the group consisting of--C0 2

R

2 -OR 3 halo,

-NHC(O)R

3 and lower R" C1-C6 alkyl -H and C1I-C6 -H and methyl -H and benzyl alkyl

R"

9 -COR', -GOR', lower alkyl, C1I-C4 alkyl, C4lower aryl, lower C6 aryl, C2-C7 alicyclic, and alicyclic, and __lower aralkcyl C5-C7 aralkyl

R'

0 -CaR 2 and -COR 2 and __lower alkyl C1-C4 allkyl A -NR 4 2

-CONR

4 2 -C0 2

R

3 halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CI-C6 perhaloalkyl, CI-C6 haloalicyl, aryl, -CH 2 OH, -CH 2

NR

4 2

CH

2 CN, -CN, -C(S)NI{ 2

-OR

2

-N

3

-NHC(S)NR

4 2 -NHAc, and

IND

;Z

CA

Markush Markush Markusli Markush Group A Group B Group C Group D B ailcyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, arailcyl, aLkoxvalkyl, O)R 11 I, -C(O)SR',

SO

2 -S(O)R -ON, -NR' 2

-OR',

-SR

3 perhaloallcyl, halo, and null, all except -ON, perhalo-alkyl, and halo are optionally substituted D alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, aralkyl, alkoxyalkyl, -C(O)SR',

SO

2

R

11 -S(O)R -ON, NR 2 2

-OR',

-SR, perhalonilcyl, halo, and null, all except -ON, perhalo-alkyl, and halo are optionally substituted E 01-06 alkyl, 02-06 alkenyl, 02- 06 alkynyl, aryl, 04-06 alicyclic, alkoxyalkl'1, -OONR 4 2 -ON, -NR 2 01-06 perhaloalkcyl, halo, and null, all except -ON, perhaloalcyl, and halo are optionally substituted X -heteroaryl-, -heteroaryl-, methylenoxycarbonyl -alkylcarbonyl- -alkcylamnino- and amino-, -ailkyl- carbonyl-, and amninocarbonyl-, -aikoxyand -aikoxy- carbonyl-, all carbonyl- optionally substituted -heteroaryl-, -heteroaryl- and methylenoxycarbonyl -alkoxyallcyl- -alkoxy- -alkylcarbonyl- carbonylamino-, -alkylaminocarbonyl-, -alkoxyalcyl and -alkoxycarbonyl- Markush Markush 1 Markush Markush Group A Group B Group C Group D G' C, and N A" -NR 2

-NH

2

-CONH

2

-NH

2 -Cl, -Br, and -NH 2

-CONR

4 2 halo, -CH 3

-CF

3

-OH

3 -C0 2

R

3 halo, -CH 2 -halo, -ON, C I1-C6 alkyl, C2- -OCH 3

-SCH

3 C6 alk~enyl, C2- and -H C6 alkynyl, ClI- C6 perhaloalkyl, ClI -C6 halo alkyl, aryl, -CH 2

OH,

-011 2 NRe 2

-CH

2 CN, -ON, 2

-C(S)NH

2

-OR,

-SR

2

-N

3

-NHC(S)NR

4 2 and -NI{Ac B" alkyl, -C(O)0R 3

-S(CH

2 2

CH

3 alkenyl, alkynyl, -C(O)SR 3 alkyl, ClI-C6 aryl, heteroaryl, aryl, heteroaryl, ailkyl, alicyclic, aryl, -m alicyclic, aralkyl, alicycli, halo, heteroaryl, and -SR 3 alkoxyalicyl, -ON, -SR 3

OR

3 1, and -NR 9 2 -S(0H 2 2

CH

3

-CH

2

-CH(CH

3 2 -C(O)SR 3

CH(CH

3 2 -COGEt, -S0R",-SMe, -CH(CF 3 2

-CH

2

-CH(CH

3 2 -S(O)R 3

-CN,

-NR92, -OR3, cyclopropyl and -COOEt

-SR

3 perhalo- n-propyl.

ailcyl, and halo, all except -H, -ON, perhaloailcyl, and halo are optionally substituted Markusli Markush Markush Markush Group A Group B Group C Group D D" alkyl, -C(O)0R 3 lower -H alkenyl, alk~ynyl, -C(O)SR 3 alkyl, alkyl, alicyclic, and aryl, heteroaryl, aryl, heteroaryl, halo alicyclic, aralkyl, alicyclic, halo, alkoxyalkyl, -NR,2, and -SR'

-C(O)SR',

-S0 2

R

11

-ON,

-i\R' 2

-SR',

perhaloalkyl, and halo, all except -ON, perhaloalkyl, and halo are optionally substituted Ell 01-06 alkcyl, 01-06 alkyl, 01-06 alkyl, -H 02-06 alkenyl, lower alicyclic, lower alicyclic, halo, 02-06 alkynyl, halo, -ON, -ON, and aryl, 04-06 -C(O)WR, -SR' alicyclic, and -CONR 2 alkoxyalkyl, -C(O)OR',H,-ran

C

-00NR 4 2 -ON, H BadC -R9 2 R37 C01-C6 perhaloalkyl, and halo, all except H, -ON, perhaloalkcyl, and halo are optionally I_ substituted ci" Niarkush Markush Markush Markush Group A Group B Group C Group D A' -W 2 -CN, -NR! 2

-NI

2

-NH

2 -NHAc, halogen, halogen, and Cl- halo, and -NH 2

-OR

3 perhalo- C5 alkyl, Cl-C5 alkyl -Cl, alkyl, -Br,

NR

4 2 C 1-06 and alkyl, C2-C6 -CH 3 alkcenyl, 02-C6 aflcynyl -NR'z, -NO 2 -CN, halogen, -O 3, hydroxy, lower alkoxymethylene, -alkyl(OH), aryl, alkyloxycarbonyl, -OO(OH), -SR 3 -SH, lower perhaloalkyl, heteroaryl, lower alicyclic and Cl- C6 alkyl, or

-NR

4 2

-C(O)OH,

halogen, lower alkoxy, lower alkyithjo, hydroxy, lower allcyl(hydroxy), lower alkoxymethylene, lower aryl, lower heteroaryl, and C0I-C5 alkcyl, or -N1R 4 2

-ON,

-0(0)011, lower ailkoxy, lower alkylthio, 01-05 alkyl, lower alkyl(hydro xy), lower aryl, and halogen, or

-H,

-SON,

halogen,

-ON,

C1-C6 aikyl, C1-C6 aikoxy, or Hi, lower alkyl, halogen,

-SON,

-OR',

lower alkyloxycarbonyl, lower alkcyloxy,

-ON,

lower alkylthio, or

-SCN,

Cl-C6 alkyl, 01-C6 alicoxy, 01-06 alkylthio, and -Br Me OMe OEt

CH

2

-CH-

OH-

(OH

3 2 Markush Markush Markush Markush Group A Group B Group C Gro p together L 2 and together L 2 and together L 2 and E 2 together

E

2 form an E 2 form an form an annulated L' and E 2 annulated cyclic annulated cyclic cyclic group form a group group containing an cyclic additional 4 carbon group atoms including aryl, cyclic alkyl, heteroaryl, or heterocyclic J' -NR 4 2

-NO

2 -NR4, halo, H, Cl, -H -NHAc, -S-CaN, and Cl-C5 and -CN, halogen, C(O)OH, alkyl -CH 3

-OR

3 hydroxy, halogen, lower lower alkoxy- aLkoxy, lower methylene, alkylthio, -allcyl(OH), aryl, hydroxy, lower alkyloxy- alkyl(hydroxy), carbonyl, lower alkoxy- *CO(OH), -SR methylene, lower -SH, lower aryl, lower p erhaloalkyl, heteroaryl, and heteroaryl, lower 01-05 alkyl alicyclic and Cl- 06 Markush Markush Markush Markush Group A Group B Group C GroupD L' NR 2

-NO

2

-NE.

2 -H1, -NE.

4 2 Y -ON, -H, -NHAc, -S--OmN, -ON, -SON, methyl, -CN, halogen, -O(O)OH, -ON, -SCN, lower ethyl,

-OR

3 hydroxy, halogen, lower -O(O)OH, 01-06 alkyl, propyl, lower alkoxy- alkoxy, lower lower alkyl, alicyclic, -SON and methylene, alkylthio, ailcoxy, halo- aryl, -CI -allcyl(OH), aryl, hydroxy, lower lower gen, halogen, allcyloxy- alkyl(hydroxy), allcylthio, and lower carbonyl, lower alkoxy- 01 -CS lower alkyloxy, -CO(OH), -SE.

3 methylene, lower alkyl, lower allkoxy, hydroxy, -SH, lower aryl, lower ailcyl- or and perhaloalkyl, heteroaryl, and (hydroxy), alkenheteroaryl, lower C 1-05 alkyl; or lower aryl, ylenealicyclic and C01- and OH, or together L 2 and together L? and together L 2 and E 2 together L 2 E 2 form an E 2 form an form an annulated and E 2 form annulated cyclic annulated cyclic cyclic group a cyclic group group containing an group additional 4 carbon including atoms aryl, cyclic alkyl, heteroaryl, or heteroalkyl____ X2 -OR 2 2

-OF

2 -0H 2 and -0H 2 -0- 2 -OR 2_S,-0 2

S

-CH

2 and -CR 2 2

-NR

2

IND

CA

Markush Markush Markush 1 Markush Group A Group B Group C Group D A' -N' 2

-NO

2

-NH

2

-NH

2 hydroxy, and -CH 3 halogen, -oP?, alkylaminocarbonyl, -SR 7 lower perhaloalkyl, and allcyl E3 -NR8 2 -N0 2 -H and -Cl -H hydroxy, halogen, -OR, alkylamninocarbonyl, -SR 7 lower perhaloalkyl, and Cl-CS alkylA r together E 3 and 13 together form a cyclic group J3 halogen, halo, Cl-C5 -ethyl lower alkyl, hydroxyalkyl, lower hydroxy- Cl-C5 haloalkyl, alkcyl, _W 2, R 8 2 N-ClI-C5 lower R 8 2 N- alkyl, Cl-C5 -NN-dimethylaminoalkcyl, lower alidyclic, and propyl haloalkyl, lower Cl-CS alkyl perhaloalkyl, lower alcenyl, lower allcynyl, lower aryl, heterocyclic, and alicyclic or together E 3 and j 3 together form a cyclic group Markush Markush Markush Markush Group A Group B Group C Group D

L

3 -NR'2, -NO 2

-OCH

3

-F

hydroxy, -Cl, and -CH 3 halogen, -OR 7 alkylaminocarbonyl, -SR 7 lower perhaloalkyl, and alkyl Y3 alicyclic and lower alkyl -i-butyl lower alcyl

X

3 -heteroaryl-, -CH 2 0CH 2 -alkylcarbonyl- -methyleneoxyamino-, carbonyl- and -alkylamino- carbonyl-, and -alkoxycarbonyln 1,2 1 Compounds of formula IA may have oral bioavailability of at least 5% and some may have oral bioavailability of at least The prodrugs of the present invention may have two isomeric forms around the phosphorus. In one aspect, the compounds of the invention are not chiral at the phosphorus.

In another aspect, there is no chiral center in the amino groups attached to the phosphorus.

The prodrugs of the present invention may have isomers at the carbon substituted with R 12 and R' 3 The invention contemplates mixtures of isomers as well as individual stereoisomers.

For instance, when n is 1, and R 12 is H, the carbon attached to R 12 and R 13 can have R stereochemistry. In another aspect, when n is 1 and R 12 is the carbon attached to R 1 2 and

R

13 can have S stereochemistry.

The present invention includes compounds designated in Table 1 as defined in the following formulae: formula i, formula ii, and formula iii.

0 0 11 0 0 0 0

R

5 -C-0-CH 2 -P-Q R -C-N-CH 2

-P--Q

12 12 Q Q 2 Formula i Formula ii Formula iii In the above formulae i, ii, and iii, R 5 may be substituted by A and B. The compounds of formulae i, ii, and iii are listed in Table 1 by designated numbers assigned to

R

55 A, B, and Q 2 in the above formulae i, ii, and iii according to the following convention:

QI.Q

2

.R

5 For each moiety, structures assigned to a number shown in the following tables for R 5 A, B, Q' and Q 2 Variable R 55 is divided into two groups, each listing four different structures.

Compounds named in Table 1 of formulae i, ii, and iii wherein the R 55 moieties are assigned the following numbers: Group 1: Group 2: 2 3 4 H B Variable A moieties are assigned the following numbers: 1 2 3 4 A= NH 2 H Me Cl

CA

Variable B moieties are assigned the following numbers: 1 2 3 4 5 6 7 8 B -SCIH 3 -iBu -cPr -S-nPr -SEt -iPr -nPr -G cr Variables Q1 and Q 2 are divided into three groups, each listing eight different substituents.

Q1 and Q 2 moieties are assigned the following numbers: Group 1: Q' and Q' 1 -NH-CH,-C(O)R' 4 2. -NHi-CH(CH 3

)-C(O)R

1 4 3. -NH-C(CH3)-C(O)R1 4 1 4. -NHi-C(CH3) 2

CH

2

-C(O)R

4

-NI{-CH(CH(CH

3 2 1 6. -N}{-CH(CH 2

(CH(CH

3 2 )))-C(0PR 7. -NI-CH(CH 2

CH

2

SCH

3

)-C(O)R

4 8. -NH-CH(CH 2

SCH

2 Ph)-C(O)R 14 Group 2: Q' and

Q

2 1. -Nl- CHCH,-C(O)R 1 4 2. -NI{-CH(CH 2

CH

2

COR

4

)-C(O)R

3. -NH-CH(CH 2 00R 4 14 4. -NI{-CH(CH 2

GONI{

2 1 4 -NI{-GH(COR 1 4

)CH

2

-C(O)R

4 7. -NI{-CH(CH 2

CH

2 COR 4 1 4 8. -NH-CH(CH 2 OH)-C(O)R1 4 Group 3: Q' andQ2 1. -NI{-CH(CH 2

-C

6 H5OH)-C(O)R 1 4 2. -NI{-C(c-propyl)-C(O)R 1 4 3. -NI{-C(c-pentyl)-C(O)R 1 4. -NIH-C(c-hexyl)-C(O)R 1 4 -NT-CH(CH 2 Ph)-C(OR 1 4 6. -N(CH 3

)-CH

2 -C(O)R 14 7.

R

8. -NR 22

R

23 where R 1 4 is selected from the groups consisting of OMe, GEt, OBn, O-ir, 0-neoperityl, 0tBu, 0-nPr, OPh, -N(Me) 2 oxyethylene-N-morpholino, SMe, SEt;- R 2 is methyl, ethyl, benzyl, and prop yl; R22 is H, Me, Et, Bn, Pr and Ph; and Re is Me, Et, Bn, Pr and Ph; or R22 and R 23 is morpholinyl and pyrrolidinyl.

Thus, the compound 3.3.1.2.1 in Group I corresponds to the structure below for formula i: and when R 1 4 is ethoxy the structure would be: The numbers designated in Table I also refer to benzotliiazole and benizoxazole compounds of formula X. These compounds are shown in formulae iv and v.

AA

B O+ 110 B 0 Q 1O 2 H 2 D H D H Formula ivFomlv CK1 The compounds of formulae iv and formula v are listed in Table 1 by designated numbers assigned to A, B, D, Q1, and Q 2 in the above formulae iv and v according to the following convention: Q'.Q 2 A.B.D. For each moiety, structures assigned to a number shown in the following tables for A, B, D, Q1 and Q 2 Variables Q1 and Q 2 are divided into three groups, each listing eight different substituents.

Group 1:

Q

1 and Q 2 moieties are assigned the following numbers: Q' and Q' 1. -NH-CH 2

-C(O)R'

4 2. -NH-CH(CH 3 4 3. -NH-C(CH 3 h) R' 4 4. -NH-C(CH 3 2

CH

2 -C(O)R 4

-NI{-CH(CH(CH

3 2 6. -NH-CH(CH 2

(CH(CH

3 2 4 7. -NH-CH(CH 2

CH

2

SCH

3 )-C(O)R1 4 8. -NHi-CH(CH 2 SCH7 2 Ph)-C(O)R' 4 Group 2: Q' and Q 2 1 -NH-CH 2

CH

2 -C(O)R 1 4 2. -N}I-CH(CH 2

CH

2 COR1 4

)-C(O)R

4 3. -NH-CH(CH 2 COR 14 1 4 4. -NT{-CH(CH 2 CONrH 2

)-C(O)R

4 -NI{-CH(COR 1 4

)CH

2 -C(O)R 1 4 6. -NH-CH(C 2 0R 2 14 7. -NH-CH(CH 2

CH

2 COR1 4 1 4 8. -NH-CH(CH 2 OH)-C(O)R 1 4 Group 3: Q' and Q' 1. -N~HCH(CH2-C 6 THOH)-C(O)R 1 2. -NH-C(c-propyl)-C(O)R 14 3. -NH-C(c-pentyD-C(O)R 1 4 4. -NI{-C(c-hexyl)-C(O)R 1 4

-NH-CH(CH

2 Ph)-C(O)R 4 6. -N(CH 3

)-CH

2 4 7.

R

8. -NR 22

R

Variable B is divided into three groups, each listing eight different substituents.

Group 1: B moieties are assigned the following numbers: 2 M Et nrIBr iiPr SCN O~r Group 2: B N F OMe QEt SMe SEt 2-furanyI C(O OEt Group 3: 1 2 3 4 5 6 7 8 B R&D are R&D are R&D are B&D are B&D are R&D are R&D are B&D are connected connected connected connected connected connected connected connected to form to form to form to form to form to form to form to form cyclohe- phenyl furanyl furanyl cyclo- phenyl furanyl furanyl xyl ring ring ring (0 ring (0 hexyl ring ring ring (0 ring (0 attached at attached at attached at attached at I D) Group 3 for Variable B can only be combined with Group 3 variable for D.

IND

;Z

IND

CIA

Variable D is divided into nine groups, each listing four different substituents.

Group 1: 1 2 3 4 D= H Me Et SCN Group 2: Variable D is replaced with the moieties assigned in the following numbers: 1 2 3 4 DSeSEt -CH 2 OMe OMe Group 3: Group 4: D= null null j null null D= Pr 0-Et I -Pr f0-isopropyl 1 2 3 4 D 0-Bu 0-isobutyl 0-cyclopropy1 0-penty1 1 2 3 4 Group Group 6: D 0-neopentyl I0-cyclopentyl I0-cyclohexyl 0-benzyl Group 7: 1 2 3 4 D S-Pr _S-isopropy1 S-Bu S-isobutyI Group 8: I12 3 4 D S-cyclopropy1 S-Pentyl S-neoentyl S-cyclopentyl Group 9: 1 2 3 4 D cyclohexyl JS-benzyl OCH 2

OGH

3

OCH

2

SCH

3 Compounds named in Table 1 of formulae iv and v wherein the A moieties are assigned the following numbers: 1 2 3 4 A_ NH 2 H Me Cl where R 1 4 is selected from the groups consisting of OMe, QEt, OBn, O-tBu, O-nPr, OPh, 0neopentyl, -N(Me) 2 oxyethylene-N-morpholino, SMe, SEt; R 2 1 is methyl, ethyl, benzyl, and propyl; R 22 is H, Me, Et, Bn, Pr, and Ph; and R 23 is Me, Et, Bn, Pr and Ph; or R 22 and R 2 3 is morpholinyl and pyrrolidinyl.

Thus, the compound 2.2.1.7.4 from Group 1 for B, D, Q1 and Q 2 corresponds to the structure below for formula iv 0 Me 0 IIP- II 14 -P -NH 1

-R'

NCS H and when R 1 4 is ethoxy the structure would be Similarly, in group 3 for variable B, the compound 2.2.1.7.4 corresponds to the structure below for formula iv and when R 14 is ethoxy the structure would be o Table I 1. .2 1 1 1 12 2 1 1. 1.1.1.3.1 1.1.1.1.2 1.1.1.1.3 1.1.1.1.4 1.1.1.2.1 1.1.1.2.2 1.1.1.2.3 1.1.1.2.4 1.1.1.3.1 1.1.1.3.2 1.1.1.3.3 1.1.1.3.4 1.1.1.4.1 1.1.1.4.2 1.1.1.4.3 1.1.1.4.4 1.1.1.5.1 1.1.1.5.2 1.1.1.5.3 1.1.1.5.4 1.1.1.6.1 1.1.1.6.2 1.1.1.6.3 1.1.1.6.4 1.1.21.1 1.1.21.2 1.1.21..3 1.1.21.4 1.1.1.2.1 1.1.1.8.2 1.1.1.2.3 1.1.1.8.4 1.1.2.1.1 1.1.2.1.2 1.1.2.1.3 1.1.2.1.4 1.1.2.2.1 1.1.2.2.2 1.1.2.2.3 1.1.2.2.4 o1.1.2.3.1 1.1.2.3.2 1.1.2.3.3 1.1.2.3.4 1.1.2.4.1 1.1.2.4.2 1.1.2.4.3 1.1.2.4.4 cIN 1.1.2.7.1 1.1.2.5.2 1.1.2.5.3 1.1.2.5.4 1.1.2.6.1 1.1.2.6.2 1.1.2.6.3 1.1.2.6.4 1.1.2.7.1 1.1.2.7.2 1.1.2.7.3 1.1.2.7.4 1.1.32.1 1.1-.2.2 1.1.32.3 1.1.32.4 O 0 1.1.3.1.1 1.1.3.1.2 1.1.3.1.3 1.1.3.1.4 1.1.3.2.1 1.1.3.2.2 1.1.3.2.3 1.1.3.2.4 o1.1.3.3.1 1.1.3.3.2 1.1.3.3.3 1.1.3.3.4 1.1.3.4.1 1.1.3.4.2 1.1.3.4.3 1.1.3.4.4 ci1.1.3.5.1 1.1.3.5.2 1.1.3.5.3 1.1.3.5.4 1.1.3.6.1 1.1.3.68.2 1.1.3.6.3 1.1.3.6.4 1.1.3.7.1 1.1.3.7.2 1.1.3.7.3 1.1.3.7.4 1.1.3.8.1 1.1.3.8.2 1.1.3.8.3 1.1.3.8.4 1.1.4.1.1 1.1.4.1.2 1.1.4.1.3 1.1.4.1.4 1.1.4.2.1 1.1.4.2.2 1.1.4.2.3 1.1.4.2.4 1.1.4.3.1 1.1.4.5.2 1.1.4.3.3 1.1.4.3.4 1.1.4.4.1 1.1.4.4.2 1.1.4.4.3 1.1.4.4.4 1.1.4.5.1 1.1.4.7.2 1.1.4.5.3 1.1.4.5.4 1.1.4.6.1 1.1.4.6.2 1.1.4.6.3 1.1.4.6.4 1.21...1 1.21...2 1.21...3 1.21...4 1.21...1 1.21...2 1.21...3 1.21...4 1.2.1.1.1 1.2.1.1.2 1.2.1.1.3 1.2.1.1.4 1.2.1.2.1 1.2.1.2.2 1.2.1.2.3 1.2.1.2.4 1.2.1.3.1 1.2.1.3.2 1.2.1.5.3 1.2.1.3.4 1.2.1.4.1 1.2.1.4.2 1.2.1.4.3 1.2.1.4.4 1.2.1.5.1 1.2.1.5.2 1.2.1.5.3 1.2.1.5.4 1.2.1.6.1 1.2.1.6.2 1.2.1.6.3 1.2.1.6.4 1.2.21.1 1.2.21.2 1.2.21.3 1.2.21.4 1.2.1.8.1 1.2.1.8.2 1.2.1.8.3 1.2.1.8.4 1.2.2.1.1 1.2.2.1.2 1.2.2.1.3 1.2.2.1.4 1.2.2.2.1 1.2.2.2.2 1.2.2.2.3 1.2.2.2.4 1.2.2.3.1 1.2.2.3.2 1.2.2.3.3 1.2.2.3.4 1.2.2.4.1 1.2.2.4.2 1.2.2.4.3 1.2.2.4.4 1.2.2.5.'1 1.2.2.5.2 1.2.2.5.3 1.2.2.5.4 1.2.2.6.1 1.2.2.6.2 1.2.2.6.3 1.2.2.6.4 1.2.2.7.1 1.2.2.7.2 1.2.2.7.3 1.2.2.7.4 1.2.32.1 1.2.32.2 1.2.32.3 1.2.32.4 1.2.3.1.1 1.2.3.1.2 1.2.3.1.3 1.2.3.1.4 1.2.3.2.1 1.2.3.2.2 1.2.3.2.3 1.2.3.2.4 1.2.3.3.1 1.2.3.3.2 1.2.3.3.3 1.2.3.3.4 1.2.3.4.1 1.2.3.4.2 1.2.3.4.3 1.2.3.4.4 1.2.3.7.1 1.2.3.5.2 1.2.3.5.3 1.2.3.7.4 1.2.3.6.1 1.2.3.6.2 1.2.3.6.3 1.2.3.6.4 1.2.3.7.1 1.2.3.7.2 1.2.3.7.3 1.2.3.7.4 1.2.3.8.1 1.2.3.8.2 1.2.3.8.3 1.2.3.8.4 1.2.4.1.1 1.2.4.1.2 1.2.4.1.3 1.2.4.1.4 1.2.4.2.1 1.2.4.2.2 1.2.4.2.3 1.2.4.2.4 1.2.4.3.1 1.2.4.3.2 1.2.4.3.3 1.2.4.3.4 1.2.4.4.1 1.2.4.6.2 1.2.4.4.3 1.2.4.4.4 1.2.4.5.1 1.2.4.5.2 1.2.4.5.3 1.2.4.5.4 1.2.4.6.1 1.2.4.6.2 1.2.4.6.3 1.2.4.6.4 1.2.4.7.1 1.2.4.7.2 1.2.4.7.3 1.2.4.7.4 1.2.4.8.1 1.2.4.8.2 1.2.4.2.3 1.2.4.8.4 1.3.1.1.1 1.3.1.1.2 1.3.1.1.3 1.3.1.1.4 1.3.1.2.1 1.3.1.2.2 1.3.1.2.3 1.3.1.2.4 1.3.1.3.1 1.3.1.3.2 1.3.1.3.3 1.3.1.3.4 1.3.1.4.1 1.3.1.4.2 1.3.1.4.3 1.3.1.4.4 1.3.1.7.1 1.3.1.5.2 1.3.1.5.3 1.3.1.5.4 1.3.1.6.1 1.3.1.6.2 1.3.1.6.3 1.3.1.6.4 1.3.21.1 1.3.21.2 1.3.21.3 1.3.21.4 1.3.1.8.1 1.3.1.8.2 1.3.1.8.3 1.3.1.8.4 1.3.2.1.1 1.3.2.1.2 1.3.2.1.3 1.3.2.1.4 1.3.2.2.1 1.3.2.2.2 1.3.2.2.3 1.3.2.2.4 1.3.2.3.1 1.3.2.3.2 1.3.2.3.3 1.3.2.3.4 1.3.2.4.1 1.3.2.4.2 1.3.2.4.3 1.3.2.4.4 1.3.2.7.1 1.3.2.5.2 1.3.2.5.3 1.3.2.5.4 1.3.2.6.1 1.3.2.6.2 1.3.2.6.3 1.3.2.6.4 1.3.3.1.1 1.3.3.1.2 1.3.3.1.3 1.3.3.1.4 1.3.3.2.1 1.3.3.2.2 1.3.3.2.3 1.3.3.2.4 Table 1 continued 1.3.3.3.1 1.3.3.5.1 1.3.3 1 1.3.4.1.1 .1.3.4.3.1 1.3.4.5.1 1.3.4.7.1 1.4.1. 1.1 1.4.1.3.1 1.4. 1.5. 1 1.4.1.7.1 1.4.2.1. 1 1.4.2.3.1 1.4.2.5.1 1.4.2.7.1 1.4.3.1.1 1.4.3.3.1 1.4.3 1 1.4.3.7.1 1.4.4.1.1 1.4.4.3.1 1.4.4.5.1 1.4.4.7. 1 1.5.1.1.1 1.5.1.3.1 1.5.1 1.5.1.7. 1 1.5.2.1.1 1.5.2.3.1 1.5.2.5.1 1.5.2.7. 1 1.5.3.1.1 1.5.3.3.1 1.5.3.5.1 1.5.3.7.1 1.5.4. 1. 1 1.5.4.3.1 1.5.4.5.1 1.5.4.7.1 1.6.1-1.1 1.6. 1.3. 1 1.3.3 .3 .2 1.3.3.5.2 1.3 .3 .7.2 1.3 1.2 1.3 .4.3.2 1.3.4.5.2 1.3.4.7.2 1.4.1.1.2 1.4.1.3.2 1.4.1.5.2 1.4.1.7.2 1.4.2.1.2 1.4.2.3.2 1.4.2.5.2 1.4.2.7.2 1.4.3.1.2 1.4.3.3.2 1.4.3.5.2 1.4.3.7.2 1.4.4.1.2 1.4.4.3.2 1.4.4.5.2 1.4.4.7.2 1.5.1.1.2 1.5.1.3.2 1.5.1.5.2 1.5.1.7.2 1.5 .2.1.2 1.5.2.3.2 1.5 .2.5.2 1.5.2.7.2 1.5.3.1.2 1.5.3.3.2 1.5.3.5.2 1.5 .3 .7.2 1.5.4.1.2 1.5 .4.3 .2 1.5.4.5.2 1.5.4.7.2 1.6.1.1.2 1.6.1.3.2 1.3 .3.3 .3 1.3 .3 .5.3 1.3 .3 .7.3 1.3 1.3 1.3.4.3.3 1.3 .4.5 .3 1.3 .4.7 .3 1.4.1.1.3 1.4.1.3.3 1.4.1.5.3 1.4.1.7.3 1'.4.2.1.3 1.4.2.3.3 1.4.2.5.3 1.4.2.7.3 1.4.3.1.3 1.4.3.3.3 1.4.3.5.3 1.4.3.7.3 1.4.4.1.3 1.4.4.3.3 1.4.4.5.3 1.4.4.7.3 1.5.1.1.3 1.5.1.3.3 1. 5.1.5 .3 1.5.1.7.3 1.5 1.3 1.5 .2.3 .3 1.5.2.5.3 1.5.2.7.3 1.5.3.1.3 1.5 .3.3 .3 1.5.3.5.3 1.5 .3 .7.3 1.5.4.1.3 1.5 .4.3 .3 1.5 .4.5 .3 1.5.4.7.3 1.6.1.1.3 1.6.1.3.3 1.3.3.3.4 1.3 .3 .5.4 1.3.3.7.4 1.3 1.4 1.3.4.3.4 1.3 .4.5.4 1.3.4.7.4 1.4.1.1.4 1.4.1.3.4 1.4.1.5.4 1.4.1.7.4 1.4.2.1.4 1.4.2.3.4 1.4.2.5.4 1.4.2.7.4 1.4.3.1.4 1.4.3.3.4 1.4.3.5.4 1.4.3.7.4 1.4.4.1.4 1.4.4.3.4 1.4.4.5.4 1.4.4.7.4 1.5.1.1.4 1.5.1.3.4 1.5. 1.5.4 1.5. 1.7.4 1.5.2.1.4 1.5.2.3.4 1.5.2.5.4 1.5.2.7.4 1.5.3.1.4 1.5 .3.3.4 1.5.3.5.4 1.5.3.7.4 1.5.4. 1.4 1.5 .4.3.4 1.5.4.5.4 1.5.4.7.4 1.6.1.1.4 1.6. 1.3.4 1.3 .3 1 1.3.3 1 1.3.3.8.1 1.3 1 1.3 1 1.3.4.6.1 1.3 8. 1 1.4. 1.2. 1 1.4.1.4.1 1.4.1.6.1 1.4.1.8.1 1.4.2.2.1 1.4.2.4.1 1.4.2.6. 1 1.4.2. 8. 1 1.4.3.2.1 1.4.3.4.1 1.4.3 1 1.4.3.8.1 1.4.4.2.1 1.4.4.4.1 1.4.4.6. 1 1.4.4.8.1 1.5.1.2. 1 1.5.1.4. 1 1.5. 1.6. 1 1. 5. 1.8. 1 1.5.2.2. 1 1.5.2.4.1 1.5.2.6. 1 1.5.2. 8. 1 1.5 .3 1 1.5 .3 1 1.5.3.6. 1 1.5.3. 8. 1 1.5.4.2.1 1.5 1 1.5.4.6.1 1.5.4.8.1 1. 6. 1.2. 1 1.3.3.4.2 1.3.3.6.2 1.3.3.8.2 1.3.4.2.2 1.3 .4.4.2 1.3.4.6.2 1.3.4.8.2 1.4.1.2.2 1.4.1.4.2 1.4.1.6.2 1.4.1. 8.2 1.4.2.2.2 1.4.2.4.2 1.4.2.6.2 1.4.2.8.2 1.4.3.2.2 1.4.3.4.2 1.4.3.6.2 1.4.3.8.2 1.4.4.2.2 1.4.4.4.2 1.4.4.6.2 1.4.4.8.2 1.5.1.2.2 1.5.1.4.2 1.5.1.6.2 1.5 .1.8 .2 1.5.2.2.2 1.5.2.4.2 1.5.2.6.2 1.5.2.8.2 1.5.3.2.2 1.5.3.4.2 1.5.3.6.2 1.5.3.8.2 1.5.4.2.2 1.5.4.4.2 1.5.4.6.2 1.5.4.8.2 1.6.1.2.2 1.3 .3 .4.3 1.3 .3 .6.3 1.3 .3.8 .3 1.3.4.2.3 1.3.4.4.3 1.3 .4.6.3 1.3 .4.8.3 1.4.1.2.3 1.4.1.4.3 1.4.1.6.3 1.4.1.8.3 1.4.2.2.3 1.4.2.4.3 1.4.2.6.3 1.4.2.8.3 1.4.3.2.3 1.4.3.4.3 1.4.3.6.3 1.4.3.8.3 1.4.4.2.3 1.4.4.4.3 1.4.4.6.3 1.4.4.8.3 1.5.1.2.3 1.5.1.4.3 1.5.1.6.3 1.5.1.8.3 1.5 .2.2.3 1.5.2.4.3 1.5.2.6.3 1.5.2.8.3 1.5 .3.2.3 1.5.3.4.3 1.5.3.6.3 1.5.3.8.3 1.5.4.2.3 1.5.4.4.3 1.5 .4.6.3 1.5 8.3 1.6.1.2.3 1.6.1.4.3 1.3.3.4.4 1.3 .3 .6.4 1.3 .3 .8.4 1.3 .4.2.4 1.3.4.4.4 1.3 .4.6.4 1.3.4.8.4 1.4.1.2.4 1.4.1.4.4 1.4.1.6.4 1.4.1.8.4 1.4.2.2.4 1.4.2.4.4 1.4.2.6.4 1.4.2.8.4 1.4.3.2.4 1.4.3.4.4 1.4.3.6.4 1.4.3.8.4 1.4.4.2.4 1.4.4.4.4 1.4.4.6.4 1.4.4.8.4 1.5.1.2.4 1.5.1.4.4 1.5.1.6.4 1.5.1.8.4 1.5.2.2.4 1.5.2.4.4 1.5 .2.6.4 1.5.2.8.4 1.5.3.2.4 1.5 .3.4.4 1.5.3.6.4 1.5.3.8.4 1.5.4.2.4 1.5.4.4.4 1.5 .4.6.4 1.5.4.8.4 1.6.1.2.4 1.6. 1.4.4 1.6.1.4.1 1.6.1.4.2 Table 1 continued 1.6.1.5.1 1.6.1.5.2 1.6.1.5.3 1.6.1.5.4 1.6.1.6.1 1.6.1.6.2 1.6.1.6.3 1.6.1.6.4 1.6.1.7.1 1.6.1.7.2 1.6.1.7.3 1.6.1.7.4 1.6.1.8.1 1.6.1.8.2 1.6.1.8.3 1.6.1.8.4 1.6.2.1.1 1.6.2.1.2 1.6.2.1.3 1.6.2.1.4 1.6.2.2.1 1.6.2.2.2 1.6.2.2.3 1.6.2.2.4 1.6.2.3.1 1.6.2.3.2 1.6.2.3.3 1.6.2.3.4 1.6.2.4.1 1.6.2.4.2 1.6.2.4.3 1.6.2.4.4 1.6.2.5.1 1.6.2.5.2 1.6.2.5.3 1.6.2.5.4 1.6.2.6.1 1.6.2.6.2 1.6.2.6.3 1.6.2.6.4 1.6.2.7.1 1.6.2.7.2 1.6.2.7.3 1.6.2.7.4 1.6.2.8.1 1.6.2.8.2 1.6.2.8.3 1.6.2.8.4 1.6.3.1.1 1.6.3.1.2 1.6.3.1.3 1.6.3.1.4 1.6.3.2.1 1.6.3.2.2 1.6.3.2.3 1.6.3.2.4 1.6.3.3.1 1.6.3.3.2 1.6.3.3.3 1.6.3.3.4 1.6.3.4.1 1.6.3.4.2 1.6.3.4.3 1.6.3.4.4 1.6.3.5.1 1.6.3.5.2 1.6.3.5.3 1.6.3.5.4 1.6.3.6.1 1.6.3.6.2 1.6.3.6.3 4.6.3.6.4 1.6.3.7.1 1.6.3.7.2 1.6.3.7.3 1.6.3.7.4 1.6.3.8.1 1.6.3.8.2 1.6.3.8.3 1.6.3.8.4 1.6.4.1.1 1.6.4.1.2 1.6.4.1.3 1.6.4.1.4 1.6.4.2.1 1.6.4.2.2 1.6.4.2.3 1.6.4.2.4 1.6.4.3.1 1.6.4.3.2 1.6.4.3.3 1.6.4.3.4 1.6.4.4.1 1.6.4.4.2 1.6.4.4.3 1.6.4.4.4 1.6.4.5.1 1.6.4.5.2 1.6.4.5.3 1.6.4.5.4 1.6.4.6.1 1.6.4.6.2 1.6.4.6.3 1.6.4.6.4 1.6.4.7.1 1.6.4.7.2 1.6.4.7.3 1.6.4.7.4 1.6.4.8.1 1.6.4.8.2 1.6.4.8.3 1.6.4.8.4 1.7.1.1.1 1.7.1.1.2 1.7.1.1.3 1.7.1.1.4 1.7.1.2.1 1.7.1.2.2 1.7.1.2.3 1.7.1.2.4 1.7.1.3.1 1.7.1.3.2 1.7.1.3.3 1.7.1.3.4 1.7.1.4.1 1.7.1.4.2 1.7.1.4.3 1.7.1.4.4 1.7.1.5.1 1.7.1.5.2 1.7.1.5.3 1.7.1.5.4 1.7.1.6.1 1.7.1.6.2 1.7.1.6.3 1.7.1.6.4 1.7.1.7.1 1.7.1.7.2 1.7.1.7.3 1.7.1.7.4 1.7.1.8.1 1.7.1.8.2 1.7.1.8.3 1.7.1.8.4 1.7.2.1.1 1.7.2.1.2 1.7.2.1.3 1.7.2.1.4 1.7.2.2.1 1.7.2.2.2 1.7.2.2.3 1.7.2.2.4 1.7.2.3.1 1.7.2.3.2 1.7.2.3.3 1.7.2.3.4 1.7.2.4.1 1.7.2.4.2 1.7.2.4.3 1.7.2.4.4 1.7.2.5.1 1.7.2.5.2 1.7.2.5.3 1.7.2.5.4 1.7.2.6.1 1.7.2.6.2 1.7.2.6.3 1.7.2.6.4 1.7.2.7.1 1.7.2.7.2 1.7.2.7.3 1.7.2.7.4 1.7.2.8.1 1.7.2.8.2 1.7.2.8.3 1.7.2.8.4 1.7.3.1.1 1.7.3.1.2 1.7.3.1.3 1.7.3.1.4 1.7.3.2.1 1.7.3.2.2 1.7.3.2.3 1.7.3.2.4 1.7.3.3.1 1.7.3.3.2 1.7.3.3.3 1.7.3.3.4 1.7.3.4.1 1.7.3.4.2 1.7.3.4.3 1.7.3.4.4 1.7.3.5.1 1.7.3.5.2 1.7.3.5.3 1.7.3.5.4 1.7.3.6.1 1.7.3.6.2 1.7.3.6.3 1.7.3.6.4 1.7.3.7.1 1.7.3.7.2 1.7.3.7.3 1.7.3.7.4 1.7.3.8.1 1.7.3.8.2 1.7.3.8.3 1.7.3.8.4 1.7.4.1.1 1.7.4.1.2 1.7.4.1.3 1.7.4.1.4 1.7.4.2.1 1.7.4.2.2 1.7.4.2.3 1.7.4.2.4 1.7.4.3.1 1.7.4.3.2 1.7.4.3.3 1.7.4.3.4 1.7.4.4.1 1.7.4.4.2 1.7.4.4.3 1.7.4.4.4 1.7.4.5.1 1.7.4.5.2 1.7.4.5.3 1.7.4.5.4 1.7.4.6.1 1.7.4.6.2 1.7.4.6.3 1.7.4.6.4 1.7.4.7.1 1.7.4.7.2 1.7.4.7.3 1.7.4.7.4 1.7.4.8.1 1.7.4.8.2 1.7.4.8.3 1.7.4.8.4 1.8.1.1.1 1.8.1.1.2 1.8.1.1.3 1.8.1.1.4 1.8.1.2.1 1.8.1.2.2 1.8.1.2.3 1.8.1.2.4 1.8.1.3.1 1.8.1.3.2 1.8.1.3.3 1.8.1.3.4 1.8.1.4.1 1.8.1.4.2 1.8.1.4.3 1.8.1.4.4 1.8.1.5.1 1.8.1.5.2 1.8.1.5.3 1.8.1.5.4 1.8.1.6.1 1.8.1.6.2 1.8.1.6.3 1.8.1.6.4 1.8.1L.7.1 1.8.1.7.2 1.8.1.7.3 1.8.1.7.4 1.8.1.8.1 1.8.1.8.2 1.8.1.8.3 1.8.1.8.4 1.3.2.1.1 1.8.2.1.2 1.8.2.1.3 1.8.2.1.4 1.8.2.2.1 1.8.2.2.2 1.8.2.2.3 1.8.2.2.4 1.8.2.3.1 1.8.2.3.2 1.8.2.3.3 1.8.2.3.4 1.8.2.4.1 1.8.2.4.2 1.8.2.4.3 1.8.2.4.4 1.8.2.5.1 1.8.2.5.2 1.8.2.5.3 1.8.2.5.4 1.8.2.6.1 1.8.2.6.2 1.8.2.6.3 1.8.2.6.4 1.8.2.7.1 1.8.2.7.2 1.8.2.7.3 1.8.2.7.4 1.8.2.8.1 1.8.2.8.2 1.8.2.8.3 1.8.2.8.4 1.8.3.1.1 1.8.3.1.2 1.8.3.1.3 1.8.3.1.4 1.8.3.2.1 1.8.3.2.2 1.8.3.2.3 1.8.3.2.4 1.8.3.3.1 1.8.3.3.2 1.8.3.3.3 1.8.3.3.4 1.8.3.4.1 1.8.3.4.2 1.8.3.4.3 1.8.3.4.4 1.8.3.5.1 1.8.3.5.2 1.8.3.5.3 1.8.3.5.4 1.8.3.6.1 1.8.3.6.2 1.8.3.6.3 1.8.3.6.4 Table 1 continued 1.8.3.7.1 1.8.3.7.2 1 .3.7.3 1.8.3.7.4 1.8.3.8.1 1.8.3.8.2 1.8.3.8.3 1.8.3.8.4 1.8.4.1.1 1.8.4.1.2 1.S.4.1.3 1.8.4.1.4 1.8.4.2.1 1.8.4.2.2 1.8.4.2.3 1.8.4.2.4 1.8.4.3.1 1.8.4.3.2 1.8.4.3.3 1.8.4.3.4 1.8.4.4.1 1.8.4.4.2 1.8.4.4.3 1.8.4.4.4 1.8.4.5.1 1.8.4.5.2 1.8.4.5.3 1.8.4.5.4 1.8.4.6.1 1.8.4.6.2 1.8.4.6.3 1.8.4.6.4 1.8.4.7.1 1.8.4.7.2 1.8.4.7.3 1.8.4.7.4 1.8.4.8.1 1.8.4.8.2 1.8.4.8.3 1.8.4.8.4 2.1.1.1.1 2.1.1.1.2 2.1.1.1.3 2.1.1.1.4 2.1.1.2.1 2.1.1.2.2 2.1.1.2.3 2.1.1.2.4 2.1.1.3.1 2.1.1.3.2 2.1.1.3.3 2.1.1.3.4 2.1.1.4.1 2.1.1.4.2 2.1.1.4.3 2.1.1.4.4 2.1.1.5.1 2.1.1.5.2 2.1.1.5.3 2.1.1.5.4 2.1.1.6.1 2.1.1.6.2 2.1.1.6.3 2.1.1.6.4 2.1.1.7.1 2.1.1.7.2 2. 1. 1.7.3 2.1.1.7.4 2.1.1.8.1 2.1.1.8.2 2.1.1.8.3 2.1.1.8.4 2.1.2.1.1 2.1.2.1.2 2.1.2.1.3 2.1.2.1.4 2.1.2.2.1 2.1.2.2.2 2.1.2.2.3 2.1.2.2.4 2.1.2.3.1 2.1.2.3.2 2.1.2.3.3 2.1.2.3.4 2.1.2.4.1 2.1.2.4.2 2.1.2.4.3 2.1.2.4.4 2.1.2.5.1 2.1.2.5.2 2.1.2.5.3 2.1.2.5.4 2.1.2.6.1 2.1.2.6.2 2.1.2.6.3 2.1.2.6.4 2.1.2.7.1 2.1.2.7.2 2.1.2.7.3 2.1.2.7.4 2.1.2.8.1 2.1.2.8.2 2.1.2.8.3 2.1.2.8.4 2.1.3.1.1 2.1.3.1.2 2.1.3.1.3 2.1.3.1.4 2.1.3.2.1 2.1.3.2.2 2.1.3.2.3 2.1.3.2.4 2.1.3.3.1 2.1.3.3.2 2.1.3.3.3 2.1.3.3.4 2.1.3.4.1 2.1.3.4.2 2.1.3.4.3 2.1.3.4.4 2.1.3.5.1 2.1.3.5.2 2.1.3.5.3 2.1.3.5.4 2.1.3.6.1 2.1.3.6.2 2.1.3.6.3 2.1.3.6.4 2.1.3.7.1 2.1.3.7.2 2.1.3.7.3 2.1.3.7.4 2.1.3.8.1 2.1.3.8.2 2.1.3.8.3 2.1.3.8.4 2.1.4.1.1 2.1.4.1.2 2.1.4.1.3 2.1.4.1.4 2.1.4.2.1 2.1.4.2.2 2.1.4.2.3 2.1.4.2.4 2.1.4.3.1 2.1.4.3.2 2.1.4.3.3 2.1.4.3.4 2.1.4.4.1 2.1.4.4.2 2.1.4.4.3 2.1.4.4.4 2.1.4.5.1 2.1.4.5.2 2.1.4.5.3 2.1.4.5.4 2.1.4.6.1 2.1.4.6.2 2.1.4.6.3 2.1.4.6.4 2.1.4.7.1 2.1.4.7.2 2.1.4.7.3 2.1.4.7.4 2.1.4.8.1 2.1.4.8.2 2.1.4.8.3 2.1.4.8.4 2.2.1.1.1 2.2.1.1.2 2.2.1.1.3 2.2.1.1.4 2.2.1.2.1 2.2.1.2.2 2.2.1.2.3 2.2.1.2.4 2.2.1.3.1 2.2.1.3.2 2.2.1.3.3 2.2.1.3.4 2.2.1.4.1 2.2.1.4.2 2.2.1.4.3 2.2.1.4.4 2.2.1.5.1 2.2.1.5.2 2.2.1.5.3 2.2.1.5.4 2.2.1.6.1 2.2.1.6.2 2.2.1.6.3 2.2.1.6.4 2.2.1.7.1 2.2.1.7.2 2.2.1.7.3 2.2.1.7.4 2.2.1.8.1 2.2.1.8.2 2.2.1.8.3 2.2.1.8.4 2.2.2.1.1 2.2.2.1.2 2.2.2.1.3 2.2.2.1.4 2.2.2.2.1 2.2.2.2.2 2.2.2.2.3 2.2.2.2.4 2.2.2.3.1 2.2.2.3.2 2.2.2.3.3 2.2.2.3.4 2.2.2.4.1 2.2.2.4.2 2.2.2.4.3 2.2.2.4.4 2.2.2.5.1 2.2.2.5.2 2.2.2.5.3 2.2.2.5.4 2.2.2.6.1 2.2.2.6.2 2.2.2.6.3 2.2.2.6.4 2.2.2.7.1 2.2.2.7.2 2.2.2.7.3 2.2.2.7.4 2.2.2.8.1 2.2.2.8.2 2.2.2.8.3 2.2.2.8.4 2.2.3.1.1 2.2.3.1.2 2.2.3.1.3 2.2.3.1.4 2.2.3.2.1 2.2.3.2.2 2.2.3.2.3 2.2.3.2.4 2.2.3.3.1 2.2.3.3.2 2.2.3.3.3 2.2.3.3.4 2.2.3.4.1 2.2.3.4.2 2.2.3.4.3 2.2.3.4.4 2.2.3.5.1 2.2.3.5.2 2.2.3.5.3 2.2.3.5.4 2.2.3.6.1 2.2.3.6.2 2.2.3.6.3 2.2.3.6.4 2.2.3.7.1 2.2.3.7.2 2.2.3.7.3 2.2.3.7.4 2.2.3.8.1 2.2.3.8.2 2.2.3.8.3 2.2.3.8.4 2.2.4.1.1 2.2.4.1.2 2.2.4.1.3 2.2.4.1.4 2.2.4.2.1 2.2.4.2.2 2.2.4.2.3 2.2.4.2.4 2.2.4.3.1 2.2.4.3.2 2.2.4.3.3 2.2.4.3.4 2.2.4.4.1 2.2.4.4.2 2.2.4.4.3 2.2.4.4.4 2.2.4.5.1 2.2.4.5.2 2.2.4.5.3 2.2.4.5.4 2.2.4.6.1 2.2.4.6.2 2.2.4.6.3 2.2.4.6.4 2.2.4.7.1 2.2.4.7.2 2.2.4.7.3 2.2.4.7.4 2.2.4.8.1 2.2.4.8.2 2.2.4.8.3 2.2.4.8.4 2.3.1.1.1 2.3.1.1.2 2.3.1.1.3 2.3.1.1.4 2.3.1.2.1 2.3.1.2.2 2.3.1.2.3 2.3.1.2.4 2.3.1.3.1 2.3.1.3.2 2.3.1.3.3 2.3.1.3.4 2.3.1.4.1 2.3.1.4.2 2.3.1.4.3 2.3.1.4.4 2.3.1.5.1 2.3.1.5.2 2.3.1.5.3 2.3.1.5.4 2.3.1.6.1. 2.3.1.6.2 2.3.1.6.3 2.3.1.6.4 2.3.1.7.1 2.3.1.7.2 2.3.1.7.3 2.3.1.7.4 2.3.1.8.1 2.3.1.8.2 2.3.1.8.3 2.3.1.8.4 Table 1 continued 2.3.2.1.1 2.3.2.1.2 2.3.2.1.3 2.3.2.1.4 2.3.2.2.1 2.3.2.2.2 2.3.2.2.3 2.3.2.2.4 2.3.2.3.1 2.3.2.3.2 2.3.2.3.3 2.3.2.3.4 2.3.2.4.1 2.3.2.4.2 2.3.2.4.3 2.3.2.4.4 2.3.2.5.1 2.3.2.5.2 2.3.2.5.3 2.3.2.5.4 2.3.2.6.1 2.3.2.6.2 2.3.2.6.3 2.3.2.6.4 2.3.2.7.1 2.3.2.7.2 2.3.2.7.3 2.3.2.7.4 2.3.2.8.1 2.3.2.8.2 2.3.2.8.3 2.3.2.8.4 2.3.3.1.1 2.3.3.1.2 2.3.3.1.3 2.3.3.1.4 2.3.3.2.1 2.3.3.2.2 2.3.3.2.3 2.3.3.2.4 2.3.3.3.1 2.3.3.3.2 2.3.3.3.3 2.3.3.3.4 2.3.3.4.1 2.3.3.4.2 2.3.3.4.3 2.3.3.4.4 2.3.3.5.1 2.3.3.5.2 2.3.3.5.3 2.3.3.5.4 2.3.3.6.1 2.3.3.6.2 2.3.3.6.3 2.3.3.6.4 2.3.3.7.1 2.3.3.7.2 2.3.3.7.3 2.3.3.7.4 2.3.3.8.1 2.3.3.8.2 2.3.3.8.3 2.3.3.8.4 2.3.4.1.1 2.3.4.1.2 2.3.4.1.3 2.3.4.1.4 2.3.4.2.1 2.3.4.2.2 2.3.4.2.3 2.3.4.2.4 2.3.4.3.1 2.3.4.3.2 2.3.4.3.3 2.3.4.3.4 2.3.4.4.1 2.3.4.4.2 2.3.4.4.3 2.3.4.4.4 2.3.4.5.1 2.3.4.5.2 2.3.4.5.3 2.3.4.5.4 2.3.4.6.1 2.3.4.6.2 2.3.4.6.3 2.3.4.6.4 2.3.4.7.1 2.3.4.7.2 2.3.4.7.3 2.3.4.7.4 2.3.4.8.1 2.3.4.8.2 2.3.4.8.3 2.3.4.8.4 2.4.1.1.1 2.4.1.1.2 2.4.1.1.3 2.4.1.1.4 2.4.1.2.1 2.4.1.2.2 2.4.1.2.3 2.4.1.2.4 2.4.1.3.1 2.4.1.3.2 2.4.1.3.3 2.4.1.3.4 2.4.1.4.1 2.4.1.4.2 2.4.1.4.3 2.4.1.4.4 2.4.1.5.1 2.4.1.5.2 2.4.1.5.3 2.4.1.5.4 2.4.1.6.1 2.4.1.6.2 2.4.1.6.3 2.4.1.6.4 2.4.1.7.1 2.4.1.7.2 2.4.1.7.3 2.4.1.7.4 2.4.1.8.1 2.4.1.8.2 2.4.1.8.3 2.4.1.8.4 2.4.2.1.1 2.4.2.1.2 2.4.2.1.3 2.4.2.1.4 2.4.2.2.1 2.4.2.2.2 2.4.2.2.3 2.4.2.2.4 2.4.2.3.1 2.4.2.3.2 2.4.2.3.3 2.4.2.3.4 2.4.2.4.1 2.4.2.4.2 2.4.2.4.3 2.4.2.4.4 2.4.2.5.1 2.4.2.5.2 2.4.2.5.3 2.4.2.5.4 2.4.2.6.1 2.4.2.6.2 2.4.2.6.3 2.4.2.6.4 2.4.2.7.1 2.4.2.7.2 2.4.2.7.3 2.4.2.7.4 2.4.2.8.1 2.4.2.8.2 2.4.2.8.3 2.4.2.8.4 2.4.3.1.1 2.4.3.1.2 2.4.3.1.3 2.4.3.1.4 2.4.3.2.1 2.4.3.2.2 2.4.3.2.3 2.4.3.2.4 2.4.3.3.1 2.4.3.3.2 2.4.3.3.3 2.4.3.3.4 2.4.3.4.1 2.4.3.4.2 2.4.3.4.3 2.4.3.4.4 2.4.3.5.1 2.4.3.5.2 2.4.3.5.3 2.4.3.5.4 2.4.3.6.1 2.4.3.6.2 2.4.3.6.3 2.4.3.6.4 2.4.3.7.1 2.4.3.7.2 2.4.3.7.3 2.4.3.7.4 2.4.3.8.1 2.4.3.8.2 2.4.3.8.3 2.4.3.8.4 2.4.4.1.1 2.4.4.1.2 2.4.4.1.3 2.4.4.1.4 2.4.4.2.1 2.4.4.2.2 2.4.4.2.3 2.4.4.2.4 2.4.4.3.1 2.4.4.3.2 2.4.4.3.3 2.4.4.3.4 2.4.4.4.1 2.4.4.4.2 2.4.4.4.3 2.4.4.4.4 2.4.4.5.1 2.4.4.5.2 2.4.4.5.3 2.4.4.5.4 2.4.4.6.1 2.4.4.6.2 2.4.4.6.3 2.4.4.6.4 2.4.4.7.1 2.4.4.7.2 2.4.4.7.3 2.4.4.7.4 2.4.4.8.1 2.4.4.8.2 2.4.4.8.3 2.4.4.8.4 2.5.1.1.1 2.5.1.1.2 2.5.1.1.3 2.5.1.1.4 2.5.1.2.1 2.5.1.2.2 2.5.1.2.3 2.5.1.2.4 2.5.1.3.1 2.5.1.3.2 2.5.1.3.3 2.5.1.3.4 2.5.1.4.1 2.5.1,4.2 2.5.1.4.3 2.5.1.4.4 2.5.1.5.1 2.5.1.5.2 2.5.1.5.3 2.5.1.5.4 2.5.1.6.1 2.5.1.6.2 2.5.1.6.3 2.5.1.6.4 2.5.1.7.1 2.5.1.7.2 2.5.1.7.3 2.5.1.7.4 2.5.1.8.1 2.5.1.8.2 2.5.1.8.3 2.5.1.8.4 2.5.2.1.1 2.5.2.1.2 2.5.2.1.3 2.5.2.1.4 2.5.2.2.1 2.5.2.2.2 2.5.2.2.3 2.5.2.2.4 2.5.2.3.1 2.5.2.3.2 2.5.2.3.3 2.5.2.3.4 2.5.2.4.1 2.5.2.4.2 2.5.2.4.3 2.5.2.4.4 2.5.2.5.1 2.5.2.5.2 2.5.2.5.3 2.5.2.5.4 2.5.2.6.1 2.5.2.6.2 2.5.2.6.3 2.5.2.6.4 2.5.2.7.1 2.5.2.7.2 2.5.2.7.3 2.5.2.7.4 2.5.2.8.1 2.5.2.8.2 2.5.2.8.3 2.5.2.8.4 2.5.3.1.1 2.5.3.1.2 2.5.3.1.3 2.5.3.1.4 2.5.3.2.1 2.5.3.2.2 2.5.3.2.3 2.5.3.2.4 2.5.3.3.1 2.5.3.3.2 2.5.3.3.3 2.5.3.3.4 2.5.3.4.1 2.5.3.4.2 2.5.3.4.3 2.5.3.4.4 2.5.3.5.1 2.5.3.5.2 2.5.3.5.3 2.5.3.5.4 2.5.3.6.1 2.5.3.6.2 2.5.3.6.3 2.5.3.6.4 2.5.3.7.1 2.5.3.7.2 2.5.3.7.3 2.5.3.7.4 2.5.3.8.1 2.5.3.8.2 2.5.3.8.3 2.5.3.8.4 2.5.4.1.1 2.5.4.1.2 2.5.4.1.3 2.5.4.1.4 2.5.4.2.1 2.5.4.2.2 2.5.4.2.3 2.5.4.2.4 Table 1 continued 2.5.4.3.1 2.5.4.3.2 2.5.4.3.3 2.5.4.3.4 2.5.4.4.1 2.5.4.4.2 2.5.4.4.3 2.5.4.4.4 2.5.4.5.1 2.5.4.5.2 2.5.4.5.3 2.5.4.5.4 2.5.4.6.1 2.5.4.6.2 2.5.4.6.3 2.5.4.6.4 2.5.4.7.1 2.5.4.7.2 2.5.4.7.3 2.5.4.7.4 2.5.4.8.1 2.5.4.8.2 2.5.4.8.3 2.5.4.8.4 C215 2.6.1.1.1 2.6,1.1.2 2.6.1.1.3 2.6.1.1.4 2.6.1.2.1 2.6.1.2.2 2.6.1.2.3 2.6.1.2.4 2.6.1.3.1 2.6.1.3.2 2.6.1.3.3 2.6.1.3.4 2.6.1.4.1 2.6.1.4.2 2.6.1.4.3 2.6.1.4.4 2.6.1.5.1 2.6.1.5.2 2.6.1.5.3 2.6.1.5.4 2.6.1.6.1 2.6.1.6.2 2.6.1.6.3 2.6.1.6.4 2.6.1.7.1 2.6.1.7.2 2.6.1.7.3 2.6.1.7.4 2.6.1.8.1 2.6.1.8.2 2.6.1.8.3 2.6.1.8.4 13 262 14 2622 1 2.6.2.1.1 2.6.2.1.2 2.6.2.3.3 2.6.2.3.4 2.6.2.2.1 2.6.2.2.2 2.6.2.2.3 2.6.2.2.4 2.6.2.3.1 2.6.2.3.2 2.6.2.3.3 2.6.2.3.4 2.6.2.4.1 2.6.2.4.2 2.6.2.4.3 2.6.2.4.4 2.6.2.5.1 2.6.2.5.2 2.6.2.7.3 2.6.2.7.4 2.6.2.6.1 2.6.2.6.2 2.6.2.8.3 2.6.2.6.4 2.6.2.1.1 2.6.2.7.2 2.6.2.7.3 2.6.2.7.4 2.6.328.1 2.6.328.2 2.6.32.3 2.6.32.4 2.6.3.3.1 2.6.3.1.2 2.6.3.1.3 2.6.3.3.4 2.6.3.4.1 2.6.3.2.2 2.6.3.2.3 2.6.3.2.4 2.6.3.3.1 2.6.3.3.2 2.6.3.3.3 2.6.3.3.4 2.6.3.4.1 2.6.3.4.2 2.6.3.4.3 2.6.3.4.4 2.6.3.7.1 2.6.3.5.2 2.6.3.7.3 2.6.3.7.4 2.6.3.6.1 2.6.3.8.2 2.6.3.6.3 2.6.3.6.4 2.6.3.7.1 2.6.3.7.2 2.6.3.7.3 2.6.3.7.4 2.6.3.8.1 2.6.3.8.2 2.6.3.2.3 2.6.3.8.4 2.6.4.1.1 2.6.4.1.2 2.6.4.1.3 2.6.4.1.4 2.6.4.2.1 2.6.4.2.2 2.6.4.2.3 2.6.4.2.4 2.6.4.3.1 2.6.4.3.2 2.6.4.3.3 2.6.4.3.4 2.6.4.4.1 2.6.4.4.2 2.6.4.4.3 2.6.4.4.4 2.6.4.7.1 2.6.4.7.2 2.6.4.5.3 2.6.4.7.4 2.6.4.8.1 2.6.4.6.2 2.6.4.6.3 2.6.4.6.4 2.6.4.7.1 2.6.4.7.2 2.7.4.7.3 2.6.4.7.4 2.6.4.8.1 2.6.4.8.2 2.7.4.8.3 2.7.4.8.4 2.7.1.3.1 2.7.1.1.2 2.7.1.1.3 2.7.1.3.4 2.7.1.2.1 2.7.1.2.2 2.7.1.2.3 2.7.1.2.4 2.7.1.3.1 2.7.1.3.2 2.7.1.3.3 2.7.1.3.4 2.7.1.4.1 2.7.1.6.2 2.7.1.4.3 2.7.1.4.4 2.7.1.7.1 2.7.1.5.2 2.7.1.5.3 2.7.1.7.4 2.7.1.6.1 2.7.1.6.2 2.7.1.8.3 2.7.1.6.4 2.7.217.1 2.7.217.2 2.7.217.3 2.7.217.4 2.7.2.8.1 2.7.1.8.2 2.7.1.8.3 2.7.2.2.4 2.7.2.3.1 2.7.2.1.2 2.7.2.3.3 2.7.2.1.4 2.7.2.2.1 2.7.2.2.2 2.7.2.2.3 2.7.2.2.4 2.7.2.3.1 2.7.2.3.2 2.7.2.3.3 2.7.2.3.4 2,7.2.4.1 2.7.2.4.2 2.7.2.4.3 2.7.2.4.4 2.7.2.5.1 2.7.2.5.2 2.7.2.5.3 2.7.2.7.4 2.7.2.8.1 2.7.2.6.2 2.7.2.6.3 2.7.2.8.4 2.7.2.7.1 2.7.2.7.2 2.7.2.7.3 2.7.2.7.4 2.7.32.1 2.7.328.2 2.7.32.3 2.7.32.4 2.7.3.1.1 2.7.3.1.2 2.7.3.3.3 2.7.3.1.4 2.7.3.2.1 2.7.3.2.2 2.7.3.2.3 2.7.3.2.4 2.7.3.3.1 2.7.3.3.2 2.7.3.3.3 2.7.3.3.4 2.7.3.4.1 2.7.3.4.2 2.7.3.4.3 2.7.3.4.4 2.7.3.5.1 2.7.3.7.2 2.7.3.5.3 2.7.3.5.4 2.7.3.6.1 2.7 .3.68.2 2.7.3.6.3 2.7.3.6.4 2.7.3.7.1 2.7.3.7.2 2.7.3.7.3 2.7.3.7.4 2.7.3.8.1 2.7.3.8.2 2.7.3.8.3 2.7.3.8.4 2.7.4.3.1 2.7.4.1.2 2.7.4.1.3 2.7.4.1.4 2.7.4.2.1 2.7.4.2.2 2.7.4.2.3 2.7.4.2.4 2.7.4.3.1 2.7.4.3.2 2.7.4.3.3 2.7.4.3.4 2.7.4.4.1 2.7.4.4.2 2.7.4.4.3 2.7.4.4.4 2.7.4.7.1 2.7.4.7.2 2.7.4.5.3 2.7.4.7.4 2.7.4.6.1 2.7.4.6.2 2.7.4.8.3 2.7.4.6.4 2.7.4.7.1 2.7.4.7.2 2.7.4.7.3 2.7.4.7.4 2.7.4.2.1 2.7.4.8.2 2.7.4.8.3 2.7.4.8.4 2.8.1.3.1 2.8.1.3.2 2.8.1.1.3 2.8.1.1.4 2.8.1.2.1 2.8.124.2 2.8.1.2.3 2.8.1.2.4 2.8.1.3.1 2.8.1.3.2 2.8.1.3.3 2.8.1.3.4 2.8.1.4.1 2.8.1.4.2 2.8.1.4.3 2.8.1.4.4 2.8.1.7.1 2.8.1.5.2 2.8.1.5.3 2.8.1.7.4 2.8.1.6.1 2.8.1.6.2 2.8.1.6.3 2.8.1.6.4 2.8.217.1 2.8.217.2 2.8.217.3 2.8.217.4 2.8.1.8.1 2.8.1.8.2 2.8.1.8.3 2.8.1.8.4 2.8.2.1.1 2.8.2.1.2 2.8.2.1.3 2.8.2.3.4 2.8.2.2.1 2.8.2.2.2 2.8.2.2.3 2.8.2.2.4 Table 1 continued 2.8.2.5.1 2.8.2.5.2 2.8.2.5.3 2.8.2.5.4 2.8.2.6.1 2.8.2.6.2 2.8.2.6.3 2.8.2.6.4 2.8.2.7.1 2.8.2.7.2 2.8.2.7.3 2.8.2.7.4 2.8.2.8.1 2.8.2.8.2 2.8.2.8.3 2.8.2.8.4 2.8.3.1.1 2.8.3.1.2 2.8.3.1.3 2.8.3.1.4 2.8.3.2.1 2.8.3.2.2 2.8.3.2.3 2.8.3.2.4 2.8.3.3.1 2.8.3.3.2 2.8.3.3.3 2.8.3.3.4 2.8.3.4.1 2.8.3.4.2 2.8.3.4.3 2.8.3.4.4 2.8.3.5.1 2.8.3.5.2 2.8.3.5.3 2.8.3.5.4 2.8.3.6.1 2.8.3.6.2 2.8.3.6.3 2.8.3.6.4 2.8.3.7.1 2.8.3.7.2 2.8.3.7.3 2.8.3.7.4 2.8.3.8.1 2.8.3.8.2 2.8.3.8.3 2.8.3.8.4 2.8.4.1.1 2.8.4.1.2 2.8.4.1.3 2.8.4.1.4 2.8.4.2.1 2.8.4.2.2 2.8.4.2.3 2.8.4.2.4 2.8.4.3.1 2.8.4.3.2 2.8.4.3.3 2.8.4.3.4 2.8.4.4.1 2.8.4.4.2 2.8.4.4.3 2.8.4.4.4 2.8.4.5.1 2.8.4.5.2 2.8.4.5.3 2.8.4.5.4 2.8.4.6.1 2.8.4.6.2 2.8.4.6.3 2.8.4.6.4 2.8.4.7.1 2.8.4.7.2 2.8.4.7.3 2.8.4.7.4 2.8.4.8.1 2.8.4.8.2 2.8.4.8.3 2.8.4.8.4 3.1.1.1.1 3.1.1.1.2 3.1.1.1.3 3.1.1.1.4 3.1.1.2.1 3.1.1.2.2 3.1.1.2.3 3.1.1.2.4 3.1.1.3.1 3.1.1.3.2 3.1.1.3.3 3.1.1.3.4 3.1.1.4.1t 3.1.1.4.2 3.1.1.4.3 3.1.1.4.4 3.1.1.5.1 3.1.1.5.2 3.1.1.5.3 3.1.1.5.4 3.1.1.6.1 3.1.1.6.2 3.1.1.6.3 3.1.1.6.4 3.1.1.7.1 3.1.1.7.2 3.1.1.7.3 3.1.1.7.4 3.1.1.8.1 3.1.1.8.2 3.1.1.8.3 3.1.1.8.4 3.1.2.1.1 3.1.2.1.2 3.1.2.1.3 3.1.2.1.4 3.1.2.2.1 3.1.2.2.2 3.1.2.2.3 3.1.2.2.4 3.1.2.3.1 3.1.2.3.2 3.1.2.3.3 3.1.2.3.4' 3.1.2.4.1 3.1.2.4.2 3.1.2.4.3 3.1.2.4.4 3.1.2.5.1 3.1.2.5.2 3.1.2.5.3 3.1.2.5.4 3.1.2.6.1 3.1.2.6.2 3.1.2.6.3 3.1.2.6.4 3.1.2.7.1 3.1t.2.7.2 3.1.2.7.3 3.1.2.7.4 3.1.2.8.1 3.1.2.8.2 3.1.2.8.3 3.1.2.8.4 3.1.3.1.1 3.1.3.1.2 3.1.3.1.3 3.1.3.1.4 3.1.3.2.1 3.1.3.2.2 3.1.3.2.3 3.1.3.2.4 3.1.3.3.1 3.1.3.3.2 3.1.3.3.3 3.1.3.3.4 3.1.3.4.1 3.1.3.4.2 3.1.3.4.3 3.1.3.4.4 3.1.3.5.1 3.1.3.5.2 3.1.3.5.3 3.1.3.5.4 3.1.3.6.1 3.1.3.6.2 3.1.3.6.3 3.1.3.6.4 3.1.3.7.1 3.1.3.7.2 3.1.3.7.3 3.1.3.7.4 3.1.3.8.1 3.1.3.8.2 3.1.3.8.3 3.1.3.8.4 3.1.4.1.1 3.1.4.1.2 3.1.4.1.3 3.1.4.1.4 3.1.4.2.1 3.1.4.2.2 3.1.4.2.3 3.1.4.2.4 3.1.4:3.1 3.1.4.3.2 3.1.4.3.3 3.1.4.3.4 3.1.4.4.1 3.1.4.4.2 3.1.4.4.3 3.1.4.4.4 3.1.4.5.1 3.1.4.5.2 3.1.4.5.3 3.1.4.5.4 3.1.4.6.1 3.1.4.6.2 3.1.4.6.3 3.1.4.6.4 3.1.4.7.1 3.1.4.7.2 3.1.4.7.3 3.1.4.7.4 3.1.4.8.1 3.1.4.8.2 3.1.4.8.3 3.1.4.8.4 3.2.1.1.1 3.2.1.1.2 3.2.1.1.3 3.2.1.1.4 3.2.1.2.1 3.2.1.2.2 3.2.1.2.3 3.2.1.2.4 3.2.1.3.1 3.2.1.3.2 3.2.1.3.3 3.2.1.3.4 3.2.1.4.1 3.2.1.4.2 3.2.1.4.3 3.2.1.4.4 3.2.1.5.1 3.2.1.5.2 3.2.1.5.3 3.2.1.5.4 3.2.1.6.1 3.2.1.6.2 3.2.1.6.3 3.2.1.6.4 3.2.1.7.1 3.2.1.7.2 3.2.1.7.3 3.2.1.7.4 3.2.1.8.1 3.2.1,.8.2 3.2.1.8.3 3.2.1.8.4 3.2.2.1.1 3.2.2.1.2 3.2.2.1.3 3.2.2.1.4 3.2.2.2.1 3.2.2.2.2 3.2.2.2.3 3.2.2.2.4 3.2.2.3.1 3.2.2.3.2 3.2.2.3.3 3.2.2.3.4 3.2.2.4.1 3.2.2.4.2 3.2.2.4.3 3.2.2.4.4 3.2.2.5.1 3.2.2.5.2 3.2.2.5.3 3.2.2.5.4 3.2.2.6.1 3.2.2.6.2 3.2.2.6.3 3.2.2.6.4 3.2.2.7.1 3.2.2.7.2 3.2.2.7.3 3.2.2.7.4 3.2.2.8.1 3.2.2.8.2 3.2.2.8.3 3.2.2.8.4 3.2.3.1.1 3.2.3.1.2 3.2.3.1.3 3.2.3.1.4 3.2.3.2.1 3.2.3.2.2 3.2.3.2.3 3.2.3.2.4 3.2.3.3.1 3.2.3.3.2 3.2.3.3.3 3.2.3.3.4 3.2.3.4.1 3.2.3.4.2 3.2.3.4.3 3.2.3.4.4 3.2.3.5.1 3.2.3.5.2 3.2.3.5.3 3.2.3.5.4 3.2.3.6.1 3.2.3.6.2 3.2.3.6.3 3.2.3.6.4 3.2.3.7.1 3.2.3.7.2 3.2.3.7.3 3.2.3.7.4 3.2.3.8.1 3.2.3.8.2 3.2.3.8.3 3.2.3.8.4 3.2.4.1.1 3.2.4.1.2 3.2.4.1.3 3.2.4.1.4 3.2.4.2.1 3.2.4.2.2 3.2.4.2.3 3.2.4.2.4 3.2.4.3.1 3.2.4.3.2 3.2.4.3.3 3.2.4.3.4 3.2.4.4.1 3.2.4.4.2 3.2.4.4.3 3.2.4.4.4 3.2.4.5.1 3.2.4.5.2 3.2.4.5.3 3.2.4.5.4 3.2.4.6.1 3.2.4.6.2 3.2.4.6.3 3.2.4.6.4 Table 1 continued 3.2.4.7.1 3.2.4.7.2 3.2.4.7.3 3.2.4.7.4 3.2.4.8.1 3.2.4.8.2 3.2.4.8.3 3.2.4.8.4 3.3.1.1.1 3.3.1.1.2 3.3.1.1.3 3.3.1.1.4 3.3.1.2.1 3.3.1.2.2 3.3.1.2.3 3.3.1.2.4 3.3.1.3.1 3.3.1.3.2 3.3.1.3.3 3.3.1.3.4 3.3.1.4.1t 3.3.1.4.2 3.3.1.4.3 3.3.1.4.4 3.3.1.5.1 3.3.1.5.2 3.3.1.5.3 3.3.1.5.4 3.3.1.6.1 3.3.1.6.2 3.3.1.6.3 3.3.1.6.4 3.3.1.7.1 3.3.1.7.2 3.3.1.7.3 3.3.1.7.4 3.3.1.8.1 3.3.1.8.2 3.3.1.8.3 3.3.1.8.4 3.3.2. 1.1t 3.3.2.1.2 3.3.2.1.3 3.3.2.1.4 3.3.2.2.1 3.3.2.2.2 3.3.2.2.3 3.3.2.2.4 3.3.2.3.1 3.3.2.3.2 3.3.2.3.3 3.3.2.3.4 3.3.2.4.1 3.3.2.4.2 3.3.2.4.3 3.3.2.4.4 3.3.2.5.1 3.3.2.5.2 3.3.2.5.3 3.3.2.5.4 3.3.2.6.1 3.3.2.6.2 3.3.2.6.3 3.3.2.6.4 3.3.2.7.1 3.3.2.7.2 3.3.2.7.3 3.3.2.7.4 3.3.2.8.1 3.3.2.8.2 3.3.2.8.3 3.3.2.8.4 3.3.3.1.1 3.3.3.1.2 3.3.3.1.3 3.3.3.1.4 3.3.3.2.1 3.3.3.2.2 3.3.3.2.3 3.3.3.2.4 3.3.3.3.1 3.3.3.3.2 3.3.3.3.3 3.3.3.3.4 3.3.3.4.1 3.3.3.4.2 3.3.3.4.3 3.3.3.4.4 3.3.3.5.1 3.3.3.5.2 3.3.3.5.3 3.3.3.5.4 3.3.3.6.1 3.3.3.6.2 3.3.3.6.3 3.3.3.6.4 3.3.3.7.1 3.3.3.7.2 3.3.3.7.3 3.3.3.7.4 3.3.3.8.1 3.3.3.8.2 3.3.3.8.3 3.3.3.8.4 3.3.4.1.1 3.3.4.1.2 3.3.4.1.3 3.3.4.1.4 3.3.4.2.1 3.3.4.2.2 3.3.4.2.3 3.3.4.2.4 3.3.4.3.1 3.3.4.3.2 3.3.4.3.3 3.3.4.3.4 3.3.4.4.1 3.3.4.4.2 3.3.4.4.3 3.3.4.4.4 3.3.4.5.1 3.3.4.5.2 3.3.4.5.3 3.3.4.5.4 3.3.4.6.1 3.3.4.6.2 3.3.4.6.3 3.3.4.6.4 3.3.4.7.1 3.3.4.7.2 3.3.4.7.3 3.3.4.7.4 3.3.4.8.1 3.3.4.8.2 3.3.4.8.3 3.3.4.8.4 3.4.1.1.1 3.4.1.1.2 3.4.1.1.3 3.4.1.1.4 3.4.1.2.1 3.4.1.2.2 3.4.1.2.3 3.4.1.2.4 3.4.1.3.1 3.4.1.3.2 3.4.1.3.3 3.4.1.3.4 3.4.1.4.1 3.4.1.4.2 3.4.1.4.3 3.4.1.4.4 3.4.1.5.1 3.4.1.5.2 3.4.1.5.3 3.4.1.5.4 3.4.1.6.1 3.4.1.6.2 3.4.1.6.3 3.4.1.6.4 3.4.1.7.1 3.4.1.7.2 3.4.1.7.3 3.4.1.7.4 3.4.1.8.1 3.4.1.8.2 3.4.1.8.3 3.4.1.8.4 3.4.2.1.1 3.4.2.1.2 3.4.2.1.3 3.4.2.1.4 3.4.2.2.1 3.4.2.2,2 3.4.2.2.3 3.4.2.2.4 3.4.2.3.1 3.4.2.3.2 3.4.2.3.3 3.4.2.3.4 3.4.2.4.1 3.4.2.4.2 3.4.2.4.3 3.4.2.4.4 3.4.2.5.1 3.4.2.5.2 3.4.2.5.3 3.4.2.5.4 3.4.2.6.1 3.4.2.6.2 3.4.2.6.3 3.4.2.6.4 3.4.2.7.1 3.4.2.7.2 3.4.2.7.3 3.4.2.7.4 3.4.2.8.1 3.4.2.8.2 3.4.2.8.3 3.4.2.8.4 3.4.3.1.1 3.4.3.1.2 3.4.3.1.3 3.4.3.1.4 3.4.3.2.1 3.4.3.2.2 3.4.3.2.3 3.4.3.2.4 3.4.3.3.1 3.4.3.3.2 3.4.3.3.3 3.4.3.3.4 3.4.3.4.1 3.4.3.4.2 3.4.3.4.3 3.4.3.4.4 3.4.3.5.1 3.4.3.5.2 3.4.3.5.3 3.4.3.5.4 3.4.3.6.1 3.4.3.6.2 3.4.3.6.3 3.4.3.6.4 3.4.3.7.1 3.4.3.7.2 3.4.3.7.3 3.4.3.7.4 3.4.3.8.1 3.4.3.8.2 3.4.3.8.3 3.4.3.8.4 3.4.4.1.1 3.4.4.1.2 3.4.4.1.3 3.4.4.1.4 3.4.4.2.1 3.4.4.2.2 3.4.4.2.3 3.4.4.2.4 3.4.4.3.1 3.4.4.3.2 3.4.4.3.3 3.4.4.3.4 3.4.4.4.1 3.4.4.4.2 3.4.4.4.3 3.4.4.4.4 3.4.4.5.1 3.4.4.5.2 3.4.4.5.3 3.4.4.5.4 3.4.4.6.1 3.4.4.6.2 3.4.4.6.3 3.4.4.6.4 3.4.4.7.1 3.4.4.7.2 3.4.4.7.3 3.4.4.7.4 3.4.4.8.1 3.4.4.8.2 3.4.4.8.3 3.4.4.8.4 3.5.1.1.1 3.5.1.1.2 3.5.1.1.3 3.5.1.1.4 3.5.1.2.1 3.5.1.2.2 3.5.1.2.3 3.5.1.2.4 3.5.1.3.1 3.5.1.3.2 3.5.1.3.3 3.5.1.3.4 3.5.1.4.1 3.5.1.4.2 3.5.1.4.3 3.5.1.4.4 3.5.1.5.1 3.5.1.5.2 3.5.1.5.3 3.5.1.5.4 3.5.1.6.1 3.5.1.6.2 3.5.1.6.3 3.5.1.6.4 3.5.1.7.1 3.5.1.7.2 3.5.1.7.3 3.5.1.7.4 3.5.-1.8.1 3.5.1.8.2 3.5.1.8.3 3.5.1.8.4 3.5.2.1.1 3.5.2.1.2 3.5.2.1.3 3.5.2.1.4 3.5.2.2.1t 3.5.2.2.2 3.5.2.2.3 3.5.2.2.4 3.5.2.3.1 3.5.2.3.2 3.5.2.3.3 3.5.2.3.4 3.5.2.4.1 3.5.2.4.2 3.5.2.4.3 3.5.2.4.4 3.5.2.5.1 3.5.2.5.2 3.5.2.5.3 3.5.2.5.4 3.5.2.6.1 3.5.2.6.2 3.5.2.6.3 3.5.2.6.4 3.5.2.7.1 3.5.2.7.2 3.5.2.7.3 3.5.2.7.4 3.5.2.8.1 3.5.2.8.2 3.5.2.8.3 3.5.2.8.4 Table 1 continued .13 353 14 353 2 1 35.. 3.5.3.3.1 3.5.3.1.2 3.5.3.3.3 3.5.3.3.4 3.5.3.2.1 3.5.3.2.2 3.5.3.2.3 3.5.3.2.4 3.5.3.3.1 3.5.3.3.2 3.5.3.3.3 3.5.3.3.4 3.5.3.4.1 3.5.3.4.2 .3.5.3.4.3 3.5.3.4.4 3.5.3.5.1 3.5.3.5.2 3.5.3.7.3 3.5.3.7.4 3.5.3.6.1 3.5.3.6.2 3.5.3.6.3 3.5.3.6.4 3.5.3.7.1 3.5.3.7.2 3.5.3.1.3 3.5.3.7.4 3.5.3.8.1 3.5.3.8.2 3.5.3.8.3 3.5.3.2.4 3.5.4.3.1 3.5.4.3.2 3.5.4.3.3 3.5.4.3.4 3.5.4.2.1 3.5.4.2.2 3.5.4.2.3 3.5.4.2.4 3.5.4.3.1 3.5.4.3.2 3.5.4.3.3 3.5.4.5.4 3.5.4.4.1 3.5.4.4.2 3.5.4.4.3 3.5.4.4.4 3.5.4.5.1 3.5.4.5.2 3.5.4.5.3 3.5.4.7.4 3.5.4.8.1 3.5.4.6.2 3.5.4.8.3 3.5.4.6.4

IND

3.6.4.7.1 3.5.4.7.2 3.5.4.7.3 3.6.4.7.4 3.6.4.2.1 3.5.4.2.2 3.5.4.2.3 3.5.4.8.4 3.6.1.3.1 3.6.1.1.2 3.6.1.1.3 3.6.1.1.4 3.6.1.4.1 3.6.1.2.2 3.6.1.2.3 3.6.1.2.4 3.6.1.3.1 3.6.1.3.2 3.6.1.3.3 3.6.1.3.4 3.6.1.4.1 3.6.1.4.2 3.6.1.6.3 3.6.1.6.4 (213.6.1.7.1 3.6.1.5.2 3.6.1.5.3 3.6.1.5.4 3.6.1.8.1 3.6.1.6.2 3.6.1.8.3 3.6.1.6.4 3.6.21.1 3.6.217.2 3.6.217.3 3.6.217.4 3.6.1.2.1 3.6.2.2.2 3.6.2.2.3 3.6.2.8.4 3.6.2.3.1 3.6.2.1.2 3.6.2.3.3 3.6.2.3.4 3.6.2.2.1 3.6.2.2.2 3.6.2.4.3 3.6.2.2.4 3.6.2.3.1 3.6.2.3.2 3.6.2.3.3 3.6.2.5.4 3.6.2.4.1 3.6.2.6.2 3.6.2.4.3 3.6.2.4.4 3.6.2.7.1 3.6.2.5.2 3.6.2.7.3 3.6.2.5.4 3.6.2.6.1 3.6.2.6.2 3.6.2.6.3 3.6.2.6.4 3.6.2.7.1 3.6.3.7.2 3.6.2.7.3 3.6.2.1.4 3.6.328.1 3.6.32.2 3.6.32.3 3.6.32.4 3.6.3.1.1 3.6.3.3.2 3.6.3.3.3 3.6.3.1.4 3.6.3.2.1 3.6.3.2.2 3.6.3.2.3 3.6.3.2.4 3.6.3.3.1 3.6.3.3.2 3.6.3.3.3 3.6.3.3.4 3.6.3.4.1 3.6.3.4.2 3.6.3.4.3 3.6.3.4.4 3.6.3.5.1 3.6.3.5.2 3.6.3.7.3 3.6.3.5.4 3.6.3.6.1 3.6.3.6.2 3.6.3.6.3 3.6.3.6.4 3.6.4.1.1 3.6.4.7.2 3.6.3.7.3 3.6.3.7.4 3.6.3.2.1 3.6.3.8.2 3.6.3.2.3 3.6.3.8.4 3.6.4.3.1 3.6.4.1.2 3.6.4.1.3 3.6.4.1.4 3.6.4.2.1 3.6.4.2.2 3.6.4.2.3 3.6.4.2.4 3.6.4,3.1 3.6.4.3.2 3.6.4.3.3 3.6.4.3.4 3.6.4.4.1 3.6.4.4.2 3.6.4.4.3 3.6.4.4.4 3.6.4.5.1 3.6.4.5.2 3.6.4.7.3 3.6.4.5.4 3.6.4.6.1 3.6.4.6.2 3.6.4.8.3 3.6.4.6.4 3.6.4.1.1 3.6.4.7.2 3.6.4.7.3 3.6.4.1.4 3.6.4.8.1 3.6.4.8.2 3.6.4.2.3 3.6.4.8.4 3.7.1.3.1 3.7.1.1.2 3.7.1.1.3 3.7.1.3.4 3.7.1.2.1 3.7.1.2.2 3.7.1.2.3 3.7.1.2.4 3.7.1.3.1 3.7.1.3.2 3.7.1.3.3 3.7.1.3.4 3.7.1.4.1 3.7.1.4.2 3.7.1.4.3 3.7.1.4.4 3.7.1.7.1 3.7.1.5.2 3.7.1.7.3 3.7.1.5.4 3.7.1.8.1 3.7.1.6.2 3.7.1.6.3 3.7.1.6.4 3.7.217.1 3.7.217.2 3.7.217.3 3.7.217.4 3.7.1.8.1 3.7.1.8.2 3.7.1.2.3 3.7.1.8.4 3.7.2.1.1 3.7.2.1.2 3.7.2.1.3 3.7.2.1.4 3.7.2.2.1 3.7.2.2.2 3.7.2.2.3 3.7.2.2.4 3.7.2.3.1 3.7.2.3.2 3.7.2.3.3 3.7.2.3.4 3.7.2.4.1 3.7.2.4.2 3.7.2.4.3 3.7.2.4.4 3.7.2.5.1 3.7.2.5.2 3.7.2.7.3 3.7.2.5.4 3.7.2.6.1 3.7.2.6.2 3.7.2.8.3 3.7.2.6.4 3.7.2.7.1 3.7.2.7.2 3.7.2.7.3 3.7.2.7.4 3.7.32.1 3.7.32.2 3.7.32.3 3.7.32.4 3.7.3.1.1 3.7.3.1.2 3.7.3.1.3 3.7.3.1.4 3.7.3.2.1 3.7.3.2.2 3.7.3.2.3 3.7.3.2.4 3.7.3.3.1 3.7.3.3.2 3.7.3.3.3 3.7.3.3.4 3.7.3.4.1 3.7.3.4.2 3.7.3.4.3 3.7.3.4.4 3.7.3.7.1 3.7.3.5.2 3.7.3.5.3 3.7.3.5.4 3.7.3.6.1 3.7.3.6.2 3.7.3.6.3 3.7.3.6.4 3.7.3.7.1 3.7.3.7.2 3.7.3.7.3 3.7.3.7.4 3.7.3.8.1 3.7.3.8.2 3.7.3.2.3 3.7.3.8.4 3.7.4.3.1 3.7.4.1.2 3.7.4.1.3 3.7.4.1.4 3.7.4.2.1 3.7.4.2.2 3.7.4.2.3 3.7.4.2.4 3.7.4.3.1 3.7.4.3.2 3.7.4.3.3 3.7.4.3.4 3.7.4.4.1 3.7.4.4.2 3.7.4.4.3 3.7.4.4.4 3.7.4.5.1 3.7.4.5.2 3.7.4.5.3 3.7.4.7.4 3.7.4.6.1 3.7.4.6.2 3.7.4.6.3 3.7.4.6.4 3.8.1.1.1 3.8.1.1.2 3.8.1.1.3 3.8.1.1.4 3.8.1.2.1 3.8.1.2.2 3.8.1.2.3 3.8.1.2.4 Table 1 continued 3.8.1.3.1 3.8.1.3.2 3.8.1.3.3 3.8.1.3.4 3.8.1.4.1 3.8.1.4.2 3.8.1.4.3 3.8.1.4.4 3.8.1.5.1 3.8.1.5.2 3.8.1.5.3 3.8.1.5.4 3.8.1.6.1 3.8.1.6.2 3.8.1.6.3 3.8.1.6.4 3.8.1.7.1 3.8.1.7.2 3.8.1.7.3 3.8.1.7.4 3.8.1.8.1 3.8.1.8.2 3.8.1.8.3 3.8.1.8.4 3.8.2.1.1 3.8.2.1.2 3.8.2.1.3 3.8.2.1.4 3.8.2.2.1 3.8.2.2.2 3.8.2.2.3 3.8.2.2.4 3.8.2.3.1 3.8.2.3.2 3.8.2.3.3 3.8.2.3.4 3.8.2.4.1 3.8.2.4.2 3.8.2.4.3 3.8.2.4.4 3.8.2.5.1 3.8.2.5.2 3.8.2.5.3 3.8.2.5.4 3.8.2.6.1 3.8.2.6.2 3.8.2.6.3 3.8.2.6.4 3.8.2.7.1 3.8.2.7.2 3.8.2.7.3 3.8.2.7.4 3.8.2.8.1 3.8.2.8.2 3.8.2.8.3 3.8.2.8.4 3.8.3.1.1 3.8.3.1.2 3.8.3.1.3 3.8.3.1.4 3.8.3.2.1 3.8.3.2.2 3.8.3.2.3 3.8.3.2.4 3.8.3.3.1 3.8.3.3.2 3.8.3.3.3 3.8.3.3.4 3.8.3.4.1 3.8.3.4.2 3.8.3.4.3 3.8.3.4.4 3.8.3.5.1 3.8.3.5.2 3.8.3.5.3 3.8.3.5.4 3.8.3.6.1 3.8.3.6.2 3.8.3.6.3 3.8.3.6.4 3.8.3.7.1 3.8.3.7.2 3.8.3.7.3 3.8.3.7.4 3.8.3.8.1 3.8.3.8.2 3.8.3.8.3 3.8.3.8.4 3.8.4.1.1 3.8.4.1.2 3.8.4.1.3 3.8.4.1.4 3.8.4.2.1 3.8.4.2.2 3.8.4.2.3 3.8.4.2.4 3.8.4.3.1 3.8.4.3.2 3.8.4.3.3 3.8.4.3.4 3.8.4.4.1 3.8.4.4.2 3.8.4.4.3 3.8.4.4.4 3.8.4.5.1 3.8.4.5.2 3.8.4.5.3 3.8.4.5.4 3.8.4.6.1 3.8.4.6.2 3.8.4.6.3 3.8.4.6.4 3.8.4.7.1 3.8.4.7.2 3.8.4.7.3 3.8.4.7.4 3.8.4.8.1 3.8.4.8.2 3.8.4.8.3 3.8.4.8.4 4.1.1.1.1 4.1.1.1.2 4.1.1.1.3 4.1.1.1.4 4.1.1.2.1 4.1.1.2.2 4.1.1.2.3 4.1.1.2.4 4.1.1.3.1 4.1.1.3.2 4.1.1.3.3 4.1.1.3.4 4.1.1.4.1 4.1.1.4.2 4.1.1.4.3 4.1.1.4.4 4.1.1.5.1 4.1.1.5.2 4.1.1.5.3 4.1.1.5.4 4.1.1.6.1 4.1.1.6.2 4.1.1.6.3 4.1.1.6.4 4.1.1.7.1 4.1.1.7.2 4.1.1.7.3 4.1.1.7.4 4.1.1.8.1 4.1.1.8.2 4.1.1.8.3 4.1.1.8.4 4.1.2.1.1 4.1.2.1.2 4.1.2.1.3 4.1.2.1.4 4.1.2.2.1 4.1.2.2.2 4.1.2.2.3 4.1.2.2.4 4.1.2.3.1 4.1.2.3.2 4.1.2.3.3 4.1.2.3.4 4.1.2.4.1 4.1.2.4.2 4.1.2.4.3 4.1.2.4.4 4.1.2.5.1 4.1.2.5.2 4.1.2.5.3 4.1.2.5.4 4.1.2.6.1 4.1.2.6.2 4.1.2.6.3 4.1.2.6.4 4.1.2.7.1 4.1.2.7.2 4.1.2.7.3 4.1.2.7.4 4.1.2.8.1 4.1.2.8.2 4.1.2.8.3 4.1.2.8.4 4.1.3.1.1 4.1.3.1.2 4.1.3.1.3 4.1.3.1.4 4.1.3.2.1 4.1.3.2.2 4.1.3.2.3 4.1.3.2.4 4.1.3.3.1 4.1.3.3.2 4.1.3.3.3 4.1.3.3.4 4.1.3.4.1 4.1.3.4.2 4.1.3.4.3 4.1.3.4.4 4.1.3.5.1 4.t. 3.5.2 4.1.3.5.3 4.1.3.5.4 4.1.3.6.1 4.1.3.6.2 4.1.3.6.3 4.1.3.6.4 4.1.3.7.1 4.1.3.7.2 4.1.3.7.3 4.1.3.7.4 4.1.3.8.1 4.1.3.8.2 4.1.3.8.3 4.1.3.8.4 4.1.4.1.1 4.1.4.1.2 4.1.4.1.3 4.1.4.1.4 4.1.4.2.1 4.1.4.2.2 4.1.4.2.3 4.1.4.2.4 4.1.4.3.1 4.1.4.3.2 4.1.4.3.3 4.1.4.3.4 4.1.4.4.1 4.1.4.4.2 4.1.4.4.3 4.1.4.4.4 4.1.4.5.1 4.1.4.5.2 4.1.4.5.3 4.1.4.5.4 4.1.4.6.1 4.1.4.6.2 4.1.4.6.3 4.1.4.6.4 4.1.4.7.1 4.1.4.7.2 4.1.4.7.3 4.1.4.7.4 4.1.4.8.1 4.1.4.8.2 4.1.4.8.3 4.1.4.8.4 4.2.1.1.1 4.2.1.1.2 4.2.1.1.3 4.2.1.1.4 4.2.1.2.1 4.2.1.2.2 4.2.1.2.3 4.2.1.2.4 4.2.1.3.1 4.2.1.3.2 4.2.1.3.3 4.2.1.3.4 4.2.1.4.1 4.2.1.4.2 4.2.1.4.3 4.2.1.4.4 4.2.1.5.1 4.2.1.5.2 4.2.1.5.3 4.2.1.5.4 4.2.1.6.1 4.2.1.6.2 4.2.1.6.3 4.2.1.6.4 4.2.1.7.1 4.2.1.7.2 4.2.1.7.3 4.2.1.7.4 4.2.1.8.1 4.2.1.8.2 4.2.1.8.3 4.2.1.8.4 4.2.2.1.1 4.2.2.1.2 4.2.2.1.3 4.2.2.1.4 4.2.2.2.1 4.2.2.2.2 4.2.2.2.3 4.2.2.2.4 4.2.2.3.1 4.2.2.3.2 4.2.2.3.3 4.2.2.3.4 4.2.2.4.1 4.2.2.4.2 4.2.2.4.3 4.2.2.4.4 4.2.2.5.1 4.2.2.5.2 4.2.2.5.3 4.2.2.5.4 4.2.2.6.1 4.2.2.6.2 4.2.2.6.3 4.2.2.6.4 4.2.2.7.1 4.2.2.7.2 4.2.2.7.3 4.2.2.7.4 4.2.2.8.1 4.2.2.8.2 4.2.2.8.3 4.2.2.8.4 4.2.3.1.1 4.2.3.1.2 4.2.3.1.3 4.2.3.1.4 4.2.3.2.1 4.2.3.2.2 4.2.3.2.3 4.2.3.2.4 4.2.3.3.1 4.2.3.3.2 4,2.3.3.3 4.2.3.3.4 4.2.3.4.1 4.2.3.4.2 4.2.3.4,3 4.2.3.4.4 Table 1 continued 4.2.3.5.1 4.2.3.5.2 4.2.3.5.3 4.2.3.5.4 4.2.3.6.1 4.2.3.6.2 4.2.3.6.3 4.2.3.6.4 4.2.3.7.1 4.2.3.7.2 4.2.3.7.3 4.2.3.7.4 4.2.3.8.1 4.2.3.8.2 4.2.3.8.3 4.2.3.8.4 4.2.4.1.1 4.2.4.1.2 4.2.4.1.3 4.2.4.1.4 4.2.4.2.1 4.2.4.2.2 4.2.4.2.3 4.2.4.2.4 4.2.4.3.1 4.2.4.3.2 4.2.4.3.3 4.2.4.3.4 4.2.4.4.1 4.2.4.4.2 4.2.4.4.3 4.2.4.4.4 4.2.4.5.1 4.2.4.5.2 4.2.4.5.3 4.2.4.5.4 4.2.4.6.1 4.2.4.6.2 4.2.4.6.3 4.2.4.6.4 4.2.4.7.1 4.2.4.7.2 4.2.4.7.3 4.2.4.7.4 4.2.4.8.1 4.2.4.8.2 4.2.4.8.3 4.2.4.8.4 4.3.1.1.1 4.3.1.1.2 4.3.1.1.3 4.3.1.1.4 4.3.1.2.1 4.3.1.2.2 4.3.1.2.3 4.3.1.2.4 4.3.1.3.1 4.3.1.3.2 4.3.1.3.3 4.3.1.3.4 4.3.1.4.1 4.3.1.4.2 4.3.1.4.3 4.3.1.4.4 4.3.1.5.1 4.3.1.5.2 4.3.1.5.3 4.3.1.5.4 4.3.1.6.1 4.3.1.6.2 4.3.1.6.3 4.3.1.6.4 4.3.1.7.1 4.3.1.7.2 4.3.1.7.3 4.3.1.7.4 4.3.1.8.1 4.3.1.8.2 4.3.1.8.3 4.3.1.8.4 4.3.2.1.1 4.3.2.1.2 4.3.2.1.3 4.3.2.1.4 4.3.2.2.1 4.3.2.2.2 4.3.2.2.3 4.3.2.2.4 4.3.2.3.1 4.3.2.3.2 4.3.2.3.3 '4.3.2.3.4 4.3.2.4.1 4.3.2.4.2 4.3.2.4.3 4.3.2.4.4 4.3.2.5.1 4.3 .2 .5.2 4.3.2.5.3 4.3.2.5.4 4.3.2.6.1 4.3.2.6.2 4.3.2.6.3 4.3.2.6.4 4.3.2.7.1 4.3.2.7.2 4.3.2.7.3 4.3.2.7.4 4.3.2.8.1 4.3.2.8.2 4.3.2.8.3 4.3.2.8.4 4.3.3.1.1 4.3.3.1.2 4.3.3.1.3 4.3.3.1.4 4.3.3.2.1 4.3.3.2.2 4.3.3.2.3 4.3.3.2.4 4.3.3.3.1 4.3.3.3.2 4.3.3.3.3 4.3.3.3.4 4.3.3.4.1 4.3.3.4.2 4.3.3.4.3 4.3.3.4.4 4.3.3.5.1 4.3.3.5.2 4.3.3.5.3 4.3.3.5.4 4.3.3.6.1 4.3.3.6.2 4.3.3.6.3 4.3.3.6.4 4.3.3.7.1 4.3.3.7.2 4.3.3.7.3 4.3.3.7.4 4.3.3.8.1 4.3.3.8.2 4.3.3.8.3 4.3.3.8.4 4.3.4.1.1 4.3.4.1.2 4.3.4.1.3 4.3.4.1.4 4.3.4.2.1 4.3.4.2.2 4.3.4.2.3 4.3.4.2.4 4.3.4.3.1 4.3.4.3.2 4.3.4.3.3 4.3.4.3.4 4.3.4.4.1 4.3.4.4.2 4.3.4.4.3 4.3.4.4.4 4.3.4.5.1 4.3.4.5.2 4.3.4.5.3 4.3.4.5.4 4.3.4.6.1 4.3.4.6.2 4.3.4.6.3 4.3.4.6.4 4.3.4.7.1 4.3.4.7.2 4.3.4.7.3 4.3.4.7.4 4.3.4.8.1 4.3.4.8.2 4.3.4.8.3 4.3.4.8.4 4.4.1.1.1 4.4.1.1.2 4.4.1.1.3 4.4.1.1.4 4.4.1.2.1 4.4.1.2.2 4.4.1.2.3 4.4.1.2.4 4.4.1.3.1 4.4.1.3.2 4.4.1.3.3 4.4.1.3.4 4.4.1.4.1 4.4.1.4.2 4.4.1.4.3 4.4.1.4.4 4.4.1.5.1 4.4.1.5.2 4.4.1.5.3 4.4.1.5.4 4.4.1.6.1 4.4.1.6.2 4.4.1.6.3 4.4.1.6.4 4.4.1.7.1 4.4.1.7.2 4.4.1.7.3 4.4.1.7.4 4.4.1.8.1 4.4.1.8.2 4.4.1.8.3 4.4.1.8.4 4.4.2.1.1 4.4.2.1.2 4.4.2.1.3 4.4.2.1.4 4.4.2.2.1 4.4.2.2.2 4.4.2.2.3 4.4.2.2.4 4.4.2.3.1 4.4.2.3.2 4.4.2.3.3 4.4.2.3.4 4.4.2.4.1 4.4.2.4.2 4.4.2.4.3 4.4.2.4.4 4.4.2.5.1 4.4.2.5.2 4.4.2.5.3 4.4.2.5.4 4.4.2.6.1 4.4.2.6.2 4.4.2.6.3 4.4.2.6.4 4.4.2.7.1 4.4.2.7.2 4.4.2.7.3 4.4.2.7.4 4.4.2.8.1 4.4.2.8.2 4.4.2.8.3 4.4.2.8.4 4.4.3.1.1 4.4.3.1.2 4.4.3.1.3 4.4.3.1.4 4.4.3.2.1 4.4.3.2.2 4.4.3.2.3 4.4.3.2.4 4.4.3.3.1 4.4.3.3.2 4.4.3.3.3 4.4.3.3.4 4.4.3.4.1 4.4.3.4.2 4.4.3.4.3 4.4.3.4.4 4.4.3.5.1 4.4.3.5.2 4.4.3.5.3 4.4.3.5.4 4.4.3.6.1 4.4.3.6.2 4.4.3.6.3 4.4.3.6.4 4.4.3.7.1 4.4.3.7.2 4.4.3.7.3 4.4.3.7.4 4.4.3.8.1 4.4.3.8.2 4.4.3.8.3 4.4.3.8.4 4.4.4.1.1 4.4.4.1.2 4.4.4.1.3 4.4.4.1.4 4.4.4.2.1 4.4.4.2.2 4.4.4.2.3 4.4.4.2.4 4.4.4.3.1 4.4.4.3.2 4.4.4.3.3 4.4.4.3.4 4.4.4.4.1 4.4.4.4.2 4.4.4.4.3 4.4.4.4.4 4.4.4.5.1 4.4.4.5.2 4.4.4.5.3 4.4.4.5.4 4.4.4.6.1 4.4.4.6.2 4.4.4.6.3 4.4.4.6.4 4.4.4.7.1 4.4.4.7.2 4.4.4.7.3 4.4.4.7.4 4.4.4.8.1 4.4.4.8.2 4.4.4.8.3 4.4.4.8.4 4.5.1.1.1 4.5.1.1.2 4.5.1.1.3 4.5.1.1.4 4.5.1.2.1 4.5.1.2.2 4.5.1.2.3 4.5.1.2.4 4.5.1.3.1 4.5.1.3.2 4.5.1.3.3 4.5.1.3.4 4.5.1.4.1 4.5.1.4.2 4.5.1.4.3 4.5.1.4.4 4.5.1.5.1 4.5.1.5.2 4.5.1.5.3 4.5.1.5.4 4.5.1.6.1 4.5.1.6.2 4.5.1.6.3 4.5.1.6.4 Table 1 continued 4.5.1.7.1 4.5.1.7.2 4.5.1.7.3 4.5.1.7.4 4.5.1.8.1 4.5.1.8.2 4.5.1.8.3 4.5.1.8.4 4.5.2.1.1 4.5.2.1.2 4.5.2.1.3 4.5.2.1.4 4.5.2.2.1 4.5.2.2.2 4.5.2.2.3 4.5.2.2.4 4.5.2.3.1 4.5.2.3.2 4.5.2.3.3 4.5.2.3.4 4.5.2.4.1 4.5.2.4.2 4.5.2.4.3 4.5.2.4.4 4.5.2.5.1 4.5.2.5.2 4.5.2.5.3 4.5.2.5.4 4.5.2.6.1 4.5.2.6.2 4.5.2.6.3 4.5.2.6.4 4.5.2.7.1 4.5.2.7.2 4.5.2.7.3 4.5.2.7.4 4.5.2.8.1 4.5.2.8.2 4.5.2.8.3 4.5.2.8.4 4.5.3.1.1 4.5.3.1.2 4.5.3.1.3 4.5.3.1.4 4.5.3.2.1 4.5.3.2.2 4.5.3 .2.3 4.5.3.2.4 4.5.3.3.1 4.5.3.3.2 4.5.3.3.3 4.5.3.3.4 4.5.3.4.1 4.5.3.4.2 4.5.3.4.3 4.5.3.4.4 4.5.3.5.1 4.5.3.5.2 4.5.3.5.3 4.5.3.5.4 4.5.3.6.1 4.5.3.6.2 4.5.3.6.3 4.5.3.6.4 4.5.3.7.1 4.5.3.7.2 4.5.3.7.3 4.5.3.7.4 4.5.3.8.1 4.5.3.8.2 4.5.3.8.3 4.5.3.8.4 4.5.4.1.1 4.5.4.1.2 4.5.4.1.3 4.5.4.1.4 4.5.4.2.1 4.5.4.2.2 4.5.4.2.3 4.5.4.2.4 4.5.4.3.1 4.5.4.3.2 4.5.4.3.3 4.5.4.3.4 4.5.4.4.1 4.5.4.4.2 4.5.4.4.3 4.5.4.4.4 4.5.4.5.1 4.5.4.5.2 4.5.4.5.3 4.5.4.5.4 4.5.4.6.1 4.5.4.6.2 4.5.4.6.3 4.5.4.6.4 4.5.4.7.1 4.5.4.7.2 4.5.4.7.3 4.5.4.7.4 4.5.4.8.1 4.5.4.8.2 4.5.4.8.3 4.5.4.8.4 4.6.1.1.1 4.6.1.1.2 4.6.1.1.3 4.6.1.1.4 4.6.1.2.1 4.6.1.2.2 4.6.1.2.3 4.6.1.2.4 4.6.1.3.1 4.6.1.3.2 4.6.1.3.3 4.6.1.3.4 4.6.1.4.1 4.6.1.4.2 4.6.1.4.3 4.6.1.4.4 4.6.1.5.1 4.6.1.5.2 4.6.1.5.3 4.6.1.5.4 4.6.1.6.1 4.6.1.6.2 4.6.1.6.3 4.6.1.6.4 4.6.1.7.1 4.6.1.7.2 4.6.1.7.3 4.6.1.7.4 4.6.1.8.1 4.6.1.8.2 4.6.1.8.3 4.6.1.8.4 4.6.2.1.1 4.6.2.1.2 4.6.2.1.3 4.6.2.1.4 4.6.2.2.1 4.6.2.2.2 4.6.2.2.3 4.6.2.2.4 4.6.2.3.1 4.6.2.3.2 4.6.2.3.3 4.6.2.3.4 4.6.2.4.1 4.6.2.4.2 4.6.2.4.3 4.6.2.4.4 4.6.2.5.1 4.6.2.5.2 4.6.2.5.3 4.6.2.5.4 4.6.2.6.1 4.6.2.6.2 4.6.2.6.3 4.6.2.6.4 4.6.2.7.1 4.6.2.7.2 4.6.2.7.3 4.6.2.7.4 4.6.2.8.1 4.6.2.8.2 4.6.2.8.3 4.6.2.8.4 4.6.3.1.1 4.6.3.1.2 4.6.3.1.3 4.6.3.1.4 4.6.3.2.1 4.6.3.2.2 4.6.3.2.3 4.6.3.2.4 4.6.3.3.1 4.6.3.3.2 4.6.3.3.3 4.6.3.3.4 4.6.3.4.1 4.6.3.4.2 4.6.3.4.3 4.6.3.4.4 4.6.3.5.1 4.6.3.5.2 4.6.3.5.3 4.6.3.5.4 4.6.3.6.1 4.6.3.6.2 4.6.3.6.3 4.6.3.6.4 4.6.3.7.1 4.6.3.7.2 4.6.3.7.3 4.6.3.7.4 4.6.3.8.1 4.6.3.8.2 4.6.3.8.3 4.6.3.8.4 4.6.4.1.1 4.6.4.1.2 4.6.4.1.3 4.6.4.1.4 4.6.4.2.1 4.6.4.2.2 4.6.4.2.3 4.6.4.2.4 4.6.4.3.1 4.6.4.3.2 4.6.4.3.3 4.6.4.3.4 4.6.4.4.1 4.6.4.4.2 4.6.4.4.3 4.6.4.4.4 4.6.4.5.1 4.6.4.5.2 4.6.4.5.3 4.6.4.5.4 4.6.4,6.1 4.6.4.6.2 4.6.4.6.3 4.6.4.6.4 4.6.4.7.1 4.6.4.7.2 4.6.4.7.3 4.6.4.7.4 4.6.4.8.1 4.6.4.8.2 4.6.4.8.3 4.6.4.8.4 4.7.1.1.1 4.7.1.1.2 4.7.1.1.3 4.7.1.1.4 4.7.1.2.1 4.7.1.2.2 4.7.1.2.3 4.7.1.2.4 4.7.1.3.1 4.7.1.3.2 4.7.1.3.3 4.7.1.3.4 4.7.1.4.1 4.7.1.4.2 4.7.1.4.3 4.7.1.4.4 4.7.1.5.1 4.7.1.5.2 4.7.1.5.3 4.7.1.5.4 4.7.1.6.1 4.7.1.6.2 4.7.1.6.3 4.7.1.6.4 4.7.1.7.1 4.7.1.7.2 4.7.1.7.3 4.7.1.7.4 4.7.1.8.1 4.7.1.8.2 4.7.1.8.3 4.7.1.8.4 4.7.2.1.1 4.7.2.1.2 4.7.2.1.3 4.7.2.1.4 4.7.2.2.1 4.7.2.2.2 4.7.2.2.3 4.7.2.2.4 4.7.2.3.1 4.7.2.3.2 4.7.2.3.3 4.7.2.3.4 4.7.2.4.1 4.7.2.4.2 4.7.2.4.3 4.7.2.4.4 4.7.2.5.1 4.7.2.5.2 4.7.2.5.3 4.7.2.5.4 4.7.2.6.1 4.7.2.6.2 4.7.2.6.3 4.7.2.6.4 4.7.2.7.1 4.7.2.7.2 4.7.2.7.3 4.7.2.7.4 4.7.2.8.1 4.7.2.8.2 4.7.2.8.3 4.7.2.8.4 4.7.3. 1.1i 4.7.3.1.2 4.7.3.1.3 4.7.3.1.4 4.7.3.2.1 4.7.3.2.2 4.7.3.2.3 4.7.3.2.4 4.7.3.3.1 4.7.3.3.2 4.7.3.3.3 4.7.3.3.4 4.7.3.4.1 4.7.3.4.2 4.7.3,4.3 4.7.3.4.4 4.7.3.5.1 4.7.3.5.2 4.7.3.5.3 4.7.3.5.4 4.7.3.6.1 4.7.3.6.2 4.7.3.6.3 4.7.3.6.4 4.7.3.7.1 4.7.3.7.2 4.7.3.7.3 4.7.3.7.4 4.7.3.8.1 4.7.3.8.2 4.7.3.8.3 4.7.3.8.4 Table 1 continued 4.7.4.1.1 4.7.4.1.2 4.7.4.1.3 4.7.4.1.4 4.7.4.2.1 4.7.4.2.2 4.7.4.2.3 4.7.4.2.4 4.7.4.3.1 4.7.4.5.1 4.7.4.7.1 4.8.1.1.1 4.8.1.3.1 4.8.1.5.1 4. 8. t.7.1 4.8.2.1.1 4.8.2.3.1 4.8.2.5.1 4.8.2.7.1 4.8.3.1.1 4.8.3.3.1 4.8.3.5.1 4.8.3.7,1 4.8.4.1.1 4.8.4.3.1 4.8.4.5.1 4.8.4.7.1 1.1.1. 1 5.1.1.3.1 5.1.1.7.1 5.1.2.1.1 5.1.2.3.1 1.2.5. 1 5.1.2.7.1 5.1.3.1.1 5.1.3.3.1 5.1.3.5.1 1.3 .7.1 5.1.4.1.1 5.1.4.3.1 1.4.5. 1 5.1.4.7.1 5.2.1.1.1 1.3.1 5.2.1.5.1 1.7.1 1.1 4.7.4.3.2 4.7.4.5.2 4.7.4.7.2 4.8.1.1.2 4.8. 1.3 .2 4.8.1.5.2 4.8.1.7.2 4.8 1.2 4.8.2.3.2 4.8.2.5.2 4.8.2.7.2 4.8.3.1.2 4.8.3.3.2 4.8.3.5.2 4. 8.3 .7.2 4.8.4.1.2 4.8.4.3.2 4.8.4.5.2 4.8.4.7.2 5.1.1.1.2 5.1.1.3.2 5.1.1.5.2 5. 1.1.7.2 5. 1.2.1.2 5.1.2.3.2 5. 1.2.5 .2 5.1.2.7.2 5.1.3.1.2 5.1.3.3.2 5.1.3.5.2 5. 1.3 .7.2 5. 1.4. 1.2 5.1.4.3.2 5.1.4.5.2 5.1.4.7.2 5 1. 1.2 5 1.3 .2 5 1.5 .2 5 1.7.2 5.2.2.1.2 4.7.4.3.3 4.7.4.5.3 4.7.4.7.3 4. 8.1. 1.3 4.8.1.3.3 4.8.1.5.3 4.8.1.7.3 4.8.2.1.3 4.8.2.3.3 4.8.2.5.3 4.8.2.7.3 4.8.3.1.3 4.8.3.3.3 4.8.3.5.3 4.8.3.7.3 4.8.4.1.3 4.8.4.3.3 4.8.4.5.3 4.8.4.7.3 5.1.1.1.3 5.1.1.3.3 5.1.1.5.3 5.1.1.7.3 5.1.2.1.3 5.1.2.3.3 5.1.2.5.3 5.1.2.7.3 5 .1.3 .1.3 5.1.3.3.3 5.1.3.5.3 5.1.3.7.3 5.1.4.1.3 5.1.4.3.3 5.1.4.5.3 5 .1.4.7.3 5 .2.1.1.3 5 1.3 .3 5.2.1.5.3 5.2.1.7.3 5.2.2.1.3 4.7.4.3.4 4.7.4.5.4 4.7.4.7.4 4.8.1. 1.4 4.8.1.3.4 4.8.1.5.4 4.8.1.7.4 4.8.2.1.4 4.8.2.3.4 4.8.2.5.4 4.8.2.7.4 4.8.3.1.4 4.8.3.3.4 4.8.3.5.4 4.8.3.7.4 4.8.4. 1.4 4.8.4.3.4 4.8.4.5.4 4.8.4.7.4 5.1.1.1.4 5.1.1.3.4 5 1.5.4 5 1.7.4 5.1.2.1.4 5.1.2.3.4 5.1.2.5.4 5.1.2.7.4 5.1.3.1.4 5.1.3.3.4 5.1.3.5.4 5.1.3.7.4 5. 1.4.1.4 5.1.4.3.4 5.1.4.5.4 5.1.4.7.4 5 1. 1.4 5 .2.1.3.4 5.2.1.5.4 5 1.7.4 5.2.2.1.4 4.7.4.4.1 4.7.4.6.1 4.7.4.8.1 4. 8. 1.2. 1 4.8.1.4.1 4.8. 1.6. 1 4. 8.1.8. 1 4.8.2.2.1 4.8.2.4.1 4.8.2.6.1 4.8.2.8.1 4.8.3.2.1 4.8.3.4.1 4.8.3.6.1 4.8.3.8.1 4.8.4.2.1 4.8.4.4.1 4.8.4.6.1 4.8.4.8.1 5.1.1.2.1 5.1. 1.4.1 5. 1.1.6. 1 5.1.1.8.1 5. 1.2.2.1 5.1.2.4.1 5.1.2.6.1 5. 1.2.8.1i 5.1.3.2.1 5.1.3.4.1 5.1.3.6.1 5.1.3.8.1 5.1.4.2.1 5. 1.4.4. 1 5.1.4.6.1 5. 1.4.8.1 5.2.1.2.1 5.2. 1.4.1 5.2.1.6.1 4.7.4.4.2 4.7.4.6.2 4.7.4.8.2 4.8.1.2.2 4.8.1.4.2 4.8. 1.6.2 4.8.1.8.2 4.8.2.2.2 4.8.2.4.2 4.8.2.6.2 4.8.2.8.2 4.8.3.2.2 4.8.3.4.2 4.8.3.6.2 4.8.3.8.2 4.8.4.2.2 4.8.4.4.2 4.8.4.6.2 4.8.4.8.2 5.1. 1.2.2 5.1. 1.4.2 5.1.1.6.2 5. 1.1.8.2 5.1.2.2.2 5. 1.2.4.2 5. 1.2.6.2 5.1.2.8.2 5.1.3.2.2 5.1.3.4.2 5.1.3.6.2 5.1.3.8.2 5.1.4.2.2 5.1.4.4.2 5. 1.4.6.2 5.1.4.8.2 5.2.1.2.2 5.2.1.4.2 5.2.1.6.2 4.7.4.4.3 4.7.4.6.3 4.7.4.8.3 4.8.1.2.3 4.8.1.4.3 4.8.1.6.3 4.8.1.8.3 4.8.2.2.3 4.8.2.4.3 4.8.2.6.3 4.8.2.8.3 4.8.3.2.3 4.8.3.4.3 4.8.3.6.3 4.8.3.8.3 4.8.4.2.3 4.8.4.4.3 4.8.4.6.3 4.8 .4.8.3 5 1.2 .3 5.1.1.4.3 5 1.6 .3 5.1.1.8.3 5.1.2.2.3 5.1.2.4.3 5 .1.2.6.3 5.1.2.8.3 5.1.3.2.3 5.1.3.4.3 5 .1.3 .6.3 5.1.3.8.3 5.1.4.2.3 5.1.4.4.3 5.1.4.6.3 5.1.4.8.3 5.2.1.2.3 5 1.4.3 5 1.6.3 5 1.8 .3 4.7.4.4.4 4.7.4.6.4 4.7.4.8.4 4.8. 1.2.4 4.8.1.4.4 4.8. 1.6.4 4.8.1.8.4 4.8.2.2.4 4.8.2.4.4 4.8.2.6.4 4.8.2.8.4 4.8.3.2.4 4.8.3.4.4 4.8.3.6.4 4.8.3.8.4 4.8.4.2.4 4.8.4.4.4 4.8.4.6.4 4.8.4.8.4 5.1.1.2.4 5. 1.1.4.4 5. 1. 1.6.4 5.1. 1.8.4 5.1.2.2.4 5.1.2.4.4 5.1.2.6.4 5. 1.2.8.4 5.1.3.2.4 5.1.3.4.4 5.1.3.6.4 5.1.3.8.4 5.1.4.2.4 5. 1.4.4.4 5. 1.4.6.4 5.1.4.8.4 5.2.1.2.4 5.2.1.4.4 5 1.6.4 5 1.8.4 5.2.1.8.1 5.2.1.8.2 5.2.2.2.1 5.2.2.2.2 5.2.2.2.3 5.2.2.2.4 Table 1 continiued 5.2.2.3.1 5.2.2.3.2 5.2.2.3.3 5.2.2.3.4 5.2.2.4.1 5.2.2.4.2 5.2.2.4.3 5.2.2.4.4 5.2.2.5.1 5.2.2.5.2 5.2.2.5.3 5.2.2.5.4 5.2.2.6.1 5.2.2.6.2 5.2.2.6.3 5.2.2.6.4 5.2.2.7.1 5.2.2.7.2 5.2.2.7.3 5.2.2.7.4 5.2.2.8.1 5.2.2.8.2 5.2.2.8.3 5.2.2.8.4 5.2.3.1.1 5.2.3.1.2 5.2.3.1.3 5.2.3.1.4 5.2.3.2.1 5.2.3.2.2 5.2.3.2.3 5.2.3.2.4 5.2.3.3.1 5.2.3.3.2 5.2.3.3.3 5.2.3.3.4 5.2.3.4.1 5.2.3.4.2 5.2.3.4.3 5.2.3.4.4 5.2.3.5.1 5.2.3.5.2 5.2.3.5.3 5.2.3.5.4 5.2.3.6.1 5.2.3.6.2 5.2.3.6.3 5.2.3.6.4 5.2.3.7.1 5.2.3.7.2 5.2.3.7.3 5.2.3.7.4 5.2.3.8.1 5.2.3.8.2 5.2.3.8.3 5.2.3.8.4 5.2.4.1.1 5.2.4.1.2 5.2.4.1.3 5.2.4.1.4 5.2.4.2.1 5.2.4.2.2 5.2.4.2.3 5.2.4.2.4 5.2.4.3.1 5.2.4.3.2 5.2.4.3.3 5.2.4.3.4 5.2.4.4.1 5.2.4.4.2 5.2.4.4.3 5.2.4.4.4 5.2.4.5.1 5.2.4.5.2 5.2.4.5.3 5.2.4.5.4 5.2.4.6.1 5.2.4.6.2 5.2.4.6.3 5.2.4.6.4 5.2.4.7.1 5.2.4.7.2 5.2.4.7.3 5.2.4.7.4 5.2.4.8.1 5.2.4.8.2 5.2.4.8.3 5.2.4.8.4 5.3.1.1.1 5.3.1.1.2 5.3.1.1.3 5.3.1.1.4 5.3.1.2.1 5.3.1.2.2 5.3.1.2.3 5.3.1.2.4 5.3.1.3.1 5.3.1.3.2 5.3.1.3.3 5.3.1.3.4 5.3.1.4.1 5.3.1.4.2 5.3.1.4.3 5.3.1.4.4 5.3.1.5.1 5.3.1.5.2 5.3.1.5.3 5.3.1.5.4 5.3.1.6.1 5.3.1.6.2 5.3.1.6.3 5.3.1.6.4 5.3.1.7.1 5.3.1.7.2 5.3.1.7.3 5.3.1.7.4 5.3.1.8.1 5.3.1.8.2 5.3.1.8.3 5.3.1.8.4 5.3.2.1.1 5.3.2.1.2 5.3.2.1.3 5.3.2.1.4 5.3.2.2.1 5.3.2.2.2 5.3.2.2.3 5.3.2.2.4 5.3.2.3.1 5.3.2.3.2 5.3.2.3.3 5.3.2.3.4 5.3.2.4.1 5.3.2.4.2 5.3.2.4.3 5.3.2.4.4 5.3.2.5.1 5.3.2.5.2 5.3.2.5.3 5.3.2.5.4 5.3.2.6.1 5.3.2.6.2 5.3.2.6.3 5.3.2.6.4 5.3.2.7.1 5.3.2.7.2 5.3.2.7.3 5.3.2.7.4 5.3.2.8.1- 5.3.2.8.2 5.3.2.8.3 5.3.2.8.4 5.3.3.1.1 5.3,3.1.2 5.3.3.1.3 5.3.3.1.4 5.3.3.2.1 5.3.3.2.2 5.3.3.2.3 5.3.3.2.4 5.3.3.3.1 5.3.3.3.2 5.3.3.3.3 5.3.3.3.4 5.3.3.4.1 5.3.3.4.2 5.3.3.4.3 5.3.3.4.4 5.3.3.5.1 5.3.3.5.2 5.3.3.5.3 5.3.3.5.4 5.3.3.6.1 5.3.3.6.2 5.3.3.6.3 5.3.3.6.4 5.3.3.7.1 5.3.3.7.2 5.3.3.7.3 5.3.3.7.4 5.3.3.8.1 5.3.3.8.2 5.3.3.8.3 5.3.3.8.4 5.3.4.1.1 5.3.4.1.2 5.3.4.1.3 5.3.4.1.4 5.3.4.2.1 5.3.4.2.2 5.3.4.2.3 5.3.4.2.4 5.3.4.3.1 5.3.4.3.2 5.3.4.3.3 5.3.4.3.4 5.3.4.4.1 5.3.4.4.2 5.3.4.4.3 5.3.4.4.4 5.3.4.5.1 5.3.4.5.2 5.3.4.5.3 5.3.4.5.4 5.3.4.6.1 5.3.4.6.2 5.3.4.6.3 5.3.4.6.4 5.3.4.7.1 5.3.4.7.2 5.3.4.7.3 5.3.4.7.4 5.3.4.8.1 5.3.4.8.2 5.3.4.8.3 5.3.4.8.4 5.4.1.1.1 5.4.1.1.2 5.4.1.1.3 5.4.1.1.4 5.4.1.2.1 5.4.1.2.2 5.4.1.2.3 5.4.1.2.4 5.4.1.3.1 5.4.1.3.2 5.4.1.3.3 5.4.1.3.4 5.4.1.4.1 5.4.1.4.2 5.4.1.4.3 5.4.1.4.4 5.4.1.5.1 5.4.1.5.2 5.4.1.5.3 5.4.1.5.4 5.4.1.6.1 5.4.1.6.2 5.4.1.6.3 5.4.1.6.4 5.4.1.7.1 5.4.1.7.2 5.4.1.7.3 5.4.1.7.4 5.4.1.8.1 5.4.1.8.2 5.4.1.8.3 5.4.1.8.4 5.4.2.1.1 5.4.2.1.2 5.4.2.1.3 5.4.2.1.4 5.4.2.2.1 5.4.2.2.2 5.4.2.2.3 5.4.2.2.4 5.4.2.3.1 5.4.2.3.2 5.4.2.3.3 5.4.2.3.4 5.4.2.4.1 5.4.2.4.2 5.4.2.4.3 5.4.2.4.4 5.4.2.5.1 5.4.2.5.2 5.4.2.5.3 5.4.2.5.4 5.4.2.6.1 5.4.2.6.2 5.4.2.6.3 5.4.2.6.4 5.4.2.7.1 5.4.2.7.2 5.4.2.7.3 5.4.2.7.4 5.4.2.8.1 5.4.2.8.2 5.4.2.8.3 5.4.2.8.4 5.4.3.1.1 5.4.3.1.2 5.4.3.1.3 5.4.3.1.4 5.4.3.2.1 5.4.3.2.2 5.4.3.2.3 5.4.3.2.4 5.4.3.3.1 5.4.3.3.2 5.4.3.3.3 5.4.3.3.4 5.4.3.4.1 5.4.3.4.2 5.4.3.4.3 5.4.3.4.4 5.4.3.5.1 5.4,3.5.2 5.4.3.5.3 5.4.3.5.4 5.4.3.6.1 5.4.3.6.2 5.4.3.6.3 5.4.3.6.4 5.4.3.7.1 5.4.3.7.2 5.4.3.7.3 5.4.3.7.4 5.4.3.8.1 5.4.3.8.2 5.4.3.8.3 5.4.3.8.4 5.4.4.1.1 5.4.4.1.2 5.4.4.1.3 5.4.4.1.4 5.4.4.2.1 5.4.4.2.2 5.4.4.2.3 5.4.4.2.4 5.4.4.3.1 5.4.4.3.2 5.4.4.3.3 5.4.4.3.4 5.4.4.4.1 5.4.4.4.2 5.4.4.4.3 5.4.4.4.4 Table 1 continued 5.4.4.5.1 5.4.4.5.2 5.4.4.5.3 5.4.4.5.4 5.4.4.6.1 5.4.4.6.2 5.4.4.6.3 5.4.4.6.4 5.4.4.7.1 5.4.4.7.2 5.4.4.7.3 5.4.4.7.4 5.4.4.8.1 5.4.4.8.2 5.4.4.8.3 5.4.4.8.4 5.5.1.1.1 5.5.1.1.2 5.5.1.1.3 5.5.1.1.4 5.5.1.2.1 5.5.1.2.2 5.5.1.2.3 5.5.1.2.4 5.5.1.3.1 5.5.1.3.2 5.5.1.3.3 5.5.1.3.4 5.5.1.4.1 5.5.1.4.2 5.5.1.4.3 5.5.1.4.4 5.5.1.5.1 5.5.1.5.2 5.5.1.5.3 5.5.1.5.4 5.5.1.6.1 5.5.1.6.2 5.5.1.6.3 5.5.1.6.4 5.5.1.7.1 5.5.1.7.2 5.5.1.7.3 5.5.1.7.4 5.5.1.8.1 5.5.1.8.2 5.5.1.8.3 5.5.1.8.4 5.5.2.1.1 5.5.2.1.2 5.5.2.1.3 5.5.2.1.4 5.5.2.2.1 5.5.2.2.2 5.5.2.2.3 5.5.2.2.4 5.5.2.3.1 5.5.2.3.2 5.5.2.3.3 5.5.2.3.4 5.5.2.4.1 5.5.2.4.2 5.5.2.4.3 5.5.2.4.4 5.5.2.5.1 5.5.2.5.2 5.5.2.5.3 5.5.2.5.4 5.5.2.6.1 5.5.2.6.2 5.5.2.6.3 5.5.2.6.4 5.5.2.7.1 5.5.2.7.2 5.5.2.7.3 5.5.2.7.4 5.5.2.8.1 5.5.2.8.2 5.5.2.8.3 5.5.2.8.4 5.5.3.1.1 5.5.3.1.2 5.5.3.1.3 5.5.3.1.4 5.5.3.2.1 5.5.3.2.2 5.5.3.2.3 5.5.3.2.4 5.5.3.3.1 5.5.3.3.2 5.5.3.3.3 5.5.3.3.4 5.5.3.4.1 5.5.3.4.2 5.5.3.4.3 5.5.3.4.4 5.5.3.5.1 5.5.3.5.2 5.5.3.5.3 5.5.3.5.4 5.5.3.6.1 5.5.3.6.2 5.5.3.6.3 5.5.3.6.4 5.5.3.7.1 5.5.3.7.2 5.5.3.7.3 5.5.3.7.4 5.5.3.8.1 5.5.3.8.2 5.5.3.8.3 5.5.3.8.4 5.5.4.1.1 5.5.4.1.2 5.5.4.1.3 5.5.4.1.4 5.5.4.2.1 5.5.4.2.2 5.5.4.2.3 5.5.4.2.4 5.5.4.3.1 5.5.4.3.2 5.5.4.3.3 5.5.4.3.4 5.5.4.4.1 5.5.4.4.2 5.5.4.4.3 5.5.4.4.4 5.5.4.5.1 5.5.4.5.2 5.5.4.5.3 5.5.4.5.4 5.5.4.6.1 5.5.4.6.2 5.5.4.6.3 5.5.4.6.4 5.5.4.7.1 5.5.4.7.2 5.5.4.7.3 5.5.4.7.4 5.5.4.8.1 5.5.4.8.2 5.5.4.8.3 5.5.4.8.4 5.6.1.1.1 5.6.1.1.2 5.6.1.1.3 5.6.1.1.4 5.6.1.2.1 5.6.1.2.2 5.6.1.2.3 5.6.1.2.4 5.6.1.3.1 5.6.1.3.2 5.6.1.3.3 5.6.1.3.4 5.6.1.4.1 5.6.1.4.2 5.6.1.4.3 5.6.1.4.4 5.6.1.5.1 5.6.1.5.2 5.6.1.5.3 5.6.1.5.4 5.6.1.6.1 5.6.1.6.2 5.6.1.6.3 5.6.1.6.4 5.6.1.7.1 5.6.1.7.2 5.6.1.7.3 5.6.1.7.4 5.6.1.8.1 5.6.1.8.2 5.6.1.8.3 5.6.1.8.4 5.6.2.1.1 5.6.2.1.2 5.6.2.1.3 5.6.2.1.4 5.6.2.2.1 5.6.2.2.2 5.6.2.2.3 5.6.2.2.4 5.6.2.3.1 5.6.2.3.2 5.6.2.3.3 5.6.2.3.4 5.6.2.4.1 5.6.2.4.2 5.6.2.4.3 5.6.2.4.4 5.6.2.5.1 5.6.2.5.2 5.6.2.5.3 5.6.2.5.4 5.6.2.6.1 5.6.2.6.2 5.6.2.6.3 5.6.2.6.4 5.6.2.7.1 5.6.2,7.2 5.6.2.7.3 5.6.2.7.4 5.6.2.8.1 5.6.2.8.2 5.6.2.8.3 5.6.2.8.4 5.6.3.1.1 5.6.3.1.2 5.6.3.1.3 5.6.3.1.4 5.6.3.2.1 5.6.3.2.2 5.6.3.2.3 5.6.3.2.4 5.6.3.3.1 5.6.3.3.2 5.6.3.3.3 5.6.3.3.4 5.6.3.4.1 5.6.3.4.2 5.6.3.4.3 5.6.3.4.4 5.6.3.5.1 5.6.3.5.2 5.6.3.5.3 5.6.3.5.4 5.6.3.6.1 5.6.3.6.2 5.6.3.6.3 5.6.3.6.4 5.6.3.7.1 5.6.3.7.2 5.6.3.7.3 5.6.3.7.4 5.6.3.8.1 5.6.3.8.2 5.6.3.8.3 5.6.3.8.4 5.6.4.1.1 5.6.4.1.2 5.6.4.1.3 5.6.4.1.4 5.6.4.2.1 5.6.4.2.2 5.6.4.2.3 5.6.4.2.4 5.6.4.3.1 5.6.4.3.2 5.6.4.3.3 5.6.4.3.4 5.6.4.4.1 5.6.4.4.2 5.6.4.4.3 5.6.4.4.4 5.6.4.5.1 5.6.4,5.2 5.6 .4 .5.3 5.6.4.5.4 5.6.4.6.1 5.6 .4.6 .2 5.6.4.6.3 5.6.4.6.4 5.6.4.7.1 5.6.4.7.2 5.6.4.7.3 5.6.4.7.4 5.6.4.8.1 5.6.4.8.2 5.6.4.8.3 5.6.4.8.4 5.7.1.1.1 5.7.1.1.2 5.7.1.1.3 5.7.1.1.4 5.7.1.2.1 5.7.1.2.2 5.7.1.2.3 5.7.1.2.4 5.7.1.3.1 5.7.1.3.2 5.7.1.3.3 5.7.1.3.4 5.7.1.4.1 5.7.1.4.2 5.7.1.4.3 5.7.1.4.4 5.7.1.5.1 5.7.1.5.2 5.7.1.5.3 5.7.1.5.4 5.7.1.6.1 5.7.1.6.2 5.7.1.6.3 5.7.1.6.4 5.7.1.7.1 5.7.1.7.2 5.7.1.7.3 5.7.1.7.4 5.7.1.8.1 5.7.1.8.2 5.7.1.8.3 5.7.1.8.4 5.7.2.1.1 5.7.2.1.2 5.7.2.1.3 5.7.2.1.4 5.7.2.2.1 5.7.2.2.2 5.7.2.2.3 5.7.2.2.4 5.7.2.3.1 5.7.2.3.2 5.7.2.3.3 5.7.2.3.4 5.7.2.4.1 5.7.2.4.2 5.7.2.4.3 5.7.2.4.4 5.7 .2 .5.1 5.7.2.5.2 5.7.2.5.3 5.7.2.5.4 5.7.2.6.1 5.7.2.6.2 5.7.2.6.3 5.7.2.6.4 Table 1 continued 5.7.2.7.1 5.7.2.7.2 5.7.2.7.3 5.7.2.7.4 5.7.2.8.1 5.7.2.8.2 5.7.2.8.3 5.7.2.8.4 5.7.3.1.1 5.7.3.1.2 5.7.3.1.3 5.7.3.1.4 5.7.3.2.1 5.7.3.2.2 5.7.3.2.3 5.7.3.2.4 5.7.3.3.1 5.7.3.3.2 5.7.3.3.3 5.7.3.3.4 5.7.3.4.1 5.7.3.4.2 5.7.3.4.3 5.7.3.4.4 5.7.3.5.1 5.7.3.5.2 5.7.3.5.3 5.7.3.5.4 5.7.3.6.1 5.7.3.6.2 5.7.3.6.3 5.7.3.6.4 5.7.3.7.1 5.7.3.7.2 5.7.3.7.3 5.7.3.7.4 5.7.3.8.1 5.7.3.8.2 5.7.3.8.3 5.7.3.8.4 5.7.4.1.1 5.7.4.1.2 5.7.4.1.3 5.7.4.1.4 5.7.4.2.1 5.7.4.2.2 5.7.4.2.3 5.7.4.2.4 5.7.4.3.1 5.7.4.3.2 5.7.4.3.3 5.7.4.3.4 5.7.4.4.1 5.7.4.4.2 5.7.4.4.3 5.7.4.4.4 5.7.4.5.1 5.7.4.5.2 5.7.4.5.3 5.7.4.5.4 5.7.4.6.1 5.7.4.6.2 5.7.4.6.3 5.7.4.6.4 5.7.4.7.1 5.7.4.7.2 5.7.4.7.3 5.7.4.7.4 5.7.4.8.1 5.7.4.8.2 5.7.4.8.3 5.7.4.8.4 5.8.1.1.1 5.8.1.1.2 5.8.1.1.3 5.8.1.1.4 5.8.1.2.1 5.8.1.2.2 5.8.1.2.3 5.8.1.2.4 5.8.1.3.1 5.8.1.3.2 5.8.1.3.3 5.8.1.3.4 5.8.1.4.1 5.8.1.4.2 5.8.1.4.3 5.8.1.4.4 5.8.1.5.1 5.8.1.5.2 5.8.1.5.3 5.8.1.5.4 5.8.1.6.1 5.8.1.6.2 5.8.1.6.3 5.8.1.6.4 5.8.1.7.1 5.8.1.7.2 5.8.1.7.3 5.8.1.7.4 5.8.1.8.1 5,8.1.8.2 5.8.1.8.3 5.8.1.8.4 5.8.2.1.1 5.8.2.1.2 5.8.2.1.3 5.8.2.1.4 5.8.2.2.1 5.8.2.2.2 5.8.2.2.3 5.8.2.2.4 5.8.2.3.1 5.8.2.3.2 5.8.2.3.3 5.8.2.3.4 5.8.2.4.1 5.8.2.4.2 5.8.2.4.3 5.8.2.4.4 5.8.2.5.1 5.8.2.5.2 5.8.2.5.3 5.8.2.5.4 5.8.2.6.1 5.8.2.6.2 5.8.2.6.3 5.8.2.6.4 5.8.2.7.1t 5.8.2.7.2 5.8.2.7.3 5.8.2.7.4 5.8.2.8.1 5.8.2.8.2 5.8.2.8.3 5.8.2.8.4 5.8.3.1.1 5.8.3.1.2 5.8.3.1.3 5.8.3.1.4 5.8.3.2.1 5.8.3.2.2 5.8.3.2.3 5.8.3.2.4 5.8.3.3.1 5.8.3.3.2 5.8.3.3.3 5.8.3.3.4 5.8.3.4.1 5.8.3.4.2 5.8.3.4.3 5.8.3.4.4 5.8 .3.5.1 5.8.3.5.2 5.8.3.5.3 5.8.3.5.4 5.8.3.6.1 5.8.3.6.2 5.8.3.6.3 5.8.3.6.4 5.8.3.7.1 5.8.3.7.2 5.8.3.7.3 5.8.3.7.4 5.8.3.8.1 5.8.3.8.2 5.8.3.8.3 5.8.3.8.4 5.8.4.1.1 5.8.4.1.2 5.8.4.1.3 5.8.4.1.4 5.8.4.2.1 5.8.4.2.2 5.8.4.2.3 5.8.4.2.4 5.8.4.3.1 5.8.4.3.2 5.8.4.3.3 5.8.4.3.4 5.8.4.4.1 5.8.4.4.2 5.8.4.4.3 5.8.4.4.4 5.8 .4 .5.1 5.8 .4 .5.2 5.8.4.5.3 5.8.4.5.4 5.8.4.6.1 5.8.4.6.2 5.8.4.6.3 5.8.4.6.4 5.8.4.7.1 5.8.4.7.2 5.8.4.7.3 5.8.4.7.4 5.8.4.8.1 5.8.4.8.2 5.8.4.8.3 5.8.4.8.4 6.1.1.1.1 6.1.1.1.2 6.1.1.1.3 6.1.1.1.4 6.1.1.2.1 6.1.1.2.2 6.1.1.2.3 6.1.1.2.4 6.1.1.3.1 6.1.1.3.2 6.1.1.3.3 6.1.1.3.4 6.1.1.4.1 6.1.1.4.2 6.1.1.4.3 6.1.1.4.4 6.1.1.5.1 6.1.1.5.2 6.1.1.5.3 6.1.1.5.4 6.1.1.6.1 6.1.1.6.2 6.1.1.6.3 6.1.1.6.4 6.1.1.7.1 6.1.1.7.2 6.1.1.7.3 6.1.1.7.4 6.1.1.8.1 6.1.1.8.2 6.1.1.8.3 6.1. ,1.8.4 6.1.2.1.1 6.1.2.1.2 6.1.2.1.3 6.1.2.1.4 6.1.2.2.1 6.1.2.2.2 6.1.2.2.3 6.1.2.2.4 6.1.2.3.1 6.1.2.3.2 6.1.2.3.3 6.1.2.3.4 6.1.2.4.1 6.1.2.4.2 6.1.2.4.3 6.1.2.4.4 6.1.2.5.1 6.1.2.5.2 6.1.2.5.3 6.1 .2 .5.4 6.1.2.6.1 6.1.2.6.2 6.1.2.6.3 6.1.2.6.4 6.1.2.7.1 6.1.2.7.2 6.1.2.7.3 6.1.2.7.4 6.1.2.8.1 6.1.2.8.2 6.1.2.8.3 6.1.2.8.4 6.1.3.1.1 6.1.3.1.2 6.1.3.1.3 6.1.3.1.4 6.1.3.2.1 6.1.3.2.2 6.1.3.2.3 6.1.3.2.4 6.1.3.3.1 6.1.3.3.2 6.1.3.3.3 6.1.3.3.4 6.1.3.4.1 6.1.3.4.2 6.1.3.4.3 6.1.3.4.4 6.1.3.5.1 6.1.3.5.2 6.1.3.5.3 6.1.3.5.4 6.1.3.6.1 6.1.3.6.2 6.1.3.6.3 6.1.3.6.4 6.1.3.7.1 6.1.3.7.2 6.1.3.7.3 6.1.3.7.4 6.1.3.8.1 6.1.3.8.2 6.1.3.8.3 6.1.3.8.4 6.1.4.1.1 6.1.4.1.2 6.1.4.1.3 6.1.4.1.4 6.1.4.2.1 6.1.4.2.2 6.1.4.2.3 6.1.4.2.4 6.1.4.3.1 6.-1.4.3.2 6.1.4.3.3 6.1.4.3.4 6.1.4.4.1 6.1.4.4.2 6.1.4.4.3 6.1.4.4.4 6.1.4.5.1 6.1.4.5.2 6.1.4.5.3 6.1.4.5.4 6.1.4.6.1 6.1.4.6.2 6.1.4.6.3 6.1.4.6.4 6.1.4.7.1 6.1.4.7.2 6.1.4.7.3 6.1.4.7.4 6.1.4.8.1 6.1.4.8.2 6.1.4.8.3 6.1.4.8.4 Table 1 continued 13 62 1 14 62 12 1 62. 6.2.1.3.1 6.2.1.1.2 6.2.1.3.3 6.2.1.3.4 6.2.1.2.1 6.2.1.2.2 6.2.1.2.3 6.2.1.2.4 6.2.1.3.1 6.2.1.3.2 6.2.1.3.3 6.2.1.3.4 6.2.1.4.1 6.2.1.4.2 6.2.1.4.3 6.2.1.4.4 6.2.1.5.1 6.2.1.5.2 6.2.1.5.3 6.2.1.7.4 6.2.1.8.1 6.2.1.6.2 6.2.1.6.3 6.2.1.6.4 IND 6.2.21.1 6.2.21.2 6.2.21.3 6.2.21.4 6.2.1.8.1 6.2.1.8.2 6.2.1.8.3 6.2.1.8.4 6.2.2.1.1 6.2.2.1.2 6.2.2.1.3 6.2.2.1.4 6.2.2.2.1 6.2.2.2.2 6.2.2.2.3 6.2.2.2.4 6.2.2.3.1 6.2.2.3.2 6.2.2.3.3 6.2.2.3.4 6.2.2.4.1 6.2.2.4.2 6.2.2.4.3 6.2.2.4.4 6.2.2.5.1 6.2.2.5.2 6.2.2.5.3 6.2.2.5.4 6.2.2.6.1 6.2.2.6.2 6.2.2.8.3 6.2.2.6.4 6.2.2.7.1 6.2.2.7.2 6.2.2.1.3 6.2.2.7.4 6.2.32.1 6.2.32.2 6.2.328.3 6.2.32.4 6.2.3.1.1 6.2.3.1.2 6.2.3.1.3 6.2.3.1.4 6.2.3.2.1 6.2.3.2.2 6.2.3.2.3 6.2.3.4 6.2.3.3.1 6.2.3.3.2 6.2.3.3.3 6.2.3.3.4 6.2.3.4.1 6.2.3.4.2 6.2.3.4.3 6.2.3.4.4 6.2.3.7.1 6.2.3.5.2 6.2.3.5.3 6.2.3.5.4 6.2.3.6.1 6.2.3.6.2 6.2.3.6.3 6.2.3.8.4 6.2.3.7.1 6.2.3.7.2 6.2.3.7.3 6.2.4.7.4 6.2.4.8.1 6.2.3.2.2 6.2.3.8.3 6.2.3.2.4 6.2.4.3.1 6.2.4.1.2 6.2.4.1.3 6.2.4.3.4 6.2.4.2.1 6.2.4.2.2 6.2.4.2.3 6.2.4.2.4 6.2.4.3.1 6.2.4.3.2 6.2.4.3.3 6.2.4.5.4 6.2.4.4.1 6.2.4.4.2 6.2.4.4.3 6.2.4.4.4 6.2.4.7.1 6.2.4.5.2 6.2.4.5.3 6.2.4.5.4 6.2.4.8.1 6.2.4.8.2 6.2.4.8.3 6.2.4.6.4 6.2.4.7.1 6.2.1.7.2 6.2.4.7.3 6.2.4.1.4 6.2.4.8.1 6.2.4.8.2 6.2.4.2.3 6.2.4.8.4 6.3.1.1.1 6.3.1.3.2 6.3.1.1.3 6.3.1.1.4 6.3.1.2.1 6.3.1.2.2 6.3.1.2.3 6.3.1.2.4 6.3.1.3.1 6.3.1.3.2 6.3.1.3.3 6.3.1.3.4 6.3.1.6.1 6.3.1.4.2 6.3.1.4.3 6.3.1.4.4 6.3.1.5.1 6.3.1.5.2 6.3.1.5.3 6.3.1.5.4 6.3.1.6.1 6.3.1.6.2 6.3.1.6.3 6.3.1.6.4 6.3.217.1 6.3.217.2 6.3.217.3 6.3.217.4 6.3.1.8.1 6.3.1.8.2 6.3.1.2.3 6.3.2.8.4 6.3.2.1.1 6.3.2.3.2 6.3.2.3.3 6.3.2.1.4 6.3.2.2.1 6.3.2.2.2 6.3.2.2.3 6.3.2.2.4 6.3.2.3.1 6.3.2.3.2 6.3.2.3.3 6.3.2.3.4 6.3.2.4.1 6.3.2.4.2 6.3.2.4.3 6.3.2.4.4 6.3.2.5.1 6.3.2.5.2 6.3.2.7.3 6.3.2.7.4 6.3.2.6.1 6.3.2.6.2 6.3.2.6.3 6.3.2.6.4 6.3.2.7.1 6.3.2.71.2 6.3.2.7.3 6.3.2.7.4 6.3.328.1 6.3.328.2 6.3.32.3 6.3.32.4 6.3.3.1.1 6.3.3.1.2 6.3.3.3.3 6.3.3.3.4 6.3.3.2.1 6.3.3.2.2 6.3.3.2.3 6.3.3.2.4 6.3.3.3.1 6.3.3.3.2 6.3.3.3.3 6.3.3.3.4 6.3.3.4.1 6.3.3.4.2 6.3.3.4.3 6.3.3.4.4 6.3.3.5.1 6.3.3.7.2 6.3.3.7.3 6.3.3.5.4 6.3.3.8.1 6.3.3.6.2 6.3.3.6.3 6.3.3.6.4 6.3.3.7.1 6.3.3.7.2 6.3.3.7.3 6.3.3.7.4 6.3.3.8.1 6.3.3.2.2 6.3.3.2.3 6.3.3.8.4 6.3.4.1.1 6.3.4.3.2 6.3.4.1.3 6.3.4.1.4 6.3.4.2.1 6.3.4.2.2 6.3.4.2.3 6.3.4.2.4 6.3.4.3.1 6.3.4.3.2 6.3.4.3.3 6.3.4.3.4 6.3.4.4.1 6.3.4.4.2 6.3.4.4.3 6.3.4.4.4 6.3.4.5.1 6.3.4.5.2 6.3.4.5.3 6.3.4.5.4 6.3.4.6.1 6.3.4.6.2 6.3.4.6.3 6.3.4.6.4 6.34.7..1 6.34.7..2 6.34.7..3 6.34.7..4 6.34.8..1 6.34...2 6.34.8..3 6.34.8..4 3 6.4.1.1.1 6.4.1.1.2 6.4.1.1.3 6.4.1.1.4 6.4.1.2.1 6.4.1.2.2 6.4.1.2.3 6.4.1.2.4 6.4.1.3.1 6.4.1.3.2 6.4.1.3.3 6.4.1.3.4 6.4.1.4.1 6.4.1.4.2 6.4.1.4.3 6.4.1.4.4 6.4.1.5.1 6.4.1.7.2 6.4.1.5.3 6.4.1.5.4 6.4.1.6.1 6.4.1.8.2 6.4.1.6.3 6.4.1.6.4 6.4.21.1 6.4.217.2 6.4.217.3 6.4.217.4 6.4.1.2.1 6.4.1.8.2 6.4.1.8.3 6.4.1.2.4 6.4.2.1.1 6.4.2.1.2 6.4.2.1.3 6.4.2.1.4 6.4.2.2.1 6.4.2.2.2 6.4.2.2.3 6.4.2.2.4 6.4.2.3.1 6.4.2.3.2 6.4.2.3.3 6.4.2.3.4 6.4.2.4.1 6.4.2.4.2 6.4.2.4.3 6.4.2.4.4 6.4.2.5.1 6.4.2.5.2 6.4.2.5.3 6.4.2.5.4 6.4.2.6.1 6.4.2.6.2 6.4.2.6.3 6.4.2.6.4 6.4.3.1.1 6.4.3.1.2 6.4.3.1.3 6.4.3.1.4 6.4.3.2.1 6.4.3.2.2 6.4.3.2.3 6.4.3.2.4 Table 1 continued 6.4.3.3.1 6.4.3.3.2 6.4.3.3.3 6.4.3.3.4 6.4.3.4.1 6.4.3.4.2 6.4.3.4.3 6.4.3.4.4 6.4.3,5.1 6.4.3.5.2 6.4.3.5.3 6.4.3.5.4 6.4.3.6.1 6.4.3.6.2 6.4.3.6.3 6.4.3.6.4 6.4.3.7.1 6.4.3.7.2 6.4.3.7.3 6.4.3.7.4 6.4.3.8.1 6.4.3.8.2 6.4.3.8.3 6.4.3.8.4 6.4.4.1.1 6.4.4.1.2 6.4.4.1.3 6.4.4.1.4 6.4.4.2.1 6.4.4.2.2 6.4.4.2.3 6.4.4.2.4 6.4.4.3.1 6.4.4.3.2 6.4.4.3.3 6.4.4.3.4 6.4.4.4.1 6.4.4.4.2 6.4.4.4.3 6.4.4.4.4 6.4.4.5.1 6.4.4.5.2 6.4.4.5.3 6.4.4.5.4 6.4.4.6.1 6.4.4.6.2 6.4.4.6.3 6.4.4.6.4 6.4.4.7.1 6.4.4.7.2 6.4.4.7.3 6.4.4.7.4 6.4.4.8.1 6.4.4.8.2 6.4.4.8.3 6.4.4.8.4 6.5.1.1.1 6.5.1.1.2 6.5.1.1.3 6.5.1.1.4 6.5.1.2.1 6.5.1.2.2 6.5.1.2.3 6.5.1.2.4 6.5.1.3.1 6.5.1.3.2 6.5.1.3.3 6.5.1.3.4 6.5. t.4.1 6.5.1.4.2 6.5.1.4.3 6.5.1.4.4 6.5.1.5.1 6.5.1.5.2 6.5.1.5.3 6.5.1.5.4 6.5.1.6.1 6.5.1.6.2 6.5.1.6.3 6.5.1.6.4 6.5.1.7.1 6.5.1.7.2 6.5.1.7.3 6.5.1.7.4 6.5.1.8.1 6.5.1.8.2 6.5.1.8.3 6.5.1.8.4 6.5.2.1.1 6.5.2.1.2 6.5.2.1.3 6.5.2.1.4 6.5.2.2.1 6.5.2.2.2 6.5.2.2.3 6.5.2.2.4 6.5.2.3.1 6.5.2.3.2 6.5.2.3.3 6.5.2.3.4 6.5.2.4.1 6.5.2.4.2 6.5.2.4.3 6.5.2.4.4 6.5.2.5.1 6.5.2.5.2 6.5.2.5.3 6.5.2.5.4 6.5.2.6.1 6.5.2.6.2 6.5.2.6.3 6.5.2.6.4 6.5.2.7.1 6.5.2.7.2 6.5.2.7.3 6.5.2.7.4 6.5.2.8.1 6.5.2.8.2 6.5.2.8.3 6.5.2.8.4 6.5.3.1.1 6.5.3.1.2 6.5.3.1.3 6.5.3.1.4 6.5.3.2.1 6.5.3.2.2 6.5.3.2.3 6.5.3.2.4 6.5.3.3.1 6.5.3.3.2 6.5.3.3.3 6.5.3.3.4 6.5.3.4.1 6.5.3.4.2 6.5.3.4.3 6.5.3.4.4 6.5.3.5.1 6.5.3.5.2 6.5.3.5.3 6.5.3.5.4 6.5.3.6.1 6.5.3.6.2 6.5.3.6.3 6.5.3.6.4 6.5.3.7.1 6.5.3.7.2 6.5.3.7.3 6.5.3.7.4 6.5.3.8.1 6.5.3.8.2 6.5.3.8.3 6.5.3.8.4 6.5.4.1.1 6.5.4.1.2 6.5.4.1.3 6.5.4.1.4 6.5.4.2.1 6.5.4.2,2 6.5.4.2.3 6.5.4.2.4 6.5.4.3.1 6.5.4.3.2 6.5.4.3.3 6.5.4.3.4 6.5.4.4.1 6.5.4.4.2 6.5.4.4.3 6.5.4.4.4 6.5.4.5.1 6.5.4.5.2 6.5.4.5.3 6.5.4.5.4 6.5.4.6.1 6.5.4.6.2 6.5.4.6.3 6.5.4.6.4 6.5.4.7.1 6.5.4.7.2 6.5.4.7.3 6.5.4.7.4 6.5.4.8.1 6.5.4.8.2 6.5.4.8.3 6.5.4.8.4 6.6.1.1.1 6.6.1.1.2 6.6.1.1.3 6.6.1.1.4 6.6.1.2.1 6.6.1.2.2 6.6.1.2.3 6.6.1.2.4 6.6.1.3.1 6.6.1.3.2 6.6.1.3.3 6.6.1.3.4 6.6.1.4.1 6.6.1.4.2 6.6.1.4.3 6.6.1.4.4 6.6.1.5.1 6.6.1.5.2 6.6.1.5.3 6.6.1.5.4 6.6.1.6.1 6.6.1.6.2 6.6.1.6.3 6.6.1.6.4 6.6.1.7.1 6.6.1.7.2 6.6.1.7.3 6.6.1.7.4 6.6.1.8.1 6.6.1.8.2 6.6.1.8.3 6.6.1.8.4 6.6.2.1.1 6.6.2.1.2 6.6.2.1.3 6.6.2.1.4 6.6.2.2.1 6.6.2.2.2 6.6.2.2.3 6.6.2.2.4 6.6.2.3.1 6.6.2.3.2 6.6.2.3.3 6.6.2.3.4 6.6.2.4.1 6.6.2.4.2 6.6.2.4.3 6.6.2.4.4 6.6.2.5.1 6.6.2.5.2 6.6.2.5.3 6.6.2.5.4 6.6.2.6.1 6.6.2.6.2 6.6.2.6.3 6.6.2.6.4 6.6.2.7. 1 6.6.2.7.2 6.6.2.7.3 6.6.2.7.4 6.6.2.8.1 6.6.2.8.2 6.6.2.8.3 6.6.2.8.4 6.6.3.1.1 6.6.3.1.2 6.6.3.1.3 6.6.3.1.4 6.6.3.2.1 6.6.3.2.2 6.6.3.2.3 6.6.3.2.4 6.6.3.3.1 6.6.3.3.2 6.6.3.3.3 6.6.3.3.4 6.6.3.4.1 6.6.3.4.2 6.6.3.4.3 6.6.3.4.4 6.6.3.5.1 6.6.3.5.2 6.6.3.5.3 6.6.3.5.4 6.6.3.6.1 6.6.3.6.2 6.6.3.6.3 6.6.3.6.4 6.6.3.7.1 6.6.3.7.2 6.6.3.7.3 6.6.3.7.4 6.6.3.8.1 6.6.3.8.2 6.6.3.8.3 6.6.3.8.4 6.6.4.1.1 6.6.4.1.2 6.6.4.1.3 6.6.4.1.4 6.6.4.2.1 6.6.4.2.2 6.6.4;2.3 6.6.4.2.4 6.6.4.3.1 6.6.4.3.2 6.6.4.3.3 6.6.4.3.4 6.6.4.4.1 6.6.4.4.2 6.6.4.4.3 6.6.4.4.4 6.6.4.5.1 6.6.4.5.2 6.6.4.5.3 6.6.4.5.4 6.6.4.6.1 6.6.4.6.2 6.6.4.6.3 6.6.4.6.4 6.6.4.7.1 6.6.4.7.2 6.6.4.7.3 6.6.4.7.4 6.6.4.8.1 6.6.4.8.2 6.6.4.8.3 6.6.4.8.4 6.7.1.1.1 6.7.1.1.2 6.7.1.1.3 6.7.1.1.4 6.7.1.2.1 6.7.1.2.2 6.7.1.2.3 6.7.1.2.4 6.7.1.3.1 6.7.1.3.2 6.7.1.3.3 6.7.1.3.4 6.7.1.4.1 6.7.1.4.2 6.7.1.4.3 6.7.1.4.4 Table 1 continued 6.7.1.5.1 6.7.1.5.2 6.7.1.5.3 6.7.1.5.4 6.7.1.6.1 6.7.1.6.2 6.7.1.6.3 6.7.1.6.4 6.7.1.7.1 6.7.1.7.2 6.7.1.7.3 6.7.1.7.4 6.7.1.8.1 6.7.1.8.2 6.7.1.8.3 6.7.1.8.4 6.7.2.1.1 6.7.2.1.2 6.7.2.1.3 6.7.2.1.4 6.7.2.2.1 6.7.2.2.2 6.7.2.2.3 6.7.2.2.4 6.7.2.3.1 6.7.2.3.2 6.7.2.3.3 6.7.2.3.4 6.7.2.4.1 6.7.2.4.2 6.7.2.4.3 6.7.2.4.4 6.7.2.5.1 6.7.2.5.2 6.7.2.5.3 6.7.2.5.4 6.7.2.6.1 6.7.2.6.2 6.7.2.6.3 6.7.2.6.4 6.7.2.7.1 6.7.2.7.2 6.7.2.7.3 6.7.2.7.4 6.7.2.8.1 6.7.2.8.2 6.7.2.8.3 6.7.2.8.4 6.7.3.1.1 6.7.3.1.2 6.7.3.1.3 6.7.3.1.4 6.7.3.2.1 6.7.3.2.2 6.7.3.2.3 6.7.3.2.4 6.7.3.3.1 6.7.3.3.2 6.7.3.3.3 6.7.3.3.4 6.7.3.4.1 6.7.3.4.2 6.7.3.4.3 6.7.3.4.4 6.7.3.5.1 6.7.3.5.2 6.7.3.5.3 6.7.3.5.4 6.7.3.6.1 6.7.3.6.2 6.7.3.6.3 6.7.3.6.4 6.7.3.7.1 6.7.3.7.2 6.7.3.7.3 6.7.3.7.4 6.7.3.8.1 6.7.3.8.2 6.7.3.8.3 6.7.3.8.4 6.7.4.1.1 6.7.4.1.2 6.7.4.1.3 6.7.4.1.4 6.7.4.2.1 6.7.4.2.2 6.7.4.2.3 6.7.4.2.4 6.7.4.3.1 6.7.4.3.2 6.7.4.3.3 6.7.4.3.4 6.7.4.4.1 6.7.4.4.2 6.7.4.4.3 6.7.4.4.4 6.7.4.5.1 6.7.4.5.2 6.7.4.5.3 6.7.4.5.4 6.7.4.6.1 6.7.4.6.2 6.7.4.6.3 6.7.4.6.4 6.7.4.7.1 6.7.4.7.2 6.7.4.7.3 6.7.4.7.4 6.7.4.8.1 6.7.4.8.2 6.7.4.8.3 6.7.4.8.4 6.8.1.1.1 6.8.1.1.2 6.8.1.1.3 6.8.1.1.4 6.8.1.2.1 6.8.1.2.2 6.8.1.2.3 6.8.1.2.4 6.8.1.3.1 6.8.1.3.2 6.8.1.3.3 6.8.1.3.4 6.8.1.4.1 6.8.1.4.2 6.8.1.4.3 6.8.1.4.4 6.8.1.5.1 6.8.1.5.2 6.8.1.5.3 6.8.1.5.4 6.8.1.6.1 6.8.1.6.2 6.8.1.6.3 6.8.1.6.4 6.8.1.7.1 6.8.1.7.2 6.8.1.7.3 6.8.1.7.4 6.8.1.8.1 6.8.1.8.2 6.8.1.8.3 6.8.1.8.4 6.8.2.1.1 6.8.2.1.2 6.8.2.1.3 6.8.2.1.4 6.8.2.2.1 6.8.2.2.2 6.8.2.2.3 6.8.2.2.4 6.8.2.3.1 6.8.2.3.2 6.8.2.3.3 6.8.2.3.4 6.8.2.4.1 6.8.2.4.2 6.8.2.4.3 6.8.2.4.4 6.8.2.5.1 6.8.2.5.2 6.8.2.5.3 6.8.2.5.4 6.8.2.6.1 6.8.2.6.2 6.8.2.6.3 6.8.2.6.4 6.8.2.7.1 6.8.2.7.2 6.8.2.7.3 6.8.2.7.4 6.8.2.8.1 6.8.2.8.2 6.8.2.8,3 6.8.2.8.4 6.8.3.1.1 6.8.3.1.2 6.8.3.1.3 6.8.3.1.4 6.8.3.2.1 6.8.3.2.2 6.8.3.2.3 6.8.3.2.4 6.8.3.3.1 6.8.3.3.2 6.8.3.3.3 6.8.3.3.4 6.8.3.4.1 6.8.3.4.2 6.8.3.4.3 6.8.3.4.4 6.8.3.5.1 6.8.3.5.2 6.8.3.5.3 6.8.3.5.4 6.8.3.6.1 6.8.3.6.2 6.8.3.6.3 6.8.3.6.4 6.8.3.7.1 6.8.3.7.2 6.8.3.7.3 6.8.3.7.4 6.8.3.8.1 6.8.3.8.2 6.8.3.8.3 6.8.3.8.4 6.8.4.1.1 6.8.4.1.2 6.8.4.1.3 6.8.4.1.4 6.8.4.2.1 6.8.4.2.2 6.8.4.2.3 6.8.4.2.4 6.8.4.3.1 6.8.4.3.2 6.8.4.3.3 6.8.4.3.4 6.8.4.4.1 6.8.4.4.2 6.8.4.4.3 6.8.4.4.4 6.8.4.5.1 6.8.4.5.2 6.8.4.5.3 6.8.4.5.4 6.8.4.6.1 6.8.4.6.2 6.8.4.6,3 6.8.4.6.4 6.8.4.7.1 6.8.4.7.2 6.8.4.7.3 6.8.4.7.4 6.8.4.8.1 6.8.4.8.2 6.8.4.8.3 6.8.4.8.4 7.1.1.1.1 7.1.1.1.2 7.1.1.1.3 7.1.1.1.4 7.1.1.2.1 7.1.1.2.2 7.1.1.2.3 7.1.1.2.4 7.1.1.3.1 7.1.1.3.2 7.1.1.3.3 7.1.1.3.4 7.1.1.4.1 7.1.1.4.2 7.1.1.4.3 7.1.1.4.4 7.1.1.5.1 7.1.1.5.2 7.1.1.5.3 7.1.1.5.4 7.1.1.6.1 7.1.1.6.2 7.1.1.6.3 7.1.1.6.4 7.1.1.7.1 7.1.1.7.2 7.1.1.7.3 7.1.1.7.4 7.1.1.8.1 7.1.1.8.2 7.1.1.8.3 7.1.1.8.4 7.1.2.1.1 7.1.2.1.2 7.1.2.1.3 7.1.2.1.4 7.1.2.2.1 7.1.2.2.2 7.1.2.2.3 7.1.2.2.4 7.1.2.3.1 7.1.2.3.2 7.1.2.3.3 7.1.2.3.4 7.1.2.4.1 7.1.2.4.2 7.1.2.4.3 7.1.2.4.4 7.1.2.5.1 7.1.2.5.2 7.1.2.5.3 7.1.2.5.4 7.1.2.6.1 7.1.2.6.2 7.1.2.6.3 7.1.2.6.4 7.1.2.7.1 7.1.2.7.2 7.1.2.7.3 7.1.2.7.4 7.1.2.8.1 7.1.2.8.2 7.1.2.8.3 7.1.2.8.4 7.1.3.1.1 7.1.3.1.2 7.1.3.1.3 7.1.3.1.4 7.1.3.2.1 7.1.3.2.2 7.1.3.2.3 7.1.3.2.4 7.1.3.3.1 7.1.3.3.2 7.1.3.3.3 7.1.3.3.4 7.1.3.4.1 7.1.3.4.2 7.1.3.4.3 7.1.3.4.4 7.1.3.5.1 7.1.3.5.2 7.1.3.5.3 7.1.3.5.4 7.1.3.6.1 7.1.3.6.2 7.1.3.6.3 7.1.3.6.4 Table 1 continued 7.1.3.7.1 7.1.3.7.2 7.1.3.7.3 7.1.3.7.4 7.1.3.8.1 7.1.3.8.2 7.1.3.8.3 7.1.3.8.4 7.1.4.1.1 7.1.4.1.2 7.1.4.1.3 7.1.4.1.4 7.1.4.2.1 7.1.4.2.2 7.1.4.2.3 7.1.4.2.4 7.1.4.3.1 7.1.4.3.2 7.1.4.3.3 7.1.4.3.4 7.1.4.4.1 7.1.4.4,2 7.1.4.4.3 7.1.4.4.4 7.1.4.5.1 7.1.4.5.2 7.1.4.5.3 7.1.4.5.4 7.1.4.6.1 7.1.4.6.2 7.1.4.6.3 7.1.4.6.4 7.1.4.7.1 7.1.4.7.2 7.1.4.7.3 7.1.4.7.4 7.1.4.8.1 7.1.4.8.2 7.1.4.8.3 7.1.4.8.4 7.2.1.1.1 7.2.1.1.2 7.2.1.1.3 7.2.1.1.4 7.2.1.2.1 7.2.1.2.2 7.2.1.2.3 7.2.1.2.4 7.2.1.3.1 7.2.1.3.2 7.2.1.3.3 7.2.1.3.4 7.2.1.4.1 7.2.1.4.2 7.2.1.4.3 7.2.1.4.4 7.2.1.5.1 7.2.1.5.2 7.2.1.5.3 7.2.1.5.4 7.2.1.6.1 7.2.1.6.2 7.2.1.6.3 7.2.1.6.4 7.2.1.7.1 7.2.1.7.2 7.2.1.7.3 7.2.1.7.4 7.2.1.8.1 7.2.1.8.2 7.2.1.8.3 7.2.1.8.4 7.2.2.1.1 7.2.2.1.2 7.2.2.1.3 7.2.2.1.4 7.2.2.2.1 7.2.2.2.2 7.2.2.2.3 7.2.2.2.4 7.2.2.3.1 7.2.2.3.2 7.2.2.3.3 7.2.2.3.4 7.2.2.4.1 7.2.2.4.2 7.2.2.4.3 7.2.2.4.4 7.2.2.5.1 7.2.2.5.2 7.2.2.5.3 7.2.2.5.4 7.2.2.6.1 7.2.2.6.2 7.2.2.6.3 7.2.2.6.4 7.2.2,7.1 7.2.2.7.2 7.2.2.7.3 7.2.2.7.4 7.2.2.8.1 7.2.2.8.2 7.2.2.3.3 7.2.2.8.4 7.2.3.1.1 7.2.3.1.2 7.2.3.1.3 7.2.3.1.4 7.2.3.2.1 7.2.3.2.2 7.2.3.2.3 7.2.3.2.4 7.2.3.3.1 7.2.3.3.2 7.2.3.3.3 7.2.3.3.4 7.2.3.4.1 7.2.3.4.2 7.2.3.4.3 7.2.3.4.4 7.2.3.5.1 7.2.3.5.2 7.2.3.5.3 7.2.3.5.4 7.2.3.6.1 7.2.3.6.2 7.2.3.6.3 7.2.3.6.4 7.2.3.7.1 7.2.3.7.2 7.2.3.7.3 7.2.3.7.4 7.2.3.8.1 7.2.3.8.2 7.2.3.8.3 7.2.3.8.4 7.2.4.1.1 7.2.4.1.2 7.2.4.1.3 7.2.4.1.4 7.2.4.2.1 7.2.4.2.2 7.2.4.2.3 7.2.4.2.4 7.2.4.3.1 7.2.4.3.2 7.2.4.3.3 7.2.4.3.4 7.2.4.4.1 7.2.4.4.2 7.2.4.4.3 7.2.4.4.4 7.2.4.5.1 7.2.4.5.2 7.2.4.5.3 7.2.4.5.4 7.2.4.6.1 7.2.4.6.2 7.2.4.6.3 7.2.4.6.4 7.2.4,7.1 7.2.4.7.2 7.2.4.7.3 7.2.4.7.4 7.2.4.8.1 7.2.4.8.2 7.2.4.8.3 7.2.4.8.4 7.3.1.1.1 7.3.1.1.2 7.3.1.1.3 7.3.1.1.4 7.3.1.2.1 7.3.1.2.2 7.3.1.2.3 7.3.1.2.4 7.3.1.3.1 7.3.1.3.2 7.3.1.3.3 7.3.1.3.4 7.3.1.4.1 7.3.1.4.2 7.3.1.4.3 7.3.1.4.4 7.3.1.5.1 7.3.1.5.2 7.3.1.5.3 7.3.1.5.4 7.3.1.6.1 7.3.1.6.2 7.3.1.6.3 7.3.1.6.4 7.3.1.7.1 7.3.1.7.2 7.3.1.7.3 7.3.1.7.4 7.3.1.8.1 7.3.1.8.2 7.3.1.8.3 7.3.1.8.4 7.3.2.1.1 7.3.2.1.2 7.3.2.1.3 7.3.2.1.4 7.3.2.2.1 7.3.2.2.2 7.3.2.2.3 7.3.2.2.4 7.3.2.3.1 7.3.2.3.2 7.3.2.3.3 7.3.2.3.4 7.3.2.4.1 7.3.2.4.2 7.3.2.4.3 7.3.2.4.4 7.3.2.5.1 7.3.2.5.2 7.3.2.5.3 7.3.2.5.4 7.3.2.6.1 7.3.2.6.2 7.3.2.6.3 7.3.2.6.4 7.3.2.7.1 7.3.2.7.2 7.3.2.7.3 7.3.2.7.4 7.3.2.8.1 7.3.2.8.2 7.3.2.8.3 7.3.2.8.4 7.3.3.1.1 7.3.3.1.2 7.3.3.1.3 7.3.3.1.4 7.3.3.2.1 7.3.3.2.2 7.3.3.2.3 7.3.3.2.4 7.3.3.3.1 7.3.3.3.2 7.3.3.3.3 7.3.3.3.4 7.3.3.4.1 7.3.3.4.2 7.3.3.4.3 7.3.3.4.4 7.3.3.5.1 7.3.3.5.2 7.3.3.5.3 7.3.3.5.4 7.3.3.6.1 7.3.3.6.2 7.3.3.6.3 7.3.3.6.4 7.3.3.7.1 7.3.3.7.2 7.3.3.7.3 7.3.3.7.4 7.3.3.8.1 7.3.3.8.2 7.3.3.8.3 7.3.3.8.4 7.3.4.1.1 7.3.4.1.2 7.3-.4.1.3 7.3.4.1.4 7.3.4.2.1 7.3.4.2.2 7.3.4.2.3 7.3.4.2.4 7.3.4.3.1 7.3.4.3.2 7.3.4.3.3 7.3.4.3.4 7.3.4.4.1 7.3.4.4.2 7.3.4.4.3 7.3.4.4.4 7.3.4.5.1 7.3.4.5.2 7.3.4.5.3 7.3.4.5.4 7.3.4.6.1 7.3.4.6.2 7.3.4.6.3 7.3.4.6.4 7.3.4.7.1 7.3.4.7.2 7.3.4.7.3 7.3.4.7.4 7.3.4.8.1 7.3.4.8.2 7.3.4.8.3 7.3.4.8.4 7.4.1.1.1 7.4.1.1.2 7.4.1.1.3 7.4.1.1.4 7.4.1.2.1 7.4.1.2.2 7.4.1.2.3 7.4.1.2.4 7.4.1.3.1 7.4.1.3.2 7.4.1.3.3 7.4.1.3.4 7.4.1.4.1 7.4.1.4.2 7.4.1.4.3 7.4.1.4.4 7.4.1.5.1 7.4.1.5.2 7.4.1.5.3 7.4.1.5.4 7.4.1.6.1 7.4.1.6.2 7.4.1.6.3 7.4.1.6.4 7.4.1.7.1 7.4.1.7.2 7.4.1.7.3 7.4.1.7.4 7.4.1.8.1 7.4.1.8.2 7.4.1.8.3 7.4.1.8.4 Table 1 continued 7.4.2.1.1 7.4.2.1.2 7.4.2.1.3 7.4.2.1.4 7.4.2.2.1 7.4.2.2.2 7.4.2.2.3 7.4.2.2.4 7.4.2.3.1 7.4.2.5.1 7.4.2.7.1 7.4.3.1.1 7.4.3.3.1 7.4.3.5.1 7.4.3.7.1 7.4.4.1.1 7.4.4.3.1 7.4.4.5.1 7.4.4.7.1 7.5.1.1.1 7.5.1.3.1 7.5.1.5.1 7.5.1.7.1 1. 1 7.5.2.3.1 7.5.2.5.1 7.5.2.7.1 7.5.3.1.1 7.5.3.3.1 7.5.3.5.1 7.5.3.7.1 1. 1 7.5.4.3.1 7.5.4.5.1 7.5.4.7.1 7.6.1.1.1 7.6. 1.3. 1 7.6.1.5.1 7.6. 1.7.1 7.6.2.1. 1 7.6.2.3.1 7.6.2.5.1 7.6.2.7.1 7.6.3.1. 1 7.6.3.3.1 7.6.3.5.1 7.6.3.7.1 7.6.4.1.1 7.4.2.3.2 7.4.2.5.2 7.4.2.7.2 7.4.3.1.2 7.4.3.3.2 7.4.3.5.2 7.4.3.7.2 7.4.4.1.2 7.4.4.3.2 7.4.4.5.2 7.4.4.7.2 7.5.1.1.2 7.5.1.3.2 7.5.1.5.2 7.5.1.7.2 7.5 1.2 7.5 .2.3 .2 7.5.2.5.2 7.5.2.7.2 7.5.3.1.2 7.5 .3 .3.2 7.5.3.5.2 7.5.3.7.2 7.5 .4.1.2 7.5 .4.3.2 7.5.4.5.2 7.5.4.7.2 7.6.1.1.2 7.6.1.3.2 7.6.1.5.2 7.6.1.7.2 7.6.2.1.2 7.6.2.3.2 7.6.2.5.2 7.6.2.7.2 7.6.3.1.2 7.6.3.3.2 7.6.3.5.2 7.6.3.7.2 7.6.4.1.2 7.4.2.3.3 7.4.2.5.3 7.4.2.7.3 7.4.3.1.3 7.4.3.3.3 7.4.3.5.3 7.4.3.7.3 7.4.4.1.3 7.4.4.3.3 7.4.4.5.3 7.4.4.7.3 7.5.1.1.3 7.5.1.3.3 7.5.1.5.3 7.5.1.7.3 7.5 .2.1.3 7.5 .2.3 .3 7.5 .2.5.3 7.5.2.7.3 7.5 1.3 7.5 .3.3.3 7.5.3.5.3 7.5.3.7.3 7.5.4.1.3 7.5 .4.3 .3 7.5.4.5.3 7.5.4.7.3 7.6.1.1.3 7.6.1.3.3 7.6.1.5.3 7.6.1.7.3 7.6.2.1.3 7.6.2.3.3 7.6.2.5.3 7.6.2.7.3 7.6.3.1.3 7.6.3.3.3 7.6.3.5.3 7.6.3.7.3 7.6.4.1.3 7.4.2.3.4 7.4.2.4.1 7.4.2.5.4 7.4.2.6.1 7.4.2.7.4 7.4.2.8.1 7.4.3.1.4 7.4.3.2.1 7.4.3.3.4 7.4.3.4.1 7.4.3.5.4 7.4.3.6.1 7.4.3.7.4 7.4.3.8.1 7.4.4.1.4 7.4.4.2.1 7.4.4.3.4 7.4.4.4.1 7.4.4.5.4 7.4.4.6.1 7.4.4.7.4 7.4.4.8.1 7.5.1.1.4 7.5.1.2.1 7.5.1.3.4 7.5.1.4.1 7.5.1.5.4 7.5.1.6.1 7.5.1.7.4 7.5.1.8.1 7.5.2.1.4 7.5.2.2.1 7.5.2.3.4 .7.5.2.4.1 7.5.2.5.4 7.5.2.6.1 7.5.2.7.4 7.5.3. 1.4 7.5.3.3.4 7.5.3.5.4 7.5.3.7.4 7.5.4.1.4 7.5.4.3.4 7.5.4.5.4 7.5.4.7.4 7.6.1.1.4 7.6.1.3.4 7.6.1.5.4 7.6.1.7.4 7.6.2.1.4 7.6.2.3.4 7.6.2.5.4 7.6.2.7.4 7.6.3. 1.4 7.6.3.3.4 7.6.3.5.4 7.6.3.7.4 7.6.4.1.4 7.5.2.8.1 7.5.3.2.1 7.5.3.4.1 7.5.3.6.1 7.5.3.8.1 7.5.4.2.1 7.5.4.4.1 7.5.4.6.1 7.5.4.8.1 7.6.1.2.1 7.6. 1.4.1 7.6.1.6.1 7.6.1.8.1 7.6.2.2.1 7.6.2.4.1 7.6.2.6.1 7.6.2.8.1 7.6.3 1 7.6.3.4.1 7.6.3.6.1 7.6.3.8.1 7.6.4.2.1 7.4.2.4.2 7.4.2.4.3 7.4.2.6.2 7.4.2.6.3 7.4.2.8.2 7.4.2.8.3 7.4.3.2.2 7.4.3.2.3 7.4.3.4.2 7.4.3.4.3 7.4.3.6.2 7.4.3.6.3 7.4.3.8.2 7.4.3.8.3 7.4.4.2.2 7.4.4.2.3 7.4.4.4.2 7.4.4.4.3 7.4.4.6.2 7.4.4.6.3 7.4.4.8.2 7.4.4.8.3 7.5.1.2.2 7.5.1.2.3 7.5.1.4.2 7.5.1.4.3 7.5.1.6.2 7.5.1.6.3 7.5.1.8.2 7.5.1.8.3 7.5.2.2.2 7.5.2.2.3 7.5.2.4.2 7.5.2.4.3 7.5.2.6.2 7.5.2.6.3 7.5.2.8.2 7.5.2.8.3 7.5.3.2.2 7.5.3.2.3 7.5.3.4.2 7.5.3.4.3 7.5.3.6.2 7.5.3.6.3 7.5.3.8.2 7.5.3.8.3 7.5.4.2.2 7.5.4.2.3 7.5.4.4.2 7.5.4.4.3 7.5.4.6.2 7.5.4.6.3 7.5.4.8.2 7.5.4.8.3 7.6.1.2.2 7.6.1.2.3 7.6.1.4.2 7.6.1.4.3 7.6.1.6.2 7.6.1.6.3 7.6.1.8.2 7.6.1.8.3 7.6.2.2.2 7.6.2.2.3 7.6.2.4.2 7.6.2.4.3 7.6.2.6.2 7.6.2.6.3 7.6.2.8.2 7.6.2.8.3 7.6.3.2.2 7.6.3.2.3 7.6.3.4.2 7.6.3.4.3 7.6.3.6.2 7.6.3.6.3 7.6.3.8.2 7.6.3.8.3 7.6.4.2.2 7.6.4.2.3 7.4.2.4.4 7.4.2.6.4 7.4.2.8.4 7.4.3.2.4 7.4.3.4.4 7.4.3.6.4 7.4.3.8.4 7.4.4.2.4 7.4.4.4.4 7.4.4.6.4 7.4.4.8.4 7.5.1.2.4 7.5.1.4.4 7.5.1.6.4 7.5.1.8.4 7.5.2.2.4 7.5.2.4.4 7.5.2.6.4 7.5.2.8.4 7.5.3.2.4 7.5.3.4.4 7.5.3.6.4 7.5.3.8.4 7.5.4.2.4 7.5.4.4.4 7.5.4.6.4 7.5.4.8.4 7.6.1.2.4 7.6.1.4.4 7.6.1.6.4 7.6.1.8.4 7.6.2.2.4 7.6.2.4.4 7.6.2.6.4 7.6.2.8.4 7.6.3.2.4 7.6.3.4.4 7.6.3.6.4 7.6.3.8.4 7.6.4.2.4 Table 1 continued 7.6.4.3.1 7.6.4.3.2 7.6.4.3.3 7.6.4.3.4 7.6.4.4.1 7.6.4.4.2 7.6.4.4.3 7.6.4.4.4 7.6.4.5.1 7.6.4.5.2 7.6.4.5.3 7.6.4.5.4 7.6.4.6.1 7.6.4.6.2 7.6.4.6.3 7.6.4.6.4 7.6.4.7.1 7.6.4.7.2 7.6.4.7.3 7.6.4.7.4 7.6.4.8.1 7.6.4.8.2 7.6.4.8.3 7.6.4.8.4 7.7.1.1.1 7.7. 1. 1.2 7.7.1.1.3 7.7.1.1.4 7.7.1.2.1 7.7.1.2.2 7.7.1.2.3 7.7.1.2.4 7.7.1.3.1 7.7.1.3.2 7.7.1.3.3 7.7.1.3.4 7.7.1.4.1 7.7.1.4.2 7.7.1.4.3 7.7.1.4.4 7.7.1.5.1 7.7.1.5.2 7.7.1.5.3 7.7.1.5.4 7.7.1.6.1 7.7.1.6.2 7.7.1.6.3 7.7.1.6.4 7.7.1.7.1 7.7.1.7.2 7.7.1.7.3 7.7.1.7.4 7.7.1.8.1 7.7.1.8.2 7.7.1.8.3 7.7.1.8.4 IND 7.7.2.1.1 7.7.2.1.2 7.7.2.1.3 7.7.2.1.4 7.7.2.2.1 7.7.2.2.2 7.7.2.2.3 7.7.2.2.4 7.7.2.3.1 7.7.2.3.2 7.7.2.3.3 7.7.2.3.4 7.7.2.4.1 7.7.2.4.2 7.7.2.4.3 7.7.2.4.4 7.7.2.7.1 7.7.2.7.2 7.7.2.7.3 7.7.2.7.4 7.7.2.6.1 7.7.2.8.2 7.7.2.6.3 7.7.2.6.4 7.7.2.7.1 7.7.2.7.2 7.7.2.7.3 7.7.2.7.4 7.7.32.1 7.7.32.2 7.7.32.3 7.7.32.4 7.7.3.3.1 7.7.3.1.2 7.7.3.1.3 7.7.3.1.4 7.7.3.2.1 7.7.3.2.2 7.7.3.2.3 7.7.3.2.4 7.7.3.3.1 7.7.3.2 7.7.3.3.3 7.7.3.3.4 7.7.3.4.1 7.7.3.4.2 7.7.3.4.3 7.7.3.4.4 7.7.3.7.1 7.7.3.5.2 7.7.3.5.3 7.7.3.7.4 7.7.3.6.1 7.7.3.6.2 7.7.3.6.3 7.7.3.6.4 7.7.3.7.1 7.7.3.7.2 7.7.3.7.3 7.7.3.7.4 7.7.3.8.1 7.7.3.8.2 7.7.3.8.3 7.7.3.2.4 7.7.4.1.1 7.7.4.1.2 7.7.4.1.3 7.7.4.1.4 7.7.4.2.1 7.7.4.2.2 7.7.4.2.3 7.7.4.2.4 7.7.4.3.1 7.7.4.3.2 7.7.4.3.3 7.7.4.3.4 7.7.4.4.1 7.7.4.4.2 7.7.4.4.3 7.7.4.4.4 7.7.4.5.1 7.7.4.5.2 7.7.4.5.3 7.7.4.7.4 7.7.4.6.1 7.7.4.6.2 7.7.4.6.3 7.7.4.6.4 7.7.4.7.1 7.7.4.7.2 7.7.4.7.3 7.7.4.7.4 7.7.4.8.1 7.7.4.8.2 7.7.4.8.3 7.7.4.8.4 7.8.1.1.1 7.8.1.1.2 7.8.1.1.3 7.8.1.1.4 7.8.1.2.1 7.8.1.2.2 7.8.1.2.3 7.8.1.2.4 7.8.1.3.1 7.8.1.3.2 7.8.1.3.3 7.8.1.3.4 7.8.1.4.1 7.8.1.4.2 7.8.1.4.3 7.8.1.4.4 7.8.1.7.1 7.8.1.5.2 7.8.1.5.3 7.8.1.5.4 7.8.1.6.1 7.8.1.6.2 7.8.1.6.3 7.8.1.6.4 7.8.2171 7.8.217.2 7.8.21.3 7.8.21.4 7.8.1.8.1 7.8.1.8.2 7.8.1.8.3 7.8.1.8.4 7.8.2.1.1 7.8.2.3.2 7.8.2.1.3 7.8.2.1.4 7.8.2.2.1 7.8.2.2.2 7.8.2.2.3 7.8.2.2.4 7.8.2.3.1 7.8.2.3.2 7.8.2.3.3 7.8.2.3.4 7.8.2.4.1 7.8.2.4.2 7.8.2.4.3 7.8.2.4.4 7.8.2.5.1 7.8.2.5.2 7.8.2.5.3 7.8.2.5.4 7.8.2.6.1 7.8.2.6.2 7.8.2.6.3 7.8.2.6.4 7.8.2.7.1 7.8.2.7.2 7.8.2.7.3 7.8.2.7.4 7.8.32.1 7.8.32.2 7.8.32.3 7.8.32.4 7.8.3.3.1 7.8.3.1.2 7.8.3.1.3 7.8.3.1.4 7.8.3.2.1 7.8.3.2.2 7.8.3.2.3 7.8.3.2.4 7.8.3.3.1 7.8.3.3.2 7.8.3.3.3 7.8.3.3.4 7.8.3.4.1 7.8.3.4.2 7.8.3.4.3 7.8.3.4.4 7.8.3.5.1 7.8.3.5.2 7.8.3.5.3 7.8.3.5.4 7.8.3.6.1 7.8.3.6.2 7.8.3.6.3 7.8.3.6.4 7.8.3.7.1 7.8.3.7.2 7.8.3.7.3 7.8.3.7.4 7.8.3.8.1 7.8.3.8.2 7.8.3.8.3 7.8.3.8.4 7.8.4.3.1 7.8.4.1.2 7.8.4.1.3 7.8.4.1.4 7.8.4.2.1 7.8.4.2.2 7.8.4.2.3 7.8.4.2.4 7.8.4.3.1 7.8.4.3.2 7.8.4.3.3 7.8.4.3.4 7.8.4.4.1 7.8.4.4.2 7.8.4.4.3 7.8.4.4.4 7.8.4.7.1 7.8.4.5.2 7.8.4.5.3 7.8.4.5.4 7.8.4.6.1 7.8.4.6.2 7.8.4.6.3 7.8.4.6.4 78..7..1 78..7..2 78..7..3 78..7..4 78..8..1 78..8..2 78..8..3 78..8..4 8.1.1.3.1 8.1.1.1.2 8.1.1.1.3 8.1.1.1.4 8.1.1.2.1 8.1.1.2.2 8.1.1.2.3 8.1.1.2.4 8.1.1.3.1 8.1.1.3.2 8.1.1.3.3 8.1.1.3.4 8.1.1.4.1 8.1.1.4.2 8.1.1.4.3 8.1.1.4.4 8.1.1.7.1 8.1.1.5.2 8.1.1.5.3 8.1.1.5.4 8.1.1.6.1 8.1.1.6.2 8.1.1.6.3 8.1.1.6.4 8.1.21.1 8.1.21.2 8.1.21.3 8.1.217.4 8.1.1.8.1 8.1.1.8.2 8.1.1.8.3 8.1.1.8.4 8.1.2.3.1 8.1.2.1.2 8.1.2.3.3 8.1.2.1.4 8.1.2.2.1 8.1.2.2.2 8.1.2.2.3 8.1.2.2.4 Table 1 continued 8.1.2.5.1 8.1.2.5.2 8.1.2.5.3 8.1.2.5.4 8.1.2.6.1 8.1.2.6.2 8.1.2.6.3 8.1.2.6.4 8.1.2.7.1 8.1.2.7.2 8.1.2.7.3 8.1.2.7.4 8.1.2.8.1 8.1.2.8.2 8.1.2.8.3 8.1.2.8.4 8.1.3.1.1 8.1.3.1.2 8.1.3.1.3 8.1.3.1.4 8.1.3.2.1 8.1.3.2.2 8.1.3.2.3 8.1.3.2.4 8.1.3.3.1 8.1.3.3.2 8.1.3.3.3 8.1.3.3.4 8.1.3.4.1 8.1.3.4.2 8.1.3.4.3 8.1.3.4.4 8.1.3.5.1 8.1.3.5.2 8.1.3.5.3 8.1.3.5.4 8.1.3.6.1 8.1.3.6.2 8.1.3.6.3 8.1.3.6.4 8.1.3.7.1 8.1.3.7.2 8.1.3.7.3 8.1.3.7.4 8.1.3.8.1 8.1.3.8.2 8.1.3.8.3 8.1.3.8.4 8.1.4.1.1 8.1.4.1.2 8.1.4.1.3 8.1.4.1.4 8.1.4.2.1 8.1.4.2.2 8.1.4.2.3 8.1.4.2.4 8.1.4.3.1 8.1.4.3.2 8.1.4.3.3 8.1.4.3.4 8.1.4.4.1 8.1.4.4.2 8.1.4.4.3 8.1.4.4.4 8.1.4.5.1 8.1.4.5.2 8.1.4.5.3 8.1.4.5.4 8.1.4.6.1 8.1.4.6.2 8.1.4.6.3 8.1.4.6.4 8.1.4.7.1 8.1.4.7.2 8.1.4.7.3 8.1.4.7.4 8.1.4.8.1 8.1.4.8.2 8.1.4.8.3 8.1.4.8.4 8.2.1.1.1 8.2.1.1.2 8.2.1.1.3 8.2.1.1.4 8.2.1.2.1 8.2.1.2.2 8.2.1.2.3 8.2.1.2.4 8.2.1.3.1 8.2.1.3.2 8.2.1.3.3 8.2.1.3.4 8.2.1.4.1 8.2.1.4.2 8.2.1.4.3 8.2.1.4.4 8.2.1.5.1 8.2.1.5.2 8.2.1.5.3 8.2.1.5.4 8.2.1.6.1 8.2.1.6.2 8.2.1.6.3 8.2.1.6.4 8.2.1.7.1 8.2.1.7.2 8.2.1.7.3 8.2.1.7.4 8.2.1.8.1 8.2.1.8.2 8.2.1.8.3 8.2.1.8.4 8.2.2.1.1 8.2.2.1.2 8.2.2.1.3 8.2.2.1.4 8.2.2.2.1 8.2.2.2.2 8.2.2.2.3 8.2.2.2.4 8.2.2.3.1 8.2.2.3.2 8.2.2.3.3 8.2.2.3.4 8.2.2.4.1 8.2.2.4.2 8.2.2.4.3 8.2.2.4.4 8.2.2.5.1 8.2.2.5.2 8.2.2.5.3 8.2.2.5.4 8.2.2.6.1 8.2.2.6.2 8.2.2.6.3 8.2.2.6.4 8.2.2.7.1 8.2.2.7.2 8.2.2.7.3 8.2.2.7.4 8.2.2.8.1 8.2.2.8.2 8.2.2.8.3 8.2.2.8.4 8.2.3.1.1 8.2.3.1.2 8.2.3.1.3 8.2.3.1.4 8.2.3.2.1 8.2.3.2.2 8.2.3.2.3 8.2.3.2.4 8.2.3.3.1 8.2.3.3.2 8.2.3.3.3 8.2.3.3.4 8.2.3.4.1 8.2.3.4.2 8.2.3.4.3 8.2.3.4.4 8.2.3.5.1 8.2.3.5.2 8.2.3.5.3 8.2.3.5.4 8.2.3.6.1 8.2.3.6.2 8.2.3.6.3 8.2.3.6.4 8.2.3.7.1 8.2.3.7.2 8.2.3.7.3 8.2.3.7.4 8.2.3.8.1 8.2.3.8.2 8.2.3.8.3 8.2.3.8.4 8.2.4.1.1 8.2.4.1.2 8.2.4.1.3 8.2.4.1.4 8.2.4.2.1 8.2.4.2.2 8.2.4.2.3 8.2.4.2.4 8.2.4.3.1 8.2.4.3.2 8.2.4.3.3 8.2.4.3.4 8.2.4.4.1 8.2.4.4.2 8.2.4.4.3 8.2.4.4.4 8.2.4.5.1 8.2.4.5.2 8.2.4.5.3 8.2.4.5.4 8.2.4.6.1 8.2.4.6.2 8.2.4.6.3 8.2.4.6.4 8.2.4.7.1 8.2.4.7.2 8.2.4.7.3 8.2.4.7.4 8.2.4.8.1 8.2.4.8.2 8.2.4.8.3 8.2.4.8.4 8.3.1.1.1 8.3.1.1.2 8.3.1.1.3 8.3.1.1.4 8.3.1.2.1 8.3.1.2.2 8.3.1.2.3 8.3.1.2.4 8.3.1.3.1 8.3.1.3.2. 8.3.1.3.3 8.3.1.3.4 8.3.1.4.1 8.3.1.4.2 8.3.1.4.3 8.3.1.4.4 8.3.1.5.1 8.3.1.5.2 8.3.1.5.3 8.3.1.5.4 8.3.1.6.1 8.3.1.6.2 8.3.1.6.3 8.3.1.6.4 8.3.1.7.1 8.3.1.7.2 8.3.1.7.3 8.3.1.7.4 8.3.1.8.1 8.3.1.8.2 8.3.1.8.3 8.3.1.8.4 8.3.2.1.1 8.3.2.1.2 8.3.2.1.3 8.3.2.1.4 8.3.2.2.1 8.3.2.2.2 8.3.2.2.3 8.3.2.2.4 8.3.2.3.1 8.3.2.3.2 8.3.2.3.3 8.3.2.3.4 8.3.2.4.1 8.3.2.4.2 8.3.2.4.3 8.3.2.4.4 8.3.2.5.1 8.3.2.5.2 8.3.2.5.3 8.3.2.5.4 8.3.2.6.1 8.3.2.6.2 8.3.2.6.3 8.3.2.6.4 8.3.2.7.1 8.3.2.7.2 8.3.2.7.3 8.3.2.7.4 8.3.2.8.1 8.3.2.8.2 8.3.2.8.3 8.3.2.8.4 8.3.3.1.1 8.3.3.1.2 8.3.3.1.3 8.3.3.1.4 8.3.3.2.1 8.3.3.2.2 8.3.3.2.3 8.3.3.2.4 8.3.3.3.1 8.3.3.3.2 8.3.3.3.3 8.3.3.3.4 8.3.3.4.1 8.3.3.4.2 8.3.3.4.3 8.3.3.4.4 8.3.3.5.1 8. 3.3. 5. 2 8.3.3.5.3 8.3.3.5.4 8.3.3.6.1 8.3.3.6.2 8.3.3.6.3 8.3.3.6.4 8.3.3.7.1 8.3.3.7.2 8.3.3.7.3 8.3.3.7.4 8.3.3.8.1 8.3.3.8.2 8.3.3.8.3 8.3.3.8.4 8.3.4.1.1 8.3.4.1.2 8.3.4.1.3 8.3.4.1.4 8.3.4.2.1 8.3.4.2.2 8.3.4.2.3 8.3.4.2.4 8.3.4.3.1 8.3.4.3.2 8.3.4.3.3 8.3.4.3.4 8.3.4.4.1 8.3.4.4.2 8.3.4.4.3 8.3.4.4.4 8.3.4.5.1 8.3.4.5.2 8.3.4.5.3 8.3.4.5.4 8.3.4.6.1 8.3.4.6.2 8.3.4.6.3 8.3.4.6.4 Table 1 continued 8.3.4.7.1 8.3.4.7.2 8.3.4.7.3 8.3.4.7.4 8.3.4.8.1 8.3.4.8.2 8.3.4.8.3 8.3.4.8.4 8.4.1.1.1 8.4.1.3.1 8.4.1.5.1 8.4.1.7.1 8.4.2.1. 1 8.4.2.3.1 8.4.2.5.1 8.4.2.7.1 8.4.3.1.1 8.4.3.3.1 8.4.3.5.1 8.4.3.7.1 8.4.4.1.1 8.4.4.3.1 8.4.4.5.1 8.4.4.7.1 8.5.1.1.1 8.5.1.3.1 8.5.1.5. 1 1.7. 1 8.5.2.1.1 8.5.2.3.1 8.5.2.5.1 8.5.2.7.1 8.5.3.1. 1 8.5.3.3.1 8.5.3.5.1 8.5.3.7.1 8.5.4. 1.1 8.5.4.3.1 8.5.4.5.1 8.5.4.7.1 8.6.1.1.1 8.6.1.3.1 8.6.1.5.1 8.6.1.7.1 8.6.2.1.1 8.6.2.3.1 8.6.2.5.1 8.6.2.7.1 8 1.1.2 8.4.1.3.2 8.4. 1.5 .2 8.4.1.7.2 8.4.2. 1.2 8.4.2.3.2 8.4.2.5.2 8.4.2.7.2 8.4.3.1.2 8.4.3.3.2 8.4.3.5.2 8.4.3.7.2 8.4.4.1.2 8.4.4.3.2 8.4.4.5.2 8.4.4.7.2 8.5. 1.1.2 8.5.1.3.2 8.5. 1.5 .2 8.5.1.7.2 8 .5 1.2 8.5 .2.3 .2 8.5.2.5.2 8.5.2.7.2 8.4.1.1.3 8 1.3 .3 8 1.5 .3 8 1.7.3 8.4.2.1.3 8.4.2.3.3 8.4.2.5.3 8 .4.2.7.3 8.4.3.1.3 8.4.3.3.3 8.4.3.5.3 8.4.3.7.3 8.4.4.1.3 8.4.4.3.3 8 .4.4.5.3 8.4.4.7.3 8.5.1.1.3 8 1.3 .3 8.5.1.5.3 8.5. 1.7.3 8 .5 1.3 8.5.2.3.3 8.5 .2.5 .3 8.5.2.7.3 8 1.1.4 8.4.1.3.4 8.4.1.5.4 8.4.1.7.4 8.4.2.1.4 8.4.2.3.4 8.4.2.5.4 8.4.2.7.4 8.4.3.1.4 8.4.3.3.4 8.4.3.5.4 8.4.3.7.4 8.4.4.1.4 8.4.4.3.4 8.4.4.5.4 8.4.4.7.4 8.5.1.1.4 8.5.1.3.4 8.5.1.5.4 8.5.1.7.4 8.5.2.1.4 8.5.2.3.4 8.5.2.5.4 8.5.2.7.4 8 .5 .3.1.4 8.5.3.3.4 8 .5.3.5.4 8.5.3.7.4 8.5.4.1.4 8.5.4.3.4 8.5.4.5.4 8.5.4.7.4 8 1. 1.4 8.6.1.3.4 8.6.1.5.4 8.6.1.7.4 8.6.2.1.4 8.6.2.3.4 8.6.2.5.4 8.6.2.7.4 8.4.1.2. 1 8.4.1.4. 1 8.4. 1.6.1 8.4. 1.8. 1 8.4.2.2.1 8.4.2.4.1 8.4.2.6.1 8.4.2.8.1 8.4.3.2.1 8.4.3 1 8.4.3 1 8.4.3 1 8.4.4.2.1 8.4.4.4.1 8.4.4.6.1 8.4.4.8.1 8.5.1.2.1 8.5.1.4.1 8.5.1.6.1 8.5.1. 8. 1 8.5 1 8.5.2.4.1 8.5.2.6.1 8.5.2.8.1 8.5.3.2.1 8.5.3.4.1 8.5.3.6.1 8.5.3.8.1 8.5.4.2.1 8.5.4.4.1 8.5.4.6.1 8.5.4.8.1 8.6.1.2.1 8.6.1.4.1 8.6.1.6.1 8.6.1.8.1 8.6.2.2.1 8.6.2.4.1 8.6.2.6.1 8.6.2.8.1 8.4.1.2.2 8.4.1.2.3 8.4.1.4.2 8.4.1.4.3 8.4.1.6.2 8.4.1.6.3 8.4.1.8.2 8.4.1.8.3 8.4.2.2.2 8.4.2.2.3 8.4.2.4.2 8.4.2.4.3 8.4.2.6.2 8.4.2.6.3 8.4.2.8.2 8.4.2.8.3 8.4.3.2.2 8.4.3.2.3 8.4.3.4.2 8.4.3.4.3 8.4.3.6.2 8.4.3.6.3 8.4.3.8.2 8.4.3.8.3 8.4.4.2.2 8.4.4.2.3 8.4.4.4.2 8.4.4.4.3 8.4.4.6.2 .8.4.4.6.3 8.4. 1.2.4 8.4.1.4.4 8.4. 1.6.4 8.4.1.8.4 8.4.2.2.4 8.4.2.4.4 8.4.2.6.4 8.4.2.8.4 8.4.3.2.4 8.4.3.4.4 8.4.3.6.4 8.4.3.8.4 8.4.4.2.4 8.4.4.4.4 8.4.4.6.4 8.4.4.8.2 8.4.4.8.3 8.4.4.8.4 8.5.3.1.2. 8.5.3.1.3 8.5.3.3.2 8.5.3.3.3 8.5.3.5.2 8.5.3.5.3 8.5.3.7.2 8.5.3.7.3 8.5.4.1.2 8.5.4.1.3 8.5.4.3.2 8.5.4.3.3 8.5.4.5.2 8.5.4.5.3 8.5.4.7.2 8.5.4.7.3 8.6.1.1.2 8.6.1.1.3 8.6.1.3.2 8.6.1.3.3 8.6.1.5.2 8.6.1.5.3 8.6.1.7.2 8.6.1.7.3 8.6.2.1.2 8.6.2.1.3 8.6.2.3.2 8.6.2.3.3 8.6.2.5.2 8.6.2.5.3 8.6.2.7.2 8.6.2.7.3 8.5.1.2.2 8.5.1.4.2 8.5.1.6.2 8.5.1.8.2 8.5 .2.2.2 8.5 .2.4.2 8.5.2.6.2 8.5.2.8.2 8.5.3.2.2 8.5.3.4.2 8.5 .3 .6.2 8.5 .3 .8.2 8.5 .4.2.2 8.5.4.4.2 8.5 .4.6.2 8.5.4.8.2 8 1.2.2 8.6.1.4.2 8.6.1.6.2 8.6.1.8.2 8.6.2.2.2 8.6.2.4.2 8.6.2.6.2 8.6.2.8.2 8.5.1.2.3 8.5.1.4.3 8.5.1.6.3 8 1. 8.3 8.5 .2.2.3 8.5 .2.4.3 8.5.2.6.3 8.5.2.8.3 8.5.3.2.3 8.5.3.4.3 8.5.3.6.3 8.5.3.8.3 8.5.4.2.3 8.5.4.4.3 8.5.4.6.3 8.5.4.8.3 8.6.1.2.3 8.6.1.4.3 8.6.1.6.3 8.6.1.8.3 8.6.2.2.3 8.6.2.4.3 8.6.2.6.3 8.6.2.8.3 8.5. 1.2.4 8.5.1.4.4 8.5. 1.6.4 8. 5.1. 8.4 8.5.2.2.4 8.5.2.4.4 8.5.2.6.4 8.5.2.8.4 8.5.3.2.4 8.5.3.4.4 8.5.3.6.4 8.5.3.8.4 8.5.4.2.4 8.5.4.4.4 8.5.4.6.4 8.5.4.8.4 8.6.1.2.4 8.6.1.4.4 8.6.1.6.4 8.6. 1.8.4 8.6.2.2.4 8.6.2.4.4 8.6.2.6.4 8.6.2.8.4 Table 1 continued 8.6.3.1.1 8.6.3.1.2 8.6.3.1.3 8.6.3.1.4 8.6.3.2.1 8.6.3.2.2 8.6.3.2.3 8.6.3.2.4 8.6.3.3.1 8.6.3.3.2 8.6.3.3.3 8.6.3.3.4 8.6.3.4.1 8.6.3.4.2 8.6.3.4.3 8.6.3.4.4 8.6.3.5.1 8.6.3.5.2 8.6.3.5.3 8.6.3.5.4 8.6.3.6.1 8.6.3.6.2 8.6.3.6.3 8.6.3.6.4 8.6.3.7.1 8.6.3.7.2 8.6.3.7.3 8.6.3.7.4 8.6.3.8.1 8.6.3.8.2 8.6.3.8.3 8.6.3.8.4 IND 8.6.4.1.1 8.6.4.1.2 8.6.4.1.3 8.6.4.1.4 8.6.4.2.1 8.6.4.2.2 8.6.4.2.3 8.6.4.2.4 8.6.4.3.1 8.6.4.3.2 8.6.4.3.3 8.6.4.3.4 8.6.4.4.1 8.6.4.4.2 8.6.4.4.3 8.6.4.4.4 8.6.4.5.1 8.6.4.5.2 8.6.4.5.3 8.6.4.5.4 8.6.4.6.1 8.6.4.6.2 8.6.4.6.3 8.6.4.6.4 8.6.4.7.1 8.6.4.7.2 8.6.4.7.3 8.6.4.7.4 8.6.4.8.1 8.6.4.8.2 8.6.4.8.3 8.6.4.8.4 8.7.1.1.1 8.7.1.1.2 8.7.1.1.3 8.7.1.1.4 8.7.1.2.1 8.7.1.2.2 8.7.1.2.3 8.7.1.2.4 8.7.1.3.1 8.7.1.3.2 8.7.1.3.3 8.7.1.3.4 8.7.1.4.1 8.7.1.4.2 8.7.1.4.3 8.7.1.4.4 (218.7.1.5.1 8.7.1.5.2 8.7.1.5.3 8.7.1.5.4 8.7.1.6.1 8.7.1.6.2 8.7.,1.6.3 8.7.1.6.4 8.7.1.7.1 8.7.1.7.2 8.7.1.7.3 8.7.1.7.4 8.7.1.8.1 8.7.1.8.2 8.7.1.8.3 8.7.1.8.4 8.7.2.1.1 8.7.2.1.2 8.7.2.1.3 8.7.2.1.4 8.7.2.2.1 8.7.2.2.2 8.7.2.2.3 8.7.2.2.4 8.7.2.3.1 8.7.2.3.2 8.7.2.3.3 8.7.2.3.4 8.7.2.4.1 8.7.2.4.2 8.7.2.4.3 8.7.2.4.4 8.7.2.5.1 8.7.2.5.2 8.7.2.5.3 8.7.2.5.4 8.7.2.6.1 8.7.2.6.2 8.7.2.6.3 8.7.2.6.4 8.7.2.7.1 8.7.2.7.2 8.7.2.7.3 8.7.2.7.4 8.7.2.8.1 8.7.2.8.2 8.7.2.8.3 8.7.2.8.4 8.7.3.1.1 8.7.3.1.2 8.7.3.1.3 8.7.3.1.4 8.7.3.2.1 8.7.3.2.2 8.7.3.2.3 8.7.3.2.4 8.7.3.3.1 8.7.3.3.2 8.7.3.3.3 8.7.3.3.4 8.7.3.4.1 8.7.3.4.2 8.7.3.4.3 8.7.3.4.4 8.7.3.5.1 8.7.3.5.2 8.7.3.5.3 8.7.3.5.4 8.7.3.6.1 8.7.3.6.2 8.7.3.6.3 8.7.3.6.4 8.7.3.7.1 8.7.3.7.2 8.7.3.7.3 8.7.3.7.4 8.7.3.8.1 8.7.3.8.2 8.7.3.8.3 8.7.3.8.4 8.7.4.1.1 8.7.4.1.2 8.7.4.1.3 8.7.4.1.4 8.7.4.2.1 8.7.4.2.2 8.7.4.2.3 8.7.4.2.4 8.7.4.3.1 8.7.4.3.2 8.7.4.3.3 8.7.4.3.4 8.7.4.4.1 8.7.4.4.2 8.7.4.4.3 8.7.4.4.4 8.7.4.5.1 8.7.4.5.2 8.7.4.5.3 8.7.4.5.4 8.7.4.6.1 8.7.4.6.2 8.7.4.6.3 8.7.4.6.4 8.7.4.7.1 8.7.4.7.2 8.7.4.7.3 8.7.4.7.4 8.7.4.8.1 8.7.4.8.2 8.7.4.8.3 8.7.4.8.4 8.8.t. 1. 1 8.8.1.1.2 8.8.1.1.3 8.8.1.1.4 8.8.1.2.1 8.8.1.2.2 8.8.1.2.3 8.8.1.2.4 8.9.1.3.1 8.8.1.3.2 8.8.1.3.3 8.8.1.3.4 8.8.1.4.1 8.8.1.4.2 8.8.1.4.3 8.8.1.4.4 8.8.1.5.1 8.8.1.5.2 8.8.1.5.3 8.8.1.5.4 8.8.1.6.1 8.8.1.6.2 8.8.1.6.3 8.8. 1:6.4 8.8.1.7.1 8.8.1.7.2 8.8.1.7.3 8.8.1.7.4 8.8.1.8.1 8.8.1.8.2 8.8.1.8.3 8.8.1.8.4 8.8.2.1.1 8.8.2.1.2 8.8.2.1.3 8.8.2.1.4 8.8.2.2.1 8.8.2.2.2 8.8.2.2.3 8.8.2.2.4 8.8.2.3.1 8.8.2.3.2 8.8.2.3.3 8.8.2.3.4 8.8.2.4.1 8.8.2.4.2 8.8.2.4.3 8.8.2.4.4 8.8.2,5.1 8.8.2.5.2 8.8.2.5.3 8.8.2.5.4 8.8.2.6.1 8.8.2.6.2 8.8.2.6.3 8.8.2.6.4 8.8.2.7.1 8.8.2.7.2 8.8.2.7.3 8.8.2.7.4 8.8.2.8.1 8.8.2.8.2 8.8.2.8.3 8.8.2.8.4 8.8.3.1.1 8.8.3.1.2 8.8.3.1.3 8.8.3.1.4 8.8.3.2.1 8.8.3.2.2 8.8.3.2.3 8.8.3.2.4 8.8.3.3.1 8.8.3.3.2 8.8.3.3.3 8.8.3.3.4 8.8.3.4.1 8.8.3.4.2 8.8.3.4.3 8.8.3.4.4 8.8.3.5.1 8.8.3.5.2 8.8.3.5.3 8.8.3.5.4 8.8.3.6.1 8.8.3.6.2 8.8.3.6.3 8.8.3.6.4 8.8.3.7.1 8.8.3.7.2 8.8.3.7.3 8.8.3.7.4 8.8.3.8.1 8.8.3.8.2 8.8.3.8.3 8.8.3.8.4 8.8.4.1.1 8.8.4.1.2 8.8.4.1.3 8.8.4.1.4 8.8.4.2.1 8.8.4.2.2 8.8.4.2.3 8.8.4.2.4 8.8.4.3.1 8.8.4.3.2 8.8.4.3.3 8.8.4.3.4 8.8.4.4.1 8.8.4.4.2 8.8.4.4.3 8.8.4.4.4 8.8.4.5.1 8.8.4.5.2 8.8.4.5.3 8.8.4.5.4 8.8.4.6.1 8.8.4.6.2 8.8.4.6.3 8.8.4.6.4 8.8.4.7.1 8.8.4.7.2 8.8.4.7.3 8.8.4.7.4 8.8.4.8.1 8.8.4.8.2 8.8.4.8.3 8.8.4.8.4 The best mode of practicing the invention is with Compounds of Example numbers 50.6, 50.9, 50.15, and 50.20.

Section 1.

Synthesis of Compounds of Formula I Synthesis of compounds encompassed by the present invention typically includes some or all of the following general steps: preparation of a phosphonate prodrug; (2) deprotection of a phosphonate ester; modification of a heterocycle; coupling of a heterocycle with a phosphonate component; construction of a heterocycle; ring closure to construct a heterocycle with a phosphonate moiety present and preparation of useful intermediates. These steps are illustrated in the following scheme for compounds of formula I wherein R 5 is a 5-membered heteroaromatic ring. Compounds of formula I wherein R s is a 6member heteroaromatic ring or other heteroaromatic rings are prepared in an analogous manner.

A, 0 FORMULA Rs-X-P-OH -X-P-OR' OH B OR' 2 B 3 (t 3) At, A M-P-OR '-X-I--OR B OR' OR

B

2

B

6 5 4 f t (6) t B

OR

7 Preparation of a bisamidate phosphonate General synthesis of bis-phosphoroamidate prodrugs: In general, the bis-phosphoroamidates of formula I, where both -NR s

R

6 and

-N(R

18

)-(CR

2 R 3 )n-C(O)-R 14 are firom the same amino acid residues, can be prepared from the activated phosphonates for example, dichlorophosphonate, by coupling with an amino acid ester for example, glycine ethylester with or without base for example, N-methylimidazole. The reactive dichloridates, can be prepared from the corresponding phosphonic acid and a chlorinating agent for example, thionyl chloride (Starrett, et al., J Med. Chem., 1994, 1857), oxalyl chloride (Stowell, et al., Tetrahedron Lett., 1990, 31, 3261), or phosphorous pentachloride (Quast, et al., Synthesis, 1974, 490). These dichloridates can also be prepared from their corresponding disilyl esters (Bhongle, et al., Synth. Commun., 1987, 17, 1071) and dialkyl esters (Still, et al., Tetrahedron Lett., 1983, 24, 4405; Patois, et al., Bull. Soc. Chim. Fr., 1993, 130, 485).

Alternatively, these bis-phosphoroamidates can be prepared by reacting the corresponding phosphonic acid with an amino acid ester for example, glycine ethylester in presence of PPh 3 and 2,2'-dipyridyl disulfide in pyridine as described in WO 95/07920 or Mukaiyama, T. et al, JAm. Chem. Soc., 1972, 94, 8528.

Synthesis of mixed bis-phosphoroamidates of formula I, where -NR' 5

R

16 and -N(Rls)-(CR2 R'3),C(O)-R 1 4 are different amino acid esters or a combination of an amino acid ester and a substituted amine, can be prepared by direct conversion via dichloridate as described above (sequential addition) followed by purification of the desired product by column chromatography). Alternatively, these unsymmetrical bis-phosphoroamidates can be prepared starting with an appropriate phosphonate monoester such as phenyl ester or benzyl ester to give the mixed phosphonoesteramide via the chloridate, followed by ester hydrolysis under conditions where the amide bond is stable. The resultant mono-amide can be converted to a mixed bisamide by condensation with a second amino ester or a substituted amine via the chloridate, as described above. Synthesis of such monoesters can be prepared using the reported procedure (EP 481 214).

Deprotection of a phosphonate ester Compounds of formula 2 may be prepared from phosphonate esters using known phosphate and phosphonate ester cleavage conditions. Silyl halides are generally used to cleave various phosphonate esters, and subsequent mild hydrolysis of the resulting silyl phosphonate esters give the desired phosphonic acids. When required, acid scavengers (e.g.

1,1,1,3,3,3-hexamethyldisilazane, 2,6-lutidine, etc.) can be used for the synthesis of acid labile compounds. Such silyl halides include chlorotrimethylsilane (Rabinowitz, J. Org.

Chem., 1963, 28: 2975), and bromotrimethylsilane (McKenna, et al, Tetrahedron Lett., 1977, 155), and iodotrimethylsilane (Blackburn, et al, J. Chem. Soc., Chem. Commun., .1978, 870).

Alternately, phosphonate esters can be cleaved under strong acidic conditions HBr or HCI: Moffatt, et al, U.S. Patent 3,524,846, 1970). These esters can also be cleaved via dichlorophosphonates, prepared by treating the esters with halogenating agents (e.g.

phosphorus pentachloride, thionyl chloride, BBr 3 Pelchowicz et al, J Chem. Soc., 1961, 238) followed by aqueous hydrolysis to give phosphonic acids. Aryl and benzyl phosphonate esters can be cleaved under hydrogenolysis conditions (Lejczak, et al, Synthesis, 1982, 412; Elliott, et al, J. Med. Chem., 1985, 28: 1208; Baddiley, et al, Nature, 1953, 171: 76 or metal reduction conditions (Shafer, et al, J. Am. Chem. Soc., 1977, 99: 5118). Electrochemical (Shono, et al, J. Org. Chem., 1979, 44: 4508) and pyrolysis (Gupta, et al, Synth. Commun., 1980, 10: 299) conditions have also been used to cleave various phosphonate esters.

Modification of an existing heterocvcle Syntheses of the heterocycles encompassed in the disclosed compounds have been well studied and described in numerous reviews (see section Although it is advantageous to have the desired substituents present in these heterocycles before synthesis of compounds of formula 4, in some cases, the desired substituents are not compatible with subsequent reactions, and therefore modifications of an existing heterocycle are required late in the synthetic scheme using conventional chemistry (Larock, Comprehensive organic transformations, VCH, New York, 1989; Trost, Comprehensive organic synthesis; Pergamon press, New York, 1991). For example, compounds of formula I wherein A, or B is a halo or a cyano group can be prepared from the corresponding amine group by conversion to the diazonium group and reaction with various copper salts Cul, CuBr, CuCl, CuCN).

Halogens can also be introduced by direct halogenations of various heterocycles. For example, 5-unsubstituted-2-aminothiazoles can be converted to 2-amino-5-halothiazoles using various reagents NIS, NBS, NCS). Heteroaryl halides are also useful intermediates and are often readily converted to other substituents (such as A, B, D, E and E") via transition metal assisted coupling reactions such as Suzuki, Heck or Stille reactions (Farina et al, Organic Reactions, Vol. 50; Wiley, New York, 1997; Mitchell, Synthesis, 1992, 808; Suzuki, Pure App. Chem., 1991, 63, 419; Heck Palladium Reagents in Organic Synthesis; Academic Press: San Diego, 1985). Compounds of formula I wherein A is a carbamoyl group can be made from their corresponding alkyl carboxylate esters via aminolysis with various amines, and conventional functional group modifications of the alkyl carboxylate esters are useful for syntheses of compounds of formula I wherein A is a -CH 2 0H group or a -CH 2 -halo group. Substitution reactions of haloheterocycles 2-bromothiazole, 5-bromothiazole) with various nucleophiles HSMe, HOMe, etc.) represents still another method for introducing substituents such as A, B and For example, substitution of a 2-chlorothiazole with methanethiol gives the corresponding 2-methylthiothiazole.

It is envisioned that when necessary alkylation of nitrogen atoms in the heterocycles imidazoles, 1,2,4-triazoles and 1,2,3,4-tetrazoles) can be readily performed using for example standard alkylation reactions (with an alkyl halide, an aralkyl halide, an alkyl sulfonate or an aralkyl sulfonate), or Mitsunobu reactions (with an alcohol).

Coupling of a heterocycle with a phosphonate component When feasible compounds disclosed in the present invention are prepared via a convergent synthetic route entailing the coupling of a heterocycle with a phosphonate diester component.

Transition metal catalyzed coupling reactions such as Stille or Suzuki reactions are particularly suited for the synthesis of compounds of formula I. Coupling reactions between a heteroaryl halide or triflate 2-bromopyridine) and a M-PO 3 R' wherein M is a O tributylstannyl)furanyl or a 2-(5-boronyl)furanyl group under palladium catalyzed reaction conditions (Farina et al, Organic Reactions, Vol. 50; Wiley, New York, 1997; Mitchell, Synthesis, 1992, 808; Suzuki, Pure App. Chem., 1991, 63, 419) yield compounds of formula I wherein X is a furan-2,5-diyl group. It is envisioned that the nature of the coupling partners for these reactions can also be reversed coupling of trialkylstannyl or boronyl heterocycles with a halo-X-P(O)(O-alkyl) 2 Other coupling reactions between organostannes ND and an alkenyl halide or an alkenyl triflate are also reported which may be used to prepared 0 compounds of formula I wherein X is an alkenyl group. The Heck reaction may be used to prepare compounds of formula I wherein X is an alkenyl group (Heck Palladium Reagents in Organic Synthesis; Academic Press: San Diego, 1985). These reactions are particularly suited for syntheses of various heteroaromatics as R 5 for compounds of formula I given the availability of numerous halogenated heterocycles, and these reactions are particularly suitable for parallel synthesis combinatorial synthesis on solid phase (Bunin, B. The Combinatorial Index; Academic Press: San Diego, 1998) or in solution phase (Flynn, D. L. et al., Curr. Op. Drug. Disc. Dev., 1998, 1, 1367)) to generate large combinatorial libraries. For example, ethyl 5-iodo-2-furanylphosphonate can be coupled to Wang's resin under suitable coupling reaction conditions. The resin-coupled 5-iodo-2-[5-(O-ethyl-O-Wang's resin)phosphono]furan can then be subjected to transition metal catalyzed Suzuki and Stille reactions (as described above) with organoboranes and organotins in a parallel manner to give libraries of compounds of formula 3 wherein X is Substitution reactions are useful for the coupling of a heterocycle with a phosphonate diester component. For example, cyanuric chloride can be substituted with dialkyl mercaptoalkylphosphonates or dialkyl aminoalkylphosphonates to give compounds of formula I wherein R 5 is a 1,3,5-triazine, X is an alkylthio or an alkylamino group. Alkylation reactions are also used for the coupling of a heterocycle with a phosphonate diester component. For example, a heteroaromatic thiol a 1,3,4-thiadiazole-2-thiol) can be alkylated with a dialkyl methylphosphonate derivative ICH 2 P(O)(OEt) 2 TsOCH 2 P(O)(OEt) 2 TfOCH 2 P(O)(OEt) 2 to lead to compounds of formula I wherein X is an 0 alkylthio group. In another aspect, alkylation reactions of a heteroaromatic carboxylic acid a thiazole-4-carboxylic acid) with a dialkyl methylphosphonate derivative (e.g.

ICH

2 P(O)(OEt) 2 TsOCH 2 P(O)(OEt) 2 TfOCH 2 P(O)(OEt) 2 lead to compounds of formula I wherein X is an alkoxycarbonyl group, while alkylation reactions of a heteroaromatic thiocarboxylic acid a thiazole-4-thiocarboxylic acid) with a dialkyl methylphosphonate derivative ICH 2 P(O)(OEt) 2 TsOCH 2 P(O)(OEt) 2 TfOCH 2 P(O)(OEt) 2 lead to IN compounds of formula I wherein X is an alkylthiocarbonyl group. Substitutions of haloalkyl 0heterocycles 4-haloallkylthiazole) with nucleophiles containing the phosphonate group (diethyl hydroxymethylphosphonate) are useful for the preparation of compounds of formula I wherein X is an alkoxyalkyl or an alkylthioalkyl group. For example, compounds of formula I where X is a -CH 2

OCH

2 group can be prepared from 2-chloromethylpyridine or 4chloromethylthiazole using dialkyl hydroxymethylphosphonates and a suitable base (e.g.

sodium hydride). It is possible to reverse the nature of the nucleophiles and electrophiles for the substitution reactions, i.e. haloalkyl- and/or sulfonylalkylphosphonate esters can be substituted with heterocycles containing a nucleophile a 2-hydroxyalkylpyridine, a 2mercaptoalkylpyridine, or a 4-hydroxyalkyloxazole).

Known amide bond formation reactions the acyl halide method, the mixed anhydride method, the carbodiimide method) can also be used to couple a heteroaromatic carboxylic acid with a phosphonate diester component leading to compounds of formula I wherein X is an alkylaminocarbonyl or an alkoxycarbonyl group. For example, couplings of a thiazole-4-carboxylic acid with a dialkyl aminoalkylphosphonate or a dialkyl hydroxyalkylphosphonate give compounds of formula I wherein R 5 is a thiazole, and X is an alkylaminocarbonyl or an alkoxycarbonyl group. Alternatively, the nature of the coupling partners can be reversed to give compounds of formula I wherein X is an alkylcarbonylamino group. For example, 2-aminothiazoles can be coupled with (RO) 2 P(O)-alkyl-CO2H (e.g.

diethylphosphonoacetic acid) under these reaction conditions to give compounds of formula I wherein R 5 is a thiazole and X is an alkylcarbonylamino group. These reactions are also useful for parallel synthesis of compound libraries through combinatorial chemistry on solid phase or in solution phase. For example, HOCH 2 P(O)(OEt)(O-resin), H 2

NCH

2 P(O)(OEt)(Oresin) and HOOCCH 2 P(O)(OEt)(O-resin) (prepared using known methods) can be coupled to various heterocycles using the above described reactions to give libraries of compounds of formula 3 wherein X is a -C(O)OCH 2 or a -C(O)NHCH 2 or a NHC(O)CH 2 Rearrangement reactions can also be used to prepare compounds covered in the present invention. For example, the Curtius' rearrangement of a thiazole-4-carboxylic acid in the presence of a dialkyl hydroxyalkylphosphonate or a dialkyl aminoalkylphosphonate lead to compounds of formula I wherein X is an alkylaminocarbonylamino or an alkoxycarbonylamino group. These reactions can also be adopted for combinatorial synthesis of various libraries of compounds of formula 3. For example, Curtius' rearrangement reactions between a heterocyclic carboxylic acid and HOCH 2 P(O)(OEt)(O-resin), or H2NCH2P(O)(OEt)(O-resin) can lead to libraries of compounds of formula I wherein X is a

NHC(O)OCH

2 or a NHC(O)NHCH 2 For compounds of formula I wherein X is an alkyl group, the phosphonate group can be introduced using other common phosphonate formation methods such as Michaelis- Arbuzov reaction (Bhattacharya et al., Chem. Rev., 1981, 81: 415), Michaelis-Becker reaction (Blackburn et al., J. Organomet. Chem., 1988, 348: 55), and addition reactions of phosphorus to electrophiles (such as aldehydes, ketones, acyl halides, imines and other carbonyl derivatives).

Phosphonate component can also be introduced via lithiation reactions. For example, lithiation of an 2-ethynylpyridine using a suitable base followed by trapping the thus generated anion with a dialkyl chlorophosphonate lead to compounds of formula I wherein R is a pyridyl, X is a 1-(2-phosphono)ethynyl group.

Construction of a heterocvcle Although existing heterocycles are useful for the synthesis of compounds of formula I, when required, heterocycles can also be constructed leading to compounds in the current invention. The construction of heterocycles have been well described in the literature using a variety of reaction conditions (Joule et al., Heterocyclic Chemistry; Chapman hall, London, 1995; Boger, Weinreb, Hetero Diels-Alder Methodology In Organic Synthesis; Academic press, San Diego, 1987; Padwa, 1,3-Dipolar Cycloaddition Chemistry; Wiley, New York, 1984; Katritzsky et al., Comprehensive Heterocyclic Chemistry; Pergamon press, Oxford; Newkome et al., Contemporary Heterocyclic Chemistry: Syntheses, Reaction and Applications; Wiley, New York, 1982; Syntheses of Heterocyclic Compounds; Consultants Bureau, New York). Some of the methods which are useful to prepare compounds in the present invention are given as examples in the following discussion.

Construction of a thiazole ring system Thiazoles useful for the present invention can be readily prepared using a variety of well described ring-forming reactions (Metzger, Thiazole and its derivatives, part 1 and part 2; Wiley Sons, New York, 1979). Cyclization reactions of thioamides thioacetamide, thiourea) and alpha-halocarbonyl compounds (such as alpha-haloketones, alphahaloaldehydes) are particularly useful for the construction of a thiazole ring system. For example, cyclization reactions between thiourea and 5-diethylphosphono-2-[(-2-bromo-loxo)alkyl]furans are useful for the synthesis of compounds of formula I wherein R 5 is a thiazole, A is an amino group and X is a furan-2,5-diyl group; cyclization reaction between thiourea and a bromopyruvate alkyl ester give a 2-amino-4-alkoxycarbonylthiazole which is useful for the preparations of compounds of formula I wherein R s is a thiazole and X is an alkylaminocarbonyl, an alkoxycarbonyl, an alkylaminocarbonylamino, or an alkoxyacarbonylamino group. Thioamides can be prepared using reactions reported in the literature (Trost, Comprehensive organic synthesis, Vol. 6; Pergamon press, New York, 1991, pages 419 434) and alpha-halocarbonyl compounds are readily accessible via conventional reactions (Larock, Comprehensive organic transformations, VCH, New York, 1989). For example, amides can be converted to thioamides using Lawesson's reagent or P 2 S5, and ketones can be halogenated using various halogenating reagents NBS, CuBr 2 (ii) Construction of an oxazole ring system Oxazoles useful for the present invention can be prepared using various methods in the literature (Turchi, Oxazoles; Wiley Sons, New York, 1986). Reactions between isocyanides tosylmethylisocyanide) and carbonyl compounds aldehydes and acyl chlorides) can be used to construct oxazole ring systems (van Leusen et al, Tetrahedron Lett., 1972, 2369). Alternatively, cyclization reactions of amides urea, carboxamides) and alpha-halocarbonyl compounds are commonly used for the construction of an oxazole ring system. For example, the reactions of urea and 5-diethylphosphono-2-[(-2-bromo-loxo)alkyl]furans are useful for the synthesis of compounds of formula I wherein R 5 is an oxazole, A is an amino group and X is a furan-2,5-diyl group. Reactions between amines and imidates are also used to construct the oxazole ring system (Meyers et al, J. Org. Chem., 1986, 51(26), 5111).

(iii) Construction of a pyridine ring system Pyridines useful for the synthesis of compounds of formula I can be prepared using various known synthetic methods (Klingsberg, Pyridine and Its Derivatives; Interscience Publishers, New York, 1960 -1984). 1,5-Dicarbonyl compounds or their equivalents can be reacted with ammonia or compounds which can generate ammonia to produce 1,4dihydropyridines which are easily dehydrogenated to pyridines. When unsaturated dicarbonyl compounds, or their equivalents pyrylium ions) are used to react with ammonia, pyridines can be generated directly. 1,5-Dicarbonyl compounds or their equivalents can be prepared using conventional chemistry. For example, 1,5-diketones are accessible via a number of routes, such as Michael addition of an enolate to an enone (or precursor Mannich base (Gill et al, J. Am. Chem. Soc., 1952, 74, 4923)), ozonolysis of a cyclopentene precursor, or reaction of silyl enol ethers with 3-methoxyallylic alcohols (Duhamel et al, Tetrahedron, 1986, 42, 4777). When one of the carbonyl carbons is at the acid oxidation state, then this type of reaction produces 2-pyridones which can be readily converted to 2-halopyridines (Isler et al, Helv. Chinz. Acta, 1955, 38, 1033) or 2aminopyridines (Vorbruggen etal, Chem. Ber., 1984, 117, 1523). Alternatively, a pyridine can be prepared from an aldehyde, a 1,3-dicarbonyl compound and ammonia via the classical Hantzsch synthesis (Bossart et al, Angew. Chem. Int. Ed. Engl.,1981, 20, 762). Reactions of 1,3-dicarbonyl compounds (or their equivalents) with 3-amino-enones or 3-amino-nitriles have also been used to produce pyridines (such as the Guareschi synthesis, Mariella, Org.

Synth., Coll, Vol. IV, 1963, 210). 1,3-Dicarbonyl compounds can be made via oxidation reactions on corresponding 1,3-diols or aldol reaction products (Mukaiyama, Org, Reactions, 1982, 28, 203). Cycloaddition reactions have also been used for the synthesis of pyridines, for example cycloaddition reactions between oxazoles and alkenes (Naito et al., Chem.

Pharm. Bull., 1965, 13, 869), and Diels-Alder reactions between 1,2,4-triazines and enamines (Boger et al., J. Org. Chem., 1981, 46, 2179).

(iv) Construction of a pvrimidine ring system Pyrimidine ring systems useful for the synthesis of compounds of formula I are readily available (Brown, The pyrimidines; Wiley, New York, 1994). One method for pyrimidine synthesis involves the coupling of a 1,3-dicarbonyl component (or its equivalent) with an N- C-N fragment. The selection of the N-C-N component urea (Sherman et al., Org. Synth., Coll. Vol. IV, 1963, 247), amidine (Kenner et al., J. Chem. Soc., 1943, 125) or guanidine (Burgess, J Org. Chem., 1956, 21, 97; VanAllan, Org. Synth., Coll. Vol. IV, 1963, 245) governs the substitution at C-2 in the pyrimidine products. This method is particular useful for the synthesis of compounds of formula I with various A groups. In another method, pyrimidines can be prepared via cycloaddition reactions such as aza-Diels-Alder reactions between a 1,3,5-triazine and an enamine or an ynamine (Boger et al., J. Org. Chem., 1992, 57, 4331 and references cited therein).

Construction of an imidazole ring system Imidazoles useful for the synthesis of compounds of formula I are readily prepared using a variety of different synthetic methodologies. Various cyclization reactions are generally used to synthesize imidazoles such as reactions between amidines and alphahaloketones (Mallick et al, J Am. Chem. Soc., 1984, 106(23), 7252) or alpha-hydroxyketones (Shi et al, Synthetic Comm., 1993, 23(18), 2623), reactions between urea and alphahaloketones, and reactions between aldehydes and 1,2-dicarbonyl compounds in the presence of amines.

(vi) Construction of an isoxazole ring system Isoxazoles useful for the synthesis of compounds of formula I are readily synthesized using various methodologies (such as cycloaddition reactions between nitrile oxides and alkynes or active methylene compounds, oximation of 1,3-dicarbonyl compounds or alpha, beta-acetylenic carbonyl compounds or alpha,beta-dihalocarbonyl compounds, etc.) can be used to synthesize an isoxazole ring system (Grunanger et al., Isoxazoles; Wiley Sons, New York, 1991). For example, reactions between alkynes and 5-diethylphosphono-2chlorooximidofuran in the presence of base triethylamine, Hunig's base, pyridine) are useful for the synthesis of compounds of formula I wherein R 5 is an isoxazole and X is a group.

,(vii) Construction of a pvrazole ring system Pyrazoles useful for the synthesis of compounds of formula I are readily prepared using a variety of methods (Wiley, Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles, and Condensed Rings; Interscience Publishers, New York, 1967) such as reactions between hydrazines and 1,3-dicarbonyl compounds or 1,3-dicarbonyl equivalents one of the carbonyl group is masked as an enamine or ketal or acetal), and additions of hydrazines to acrylonitriles followed by cyclization reactions (Dom et al, Org. Synth., 1973, Coll. Vol. V, 39). Reaction of 2-(2-alkyl-3-N,N-dimethylamino)acryloyl-5-diethylphosphonofurans with hydrazines are useful for the synthesis of compounds of formula I wherein R 5 is a pyrazole, X is a furan-2,5-diyl group and B" is an alkyl group.

(viii) Construction of a 1,2,4-triazole ring system 1,2,4-Triazoles useful for the synthesis of compounds of formula I are readily available via various methodologies (Montgomery, 1,2,4-Triazoles; Wiley, New York, 1981).

For example, reactions between hydrazides and imidates or thioimidates (Sui et al., Bioorg.

Med. Chem. Lett., 1998, 8, 1929; Catarzi et J Med. Chemn., 1995, 38(2), 2196), reactions r~l between 1,3,5-triazine and liydrazines (Grundmann et al., J Org. Chem., 1956, 21, 1037), and reactions between aminoguanidine and carboxylic esters (Ried et al., Chemn. Ber., 1968, 101, 2117) are used to synthesize 1,2,4-triazoles.

Ring closure to construct a heterocycle with a phosphonate Compounds of formula 4 can also be prepared using a ring closure reaction to construct the heterocycle from precursors that contain the phosphonate component. For ~K1 example, cyclization reactions between thiourea and 5-diethylphosphono-2-[(-2-bromo-loxo)alkyl]furans are useful for the synthesis of compounds of formula I wherein R5 is a thiazole, A is an amrino group and X is a furan-2,5-diyl group. Oxazoles of the present invention can also be prepared using a ring closure reaction. In this case, reactions of urea and 5-diethylphosphono-2-[(-2-bromo--oxo)alkyl]furans are useful for the synthesis of compounds of formula I wherein R 5 is an oxazole, A is an amino group and X is a diyl group. Reactions between 5-diethylphosphono-2-furaldehyde, an alkyl amine, a 1,2diketone and ammonium acetate are useful to synthesize compounds of formula I wherein R is an imidazole and X is a fiaran-2,5-diyl group. These types of ring closure reactions can also be used for the synthesis of pyridines or pyrim-idines useful in the present invention. For example, reaction of 5-diethylphosphono-2-[3-dimethylam-ino-2-alkyl)acryloyl] furans and cyanoacetamide in the presence of base gives 5-alkyl-3-cyano-6-[2-(5diethylphosphono)fiiranyl]-2-pyridones (Jain et al., Tetrahedron Lett., 1995, 36, 3307).

Subsequent conversion of these 2-pyridones to the corresponding 2-halopyridines (see references cited in section 3 for the modifications of heterocycles) will lead to compounds of formula I wherein R 5 is a pyridine, A is a halo group, X is a furan-2,5-diyl group, and B is an alkyl group. Reactions of 5-diethylphosphono-2-[3-dimethylamino-2-alkyl)acryloyl]furans and amidines in the presence of base give 5-alkyl-6-[2-(5-diethylphosphono)furanyl]pyrimidines which will lead to compounds of formula I wherein R' is a pyrimidine, X is a faran-2,5-diyl group and B is an ailkyl group.

Preparation of various precursors useful for cyclization reactions Intermediates required for the synthesis of compounds in the present invention are generally prepared using either an existing method in the literature or a modification of an existing method. Syntheses of some of the intermediates useful for the synthesis of compounds in the present invention are described herein.

Various aryl phosphonate dialkyl esters are particularly useful for the synthesis of compounds of formula I. For example, compounds of formula I wherein X is a group can be prepared fi-om a variety of furanyl precursors. It is envisioned that synthesis of other precursors may follow some or all of these reaction steps, and some modifications of these reactions may be required for different precursors. 5-Dialkylphosphono-2furancarbonyl compounds 5-diethylphosphono-2-furaldehyde, 5-diethylphosphono-2acetylfuran) are well suited for the synthesis of compounds of formula I wherein X is a furangroup. These intermediates are prepared from furan or furan derivatives using conventional chemistry such as lithiation reactions, protection of carbonyl groups and deprotection of carbonyl groups. For example, lithiation of furan using known methods (Gschwend Org. React., 1979, 26: 1) followed by addition of phosphorylating agents (e.g.

CLPO

3

R

2 gives 2-dialkylphosphono-furans 2-diethylphosphonofuran). This method can also be applied to a 2-substituted furan 2-furoic acid) to give a 5-dialkylphosphono-2substituted furan 5-diethylphosphono-2-furoic acid). It is envisioned that other aryl phosphonate esters can also be prepared using this approach or a modification of this approach. Alternatively, other methods such as transition metal catalyzed reactions of aryl halides or triflates (Balthazar et al. J Org. Chem., 1980, 45: 5425; Petrakis et al. J. Am.

Chem. Soc., 1987, 109:2831; Lu et al. Synthesis, 1987, 726) are used to prepare aryl phosphonates. Aryl phosphonate esters can also be prepared from aryl phosphates under anionic rearrangement conditions (Melvin, Tetrahedron Lett., 1981, 22: 3375; Casteel et al.

Synthesis, 1991, 691). N-Alkoxy aryl salts with alkali metal derivatives of dialkyl phosphonate provide another general synthesis for heteroaryl-2-phosphonate esters (Redmore J. Org. Chem., 1970, 35: 4114).

A second lithiation step can be used to incorporate a second group on the aryl phosphonate dialkyl ester such as an aldehyde group, a trialkylstannyl or a halo group, although other methods known to generate these functionalities aldehydes) can be envisioned as well Vilsmeier-Hack reaction or Reimar-Teimann reaction for aldehyde synthesis). In the second lithiation step, the lithiated aromatic ring is treated with reagents that either directly generate the desired functional group for an aldehyde using DMF,

HCO

2 R, etc.) or with reagents that lead to a group that is subsequently transformed into the desired functional group using lknown chemistry alcohols, esters, nitriles, alkenes can be transformed into aldehydes). For example, lithiation of a 2-dialkylphosphonofuran 2diethylphosphonofuran) under normal conditions LDA in THF) followed by trapping of the thus generated anion with an electrophile tributyltin chloride or iodine) produces a functionalized-2-dialkylphosphonofuran 5-tributylstannyl-2-diethylphosphonofuran or iodo-2-diethylphosphonofuran). It is also envisioned that the sequence of these reactions can be reversed, i.e. the aldehyde moiety can be incorporated first followed by the phosphorylation reaction. The order of the reaction will be dependent on reaction conditions and protecting groups. Prior to the phosphorylation, it is also envisioned that some of these functional groups may be protected using a number of well-known methods protection of aldehydes as acetals, aminals; protection of ketones as ketals). The protected functional group is then unmasked after phosphorylation. (Protective groups in Organic Synthesis, Greene, T.

1991, Wiley, New York). For example, protection of 2-furaldehyde as 1,3-propanediol acetal followed by a lithiation step (using for example LDA) and trapping the anion with a dialkyl chlorophosphate diethyl chlorophosphate), and subsequent deprotection of the acetal functionality under normal deprotection conditions produces the 5-dialkylphosphono-2furaldehyde 5-diethylphosphono-2-furaldehyde). Another example is the preparation of 5-keto-2-dialkylphosphonofurans which encompass the following steps: acylations of furan under Friedel-Crafts reaction conditions give 2-ketofuran, subsequent protection of the ketone as ketals 1,3-propanediol cyclic ketal) followed by a lithiation step as described above gives the 5-dialkylphosphono-2-furanketone with the ketone being protected as a 1,3propanediol cyclic ketal, and final deprotection of the ketal under, for example, acidic conditions gives 2-keto-5-dialkylphosphonofurans Alternatively, 2-ketofurans can be synthesized via a palladium catalyzed reaction between 2trialkylstannylfurans 2-tributylstannylfuran) and an acyl chloride acetyl chloride, N 5 isobutyryl chloride). The phosphonate moiety may be present in the 2-trialkylstannylfurans 2-tributylstannyl-5-diethylphosphonofuran). 2-Keto-5-dialkylphosphonofurans can also IL be prepared from a 5-dialkylphosphono-2-furoic acid 5-diethylphosphono-2-furoic acid) Sby conversion of the acid to the corresponding acyl chloride and followed by additions of a Grignard reagent.

Some of the above described intermediates can also be used for the synthesis of other useful intermediates. For example, a 2-keto-5-dialkylphosphonofuran can be further converted to a 1,3-dicarbonyl derivative which is useful for the preparation ofpyrazoles, pyridines or pyrimidines. Reaction of a 2-keto-5-dialkylphosphonofuran diethylphosphonofuran) with a dialkylformamide dialkyl acetal dimethylformamide dimethyl acetal) gives a 1,3-dicarbonyl equivalent as a 2-(3-dialkylamino-2-alkyl-acryloyl)-5dialkylphosphonofuran 2-(3-dimethylaminoacryloyl)-5-diethylphosphonofuran).

It is envisioned that the above described methods for the synthesis of furan derivatives can be, either directly or with some modifications, applied to syntheses of various other useful intermediates such as aryl phosphonate esters thienyl phosphonate esters, phenyl phosphonate esters or pyridyl phosphonate esters).

It is conceivable that when applicable the above described synthetic methods can be adopted for parallel synthesis either on solid phase or in solution to provide rapid SAR (structure activity relationship) exploration of FBPase inhibitors encompassed in the current invention, provided method development for these reactions are successful.

Section 2.

Synthesis of Compounds of Formula X Synthesis of the compounds encompassed by the present invention typically includes some or all of the following general steps: preparation of a phosphonate prodrug; (2) deprotection of a phosphonate ester; construction of a heterocycle; introduction of a phosphonate component; synthesis of an aniline derivative. Step and step were discussed in section 1, and discussions of step step and step are given below.

These methods are also generally applicable to compounds of Formula X.

A

2 G.,/zN (1) Formula X 0 2 11 x-P-OH

OH

M, NH 2 II (3) L X -P-OR' S OR'

E

2 ~j 2

E

2 2 Construction of a heterocycle Benzothiazole ring system Compounds of formula 3 wherein G" S, i.e. benzothiazoles, can be prepared using various synthetic methods reported in the literature. Two of these methods are given as examples as discussed below. One method is the modification of commercially available benzothiazole derivatives to give the appropriate functionality on the benzothiazole ring.

Another method is the annulation of various anilines compounds of formula 4) to construct the thiazole portion of the benzothiazole ring. For example, compounds of formula 3 wherein G" S, A 2

=NH

2

L

2

E

2

J

2

X

2

=CH

2 0, and R'=Et can be prepared from the commercially available 4-methoxy-2-amino thiazole via a two-step sequence: conversion 4methoxy-2-aminobenzothiazole to 4-hydroxy-2-aminobenzothiazole with reagents such as BBr 3 (Node, et al. J. Org. Chem. 45, 2243-2246, 1980) or AIC13 in presence of a thiol EtSH) (McOmie, J. F. et al. Org. Synth., Collect. Vol. V, 412, 1973) followed alkylation of the phenol group with diethylphosphonomethyl trifluoromethylsulfonate (Phillion, D. et al. Tetrahedron Lett. 27, 1477-1484, 1986) in presence of a suitable base NaH) in polar aprotic solvents DMF) provide the required compound.

Several methods can be used.to convert various anilines to benzothiazoles (Sprague, J.

Land, A. H. Heterocycle. Compd. 5, 506-13, 1957). For example, 2-aminobenzothiazoles (formula 3 wherein A=NH2) can be prepared by annulation of compounds of formula 4 wherein W 2 using various common methods. One method involves the treatment of a suitably substituted aniline with a mixture of KSCN and CuSO 4 in methanol to give a substituted 2-aminobenzothiazole (Ismail, I. Sharp, D. E; Chedekel, M. R. J. Org. Chem.

2243-2246, 1980). Alternatively, a 2-aminobenzothiazole can also be prepared by the treatment of Br 2 in presence of KSCN in acetic acid (Patil, D. Chedekel, M. R. J Org.

Chem. 49, 997-1000, 1984). This reaction can also be done in two step sequence. For example treatment of substituted phenylthioureas with Br 2 in CHC13 gives substituted 2aminobenzothiazoles (Patil, D. Chedekel, M. R. J. Org. Chem. 49, 997-1000, 1984). 2- Aminobenzothiazoles can also be made by condensation of ortho iodo anilines with thiourea in presence of Ni catalyst (NiC1 2 (PPh 3 2 (Takagi, K. Chem. Lett. 265-266, 1986).

Benzothiazoles can undergo electrophilic aromatic substitution to give 6-substituted benzothiazoles (Sprague, J. Land, A. H. Heterocycle. Compd. 5, 606-13, 1957). For example bromination of formula 3 wherein A 2

=NH

2

L

2

E

2

J

2

X

2

=CH

2 0 and R'=Et with bromine in polar solvents such as AcOH gave compound of formula 3 wherein

E

2 =Br.

Furthermore, compounds of formula 3 wherein A is a halo, H, alkoxy, alkylthio or an alkyl can be prepared from the corresponding amino compound (Larock, Comprehensive organic transformations, VCH, New York, 1989; Trost, Comprehensive organic synthesis; Pergamon press, New York, 1991).

(ii) Benzoxazoles Compounds of formula 3 wherein i.e. benzoxazoles, can be prepared by the annulation of ortho aminophenols with suitable reagent cyanogen halide (A=NH 2 Alt, K. et al J Heterocyclic Chem. 12, 775, 1975) or acetic acid (A=CH 3 Saa, J. J. Org.

Chem. 57, 589-594, 1992) or trialkyl orthoformate Org. Prep. Proced. Int., 22, 613, 1990)).

Introduction of a Phosphonate Component Compounds of formula 4 (wherein X 2

=CH

2 0 and R'=alkyl) can made in different ways using alkylation and nucleophilic substitution reactions). Typically, compounds of formula 5 wherein M'=OH is treated with a suitable base NaH) in polar aprotic solvent DMF, DMSO) and the resulting phenoxide anion can be alkylated with a suitable electrophile often with a phosphonate component present diethyl iodomethylphosphonate, diethyl trifluoromethylsulphonomethyl phosphonate, diethyl pmethyltoluenesulphonomethylphosphonate). The alkylation method can also be applied to the precursor compounds to compounds of formula 5 wherein a phenol moiety is present and it can be alkylated with a phosphonate containing component. Alternately, compounds of formula 4 can also be made from the nucleophilic substitution of the precursor compounds to compounds of formula 5, for example, wherein a halo group, such as a fluoro or a chloro, is present ortho to a nitro group. For example, a compound of formula 4 (wherein X2=CH 2 0 and R'=Et) can be prepared from a 2-chloro-l-nitrobenzene derivative by treatment with NaOCH 2 P(O)(OEt) 2 in DMF. Similarly, compounds of formula 4 where X 2 -alkyl-S- or -alkyl-N- can also be made.

Synthesis of an aniline derivative Numerous synthetic methods have been reported for the synthesis of aniline derivatives, these methods can be applied to the synthesis of useful intermediates which can lead to compounds of formula X. For example, various alkenyl or aryl groups can be introduced on to a benzene ring via transition metal catalyzed reactions (Kasibhatla, S. et al. WO 98/39343 and the references cited in); anilines can be prepared from their corresponding nitro derivatives via reduction reactions hydrogenation reactions in presence of 10 Pd/C, or reduction reactions using SnC12 in HCI (Patil, D. Chedekel, M.

R.J. Org. Chem. 49, 997-1000, 1984)).

Section 3.

Synthesis of compounds of Formula XI WO 98/39343 describes the synthesis ofphosphonic acids and esters oftihe benzimidazoles of Formula XI. The bisamidate phosphonates of the present invention can be prepared by using procedures described supra for compounds of Formula I.

Formulations Compounds of the invention are administered orally in a total daily dose in a range of about 0.01 mg/kg/dose to about 100 mg/kg/dose; and from about 0.1 mg/kg/dose to about mg/kg/dose. The use of time-release preparations to control the rate of release of the active ingredient is contemplated. The dose may be administered in as many divided doses as is convenient. When other methods are used intravenous administration), compounds are administered to the affected tissue at a rate in the range from 0.05 to 10 mg/kg/hour; and from 0:1 to I mg/kg/hour. Such rates are easily maintained when these compounds are intravenously administered as discussed below.

For the purposes of this invention, the compounds may be administered by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through catheters. Oral administration is generally preferred.

Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide lecithin), a condensation product of an alkylene oxide with a fatty acid polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride polyoxyethylene sorbitan monooleate).

The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above.

Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-inwater emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions. The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion should contain from about 3 to 330 Pg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.

As noted above, formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste: A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant sodium starch glycolate, cross-linked povidone, crosslinked sodium carboxymethyl cellulose) surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach, especially when the active ingredient is susceptible to acid hydrolysis.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Suitable unit dosage formulations include those containing a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a fructose 1,6-bisphosphatase inhibitor compound.

It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.

Utility One aspect of the invention is directed to novel bis-phosphoramidate prodrugs of FBPase inhibitors to increase the oral bioavailability of the parent drugs.

FBPase inhibitors and their prodrugs may be used to treat diabetes mellitus, lower blood glucose levels, and inhibit gluconeogenesis.

FBPase inhibitors and their prodrugs may also be used to treat excess glycogen storage diseases. Excessive hepatic glycogen stores are found in patients with some glycogen storage

ID

diseases. Since the indirect pathway contributes significantly to glycogen synthesis (Shulman, G.I. Phys. Rev. 72:1019-1035, 1992), inhibition of the indirect pathway (gluconeogenesis flux) decreases glycogen overproduction.

FBPase inhibitors and their prodmrugs may also be used to treat or prevent diseases associated with increased insulin levels. Increased insulin levels are associated with an N increased risk of cardiovascular complications and atherosclerosis (Folsom, et al., Stroke, 25:66-73, 1994; Howard, G. et al., Circulation, 93:1809-1817, 1996). FBPase inhibitors and their prodrugs are expected to decrease postprandial glucose levels by enhancing hepatic glucose uptake. This effect is postulated to occur in individuals that are non-diabetic (or prediabetic, i.e. without elevated hepatic glucose output "hereinafter HGO" or fasting blood glucose levels). Increased hepatic glucose uptake will decrease insulin secretion and thereby decrease the risk of diseases or complications that arise from elevated insulin levels.

These aspects are described in greater detail below.

EXAMPLES

1. Synthesis of Compounds of Formula IA.

Example 1.

Preparation of 5-diethylnhosphono-2-furaldehyde (1) Step A. A solution of 2-furaldehyde diethyl acetal (I mmole) in THF (tetrahydrofuran) was treated with nBuLi (1 mmole) at -78 0 C. After 1 h, diethyl chlorophosphate (1.2 mmole) was added and the reaction was stirred for 40 min. Extraction and evaporation gave a brown oil.

Step B. The resulting brown oil was treated with 80 acetic acid at 90 0 C for 4 h.

Extraction and chromatography gave compound 1 as a clear yellow oil. Alternatively this aldehyde can be prepared from furan as described below.

Step C. A solution of furan (1 mmole) in diethyl ether was treated with TMEDA (N,N,N'N'-tetramethylethylenediamine) (1 mmole) and nBuLi (2 mmole) at -78 0 C for 0.5 h.

Diethyl chlorophosphate (1.2 mmole) was added to the reaction mixture and stirred for another hour. Extraction and distillation gave diethyl 2-furanphosphonate as a clear oil.

Step D. A solution of diethyl 2-furanphosphonate (1 mmole) in TBF was treated with LDA (1.12 mmole, lithium N,N-diisopropylamide) at -78 0 C for 20 min. Methyl formate mmole) was added and the reaction was stirred for 1 h. Extraction and chromatography gave compound 1 as a clear yellow oil. Preferably this aldehyde can be prepared from 2furaldehyde as described below.

Step E. A solution of 2-furaldehyde (1 mmole) and N,N'-dimethylethylene diamine (1 mmole) in toluene was refluxed while the resulting water being collected through a Dean- Stark trap. After 2 h the solvent was removed in vacuo and the residue was distilled to give.

furan-2- (N,N'-dimethylimidazolidine) as a clear colorless oil. bp 59 61 0 C (3 mm Hg).

Step F. A solution of furan-2-(N,N'-dimethylimidazolidine) (1 mmole) and TMEDA (1 mmole) in THF was treated with nBuLi (1.3 mmole) at -40 to -48 0 C. The reaction was stirred at 0 C for 1.5 h and then cooled to -55 0 C and treated with a solution of diethylchlorophosphate (1.1 mmole) in THF. After stirring at 25 0 C for 12 h the reaction mixture was evaporated and subjected to extraction to give 5-diethylphosphono-furan-2- (N,N'-dimethylimidazolidine) as a brown oil.

Step G. A solution of 5-diethylphosphonofuran-2-(N,N'-dimethyl- imidazolidine) (1 mmole) in water was treated with concentrated sulfuric acid until pH 1. Extraction and chromatography gave compound I as a clear yellow oil.

Example 2.

Preparation of 5-diethylphosphono-2-1f(1-oxo)alkylfurans and 6-diethylphosphono-2- [(1-oxo)alkyllpyridines.

Step A. A solution of furan (1.3 mmole) in toluene was treated with 4-methyl pentanoic acid (1 mmole), trifluoroacetic anhydride (1.2 mmole) and boron trifluoride etherate (0.1 mmole) at 56 0 C for 3.5 h. The cooled reaction mixture was quenched with aqueous sodium bicarbonate (1.9 mmole), filtered through a celite pad. Extraction, evaporation and distillation gave 2-[(4-methyl-l-oxo)pentyl]furan as a brown oil (bp 65 77"C, 0. 1 mm Hg).

Step B. A solution of 2-[(4-methyl-l-oxo)pentyl]furan (1 mmole) in benzene was treated with ethylene glycol (2.1 mmole) and p-toluenesulfonic acid (0.05 mmole) at reflux for 60 h while removing water via a Dean-Stark trap. Triethyl orthoformate (0.6 rumole) was added and resulting mixtue was heated at reflux for an additional hour. Extraction and evaporation gave 2-(2-furanyl)-2-[(3-methyl)butyll-1,3-dioxolane as an orange liquid.

Step C. A solution of 2-(2-furanyl)-2-[(3-rnethyl)butyl]-l1,3-dioxolane (1 mmole) in THF was treated with TMIEDA (1 mmole) and nBuLi (I.1I mmole) at -45'C, and the resulting reaction mixture was stirred at -5 to 0 0 C for I h. The resulting reaction mixture was cooled to and cannulated into a solution of diethyl chiorophosphate in THF at -45'C. The reaction mixture was gradually warmed to ambient temperature over 1.25 h. Extraction and evaporation gave 2-[2-(5-diethylphosphono)furanyl]-2-[(3-methyl)butyl]-1I,3-dioxolane as a dark oil.

Step D. A solution of 2-[2-(5-diethiylphosphono)ffiranyl]-2-[(3-methyl)butylj- 1,3dioxolane (1 mmole) in methanol was treated with 1 N hydrochloric acid (0.2 minole) at for 18 h. Extraction and distillation gave 5-diethylphosphono-2-[(4-methyl-loxo)pentyl]futran as a light orange oil (bp 152 156'C, 0.1 mm Hg).

The following compounds were prepared according to this Procedure: 5-diethylphosphono-2-acetylfuran: by 125 136'C, 0. 1 mm Hg.

5-diethylphosphono-2-[(1-oxo)butyl]faran: by 130 145'C, 0.08 mm Hg.

Alternatively these compounds can be prepared using the following procedures: Step E. A solution of 2-[(4-methyl-l-oxo)pentyl]furan (1 mniole, prepared as in Step A) in benzene was treated with NN-dimethyl hydrazine (2.1 mmole) and trifluoroacetic acid (0.05 mmole) at reflux. for 6 h. Extraction and evaporation gave 2-[(4-methyl-loxo)pentyl]furan N,N-dimethyl hydrazone as a brown liquid.

Step F. 2-[(4-Methyl-l-oxo)pentyl]furaii N,N-dimethyl hydrazone was subjected to the procedures of Step C to give 2-[(4-methyl- 1-oxo)pentyl]-5-diethylphosphonofuran N,Ndimethyl hydrazone as a brown liquid which was treated with copper (HI) chloride (1.1I equivalent) in ethanol-water at 25'C for 6 h. Extraction and distillation gave compound 2.1 as a light orange oil.

Some of 5-diethiylphosphono-2-[Vl-oxo)alkyllfarans are prepared using the following procedures: Step G. A solution of compound 1 (I ramole) and 1,3-propanedithiol (1.1I mmole) in chloroform was treated with borontrifluoride etherate (0.1 mmole) at 25'C for 24 h.

Evaporation and chromatography gave 2-(2-(5-diethylphosphono)furanyl)- 1,3-dithiane as a light yellow oil.

A solution of 2-(2-(5-diethylphosphono)furanyl)-l,3-dithiane (1 mmole) in THF was cooled to -78'C and treated with nduLi (1.2 mmole). After 1 h. at -78'C the reaction mixture was treated with cyclopropanemnethyl bromide and reaction was stirred at -78*C for another hour. Extraction and chromatography gave 2-(2-(5-diethylphosphono)furany)-2cyclopropaniemethyl-1,3-dithiane as an oil.

A solution of 2-(2-(5-diethylphosplaono)furanyl)-2-cyclopropaneinethyl-1I,3-ditbiane (1 mimole) in acetonitrile water was treated with [bis(trifluoroacetoxy)iodolbenzene (2 mmole) at 25'C for 24 h. Extraction and chromatography gave 5-diethylphosphono-2-(2cyclopropylacetyl)furan as a light orange oil.

The following compounds were prepared according to this procedure: 5-Diethylphosphono-2-(2-ethoxycarbonylacetyl)furafl 5-Diethylphosphono-2-(2-methyltioacetyl)fuiran 6-Diethylphosphono-2-acetylpyridine Example 3.

Preparation of 4-r24(5-phosphono)furanyllthiazoles. 44 246phosphono)pyridyll thiazoles and 4-[2-(5-phosphono)furaa'yllselen azoles.

Step A. A solution of compound 2.1 (1 mmole) in ethanol was treated with copper (II) bromide (2.2 mmole) at reflux for 3 h. The cooled reaction mixture was filtered and the (Ni filtrate was evaporated to dryness. The resulting dark oil was purified by chromatography to give 5-diethylphosphono-2-[(2-bromo-4-methyl-l-oxo)pentyl]furan as an orange oil.

Step B. A solution of 5-diethylphosphono-2-[(2-bromo-4-methyl-l-oxo)pentyl]furan (I mmole) and thiourea (2 mrnole) in ethanol was heated at reflux for 2 h. The cooled reaction mixture was evaporated to dryness and the resulting yellow foam was suspended in saturated sodium bicarbonate and water (pH The resulting yellow solid was collected through filtration to give 2-amino-5-isobutyl-4-[2-(5-diethylphosphono)furanyllthiazole.

Step C. A solution of 2-amino-5-isobutyl-4-[2-(5-diethylphosphono)-furanyl]thiazole (1 mmole) in methylene chloride was treated with bromotrirnethylsilane (10 mmole) at for 8 h. The reaction mixture was evaporated to dryness and the residue was suspended in water. The resulting solid was collected through filtration to give 2-amino-5-isobutyl-4-[2-(5phosphono)fiiranyl]thiiazole as an off-white solid. mp 250'C. Anal. calcd. for

C

11

H

15

N

2 0 4 PS l.2SHBr: C: 32.75; H: 4.06; N: 6.94. Found: C: 32.39; H: 4.33; N: 7.18.

According to the above procedures or in some cases with minor modifications of these procedures using conventional chemistry the following compounds were prepared: 2-Methyl-5-isobutyl4-[2-(5-phosphono)furnyl~thiazole. Anal. calcd. for

C

12

H

1 6 N0 4 PS HBr 0.lCH 2 Cl 2 C: 37.20; H: 4.44; N: 3.58. Found: C: 37.24; H: 4.56; N: 3.30.

4-[2-(5-Phosphono)furanyl~thiazole. Anal. calcd. for C 7

H

6

NO

4 PS 0.65 H-Mr: C: 29.63; H: 2.36; N: 4.94. Found: C: 29.92; H: 2.66; N: 4.57.

2-Methyl-4-[2-(5-phosphono)fiuanyl]thiazole. mp 235 236'C. Anal. calcd. for CsHSNO 4 PS 0.25H 2 0: C: 38.48; H: 3.43; N: 5.61. Found: C: 38.68; H: 3.33; N: 5.36.

2-Phenyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for

C

1 7

HI

8

NO

4 PS HBr: C: 45.96; H: 4.31; N: 3.15. Found: C: 45.56; H: 4.26; N: 2.76.

2-Isopropyl-4-[2-(5-phosphono)furanyl]thiazole. mp 194 197 0 C. Anal. calcd. for

C

1 oH 1 2

NO

4 PS: C: 43.96; H: 4.43; N: 5.13. Found: C: 43.70; H: 4.35; N: 4.75.

5-Isobutyl-4-[2-(5-phosphono)furanyl]thiazole. mp 164 166 0 C. Anal. calcd. for

C

1 1 Hi 4

NO

4 PS: C: 45.99; H: 4.91; N: 4.88. Found: C: 45.63; H: 5.01; N: 4.73.

2-Aminothiocarbonyl-4-[2-(5-phosphono)furanyl]thiazole. mp 189 191C. Anal.

calcd. for C 8

H

7

N

2 0 4 PS2: C: 33.10; H: 2.43; N: 9.65. Found: C: 33.14; H: 2.50; N: 9.32.

2-(1-Piperidyl)-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for

C

16

H

23

N

2 0 4 PS 1.3HBr: C: 40.41; H: 5.15; N: 5.89. Found: C: 40.46; H: 5.36; N: 5.53.

(3.10) 2-(2-Thienyl)-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal, calcd. for CjsHI 6

NO

4

PS

2 0.75H 2 0: C: 47.05; H: 4.61; N: 3.66. Found: C: 47.39; H: 4.36; N: 3.28.

(3.11) 2-(3-Pyridyl)-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for

C

16

H

1 7

N

2 0 4 PS 3.75HBr: C: 28.78; H: 3.13; N: 4.20. Found: C: 28.73; H: 2.73; N: 4.53.

(3.12) 2-Acetamido-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. mp 179 181 0 C. Anal.

calcd. for CH 1 0 7

N

2 0 5 PS 0.25H 2 0: C: 44:76; H: 5.06; N: 8.03. Found: C: 44.73; H: 5.07; N: 7.89.

(3.13) 2-Amino-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C 7

H

7

N

2 0 4 PS: C: 34.15; H: 2.87; N: 11.38. Found: C: 33.88; H: 2.83; N: 11.17.

(3.14) 2-Methylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. mp 202 205 0 C. Anal.

calcd. for C 1 2

HI

7

N

2 0 4 PS 0.5H 2 0: C: 44.30; H: 5.58; N: 8.60. Found: C: 44.67; H: 5.27; N: 8.43.

(3.15) 2-(N-amino-N-methyl)amino-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. mp 179 181 0 C. Anal. calcd. for Cj 2

H

18

N

3 0 4 PS 1.25HBr: C: 33.33; H: 4.49; N: 9.72. Found: C: 33.46; H: 4.81; N: 9.72.

(3.16) 2-Amino-5-methyl-4-[2-(5-phosphono)furanyl]thiazole. mp 200-220C. Anal. calcd.

for CsHqN 2 0 4 PS 0.65HBr: C: 30.72; H: 3.11; N: 8.96. Found: C: 30.86; H: 3.33; N: 8.85.

(3.17) 2,5-Dimethyl-4-[2-(5-phosphono)furanyl]thiazole. mp 195 0 C (decomp). Anal. calcd.

for C 9 HjoNO 4 PS 0.7HBr: C: 34.22; H: 3.41; N: 4.43. Found: C: 34.06; H: 3.54; N: 4.12.

(3.18) 2-Aminothiocarbonyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for

C

1 2

H

15

N

2 0 4

PS

2 O.IHBr 0.3EtOAc: C: 41.62; H: 4.63; N: 7.35. Found: C: 41.72; H: 4.30; N: 7.17.

(3.19) 2-Ethoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. mp 163 165 0 C. Anal. calcd.

for CloH 1 oNO 6 PS 0.5H 2 0: C: 38.47; H: 3.55; N: 4.49. Found: C: 38.35; H: 3.30; N: 4.42.

(3.20) 2-Amino-5-isopropyl-4-[2-(5-phosphono)furanylthiazole. Anal. calcd. for CjoH 1 3

N

2 0 4 PS IHBr: C: 32.53; H: 3.82; N: 7.59, Found: C: 32.90; H: 3.78; N: 7.65.

(3.21) 2-Amino-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole. mp 250 0 C. Anal. calcd. for CH N 2 0 4 PS: C: 39.42; H: 4.04; N: 10.22. Found: C: 39.02; H: 4.15; N: 9.92.

(3.22) 2-Cyanomethyl-4-[2-(5-phosphono)furanyl]thiazole. mp 204 206 0 C. Anal. calcd. for CqH 7

N

2 0 4 PS: C: 40.01; H: 2.61; N: 10.37. Found: C: 39.69; H: 2.64; N: 10.03.

(3.23) 2-Aminothiocarbonylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. mp 177 182 0 C. Anal. calcd. for C 1 2

H

16

N

3 0 4

PS

2 0.2hexane 0.3HBr: C: 39.35; H: 4.78; N: 10.43.

Found: C: 39.61; H: 4.48; N: 10.24.

(3.24) 2-Amino-5-propyl-4-[2-(5-phosphono)furanyl]thiazole mp 235-237 0 C. Anal. calcd.

for CjoH 13

N

2 0 4 PS 0.3H 2 0: C: 40.90; H: 4.67; N: 9.54. Found: C: 40.91; H: 4.44; N: 9.37.

(3.25) 2-Amino-5-ethoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. mp 248-250 0 C. Anal.

calcd. for CioH 1 iN 2 0 6 PS O.lHBr: C: 36.81; H: 3.43; N: 8.58. Found: C: 36.99; H: 3.35; N: 8.84.

(3:26) 2-Amino-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole. mp 181-184C. Anal.

calcd. for CsHqN 2 04PS 2 0.4H20: C: 32.08; H: 3.30; N: 9.35. Found: C:32.09; H: 3.31; N: 9.15.

(3.27) 2-Amino-5-cyclopropyl-4-[2-(5-phosphono)furanyl]thiazole Anal. calcd. for CioHiiN 2 0 4 PS 1H 2 0 0.75HBr: C: 32.91; H: 3.80; N: 7.68. Found: C: 33.10; H: 3.80; N: 7.34.

(3.28) 2-Amino-5-methanesulfinyl-4-[2-(5-phosphono)furanyl]thiazole. mp 250C. Anal.

calcd. for C 8 HqN 2 0 5

PS

2 0.35NaCl: C: 29.23; H: 2.76; N: 8.52. Found: C: 29.37; H: 2.52; N: 8.44.

(3.29) 2-Amino-5-benzyloxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for

C

1 sH 13

N

2 06PS 0.2H20: C: 46.93; H: 3.52; N: 7.30. Found: C: 46.64; H: 3.18; N: 7.20.

(3.30) 2-Amino-5-cyclobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for

C

11

H

13

N

2 0 4 PS 0.15 HBr 0.15H20: C: 41.93; H: 4.30; N: 8.89. Found: C: 42.18; H: 4.49; N: 8.53.

(3.31) 2-Amino-5-cyclopropyl-4-[2-(5-phosphono)furanyl]thiazole hydrobromide. Anal.

calcd. for CIoH 1

N

2 0 4 PSBr 0.73HBr 0.15MeOH 0.5H20: C: 33.95; H: 3.74; N: 7.80; S: 8.93; Br: 16.24. Found: C: 33.72; H: 3.79; N: 7.65; S: 9.26; Br: 16.03.

(3.32) 2-Amino-5-[(N,N-dimethyl)aminomethyl]-4-[2-(5-phosphono)furanyl]thiazole dihydrobromide. Anal. calcd. for C 1 oH 16

N

3 0 4 Br 2 PS+ 0.8CH 2

C

2 C: 24.34; H: 3.33; N: 7.88.

Found: C: 24.23; H: 3.35; N: 7.64.

(3.33) 2-Arnino-5-methoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Mp 227 0

C

(decomp). Anal. calcd. for CgHgN 2 0 6 PS 0.1120 0.2HBr: C: 33.55; H: 2.94; N: 8.69.

Found: C: 33.46; H: 3.02; N: 8.49.

(3.34) 2-Amino-5-ethylthiocarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Mp 245 0

C

(decomp). Anal. calcd. for CjoHIIN 2 0 5

PS

2 C: 35.93; H: 3.32; N: 8.38. Found: C: 35.98; H: 3.13; N: 8.17.

(3.35) 2-Amino-5-propyloxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Mp 245 0

C

(decomp). Anal. calcd. for C 11

H

13

N

2 0 6 PS C: 39.76; H: 3.94; N: 8.43. Found: C: 39.77; H: 3.72; N: 8.19.

(3.36) 2-Amino-5-benzyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for

C

1 4

H

1 3

N

2 0 4 PS +H20: C: 47.46; H: 4.27; N: 7.91. Found: C: 47.24; H: 4.08; N: 7.85.

(3.37) 2-Amino-5-[(N,N-diethyl)aminomethyll-4-[2-(5-phosphono)furanyl]thiazole dihydrobromide. Anal. calcd. for C, 2

H

2 oN 3 0 4 Br 2 PS 0.lHBr 1.4 MeOH C: 29.47; H: 4.74; N: 7.69. Found: C: 29.41; H: 4.60; N: 7.32.

(3.38) 2-Amino-5-[(N,N-dimethyl)carbamoyl]-4-[2-(5-phosphono)furanyl]thiazole. Anal.

calcd. for CioHi 2

N

3 0 5 PS 1.3HBr I.0H 2 0 0.3 Acetone: C: 28.59; H: 3.76; N: 9.18.

Found: C: 28.40; H: 3.88; N: 9.01.

(3.39) 2-Amino-5-carboxyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for

C

8

H

7

N

2 0PS 0.2HBr 0.1 H 2 0: C: 31.18; H: 2.42; N: 9.09. Found: C: 31.11; H: 2.42; N: 8.83.

(3.40) 2-Amino-5-isopropyloxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Mp 240 0

C

(decomp). Anal. calcd. for C 1 iH 1 3

N

2 0 6 PS C: 39.76; H: 3.94; N: 8.43. Found: C: 39.42; H: 3.67; N: 8.09.

(3.41) 2-Methyl-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for CloH 12 0 4

PNS

0.75HBr 0.35H70: C: 36.02; H: 4.13; N: 4.06. Found: C: 36.34; H: 3.86; N: 3.69.

(3.42) 2-Methyl-5-cyclopropyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for

C

11

H

12

NO

4 PS 0.3HBr 0.5CHC1 3 C: 37.41; H: 3.49; N: 3.79. Found: C: 37.61; H: 3.29; N: 3.41.

(3.43) 2-Methyl-5-ethoxycarbonyl-4-[2-(5-phosphono)furanylJthiazole. Anal. calcd. for

C

11

H

2

NO

6 PS C: 41.64; H: 3.81; N: 4.40. Found: C: 41.61; H: 3.78; N: 4.39.

(3.44) 2-[(N-acetyl)amino]-5-methoxymethyl-4-[2-(5-phosphono)furanyl]thiazole. Anal.

calcd. for CjjH 13

N

2 0 6 PS 0.15HBr: C: 38.36; H: 3.85; N: 8.13. Found: C: 38.74; H: 3.44; N: 8.13.

(3.45) 2-Amino-5-(4-morpholinyl)methyl-4-[2-(5-phosphono)furanyl]thiazole dihydrobroniide. Anal. calcd. for C 1 2 Hj 8 Br 2

N

3 0sPS 0.25HBr: C: 27.33; H: 3.49; N: 7.97.

Found: C: 27.55; H: 3.75; N: 7.62.

(3.46) 2-Amino-5-cyclopropylmethoxycarbonyl-4-[2-(5-phosphono)furanyllthiazole. Mp 238 0 C (decom Anal. calcd. for C 12

H

13

N

2 0 6 PS C: 41.86; H: 3.81; N: 8.14. Found: C: 41.69; H: 3.70; N: 8.01.

(3.47) 2-Amino-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole N,Ndicyclohexylammonium salt. Mp>250 0 C. Anal, calcd. for CgHqN 2 0 4

PS

2 1.15 C 12

H

2 3 N: C: 52.28; H: 7.13; N: 8.81. Found: C: 52.12; H: 7.17; N: 8.81.

(3.48) 2-[(N-Dansyl)amino]-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for

C

23

H

26

N

3 0 6

PS

2 0.5HBr: C: 47.96; H: 4.64; N: 7.29. Found: C: 48.23; H: 4.67; N: 7.22.

(3.49) 2-Anino-5-(2,2,2-trifluoroethyl)-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for CqH 8

N

2

F

3 0 4 PS C:32.94, H:2.46, N:8.54. Found: C:32.57, H:2.64, N:8.14.

(3.50) 2-Methyl-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole. Anal. calod for

C

9 HioNO 4

PS

2 C: 37.11; H: 3.46; N: 4.81. Found: C: 36.72; H: 3.23; N: 4.60.

(3.51) 2-Amino-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole amonium salt. Anal.

calcd for CsH 12

N

3 0 4

PS

2 C: 31.07; H: 3.91; N: 13.59. Found: C: 31.28; H: 3.75; N: 13.60.

(3.52) 2-Cyano-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for CjoHqN 2 0 4

PS:

C: 42.26; H: 3.19; N: 9.86. Found: C: 41.96; H: 2.95; N: 9.76.

(3.53) 2-Amino-5-hydroxynethyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calod for CsH9N 2 0 5 PS: C: 34.79; H: 3.28; N: 10.14. Found: C: 34.57; H: 3.00; N: 10.04.

(3.54) 2-Cyano-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for

C

12

HI

3

N

2

O

4 SP+ 0.09HBr: C: 46.15; H: 4.20; N: 8.97. Found: C: 44.81; H: 3.91; N: 8.51.

(3.55) 2-Amino-5-isopropylthio-4-[2-(5-phosphono)furanyl]thiazole hydrobromide. Anal.

calcd for CioHi 4 BrN 2 0 4

PS

2 C: 29.94; H: 3.52; N: 6.98. Found: C: 30.10; H: 3.20; N: 6.70.

(3.56) 2-Amino-5-phenythio-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for

C

13

H

1 iN 2 0 4

PS

2 C: 44.07; H: 3.13; N: .91. Found: C: 43.83; H: 3.07; N: 7.74.

(3.57) 2-Amino-5-tert-butylthio-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for Ci 1

H

15

N

2 0 4

PS

2 0.6CH 2

C

2 C: 36.16; H: 4.24; N: 7.27. Found: C: 36.39; H: 3.86; N: 7.21.

(3.58) 2-Amino-5-propylthio-4-[2-(5-phosphono)furanyl]thiazole hydrobromide. Anal. calcd for CjoH1 4 BrN 2 0 4

PS

2 C: 29.94; H: 3.52; N: 6.98. Found: C: 29.58; H: 3.50; N: 6.84.

(3.59) 2-Amino-5-ethylthio-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for CgHitN 2 0 4

PS

2 0.25HBr: C: 33.11; H: 3.47; N: 8.58. Found: C: 33.30; H: 3.42; N: 8.60.

(3.60) 2-[(N-tert-butyloxycarbonyl)amino]-5-methoxymethyl-4-[2-(5phosphono)furanyl]thiazole. Anal, calcd for C1 4 HIgN 2 0 7 PS: C: 43.08; H: 4.91; N: 7.18.

Found: C: 42.69; H: 4.58; N: 7.39.

(3.61) 2-Hydroxyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C7H 6

NO

5 PS: C: 34.02; H: 2.45; N: 5.67. Found: C: 33.69; H: 2.42; N: 5.39.

(3.62) 2-Hydroxyl-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C 9 HioNO 5

PS:

C: 39.28; H: 3.66; N: 5.09. Found: C: 39.04; H: 3.44; N: 4.93.

(3.63) 2-Hydroxyl-5-isopropyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for CIoH 1 2

NO

5 PS +0.1HBr: C: 40.39; H: 4.10; N: 4.71. Found: C: 40.44; H: 4.11;N: 4.68.

(3.64) 2-Hydroxyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for

CIH

1 4

NO

5 PS: C: 43.57; H: 4.65; N: 4.62. Found: C: 43.45; H: 4.66; N: 4.46.

(3.65) 5-Ethoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for CjoHioNOPS: C: 39.61; H: 3.32; N: 4.62. Found: C: 39.60; H: 3.24; N: 4.47.

(3.66) 2-Amino-5-vinyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. caled for CgHgN 2 0 4 PS 0.28HCl: C: 37.66; H: 3.26; N: 9.46. Found: C: 37.96; H: 3.37; N: 9.10.

(3.67) 2-Amino-4-[2-(6-phosphono)pyridyl]thiazole hydrobromide.

(3.68) 2-Methylthio-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C21Hi 6

NO

4

PS

2 C: 43.24; H: 4.84; N: 4.20. Found: C: 43.55; H: 4.63; N: 4.46.

(3.69) 2-Amino-5-isobutyl-4-[2-(3-phosphono)furanyl]thiazole. Anal. calcd for

CIIH

15

N

2 0 4 PS 0.1 H 2 0 C: 43.45; H: 5.04; N: 9.21. Found: C: 43.68; H: 5.38; N: 8.98.

(3.70) 2-Amino-5-isobutyl-4-[2-(5-phosphono)furanyl]selenazole. Anal. calcd for

C

11 Hi 5

N

2 0 4 PSe 0.14HBr 0.6 EtOAc: C: 38.93; H: 4.86; N: 6.78. Found: C: 39.18; H: 4.53; N: 6.61.

(3.71) 2-Amino-5-methylthio-4-[2-(5-phosphono)furanyl]selenazole. Anal. calcd for C8H 9

N

2 0 4 PSSe 0.7 HBr 0.2 EtOAc: C: 25.57; H: 2.75; N: 6.78. Found: C: 25.46; H: 2.49; N: 6.74.

(3.72) 2-Amino-5-ethyl-4-[2-(5-phosphono)furanyl]selenazole. Anal. calcd for

C

9

HI

1

N

2 0 4 PSe HBr: C: 26.89; H: 3.01; N: 6.97. Found: C: 26.60; H: 3.16; N: 6.81.

109 Example 4.

Preparation of 5-halo-4-[2-(5-phosphono)furanyllthiazoles.

Step A. A solution of 2-amino-4-[2-(5-diethylphosphono)furanyl]thiazole (prepared as in Step B of Example 3) (1 mmole) in chloroform was treated with N-bromo succinimide (NBS) (1.5 nmole) at 25 0 C for I h. Extraction and chromatography gave 4-[2-(5-diethylphosphono)furanyl]-thiazole as a brown solid.

Step B. 2-Amino-5-bromo-4-[2-(5-diethylphosphono)furanyl]thiazole was subjected to Step C of Example 3 to give 2-amino-5-bromo-4-[2-(5-phosphono)furanyl]thiazole as a yellow solid. mp 2300C. Anal. calcd. for C 7

H

6

N

2 0 4 PSBr: C: 25.86; H: 1.86; N: 8.62.

Found: C: 25.93; H: 1.64; N: 8.53.

The following compounds were prepared according to this procedure: 2-Amino-5-chloro-4-[2-(5-phosphono)furanyllthiazole. Anal. calcd. for

C

7

H

6

N

2 0 4 PSCl: C: 29.96; H: 2.16; N: 9.98. Found: C: 29.99; H: 1.97; N: 9.75.

2-Amino-5-iodo-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C 7

H

6

N

2 0 4 PSI: C: 22.42; H: 2.28; N: 6.70. Found: C: 22.32; H: 2.10; N: 6.31.

2,5-Dibromo-4-[2-(5-phosphono)furanyl]thiazole. Anal. caled. for C 7 H4NO 4 PSBr 2

C:

21.62; H: 1.04; N: 3,60. Found: C: 21.88; H: 0.83; N: 3.66.

Example Preparation of 2-halo-4-[2-(5-phospliono)furanyllthiazoles.

Step A. A solution of 2-amino-5-isobutyl-4-[2-(5-diethylphosphono)-furanyl]thiazole (prepared as in Step B ofExample 3) (1 mmole) in acetonitrile was treated with copper (fl) bromide (1.2 mmole) and isoamyl nitrite (1.2 mmole) at 0 0 C for 1 h. Extraction and chromatography gave 2-bromo-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole as a brown solid.

Step B. 2-Bromo-5-isobutyl-4-[2-(5-dietiylphosphono)furanyl]thiazole was subjected to Step C of Example 3 to give 2-bromo-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (5.1) as a yellow hygroscopic solid. Anal. calcd. for C, 1

H

1 3

NO

4 PSBr: C: 36.08; H: 3.58; N: 3.83.

Found: C: 36.47; H: 3.66; N: 3.69.

The following compounds were prepared according to this procedure:.

2-Chloro-S-isobutyl-4-[2-(5-phosphono)furanyl]thiazole: Anal. calcd. for CIjIH 3

NO

4 PSCl: C: 41.07; H: 4.07; N: 4.35. Found: C: 40.77; H: 4.31; N: 4.05.

2-Bromo-5-methylthio-4-[2-(5 -phosphono)furanyl]thiazole: Anal. calcd. for

CSH

7 NO4~PS 2 Br: C: 26.98; H: 1.98; N: 3.93. Found: C: 27.21; H: 1.82; N: 3.84.

Example 6.

Preparation of Various 2- and 5-substituted 4-[2-(5-phosphono)furanvllthiazoles.

Step A. A solution of 2-bromo-5-isobutyl-4-[2-(5-diethylphosphono)-furanyllthiazole (1 mrnole, prepared as in the Step A of Example 5) in DIVF was treated with tributyl(vinyl)tin mimole) and palladiumn bis(triphenylphosphine) dichloride (0.05 mmole) at 100 0 C under nitrogen. After 5 h the cooled reaction mixture was evaporated and the residue was subjected to chromatography to give 2-vinyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole as a yellow solid.

Step B. 2-Vinyl-S -isobutyl-4-[2-(5-diethylphosphiono)furanyljjthiazole was subjected to Step C of Example 3 to give 2-vinyl-5-isobutyl-4-[2-(5-phosphono)-fuiranyl]thiazole as a yellow solid. Anal. calcd. for C 13

HI

6 NQ4PS IHBr 0.11H 2 0: C: 39.43; H: 4.38; N: 3.54.

Found: C: 39.18; H: 4.38; N: 3.56.

This method can also be used to prepare various 5-substituted phosphono)furanyllthiazoles from their corresponding halides.

Step C. 2-Amino-5-bromo-4-[2-(5-diethylphosphono)furanylthiazole was subjected to Step A using 2-tributyistannylfuran as the coupling partner to give 2-amino-5-(2-furanyl)-4- Step D. -nin--2frnl--2(-itypopoofrnltizl was subjected to Step C of Example 3 to give 2-amino-5-(2-fiaranyl)-4-[2-(5phosphono)furanyl]thiazole mp 190-210'C. Anal. calcd. for C 11 HqN 2 0 5 PS 0.25HiBr: C: 39.74; H: 2.80; N: 8.43. Found: C: 39.83; H: 2.92; N: 8.46.

The following compound was prepared according to this procedure: 2-Amino-5-(2-thienyl)-4-[2-(5-diethylphosphono)furanyllthiazole. Anal. calcd. for

C

11

H

9

N

2 0 4

PS

2 +0.3EtOAc+O.IlHBr: C: 40.77; H: 3.40;N: 7.79. Found: C: 40.87; H: 3.04; N: 7.45.

Example 7.

Preparation of 2-ethyl-4-f2-(5-phosplxono)furanyllthiazoles.

Step A. A solution of 2-vinyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-thiazole

(I

mmole, prepared as in the Step A of Example 6) in ethanol was treated with palladium on carbon (0.05 minnle) under 1 atmosphere of hydrogen for 12 h. The reaction mixture was filtered, the filtrate was evaporated and the residue was purified by chromatography to give 2ethyi-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole as a yellow foamn.

Step B. 2-ty--sbtl4[-5dehlhshn~uailtizl was subjected to Step C of Example 3 to give 2-ty--sbtl4[-5phshn)frnltizl as a yellow solid. Anal. calcd. for C 13

HI

8 N0 4 PS lHBr: C: 39.41; H: 4.83; N: 3.53. Found: C:39.65; H: 4.79; N: 3.61.

Example 8.

Preparation of 4-phosphonomethoxymethlthiazoles.

Step A. A solution of diethyl hydroxymethylphosphonate (I minole) in DMF was treated with sodium hydride (1.2 rnmole) followed by 2.methyl-4-chloromethylthiazole (1 mmole) at 0 0 C and stirred at 25'C for 12 h. Extraction and chromatography gave 2-methyl-4- (diethylphosphonomethoxymethyl)thiazole.

Step B. 2-Methyl-4-diethylphosphonomethioxymethylthiazole was subjected to Step C of Example 3 to give 2-methyl-4-phosphonomethoxymethylthiazole Anal. calcd. for

C

6

H

1

O

0 4 PS 0.5HiBr 0.5H 2 0: C: 26.43; H: 4.25; N: 5.14. Found: C: 26.52; H: 4.22; N: 4.84.

Step C. 2-Methyl-4-diethylphosphonomethoxynethylthiazole was subjected to Step A of Example 4 and followed by Step C of Example 3 to give 5-bromo-2-methyl-4phosphonomethoxymethylthiazole Anal. calcd. for C 6 H9NO 4 PSBr 0.5HBr: C: 21.04; H: 2.80; N: 4.09. Found: C: 21.13; H: 2.69; N: 4.01.

Step D. A solution of ethyl 2-[(N-Boc)arnilno]-4-thiazolecarboxylate (1 mmole) in

CH

2

CI

2 (10 xnL) was cooled to -78'C, and treated with DIBAL-H (IM, 5 mL). The reaction was stirred at -60 0 C for 3 h, and quenched with a suspension of NaF/H 2 0 (1 g/l mL). The resulting mixture was filtered and the filtrate was concentrated to give 2-[(N-Boc)amino]-4hydroxymethylthiazole as a solid.

Step E. A solution of 2-[(N-Boc)aminojj-4-hydroxymethylthiazole (1 mmole) in DMIF mL) was cooled to 0 0 C, and treated with NaH (1.1 mmole). The mixture was stirred at room temperature for 30 min, then phosphonomethyl trifluoromethianesulfonate 1 Inole) was added. After stirring at room temperature for 4 h, the reaction was evaporated to dryness.

Chromatography of the residue gave 2-[(N-Boc)amino]-4diethylphosphonomethoxylinethythiazole as a solid.

Step 2-[(N-Boc)amino]-4-diethylphosphonomethoxylmethylthi azol e was subjected to Step C of Example 3 to give 2-anino-4-phosphonomethoxymethylthiazole as a solid.

Anal. caled. for C5H 9

N

2 0 4 PS 0. 16 HIBr 0. 1 MeOH: C: 25.49; H: 4.0 1; N: 11.66. Found: C: 25.68; H: 3.84; N: 11.33.

Example 9.

Preparation of 2-carbamoyl-4-12-(5-phosphono)furanyllthazoles.

Step A. A solution of 2-ethoxycarbonyl-5-isobutyl-4-[2-(5diethylphosphono)fuiranyl]thiazole (I nimole) in saturated methanolic ammonia solution at for 12 h. Evaporation and chromatography gave 2-carbamoyl-5-isobutyl-4-[2-(5diethylphosphono)furanyllthiazole as a white solid.

Step B. 2-Carbamoyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole was subjected to Step C of Example 3 to give 2-carbamoyl-5-isobutyl-4-[2-(5phosphono)furanyl]thiazole as a solid. mp 185 186'C. Anal. calcd. for C 1 2 1 1 5

N

2 0 5

PS:

C: 43.64; H: 4.58; N: 8.48. Found: C: 43.88; H: 4.70; N: 8.17.

The following compound was prepared according to this procedure: 2-Carbamoyl-4-[2-(5-phosphono)furanyl]thiazole. mp 195 200 0 C. Anal. calcd. for

C

3

H

7

N

2 0 5 PS 0.25H 2 0: C: 34.48; H: 2.71; N: 10.05. Found: C: 34.67; H: 2.44; N: 9.84.

2-Ethoxycarbonyl-4-[2-(5-diethylphosphono)furanyl]thiazoles can also be converted to other 2-substituted 4-[2-(5-phosphono)faranyl]thiazoles.

Step C. A solution of 2-ethoxycarbonyl-4-[2-(5-diethylphosphono)furanyl]thiazole (1 mmole) in methanol was treated with sodium borohydride (1.2 mmole) at 25 0 C for 12 h.

Extraction and chromatography gave 2-hydroxymethyl diethylphosphono)furanyl]thiazole.

Step D. 2-Hydroxymethyl-4-[2-(5-diethylphosphono)furanyl]-thiazole was subjected to Step C of Example 3 to give 2-hydroxymethyl-4-[2-(5-phosphono)furanyl]thiazole mp 205-207 0 C. Anal. calcd. for CgH 8

NO

5 PS+ 0.25H 2 0: C: 36.16; H: 3.22; N: 5.27. Found: C: 35.98; H: 2.84; N: 5.15.

The following compound was prepared according to this procedure: 2-Hydroxymethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. mp 160-170 0 C. Anal.

calcd. for C 1 2

H

1 6

NO

5 PS 0.75HBr: C: 38.13; H: 4.47; N: 3.71. Found: C: 37.90; H: 4.08; N: 3.60.

Step E. A solution of 2-hydroxymethyl-5-isobutyl-4-[2-(5diethylphosphono)furanyl]thiazole (1 mmole) in methylene chloride was treated with phosphor-us tribroinide (1.2 inmole) at 25'C for 2 h. Extraction and chromatography gave 2bromomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyltiazole.

Step F. 2-Bromoinethyl-5 -isobutyl-4-j2-(5 -diethylphosphono)furanyl]-thiazole was subjected to Step C of Example 3 to give 2-bromomethyl-5-iso~butyl-4-[2-(5phosphono)furanyl]thiazole mp 161-163'C. Anal. calcd, for C 12 H, 5BrNO 4 PS -I 0.25HiBr: C: 35.99; H: 3.84; N: 3.50. Found: C: 36.01; H: 3.52; N: 3.37.

The following compound was prepared according to this procedure: 2-Bromomethyl-4-[2-(5-phosphono)furanyllthiazole. mp 250'C. Anal. calcd. for C8H 7 BrNO 4 PS: C: 29.65; H: 2.18; N: 4.32. Found: C: 29.47; H: 1.99; N: 4.16.

Step G. A solution of 2-hydroxymethyl-5-isobutyl-4-[2-(5diethylphosphono)furanyljtbiazole (1 mmole) in methylene chloride was treated with thionyl chloride (1.2 rumole) at 25*C for 2 h. Extraction and chromatography gave 2-chioromethyl- S-isobutyl-4-[2-(5-diethylphosphono)fuiranyl]thi azole.

Step R. 2-Chloromethyl-5-isobutyl-4-[2-(5-diethylphosphono)fiuranyl]-thiazole was subjected to Step C of Example 3 to give 2-chloromethyl-5-isobutyl phosphono)furanyilthiazole mp 160-162'C. Anal. calcd. for C 12 HISCIN04PS 0.45HBr: C: 38.73; H: 4.18; N: 3.76. Found: C: 38.78; H: 4.14; N: 3.73.

Step 1. A solution of 2-bromomethyl-5-isobutyl-4-72-(5diethylphosphono)furanyllthiazole (I n-imole) in DMIF was treated with potassium phithalimide (1.2 inmole) at 25'C for 12 h. Extraction and chromatography gave 2phthalimidomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole.

Step JI 2-Phthalimidomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-tbiazole (1 mmole) in ethanol was treated with hydrazine (1.5 mmole) at 25*C for 12 h. Filtration, evaporation and chromatography gave 2-aminomethyl-5-isobutyl-4-[2-(5diethylphosphono)furanyljthiazole.

Step K 2-Aninomethyl-5-isobutyl4-[2-(5-diethylphosphono)furanyl]-thiazole was subjected to Step C of Example 3 to give 2-aminomethyl-5-isobutyl phosphono)furanyl]thiazole mp 235-237 0 C. Anal. calcd. for C 12

HI

7

N

2 0 4 PS 0.205HBr: C: 43.30; H: 5.21; N: 8.41. Found: C: 43.66; H: 4.83; N: 8.02.

According to the above procedures or in some cases with some minor modifications of the above procedures, the following compounds were prepared: 2-Carbamoyl-5-cyclopropyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. caled for

CIIHIIN

2 0 5 PS 0.15HBr: C: 40.48; H: 3.44; N: 8.58. Found: C: 40.28; H: 3.83; N: 8.34.

(9.10) 2-Carbamoyl-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for

C

lo

HI

1

N

2 0 5 PS 0.75H20: C: 38.04; H: 3.99; N: 8.87. Found: C: 37.65; H: 3.93; N: 8,76.

Example Preparation of 4-[2-(5-phosphono)furanvi oxazoles and 4-12-(5phosphono)furanyllimidazoles.

Step A. A solution of 5-diethylphosphono-2-[(2-bromo-4-methyl-oxo)pentyl]furanyl (1 mmole) in t-BuOH was treated with urea (10 mmole) at reflux for 72 h. Filtration, evaporation and chromatography gave 2-amino-5-isobutyl-4-[2-(5diethylphosphono)furanyl]oxazole, and 2-hydroxy-5-isobutyl-4-[2-(5diethylphosphono)furanyl]imidazole.

Step B. 2-Amino-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]oxazole was subjected to Step C of Example 3 to give 2-amino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole (10.1).

mp 25000 (decomp.). Anal. caled. for CliHl 5

N

2 0 5 P: C: 46.16; H: 5.28 N: 9.79. Found: C: 45.80; H: 5.15; N: 9.55.

Step C. 2-Hydroxy-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]imidazole was subjected to Step C of Example 3 to give 2-hydroxy-5-isobutyl-4-[2-(5phosphono)furanyl]imidazole (10.14). mp 20500 (decomp). Anal. calcd. for CI 1

HI

5

N

2 C: 46.16; H: 5.28 N: 9.79. Found: C: 45.80; H: 4.90 N: 9.73: Alternatively 4-[2-(5-phosphono)furanyl]oxazoles and phosphono,)furanylimidazoles can be prepared as follows: Step D. A solution of 5-diethylphosphono-2-[(2-bromo-4-rnethyl-1-oxo)pentyl]furan (I mmole) in acetic acid was treated with sodium acetate (2 mnmole) and ammnonium acetate (2 mmole) at 100'C for 4 h. Evaporation and chromatography gave 2-methyl-5-isobutyl-4-[2- 2-methyl-4-isobutyl-5-[2-(5diethylphosphono)furanyl]oxazole and 2-methyl-5-isobutyl-4-1i2-(5diethylphosphono)ftiranyl]imidazole.

Step E. 2-Methyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]oxazole, 2-methyl-4isobutyl-5-[2-(5-diethylphosphono)furanylloxazole and 2-methyl-5-isobutyl-4-[2-(5diethylphosphono)furanyl]imidazole were subjected to Step C of Example 3 to give the following compounds: (10.18) 2-Methyl-4-isobutyl-S-[2-(S-phosphono)furanyl]oxazole hydrogen bromide. mp> 230*C Anal. calcd. for C 12 Hl 7 BrNO 5 P 0.411 2 0: C: 38.60; H: 4.81; N: 3.75. Found: C: 38.29; H: 4.61 N: 3.67.

(10.19) 2-Methyl-5-isobutyl-4-[2-(5-phosphono)fiiranyl]oxazole hydrogen bromide. Anal.

Calcd. for C1 2

HI

7 BrNOsP: C: 39.36; H: 4.68 N: 3.83. Found: C: 39.33; H: 4.56; N: 3.85.

(10.21) 2-Methyl-5-isobutyl-4-[2-(5-phosphono)furanyl]imidazole hydrogen bromide. Anal.

Calcd. for C 12 HISBrN 2 04P 0.2NHI 4 Br: C: 37.46 H: 4.93; N: 8.01. Found: C: 37.12; H: 5.11; N: 8.28.

Alternatively 4-(2-(5-phosphono)furanyl]imidazoles can be prepared as follows: Step F. A solution of 5-diethylphosphono-2-(bromoacetyl)furan (I mmuole) in ethanol was treated with trifluoroacetainidine (2 mmole) at 80TC for 4 h. Evaporation and chromatography gave 2-trifluoromethyl-4-[2-(5-diethylphosphono)furanyl]imidazole as an oil.

Step G. 2-Trifluoromethyl-4-[2-(5-diethylphosphono)faranyl]imidazole was subjected to Step C of Example 3 to give 2-trifluorornethyl-4-[2-(5-phosphono)-furanyl]imidazole (10.22). mp 188C Anal. calcd. for C 8

H

6

F

3

N

2 0 4 P 0.5HBr: C: 29.79; H: 2.03; N: 8.68. Found: C: 29.93; H: 2.27; N: 8.30.

Alternatively 4,5-dimethyl-l-isobutyl-2-[2-(5-phosphono)furanyl]-imidazole can be prepared as follows: Step H. A solution of 5-diethylphosphono-2-furaldehyde (1 mmole), ammonium acetate (1.4 mnole), 3,4-butanedione (3 mmole) and isobutylamine (3 mmole) in glacial acetic acid was heated at 100 0 C for 24 h. Evaporation and chromatography gave dimethyl-l-isobutyl-2-[2-(5-diethylphosphono)furanyl]imidazole as an yellow solid.

Step I. 4,5-Dimethyl-l-isobutyl-2-[2-(5-diethylphosphono)furanyl]-imidazole was subjected to Step C of Example 3 to give 4,5-dimethyl-l-isobutyl-2-[2-(5phosphono)furanyl]imidazole (10.23); Anal. calcd. for C13HiqN 2 0 4 P 1.35HBr: C: 38.32; H:5.03; N: 6.87. Found: C: 38.09; H: 5.04; N: 7.20.

According to the above procedures or in some cases with some minor modifications of the above procedures, the following compounds were prepared: (10.2) 2-Amino-5-propyl-4-[2-(5-phosphono)furanyl]oxazole. mp 250'C (decomp.); Anal.

Calcd. for CIoH13N20 5 P: C: 44.13; H: 4.81 N: 10.29. Found: C: 43.74; H: 4.69; N: 9.92.

(10.3) 2-Amino-5-ethyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for CqH 1

N

2 0 5 P 4 0.4H 2 0: C: 40.73; H: 4.48; N: 10.56. Found: C: 40.85; H: 4.10; N: 10.21.

(10.4) 2-Amino-5-methyl-4-[2-(5-phosphono)furanylloxazole. Anal. calcd. for C 8 HqN 2 0 5 P 0.1H20: C: 39.07 H: 3.77 N: 11.39. Found: C: 38.96; H: 3.59; N: 11.18.

(10.5) 2-Amino-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for C 7

H

7

N

2 0 5 P 0.61420: C: 34.90; H: 3.43; N: 11.63. Found: C: 34.72; H: 3.08 N: 11.35.

(10.6) 2-Amino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole hydrogen bromide. Anal.

calcd. for CIIH 1 6

N

2 0BrP 0.4H 2 0: C: 35.29; H: 4.52; N: 7.48. Found: C: 35.09; H: 4.21; N: 7.34.

(10.7) 2-Amino-5-phenyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for C 1 3

HIIN

2 0 5

P:

C: 50.99; H: 3.62; N: 9.15. Found: C: 50.70; H: 3.43 N: 8.96.

(10.8) 2-Amino-5-benzyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for C 14 Hi 3

N

2 0 5

P

1.1H 2 0: C: 49.45; H: 4.51 N: 8.24. Found: C: 49.35; H: 4.32 N: 8.04.

(10.9) 2-Amino-5-cyclohexylmethyl-4-[2-(5-phosphono)furanyloxazole. Anal. calcd. for

C

14

H

19

N

2 0 5 P 0.3H 2 0: C: 50.70; H: 5.96; N: 8.45. Found: C: 50.60; H: 5.93 N: 8.38.

(10.10) 2-Amino-5-allyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for C 1 oHI N 2 0 5 P 0.4HBr 0.3H 2 0: C: 39.00; H: 3.93; N: 9.10. Found: C: 39.31; H: 3.83;,N: 8.76.

(10:11) 5-Isobutyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for CI 1

H

14

NO

5 P: C: 48.72; H: 5.20 N: 5.16. Found: C: 48.67; H: 5.02 N: 5.10.

(10.12) 2-Amino-5-butyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for C IH 15

N

2 0 5

P

0.2H 2 0: C: 45.59; H: 5.36 N: 9.67. Found: C: 45.32; H: 5.29; N: 9.50.

(10.13) 5-Isobutyl-4-[2-(5-phosphono)furanyl]oxazole-2-one. Anal. calcd. for CI 1

H

1 4

NO

6 P 0.39HBr: C: 41.45; H: 4.55 N: 4.39. Found: C: 41.79; H: 4.22; N: 4.04.

(10.15) 5-Cyclohexylmethyl-2-hydroxy-4-[2-(5-phosphono)furanyl]imidazole. Anal. calcd.

for C 14

H

19

N

2 0 5 P 0.05HBr: C: 50.90; H:5.81; N:8.48. Found: C: 51.06; H: 5.83; N: 8.25.

(10.16) 5-Butyl-2-hydroxy-4-[2-(5-phosphono)furanyl]. Anal. calcd. for ClIH 15

N

2 0 5 P 0.2H20: C: 45.59; H: 5.36; N: 9.67. Found: C: 45.77; H: 5.34; N: 9.39.

(10.17) 5-Benzyl-2-hydroxy-4-[2-(5-phosphono)furanyl]imidazole. Anal. calcd. for

C

14

H

1 3

N

2 0 5 P: C: 52.51; H: 4.09; N: 8.75. Found: C: 52.29; H: 4.15; N: 8.36.

(10.20) 2-Methyl-5-propyl-4-[2-(5-phosphono)furanyl]imidazole hydrogen bromide. Anal.

calcd. for CIIH 16 BrN 2 0 4 P 0.5H 2 0: C: 36.69; H: 4.76; N: 7.78. Found: C: 36.81; H: 4.99; N: 7.42.

(10.24) 2-Amino-5-(2-thienyhnethyl)-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd for

C

12 HtiN 2 0 5 PS 0.9HIBr: C: 36.12; H: 3.01; N: 7.02. Found: C: 36.37; H: 2.72; N: 7.01.

(10.25) 2-Dimethylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole hydrogen bromide.

Anal. Calcd for C 13

H

2 OBrN 2 0 5 P 0.05HBr: C: 39.11; H: 5.06; N: 7.02. Found: C: 39.17; H: 4.83; N: 6.66 (10.26) 2-Isopropyl-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. Calcd for

C

14

H

20 NOSP 0.8HBr: C: 44.48; H: 5.55; N: 3.71. Found: C: 44.45; H: 5.57; N: 3.73.

(10.27) 2-Anino-5-ethoxycarbonyl-4-[2-(5-phosphono)furanyl]oxazole. mp 245 0

C

(decomp.). Anal. Calcd for C 1 oH 1

N

2 0 7 P: C: 39.75; H: 3.67; N: 9.27. Found: C: 39.45; H: .3.71; N: 8.87 (10.28) 2-Methylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole hydrogen bromide.

Anal. Calcd for C 12 Hi8BrN 2 0sP 0.7H20: C: 36.60; H: 4.97; N: 7.11. Found: C: 36.50; H: 5.09; N: 7.04.

(10.29) 2-Ethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole hydrogen bromide. Anal.

Caled for C 13

H

1 ,BrNO 5 P: C: 41.07; H: 5.04; N: 3.68. Found: C: 41.12; H: 4.84; N: 3:62.

(10.30) 2-Ethylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole hydrogen bromide.

Anal. Calcd for C13H2OBrN 2 0sP: C- 39.51; H: 5.10; N: 7.09. Found: C: 39.03; H: 5.48; N: 8.90.

(10.31) 2-Vinyl-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. Calcd for C 1 3 Hj 6

NO

5

P

0.25HBr: C: 49.18; H: 5.16; N: 4.41. Found: C: 48.94; H: 5.15; N: 4.40.

(10.32) 2-Amino-5-pentyl-4-[2-(5-phosphono)furany]oxazole. Anal. Calcd for C, 2

H

17

N

2 0 5

P

0.5H20: C: 46.61; H: 5.87; N: 9.06. Found: C: 46.38; H: 5.79; N: 9.07.

(10.33) 5-Pentyl-2-hydroxy-4-[2-(5-phosphono)furanyl]imidazole. Anal. caled. for

C

12

H

1 7

N

2 0 5 P: C: 48.00; H: 5.71; N: 9.33. Found: C: 48.04; H: 5.58; N: 9.26.

(10.45) 2-Amino-5-methylthio-4-[2-(5-phosphono)furanyl]oxazole. mp 196'C (decomp).

Anal. calcd. for C 8 HqN 2 0sPS: C:34.79; H:3.28; N: 10.14. Found: C: 34.60; H: 2.97; N: 10.00.

(10.35) 2-Amino-5-benzyloxycarbonyl-4-[2-(5-phosphono)furanyloxazole. mp 230 0

C

(decomp). Anal. caled for CjsH 1 3

N

2 07P 0.7H20: C: 47.81; H: 3.85; N: 7.43. Found: C: 47.85; H: 3.88; N: 7.21.

(10.36) 2-Amino-5-isopropyloxycarbonyl-4-[2-(5-phosphono)furanyl]oxazole. mp 221 0

C

(decomp). Anal. caled for ClIH 13

N

2 0 7 P 0.9H 2 0: C: 39.75; H: 4.49; N: 8.43. Found: C: 39.72; H: 4.25; N: 8.20.

(10.37) 2-Amino-5-methoxycarbonyl-4-[2-(5-phosphono)furanyl]oxazole. mp 240 0

C

(decomp). Anal. calcd for CqH 9

N

2 0 7 P 0.3H 2 0 0.1 Acetone: C: 37.31; H: 3.43; N: 9.36.

Found: C: 37.37; H: 3.19; N: 9.01.

(10.38) 2-Amino-5-[(N-methyl)carbamoyl]-4-[2-(5-phosphono)furanyl]oxazole. mp 235 0

C

(decomp). Anal. calcd for C 9

HION

3 0 6 P: C: 37.64; H: 3.51; N: 14.63. Found: C: 37.37; H: 3.22; N: 14.44.

(10.39) 2-Amino-5-ethylthiocarbonyl-4-[2-(5-phosphono)furanyl]oxazole. mp 225 0

C

(decomp). Anal. calcd for CIoHIIN 2 0 6 PS: C: 37.74; H: 3.48; N: 8.80. Found: C: 37.67; H: 3.27; N: 8.46.

(10.40) 2-Amino-5-isopropylthio-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd for CloHl 3

N

2 0sPS+ 0.2HBr: C: 37.48; H: 4.15; N: 8.74. Found: C: 37.39; H: 4.11; N: 8.56.

(10.41) 2-Amino-5-phenylthio-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd for

C

13

HIIN

2 0 5 PS 0.25 HBr: C: 43.55; H: 3.16; N: 7.81. Found: C: 43.82 H: 3.28; N: 7.59.

(10.42) 2-Amino-5-ethylthio-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd for

C

9 HiiN 2 0 5 PS 0.85HBr: C: 30.11; H: 3.33; N: 7.80. Found: C: 30.18; H: 3.44; N: 7.60.

(10.43) 2-Amino-5-propylthio-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd for CjoH 13

N

2 0 5

H

2 0: C: 37.27; H: 4,69; N: 8.69; H 2 0: 5.59. Found: C: 37.27; H: 4.67; N: 8.60; H20: 5,66.

(10.44) 2-Amino-5-tert-butylthio-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd for C 1

H

15

N

2 0 5 PS 0.25HBr: C: 39.03; H: 4.54; N: 8.28. Found: C: 39.04; H: 4.62; N: 8.06.

(10.34) 4,5-Dimethyl-2-[2-(5-phosphono)furanyl]imidazole. Anal. calcd. for C 9

H

1

IN

2 0 4 P 1.25 H20: C: 40.84; H:5.14; N: 10.58. Found: C: 41.02; H: 5.09; N: 10.27.

Example 11.

Preparation of N-alkylated 4-12-(5-phosphono)furanyllimidazoles and 4-12-(5phosphonofuranylloxazoles.

Step A. A suspension of cesium carbonate (1.5 mmole) and 2-methyl-5-isobutyl-4-[2- (1 mmole) in DMF was treated with iodomethane mmole) at 251C for 16 h. Extraction and chromatography gave 1,2-dimethyl-4-isobutyl-5-[2and I ,2-dimethyl-5-isobutyl-4-[2-(5diethylphosphono)-furanyllimidazole.

Step B. 1 ,2-Dimethyl-4-isobutyl-5-[2-(5-diethiylphosphono)furanyl]-imidazole and 1,2dimethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-imidazole were subjected to Step C of Example 3 to give the following compounds: (11.1) 1, 2-Dimethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]imnidazole hydrogen bromide.

Anal. calcd. for C13H 2 oN 2

O

4 PBr 0.8H 2 0: C: 39.67; H: 5.53; N: 7.12. Found: C: 39.63; H: 5.48 N: 7.16.

Example 12.

Preparation of 2-[2-(6-phosphono)pyridyllpyridine.

Step A. A solution of 2,2'-bipyridyl (I mmole) in dichioromethane was treated with mchloroperoxybenzoic acid (2 mmole) at 0 0 C, and the reaction mixture was stirred at 25TC for 2 h. Extraction and chromatography gave 2,2'-bipyridyl-N-oxide.' Step B. (Redmore, J Org. Chem., 1970, 35, 4114) A solution of 2,2'-bipyridyl-Noxide methyl ether (1 namole, prepared from dimethyl sulfate and 2,2'-bipyridyl-N-oxide in diethyl phosphite) was added slowly at -30TC to a solution of n-butyl lithium (I inmole) in diethyl phosphite at -30TC. The resulting reaction mixture was stirred at 25*C for 12 h.

Extraction and chromatography gave 2-[2-(6-diethylphosphono)pyridyllpyridine.

Stev C. 24[2-(6-Diethylphosphono)pyridyllpyridine was subjected to Step C of Example 3 to give 2-[2-(6-phosphono)pyridyl]pyridine mp 158 162TC. Anal. caicd.

for C 1

H

9

N

2 0 3 F 0. 5H 2 0 0. 1HBr: C: 47.42; H: 4.02; N: 11. 06. Found: C: 47.03; H: 3.67; N:10.95.

Example 13.

r~l Preparation of 4.6-dimethyl-2-(phosphonomethoxymethyl)pyridine.

Step A. A solution of 2,4,6-collidine (I mmole) in carbon tetrachloride was treated IND with NBS (5 rnmole) and dibenzoyl peroxide (0.25 mmole) at 80'C for 12 h. The reaction mixture was cooled to 0 0 C and the precipitate was filtered. The filtrate was concentrated under vacuum. Chromatography gave 2-bromomethyl-4,6-dimethylpyridine.

Step B. A solution of diethyl hiydroxymethyiphosphonate (1 inmole) in toluene was ~~KItreated with sodium hydride (1.1 mmole) at 0 0 C, and after 15 min 2-bromomethyl-4,6dimethylpyridine (1 n-ole) was added. After 3 h the reaction mixture was subjected to extraction and chromatography to give 2-diethylphosphonomethyl-4,6-dimethylpyridine.

Step C. 2-Diethylphosphonomethyl-4,6-dimethylpyridine was subjected to Step C of Example 3 to give 4,6-dimethyl-2-(phosphonomethoxymethyl)pyridine mp 109 112*C. Anal. calcd. for C 9 Hi 4 N0 4 P L.0H 2 0 0.5HBr: C: 37.32; H: 5.74; N: 4.84. Found: C: 37.18; H: 5.38; N: 4.67.

The following compound was prepared similarly: (13.2) 2-Amino-4-methyl-5-propyl-6-phosphonomethoxymeth-ylpyrirnidine. mnp 153 156'C. Anal. calcd. for CIDHISN 3 0 4 P 1.25H 2 0 1.6HBr: C: 28. t1; H: 5.21; N: 9.84.

Found: C: 28.25; H: 4.75; N: 9.74.

Example 14.

Preparation of diethyl 5-tribu tylstannyl-2-furanphosphonate.

A solution of diethyl 2-furanphosphonate (I mmole, prepared as in Step C of Example 1) in THY was cooled at -78"C and cannulated to a solution of lithium N-isopropyl-Ncyclohexylamide in TI{F at -78*C over 15 min. The resulting mixture was stirred at -78'C for 2 h and cannulated into a solution of tributyltin chloride (1 minole) in THfF at -78'C over min. The mixture was then stirred at -78"C for 1 h, and at 25'C for 12 h. Extraction and chromatography gave compound (14) as a light yellow oil.

123 Example Preparation of 6-[2-(5-phosphono)furanyll pyridines.

Step A. A solution of 2,6-dichioropyridine (120 mniol) in ethanol was treated with aqueous ammonia solution (28 excess) at 160 165'C for 60 h in a sealed tube.

Extraction and chromatography gave 2-amino-6-chloropyridine as a white solid.

Step B. A solution of 2-amino-6-chloropyridine (1 mmole) and compound 14 (1 mmole) in p-xylene was treated with tetrakis(triphenylphosphine) palladium (0.05 nimole) at reflux for 12 h. Extraction and chromatography gave 2-amino-6-[2-(5diethylphosphono)furanyllpyridine as a light yellow solid.

Step C. 2-Amino-6-[2-(5-diethiylphosphono)furanyl]pyridine was subjected to Step C of Example 3 to give 2-amilio-6-(2-(5-phosphono)furany1]pyridine mp 186 187TC.

Anial. calcd. for C 9

H

9

N

2 0 4 P 0.4HBr: C: 39.67; H: 3.48; N: 10.28. Found: C: 39.95; H: 3.36; N: 10.04.

Step D. A solution of 2-amino-6-[2-(5-diethylphosphono)furanyl]pyridine (1 rnmole) in acetic acid was treated with a solution of bromine in acetic acid (IN, 1 mmnole) at 25'C for h. Evaporation and chromatography gave 2-amnino-5-bromo-6-[2-(5diethylphosphono)furanyljpyridine and 2-amino-3,5-dibromo-6-[2-(5diethylphosphono)furanyllpyridine.

Step E. 2-Amiino-5-bromo-6-[2-(5-diethylphosphono)furanyl]pyridine and 2-amino- 3,5-dibromo-6-[2-(5-diethylphosphono)furanyl]pyridine were subjected to Step C of Example 3 to give the following compounds: (15.2) 6-Amino-3-bromo-2-[2-(5-phosphono)furanyl]pyridine. Anal. calcd. for C 9 HaBrN 2

O

4

P

0.7H 2 0 .9HBr 0.12PhCH 3 C: 28.44; H: 2.73; N: 6.74. Found: C: 28.64; H: 2.79; N: 6.31.

(15.3) 6-Amino-3,5-dibromo-2-[2-(5-phosphono)furanyl]pyridine. mp, 233 235TC. Anal.

calcd. for C9H 7 Br 2

N

2

O

4 P 1.2HBr: C: 21.84; H: 1.67; N: 5.66. Found: C: 21.90; H: 1.52; N: 5.30.

Step F. A solution of 2-amino-3,5-dibromo-6-1j2-(5-diethylphosphono)furanyl]pyridine (1 nimole) in DMIF was treated with tributyl(vinyl)tin (1.2 nunole) and tetrakis(tripheniylphosphine) palladium (0.2 mmc) at 85'C for 4 h. Evaporation and chromatography gave 2-amiio-3,5-bis(vinyl)-6-[2-(5-diethylphosphono)furanyl]pyridifle.

Step G. A solution of 2-amino-3,5-bis(vinyl)-6-[2-(5-diethylphosphono)furanylpyridine (I mmole) in ethyl acetate was treated with palladium on carbon (10 at under I atmosphere of hydrogen for 12 hI. Filtration, evaporation and chromatography gave 2-amino-3 ,5-diethyl-6-[2-(5-diethylphosphono)filranyl]pyridine.

Step H. 2-Amino-3,5-diethyl-6-[2-(5-diethylphosphono)furanyl]pyridine was subjected to Step C of Example 3 to give 2-amnino-3,5-diethyl-6-[2-(5-phosphono)furanyl]pyridifle mp 217 2181C. Anal. calcd. for C13H1 7

N

2

O

4 P 0.7H 2 0 1.OHBr: C: 40.06; H: 5.02; N: 7.19. Found: C: 40.14; H: 4.70; N: 6.87.

Step 1. A solution of 2-amino-6-picoline (I mmole) in 48% hydrobromic acid (4.4 mmole) was treated with bromine (3 mmole) at 0 0 C for 1 h. An aqueous solution of sodium nitrite (2.5 mmole) was then added and the reaction mixture was stir-red at 0 0 C for 0.5 h. An aqueous solution of sodium hydroxide (9.4 mmole) was then added and the reaction mixture was stirred at 25'C for 1 h. Extraction and chromatography gave 2,3-dibromo-6-picoline and 2,3,5-tribromo-6-picoline.

Step J. 2,3-Dibromo-6-picoline was subjected to Step B of Example 15 and followed by Step C of Example 3 to give 5-bromo-2-methyl-6-[2-(5-phosphono)furanyl]pyridile mp 207 208'C. Anal. calcd. for C 10 HgBrNO 4 P 0.6HBr: C: 32.76; H: 2.64; N: 3.88.

Found: C: 32.62; H: 2.95; N: 3.55.

Following compounds were prepared according to the above described procedures or with some minor modifications of these procedures using conventional chemistry.

(15.6) 2-(2-(5-Phosphono)faranyllpyridine. mp 220 221TC. Anal. calcd. for C 9

H

8 IN0 4 P 0.1H 2 0 0.45EBr: C: 41.05; H: 3.31; N: 5.32. Found: C: 41.06; H: 3.10; N: 5.10.

(15.7) 2-Amino-3-nitro-6-[2-(5-phosphono)furanyl]pyridine. mp 221 222 0 C. Anal. calcd.

for CgHsN 3 0 6 P 0.55HBr 0.02PhCH 3 C: 33.12; H: 2.65; N: 12.68. Found: C: 33.22; H: 2:43; N: 12.26.

(15.8) 2,3-Diamino-6-[2-(5-phosphono)furanyl]pyridine. nip 150 153 0 C. Anal. calcd. for

C

9 HIoN 3 0 4 P 1.5HBr 0.05PhCH 3 C: 29.46; H: 3.15; N: 11.02. Found: C: 29.50; H: 3.29; N: 10.60.

(15.9) 2-Chloro-6-[2-(5-phosphono)furanyl]pyridine. mp 94 96 0 C. Anal. calcd. for CqH 7 C1NO 4 P 0.25HBr: C: 38.63; H: 2.61; N: 5.01. Found: C: 38.91; H: 3.00; N: 5.07.

(15.10) 3,5-Dichloro-2-[2-(5-phosphono)furanyllpyridine. mp 180 181 0 C. Anal. calcd. for

C

9

H

6 C1 2

NO

4 P 0.7HBr: C: 31.61; H: 2.01; N: 3.94. Found: C: 31.69; H: 2.09; N: 3.89.

(15.11) 3-Chloro-5-trifluoromethyl-2-[2-(5-phosphono)furanyl]pyridine. mp 253 254T.

Anal. calcd. for C 1 oH 6 C1F 3

NO

4 P: C: 36.67; H: 1.85; N: 4.28. Found: C: 36.69; H: 1.89; N:4.30.

(15.12) 2-Amino-3-ethyl-6-[2-(5-phosphono)furanyl] pyridine. mp 220 221 0 C. Anal.

calcd. for C 11 H13N 2 0 4 P 0.6HBr 0.2H 2 0: C: 41.24; H: 4.40; N: 8.74. Found: C:41.02; H: 4.57; N: 8.68.

(15.13) 6-Amino-3-ethyl-2-[2-(5-phosphono)furanyl] pyridine. Anal. calcd. for CuIH 13

N

2 0 4

P

1.OHBr +0.3H 2 0: C: 37.27; H: 4.15; N: 7.90. Found: C: 37.27; H: 4.19; N:7.51.

(15.14) 6-Amino-3-propyl-2-[2-(5-phosphono)furanyl]pyridine. mp 252 253*C. Anal.

calcd. for C 12 Hj 5

N

2 0 4 P 1.OHBr+ 1.0H 2 0 0.32PhCH 3 C: 41.65; H: 5.05; N: 6.82. Found: C: 41.97; H: 5.19; N: 6.83.

(15.15) 2,4-Dimethyl-3-bromo-6-[2-(5-phosphono)furanyl]pyridine. mp 232 233'C. Anal.

Calcd. for C,,H,,BrNO 4 P 0.45HBr: C: 35.85; H: 3.13; N: 3.80. Found: C: 35.98; H: 3.10; N: 3.71.

(15.16) 2-Chloro-4-amino-6-[2-(5-phosphono)furanylpyridine. Anal. caled. for

C

9

H

8

N

2 0 4 PCI HBr 0.5 H20 MeOH: C: 30.99; H: 3.38; N: 7.23. Found: C: 31.09; H: 3.21; N: 6.96.

(15.17) 3-Hydroxyl-2-[2-(5-phosphono)furanyl]pyridine. Anal. calcd. for CqH 8

NO

5 P 1.1HBr 0.3 CH 3 Ph: C: 37.26; H: 3.24; N: 3.91. Found: C: 37.66; H: 3.55; N: 3.84.

(15.19) 2-Amino-3-cyclopropyl-6-[2-(5-phosphono)furanyllpyridine. Anal. calcd. for

C

12

H

1 3

N

2 0 4 PCl HBr 0.4 H20: C: 3913; H: 4.05; N: 7.61. Found: C: 39.06; H: 3.85; N: 7.37.- (15.20) 2-Amino-5-cyclopropyl-6-[2-(5-phosphono)flranyl]pyridine. Anal. calcd. for Cj 2

H

13

N

2 0 4 P HBr 0.7 CH 3 Ph: C: 47.69; H: 4.64; N: 6.58. Found: C: 47.99; H: 4.62; N: 6.91.

(15.21) 5-Amino-2-methoxy-6-[2-(5-phosphono)furanyl]pyridine. Anal. calcd. for

C

1 oHI N 2 05P 0.2 H 2 0: C: 43.87; H: 4.20; N: 10.23. Found: C: 43.71; H: 3.77; N: 9.77.

(15.22) 2-Methyl-5-cyano-6-[2-(5-phosphono)furanyllpyridine. Anal. Calcd. for C1 1

H

9

N

2 0 4

P

0.75 HBr 0.5 H 2 0 0.5 MePh: C: 45.84; H: 3.91; N: 7.37. Found: C: 45.93; H: 3.56; N: 7.36.

(15.23) 2-Amino-3,5-bis(cyano)-4-methyl-6-[2-(5-phosphono)furanyl]pyridine. Anal. calcd.

for C 12 HqN 4 04P 0.7 H20: C: 45.49; H: 3.31; N: 17.68. Found: C: 45.48; H: 3.06; N: 17.51.

(15.24) 2-Chloro-4-cyano-6-[2-(5-phosphono)furanyl]pyridine. Anal. calcd. for CjoH 6

N

2 0 4 PCl: C: 42.20; H: 2.13; N: 9.84. Found: C: 41.95; H: 2.10; N: 9.47.

Example 16.

Preparation of 2-r2-(5-phosphono)furanyllpyrimidines and 4-2-(5phosphono)furanyllpyrimidines.

Step A. A solution of 5-diethylphosphono-2-[(I-oxo)pertyl]furan in N, Ndimethylformamide dimethyl acetal was heated at reflux for 12 h. Evaporation and chromatography gave diethyl 5-(2-propyl-3-N,N-dimethylamino)acryloyl-2furanphosphonate.

Step B. A solution of diethyl 5-(2-propyl-3-N,N-dimethylamino)acryloyl-2furanphosphonate (1 mmole) in ethanol was treated with guanidine hydrogen chloride (1.2 mmole) and sodium ethoxide (I rmmole) at 80 0 C for 12 h. The reaction mixture was evaporated, and residue was dissolved in water. The aqueous solution was neutralized with HCI (2 and concentrated under reduced pressure. The residue was co-evaporated with toluene to give 2-aniino-5-propyl-4-[2-(5-ethylphosphono)-furanyl]pyrimidine as a yellow solid.

Step C. 2-Amino-5-propyl-4[2-(5-ethylphosphono)furanyllpyrimidine (1 rnmole) and thionyl chloride was heated at reflux for 2 h. The reaction mixture was evaporated to dryness and the residue was dissolved in methylene chloride, and treated with excess pyridine and ethanol at 25 0 C for 12 h. Evaporation and chromatography gave 2-amiino-5-propyl-4-[2-(5diethylphosphono)furanyl]pyrimidine.

Step D. 2-Arnino-5-propyl-4-[2-(5-diethylphosphono)furanyllpyiidine was subjected to Step C of Example 3 to give 2-amino-5-propyl-4-[2-(5phosphono)furanyl]pyrintidine mp 258- 259'C. Anal. calcd. for CIIH 14

N

3 0 4 P 1.33H 2 0: C: 43.0 1; H: 5.47; N: 13.68. Found: C: 43. 18; H: 5.3 1; N: 13.30.

The following compound was prepared according to this procedure: (16.2) 2-Amino-5-isobutyl-4[2-(5-phosphono)fiarany1]pyrimidine. mp 218 220'C. Anal.

calcd. for C 12

H

1 6

N

3 0 4 P 0.75HBr 0.3PhCH 3 C: 43.92; H: 5.01; N: 10.90. Found: C: 44.02; 4.62 N: 10.69.

Alternatively other 4-[2-(5-phosphono)furanyl]pyrimidines can be prepared according to the following procedures: Step E. Compound 2.2 was subjected to Step A of Example 16 to give diethyl 5-(3- N,N-dimethylamino)acryloyl-2-fiiranphosphonate as an orange sohid.

Step F. A solution of diethyl 5-(3-N,N-dimethylam-ino)acryloyl-2-furanphosphonate (1 mmole), sodium ethoxide ethanol solution (2 mmole) and guanidine hydrochloride (1.1 mmole) was heated at 55"C for 2 h. The reaction mixture was cooled in an ice bath and was neutralized with 1N HCL. Evaporation and chromatography gave 2-amino-4-[2-(5diethylphosphono)-fiaranyl]pyrimidine as a yellow solid.

Step G. 2-Amino-4-[2-(5-diethylphosphono)furanyl]pyrinaidine was subjected to Step C of Example 3 to give 2-ainino-4-[2-(5-phosphono)furanyl]-pyrimnidine mp, 230'C.

Anal. calcd. for C 8 H8N 3 0 4 P 0.7511 2 0 O.2HBr: 0: 35.48; H: 3.61; N: 15.51. Found: C: 35.42; H: 3.80; N: 15.30.

Step H. A solution of 2-amino.4-[2-(5-diethylphosphono)fuaylpyriidifle (1 mmole) in methanol and chloroform was treated with NBS (1.5 mmole) at 25'C for 1 h.

Extraction and chromatography gave 2-amino-5-bromo-4-[2-(5diethylphosphono)furanyl]pyrimidine as a yellow solid.

Step 1. 2-Amino-5-bromo-4-[2-(5-diethylphosphono)furanyl]pyrimlidifle was subjected to Steps F and G of Example 15 followed by Step C of Example 3 to give 2-am-ino-5-ethyl-4mp 225'C. Anal. caled. for C 10

HI

2

N

3 0 4 P 1.4H 2 0 0.2HBr 0.25PhCH 3 C: 42.30; H: 5.14; N: 12.59. Found: C: 42.74; H: 4.94; N: 12.13.

The following compounds were prepared according to the above described procedures or with some minor modifications using conventional chemistry: (16.5) -Phosphono)Ruanyl]pyritniidine. mp 194 196T0. Anal. calcd. for C8H 7

N

2

OJP

0.1H 2 0 0.55HBr: C: 35.27; H: 2.87; N: 10.28. Found: C: 35.26; H: 2.83; N: 9.89.

(16.6) 2-Amino-6-rmethy1-4-[2-(5-phosphono)furanylpyridifle. mp, 238 -239'C. Anal.

calcd. for C 9

HI

0

N

3 0 4 P 0.9HBr: C: 32.96; H: 3.35; N: 12.81. Found: C: 33.25; H: 3.34; N: 12.46.

(16.7) 2-Methylthio-4-[2-(5-phosphono)furanyl]pyrinmidine. mp 228 229'C. Anal. calcd.

for CqHqN 2

O

4 PS 0.5H 2 0: C: 38.44; H: 3.58; N: 9.96. Found: C: 38.19; H: 3.25; N: 9.66.

(16.8) 2-Methyl-4-[2-(5-phosphono)furany1pyrimidUne. mp 206 212T0. Anal. calcd. for CqHqN 2 0 4 P 0.911 2 0 0.25IiBr: C: 34.05; H: 3.30; N: 8.82. Found: C: 34.02; H: 3.06; N: 8.75.

(16.9) 4,6-Dimethyl-5-bromo-2-[2-(5-phosphono)furanyl]pyrimidine. mp 251 252 0

C.

Anal. calcd. for C 1 oHIOBrN 2 0 4 P: C: 36.06; H: 3.03; N: 8.41. Found: C: 35.89; H: 2.82; N: 8.11.

(16.10) 2-Amino-5-chloro-4-[2-(5-phosphono)furanyl]pyrimidine. Anal. calcd. for CgH 7

CIN

3

O

4 P 0.5H 2 0: C: 33.76; H: 2.83; N: 14.76. Found: C: 33.91; H: 2.86; N: 14.20.

(16.11) 2-Amino-6-methylthio-4-[2-(5-phosphono)furanyl]pyrimidine. Anal. calcd. for

C

9

H

1 oN 3 0 4 PS -IBr: C: 29.36; H: 3.01; N: 11.41. Found: C: 29.63; H: 3.02; N: 11.27.

(16.12) 2-Amino-5-bromo-6-methylthio-4-[2-(5-phosphono)furanyl]pyrimidine. Anal. calcd.

for CqHqN 3 0 4 PSBr 0.8 HBr 0.2 MePh: C: 27.80; H: 2.56; N: 9.35. Found: C: 27.74; H: 2.40; N: 8.94.

(16.13) 2-Amino-(4-morpholino)-4-[2-(5-phosphono)furanyl]pyrimidine. Mp 230 0

C.

Anal. calcd. for C 12

H

15

N

4 0 5 P HBr 0.05 MePh: C: 36.02; H: 4.01; N: 13.61. Found: C: 35.98; H: 4.04; N: 13.33.

(16.14) 6-Amino-4-chloro-2-[2-(5-phosphono)furanyl]pyrimidine. Mp 230 0 C. Anal. calcd.

for C 8

H

7

N

3 0 4 PCI 0.5 H 2 0: C: 33.76; H: 2.83; N: 14.76. Found: C: 33.83; H: 2.54; N: 14.48.

Example 17.

Preparation of 2-[2-(5-phosphono)furanvllpyrazines and pliospliono)furaniylltilazines.

Step A. The procedures described in Example 16 can also be applied to the synthesis of 2-[2-(5-phosphono)furanyl]pyrazine and 2-[2-(5-phosphono)furanyl]triazine analogs and in some cases with minor modifications of these procedures using conventional chemistry methods.

The following compounds were prepared accordingly: (17.1) 2,5-Dimethyl-3-[2-(5-phosphono)furanyl]pyrazine. mp 212 213 0 C. Anal. calcd. for CioH 1

N

2 0 4 P 0.75HBr: C: 38.15; H: 3.76; N: 8.90. Found: C: 38.41; H: 3.93; N: 8.76.

(17.2) 2-Chloro-6-[2-(5-phosphono)furanyl]pyrazine. mp 204 205 0 C. Anal. caled. for

C

8

H

6

CIN

2

O

4 P 0.3HBr 0,02PhCH 3 C: 34.10; H: 2.27; N: 9.77. Found: C: 34.36; H: 2.07; N: 9.39.

(17.3) 2-Amino-3-propyl-6-[2-(5-phosphono)furanyl]pyrazine. mp 227 228 0 C. Anal.

calcd. for C, Hi 4

N

3 0 4 P 0.7HBr: C: 38.87; H: 436; N: 12.36. Found: C: 39.19; H: 4.36; N: 11.92.

(17.4) 2-Amino-6-[2-(5-phosphono)furanyl]pyrazine. mp 235 236 0 C. Anal. calcd. for

C

s

H

8

N

3 0 4 P 1.15H 2 0 0.03PhCH 3 C: 37.26; H: 4.01; N: 15.88. Found: C: 37.09; H: 3.67; N: 15.51.

(17.5) 2-Amino-3-bromo-6-[2-(5-phosphono)furanyl]pyrazine. Anal. calcd. for CaH7N 3 0 4 PBr IHBr: C: 23.97; H: 2.01; N: 10.48. Found: C: 24.00; H: 2.00; N: 10.13.

(17.6) 3-Methylthio-2-[2-(5-phosphono)furanyl]pyrazine. Anal. calcd. for CqH 9

N

2 0 4 PS 0.3

H

2 0: C: 38.94; H: 3.49; N: 10.09. Found: C: 38.99; H: 3.11; N: 9.67.

(17.7) 6-Amino-3-methylthio-2-[2-(5-phosphono)furanyl]pyrazine. Anal. calcd. for

C

9

H

1 oN 3 0 4 PS 1.5 H 2 0 1.7 HBr 0.25 MePh: C: 27.19; H: 3.54; N: 8.85. Found: C: 27.10; H: 3.85; N: S.49.

(17.8) 6-Amino-5-methylthio-2-[2-(5-phosphono)furanyl]pyrazine. Anal. calcd. for

C

9 HION30 4 PS 1.1 HBr 0.05 MePh: C: 29.49; H: 3.04; N: 11.03. Found: C: 29.23; H: 2.79; N: 10.87.

(17.9) 6-Amino-5-methoxycarbonyl-3-chloro-2-[2-(5-phosphono)furanyl]pyrazine. Anal.

calcd. for CoHqN 3 0PCl 0.3 HBr 0.04 MePh: C: 34.15; H: 2.68; N: 11.62. Found: C: 34.20; H: 2.90; N: 11.21.

(17.10) 6-Amino-3-methylthio-2-f2-(5-phosphono)furanyl]pyrazine ammonium salt. Anal.

calcd. for C 9

H

1 3N 4 0 4 PS 0.8 HBr: C: 29.30; H: 3.77; N: 15.18. Found: C: 29.03; H: 3.88; N: 15.08.

(17.11) 2-Amino-4-phenyl-6-[2-(5-phosphono)furanyl]triazine. Anal. calcd. for C 3 H N 4 0 4

P

HBr 0.1 EtOAc: C: 39.45; H: 3.16; N: 13.73. Found: C: 39.77; H: 3.26; N: 13.48.

Example 18.

Preparation of analogs with X being methoxycarbonyl methyithiocarbonyl, methylaminocarbonyl and methylearbonylamino.

Preparations of 4-phosphonomethoxycarbonylthiazoles and 4phosphonomethoxycarbonyloxazoles Step A. A solution of 2-amino-4-ethioxycarbonylthiazole (1 mmole) in 1,4-dioxane mL) was treated with di-tert-butyl dicarbonate (1.2 mnaole), TMEDA (0.1 mmole) and DMAP 1 inmole) at room temperature. After the reaction was stir-red for 20 hi, it was evaporated to dryness. The residue was subjected to extraction to give 2-[N-Boc(amino)]-4-ethoxycarbonyl thiazoic as a yellow solid..

Step B. A solution of 2-[N-Boc(arnino)]-4-ethcxycarbonylthiazole (1 mmole) in a 2:1 mixture of EtOH:H 2 0 (10 mL) was treated with NaOH (3N, 3 mnmole) and the reaction was stirred at 60'C for 4 h. The reaction was cooled to 0 0 C and neutralized to pH 5 with 3 N HCI, and the resulting solid was collected via filtration to give 2-[N-Boc(amino)1-4carboxylthiazole as a white solid.

Step C. A suspension of 2-[N-Boc(aniino)]-4-carboxylthiazole (1 mmole) in CI{ 2 C1 2 mL) was treated with thionyl chloride (4 nmmole) at room temperature. After stirring for 4 h the reaction was evaporated to dryness. The residue was dissolved in CH 2 C1 2 (5 mL) and added to a solution of diethyl (hydroxymnethyl)phosphonate (1.5 mmole) and pyridine (2 mmole) in CH 2 C1 2 (5 rnL) at 0 0 C. The reaction was warmed to room temperature and stirred for 4 h. The reaction was quenched with water and the mixture was subjected to extraction to give 2-[N-Boc(amino)]-4-diethylphosphonomethoxycarbonylthiazole as a thick yellow oil.

Alternatively the ester linkage can be formed using a mixed anhydride method as exemplified in the following procedures: A solution of 2-[N-Boc(amino)]-4-carboxylthiazole (1 mmole) in pyridine (5 mL) was treated with para-toluenesulfonyl chloride (2 mmole) followed by diethyl (hydroxymethyl)phosphonate (2 mmole) at room temperature for 4 hi. Evaporation, extraction and chromatography gave 2-[N-Boc(arnino)]-4-diethylphosphonomethoxycarbonylthiazole as a thick yellow oil.

Step D. A solution of 2-[N-Boc(amnino)]-4-diethylphosphonomethoxycarbonylthiazole (1 mmole) and anisole 1 mmole) in methylene chloride (5 ml) and trifluoroacetic acid xnL) was stirred at 0 0 C for I hi, and at room temperature for 1 h. Evaporation, extraction and chromatography gave 2-amino-4-diethyllphosphonomethoxycarbonylthiazole as a solid.

S tep E. 2-Amino-4-diethyllphcsphonomethoxycarbonylthiazole was subjected to Step C of Example 3 to give 2-amino-4-phosphonomethoxycarbonylthiazole (18.1) as a solid.

Mp 240'C (decomp). Anal. calcd. for C 5 1

N

2 OsPS: C: 25.22; H: 2.96; N: 11.76. Found: C: 25.30; H: 2.86; N: 11.77.

Step F. A solution of 2-[N-Boc(amino)]-4-diethylphosphonometlaoxycarbonylthiazole (I mmole) in CH 2

CI

2 (5 mL) was treated with bromine (2 mimole) at room, temperature for 4 h. Evapotation and extraction gave 2-[N-Boc(amino)]-5-bromo-4diethyiphosphonomethoxycarbonylthiazole as an orange oil which was subjected to Step D of Example 18 followed by Step C of Example 3 to give 2-amino-5-bromo-4phosphonomethoxycarbonylthiazole (18.2) as a solid. Mp 230'C (decomp). Anal. calcd. for

C

5

H

6

-N

2 OsPSBr: C: 18.94; H: 1.91; N: 8.84. Found: C: 19.08; H: 1.76; N: 8.67.

Step G. A solution of 2-[N-Boc(amino)]-5-bromo-4diethylphosphonomethoxycarbonylthiazole (1 mmole) and dichlorobis(triphenylphosphine)palladium(Il (0.1 mmole) in DMNF (5 mL) was treated with tributyl(vinyl)tin (2.5 rmuole) and the reaction was stirred at 6000 for 2 h. The solvent was removed and the residue taken up in EtOAc and stirred with 2 mmol NaF in 5 ml wvater for I h. Extraction and chromatography gave 2-[N-Boc(amino)]-5-vinyl-4diethylphosphonomethoxycarbonylthiazole as a yellow solid.

Step H. A suspension of 2-[N-Boc(amidno)]-5-vinyl-4diethylphosphononaethoxycarbonyl thiazole (1 mmole) and 10 Pd/C (0.5 inmole) in MeOH mL) was stirred under an atmosphere of H 2 (balloon) at room temperature for 15 h.

Filtration and evaporation gave 2-[N-Boc(amino)]-5-ethyl-4diethylphosphonomethoxycarbonylthiazole as a yellow solid, which was subjected to Step D of Example 18 followed by Step C of Example 3 to give 2-amino-5-ethyl-4phosphonomethoxycarbonylthiazole (18.3) as a solid. Mp 230°C (decomp). Anal. Calcd.

for C 7 HIINzOsPS: 31.58; H: 4.16; N: 10.52. Found: C: 31.80; H: 4.04; N: 10.18.

Step I. A solution of N-[Bis(methylthio)methylene]glycine methyl ester (1 mmole) in anhydrous THF (2 mL) was added to a solution of t-BuOK (1.4 mmole) in anhydrous THF mL) at -78 0 C and the mixture was stirred for 30 min. Then a solution of ethyl isothiocyanate (1 mmole) in anhydrous THF (2 mL) was added and the reaction was stirred at -78 0 C for 30 min and at room temperature for 2 h. The reaction was quenched with water.

Extraction and chromatography gave 2-methylthio-5-(N-ethylamino)-4methoxycarbonylthiazole as a yellow solid, which was subjected to Step B and C of Example 18 followed by Step C of Example 3 to give 2-methylthio-5-(N-ethylamino)-4phosphonomethoxycarbonylthiazole (18.4) as a solid. Mp 200 0 C (decomp). Anal. calcd. for CsH 3

N

2 0 5

PS

2 0.1 HBr: C: 29.99; H: 4.12; N: 8.74. Found: C: 29.71; H: 4.10; N: 8.60.

Step J. A solution of I mmol of 2-(N-Boc(amino)]-4-thiazolecarboxylate acid chloride (1 mmole) and pyridine (2 mmole) in CH 2

CI

2 (5 mL) was cooled to -78 0 C and H2S(g) was bubbled through the solution for 10 min. The reaction was stirred at -78 0 C for 30 min and then warmed to room temperature. The mixture was washed with 3 N HC1. The organic phase was separated, dried and concentrated to give 2-[N-Boc(amino)]-4thiazolethiocarboxylic acid as a yellow solid.

Step K. A solution of give 2-[N-Boc(amino)]-4-thiazolethiocarboxylic acid (1 mmole) in THF (5 mL) was cooled to -78 0 C and treated with NaH (2 mmole) in small portions. After min the reaction was treated with a solution of diethylphosphonomethyl triflate in THF mL). The reaction was stirred at -78 0 C for 1 h, and then quenched with H 2 0. Extraction and chromatography gave 2-[N-Boc(amino)]-4-diethylphosphonomethylthiocarbonylthiazole as a thick oil, which was subjected to Step D of Example 18 followed by Step C of Example 3 to give 2-amino-4-phosphonomethylthiocarbonylthiazole (18.5) as a solid. Mp 230 0

C

(decomp). Anal. calcd. for C 5

H

7

N

2 0 4 1'S 2 C: 23.62; H: 2.78; N: 11.02. Found: C: 23.77; H: 2.61; N: 10.73.

Preparation of 4-[(N-phosphonomethyl)carbamoyl]thiazole, 3-[N-phiosphonomethy1)carbamnoyl]isothidazole and 2-[N-phosphonomnethyl)carbamnoyl]pyridine Step L. A solution of 2-[N-Boc(amino)]-4-thiazolecarboxylic acid (1 mmole) in DMIF mL) was treated with 1-(3-dimethylaininopropyl)-3-ethylcarbodiimiide hydrochloride (EDCI, 1.5 mmole) and 1-bydroxylbenzotriazole hydrate (HOBt, 1.5 mmole) followed by addition of diethyl aminoniethylphosphonate (1.5 mniole) at room temperature for 24 h. The reaction was subjected to evaporation, extraction and chromatography to give 2-[N- Boc(amino)]-4-[(N-diethylphosphonomethy)carbamoyl]thiazole as a white solid, which was subjected to Step D of Example 18 followed by Step C of Example 3 to give 2-amino-4-[(Nphosphonomethyl)carbarnoyl]thiazole (18.6) as a light brown solid. Mp 245'C (decomp).

Anal. calcd. for C 5

H

8

N

3

O

4 PS 1.05 HBr: C: 18.64; H: 2,83; N: 13.04. Found: C: 18.78; H:2.43; N: 12.97.

Preparation of 2-[(N-phosphonoacetyl)amino]thiazole and phosphonoacetyl)ammiojpyridine Step M. A solution of 2-amnino-4,5-dimethylthiazole hydrochloride (2 mmole) and diethyl phosphonoacetica acid (I mxnole) in DIVF (5 rnL) was treated with EDCI mmnole), HOBt (1.5 mmole) and triethylamine (2 inmole) at room temperature for 24 h. The reaction was subjected to evaporation, extraction and chromatography to give as a yellow solid, which was subjected to Step D of Example 18 followed by Step C of Example 3 to give 4,5-dimethyl-2-[(Nphosphonoacetyl) amino] thiazole (18.7) as a light brown solid. Mp 250'C. Anal. calcd. for

C

7

H

11

N

2 0 4 PS: C: 33.60; H: 4.43; N: 11.20. Found: C: 33.62; H: 4.29; N: 10.99.

The following compounds were prepared using some of the above described procedures or some of the above procedures with some minor modifications using conventional chemistry: (18.8) 2-[(N-phosphonomethyl)carbamoyl]pyridine. Anal. calcd for C 7 HqN 2 0 4 P HBr 0.67 H 2 0: C: 27.20; H: 3.70; N: 9.06. Found: C: 27.02; H: 3.71; N: 8.92.

(18.9) 2-[(N-phosphonoacetyl)amino]pyridine. Anal. calcd. for C 7

H

9

N

2 04P HBr 0.67

H

2 0: C: 27.20; H: 3.70; N: 9.06. Found: C: 27.05; H: 3.59; N: 8.86.

(18.10) 4-Ethoxycarbonyl-2-[(N-phosphonoacetyl)amilnolthiazole. Anal. calcd. for

CSHIIN

2 0 6 PS: C: 32.66; H: 3.77; N: 9.52. Found: C: 32.83; H: 3.58; N: 9.20.

(18.11) 2-Amino-5-bromo-4-[(N-phosphonomethyl)carbamoyl]thiazole. Mp 232'C (decomp). Anal. calcd. for C 5

H

7

N

3 0 4 PSBr 0.1 5HBr 0.1 hexane: C: 19.97; H: 2.56; N: 12.48. Found: C: 19.90; H: 2.29; N: 12.33.

(18.12) 2-Amino-5-(2-thienyl)-4-[(N-phosphonomethyl)carbamoyl]thiazole. Mp 245 0

C

(decomp). Anal. calcd. for C 9

HION

3 0 4

PS

2 HBr 0.1 EtOAc: C: 27.60; H: 2.91; N: 10.27.

Found: C: 27.20; H: 2.67; N: 9.98.

(18.13) 4,5-Dichloro-3-[(N-phosphonomethyl)carbamoyl]isothiazole. Mp 189 191 0 C. Anal.

calcd. for C 5

H

5

N

2 0 4 PSCl 2 C: 20.63; H: 1.73; N: 9.62. Found: C: 20.43; H: 1.54; N: 9.51.

(18.14) 2-Amino-5-bromo-4- {[N-(1-phosphono-l-phenyl)methyl]carbamoyl)thiazole. Mp 250*C. Anal. calcd. for CIIH 11

N

3 0 4 PSBr: C: 33.69; H: 2.83; N: 10.71. Found: C: 33.85; H: 2.63; N: 10.85.

(18.15) 2-Amino-5-(2-thienyl)-4-phosphonomethoxycarbonylthiazole. Mp 230 0

C

(decomp). Anal. calcd. for CqHqN 2 0 5 PS2: C: 33.75; H: 2.83; N: 8.75. Found: C: 33.40; H: 2.74; N: 8.51.

(18.16) 2-Amino-5-benzyl-4-phosphonomethoxycarbonylthiazole. Mp 230'C (decomp).

Anal. calcd. for C 12

H

0 3N 2 0 5 PS: C: 43.91; H: 3.99; N: 8.53. Found: C: 43.77; H: 4.03; N: 8.25.

(18.17) 2-Methythio-5-methylamino-4-phosphonomethoxycarbonylthiazole. Anal. calcd. for

C

7

H

1 iN 2 0 5

PS

2 0.2 HBr: C: 26.74; H: 3.59; N: 8.91. Found: C: 26.79; H: 3.89; N: 8.89.

(18.18) 2-Amino-5-ethyl-4-[(N-phosphonomethyl)carbamoyl]thiazole. Mp 180'C (decomp).

Anal. calcd. for C 7

HI

2

N

3 0 4 PS HBr 0.4 CH 2 C1 2 C: 23.49; H: 3.67; N: 11.18. Found: C: 23.73; H: 3.29; N: 11.42.

(18.19) 2-Amino-5-isopropyl-4-[(N-phosphonomethyl)carbamoyl]thiazole. Mp 247 250 0

C.

Anal. calcd. for C 8

HI

4

N

3 0 4 PS: C: 34.41; H: 5.05; N: 15.05. Found: C: 34.46; H: 4.80; N: 14.68.

(18.20) 2-Amino-5-isopropyl-4-phosphonomethoxycarbonylthiazole. Mp 230 0 C. Anal.

calcd. for CSH 1 3

N

2 0sPS: C: 34.29; H: 4.68; N: 10.00. Found: C: 33.97; H: 4.49; N: 9.70.

(18.21) 2-Amino-5-phenyl-4-phosphonomethoxycarbonythiazole. Mp 230 0 C. Anal. calcd.

for C 11

HIIN

2 0 5 PS: C: 42.04; H: 3.53; N: 8.91. Found: C: 42.04; H: 3.40; N: 8.72.

(18.22) 2-Amino-4-phosphonomethoxycarbonyloxazole. Anal. calcd. for C 5

H

7

N

2 0 6 P 0.09 HBr: C: 26.18; H: 3.12; N: 12.21. Found: C: 26.29; H: 3.04; N: 11.90.

(18.23) 2-Amino-6-[(N-phosphonoacetyl)amino]pyridine. Anal. calcd. for C 7

HION

3 0 4 P 1.1 HBr 0.25 MeOH: C: 26.54; H: 3.72; N: 12.80. Found: C: 26.79; H: 3.63; N: 12.44.

(18.24) 2-Amino-5-methyl-4-[(N-phosphonomethyl)carbamoyl]thiazole. Mp 250C. Anal.

calcd. for C 6

HION

3 0 4 PS 0.06 EtOAc: C: 29.22; H: 4.12; N: 16.38. Found: C: 29.03; H: 3.84; N: 16.01.

(18.25) 2-Amino-3-bromo-6-[(N-phosphonoacetyl)amino]pyridine. Anal. calcd. for

C

7

H

9

N

3 0 4 PBr 1.25 HBr 0.8 EtOAc: C: 25.43; H: 3.48; N: 8.72. Found: C: 25.58; H: 3.71; N: 8.56.

(18.26) 2-Amino-3,5-dibromo-6-[(N-phosphonoacetyl)amino]pyridine. Anal. calcd. for

C

7

H

8

N

3 0 4 PBr 2 HBr 0.5 EtOAc: C: 21.03; H: 2.55; N: 8.18. Found: C: 21.28; H: 2.55; N: 7.91.

(18.27) 2-Anino-5-methyl-4-phosphonomethoxycarbonylthiazole. Mp 230 0 C (decomp).

Anal. calcd. for C 6 HqN 2 0 5 PS: C: 28.58; H: 3.60; N: 11.11. Found: C: 28.38; H: 3.49; N: 11.10.

(18.28) 2-Amino-3,5-diethyl-6-[(N-phosphonoacetyl)amino]pyridine. MS calcd. for CiiHi 8

N

3 0 4 P H: 288, found 288.

(18.29) 2-Amino-3,5-dibromo-6- [N-(2,2-dibromo-2-phosphono)acetyl]amino}pyridine.

Anal. calcd. for C 7

H

6

N

3 0 4 PBr 4 0.5 HBr EtOAc: C: 19.56; H: 2.16; N: 6.22. Found: C: 19.26; H: 2.29; N: 5.91.

(18.30) 2-Amino-5-isopropyl-4-phosphonomethoxycarbonyloxazole. Anal. caled. for CsH 13

N

2 06P 0.2 HBr: C: 34.27; H: 4.75; N: 9.99. Found: C: 34.47; H: 4.84; N: 9.83.

(18.31) 2-Amino-5-[I-(2-cyclohexylmethyl)ethynyl]-4-phosphonomethoxycarbonylthiazole.

Mp 230*C (decomp). Anal. calcd. for C 14 H1 9

N

2 0 5 PS 0.1 HBr: C: 45.89; H: 5.25; N: 7.64.

Found: C: 45.85; H: 4.96; N: 7.44.

(18.32) 2-Amino-5-[1-(4-cyano)butynyl]-4-phosphonomethoxycarbonylthiazole. Mp 230 0

C

(decomp). Anal. calcd. for C 1 oHIoN 3 0 5 PS 0.25 HBr: C: 35.80; H: 3.08; N: 12.53. Found: C: 35.92; H: 2.99; N: 12.20.

(18.33) 2-Amino-5-nethyl-4-phosphonomethoxycarbonyloxazole. Anal. calcd. for

C

6 HqN 2 0 6 P 0.15 iBr: C: 29.03; H: 3.71; N: 11.28. Found: C: 28.98; H: 3.66; N: 11.21.

(18.34) 2-Amino-5-[1-(4-cyano)butyl]-4-phosphonomethoxycarbonylthiazole. Mp 230 0

C

(decomp). Anal. calcd. for CjoH 1 4

N

3 0 5 PS: C: 37.62; H: 4.42; N: 13.16. Found: C: 37.23; H: 4.18; N: 12.79.

(18.35) 2-Amino-5-pentyl-4-phosphonomethoxycarbonyloxazole. Anal. calcd. for CIoHIN 2 0 6 P: C: 41.10; H: 5.86; N: 9.59. Found: C: 41.16; H: 5.75; N: 9.50.

(18.36) 2-[N-Boc(amino)]-4-[(2-phosphono)ethoxycarbonyl]thiazole. Anal. calcd. for

C,

1

H

1 7

N

2 0 7 PS: C: 37.50; H: 4.86; N: 7.95. Found: C: 37.10; H: 4.59; N: 7.84.

(18.37) 2-Amino-4-[(2-phosphono)ethoxycarbonyl]thiazole hydrobromide. Anal. calcd. for

C

6 HqN 2 0 5 PS HBr: C: 21.63; H: 3.03; N: 8.41. Found: C: 22.01; H: 2.99; N: 8.15.

(18.38) 2-Amino-5-butyl-4-phosphonomethoxycarbonyloxazole. Anal. calcd. for CgHisN 2 0 6 P: C: 38.86; H: 5.43; N: 10.07. Found: C: 38.59; H: 5.43; N: 9.96.

(18.39) 2-Amino-5-[1-(1-oxo-2,2-dimethyl)propyl]-4-phosphonomethoxycarbonylthiazole.

Anal. Calcd. for CjoH 15

N

2 0 6 PS: C: 37.27; H: 4.69; N: 8.69. Found: C: 37.03; H: 4.69; N: 8.39.

(18.40) 2-Amino-5-propyl-4-phosphonomethoxycarbonyloxazole. Anal. calcd. for C&Hi 3

N

2 0 6 P 0.35 EtOAc 0.05 HBr: C: 37.75; H: 5.34; N: 9.37. Found: C: 37.69; H: 5.21; N: 9.03.

(18.41) 2-Amino-5-propyl-4-phosphonomethoxycarbonylthiazole. Mp 134'C (decomp).

Anal. calcd. for C&H 13

N

2 0sPS: C: 34.29; H: 4.68; N: 10.00. Found: C: 33.90; H: 4.30; N: 9.61L (18.42) 2-Amino-5-pentyl-4-phosphonomethoxycarbonylthiazole. Mp 130 0 C (decomp).

Anal. calcd. for C 1 oH 1 7

N

2 0 5 PS: C: 38.96; H: 5.56; N: 9.09. Found: C: 38.69; H: 5.25; N: 8.85.

(18.43) 2-Amino-5-bromo-4-phosphonomethylthiocarbonylthiazole. Mp 230 0 C (decomp).

Anal. caled. for C 5

H

6

N

2 0 5

PS

2 Br: C: 18.03; H: 1.82; N: 8.41. Found: C: 18.40; H: 1.93; N: 8.18.

(18.44) 2-Amino-5-(2-furanyl)-4-phosphonomethoxycarbonylthiazole. Mp 230 0 C (decomp).

Anal. calcd. for CqHqN 2 0PS: C: 35.53; H: 2.98; N: 9.21. Found: C: 35.78; H: 3.05; N: 8.11.

(18.45) 2-Amino-5-ethyl-4-phosphonomethoxycarbonyloxazole. Mp 141 0 C (decomp). Anal.

calcd. for CH 11

N

2 0 6 P: C: 33.61; H: 4.43; N: 11.20. Found: C: 33.79; H: 4.47; N: 11.09.

(18.46) 5-Methyl-4-[(N-phosphonomethyl)carbamoyl]imidazole. Anal. calcd. for

C

6 HIoN 3 0 4 P: C: 32.89; H: 4.60; N: 19.18. Found; C: 33.04; H: 4.65; N: 18.84.

Example 19.

Preparation of 3-[2-(5-phosphono)furanvllpyrazoles.

Step A. A solution of diethyl 5-(2-isobutyl-3-N,N-dimethylamino)acryloyl-2furanphosphonate (1 mmole, prepared according to Step A of Example 17) in ethanol was treated with hydrazine (1.2 mmole) 80 0 C for 12 h. Evaporation and chromatography gave 4isobutyl-3-[2-(5-diethylphosphono)furanyl]pyrazole.

Step B. 4-Isobutyl-3-[2-(5-diethylphosphono)furanyl]pyrazole was subjected to Step C of Example 3 to give 4-isobutyl-3-[2-(5-phosphono)furanyl]pyrazole mp 210 215 0

C.

Anal. calcd. for C 1 1

H

15

N

2 0 4 P: C: 48.89; H: 5.60; N: 10.37. Found: C: 48.67; H: 5.55; N: 10.20.

Step C. 4-Isobutyl-3-[2-(5-diethylphosphono)furanyl]pyrazole was subjected to Step A of Example 11 to give 1-methyl-4-isobutyl-3-[2-(5-diethylphosphono)furanyl]pyrazole.

Step D. 1-Methyl-4-isobutyl-3-[2-(5-diethylphosphono)furanyl]pyrazole was subjected to Step C of Example 3 to give 1-methyl-4-isobutyl-3-[2-(5-phosphono)furanyllpyrazole Anal. calcd. for C 12

H

17

N

2 0 4 P 0.85HBr 0.75 H 2 0: C: 39.32; H: 5.32; N: 7.64.

Found: C: 39.59; H: 5.30; N: 7.47.

Example Preparation of 3-[2-(5-phosphono)furanyllisoxazoles.

Step A. A solution of 5-diethylphosphono-2-furaldehyde (1 mmole) in ethanol was treated with hydroxylamine (1.1 nnole) and sodium acetate (2.2 mmole) at 25 0 C for 12 h.

Extraction and chromatography gave 5-diethylphosphono-2-furaldehyde oxime.

Step B. A solution of 5-diethylphosphono-2-furaldehyde oxime (1 mmole) in DMF was treated with N-chlorosuccinimide (1.1 mmole) at 25 0 C for 12 h. Extraction gave diethylphosphono-2-chlorooximidofuran.

step C. A solution of 5-diethylphosphono-2-chlorooximidofuran (1 mmole) and ethyl propiolate (5 mmole) in diethyl ether was treated with triethylamine (2 mmole) at 25 0 C for 12 h. Extraction and chromatography gave 5-ethoxycarbonyl-3- diethylphosphono)furanyl]isoxazole.

Step D. 5-Ethoxycarbonyl-3- {2-(5-diethylphosphono)furanyl]isoxazole was subjected to Step A of Example 9 followed by Step C of Example 3 to give 5-carbamoyl-3-[2-(5phosphono)furanyl]isoxazole mp 221 225 0 C. Anal. calcd. for CgH 7

N

2 0 6 P 0.25EtOH: C: 37.86; H: 3.18; N: 10.39. Found: C: 37.90; H: 3.02; N: 10.05.

The following compound was prepared according to this procedure: (20.2) 5-Ethoxycarbonyl-4-methyl-3-[2-(5-phosphono)furanyl]isoxazoe. rap 150 152 0

C.

Anal. calcd. for C 1 IH1 2

NO

7 P 0.25H 2 0 0.15HBr: C: 41.57; H: 4.01; N: 4.41. Found: C: 41.57; H: 4.20; N: 4.54.

(20.3) 4,5-Bis(ethoxycarbonyl)-3-[2-(5-phosphono)furanyl]isoxazole. Anal. caled for C1 3

HI

4

NO

9 P: C: 43.47; H: 3.93; N: 3.90. Found: C: 43.26; H: 3.92; N: 3.97.

(20.4) 5-Amino-4-ethoxycarbonyl-3-[2-(5-phosphono)furanyl]isoxazole. mp 190 0

C

(decomp). Anal. calcd for C 1 oHIIN 2 0 7 P+ 0.25EBr: C: 37.25; H: 3.52; N: 8.69. Found: C: 37.56; H: 3.50; N: 8.85.

(20.5) 4,5-bis(carbamoyl)-3-[2-(5-phosphono)furanyl]isoxazole. mp 220C. Anal. calcd for C 9

H

8

N

3 0 7 P: C: 35.90; H: 2.68; N: 13.95. Found: C: 35.67; H: 2.55; N: 13.62.

(20.6) 4-Ethoxycarbonyl-5-trifluoromethyl-3-[2-(5-phosphono)furanyl]isoxazole. Anal. calcd for C 1 iH 9

F

3

NO

7 P +0.25HBr: C: 35.20; H: 2.48; N: 3.73. Found: C: 35.25; H: 2.34; N: 3.98.

(20.7) 5-Amino-4-(2-furyl)-3-[2-(5-phosphono)furanyl]isoxazole. mp 220 0 C. Anal. calcd for C 1 2

H

9

N

2 0 7 P 0.lAcOEt: C: 44.73; H: 2.97; N: 8.41. Found: C: 45.10; H: 2.58; N: 8.73.

(20.8) 4-Amino-5-cyano-3-[2-(5-phosphono)furanyl]isoxazole. Anal. caled for CsH 6

N

3 0 5 P 0.1H20 0.2HBr: C: 35.18; H: 2.36; N: 15.39. Found: C: 35.34; H: 2.50; N: 15.08.

(20.9) 4-Cyano-5-phenyl-3-[2-(5-phosphono)furanyl]isoxazole. Anal. calcd for C 14

H

9

N

2 0 5

P

0.15HBr: C: 51.21; H: 2.81; N: 8.53. Found: C: 51.24; H: 3.09; N: 8.33.

Example 21.

Preparation of 2-[2-(5-phosphono)furanyllthiazoles.

Step A. Diethyl 5-tributylstannyl-2-furanphosphonate (14) and 2-bromo-4ethoxycarbonylthiazole was subjected to Step A of Example 6 to give 4-ethoxycarbonyl-2-[2- Step B. 4-Ethoxycarbonyl-2-[2-(5-diethylphosphono)furanyl]thiazole was subjected to Step A of Example 9 followed by Step C of Example 3 to give 4-carbamoyl-2-[2-(5phosphono)furanyl]thiazole mp 239 240C. Anal. calcd. for C 8

H

7

N

2 0 5 PS 0.2H 2 0: C: 34.59; H: 2.68; N: 10.08. Found: C: 34.65; H: 2.69; N: 9.84.

Example 22.

Preparation of 4-(3.3-difluoi-o-3-phosphono-l-propvl)thiazoles.

Step A. A solution of 3-(tert-butyl-diphenylsilyloxy)-l-propanol (I mmole) in methylene chloride (7 mL) was treated with powder molecular sieves (4 A, 0.5 equiv. wt/wt) and pyridiniumn chlorochromate (1.5 mmnole) at 0 0 C. The resulting mixture was stirred at room temperature for 2 h, and diluted with diethyl ether (7 rnL) and stirred at room temperature for another 30 min. Filtration, evaporation and chromatography gave 3-(tertbutyldiphenylsilyloxy)-1 -prop anal as a clear oil.

Step B. A solution of LIDA (1.06 mmole) in THF was treated with a solution of diethyl difluoromethylphosphonate (1 nunole) at -78*C for 45 min. The reaction was then treated with a TIF solution of 3-(tert-butyldiphenylsilyloxy)-l-propanaI (1.07 mmole) and the resulting solution was stirred at -78'C for another 4 h. The reaction was quenched with phenyl chlcrothioformate (2.14 namole), and the reaction mixture was subjected to extraction and chromatography to give diethyl 4-(tert-butyldiphenylsilyloxy)-3phenoxythiocarbonyloxy-2,2-difluorobutylphosphonate as a clear oil.

Sten C. A solution of diethyl 4-(tert-butyldiphenylsilyloxy)-3phenoxythiocarbonyloxy-2,2-difluorobutylphosphonate (I mmole) in toluene (I mL) was treated with tri-n-butyltin hydride (1.5 numole) and AIBN (0.1 manole), and the resulting reaction mixture was heated to refiux for 2 h. Evaporation and chromatography gave diethyl 4-(tert-butyldiphenylsilyloxy)-2,2-difluorobutylphosphonate as a clear oil.

Step D. A solution of diethyl 4-(tert-butyldiphenylsilyloxy)-2,2difluorobutyiphosphonate (I mmole) in methanol (I mL) was treated with hydrochloric acid (4 N, 4 namole) at 0 0 C, and the resulting reaction was stirred at room temperature for 2 h.

Evaporation and chromatography gave diethyl 4-hydroxy-2,2-difluorob utylphosphonate as a clear oil.

Step E. A solution of gave diethyl 4-hydroxy-2,2-difluorobutylphosphonate (1 mmole) in acetone (10 naL) was treated with Jones's reagent (10 namole) at 0 0 C for 30 min. The reaction was quenched with 2-propanol (10 mL), and the resulting mixture was filtered through a Celite pad. Evaporation of the filtrate followed by extraction gave diethyl 3carboxyl-2,3- difluoropropyiphosphonate as an oil.

Step F. A solution of diethyl 3-carboxyl-2,3-difluoropropylphosphonate (1 mmole) in thionyl chloride (3 mL) was heated to reflux for 2 h. The reaction was evaporated to dryness, and the residue was dissolved in diethyl ether (1 mL) was treated with an etheral solution of diazomethane (10 mmole) at OTC for 30 min. A solution of HBr in acetic acid 1 inL) was added to the reaction, and the resulting solution was stirred at room temperature for 1 h.

The reaction was evaporated to dryness and the residue was dissolved in THF-EtOH 1, mL) and treated with thiourea (I mmole). The resulting reaction mixture was heated to for I h. Evaporation followed by extraction and chromatography gave 2-ainino-4-[l-(3diethylphosphono-3,3-difluoro)propyllthiazole as a solid, which was subjected to Step C of Example 3 to give gave 2-amino-4-[1-(3-phosphono-3,3-difluoro)propyl]thiazole (22.1) as a solid. Anal. calcd. for C 6

H

9

N

2

O

3

PSF

2 +HBr: C: 21.25; H: 2.97; N: 8.26. Found: C: 21.24; H-:3.25; N: 8.21.

The following compound was prepared in a similar manner: 2-Amiino-5-methylthio-4- -phosphono-3,3 -difluoro)propyl]thiazole MS m/e 3 05 Example 23.

Preparation of 2-methylthio-5-ph iosphonomethylthio-1 .3.4-thiadiazole-and 2phosphonomethylthlopyridine.

Step A. A solution of 2-methylthio-1,3,4-thi adiazole-5-thiol (1 mmole) in THF (5 mL) was treated with sodium hydride (60 1.1 mmole) at 0 0 C and the resulting mixture was stirred at room temperature for 30 mini. The reaction was then cooled to 0CC and treated with diethylphosphonomethyl trifluoromethanesulfonate 1 mmole). After stirring at room temperature for 12 h, the reaction was quenched with saturated ammoniumn chloride.

Extraction and chromatography gave 2-methylthio-5-diethylphosphonomethylthio-1 ,3 ,4thiadiazole as an oil.

Step B. 2-Methylthio-5-diethylphosphonomethylthio- 1,3,4-thiadiazole was subjected to Step C of Example 3 to give 2-nmetliylthio-5-phosphonomethylthio-1I,3,4-thiadiazole (23.1) as a yellow solid. Anal. calcd. for C 4

H

1

N

2 0 3

PS

3 0.2 HBr: C: 17.50; H: 2.64; N: 10.21.

Found: C: 17.64; H: 2.56; N: 10.00.

Alternatively, phosphonomethylthio substituted heteroaromatics are made using the following method as exenmplified by the synthesis of 2-phosphonomethylthiopyri dine: Step C. A solution of 2,2'-dipyridyl disulfide (1 mmole) in THF was treated with tri-nbutyiphosphine (I mmrole) and diethyl hydroxymethyiphosphonate at 0 0 C. The resulting reaction solution was stirred at room temperature for 18 h. Extraction and chromatography gave 2-diethiylphosphoinomethyltlhiopyridine as a yellow oil.

Step D. 2-Diethylphosphonomethylthiopyiidine was subjected to Step C of Example 3 to give 2-phosphonomethyithi opyridine (23.2) as a yellow solid. Anal. calcd. for C 6 HsNO 3

PS

0.62 HBr: C: 28.22; H: 3.40; N: 5.49. Found: C: 28.48; H: 3.75; N: 5.14.

Example 24.

Preparation of 2-I(2-phosphono)ethynyllpyridine.

Step A. A solution of 2-ethynylpyridine (I inmole) in THF (5 mL) was treated with LDA (1.2 mmole) at 0 0 C for 40 min. Diethyl chlorophosphate (1.2 mmole) was added to the reaction and the resulting reaction solution was stirred at room temperature for 16 h. The reaction was quenched with saturated ammnonium chloride followed by extraction and chromatography to give 2-[(2-diethylphosphono)ethynyl]pyridine as a yellow oil.

Step B. 2-[(2-Diethylphosphono)ethynyl]pyridine was subjected to Step C of Example 3 to give 2-[1-(2-phosphono)ethynyl]pynidine (24.1) as a brown solid. Mp 160*C (decomp).

MS in/e 184 (M H).

Examiple Preparation of 5- Step A. To a mixture of tetrazole (1 rinole) and powdered K 2 C0 3 (1.5 minole) in 1 mL DMvF cooled to 0 0 C was added benzyl chioromethyl ether (1.2 mmole) and the resulting mixture stirred for 30 min at 0 0 C and then for 16 h at rt, The mixture was diluted with water and ether. Extraction and chiromatography provided 2-benzyloxymnethyltetrazole as a colorless oil.

Step B. To a solution of 2-benzyloxymnethyltetrazole (1 nimole) and TMIEDA (2 minole) in 3 mL diethyl ether at -78 0 C was added n-BuLi in hexanes (I mmole). This was let stir for 5 min at -78'C and then it was added to a precooled solution of (n-BU) 3 SnCI (1 mmole) in 2 niL of diethyl ether. After stining at -78'C for 30 min it was diluted with water and diethyl ether. Extraction and chromatography provided (tributylstannyl)tetrazole as a colorless oil.

Step C. A mixture of 5-iodo-2-diethylphosphonofuran (1 inmole), 2-benzyloxymethyl- 5-(tributylstannyl)tetrazole (1.05 mmole), tetralkis(triphenylphosphine) palladium(O) (0.03 mmole) and copper(I) iodide (0.07 mmole) in 3 niL of toluene was refluxed at for 20 h. Evaporation and chromatography provided 2-benzyloxymethyl-5-[2-(5diethylphosphono)furanyltetrazole as an oil.

Step D. A mixture of 2-benzyloxymethyl-5-[2-(5-diethylphosphono)furanyl]tetrazole (1 nimole) and 6 M HCI (1 mL) in 10 niL ethanol was heated at 70'C for 20 h and then the solvent concentrated by evaporation, made basic with 1 N NaOH and extracted with EtOAc.

The aqueous layer was made acidic and extracted with EtOAc. This EtOAc extract was evaporated to provide 5-[2-(5-diethylphosphono)furanyl]tetrazole as a solid, which was subjected to Step C of Example 3 to give 5-[2-(5-phosphono)furanylltetrazole (25.1) as a solid: mp 186-188'C. Anal. calcd. for C 5

H

5

N

4 0 4 P 1.5 H 2 0: C, 24.70; H, 3.32; N, 23.05.

Found: C, 24.57; H, 2.57; N: 23.05.

Step E.

Step LA mixture of 5-[2-(5-diethylphosphono)furanylltetrazole (I mmole), 1-iodo-2methylpropane (2 rnmole) and powdered K 2 C0 3 (2 mmole) in 5 m.L DMIIF was stirred at for 48 hi and then diluted with CH 2

CI

2 and water and the layers separated. The CH 2 0 2 layer was evaporated and combined with the product of the following reaction for chromatography.

Step 2. The aqueous layer of Step 1 was made acidic and extracted with EtOAc. This extract was evaporated and the residue heated at 80'C in 2 mL Of SOC1 2 for 3 h and then the solvent evaporated. The residue was dissolved in 5 mL CH 2 Cl 2 and 0.3 niL N-Et 3 and 0.5 mL of EtOH was added. After stirring for 1 h at rt the mixture was diluted with CH 2 Cl 2 and water.

This organic extract was combined with that kept from Step I and chromatography provided l-isobutyl-5-[2-(5-diethylphosphono)fiiranyl]tetrazole and- 2-isobutyl-5-[2-(5diethylphosphono)furanyl]tetrazole each as an oil.

Step 3. l-Isobutyl.5-(2-(5-diethylphosphono)fuiranyl]tetrazole was subjected to Step C of Example 3 to give l-isobutyl-5-[2-(5-phosphono)furanyl]tetrazole (25.2) as a solid: mp 200- 202'C. Anal. calcd. for C 9

H

13

N

4 0 4 P: C: 39.71; H: 4.81; N: 20.58. Found: C 39.64; H: 4.63; N:20.21.

Step F. A mixture of 2-isobutyl-5-[2-(5-diethylphosphono)furanyl]tetrazole (I mmnole) and TMSBr (10 mmole) in 10 m.L of CH 2 Cl 2 was stirred at room temperature for 16 h. The solvent was evaporated and the residue dissolved in 10: 1 CH 3 CN:water, the solvent evaporated and the residue precipitated from acetone by addition of dicyclohexylamine (2 minole) to provide 2-isobutyl-5-[2-(5-phosphono)furanyl]tetrazole N,N-dicyclohexyl ammonium salt.

(25.3) as a solid: mp 226-228'C. Anal. calcd. for C 9

HI

3

N

4 0 4 P C 12

H

23 N: C: 55.62; H: 8.00; N: 15.44. Found: C 55.55; H: 8.03; N: 15.07.

Example 26.

Hidh throughput synthesis of various 2-(5-phosphono)furanyl substituted hetcroaroniatic comounds.

Step A. Various 2-(5-diethylphosphono)ftiranyl substituted heteroaromatic compounds were prepared in a similar manner as Step B of Example 15, and some of these compounds were used for the high throughput synthesis of compounds listed in Table 26.1 and Table 26.2.

Step B. A mixture of 2-chloro-6-[2-(5-diethylphosphono)furanyl]pyridine (0.01 mmole) and TMSBr (Oi1 mL) in C11 2

C

2 (0.5 mL) was stirred at room temper ature for 16 h and then evaporated and diluted with 0.5 rnL of 9:1 CH 3 CN:water. Evaporation provided 2chloTO-6-[2-(5-phosphono)furanyl]pyridine.

Step C. A mixture of 2-chloro-6-[2-(5-diethylphosphono)furanyl]pyridine (0.01 mmole) and a solution of freshly prepared sodium propoxide in propanol (0.25 M, 0.4 mnL) was let sit at 85'C for 14 h. The reaction mixture was evaporated and the residue was subjected to Step B of Example 26 to give 2-propyloxy-6-[2-(5-phosphonio)furanyl]pyridine.

Step D. A mixture of 2-chloro-6-[2-(5-diethylphosphono)furanyl]pyridine (0.01 rnol) and I1-methylpiperazine (0.2 rnL) in ethylene glycol (0.2 mL) was heated at 145*C for 24 h.

The mixture was further diluted with 0.5 mL of CH 3 CN and 0. 1 mL of water and then. 150 mg of Dowex 1 2 100 formate resin was added. After stirring this mixture 3 0 min it was filtered and the resin washed with DMIF (2x10 mL), CH 3 CN (2x10 mL) and then 9:1 CH 3 CN:water (Wx 1 mL). Finally the resin was stirred with 9:1 TFA:water for 30 min, filtered and the filtrate evaporated. The residue obtained subjected to Step B of Example 26 to give methyl)piperazinyl]-6-[2-(5-phosphono)furanyl]pyridine.

Step E. A mixture of 3-chloro-5.{2-(5-diethylphosphono)furanyl]pyrazine (0.01 mmole), 5-tributyistannylthiophene (0.04 mmole), Pd(PPh 3 4 (0.001 mmole) and Cu! (0.002 mmole) in dioxane (0.5 mL) was heated at 85'C for 16 h then the solvent was evaporated.

The resulting residue and TMSBr (0.1i mL) in 0. 5 mL CH 2 C1 2 was stirred at rt for 16 h and then evaporated and diluted with 0.5 mL of 9:1 CH 3 CN:water. To this solution 150 mg of Dowex 1 2-100 formate resin was added and after stirring 30 min it was filtered and the resin washed with DMF (2x10 mL), CH 3 CN (2x10 mL) and then 9:1 CH 3 CN:water (lx10 mL).

Finally the resin was stirred with 9:1 TFA:water for 30 min, filtered and the filtrate evaporated to give 3-(2-thienyl)-5-[2-(5-phosphono)furanyl]pyrazine.

Step F. A mixture of 3-chloro-5-[2-(5-diethylphosphono)furanyl]pyrazine (0.01 mmole), 1-hexyne (0.04 mmole), diisopropylethylamine (0.1 mmole), Pd(PPh 3 4 (0.001 mmole) and Cul (0.002 mmole) in dioxane (0.5 mL) was heated at 85 0 C for 16 h then the solvent was evaporated. The resulting residue was subjected to Step B of Example 26 to give 3-(1-hexyn-1-yl)-5-[2-(5-phosphono)furanyl]pyrazine.

Preparation of the Carboxvmethylphosphonate Resin Step G, A solution of trimethylphosphonoacetate (30.9 mmnol), 2-(trimethylsiyl) ethanol (10.4 mmol) and DMAP (3.1 mmol) in toluene (25 mL) was refluxed for 48 h under

N

2 After cooling, the solution was diluted with EtOAc and washed with IN HC1 followed by water. The organic solution was dried over sodium sulfate and concentrated under vacuum to give an oil. The residue was treated with Lil (10.4 mmol) in 2-butanone (30 mL), and refluxed overnight under N 2 The solution was diluted with EtOAc, washed with IN HCI, dried over Na 2

SO

4 and concentrated under vacuum to afford the SEM protected carboxy monomethylphosphonate as a colorless oil.

Step H. Hydroxymethylpolystyrene (2.35 mmol) was prepared for coupling by combining with anhydrous THF (40 mL), gently shaking for 20 min. and then removing the excess solvent by cannula. This procedure was repeated 3 times. The swollen resin was then suspended in THF (40 mL) and DIPEA (21.2 mmol). To this mixture was added, by cannula, a solution of the SEM protected carboxy monomethylphosphonate (prepared in Step G) (7.1 mmol), DIAD (7.1 mmol) and tris(4-chlorophenyl)phosphine (7.1 mmol) in THF (15 mL) which had been stirred for 15 min. prior to addition. After shaking the mixture overnight under a blanket of N 2 the resin was filtered, rinsed with THF 3x 40 mL), DMF (3 x 40 mL), and THF again (3 x 40 mL) before drying under vacuum to afford 3.8 g of the coupled phosphonate resin.

Step I. To coupled phosphonate resin (2.41 mnuol) in THF (100 mL) was added IM TBAF in THF solution (12 mL). The mixture was shaken overnight before being filtered and the resin rinsed with THF (3 x 40 mL) to afford the desired carboxymethylphosphonate resin as the tetrabutylammonium salt.

Coupling of the carboxymethylphosphonate resin to a heteroaromatic amine Step J. In a 2 mL well, a heteroaromatic amine (0.14 mmol), resin (0.014 mmol), PyBOP (0.14 mmol) and TEA (0.36 mmol) in DMF (1.45 mL) were combined and shaken for 48 h at room temperature. The treated resin was then filtered, washed with DMF (3x) and

CH

2 C1 2 The isolated resin was resuspended in CH 2 2Cl (900 combined with TMSBr (100 g.L) and mixed for 6 h. The mixture was filtered, the resin washed with anhydrous

CH

2 C1 2 (500 piL) and the filtrate concentrated under vacuum. To the isolated residue was added a solution of CH 3

CN/H

2 0 300 gL). After shaking for 30 min. the solvents were removed to provide the desired [{N-(phosphono)acetyl]amino} substituted heteroaromatic analogs. Compounds 26.97 26,119 and 26.146 26.164 were synthesized according to these procedures and they are listed in Table 26.1 and Table 26.2.

Preparation of the Aminomethylphosphonate Resin Step K. To a solution of dimethyl phthalimidomethylphosphonate (37 mmole) in 2butanone (150 mL) was added Lil (38.9 mmol). After refluxing overnight under N 2 the solution was diluted with EtOAc, washed with IN HCI, dried over MgSO 4 and concentrated under vacuum to afford monomethyl phthalimidomethylphosphonate as a white solid.

Step L. As described above in Step H, monomethyl phthalimidomethyl-phosphonate was coupled to hydroxymethylpolystyrene to give the resin-coupled phthalimidomethylphosphonate monomethyl ester.

Step M. To the resin-coupled phthalimidomethylphosphonate monomethyl ester (6.8 mmol) in DMF (7 mL) was added anhydrous hydrazine (3 mL). After shaking at room temperature for 24 h the resin was filtered, rinsed with DMF (3 x 10 mL), CH 2 Cl 2 (3 x 10 mL) and then dried under vacuum to afford 832 mg the desired resin-coupled aminomethylphosphonate monomethyl ester.

Coupling of various heteroaromatic carboxylic acids to the resin-coupled aminomethylphosphonate monomethyl ester.

Step N. In a 2 mL well, a heteroaromatic carboxylic acid (0.2 mmol), resin (0.02 mmol), EDC (0.2 mmol) and HOBT (0.2 mmol) in DMF (0.5 mL) were combined and shaken for 24 h at room temperature. The treated resin was then filtered, washed with DMF (3x) and

CH

2 Cl 2 The isolated resin was resuspended in CH 2

CI

2 (500 ptL), combined with TMSBr piL) and mixed for 6 h. The mixture was filtered, the resin washed with anhydrous

CH

2

CI

2 (500 pL) and the filtrate concentrated under vacuum. To the isolated residue was added a solution of CH 3

CN/H

2 0 300 pL). After shaking for 30 min the solvents were evaporated to provide the desired (N-phosphonomethyl)carbamoyl substituted heteroaromatic analogs. Compounds 26.120 26.145 were synthesized according to these procedures and they are listed in Table 26.2.

The following compounds were prepared according to some or all of the above described procedures. These compounds were characterized by HPLC (as described below) and mass spectroscopy (APCI negative ion), and these characterization data are listed in Table 26.1 and Table 26.2.

HPLC was performed using a YMC ODS-Aq, Aq-303-5, 250 4.6 mm ID, S-5 pm, 120 A column with the UV detector set at 280 rm.

HPLC Ehution Program: 1.5 mlimin flow rate Time (min) Acetonitrile Buffered' (B) 12.4 12.5 a Buffer 95:5:0.1 water:methanol:acetic acid TABLE 26.1 i~C >-X-P(OH)2 synthetic A B X Y9 HPLC M-1 example Rt found number (min.) 26.146 H Br NHC(O)CH 2 S 6.58 299/301 26.147 H Ph NHC(O)CH 2 S 6.57 297 26.148 Ph H1 NHC(O)CH 2 S 6.06 297 26.149 Ph Et NHC(O)CH 2 0 309 26.150 H H NHC(O)CH 2 S 4.22 221 26.151 adaman- Me NHC(O)CH 2 S 6.59 369 26.152 Bu-t Br NHG(0 CH 2 S 6.62 355/357 26.153 H Ph(-4-B) NHC(O)CH 2 S 6.62 375/377 yi N 0 I>X-P(OH)2 synthetic A* B*X Y7 HPLC M-1 example Rt found number _(min.) 26.154 H H NHC(O)CH 2 0 6.68 205 26.155 null NH 2 NHC O)CH 2 0 6.6 221 26.156 NH~ve null NHC(O)CH 2 S 3.82 251 26.157 Me H NHC(O)CH 2

NH

26.158 H H NHC(O)CH 2

NH

26.159 OH H NHC(0)CH 2

NH

26.160 Bu-t H NHC(0)CH 2 0 6.62 261 26.161 null 3-pyridyl NHC(O)CH 2 0 6.58 283 26.162 CH 2 null NHC(O)CH 2 0 Ph-(2,6- 26.163 Br null furan-2,5-diyl NH 4.46 292/294 26.164 Br null furan-2,5-diyl S 5.96 309/311 *when A or B is null, then the corresponding G is N.

IND

;Z

TABLE 26.2 E IG G B synthetic A* B*X DE* HLPLC M-1 example Rt found number 26.1 NHl 2 Cl furan-2,5-diy1 Me null 11.06 288 26.2 H OC(O)(Ph furan-2,5-diyl H H 3.99 413 -2,6dichloro)_____ 26.3 OMe H furan-2,5-diyl CH 2 0H H 8.34 284 26.4 OMe H fiiran-2,5-diyl C(O)NH 2 H 8.23 297 26.5 OMe H furan-2,5-diyl C0 2 H H 9.54 298 26.6 .OH H furan-2,5-diyl CF 3 C(O)N11 2 3.91 351 26.7 OMe H furan-2,5-diyl CF 3

C(O)NTH

2 9.14 365 26.8 null H furan-2,5-diyl H OMe 9.72 255 26.9 null H furan-2,5-diyi H OH 4.52 241 26.10 OH H furan-2,5-diyl Me null 3.79 255 26.11 OMe H furan-2,5-diyl Me null 6.44 269 26.12 NH null furan-2,5-diyl OH H 3.96 256 26.13 NI- 2 null furan-2,5-diyl OMe H 8.02 270 26.14 H OMe furan-2,5-diyl null H 7.22 255 26.15 H OH furan-2,5-diyl null H 4.82 241 26.16 OMe H furan-2,5-diyl_ null H 7.48 255 26.17 OEt H furan-2,5-diyl H H 9.72 268 26.18 OEt H furan-2,5-diyl CH 2 0H H 5.26 298 26.19 null H furan-2,5-diyl Me OEt 7.80 283 26.20 null H furan-2,5-ciy] Me -OH 3.80 255 26.21 OH H furan-2,5-diyl Me null 3.77 255 26.22 OEt H furan-2,5-diyl Me null 7.33 283 26.23 NHl 2 null furan-2,5-diyl OH H 3.94 256 26.24 NHl 2 null furan-2,5-diyl QEt H 5.66 284 26.25 NH 2 H furan-2,5-diyi OEt null 5.90 284 26.26 NH 2 H furan-2,5-diyl OH null 3.78 256 26.27 H OEt furan-2,5-diyl null H 9.74 269 26.28 H OH ftiran-2,5-diyl null H 4.81 241 26.29 OEt H furan-2,54dIy null -H 9.78 269 synthetic A* B* X D* E* HPLC M-1 example Rt found number (min.) 26.30 Br H furan-2,5-diyl H NO 2 7.78 347/349 26.31 Cl H furan-2,5-diyl H C(O)OEt 9.69 330 26.32 Br H furan-2,5-diyl H C(O)OEt 9.69 374/376 26.33 Cl H furan-2,5-diyl Me C(O)NH 2 3.72 315 26.34 Cl CF 3 furan-2,5-diyl H CF 3 9.04 394 26.35 Cl H furan-2,5-diyl NH 2 H 4.89 273 26.36 Cl H furan-2,5-diyl CN H 7.93 283 26.37 Cl H furan-2,5-diyl CH 2 0H H 5.38 288 26:38 Cl H furan-2,5-diyl C(O)NH 2 H 5.57 301 26.39 Cl H furan-2,5-diyl C(O)OEt H 8.54 330 26.40 Cl I- furan-2,5-diyl H H 8.91 398 triazinyl- (3-aminothio) 26.41 Cl H furan-2,5-diyl Me CN 8.22 297 26.42 Cl H furan-2,5-diyl CF 3

NH

2 8.60 341 26.43 C1 H furan-2,5-diyl CF 3 CN 8.66 351 26.44 null CH 3 furan-2,5-diyl Me Br 9.25 331/333 26.45 null CH 3 furan-2,5-diyl Me Cl 9.25 287 26.46 Br CH 3 furan-2,5-diyl H null 5.62 317/319 26.47 Br Br furan-2,5-diyl H null 3.54 381/383/ 385 26.48 Br H furan-2,5-diyl Me null 5.55 317/319 26.49 H NH 2 furan-2,5-diyl Br null 4.78 318 320 26.50 Br Cl furan-2,5-diyl Br null 8.38 417/419 26.51 SMe Ph furan-2,5-diyl Br null 9.26 425 427 26.52 NH 2 H furan-2,5-diyl Br null 4.87 318 320 26.53 NH 2 H furan-2,5-diyl OH null 3.70 256 26.54 Br H furan-2,5-diyl Br null 9.64 381/383/ 385 26.55 Br H furan-2,5-diyl Cl null 9.64 337/339 26.56 H Br furan-2,5-diyl null H 5.08 303 305 26.57 NH 2 Cl furan-2,5-diyl null C(O)OMe 3.34 332 26.58 OPr-n H furan-2,5-diyl Me null 8.14 297 26.59 H OPr-n furan-2,5-diyl null H 8.45 283 26.60 H O(CHz) 2 furan-2,5-diyl null H 7.82 313 OEt synthetic A* B* X D* E* HPLC M-1 example Rt found number (min.) 26.61 NH 2 null furan-2,5-diyl OH H 3.97 256 26.62 NH 2 null furan-2,5-diyl OPr-n H 7.84 298 26.63 OPr-n H furan-2,5-diyl CH 2 0H H 4.36 312 26.64 OBu-n H furan-2,5-diyl CH 2 0H H 8.58 326 26.65 0- H furan-2,5-diyl CH 2 0H H 4.13 342

(CH

2 2 -OEt 26.66 NH 2 H furan-2,5-diyl OPr-n null 7.96 298 26.67 NH2 H ftran-2,5-diyl OBu-n null 3.86 312 26.68 H OBu-i furan-2,5-diyl null H 8.80 297 26.69 H O(CH 2 2 furan-2,5-diyl null H 7.14 299 OEt 26.70 H O(CH 2 2 furan-2,5-diyl null H 4.57 312 NMe 2 26.71 NH 2 null furan-2,5-diyl OBu-i H 8.06 312 26.72 NH 2 null furan-2,5-diyl O(CHZ) 2 H 4.84 314 OMe 26.73 NH 2 H furan-2,5-diyl OBu-i null 8.70 312 26.74 Br H furan-2,5-diyl C(O)NH 2 H 7.68 346/348 26.75 NH 2 null furan-2,5-diyl Cl H 4.77 274 26.76 NH- H furan-2,5-diyl Me null 4.56 298

(CH

2 2

-OH

26.77 H NH(CH 2 2 furan-2,5-diyl null H 4.55 284

OH

26.78 NH 2 null furan-2,5-diyl NH- H 4.58 299

(CH)

2 0H 26.79 NH- H furan-2,5-diyl NH 2 null 4.58 299

(CH

2 2

-OH

26.80 NH- H faran-2,5-diyl CH 2 0H H 4.44 313

(CH

2 2

-OH

26.81 NH 2 H furan-2,5-diyl NH- null 4.33 299 (CH2) 2 0H

IND

;Z

synthetic A* B* X D* E* HPLC M-1 example Rt found number (min.) 26.82 NH- H furan-2,5-diyl CH null 4.65 312

CH-

(OH)-

Me 26.83 NH 2 null furan-2,5-diyl NHCH 2 H 4.63 313

CH(OH)-

Me 26.84 NH- H furan-2,5-diyl NH 2 null 4.63 313

CH

2

CH-

(OH)-

Me 26.85 NH- H furan-2,5-diyl CH 2 0H H 4.52 327

CH

2

CH-

(OH)-

Me 26.86 NH 2 H furan-2,5-diyl NHCH 2 null 4.65 313

CH(OH)-

Me 26.87 NH- H furan-2,5-diyl Me null 4.62 312

(CH

2 3

-OH

26.88 NH 2 null furan-2,5-diyl NH- H 4.48 313

(CH

2 3 0H 26.89 NH- H furan-2,5-diyl NH 2 null 4.48 313

(CH

2 3

-OH

26.90 NH 2 NH- furan-2,5-diyl null C(O)NH- 4.76 414

(CH

2 3 0H

(CH

2 26.91 H 4- furan-2,5-diyl null H 6.46 310 morpholinyl 26.92 4- H furan-2,5-diyl Me null 6.53 324 morph -olinyl 26.93 NH 2 null furan-2,5-diyl 4-morph- H 6.15 325 olinyl synthetic A* B* X D* E* HPLC M-1 example Rt found number (min.) 26.94 4- H furan-2,5-diyl NH 2 null 4.84 325 morph -olinyl 26.95 NH 2 4-morpho furan-2,5-diyl null 7.47 438 -linyl morpholinyl) 26.96 NH 2 H furan-2,5-diyl 4-morph- null 5.30 325 olinyl 26.97 Me H NHC(O)CH 2 H H 6.58 229 26.98 H Me NHC(O)CH 2 H H 6.60 229 26.99 NH 2 H NHC(O)CH 2 H Cl 6.63 264 26.100 NH 2 Cl NHC(O)CH 2 H H 6.63 264 26.101 H OH NHC(O)CH2 H H 6.54 231 26.102 Me H NHC(O)CH 2 Me H 6.59 243 26.103 H H NHC(O)CH 2 H Cl 7.02 249 26.104 H H NHC(O)CH 2 H Br 8.01 293/295 26.105 Me H NHC(O)CH 2 H Br 6.64 307/309 26.106 H H NHC(O)CH 2 H H 6.72 215 26.107 H H NHC(O)CH 2 H Me 6.54 229 26.108 H H NHC(O)CH 2 Me H 6.53 229 26.109 Me Cl NHC(O)CH 2 Me null 3.93 279 26.110 Cl H NHC(O)CH 2 null H 4.20 251 26.111 H Br NHC(O)CH 2 H Me 6.44 307/309 26.112 NH 2 H NHC(O)CH 2 NH-(Ph- null 4.42 401/403 ~4-Br) 26.113 NH 2 Bn NHC(O)CH 2 H Bn 6.49 410 26.114 H H NHC(O)CH 2 Et H 6.57 243 26.115 Me Et NHC(O)CH2 H H 6.54 257 26.116 Me H NHC(O)CH 2 H Br 6.55 307/309 26.117 H Br NHC(O)CH 2 H Me 6.51 307/309 26.118 H Me NHC(O)CH 2 H Br 6.52 307/309 26.119 Me Br NHC(O)CH 2 H Br 6.19 385/387/ 389 26.120 H H C(O)NHCH 2 H H 3.74 215 26.121 Me H C(O)NHCH 2 H H 229 26.122 OH H C(O)NHCH 2 H H 3.72 231 26.123 Br H C(O)NHCH 2 H H 5.02 293/295 26.124 Cl H C(O)NHCH 2 H H 4.60 249/251 synthetic A* B*X D* IPLC NI-1 example Rt found number (min.) 26.125 H H C(O)NHiCH 2 Cl H 5.18 2491251 26.126 H Br C(O)NHCH 2 OH H 3.60 310/312 26.127 H H C(O)NHCH 2 null H 3.70 216 26.128 H H C(O)NHCH 2

NO

2 H 5.00 260 26.129 H H C(O)N}ICH 2 H Bu-n 8.35 271 26.130 H- OPr-n C(O)NHCH 2 HH 7.46 273 26.131 C1 Cl C(O)NHCH 2 H H 4.23 283/285/ 287 26.132 Cl CF 3

C(O)NHCH

2 HI H 8.05 317/319 26.133 H Cl C(O)NHCH 2 H CF 3 6.49 3171319 26.134 H Cl C(O)NHCH 2 C1 Cl 7.20 318/320/ 1 322 26.135 H C(O)Ph C(O)NIICH 2 H H 7.00 319 26.136 H OEt C(O)NHCH 2

HCF

3 6.65 327 26.137 SMe Cl C(O)NIICH 2 Hnull 5.82 296/298 26.138 SMe Br C(0 NHCH 2 Hnull 5.40 340/342 26.139 H O(Ph-3- C(O)NHCH 2 nul H 376

CF

3 26,140 H H C(O)NFICH 2 null Me 3.75 230 26.141 H Me C(O)NHCH 2 H H 4.96 229 26.142 Cl Cl C(O)NHCH 2 Cl Cl 9.18 351/353/ 26. 143 H F C(O)NI-ICH 2 OH null 250 26.144 Me F C(O)NIICH 2 OH null 264 26.145 OH F C(O)NI{CH 2 OH null 3.93 266 *When A, B, D or E is null, then the corresponding G' is N.

Section 2.

Synthesis of.Compounds of Formula X Example 27.

Preparation of 2-a min o4-phosphon omethyloxy-6-b romobenzothiazole.

Step A. A solution of AIC1 3 (5 mmole) in EtSH (10 mL) was cooled to 0 0 C and treated with 2-amino-4-methoxybenzothiazole (I mmole). The mixture was stirred at 0-5 0 C for 2 h.

r~l Evaporation and extraction gave 2-amino-4-hydroxybenzothiazole as white solid.

Step B. A mixture of 2-amnino-4-hydroxybenzothi azole (1 mmole) and NaH (1.3 rnmole) in DMF (5 mL) was stirred at 0 0 C for 10 min, and then treated with diethyiphosphonornethyl trifluoromethylsulfonate (1.2 mmole). After being stirred at room temperature for 8 ha, the reaction was subjected to extraction and chromatography to give 2amino-4-diethylphosphonomethyloxybenzothiazole as an oil.

Step C. A solution of 2-ainino-4-(diethylphosph~onomethyloxy)benzothiazole (1 mrnole) in AcOH (6 m.L) was cooled to I10 0 C and treated with bromine (1.5 mmole) in AcOH (2 After 5 rain the mixture was stirred at room temperature for 2.5 h. The yellow precipitate was collected via filtration and washed with CH 2 Cl 2 to give 2-amino-4diethylphosphonomcthyloxy-6-bromobenzothiazole.

Step D. A solution of 2-amno-4-diethylphosphonomethyloxy-6-bromobenzothiazole (I mmole) in CH 2

CI

2 (4 m.L) was treated with TMSBr (10 inmole) at 0 0 C. After stirred for 8 Ia at room temperature the reaction was evaporated to dryness and the residue was taken into water (5 rnL). The resulting precipitate was collected via filtration and washed with water to give 2-anaino-4-phosphonomethyloxy-6-bromobenzothiazole (27.1) as white solid. mp >220'C Anal. calcd. for C8HsN 2

O

4 PSBr: C:28.34; H:2.38; N:8.26. Found: C:28.32; H:2.24; N:8.06.

Similarly, the following compounds were prepared according to the above described procedures: (27.2) 2-Amino-4-phosphononaethyloxybenzothidozole. mp 250'C. Anal. calcd. for CaH 9

N

2

O

4 PS 0.4 H 2 0: C:35.93; H:3.69; N: 10.48. Found: C:35.90; H{:3.37; N:1 0.37.

Example 28.

Preparation of 2-arnin o4-phosphonomethyloxy-6-b romo-7-chlo rob enzothiazole.

Step A. A solution of 1-(2-methoxy-5-chlorophenyl)-2-thiourea (1 mmole) in chloroform (10 mL) was cooled to I0 0 C and treated with bromine (2.2 mnmole) in chloroform mL). The reaction was stirred at 10 0 C for 20 min and at room temperature for 0.5 h. The resulting suspension was heated at reflux for 0.5 h. The precipitate was collected via filtration (washed with CH 2 Cl 2 to give 2-amino-4-methoxy-7-chlorobenzothiazole which was subjected to Steps A, B, C and D of Example 27 to give 2-amino-4-phosphonomethoxy-6bromo-7-cliloro benzothiazole mnp 220'C(dec.). Anal. calcd. for C8H 7

N

2 O4PSClBr: C:25.72; H: 1.89; N:7.50, Found: C:25.66; H:l1.67; N:7.23.

Similarly, the following compounds were prepared according to the above described procedures: (28.2) 2-Amino-4-phosphonornethoxy-6-bromo-7-methy benzothiazole. nip 220'C (dec.).

Anal. calcd. for CgH 10

N

2

O

4 PSBr: C:30.61; H:2.85; N:7.93 Found: 030.25; H:2.5; 1N:7.77.

(28.3) 2-Amino-4-phosphonomethoxy-7-methylbenzothiazole. mp 220*C Anal: calcd. for C 9

H

11

N

2 0 4 PS+1.0 H 2 0: C:36.99; H:4.48; N:9.59. Found: C:36.73; H:423; N:9.38.

(28.4) 2-Amino-4-phosphonomethoxy-7-chlorobenzothiazole. nip 220'C(dec.). Anal.

calcd. for C&14 8

N

2

O

4 PSCI 0.1IH20: C:32.41; H:2.79; N:9.45. Found: C:32.2 1; H:2.74; N:9.22.

Example 29.

Preparation of 2-Amino-4-phosplionomethox'v-5,6,7,8-tetrahydroriaphtho1 .2-di thiazole.

Step A. 3-Amino-2-hydroxy-5,6,7,8-tetrahydronaphthalene was subjected to Step B of Example 27 to give 3-amino-2-diethylphosphonometlhyloxy-5,6,7,8-tetrahydronaphthlenie.

Step B. A solution of KSCN (16 mmole) and CUS0 4 (7.7 inmole) inMeOH (10 mL) was treated with a solution of 3-amino-2-diethylphosphonoinethyloxy-S ,6,7,8tetrahydronaphthalene (1 mmole) in MeQH (5 mL) at room temperature. The mixture was heated at reflux for 2 h. Filtration, extraction and chromatography provided 2-amino-4- ,6,7,8-tetrahydronaphtho[ 1,2-djthiazole as light brown solid.

Step C. 2-Amino-4-diethylphosphonomethyloxy-5,6,7, 8-tetrahydronaplitho[1 ,2d]thiazole was subjected to Step D of Example 27 to give 2-An-ino-4-phosphonornethoxy- 5,6,7,8-tetrahydronaphtho[l,2-d]tbiazole mp 220'C Anal. calcd. for

C

12

HI

5

N

2 0 4 PS 0.5 H 2 0: C:45.86; H:4.81; N:8.91 Found: C:44.68; 1-1:.77; N:8.73.

The following compounds were also prepared according to above procedures: (29.2) 2-Amino-4-phosphonomethoxy-[1,2-d]naphthothi azole mp 240*C(dec.). Anal.

calcd. for C 12 Hi N 2 0 4 PS 0.2HBr; C:44.15; H:3.46; N:8.58. Found: C:44.13; H:3.46; N:8.59.

(29.3) 2-Arnino-5,7-dimethyl-6-thiocyanato-4-phosphonomethoxybelzothiazole.

mp> 240'C(dec.). Anal. calcd. for CIIH 12

N

3

O

4

PS

2 0.2CH 2 C1 2 C:37.13; H:3.45; N:11.60.

Found: C:37.03; H:3.25; N: 11.65.

(29.4) Starting with 2-hydroxy-5-phenyl aniline and using the same reaction sequence as above gave 2-Amino-7-phenyl-6-thiocyanato-4-phosphonomethoxybenzothiazole.

mp. 250'C(dec.). Anal. calcd. for C 15

H

12

N

3 0 4

PS

2

O.H

2 0: C: 45.38; H: 3.15; N: 10.58.

Found: C: 45.25; H: 3.21; N: 10.53.

(29.5) Starting with 2-hydroxy-3,5-dichloro-4-methyl aniline and using the same reaction sequence as above (except the cyclization step was done using B- 2 AcOH method i.e. Step A of Example 33) gave 2-Axnino-5 ,7-dichloro-6-methyl-4-phosphonomethoxybezotlazole mp. 230'C(dec.). Anal. calcd. for C9H 9

N

2

O

4 PSC1 2 C: 31.50; H: 2.64; N: 8.16. Found: C: 31.61; 2.66; N: 8.08.

(29.6) Starting with 2-hydroxy-4-methoxycarbonyl aniline and using the same reaction sequence as above gave 2-Amino-4-phosphonometboxy-6-carboxybenzothiazole.

mp. 230'C(dec.). Anal. calcd. for C 9

H

9

N

2 04'S: C: 35.53; H: 2.98; N: 9.21. Found: C: 35.56; H: 3.26; N: 9.03.

Example Prepairation of 2-Amino-7-methoxy-6-thiocyanato-4-phosphonomethoxv-benzothiazole.

Step A. 2-Hydroxy-5-methoxynitrobenzene was subjected to Step B of Example 27 to give Step B. A solution of SnCl 2 (4 rnmole) in freshly prepared methonolic HCI (10 raL) was added to a cold (0 0 C) solution of (I mmole) in MeOH (5 rnL). The mixture was warmed to room temperature and stirred for 3 h. Evaporation, extraction and chromatography provided methoxyaniline.

Step C. 2-Diethylphosphonomethyloxy-5-methoxyaniline was subjected to Step B of Example 29 to give 2-amino-4- diethylphosphonomethyloxy-6-tbiocyano-7naethoxybenzothiazole, which was subjected to Step D of Example 27 to give 2-amino-7methoxy-6-thiocyanato-4-phosphonometlioxybenzothiazole mp 170'C(dec.).

Anal.calcd. for C~oH 10

N

3 0 5

PS

2 C:34.58; H:2.90; N:12.10. Found: C:34.23; H:2.68; N:1 1.77.

Similarly, the following compounds were prepared according to above procedures: (30.2) 2-Amino-5,6-difluoro-4-phosphonomethoxybenzothiazole. mp 240'C(dec.). Anal.

calcd. for CgH 7

N

2 0 4

PSF

2 0:32.44; H:2.38; N:9.46. Found: C:32.30; H:2.26; N:9.17.

(30.3) 2-Amino-5-fluoro-7-bromo-4-phosphonomethoxybenzothiazole. mp 1 Anal. calcd. for C 8

H

7

N

2

O

4 PSBrF: C:26,91; H:1.98; N:7.84. Found: C:27.25; H:1.92; N:7.54.

(30.4) 2-Arnino-7-ethoxycarbonyl-4-phosphonomethoxybenzothiazole. mp 240'C(dec.).

Anal. calcd. for CI 1

H

13

N

2 0 6 PS 0.2HBr 0.IDMF: C:38.15; H:3.94; N:8.27. Fou-nd: C: 38.51; H: 3.57; N: 8.66.

Example 31.

Preparation of 2-Amino-7-bromo-6-thiocyanato-4-phosphonomethoxy benzothiazole.

Step A. A solution of 2-fluoro-5-bromonitrobenzene (1 mmole) in DMF (5 mL) was cooled to 0 0 C, and treated with a solution of freshly prepared sodium salt of diethylhydroxymethylphosphonate (1.2 inmole) in DMF (5 mL). The mixture was stirred at room, temperature for 16 h. Evaporation, extraction and chromatography provided 2- Step B. 2-Diethylphosphonomethyloxy-5-bromonitrobenzene was subjected to Step B of Example 30, Step B of Example 29, and Step D of Example 27 to give 2-arnino-7-bromo- 6-thiocyanato-4-phosphonomethoxybenzothiazole mp 250*C(dec.). Anal. calcd. for

C

9

H

7

N

3 0 4

PS

2 Br: C:27.29; HA.78; N:10.61. Found: C:26.90; H:1.58; N:10.54.

Similarly, the following compounds were prepared according to above procedures: (31.2) 2-Amino-7-fluoro-6-thiocyanato-4-phosphonomethoxybezothiazole. nip >1 36 0 C(dec.). Anal. calcd. for C 9

H

7

N

3

O

4

PFS

2 0.3HBr: C:30.07; H:2.05; N: 11.69. Found: C:30.27; H:2.O1;N: 11:38.

(31.3) Starting with 2-fluoro-4-chloro nitrobenzene and using the same reaction sequence as above gave 2-Amino-6-chloro-4-phosphonomethoxybenzothiazole. mp. 250*C(dec.). Anal.

calod. for CgH 8

N

2

O

4 PSCI: C: 32.61; H: 2.74; N: 9.5L. Found: C: 32.27; H: 2.67;- N: 9.18.

(31.4) Starting with 2-fluoro-4,5-dichloro nitrobenzene and using the same reaction sequence as above gave 2-Anaino-6,7-dichloro-4-phosphonomethoxybenzothiazole. mp. 250'C(dec.).

Anal. calcd. for C 8

H

7

N

2 0 4 PSC1 2 C: 29.20; H: 2.14; N: 8.51. Found: C: 29.11; H: 2.11; N: 8.36.

Example 32.

Preparatiou of 2-Amino-7-hydroxymethyl-6-thiocyano-4-phosphonomethoxy benzothiazole.

Step A. 2-Chloro-5-formylnitrobenzene 'was subjected to Step A of Example 31 to give Step B. A solution of 2-diethylphosphonomethyloxy-5-formylnitrobeizene (I mmole) in methanol (5 mL) was treated with 10% palladium on carbon (0.05 mmole) under I atmosphere of hydrogen at room temperature for 12 hi. Filtration followed by evaporation gave 2-diethylphosphonomethyloxy-5-hydroxymethylaniline which was subjected to Step B of Example 29 followed by Step D of Example 27 to give 2-amino-7-hydroxymethyl-6thiocyanato-4-phosphonomethoxybenzothiazole mp 181-184'C. Anal. calcd. for

C

10

H

10

N

3 0 5

PS

2 0.35 H 2 0: C:33.97; 11:3.05; N:l 1.88. Found: C:33.76; 11:2.66; N:l 1.61.

A similar procedure was used to prepare the following compounds: (32.2) Starting with 2-fluoro-4-methyl nitrobenzene and using the same reaction sequence as above gave 2-Amino-6-methyl-4-phosphonomethoxybenzotlhiazole. mp. 250*C(dec.). Anal.

calcd. for C 9

H,

1

N

2

O

4 PS 0.2 CH 2 Cl 2 C: 37.94; H: 3.95; N: 9.62. Found: C: 38.16; H: 4.18; N: 9.39.

(32.3) Starting with 2-chloro-5-cyano nitrobenzene and using the same reaction sequence as above gave 2-Amino-7-cyano-4-phosphonomethoxybenzothiazole. mp. 250'C(dec.). Anal.

calcd. for C 9

H

8

N

3 0 4 PS+ 0.9 H 2 0: C: 35.86; H: 3.28; N: 13.94. Found: C: 35.07;'H: 2.88; N: 13.58.

Example 33.

Preparation of 2-Amino-6-bromo-7-fluoro-4-ohosphonomethoxvbenzotiazole.

Step A. A solution of 2-diethylphosphonornethyloxy-4-bromo-5-fluoroaniline (1 mniole, prepared as in Example 4, Step B) and KSCN (2 mrnole) in AcOH (8 mL) was cooled to 10TC, and treated with a solution of bromine (2 mnmole) in AcOH (5 rnL). After being 164 stirred at room temperature for 0.5 h, the reaction mixture was evaporated to dryness and the residue was purified by chromatography to provide 2-an-iino-7-fluorol-6-bromo-.4diethylphosphonomethyoxybenzothiazole which was subjected to Step D of Example 27 to give 2-aniino-6-broxno-7-fluoro-4-phosphonomethoxybenzothiazole Anal. calcd. for C8H 7

N

2

O

4 PSBrF +O.1HBr: 0:26.31,11:1.96; N:7.67. Found: 0:25.96;1 1:1.94; N:7.37.

Example 34.

Preparation of 2-Amino-7-ethyl-6-thiocyano-4-phosphonomethoxybenzothiazole.

Step A. A solution of 2-diethylphosphonomethyloxy-5-bromonitrobenzene (I mmole, prepared as in Example 3 1, Step A from 2-fluoro-5-bromonitrobenzene) in DMF (5 mL) was treated with tributyl(vinyl)tin (1.2 mmole) and palladium bis(triphenylphosphine) dichloride 1 mmole), and the mixture was heated at 60'C under nitrogen for 6 h. Evaporation and chromatography gave 2-diethylphosphonomethyloxy-5-vinylnlitrobenzene as an oil which was subjected to Step B of Example 31, Step B of Example 29, and Step D of Example 27 to give 2-amnino-7-ethyl-6-thiocyano-4-phosphonomethoxybenzothiazole mp> I 67 0 C(dec.).

Anal. catcd. for C 11

H

12

N

3 0 4

PS

2 C:38.26; H:3.50; N:12.17. Found: C:37.87; H:3.47; NAl1.93.

A similar procedure was used to prepare the following compounds: (34.2) 2-Amino-7-propyl-6-thiocyanato-4-phosphonomethoxybenzothiazole.

mp. 250'C(dec.). Anal. calcd. for C 1 2

H

1 4

N

3 0 4

PS

2 C: 40.11; H: 3.93; N: 11.69. Found: C: 39.72; H: 3.82; N: 11.50. Using allyl tributyltin.

(34.3) 2-Arnino-7-(2-fiuryl)-6-th-iocyanato-4-phosphonomethoxybenzothiiazole. Anal. calcd.

for C 1 4R 11

N

3 OsBrPS 2 0.6 MeQE: C: 33.79; H: 2.79; N: 8.69. Found: C: 34.10; H: 2.83; N: 8.35. Using 2-furanyl tributyltin.

(34.4) 2-Amino-6-thiocyanato-7-(2-thienyl)-4-phosphonomethoxybenzothiazole.

mp. 250*C(dec.). Anal. calcd. for C 1 3

HI

0

N

3 0 4

PS

3 C: 39.09; H: 2.52; N: 10.52. Found: C: 38.91; H: 2.41; N: 10.34. Using 2-thienyl tributyltin.

(34.5) 2,5-Difluoro-4-bromo nitrobeuzene was treated the same wvay to give 2-Amnino-6ethyl-7-fluoro-4-phosphonomethoxybenzotiazole. mp. 250'C(dec.). Anal. calcd. for Cl 0

H

12

N

2 0 4 PSF: C: 39.22; H: 3.95; N: 9.15. Found: C: 38.83; H: 3.55; N: 9.02.

(34.6) 2,5-Difluoro-4-bromo nitroberizene was treated with 2-thienyl tributyltin in the second step to give 2-Axnino-7-fluoro-6-[2-(5-thi ocyanato)thienyl]-4phosphonomethoxybeazothiazole. mp. 250'C(dec.). Anal. calcd. for C 13

H

9

N

3 0 4

PS

3 F+ 0.6

H

2 0: C: 3 6.46; H: 2.40; N: 9.8 1. Found: C: 3 6.16; H: 2.10; N: 9.6 8.

Example Preparation of 2-Amnino-7-cvclop ro pyl-6-th iocyan ato-4-phosp ton omethoxy beuzotbiazole.

Step A. A suspension of 2-diethylphosphoniomethyloxy-5-vinylnitrobenzene (1 mmole, prepared as in Step A of Example 33) and Pd(OAC)2 (0.1 rnrole) in ether (8 mL) was treated with a solution of diazomiethane (generated from 3. 0 g of I -methyl-3 -nitro-1 nitrosoguanidine) in ether at O'C. After being stirred at room temperature for 20 h the reaction was evaporated to dryness and the residue was chroinatographed to give 2which was subjected to Step B of Example 30, Step B of Example 29, and Step D of Example 27 to give 2-amino-7cyclopropyl-6-thiocyanato-4-phosphonomethoxybenzothiazole hydrogen bromide (35.1).

Anal. calcd. for C 12

HI

3

N

3 4

PS

2 Br OlH~r: C:27.76; H:2.72;N: 8.09. Found: C:27.54; H:3.05; N:7.83.

Example 36.

Preparation of 2-Amino-4-phosphononlethox-6-chloro-7-fethyI benzothiazole.

Step A. 2-Methoxy-4-chloro-5-methylaniline was subjected to Steps A and B of Example 27, Step B of Example 29, and Step D of Example 27 to give 2-amino-4phosphonomethoxy-6-chloro-7-methyl benzothiazole mp 250*C(dec.). Anal. calcd.

for C 9

H

10

N

2 0 4

PS

2 C1+0.3H 2 0 0.4 HBr: C031.20; H:3.20; N:8.09. Found: 031.37; H:2.87; N:7.89.

Similarly, the following compounds were prepared according to above procedures: (36.2) 2-Amino-7-phenyl-6-thiocyanato-4-phosphonomethoxybenzothiazole. mp 250'C Anal. calcd. for C1 5

HI

2

N

3

O

4

FS

2 0.211 2 0: C:45.38; H:3.15; N: 10.58. Found: C:45.25; H:3.21; N:10.53.

Example 37.

Preparation of 2-bromo-4-diethylphosphonomethoxV-5,6,7,8-tetrahvdronltho 11.2dl tb azole.

Step A. A solution of 2-aimino-4-diethylphosphonomethoxy-5,6,7,8tetrahydronaphtho[1,2-d]thiazole (1 namole) in CH 3 CN (4 mL) was cooled to O'C, and treated with CuIr 2 (1.2 mmole) followed by isoarnylnitrite (1.5 mmole) in a dropwise fashion. The resulting dark mixture was stirred for 3.5 h. Evaporation and chromatography gave 2-bromo- 4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[l1 ,2-d]thiazole as an oil.

Step B. 2-Bromo-4-diethylphosphonomethoxy-5,6,7,8-tetrahydrolaphtho[ 1,2d]thiazole was subjected to Step D of Example 27 to give 2-bromo-4-phosphonomethoxy- 5,6,7,8- tetrahydronaphtho[1,2-d]tbiazole (37.1) as a solid. Mp 220 230'C. Anal. calcd. for

C

12

HI

3 NO4PSBr: C:38.1 1; H:3.46; N:3.70. Found: C:37.75; H:3.26; N:3.69.

(37.2) The same procedure was used to react 2-amino-4-diethylphosphonomethoxy-6-chloro- 7-methyl benazothiazole with CUC1 2 to give 2-Chloro-4-phosphonomethoxy-6-chloro-7-methy benzothiazole. mp. 250'C(dec.). Anal. calcd. for C 9 HgNO 4

PSCI

2 +0.7 HBr: C: 28. 10; H: 2.28; N: 3.64. Found: C: 28.23; H: 2.20; N: 3.79.

Example 38.

Preparation of 4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphthol.2-dl thiazole.

Step A. A solution of isoamnylnitrite (1.5 mmole) in DMF (I1 mL) at 65'C was treated with 2-amino-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1I,2-d]thiazole (1 mmole) in DM:F (3 mL). After 30 min, the cooled reaction solution was subjected to evaporation and chromatography to provide 4-diethylphosphonomethoxy-5,6,7, 8tetrahydronaphtho[1,2-d]thiazole as an oil, which was subjected to Step D of Example 27 to give 4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho(1,2-d]thiazole (38.1) as a solid. MIP 215 220*C. Anal. calcd. for C 12

HI

4 N0 4 PS 1.3HBr: C:35.63; H:3.81; N:3.46. Found: C:35.53; H:3.46; N:3.40.

(38.2) The same reaction sequence was used to transform 2-ainino-4diethylphosphonomethoxy-6-chloro-7-methyl benzothia~ole to 4-Phosphonomethoxy-6chloro-7-methyl benzothiazole. mp. 195-198TC. Anal. calcd. for CgH9NO 4 PSC1±0.5H 2 0: C: 35.71; H: 3.33; N: 4.63. Found: C: 35.49; H: 3.19; N: 4.65.

Example 39.

Preparation of 2-Arnino-4-phosphonomnethytbio beazothiazole.

Step A. 2-Diethylphosphonomethyltioani line, prepared according to Step B of Example 27, was subjected to Step B of Example 29 to give 2-amino-4diethylphospbonomethythio-benzothiazole.

Step B. 2-Axino-4-diethylphosphonomethythobenzothiazole was subjected to Step D of Example 34 to give 2-amino-4-phosphonomethythiobenzothiazole (39.1) as a foam. Anal.

calcd. for C 8

H

10

N

2 0 3

PS

2 0.4H 2 0: C:35.63; H:3.81; N:3.46. Found: C:35.53; H:3.46; N:3.40.

Example Preparation of 2-Amino-7-hexyl-6-thiocyano-4-phosphonomethoxy benzothiazole.

Step A. A solution of 1 mmole of (prepared as in Example 30, step A) in diethyl amine (5 mL) was treated with 1-hexyne (1.2 mmole), Cul (0.1 mmole) and palladium bis(triphenylphosphine) dichloride (0.1 mmole), and the mixture was heated at 60°C under nitrogen for 14 h. Evaporation and chromatography gave 2-diethylphosphonomethoxy-5-(l-hexyn) benzene as an oil, which was subjected to Step B of Example 32, Step B of Example 29, and Step D of Example 27 to give 2-amino-7-hexyl- 6-thiocyano-4-phosphonomethoxybenzothiazole.

(40.1) 2-Amino-6-thiocyanato-7-(n-hexyl)- 4-phosphonomethoxybenzothiazole.

mp. 250 0 C(dec.). Anal. calcd. for CI 5

H

20

N

3 04PS 2 C: 44.88; H: 5.02; N: 10.47. Found: C:44.54; H: 4.75; N: 10.37.

Similarly, the following compounds were prepared: (40.2) A solution of 1 mmole of (prepared as in Example 30, step A) was subjected to Step C of Example 27, followed a similar sequence as compound 40.1 to give 2-Amino-6-methyl-7-(n-hexyl)- 4phosphonomethoxybenzothiazole. mp. 250 0 C(dec.). Anal. calcd. for

C

15

H

23

N

2 0 4 PS+0.25HBr: C: 47.58; H: 6.19; N: 7.40. Found: C: 47.40; H: 6.07; N: 7.54.

Example 41.

Preparation of 2-Amino-6-methoxy-7-methyl-4-phosphonomethoxybenzothiazole.

Step A. A solution of 2-chloro-4-floro-5-methylnitrobenzene (1 mmole) in DMF mL) was treated with fresh sodium methoxy (1.1 mmole), and the mixture was stirred for 6h.

Evaporation and chromatography gave 2-chloro-4-methoxy-5-methylnitrobenzene.

Step B. 2-chloro-4-methoxy-5-methylnitrobenzene was subjected to Step A of Example 31, Step B of Example 32, Step A of Example 33, and Step D of Example 27 to give 2-Amino-6-methoxy-7-methyl-4-phosphonomethoxybenzothiazole 41.1. nip. 250'C(dec.).

Anal. calcd. for CioH 13

N

2 0 4 S: C: 39.48; H: 4.3 1; N: 9.21. Found: C: 39.39; H: 4.17; N: 8.98, Similarly, the following compounds were prepared: (41.2) 2-Amino-7-methyl-6-methylthio-4-phosphonomethoxybenzothiazole.

nip. 250'C(dec.). Anal. calcd. for C 10

HI

3

N

2 &0.PS 2 +O.45 H13r: C: 33.67; H: 3.80; N: 7.85.

Found: C: 33.62; H: 3.86; N: 7.76.

(41.3) 2-Amino-6-ethoxy-7-methyl-4-phosphonomethoxybenzothiazole. mp. 250'C(dec.).

Anal. calcd. for C, 1

H

15

N

2 0 5 PS: C: 41.5 1; H: 4.75; N: 8.80. Found: C: 41.80; H: 4.59; N: 8.95.

(41.4) 2-Amino-6-isobutoxy-7-methyl-4-phosphonomethoxybenzothiazole.

nip. 250*C(dec.). Anal. calod. for C 13

H

1 qN 2 0 5 PS+0.15 H~r: C: 43.56; H: 5.38; N: 7.81.

Found: C: 43.59; H: 5.38; N: 7.86.

Example 42.

Preparation of 2-A mino-6-eth vl-4-phosph onomethoxyb enzoth iazole.

Step A. To a solution of 1 mmot of 3-bromo chlorobenzene in 2 rnL of con. H 2 S0 4 was added 1.5 mrnol of 79 H{N0 3 at -10*C. After it was stirred for 30 min. the mixture was poured onto ice/water mixture. The yellow precipitate was filtered and dried to give a mixture of 2-chloro-4-brorno nitrobenzene (desired) and 4-chloro-2-bromo nitrobenzene.

Step B. 2-Chloro-4-bronao nitrobenzene was subjected to Step A of Example 34, Step B of Example 32, Step B of Example 29, and Step D of Example 27 to give 2-Amino-6ethyl-4-phosphonomethoxybenzothiazole (42.1) mp. 220'C(dec.). Anal. calcd. for

C

10 Hl 3

N

2 0 4 PS+0.3 H~r: C: 38.43; H: 4.29; N: 8.96. Found: C: 38.35; H: 4.44; N: 8.75.

Similarly, the following compound was prepared: (42.2) 2-Amino-6-propyl-4-phosphonomethoxybenzotbiazole. nip. 220'C(dec.). Anal.

calcd. for C, IH 15

N

2 0 4 PS+0.2 I-Mr: C: 41.49; H: 4.81; N: 8.80. Found: C: 41.85; H: 4.12; N: 8.31.

Example 43.

Preparation of 2-Amino-6-thio-7-ethyl-4-phosphonomethoxybenzothiazole.

Step A. A solution of 1 mmol of 2-Amino-6-thio-7-ethyl-4diethylphosphonomethoxybenzothiazole (for preparation see Example 34) in 3 mL of 48 }iBr in AcOH was heated at 90'C for 1 6h. Solvent was removed and the residue was washed with water to give 2-Amino-6-tbio-7-ethyl-4-phiosphonomethoxybenzoth3iazole (43.1).

mp. 220'C(dec.). Anal. calcd. for Cl 0

H

13

N

2 0 4

PS

2 +0.2 H13r: C: 35.69; H: 3.95; N: 8.33.

Found: C: 35.49; H: 3.74; N: 8.33.

Example 44.

Prenaration of 2-Amino-7-p~ropyloxv-6-thiocvano-4-phosphon omethoxvbenzothiazole.

Step A. To a solution of 1 mmol of 2-chloro-5-hydroxy nitrobenzene in 5 mL of DMF was added 1.2 mmol of NaH at O 0 C. After 30 min, allyl bromide was added and the mixture was stirred at rt for 16 IL Solvent was removed and the residue was washed with water and extracted with EtOAc to give 2-chloro-5-propenyloxy nitrobenzene.

Step B. 2-Chloro-5-propenyloxy nitrobenzene was subjected to Step A of Example 31, Step B of Example 32, Step A of Example 33, and Step D of Example 27 to give 2-Amino-7propyloxy-6-thiocyano-4-phosphionomethoxy benzothiazole. mp. 220 0 C(dec.). Anal.

calcd. for C 12 H,44 3 0 5

PS

2 +0.15 HBr+0.08 H420: C: 37.06; H: 3.71; N: 10.8. Found: C: 37.46; H: 3.48; N: 10.38.

Example Preparation of 2-Amino-6-methoxv-4-p~hosphonometbioxvbenzothiazole.

Step A. 2-Hydroxy-4-methoxy nitrobenzene was subjected to Step B of Example 32, Step B of Example 27, Step B of Example 29, Step D of Example 27 to give 2-Am-ino-6methoxy-4-phosphonomethoxybenzothiazole (45.1) inp. 230'C(dec.). Anal. calcd. for

C

9

H

11

IN

2 0 5 PS 0.5H 2 0: C: 36.12; H: 4.04; N: 9.36. Found: C: 36.18; H: 3.8 1; N: 9.47.

Example 46.

2-Arnino-7-etliyl-6-ntetlhyl-4-pbosphonomethoxybelzothiazole.

Step A.2-Fluoro-4-methyl nitrobenzene was subjected to Step A of Example 3 1, Step C of Example 27, Step A of Example 34, Step B of Example 32, Step B of Example 29, Step D of Example 27 to give (46.1) 2-Amino-7-ethyl-6-methyl-4phosphonomethoxybenzothi azole mnp. 250 0 C(dec.). Anal. calcd. for CIIH 15

N

2 0 4 PS+ 0.1 HBr: C: 42.57; H: 4.90; N: 9.03. Found: C: 42.32; H: 4.71; N: 8.87.

Example 47.

2-mn--rm--ehl4popooehxbnohaoe Stet) A. 2-Fluoro-4-methyl nitrobenzene was subjected to Step A of Example 3 1, Step C of Example 27, Step B of Example 30, Step A of Example 33, Step D of Example 27 to give 2-Amino-7-bromo-6-methyl-4-phosphonomethoxybelzothiazol. (47.1) mp. 250'C(dec.). Anal. calcd. for C 9

EION

2

O

4 PSBr+-0.3HBr: C: 28.64; H: 2.75; N: 7.42.

Found: C: 28.62; H: 2.60; N: 7.42.

Example 48.

2-mn--loo6mtY4popooehxbnohaoe Steip A. 2-Hydroxy-4-methyl-5-fluoro nitrobenzene was subjected to Step B of Example 27, Step B of Example 32, Step A of Example 33, Step D of Example 27 to give (48.1) 2-Anino-7-fluoro-6-methyl-4-phosphonomethoxybelzothiazole. mp. 250'C(dec.).

Anal. calcd. for C 9

HI

0

N

2

O

4 PSF+0.l ITMr: C: 35.99; H: 3.39; N: 9.33. Found: C: 35.84; H: 3.32; N: 9.3 1.

(48.2) Starting with 2-hydroxy-5-chloro-4-methyl aniline and using the same reaction sequence as above (except the reduction of NO 2 step was done using SnCl 2 method i.e. Step B of Example 30) gave 2-mn--hoo6mty--hopooehxbnohaoe (48.2) mp. 250'C(dec.). Anal. calcd. for C 9 Hl 0

N

2

O

4 PSCl+-0.6 H 2 0: C: 34.62; H: 3.36; N: 8.97.

Found: C: 34.48; H: 3.40; N: 8.72.

Example 49.

2-Amino-6-b romo-7-methoxy-4-phosphonomethoxybenzothiazole.

Step A. 2-Arnino-4,7-dimethoxy benzothiazole [prepared from 1-(2,5dimethoxyphenyl)-2- thiourea using the procedure Step A of Example 28] was subjected to Step C to give 2-Amino-4,7-dimethoxy-6-bromo benzothiazole.

Step B. To a solution of I mmol of 2-Arniio-4,7-dimethoxy-6-bromo benzothiazole in

CH

2 Cl 2 was a dded 2.2 rumol of BBr 3 in CH 2 CIl 2 at O 0 C for 16 h. Aqueous work-up and chromatography gave 2-amino-4-hydroxy-6-bromo-7-methoxy benzothiazole.

Step C. 2-amino-4-hydroxy-6-bromo-7-methoxy benzotbiazole was subjected to Step B of Example 27, Step D of Example 27 to give (49.1) 2-Amino-6-bromo-7-methoxy-4phosphonomethoxybenzothiazole. mp. 250'C(dec.). Anal. calcd. for CgHION 2

O

5 PSBr: C: 29.28; H: 2.73; N: 7.59. Found: C: 28.90; H: 3.05; N: 7.20.

Example General procedure for bis-phosphoroamide prodrups: Dichioridate formation.

To a suspension of I rnmol of phosphonic acid in 5 mL of dichioroethane was added 0. 1 mmol of pyridine (or 0. 1 mmol of DMF) followed by 6 mmol of thionyl chloride and was heated to reflux for 2.5 h. Solvent and excess th-ionyl chloride were removed under reduced pressure and dried to give the dichioridate.

Coupling reaction: Method A: The crude dichioridate was taken into 5 mL of dry CI- 2 C1 2 and was added 8 nimol of amino acid ester at 0 The resultant mixture was allowed to come to rt where it was stirred for 1 6h. The reaction mixture was subjected to aq. work up and chromatography.

Method B: The crude dichioridate was taken into 5 mL of dry CH 2 Cl 2 and was added a mixture of 4 inmol of amino acid ester and 4 nimol of N-methylimidazole at 0: The 173 resultant mixture was allowed to come to rt where it was stirred for 16 h. The reaction mixture was subjected to aq. work up and chromatography.

The following compounds were prepared in this manner.

(50.1) 2-Amino-5-isobutyl-4-f2-(5-N,N-bis(L-glutamic acid diethylester) phosphonoamido)furanyllthiazole. Anal. caled. for C 29

H

45

N

4 0 10 PS: C: 51:78; H: 6.74; N: 8.33. Found: C: 51.70; H: 6.64; N: 8.15.

(50.2) 2-Amino-5-isobutyl-4-[2-(5-N,N-bis(L-alanine acid dibenzyl ester)phosphonoamido)furanyl]thiazole. Anal. calcd. for C 3 1

H

37

N

4 0 6 PS: C: 59.60; H: 5.97; N: 8.97. Found: C: 59.27; H: 5.63; N: 8.74.

(50.3) 2-Amino-5-isobutyl-4- phosphonodiar-nido]furanyllthiazole. Anal. calcd. for Cl 9

H

25

N

4 0) 6 PS 0.3 CH 2 Cl 2 C: 46.93; H: 5.22; N: 11.34. Found: C: 46.92; H: 5.00; N: 11.22.

(50.4) 2-Amino-5-isobutyl-4- phosphonodiamiddo]furanyllthiazole. AMal. calcd. for C 29 H33N 4

O

5 PS: C: 58.38; H: 5.57; N: 9.39. Found: C: 58.20; H: 5.26; N: 9.25.

(50.5) 2-Amino-5-isobutyl-4- 1-methoxycarbonyl)ethyl) phosphonanaidojfuranyl~thiazole. Anal. calcd. for C 19

H

29

N

4 0 6 PS 4+ 0.6 CH 2 C 12: C: 44.97; H: 5.82; N: 10.70. Found: C: 44.79; H: 5.46; N: 10.48.

(50.6) 2-Amino-5-isobutyl-4- {2-[5-(N,N'-bis((S)-l1-ethoxycarbonyl)ethyl) phosphonamido~ftiranyl)thiazole. nap. 164-165'C: Anal. calcd. for C 21

H

33

N

4 0 6 PS 0.61

CH

2

CI

2 C: 46.99; H: 6.24; N: 10.14. Found: C: 47.35; H: 5.85; N: 9.85.

(50.7) 2-Amino-5-isobutyl-4- -bis((t-butoxycarbonyl)methyl) phosphonanaido]furanyl~thiazole. Anal. calcd. for C23H 3 7N 4

O

6 PS 0.15 CH 2 C1 2 C: 51.36; 11: 6.94; N: 10.35. Found: C: 51.34; H: 6.96; N: 10.06.

(50.8) 2-Amino-5-isobutyl-4- -bis(ethoxycarbonyl) methyl)phosphonamido)]furanylthiazole. Anal. calcd. for C 19

H

29

N

4 0 6 PS 0. 1 EtOAc 0.47

CH

2 Cl 2 C: 45.79; H: 5.94; N: 10.75. Found: C: 46.00; H: 5.96; N: 10.46.

(50.9) 2-Amino-5-isobutyl-4- -methyl-lethoxycarbonyl)ethyl)phosphonaniido] furanyl} thiazole. mp. 1 42-145'C: Anal. calcd. for

C

23

H

37

N

4 0 6 PS: C: 52.26; 7.06; 10.60. Found: C: 52.21; 6.93; 10.62.

(50.10) 2-Amino-S-isobutyl-4- -bis(ethoxycarbonylinethyl) dixnethylphosphonamiido)]furanyl~thiazole. Anal. calcd. for C 21

H

33

N

4 0 6 PS: C: 50.39; H: 6.65; N: 11.19. Found: C: 50.57; H: 6.56; N: 11.06.

(50.11) 2-Axnino-5-isobutyl-4- 1-berizyloxycarbonyl-2-methyl)propyl) phosphonanaido]furanyl~thiazole. Anal. calcd. for C 35

H

45

N

4 0 6 PS +.0.5H 2 0: C: 60.94; H: 6.72; N: 8. 12. Found: C: 6 1.0 1: H: 6.48; N: 7.82.

(50.12) 2-Amiino-5-isobutyl-4- 1-methoxycarbonyl-3-methyl)butyl) phosphoinamidojfuiranyl~thiazole. Anal. calcd. for C 2 5H 4 1N 4

O

6 PS: C: 53.94; H: 7.42; N: 10.06. Found: C: 54.12; H: 7.62; N: 9.82.

(50.13) 2-Amino-5-isobutyl-4- {2-[5-(N,N'-bis((R)-l-ethoxycarbonyl-2-(S-benzyl))ethyl) phosphonamido]furanyl)thiazole. Anal. calcd. for C3 5

H

45

N

4

O

6

PS

3 t 0.4 toluene: C: 58.07; H: 6.2 1; N: 7.17. Found: C: 57.87; H: 6.14; N: 6.8 1.

(50.14) 2-Anaino-5-isobutyl-4- i-ethoxycarbonyl-3-(Smethyl))butyl)phosphonamidolfuranyl}thiazole. Anat. calcd. for C 23

H

37

N

4 0 6

PS

3 C: 46.6 1; H: 6.92; N: 9.45. Found: C: 46.26; H: 6.55; N: 9.06.

(50.15) 2-Amihlo-5-propylthio-4- (S)ethoxycarbonyl)ethyl)phosphonamido]furanyl} thiazole. Anal. calcd. for C 20

H

3

,N

4 0 6

PS

2 C: 46.32; H: 6.03; N: 10.80. Found: C: 46.52; H: 6.18; H: 10.44.

(50.16) 2-Amino-5-isobutyl-4- -bis((S)-l1-benzyloxycarbonyl-2-methyl)isobutyl) phosphonamido] furanyl) thiazole. Anal. calcd. for C 37

H

49

N

4 0 6 PS: C: 62.69; H: 6.97; H: 7.90.

Found: C: 62.85; h 7.06, 7.8 1.

(50.17) 2-Amino-5-isobutyl-4- -bis((S)-lI-ethoxycarbonyl-3-methyl)butyl) phosphonarnido]fiiranyl~thiazole. Anal. caled. for C 27

H

45

N

4 0 6 PS: C: 55.46; H: 7.76; N: 9.58.

Found: C: 55.35; H: 7.94; N: 9.41.

(50.18) 2-Amino-5-isobutyl-4- {2-[5-(N,N'-bis((S)-l1-ethoxycarbonyl-2-methyl)propyl) ri phosphonam-ido]furanyl~thiazole. Anal. calcd. for C 25

H

4 1

N

4 0 6 PS: C: 53.94; H: 7.42; N: 10.06. Found: C: 54.01; H: 7.58; N: 9.94.

(50.19) 2-Amino-5-isobutyl-4- -bis((S)-l1-ethoxycaxbonyl-2-phenyl)ethyl) phosphonamido]furanyltiazole. Anal. calcd. for C 3 3

H

4

IN

4 0 6 PS 0.15 CH 2

CI

2 C: 59.83; H: 6.26; H: 8.42. Found: C: 59.88; H: 6.28; H: 8.32.

(50.20) 2-Amino-5-propylthio-4- {2-[5-(N,N'-(l1-methyl-ethoxycarbonyl)ethyl) phosphonamido]:furanylthiazole. mp. 110-115 Anal. calcd. for C 22

H

35

N

4 0 6

PS

2 (Ni 0.4HC1 0.5Et 2 0: C: 48.18; H: 6.81; N: 9.36. Found: C: 48.38; H: 6.60; H: 8.98.

(50.21) 2-Amino-5-methylthiio-4-{2-[5-(NN'-bis(1 -methyl-l-ethioxycarbonyl)ethyl) phosphonarnido]furanyl}tbiazole. Anal. calcd. for C 20

H

3

IN

4 0 6

PS

2 +O.5H 2 0: C: 45.53; H: 6.11; N: 10.62. Found: C: 45.28; H: 5.85; N 10.56.

Example 51L General procedure for mixed bis-phosphoroamidate prodrugs.

To a solution of crude dichioridate (1 mmnol, prepared as described in Example 50) in mL of dry CH 2 Cl 2 was added amine (1 mmiol) followed by 4-dimethylaminopynidine (3 mmol) at 0 0 C. The resulting mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was cooled back to 0 0 C before adding amino acid ester (2 mmol) and left at room temperature for 1 6h. The reaction mixture was subjected to aq. work up and the mixed bis-phosphoroamidate prodrug was purified by column chromatography.

The following compounds were prepared in this manner.

(51.1) 2-Amino-5-isobutyl-4- {2-[5-(N-morpholirio-N' -methyl-lethoxycarbonyl)ethyl)phosphonamido]furanyl} thiazole. mp. 1 82-1 83'C: Anal. calcd. for

C

21 H1 3 3

N

4 0 5 PS: C: 52.05; H: 6.86; N: 11.56. Found: C: 51.66; H:6.68; N: 11.31.

(51.2) 2-Aniino-5-isobuty]-4- {2-[5-(N-pyrrolidino-N' -(1-methyl-iethoxycarbonyl)ethyl)phosphonamidolfuranyl~thiazole. mp. 1 89-1 90'C: Anal. calcd. for

C

21

H

33

N

4 O0.PS: C: 53.83; H: 7.10; N: 11.96. Found: C: 54.15; H: 7.48; N: 12.04.

Example 52.

Bis-phosphoroninide prodrug synthesis using Mukaiyama 's method with some modifications.

.J Am. Clzeyn. Soc. 1972, 94, 8528.

To a suspension of 1.0 mmol. phosphonic acid and 2.0 nnnol of amino acid ester salt (for example alanine ethyl ester HCI salt) in 9 mL of pyridine, Et 3 N and 1,3-dimethyl-3,4,5,6tetrahydro-2(1H)-pyriimidione (DMPUJ) (1:l1d was added a premixed solution of 4 mrmol of aidrithiol and 4 nimol of PPh 3 in 3 rnL of pyridine. After 16 h at 90'C, the solvents pyridine and Et 3 N were removed under reduced pressure. The remaining solution upon dilution with hexane (100 mL) the crude product was oiled out and was subjected to chromatography purification.

The following compounds were prepared using this method.

(52.1) 2-Amino-4-[(N,N'-(l -(S)-ethoxycarbonyl)ethyl)phosphonodiaraidomethoxy]-5,6,7,8tetrahydronaphtho[l,2-d]thiazole. Mp. 153 156'C: Anal. calcd. for C 22

H

33

N

4 0 6 PS: C: 51.55; H: 6.49; N: 10.93. Found: C:51.39; H: 6.24; N: 10.96.

(52.2) 2-Amino-5-isopropyl-4-[(N,N'-(1-(S)ethoxycarbonyl)ethyl)phosphonodiamnidomethoxycarbonyl]-thiazole Anal. calcd. for Ct 8

H

3

,N

4 0 7 PS: C: 45.18; H: 6.53; N: 11.71. Found: C:45.33; H: 6.56; N: 11.46.

(52.3) 4-Amino-7-ethyl-5-fluoro-1 -isobutyl-2-[5-((N,N'-(1-(S) ethoxycarbonyl)ethyl~phosphonodiamido) furanyl]benziniidazole. Anal. calcd. for

C

27

H

39 Ns0 6 PF: C: 55.95; H: 6.78; N: 12.08. Found: C:55.73; H: 6.65; N: 11.72.

(52.4) 2-Amino-5-ethoxycarbonyl-4-[2-(5-( {N,N (S)ethoxycarbonyl)ethyl~phosphono)furanyl] thiazole. Anal. calcd. for C 2 01- 2

N

4 08PS 0.3

CH

2 Cl 2 C: 44.99; H: 5.50; N: 10.34. Found: C:44.68; H: 5.30; N: 10.37.

(52.5) 2-Amixio-4-[(N,N'-(1 -(S)-ethoxycarbonyl)rnethyl) phosplionodiamidotnethoxy]- 5,6,7,8-tetrahydronaphtho l,2-d]thiazole. Mp. 177 178'C: Anal. calcd. for C 20 H1 29

N

4 0 6

PS:

C: 49.58; H: 6.03; N: 11.56. Found: C049.20; H: 5.95; N: 11.51.

(52.6) 2-Amino-5-isopropyl-4-[(N,N'-(1 ethoxycarbonyl)methyl)phosphonodiamidomethoxycarbonyl]-thiazole. Mp. 122 1 Anal. calcd. for C 16

H

27

N

4 0 7 PS: C:42.66; H: 6.04; N: 12.44. Found: C:42.60; H: 6.08; N: 12.43.

(52.7) 2-Amino-4- -(S)-ethoxycarbonyl)ethyl} phosphonomethoxy-6-bromo-7chloro-benzothiazole. Mp. 210-212'C: Anal. calcd. for C 18 H25N 4

O

6 PSBrC1: C: 37.8 1; H: 4.41; N: 9.80. Found: C: 37.88; 4.35; N: 9.84.

(52.8) 2-Amino-5-propylthio-4- {2-[5-(N,N'-bis(S)-l1-methoxycarbonyl-2-(tbutoxy)ethyl)phiosphonamido]furanyllthiazole. Anal. calcd. for C 26

H

43

N

4 0 8

PS

2 C: 49.20; H: 6.83; N: 8.83. Found: C: 49.38; H: 6.68; N: 8.65.

(52.9) 2-Ainino-5-propylthio-4- -bis(S)-lI-ethoxycarbonyl-2methylbutyl)phosphonamido]furanylI thiazole. Anal. calcd. for C 2 J1 43

N

4 0 6

PS

2 C: 51.8 1; H: 7.19; N: 9.30. Found: C:52.03; H: 6.78; N: 9.04.

(52.10) 2-Amino-5-propylthio-4-[2- {5-(N,N'-bis(S)-l1-ethoxycarbonyl-2rnethylpropyl)phosphonamido~firanyl]thiazole. Anal. calcd for C 24

H

39

N

4 0 6

PS

2 C: 50.16; H: 6.84; N: 9.75. Found: C:50.01; H: 6.76; N: 9.66.

(52.11) 2-Arnino.-5-propylthio-4-[2- N'-bis(S)-lI-methoxycarbonyl-2-(tbutoxy)propyl)phosphonamido~furanyljthiazole. Anal. calcd. for C 28

H

47

N

4 0 8

PS

2 C: 50.74; H: 7.15; N: 8.45. Found: C:51.08; H: 7.33; N: 8.25.

(52.12) 2-Amino-propylthio-4-[2- {5-(N,N'-bis(1 ethoxycarbonyl)cyclopentyl)phosphonamido~furanyl]thiazole. Anal. calcd. for

C

26

H

39

N

4 0 6

PS

2 C: 52.16; H: 6.57; N: 9.36. Found: C: 52.55; H: 6.53; N: 9.31.

(52.13) 2-Amino-S -propylthio-4-[2- 1ethoxycarbonyl)propylphosphonamido} furanylithiazole. Anal. calcd. for C 22

H

35

N

4 0 6

PS

2

C:

48.34; H: 6.45; N: 10.25. Found: C: 48.65; H: 6.29; N: 10.23.

(52.14) 2-Amino-4- -(S)-ethoxycarbonyl)ethyl}phosphonomethoxy-6-chloro-7methyl-benzothiazole. Mp. 178 180'C: Anal. calcd. for Cj9H 2 8N 4

O

6 PSCl: C: 45.02; H: 5.57; N: 11.05. Found: C: 45.12; H: 5.49; N: 10.92.

(52.15) 2-Amino-5-methylthio-4- 1ethoxycarbonyl)ethyl)phosphonarnido]furanyl) thiazole. Mp. 94 95 Anal. calcd. for C18H 27

N

4

O

6

,PS

2 C 44.07; H: 5.55; N: 11.42. Found: C:44.42; H: 5.44; N: 11.29.

(52.16) 2-Amino-propylthi 1ethoxycarbonyl)butyl)phosphonamido)} fulranylithiazole.: Anal. calcd. for C2 4

H

3 9N 4

O

6

PS

2

C:

50.16; H: 6.84; N: 9.75. Found: C:49.96; H: 6.91; N: 9.68.

(52.17) 2-Amino-propylthio-4-[2- {5 1ethoxycarbonyl)cyclohexanylmethyl)phosphonamido)} fiuranyl]thiazole. Anal. calcd. for

C

30

H

47

N

4 0 6

PS

2 C: 55.03; H: 7.23; N: 8.56. Found: C:54.89; H: 7.14; N: 8.42.

(52.18) 2-Ainino-4- 1-(S)-ethoxycarbonyl)ethyl)phosphonomethoxy-6-methoxybenzothiazole. Mp. 144 146'C: Anal. calcd. for C 19

H

29

N

4 0 7 PS: C 46.72; H: 5.98; N: 11.47.

Found: C: 46.76; H: 5.72; N: 11.33.

(52.19) 2-Amino-4-{NN'-(ethoxycabonyl)methyl)phosphonornethoxy-6-methoxybenzothiazole. Mp. 150 152'C: Anal. calcd. for C 17

H

25

N

4 0 7 PS: C: 44.35; H: 5.47; N: 12.17.

Found: C:44.74; H: 5.45; N: 11.99.

(52.20) 2-Amino-7-ethyl-4- -(S)-ethoxycarbonyl)ethyl} phosphononaethoxy-6methyl-benzothiazole. Anal. calcd. for C 21

H

33

N

4 0 6 PS: C: 50.39; H: 6.65; N: 11.19. Found: C:50.22; H: 6.34; N: 11.30.

(52.21) 2-Amino-4- {N,N'-(lI-(S)-ethoxycarbonyl)ethyl)phosphonomethoxy-6-inethylbenzothiazole. Anal. calcd. for C 1 9

H

29

N

4 0 6 PS: C: 48.30; H: 6.19; N: 11.86. Found: C: 48.67; H: 5.90; N: 11.86.

179 (52.22) 2-Amino-4- -(1-methyl-I -ethoxcycarbonyl)ethy1} phosphonomethoxy-6-chloro- 7-methyl-benzothiazole. Mp. 170 172'C: Anal. calcd. for C 21 H1 32

N

4 0 6 PSC1: C: 47.15; H: 6.03; N: 10.47. Found: C: 47.22; H: 5.87; N: 10O.08 (52.23) 2-Amino-7-ethyl-4-{NN'-bis(ethoxycarbonylmnethyl)}phosphonomethoxy-6-methylbenzothiazole. Anal. calcd. for C 19

H

29

N

4 0 6 PS: C: 48.30; H: 6.19; N: 11.86. Found: C: 47.98; H: 6.36; N: 11.88.

(52.24) 2-Amino-4- {N,N'-bis(ethoxycarbonylmetlhyl)}phosphonomethoxy-6-methylbenzothiazole. Anal. calcd. for C 17

H

25

N

4 0 6 PS+ 0.5 H 2 0 C: 45.03; H: 5.78; N: 12.36. Found: C: 44.80; H: 6. 10; N: 12.40.

(52.25) 2-Amino-5-propyltbio-4-[2- 1-tbutoxycarbonyl)ethyl)phosphonamido)} furanylithiazole. Anal. calcd. for C 24

H

39

N

4 0 6

PS

2

C:

0.16; H: 6.84; N: 9.75. Found: C: 50.26; H: 6.7 1; N: 9.5 1.

(52.26) 2-Amino-5-propylthio-4-[2- -bis((S) 1-nbutoxycarbonyl)eihyl)phosphonamido)} furanyl]thiazole. Anal. calcd. for C 24

H

39

N

4 0 6

PS

2

C:

50.16; H: 6.84; N: 9.75.. Found: 0:50.38; H: 6.64; N: 9.64.

(52.27) 2-Amino-5-ethoxycarbonyl-4-[2-(5-( ethoxycarbonyl)propyllphosphono)furanylthiazole. Anal. calcd. for C 22

H

33

N

4 OgPS: C: 48.52; H: 6.11; N: 10.29. Found: C: 48.62; H: 6.02; N: 10.26.

(52.28) 2-Amino-5-ethoxycarbonyl-4-[2-(5-( ethoxycarbonyl)butyllphosphono)furanyl]thiazole. Anal. calcd. for C 24

H

37

N

4 0 8 PS: C: 50.34; H: 6.5 1; N: 9.78. Found: C:50.34; H: 6.57; N: 9.65.

(52.29) 2-Amino-5-ethoxycarbonyl-4-12-(5-( ethoxycarbonyl)cyclopentyl) phosphono)furanyl] thiazole. Anal. caled. for C 26

H

37

N

4 0 8 PS: C: 52.34; H: 6.25; N: 9.39. Found: C: 52.02; HI: 6.20; N: 9.34.

(52.30) 2-Amino-5-etlioxycarbonyl-4-[2- {5-(NN'-bis(S)-lI-ethoxycarbonyl-2rnethylpropyl)phosphonamido~furanyl]tiiazole. Anal. calod. for C 24

H

37

N

4 0 8 PS: C: 50.34; H: 6.51; N: 9.78. Found: C:50.56; H: 6.40; N: 9.65.

(52.31) 2-Amino-5-propylthio-4-[2- -biscoumarin)phosphonainidol furanyllthiazole. Anal. calcd. for C 2 gH 23

N

4 0 6

PS

2 C: 55.44; H: 3.82; N: 9.24. Found: C:55.52; H: 3.66; N: 9.01.

(52.32) 2-Amino-5-propylthio-4-[2- 1-isopropoxycarbonyl)ethyl)phosphonamnido)) furanyl]thiazole. Anal. calcd. For C22H 3 5N 4

O

6

PS

2 C: 48.34; H: 6.45; N: 10.25. Found: C:48.03; H: 6.45; N: 10.09.

(52.33) 2-Ainino-5-propylthio-4-[2- -npropoxycarbonyl)ethyl)phosphonamido)) furanyljthiazole. Anal. calcd. for C 22

H

35

N

4 0 6

PS

2 48.34; H: 6.45; N: 10.25. Found: C: 48.39; H: 6.27; N: 10.20.

(52.34) 2-Amino-5-propyltbio-4-[2- -bis((S) 1cycloheptoxycarbonyl)ethyl)phosphonanido)} furanylithiazole. Anal. calcd. for

C

26

H

3 9N 4

O

6

PS

2 C: 52.16; H: 6.57; N: 9.36. Found: C: 52.07; H: 6.5 1; N: 9. (52.35) 2-Amino-6-ethyl-7-fluoro-4- -(S)-ethoxycarbonyl)ethyllphosphonomethoxybenzothiazole,. Anal. calcd. for C 20

H

30

N

4 0 6 PSF: C: 47.6 1; H: 5.99; N: 11. 10. Found: C: 47.59; H: 5.79; N: 10.90.

(52.36) 2-Amino-6-ethyl-7-fluoro-4-{NN'-(1 -ethoxycarboniyl)methyl) phosphonomethoxybenzothiazole. Anal. calcd. for C 18

H

2 6

N

4 06PSF: C: 45.38; H: 5.50; N: 11.76. Found: C: 45.07; H: 5.25; N: 11.49.

(52.37) 2-Arnino-7-bromo-4- -(S)-ethoxycarbonyl)ethyl~phosphonomethoxy-6naethylbenzothiazole. Anal. calcd. for C 19

H

2 sN 4

O

6 PSBr: C: 41.39; H: 5.12; N: 10. 16. Found: C:41.40; H: 5.05; N: 9.94.

(52.38) 2-Amino-4- -ethoxycarbonyl)methylethyllphosphonomethoxy-6methylbenzothiazole. Anal. calcd. for C 2 lH 33

N

4 0 6 PS+0.5 H 2 0: C: 49.50; H: 6.73; N: 11.00, Found: C: 49.18; H: 6.61;N: 11,39.

(52.39) 2-Amino-5-isobutyl-4-[2- -bis((S)-l1-(1ethoxycarbonyl)propyl)phosphonamido) ftu-anyljthiazole. Anal. calcd. for C 23

H

37

N

4 0 6 PS: C: 52.26; H: 7.06; N: 10.60. Found: C:52.47; H: 7.29; N: 10.77.

(52.40) 2-Amino-5-propylthio-4-[2- 1cyclohexylmethoxycarbonyl)ethyl)phosphoiinmdo) }furanyl]thiazole. Anal. calcd. for

C

30

H

47

N

4 0 6

PS

2 C: 55.03; H: 7.23; N: 8.56. Found: C: 55.08; H: 7.35; N: 8.39.

(52.41) 2-Axnino-5-isobutyl-4-12- etlioxycarbonyl)cyclopentyl)phosphonamidu)}furanyl]thiazole. Anal. calcd. for

C

27

H

41

N

4 0 6 PS: C: 55.85; H: 7.12; N: 9.65. Found: C:55.62; H: 6.81; N: 9.66.

(52.42) 2-Amino-4- -ethoxycarbonyl)cyclopentyl} phosphonomethoxy-7-fluoro-6methyl benzothiazole. Anal. calcd. for C 26

H

38

N

4 0 6 PSF+ 0.15 Et 2 O: C: 53.63; H: 6.68; N: 9.40. Found: C:53.93;,H: 6.39; N: 9.50.

(52.43) 2-Amino-5-isobutyl-4-[2- 1-(1neopentoxycarbonyl)ethyl)phosphonamnido)} furanyllthiazole. Anal. calcd. for C27H 45

N

4

O

6 PS+ 0.1 H 2 0: C: 55.29; H: 7.77; N: 9.55. Found: C: 54.90; H: 7.68; N: 9.44.

(52.44) 2-Amino-5-isobutyl-4- -bis((RS)- 1-(1ethoxycarbonyl)ethyl)phosphonamido)]furanyl)thiazole. Mp. 143 146'C: Anal. calcd. for

C

21

H

33

N

4 0 6 PS: C: 50.39; H: 6.65;N: 11.19. Found: C:50.33;H: 6.58;N: 11.00.

(52.45) 2-Amino-5-isobutyl-4-[2- -bis((S)-1 isopropoxycarbonyl)ethyl)phosphonamido)} faranyl]thiazole. Anal. calcd. for C 23

H

37

N

4 0 6

PS:

C: 52.26; H: 7.06; N: 10.60. Found: C:52.34; H: 7.02; N: 10.50.

(52.46) 2-Anaino-5-isobutyi-4-[2- {5-(iNN' -bis((S)-l1-(1propoxycarbonyl)ethyl)phosphonamido)} furanylithiazole. Anal. calcd. for C 23

H

37

N

4 0 6

PS+..

0.1 CH7Cl 2 C: 51.66; H: 6.98; N: 10.43. Found: C:51.50; H: 7.01; N: 10.63.

(52.47) 2-Anino-5.isobutyl-4-[2-{5-(NN'-bis((S)-1-(1 isobutoxycarbonyl)ethyl)phosphonamido)} furanylithiazole. Anal. calcd. for C 25

H

41

N

4 0 6

PS:

C: 53.94; H: 7.42; N: 10.06. Found: C:53.59; H: 7.64; N: 9.98.

(52.48) 2-Amino-5-propylthio-4- 1ethoxycarbonyl)ethyl)phosphonamido]furanyl} oxazole. Anal. calcd. for C 20

H

3 lN 4 0) 7 PS: C: 47.80; H: 6.22; N: 11. 15. Found: C: 47.90; H: 6.17; N: 10.92.

(52.49) 2-Amino-5-propyltbio-4- 1etlioxycarbonyl)methiyl)phosphonamido]furaniyl} oxazole. Anal. calcd. for C 1 1

H

27

N

4 0 7 PS: C: 45.57; H: 5.74; N: 11.81. Found: C: 45.87; H: 5.68; N: 11.68.

(52.50) 2-Amino-5-(isobutyl-d 9 -bis(S)- 1-(1ethoxycarbonyl)ethylphosphonamrido} furanyl]thiazole. Anal. calcd. for C 21

H

24 DqN 4 0 6

SP:

C:49.50; H: 4,75; N:10.99. Found: C:49.89; H: 6.55; N:10.97.

Examples of use of the method of the invention include the following. It will be understood that these examples are exemplary and that the method of the invention is not limited solely to these examples.

For the purposes of clarity and brevity, chemical compounds are referred to by synthetic Example number in the biological examples below.

Compound A is 4-Amino-S -fluoro-7-ethyl-l-isobutyl-2-(2-phosphono-5fiaranyl)benzimidazole; Compound B is 4-Amino-5-fluoro-l-cyclopropyhnethyl-2-(2-phosphono-5furanyl)benzimidazole.

Compound C is 2-Arnino-5-isobutyl-4- {2-[N-(l-methyl-1carboxy)ethylmonophosphonamido]furanyl} thiazole Besides the following Examples, assays that may be useful for identifying compounds which inhibit gluconeogenesis include the following animal models of diabetes: i. Animals with pancreatic b-cells destroyed by specific chemical cytotoxins such as Alloxan or Streptozotocin the Streptozotocin-treated mouse, rat, dog, and monkey).

Kodama, Fujita, Yamaguchi, Japanese Journal of Pharmacology 66, 331-3 36 (1994) (mouse); Youn, Kim, Buchanan, Diabetes 43, 564-571 (1994) (rat); Le Marchand, Loten, Assimacopoulos-Jannet, et aL, Diabetes 27, 1182-88 (1978) (dog); and Pitkin, Reynolds, Diabetes 19, 70-85 (1970) (monkey).

ii. Mutant mice such as the C57BL/Ks db/db, C57BL/Ks ob/ob, and C57BL/6J ob/ob strains from Jackson Laboratory, Bar Harbor, and others such as Yellow Obese, T-KK, and New Zealand Obese. Coleman, Humimel, Diabetologia 3, 23 8-248 (1967) 183 (C57BL/Ks db/db); Coleman, Diabetologia 14, 141-148 (1978) (C57BL/6J ob/ob); Wolff, Pitot, Genetics 73, 109-123 (1973) (Yellow Obese); Dulin, Wyse, Diabetologia 6, 317-323 (1970) and Bielschowsky, Bielschowsky, F.

Proceedings of the University of Otago Medical School 31, 29-31 (1953) (New Zealand Obese).

iii. Mutant rats such as the Zucker fa/fa Rat rendered diabetic with Streptozotocin or Dexamethasone, the Zucker Diabetic Fatty Rat, and the Wistar Kyoto Fatty Rat. Stolz, K.J., Martin, R.J. Journal of Nutrition 112, 997-1002 (1982) (Streptozotocin); Ogawa, Johnson, Ohnbeda, McAllister, Inman, Alam, Unger, The Journal of Clinical Investigation 90, 497-504 (1992) (Dexamethasone); Clark, Palmer, Shaw, WN., Proceedings of the Society for Experimental Biology and Medicine 173, 68-75 (1983) (Zucker Diabetic Fatty Rat); and Idida, Shino, Matsuo, et al., Diabetes 30, 1045- 1050 (1981) (Wistar Kyoto Fatty Rat).

iv. Animals with spontaneous diabetes such as the Chinese Hamster, the Guinea Pig, the New Zealand White Rabbit, and non-human primates such as the Rhesus monkey and Squirrel monkey. Gerritsen, Connel, Blanks, Proceedings of the Nutrition Society 40, 237 245 (1981) (Chinese Hamster); Lang, Munger, Diabetes 25, 434- 443 (1976) (Guinea Pig); Conaway, Brown, Sanders, L.L. et al., Journal of Heredity 71, 179-186 (1980) (New Zealand White Rabbit); Hansen, Bodkin, M.L., Diabetologia 29, 713-719 (1986) (Rhesus monkey); and Davidson, Lang, C.M., Blackwell, Diabetes 16, 395-401 (1967) (Squirrel monkey).

v. Animals with nutritionally induced diabetes such as the Sand Rat, the Spiny Mouse, the Mongolian Gerbil, and the Cohen Sucrose-Induced Diabetic Rat. Schmidt- Nielsen, Hainess, Hackel, Science 143, 689-690 (1964) (Sand Rat); Gonet, Stauffacher, Pictet, et al., Diabetologia 1, 162-171 (1965) (Spiny Mouse); Boquist, Diabetologia 8, 274-282 (1972) (Mongolian Gerbil); and Cohen, A.M., Teitebaum, Salitemik, Metabolism 21, 235-240 (1972) (Cohen Sucrose-Induced Diabetic Rat).

vi. Any other animal with one of the following or a combination of the following characteristics resulting from a genetic predisposition, genetic engineering, selective breeding, or chemical or nutritional induction: impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, accelerated gluconeogenesis, increased hepatic glucose output.

Example A: Inhibition of Human Liver FBPase E. coli strain BL21 transformed with a human liver FBPase-encoding plasmid was obtained from Dr. M. R. EI-Maghrabi at the State University of New York at Stony Brook.

The enzyme was typically purified from 10 liters of recombinant E. coli culture as described Gidh-Jain et al. ,1994, The Journal of Biological Chemistry 269, pp 27732-27738).

Enzymatic activity was measured spectrophotometrically in reactions that coupled the formation of product (fructose 6-phosphate) to the reduction of dimethylthiazoldiphenyltetrazolium bromide (MTT) via NADP and phenazine methosulfate (PMS), using phosphoglucose isomerase and glucose 6-phosphate dehydrogenase as the coupling enzymes. Reaction mixtures (200 pl) were made up in 96-well microtitre plates, and consisted of 50 mM Tris-HCl, pH 7.4, 100 mM KC1, 5 mM EGTA, 2 mM MgC1 2 0.2 mM NADP, 1 mg/ml BSA, 1 mM MTT, 0.6 mM PMS, 1 unit/ml phosphoglucose isomerase, 2 units/ml glucose 6-phosphate dehydrogenase, and 0.150 mM substrate (fructose 1,6bisphosphate). Inhibitor concentrations were varied from 0.01 1 iM to 10 pM. Reactions were started by the addition of 0.002 units of pure hlFBPase, and were monitored for 7 minutes at 590 nm in a Molecular Devices Plate Reader (37 0

C).

The table below provides the IC5o values for several compounds prepared. The ICs for AMP is 1 gLM.

Compound ICso 0 (hlFBPase), pM 3.1 0.025 3.2 0.1 3.25 0.014 Compound 3.26 3.58* 3.67 3.69 3.70 6.3 10.1 10.27 10.43 15.20 15.14 16.1 17.6 17.11 18.3 18.11 18.20 18.25 19.2 22.2 34.1

A

B

IC50 (hIFBPase), pM 0.015 0. 018 (*non-HBr salt) 2 1 0.04 0.044 0.12 0.038 0.07 0.04 0.032 0.06 0.62 0.78 0.05 0.33 0.039 2 0.4 2.8 0.022 0.055 0.055 Inhibition of Rat Liver FBPase E. coli strain BL21 transformed with a rat liver FBPase-encoding plasmid was obtained from Dr. M. R. El-Maghrabi at the State University of New York at Stony Brook.

Recombinant FBPase was purified as described (El-Maghrabi, and Pilkis, S.J. (1991) BioChem. Biophys. Res. Commun. 176, 137-144) The enzyme assay was identical to that described above for human lEver EBPase.

The table below provides the IC 50 values for several compounds prepared. The IC 50 for ANDis 20 M.

Compound IC 50 (rlFBPase), AM ID3.1 0.18 3.2 3.25 3.26 0.25 3.58* 0.05 (*non-HBr salt) .3.70 0.15 6.3 10.1 2 10.2 10.27 2.9 10.43 0.8 15.2 1.3 15.4 4.1 15.6 7 15.20 0.6 15.14 0.68 16.1 1.8 18.20 0.28 18.3 0.49 34.1 0.16 A 0.55 B 2.1 Example B: AMP Site Binding To assess whether compounds bind to the allosteric AMP binding site ofhlFBPase, the enzyme is incubated with radio-labeled AMP in the presence of a range of test compound concentrations. The reaction mixtures consist of 25 mM 3H-AMP (54 mCi/mmole) and 0- 1000 mM test compound in 25 mM Tris-HCI, pH 7.4, 100 mM KCI and 1 mM MgCl 2 C-K 1.45 mg of homogeneous FBPase nmole) is added last. After a 1 minute incubation, AMP Sbound to FBPase is separated from unbound AMP by means of a centrifugal ultrafiltration unit ("Ultrafree-MC", Millipore) used according to the instructions of the manufacturer. The radioactivity in aliquots (100 jtl) of the upper compartment of the unit (the retentate, which contains enzyme and label) and the lower compartment (the filtrate, which contains unbound label) is quantified using a Beckman liquid scintillation counter. The amount of AMP bound to the enzyme is estimated by comparing the counts in the filtrate (the unbound label) to the total counts in the retentate.

Example C: Inhibition of Gluconeogenesis in Rat Hepatocytes Hepatocytes were prepared from overnight fasted Sprague-Dawley rats (250-300 g) according to the procedure of Berry and Friend (Berry, Friend, 1969, J. Cell. Biol.

43, 506-520) as modified by Groen (Groen, Sips, Vervoom, Tager, J.M., 1982, Eur. J. BioChem. 122, 87-93). Hepatocytes (75 mg wet weight/ml) were incubated in I ml Krebs-bicarbonate buffer containing 10 mM Lactate, 1 mM pyruvate, 1 mg/ml BSA, and test compound concentrations from 1 to 500 pM. Incubations were carried out in a oxygen, 5% carbon dioxide atmosphere in closed, 50-ml Falcon tubes submerged in a rapidly shaking water bath (37 After 1 hour, an aliquot (0.25 ml) was removed, transferred to an Eppendorf tube and centrifuged. 50 pl of supernatant was then assayed for glucose content using a Sigma Glucose Oxidase kit as per the manufacturer's instructions.

IC

50 's for select compounds in this assay are shown in the table below.

Compound ICso Glucose Production, tM 3.1 3.2 26 3.26 3.58* 2.0 (*non-HBr salt) 10.1 10.2 16 16.1 50.6 50.9 2.2 50.2 2.1 Example D: Glucose Production Inhibition and Fructose-1.6-bisphosphate Accumulation in Rat Hepatocytes.

Isolated rat hepatocytes are prepared as described in Example C and incubated under the identical conditions described. Reactions are terminated by removing an aliquot (250 uL) of cell suspension and spinning it through a layer of oil (0.8 ml silicone/mineral oil, 4/1) into a perchloric acid layer (100 gL). After removal of the oil layer, the acidic cell extract layer is neutralized by addition of 1/3rd volume of 3 M KOH/3 M KHCO3. After thorough mixing and centrifugation, the supernatant is analyzed for glucose content as described in Example C, and also for fructose-1,6-bisphosphate. Fructose 1,6-bisphosphate is assayed spectrophotometrically by coupling its enzymatic conversion to glycerol 3-phosphate to the oxidation of NADH, which is monitored at 340 runm. Reaction mixtures (1 mL) consist of 200 mM Tris-HCl, pH 7.4, 0.3 mM NADH, 2 units/ml glycerol 3-phosphate dehydrogenase, 2 units/ml triosephosphate isomerase, and 50-100 ul cell extract. After a 30 minute preincubation at 37 0 C, 1 unit/ml of aldolase is added and the change in absorbance measured until a stable value is obtained. 2 moles of NADH are oxidized in this reaction per mole of fructose-1,6-bisphosphate present in the cell extract.

A dose-dependent inhibition of glucose production accompanied by a dose-dependent accumulation of fructose-1,6-bisphosphate (the substrate of FBPase) is an indication that the target enzyme in the gluconeogenic pathway, FBPase, is inhibited.

Example E: Chemical Stability Aim: To assess the stability of prodrugs 50.6, 50.9, 50.15, and 50.20 in a phosphate LO buffered, aqueous solution at neutral pH.

Methods: A 50 or 100 jtg/mL solution of prodrug in potassium phosphate buffer at SpH 7 (room temperature) was sampled daily for up to 10 days. Samples were analyzed by reverse phase HPLC with use of a Beckman Ultrasphere C18 column (4.6 X 250 mm). The column was equilibrated and eluted with a gradient from 50 mM sodium phosphate pH 5.5 to acetonitrile at a flow rate of 1.5 mL/min. Detection was at 300 or 315 nm, column temperature at 40 0 C. Under these conditions, the prodrugs were well separated from parent compound standards; the retention time for the prodrugs was between 16 and 18 minutes, whereas the parent compounds, 3.1 and 3.58 (non-HBr salt), eluted at 9 and 10 minutes, respectively.

Results: The prodrugs evaluated exhibited good stability at neutral pH. Less than decomposition of the prodrugs was noted over a 4 day incubation period. The t90's for 50.6, 50.9, 50.15, and 50.20 at pH 7 were thus >96 hours.

Example F: Estimation of Oral Bioavailability in the Rat Aim: To estimate the oral bioavailability of prodrugs by means of the urinary parent compound excretion method in the rat.

Methods: Prodrugs were dissolved in 10% ethanol/90% polyethylene glycol (mw 400) and administered by oral gavage at doses of 10 to 40 mg/kg parent compound equivalents to 6-hour fasted, Sprague Dawley rats (220-240 Parent compounds were typically dissolved in deionized water, neutralized with sodium hydroxide, and then administered via the tail vein at -10 mg/kg to rats that were briefly anesthetized with halothane. The rats were subsequently placed in metabolic cages and urine was collected for 24 hours. The quantity of parent compound excreted into urine was determined by HPLC analysis. Analysis was performed as described in Example E. The percentage oral bioavailability was estimated by comparison of the recovery in urine of the parent compound generated from the prodrug administered orally, to that recovered in urine following intravenous administration of unsubstituted parent compound.

Results: The estimated oral bioavailability of select prodrugs is shown below.

Parent Oral Prodrug compound Bioavailability, 50.2 3.1 11 50.3 3.1 7 50.4 3.1 17 50.5 3.1 22 50.6 3.1 21.5 50.8 3.1 26 50.9 3.1 50.15 3.8 22 50.20 3.8 42 50.17 3.1 7 50.21 3.26 51.2 3.1 37 52.1 29.1 16 52.4 3.25 52.15 3.26 23 52.18 45.1 22 Parent compound Oral Bioavailability, Prodrug D m 52.21 52.22 52.32 52.33 52.38 52.41 52.43 52.44 52.45 52.46 32.2 36.1 3.58 3.58 32.2 3.1 3.1 3.1 3.1 3.1 Example G: Oral Pharmacokinetics in the Rat Aim: To determine the pharmacokinetic parameters of 50.6 and 50.9 (prodrugs of 3.1), and of 50.2 (prodrug of 3.58) following oral administration in the rat.

Methods: Prodrugs were administered orally at 10 mg/kg to fed rats instrumented with tail artery catheters. At appropriate time points following drug administration, blood samples were removed via the tail vein catheters. Plasma was prepared from the samples by centrifugation and plasma protein subsequently precipitated by addition of methanol to The methanolic extracts were clarified by centrifugation and then analyzed for prodrug and parent compound content by HPLC as described in Example E. Pharmacokinetic parameters were calculated from the parent compound plasma concentration-time profiles using noncompartmental analysis (WinNonLin v. 1.1 software).

Results: Prodrugs were not detected in plasma indicating rapid in vivo conversion to their respective parent compounds. Pharmacokinetic parameters are summarized below.

Parent Compound Compound Cmax Tmax Clearance Half-life (gg/ml) (L/kg/h) (h) 50.6 0.78 1.5 1.31 5.1 50.9 0.99 1.1 1.6 50.2 1 3.1 0.54 Example H: Acute Oral Efficacy in the ZDF Rat Aim: To determine the blood glucose lowering effect of acute 50.6, 50.9 and 50.2 administration in the Zucker Diabetic Fatty (ZDF rat).

Methods: ZDF rats were purchased from Genetics Inc (Indianapolis, Indiana) at 8 weeks of age. Animals were maintained under standard vivarium conditions and provided with Purina 5008 chow and water ad libitum. At 10-12 weeks of age, rats with blood glucose levels >500 mg/dl were selected and dosed orally either with vehicle (PEG 400), or prodrug mg/kg). Blood glucose levels were monitored at regular intervals for 6 hours following dosing. Blood samples were taken from tail vein nicks and analyzed by means of a HemoCue glucose analyzer (Hemocue, Mission Viejo, CA). Statistical analysis was performed using the Student's t test. Means standard error of the means are shown.

Results: The three prodrugs were orally efficacious as indicated by the significant blood glucose lowering effects observed (see table below).

Blood Glucose, mg/dl Treatment Tbaseline T6h Change Vehicle(n=8) 562±38 528±29 -6% 50.6 544±25 406±12* 50.9 602±26 410±18* -32% Treatment Tbaseline T6h Change 50.2 591±35 415+15* *P<0.005 versus vehicle Example 1: Chronic Oral Efficacy in the ZDF Rat Aim: To determine the glucose lowering effects of 50.6 in the ZDF rat during 3 weeks of chronic, oral treatment.

Methods: ZDF rats (10 weeks of age) were maintained either on powdered Purina 5008 rat-chow (n=10) or the same powdered chow supplemented with 0.4% 50.6 (n 8).

Blood glucose measurements were made as described in Example E at baseline and at weekly intervals thereafter for a total of 3 weeks. Statistical analysis was performed using the Student's t test. Means standard error of the means are shown.

Results: As illustrated in the table below, efficacy was maintained throughout the 3week treatment period, with 45% blood glucose lowering evident in the drug treated group (relative to vehicle) at the end of the study.

Blood glucose, mg/dl, Treatment tbaseline t21 days Vehicle 678±19 776±28 50.6 674±20 436±41* *p<0.0001 versus vehicle Example J: Identification of the Intermediate Formed During Activation 50.6 The metabolism of 50.6 was evaluated in rat, monkey, and human plasma by reverse phase HPLC with use of a Beckman Ultrasphere ODS column (4.6 x 150 mm) equipped with an Alltech All-Guard column. The column was equilibrated with 20 mM potassium phosphate, pH 6.2 and eluted with a linear gradient of 0-60% acetonitrile over 20 minutes at a 194 flow rate of 1.5 mL/min and at a temperature of40 0 C. UV absorbance was monitored at 300 nM. Exposure of 50.6 (100 pM) to the plasma samples resulted in the formation of a single metabolite. This metabolite had the same retention time and UV spectrum as a product formed following incubation of the prodrug with pig liver esterase (Sigma Chemical Co, MO), suggesting that it was a product of an esterase-catalyzed reaction. The metabolite formed in rat plasma was collected and subjected to mass spectrum analysis at Mass Consortium Corporation (San Diego, CA). The sample yielded a negative ion peak at 372, indicating that the metabolite formed had a molecular weight of 373. This molecular weight is consistent with that of a monophosphoramidate intermediate. This intermediate is likely formed via a reaction mechanism in which the prodrug first undergoes full de-esterification followed by intramolecular, hydrolytic cleavage of one of the amino acyl substituents.

Formation of the postulated monophosphoramidate intermediate was confirmed following the synthesis of a synthetic standard, Compound C. The standard had the identical HPLC and UV profile as the metabolite formed in plasma samples.

Example K: Metabolism of 50.6 in Human Hepatocytes Cryopreserved human hepatocytes were obtained from In Vitro Technologies and thawed according to the vendor's recommendations. Cells were incubated at 37 0 C in a Krebs-bicarbonate based buffer containing 50.6 at 10 pM. At various time points over the course of 4 hours, aliquots of cells were removed and extracted by addition of methanol to 60%. Cell extracts were clarified by centrifugation and analyzed by reverse phase HPLC with use of a Beckman Ultrasphere ODS column (4.6 x 150 mm) equipped with an Alltech All- Guard column. The column was equilibrated with 20 mM potassium phosphate, pH 6.2 and eluted with a linear gradient of 0-60% acetonitrile over 20 minutes at a flow rate of mL/min and at a temperature of 40 0 C. UV absorbance was monitored at 300 nM. 50.6, Compound C, and 3.1 were quantified by comparison to authentic standards. Disappearance of 50.6 was rapid and essentially complete within 60 minutes of incubation. Two metabolites of 50.6 were detected: Compound C and 3.1. The initial rate of 3.1 formation was 195 24 pmol/million cells/minute. This study indicates that 50.6 is converted to the active FBPase inhibitor, 3.1, in intact human hepatocytes.

Example L: Structure Activity Relationship of Human Liver Phosphoramidase Human liver, purchased from the Anatomic Gift Foundation (Laurel, MD), was homogenized in Krebs-bicarbonate buffer and clarified by a slow-speed centrifugation.

Prodrug metabolism was evaluated in reaction mixtures containing human liver homogenate (4 mgs protein), 50 mM Tris-HCl, pH 7.4, 10 mM MgC12, and 10 mM dithiothreitol. At various time intervals over the course of 2 hours, aliquots were removed from the reaction mixtures and deproteinated by addition of methanol to 60%. Following clarification by centrifugation, metabolites were analyzed by reverse phase HPLC with use of a Beckman Ultrasphere ODS column (4.6 x 150 mm) equipped with an Alltech All-Guard column. The column was equilibrated with 20 mM potassium phosphate, pH 6.2 and eluted with a linear gradient of 0-60% acetonitrile over 20 minutes at a flow rate of 1.5 mL/min and at a temperature of 40°C. UV absorbance was monitored at 300 nM. Most of the prodrugs evaluated were metabolized via a non-rate limiting, esterase-catalyzed step to their monophosphoramidate form within 5 minutes of incubation. The rate of phosphonic acid appearance was therefore essentially a reflection of the rate of the final phosphoramidatecatalyzed cleavage step. Results for representative prodrugs for which the esterase-catalyzed step was non-rate limiting are shown below: Phosphoramidase Activity (Rate of 3.1 or 3.58 production, Prodrug nmoles/mn/mg liver protein) 50.6 0.022 50.8 0.019 50.10 0.005 50.12 0.022 50.20 0.085 Phosphoramidase Activity (Rate of 3.1 or 3.58 production, Prodrug nmoles/mn/mg liver protein) 50.19 0.029 52.8 0.025 52.12 0.032 52.16 0.033 The results indicate that human liver phosphoramidase readily cleaves the phosphorusnitrogen bond of a variety of phosphonic acid-monoamidate substrates, thereby liberating the free phosphonic acid FBPase inhibitor. The lowest P-N cleavage rate was observed with a secondary amine substrate, the monophosphoramidate of 50.10. The first step in prodrug activation, esterase-catalyzed de-esterification, was not rate-limiting for the majority of substrates evaluated.

While in accordance with the patent statutes, description of the various embodiments and processing conditions have been provided, the scope of the invention is not to be limited thereto or thereby. Modifications and alterations of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention.

Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims, rather than by the specific examples which have been presented by way of example.

Claims

1. A compound of formula IA 0 R 18 1I I 12 14 M-P-N-(CR R")n-C(O)-R NRsR 16 (IA) wherein compounds of formula IA are converted in vivo or in vitro to M-PO 3 H 2 which is an inhibitor of fructose -1,6-bisphosphatase and n is an integer from 1 to 3: RP is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R 1 2 and R 1 3 is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R 1 2 and R 13 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group; each R' 4 is independently selected from the group consisting of -OR 1 7 2 -NHR 17 -NR 2 OR 1 9 and -SR 17 R 15 is selected from the group consisting of-H, lower alkyl, lower aryl, lower aralkyl, or together with R 16 is connected via 2-6 atoms, optionally including t heteroatom selected from the group consisting of 0, N, and S; R 1 6 is selected from the group consisting of-(CR"R')n-C(O)-R 14 lower alkyl, lower aryl, lower aralkyl, or together with R 1 5 is connected via 2-6 atoms, optionally including I heteroatom selected from the group consisting of 0, N, and S; each R 17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R 17 and R 1 7 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of 0, N, and S; IND CA R1 8 is independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R 12 is connected via 1-4 carbon atoms to form a cyclic group; each R 19 is independently selected from the group consisting of-H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR 3 and pharmaceutically acceptable salts thereof.

2. The compounds of claim I wherein M-PO 3 H 2 has an ICso on isolated human liver FBPase enzyme of less than or equal to 10 IM.

3. The compounds of claim 2 wherein said ICso is less than or equal to 1 4M.

4. The compounds of claim 1 wherein M is R 5 -X- wherein R 5 is selected from the group consisting of: J /G G. and wherein: each G is independently selected from the group consisting of C, N, 0, S, and Se, and wherein only one G may be 0, S, or Se, and at most one G is N; each G' is independently selected from the group consisting of C and N and wherein no more than two G' groups are N; A is selected from the group consisting of -NR 4 2 -CONR 4 2 -C0 2 R 3 halo, -S(O)R 3 -SO 2 R 3 alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, -CH 2 OH, -CH 2 NR 4 2 -CH 2 CN, -CN, -C(S)NH 2 -OR 2 -SR 2 -N 3 -NHC(S)NR 4 2 -NHAc, and null; each B and D are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, -C(O)R 1 1 -C(O)SR 3 -SO 2 R" 1 -S(O)R 3 -CN, -NR 9 2 -OR 3 -SR 3 perhaloallcyl, halo, -NO 2 and null, all except -CN, perhaloalkyl, -NO 2 and halo are optionally substituted; E is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, -C(0)OR 3 -CONR 4 2 -CN, -NR'2, -NO 2 -OR 3 -SR 3 perhaloalkyl, halo, and null, all except -CN, perhaloalkyl, and halo are optionally substituted; J is selected from the group consisting of -H and null; X is an optionally substituted linking group that links R 5 to the phosphorus atom via 2- 4 atoms, including 0-1 heteroatoms selected from N, 0, and S, except that if X is urea or carbamate there is 2 heteroatoms, measured by the shortest path between R 5 and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein X is selected from the group consisting of -alkyl(hydroxy)-, -alkynyl-, -heteroaryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X is not substituted with -COOR 2 -SO 3 H, or -PO3R22; R 2 is selected from the group consisting of R and -H; R 3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R 4 is independently selected from the group consisting of and alkcyl, or together R 4 and R 4 form a cyclic alkyl group; each R 9 is independently selected from the group consisting of alkyl, aryl, aralkyl, and alicyclic, or together R 9 and R 9 form a cyclic alkyl group; R1 1 is selected from the group consisting of alkyl, aryl, -NRP 2 and -OR 2 and with the proviso that: 1) when G' is N, then the respective A, B, D, or E is null; 2) at least one of A and B, or A, B, D, and E is not selected from the group consisting of -H or null; 3) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom; and pharmaceutically acceptable salts thereof. The compounds of claim 4 wherein R 5 is selected from the group consisting of pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, pyrazolyl, isoxazolyl, 1 ,2,3-oxacliazolyl, I ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1,3 ,4-O'xadiazolyl, I ,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridinyl, pyrimidinyl, pyrrazinyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4- triazinyl, and l,3-selenazolyl, all of which contain at least one substituent.

6. The compounds of claim 4 wherein A is selected from the group consisting of-H, -WR 2 -CONk 4 2 -C0 2 R 3 halo, C I-C6 allcyl, C2-C6 alkcenyl, C2-C6 alkynyl, CI-C6 perhaloalcyl, C1-C6 haloalkyl, aryl, -CH 2 OH, -CH 2 NR 4 2 CH 2 CN, -CN, -C(S)NH 2 -OR 2 -SR 2 -N 3 -NHC(S)NR 4 2 -NHAc, and null; each B and D are independently selected from the group consisting of alkyl, alkcenyl, alkynyl, aryl, heteroaryl, alicyclic, aralkyl, alkoxyalkyl, -C(O)R 11 -C(O)SR 3 -S0 2 R 11 -CN, -SR 3 perhaloalkyl, halo, and null, all except -CN, perhaloalkyl, and halo are optionally substituted; E is selected from the group consisting of CI-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, C4-C6 alicyclic, aLkoxyallcyl, -CONK 2 -CN, -NR 9 2 -SR', CI-C6 perhaloalkyl, halo, and null, all except -CN, perhaloalkyl, and halo are optionally substituted; and each R 4 is independently selected from the group consisting of and C1-C2 alkyl.

7. The compounds of claim 4 wherein R 5 is:

8. The compounds of claim 4 wherein R 5 is:

9. The compounds of claim 4 wherein R 5 is selected from the group consisting of: B. 0 E., wherein A" is selected from the group consisting of -Wa 2 -CONK 4 2 -C0 2 W 3 halo, C I-C6 ailcyl, C2-C6 alkenyl, C2-C6 alkynyl, CI-C6 perhaloalkyl., CI-C6 haloalkyl, aryl, -CH1 2 OH, -CH 2 NR 4 2 -CH 2 CN, -CN, -C(S)NH 2 -OR 2 -SR 2 -N 3 -NHC(S)NR 4 2 and -NHAc; B" and D" are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, aralkyl, alcoxyalkyl, -C(O)R 11 -C(O)SR 3 -SO 2 R1', -S(O)R 3 -CN, -NR9 2 -OR 3 -SR 3 perhaloalkyl, and halo, all except -CN, perhaloalkyl, and halo are optionally substituted; E" is selected from the group consisting of C1-C6 alkyl, C2-G6 alkcenyl, C2-C6 alkynyl, aryl, C4-C6 alicyclic, alkcoxyallkyl, -CONR 4 2 -CN, -NR 9 2 -ORW, -SR', C1-C6 perhaloallcyl, and halo, all except H, -CN, perhaloalkyl, and halo are optionally substituted; and each R 4 is independently selected froma the group consisting of -H and C I-C2 ailcyl. The compounds of claim 4 wherein X is selected from the group consisting of -heteroaryl-, -alkylcarbonylamino-, -alkylaminocarbonyl-, anid -alkoxycarbonyl-.

11. The compounds of claim 4 wherein said compound is a compound of formulae UI, III, or IV: 0 OR 8 II 1 I 1 2 31 R -C-NH-CH 2 -P-N-(CR R' NR 5 R' 8 and (1 0 0R1 8 11 12 14 RS-C-O-0H 2 -P-N-(CR R NR'SR'e (IV)

12. The compounds of claim 9 wherein X is selected from the group consisting of -heteroaryl-, -alkoxyalkyl-, -alkylcarbonylamino-, -alkylaminocarbonyl-, and -alkoxycarbonyl-.

13. The compounds of claim 4 wherein n is 1; R 1 2 and R 1 3 are independently selected from the group consisting of-H, lower alkyl, lower perhaloalkyl, and lower aryl, optionally substituted with -OR" 9 -NR 9 2 -SR 1 9 -C(O)NR 2 R 3 halo, -C0 2 R 2 3-indolyl, 4-imidazolyl, or guanidinyl, or R 1 2 and R 1 3 are connected via 2-5 carbon atoms to form a cycloalkyl group; R 1 4 is selected from the group consisting of-OR" 1 -SR 17 and -NR 2 OR 1 9 R 1 5 and R 1 6 are independently selected from the group consisting of-H, and C 1-C6 alkyl, or together R 15 and R 1 6 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of 0O, N and S; R 1 7 is selected from the group consisting of Cl-C7 alkyl, phenyl, indolyl, sesimol and benzyl, wherein said phenyl, indolyl, sesimol and benzyl may be optionally substituted with 1-3 groups selected from the group of-COzR 2 -OR 2 -NHC(O)R 3 halo and lower alkyl; and R 1 8 is selected from the group consisting of-H, C1-C6 alkyl and benzyl;

14. The compounds of claim 4 wherein R 1 8 is selected from the group consisting of-H, C1-C6 alkyl. The compounds of claim 14 wherein R' 8 is selected from the group consisting of -H and methyl.

16. The compounds of claim 15 wherein R 1 8 is -H.

17. The compounds of claim 4 wherein each R 12 and R 1 3 is independently selected from the group consisting of-H, lower alkyl, lower perhaloalkyl, lower aralkyl, lower aryl, optionally substituted with -OR 1 9 -NR' 9 2 -SR 1 9 -C(0)NRR 3 halo, -C0 2 R 2 3-indolyl, 4- imidazolyl, or guanidinyl, or together R 1 2 and R 1 3 are connected via 2-5 carbon atoms to form a cycloalkyl group.

18. The compounds of claim 17 wherein each R 1 2 and R 13 is independently selected from the group consisting of-H, C1-C4 alkyl, -CH 2 -O-C(CH 3 3 phenyl, and benzyl, or together R 12 and R' 3 are connected via 2 or 4 carbon atoms to form a cyclopropyl or cyclopentyl group.

19. The compounds of claim 18 wherein each R 12 and R 13 is independently selected from the group consisting of-H, and methyl, or together R 1 2 and R 1 3 are connected via 4 carbon atoms to form a cyclopentyl group.

20. The compounds of claim 18 wherein R 12 and R 13 are both both methyl, or R, 2 is H and R 13 is selected from the group consisting of methyl, i-propyl, and benzyl.

21. The compounds of claim 20 wherein n is 1, and R 12 is then the carbon attached to R 12 and R 13 has S stereochemistry.

22. The compounds of claim 4 wherein n is an integer of from 1-2.

23. The compounds of claim 22 wherein n is 1.

24. The compounds of claim 4 wherein each R 1 4 is independently selected from the group consisting of -OR' 7 -SR 17 and -NR 2 OR 19 and R 17 is selected from the group consisting of C1-C7 alkyl, phenyl, indolyl, sesimol and benzyl, wherein said phenyl, indolyl, sesimol and benzyl may be optionally substituted with 1-3 groups selected from the group consisting of -CO 2 R 2 -OR 2 -NHC(O)R 3 halo, and lower alkyl. The compounds of claim 24 wherein R 14 is -OR" 7 N

26. The compounds of claim 25, wherein R 17 is selected from the group consisting of IND methyl, ethyl, i-propyl, n-propyl, t-butyl, isobutyl, neopentyl, cyclopentyl, and unsubstituted benzyl.

27. The compounds of claim 4 wherein R 15 and R 1 6 are independently selected from the group consisting of-H, and C1-C6 alkyl, or together R' 5 and R 16 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of, 0, N, and S.

28. The compounds of claim 27 wherein -NR 5 R 16 is selected from the group consisting of morpholinyl and pyrrolidinyl.

29. The compounds of claim 4 wherein R 16 is -(CR" 2 R' 3 4 and each n is 1. The compounds of claim 4 wherein n is 1; R 12 and R 13 are independently selected from the group consisting of lower alkyl, lower perhaloalkyl, and lower aryl, optionally substituted with -OR 1 9 -NR' 9 2 -SR g 9 -C(O)NRR 3 halo, -CO 2 R 3-indolyl, 4-imidazolyl, and guanidinyl, or R 12 and R' 3 are connected via 2-5 carbon atoms to form a cycloalkyl group; R' 4 is selected from the group consisting of -OR" 7 -SR 17 and -NR 2 OR 19 R 15 is selected from the group consisting of-H and C1-C6 alkyl; R 16 is selected from the group consisting of-H, C1-C6 alkyl, and -(CRR12R)n-C(O)-RI4; or together R is and R 1 6 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of N, 0 and S. R 1 7 is selected from the group consisting of C1-C7 alkyl, phenyl, indolyl, sesimol, and benzyl, wherein said phenyl, indolyl, sesimol, and benzyl may be optionally substituted with 1-3 groups selected from the group of--CO 2 R 2 -OR 3 -NHC(O)R 3 halo and lower alkyl; and R 1 8 is selected from the group consisting of-H, C1-C6 alkyl, and benzyl.

31. The compounds of claim 30 that are of the formula: Rs-X-P-N-(CR R)--C(O)-R14

32. The compounds of claim 31 wherein n is 1.

33. The compounds of claim 32 wherein when R 1 2 and R 1 3 are not the same, then R"HN-CR 1 2 R 3 -C(O)-R 1 4 is an ester or thioester of a naturally occurring amino acid; and R 1 4 is selected from the group consisting of-OR 1 7 and -SR 1 7

34. The compounds of claim 9 wherein A" is selected from the group consisting of-NH 2 -CONH-z, halo, -CH 3 -CF 3 -CH 2 -halo, -CN, -OCH 3 -SCH 3 and -H; B" is selected from the group consisting of-H, -C(O)SR 3 alkyl, aryl, alicyclic, halo, -CN, -SR 3 OR 3 and -NRz; D" is selected firom the group consisting of-H, -C(O)SR 3 -NR 9 2 alkyl, aryl, alicyclic, halo, and -SR 3 E" is selected from the group consisting of-H, C1-C6 alkyl, lower alicyclic, halo, -CN, and -SR 3 X is selected from the group consisting of -heteroaryl-, -alkoxycarbonyl-, and -alkylaminocarbonyl-, all optionally substituted; R 2 is selected from the group consisting of R and -H; R 3 is selected from the group consisting of C1-C4 alkyl, C4-C6 aryl, C2-C7 alicyclic, and C5-C7 aralkyl, wherein said aryl, alicyclic, and aralkyl maybe optionally substituted with 1-2 heteroatoms; each R 12 and R 13 is independently selected from the group consisting of-H, C1-C4 alkyl, -CH 2 -O-C(CH 3 3 phenyl, and benzyl, or together R 12 and R 1 3 are connected via 2 or 4 carbon atoms to form a cyclopropyl or cyclopentyl group; nis 1; each R1 4 is independently selected from the group consisting of -OR 17 -SR 17 and -NR 2 OR' 9 R 1 5 is selected from the group consisting of-H, methyl, ethyl, propyl; R 16 is -(CR 12 R 13 )n-C(O)-R 14 R 1 7 is selected from the group consisting of C1-C7 alkyl, phenyl, indolyl, and benzyl, wherein said phenyl, indolyl, and benzyl may be optionally substituted with 1-3 groups selected from the group consisting of-C0 2 R 2 -OR 3 -NHC(O)R 3 halo and lower alkyl; R 18 is selected from the group consisting of -H and methyl; and R 19 is selected from the group of-H, C1-C4 alkyl, C4-C6 aryl, C2-C7 alicyclic, C7 aralkyl, -COR 3 The compounds of claim 34 wherein 0 R 18 R 12 0 -P-N--CI I I II-R14 NR2R 1 R 1 is selected from the group consisting of o OH 3 -P OOR 17] OH 3 and 0- OH 3 11 1 2 wherein R1 7 is selected from the group consisting of ethyl, i-propyl, n-propyl, and neopentyl.

36. The compounds of claim 35 wherein C* has S stereochemistry.

37. The compounds of claim 34 wherein R5 is S B. X is selected from the group consisting of methylenoxycarbonyl, and furan-2,5-diyl, and pharmaceutically acceptable salts thereof.

38. The compounds of claim 37 wherein A" is -NH 2 X is furan-2,5-diyl, and B" is -S(CH 2 2 CH 3

39. The compounds of claim 37 wherein A" is -NH 2 X is furan-2,5-diyl, and B" is -CH 2 -CH(CH 3 )2. The compounds of claim 37 wherein A" is -NH 2 X is fturan-2,5-diyl, and B" is -COOEt.

41. The compounds of claim 37 wherein A" is -NH 2 X is furan-2,5-diyl, and B" is -SMe.

42. The compounds of claim 37 wherein A" is -Nil 2 X is methyleneoxycarbonyl, and B" is -CH(CH 3 2

43. The compounds of claim 38 wherein .0 fRI 8 R 12 0 I II 416 11 is 0 CH 3 H11 CO017] CH 3 wherein R 1 7 is selected from the group consisting of ethyl, i-propyl, n-propyl, and neopentyl.

44. The compounds of claim 38 wherein 0 RIB R 12 0 II I 1R 16 R 1 is CO17] wherein C* has S stereochemistry and wherein R 1 7 is selected from the group consisting of ethyl, i-propyl, n-propyl and neopentyl.

45. The compounds of claim 39 wherein o R 1 8 R1 2 0 NR' R 1 R 1 is H~-j--COOEt CH 3

46. The compounds of claim 39 wherein 0 R' 8 R 12 0 1 16 113 NRR R 0 CH3 -P NH--COOEt H wherein C* has S stereochemistry.

47. The compounds of claim 46 that are selected from the group consisting of a hydrochloride salt, a hydrobromide salt, an acetic acid salt, a trifluoroacetic acid salt, a methanesulfonic acid salt, a p-toluenesulfonic acid salt, and a maleic acid salt.

48. The compounds of claim 39 wherein 0 R 18 R 12 O S I I II -P-N-C-C-R 14 1 6 1 13 NR1N 6 R 3 is selected from the group consisting of 0 CH 3 P- NH- -COOR'7 1I 2 H and 0 CH 3 -NH----COOR I 2 CH 3 wherein R 1 7 is ethyl, n-propyl, i-propyl, and neopentyl and wherein C* has S stereochemistry.

49. The compounds of claim 48 that are selected from the group consisting of a hydrochloride salt, a hydrobromide salt, an acetic acid salt, a trifluoroacetic acid salt, a methanesulfonic acid salt, a p-toluenesulfonic acid salt, and a maleic acid salt.

50. The compounds of claim 39 wherein 0 R18 R 12 0 S I I II -P-N-C-C-R 14 NR Nis R13 O R t 2 P--NH--C COOEl R13 wherein R 12 and R 13 together form a cyclopentyl group.

51. The compounds of claim 50 that are selected from the group consisting of a hydrochloride salt, a hydrobromide salt, an acetic acid salt, a trifluoroacetic acid salt, a methanesulfonic acid salt, a p-toluenesulfonic acid salt, and a maleic acid salt.

52. The compounds of claim 41 wherein 0 R 1 8 R 1 2 O -P-N-C-C-R AR1R16 1 13 NRisR R is 0 CH 3 *--COOEt H wherein C* has S stereochemistry.

53. The compounds of claim 52 that are selected from the group consisting of a hydrochloride salt, a hydrobromide salt, an acetic acid salt, a trifluoroacetic acid salt, a methanesulfonic acid salt, a p-toluenesulfonic acid salt, and a maleic acid salt.

54. The compounds of claim 34 wherein R 5 is 0 B" X is selected from the group consisting of furan-2,5-diyl, and methyleneoxycarbonyl, A" is -NH 2 and pharmaceutically acceptable salts thereof. The compounds of claim 54 wherein X is furan-2,5-diyl and B" is -SCH 2 CH 2 CH 3

56. The compounds of claim 34 wherein R 5 is A" is -NH 2 E" and D" are B" is selected from the group consisting of cyclopropyl, and n-propyl, X is selected from the group consisting of methyleneoxycarbonyl and and pharmaceutically acceptable salts thereof.

57. The compounds of claim 34 wherein R 5 is A" is -NH 2 D" is B" is selected from the group consisting of n-propyl, and cyclopropyl, X is selected from the group consisting of furan-2,5-diyl, and methyleneoxycarbonyl, and pharmaceutically acceptable salts thereof.

58. A method of treating diabetes, by administering to an animal in need thereof a pharmaceutically effective amount of a compound of formula OR 1 8 11 I R-X-P-N-(CR 2R )n-C(0)-R4 (I) NRom the group consisting of 6 wherein R 5 is selected from the group consisting of: and E- 1- D wherein: each G is independently selected from the group consisting of C, N, 0, S, and Se, and wherein only one G may be 0, S, or Se, and at most one G is N; each G' is independently selected from the group consisting of C and N and wherein no more than two G' groups are N; A is selected from the group consisting of-H, -NR 4 2 -CONR 4 2 -CO2R 3 halo, -S(O)R 3 -SO 2 R 3 alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, -CH 2 0H, -CH 2 NR 4 2 -CH 2 CN, -CN, -C(S)NH 2 -OR 2 -SR 2 -N 3 -NHC(S)NR 2, -NHAc, and null; each B and D are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, -C(O)R 11 -C(O)SR 3 -SO 2 R" 1 -S(O)R 3 -CN, -NR'2, -OR 3 -SR 3 perhaloalkyl, halo, -NO 2 and null, all except -CN, perhaloalkyl, -NO 2 and halo are optionally substituted; E is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, -C(0)OR 3 -CONR 4 2 -CN, -NR? 2 -NO 2 -OR 3 -SR 3 perhaloalkyl, halo, and null, all except -CN, perhaloalkyl, and halo are optionally substituted; I is selected from the group consisting of -H and null; X is an optionally substituted linking group that links R s to the phosphorus atom via 2- 4 atoms, including 0-1 heteroatoms selected from N, 0, and S, except that if X is urea or carbamate there is 2 heteroatoms, measured by the shortest path between R 5 and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein X is selected from the group consisting of -alkyl(hydroxy)-, -alkynyl-, -heteroaryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X is not substituted with -COOR 2 -SO 3 H, or -P0 3 R22; n is an integer from 1 to 3; R 2 is selected from the group consisting of R and -H; R 3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R 4 is independently selected from the group consisting of and alkyl, or together R 4 and R 4 form a cyclic alkyl group; each R 9 is independently selected from the group consisting of alkyl, aralkyl, and alicyclic, or together R 9 and R 9 form a cyclic alkyl group; R" 1 is selected from the group consisting of alkyl, aryl, -NR 2 2 and -OR 2 each R 12 and R 1 3 is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R 1 2 and R 13 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of 0, N and S, to form a cyclic group; each R 1 4 is independently selected from the group consisting of -OR 1 7 -N(R 7 2 -NHR 1 7 -NR 2 OR 19 and -SR' 7 R 1 5 is selected from the group consisting of lower alklyl, lower aryl, lower aralkyl, or together with R 1 6 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of 0, N, and S; R' 6 is selected from the group consisting of-(CR' 2 R")n-C(O)-R1 4 lower alkyl, lower aryl, lower aralkyl, or together with R 1 5 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S; each R 17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R' 7 and R 17 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S; R 1 8 is independently selected, from the group consisting of H, lower allcyl, aryl, aralkyl, or together with R 1 2 is connected via 1-4 carbon atoms to form a cyclic group; each R 1 9 is independently selected from the group consisting of-H, lower alcyl, lower aryl, lower alicyclic, lower aralkyl, and COR 3 and with the proviso that: 1) when G' is N, then the respective A, B, D, or E is null; 2) at least one of A and B, or A, B, D, and E is not selected from the group consisting of -H or null; 3) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom; and pharmaceutically acceptable salts thereof.

59. A method of inhibiting fructose-1,6-bisphosphatase in an animal in need thereof comprising the administration of a pharmaceutically effective amount of a compound of formula O R 18 SII 12 13 I4 R'-X-P-N-(CR 2 RI)n-C(0)-R 4 (I) NR 5 R 1 6 wherein R 5 is selected from the group consisting of: AG A S/--and E G B D wherein: each G is independently selected from the group consisting of C, N, 0, S, and Se, and wherein only one G may be 0, S, or Se, and at most one G is N; each G' is independently selected from the group consisting of C and N and wherein no more than two G' groups are N; A is selected from the group consisting of-H, -NR 4 2 -CONR 4 2 -CO 2 R 3 halo, -S(O)R 3 -SO2R 3 alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, -CH 2 OH, -CH 2 NR 2 -CH 2 CN, -CN, -C(S)NH2, -OR 2 -SR 2 -N 3 -NHC(S)NR 4 2 -NHAc, and null; each B and D are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, -C(O)SR 3 -SO 2 -S(O)R 3 -CN, -NR'2, -OR 3 -SR 3 perhaloalkyl, halo, -NO 2 and null, all except -CN, perhaloalkyl, -NO 2 and halo are optionally substituted; E is selected from the group consisting of-H, allcyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, -C(O)OR 3 -CONR 2 -CN, -NR'2, -NO 2 -OR 3 -SR 3 perhaloalkyl, halo, and null, all except -CN, perhaloalkyl, and halo are optionally substituted; J is selected from the group consisting of -H and null; X is an optionally substituted linking group that links R 5 to the phosphorus atom via 2- 4 atoms, including 0-1 heteroatoms selected from N, 0, and S, except that if X is urea or carbamate there is 2 heteroatoms, measured by the shortest path between R 5 and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein X is selected from the group consisting of -alkyl(hydroxy)-, -alkynyl-, -heteroaryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X is not substituted with -COOR 2 -SO 3 H, or -PO3R 2; n is an integer from 1 to 3; R 2 is selected from the group consisting of R 3 and -H; R 3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; 220 each R 4 is independently selected from the group consisting of-H, and alkyl, or together R 4 and R 4 form a cyclic alkyl group; each R 9 is independently selected from the group consisting of alkyl, aralkyl, and alicyclic, or together R 9 and R 9 form a cyclic alkyl group; R 11 is selected from the group consisting of alkyl, aryl, -NR22, and -OR 2 each R 12 and R 13 is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R 12 and R 13 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of 0O, N and S, to form a cyclic group; each R 14 is independently selected from the group consisting of -OR 17 2 -NHR 17 -NR2 OR 19 and -SR' 7 R 15 is selected from the group consisting of-H, lower alkyl, lower aryl, lower aralkyl, or together with R 1 6 is connected via 2-6 atoms, optionally including I heteroatom selected from the group consisting of O, N, and S; R 16 is selected from the group consisting of -(CR R' 3 4 lower alkyl, lower aryl, lower aralkyl, or together with R 15 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S; each R 17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R 17 and R 17 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of 0, N, and S; R 18 is independently selected, from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R 12 is connected via 1-4 carbon atoms to form a cyclic group; each R 19 is independently selected from the group consisting of-H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR 3 and with the proviso that: 1) when G' is N, then the respective A, B, D, or E is null; 2) at least one of A and B, or A, B, D, and E is not selected from the group consisting of-H or null; 3) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom; and pharmaceutically acceptable salts thereof. A method of lowering blood glucose, by administering to an animal in need thereof a pharmaceutically effective amount of compound of Formula O R 8 R'-X-P-N-(CR2Ri),-C(O)-R 14 (I) NR'sR 1 6 wherein R 5 is selected from the group consisting of: A -G A NNb G- GB and E G G D wherein: each G is independently selected from the group consisting of C, N, 0, S, and Se, and wherein only one G may be 0, S, or Se, and at most one G is N; each G' is independently selected from the group consisting of C and N and wherein no more than two G' groups are N; A is selected from the group consisting of-H, -NR 4 2 -CONR4 2 -C0 2 R 3 halo, -S(O)R 3 -SO 2 R 3 alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, -CH 2 OH, -CH 2 NR 4 2 -CH 2 CN, -CN, -C(S)NH 2 -OR 2 -SR 2 -N 3 -NHC(S)NR 4 2 -NHAc, and null; 222 each B and D are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, -C(O)SR 3 -S0 2 -S(O)R 3 -CN, -NR92, -OR 3 -SR 3 perhaloalkyl, halo, -NO 2 and null, all except -CN, perhaloalkyl, -NO 2 and halo are optionally substituted; E is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, -C(0)OR 3 -CONR 4 2 -CN, -NR 2 -NO 2 -OR 3 -SR 3 perhaloalkyl, halo, and null, all except -CN, perhaloalkyl, and halo are optionally substituted; J is selected from the group consisting of-H and null; X is an optionally substituted linking group that links R 5 to the phosphorus atom via 2- 4 atoms, including 0-1 heteroatoms selected from N, 0, and S, except that if X is urea or carbamate there is 2 heteroatoms, measured by the shortest path between R 5 and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein X is selected from the group consisting of-alkyl(hydroxy)-, -alkynyl-, -heteroaryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X is not substituted with -COOR 2 -SO 3 H, or -PO 3 R22; n is an integer from 1 to 3; R 2 is selected from the group consisting of R 3 and -H; R 3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R 4 is independently selected from the group consisting of and alkyl, or together R 4 and R 4 form a cyclic alkyl group; each R 9 is independently selected from the group consisting of alkyl, aralkyl, and alicyclic, or together R 9 and R 9 form a cyclic alkyl group; R" is selected from the group consisting of alkyl, aryl, -NR 2 2 and -OR 2 each R 1 2 and R 13 is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R 12 and R 13 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of 0O, N and S, to form a cyclic group; each R 1 4 is independently selected from the group consisting of-OR17, -N(R" 7 2 -NHR 17 -NROR 19 and -SR 17 R 1 5 is selected from the group consisting of-H, lower alkyl, lower aryl, lower aralkyl, or together with R 16 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S; R 16 is selected from the group consisting of -(CR' 2 14 lower alkyl, lower aryl, lower aralkyl, or together with R s 1 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S; each R 17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkcyl, all optionally substituted, or together R 1 7 and R 17 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S; R18 is independently selected, from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R 1 2 is connected via 1-4 carbon atoms to form a cyclic group; each R 1 9 is independently selected from the group consisting of-H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR 3 and with the proviso that: 1) when G' is N, then the respective A, B, D, or E is null; 2) at least one of A and B, or A, B, D, and E is not selected from the group consisting of-H or null; 3) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom; and pharmaceutically acceptable salts thereof.

61. A method of treating glycogen storage diseases, by administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula II NRR6 wherein R 5 is selected from the group consisting of.- \and E <G. B B D wherein: each G is independently selected from the group consisting of C, N, 0, S, and Se, and wherein only one G may be 0, S, or Se, and at most one G is N; each G' is independently selected from the group consisting of C and N and wherein no more than two G' groups are N; A is selected from the group consisting of -NR 4 2 -CONR 4 2 -C0 2 R 3 halo, -S0 2 R 3 alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, -CH 2 OH, -CH 2 NR 2 -GH 2 CN, -CN, -C(S)NH 2 -OR 2 -SR 2 -N 3 -NHC(S)NR 4 2 -NT{Ac, and null; each B and D are independently selected from the group consisting of alkyl, alicenyl, alkynyl, aryl, alicyclic, aralkyl, alicoxyalkyl, -C(O)R11, -SO 2 -S(O)R 3 -CN, -WR 2 -SR 3 perhaloalcyl, halo, -NO 2 and null, all except -CN, perhaloalkyl, -NO 2 and halo are optionally substituted;, E is selected from the group consisting of ailcyl, ailcenyl, alkynyl, aryl, alicyclic, alkoxyallcyl, -CONR 4 2 -CN, -NR 9 2 -NO 2 perhaloalkyl, halo, and null, aU except -CN, perhaloalkyl, and halo are optionally substituted; J is selected from the group consisting of -H and null; 225 X is an optionally substituted linking group that links R 5 to the phosphorus atom via 2- 4 atoms, including 0-1 heteroatoms selected from N, 0, and S, except that if X is urea or carbamate there is 2 heteroatoms, measured by the shortest path between R 5 and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein X is selected from the group consisting of-alkyl(hydroxy)-, -alkynyl-, -heteroaryl-, -carbonylalkcyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyallcyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X is not substituted with -COOR 2 -SO 3 H, or -P0 3 R 2 2 n is an integer from 1 to 3; R 2 is selected from the group consisting of R 3 and -H; R 3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R 4 is independently selected from the group consisting of and alkyl, or together R 4 and R 4 form a cyclic alkyl group; each R 9 is independently selected from the group consisting of alkyl, aralkyl, and alicyclic, or together R 9 and R 9 form a cyclic alkyl group; R"1 is selected from the group consisting of alkyl, aryl, -NR22, and -OR2; each R 12 and R 13 is independently selected from the group consisting of H, lower alIcyl, lower aryl, lower aralkyl, all optionally substituted, or R 12 and R13 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of 0, N and S, to form a cyclic group;. each R 14 is independently selected from the group consisting of-OR 17 -N(R 7 2 -NHR' 7 -NR'OR" and -SR 17 R s 5 is selected from the group consisting of-H, lower alkyl, lower aryl, lower aralkyl, or together with R 16 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S; R 1 6 is selected from the group consisting of 14 lower alkyl, lower aryl, lower aralkyl, or together with R 13 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S; each R 17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R 17 and R 17 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S; R1 8 is independently selected, from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R 12 is connected via 1-4 carbon atoms to form a cyclic group; each R 1 9 is independently selected from the group consisting of-H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR 3 and with the proviso that: 1) when G' is N, then the respective A, B, D, or E is null; 2) at least one of A and B, or A, B, D, and E is not selected from the group consisting of -H or null; 3) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom; and pharmaceutically acceptable salts thereof.

62. The compounds of claim I wherein M is A' G' *E 2 j wherein: G" is selected from the group consisting of and A 2 is selected from the group consisting of -NR 4 2 -NRAc, -SR', -C(O)NR 4 2 halo, -COR' 1 -CN, perhaloallcyl, C1I-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl; L 2 E 2 and j 2 are selected from the group consisting of -NR4 2 -NHAc, -NO 2 -H, 2OR, -SR 2 -C(O)NR 4 2 halo, -COR 11 -S0 2 R 3 guanidinyl, arnidinyl, aryl, aralkyl, alkcyloxyalkyl, -SCN, -NHSO 2 -S0 2 NR 2 -CN, -S(O)W 3 perhaloacyl, perhaloalcyl, perhaloalkoxy, CI-C6 alkcyl(OH), CI-C6 alkyl(SH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ailcynyl, heteroaryl, and lower alicyclic, or together L 2 and E 2 or E 2 and j 2 form an annulated cyclic group; X 2 is selected from the group consisting of -CR 2 2 -CF 2 -CR? 2 -CR 2 2 -CH 2 and -CR 2 2 -NR 20 and wherein in the atom attached to the phosphorus is a carbon atom; with the proviso that X 2 is not substituted with -COOR 2 -S0 3 H, or -P0 3 R 2; R 2 is selected from the group consisting of R 3 and -H; R 3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R 4 is independently selected from the group consisting of and alkyl, or together R 4 and R 4 form a cyclic alkyl group; R" is selected from the group consisting of alkyl, aryl, -NR 2 and -OR 2 R 20 is selected from the group consisting of lower allcyl, and -COR 2 and pharmaceutically acceptable salts thereof.

63. The compounds of claim 62 wherein G" is A 2 is selected from the group consisting of-H, -NR 4 2 -NHAc, -CN, halogen, -OR 3 -C(O)NR 2 C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl; and L 2 E 2 and J 2 are independently selected from the group consisting of -NR 4 2 -NHAc, -NO 2 -CN, halogen, -OR 3 hydroxy, lower alkoxymethylene, -alkyl(OH), aryl, alkyloxycarbonyl, -CO(OH), -SR 3 -SH, lower perhaloalkyl, heteroaryl, lower alicyclic, and C1-C6 alkyl, or together L 2 and E 2 form an annulated cyclic group.

64. The compound of claim 63 wherein A 2 is selected from the group consisting of-H, -NRW 2 halogen, Cl-C5 alkyl; and L 2 E 2 and J 2 are independently selected from the group consisting of -NR 4 2 -CN, -C(0)OH, halogen, lower alkoxy, lower alkylthio, hydroxy, lower alkyl(hydroxy), lower alkoxymethylene, lower aryl, lower heteroaryl, and C1-C5 alkyl, or together L 2 and E 2 form an annulated cyclic group; and R 4 is independently selected from the group of-H, and Cl-C4 alkyl, or R 4 and R 4 are connected by 4-5 atoms to form a cyclic group.

65. The compounds of claim 64, wherein A 2 is selected from the group of-NH 2 -Cl, -Br and -CH 3

66. The compounds of claim 64 wherein L 2 and E 2 are independently selected from the group consisting of-H, -NR 4 2 -CN, -C(O)OH, lower alkoxy, lower alkylthio, alkyl, lower alkyl(hydroxy), lower aryl, and halogen, or together L 2 and E 2 form an annulated cyclic group containing an additional 4 carbon atoms.

67. The compounds of claim 64 wherein J 2 is selected from the group consisting of-H, halo, and C1-C5 alkyl.

68. The compounds of claim 62 wherein X 2 is selected from the group -CF 2 -CH 2 -CH 2 -CH 2 -CH 2 and -CH 2 -N(C(O)CH 3

69. The compounds of claim 68 wherein X 2 is -CH 2 The compounds of claim 62 wherein A 2 is selected from the group consisting of-H, -NH 2 -CH 3 Cl, and Br; L 2 is -CN, alicyclic, aryl, -SCN, lower alkyl, halogen, lower alkyloxy, hydroxy, -alkenylene-OH, or together with E 2 forms a cyclic group including aryl, cyclic alkyl, heteroaryl, heterocyclic alkyl; E 2 is selected from the groups consisting of H, -CN, lower alkylthio, lower alkyl, halogen, -SCN, -OR 3 lower alkyloxycarbonyl, lower alkyloxy, or together with L 2 forms a cyclic group including aryl, cyclic alkyl, heteroaryl, or heterocyclic alkyl; j2 is selected from the groups consisting of-H, halo, and C1-C5 alkyl; G" is X 2 is -CH 2 and pharmaceutically acceptable salts thereof.

71. The compounds of claim 62 wherein each R 12 and R 1 3 is independently selected from the group consisting of-H, lower allcyl, lower perhaloalkyl, lower aralkyl, lower aryl, optionally substituted with -OR 9 -NR' 2 -SR 9 -C(O)NR 2 R 3 halo, -CO 2 R 2 3-indolyl, 4- imidazolyl or guanidinyl, or together R 12 and R 13 are connected via 2-5 carbon atoms to form a cycloalkyl group.

72. The compounds of claim 71 wherein each R 1 2 and R 13 is independently selected from the group consisting of-H, C1-C4 alkyl, -CH 2 -O-C(CH 3 3 phenyl, and benzyl, or together R 12 and R 13 are connected via 2 or 4 carbon atoms to form a cyclopropyl or cyclopentyl group.

73. The compounds of claim 72 wherein each R 1 2 and R 13 is independently selected from the group consisting of-H, and methyl, or together R 1 2 and R 13 are connected via 4 carbon atoms to form a cyclopentyl group.

74. The compounds of claim 72 wherein R 12 and R 1 3 are both both methyl, or R 1 2 is H and R 13 is selected from the group consisting of methyl, i-propyl, and benzyl. The compounds of claim 74 wherein n is 1, and R 1 2 is then the carbon attached to R 1 2 and R 1 3 has S stereochemistry.

76. The compounds of claim 62 wherein n is an integer of from 1-2.

77. The compounds of claim 76 wherein n is 1.

78. The compounds of claim 62 wherein each R 1 4 is independently selected from the group consisting of-OR 1 7 -SR 17 and -NR 2 OR 19 and R 1 7 is selected from the group consisting of C1-C7 alkyl, phenyl, indolyl, sesimol, and benzyl, wherein said phenyl, indolyl, sesimol and benzyl may be optionally substituted with 1-3 groups selected from the group consisting of-CO2R 2 -OR 2 -NHC(O)R 3 halo and lower alkyl.

79. The compounds of claim 78 wherein R" is -OR 7 The compounds of claim 79, wherein R 17 is selected from the group consisting of methyl, ethyl, i-propyl, n-propyl, t-butyl, isobutyl, neopentyl, cyclopentyl and unsubstituted benzyl.

81. The compounds of claim 62 wherein R 15 and R 1 6 are independently selected from the group consisting of-H, and C1-C6 alkyl, or together R 15 and R 16 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of, 0, N, and S.

82. The compounds of claim 81 wherein -NR"R 16 is selected from the group consisting of morpholinyl and pyrrolidinyl.

83. The compounds of claim 62 wherein R 16 is -(CR 2 R' 3 )n-C(O)-R 14 and each n is 1.

84. The compounds of claim 62 wherein nis 1; R 12 and R 13 are independently selected from the group consisting of lower alkyl, lower perhaloalkyl, and lower aryl, optionally substituted with -OR' 9 -NR" 2 -SR' 9 -C(O)NR 2 R 3 halo, -C0 2 R 2 3-indolyl, 4-imidazolyl, and guanidinyl, or R 12 and R' 3 are connected via 2-5 carbon atoms to form a cycloalkyl group; R 14 is selected from the group consisting of -OR 17 -SR 17 and -NR'OR 19 R 15 is selected from the group consisting of-H and C1-C6 alkyl; R 16 is selected from the group consisting of-H, C1-C6 alkyl, and -(CR' 2 R' 3 1 4 or together R 1 5 and R 16 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of N, 0 and S. IND ;Z CA R 1 7 is selected from the group consisting of CI-C7 alkyl, phenyl, indolyl, sesimol and benzyl, wherein said phenyl, indolyl, sesimol and benzyl may be optionally substituted with 1-3 groups selected from the group of -COzR 2 -NHC(O)R 3 halo and lower alkyl; and R 1 8 is selected from the group consisting of-H, C1-C6 alkyl, and benzyl. The compounds of claim 84 that are of the formula:

86. The compounds of claim 85 wherein n is 1.

87. The compounds of claim 86 wherein when R 1 2 and R 1 3 are not the same, then R 1 HN-CR R'I-C(O)-R 1 4 is an ester or thioester of a naturally occurring amino acid; and R 1 4 is selected from the group consisting of-OR 1 7 and -SR 1 7

88. The compounds of claim 70 where A 2 is NH 2 L 2 is selected from the group consisting of-H, methyl, ethyl, propyl, -SCN, and -Cl, E 2 is selected from the group consisting of-SCN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, and -Br, and J 2 is -H.

89. The compounds of claim 88 wherein 0 R 18 R 12 0 -P-N- NR 5 N' 16 is selected from the group consisting of 1k 4 R 1 3 and 0 CH3 P- NH-C*-COOR 17 H wherein R 1 7 is selected from the group consisting of ethyl, i-propyl, n-propyl, n-butyl and neopentyl. The compounds of claim 89 wherein C* has S stereochemistry.

91. The compounds of claim 62 wherein A 2 is selected from the group consisting of-H, -NH 2 -CH3, -Cl, and -Br L 2 is selected from the group consisting of-H, -CN, -SCN, C1-C6 alkyl, halogen, lower alkoxy, or together with E 2 forms a cyclic group including aryl, cyclic alkyl, heteroaryl, heterocyclic alkyl; E 2 is selected from the group consisting of-H, -SCN, halogen, -CN, C1-C6 alkyl, Cl- C6 alkoxy, or together with L 2 forms a forms a cyclic group including aryl, cyclic alkyl, heteroaryl, heterocyclic alkyl; J2 is selected from the group consisting of-H, -C1, and -CH 3 nis 1; each R 1 2 and R 1 3 is independently selected from the group consisting of C1-C4 alkyl, -CH 2 -O-C(CH 3 3 phenyl, and benzyl, or together R 1 2 and R 1 3 are connected via 2 or 4 carbon atoms to form a cyclopropyl or cyclopentyl group. R 1 4 is selected from the group consisting of-OR 1 7 -SR 1 7 and -N OR19; R 15 is selected from the group consisting of-H, methyl, ethyl, propyl; 234 R 16 is -(CR1 2 R 1 3b,IC(O) -R" 4 R 1 7 is selected from the group consisting of CI-C7 alkyl, phenyl, indolyl, sesimol, and benzyl, wherein said phenyl, indolyl, sesimol, and benzyl may be optionally substituted with 1-3 groups selected from the group consisting of-C0 2 -OR 3 -NHC(O)R 3 halo, and lower alkyl; R1 8 is selected from the group consisting of -H and methyl; and R1 9 is selected from the group of GI-C4 alkyl, C4-C6 aryl, C2-C7 alicyclic, C7 aralkcyl, and -COR.

92. The compounds of claim 91 wherein 0 R 18 R 12 0 I 1 1 1 I I NR 5 N16 R 1 is selected from the group consisting of 0 OH 3 OH 3 04N C-3 P N COOR 17] wherein R 1 7 is selected from the group consisting of ethyl, i-propyl, neopentyl, and n-propyl.

93. The compounds of claim 92 wherein C* has S stereochemnistry.

94. The compounds of claim 91 wherein. 2 is -NH 2 L' is E 2 is methyl, and j 2 is -H. 235 I The compounds of claim 91 wherein A 2 is -NH 2 L 2 is E 2 is methoxy, and j2 is -H.

96. The compounds of claim 91 wherein A 2 is -NH 2 L2 is methyl, E 2 is ethoxy, and j 2 is -H.

97. The compounds of claim 91 wherein A 2 is -NH 2 iJ is methyl, E 2 is -(O)-CH 2 -CH-(CH 3 2 and J' is -H.

98. The compounds of claim 94 wherein 0 R 18 R 12 0 INIs 16 ~13 is 0 CH 3 -P N ;C OOEt 2 OH 3 and pharmaceutically acceptable salts thereof.

99. The compounds of claim 94 wherein 0 R18 R 12 o -p-N1 14 isN 15 16 1R 13 CA 0 OH 3 1 p NM- COEt 1 wherein C* has S stereochemistry and pharmaceutically acceptable salts thereof

100. The compounds of claimn 95 wherein 0 R18 R120 113 NR 15 N 16 R is selected from the group consisting of 0 OH 3 H000R"7 -114 2 wherein R 17 is ethyl, n-propyl, i-propyl, and neopentyl and wherein C* has S stereochemistry and pharmaceutically acceptable salts thereof.

101. A method of inhibiting a fructose-1,6-bisphiosphatase in an animal in need thereof which comprises the administration of a pharmaceutically effective amiount of a compound of formula A' G' N NR 15 R 1 E 2 j2XN wherein: G" is selected from the group consisting of and A 2 is selected from the group consisting of -NR 4 2 -NHAc, -OR 2 -SR 2 C(O)NR 4 2 halo, -COR", -CN, perhaloall, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl; L 2 E 2 and j 2 are selected from the group consisting of-_NR 4 2 -NHAc, -NO 2 -OR 2 -SR2, -C(O)NR 4 2 halo, -COR 1 -S0 2 R 3 guanidinyl, amidinyl, aryl, aralkyl, alkyloxyalkyl, -SCN, -NHiSO 2 R 3 -S0 2 NR! 2 -CN, -S(O)R 3 perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C6 alkcyl(OH), C1-C6 alkyl(SH), CI-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, and lower alicyclic, or together L2 and E 2 or E 2 and 1 2 form an annulated cyclic group; X 2 is selected from the group consisting of -CR22, -CF 2 -CR 2 2 -CR 2 2 -CH 2 and -CR 2 2 -NR 2 and wherein in the atom attached to the phosphorus is a carbon atom; with the proviso that X 2 is not substituted with -COOR 2 -SO 3 H, or -0R22 n is an integer from 1 to 3; R. 2 is selected from the group consisting of R 3 and -H; R. 3 is-selected from the group consisting of alkyl, aryl, alicyclic, and aralkcyl; 238 each R 4 is independently selected from the group consisting of and alkyl, or together R 4 and R 4 form a cyclic alkyl group; R 1 is selected from the group consisting of alkyl, aryl, -NR 2, and -OR 2 each R 1 2 and R 13 is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R 1z and R 13 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group; each R 1 4 is independently selected from the group consisting of-OR 7 -N(R1 7 2 -NHR 17 -NR20R" and -SR 17 R 1 5 is selected from the group consisting of-H, lower alkyl, lower aryl, lower aralkyl, or together with R 1 6 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of 0, N, and S; R 1 6 is selected from the group consisting of-(CR 2 R 3 )n-C(O)-R 14 lower alkyl, lower aryl, lower aralkyl, or together with R 15 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S; each R 17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R' 7 and R 17 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of 0, N, and S; R 18 is independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R 1 2 is connected via 1-4 carbon atoms to form a cyclic group; each R 19 is independently selected from the group consisting of-H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR 3 R 20 is selected from the group consisting of lower alkyl, and -COR 2 and pharmaceutically acceptable salts thereof.

102. A method of treating diabetes, by administering to an animal in need thereof a pharmaceutically effective amount of an FBPase inhibitor of formula A 2 G' L3 K-I N4CX2N(RIRI )-C(OR 4 NR 15 R'S E 2 2 N wherein: G" is selected from the group consisting of and -S-;I A 2 is selected from the group consisting of -NR 4 2 -NLIAC, -OR 2 -SR,. C(O)NR 4 2 halo, -COR", -CN, perhaloallcyl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl; L 2 E 2 and j 2 are selected from the group consisting of -NR 4 2 -NHAc, -NO 2 -Hl, -OR 2 -C(O)NR 4 halo, -COR' 1 -S0 2 R 3 guanidinyl, amidinyl, aryl, arailcyl, alkyloxyalkyl, -SCN, -NHSO 2 R 3 -S0 2 NR 4 2 -CN, perhaloacyl, perhaloalkyl, perhaloalkoxy, Cl-C6 alkyl(OH), C1-C6 alkyl(SH), CI-C6 alkyl, C2-C6 allenyl, C2-C6 alcynyl, heteroaryl, and lower alicyclic, or together L 2 and E 2 or E 2 and J 2 form an annulated cyclic group; X 2 is selected from the group consisting of -CR 2 2 -CF 2 -CR 2 2 -CR 2 2 -CH 2 and -CR2 2 -NR and wherein in the atom attached to the phosphorus is a carbon atom; with the proviso that X 2 is not substituted with -COOR 2 -SO 3 H, or -0R22 n is an integer from I to 3; Rz is selected from the group consisting of R3 and -H; R 3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R is independently selected from the group consisting of and alkyl, or together R 4 and R 4 form a cyclic alkyl group; R" is selected from the group consisting of alkyl, aryl, -NR 2 2 and -OR 2 each R 12 and R 13 is independently selected from the group consisting of H, lower 0 5 alkyl, lower aryl, lower arallcyl, all optionally substituted, or R 12 and R 13 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group O consisting of 0O, N and S, to form a cyclic group; each RI 4 is independently selected from the group consisting of-OR 1 7 -N(R) 7 2 S-NHR 17 -NR2OR" and -SR7; R 1 5 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, or together with R16 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S; R 1 6 is selected from the group consisting of-(CR1 2 1 4 lower alkyl, lower aryl, lower aralkyl, or together with R 15 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S; each R 17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R 17 and R 17 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S; R 18 is independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R' 2 is connected via 1-4 carbon atoms to form a cyclic group; each R 19 is independently selected from the group consisting of-H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR 3 R 2 0 is selected from the group consisting of lower alkyl, and -COR2; and pharmaceutically acceptable salts thereof.

103. The compounds of claim I wherein M is A 3 L 3 N\ E 3 N J 3 Y 3 wherein: A 3 E 3 and L 3 are selected from the group consisting Of -NR32, -NO 2 -SR,. -C(O)NR 4 2 halo, -COR", -S0 2 guanidine, amidine, -NHSO 2 -S0 2 NRW 2 -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, Cl1-C5 alkyl, C2-C5 alkenyl, alkynyl, and lower alicyclic, or together A 3 and L 3 form a cyclic group, or together L 3 and E 3 form a cyclic group, or together E 3 and j 3 form a cyclic group including aryl, cyclic alkyl, and heterocyclic; J 3 is selected from the group consisting Of -NR 2 -NO 2 -OR 7 -C(O)NR 2 halo, -CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloallcyl, aminoalkyl, alkenyl, alkynyl; alicydlic, aryl, and aralkyl, or together with y 3 forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl; X 3 is selected from the group consisting of -alkcyl(hydroxy)-, -alkyl-, -alkynyl-, -aryl-, -carbonylalkcyl-, -1,1-dihaloalkyl-, -alkcoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylanainocarbonyl-, -alkylcarbonylamnino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -ailcoxycarbonylamino-, and -alkylaminocarbonylam-ino-, all optionally substituted; with the proviso that X 3 is not substituted with -COOR 2 -SO 3 H, or -P0 3 R 2 2 y 3 is selected from the group consisting of alkyl, alkenyl, ailkynyl, aryl, alicyclic, aralkcyl, aryloxyalkyl, alk~oxyalkyl, -C(O)R 3 -S(O)2I(3, -CONHR', -NR 2 and -OR 3 all except H are optionally substituted-, R 2 is selected from the group consisting of R 3 and -H; R 3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R is independently selected from the group consisting of-H, and alkyl, or together R 4 and R 4 form a cyclic alkyl group; R 7 is independently selected from the group consisting of lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and -C(O)R' 0 R 8 is independently selected from the group consisting of-H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, -C(O)R 1 or together they form a bidentate alkyl; each R 9 is independently selected from the group consisting of -alkyl, aralkyl, and alicyclic, or together R 9 and R 9 form a cyclic alkyl group; R1 0 is selected from the group consisting of-H, lower alkyl, -NH 2 lower aryl, and lower perhaloalkyl; R 1 is selected from the group consisting of alkyl, aryl, -NR 2, and -OR 2 and pharmaceutically acceptable salts thereof.

104. The compounds of claim 103 wherein A 3 L 3 and E 3 are independently selected from the group consisting of -NR 8 2 -NO 2 hydroxy, halogen, -OR 7 alkylaminocarbonyl, -SR 7 lower perhaloalkyl, and CI-C5 alkyl, or together E 3 and J 3 together form a cyclic group; and wherein j 3 is selected from the group consisting of-H, halogen, lower alkyl, lower hydroxyalkyl, -NR 8 2 lower R 8 2 N-alkyl, lower haloalkyl, lower perhaloalkyl, lower alkenyl, lower alkynyl, lower aryl, heterocyclic, and alicyclic; and wherein Y 3 is selected from the group consisting of alicyclic and lower alkyl; wherein X 3 is selected from the group consisting of -heteroaryl-, -alkylcarbonylamino-, -alkylaminocarbonyl-, and -alkoxycarbonyl-.

105. The compounds of claim 104 wherein nis 1; R 1 2 and R 1 3 are independently selected from the group consisting of lower alkyl, lower perhaloalkyl, and lower aryl, optionally substituted with -OR 19 -NR12, -SR 1 9 -C(O)NR halo, -C0 2 R 2 3-indolyl, 4-imidazolyl, and guanidinyl, or R 12 and R 1 3 are connected via 2-5 carbon atoms to form a cycloalkyl group; R' 4 is selected from the group consisting of-OR 7 -SR 17 and -NROR 19 R 1 is selected from the group consisting of-H and C1-C6 alkyl; R 16 is selected from the group consisting of-H, C1-C6 alkyl, and -(CR12R )n-C(O)-R 1 4; or together R 15 and R 1 6 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of N, 0 and S. R 1 7 is selected from the group consisting of CI-C7 alkyl, phenyl, indolyl, sesimol, and benzyl, wherein said phenyl, indolyl, sesimol, and benzyl may be optionally substituted with 1-3 groups selected from the group of-CO 2 R 2 -OR 3 -NHC(O)R 3 halo and lower alkyl; and R 1 8 is selected from the group consisting of-H, C1-C6 alkyl, and benzyl.

106. The compounds of claim 105 wherein A 3 is selected from the group consisting of-H, -NH 2 and -CH 3 L 3 is selected from the group consisting of-H, -OCH 3 Cl and -CH 3 E 3 is selected from the group consisting of and -Cl; J 3 is selected from the group consisting of-H, halo, C1-C5 hydroxyalkyl, haloalkyl, R 8 2 N-Cl-C5 alkyl, C1-C5 alicyclic, and C1-C5 alkyl; X 3 is selected from the group consisting of-CH 2 0CH 2 -methyleneoxycarbonyl- and and Y 3 is lower alkyl.

107. The compounds of claim 106 where A 3 is -NH 2 L 3 is E 3 is j3 is ethyl, Y 3 is isobutyl, and X 3 is

108. The compounds of claim 106 where A 3 is -NH 2 L 3 is E 3 is J 3 is N,N-dimethylaminopropyl, Y 3 is isobutyl, and X 3 is

109. The compounds of claim 107 wherein 0ORS R 12 o I11 1 I N--C-R NR 15 R 18 R 13 is selected from the group consisting of CH3 -P NH-C-COOEt OH 3 and ~-P{NH-CF*COOE!] wherein C* has S stereochemistry. 11.0. The compounds of claim 108 wherein O R 1 8 R 12 0 NR' 5 R 1 6 R 1 is selected from the group consisting of -PjNH-C-COOEt] 1 2 t-011 wherein C* has S stereochemnistry.

111. A method of treating an animal for diabetes, comprising administering to said animal a therapeutically effective amount of a compound of formula XI: wherein: A3, E3 and L 3 are selected from the group consisting of -NR 8 2 -NO 2 -Hi, -OR 7 -SR', -C(O)NR 2 halo, -COR' 1 -S0 2 R 3 guanidine, amidine, -NHSO 2 -S0 2 WR 2 -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, Cl-C5 alkyl, C2-C5 alkenlyl, alkynyl, and lower alicyclic, or together A 3 and L 3 form a cyclic group, or together L 3 and E 3 form a cyclic group, or together E3 and j3 form a cyclic group including aryl, cyclic alkyl, and heterocyclic; J 3 is selected from the group consisting of -NR82, -NO 2 -OR 7 -SR 7 -C(O)NR 4 2 halo, -CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl; alicyclic, aryl, and aralkyl, or together with Y 3 forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl; X 3 is selected from the group consisting of -alkyl(hydroxy)-, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X 3 is not substituted with -COOR 2 -SO 3 H, or -P0 3 R22; Y 3 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkcoxyalkyl, -C(O)R 3 -S(O) 2 R 3 -CONHR 3 -NR 2 2 and -OR 3 all except H are optionally substituted; n is an integer from 1 to 3; R 2 is selected from the group consisting of R 3 and -H; R 3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; each R 4 is independently selected from the group consisting of and alkyl, or together R 4 and R 4 form a cyclic alkyl group; R 7 is independently selected from the group consisting of lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and R 8 is independently selected from the group consisting of-H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, -C(O)R 10 or together they form a bidentate alkyl; each R 9 is independently selected from the group consisting of -alkyl, aralkyl, and alicycic, or together R 9 and R 9 form a cyclic alkyl group; R i is selected from the group consisting of-H, lower alkyl, -NH 2 lower aryl, and lower perhaloalkyl; R" is selected from the group consisting of alkyl, aryl, -NR 2 2 and -OR 2 each R 12 and R 1 3 is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R 1 2 and R 1 3 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of 0, N and S, to form a cyclic group; each R 1 4 is independently selected from the group consisting of -OR" 7 -N(R17) 2 -NHR 17 -NR 2 OR" and -SR"; R 1 5 is selected from the group consisting of-H, lower alkyl, lower aryl, lower aralkyl, or together with R 1 6 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S; R 1 6 is selected from the group consisting of-(CR1 2 R 3 1 4 -H lower alkyl, lower aryl, lower aralkyl, or together with R 15 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S; each R' 7 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R 1 7 and R 17 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S; R 1 8 is independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R 12 is connected via 1-4 carbon atoms to form a cyclic group; each R 1 9 is independently selected from the group consisting of-H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR 3 and pharmaceutically acceptable salts thereof.

112. A method of lowering blood glucose levels in an animal in need thereof, comprising administering to said animal a pharmaceutically acceptable amount of a compound of claim 103.

113. A method of inhibiting gluconeogenesis in an animal in need thereof comprising administering to said animal a phannrmaceutically effective amount of a compound of claim 4.

114. A method of inhibiting gluconeogenesis in an animal in need thereof comprising administering to said animal a pharmaceutically effective amount of a compound of claim 62.

115. A method of lowering blood glucose in an animal in need thereof comprising administering to said animal a pharmaceutically effective amount of a compound of claim 62. Dated 19 June, 2006 Metabasis Therapeutics, Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON