KR20060061930A - Anti-cancer phosphonate analogues - Google Patents

Abstract

The invention is related to phosphorus substituted anti-cancer compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

Description

Anticancer phosphonate analogs {ANTI-CANCER PHOSPHONATE ANALOGUES}

This non-temporary application is filed at 35 U.S.C. US Provisional Patent Application Nos. 60 / 465,588, 60 / 465,594, 60 / 465,465, 60 / 465,569, 60 / 465,467, filed April 25, 2003, by § 119 (e); 60 / 465,631, 60 / 465,714, 60 / 465,589, 60 / 465,586, 60 / 465,607, 60 / 465,668, 60 / 465,287, 60 / 465,343, 60 / 465,471, 60 / 465,567, 60 / 465,545, 60 / 465,394, 60 / 465,603, 60 / 465,614, 60 / 465,339, 60 / 465,325, 60 / 465,377 60 / 465,415, 60 / 465,575, 60 / 465,844, 60 / 465,559, 60 / 495,387 and 60 / 465,531, U.S. Provisional Patents, filed August 7, 2003 60 / 493,303 and 60 / 493,310, U.S. Provisional Patent Applications 60 / 495,382, 60 / 495,685, 60 / 495,527, 60 / 495,686, 60, filed August 15, 2003. 60 / 495,525, 60 / 495,629, 60 / 495,484, 60 / 495,644, 60 / 495,297, 60 / 495,682, 60 / 495,784, 60 / 495,751, 60 / 495,565, 60 / 495,789 60 / 495,736, 60 / 495,769, 60 / 495,647, 60 / 495,645, 60 / 495,362, 60 / 495,339, 60 / 495,534, 60 / 495,669, US Provisional Patent Application No. 60, filed 60 / 495,425, 60 / 495,524, 60 / 495,426, 60 / 495,393, 60 / 495,387 and 60 / 495,416, filed August 24, 2003 / 514,462, 60 / 513,971, 60 / 513,969, 60 / 514,394, 60 / 514,393, 60 / 513,944, 60 / 513,956, 60 / 513,923, 60 / 514,202 60 / 514,247, 60 / 514,461, 60 / 514,369, 60 / 514,452, 60 / 514,439, 60 / 513,948, 60 / 514,424, 60 / 513,972, 60 / 513,925, 60 / 513,926, 60 / 513,927, 60 / 514,368, 60 / 514,207, 60 / 514,115, 60 / 513,980, 60 / 514,131, 60 / 514,105, 60 / 514,280, 60 / 513,963, 60 / 514,145, 60 / 514,159, 60 / 514,083, 60 / 513,949, 60 / 514,144, 60/51 , 4481, 60 / 513,974, 60 / 514,108, 60 / 513,979, 60 / 514,0 84, 60 / 514,161, 60 / 514,304, 60 / 514,235, 60 / 514,325, 60 / 514,359, 60 / 514,113, 60 / 514,114, 60 / 514,112 60 / 513,968, 60 / 514,345, 60 / 514,346, 60 / 513,564, 60 / 513,588, 60 / 514,298, 60 / 514,330, 60 / 513,932, 60 / 513,976, 60 / 513,562, 60 / 514,258 and 60 / 514,258, US Provisional Patent Applications 60 / 519,476 and 60 / 519,476, filed November 12, 2003, 11 2003 US Provisional Patent Applications 60 / 524,340, filed May 20, US Provisional Patent Applications 60 / 532,230, 60 / 531,960, 60 / 532,160, and 60 /, filed December 22, 2003 531,940, US Provisional Patent Application No. 60 / 532,591, filed December 23, 2003, and US Provisional Patent Application Nos. 60 / 536,007, 60 / 536,006, 60, filed January 12, 2004 / 536,005, 60 / 536,054 and 60 / 536,054 claim the benefit of priority. The entirety of these provisional applications is incorporated herein by reference.

 The present invention relates generally to compounds having anticancer activity.

Improving drug and other drug delivery to target cells and tissues has been the focus of major research for many years. Many attempts have been made to develop effective methods for introducing biologically active molecules into cells in vivo and in vitro, but none have been found to be completely satisfactory. While minimizing intracellular redistribution of drugs to neighboring cells, optimizing the binding of drugs to intracellular targets is often difficult or inefficient.

Most drugs that are generally administered parenterally to a patient are not targeted and are usually undesirable because systemic delivery of drugs to unwanted cells and tissues occurs. This can cause harmful drug side effects and usually limits the dose of drugs that can be administered (eg, glucocrticoids and other anti-inflammatory agents).

In comparison, oral administration of drugs is usually recognized as a convenient and economical method of administration, but oral administration (a) leads to ingestion of drugs through cell and tissue walls such as blood / brain, epithelial tissue, and cell walls, which is undesirable. Systemic distribution or (b) transient retention of the drug in the gastrointestinal tract. Therefore, developing a method of specifically targeting drugs to cells and tissues has been a major goal. The advantages of such treatments include the avoidance of the general physiological effects that may arise from inappropriate delivery of such agents to other cells and tissues, such as uninfected cells.

Intracellular targeting can be achieved by methods and compositions that allow for the accumulation and preservation of biologically active agents inside cells.

Many current therapies for cell proliferative diseases such as psoriasis and cancer utilize compounds that inhibit DNA synthesis. Such compounds are generally toxic to cells, but their toxic effects on rapidly dividing cells, such as tumor cells, can be advantageous. Alternative approaches to antiproliferative agents acting by mechanisms besides inhibition of DNA synthesis are likely to show enhanced selectivity of action.

In recent years, it has been found that cells can become cancerous by some modification of the DNA in tumor genes, ie genes that cause the formation of malignant tumor cells upon activation (Bradshaw, Mutagenesis 1986, 1, 91). Some such tumor genes cause the production of peptides that are receptors for growth factors. The growth factor receptor complex then induces an increase in cell proliferation. For example, some oncogenes encode tyrosine kinase enzymes and some growth factor receptors are also tyrosine kinase enzymes (Yarden et al., Ann. Rev. BiOCHem., 1988, 57, 443; Larsen et al. Ann. Reports in Med Chem. 1989, Chpt. 13).

Receptor tyrosine kinases are important for the transmission of biochemical signals that initiate cell replication. They are large enzymes that fill the cell wall, and act as kinases to phosphorylate tyrosine amino acids in extracellular binding regions and proteins for growth factors such as epidermal growth factor (EGF) and thus intracellular effects It has a part.

Several types of receptor tyrosine kinases are known based on the family of growth factors that bind to different receptor tyrosine kinases (Wilks, Advances in Cancer Research, 1993, 60, 43-73).

Its classification includes Class I receptor tyrosine kinases, insulin, IGFI, and insulin-related receptor (IRR) receptors, including EGF family tyrosine kinases, such as EGF, TGF.alpha., NEU, erbB, Xmrk, HER and let23 receptors. Class II receptor tyrosine kinases and PDGF.alpha., PDGF.beta. And class III receptor tyrosine kinases comprising receptor tyrosine kinases of the platelet-derived growth factor (PDGF) family such as colony stimulating factor 1 (CSF1) receptors.

 Type I kinases, such as the receptor tyrosine kinases of the EGF family, are characterized by chest cancer (Sainsbury et. Al., Brit. J. Cancer, 1988, 58, 458; Guerin et al., Oncogene Res., 1988, 3, 21 and Klijn et. al., Breast Cancer Res. Treat., 1994, 29, 73), adenocarcinoma (Cerny et al., Brit. J. Cancer, 1986, 54, 265; Reubi et al., Int. J. Cancer, 1990, 45 , 269; and Rusch et al., Cancer Research, 1993, 53, 2379) and non-small cell lung cancer (NSCLCs), including bladder cancer (Hendler et al., Cancer Cells, 1989, 7, 347), bladder cancer (Neal et. Al., Lancet, 1985, 366), gastrointestinal cancers such as esophageal cancer (Mukaida et al., Cancer, 1991, 68, 142), colon, rectum or gastric cancer (Bolen et al., Oncogene Res., 1987). , 1, 149), prostate cancer (Visakorpi et al., HistOCHem. J., 1992, 24, 481), leukemia (Konaka et al., Cell, 1984, 37, 1035) and ovarian, bronchial or pancreatic cancer (European Patent Specification No. 0400586) and the like are frequently present in common human cancers.

Testing of additional human tumor tissues for the EGF family of receptor tyrosine kinases is expected to demonstrate their widespread distribution in additional cancers such as thyroid and uterine cancers. EGF-type tyrosine kinase activity is also known to be detected more frequently in malignant cells, whereas it is rarely detected in normal cells (Hunter, Cell, 1987, 50, 823). More recently, it has been shown that EGF receptors with tyrosine kinase activity are overexpressed in many human cancers, including brain, lung squamous cells, bladder, stomach, chest, head and neck, esophagus, gynecology and thyroid tumors. Therefore, it has been recognized that receptor tyrosine kinase inhibitors will be as useful as selective growth inhibitors of mammalian cancer cells (Yaish et al. Science, 1988, 242, 933). This view reliably attenuates the growth of EGF receptor tyrosine kinase inhibitor erbstatin in athymic nude mice implanted with human breast carcinoma that exhibits EGF receptor tyrosine kinase but does not exhibit EGF receptor tyrosine kinase. This is supported by evidence of no effect on the growth of other carcinomas (Toi et al., Eur. J. Cancer Clin. Oncol., 1990, 26, 722.). Various styrene derivatives that also have tyrosine kinase inhibitory (European Patent Application Nos. 0211363, 0304493 and 0322738) and are useful as antitumor agents are also described. In vivo inhibitory effects of these two styrene derivatives, EGF receptor tyrosine kinase inhibitors, on the growth of human squamous cell carcinoma inoculated in nude mice have been demonstrated (Yoneda et al., Cancer Research, 1991, 51, 4430). A recent commentary by T. R. Burke Jr. discloses several known tyrosine kinase inhibitors (Drugs of the Future, 1992, 17, 119).

Cancer is a major health problem worldwide. Drugs targeting tumors and cancer cells have been widely used and effective, but toxicity and side effects have limited their use.

Analytical methods that can determine the presence, absence, or amount of cancer are actually used in studies for diagnosing the presence of cancer as well as in anticancer compounds.

Tumor growth inhibitors are useful for limiting cancer production and progression, and are also useful for diagnostic tests of cancer.

There is a need for anticancer drugs, ie drugs with improved anticancer properties as well as pharmacokinetic properties, including enhanced activity against cancer growth, improved oral bioavailability, greater efficacy and extended in vivo half-life. Such anticancer compounds must be active against various cancers, have a unique resistance profile, have fewer side effects, have a less complex dosing schedule, and have oral activity. In particular, there is a need for less annoying dosage regimens, such as taking a pill once a day.

Summary of the Invention

Intracellular targeting can be achieved by methods and compositions that allow for the accumulation and preservation of biologically active agents inside cells. The present invention provides novel anticancer compound analogs. Such novel anticancer compound analogues have all the utility of anticancer compounds and provide for cell accumulation as described below as needed. The invention also provides compositions and methods for the treatment of cancer or therapeutic activity against cancer.

The present invention generally relates to the accumulation and integrity of therapeutic compounds inside cells. More particularly, the present invention relates to obtaining high concentrations of phosphonate containing molecules in cancer cells. Such effective targeting can be applied to various therapeutic formulations and methods.

Thus, in one embodiment, the present invention provides a compound of the present invention that is a conjugate comprising a chemotherapeutic agent linked to one or more phosphonate groups.

In another embodiment, the present invention provides a compound of any one of Formulas 500-601 substituted with one or more groups A ⁰ .

here,

A ^{0 is} A ¹ , A ² or W ³ provided that the complex contains at least one A ¹ ego,

A ¹ is

A ²

A ³ is

이며,

Is,

Y ¹ is independently O, S, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ) or N (N (R ^x ) (R ^x ) )ego,

Y ^{2 is} independently bonded, O, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), N (N (R ^x ) (R ^x ) ), -S (O) _M2 -or -S (O) _M2 -S (O) _M2 -and when Y ² bonds two phosphorus atoms, Y ^{2 is} also C (R ² ) (R ² ) Can be,

R ^{x is} independently H, R ¹ , R ² , W ³ , a protecting group or the following formula,

here,

R ^y is H, W ³ , R ² or a protecting group,

R ¹ is independently H or alkyl of 1 to 18 carbon atoms,

R ² is independently H, R ¹ , R ³ or each R ⁴ end Independently 0 to 3 R ³ groups optionally substituted, and the R ⁴ combine together at one carbon atom, two R ² groups to form a three to eight carbon ring that ring may be substituted with 0 to 3 R ³ ,

And when R ³ is bonded to the hetero atom include the assumption that R ³ is R ^3c or R ^3d is, R ³ is R ^3a, R ^3b, R ^3c or R ^3d,

R ^3a is F, Cl, Br, I, -CN, N ₃ or -NO ₂ ,

R ^3b is Y ¹ ,

R ^3c is -R ^x , -N (R ^x ) (R ^x ), -SR ^x , -S (O) R ^x , -S (O) ₂ R ^x , -S (O) (OR ^x ),- S (O) ₂ (OR ^x ), -OC (Y ¹ ) R ^x , -OC (Y ¹ ) OR ^x , -OC (Y ¹ ) (N (R ^x ) (R ^x )), -SC (Y ¹ ) R ^x , -SC (Y ¹ ) OR ^x , -SC (Y ¹ ) (N (R ^x ) (R ^x )), -N (R ^x ) C (Y ¹ ) R ^x , -N (R ^x ) C (Y ¹ ) OR ^x or -N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ))

R ^3d is -C (Y ¹ ) R ^x , -C (Y ¹ ) OR ^x or -C (Y ¹ ) (N (R ^x ) (R ^x )),

R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms or alkynyl of 2 to 18 carbon atoms,

R ⁵ is R ⁴ substituted with each of the R ⁴ groups 0-3 R ^3,

W ³ is W ⁴ or W ⁵ ,

W ⁴ is R ⁵ , -C (Y ¹ ) R ⁵ , -C (Y ¹ ) W ⁵ , -SO _M2 R ⁵ or SO _M2 W ⁵ ,

W _⁵ is a carbon ring or heterocycle, W ⁵ is independently substituted with 0 to 3 R _² groups,

W ⁶ is W ³ independently substituted with 1, 2 or 3 A ³ groups,

M2 is 0, 1 or 2,

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

M1a, M1c and M1d are independently 0 or 1,

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another embodiment, the following compounds or pharmaceutically acceptable salts or solvates thereof are provided.

[DRUG]-(A ⁰ ) _nn

here,

DRUG is a compound of any one of formulas 500-601 ,

nn is 1, 2 or 3,

A ⁰ is A ¹ , A ² or W ³ provided that the complex contains at least one A ¹ ego,

A ¹ is

A ² is

A ³ is

이며,

Is,

Y ¹ is independently O, S, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ) or N (N (R ^x ) (R ^x ) )ego,

Y ² is independently bonded, O, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), N (N (R ^x ) (R ^x ) ), -S (O) _M2 -or -S (O) _M2 -S (O) _M2 -and when Y ² bonds two phosphorus atoms, Y ² is also C (R ² ) (R ² ) Can be,

R ^x is independently H, R ¹ , R ² , W ³ , a protecting group or the following formula,

here,

R ^y is H, W ³ , R ² or a protecting group,

R ¹ is independently H or alkyl of 1 to 18 carbon atoms,

R ² is independently H, R ¹ , R ³ or each R ⁴ end Independently 0 to 3 R ³ groups optionally substituted, and the R ⁴ combine together at one carbon atom, two R ² groups to form a three to eight carbon ring that ring may be substituted with 0 to 3 R ³ ,

And when R ³ is bonded to the hetero atom include the assumption that R ³ is R ^3c or R ^3d is, R ³ is R ^3a, R ^3b, R ^3c or R ^3d,

R ^3a is F, Cl, Br, I, -CN, N ₃ or -NO ₂ ,

R ^3b is Y ¹ ,

R ^3c is -R ^x , -N (R ^x ) (R ^x ), -SR ^x , -S (O) R ^x , -S (O) ₂ R ^x , -S (O) (OR ^x ),- S (O) ₂ (OR ^x ), -OC (Y ¹ ) R ^x , -OC (Y ¹ ) OR ^x , -OC (Y ¹ ) (N (R ^x ) (R ^x )), -SC (Y ¹ ) R ^x , -SC (Y ¹ ) OR ^x , -SC (Y ¹ ) (N (R ^x ) (R ^x )), -N (R ^x ) C (Y ¹ ) R ^x , -N (R ^x ) C (Y ¹ ) OR ^x or -N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ))

R ^3d is -C (Y ¹ ) R ^x , -C (Y ¹ ) OR ^x or -C (Y ¹ ) (N (R ^x ) (R ^x )),

R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms or alkynyl of 2 to 18 carbon atoms,

R ⁵ is R ⁴ substituted with each of the R ⁴ groups 0-3 R ^3,

W ³ is W ⁴ or W ⁵ ,

W ⁴ is R ⁵ , -C (Y ¹ ) R ⁵ , -C (Y ¹ ) W ⁵ , -SO _M2 R ⁵ or SO _M2 W ⁵ ,

W _⁵ is a carbon ring or heterocycle, W ⁵ is independently substituted with 0 to 3 R _² groups,

W ⁶ is W ³ independently substituted with 1, 2 or 3 A ³ groups,

M2 is 0, 1 or 2,

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

M1a, M1c and M1d are independently 0 or 1,

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another embodiment, the present invention provides a compound of any one of formulas 1-336 .

here,

A ⁰ is A ¹ ,

A ¹ is

A ³ is

이며,

Is,

Y ¹ is independently O, S, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ) or N (N (R ^x ) (R ^x ) )ego,

Y ² is independently bonded, O, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), N (N (R ^x ) (R ^x ) ), -S (O) _M2 -, or _{-S (O) M2 -S (O} ) M2 - and, if Y ² is bonded to the two phosphorous atoms Y ² can also ^{C (R 2) (R 2} ) days Can,

R ^x is independently H, R ² , W ³ , a protecting group or the following formula,

R ^y is H, W ³ , R ² or a protecting group,

R ¹ is independently H or alkyl of 1 to 18 carbon atoms,

R ² is independently H, R ³ or each R ⁴ end Independently R ⁴ substituted with 0 to 3 R ³ groups,

R ² is independently H, R ³ or each R ⁴ end Independently R ⁴ substituted with 0 to 3 R ³ groups,

And when R ³ is bonded to the hetero atom include the assumption that R ³ is R ^3c or R ^3d is, R ³ is R ^3a, R ^3b, R ^3c or R ^3d,

R ^3a is F, Cl, Br, I, -CN, N ₃ or -NO ₂ ,

R ^3b is Y ¹ ,

R ^3c is -R ^x , -N (R ^x ) (R ^x ), -SR ^x , -S (O) R ^x , -S (O) ₂ R ^x , -S (O) (OR ^x ),- S (O) ₂ (OR ^x ), -OC (Y ¹ ) R ^x , -OC (Y ¹ ) OR ^x , -OC (Y ¹ ) (N (R ^x ) (R ^x )), -SC (Y ¹ ) R ^x , -SC (Y ¹ ) OR ^x , -SC (Y ¹ ) (N (R ^x ) (R ^x )), -N (R ^x ) C (Y ¹ ) R ^x , -N (R ^x ) C (Y ¹ ) OR ^x or -N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ))

R ^3d is -C (Y ¹ ) R ^x , -C (Y ¹ ) OR ^x or -C (Y ¹ ) (N (R ^x ) (R ^x )),

R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms or alkynyl of 2 to 18 carbon atoms,

R ⁵ is R ⁴ substituted with each of the R ⁴ groups 0-3 R ^3,

R ^5a is independently alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms or alkynylene of 2 to 18 carbon atoms, wherein any of alkylene, alkenylene or alkynylene is 0 to 3 R Substituted by ³ groups,

W ³ is W ⁴ or W ⁵ ,

W ⁴ is R ⁵ , -C (Y ¹ ) R ⁵ , -C (Y ¹ ) W ⁵ , -SO ₂ R ⁵ or -SO ₂ W ⁵ ,

W _⁵ is a carbon ring or heterocycle, W ⁵ is independently substituted with 0 to 3 R _² groups,

W ⁶ is W ³ independently substituted with 1, 2 or 3 A ³ groups,

M2 is 0, 1 or 2,

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

M1a, M1c and M1d are independently 0 or 1,

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

X ⁵⁰ is HF or Cl,

X ⁵¹ is H or Cl.

The present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier.

The present invention provides a method of increasing cellular accumulation and integrity of drug compounds, thereby improving their therapeutic and diagnostic efficacy, wherein the method comprises one or more (eg , 1, 2, 3 or 4) phosphonates of the compound. Connecting to the group.

The invention also relates to a method of increasing cellular accumulation and integrity of a chemotherapeutic agent comprising linking the compound to one or more phosphonate groups.

The invention also provides a method of treating cancer in a mammal comprising administering a compound of the invention to the mammal.

The present invention provides the use of the compounds of the invention for the manufacture of a medicament useful for the treatment of cancer, as well as for the treatment of cancer, preferably for the treatment of cancer.

Another feature of the invention is also to provide a method for inhibiting cancer activity comprising contacting a sample in need thereof with a compound or composition of the invention.

The invention also provides processes useful for the preparation of the compounds of the invention and the novel intermediates disclosed herein. Some of the compounds of the invention are useful for preparing other compounds of the invention. The present invention also provides new methods for the synthesis of the compounds of the present invention.

Reference will be made in order to detail the claims of the invention. In these examples, the structure and formula will be described together. While the invention will be described in conjunction with the enumerated claims, it should be understood that it is not intended to limit the invention to those claims. On the other hand, the invention is intended to cover all alternatives, modifications and equivalents falling within the scope of the invention as defined by the claims.

Justice

Unless otherwise stated, the following terms and phrases used herein have the following meanings:

If a trade name is used herein, the applicant is intended to include the product of that trade name independently and the active pharmaceutical ingredient (s) of the product.

"Bioavailability" refers to the extent to which a pharmaceutical active is applicable to a target tissue after introduction into the body. Increasing the bioavailability of the pharmaceutically active agent enables more efficient and effective treatment for the patient. This is because more pharmaceutically active agents act on the target tissue site at a given dose.

The terms " phosphonate " and " phosphonate group " refer to 1) a single bond to carbon, 2) a double bond to heteroatoms, 3) a single bond to heteroatoms, and 4) a single bond to another heteroatom. It includes a functional group or part in the molecule consisting of. Here, each heteroatom may be the same or different. The terms " phosphonate " and " phosphonate group " also refer to a functional group or moiety consisting of a phosphorus in the same oxidation state as the aforementioned phosphorus and a prodrug moiety containing a phosphorus separated from the compound and containing the above characteristics. Include the part. For example, the terms phosphonate and phosphonate groups include phosphonic acid, phosphorous acid monoesters, phosphorous acid diesters, phosphonamidates and phosphonthioic acid functional groups. In one particular embodiment of the invention, the terms "phosphonate" and "phosphonate group" are used to refer to 1) a single bond to carbon, 2) a double bond with oxygen, 3) a single bond with oxygen, and 4) another It includes a functional group or moiety in a molecule consisting of a phosphorus that single bonds with oxygen, and includes a functional group or moiety consisting of a prodrug moiety separated from a phosphorus containing compound having this characteristic. In another particular embodiment of the invention, the terms "phosphonate" and "phosphonate group" are used to refer to 1) a single bond to carbon, 2) a double bond with oxygen, 3) a single bond with oxygen or nitrogen, and 4 ) Includes a functional group or moiety in a molecule composed of phosphorus that is single-bonded with another oxygen or nitrogen, and includes a functional group or moiety consisting of a prodrug moiety that contains a phosphorus that is separated from the compound and that the compound can retain these properties do.

As used herein, the term “prodrug drug” means a drug, when administered to the biological system as a result of spontaneous chemical reaction (s), such as enzyme catalyzed chemical reaction (s), photolysis and / or metabolic chemical reaction (s), etc. In other words, all compounds that produce the active ingredient. Prodrugs are therefore latent forms of analogs or therapeutically active compounds that have been covalently modified.

"Prodrug drug moiety" refers to an unstable functional group that is isolated from an active inhibitory compound in cells during systemic metabolism by hydrolysis, enzymatic digestion, or other reaction procedures (Bundgaard, Hans, Design and Application of Prodrugs α Textbook of Drug Design and Develpment (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymes that enable enzymatic activation mechanisms using phosphonate prodrug compounds of the present invention include, but are not limited to, amidase, esterase, microbial enzyme, phospholipase, cholinesterase and phosphase. The prodrug moiety enhances solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficiency. The prodrug moiety may comprise an active metabolite or the drug body thereof.

Representative prodrug moieties include acyloxymethylesters -CH ₂ ° C (= 0) R ⁹ and acyloxymethylcarbonate -CH ₂ ° C (= 0) OR ⁹ that are sensitive or unstable to hydrolysis. Wherein R ⁹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ substituted alkyl, C ₆ -C ₂₀ aryl or C ₆ -C ₂₀ substituted aryl. Acyloxyalkylesters were first used as prodrug strategies for carboxylic acids, followed by Farquhar et al. (1983) J. Pharm . Sci . 72: 324; It was also applied to phosphates and phosphonates by US Pat. Nos. 4816570, 4968788, 5631159 and 5792756. Acyloxyalkylesters were then used to deliver phosphonic acid across the cell membrane to enhance oral bioavailability. Alkoxycarbonyloxyalkylesters (carbonates), a similar variant of acyloxy alkyl esters, also enhance oral bioavailability as prodrug moiety in the compounds combined in the present invention. Representative acyloxymethyl esters are pivaloyloxymethoxy (POM) -CH ₂ ° C (= O) C (CH ₃ ) ₃ . An exemplary acyloxymethylcarbonate prodrug moiety is pivaloyloxymethylcarbonate (P ° C.) —CH ₂ ° C. (═O) ° C. (CH ₃ ) ₃ .

The phosphonate group can be a phosphonate prodrug moiety. The prodrug moiety is sensitive to hydrolysis, such as but not limited to pivaloyloxymethyl carbonate (P ° C.) or POM groups. As an alternative, the prodrug moiety may be susceptible to enzymatic potential degradation, such as lactate ester or phosphonamide acid-ester groups.

Aryl esters of phosphorus groups, especially phenyl esters, have been reported to enhance oral bioavailability (De Lombaert et al. (1994) J. Med . Chem . 37: 498). Phenyl esters containing a carboxyl ester at the ortho position for phosphate have also been reported (Khamnei and Torrence, (1996) J. Med . Chem . 39: 4109-4115). Benzyl esters have been reported to produce maternal phosphonic acid. In some cases, substituents in the ortho or para position may promote hydrolysis. Benzyl analogs with acylated phenols or alkylated phenols can produce phenolic compounds by, for example, enzymatic reactions such as esterases, oxidases and the like. This in turn decomposes the benzyl CO bond to produce phosphoric acid and quinone metide intermediates. Examples of this class of prodrugs are described in Mitchell et al. (1992) J. Chem . Soc . Perkin Trans. II 2345; Glazier WO 91/19721. Another benzyl-based prodrug comprising a group containing a carboxylic acid ester in the benzyl methylene is described (Glazier WO 91/19721). They are known to be useful for the delivery of phosphonate drugs in cells containing thio groups. Such proesters include ethylthio groups in which thiol groups are esterified with acyl groups or combined with other thiol groups to form disulfides. Ester elimination reaction or reduction of disulfide produces free thio intermediates. It is broken down into phosphoric acid and episulfide (Puech et al. (1993) Antiviral Res ., 22: 155-® Benzaria et al. (1996) J. Med . Chem . 39: 4958). Cyclic phosphonate esters have also been described as prodrugs of compounds containing phosphorus (Erion et al., US Pat. No. 6,312,662).

A "protecting group" refers to a compound moiety that blocks or alters the properties of a functional group or the properties of the entire compound. The chemical substructure of the protecting group is very diverse. One function of the protecting group is to serve as an intermediate in the synthesis of the parent drug substance. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See Protective group in Organic Chemistry , Theodora W. Greene, John Wiley & Sons, Inc., Neω York, 1991.

Protecting groups are often used to block the reactivity of certain functional groups, thereby increasing the efficiency of the desired chemical reaction, eg, to form and break chemical bonds sequentially in a planned manner. When protecting a functional group of a compound, in addition to the reactivity of the protected functional group, other physical properties, such as polarity, lipophilic (hydrophobic) and other properties that can be measured by common analytical instruments, are altered. Chemically protected intermediates are themselves biologically active or inactive.

Protected compounds may also optimize in vitro and in vivo properties such as resistance or sequestration to transport through cell membranes or enzymatic degradation in some cases. In this role, protected compounds with an intended therapeutic effect may be referred to as prodrugs. Another function of the protecting group is to convert the parent drug into a prodrug, thereby releasing the parent drug in vivo by the conversion of the prodrug. Since the active prodrug can be absorbed more effectively than the parent drug, the prodrug can have greater viscosity in vivo than the parent drug. The protecting group is removed in vitro for chemical intermediates and in vivo for prodrugs. In the case of chemical intermediates, the resulting product, such as alcohol, after deprotection, although it is more preferred that the product is pharmaceutically harmless, is not very important whether it should be physiologically acceptable.

Any expressions for the compounds of the present invention include those for physiologically acceptable salts thereof. Physiologically acceptable salt thereof Examples of compounds of the invention include alkali metal (e.g., sodium), alkaline earth metal (e.g. magnesium), ammonium and NX ₄ ⁺ (wherein, X is alkyl of C _{1 -4)} with a suitable base such as And salts derived from them. Physiologically acceptable salts of compounds having a hydrogen atom or an amino group include organic carboxylic acids such as acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid and succinic acid; Organic sulfonates such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; And organic acid solutions such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid. Physiologically acceptable salts of compounds having hydroxy groups include anions of the compounds with suitable cations such as Na ⁺ and NX ₄ ⁺ , where X is independently selected from H or C ₁ -C ₄ alkyl groups do.

For therapeutic use, the salts of the active ingredients of the compounds of the invention should be physiologically acceptable, ie they will be salts derived from physiologically acceptable acids or bases. However, salts of acids or bases that are not physiologically acceptable may also be used, for example, in the manufacture or purification of physiologically acceptable compounds. All salts, whether derived from physiologically acceptable acids or bases, fall within the scope of the present invention.

"Alkyl" is a normal, secondary, tertiary or cyclic carbon atom containing C ₁ -C ₁₈ hydrocarbons. For example, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), 1-propyl ( n -Pr, n -propyl, -CH ₂ CH ₂ CH ₃ ), 2-propyl ( i -Pr, i -propyl, -CH (CH ₃ ) ₂ ), 1-butyl ( n -Bu, n -butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propyl ( i -Bu , i -butyl, -CH ₂ CH (CH ₃ ) ₂ ), 2-butyl ( s -Bu, s -butyl, -CH (CH ₃ ) CH ₂ CH ₃ ), 2-methyl-2-propyl ( t- Bu, t -butyl, -C (CH ₃ ) ₃ ), 1-pentyl ( n -pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH (CH ₃ ) CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH (CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C (CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH (CH ₃ ) CH (CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH (CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH (CH ₃ ) CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH (CH ₃ ) CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH (CH ₂ CH ₃ ) (CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C (CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH ( CH ₃ ) CH (CH ₃ ) CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH (CH ₃ ) CH ₂ CH (CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C (CH ₃ ) (CH ₂ C H ₃ ) ₂ ), 2-methyl-3-pentyl (-CH (CH ₂ CH ₃ ) CH (CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C (CH ₃ ) ₂ CH (CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH (CH ₃ ) C (CH ₃ ) ₃ .

"Alkenyl" refers to a C ₂ -C ₁₈ hydrocarbon that contains a normal, secondary, tertiary or cyclic carbon atom having at least one carbon-carbon unsaturated bond, ie, an sp ² double bond. Examples include ethylene or vinyl (-CH = CH ₂ ), allyl (-CH ₂ CH = CH ₂ ), cyclopentenyl (-C ₅ H ₇ ) and 5-hexenyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH = CH ₂ ), including but not limited to.

"Alkynyl" refers to a C ₂ -C ₁₈ hydrocarbon containing at least one carbon-carbon unsaturated bond, ie, a normal, secondary, tertiary or cyclic carbon atom with sp triple bonds. Acetylene (-C≡H) and propazyl (-CH ₂ C≡H).

The term "alkylene" refers to a saturated, branched or straight or cyclic hydrocarbon radical of 1 to 18 carbon atoms, which is derived by removing two hydrogen atoms from the same or different two carbon atoms of the moalkanes. , A group having two monovalent radical centers. Typical alkylene radicals include methylene (-CH _2- ) 1,2-ethyl (-CH ₂ CH _2- ), 1,3-propyl (-CH ₂ CH ₂ CH _2- ), 1,4-butyl (-CH ₂ CH ₂ CH ₂ CH _2- ), and the like, and the like.

"Alkenylene" is an unsaturated, branched or straight-chain or cyclic hydrocarbon radical of 2-18 carbon atoms, two of which are derived by removing two hydrogen atoms from the same or different two carbon atoms of the moalkene. Monovalent radical centers, ie groups having a double carbon-carbon bond moiety. Typical alkenylene radicals include, but are not limited to, 1,2-ethylene (-CH = CH-).

"Alkynylene" is an unsaturated, branched or straight-chain or cyclic hydrocarbon radical of 2-18 carbon atoms derived from the removal of two hydrogen atoms from the same or different two carbon atoms of moalkin. Monovalent radical centers, ie groups having triple carbon-carbon bond moieties. Typical alkynylene radicals include acetylene (-C≡C-), propargyl (-CH ₂ C≡C-), and 4-pentynyl (-CH ₂ CH ₂ CH ₂ C≡CH-) It is not limited to this.

"Aryl" means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by removing one hydrogen atom from a single carbon atom of the parent aromatic ring system. Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzenes, naphthalenes, anthracenes, biphenyls, and the like.

"Arylalkyl" refers to an acyclic alkyl radical wherein one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp ³ carbon atom, is replaced by an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like. It is not limited. The arylalkyl group contains 6 to 20 carbon atoms, for example the alkyl portion of the arylalkyl group is 1 to 6 carbon atoms, including alkanyl, alkenyl or alkynyl groups, and the aryl portion is 5 to 14 carbon atoms.

Substituted substituents such as "substituted alkyl", "substituted aryl" and "substituted arylalkyl" refer to alkyl, aryl and arylalkyl, each of which one or more hydrogen atoms are independently replaced with non-hydrogen substituents. Typical substituents include, but are not limited to: ^{-X, -R, -O -, -OR} , -SR, -S, -NR 2, -NR 3, = NR, -CX 3, -CN, -OCN, -SCN, -N = C = O, _{-NCS, -NO, -NO 2, =} N 2, -N 3, NC (= O) R, -C (= O) R, -C (= O) NRR -S (= O) 2 O -, -S (= O) ₂ OH, -S (= O) ₂ R, -OS (= O) ₂ OR, -S (= O) ₂ NR, -S (= O) R, -OP (= O) O ₂ RR, _{-P (= O) O 2 RR} , -P (= O) (O -) 2, -P (= O) (OH) 2, -C (= O) R, -C (= O) X, - C (s) R, -C (O) OR , -C (O) O -, -C ( s) OR, -C (O) SR , -C ( s) SR, -C (O) NRR , - C (s) NRR, -C (NR) NRR, wherein each X is independently halogen. F, Cl, Br, or I; And each R is independently —H, alkyl, aryl, heterocycle, protecting group or prodrug moiety. Alkylene, alkenylene, and alkynylene groups may likewise be substituted.

As used herein, the term "heterocycle" refers to Paquette, Leo A .; Principles of Modern Heter ° C yclic Chemistry (WA Benjamin, Neω York, 1968), in particular Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heter C yclic Compound, α Series of Monographs (John Wiley & Sons, Neω York, 1950), in particular volumes 13, 14, 16, 19, and 28; And J. Am. Chem . Soc . (1960) 82: 5566, but are not limited to these. In certain embodiments of the invention, the heterocycle includes a carbocycle as defined herein. Here, one or more (eg 1, 2, 3, or 4) carbon atoms have been substituted with heteroatoms (eg, O, N, or S).

Heterocycles include, but are not limited to, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidinyl), thiazolyl, tetrahydrothiophenyl, sulfur oxides tetrahydrothiophenyl, pyrimididi Neil, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, cyanaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl , Piperidinyl, 4-piperidoneyl, pyrrolidinyl, 2-pyrrolidoneyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, Octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H, 6H-1,5,2-dithiazinyl, thienyl, thiandrenyl, pyranyl, Isobenzofuranyl, chromenyl, xanthenyl, phenoxatinyl, 2H-pyrrolyl, isothiazolyl, Isoxazolyl, pyrazinyl, pyridazinyl, indolinyl, isoindolinyl, 3H-indolyl, 1H-indazole, purinyl, 4H-quinolininyl, phthalazinyl, naphthyridinyl, quinoxalinyl, Quinazolinyl, cynolinyl, putridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenantridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenocyaninyl, pur Lazanyl, phenoxazinyl, isochromenyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholi Nil, oxazolidinyl, benzotriazolyl, benzisooxazolyl, oxindolyl, benzozazolinyl, isatinoyl, and bis-tetrahydrofuranyl:

Heterocycles bonded with carbon are 2, 3, 4, 5 or 6 positions of pyridine, 3, 4, 5 or 6 positions of pyridazine, 2, 4, 5 or 6 positions of pyrimidine and 2, 3 of pyrazine , 5 or 6 position, furan, tetrahydrofuran, thiofuran, thiophene, 2, 3, 4, or 5 position of pyrrole or tetrahydropyrrole, 2, 4, or 5 position of oxazole, imidazole or thiazole , 3, 4, or 5 position of isoxazole, pyrazole, or isothiazole, 2 or 3 position of aziridine, 2, 3, or 4 position of azetidine, 2, 3, 4, 5, 6 of quinoline , 7 or 8, or 1, 3, 4, 5, 6, 7 or 8 of isoquinoline, but is not limited thereto. More generally, heterocycles bonded with carbon include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3- pyridazinyl, 4-pyridazinyl, 5 -Pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

Heterocycles associated with nitrogen include aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrrolidine, 3-pyrrolidine, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline , Pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indolin, 1 position of 1H-indazole, isoindole, or 2 position of isoindolin, morpholine 4, and carbazole or β-carboline is bound to 9, but is not limited thereto. More generally, heterocycles associated with nitrogen include, but are not limited to, 1-aziridyl, 1-azededyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl and 1-piperidinyl Do not.

"Carbocycle" means a saturated, unsaturated or aromatic ring system having from 3 to 7 carbon atoms as a monocyclic ring or from 7 to 12 carbon atoms as two rings and up to about 20 carbon atoms as a polycyclic ring. Monocyclic carbocycles have 3 to 6 ring atoms, more generally 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, for example two [4,5], [5,5], [5,6] or [6,6] or two rings Having 9 or 10 ring atoms disposed as [5,6] or [6,6] systems. Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclophen-1-tenyl, 1-cyclopent-2-tenyl, 1-cyclophen-3-tenyl, cyclohexyl, 1-cyclo Hex-1-senyl, 1-cyclohex-2-senyl, 1-cyclohex-3-senyl, phenyl, spiryl and naphthyl.

"Linker" or "linker" refers to a chemical moiety comprising a covalent bond or a chain or group of atoms that covalently attaches a phosphonate group to a drug. The linker comprises repeating units of alkyloxy (eg polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (eg polyethyleneamino, Jeffamine ^™ ) and succinate, succinamide, diglycolate, malonate and Diacid esters including caproamides and parts of substituents A ¹ and A ³ comprising such moieties as amides.

The term "chiral" refers to molecules with non-overlapping properties of the mirror image partner, and the term "bichiral" refers to molecules superimposed on their mirror image partner.

"Stereoisomers" refer to compounds having the same chemical structure but different spatial arrangements of atoms or groups.

A "diastereoisomer" refers to a stereoisomer that has two or more chiral centers and the molecules are not mirror images of each other. Diastereomers differ from one another in physical properties such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereoisomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography.

 The term "enantiomer" refers to two stereoisomers of a compound that have mirror images that do not overlap each other.

The term treatment or treatment within the scope associated with the disease or condition includes preventing or preventing the occurrence of the disease or condition, removing the disease or condition, and / or alleviating one or more disease or condition symptoms. .

Stereochemical definitions and concepts used herein are generally described in SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, Neω York; And Eliel, E. and Wilen, S., Stere O Chemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of planar polarization. In describing an optically active compound, and prefixes such as L or R and S are used to indicate the absolute placement of the molecule relative to its chiral center (s). The prefixes d and l or (+) and (-) are used to indicate the rotational signal of the planar polarization of the compound, where (-) or l means that the compound is left linear. Compounds with (+) or d are preferred compounds. In a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. Specific stereoisomers may be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to a mixture of the same moles of two enantiomeric species, without optical activity.

Saver

Protecting groups in the context of the present specification include prodrug moieties and chemical protecting groups.

Protecting groups are generally known to be used to prevent side reactions using protected groups during the course of using synthetic procedures, ie, routes or methods for preparing compounds of the present invention. Most of the time, when determining which group to protect, the nature of the chemical protecting group "PG" depends on the reaction to be protected (eg acidic, basic, oxidation, reducing or other reaction state) and the direction of the desired synthesis. When a compound is substituted with several PGs, the PG groups do not need to be identical, and generally do not. In general, PG is used to protect functional groups such as carboxyl, hydroxyl, thio, or amino groups to prevent side reactions or promote synthesis efficiency. The order of deprotection to obtain the liberated, deprotected group depends on the direction of the desired synthesis and the reaction conditions encountered, and can be in any order depending on the intention of the experimenter.

Various functional groups of the compounds of the present invention may be protected. For example, -OH group protecting groups (hydroxyl, carboxylic acid, phosphonic acid or other functional groups) include "ether- or ester forming groups". Ether- or ester formers can act as chemical protecting groups in the synthetic reactions described herein. However, some hydroxyl and thio protecting groups are not ether- or ester forming groups and include the amides discussed below, as understood by those skilled in the art.

Groups forming a large number of hydroxyl protecting groups and amides and corresponding chemical decomposition reactions are described in Protective Groups in Organic synthesis , Theodora W. Greene (John Wiley & Sons, Inc., Neω York, 1991, ISBN 0-471-62301 -6) (Greene). K ° C. ienski, Philip J .; See also Protecting Groups (GeOrg Thieme Verlag Stuttgart, Neω York, 1994), which are incorporated by reference. Especially Chapter 1, protecting groups: overview, p 1-20, Chapter 2, hydroxyl protecting groups, p 21-94, Chapter 3, diol protecting groups, p 95-117, Chapter 4, carboxyl protecting groups, p 118-154, Chapter 5, Carbonyl protecting group, p 155-184. See Greene as described below for carboxylic acids, phosphonic acids, phosphonates, protecting groups for sulfonic acids and other protecting groups for acids. Such groups include, but are not limited to, esters, amides, hydrazides, and the like.

Ether- and ester-forming protecting groups

Ester formers include: (1) phosphonate ester formers such as phosphonamidate esters, phosphorothioate esters, phosphonate esters and phosphon-bis-amidates; (2) carboxyl ester formers, and (3) sulfur ester formers such as sulfonic acid, sulfuric acid, and sulfinate.

The phosphonate moiety of the compound of the invention may or may not be a prodrug moiety. In other words, they may be susceptible to hydrolysis or enzymatic degradation or modification. Certain phosphonate moieties are stable in most or almost all metabolic conditions. For example, dialkylphosphonates wherein the alkyl group is at least two carbons can have significant in vivo stability because of the slow rate of hydrolysis.

Within the scope of the phosphonate prodrug moiety, numerous types of structurally diverse prodrugs for phosphonic acids have been described ( Progress in Medicinal Chemistry 34: 112-147 (1997) by Freeman and Ross, which is within the scope of the present invention). Exemplary phosphonate ester formers are the phenyl carbocycles of substructure A ₃ having the formula:

Wherein R ₁ may be H or C ₁ -C ₁₂ alkyl; m1 is 1, 2, 3, 4, 5, 6, 7 or 8, and the phenyl carbocycle is substituted with 0 to 3 R ₂ groups. Wherein when Y ₁ is O, lactate esters are formed, wherein when Y ₁ is N (R ₂ ), N (OR ₂ ) or N (N (R ₂ ) ₂ , the phosphonamidate ester is Obtained.

In the role of forming their esters, the protecting group typically forms CO ₂ R ^x by combining with any acidic group such as, for example, -CO ₂ H or -C (s) OH group, where R ^{x is} As defined herein, or R ^x includes, for example, ester groups listed in WO 95/07920, which are by way of example and not limited thereto.

Examples of savers:

C ₃ -C ₁₂ heterocycle (as described above) or aryl. Such aromatic groups are optionally polycyclic or monocyclic. Examples include phenyl, spiryl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4- and 5-oxazolyl, 3- and 4-iso Oxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and 5-isothiazolyl, 3- and 4-pyrazolyl, 1-, 2-, 3- and 4-pyridyl, and 1-, 2-, 4- and 5-pyrimidinyl,

;

;

;C_{4 -} C₈ 2-카복실페닐의 에스테르; 및 할로겐, C₁-C₁₂ 알콕시 (메톡시 및 에톡시를 포함), 시아노, 니트로, OH, C₁-C₁₂ 할로겐화알킬 (1 내지 6개의 할로겐 원자; -CH₂CCl₃을 포함), C₁-C₁₂ 알킬 (메틸 및 에틸을 포함), C₂-C₁₂ 알케닐 또는 C₂-C₁₂ 알키닐; 알콕시 에틸 [C₁-C₆ 알킬 -CH₂-CH₂-O-CH₃ (메톡시 에틸)을 포함]; 아릴기에서 설명된 기, 특히 OH에의해서 또는 1 내지 3 개의 할로겐화 원자에의해서 치환된 알킬(-CH_{3 ,} -CH(CH₃)₂, -C(CH₃)₃, -CH₂CH₃, -(CH₂)₂CH₃, -(CH₂)₃CH₃, -(CH₂)₄CH₃, -(CH₂)₅CH₃, -CH₂CH₂F, -CH₂CH₂Cl, -CH₂CF₃, 및 -CH₂CCl₃을 포함)이고,

;-N-2-프로필모르폴리노, 2,3-디하이드로-6-하이드록시인덴, 세사몰, 카테콜 모노에스테르, -CH₂-C(O)-N(R¹)₂, -CH₂-S(O)(R¹), -CH₂-S(O)₂(R¹), -CH₂-CH(℃(O)CH₂R¹)-CH₂(℃(O)CH₂R¹), 콜레스테릴, 엔올피루베이트 (HO℃-C(=CH₂)-), 글리세롤 중에서 선택된 기, 3 내지 5개의 할로겐 원자 또는 1 내지 2개의 원자가 아릴부분에 치환된 C₁-C₄ 알킬렌-C₃-C₆ 아릴(벤질, -CH₂-피롤릴, -CH₂-티엔일, -CH₂-이미다졸릴, -CH₂-옥사졸릴, -CH₂-이소옥사졸릴, -CH₂-티아졸릴, -CH₂-이소티아졸릴, -CH₂-파이라졸릴, -CH₂-피리딜 및 -CH₂-피리미디닐을 포함)이고, _{^{Halo, R 1, R 1 -OC 1}} - C 12 alkylene, C ₁ -C ₁₂ alkoxy, CN, NO _2, OH, carboxyl, carboxyl ester, thiol, thioester, C ₁ -C ₁₂ halogenated alkyl (1 to substituted to 6 halogen atoms), C ₂ -C ₁₂ alkenyl or C ₂ -C ₁₂ alkynyl group, etc. C ₃ -C ₁₂ heterocycle or aryl have. Such groups include 2-, 3- and 4-alkoxyphenyl (C ₁ -C ₁₂ alkyl), 2-, 3- and 4-methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2,3- , 2,4-, 2,5-, 2,6-, 3,4- and 3,5-diethoxyphenyl, 2- and 3-carboethoxy-4-hydroxyphenyl, 2- and 3- Methoxy-4-hydroxyphenyl, 2- and 3-ethoxy-5-hydroxyphenyl, 2- and 3-ethoxy-6-hydroxyphenyl, 2-, 3- and 4-O-acetylphenyl, 2 -, 3- and 4-dimethylaminophenyl, 2-, 3- and 4-methylmercaptophenyl, 2-, 3- and 4-halogenated phenyl (2-, 3- and 4-fluorophenyl and 2-, 3- and 4-chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylphenyl, 2,3-, 2, 4-, 2,5-, 2,6-, 3,4- and 3,5-biscarboxylethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4 And 3,5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dihalogenated phenyl (2,4-difluoro Phenyl and 3,5-difluorophenyl), 2-, 3- and 4-halogenatedalkylphenyl (1 to 5 halogen atoms, 4-trifluoromethylphenyl Comprising C ₁ -C ₁₂ alkyl), 2-, 3-, and 4-cyanophenyl, 2-, 3-, and 4-nitrophenyl, 2-, 3-, and 4-halogenated alkylbenzyl (1-5 halogens Atom, 4-trifluoromethylbenzyl and C ₁ -C ₁₂ alkyl comprising 2-, 3- and 4-trichloromethylphenyl and 2-, 3- and 4-trichloromethylphenyl), 4-N-methylpipe Ridinyl, 3-N-methylpiperidinyl, 1-ethylpiperazinyl, benzyl, alkylsalicylphenyl (C ₁ -C ₄ alkyl including 2-, 3- and 4-ethylsalicylphenyl), 2 -, 3- and 4-acetylphenyl, 1,8-dihydroxynaphthyl (-C ₁₀ H ₆ -OH) and aryloxy ethyl [C ₆ -C ₉ aryl (including phenoxy ethyl)], 2, 2'-dihydroxybiphenyl, 2-, 3- and 4-N, N-dialkylaminophenol, -C ₆ H ₄ CH ₂ -N (CH ₃ ) ₂ , trimethoxybenzyl, triethoxybenzyl , and 2-alkyl-pyridyl (C _{1 -4} alkyl),

;

;

C _{4 -} C ₈ Esters of 2-carboxylphenyl; And halogen, C ₁ -C ₁₂ alkoxy (including methoxy and ethoxy), cyano, nitro, OH, C ₁ -C ₁₂ alkyl halide (including 1 to 6 halogen atoms; —CH ₂ CCl ₃ ), C ₁ -C ₁₂ alkyl (including methyl and ethyl), C ₂ -C ₁₂ alkenyl or C ₂ -C ₁₂ alkynyl; Alkoxy ethyl [including C ₁ -C ₆ alkyl -CH ₂ -CH ₂ -O-CH ₃ (methoxy ethyl)]; Groups described in the aryl group, in particular alkyl (-CH _{3 ,} -CH (CH ₃ ) ₂ , -C (CH ₃ ) ₃ , -CH ₂ CH ₃ , substituted by OH or by 1 to 3 halogenated atoms; -(CH ₂ ) ₂ CH ₃ ,-(CH ₂ ) ₃ CH ₃ ,-(CH ₂ ) ₄ CH ₃ ,-(CH ₂ ) ₅ CH ₃ , -CH ₂ CH ₂ F, -CH ₂ CH ₂ Cl, -CH ₂ CF ₃ , and -CH ₂ CCl ₃ );

; -N-2-propylmorpholino, 2,3-dihydro-6-hydroxyindene, sesamol, catechol monoester, -CH ₂ -C (O) -N (R ¹ ) ₂ ,- CH ₂ —S (O) (R ¹ ), —CH ₂ —S (O) ₂ (R ¹ ), —CH ₂ —CH (° C. (O) CH ₂ R ¹ ) —CH ₂ (° C. (O) CH ₂ R ¹ ), cholesteryl, enolpyruvate (HO ° C-C (= CH ₂ )-), a group selected from glycerol, C ₁ -with 3 to 5 halogen atoms or 1 to 2 atoms substituted at the aryl moiety C ₄ alkylene -C ₃ -C ₆ aryl (benzyl, -CH ₂ - pyrrolyl, -CH ₂ - thienyl, -CH ₂ - imidazolyl, -CH ₂ - oxazolyl, -CH ₂ - iso-oxazolyl , -CH ₂ -thiazolyl, -CH ₂ -isothiazolyl, -CH ₂ -pyrazolyl, -CH ₂ -pyridyl and -CH ₂ -pyrimidinyl)

5 or 6 carbon monosaccharides, disaccharides or oligosaccharides (3 to 9 monosaccharide residues),

Triglycerides such as α-D-βdiglycerides bound to the acyl of the parent compound via the glyceryl oxygen of the triglycerides, wherein the fatty acids that make up the glyceride lipids are generally saturated or unsaturated C _{6 -26} , C and _6-18 or C _{6 -10} fatty acids, e.g., linoleic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, palmitoleic resan, linolenic acid, and this fatty acid of the same kind),

Phospholipids linked to carboxyl groups via phosphates of phospholipids;

Phthalidyl (FIG. 1, Clayton et al . , Antimicrob . Agents Chemo . (1974) 5 (6): 670-671;

를 포함한다.Cyclic carbonates such as (5-R _d -2-oxo-1,3-dioxolen-4-yl) methyl ester (Sakamoto et al . , Chem . Pharm . Bull. (1984) 32 (6) 2241-2248) where , R _d is R ₁ , R ₄ or aryl; And

It includes.

The hydroxyl groups of the compounds of the invention are alternatively substituted with III, IV or V groups or isopropyl as disclosed in WO 94/21604.

Table α lists examples of ester moieties of protecting groups capable of bonding with —C (O) O— and —P (O) (O—) ₂ groups via oxygen. Also shown are several amidates that are directly bonded to -C (O)-or -P (O) ₂ . Esters of structures 1-5, 8-10 and 16, 17, 19-22 are compounds of the invention having free hydroxyls and corresponding halides (such as chlorides or acyl chlorides) and N, N-dicyclohexyl-N In DMF (or other solvent such as acetonitrile or N-methyl pyrrolidone) of morpholine carboxamidine (or other bases such as DBU, triethylamine, CsCO ₃ , N, N-dimethylaniline, etc.) Reacted and synthesized. When the compound to be protected is a phosphonate, the esters of structures 5-7, 11, 12, 21, and 23-26 are monohydric to alcohols or alkoxide salts (or corresponding amines for compounds such as 13, 14 and 15). It is synthesized by reacting with chlorophosphonate or dichlorophosphonate (or another activated phosphonate).

TABLE A

1.-CH ₂ -C (O) -N (R ₁ ) ₂ * 10. -CH ₂ -OC (O) -C (CH ₃ ) ₃

2.-CH ₂ -S (O) (R ₁ ) 11.-CH ₂ -CCl ₃

3.-CH ₂ -S (O) ₂ (R ₁ ) 12.-C ₆ H ₅

4.-CH ₂ -OC (O) -CH ₂ -C ₆ H ₅ 13. -NH-CH ₂ -C (O) O-CH ₂ CH ₃

5. 3-cholesteryl 14. -N (CH ₃ ) -CH ₂ -C (O) O-CH ₂ CH ₃

6. 3-Pyridyl 15. -NHR ₁

7.N-ethylmorpholino 16. -CH ₂ -OC (O) -C ₁₀ H ₁₅

8.-CH ₂ -OC (O) -C ₆ H ₅ 17. -CH ₂ -OC (O) -CH (CH ₃ ) ₂

9.-CH ₂ -OC (O) -CH ₂ CH ₃ 18.-CH ₂ -CδH (° C. (O) CH ₂ R ₁ )-

CH _2- (° C (O) CH ₂ R ₁ ) *

19.

20.

21.

22.

23.

24.

25.

26.

δ-chiral center is (R), (S) or racemate.

Other esters suitable for use in the present invention are described in EP 632048.

-CH₂SCOCH₃, -CH₂℃ON(CH₃)₂, 또는 (산성기의 산소에 결합된)-CH(R¹ 또는 W⁵)O((CO)R³⁷) 또는 -CH(R¹ 또는 W⁵)((CO)OR³⁸) 구조의 알킬- 또는 아릴-아실옥시알킬기로서, 여기서, R³⁷ 및 R³⁸은 알킬, 아릴 또는 알킬아릴기이다 (미국 특허 제 4968788호 참조). 종종 R³⁷ 및 R³⁸는 벌크 기, 예컨대, 분지형 알킬, 오르토 치환 아릴, 메타 치환 아릴 또는 이들의 조합이며 탄소 원자가 1 내지 6개인 노말, 2차, 이소- 및 3차 알킬을 포함한다. 예로는, 피발로일옥시메틸기가 있다. 이들은 경구투여용 전구 약물에 사용된다. 이러한 유용한 보호기의 예에는 알킬아실옥시메틸 에스테르 및 이들의 유도체가 있으며, 여기에는 -CH(CH₂CH₂OCH₃)℃(O)C(CH₃)₃,

-CH₂℃(O)C₁₀H₁₅, -CH₂℃(O)C(CH₃)₃, -CH(CH₂OCH₃)℃(O)C(CH₃)₃, -CH(CH(CH₃)₂)℃(O)C(CH₃)₃, -CH₂℃(O)CH₂CH(CH₃)₂, -CH₂℃(O)C₆H₁₁, -CH₂℃(O)C₆H₅, -CH₂℃(O)C₁₀H₁₅, -CH₂℃(O)CH₂CH₃, -CH₂℃(O)CH(CH₃)₂ , -CH₂℃(O)C(CH₃)₃ 및 -CH₂℃(O)CH₂C₆H₅가 포함된다.Protecting groups also include double esters that form linearity. For example, -CH ₂ ° C (O) OCH ₃ ,

-CH ₂ SCOCH ₃ , -CH ₂ ° C ON (CH ₃ ) ₂ , or -CH (R ¹ or W ⁵ ) O ((CO) R ³⁷ ) or -CH (R ¹ Or W ⁵ ) ((CO) OR ³⁸ ) alkyl- or aryl-acyloxyalkyl group, wherein R ³⁷ and R ³⁸ are alkyl, aryl or alkylaryl groups (see US Pat. No. 4968788). Often R ³⁷ And R ³⁸ is a bulk group such as branched alkyl, ortho substituted aryl, meta substituted aryl or combinations thereof and includes normal, secondary, iso- and tertiary alkyl having 1 to 6 carbon atoms. An example is a pivaloyloxymethyl group. These are used in prodrugs for oral administration. Examples of such useful protecting groups include alkylacyloxymethyl esters and derivatives thereof, including —CH (CH ₂ CH ₂ OCH ₃ ) ° C. (O) C (CH ₃ ) ₃ ,

-CH ₂ ° C (O) C ₁₀ H ₁₅ , -CH ₂ ° C (O) C (CH ₃ ) ₃ , -CH (CH ₂ OCH ₃ ) ° C (O) C (CH ₃ ) ₃ , -CH (CH ( CH ₃ ) ₂ ) ° C (O) C (CH ₃ ) ₃ , -CH ₂ ° C (O) CH ₂ CH (CH ₃ ) ₂ , -CH ₂ ° C (O) C ₆ H ₁₁ , -CH ₂ ° C (O C ₆ H ₅ , -CH ₂ ° C (O) C ₁₀ H ₁₅ , -CH ₂ ° C (O) CH ₂ CH ₃ , -CH ₂ ° C (O) CH (CH ₃ ) ₂ , -CH ₂ ° C (O ) C (CH ₃ ) ₃ and -CH ₂ ° C (O) CH ₂ C ₆ H ₅ .

In some claims the protected acid groups are esters of acidic groups and residues of hydroxyl containing functional groups. In another claim, amino compounds are used to protect acid functionality. Residues of suitable hydroxyl or amino containing functional groups are described above or can be found in WO 95/07920. Of particular interest are residues of amino acids, amino acid esters, polypeptides or aryl alcohols. Typical amino acid, polypeptide and carboxyl-esterified amino acid residues are described as L1 or L2 groups on pages 11-18 and related parts of WO 95/07920. WO 95/07920 discloses amidates of phosphonic acids, but it is understood that such amidates can be formed by any of the acid groups described herein and the amino acid residues described in WO 95/07920.

Typical esters for acidic protecting functionalities are also disclosed in WO 95/07920, where it is understood that the same ester can be formed from the acidic groups described herein as well as the phosphonates in WO 95/07920. Typical ester groups are defined as at least pages 89 to 93 (in R ³¹ or R ³⁵ ), tables in page 105 and (R) in pages 21-23 of WO 95/07920. Esters of unsubstituted aryl, such as aryl alkyl or hydroxy-, halo-, alkoxy-, carboxy- and / or alkylestercarboxy substituted aryl or alkyl aryl, in particular phenyl, ortho-ethoxyphenyl, such as phenyl or benzyl, Or C ₁ -C ₄ alkylester carboxylphenyl (salicylic acid C ₁ -C ₁₂ alkylester) are of particular interest.

Especially when using the esters or amides of WO 95/07920, protected acidic groups are useful as prodrugs for oral administration. However, it is not necessary to protect the acidic groups in order for the compounds of the present invention to be effectively orally administered. In the case of systemic or oral administration of a compound of the invention having a protected group, in particular a protecting group such as amino acid amidate or substituted and unsubstituted aryl esters, they can be hydrolyzed in vivo to produce free acid.

One or more acidic hydroxyl groups are protected. If one or more acidic hydroxyl groups are protected, the same or different protecting groups are used, for example the esters may be different or identical, or mixed amidates and esters may be used.

Typical hydroxy protecting groups described in Greene (pp. 14-118) include substituted methyl and alkyl ethers, substituted benzyl ethers, silyl ethers, esters including sulfonic acid esters and carbonates. For example:

Ether (methyl, t -butyl, allyl),

Substituted methyl ether (methoxymethyl, methylthiomethyl, t -butylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p -methoxybenzyloxymethyl, (4-methoxyphenoxy) methyl , Guoacolmethyl, t -butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy ) Methyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydropthiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydropthiopyranyl S, S -dioxido, 1-[(2-chloro-4-methyl) phenyl] -4-methoxypiperidine-4 -Yl, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a, 4,5,6,7,7a-octahydro-7,8,8-trimethyl -4,7-methanobenzofuran-2-yl)) ,

Substituted ethyl ether (1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyl Oxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl) ethyl,

P -chlorophenyl, p -methoxyphenyl, 2,4-dinitrophenyl, benzyl),

Substituted benzyl ethers ( p -methoxybenzyl, 3,4-dimethoxybenzyl, o -nitrobenzyl, p -nitrobenzyl, p -halobenzyl, 2,6-dichlorobenzyl, p -cyanobenzyl, p- benzyl, 2-and 4-picolyl, 3-methyl-2-picolyl N - oxido, diphenylmethyl, p, p '- dinitro benzhydryl, 5-dibenzo-standing beryl, triphenylmethyl, α-naphthyldiphenylmethyl, p -methoxyphenyldiphenylmethyl, di ( p -methoxyphenyl) phenylmethyl, tri ( p -methoxyphenyl) methyl, 4- (4'-bromophenacryloxy) phenyl Diphenylmethyl, 4,4 ', 4-tris (4,5-dichlorophthalimidophenyl) methyl, 4,4', 4-tris (revulinoyloxyphenyl) methyl, 4,4 ', 4-tris (Benzoyloxyphenyl) methyl, 3- (imidazol-1-ylmethyl) bis (4 ', 4-dimethoxyphenyl) methyl, 1,1-bis (4-methoxyphenyl) -1'-pyrenylmethyl , 9-anthryl, 9- (9-phenyl) xanthenyl, 9- (9-phenyl-10-oxo) anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S, S Dioxydo),

Silyl ether (trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t -butyldimethylsilyl, t -butyldiphenylsilyl, tribenzylsilyl, tri p -xylylsilyl, triphenylsilyl, diphenylmethylsilyl, t -butylmethoxyphenylsilyl),

Ester (formate, benzoylformate, acetate, ultraacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p -chlorophenoxyacetate, p- Poly-phenylacetate, 3-phenylpropionate, 4-oxopentanoate (Levulinate), 4,4- (ethylenedithio) pentanoate, pivaloate, adamantatoate, crotonate, 4- Methoxycrotonate, benzoate, p -phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate)),

Carbonates (methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl, 2- (phenylsulfonyl) ethyl, 2- (triphenylphosphonio)) Ethyl, isobutyl, vinyl, allyl, p -nitrophenyl, benzyl, p -methoxybenzyl, 3,4-dimethoxybenzyl, o -nitrobenzyl, p -nitrobenzyl, S -benzyl thiocarbonate, 4-ethoxy -1-naphthyl, methyl dithiocarbonate),

Secondary crackers (2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formylbenzenesulfonate, 2- (methyl Thiomethoxy) ethyl carbonate, 4- (methylthiomethoxy) butyrate, 2- (methylthiomethoxymethyl) benzoate), and other esters (2,6-dichloro-4-methylphenoxyacetate, 2,6 -Dichloro-4- (1,1,3,3 tetramethylbutyl) phenoxyacetate, 2,4-bis (1,1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinic acid, ( E ) -2-methyl-2-butenoate (taigroate), o- (methoxycarbonyl) benzoate, p -poly-benzoate, α-naphthoate, nitrate, alkyl N, N, N ', N' -tetramethylphosphorodiamidate, N -phenylcarbamate, borate, dimethylphosphinothionyl, 2,4-dinitrophenyl sulfenate),

Sulfonates (sulfates, methanesulfonates (mesylate), benzylsulfonates, tosylate).

Typical 1,2-diol protecting groups (hence generally two OH groups are bonded together as protecting groups) are described on pages 118-142 of Greene, which include cyclic acetals and ketals (methylene, ethylidene, 1- t −). Butylethylidene, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexyl Den, cycloheptylidene, benzylidene, p -methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, 2-nitrobenzylidene) and cyclic ortho esters Methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1-ethoxyethylidene, 1,2-dimethoxyethylidene, α-methoxybenzylidene, 1- ( N, N -Dimethylamino) ethylidene derivative, α- ( N, N -dimethylamino) benzylidene derivative, 2-oxacyclopentylidene) and a silyl derivative thereof (di- t -butylsilylene group, 1,3- ( One , 1,3,3-tetraisopropyldisiloxanilidene), and tetra- t -butoxydisiloxane-1,3-diylidene), cyclic carbonate, cyclic boronate, ethyl boronate and phenyl Boronates are included.

More typically 1,2-diol protecting groups include those shown in Table B. More typical include epoxides, acetonides, cyclic ketals and aryl acetals.

TABLE B

Where R ⁹ Is C ₁ -C ₆ alkyl.

Amino protecting group

Another group of protecting groups includes the typical amino protecting groups described in Greene, pp. 315-385, including the following.

Carbamate: (methyl and ethyl, 9-fluorenylmethyl, 9 (2-sulfo) fluorenylmethyl, 9- (2,7-dibromo) fluorenylmethyl, 2,7-di- t -Butyl- [9- (10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)] methyl, 4-methoxyphenacryl),

Substituted ethyl: (2,2,2-trichoethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1- (1-adamantyl) -1-methylethyl, 1,1-dimethyl-2- Ethyl halide, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1- (4-biphenylyl) ethyl, 1 -(3,5-di- t -butylphenyl) -1-methylethyl, 2- (2'- and 4'-pyridyl) ethyl, 2- ( N, N -dicyclohexylcarboxamido) ethyl , t -butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamil, 4-nitrocinamyl, 8-quinolyl, N -hydroxypiperidinyl, alkyldithio, benzyl, p Methoxybenzyl, p -nitrobenzyl, p -bromobenzyl, p -chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, diphenylmethyl),

Auxiliary cracker: (2-methylthioethyl, 2-methylsulfonylethyl, 2- ( p -toluenesulfonyl) ethyl, [2- (1,3-dicyanyl)] methyl, 4-methylthiophenyl, 2 , 4-dimethylthiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m -secondary- p -acyloxybenzyl, p- (dihydr Hydroxyboryl) benzyl, 5-benzisooxazolylmethyl, 2- (trifluoromethyl) -6-chromonylmethyl),

Photodegradable groups: ( m -nitrophenyl, 3,5-dimethoxybenzyl, o -nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, phenyl ( o -nitrophenyl) methyl), urea- Derivatives (phenothiazinyl- (10) -carbonyl, N' - p -toluenesulfonylaminocarbonyl, N' -phenylaminothiocarbonyl),

Other carbamate: ( t -amyl, S -benzyl thiocarbamate, p -cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p -decyloxybenzyl, diisopropylmethyl, 2,2 -Dimethoxycarbonylvinyl, o- ( N, N -dimethylcarboxamido) benzyl, 1,1-dimethyl-3- ( N, N -dimethylcarboxamido) propyl, 1,1-dimethylpropynyl , di (2-pyridyl) methyl, 2-furanyl-methyl, 2-iodo ethyl, isopropyl barley carbonyl, iso-butyl, iso-nicotinyl, p - (p '- methoxy phenyl azo) benzyl, 1-methylcyclohexyl Butyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-1- (3,5-dimethoxyphenyl) ethyl, 1-methyl-1- ( p -phenylazophenyl) ethyl, 1-methyl-1-phenylethyl, 1-methyl-1- (4-pyridyl) ethyl, phenyl, p- (phenylazo) benzyl, 2,4,6-tri- t -butylphenyl, 4- (trimethyl Ammonium) benzyl, 2,4,6-trimethylbenzyl),

● amide: (N - formyl, N - acetyl, N - sec-acetyl, N - tree seconds acetyl, N - trifluoroacetyl, N - phenylacetyl, N -3- phenylpropionyl, N - avoid collision alkanoyl, N -3-pyridylcarboxamide, N -benzoylphenylalanyl, N -benzoyl, N - p -phenylbenzoyl),

Secondary decomposition amides: ( N - o -nitrophenylacetyl, N - o -nitrophenoxyacetyl, N -acetoacetyl, ( N' -dithiobenzyloxycarbonylamino) acetyl, N- 3- ( p -hydride) Oxyphenyl) propionyl, N- 3- ( o -nitrophenyl) propionyl, N -2-methyl-2- ( o -nitrophenoxy) propionyl, N -2-methyl-2- ( o -phenyla Zofenoxy) propionyl, N -4-chlorobutyryl, N -3-methyl-3-nitrobutyryl, N - o -nitrocinnamoyl, N -acetylmethionine, N - o -nitrobenzoyl, N - o -(Benzoyloxymethyl) benzoyl, 4,5-diphenyl-3-oxazolin-2-one),

● cyclic imide derivatives: (N - phthalimide, N - O-dish succinate alkanoyl, N -2,3- diphenyl maleic five days, -2,5- dimethyl-N-pyrrolyl, N -1,1,4, 4-tetramethyldisilylazacyclopentane adduct, 1,3-dimethyl-1,3,5-triazacyclohexan-2-one substituted with 5, 1,3-dibenzyl-1 substituted with 5, 3-5-triazacyclohexan-2-one, 3,5-dinitro-4-pyridonyl substituted with 1),

N -alkyl and N -aryl amines: ( N -methyl, N -allyl, N- [2- (trimethylsilyl) ethoxy] methyl, N- 3-acetoxypropyl, N- (1-isopropyl-4 -Nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salt, N -benzyl, N -di (4-methoxyphenyl) methyl, N -5-dibenzoserveryl, N -tri Phenylmethyl, N- (4-methoxyphenyl) diphenylmethyl, N- 9-phenylfluorenyl, N- 2,7-dichloro-9-fluorenylmethylene, N -peroxenylmethyl, N- 2 Picolylamine N' -oxide),

Imine derivatives: ( N -1,1-dimethylthiomethylene, N -benzylidene, N - p -methoxybenylidene, N -diphenylmethylene, N -[(2-pyridyl) methyl] methylene, N , ( N ', N' -dimethylaminomethylene, N , N' -isopropylidene, N - p -nitrobenzylidene, N -salicylidene, N -5-chlorosalicylidene, N- (5 -Chloro-2-hydroxyphenyl) phenylmethylene, N -cyclohexylidene),

Enamine derivatives: ( N- (5,5-dimethyl-3-oxo-1-cyclohexenyl)),

N -metal derivatives ( N -boron derivatives thereof, N -diphenylborinic acid derivatives, N- [phenyl (pentacarbonylchrome- or -tungsten)] carbenyl, N -copper or N -zinc chelate),

NN derivative: ( N -nitro, N -nitroso, N -oxide),

NP derivative: ( N -diphenylphosphinyl, N -dimethylthiophosphinyl, N -diphenylthiophosphinyl, N -dialkyl phosphoryl, N -dibenzyl phosphoryl, N -diphenyl phosphoryl),

N-Si derivatives, NS derivatives, and N-sulphenyl derivatives: ( N -benzenesulphenyl, No- nitrobenzenesulphenyl, N -2,4-dinitrobenzenesulphenyl, N -pentachlorobenzenesulphenyl, N -2-nitro-4-methoxybenzenesulphenyl, N -triphenylmethylsulphenyl, N- 3-nitropyridinesulphenyl) and N -sulfonyl derivatives ( N - p -toluenesulfonyl, N -benzene Sulfonyl, N- 2,3,6-trimethyl-4-methoxybenzenesulfonyl, N- 2,4,6-trimethoxybenzenesulfonyl, N -2,6-dimethyl-4-methoxybenzenesulfur Ponyl, N -pentamethylbenzenesulfonyl, N- 2,3,5,6, -tetramethyl-4-methoxybenzenesulfonyl, N -4-methoxybenzenesulfonyl, N- 2,4,6- Trimethylbenzenesulfonyl, N -2,6-dimethoxy-4-methylbenzenesulfonyl, N- 2,2,5,7,8-pentamethylchroman-6-sulfonyl, N -methanesulfonyl, N -βtrimethylsilethanesulfonyl, N- 9-anthracenesulfonyl, N -4- (4 ', 8'-dimethoxynaphthylmethyl) benzenesulfonyl, N -benzylsulfonyl, N -trifluoromethylsulfonyl , N -phenacrylsulfonyl).

More typical protected amino groups include carbamates and amides, and even more typical include -NHC (O) R ¹ or -N = CR ¹ N (R ¹ ) ₂ . Another protecting group useful as a prodrug of amino or -NH (R ⁵ ) is:

이다.

to be.

For example, Alexander, J. et al. (1996) J. Med . Chem . See 39: 480-486.

Amino acids and Polypeptide  Protectors and complexes

Amino acid or polypeptide protecting groups of the compounds of the invention have a R ¹⁵ NHCH (R ¹⁶ ) C (O) -structure, wherein R ^{15 is} H, an amino acid or polypeptide residue, and R ⁵ and R ¹⁶ are defined below do.

R ¹⁶ is lower alkyl, or amino, carboxyl, amide, carboxyl ester, hydroxyl, C ₆ -C ₇ Lower alkyl (C ₁ -C ₆ ) substituted with aryl, guanidinyl, imidazolyl, indolyl, sulfidyl, sulfoxide, and / or alkylphosphate. R ¹⁰ silver Proline residues along with amino acid αN (R ¹⁰ = -CH ₂ ) _3- ). However, R ¹⁰ is generally, for example, H, —CH ₃ , —CH (CH ₃ ) ₂ , —CH ₂ —CH (CH ₃ ) ₂ , —CHCH ₃ —CH ₂ —CH ₃ , —CH ₂ —C ₆ H ₅ , -CH ₂ CH ₂ -S-CH ₃ , -CH ₂ OH, -CH (OH) -CH ₃ , -CH ₂ -SH, -CH ₂ -C ₆ H ₄ OH, -CH ₂ -CO -NH ₂ , -CH ₂ -CH ₂ -CO-NH ₂ , -CH ₂ -COOH, -CH ₂ -CH ₂ -COOH,-(CH ₂ ) ₄ -NH ₂ and-(CH ₂ ) ₃ -NH- It is a side chain group of natural amino acids, such as C (NH ₂ ) -NH ₂ . R ¹⁰ may also include 1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.

Another group of protecting groups includes residues of amino containing compounds, especially amino acids, polypeptides, protecting groups, -NHSO ₂ R _, NHC (O) R, -N (R) ₂ , NH ₂ or -NH (R) (H) Thus, here, for example, the carboxylic acid reacts with the amine, i.e., is coupled to form an amide, such as C (O) NR ₂ . Phosphonic acid reacts with the amine to form phosphonamidate, which is -P (O) (OR) (NR ₂ ).

In general, amino acids have the structure R ¹⁷ C (O) CH (R ¹⁶ ) NH—. Wherein R ¹⁷ is —OH, —OR, an amino acid or a P (O) (OR) (NR ₂ ) residue. Amino acids are low molecular weight compounds, less than about 1000 Mω, which include at least one amino or imino group and at least one carboxyl group. Generally, amino acids can be found in nature. In other words, it can be detected in biomaterials such as bacteria or other microorganisms, plants, animals or humans. Suitable amino acids are typically compounds characterized by one amino or imino nitrogen atom separated by an α amino acid, ie by a single substituted or unsubstituted α carbon atom from the carbon atom of one carboxyl group. Of particular interest are hydrophobic residues such as mono- or di-alkyl or aryl amino acids, cycloalkylamino acids and the like. These residues contribute to cell permeability by increasing the partition coefficient of the parent drug. Typically, such residues do not contain sulfhydryl or guanidino substituents.

Natural amino acid residues are residues that are naturally present in plants, animals or microorganisms, especially their proteins. Most typically, the polypeptide consists essentially of these natural amino acid residues. These amino acids include glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxy There is proline. In addition, artificial amino acids such as v-alanine, phenylglycine and homoarginine are also included. Amino acids that do not encode the genes encountered in general may also be used in the present invention. All amino acids used in the present invention may be D- or L-type optical isomers. In addition, other peptide structural analogues are also useful in the present invention. For a general overview, see Spatola , AF, Chemistry and BiO Chemistry of Amino acids, Peptides and Proteins , B. Weinstein, eds., Marcel Dekker, Neω York, p. 267 (1983).

If the protecting group is a single amino acid residue or polypeptide, they are alternatively substituted at R ³ of substituent A ¹ , A ² or A ³ of the compounds of the invention. Such complexes are produced by the formation of amide bonds between carboxyl groups of amino acids (or, for example, C-terminal amino acids of a polypeptide). Similarly, the complex is formed between R ³ and amino groups of an amino acid or polypeptide. In general, the introduction of amino acids at one or more possible positions is within the scope of the present invention, but only one of any sites in the parent molecule is amidated with the aforementioned amino acids. In general, the carboxyl group of R ³ is amidated with amino acids. In general, the α-amino or α-carboxyl group of an amino acid or the terminal amino or carboxyl group of a polypeptide is bound to a parent functional group, that is, the carboxyl or amino group in the amino acid side chain, in general, (described further below). Although these groups need to be protected during the synthesis of the complex, they are not used to form amide bonds with the parent compound.

With regard to the carboxyl group-containing side chain of the amino acid or polypeptide, the carboxyl group is alternatively blocked, for example ^by R ¹ , or esterified or amidated with R ⁵ . Similarly, amino side chain R ¹⁶ is alternatively blocked by R ¹ or substituted with R ⁵ .

As bound to the parent molecule, such esters or amides bound to side chain amino groups or carboxyl groups can, alternatively, be hydrolyzed under acidic (pH "3) or basic (pH" 10) conditions in vivo or in vitro. . Alternatively, they are substantially stable in the human gastrointestinal tract but enzymatically hydrolyze in the environment in the blood or cells. Ester or amino acid or polypeptide amidates are also useful as intermediates for the preparation of parent molecules containing free amino or carboxyl groups. The free acid or base of the parent compound is readily formed from the ester or amino acid or polypeptide complex of the invention, for example by known hydrolysis methods.

If the amino acid residue has one or more chiral centers, any of D, L, meso, treo or erythro (if appropriate) racemates, scalemates or mixtures thereof may be used. In general, isomers are useful if the intermediate is non-enzymatically hydrolyzed (as is the case when amides are used as chemical intermediates for free acids or free amines). On the other hand, the L isomer is more general because it is susceptible to both non-enzymatic and enzymatic hydrolysis and is more efficiently transported by amino acid or dipeptidyl transport systems in the gastrointestinal tract.

Examples of suitable amino acids whose residues are represented by R ^x or R ^y include:

Glycine;

Aminopolycarboxylic acids such as aspartic acid, β-hydroxyaspartic acid, glutamic acid, β-hydroxyglutamic acid, β-methylaspartic acid, β-methylglutamic acid, β, β-dimethylaspartic acid, γ-hydroxyglutamic acid , β, γ-dihydroxyglutamic acid, β-phenylglutamic acid, γ-methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic acid, 2-aminosveric acid and 2-aminosebacic acid;

 Amino acid amides such as glutamine and asparagine;

Polyamino- or polybase-monocarboxylic acids such as arginine, lysine, β-aminoalanine, γ-aminobutyrin, ornithine, citrulline, homoarginine, homocitrulline, hydroxylysine, allohydroxylcin and diaminobutyric acid;

 Other base amino acid residues such as histidine;

Diamino dicarboxylic acids such as α, α-diisuccinic acid, α, α-diaminoglutaric acid, α, α-diaminoadipic acid, α, α-diaminopimelic acid, α, α-diamino -β- hydroxypimelic acid, α, α-diaminosveric acid, α, α-diaminoazelaic acid, and α, α-diamino sebacic acid;

Imino acids such as proline, hydroxyproline, allohydroxyproline, g-methylproline, pipecolic acid, 5-hydroxypipecolic acid, and azetidine-2-carboxylic acid;

Mono- or di-alkyl (typical C ₁ -C ₈ branched or normal) amino acids such as alanine, valine, leucine, allylglycine, butyrin, norvaline, norleucine, heptyline, α-methylserine, α- Amino-α-methyl-γ-hydroxy valeric acid, α-amino- α-methyl-δ-hydroxy valeric acid, α-amino-α-methyl-ε-hydroxycaproic acid, isovaline, α-methylglutamic acid α-aminoisobutyric acid, α-aminodiethylacetic acid, α-aminodiisopropylacetic acid, α-aminodi-n-propylacetic acid, α-aminodiisobutylacetic acid, α-aminodi-n-butylacetic acid, α-aminoethylisopropylacetic acid, α-amino-n-propylacetic acid, α-aminodiisoamiacetic acid, α-methylaspartic acid, α-methylglutamic acid, 1-aminocyclopropane-1-carboxylic acid, isoleucine, alloleucine Tert-leucine, β-methyltryptophan and α-amino-β-ethyl-β-phenylpropionic acid;

β-phenylserinyl;

Aliphatic α-amino-β-hydroxy acids such as serine, β-hydroxyleucine, β-hydroxynorleucine, β-hydroxynorvaline, and α-amino-β-hydroxystearic acid;

α-amino, α-, γ-, δ- or ε-hydroxy acids such as homoserine, δ-hydroxynorvaline, γ-hydroxynorvaline and ε-hydroxynorleucine residues; Cannabin and canaryrin; γ-hydroxyornithine;

D-glucosamine acid or D-galactosamic acid, such as 2-hexosamic acid;

α-amino-β-thiols such as penicylamine, β-thiolnorvaline or β-thiolbutyrin;

Sulfur containing amino acid residues comprising cysteine, homocystine, β-phenylmethionine, methionine, S-allyl-L-cysteine sulfoxide, 2-thiol histidine, cystathionine, and thiol ethers of cysteine or homocysteine;

Phenylalanine, tryptophan and ring-substituted α-amino acids such as phenyl- or cyclohexylamino acid α-aminophenylacetic acid, α-aminocyclohexyl acetic acid and α-amino-β-cyclohexylpropionic acid; Aryl substituted with aryl, lower alkyl, hydroxy, guanidino, oxyalkylether, nitro, sulfur or halogen (e.g., tyrosine, methyltyrosine and o-chloro-, p-chloro-, 3,4-dichloro , o- , m- or p -methyl-, 2,4,6-trimethyl-, 2-ethoxy-5-nitro-, 2-hydroxy-5-nitro- and p-nitro-phenylalanine) Phenylalanine analogs and derivatives thereof; Furyl-, thienyl-, pyridyl-, pyrimidinyl-, purinyl- or naphthyl-alanine; And tryptophan analogs and derivatives thereof including kynurenine, 3-hydroxykynurenine, 2-hydroxytryptophan and 4-carboxytryptophan;

Α-amino substitutions including sarcosine (N-methylglycine), N-benzylglycine, N-methylalanine, N-benzylalanine, N-methylphenylalanine, N-benzylphenylalanine, N-methylvaline and N-benzylvaline amino acid; And

Α-hydroxy and substituted α-hydroxy amino acids, including serine, threonine, allothreonine, phosphoserine, and phosphorreonine.

A polypeptide is a polymer of amino acids in which the carboxyl group of one amino acid monomer is bonded to an amino or imino group of an adjacent amino acid monomer by an amide bond. Polypeptides include dipeptides, low molecular weight polypeptides (about 1500-5000 MW) and proteins. The protein alternatively contains 3, 5, 10, 50, 75, 100 or more residues and is suitably substantially identical in sequence to human, animal, plant or microbial protein. These include enzymes (eg, hydrogen peroxidase) and immunogens that elicit an immune response, such as KLH, or the type of antibody or protein, and the like. The nature and identity of polypeptides vary widely.

Polypeptide amidates are useful as immunogens to form antibodies against polypeptides (if they are not immunogens in administered animals) or against epitopes on the remainder of the compounds of the invention.

Antibodies that can bind to the parent bipeptidyl compound are used to separate the parent compound from the mixture, for example in the diagnosis or preparation of the parent compound. Complexes of the parent compound and polypeptide are generally more immunogenic than polypeptides of similar species of animals, thus making the polypeptide more immunogenic by promoting antibody formation against it. Thus, the polypeptide or protein need not be an immunogen in the body of an animal, such as a rabbit, mouse, horse, or rat, typically used to form an antibody. However, the final product complex must be immunogenic in at least one of said animals. The polypeptide may alternatively comprise a peptidase cleavage site at the peptide bond between the first and second residues adjacent to the acidic heteroatoms. This cleavage site is flanked by the enzyme recognition structure. For example, certain sequences of residues are recognized by peptide degrading enzymes.

Peptide degrading enzymes for the degradation of polypeptide complexes of the present invention are well known and in particular include carboxyl peptidase.

Carboxypeptidase degrades polypeptides by removing C-terminal residues and is specific in many cases for certain C-terminus sequences. Conditions for these enzymes and their substrates are generally known. For example, dipeptides (with given pairs of residues and free carboxyl terminations) are covalently bonded to their α-amino groups with the phosphorus or carbon atoms of the compounds of the invention. In the claims, if W ₁ is a phosphonate, the peptide is expected to cleave the phosphonoamidate bonds by automatic catalysis by leaving the carboxyl of adjacent amino acid residues by an appropriate peptide degrading enzyme.

Suitable dipeptidyl groups (designated by their single letter code) are AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT, AW, AY , AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND , NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH , DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, CQ, CG, CH, CI, CL, CK, CM, CF , CP, CS, CT, CW, CY, CV, EA, ER, EN, ED, EC, EE, EQ, EG, EH, EI, EL, EK, EM, EF, EP, ES, ET, EW, EY , EV, QA, QR, QN, QD, QC, QE, QQ, QG, QH, QI, QL, QK, QM, QF, QP, QS, QT, QW, QY, QV, GA, GR, GN, GD , GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, GY, GV, HA, HR, HN, HD, HC, HE, HQ, HG, HH , HI, HL, HK, HM, HF, HP, HS, HT, HW, HY, HV, IA, IR, IN, ID, IC, IE, IQ, IG, IH, II, IL, IK, IM, IF , IP, IS, IT, IW, IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI, LL, LK, LM, LF, LP, LS, LT, LW, LY , LV, KA, KR, KN, KD, KC, KE, KQ, KG, KH, KI, KL, KK, KM, KF, KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ, MG, MH, MI, ML, MK, MM, MF, MP, MS, MT, MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ, FG, FH, FI, FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN, PD, PC, PE, PQ, PG, PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA, SR, SN, SD, SC, SE, SQ, SG, SH, SI, SL, SK, SM, SF, SP, SS, ST, SW, SY, SV, TA, TR, TN, TD, TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, TP, TS, TT, TW, TY, TV, WA, WR, WN, WD, WC, WE, WQ, WG, WH, WI, WL, WK, WM, WF, WP, WS, WT, WW, WY, WV, YA, YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM, YF, YP, YS, YT, YW, YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM, VF, VP, VS, VT, VW, VY and VV.

Tripeptide residues are also useful as protecting groups. When the phosphonate group is protected, its sequence -X ⁴ -pro-X ^5- (wherein X ^{4 can} be any ^of amino acid residues and X ^{5 is an} amino acid residue, a carboxyl ester of proline, or hydrogen) It is cleaved by raw carboxypeptidase to give X ⁴ with free carboxyl groups, which in turn cleaves phosphonoamidate bonds by an automatic catalytic reaction. The carboxyl group of X ⁵ is, alternatively, esterified with benzyl.

Dipeptides or tripeptides can be selected based on known transport properties and / or susceptibility to peptidase, which can affect delivery to intestinal mucosa or other cell types. Dipeptides and tripeptides without α-amino groups serve as transport substrates for peptide transporters found in the chorionic membranes of intestinal mucosal cells (Bai, JPF, (1992) Pharm Res . 9: 969-978). Peptides with transport capacity can therefore be used to enhance the bioavailability of amidate compounds. Di- or tripeptides having one or more amino acids in an array state are also compatible with peptide delivery and may be utilized in the amidate compounds of the invention. The amino acids in the sequence can be used to reduce the susceptibility to hydrolysis by proteases common to the villi boundary, such as aminopeptidase N of di- or tripeptides. In addition, di- or tripeptides are alternatively selected based on their relative resistance to hydrolysis by proteases found in the intestinal lining. For example, tripeptides or polypeptides lacking asp and / or glu are poor substrates for aminopeptidase A, and have no amino acid residues at the N-terminal portion of the hydrophobic amino acids (leu, tyr, phe, val, trp). Or tripeptides are poor substrates for endopeptidase and peptides without the precursor residue at the second position at the end of the free carboxyl termini are poor substrates for carboxypeptidase P. Similar considerations can be applied to select peptides that are relatively resistant or relatively sensitive to hydrolysis by cytoplasm, kidney, liver, serum or other peptidase. Such poorly cleaved polypeptide amidates are useful for binding to proteins to become immunogens or generate immunogens.

Specific Embodiments of the Invention

Particular values of radicals, substituents, and ranges, and the particular embodiments of the invention described herein, are illustrative only and are not intended to exclude other defined values or other values within the defined ranges.

In certain embodiments of the invention, the complex is a compound substituted directly or indirectly via a linking group with one or more phosphonate groups, which is optionally substituted with one or more groups A ⁰ , or pharmaceutically acceptable thereof Salt. here:

A ^{0 is} A ¹ , A ² or W ³ ,

A ^{1 is} :

A ^{2 is} :

A ^{3 is} :

Y ¹ is independently O, S, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), or N (N (R ^x ) (R ^x ))ego,

Y ² is independently bonded, O, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), N (N (R ^x ) (R ^x ) ), -S (O) _M2 - a, or _{-S (O) M2 -S (O} ) M2-,

R ^x is independently represented by H, R ¹ , W ³ , a protecting group, or the following formula.

here:

R ^{y is} independently H, W ³ , R ² or a protecting group,

R ^{1 is} independently H or alkyl having 1 to 18 carbon atoms,

R ^{2 is} independently H, R ¹ , R ³ or R ⁴ , wherein each R ^{4 is} independently substituted with 0 to 3 R ³ groups or is bonded together at a carbon atom so that two R ² groups are 3 To eight carbon rings, which ring may be substituted with 0 to 3 R ³ groups;

R ³ is R ^3a , R ^3b , R ^3c or R ^3d , if R ³ is bonded to a heteroatom, R ³ is R ^3c or R ^3d ,

R ^3a is F, Cl, Br, I, -CN, N ₃ or -NO ₂ ,

R ^3b is Y ¹ ,

R ^3c is -R ^x , -N (R ^x ) (R ^x ), -SR ^x , -S (O) R ^x , -S (O) ₂ R ^x , -S (O) (OR ^x ),- S (O) ₂ (OR ^x ), -OC (Y ¹ ) R ^x , -OC (Y ¹ ) OR ^x , -OC (Y ¹ ) (N (R ^x ) (R ^x )), -SC (Y ¹ ) R ^x , -SC (Y ¹ ) OR ^x , -SC (Y ¹ ) (N (R ^x ) (R ^x )), -N (R ^x ) C (Y ¹ ) R ^x , -N (R ^x ) C (Y ¹ ) OR ^x , or -N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ))

R ^3d is -C (Y ¹ ) R ^x , -C (Y ¹ ) OR ^x or -C (Y ¹ ) (N (R ^x ) (R ^x )),

R ⁴ is alkyl having 1 to 18 carbon atoms, alkenyl having 2 to 18 carbon atoms, or alkynyl having 2 to 18 carbon atoms;

R ⁵ is R ⁴ , wherein each R ^{4 is} substituted with 0-3 R ³ groups;

R ^5a is independently alkylene having 1 to 18 carbon atoms, alkenylene having 2 to 18 carbon atoms, or alkynylene having 2 to 18 carbon atoms, and any one of alkylene, alkenylene or alkynylene is 0 to 3 Substituted with a R ³ group;

W ³ is W ⁴ or W ⁵ ;

W ⁴ is R ⁵ , -C (Y ¹ ) R ⁵ , -C (Y ¹ ) W ⁵ , -SO ₂ R ⁵ , or -SO ₂ W ⁵ ;

W _{^{5 is a}} carbocycle or heterocycle, wherein W ⁵ is independently substituted with 0 to 3 R _² groups;

W ^{6 is} independently W ³ substituted with 1, 2 or 3 A ³ groups;

M 2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M 12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1,

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another specific embodiment of the present invention, A ¹ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ^{1 is} represented by the following formula.

;

;

In another specific embodiment of the present invention, A ^{1 is} represented by the following formula.

;

;

In another specific embodiment of the present invention, A ^{1 is} represented by the following formula.

;

;

In another specific embodiment of the present invention, A ^{1 is} represented by the following formula.

And W ^5a is carbocycle or heterocycle, wherein W ^5a is independently substituted with 0 or 1 R ² groups. The specific value of M12a is 1.

In another specific embodiment of the present invention, A ^{1 is} represented by the following formula.

;

;

In another specific embodiment of the present invention, A ¹ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ^{1 is} represented by the following formula.

;

;

Wherein W ^5a is a carbocycle and is independently substituted with 0 or 1 R ² groups;

In another specific embodiment of the present invention, A ¹ is represented by the following formula.

;

;

Wherein Y ^2b is O or N (R 2) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the present invention, A ¹ is represented by the following formula.

;

;

Wherein W ^5a is carbocycle and is independently substituted with 0 or 1 R ² groups.

In another specific embodiment of the present invention, A ¹ is represented by the following formula.

;

;

Wherein W ^5a is carbocycle or heterocycle, where W ^5a is independently substituted with 0 or 1 R ² groups.

In another specific embodiment of the present invention, A ^{1 is} represented by the following formula.

;

;

Wherein Y ^2b is O or N (R 2) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In certain embodiments of the present invention, A ² is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ² is represented by the following formula.

;

;

In another specific embodiment of the present invention, M12b is one.

In another specific embodiment of the invention, M12b is 0, Y ² is a bond and W ⁵ is a carbocycle or heterocycle, wherein W ⁵ is, alternatively, independently 1, 2 or 3 R Substituted with ² groups.

In another specific embodiment of the present invention, A ² is represented by the following formula.

;

;

Wherein W ^5a is a carbocycle or heterocycle, where W ^5a is, alternatively and independently, substituted with 1, 2 or 3 R ² groups.

In another specific embodiment of the present invention, M12a is one.

In another specific embodiment of the present invention, A ² is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl and substituted pyridyl.

In another specific embodiment of the present invention, A ² is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ² is represented by the following formula.

;

;

In another specific embodiment of the present invention, M12b is one.

In a particular embodiment of the present invention, A ³ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^{1a is} O or S, and Y ^{2a is} O, N (R ^x ) or S.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^2b is O or N (R ^x ).

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^2b is O or N (Rx) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^{2b is} O or N (Rx) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the present invention, M12d is one.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In another particular embodiment of the invention, W ⁵ is carbocycle.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In another particular embodiment of the invention, W ⁵ is phenyl.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^1a is O or S, and Y ^{2a is} O, N (R ^x ) or S.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^2b is O or N (R ^x ).

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^2b is O or N (Rx) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another particular embodiment of the invention, R ¹ is H.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R ² groups.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^1a is O or S, and Y ^2a is O, N (R ² ) or S.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^1a is O or S, Y ^2b is O or N (R 2), and Y ^2c is O, N (R ^y ) or S.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^{1a is} O or S, Y ^{2b is} O or N (R 2), Y ^{2d is} O or N (Ry), and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8 .

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^2b is O or N (R 2) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

Wherein Y ^2b is O or N (R ² ).

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In another specific embodiment of the present invention, A ^{3 is} represented by the following formula.

;

;

In another specific embodiment of the present invention, A ^{3 is} represented by the following formula.

;

;

Wherein Y ^1a is O or S, and Y ^2a is O, N (R ² ) or S.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^{1a is} O or S, Y ^{2b is} O or N (R 2), and Y ^{2c is} O, N (R ^y ) or S.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^{1a is} O or S, Y ^{2b is} O or N (R 2), Y ^{2d is} O or N (Ry), and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8 .

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^2b is O or N (R 2) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein Y ^2b is O or N (R ² ).

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein: Y ^2b is O or N (Rx) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R ² groups.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

Wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R ² groups.

In another specific embodiment of the present invention, A ³ is represented by the following formula.

;

;

In a particular embodiment of the invention, A ^{0 is} represented by the following formula.

;

;

Wherein each R is independently (C ₁ -C ₆ ) alkyl.

In certain embodiments of the invention, R ^x is independently represented by H, R ¹ , W ³ , a protecting group, or the following formula:

here:

R ^y is independently H, W ³ , R ² or a protecting group,

R ¹ is independently H or alkyl having 1 to 18 carbon atoms,

R ² is independently H, R ¹ , R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups or is bonded together at a carbon atom such that two R ² groups are 3 to Forms eight carbon rings, which ring is substituted with from 0 to 3 R ³ groups.

In certain embodiments of the present invention, R ^x is represented by the following formula.

;

;

Wherein Y ^1a is O or S and Y ^2c is O, N (R ^y ) or S.

In certain embodiments of the present invention, R ^x is represented by the following formula.

;

;

Wherein Y ^1a is O or S and Y ^2d is O or N (R ^y ).

In certain embodiments of the present invention, R ^x is represented by the following formula.

;

;

In certain embodiments of the invention, R ^y is hydrogen or alkyl of 1 to 10 carbons.

In certain embodiments of the present invention, R ^x is represented by the following formula.

;

;

In certain embodiments of the present invention, R ^x is represented by the following formula.

In certain embodiments of the present invention, R ^x is represented by the following formula.

;

;

In certain embodiments of the invention, Y ¹ is O or S.

In certain embodiments of the invention, Y ² is O, N (R ^y ) or S.

In certain embodiments of the invention R ^x is a group of the formula:

;

;

here:

m1a, m1b, m1c, m1d and m1e are independently 0 or 1;

m12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

R ^y is H, W ³ , R ² or a protecting group,

only,

if m1a, m12c, and m1d are 0, m1b, m1c and m1e are 0,

If m1a and m12c are 0 and m1d is nonzero, m1b and m1c are 0,

if m1a and m1d are 0 and m12c is not 0, then m1b and at least one of m1c and m1e is 0;

 If m1a is 0 and m12c and m1d are not zero, m1b is 0,

 if m12c and m1d are 0 and m1a is nonzero, at least two of m1b, m1c and m1e are 0,

If m12c is 0 and m1a and m1d are not zero, at least one of m1b and m1c is 0, and if m1d is 0 and m1a and m12c are nonzero, at least one of m1c and m1e is zero.

In another specific embodiment, the present invention provides a compound of the formula or a pharmaceutically acceptable salt thereof.

[DRUG]-(A ⁰ ) _nn

here,

DRUG is a compound of any one of formulas 500-601 ,

nn is 1, 2 or 3,

A ⁰ is A ¹ , A ² or W ³ , provided that the compound contains at least one A ¹ ,

A ¹ is

A ² is

A ³ is

이며,

Is,

Y ¹ is independently O, S, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ) or N (N (R ^x ) (R ^x ) ),

Y ² is independently bonded, O, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), N (N (R ^x ) (R ^x ) ), -S (O) _M2 -or -S (O) _M2 -S (O) _M2- ,

R ^x is independently H, R ¹ , W ³ , a protecting group or the following formula,

here,

R ^y is H, W ³ , R ² or a protecting group,

R ¹ is independently H or alkyl of 1 to 18 carbon atoms,

R ² is independently H, R ¹ , R ³ or each R ⁴ end Independently 0 to 3 R ³ groups optionally substituted, and the R ⁴ combine together at one carbon atom, two R ² groups to form a three to eight carbon ring that ring may be substituted with 0 to 3 R ³ ,

And when R ³ is bonded to the hetero atom include the assumption that R ³ is R ^3c or R ^3d is, R ³ is R ^3a, R ^3b, R ^3c or R ^3d,

R ^3a is F, Cl, Br, I, -CN, N ₃ or -NO ₂ ,

R ^3b is Y ¹ ,

R ^3c is -R ^x , -N (R ^x ) (R ^x ), -SR ^x , -S (O) R ^x , -S (O) ₂ R ^x , -S (O) (OR ^x ),- S (O) ₂ (OR ^x ), -OC (Y ¹ ) R ^x , -OC (Y ¹ ) OR ^x , -OC (Y ¹ ) (N (R ^x ) (R ^x )), -SC (Y ¹ ) R ^x , -SC (Y ¹ ) OR ^x , -SC (Y ¹ ) (N (R ^x ) (R ^x )), -N (R ^x ) C (Y ¹ ) R ^x , -N (R ^x ) C (Y ¹ ) OR ^x or -N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ))

R ^3d is -C (Y ¹ ) R ^x , -C (Y ¹ ) OR ^x or -C (Y ¹ ) (N (R ^x ) (R ^x )),

R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms or alkynyl of 2 to 18 carbon atoms,

R ⁵ is R ⁴ substituted with each of the R ⁴ groups 0-3 R ^3,

R ^5a is independently alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms or alkynylene of 2 to 18 carbon atoms, wherein any of alkylene, alkenylene or alkynylene is 0 to 3 R Substituted by ³ groups,

W ³ is W ⁴ or W ⁵ ,

W ⁴ is R ⁵ , -C (Y ¹ ) R ⁵ , -C (Y ¹ ) W ⁵ , -SO ₂ R ⁵ or -SO ₂ W ⁵ ,

W _⁵ is a carbon ring or heterocycle, W ⁵ is independently substituted with 0 to 3 R _² groups,

W ⁶ is W ³ independently substituted with 1, 2 or 3 A ³ groups,

M2 is 0, 1 or 2,

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

M1a, M1c and M1d are independently 0 or 1,

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another specific embodiment, the present invention provides a compound of formula 1-336 or a pharmaceutically acceptable salt thereof.

here,

A ⁰ is A ¹ ,

A ¹ is

,

,

A ³ is

이며,

Is,

Y ¹ is independently O, S, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ) or N (N (R ^x ) (R ^x ) )ego,

Y ² is independently bonded, O, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), N (N (R ^x ) (R ^x ) ), -S (O) _M2 -or -S (O) _M2 -S (O) _M2- ,

R ^x is independently H, W ³ , a protecting group or the following formula,

R ^y is H, W ³ , R ² or a protecting group,

R ¹ is independently H or alkyl of 1 to 18 carbon atoms,

R ² is independently H, R ³ or each R ⁴ end Independently R ⁴ substituted with 0 to 3 R ³ groups,

And when R ³ is bonded to the hetero atom include the assumption that R ³ is R ^3c or R ^3d is, R ³ is R ^3a, R ^3b, R ^3c or R ^3d,

R ^3a is F, Cl, Br, I, -CN, N ₃ or -NO ₂ ,

R ^3b is Y ¹ ,

R ^3c is -R ^x , -N (R ^x ) (R ^x ), -SR ^x , -S (O) R ^x , -S (O) ₂ R ^x , -S (O) (OR ^x ),- S (O) ₂ (OR ^x ), -OC (Y ¹ ) R ^x , -OC (Y ¹ ) OR ^x , -OC (Y ¹ ) (N (R ^x ) (R ^x )), -SC (Y ¹ ) R ^x , -SC (Y ¹ ) OR ^x , -SC (Y ¹ ) (N (R ^x ) (R ^x )), -N (R ^x ) C (Y ¹ ) R ^x , -N (R ^x ) C (Y ¹ ) OR ^x or -N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ))

R ^3d is -C (Y ¹ ) R ^x , -C (Y ¹ ) OR ^x or -C (Y ¹ ) (N (R ^x ) (R ^x )),

R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms or alkynyl of 2 to 18 carbon atoms,

R ⁵ is R ⁴ substituted with each of the R ⁴ groups 0-3 R ^3,

R ^5a is independently alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms or alkynylene of 2 to 18 carbon atoms, wherein any of alkylene, alkenylene or alkynylene is 0 to 3 R Substituted by ³ groups,

W ³ is W ⁴ or W ⁵ ,

W ⁴ is R ⁵ , -C (Y ¹ ) R ⁵ , -C (Y ¹ ) W ⁵ , -SO ₂ R ⁵ or -SO ₂ W ⁵ ,

W _⁵ is a carbon ring or heterocycle, W ⁵ is independently substituted with 0 to 3 R _² groups,

W ⁶ is W ³ independently substituted with 1, 2 or 3 A ³ groups,

M2 is 0, 1 or 2,

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

M1a, M1c and M1d are independently 0 or 1,

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

3. The compound of any one of formulas 1-336 , wherein

A ⁰ is A ¹ ,

A ¹ is

A ³ is

이며,

Is,

Y ¹ is independently O, S, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ) or N (N (R ^x ) (R ^x ) )ego,

Y ² is independently bonded, O, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), N (N (R ^x ) (R ^x ) ), -S (O) _M2 -or -S (O) _M2 -S (O) _M2- ,

R ^x is independently H, W ³ , a protecting group or the following formula,

R ^y is H, W ³ , R ² or a protecting group,

R ¹ is independently H or alkyl of 1 to 18 carbon atoms,

R ² is independently H, R ³ or each R ⁴ end Independently R ⁴ substituted with 0 to 3 R ³ groups,

And when R ³ is bonded to the hetero atom include the assumption that R ³ is R ^3c or R ^3d is, R ³ is R ^3a, R ^3b, R ^3c or R ^3d,

R ^3a is F, Cl, Br, I, -CN, N ₃ or -NO ₂ ,

R ^3b is Y ¹ ,

R ^3c is -R ^x , -N (R ^x ) (R ^x ), -SR ^x , -S (O) R ^x , -S (O) ₂ R ^x , -S (O) (OR ^x ),- S (O) ₂ (OR ^x ), -OC (Y ¹ ) R ^x , -OC (Y ¹ ) OR ^x , -OC (Y ¹ ) (N (R ^x ) (R ^x )), -SC (Y ¹ ) R ^x , -SC (Y ¹ ) OR ^x , -SC (Y ¹ ) (N (R ^x ) (R ^x )), -N (R ^x ) C (Y ¹ ) R ^x , -N (R ^x ) C (Y ¹ ) OR ^x or -N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ))

R ^3d is -C (Y ¹ ) R ^x , -C (Y ¹ ) OR ^x or -C (Y ¹ ) (N (R ^x ) (R ^x )),

R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms or alkynyl of 2 to 18 carbon atoms,

R ⁵ is R ⁴ substituted with each of the R ⁴ groups 0-3 R ^3,

R ^5a is independently alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms or alkynylene of 2 to 18 carbon atoms, wherein any of alkylene, alkenylene or alkynylene is 0 to 3 R Substituted by ³ groups,

W ³ is W ⁴ or W ⁵ ,

W ⁴ is R ⁵ , -C (Y ¹ ) R ⁵ , -C (Y ¹ ) W ⁵ , -SO ₂ R ⁵ or -SO ₂ W ⁵ ,

W _⁵ is a carbon ring or heterocycle, W ⁵ is independently substituted with 0 to 3 R _² groups,

W ⁶ is W ³ independently substituted with 1, 2 or 3 A ³ groups,

M2 is 0, 1 or 2,

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

M1a, M1c and M1d are independently 0 or 1,

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another specific embodiment, the present invention provides a compound of the formula or a pharmaceutically acceptable salt thereof.

[DRUG]-[LP (= Y ¹ ) -Y ² -R ^x ] _nn

here,

DRUG is a compound of any one of 500-601 ,

Y ¹ is independently O, S, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ) or N (N (R ^x ) (R ^x ) ),

Y ² is independently bonded, O, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), N (N (R ^x ) (R ^x ) ), -S (O) _M2 -or -S (O) _M2 -S (O) _M2- ,

R ^x is independently H, W ³ , a protecting group or the following formula,

R ^y is H, W ³ , R ² or a protecting group,

R ² is independently H, R ³ or each R ⁴ end Independently R ⁴ substituted with 0 to 3 R ³ groups,

And when R ³ is bonded to the hetero atom include the assumption that R ³ is R ^3c or R ^3d is, R ³ is R ^3a, R ^3b, R ^3c or R ^3d,

R ^3a is F, Cl, Br, I, -CN, N ₃ or -NO ₂ ,

R ^3b is Y ¹ ,

R ^3c is -R ^x , -N (R ^x ) (R ^x ), -SR ^x , -S (O) R ^x , -S (O) ₂ R ^x , -S (O) (OR ^x ),- S (O) ₂ (OR ^x ), -OC (Y ¹ ) R ^x , -OC (Y ¹ ) OR ^x , -OC (Y ¹ ) (N (R ^x ) (R ^x )), -SC (Y ¹ ) R ^x , -SC (Y ¹ ) OR ^x , -SC (Y ¹ ) (N (R ^x ) (R ^x )), -N (R ^x ) C (Y ¹ ) R ^x , -N (R ^x ) C (Y ¹ ) OR ^x or -N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ))

R ^3d is -C (Y ¹ ) R ^x , -C (Y ¹ ) OR ^x or -C (Y ¹ ) (N (R ^x ) (R ^x )),

R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms or alkynyl of 2 to 18 carbon atoms,

R ⁵ is R ⁴ substituted with each of the R ⁴ groups 0-3 R ^3,

W ³ is W ⁴ or W ⁵ ,

W ⁴ is R ⁵ , -C (Y ¹ ) R ⁵ , -C (Y ¹ ) W ⁵ , -SO ₂ R ⁵ or -SO ₂ W ⁵ ,

W _⁵ is a carbon ring or heterocycle, W ⁵ is independently substituted with 0 to 3 R _² groups,

M2 is 1, 2 or 3,

M1a, M1c and M1d are independently 0 or 1,

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

nn is 1, 2 or 3,

L is a linking group.

In another specific embodiment, the present invention provides a compound of the following formula and a pharmaceutically acceptable salt thereof.

[DRUG]-(A ⁰ ) _nn

here,

DRUG is a compound of any one of formulas 500-601 ,

nn is 1, 2 or 3,

A ⁰ is A ¹ , A ² or W ³ , provided that the compound contains at least one A ¹ ,

A ¹ is

A ² is

A ³ is

이며,

Is,

Y ¹ is independently O, S, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ) or N (N (R ^x ) (R ^x ) )ego,

Y ² is independently bonded, O, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), N (N (R ^x ) (R ^x ) ), -S (O) _M2 -or -S (O) _M2 -S (O) _M2- ,

R ^x is independently H, W ³ , a protecting group or the following formula,

R ^y is H, W ³ , R ² or a protecting group,

R ² is independently H, R ³ or each R ⁴ end Independently R ⁴ substituted with 0 to 3 R ³ groups,

And when R ³ is bonded to the hetero atom include the assumption that R ³ is R ^3c or R ^3d is, R ³ is R ^3a, R ^3b, R ^3c or R ^3d,

R ^3a is F, Cl, Br, I, -CN, N ₃ or -NO ₂ ,

R ^3b is Y ¹ ,

R ³ c is -R ^x , -N (R ^x ) (R ^x ), -SR ^x , -S (O) R ^x , -S (O) ₂ R ^x , -S (O) (OR ^x ), -S (O) ₂ (OR ^x ), -OC (Y ¹ ) R ^x , -OC (Y ¹ ) OR ^x , -OC (Y ¹ ) (N (R ^x ) (R ^x )), -SC ( Y ¹ ) R ^x , -SC (Y ¹ ) OR ^x , -SC (Y ¹ ) (N (R ^x ) (R ^x )), -N (R ^x ) C (Y ¹ ) R ^x , -N ( R ^x ) C (Y ¹ ) OR ^x or -N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ))

R ^3d is -C (Y ¹ ) R ^x , -C (Y ¹ ) OR ^x or -C (Y ¹ ) (N (R ^x ) (R ^x )),

R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms or alkynyl of 2 to 18 carbon atoms,

R ⁵ is R ⁴ substituted with each of the R ⁴ groups 0-3 R ^3,

W ³ is W ⁴ or W ⁵ ,

W ⁴ is R ⁵ , -C (Y ¹ ) R ⁵ , -C (Y ¹ ) W ⁵ , -SO ₂ R ⁵ or -SO ₂ W ⁵ ,

W _⁵ is a carbon ring or heterocycle, W ⁵ is independently substituted with 0 to 3 R _² groups,

W ⁶ is W ³ independently substituted with 1, 2 or 3 A ³ groups,

M2 is 0, 1 or 2,

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

M1a, M1c and M1d are independently 0 or 1,

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In the compound of the present invention, the W ⁵ carbon ring and the W ⁵ heterocycle may be independently substituted with 0 to 3 R ² groups. W ⁵ may be a substituted, unsubstituted or aromatic ring comprising a single or bicyclic carbon ring or hetero ring. W ^{5 may have 3} to 10 ring atoms, such as 3 to 7 ring atoms. The W ⁵ ring is saturated when containing 3 ring atoms, monounsaturated when containing 4 ring atoms, saturated or 1 or 2 unsaturated when containing 5 ring atoms, and containing 6 ring atoms. Saturated or 1 or 2 unsaturated or aromatic.

The W ⁵ heterocycle may be a ring having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S) or ring member having 7 to 10 carbon atoms. Phosphorus double ring (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S). W ⁵ heterocyclic monocyclic ring atoms of 3 to 6 (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O and S), or ring atoms of 5 or 6 (3 to 5 carbon atoms and N , 1-2 heteroatoms selected from O and S).

W ⁵ heterocyclic double rings of 7 to 10 ring atoms (6 to 9 carbon atoms and N arranged in bicyclo [4,5], [5,5], [5,6] or [6,6] systems) , 1 to 2 heteroatoms selected from O and S, or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 and selected from N and S) arranged in a bicyclo [5,6] or [6,6] system To 2 heteroatoms).

W ⁵ above Heterocycles may be bonded to Y ² through carbon, nitrogen, sulfur or other atoms by stable covalent bonds.

W ⁵ heterocycles include, for example, pyridyl, dihydropyridyl isomers, piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl , Pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl and pyrrolyl. W ⁵ may also include, but is not limited to:

The W ⁵ carbocycle and heterocycle may be independently substituted with 0 to 3 R ² groups as defined above. For example, a substituted W ⁵ carbon ring

It includes.

Examples of substituted phenyl carbocycles are

It includes.

Complex of formula I

In one embodiment, the present invention provides a complex of formula I or a pharmaceutically acceptable salt or solvate thereof.

here,

B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebulaline , Nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propyl Cytosine, Isocytosine, Isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothylmine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylmethylmin, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazoles and pyrazolo [3,4-D] pyrimidines,

X is selected from O, C (R ^y ) ₂ , C = C (R ^y ) ₂ , NR and S,

Z ¹ is independently selected from H, OH, OR, NR ₂ , CN, NO ₂ , SH, SR, F, Cl, Br and I,

Z ² is H, C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl and C ₁ -C ₈ Selected from substituted alkynyl,

Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR) or N-NR ₂ ,

Y ² is independently bonded, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, SS, S (O) Or S (O) ₂ ,

M2 is 0, 1 or 2,

R ^y is independently H, F, Cl, Br, I, OH, R, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR ), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR, -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR or -N (R) C (= Y ¹ ) N (R) ₂ , amino (-NH ₂ ), ammonium (-NH ₃ ⁺ ), alkylamino, dialkylamino, trialkylammonium, C ₁ -C ₈ alkyl, C ₁ -C ₈ halo Alkyl, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered cyclic sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium , C ₁ -C ₈ alkylhydroxyl, C ₁ -C ₈ alkylthiol, alkylsulfone (-SO ₂ R), arylsulfone (-SO ₂ Ar), arylsulfoxide (-SOAr), arylthio (-SAr) , Sulfonamide (-SO ₂ NR ₂ ), alkylsulfoxide (-SOR), ester (-C (= O) OR), amido (-C (= O) NR ₂ ), 5-7 member Cyclic lactams, 5-7 membered cyclic lactones, nitrile (- CN), azido (-N ₃ ), nitro (-NO ₂ ), C ₁ -C ₈ alkoxy (-OR), C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ al Kenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle , C ₂ -C ₂₀ substituted heterocycle, polyethyleneoxy, protecting group (PG) or W ³ , or when taken together, R ^y forms a carbon ring of 3 to 7 carbon atoms,

R ^x is independently R ^y , a protecting group or

here,

M1a, M1c and M1d are independently 0 or 1,

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

R is C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl , C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle or protecting group,

W ³ is W ⁴ or W ⁵ , W ⁴ is R, -C (Y ¹ ) R ^y , -C (Y ¹ ) W ⁵ , -SO ₂ R ^y or -SO ₂ W ⁵ , W ⁵ is independent It is a carbon ring or heterocyclic ring substituted with 0 to 3 R ^y groups.

In one specific embodiment of the complex of formula I, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ substituted aryl and C ₂ -C ₂₀ substituted heterocycles include F, Cl, Br, I, OH, -NH ₂ , -NH ₃ ⁺ , -NHR, -NR ₂ , -NR ₃ ⁺ , C ₁ -C ₈ haloalkyl, carboxylate, Sulfate, sulfamate, sulfonate, 5-7 membered cyclic sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium, C ₁ -C ₈ Alkylhydroxyl, C ₁ -C ₈ alkylthiol, -SO ₂ R, -SO ₂ Ar, -SOAr, -SAr, -SO ₂ NR ₂ , -SOR, -CO ₂ R, -C (= O) NR ₂ , 5-7 membered cyclic lactam, 5-7 membered cyclic lactone, -CN, -N ₃ , -NO ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ trifluoroalkyl At least one substituent selected from C ₁ -C ₈ alkyl, C ₃ -C ₁₂ carbon ring, C ₆ -C ₂₀ aryl, C ₂ -C ₂₀ heterocycle, polyethyleneoxy, phosphonate, phosphate and prodrug moieties. Independently It may be substituted by.

In one specific embodiment of the complex of formula I, the “protecting group” is selected from carboxyl esters, carboxamides, aryl ethers, alkyl ethers, trialkylsilyl ethers, sulfonic acid esters, carbonates and carbamates.

In one specific embodiment of the complex of formula I, W ⁵ is selected from the following structures.

In one specific embodiment of the complex of formula I, X is O and R ^y is H.

In one specific embodiment of the complex of formula I, X is C═CH ₂ and R ^y is H.

In one specific embodiment of the complex of formula I, Z ¹ is OH.

In one specific embodiment of the complex of formula I, Z ² is C ₁ -C ₈ alkyl or C ₁ -C ₈ substituted alkyl.

In one specific embodiment of the complex of formula I, Z ² is CH ₃ .

In one specific embodiment, the complex of Formula I has the formula

In one specific embodiment, the complex of Formula I has the formula

In one specific embodiment, the complex of Formula I has the formula

In one specific embodiment, the complex of Formula I has the formula

In one specific embodiment, the complex of Formula I has the formula

In one specific embodiment, the complex of Formula I has the formula

In one specific embodiment, the complex of Formula I has the formula

In one specific embodiment, the complex of Formula I has the formula

In one specific embodiment, the complex of Formula I has the formula

Here, in a more specific embodiment, Z ¹ is OH, Z ² is C ₁ -C ₈ alkyl or C ₁ -C ₈ substituted alkyl, Z ² is CH ₃ .

In one specific embodiment, the complex of Formula I has the formula

In one specific embodiment, the complex of Formula I has the formula

In one specific embodiment, the complex of Formula I has the formula

In one specific embodiment, the complex of Formula I has the formula

In one specific embodiment, the complex of Formula I has the formula

In one specific embodiment, the complex of Formula I has the formula

In one specific embodiment, the complex of Formula I has the formula

In one specific embodiment, the complex of Formula I has the formula

In one specific embodiment, the complex of Formula I has the formula

Wherein R ² is H or C ₁ -C ₈ alkyl.

In one specific embodiment, the complex of Formula I has the formula

In one specific embodiment, the complex of Formula I has the formula

Where Y ^2c is O, N (R ^y ) or S.

In one specific embodiment, the complex of Formula I has the formula

Here, in a more specific embodiment, Y ^2c is O, Y ^2c is N (CH ₃ ), R ^y is H or C ₁ -C ₈ alkyl.

In one specific embodiment of the complex of formula I, the substituted triazole has the structure:

In one specific embodiment, the complex of Formula I is a complex of formula or a pharmaceutically acceptable salt or solvate thereof.

here,

B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebulaline , Nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propyl Cytosine, Isocytosine, Isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothylmine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylmethylmin, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazoles and pyrazolo [3,4-D] pyrimidines,

Z ¹ is independently selected from H, OH, OR, NR ₂ , CN, NO ₂ , SH, SR, F, Cl, Br and I,

Z ² is H, C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl and C ₁ -C ₈ Selected from substituted alkynyl,

R ^y is independently H, F, Cl, Br, I, OH, R, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR ), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR, -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR or -N (R) C (= Y ¹ ) N (R) ₂ , amino (-NH ₂ ), ammonium (-NH ₃ ⁺ ), alkylamino, dialkylamino, trialkylammonium, C ₁ -C ₈ alkyl, C ₁ -C ₈ halo Alkyl, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered cyclic sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium , C ₁ -C ₈ alkylhydroxyl, C ₁ -C ₈ alkylthiol, alkylsulfone (-SO ₂ R), arylsulfone (-SO ₂ Ar), arylsulfoxide (-SOAr), arylthio (-SAr) , Sulfonamide (-SO ₂ NR ₂ ), alkylsulfoxide (-SOR), ester (-C (= O) OR), amido (-C (= O) NR ₂ ), 5-7 member Cyclic lactams, 5-7 membered cyclic lactones, nitrile (- CN), azido (-N ₃ ), nitro (-NO ₂ ), C ₁ -C ₈ alkoxy (-OR), C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ al Kenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle , C ₂ -C ₂₀ substituted heterocycle, polyethyleneoxy, protecting group (PG) or W ³ , or when bonded together, R ^y forms a carbocyclic ring of 3 to 7 carbon atoms,

R is C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl , C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle or protecting group,

W ³ is W ⁴ or W ⁵ , W ⁴ is R, -C (Y ¹ ) R ^y , -C (Y ¹ ) W ⁵ , -SO ₂ R ^y or -SO ₂ W ⁵ , W ⁵ is independent It is a carbon ring or heterocyclic ring substituted with 0 to 3 R ^y groups.

In one specific embodiment, the complex of Formula I has the formula

Wherein PG is selected from ether formers, thioether formers, ester formers, thioester formers, silyl-ether formers, amide formers, acetal formers, ketal formers, carbonate formers, carbamate formers, urea formers, amino acid complexes and polypeptide complexes. It is a protector.

In one specific embodiment, the present invention provides a complex of formula I or a pharmaceutically acceptable salt or solvate thereof having one of the following formulas.

Where B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebula Lean, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5- Propynylcytosine, isocytocin, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothylmine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine , O ⁴ -methylthylmine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazoles and pyrazolo [3,4-D] pyrimidines. In further embodiments, the compound is isolated and purified.

In one specific embodiment, the present invention provides a complex of formula I or a pharmaceutically acceptable salt or solvate thereof having one of the following formulas.

Wherein B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 2,6-diaminopurine, 5-fluorocytosine or c-propyl-2,6-diaminopurine. In further embodiments, the compound is isolated and purified.

In one specific embodiment, the present invention provides a complex of formula I or a pharmaceutically acceptable salt or solvate thereof having one of the following formulas.

In further embodiments, the compound is isolated and purified.

In one specific embodiment, the present invention provides a complex of formula I or a pharmaceutically acceptable salt or solvate thereof having one of the following formulas.

Where B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebula Lean, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5- Propynylcytosine, isocytocin, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothylmine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine , O ⁴ -methylthylmine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazoles and pyrazolo [3,4-D] pyrimidines. In further embodiments, the compound is isolated and purified.

In one specific embodiment, the present invention provides a complex of formula I or a pharmaceutically acceptable salt or solvate thereof having one of the following formulas.

Wherein B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 2,6-diaminopurine, 5-fluorocytosine or c-propyl-2,6-diaminopurine. In further embodiments, the compound is isolated and purified. In further embodiments, the compound is isolated and purified.

In one specific embodiment, the present invention provides a complex of formula I or a pharmaceutically acceptable salt or solvate thereof having one of the following formulas.

In further embodiments, the compound is isolated and purified.

Complex of formula II

In one embodiment, the present invention provides a complex of formula II or a pharmaceutically acceptable salt or solvate thereof.

here,

B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebulaline , Nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propy Nylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothylmine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthylmine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazoles and pyrazolo [3,4-D] pyrimidines,

X is selected from O, C (R ^y ) ₂ , ° C. (R ^y ) ₂ , NR and S,

Z ¹ is independently selected from H, OH, OR, NR ₂ , CN, NO ₂ , SH, SR, F, Cl, Br and I,

Z ² is H, C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl and C ₁ -C ₈ Selected from substituted alkynyl,

Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR) or N-NR ₂ ,

Y ² is independently bonded, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, SS, S (O) Or S (O) ₂ ,

M2 is 0, 1 or 2,

R ^y is independently H, F, Cl, Br, I, OH, R, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR ), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR, -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR or -N (R) C (= Y ¹ ) N (R) ₂ , amino (-NH ₂ ), ammonium (-NH ₃ ⁺ ), alkylamino, dialkylamino, trialkylammonium, C ₁ -C ₈ alkyl, C ₁ -C ₈ halo Alkyl, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered cyclic sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium , C ₁ -C ₈ alkylhydroxyl, C ₁ -C ₈ alkylthiol, alkylsulfone (-SO ₂ R), arylsulfone (-SO ₂ Ar), arylsulfoxide (-SOAr), arylthio (-SAr) , Sulfonamide (-SO ₂ NR ₂ ), alkylsulfoxide (-SOR), ester (-C (= O) OR), amido (-C (= O) NR ₂ ), 5-7 member Cyclic lactams, 5-7 membered cyclic lactones, nitrile (- CN), azido (-N ₃ ), nitro (-NO ₂ ), C ₁ -C ₈ alkoxy (-OR), C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ al Kenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle , C ₂ -C ₂₀ substituted heterocycle, polyethyleneoxy, a protecting group or W ³ , or when bonded together, R ^y forms a carbocyclic ring ^{of 3} to 7 carbon atoms,

R ^x is independently R ^y , a protecting group, or

here,

M1a, M1c and M1d are independently 0 or 1,

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

R is C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl , C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle or protecting group,

W ³ is W ⁴ or W ⁵ , W ⁴ is R, -C (Y ¹ ) R ^y , -C (Y ¹ ) W ⁵ , -SO ₂ R ^y or -SO ₂ W ⁵ , W ⁵ is independent It is a carbon ring or heterocyclic ring substituted with 0 to 3 R ^y groups.

In one specific embodiment of the complex of formula II, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ substituted aryl and C ₂ -C ₂₀ substituted heterocycles include F, Cl, Br, I, OH, -NH ₂ , -NH ₃ ⁺ , -NHR, -NR ₂ , -NR ₃ ⁺ , C ₁ -C ₈ haloalkyl, carboxylate, Sulfate, sulfamate, sulfonate, 5-7 membered cyclic sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium, C ₁ -C ₈ Alkylhydroxyl, C ₁ -C ₈ alkylthiol, -SO ₂ R, -SO ₂ Ar, -SOAr, -SAr, -SO ₂ NR ₂ , -SOR, -CO ₂ R, -C (= O) NR ₂ , 5-7 membered cyclic lactam, 5-7 membered cyclic lactone, -CN, -N ₃ , -NO ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ trifluoroalkyl At least one substituent selected from C ₁ -C ₈ alkyl, C ₃ -C ₁₂ carbon ring, C ₆ -C ₂₀ aryl, C ₂ -C ₂₀ heterocycle, polyethyleneoxy, phosphonate, phosphate and prodrug moieties. Independent It is replaced with.

In one specific embodiment of the complex of formula II, the “protecting group” is selected from carboxyl esters, carboxamides, aryl ethers, alkyl ethers, trialkylsilyl ethers, sulfonic acid esters, carbonates and carbamates.

In one specific embodiment of the complex of formula II, W ⁵ is selected from the following structures.

In one specific embodiment of the complex of formula II, X is O and R ^y is H.

In one specific embodiment, the complex of formula II has the formula

In one specific embodiment, the complex of formula II has the formula

Here, in a more specific embodiment, Z ¹ is OH and Z ² is CH ₃ .

In one specific embodiment, the complex of formula II has the formula

Here, in a more specific embodiment, Z ² is C ₁ -C ₈ alkyl or C ₁ -C ₈ substituted alkyl.

In one specific embodiment, the complex of formula II has the formula

In one specific embodiment, the complex of formula II has the formula

In one specific embodiment, the complex of formula II has the formula

In one specific embodiment, the complex of formula II has the formula

In one specific embodiment, the complex of formula II has the formula

In one specific embodiment, the complex of formula II has the formula

In one specific embodiment, the complex of formula II has the formula

Wherein R ² is H or C ₁ -C ₈ alkyl.

In one specific embodiment, the complex of formula II has the formula

In one specific embodiment, the complex of formula II has the formula

Where Y ^2c is O, N (R ^y ) or S.

In one specific embodiment, the complex of formula II has the formula

Here, in a more specific embodiment, Y ^2c is O and Y ^2c is N (CH ₃ ).

In one specific embodiment, the substituted triazole has the structure

In one specific embodiment, the complex of formula II has the formula

here,

B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebulaline , Nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propy Nylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothylmine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthylmine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazoles and pyrazolo [3,4-D] pyrimidines,

X ^a is selected from O, NR and S,

Z ¹ is independently selected from H, OH, OR, NR ₂ , CN, NO ₂ , SH, SR, F, Cl, Br and I,

Z ² is H, C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl and C ₁ -C ₈ Selected from substituted alkynyl,

R ^y is independently H, F, Cl, Br, I, OH, R, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR ), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR, -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR or -N (R) C (= Y ¹ ) N (R) ₂ , amino (-NH ₂ ), ammonium (-NH ₃ ⁺ ), alkylamino, dialkylamino, trialkylammonium, C ₁ -C ₈ alkyl, C ₁ -C ₈ halo Alkyl, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered cyclic sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium , C ₁ -C ₈ alkylhydroxyl, C ₁ -C ₈ alkylthiol, alkylsulfone (-SO ₂ R), arylsulfone (-SO ₂ Ar), arylsulfoxide (-SOAr), arylthio (-SAr) , Sulfonamide (-SO ₂ NR ₂ ), alkylsulfoxide (-SOR), ester (-C (= O) OR), amido (-C (= O) NR ₂ ), 5-7 member Cyclic lactams, 5-7 membered cyclic lactones, nitrile (- CN), azido (-N ₃ ), nitro (-NO ₂ ), C ₁ -C ₈ alkoxy (-OR), C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ al Kenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle , C ₂ -C ₂₀ substituted heterocycle, polyethyleneoxy, a protecting group or W ³ , or when bonded together, R ^y forms a carbocyclic ring ^{of 3} to 7 carbon atoms,

R is C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl , C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle or protecting group,

W ³ is W ⁴ or W ⁵ , W ⁴ is R, -C (Y ¹ ) R ^y , -C (Y ¹ ) W ⁵ , -SO ₂ R ^y or -SO ₂ W ⁵ , W ⁵ is independent It is a carbon ring or heterocyclic ring substituted with 0 to 3 R ^y groups.

In one specific embodiment, the complex of formula II has the formula

Wherein PG is selected from ether formers, thioether formers, ester formers, thioester formers, silyl-ether formers, amide formers, acetal formers, ketal formers, carbonate formers, carbamate formers, urea formers, amino acid complexes and olipeptide complexes It is a protector

Complex of formula III

In one embodiment, the present invention provides a complex of formula III or a pharmaceutically acceptable salt or solvate thereof.

here,

B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebulaline , Nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propy Nylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothylmine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthylmine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazoles and pyrazolo [3,4-D] pyrimidines,

X is selected from O, C (R ^y ) ₂ , ° C. (R ^y ) ₂ , NR and S,

Z is independently selected from H, OH, OR, NR ₂ , CN, NO ₂ , SH, SR, F, Cl, Br and I,

Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR) or N-NR ₂ ,

Y ² is independently O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, SS, S (O) or S (O) is ₂ ,

M2 is 0, 1 or 2,

R ^y is independently H, F, Cl, Br, I, OH, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR , -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR or -N (R) C (= Y ¹ ) N (R) ₂ , amino (-NH ₂ ), ammonium (-NH ₃ ⁺ ), alkylamino, dialkylamino, trialkylammonium, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, Carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered cyclic sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium, C ₁ -C ₈ alkylhydroxyl, C ₁ -C ₈ alkylthiol, alkylsulfone (-SO ₂ R), arylsulfone (-SO ₂ Ar), arylsulfoxide (-SOAr), arylthio (-SAr), sulfone Amide (-SO ₂ NR ₂ ), alkylsulfoxide (-SOR), ester (-C (= O) OR), amido (-C (= O) NR ₂ ), 5-7 member cyclic Lactams, 5-7 membered cyclic lactones, nitrile (-CN) , Azido (-N ₃ ), nitro (-NO ₂ ), C ₁ -C ₈ alkoxy (-OR), C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle, polyethyleneoxy or W ³ , or when bonded together, R ^y forms a carbocyclic ring ^{of 3} to 7 carbon atoms,

R ^x is independently R ^y , a protecting group, or

here,

M1a, M1c and M1d are independently 0 or 1,

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

R is C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl , C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle or protecting group,

W ³ is W ⁴ or W ⁵ , W ⁴ is R, -C (Y ¹ ) R ^y , -C (Y ¹ ) W ⁵ , -SO ₂ R ^y or -SO ₂ W ⁵ , W ⁵ is independent It is a carbon ring or heterocyclic ring substituted with 0 to 3 R ^y groups.

In one specific embodiment of the complex of formula II, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ substituted aryl and C ₂ -C ₂₀ substituted heterocycles include F, Cl, Br, I, OH, -NH ₂ , -NH ₃ ⁺ , -NHR, -NR ₂ , -NR ₃ ⁺ , C ₁ -C ₈ haloalkyl, carboxylate, Sulfate, sulfamate, sulfonate, 5-7 membered cyclic sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium, C ₁ -C ₈ Alkylhydroxyl, C ₁ -C ₈ alkylthiol, -SO ₂ R, -SO ₂ Ar, -SOAr, -SAr, -SO ₂ NR ₂ , -SOR, -CO ₂ R, -C (= O) NR ₂ , 5-7 membered cyclic lactam, 5-7 membered cyclic lactone, -CN, -N ₃ , -NO ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ trifluoroalkyl At least one substituent selected from C ₁ -C ₈ alkyl, C ₃ -C ₁₂ carbon ring, C ₆ -C ₂₀ aryl, C ₂ -C ₂₀ heterocycle, polyethyleneoxy, phosphonate, phosphate and prodrug moieties. Independent It is replaced with.

In one specific embodiment of the complex of formula II, the “protecting group” is selected from carboxyl esters, carboxamides, aryl ethers, alkyl ethers, trialkylsilyl ethers, sulfonic acid esters, carbonates and carbamates.

In one specific embodiment of the complex of formula III, W ⁵ is selected from the following structures.

In one specific embodiment of the complex of formula III, X is O and each R ^y is H.

In one specific embodiment, the complex of Formula III is a divided enantiomer having the structure:

In one specific embodiment, the complex of Formula III is a divided enantiomer having the structure:

In one specific embodiment, the complex of formula III has the formula

In one specific embodiment, the complex of formula III has the formula

In one specific embodiment, the complex of formula III has the formula

In one specific embodiment, the complex of formula III has the formula

In one specific embodiment, the complex of formula III has the formula

In one specific embodiment, the complex of formula III has the formula

Wherein R ² is H or C ₁ -C ₈ alkyl.

In one specific embodiment, the complex of formula III has the formula

In one specific embodiment, the complex of formula III has the formula

Here, in a more specific embodiment, Z is H and B is adenine.

In one specific embodiment, the complex of formula III has the formula

Where Y ^2c is O, N (R ^y ) or S.

In one specific embodiment, the complex of formula III has the formula

Here, in a more specific embodiment, Y ^2c is O or N (CH ₃ ).

In one specific embodiment of the complex of formula III, the substituted triazole has the structure:

In one specific embodiment, the complex of formula III has the formula

here,

B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebulaline , Nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propy Nylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothylmine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthylmine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazoles and pyrazolo [3,4-D] pyrimidines,

X is selected from O, C (R ^y ) ₂ , ° C. (R ^y ) ₂ , NR and S,

Z is independently selected from H, OH, OR, NR ₂ , CN, NO ₂ , SH, SR, F, Cl, Br and I,

Y ² is independently O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, SS, S (O) or S (O) is ₂ ,

R ^y is independently H, F, Cl, Br, I, OH, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR , -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR or -N (R) C (= Y ¹ ) N (R) ₂ , amino (-NH ₂ ), ammonium (-NH ₃ ⁺ ), alkylamino, dialkylamino, trialkylammonium, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, Carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered cyclic sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium, C ₁ -C ₈ alkylhydroxyl, C ₁ -C ₈ alkylthiol, alkylsulfone (-SO ₂ R), arylsulfone (-SO ₂ Ar), arylsulfoxide (-SOAr), arylthio (-SAr), sulfone Amide (-SO ₂ NR ₂ ), alkylsulfoxide (-SOR), ester (-C (= O) OR), amido (-C (= O) NR ₂ ), 5-7 member cyclic Lactams, 5-7 membered cyclic lactones, nitrile (-CN) , Azido (-N ₃ ), nitro (-NO ₂ ), C ₁ -C ₈ alkoxy (-OR), C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle, polyethyleneoxy or W ³ , or when bonded together, R ^y forms a carbocyclic ring ^{of 3} to 7 carbon atoms,

R is C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl , C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle or protecting group,

PG is a protecting group selected from ether formers, ester formers, silyl-ether formers, amide formers, acetal formers, ketal formers, carbonate formers, carbamate formers, amino acids and polypeptides.

coupler  And Connection (Linking groups and Linkers)

The present invention provides a complex comprising an anticancer compound linked to one or more phosphonate groups either directly (eg by covalent bonds) or via a linking group (ie, a linking group). The nature of the linker is not critical unless it interferes with the ability of the phosphonate containing compound to act as a therapeutic. The phosphonate or linkage may be removed from the compound by removing hydrogen or a portion of the compound (eg, a compound of formula 500-601 ) to provide an open valence for binding of the phosphonate or linkage. The compound may be linked at the synthesizable position.

In one embodiment of the invention, the linking group or linking group (which may be represented by "L") may include all or part of the groups A ⁰ , A ¹ , A ² or W ³ described herein. .

In another embodiment of the present invention, the linking group or linker has a molecular weight of about 200 daltons to about 400 daltons.

In yet another embodiment of the invention, the linking group or linker has a length of about 5 angstroms to about 300 angstroms.

In another embodiment of the present invention, the linker or linker separates the DRUG and P (= Y ¹ ) residues by about 5 angstroms to about 200 angstroms in length.

In another embodiment of the invention, the linking group or linking group is a divalent, branched or unbranched, saturated or unsaturated hydrocarbon chain having 2 to 25 carbon atoms, and one of the carbon atoms of the chain (I.e., 1, 2, 3 or 4) is optionally substituted with (-O-), and the chain is optionally substituted with (C ₁ -C ₆ ) alkoxy, (C ₃ -C ₆ ) cycloalkyl, ( C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkanoyloxy, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkylthio, azido, cyano, nitro, halo Is substituted on carbon with one or more (eg 1, 2, 3 or 4) substituents selected from hydroxy, oxo (═O), carboxy, aryl, aryloxy, heteroaryl and heteroaryloxy.

In another embodiment of the invention, the linking group or linking group is of formula WA, wherein A is (C ₁ -C ₂₄ ) alkyl, (C ₂ -C ₂₄ ) alkenyl, (C ₂ -C ₂₄ ) alkynyl , (C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl, or a combination thereof, W is -N (R) C (= 0)-, -C (= 0) N (R)- , -OC (= O)-, -C (= O) O-, -O-, -S-, -S (O)-, -S (O) _2- , -N (R)-, -C As (= O)-or a direct bond, each R is independently H or (C ₁ -C ₆ ) alkyl.

In another embodiment of the invention, the linking group or linking group is a divalent radical formed from a peptide.

In another embodiment of the present invention, the linking group or linking group is a divalent radical formed from an amino acid.

In another embodiment of the present invention, the linking group or linker is poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L-serine, poly- Divalent, formed from L-threonine, poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine, poly-L-lysine or poly-L-lysine-L-tyrosine It is a radical.

In another embodiment of the invention, the linking group or linking group is of formula W- (CH ₂ ) _n , wherein n is from about 1 to about 10, and W is -N (R) C (= 0)-, -C (= O) N (R)-, -OC (= O)-, -C (= O) O-, -O-, -S-, -S (O)-, -S (O) ₂ —, —C (═O) —, —N (R) — or a direct bond, each R is independently H or (C ₁ -C ₆ ) alkyl.

In another embodiment of the invention, the linking group or linking group is methylene, ethylene or propylene.

In another embodiment of the present invention, the linking group or linking group is bonded to the phosphonate group through the carbon atom of the linking group.

Intracellular Targeting (Intracellular Targeting)

The phosphonate groups of the compounds of the invention can cleave in vivo during the desired site of action, ie, after reaching the interior of the cell.

One mechanism of action within a cell can provide a negatively charged “l ° C.-in” intermediate, eg, accompanied by a first cleavage by an esterase. Thus cleavage of the terminal ester batch in the compounds of the present invention provides unstable intermediates that release negatively charged "locked" intermediates.

After changes inside the cell, intracellular enzymatic cleavage or modification of the phosphonate or prodrug compound can result in intracellular accumulation of the cleaved or modified compound by a "trapping" mechanism. The cleaved or modified compound is then modified by a significant change in charge, polarity or other physical property change that reduces the rate at which the cleaved or modified compound can leave the cell as compared to the rate at which it enters the phosphonate prodrug. Can be "locked" cells. Other mechanisms by which the therapeutic effect may be obtained may also work. Enzymes capable of enzymatic activity with the phosphonate prodrug compound of the present invention include, but are not limited to, esterases, microbial enzymes, phospholipases, cholinesterases and phosphatases.

In the case where the drug is of the nucleoside type, such as in the case of zidovudine and many other antiretroviral agents, it is known that the drug is activated in vivo by phosphorylation. Such activation may be accomplished in this system by enzymatic conversion of the "locked" intermediate to phosphonate diphosphate using phosphokinase and / or phosphorylation of the drug itself after the drug is released from the "locked" intermediate as described above. Can happen. In either case, the original nucleoside type drug will be collected in the active phosphorylated species by the derivatives of the present invention.

From the above, it will be clear that many different drugs can be induced by the present invention. Many such drugs are specifically mentioned herein. However, it should be understood that the discussion of the classes of drugs and their specific members for derivatization according to the present invention is not exhaustive and has been given by way of example only.

Anticancer compound

Compounds of the present invention include those having anticancer activity. In particular, the compounds include anticancer compounds. Compounds of the present invention have one or more (eg 1, 2, 3 or 4) phosphonate groups that can be prodrug moieties.

In general, the compounds of the present invention have a molecular weight of about 400 amu to about 10,000 amu. In a specific embodiment of the invention, the compounds have a molecular weight of about 5000 amu or less, and in another specific embodiment of the invention, the compounds have a molecular weight of about 2500 amu or less.

In another specific embodiment of the invention, the compounds have a molecular weight of about 1000 amu or less, and in another specific embodiment of the invention, the compounds have a molecular weight of about 800 amu or less, and another specific embodiment of the invention For, the compounds have a molecular weight of about 600 amu or less, and in another specific embodiment of the invention, the compounds have a molecular weight of about 600 amu or less and about 400 amu or more.

The compounds of the present invention also generally have a logD (polar) of about 5 or less. In one embodiment, the present invention provides compounds having a logD of about 4 or less, and in another embodiment, the present invention provides compounds having a logD of about 3 or less, and in another embodiment In another embodiment, the present invention provides compounds having a logD of about −5 or more, and in another embodiment, the present invention provides compounds having a logD of about −3 or more, and in another embodiment, providing compounds having a logD of about 0 or greater and about 3.

In one specific embodiment, the invention may fall within the general definition of an anticancer compound, as well as phosphonate groups such as phosphonate diesters, phosphonamidate-ester prodrugs or phosphondiamidates- Provided are compounds further comprising esters (Jiang et al., US 2002/0173490 A1).

Substituents selected within the compounds of the present invention are present recursively. In this regard, “recursive substituent” means that one substituent may list another example of itself. Because of the recursion of such substituents, in theory, many substituents may exist in certain claims. For example, R ^x contains a R ^y substituent. R ^y may be R ² , and in turn may be R ³ . When R ³ is selected as R ^3c , the second case of R ^x may be selected. If one of ordinary skill in the art of medicinal chemistry is skilled in the art, the total number of such substituents may be reasonably determined by the desired properties of the desired compound. Will understand that it is limited. Such properties include, but are not limited to, practical properties such as physical properties such as molecular weight, solubility or log P, application properties such as activity against a desired target, and ease of synthesis.

By way of example, and not limitation, in some claims W ³ , R ^y and R ³ are all recursive substituents. In general, each of these is 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 Can come 1, or 0 times. More generally, each of these may appear up to 12 times in a given claim. Even more generally, in a given claim, W ³ will be 0-8 times, R ^y 0-6 times and R ³ 0-4 times.

Recursive substituents are a desirable feature of the present invention. One of ordinary skill in the art of medicinal chemistry will appreciate the variety of such substituents. If recursive substituents are present in the claims of the present invention, the total number will be determined as described above.

It will be appreciated that when a compound described herein is substituted with one or more of the same designated groups such as “R ¹ ” or “R ^6a ”, the groups may be the same or different, ie each group is selected independently.

All. Wavy lines indicate covalent bond attachment sites for adjacent groups, parts, or reactors.

The term "anticancer compound" includes each kind and all kinds described herein as well as the above-mentioned comprehensive disclosure. The phosphonate group can be a phosphonate prodrug moiety. Although not limited, prodrug moieties such as pivaloyloxymethyl carbonate (P ° C.) or POM groups may be sensitive to hydrolysis. Instead, prodrug moieties such as lactate ester or phosphonamidate-ester groups may be sensitive to enzyme induced cleavage.

The term "anticancer compound" also refers to gefitinib, imatinib, erlotinib, vatalanib0, fosteabine, camptosar, irinotecan. (irinotecan), hycamtin, femara, letrozole, fadrozole, temozolomide, etopophos, anastrozole, aridex arimidex, carboplatin, paraplatin, exemestane, atamestan (amamestan), erubirubicin, adriamycin, ataxetrere Taxol, vinorelbine, ospemifene, troglitazone, etoposide, everolimus, vincristine, sirolimus , Raltitrexed (tomudex), aminopterin, albosidib, alv Bortezomib, VX-148, vinblastine, tipifarnib, mitoxantrone, vindesine, lonafarib, merimepodib ), Brequinar, amsacrine, CEP-701, decitabine, teniposide, midostaurin, MLN-518, PD-184352, emmetrecide ( emetrexed (ALIMTA)), 10-propargyl-10-deaza-aminopterin (PDX), tacedinaline, thalidomid, TLK-286, pixantrone, pentostatin pentostatin, enositabine, clofarabine, BCX-1777, rubitecan, suberanilohydroxamic acid, revimid, MS- 275, dexamethasone, LAQ-824, fludarabine, pyrarubicin, teriflunomide, cerrubidin HCL, idarubicin HCL, exa Exatecan, sardomozide, adriamycin, adriamycin, methopterin, mizoribine, tamoxifen citrate / toremifine citrate, laxoxifen Raloxifene hydrOCHloride, mycophenolate, dexamethasone, methotrexate, GLEEVEC, PNP-405, MDL-74428, 9- (3,3-dimethyl-5-phosphonopentyl) guanine, DADMe-IMMG, camptosar, idarubicin, leflunomide, BAY-43-9006, bicyclic nucleobase compounds, 2-fluoro, 2 ', 3' dide Hydro, 4 'phosphonate nucleoside compounds, gemcitabine, claribine, rofecoxib, ANA-245 and halobetasol propionate.

In one embodiment of the invention, the compound is not a kinase inhibitor, IMPDH, PMP, an antiviral agent or an autoimmune system enhancer. In another embodiment of the invention, the compound is of the formula 501 , 519 , 597 , 541 , 518 , 558 , 591 , 593 , 592 , 503 , 504 , 505 , 506 , 542 , 544 , 545 , 546 , 516 or It is not a compound of 512 .

Cellular accumulation

In one embodiment, the invention provides compounds that can accumulate in human PBMCs (peripheral blood mononuclear cells). PBMC refers to blood cells with circular lymphocytes and monocytes. Physiologically, PBMC is an important component of the mechanism for infection. PBMCs can be isolated from standard heparinized whole blood or buffy coats of normal healthy donors by standard density gradient centrifugation, harvested at the interface, washed (eg, phosphate buffered saline) and stored in the refrigerant. PBMCs can be cultured in multi-well plates. At various times during incubation, suspended solids can be removed or cells can be analyzed for analysis (Smith R. etal (2003) Blood . The compounds of this claim further comprise phosphonates or phosphonate prodrugs). More specifically, the phosphonate or phosphonate prodrug may have structure A ³ described herein.

In general, the compounds of the present invention demonstrate an improvement in the intracellular half-life or intracellular metabolites of the compounds in human PBMCs compared to analogs of those compounds that do not have a phosphonate or phosphonate prodrug. Specifically, the half-life is improved by at least about 50%, more specifically 50-100%, even more specifically at least about 100%, even more specifically about 100%.

In one embodiment of the present invention, the intracellular half-life of the metabolite of the compound is improved in human PBMCs when compared to analogs of such compounds without phosphonates or phosphonate prodrugs.

In such claims, the metabolite may be produced intracellularly, such as in human PBMCs. The product may be a cleavage product of phosphonate prodrugs in human PBMCs. The phosphonate prodrugs can cleave to produce metabolites with at least one negative charge at physiological pH. The phosphonate prodrugs can be enzymatic cleaved in human PBMCs to produce a posuponate having at least one active hydrogen atom of P-OH type.

Stereoisomer

The compounds of the present invention may have chiral centers such as chiral carbon or phosphorus atoms. Therefore, the compounds of the present invention include racemic mixtures of all stereoisomers, including enantiomers, diastereomers and atropisomers. In addition, the compounds of the present invention include optical isomers that are more or split on one side at any or all asymmetric chiral atoms. In other words, a chiral center apparent from the expression is provided as a chiral isomer or racemic mixture. The racemic mixtures and stereoisomeric mixtures as well as the isolated or synthesized individual optical isomers substantially free of the enantiomer or diastereomer are all within the scope of the present invention. The racemic mixture is substantially optically pure by means of known techniques such as, for example, isolating diastereomeric salts formed using optically active additives such as acids or bases and then converting them back into the optically active material. It is separated into isomers. In most cases, the desired stereoisomer starts with the appropriate stereoisomer of the desired starting material and synthesizes by stereospecific reaction.

The compounds of the present invention may also exist in some cases as tautomeric isomers. Although expressed as only one unlocalized resonance structure, all such forms will fall within the scope of the present invention. For example, enamine tautomers may be present for purine, pyrimidine, imidazole, guanidine, amidine and tetrazole systems, all of their possible tautomeric forms are within the scope of the present invention.

Salts and hydrates

The composition of the present invention comprises salts of the compounds of the invention, if necessary, in particular pharmaceutically acceptable non-toxic salts containing Na ⁺ , Li ⁺ , K ^+, Ca ⁺² and Mg ⁺² . Such salts include salts derived by a combination of suitable cations such as alkali and alkaline earth metal ions or acid anion moieties, typically ammonium with carboxylic acids and quaternary amino ions.

When a water-soluble salt is desired, a monovalent salt is preferable. Metal salts are generally prepared by reacting a metal hydroxide with a compound of the present invention. Examples of metal salts prepared in this way are salts containing Li ⁺ , Na ⁺ and K ⁺ . Less soluble salts may precipitate out of a solution of more soluble salts by the addition of a suitable metal compound.

In addition, salts may contain any organic and inorganic acid such as HCl, HBr, H ₂ SO _{4 ,} H ₃ PO ₄ Alternatively, organic sulfonic acids can be produced by addition to basic centers, typically amines or acidic groups. Finally, it should be noted that the compositions of the present invention comprise compounds of the present invention, both nonionic and zwitterionic and combinations thereof, together with stoichiometric amounts of water as in hydrates.

Also included in the scope of the invention are salts of parent compounds having one or more amino acids. Natural amino acids identified as protein components of the above-mentioned amino acids generally have a side chain having a basic or acidic group such as lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine or leucine. Genie is an amino acid but is particularly suitable.

Cancer treatment method

Another feature of the invention relates to a method of treating cancer. The composition of the present invention may be used to treat cancer, serve as an intermediate for treating cancer, or have other utility as described below. The anticancer compounds will bind to locations on the surface or in the cavity of cancer cells having a geometry unique to the anticancer compound. Compounds that combine the anticancer compounds can bind with varying degrees of reversibility. These compounds that are substantially irreversibly bound are the best compounds for use in the methods of the present invention. Once labeled, the substantially irreversibly bound composition is useful as a cancer detection probe. Accordingly, the present invention provides a process for treating a sample suspected of containing cancer using a composition comprising the compounds of the present invention bound to a label, and for observing the effect of the sample on the activity of the label. A method for detecting cancer in a sample suspected of containing cancer comprising a step. Suitable labels are well known in the field of diagnostics and include suitable free radicals, fluorophores, radioisotopes, enzymes, chemiluminators and chromogens. In the present invention the compounds are labeled in a conventional manner using functional groups such as hydroxyl or amino.

Samples suspected of containing cancer in the present invention include natural or artificial materials such as living organisms, tissues or cell cultures, biological material samples (blood, serum, urine, internal spinal fluid, tears, sputum, saliva, tissue samples, etc.), and the like. Biological sample, laboratory sample, food, water or air sample, biotechnological product sample such as cell extract, and particularly, recombinant tax for synthesizing desired glycoprotein.

Generally, the sample will be suspected to contain cancer. The cancer can be contained in any medium, including water and organic solvent / water mixtures. Samples include artificial materials such as organisms such as humans and cell cultures.

The therapeutic process of the present invention includes adding a composition of the present invention to the sample or adding a precursor of the composition to the sample. The treatment process includes any method of administration as described above.

If necessary, the activity of cancer after use of the composition can be observed by any method including direct and indirect methods of detecting cancer activity.

Both quantitative, qualitative and semiquantitative methods of determining cancer activity are contemplated. In general, one of the screening methods described above applies, but any other method, such as observing the physiological properties of an organism, may also be applied.

Organisms containing cancer include mammals such as humans. The compounds of the present invention are useful for the treatment or prevention of cancer in animals or humans.

However, it should be borne in mind that in screening compounds capable of treating cancer, the results of enzyme assays may not be correlated with cell culture assays. Thus, cell based assays would be the primary screening tool.

Screen for Anticancer Compounds

The composition of the present invention is screened for activity against cancer by any of the prior art means of assessing enzyme activity. In the present invention, the compositions are generally first screened for activity against cancer in vitro, and then compositions exhibiting activity are screened for activity in vivo. Useful in vivo screens have been described in detail and will not be discussed here in detail. However, in the Examples, a suitable in vivo assay will be described.

Pharmaceutical formulation

The compounds of the present invention are formulated with conventional carriers and excipients, which carriers and excipients will be selected according to conventional practice. The tablet will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form and will generally be isotonic when intended for delivery by a mode of administration other than oral administration. All formulations will contain excipients such as those described in Handbook of Pharmaceutical Excipients (1986) as needed. Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkylmethyl cellulose, stearic acid and the like.

The pH of the formulation is about 3 to 11 but is typically about 7 to 10.

The active ingredient may be administered alone, but is preferably provided in a pharmaceutical formulation. The inventive formulations for veterinary and human use comprise at least one active ingredient as described above and one or more acceptable carriers for it and other therapeutic ingredients as necessary. The carrier (s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically harmless to the recipient.

Such formulations include those suitable for the routes of administration described above. The formulations may conveniently be presented in unit dosage form and may be prepared by methods well known in the art of pharmacy. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methods include the step of mixing the active ingredient with a carrier consisting of one or more accessory ingredients. In general, the formulations may be prepared by mixing the active ingredient uniformly well with the liquid carrier or the finely divided solid carrier and then molding the product if necessary.

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 active ingredient, powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water liquid emulsions or It can be provided as a water-in-oil liquid emulsion. The active ingredient can also be administered as a pill, soft or paste.

Tablets are prepared by compression or molding with one or more accessory ingredients as needed. Compressed tablets may be prepared by mixing the active ingredients with binders, lubricants, inert diluents, preservatives, surfactants or dispersants, if necessary, in a suitable machine in free flowing form, such as powders or granules. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may be coated or embossed as needed and may be formulated to release sustained or controlled release of the active ingredient from the tablet as needed.

For administration to the eye or other external tissue such as the mouth and skin, the formulations may be increased by 0.1% w / w, e.g., from 0.075 to 20% w / w (0.6% w / w, 0.7% w / ω, etc.) Preference is given to topical ointments or creams containing active ingredients in the range from% to 20%), preferably from 0.2 to 15% w / ω and most preferably from 0.5 to 10% w / w. .

When formulated into ointments, the active ingredients can be used with either paraffinic or water miscible ointment bases. Optionally, the active ingredients can be formulated in a cream with an oil-in-water cream base.

If desired, the cream-based aqueous phase is, for example, a polyhydric alcohol, ie an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof and the like. At least 30% w / w. The topical formulation may preferably comprise a compound that enhances the absorption or penetration of the active ingredient through the skin or other affected site. Examples of such skin penetration enhancers include dimethylsulfoxide and related analogs.

The oily phase of the emulsions of the invention may be constructed in a known manner from known components. The phase may comprise only emulsifiers (known as running emulsions), but preferably comprises a mixture of fat or oil and at least one emulsifier or a mixture of fat and oil and at least one emulsifier. Preferably, hydrophilic emulsifiers are included together with lipophilic emulsifiers that act as stabilizers. It is also desirable to include both oils and fats. Emulsifier (s) with or without stabilizer (s) constitute so-called emulsifying wax, and those waxes with oil and fat constitute so-called emulsifying ointment bases that form the oily dispersed phase of the cream formulation.

Suitable emulsions and emulsion stabilizers for the formulations of the present invention include Tween ^R 60, Span ^R 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

The choice of oils or fats suitable for such formulations is based on achieving the desired cosmetic properties. The cream should preferably be a product that is not greasy, smeared and washable with adequate firmness to avoid leakage from tubes or other containers.

Straight or branched chains such as di-isoadiate, isocetyl stearate, propylene glycol diesters of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palate Mixtures of monobasic or dibasic alkyl esters or branched chain esters known as Crodamol CAP can be used, the last three being the preferred esters. These may be used alone or in combination depending on the properties required. Optionally, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils are used.

Pharmaceutical formulations according to the present invention comprise one or more compounds of the present invention together with one or more pharmaceutically acceptable carriers or excipients and other therapeutic agents as necessary. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the desired dosing method. For oral use, for example, tablets, troches, medicinal peppermint drops, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions intended for oral use may be prepared by any method known in the art of preparing pharmaceutical compositions, and such compositions contain one or more medicaments, including sweeteners, flavors, colorants, and preservatives, to provide tasty formulations. can do. Preference is given to tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate or sodium, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate or sodium, granulating and disintegrating agents such as corn starch or alginic acid, cellulose, microcrystalline cellulose, Binders such as starch, gelatin or acacia and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be coated or uncoated by known methods, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract, thereby providing longer lasting effects. For example, a time extension material such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with wax.

 Oral formulations also provide a gelatine capsule in which the active ingredient is mixed with an inert solid diluent such as calcium phosphate or kaolin, or as a soft gelatinous capsule in which the active ingredient is mixed with an oil medium such as water or peanut oil, liquid paraffin or olive oil. Can be.

The aqueous suspension of the present invention contains the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia and natural phosphatides (eg lecithin), alkyl Condensation products of ethylene oxide and fatty acids (eg polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (eg heptadecaethyleneoxycetanol), fatty acids and hexitol anhydrides (eg polyoxyethylene sorbate) Dispersing or wetting agents such as condensation products of partial esters and ethylene oxide derived from non-molecular monooleate).

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

Oil suspensions can be formulated by suspending the active ingredient in vegetable oils such as arachis oil, olive oil, sesame oil or coconut oil or mineral oils such as liquid paraffin. Oral suspension

The oral suspension may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweeteners and flavorings as described above may be added to provide a delicious oral formulation. These compositions can be preserved by adding antioxidants such as ascorbic acid.

Dispersible powders and granules of the invention suitable for the preparation of an aqueous suspension by addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents include those mentioned above. Additional excipients such as sweeteners, flavors and coloring agents may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water 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 thereof. Suitable emulsifiers include natural gums such as gum acacia and gum tragacanth, natural phosphatides such as soy lecithin, esters or partial esters derived from hexitol anhydrides such as fatty acids and sorbitan monooleate and these partial esters and poly And condensation products of ethylene oxide such as oxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavorings. Syrups and elixirs may be formulated with sweeteners such as glycerol, sorbitol or sucrose. Such formulations may also contain analgesics, preservatives, flavors or colorants.

The compositions of the present invention may be in the form of sterile injectable preparations, such as sterile injectable aqueous or oily suspensions. 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 preparations may also be prepared as sterile injectable solutions or suspensions in toxic or parenterally acceptable diluents or solvents such as solutions in 1,3-butane-diol or as lyophilized powders. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution (Ringer's solution) and isotonic sodium chloride solution. In addition, sterile, fixed oils can conventionally be used as a solvent or suspending medium. Non-irritating fixed oils, including synthetic monoglycerides or diglycerides, can be used for this purpose. Oleic acid and the like can also be used in the preparation of injectable formulations.

The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, time-release formulations intended for oral administration to humans may be any suitable and convenient amount of carrier and active material compound that can vary between about 5 and 95% (weight: weight) of the total composition amount. About 1 to 1000 mg may contain. The pharmaceutical composition may be prepared to provide an easily measurable amount for administration. For example, an aqueous solution for intravenous injection may contain about 3 to 500 mg of active ingredient per milliliter of solution to ensure that an appropriate volume of injection can be made at a rate of about 30 mL / hr.

Formulations suitable for ophthalmic administration include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations at a concentration of 0.5 to 20%, advantageously 0.5 to 10% and especially about 1.5% w / w.

Formulations suitable for topical administration to the oral cavity include flavoured main ingredients, usually plaques containing the active ingredient in inactive main ingredients such as medicinal peppermint drops, gelatin and glycerin or sucrose and acacia, which contain the active ingredient in sucrose and acacia or tragacanth. Mouthwashes containing the active ingredient in steel and pastilles.

Formulations for rectal administration may be presented as suppositories with suitable active ingredients containing, for example, cocoa butter or salicylate.

Formulations suitable for intrapulmonary or nasal administration include particle sizes ranging from 0.1 to 500 microns (including particle sizes ranging from 0.1 to 500 microns with increasing microns, such as 0.5, 1, 30 microns, 35 microns, etc.) Inhalation is rapidly administered through the nasal cavity or through the mouth to reach the alveolar sacs.

Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared by conventional methods and may be delivered in conjunction with other therapeutic agents such as the compounds described above for use in the treatment or prevention of cancerous infections described below.

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

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile infusion solutions and suspensions and thickeners which may contain antioxidants, buffers, fungicides and solutes that render the formulation isotonic with the blood of a desired recipient. As can be mentioned aqueous and non-aqueous bactericidal suspensions.

The formulations are provided in unit dose or multi-dose containers, such as sealed ampoules and vials, to be lyophilized (freeze-dried) simply by adding a sterile liquid carrier, such as water for injection, immediately before use. Can be stored. Instant sterilization solutions and suspensions are prepared from sterile powders, granules, and tablets of the foregoing kind. Preferred unit dosage forms are those containing the active ingredient in a daily or daily sub dose (suβ-dose) or those containing a suitable amount of the active ingredient, as described herein above.

It is to be understood that the formulations of the present invention in addition to the components described above in detail may include other agents conventional in the art with respect to the type of formulation in question. Formulations suitable for oral administration, for example, may include flavorings.

The invention further provides a veterinary composition comprising at least one active ingredient as defined above and a veterinary carrier therefor.

Veterinary carriers are materials useful for administering the composition, or else may be solid, liquid or gaseous materials which are inert or acceptable in veterinary technology and are miscible with the active ingredient. These veterinary compositions can be administered by oral, parenteral or other desired route.

In addition, the compounds of the present invention may be formulated to enable lesser administration or to improve the pharmacokinetic or toxicological profile of the active ingredient by controlled release of the active ingredient. Accordingly, the present invention also provides compositions comprising one or more compounds of the invention formulated for sustained or controlled release.

The effective dose of the active ingredient depends at least on the nature of the therapeutic condition, the toxicity, whether the compound is used prophylactically (at a lower dose) or against an active cancer infection, the method of delivery and the pharmaceutical formulation thereof, and It will be determined by the clinician using the dose escalation study. The dose is about 0.0001 to about 100 mg / kg body weight per day, generally about 0.01 to about 10 mg / kg body weight per day, more generally about 0.01 to about 5 mg / kg body weight per day, more generally It can be expected to be about 0.05 to about 5 mg / kg body weight per day. For example, the daily desired dose for an adult weighing about 70 kg will be 1 mg to 1000 mg, preferably 5 mg to 500 mg, and may be in single or multiple dosage forms.

Route of administration

One or more compounds of the invention (hereinafter referred to as active ingredients) are administered via a route suitable for the therapeutic conditions. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, endothelial, intrathecal and epidural). Preferred routes may vary, for example, depending on the conditions of the recipient. An advantage of the compounds of the present invention is that the compounds are orally biocompatible so that oral administration is possible.

Combination Therapy

The active ingredients of the present invention can also be used with other active ingredients. Such combinations are selected based on the conditions of treatment, the cross reactivity of the components and the pharmacological properties of the combination. For example, when treating cancer, the compositions of the present invention can be combined with other chemotherapeutic agents. The second chemotherapeutic agent may be any suitable compound having biological activity against one or more cancerous forms.

It is also possible to combine any compound of the invention with one or more other active ingredients in unit dosage form for simultaneous or sequential administration to cancer patients. The combination therapy may be administered concurrently or sequentially. When administered sequentially, the combination may be administered in a manner of two or more administrations. The second and third active ingredients in the combination have chemotherapy activity and include any of the additional chemotherapeutic agents described herein. Exemplary active ingredients to be administered with the compounds of the present invention are described below.

Suitable addition chemotherapeutic agents include, for example, antracyclines (eg doxorubicin, daunorubicin, epirubicin, idarubicin and mitoxantrone), (b) other DNA intercalators (eg Actinomycin C, D, B, etc., grapephytotoxin and epipodophylatoxin (etoposide, teniposide, ctoposide), (c) alkylating agents (e.g., mechloretamine, melphalan, cyclo Phosphamide, chlorambucil, ifosfamide, carmustine, romustine, busulfan, dacarbazine, cisplatin, carboplatin, oxalylplatin, iproplatin and tetraplatin), (d) hormones ( For example, antiestrogens / estrogen antagonists (tamoxifen and other SERMs), LHRH antagonists and antagonists (leuprolide acetate, goserelin, abarelix), aromatase inhibitors and antiandrogens, (e) chemical prophylactic agents (Eg, NSAIDs And cis-retinoids) and (f) cell cycle chemopreventive agents.

Optionally, the additive chemotherapeutic agent may include, for example, antineoplasts.

 Representative antineoplastic agents include, for example, auxiliaries (eg, revamisol, gallium nitrate, granistron, sargramostim strontium-89 chloride, filgrastim, pilocarpine, dexrazoic acid and ondansetron), androgens Inhibitors (eg, flutamide and leuprolide acetate); Antibiotic derivatives (e.g., doxorubicin, bleomycin sulfate, daunorubicin, dactinomycin and idarubicin), antiestrogens (e.g. tamoxifen citrate, their analogues and tormiphene, droroxifene and roloxifene, etc. Steroidal antiestrogens), anti-metabolic agents (e.g. fludarabine phosphate, interferon alpha-2b recombinants, methotrexate sodium, plicamycin, mercaptopurine and thioguanine), cytotoxic agents (e.g. doxorubicin, carmustine) [BCNU], Romustine [CCNU], Cytarabine USP, Cyclophosphamide, Estramuscin Phosphate Sodium, Altretamine, Hydroxyurea, Iphosphamide, Procarbazine, Mitomycin, Busulfan, Cyclophosphamide , Mitoxantrone, carboplati, cisplatin, cisplatin, interferon alpha-2a recombinant, paclitaxel, teniposide and streptozosi ); Hormones (eg, hydroxyprogesterone acetate, estradiol, megestrol acetate, octreotide acetate, diethylstilbestrol diphosphate, testosterone and goserelin acetate); Immunomodulators (eg aldehydes), nitrogen mustard derivatives (eg melphalan, chlorambucil, mechloretamine and thiotepa) and steroids (betamethasone sodium phosphate and betamethasone acetate).

Suitable addition chemotherapeutic agents include, for example, alkylating agents, antimitotic agents, plant alkaloids, biological agents, topoisomerase I inhibitors, topological isomerase II inhibitors and synthetics.

Representative alkylating agents include, for example, asaley, AZQ, BCNU, busulfan, bisulfan, carboxyphthalatoplatinum, CBDCA, CCNU, CHIP, chlorambucil, chlorozotocin, cis-platinum, clomesone, Cyanomorpholinodoxorubicin, Cyclodison, Cyclophosphamide, Dianhydrocaractitol, Fluorodopan, Hepsulfan, Hiccanton, Iphosphamide, Melphalan, Methyl CCNU, Mitomycin C, Mitozolamide, Nitrogen Mustard, PCNU, piperazine, piperazinedione, piperobroman, porphyromycin, spirochidantone mustard, streptozotocin, teroxylone, tetraplatin, thiotepa, triethylenemelamine, uracil nitrogen mustard and yoshi-864 ( Yoshi-864).

Representative antimitotic agents are, for example, allocolhitchin, halicondrin B, colchicine, colchicine derivatives, dolastatin 10, mystanin, lysine, paclitaxel derivatives, paclitaxel, thiocolhitchin, trityl cysteine, vinblastine sulfate and Vincristine sulfate.

Representative plant alkaloids include, for example, actinomycin D, bleomycin, L-asparaginase, idarubicin, vinblastine sulfate, vincristine sulfate, mitramycin, mitomycin, daunorubicin, VP-16-213 , VM-26, navelbin and taxotere.

Representative biological agents include, for example, alpha interferon, BCG, G-CSF, GM-CSF and interleukin-2.

Representative phase isomerase I inhibitors include, for example, camptothecin, campotethecin derivatives and morpholinodoxorubicin.

Representative phase isomerase II inhibitors include, for example, mitoxantrone, amonafide, m-AMSA, anthrapyrazole derivatives, pyrazoloacridine, bisantrene HCL, daunorubicin, deoxydoxorubicin , Menogaril, N, N-dibenzyl daunomycin, oxanthrazole, rubidazone, VM-26 and VP-16.

Representative compounds include, for example, hydroxyurea, procarbazine, o, p'-DDD, dacarbazine, CCNU, BCNU, cis-iamminedichloroplatinum, mitoxantrone, CBDCA, levamisol, hexamethylmelamine, fully trans Type retoic acid, gliadel and porpimer sodium.

Optionally, the additive chemotherapeutic agent may include tubulin binding drugs and drugs that may affect tubulin growths and functions. This includes a variety of drugs that are not chemically related to vinca alkaloids and taxanes (such as CP-248 [derivatives of axearin] and ILX-651). These drugs have specific effects on cells at the G2M-phase and can have functionally independent effects during the G1 and / or S phase.

Optionally, the adjuvant chemotherapeutic agent inhibits isolzymes 1, 2, 5 of sulindac, aptocin, CP-461, CP-248 and one or more next cyclic GMP phosphodiesterases (cGMP PDEs). And may include selective apoptotic anti-cancer drugs (SAANDs), including related sulindac inducing compounds.

Optionally, the additive chemotherapeutic agent may include a drug that inhibits proteasomes (bortezomib or Velcade). Proteosomes degrade many ubiquitinated proteins that indicate active destruction. Ubiquinolated proteins include many critical cell cycle regulatory molecules and molecules that regulate apoptosis at specific stages of the cell cycle. Proteosomes can degrade proteins throughout the cell cycle, but the proteins degraded by the proteosomes include any of the maximum critical cell cycle regulatory proteins. So-called "cell cycle activity grounds" can be applied to the treatment of various categories of diseases, including cancer, inflammatory / autoimmune diseases and neurological diseases involving irregular cell cycles and / or apoptosis.

Optionally, the additive chemotherapeutic agent inhibits heat shock protein 90 (HSP90), a 'chaperonin' that participates in the degradation of the 'client' protein in the ubiquitin mediated proteosome pathway. It may include.

Several drugs are thought to exert antitumor effects by inhibiting the intrinsic ATPase activity of HSP90 resulting in the degradation of HSP90 “client proteins” via the ubiquitin proteosome pathway. Examples include geldanamycin, 17-allylamino geldanamycin, 17-demethoxygeldanamycin and radicicol.

Suitable cell cycle-dependent biological agents or schedule-dependent biological agents can be used to prevent or delay cell cycle progression at the G1-, G1 / S, S-, G2 / M, or M-phases of the cell cycle. Or drugs, proteins or other molecules that interfere with it. These drugs are cell cycle-dependent or schedule-dependent.

Specifically, suitable cell cycle dependent or schedule dependent biological agents include

(1) analogs of uridine nucleosides, analogs of thymidine nucleosides and analogs of uridine and thymidine nucleosides. These compounds act at the S-phase in tumor cells and / or neovascular endothelial cells. These compounds include, for example, 5-fluorodeoxyuridine (floxuridine, FUDR); 5-fluurorasyl (5-FU), prodrug of 5-FU (e.g. capecitabine, 5'deoxy-5-fluorouridine, ftorafur, flucytocin), bromodeoxy Uridine and iododeoxyuridine.

(2) Modulators of fluoropyrimidine. These compounds act at the S-phase in tumor cells and / or neovascular endothelial cells. These compounds include, for example, leurovorin, methotrexate and other folates, levamisol, acivicin, phosphonacetyl-L-aspartic acid (PALA); Brequinar, 5-ethylyluracil and uracil.

(3) Cytidine analogs and Cytidine nucleoside analogs. These compounds act at the S-phase in tumor cells and / or neovascular endothelial cells. These compounds include, for example, cytarabine (Ara-C, cytosine arabinoside), gemcitabine (2'2'difluorodeoxycytidine) and 5-azacytidine.

(4) purine analogs and purine nucleoside analogs. These compounds act at the S-phase in tumor cells and / or neovascular endothelial cells. These compounds include, for example, 6-thioguanine; 6-mercaptopurine, azathioprine, adenosine arabinoside (Ara-A), 2'2'difluorodeoxyguanosine, deoxycoformycin (pentostatin), cladribine (2-chlorodeoxy Adenosine) and inhibitors of adenosine deaminoases.

(5) antifolates. These compounds act at the S-phase in tumor cells and / or neovascular endothelial cells. These compounds include, for example, methotrexate, aminopterin, trimetrexate, eddatrexate, N10-propargyl-5,8- didiazafolic acid (CB3717); ZD1694, 5,8- didiazaisofolic acid (IAHQ); 5,10- didadezatetrahydrofolic acid (DDATHF); 5-deazafoic acid (effective substrate for FPGS), PT523 (N alpha- (4-amino-4-deoxypteroyl) -N delta-hemiphthaloyl-L-ornithine), 10-ethyl- 10-deazaaminopterin (DDATHF, lomatrexol), pyritrexime, 10-EDAM, ZD1694, GW1843, PDX (10-propargyl-10-deazaaminopterin), multiple targeting folates (ie LY231514 , permetrexed), any folate inhibitor of thymidylate synthase (TS), any folate inhibitor of inhibitor dihydrofolate reductase (DHFR), any of glycineamide ribonucleotide transformillase (GARTF) Folate inhibitors, any inhibitor of polypolyglutamate synthetase (FPGS) and any folate inhibitor of GAR formyl transferase (AICAR transformillase).

(6) Other antimetabolic drugs. These compounds act at the S-phase in tumor cells and / or neovascular endothelial cells. These compounds include, for example, hydroxyurea and polyamines.

(7) S-group specific radiotoxins (deoxythymidine analogs). These compounds act at the S-phase in all cells undergoing DNA synthesis. The compounds are incorporated into chromosomal DNA during the S-group. These compounds include, for example, [125I] -iododeoxyuridine, [123I] -iododeoxyuridine, [124I] -iododeoxyuridine, [80mBr] -iododeoxyuridine, [131I] -io Dodeoxyuridine and [211At] -astatin-deoxyuridine.

(8) Inhibitors of enzymes involved in deoxynucleoside / deoxynucleotide metabolism. These compounds act at the S-phase in tumor cells and / or neovascular endothelial cells. These compounds include, for example, inhibitors of thymidylate synthetase (TS), inhibitors of dihydrofolate reductase (DHFR), inhibitors of glycineamide ribonucleotide transformillase (GARTF), polypolyglutamate synthetase (FPGS) ), Inhibitors of GAR formyl transferase (AICAR transformase), inhibitors of DNA polymerase (DNA Pol such as apidocholine), inhibitors of ribonucleotide reductase (RNR), thymidine kinase (TK) And inhibitors of phase isomerase I enzymes (eg, campotesine, irinotecan [CPT-11, camptosar], topotecan, NX-211 [lurtotecan], rubicatecan, etc.) Can be mentioned.

(9) DNA chain terminal nucleoside analogs. These compounds specifically act on S-phase cells and incorporate into the chromosomal DNA during the S-phase to terminate the growing DNA strands. These compounds are, for example, acyclovir, abacarbi ,; Valacyclovir, zidobudine (AZT), didanosine (ddI, dideoxycytidine); Salcitabine (ddC), stavudine (D4T), lavivudine (3TC), any 2'3'-dideoxy nucleoside analogues and any 2'3'-dideoxy nucleoside analogues that terminate DNA synthesis do. These compounds include, for example, growth factor receptor tyrosine kinases (eg, EGF receptors, HER-2 neu / c-erbB2 receptors, PDGF receptors, etc.) that regulate progression through the cell cycle G1-phase, G1 / S interphase or S-phase [ Inhibitors of trastusumab, iresa, abitux, tarceba]), inhibitors of non-receptor tyrosine kinases (such as tyrosine kinases of the c-src family [such as Gleevec]), G1-group of the cell cycle, G1 / Serine-threonine kinases that regulate progression through S interphase or S-phase (eg G1 cyclin dependent kinases, G1 / S cyclin dependent kinases and S cyclin dependent kinases [eg CDK2, CDK4, CDK5, CDK6], mitogen activation) Kinases, inhibitors of the MAP kinase) to signal pathways, inhibitors of the G1-group, G1 / S interphase or S-group cyclins [e.g. Cyclin D1, D2, D3, E and A]), G1-group of the cell cycle, G1 / Positive control of progression through the S interphase or S-phase Inhibitors of G-proteins and cGMP phosphodiesterases, drugs that inhibit the induction of immediate early response transcription factors (eg, N-terminal c-junkinase, c-myc) and "degrading negative cell cycle regulators Drugs that inhibit proteosomes (such as p53, p27 / Kip1, such as bortezomib).

(10) cytokine, growth factor, anti-vein tube formation

Sex factors and other proteins that inhibit cell cycle progression in the G1-phase or G1 / S interphase of the cell cycle. These compounds act in the G1, G1 / S or S-phase of the cell cycle in tumor cells and in some cases neovascular endothelial cells. These compounds include, for example, interferon, interleukin, somatostatin, and somatostatin analogs (octreotide, acidstatin LAR), and many anti-vascularization factors support endothelial cell proliferation at the G1 or G1 / S phase of the cell cycle. Suppress

 (11) Drugs that inhibit cell cycle progression in the G2 / M interphase or M-phase of the cell cycle and compounds. These compounds act in G2 / M interphase or M-phase of the cell cycle in tumor cells and in some cases neovascular endothelial cells. These compounds include, for example, (a) microtubule-targeted drug taxanes (eg, taxols, taxotels, epothilones and other taxanes and derivatives), and (b) microtubule-targeted drug vinca alkaloids (eg, vinblastine). , Vincristine, vindesine, vinflunin, vinnorelvin, vinzolidine, nocardazole and colchicine), (c) microtubule-targeted drug other (e.g., esturamustine, CP-248 and CP-461), ( d) inhibitors of serine-threonine kinases (eg, G2 / M cyclin-dependent kinases (eg CDC2)) that regulate progression through the G2 / M interphase or M-phase of the cell cycle, M-phase cyclins (eg cyclin B) Inhibitors and certain drugs that prevent, retard, or otherwise interfere with cell cycle progression in the G2 / M interphase or M-phase of the cell cycle.

(12) Radiopharmaceuticals useful for radiotherapy and / or diagnosis. Radioisotopes of the appropriate classification are disrupted by a nuclear decay process known as the "Auger Pr ° Cess" or "Auger Cascade." Auger release isotopes produce short-acting electrons that effectively degrade double DNA. Suitable auger-emitting radionuclides include, for example, 125-iodine, 123-iodine and 80m-bromine. Suitable corresponding halogenated pyrimidines and purine nucleosides are, for example, 5-125 iodo-2'deoxyuridine, 5-123iodo-2'deoxyuridine, 5-80mbromo-2'de Oxyuridine and 8-80m bromo-2'guanidine.

Growth factor

Many growth factors and cytokines have the ability to stimulate malignant cells to skip certain points in the cell cycle. For example, G-CSF or GM-CSF can stimulate leukemic blasts in acute myeloid leukemia to skip the G1 / S liver. This increases the cell's sensitivity to cell cycle specific drugs such as cytarabine. Similar strategies have been tested using EGF and cytotoxic drugs for solid tumors. To respond to growth factors, cells must be at certain stages of the cell cycle, such as the G1 / S stage. Since only a small part of the blast is at G1 / S at a given time, growth factors will be present continuously. Thus, growth factors act in a cell cycle specific manner. Similar logic can be applied to the use of hematopoietic growth factors used to treat neutropenia, anemia and hypothrombocytopenia.

Therefore, in the present invention, peptide / protein growth factors may be used to promote survival of normal non-malignant cell lineages. One advantage when using such materials is the ability to protect proliferating cells in the bone marrow, skin, oral and gastrointestinal mucosa and hair follicles.

Examples of substances in this category include, for example, hematopoietic growth factors such as G-CSF, GM-CSF, erythropoietin, thrombopoietin and biologically active derivatives of these peptides, keratinocytes for mucositis. Growth factor (KGF), β-lymphocyte stimulating pepdie (βys), platelet-induced growth factor (PDGF), epidermal growth factor (EGF), TGF-alpha and related growth factors, interleukin And peptides that stimulate the proliferation of non-malignant cells in need of protection (eg, IL-2, IL-6), other cytokines, growth factors, and protection.

Therapeutic Growth Factors / Cytokines

Certain therapeutic growth factors / cytokines may inhibit cell proliferation of cancer cells and / or neovascular cells at specific stages of the cell cycle. For example, interferons, somatostatin, octreotide and its analogs, thrombospondin and troponin-I inhibit neovascular endothelial cell proliferation by reducing the rate at which cells enter the S-group. . Therefore, one or more of these materials can be used in the present invention.

Combination therapy can provide "synergy" and "synergistic effects". That is, the effect obtained when the active ingredients are used together is greater than the sum of the effects obtained by using the compounds individually. The synergistic effect is when (1) the active ingredients are co-formulated to be administered or delivered simultaneously in a combination formulation, (2) individual formulations are delivered alternately or in parallel, or (3) by any other therapy. Can be obtained. When delivered in alternation therapy, a synergistic effect can be obtained when the compounds are administered or delivered sequentially, eg, in tablets, pills or capsules, or by different infusions in separate syringes.

In general, an effective amount of each active ingredient is administered sequentially, i.e., sequentially, during a shift therapy, whereas in combination therapy, an effective amount of two or more active ingredients is administered together.

Of the compounds of the invention Metabolites

In vivo metabolites of the compounds described herein also fall within the scope of the present invention. Such products arise essentially from the oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compounds due to enzymatic processes. Thus, the present invention includes compounds prepared by a process comprising contacting a compound of the present invention with a mammal for a period of time sufficient to obtain its product. Such products generally produce a compound represented by a radioisotope of the present invention (e.g., C ¹⁴ or H ³ ), which is detectable to an animal or human such as rat, mouse, guinea pig, monkey, etc. (e.g., about 0.5 parenteral administration in mg / kg or more, giving sufficient time (typically about 30 seconds to 30 hours) for metabolism to be followed by isolation of the transformant from urine, blood or other physiological samples. These products are easily labeled and labeled (the rest are separated by the use of antibodies capable of binding surviving epitopes in the metabolite). Metabolite structures are determined in a conventional manner, eg by MS or NMR analysis. In general, the analysis of metabolites is done in the same manner as conventional drug metabolism experiments well known to those skilled in the art. Conversion products are useful in diagnostic assays for the therapeutic administration of compounds of the invention, even if they are not anticancer in themselves, unless otherwise found in vivo.

Therapies and methods are known for determining the stability of compounds in surrogate gastrointestinal secretions. Compounds are defined herein as less than about 50 mole percent of the protected groups are stable in the gastrointestinal tract, which is deprotected in the surrogate intestine or gastric fluid upon incubation at 37 ° C. for 1 hour.

Simply because the compounds are stable in the gastrointestinal tract does not mean that they cannot be hydrolyzed in vivo. Phosphonate prodrugs of the present invention will generally be stable in the digestive system, but are substantially hydrolyzed to the parent drug in the lumen, liver or other metabolic organs or in normal cells.

In one embodiment of the invention, the compounds are in isolated and purified form. In general, the term “isolated and purified” means that the compounds are substantially free of biological material (eg blood, tissue, cells, etc.). In one specific embodiment of the invention, the term means that there is at least about 50 wt.% Of a biological material in the compound or complex of the invention, and in another specific embodiment, the term is a compound of the invention Or at least about 75 wt.% Of the biological material in the complex, and in another specific embodiment, the term means at least about 90 wt.% Of the biological material in the compound or complex of the present invention, and In another specific embodiment, the term means that at least about 99 wt.% Of the biological material is not present in the compound or complex of the present invention. In another specific embodiment, the present invention provides a compound or complex of the present invention prepared synthetically (eg, ex vivo).

Exemplary Methods of Making Compounds of the Invention .

The invention also relates to a process for preparing the composition of the invention. The composition is prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. On the other hand, many of the known techniques are described in Compendium of Organic Synthetic Methods (John Wiley & Sons, Neω York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984 and Vol. 6, Michael B. Smith; as well as March, J., Advanced Organic Chemistry, Third Edition , (John Wiley & Sons, Neω York, 1985), Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry. In 9 Volumes , Barry M. Trost, Editor-in-Chief (Pergamon Press, Neω York, 1993 printing).

Many exemplary methods for preparing the compositions of the present invention are presented below. These methods are intended to explain the features of such a preparation and are not intended to limit the scope of the applicable methods.

In general, reaction conditions such as temperature, reaction time, solvent, finishing process and the like are common conditions in the technical field for carrying out the specific reaction. The references cited above contain a detailed description of such conditions together with the substances cited therein. Generally the temperature will be from -100 ° C to 200 ° C, the solvent will be aprotic or protic and the reaction time will be 10 seconds to 10 days. Finishing generally consists of quenching the unreacted reactant and then distributing (extracting) the water / organic layer system to separate the layer containing the product.

Oxidation and reduction reactions often reduce the temperature from 0 ° C. to -100 ° C. for metal hydride reduction, but are generally carried out at temperatures near room temperature (about 20 ° C.) and solvents are generally non-reduced for reduction. It is protic, and in the case of oxidation it can be either protic or aprotic. The reaction time is adjusted to achieve the desired conversion rate.

The condensation reaction is also usually carried out at a temperature near the room temperature, although in the case of non-equilibrium a kinetic controlled condensation conversion temperature (0 ° C. to −100 ° C.) is also common. The solvent can be either protic (usually equilibrium reaction) or aprotic (usually kinetic controlled reaction).

Standard synthetic techniques such as azeotropic removal of by-products and anhydrous reaction conditions (eg inert gas environments) are common in the art and will be applied where applicable.

Schemes and Example

General features of these exemplary methods are described below and in the examples. The products of each of the following processes are separated, isolated and / or purified as necessary before use in subsequent processes.

In general, reaction conditions such as temperature, reaction time, solvent, finishing process and the like are common conditions in the technical field for carrying out the specific reaction. The references cited above contain a detailed description of such conditions together with the substances cited therein. Generally the temperature will be from -100 ° C to 200 ° C, the solvent will be aprotic or protic and the reaction time will be 10 seconds to 10 days. Finishing generally consists of stopping the unreacted reactant and then distributing (extracting) the water / organic layer system to separate the layer containing the product.

Oxidation and reduction reactions often reduce the temperature from 0 ° C. to -100 ° C. for metal hydride reduction, but are generally carried out at temperatures near room temperature (about 20 ° C.) and solvents are generally non-reduced for reduction. It is protic, and in the case of oxidation it can be either protic or aprotic. The reaction time is adjusted to achieve the desired conversion rate.

The condensation reaction is also usually carried out at a temperature near the room temperature, although in the case of non-equilibrium a kinetic controlled condensation conversion temperature (0 ° C. to −100 ° C.) is also common. The solvent can be either protic (usually equilibrium reaction) or aprotic (usually kinetic controlled reaction).

Standard synthetic techniques such as azeotropic removal of by-products and anhydrous reaction conditions (eg inert gas environments) are common in the art and will be applied where applicable.

The terms “treated”, “treating”, “treatment”, etc., when used in connection with a chemical synthesis operation, cause contact, mixing, reacting, reacting, contacting, and one or more chemicals to one or more other chemicals. By other terms, it is common in the art to indicate that it is processed in such a way that it is converted into a substance. This means that "treating compound 1 with compound 2" means "reacting compound 1 with compound 2", "contacting compound 1 with compound 2", "reacting compound 1 with compound 2" and compound 1 compound 2 is synonymous with other expressions common in the art of organic synthesis to reasonably indicate “to be processed”, “reacted”, and “reacted”.

For example, "treating" refers to a reasonable normal way of reacting an organic chemical.

Unless stated otherwise, normal concentrations (0.01M to 10M, generally 0.1M to 1M), temperature (-100 ° C to 250 ° C, generally -78 ° C to 150 ° C, more generally -78 ° C to 100 ° C, even more generally 0 ° C to 100 ° C), reaction vessels (generally glass, plastic, metal), solvents, pressure, atmosphere (generally in reactions not sensitive to oxygen and water, to air or oxygen or water In the case of sensitive reactions, nitrogen or argon) is intended. Knowledge of similar reactions known in the art of organic synthesis is used to select conditions and apparatus for "treatment" during a given process. In particular, one of ordinary skill in the art of organic synthesis will select conditions and apparatus that are expected to successfully perform the chemical reactions of the described processes based on the knowledge in the field.

Modifications in each of the exemplary schemes and examples thereof (hereinafter referred to as “exemplary schemes”) generate various analogs of particular exemplary materials. The contents of the foregoing references describing suitable organic synthesis methods can be applied to such modifications.

In each exemplary scheme, it may be advantageous to separate the reaction product from another reaction product and / or starting material. The desired product of each step or series of steps is separated and / or purified (hereinafter referred to as 'separation') to the desired degree of homogeneity by common techniques in the art. Generally such separation methods include multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation or chromatography. Chromatography methods include, for example, reverse phase and normal, size exclusion, ion exchange, high pressure, medium and low pressure liquid chromatography methods and devices, small scale analysis, simulated moving bed (SMB) and manufacturing thin layers. Or many methods including thick layer chromatography as well as small scale thin layer and flash chromatography techniques.

Another class of separation methods involves treating the mixture with a reagent selected to bind or otherwise make it separable to the desired product, unreacted starting material or reaction byproduct, and the like. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves or ion exchange media. Optionally, the reagent may be an acid for a basic substance, a base for an acidic substance, a binding reagent such as an antibody, a selective chelator such as a binding protein, a crown ether, or a liquid / liquid ion extraction reagent (LIX). Can be.

The choice of a suitable separation method depends on the nature of the material involved. For example, distillation is the boiling point and molecular weight in sublimation, the presence of polar functional groups in chromatography, and the stability of the material in acidic and basic media in multiphase extraction. Those skilled in the art will apply the most appropriate technique to achieve the desired separation.

Single stereoisomers, such as enantiomers, substantially freed from their stereoisomers can be obtained by partitioning the racemic mixture using methods such as diastereomer formation using optically active splitting agents ( Stereo Chemistry of Carbon Compounds, ( 1962) by EL Eliel, McGraω Hill; LOCHmuller, CH, (1975) J. Chromatogr ., 113: (3) 283-302).

The racemic mixture of chiral compounds of the present invention comprises (1) a method for making diastereomeric salts with chiral compounds and separating them by fractional crystallization or other methods. (2) for making diastereomeric compounds with chiral induction reagents, Separation and separation of stereoisomers into pure stereoisomers, and (3) separation of the stereoisomers in which either substantially pure or isomers are present directly under chiral conditions and by any suitable method. I can isolate it.

In method (1), the diastereomeric salts comprise enantiomerically pure bases such as boursin, quinine, ephedrine, stytrinine, a-methyl-β-phenylethylamine (amphetamine), carboxylic acid and sulfonic acid. It can be made by reacting with an asymmetric compound having an acidic functional group. The diastereomeric salts can be separated by fractional crystallization or ion chromatography. To separate the optical isomers of amino acid compounds, the addition of chiral carboxylic acids or sulfonic acids, such as camphor sulfonic acid, tartaric acid, mandelic acid or lactic acid, can produce diastereomeric salts thereof.

Optionally, by method (2), the substrate to be cleaved is reacted with an enantiomer of one of the chiral compounds to generate a diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stere Chemistry of Organic Compounds , John Wiley & Sons, Inc., p. 322). Asymmetric compounds are reacted with enantiomerically pure chiral derivatives such as methyl derivatives to form diastereomeric compounds, which are then separated and hydrolyzed to yield the enantiomers which are more free. Can be. Methods for determining optical purity include Mosher esters, a-methoxy-a- (trifluoromethyl) phenyl acetate of base or racemic mixtures (Jacob III. (1982) J. Org . Chem . 47: 4165) Preparing chiral esters such as menthyl esters such as (-) menthyl chloroformate and analyzing the NMR spectra for the presence of two atropisomer diastereomers. Diastereomers of suitable atropisomers can be separated and isolated by normal and reverse phase chromatography after separation of atropisomer naphthyl-isoquinolines (Hoye, T., WO 96/15111). By method (3), the racemic mixture of the two enantiomers can be separated by chromatography using chiral stationary phases ( Chiral Liquid Chromatography (1989) WJ Lough, Ed. Chapman and Hall, Neω York; Okamoto, (1990) J. of Chromatogr . 513: 375-378). Enantiomers with more or more of one can be identified by the method used to identify other chiral molecules with asymmetric carbon atoms such as optical rotation and circular dichroism.

Example  General section

Many exemplary methods of preparing the compounds of the present invention are provided herein. For example, in the following examples, these methods are intended to illustrate the features of such a manufacturing method and are not intended to limit the scope of the applicable method. Certain compounds of the present invention can be used as intermediates for preparing other compounds of the present invention. For example, the interconversion of various phosphonate compounds of the present invention is described below.

Phosphonates R-link-P (O) ( OR ^One ) ₂ , R-link-P (O) ( OR ^One ) (OH) and R-Link-P (O) (OH) ₂ of Mutual conversion

The following reaction schemes 32 - the general structure R- link eseo 38 and ^{-P (O) (OR 1)} 2, R 1 groups are the same or have been described process for producing a phosphonate ester, which may be different from each other. The R ¹ groups bonded to the phosphonate esters or their precursors can be altered using established chemical conversion methods. The interconversion reaction of phosphonates is illustrated in Scheme S32 . In the compounds of the present invention, or precursors thereof, the R group in Scheme 32 represents a substructure, ie, a drug support having a substituent link-P (O) (OR ¹ ) ₂ attached thereto. At certain points in the synthetic pathway that perform phosphonate interconversion, certain functional groups can be protected. The method using a given phosphonate substitution depends on the nature of the substrate to which the substituent R ¹ and the phosphonate group are bound. Methods for the preparation and hydrolysis of phosphonate esters are described in Organic Phosphrous Compounds , GM Kosolapoff, L. Maeir, eds, Wiley, 1976, p. Described in 9ff.

In general, the synthesis of phosphonate esters is accomplished by coupling the nucleophile amine or alcohol with the corresponding active phosphonate electrophilic precursor. For example, the addition of chlorophosphonate to the 5'-hydroxy of nucleosides is a well known method of preparing nucleoside phosphate monoesters. The active precursors can be prepared by several well known methods. Chlorophosphonates useful for the synthesis of prodrugs are synthesized from substituted-1,3-propanediol (Wissner, et al., (1992) J. Med Chem . 35: 1650). Chlorophosphonates are prepared by oxidizing the corresponding chlorophospholane obtained by reacting substituted diols with phosphorus trichloride (anderson, et al . (1984) J. org . Chem . 49: 1304). Alternatively, the chlorophosphonate reagent is obtained by treating substituted 1,3-diol with phosphorus oxychloride (Patois, et al . , (1990) J. Chem . Soc . Perkin Trans. I , 1577). Chlorophosphonate species are also produced instantly from the corresponding cyclic phosphites (Silverburg, et al. (1996) Tetrahedron lett ., 37: 771-774). It is in turn made from chlorophospholane or phosphoramidate intermediates. Phosphorofluorate intermediates prepared from pyrophosphate or phosphoric acid may also serve as precursors in the preparation of cyclic prodrugs (Watanabe et al. (1988) Tetrahedron lett ., 29: 5763-66).

The phosphonate prodrugs of the present invention are also described by the carbodiimide (Alexander, et al., 1994) by Mitsnobu, (1981) Synthesis , 1; Campbell, (1992) J. org . Chem . 57: 6331). ....) Collect Czech Chem Commun 59:.... 1853; Casara et al, (1992) BioOrg Med Chem Lett 2:. 145; Ohashi et al, (1988) Tetrahedron Lett, 29 : 1189) and a benzotriazolyl-oxy It can be prepared from free acids by other acid coupling agents, including but not limited to tris- (dimethylamino) phosphonium salt (Campagne et al. (1993) Tetrahedron Lett . 34: 6743).

Halogenated aryl was subjected to a Ni ⁺² catalytic reaction with a phosphite derivative to obtain an aryl phosphonate containing compound (Balthazar, et al . (1980) J. org . Chem . 45: 5425). Phosphonates can also be obtained from chlorophosphonates using aromatic triflate in the presence of a palladium catalyst (Petrakis et al . (1987) J. Am. Chem . Soc . 109: 2831; Lu et al. (1987) Synthesis 726 ). Alternatively, aryl phosphonate esters can be prepared from aryl phosphates under anion rearrangement reaction conditions (Melvin (1981) Tetrahedron Lett . 22: 3375; Casteel et al. (1991) Synthesis , 691). N-alkoxy aryl salts with alkali metal derivatives of cyclic alkyl phosphonates provide a general method for synthesizing heteroaryl-2-phosphonate linkages (Redmore (1970) J. org. Chem . 35: 4114). This aforementioned method can be extended to compounds in which the W ⁵ group is heterocycle. Cyclic-1,3-propaneyl prodrugs of phosphonates can also be prepared using a coupling agent such as 1,3-dicyclohexylcarbodiimide (DCC) in the presence of a base (e.g., pyridine). Is prepared from phosphorous acid and substituted propane-1,3-diol. Other carbodiimides based on coupling agents such as 1,3-diisopropylcarbodiimide or water-soluble reagents, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) are also cyclic phos. It can be utilized in the synthesis of phonate prodrugs.

The conversion of phosphonate diester S32 .1 to the corresponding phosphonate monoester S32.2 (Scheme 32 , Reaction 1 ) is carried out by several methods. For example, R ¹ such as benzyl The ester S32 .1 which is this aralkyl group is J. org . Chem . (1995) by the reaction with a tertiary organic base such as diazabicyclooctane (DABCO) or quinuclidin and the like as described in 60: 2946 to monoester compound S32 .2 . The reaction is carried out at about 110 ° C. in an inert hydrocarbon solvent such as toluene or xylene. R ¹ Is an aryl group, e.g., phenyl, or alkenyl group diester S32 .1 alkenyl, such as allyl is treated with a base such as lithium hydroxide, in hydro-ester .1 S32 in the aqueous solution of sodium hydroxide and acetonitrile or tetra-furan monoester Converted to S32 .2 . R ¹ One group is aralkyl such as benzyl and the other is converted to the alkyl phosphonate diester S32 .1 is a monoester S32 .2 R ¹ by hydrogenation using a catalyst such as palladium on carbon alkyl. Two R ¹ Phosphonate diesters in which the group is alkenyl, such as allyl, are described, for example, for the decomposition of allyl carboxylates, for example in J. org . Chem . (1973) using the procedure described in 38: 3224, alternatively, by refluxing with an aqueous ethanol solution of chlorotris (triphenylphosphine) rhodium (Wilkinson catalyst) in the presence of diazabicyclooctane R ¹ The Al is converted to the monoester S32 .2 alkenyl. Phosphonate diester S32 .1 or conversion of phosphonic monoester S32 .2 .3 the corresponding phosphonic acid S32 (Scheme 32, Reaction 2 and 3) which are J. Chem. Soc , Chem. As described in Comm ., (1979) 739, diesters or monoesters can be made by reacting with trimethylsilyl bromide. The reaction is alternatively performed at room temperature, in the presence of a silylating agent such as bis (trimethylsilyl) trifluoroacetamide, for example in an inert solvent such as dichloromethane. R ¹ Is a monoester S32 .2 aralkyl such as benzyl is converted to the acid by treatment with hydrogen chloride corresponding .3 S32 in ethereal solvents such as dioxane, or by the hydrogenation of the palladium catalyst. R ¹ It is alkenyl, such as allyl of monoester S32 .2, for example, Helv. Chim . Acta . (1985) using the reaction procedure described in 68: 618, is converted to phosphonic acid S32.3 by reaction with a Wilkinson catalyst in an aqueous 15% acetonitrile solution or an organic solvent solution such as an ethanol solution. Hydrolysis by the palladium catalyst of phosphonate ester S32 .1 wherein R ¹ is benzyl is described in J. org . Chem . (1959) 24: 434. R ¹ Hydrogenolysis by the palladium catalyst of the phenyl phosphonate ester S32 .1 is described in J. Am. Chem . Soc . (1956) 78: 2336.

By the large number of reactions in which substrate S32 .2 is reacted with hydroxy compound R ¹ OH in the presence of a coupling agent, the phosphonate monoester S32 .2 is newly introduced R ^1. Group is converted to an alkyl, an aralkyl, an alkyl halide such as chloroethyl, or aralkyl is phosphonate diester .1 S32 (Scheme 32, Reaction 4). Typically, the second phosphonate ester group is different from the first introduced phosphonate ester group. That is, R ¹ is introduced after the introduction of R ² , where R ¹ and R ² are each haloalkyl, such as alkyl, aralkyl, chloroethyl, or aralkyl (Scheme 32 , Reaction 4a ), and accordingly, S32 . 2 is converted to S32 .1a . Suitable coupling agents used in the preparation of the carboxylate esters include carbodiimides such as dicyclohexylcarbodiimide when the reaction is carried out in a basic organic solvent such as pyridine, or the reaction is tertiary such as diisopropylethylamine In the presence of an organic base, (benzotriazole-1-oxy) tripyrrolidinophosphonium hexafluorophosphate (PYBOP, Sigma) or also the reaction when carried out in a polar solvent solution such as dimethylformamide or triphenylphosphate Aldityol-2 (Aldrich), and the like, when carried out with a basic solvent solution such as pyridine in the presence of triaryl phosphine such as pin. Alternatively, the phosphonate monoester S32 .2 can be converted to diester S32 .1 by using the Mitsunobu reaction as described above (Scheme 7 ). The substrate can be reacted with the hydroxy compound R ¹ OH in the presence of triarylphosphine, such as diethylazodicarboxylate and triphenyl phosphine. As an alternative, the phosphonate monoester S32.2 is a phosphonate diester S32 wherein the R ¹ group introduced by reacting the monoester with the halide R ¹ Br (R ¹ is alkenyl or aralkyl) is alkenyl or aralkyl. Can be converted to .1 . The alkylation reaction is in the presence of a base such as cesium carbonate, in a polar organic solvent such as dimethylformamide or acetonitrile, as an alternative, the phosphonate monoester is converted to the phosphonate diester by a two step procedure. In the first step, phosphonate monoester S32 .2 is prepared by Organic Phosphorus Compounds , GM Kosolapoff, L. Maeir, eds, Wiley, 1976, p. As described in 17, it is converted to the chloro analog RP (O) (OR ¹ ) Cl in reaction with thionyl chloride or oxalyl chloride and the like. The product RP (O) (OR ¹ ) Cl thus obtained is reacted with the hydroxy compound R ¹ OH in the presence of a base such as triethylamine to obtain phosphonate diester S32 .1 .

Phosphonic acid R-link-P (O) (OH) ₂ is the aforementioned phosphonate diester R-link-P (O) (except that only ¹ mole of component R ¹ OH or R ¹ Br is used. OR ¹ ) ₂ is converted to phosphonate monoester RP (O) (OR ¹ ) (OH) (Scheme 32 , Reaction 5 ) by the method described in the preparation method of S32 .1 . Dialkyl phosphonates are disclosed in Quast et al. (1974) Synthesis 490; Stowell et al. (1990) Tetrahedron Lett . 3261; It can be prepared according to the method of US 5663159.

Phosphonic acid R-link-P (O) (OH) ₂ S32 .3 is subjected to a coupling reaction with the hydroxy compound R ¹ OH in the presence of a coupling agent such as aldritol-2 (Aldrich) and triphenylphosphine. Phosphonate diester R-link-P (O) (OR ¹ ) ₂ S32 .1 (Scheme 32 , Reaction 6 ). The reaction is carried out in a basic solvent such as pyridine. Alternatively, phosphonic acid S32.3 was converted to phosphorous ester S32 .1 , wherein R ¹ is aryl by a coupling reaction using dicyclohexylcarbodiimide at about 70 ° C., for example in pyridine. Alternatively, the phosphorous acid was converted to S32 S32 .3 .1 of phosphite ester R ¹ is alkenyl, by alkylation. The phosphonic acid is reacted in the presence of a base such as cesium carbonate at reflux in an alkenyl bromide R ¹ Br and in a polar organic solvent such as acetonitrile to obtain phosphite ester S32 .1 .

Scheme 32

Phosphonates Carbamate  Produce

The phosphonate esters may contain carbamate bonds. Methods for preparing carbamate are described in Comprehensive Organic Functional Group Transformations , AR Katritzky, ed., Pergamon, 1995, Vol. 6, p. 416ff, and Organic Functional Group Preparations , SR Sandler and W. Karo, Academic Press, 1986, p. Described in 260ff. Such carbamoyl groups can be formed by the reaction of hydroxy groups by methods known in the art by Ellis, US 2002/0103378 A1 and Hajima, US 6018049.

Scheme 33 illustrates various ways in which carbamate bonds are synthesized. According to Scheme 33 , in the general reaction to produce carbamate, as described herein, alcohol S33 .1 is converted to the active derivative S33 .2 where Lv is a leaving group such as halogen, imidazolyl, benztriazolyl and the like. That by following the reaction of the activated derivative with an amine S33 S33 .2 .3 .4 S33 cava to obtain the formate product. Examples 1 to 7 of Scheme 33 describe how to produce a general reaction. In Examples 8 to 10 illustrate an alternative process for producing a carbamate.

Scheme 33 , Example 1 illustrates the preparation of carbamate using a chloroformyl derivative of alcohol S33 .5 . In this reaction procedure, alcohol S33 .5 was added to Org . Syn . Coll . Vol. 3 , 167, 1965 at about 0 ° C. with an inert solvent solution such as a toluene solution of phosgene, or Org . Syn . Coll . Vol. 6715, as described in 1988 by its equivalent reagent and reaction, such as trichloromethyl chloroformate to obtain a Romero ethoxy S33 .6 chloroformate. The compound of the latter is reacted with an amine component in the presence of an organic or inorganic base to obtain a cover S33 .3 .7 mate S33. For example, the chloroformyl compound S33.6 is substituted with Org . Syn . Coll . Vol. 3167, in the presence of aqueous sodium hydroxide solution as described in 1965, it is reacted in a water-miscible solvent such as tetrahydrofuran to give the amine S33 .3 cover mate S33 .7. As an alternative, the reaction is carried out in dichloromethane in the presence of an organic base such as diisopropylethylamine or dimethylaminopyridine.

In Scheme 33 , Example 2 , the chloroformate compound S33 . 6 illustrates the reaction of reacting imidazole with 6 to give imidazolide S33 .8 . The imidazole by reaction of sleepy de product with an amine to obtain a cover S33 .3 .7 mate S33. The preparation of imidazolide is carried out with an aprotic solvent such as dichloromethane at 0 ° C., and the preparation of carbamate is carried out by J. Med. Alternatively at room temperature, as described in Chem ., 1989, 32, 357, it is carried out in a similar solvent in the presence of a base such as dimethylaminopyridine.

Scheme 33 , Example 3 is mixed carbonate ester S33 . It illustrates a chloroformate and S33 .6 activated hydroxyl compound R "OH in the reaction to 10. The reaction is dicyclohexylamine or in the presence of a base such as triethylamine in an inert organic solvent such as dichloromethane is performed. the hydroxyl component R "OH is selected from the group of compounds S33 to S33 .19 .24 and similar compounds as shown in Scheme 33. Inde for example, if the component R "OH if two hydroxy benztriazole S33 .19, N- hydroxy succinimide or pentachlorophenol S33 S33 .20 .21, mixed carbonate S33. 10 is Can. J. As described in Chem ., 1982, 60, 976, obtained by reaction of chloroformate and hydroxyl compound in an ethereal solvent in the presence of dicyclohexylamine. Component R "OH is pentafluorophenol S33 .22 or 2-hydroxypyridine S33 . Similar reactions of 23 , Syn ., 1986, 303, and Chem . Ber . As described in 118, 468, 1985, it is carried out in an ethereal solvent in the presence of triethylamine.

Scheme 33 , Example 4 illustrates a method for preparing carbamate in which alkyloxycarbonylimidazole S33 .8 is used. In this reaction procedure, alcohol S33 .5 is reacted with the same molar number of carbonyl diimidazole S33 .11 to give intermediate S33 .8 . The reaction is carried out with an aprotic organic solvent such as dichloromethane or tetrahydrofuran. Acyloxyimidazole S33 .8 is reacted with the same moles of amine R'NH ₂ to give carbamate S33 .7 . The reaction is Tet . As described in Lett ., 42, 2001, 5227, it is carried out in an aprotic organic solvent such as dichloromethane to give carbamate S33 .7 .

Scheme 33, Example 5, the intermediate alkoxycarbonyl benztriazole and S33 .13 a cover illustrate the mate to the production method. In this reaction procedure, an alcohol ROH is reacted with benzamide S33 .12 triazol-carbonyl chloride in the same molar amount at room temperature to obtain the alkoxycarbonyl product S33.13. The reaction is carried out in an organic solvent such as benzene or toluene in the presence of a tertiary organic amine such as triethylamine, as described in Synthesis ., 1977, 704. The product is reacted with amine R'NH ₂ to give carbamate S33 .7 . The reaction is carried out in toluene or ethanol at about 80 ° C. at room temperature, as described in Synthesis ., 1977, 704.

Scheme 33 , Example 6 illustrates a process for preparing carbamate by reacting carbonate (R "O) ₂ CO, S33 .14 with alcohol S33 .5 to obtain intermediate alkyloxycarbonyl intermediate S33 .15 . by reacting a reagent with an amine R'NH ₂ to obtain a cover mate S33 .7 reaction sequence is derived from a reactant 33.15 S33 .19 hydroxy benztriazole has been described in Synthesis, 1993, 908;. reactants S33. 15 is a reaction sequence the N- hydroxy-succinimide derived from the mid-S33.20 Tet Lett, 1992, was described in 2781;... 15 S33 reactants the reaction is derived from 2-hydroxy-pyridine-S33 .23 the procedure Tet Lett, 1991, was described in 4251;..... 15 S33 reaction is a reaction sequence which is derived from 4-nitrophenol S33 .24 been described in Synthesis 1993, 103 molar equivalents of an alcohol ROH and the carbonate S33. the reaction between the 14 is at ambient temperature, It is carried out by the active organic solvent.

Scheme 33 , Example 7 illustrates a process for preparing carbamate from alkoxycarbonyl azide S33 .16 . In this reaction procedure, an alkyl chloroformate, for S33 .6 an azide, for example, by reaction with sodium azide to obtain the alkoxycarbonyl azide S33 .16. The latter compound is reacted with the same molar number of amines R'NH ₂ to give carbamate S33 .7 . The reaction is carried out with a polar aprotic solvent, such as dimethylsulfoxide, at room temperature, as described, for example, in Synthesis ., 1982, 404.

Scheme 33, Example 8 illustrates a method for producing carbamates of the reaction between an alcohol ROH and chloro-formyl derivative of the amine .17 S33. Synthetic Organic Chemistry , RB Wagner, HD Zook, Wiley, 1953, p. Described in 647, in the reaction sequence, in the presence of a base such as triethylamine to the reaction at room temperature, to obtain a formate S33 .7 cava was coupled within an aprotic solvent such as acetonitrile.

Scheme 33, Example 9 illustrates the preparation of a carbamate of the reaction between an alcohol ROH and an isocyanate S33 .18. Synthetic Organic Chemistry , RB Wagner, HD Zook, Wiley, 1953, p. In this reaction procedure described at 645, the reactants are combined at room temperature in an aprotic solvent such as ether or dichloromethane to give carbamate S33 .7 .

Scheme 33 , Example 10 illustrates a method for preparing carbamate by reaction between alcohol ROH and amine R'NH ₂ . Chem . Lett . In this reaction procedure described in 1972, 373, the reaction is bound at room temperature in the presence of a tertiary base such as triethylamine and selenium in an aprotic organic solvent such as tetrahydrofuran. Passing carbon monoxide into the solution and the reaction proceeds to give the .7 S33 carbamate.

Scheme 33 Preparation of Carbamate

Carboalkoxy Substituted Phosphonate Preparation of bis amidate, mono amidate, diesters and monoesters.

Many methods of converting phosphonic acids to amidates and esters are available. In one group of methods, phosphonic acid can be converted to isolated active intermediates such as phosphoryl chloride or activated on the fly to react with amines or hydroxy compounds.

The conversion of the phosphonic acid to phosphoryl chloride is described, for example, in J. Gen. Chem . USSR , 1983, 53, 480, Zh . Obschei Khim ., 1958, 28, 1063, or J. org . By reaction with thionyl chloride described in Chem ., 1994, 59, 6144, or in J. Am. Chem . Soc ., 1994, 116, 3251, or J. org . Reaction with oxalyl chloride as described in Chem ., 1994, 59, 6144, or J. org . Chem ., 2001, 66, 329, or J. Med . By reaction of phosphorus pentachloride as described in Chem ., 1995, 38, 1372. The resulting phosphoryl chloride is then reacted with an amine or hydroxy compound in the presence of a base to give an amidate or ester product.

Phosphonic acid is described by J. Chem . Soc , Chem . Comm . (1991) 312, or as described in Nucleosides & Nucleotides (2000) 19: 1885, and converted to active imidazolyl derivatives by reaction with carbonyl diimidazole. Active sulfonyloxy derivatives are described in Tet . Lett . (1996) 7857 or BioOrg . Med . Chem . Lett . (1998) As described at 8: 663, phosphonic acid is obtained by reaction with trichloromethylsulfonyl chloride or triisopropylbenzenesulfonyl chloride. The active sulfonyloxy derivatives are reacted with amines or hydroxy compounds to yield amidates or esters.

Alternatively, the phosphonic acid and the amine or hydroxy reactant are bound in the presence of the diimide coupling agent. Processes for the preparation of phosphite amidate and esters by coupling reactions in the presence of dicyclohexyl carbodiimide are described, for example, in J. Chem . Soc , Chem. Comm . (1991) 312 or Coll . Czech. Chem . Comm . (1987) 52: 2792. The use of said ethyl dimethylaminopropyl carbodiimide for the activation and coupling of phosphonic acids is described in Tet . Lett ., (2001) 42: 8841 or Nucleosides & Nucleotides (2000) 19: 1885.

Several additional coupling agents have been disclosed for the preparation of amidates and esters from phosphonic acids. The coupling agent is J. org . Chem ., 1995, 60, 5214, and J. Med. Chem . (1997) 40: 3842 alditiol-2, and PYBOP and BOP, as described in J. Med . Chem . (1996) 39: 4958 Mesitylene-2-sulfonyl-3-nitro-1,2,4-triazole (MSNT), J. org . Chem . (1984) Diphenylphosphoryl azide, Bioorg. Med . Chem . Lett . (1998) 1- (2,4,6-triisopropylbenzenesulfonyl-3-nitro-1,2,4-triazole (TPSNT) described in 8: 1013, Tet . Lett ., (1996) 37 Bromotris (dimethylamino) phosphonium fluorophosphate (BroP) described in: 3997, 2-chloro-5,5-dimethyl-2-oxo-1,3,2 described in Nucleosides Nucleotides 1995, 14, 871 Dioxaphosphinane and diphenyl chlorophosphate as described in J. Med . Chem ., 1988, 31, 1305, and the like.

Phosphonic acid is converted to amidates and esters by a Mitsunobu reaction in which phosphonic acid and amine or hydroxy reactant bind in the presence of triaryl phosphine and dialkyl azodicarboxylate. The reaction procedure is described in Org . Lett ., 2001, 3, 643, or J. Med . Chem ., 1997, 40, 3842.

Phosphoric acid esters are also obtained by reaction between phosphonic acid and halogenated compounds in the presence of a suitable base. The method is, for example, Anal. Chem ., 1987, 59, 1056, or J. Chem . Soc . Perkin Trans., I , 1993, 19, 2303, or J. Med . Chem., 1995, 38, 1372, or Tet . Lett ., 2002, 43, 1161.

Schemes 34-37 include phosphonbisamidates (Scheme 34 ), phosphonamidates (Scheme 35 ), phosphonate monoesters (Scheme 36 ) and phosphonates with phosphonate esters and phosphonic acids substituted with carboalkoxy. Conversion to diester (Scheme 37 ) is illustrated. Scheme 38 illustrates the synthesis of a gem-dialkyl amino phosphonate reactant.

Scheme 34 illustrates various ways in which phosphonate diester S34 .1 is converted to phosphonbisamidate S34 .5 . Diester S34 prepared by the above-described method . 1 is hydrolyzed to monoester S34 .2 or phosphonic acid S34 .6 . The above methods for such substitutions are those described above. Monoester S34 . 2 reacts with aminoester S34 .9 to monoamidate S34 . Converted to 3 Wherein the group R ² is H or alkyl and the group R ^4b is a divalent alkylene moiety, for example CHCH ₃ , CHCH ₂ CH ₃ , CH (CH (CH ₃ ) ₂ ), CH (CH ₂ Ph ), And the like, or side chain groups present in natural or modified amino acids; And the group R ^5b is C ₁ -C ₁₂ alkyl, such as methyl, ethyl, propyl, isopropyl or isobutyl; C ₆ -C ₂₀ aryl, such as phenyl or substituted phenyl; Or C ₆ -C ₂₀ arylalkyl, such as benzyl or benzhydryl. The reaction was performed by J. Am. Chem . Soc . (1957) amidate products by binding in the presence of a coupling agent such as carbodiimide, for example dicyclohexyl carbodiimide, described in 79: 3575, alternatively in the presence of an active agent such as hydroxybenztriazole, etc. S34 .3 was obtained. The reaction to form the amidate is also described in J. org . Chem . (1995) Reacts in the presence of a coupling agent such as BOP, aldithiol, PYBOP and the similar coupling agents used in the preparation of amides and esters described in 60: 5214. Alternatively, the reactants S34 .2 and S34 . 9 is monoamidate S34 by Mitsunobu reaction . Transformed to 3 The method for preparing amidate by Mitsunobu reaction is described in J. Med . Chem . (1995) 38: 2742. The same molar number of reactants are bound in an inert solvent such as tetrahydrofuran in the presence of triaryl phosphine and dialkyl azodicarboxylate. The obtained mono ester amidate S34 .3 the amidate phosphonic acid S34 again. Transform it to 4 The reaction conditions of the hydrolysis reaction depend on the characteristics of the R ¹ group as described above. The phosphonic acid amidate S34 .4 was reacted with the aminoester S34 .9 described above to give the bisamidate product S34 .5 . Their amino substituents are the same or different. Alternatively, phosphonic acid S34 .6 can be treated simultaneously with two different amino ester reactants. In other words, R ² , R ^4b, or R ^5b are different By S34 .9 . The mixed product of bisamidate product S34 .5 can be separated, for example, by chromatography.

Scheme 34

Examples of reaction procedures are shown in Scheme 34 , Example 1 . In this reaction sequence, dibenzyl phosphonate S34 .14 the J. org. Chem., 1995, 60, as described in 2946, by refluxing with octane (DABCO) in toluene solution to the reaction diazabicyclo, monobenzyl phosphonate to obtain the S34 .15. The product was reacted with a pyridine solution of equal molar number of ethyl alanate S34 .16 and dicyclohexyl carbodiimide to give the amidate product S34.17 . The benzyl group is removed, for example, by hydrogenolysis with a palladium catalyst, to yield J. Med. Chem. (1997) 40 (23): 3842 to give the unstable monoacid product S34.18 . This compound S34 .18 , J. Med . Chem., 1995, 38, as described in 2742, Mitsunobu reaction with ethyl ryusi S34 .19 carbonate, triphenylphosphine and diethyl azodicarbonyl reacted with a carboxylate to give the bis S34 .20 amidate product.

Instead of ethyl leucinate S34 .19 or ethyl alanate S34 .16 , the reaction procedure using another aminoester S34 .9 was used to obtain the corresponding product S34 .5 .

Alternatively, phosphonic acid S34 .6 is converted to bisamidate S34.5 by the coupling reaction described above. The reaction is carried out in one stage where the nitrogen-based substituents in the product S34 .5 are the same or in two stages where the nitrogen-based substituents are different.

Examples of the methods are shown in Scheme 34, Example 2. In this reaction sequence, S34 .6 acid, for example, J. Chem. Soc , Chem . Comm., 1991, the excess ethyl phenylalaninate on the pyridine solution as described in the 1063 Raney S34 .21 carbonate and dicyclohexyl carbodiimide to react in Dorsett, bis amidate product was obtained .22 S34.

Instead of ethyl phenylalanineate, using the above reaction procedure using another aminoester S34 .9 , the corresponding product S34 .5 was obtained.

By further alternative, phosphonic acid S34 .6 is converted to mono or bis-active derivative S34.7 . Here, Lv is a leaving group such as chloro, imidazolyl, triisopropylbenzenesulfonyloxy and the like. Conversion of the acid chloride S34 .7 (Lv = Cl) is, Organic Phosphorus Compounds, GM Kosolapoff, L. Maeir, eds, Wiley, 1976, p. As described in 17, by reaction with thionyl chloride or oxalyl chloride and the like. The conversion of monoimidazolide S34 .7 (Lv = imidazolyl) of the phosphonic acid is described in J. Med . Chem ., 2002, 45, 1284 and J. Chem . Soc . Chem . Comm ., 1991, 312. Alternatively, phosphonic acid is reacted with triisopropylbenzenesulfonyl chloride as described in Nucleosides and Nucleotides , 2000, 10, 1885. The active product was reacted with aminoester S34 .9 in the presence of a base to give bisamidate S34.5 . The reaction can be carried out in one step, in which the nitrogen substituents of the product S34 .5 are identical, or in which the nitrogen substituents are different, passing through the intermediate S34 .11 .

Examples of such methods are shown in Scheme 34, Examples 3 and 5. In the reaction procedure illustrated in Scheme 34, Example 3, phosphonic acid S34 .6 was converted to Zh . Obschei Reaction with 10 molar equivalents of thionyl chloride as described in Khim ., 1958, 28, 1063 afforded the dichloro compound S34.23 . The product is reacted with butyl serinate S34 .24 at reflux in the presence of an aprotic solvent such as polar acetonitrile and a base such as triethylamine to give the bisamidate product S34 .25 .

Butyl serinate S34 . Instead of 24 , using the above reaction procedure using another aminoester S34 .9 , the corresponding product S34 .5 was obtained.

Using the reaction procedure illustrated in Scheme 34, Example 5, phosphonic acid S34 .6 was prepared by J. Chem . Soc . Chem . Comm., 1991, as described in 312, carbonyl di-imidazole to the reaction to give the imidazole Id Jolla S34 .32. The product was subjected to 1 molar equivalent of ethyl alanate S34 in acetonitrile at room temperature . Reaction with 33 gives monosubstituted product S34 .34 . The latter compound was reacted with carbonyl diimidazole to obtain active intermediate S34 .35 , and the product was reacted with ethyl N- methylalanineate S34 .33a under the same reaction conditions to give the bisamidate product S34 .36 . Got it.

Ethyl carbonate instead of the Raney Al S34 .33 or ethyl N- methylal Raney carbonate .33a S34, using the general procedure with different amino ester .9 S34, to obtain the corresponding products S34.5 to.

The intermediate monoamidate S34 .3 is also prepared by monoester S34 .2 by first converting the monoester to the active derivative S34 .8 having an Lv leaving group such as halo, imidazolyl, etc. using the reaction procedure described above . It became. The product S34 .8 was reacted with aminoester S34 .9 in the presence of a base such as pyridine to give the intermediate monoamidate product S34 .3 . The latter compound was converted to bisamidate S34 .5 by removal of the R ¹ group and coupling of the product with aminoester S34 .9 as described above.

The phosphonic acid is converted to the chloro derivative S34 .26 shows an example of the general procedure that is activated in Scheme 34, Example 4. In this reaction procedure, Tet . Letters., 1994, 35, as described in 4097, phosphorous acid monobenzyl ester S34 .15 reacted with thionyl chloride in dichloromethane solution to give the phosphonium chloride poril S34 .26. The product was dissolved in acetonitrile solution at room temperature in 1 molar equivalent of ethyl 3-amino-2-methylpropionate S34 . 27 and the reaction to obtain a mono amidate product S34 .28. By the hydrogenation of a compound of the latter with 5% palladium on carbon catalyst in ethyl acetate solution turned out to S34 .29 mono acid product. The product was subjected to the same molar number of butylalanininate S34.30 , triphenyl phosphine, in tetrahydrofuran by the Mitsunobu coupling reaction procedure. Treatment with diethylazodicarboxylate and triethylamine afforded bisamidate product S34 .31 .

Ethyl 3-amino-2-methylpropionate S34 .27 or Butylalanine S34 . Instead of 30 , using the above reaction procedure using another aminoester S34 .9 , the corresponding product S34 .5 was obtained.

Said active phosphonic acid derivatives S34 . 7 is also converted to bisamidate S34 .5 via diamino compound S34 .10 . Methods of reacting active phosphonic acid derivatives such as phosphoryl chloride with ammonia to the corresponding amino analog S34 .10 have been described in Organic Phosphorus Compounds , GM Kosolapoff, L. Maeir, eds, Wiley, 1976. In the presence of a base such as 4, 4-dimethylaminopyridine (DMAP) or potassium carbonate while heating the bisamino compound S34 .10 , halogenated ester S34 .12 (Hal = halogen, In other words, it was reacted with F, Cl, Br, I) to obtain bisamidate S34 .5 . Alternatively, S34 .6 can be treated simultaneously with two different amino ester reactants. In other words, R ^4b or R ^5b of S34 .12 is different from each other. The resultant mixture of the bisamidate product S34 .5 can be separated, for example, by chromatography.

Examples of such reaction procedures are shown in Scheme 34, Example 6. In this method, by reacting with ammonia to S34 .23 dichloromethane phosphonate dia obtain a mid-S34 .37. The reaction is carried out in aqueous, aqueous alcoholic solution or alcohol at reflux temperature. The diamino compound is prepared in a polar organic solvent such as N-methylpyrrolidinone, in the presence of a base such as potassium carbonate, or alternatively in the presence of potassium iodide, 2 molar equivalents of ethyl 2-bromo-3 -Methylbutyrate S34 . And allowed to react at 38 to about 150 ℃, gets S34 .39 bis amidate product.

Instead of ethyl 2-bromo-3-methylbutyrate S34 .38 , using the reaction procedure above with another halogenated ester S34.12 , the corresponding product S34 .5 was obtained.

The reaction procedure shown in Scheme 34 is also applicable to a method for preparing bisamidate in which the aminoester moiety includes other functional groups. Scheme 34, Example 7 illustrates the preparation of bisamidate derived from tyrosine. In this reaction sequence, as described in Example 5, when the mono-imidazole Jolla Id S34 .32 to profile tie carbonate S34. By reacting with 40, to give the mono amidate S34 .41. The product was reacted with carbonyl diimidazole to afford imidazolide S34 .42 . This material was then reacted with an additional 1 molar equivalent of propyl tyrosinate to afford the bisamidate product S34.43 .

Instead of propyl tyrosinate S34 .40 , using the above reaction procedure using another aminoester S34 .9 , the corresponding product S34 .5 was obtained. The aminoesters used in the two steps of the reaction procedure can be the same or different, and thus bisamidates with the same or different amino substituents can be prepared.

Scheme 35 illustrates a method for preparing phosphonate monoamidate.

Within one reaction procedure, phosphonate monoester S34 .1 is converted to active derivative S34 .8 , as described in Scheme 34. As it described above this compound, in the presence of a base, and reacting the amino ester S34 .9 to obtain a mono amidate product S35 .1.

The reaction procedure is illustrated in Scheme 35, Example 1. By this method, monophenyl phosphonate S35 .7 was prepared by J. Gen. Chem . USSR., 1983, 32, for example, such as described in 367, was reacted with thionyl chloride to give the chloride product .8 S35. The product was reacted with ethyl alaninate, as described in Scheme 34, to provide amidate S35 . 10 was obtained.

Instead of ethyl alanate S35 .9 , the reaction procedure using another aminoester S34 .9 was used to give the corresponding product S35 .1 .

Alternatively, phosphonate monoester S34 .1 was coupled with aminoester S34 .9 to produce amidate S35 .1 as described in Scheme 34. If necessary, the R ¹ substituent is changed by initial decomposition to obtain phosphonic acid S35 .2 . The reaction procedure for this substitution depends on the properties of the R ¹ group and the like. The phosphonic acid and the amine coupling reaction the same procedures described in Scheme 34 for the coupling of the acid (carbodiimide, Al -2 give thiol, PYBOP, Mitsunobu reaction etc) by using the R ³ group is an aryl, heteroaryl, Ester amidate product S35 by reacting with hydroxy compound R ³ OH which is cycle, alkyl, cycloalkyl, alkyl halide and the like . Transformed to 3

Scheme 34-1 Examples 1-7

Examples of such methods are shown in Scheme 35, Examples 1-3. In the reaction sequence shown in Example 2, monobenzyl phosphonate S35 . 11 is reacted with Raney Al ethyl carbonate by the above-mentioned method is modified to mono amidate S35 .12. By the hydrogenation of the benzyl group is 5% palladium on carbon in ethyl acetate solution to obtain a catalyst phosphonic acid amidate S35 .13. The product is, for example, Tet . Amidate esters by reacting with the same moles of 1- (dimethylaminopropyl) -3-ethylcarbodiimide and trifluoroethanol S35 .14 at room temperature as described in Lett ., 2001, 42, 8841 S35 .15 was obtained.

In the reaction sequence shown in Scheme 35, Example 3, the monoamidate S35 .13 is the same molar number of dicyclohexyl carbodiimide and 4-hydroxy-N-methylpiperidine S35 . In tetrahydrofuran at room temperature . Coupling With 16 resulted in the amidate ester product S35.17 .

Instead of ethyl alanate product S35 .12 , other monoacids S35 .2 , and instead trifluoroethanol S35 .14 or 4-hydroxy-N-methylpiperidine S35 .16 , other hydroxy compounds R ³ Using the above reaction procedure with OH, the corresponding product S35 .3 was obtained.

Alternatively, the active phosphonate ester S34 .8 was reacted with amidate S35 .4 to obtain ammonia. The product was reacted with halogenated ester S35 .5 in the presence of a base, as described in Scheme 34, to yield the amidate product S35 .6 . If necessary, the properties of the R ¹ groups were changed using the reaction procedure described above to give the product S35 .3 . The method is illustrated in Scheme 35, Example 4 . In this reaction sequence, the monophenyl phosphoryl chloride S35 .18 was reacted with ammonia, as described in Scheme 34, to yield the amino product S35 .19 . This material in N- methylpyrrolidinone solution of butyl 2-bromo-3-phenyl propionate S35 .20 and potassium carbonate were reacted at 170 ℃ and gets amidate product S35 .21.

Instead of butyl2 -bromo-3-phenylpropionate S35 .20 , this reaction procedure using another halogenated ester S35.5 was used to obtain the corresponding product S35 .6 .

The mono S35 .3 amidate product was also prepared from a dual-active phosphonate derivatives S34.7. In this reaction sequence, Synlett, 1998, 1, as described in the example 73, was reacted with the intermediate amount of the amino ester S34 S34 .7 .9 limited mono-substituted product to give the S34 .11. The latter compound was reacted with a hydroxy compound R ³ OH in a polar organic solvent such as dimethylformamide in the presence of a base such as diisopropylethylamine to obtain monoamidate ester S35 .3 .

The method is illustrated in Scheme 35, Example 5. In this method, the phosphoryl dichloride S35 .22 was reacted with 1 molar equivalent of ethyl N-methyl tyrosinate S35 .23 and dimethylaminopyridine in dichloromethane solution to give monoamidate S35 .24 . Was reacted with the product-dimethylformamide solution of phenol .25 S35 containing potassium carbonate to give the ester amidate product S35 .26.

Instead of ethyl N-methyl tyrosinate S35 .23 or phenol S35 .25 , this reaction procedure using aminoester S34 .9 and / or hydroxy compound R ³ OH was used to obtain the corresponding product S35 .3 . .

Scheme 35

Scheme 35-1 Examples 1-5

Scheme 36 illustrates a process for the preparation of phosphonate diesters in which one of the ester groups is substituted with carboalkoxy contained in a carboalkoxy substituent. In one reaction procedure, a phosphonate monoester S34 .1 prepared as described above is prepared by the method described above in which the groups R ^4b and R ^5b are hydroxyester S36 . Coupling with 1 For example, an equivalent molar amount of reactant is Aust . Dimethylaminopyridine, as described in Tet ., 1999, 55, 12997, alternatively in the presence of carbodiimides, such as dicyclohexyl carbodiimide, as described in J. Chem ., 1963, 609. Coupling in the presence of The reaction is carried out in an inert solvent at room temperature.

The reaction procedure is illustrated in Scheme 36, Example 1. In this way, Monophenyl phosphonate S36 . 9 is ethyl 3-hydroxy-2-methylpropionate S36 . In dichloromethane solution in the presence of dicyclohexyl carbodiimide . Coupled with 10 to give diester S36 .11 mixed with phosphonate.

Instead of ethyl 3-hydroxy-2-methylpropionate S36 .10 , the reaction procedure using another hydroxyester S33 .1 was used to obtain the corresponding product S33 .2 .

The conversion of the phosphonate monoester S34 .1 to the mixed diester S36 .2 is also described in Org . As described in Lett ., 2001, 643, it is carried out with hydroxyester S36 .1 by a Mitsunobu coupling reaction. In this method, the reactants S34 .1 and in the presence of a triaryl phosphine and a dialkyl azodicarboxylate S36.1, tetrahydro combined in a polar solvent such as THF to yield the mixed diester S36 .2. By the method described above, wherein the R ¹ substituent is decomposed to obtain a deformation by being .3 S36 mono acid product. By the above method, the product was coupled with the hydroxy compound R ³ OH to give diester product S36 .4 .

The reaction procedure is illustrated in Scheme 36, Example 2. In this method, a monoallyl phosphonate in the presence of a carbonate S36 .12 triphenylphosphine and diethyl azodicarboxylate, S36 .13 lock ethyl lactate in tetrahydrofuran and the coupling to the mixed diester S36 .14 Got it. To remove the allyl product (triphenylphosphine) acetonitrile to the solution and the reaction to obtain a nitrile S36 .15 mono acid product of rhodium chloride (Wilkinson's catalyst). The latter compound was coupled with 1 molar equivalent of 3-hydroxypyridine S36 .16 on pyridine solution in the presence of dicyclohexyl carbodiimide at room temperature to give mixed diester S36 .17 .

Instead of ethyl lactate S36 .13 or 3-hydroxypyridine, using the above reaction procedure using other hydroxyester S36 .1 and / or other hydroxy compound R ³ OH, the corresponding product S36 .4 was obtained.

From the above mixed diester S36 .2 and monoester S34 .1 Obtained through the mediation of active monoester S36 .5 . In this reaction procedure, the monoester S34.1 is converted to the active compound S36 .5 . This is described, for example, in J. org . Reaction with phosphorus pentachloride, as described in Chem ., 2001, 66, 329, or thionyl chloride or oxalyl chloride (Lv = Cl), or as described in Nucleosides and Nucleotides , 2000, 19, 1885, or By reaction with a pyridine solution of triisopropylbenzenesulfonyl chloride, or by J. Med . As described in Chem ., 2002, 45, 1284, it occurs in reaction with carbonyl diimidazole. As mentioned above, the active monoester resultant was converted to hydroxyester S36 . It is reacted with 1 to obtain the mixed diester S36 .2.

The reaction procedure is illustrated in Scheme 36, Example 3. In this reaction sequence, the monophenyl phosphonate S36 .9 is reacted with 10 equivalents of thionyl chloride on a acetonitrile solution of 70 ℃ turned out to S36 .19 phosphoryl chloride. The product was reacted with a dichloromethane solution of ethyl 4-carbamoyl-2-hydroxybutyrate S36 .20 containing triethylamine to give mixed diester S36 .21 .

Instead of ethyl 4-carbamoyl-2-hydroxybutyrate S36 .20 , using the above reaction procedure using another hydroxyester S36 .1 , the corresponding product S36 .2 was obtained.

The mixed phosphonate diesters or R ³ O groups can be obtained by alternative reaction routes for inclusion in intermediate S36 .3 already containing a hydroxyester moiety. In this reaction procedure, the monoacid intermediate Lv S36 .3 is a chloro, is already converted to a leaving group S36 .6 active derivatives such as imidazole, as described above. The active intermediate was reacted with the hydroxy compound R ³ OH in the presence of a base to give the mixed diester product S36 .4 .

The method is illustrated in Scheme 36, Example 4. In this reaction sequence, J. Med . As described in Chem ., 1995, 38, 4648, phosphonate monoacid S36 .22 is reacted with a tetrahydrofuran solution of trichloromethanesulfonyl chloride containing collidine to give the trichloromethanesulfonyloxy product S36 Produced .23 This compound was reacted with a dichloromethane solution of 3- (morpholinomethyl) phenol S36 .24 containing triethylamine to give a mixed diester product S36 .25 .

Instead of 3- (morpholinomethyl) phenol S36 .24 , using the above reaction procedure using another alcohol R ³ OH, the corresponding product S36 .4 was obtained.

Phosphonate ester S36 .4 is also obtained by alkylation reaction with monoester S34 .1 . Between acid S34 .1 and halogenated ester S36 .7 The reaction was Anal. Diisopropylethylamine, described in Chem ., 1987, 59, 1056, J. Med . In the presence of a base such as triethylamine as described in Chem ., 1995, 38, 1372, a polar solvent or Syn. In the presence of 18-crown-6 described in Comm ., 1995, 25, 3565, in a polar solvent such as benzene.

The method is illustrated in Scheme 36, Example 5. In this reaction procedure, the monoacid S36 .26 to 80 ℃ ethyl 2-bromo-3-phenyl propionate S36 .27 and diisopropylethylamine in dimethylformamide solution to yield a mixed diester product at S36. Get 28

Instead of ethyl 2-bromo-3-phenylpropionate S36 .27 , using the above reaction procedure using another halogenated ester S36.7 , the corresponding product S36 .4 was obtained.

Scheme 36

Scheme 36-1 Examples 1-5

Scheme 37 illustrates a process for preparing phosphonate diesters in which two ester substituents are bonded to a carboalkoxy group.

The compound was prepared directly or indirectly from phosphonic acid S34 .6 . Alternatively, the phosphonic acid is coupled with hydroxyester S37 .2 using the reaction conditions of Scheme 34-36, such as a coupling reaction using the aforementioned dicyclohexyl carbodiimide or similar reactants, or under Mitsunobu reaction conditions . Ring to give diester product S37 .3 . Here, the ester substituents are the same as each other.

This method is illustrated in Scheme 37, Example 1. In this reaction procedure, the phosphonic acid S34 .6 is reacted with 3 equivalents of butyl lactate S37 .5 at about 70 ° C. in the presence of a pyridine solution of aldritol-2 and triphenyl phosphine . Diester S37 .6 is obtained.

Using the above reaction procedure using another hydroxyester S37 .2 instead of butyl lactate S37 .5 , the product S37 .3 was obtained.

Alternatively, the diester S37 .3 is obtained by alkylation of phosphonic acid S34.6 with a halogenated ester S37 1. The alkylation reaction is carried out according to Scheme 36 for the preparation of ester S36 .4 .

This method is illustrated in Scheme 37, Example 2. In this reaction procedure, the phosphonic acid S34 .6 was analyzed by Anal. Excess at about 80 ° C. as described in Chem ., 1987, 59, 1056 Reaction with dimethylformamide of ethyl 3-bromo-2-methylpropionate S37 .7 and diisopropylethylamine gives diester S37 .8 .

Instead of ethyl 3-bromo-2-methylpropionate S37 .7 , the above reaction procedure using another halogenated ester S37.1 was used to obtain the corresponding product S37 .3 .

The diester S37 .3 is obtained by a substitution reaction of the active derivative of acid to S37 S34 .7 .2-hydroxy ester. The substitution reaction is carried out in a polar solvent in the presence of a suitable base as described in Scheme 36. In the presence of excess hydroxyester by the substitution reaction, the ester substituents yield the same diester product S37 .3 or, alternatively, the diester S37 . Get 3

The method is illustrated in Scheme 37, Examples 3 and 4. As seen in Example 3, the phosphoryl dichloride S35 .22 in a tetrahydrofuran solution containing potassium carbonate, 3 equivalent moles of ethyl 3-hydroxy-2- (hydroxymethyl) propionate S37 Reaction with .9 gave the diester product S37 .10

Instead of ethyl 3-hydroxy-2- (hydroxymethyl) propionate S37 .9 , using the above reaction procedure using another hydroxyester S37 .2 , the corresponding product S37.3 was obtained.

Scheme 37, Example 4. In the phosphoryl dichloride S35 .22 same number of moles of ethyl 2-methyl-3-hydroxy-propionate by the substitution reaction between .11 S37 to obtain a monoester product S37 .12. The reaction was carried out with acetonitrile solution at 70 ° C. in the presence of diisopropylethylamine. The product S37 .12 was reacted with 1 equivalent mole of ethyl lactate S37 .13 under the same reaction conditions to obtain a diester product S37 .14 .

Instead of ethyl 2-methyl-3-hydroxypropionate S37 .11 and ethyl lactate S37 .13 , the corresponding product S37 .3 was prepared using the above reaction procedure which was sequentially reacted with other hydroxyester S37 .2. Got it.

Scheme 37

Scheme 37-1 Examples 1-5

2,2-dimethyl-2-aminoethylphosphonic acid intermediate may be prepared by the route of Scheme 5. 2-methyl-2-propane-sulfinamide and acetone to condensation sulfinyl imine S38 to .11 (J. org. Chem. 1999, 64, 12) by the addition of the S38 .11 in dimethyl methyl phosphonate lithium S38 .12 was obtained. S38 .12 by the acidic decomposition of methane to give the amine .13 S38. The amine was protected with a Cbz group and the methyl group was removed to give phosphonic acid.

S38 .14 can be converted to the target S38 .15 (Scheme 38a) by known methods. An alternative method of synthesizing Compound S38 .14 is also shown in Scheme 38b. Commercially available 2-amino-2-methyl-1-propanol was converted to aziridine S38 .16 by literature methods ( J. org . Chem . 1992 , 57 , 5813; Syn . Lett . 1997 , 8 , 893). . The aziridine is ring-opened by phosphite to yield S38 .17 ( Tetrahedron Lett . 1980 , 21 , 1623). Reprotect S38 .17 to obtain S38 .14 .

Scheme 38a

Scheme 38b

Example 1 Preparation of Exemplary Compounds of the Invention

Schemes 1.1-1.3 It illustrates the synthesis of target molecules of types 1-12 and 1-56 whose chemical bonds are heteroatoms and carbon chains. The preparation of 1-1 is described in US Pat. No. 5,770,596. Dieter 1-1 Protective Groups in Organic Synyhesis by TW Greene and PGM Wuts (Wiley, Third Edition (1999) p. By the United States or as a method described in the Patent No. 5,770,596 described in 246) is converted to the mono-ether 1-2. Preferably, the diether 1-1 in methanesulfonic acid is refluxed Treatment with L-methionine yields phenol 1-2 . And then protect phenol 1-2 Prepare with Acetyl Compound 1-3 and convert to Chloride 1-4 . These methods are described in US Pat. No. 5,770,596. The acetoxy compound is then treated with aniline 1-5 to afford amine 1.6 , followed by deprotection of the acetyl group to give 1-7 as described in US Pat. No. 5,770,596. 1-7 in DMF in the presence of potassium carbonate Treatment with epibromohydrin 1-8 (Aldrich) yields epoxide 1-9 . Epoxide 1-9 was treated with reflux in morpholine in an aprotic solvent in the presence of a base such as triethylamine. Obtain alcohol 1-10 . The alcohol 1-10 is treated with 1 equivalent of a phosphonate alkylating agent in which Lv is a group such as mesyl, trifluoromethanesulfonyl, Br, I, Cl, tosyl, etc. in DMF in the presence of a base such as potassium carbonate or cesium carbonate. Ether 1-12 is obtained in which the chemical bonds are oxygen and carbon chains. Alternatively, the alcohol is oxidized to the ketone 1-13 1-10 are as described in book by RC Larock [Comprehensive Organic Transformations, 2 nd Edition, (1999), p.1234ff]. It is preferable that the alcohol 1-10 is treated with Dess-martin periodinone to obtain ketone 1-13 . Ketones 1-13 were then subjected to reductive amination conditions. Treatment with amino alkyl phosphonate 1-14 yields phosphonate 1-56 whose chemical bonds are nitrogen and carbon chains. Of RC Larock, for example for the manufacture of amines of the reducing amino speech book ^{[Comprehensive Organic Transformations, 2 nd edition} , p. 835. In this method, the amine component and the aldehyde component are reacted together in the presence of a reducing agent such as borane, sodium cyanoborohydride or diisobutylaluminum hydride to obtain an amine product.

Scheme 1.2

Scheme 1.3

For example, in DMF Alcohols 1-10 are described in Tetrahedron Lett . 1986, 27, 1497 is treated with triflate 1-15 , prepared as described to give ether 1-16 . Optionally, for example, the ketones 1-13 are treated with amines 1-17 (Acros) in methanol and after a period of time sodium borohydride is added to give amines 1-18 . Instead of triflate 1-15 or amines 1-17 Except for the use of phosphonates 1-11 and 1-14 , respectively , the corresponding products 1-12 and 1-56 are obtained using the method described above.

Scheme 1.4

Scheme 1.5

The reactions shown in Scheme 1.4-1.5 were It illustrates the preparation of compound 1-22 linked via a carbon chain and a heteroatom. Using conditions described in scheme about 1.1 to 1.3 for producing a 1-9 from 1-7 processes the phenol 1-7 (Scheme 1.1 to 1.3) as a dibromide 1-19 to obtain the bromide 1-20 . next Bromide 1-20 dialkyl hydroxy, thio or amino-1-22 to obtain the product by treatment with a substituted alkylphosphonate 1-21. The reaction is carried out in the presence of a base in a polar aprotic solvent such as dioxane or N -methylpyrrolidinone. The base used in the reaction is determined according to the properties of reactants 1-21 . For example, when X is O, lithium hexamethyldisilylazide or potassium tert. Strong bases such as butoxide are used, and when X is S, NH or N-alkyl, an inorganic base such as cesium carbonate is used.

For example, 1-7 as described in Scheme 1.1-1.3 Treatment with dibromoethane 1 -23 gives bromide 1-24 . Bromide 1-24 was then prepared in DMF and potassium carbonate [ J. Org. Chem . Treatment with amines 1-25 , prepared as described in 2000 , 65, 676, at about 80 ° C. yields phosphonate 1-26 . Then, optionally, bromide 1-24 can be prepared by Aust. And dialkyl 2-mercaptoethylphosphonate 1-27 as described in J. Chem ., 1990 , 43 , 1123 to reflux by heating in the presence of sodium carbonate to afford the thioether product 1-28 . Dibromoethane instead of 1-23 and the other, except that the dibromo compound 1-19 for use and / or 1-25 or 1-27 in place of other alkylphosphonate 1-21, the use of the method To obtain the corresponding product 1-22 .

Scheme 1.6

Scheme 1.7

Scheme 1.6 illustrates the synthesis of a target molecule where A is Br, Cl, [OH], [NH] or linker-P (O) (OR ¹ ) ₂ . The preparation method of 1-4 is described in Scheme 1.1. The preparation of 1-29, wherein A is linker-P (O) (OR ¹ ) ₂ , is described in Scheme 1.8-1.12 . Treatment of amines 1-30 according to the conditions described in US Pat. No. 5,770,599 affords the final product 1-31. The reaction shown in Scheme 1.6 is Illustrates the preparation of compound 1-31 wherein substituent A is one of the linking group-P (O) (OR ¹ ) ₂ or precursors such as [OH], [SH], [NH], Br and the like. Scheme 1.7 shows compound 1-31 wherein A is [OH], [SH], [NH], Br, or the like. Conversion to phosphonate ester 1-32 is shown. In this method, Compound 1-31 was prepared using the methods described in Schemes 1.1-1.6 . Compound 1-32 .

Scheme 1.8-1. 12 is It describes the preparation of phosphonate-containing derivatives 1-29 used in the preparation of phosphonate ester intermediate 1-32 .

Scheme 1.8

Scheme 1.8-1.10 illustrates the preparation of 1-29 linked through phosphonate heteroatoms such as O, S or N and carbon linkages. In this method, the protected aniline, if necessary, in the presence of a suitable base Lv reacts with alkylphosphonates 1-34 , which are leaving groups such as triflate, Br, Cl, mesyl and the like. The base required for this modification depends on the nature of the heteroatom X. For example, when X is N or S, it is suitable to use an excess of an inorganic base such as potassium carbonate in the presence of an organic solvent such as dimethylformamide. The reaction proceeds from ambient temperature to about 80 ° C. to obtain substitution product 1-35 . When X is O, in the presence of a solvent such as tetrahydrofuran, the same molar amount of a strong base such as lithium hexamethyldisilylazide or the like is used. Protective Groups in Organic Synthesis , by TW Greene and PGM Wuts, Wiley, Third Edition (1999), chapter 7 to deprotect amine groups to afford amines 1-36 .

Scheme 1.9

For example, diamine 1-37 (Aldrich) protected as CBZ carbamate ( Protective Groups in Organic Synthesis , by TW Greene and PGM Wuts, Wiley, Third Edition (1999), page 531ff, discloses a process for the preparation of dimethylformamide containing excess potassium carbonate [ Tetrahedron Lett . 1986 , 27 , 1497 in the same molar amount of triflate 1-38 Treatment at about 60 ° C. yields phosphonate product 1-39 . Amines 1-40 are obtained by deprotection by reduction through palladium on carbon in the presence of hydrogen.

Scheme 1.10

Optionally, one equivalent of aminophenol 1-41 protected as CBZ carbamate as described above Reaction with triflate 1-38 gives phosphonate 1-42 . Amine 1-43 is then obtained by catalytic reduction through palladium on carbon as described above to remove CBZ groups.

Except for using other aniline 1-33 instead of aniline 1-37 or phenol 1-41 and / or other alkylphosphonate 1-34 instead of 1-38 , the corresponding products 1- Get 36

Scheme 1.11

Scheme 1.11-1.12 illustrates the process for preparing 1-29 wherein phosphonate is bonded via an unsaturated or saturated carbon linker. In this method, the protected halo substitutions as necessary Aniline 1-44 is combined with dialkyl alkenyl phosphonate 1-45 by a palladium catalyzed Heck reaction to give binding product 1-46 . For the reaction of halogenated aryl and olefins by the Heck reaction, see, for example, Advanced Organic Chemistry , by FA Carey and RJ Sundberg, Plenum, (2001), p. 503ff and Acc . Chem . Res ., 1979 , 12 , 146.

In the presence of a palladium (0) catalyst such as tetrakis (triphenylphosphine) palladium (0) or a palladium (II) catalyst such as palladium (II) acetate and, if necessary, the presence of a base such as triethylamine or potassium carbonate Aryl bromide and olefin are combined under polar solvent such as dimethylformamide or dioxane to give the binding product 1-46 . For protection of aniline, see Protective Groups in Organic Synthesis , by TW Greene and PGM Wuts, Wiley, Third Edition. (1999), chapter 7]. Preferably the aniline is treated with a Boc reagent such as Boc chloride or Boc anhydride in the presence of DMAP and a base such as triethylamine to obtain a protected aniline. If necessary, the products 1-46 are reduced to obtain saturated phosphonate 1-47 . Reduction methods of carbon-carbon double bonds are described, for example, in Comprehensive Organic Transformations , by RC Larock, VCH, (1989), page 6. The method includes catalytic reduction and chemical reduction, the latter using for example diborane or diimide.

Scheme 1.12

For example, Boc protected 3-chloro-4-fluoro aniline 1-50 (Aldrich) is described in J. Med . Chem ., 1992 , 35 , 1371, describes the preparation thereof in the presence of bis (triphenylphosphine) palladium (II) chloride as described in J. Med . Reaction 1-52 is obtained by reacting with dialkyl propenyl phosphonate 1-51 as described in Chem ., 1996 , 39 , 949. Boc protection of the aniline is carried out by treating the corresponding aniline with Boc anhydride in the presence of DMAP. Products 1-52 are described in J. Org . Chem . 1965 , 30 , 3965 to react with diimide to give saturated products 1-53 . Treatment of 1-52 and 1-53 with TFA in THF or dioxane to remove Boc affords products 1-54 and 1-55 , respectively. Other instead of haloaniline compound 1-50 Except for using aniline 1-44 and / or other phosphonates 1-45 , the above methods are used to obtain the corresponding products 1-48 and 1-49 .

The methods described for the introduction of the phosphonate moiety (Scheme 1.1-1.12 ) are applicable to different chemicals using appropriate modifications known to those skilled in the art. Thus, the methods described for the introduction of phosphonates in 1-12, 1-56 and 1-22 are applicable to the introduction of phosphonates in aniline 1-29 and vice versa. .

Example  2: Preparation of Exemplary Compounds of the Invention

Scheme 2.1

Scheme 2.2

Scheme 2.1 shows that A is Br, I, [SH], [NH], etc. or linker-P (O) (OR ¹ ) ₂ . It illustrates the preparation of compounds 2-4 . Amine 2-1 is prepared as described in US Pat. No. 5,521,84. Amine 2- 1 is combined with acid 2-2 to afford amide 2-3 . The preparation of amides from carboxylic acids and derivatives is described, for example, in Organic Functional Group Preparations , by SR Sandler and W. Karo, Academic Press, 1968, page 274. The carboxylic acid is, for example, in the presence of an activating agent such as dicyclohexylcarbodiimide or diisopropylcarbo, for example in the presence of hydroxybenztriazole, for example, an aprotic solvent such as pyridine, DMF or dichloromethane. In the reaction with the amine to obtain an amide.

Alternatively, the amide can be obtained by first converting the carboxylic acid to an activated derivative such as an acid chloride or anhydride and then reacting with an amine in the presence of an organic base such as, for example, pyridine.

The conversion of the carboxylic acid to the corresponding acid chloride is accomplished by treating the carboxylic acid with a reagent such as thionyl chloride or oxalyl chloride in an inert organic solvent such as dichloromethane. Preferably, acid 2-2 is treated with oxalyl chloride in an inert solvent such as dichloromethane followed by the addition of a few drops of DMF followed by amine 2-1 to give amide 2-3 . The acid 2-2 can be prepared according to scheme 2.7 to 2.8 as shown in the following.

The reaction shown in Scheme 2.1 illustrates the preparation of compound 2-3 wherein substituent A is one of the linking groups-P (O) (OR ¹ ) ₂ or precursors such as [OH], [SH], [NH], Br, and the like. . Scheme 2.2 is a compound of Compounds 2- 3 wherein A is [OH], [SH], [NH], Br It shows conversion to phosphonate ester 2-4 . In this method, compound 2-3 is then Convert to compound 2-4 using the method described in Schemes 2.7-2.12 .

Scheme 2.3

Scheme 2.4

Scheme 2.3 is Illustrates the preparation of compounds 2-6 wherein A is Br, I, [SH], [NH], or the like or linking group-P (O) (OR ¹ ) ₂ . Amine 2-1 is treated with acid 2-5 , as described in Scheme 2.1 above, to obtain amide 2-6 . The preparation of acid 2-5 is described in Scheme 2.9-2.10 .

The reaction shown in Scheme 2.3 illustrates the preparation of compound 2-6 wherein substituent A is one of linker-P (O) (OR ¹ ) ₂ or precursors such as [OH], [SH], [NH], Br, and the like. . Scheme 2.4 is the A is [OH], [SH], [NH], Br etc, the compounds of 2-6 It shows conversion to phosphonate ester 2-7 . In this method, compound 2-6 Convert to compound 2-7 using the method described in Schemes 2.7-2.12 .

Scheme 2.5

Scheme 2.6

Scheme 2.5-2.6 It illustrates the preparation of compound 2-10 wherein A is Br, I, [SH], [NH], or the like or linking group-P (O) (OR ¹ ) ₂ . Amines 2-1 are treated with acids 2-8 , as described in Scheme 2.1 above, to obtain amides 2-9 . The preparation of acid 2-8 will be described in Scheme 2.11-2.12 .

The reaction shown in Scheme 2.5 to 2.6 is the substituent A is a linking group ^{-P (O) (OR 1)} 2 or [OH], [SH], illustrates the preparation of [NH], Br, one of the compounds of the precursor such as 2-9 It is. Scheme 2.6 is a compound of Compounds 2- 9 wherein A is [OH], [SH], [NH], Br It shows conversion to phosphonate ester 2-10 . In this method, compound 2-9 Convert to compound 2-10 using the method described in reaction 2.7-2.12 .

Scheme 2.7

Scheme 2.8

Scheme 2.7-2.8 A was used in the preparation of the phosphonate ester intermediate 2-4 Br, Cl, [OH], [NH] or a linker-P (O) (OR ¹ ) ₂ phosphorus The production of phosphonate-containing derivatives will be described. Piperazine 2-11 is described in Protective Groups in Organic Synthesis , by TW Greene and PGM Wuts, Wiley, Third Edition (1999) p. 518ff] to protect with Boc groups. Preferably, piperazine is treated with 1 equivalent of Boc anhydride and 1 equivalent of triethylamine in methanol or DMF to give Boc amines 2-12 . 2-12 in the presence of a suitable base Lv is treated with alkylphosphonate 2-13 which is a leaving group such as triflate, Br, Cl, mesyl and the like to give the product 2-14 . The base required for this modification is generally an inorganic base such as potassium carbonate in the presence of an organic solvent such as dimethylformamide. The reaction proceeds from ambient temperature to about 80 ° C. to obtain substitution product 2-14 . Protective Groups in Organic Synthesis , by TW Greene and PGM Wuts, Wiley, Third Edition (1999) p520ff.] Deprotection of Boc-amine groups to afford amines 2-15 . Amine 2-15 is then reacted with acid 2-16 (Aldrich) in the presence of base to afford product acid 2-17 . For example, 2-12 prepared from piperazine as described above in THF is described by Syn . Treated with bromophosphonate 2-18 and potassium carbonate prepared as described in 1999, 9 , 909 to give amine 2-19 . Then Boc Amine 2-19 Treatment with trifluoroacetic acid in dichloromethane affords amines 2-20 . Then, the in THF or dioxane in the presence of triethylamine, or aqueous potassium carbonate and the amine 2-20 treated with bromomethyl-benzoic acid to obtain the acid 2-16 2-21. Bromo phosphonate compound 2-18 instead of other The corresponding product 2-17 is obtained using the above method except that phosphonate 2-13 is used.

Scheme 2.9

Scheme 2.9-2.10 is a phosphonate Illustrates the preparation of acids 2-5 linked to the backbone via carbon chains and heteroatoms. In DMF in the presence of DCC and DMAP, Protective Groups in Organic Chemistry , by TW Greene and PGM Wuts, Wiley, Third Edition (1999), p. 373ff.] With the benzyl protected ketone 2-22 prepared from the corresponding acid by treatment with benzyl alcohol as described in the literature [Protective Groups in Organic Synthesis, by TW Greene and PGM Wuts, Wiley, Third Edition (1999), p. 373ff.] Is treated with a brominating agent to give bromo ketone 2-23 . Document [TW Greene and PGM Wuts, Wiley, Third Edition (1999), p. 312ff.], The ketones are protected with cyclic dioxalone to afford 2-24 . Then the salon dioxide 2-24 dialkyl hydroxy, thio or amino-substituted by treatment with an alkylphosphonate 2-25 gets dioxide Salon 2-26. The reaction is carried out in the presence of a base in a polar aprotic solvent such as dioxane or N -methylpyrrolidinone. The base used for the reaction is determined according to the properties of reactants 2-25 .

For example, when X is O, lithium hexamethyldisilylazide or potassium tert. Strong bases such as butoxide are used, and when X is S, NH or N-alkyl, an inorganic base such as cesium carbonate is used. TW Greene and PGM Wuts, Wiley, Third Edition (1999), p. 317ff.] To deprotect the dioxalone to give ketone 2-27 Treatment with N -methyl piperazine under reducing amination conditions gives amine 2-28 . For the preparation of the amine of the amino-reducing speech e.g. literature [Comprehensive Organic Transformations, by RC Larock , 2 nd edition, p. 835. In this method, the amine component and the aldehyde component are reacted together in the presence of a reducing agent such as borane, sodium cyanoborohydride or diisobutylaluminum hydride to obtain an amine product. Then, TW Greene and PGM Wuts, Wiley, Third Edition (1999), p. 317ff.] To deprotect the ester group to give acid 2-29 .

Scheme 2.10

For example, 4-acetyl benzoic acid is treated with benzyl bromide in the presence of potassium carbonate in aqueous THF to give ester 2-22 . Bromine in acetic acid or CCl ₄ Bromine 2-23 is obtained by treating ester 2-22 with NBS and AIBN in hexane . Bromine 2-23 is then reacted with 1,2-ethanediol in toluene under reflux conditions in a dean stark head having a catalytic amount of p-TsOH to give dioxalone 2-24 . Dioxalone 2-24 to dimethylformamide J. Org . At about 80 ° C. in the presence of potassium carbonate . Reaction with dialkyl 2-aminoethyl phosphonate 2-30 , prepared as described in Chem ., 2000 , 65 , 676, gives amine 2-31 . The dioxalone 2-31 is then treated with 1N hydrochloric acid in THF to give ketone 2-32 . Ketone 2-32 is reacted with N-methyl piperazine in the presence of triethylamine and after 30 minutes, sodium cyano borohydride is then added to give amine 2-33 . Acid 2-34 is obtained by hydrolysis with sodium hydroxide in aqueous THF to remove the benzyl ester. Other instead of amino phosphonate compounds 2-30 Using this method except using phosphonate 2-25 , the corresponding product 2-29 is obtained.

Scheme 2.11

Schemes 2.11-2.12 illustrate the preparation of acids 2-8 with phosphonates attached through unsaturated or saturated carbon linkages. In this method, acid 2-16 (Aldrich) was prepared for the preparation of 2-17 . As described in Scheme 2.7-2.8 Treatment with N-methyl piperazine affords acid 2-35 . Followed by bromination with bromine or NBS acid 2-35 bromide 2 - get 36. Bromide as needed, 2-36 Document [Protective Groups in Organic Chemistry, by TW Greene and PGM Wuts, Wiley, Third Edition (1999), page 373ff., To protect as benzyl or t-butyl ester to give 2-37 . That the following ester 2-37 by palladium catalyzed hekeu reaction was coupled with a dialkyl alkenyl phosphonate 2-38 Binding product 2-39 is obtained.

The coupling reaction of halogenated yryl and olefins by the Heck reaction is described, for example, in Advanced Organic Chemistry , by FA Carey and RJ Sundberg, Plenum, (2001), p. 503ff. And in Acc . Chem. Res ., 1979 , 12 , 146. The aryl bromide and olefins are prepared in the presence of a palladium (0) catalyst such as tetrakis (triphenylphosphine) palladium (0) or a palladium (II) catalyst such as palladium (II) acetate and, if necessary, triethylamine or carbonic acid. The binding product 2-39 is obtained by binding in the presence of a base such as potassium. If necessary, the product 2-39 is reduced to obtain saturated phosphonate 2-40 . Reduction methods of carbon-carbon double bonds are described, for example, in Comprehensive Organic Transformations , by RC Larock, VCH, (1989), page 6. The method includes catalytic reduction and chemical reduction, the latter using for example diborane or diimide.

Scheme 2.12

For example, then by treatment with NBS and AIBN in refluxing conditions the amine from 2-35 carbon tetrachloromethane bromide 2 - get 43. Then the bromide 2-43 was reacted with DCC and DMAP in t- butanol to obtain a t- butyl ester 2-44. And then ester 2-44 to J. Med . Dialkyl propenyl phosphonate 2-45 in the presence of bis (triphenylphosphine) palladium (II) chloride as described in Chem ., 1992 , 35 , 1371 J. Med . Chem ., 1996 , 39 , 949) to give the binding product 2-46 . This product 2-46 is then treated with aqueous HCl in dioxane to give acid 2-48 . If desired, the alkene 2-46 was prepared by J. Org. Reaction with diimides as described in Chem ., 1965 , 30 , 3965 oxidizes to give saturated product 2-47 . The ester is hydrolyzed by treatment with aqueous HCl as described above to give acid 2-49 . Another phosphonate 2-38 is substituted for the phosphonate compound 2-45 . Except for the use, the products 2-41 and 2-42 are obtained using the methods described above.

Example  3: Exemplary Compounds of the Invention

Scheme 3.1

Scheme 3.1 shows exemplary compounds of the present invention. In this expression The phosphonate groups can be linked through carbon atoms or heteroatoms, respectively.

Scheme 3.2

Scheme 3.3

Scheme 3.2-3. 3 illustrates the synthesis of a target molecule of type 3-11 wherein A is Br, Cl, [OH], [NH] or linker-P (O) (OR ¹ ) ₂ . The preparation of 3-4 wherein A is phosphonate is described below. The conversion of 3-4 to 3-9 in which A is methoxymethyl is described in EP 0817775 B1, and similar conditions can be used to prepare 3-9 in which A is linker-P (O) (OR ¹ ) ₂ . . To screen a nitro diether 3-4 then gained nitro compound 3-5 literature [Comprehensive Organic Transformations, by RC Larock , 2 nd Edition, (1999), p821.] Amine was reduced under standard reducing conditions, as described in Get 3-6

For example, 3-4 is treated with cold nitric acid in acetic acid and then the nitro product is catalytically hydrogenated with platinum oxide in high pressure acidic ethanol to give amine 3-6 . The isolated hydrochloride salt is then heated with ammonium formate and formamide at about 160 ° C. to produce quinazoline 3-7 . The quinazoline is converted to chloride 3-8 as described in EP 0817775 B1. Preferably, quinazoline 3-7 is treated with oxalyl chloride in chloroform and DMF to give chloride 3-8 . The chloride is substituted with amine 3-10 to give the product 3-9 . For example, chloride 3-8 is heated to reflux with 3-ethylyl-aniline in isopropanol to give 3-9 .

The reaction shown in Scheme 3.2 illustrates the preparation of compound 3-9 wherein substituent A is one of linker-P (O) (OR ¹ ) ₂ or precursors such as α [OH], [SH], [NH], Br, etc. will be. Scheme 3.3 depicts the conversion of compound 3-9 to phosphonate ester 3-11 , wherein A is [OH], [SH], [NH], Br, and the like. In this method, compound 3-9 is converted to compound 3-11 using the methods described in Schemes 3.10-3.21 .

Scheme 3.4

Scheme 3.5

Schemes 3.4-3.5 illustrate the synthesis of target molecules of type 3-14 wherein A is Br, Cl, [OH], [NH] or linker-P (O) (OR ¹ ) ₂ . Conversion to a 3-13 3-12 is accomplished using the conditions of the above reaction formula 3.2 for the conversion of 3-9 to 3-4. The preparation of 3-12 where A is phosphonate is described in the following schemes 3.14-3.17 .

The reaction shown in Scheme 3.4 illustrates the preparation of compound 3-13 wherein substituent A is one of linker-P (O) (OR ¹ ) ₂ or precursors such as α [OH], [SH], [NH], Br, etc. will be. Scheme 3.5 is A is described the conversion of [OH], [SH], [NH], Br etc, of the phosphonate esters 3-14 Compound 3-13. In this method, compound 3-13 is converted to compound 3-14 using the methods described in Schemes 3.10-3.13 .

Scheme 3.6

Scheme 3.7

Schemes 3.6-3.7 illustrate the synthesis of target molecules of type 3-20 wherein A is Br, Cl, [OH], [NH] or linker-P (O) (OR ¹ ) ₂ . The preparation of 3- 15 is described in EP 0817775 B1. Dieter 3-15 was prepared as described in Scheme 3.2 using the conditions described in EP 0817775 B1. Is converted to chloride 3 -16 . Chloride 3-16 is treated with amine 3-18 in reflux isopropanol to give 3-17 . The preparation of 3-12 where A is phosphonate is described in the following schemes 3.14-3.17 . The preparation of 3-18 , wherein A is linker-P (O) (OR ¹ ) ₂ , is shown in Scheme 3.18-3.19 .

The reaction shown in Scheme 3.6 illustrates the preparation of compound 3-17 wherein substituent A is one of linker-P (O) (OR ¹ ) ₂ or precursors such as α [OH], [SH], [NH], Br, etc. will be. Scheme 3.7 depicts the conversion of compound 3-17 to phosphonate ester 3-20 wherein A is [OH], [SH], [NH], Br, and the like. In this method, compound 3-17 is converted to compound 3-20 using the methods described in Schemes 3.10-3.21 .

Scheme 3.8

Scheme 3.9

Schemes 3.8-3.9 illustrate the synthesis of target molecules of type 3-24 wherein A is Br, Cl, [OH], [NH] or linker-P (O) (OR ¹ ) ₂ . Preparation of 3-16 is described in Scheme 3.6 . Treat the chloride 3-16 to 3-23 in refluxing isopropanol amine is converted to the amine 3-23. Preparation of 3-22 , wherein A is linker-P (O) (OR ¹ ) ₂ , is shown in Schemes 3.20-3.21 .

The reaction shown in Scheme 3.8 illustrates the preparation of compound 3-23 wherein substituent A is one of linker-P (O) (OR ¹ ) ₂ or precursors such as α [OH], [SH], [NH], Br, etc. will be. Scheme 3.9 depicts the conversion of compound 3-23 to phosphonate ester 3-24 wherein A is [OH], [SH], [NH], Br, and the like. In this method, compound 3-23 is converted to compound 3-24 using the methods described in Schemes 3.10-3.21 .

Scheme 3.10

Scheme 3.11

Schemes 3.10-3.13 illustrate the preparation of phosphonate-containing derivatives 3-19, 3-30, 3-69, 3-70 used in the preparation of phosphonate ester intermediate 3-11 (Scheme 3.3 ). Dihydroxybenzoic acid 3-25 was treated with 1 equivalent of phosphonate alkylating agent in which Lv is a leaving group such as mesyl, trifluoromethanesulfonyl, Br, I, Cl, tosyl, etc. in the presence of the base described in EP 0817775 B1. Ether 3-26 is obtained. The ether is then reacted under the same alkylation conditions in the presence of 2-bromoethylmethyl ether (Aldrich) to give diether 3-19 , 3-30 , 3-69 and 3-70 . For example, ester 3-25 prepared by refluxing the corresponding acid (Aldrich) in ethanol in concentrated HCl and acetone is synthesized by Syn . Treatment with dialkyl 4-bromobutylphosphonate 3-28 , potassium carbonate and tetrabutylammonium iodide prepared as described in 1999 , 9 , 909 affords ether 3-29 . Ether 3-29 is then treated with 2-bromoethylmethyl ether (Aldrich), potassium carbonate and tetrabutylammonium iodide to give diether 3-30 . The corresponding products 3-4, 3-19, 3-69, 3-70 were prepared using the above methods except for using other phosphonates 3-27 and 3-37 instead of bromobutylphosphonate 3-28 . Get

Scheme 3.12

Scheme 3.12-3.13 also illustrates the preparation of phosphonate-containing derivatives 3-69, 3-70 used in the preparation of phosphonate ester intermediate 3-11 (Scheme 3.3 ). Dihydric the hydroxybenzoic acid 3-25 to 1 equivalent of the alcohol of 3-31 as described in Scheme 3.10 to 3.11 Treatment gives ether 3-32 . This ether 3-32 is treated with one equivalent of 2-bromoethylmethyl ether (Aldrich) and one equivalent of base as described in Schemes 3.10-3.11 to give dieter 3-33 . Lv is then treated with a phosphonate alkylating agent in which Lv is a group of mesyl, trifluoromethanesulfonyl, Br, I, Cl, tosyl and the like in the presence of a base to give ether 3-69 .

Scheme 3.13

For example, as described above in Scheme 3.10, for the preparation of 3-26 from 3-25, and 3-25 in the treatment of acetone with 2-bromoethanol to obtain a 3-35. Then 2-bromoethylmethyl ether (Aldrich) and 1 equivalent of sodium hydride are reacted in DMF to give diether 3-36 . Dieter 3-36 in TMF in Tetrahedron Lett . Ether 3-70 is obtained by reacting with triflate 3-37 and potassium carbonate prepared as described in 1986 , 27 , 1497. Bromobutyl phosphonate 3-28 instead of using a different phosphonate 3-27, and the other instead of alcohol 3-34 Except for using alcohol 3-31 , the corresponding products 3-69 were obtained using the above methods. Get

Scheme 3.14-3.17 also illustrates the preparation of phosphonate-containing derivatives 3-12, 3-75, 3-76 used in the preparation of phosphonate ester intermediate 3-14 (Scheme 3.5 ).

Scheme 3.14

Scheme 3.15

Dihydroxybenzoic acid 3-25 is first treated with 2-bromoethylmethyl ether (Aldrich) as described in Scheme 3.10-3.11 to give ether 3-38 . Followed by treating the resulting ether 3-38 with one equivalent of the phosphonate alkylating agent, such as EP 0817775 in the mesyl, trifluoromethyl Lv in the presence of a base described in B1 methanesulfonyl, Br, I, Cl, tosyl ether 3 Get -75 Ether 3-38 in TMF Tetrahedron Lett . Ether 3-39 is obtained by reacting with triflate 3-37 and potassium carbonate prepared as described in 1986 , 27 , 1497. Phosphonate 3-37 instead of other phosphonate 3-27 using the said method, except that to obtain a corresponding product 3-75.

Scheme 3.16

Scheme 3.17

Scheme 3.16-3.17 illustrates the preparation of phosphonate-containing derivatives 3-76 used in the preparation of phosphonate ester intermediate 3-13 (Scheme 3.4 ). As described above in Scheme 3.13 for the preparation of 3-35 from 3-25 , ether 3-38 (Scheme 3.14-3.15 ) is treated with 2-bromoethanol to give 3-40 . Followed by treating the diether 3-40 as a leaving group phosphonate alkylating agent 3-27, such as in the presence of a base Lv is mesylate, trifluoromethane sulfonyl, Br, I, Cl, tosyl ether to obtain a 3-76 . For example, as described above in Scheme 3.13 for the preparation of 3-35 from 3-25 , 3-38 in acetone is treated with 2-iodoethanol 3-66 to give 3-41 . Then react with bromobutylphosphonate 3-28 as described above (Scheme 3.10-3.11 ) to give 3-42 . Bromobutyl phosphonate using the 3-28 place of other phosphonate and 3-27 using the above method except for the use of other alcohol instead of alcohol 3-63 3-66 3-76 to obtain the corresponding product.

Scheme 3.18

Scheme 3.18-3.19 describes the preparation of phosphonate-containing derivatives used to prepare phosphonate ester intermediates 3-20 (Scheme 3.6-3.7 ). First, aniline 3-43 is described in Protective Groups in Organic Chemistry , by TW Greene and PGM Wuts, Wiley, Third Edition. (1999), chapter 7 to protect using the methods described. Bromophenol 3-45 is then obtained by bromination of 3-44 under reflux conditions with bromine in acetic acid or NBS in tetrachloromethane in the presence of AIBN. Then, as described above in Schemes 3.10-3.11 , alkylation with phosphonate alkylating agent 3-77 yields phosphonate 3-46 . Coupling reaction with TMS acetylene by palladium mediated reaction yields alkane 3-47 , which is described in Protective Groups in Organic Chemistry , by TW Greene and PGM Wuts, Wiley, Third Edition (1999), chapter 7], deprotection can be used to obtain amine 3-48 . Coupling reactions of alkanes with aryl halides are described, for example, in Comprehensive Organic Chemistry , Eds. Trost and Fleming, Oxford, (1991), 3, part 2.4, page 521.

Scheme 3.19

For example, 3-aminophenol, 3-49 , is treated with 1 equivalent of mesyl chloride in the presence of pyridine to give 3-50 . The mesyl compound 3-50 is then treated with bromine in acetic acid to give chloride 3-51 . Chloride 3-51 is alkylated with 3-37 as described above (Scheme 3.12-3.13 ) to give phosphonate 3-52 . 3-52 is substituted in the presence of a palladium (0) catalyst such as tetrakis (triphenylphosphine) palladium (0) or a palladium (II) catalyst such as palladium (II) acetate and, if necessary, triethylamine or potassium carbonate or the like. The binding product 3-53 is obtained by treatment with TMS-acetylene in a polar solvent such as dimethylformamide or acetonitrile in the presence of a base and copper iodide (I). Treatment with potassium hydroxide in THF and water to deprotect the mesyl group yields amine 3-54 . The above methods are used to obtain the corresponding product 3-48 , except for using another phosphonate 3-77 instead of phosphonate 3-37 and another alcohol 3-43 instead of alcohol 3-49 .

Scheme 3.20

Scheme 3.20-3.21 To illustrate the preparation of phosphonate-containing derivatives 3-58 used in the preparation of phosphonate ester intermediate 3-24 (Scheme 3.9 ). First, 3-iodoaniline is described in Protective Groups in Organic Chemistry , by TW Greene and PGM Wuts, Wiley, Third Edition. (1999), chapter 7 to protect using the methods described. As described above (Scheme 3.18-3.19 ), alkane 3-56 is obtained by binding to propargyl alcohol by a palladium mediated reaction. It is then alkylated with phosphonate alkylating agent 3-27 as in Schemes 3.10-3.11 described above to give phosphonate 3-57 . Finally, Protective Groups in Organic Chemistry , by TW Greene and PGM Wuts, Wiley, Third Edition (1999), chapter 7 to deprotect using the conditions described in amine 3-58 .

Scheme 3.21

For example, 3-iodoaniline (Aldrich) is treated with Boc anhydride in the presence of pyridine and DMAP to give 3-59 . 3-59 in the presence of a palladium (0) catalyst such as tetrakis (triphenylphosphine) palladium (0) or a palladium (II) catalyst such as palladium (II) acetate and, if necessary, triethylamine or potassium carbonate, etc. The binding product 3-60 is obtained by treatment with propargyl alcohol in a polar solvent such as dimethylformamide or acetonitrile in the presence of a base and copper iodide (I). The alkylated 3-60 with triflate 3-37 is then obtained as described in Scheme 3.12-3.13 above to give phosphonate 3-61 . Treatment with TFA in THF or dioxane deprotects the Boc group to give amine 3-62 . Phosphorylation using carbonate 3-37 instead of different phosphonate and 3-27 to iodo using the above method but using a different aniline aniline 3-55 3-59 3-58 instead to obtain a corresponding product.

The methods described for introducing phosphonate moieties may be applicable to other chemicals by appropriate modification means known to those skilled in the art. Thus, the methods described for introducing phosphonate groups to aryl rings of 3-18 and 3-48 are also applicable to introducing phosphonates to alkane alkanes 3-22 and 3-58 , and vice versa. It is also possible.

Example  4: Exemplary Compounds of the Invention

Scheme 4.1

Scheme 4.1 is A is to illustrate the preparation of Br, I, [SH], [NH] , or a linking group such as ^{-P (O) (OR 1)} 2 The compound 4-52. The preparation of this compound is described in J. Med . Chem . Follow the method described in 2000 , 43, 12 , 2310. Anhydride 4-1 to A is Br, I, [SH], [NH] , or a linking group such as -P (O) (OR ¹⁾ with _{2-methyl-pyridin-4-2} Melting at high temperature gives 4-3 . The synthesis of 4-2 is described next. Product 4-3 is then rearranged by treatment with hydrazine in water and ethanol as needed to give ketone 4-4 . Ketone 4-4 is then converted to chloride 4- 5 by treatment with phosphorus oxychloride in an inert solvent such as acetonitrile at about 50 ° C. Chloride 4-5 is heated in the presence of an amine, if necessary, in a high boiling point solvent such as xylene or DMF to introduce amine 4-7 to obtain amine 4-6 . Optionally, pyridinone 4-4 is J. Med Chem . Can be converted directly to product 4-6 by a one-step process comprising melting pyridinone and aniline, 4-7 in the presence of a dehydrating agent such as phosphorus pentoxide, as described in 2000 , 43, 12 , 2310. .

Scheme 4.2

The reaction shown in Scheme 4.1 is the substituent A is illustrated a linking group ^{-P (O) (OR 1)} 2 or [OH], the production of [SH], [NH], Br The compound 4-6 one of the precursors such as the . Scheme 4.2 illustrates compounds 4-6 wherein A is [OH], [SH], [NH], Br, or the like. To conversion to phosphonate ester 4-52 . In this method, compound 4-6 is then Convert to compound 4-52 using the method described in Schemes 4.5-4.15 .

Scheme 4.3

Scheme 4.3 It illustrates the preparation of compound 4-52 wherein A is Br, I, [SH], [NH], or the like or linking group-P (O) (OR ¹ ) ₂ . J. Med . Chem . Chloride 4-8 described in 2000 , 43, 12 , 2310 was converted to A, Br, I, [SH], [NH], etc. or linking group-P (O) (OR ¹ ) ₂ as described above in Scheme 4.1. Treatment with phosphorus aniline 4-9 gives amine 4-10 . Optionally, J. Med. Chem. 2000, 43, 12, and processes the flutes dinon 4-11 described in p2310 A is a Br, I, [SH], [NH] , or a linking group such as ^{-P (O) (OR 1)} 2 of aniline 4-9 Amine 4-10 is obtained.

Scheme 4.4

The reaction shown in Scheme 4.3 illustrates the preparation of compound 4-10 wherein substituent A is one of the linking groups-P (O) (OR ¹ ) ₂ or precursors such as [OH], [SH], [NH], Br, and the like. . Scheme 4.4 illustrates compounds 4-10 wherein A is [OH], [SH], [NH], Br, and the like. To conversion to phosphonate ester 4-12 . In this method, compound 4-10 Convert to compound 4-12 using the method described in Schemes 4.5-4.15 .

Scheme 4.5-4.10 Of phosphonate-containing derivatives 4-2 , wherein A is Br, Cl, [OH], [NH] and a linking group-P (O) (OR ¹ ) ₂ used in the preparation of phosphonate ester intermediate 4-52 To illustrate the manufacture.

Scheme 4.5

Scheme 4.6

Scheme 4.5-4. 6 illustrates the preparation of 4-2 (Scheme 4.1 ) in which the phosphonate is directly linked to the ring. Halopyridine 4-13 Treatment with dialkyl phosphite 4-14 gives phosphonate 4-15 . For example, J. Med . The coupling reaction is carried out in the presence of a palladium (0) catalyst as described in Chem ., 1992 , 35 , 1371. For example 2-bromo-4-methyl pyridine (Aldrich) 4-16 equal molar amount of dialkyl sodium phosphite 4 in toluene under reflux conditions in the presence of tetrakis (triphenylphosphine) palladium (0) and triethylamine Reaction with -14a gives phosphonate 4-17 . The corresponding products 4-15 were prepared using the above methods except for using other pyridine 4-13 and / or other dialkyl sodium phosphite 4-14 instead of halopyridine compound 4-16 . Get

Scheme 4.7

Scheme 4.8

Schemes 4.7-4.8 illustrate the preparation of 4-2 in which phosphonates are connected via unsaturated or saturated carbon linkages. In this process, halo substituted pyridine 4-13 is combined with dialkyl alkenyl phosphonate 4-18 by a palladium catalyzed heck reaction. Bonding of olefins and halogenated aryls by the Heck reaction is described, for example, in Advanced Organic Chemistry , by FA Carey and RJ Sundberg, Plenum, (2001), p. 503ff. And in Acc . Chem . Res ., 1979 , 12 , 146. The aryl bromide and the olefin may be prepared in the presence of a palladium (0) catalyst such as tetrakis (triphenylphosphine) palladium (0) or a palladium (II) catalyst such as palladium (II) acetate and, if necessary, triethylamine or potassium carbonate. in the presence of a base, such as by combining in a polar solvent such as dimethylformamide or dioxane, to obtain a combined product 4-19. Product 4 -19 can be reduced to give saturated phosphonate 4-20 . Reduction methods of carbon-carbon double bonds are described, for example, in Comprehensive Organic Transformations, by RC Larock, VCH, (1989), p. 6]. The method includes catalytic reduction and chemical reduction, the latter using for example diborane or diimide.

For example, 2-bromo-4-methyl pyridine 4-16 is prepared by J. Med . Chem., 1992, 35, as described in 1371, bis (triphenylphosphine) is the recipe in the presence of a palladium (II) chloride, J. Med. The reaction product is reacted with dialkyl butenyl phosphonate 4-21 as described in Chem ., 1996 , 39 , 949 to give the binding product 4-22 . As needed, J. Org . The product 4-22 is reduced, for example by reaction with diimide, to obtain saturated product 4-23 as described in Chem ., 1965 , 30 , 3965. The corresponding products 4-19 and 4-20 are obtained using the above methods except that other pyridine 4-13 and / or other phosphonate 4-18 is used instead of halo pyridine compound 4-16 .

Scheme 4.9

Scheme 4.10

Scheme 4.9-4. 10 illustrates the preparation of 4-2 in which phosphonates are linked via heteroatoms such as O, S or N and carbon chains. In this method, halo substituted pyridine 4-13 is reacted with dialkyl hydroxy- or thio-alkylphosphonate 4-24 . The preparation of alkoxypyridine by reaction of halopyridine and alkoxide is described, for example, in J. Am. Chem . Soc ., 1960 , 82 , 4414. The preparation of pyridine thioethers by reaction of thiols with halopyridine is described, for example, in Chemistry of Heter® Cyclic Compounds, pyridin and its Derivatives , E. Klingsberg, Ed., Part 4, page 358.

The alcohol and thiol metal salt, for example by reaction with a halo-pyridine in the presence of copper powder catalyst, if desired, in an elevated temperature and then was transformed into a sodium or potassium salt to obtain the ether or thioether product 4-25.

For example, a tetrahydrofuran solution of 3-bromo-4-methylpyridine 4-26 (Aldrich) in the presence of sodium carbonate is prepared by Aust. Reflux heating with the same molar amount of dialkyl 2-mercaptoethylphosphonate 4-27 described in J. Chem., 43, 1123, (1990) The thioether product 4-28 is obtained. Other pyridine 4-13 and / or other hydroxy or thio-alkyl phosphonate 4-24 instead of halopyridine compound 4-26 . Except for using these methods, the corresponding product 4-25 was obtained. Get

Scheme 4.11-4.15 is Used to prepare phosphonate ester intermediates 4-12 (Scheme 4.3-4.4 ), containing phosphonates where A is Br, Cl, [OH], [NH] and linker-P (O) (OR ¹ ) ₂ It demonstrates manufacture of derivatives 4-10 .

Scheme 4.11

Schemes 4.11-4.13 illustrate the preparation of 4-9 (Scheme 4.3 ) where phosphonates are linked via heteroatoms such as O, S or N and carbon linkages. In this method, if necessary, the protected aniline is reacted with alkylphosphonate 4-30 in which Lv is a leaving group such as triflate, Br, Cl, mesyl and the like in the presence of a suitable base. The base required for this modification depends on the nature of the heteroatom X. For example, when X is N or S, it is suitable to use an excess of an inorganic base such as potassium carbonate in the presence of an organic solvent such as dimethylformamide. The reaction proceeds from ambient temperature to about 80 C to afford the substitution product 4-31 . When X is O, in the presence of a solvent such as tetrahydrofuran, the same molar amount of a strong base such as lithium hexamethyldisilylazide or the like is used. Then, Protective Groups in Organic Synthesis , by TW Greene and PGM Wuts, Wiley, Third Edition (1999), chapter 7 to deprotect the amine group to give amine 4-32 .

Scheme 4.12

See, eg, Protective Groups in Organic Chemistry , by TW Greene and PGM Wuts, Wiley, Third Edition (1999), 531 ff, a process for preparing di-protected diamine 4-33 (Aldrich) as CBZ carbamate in dimethylformamide at about 60 ° C. containing excess potassium carbonate is described in Tetrahedron Lett . Treatment with the same molar amount of triflate 4-34 as described in 1986 , 27 , 1497 affords phosphonate product 4-35 . It is then deprotected by palladium reduction on carbon in the presence of hydrogen to afford amine 4-36 . Instead of aniline 4-33 except for the use of different anilines 4-29 and / or other alkyl phosphonate and 4-30 by using the above methods to obtain the corresponding product 4-32.

Scheme 4.13

Optionally, aminophenol 4-37 , protected as CBZ carbamate as described above, is reacted with one equivalent of alkylphosphonate 4-34 to give phosphonate 4-38 . The CBZ group is then removed by palladium reduction on carbon in the presence of hydrogen to afford amine 4-39 .

Scheme 4.14

Schemes 4.14-4.15 illustrate the preparation of 4-9 in which phosphonates are linked via unsaturated or saturated carbon linkages. In this process, the halo-substituted pyridine 4-40 protected as required is subjected to the palladium catalyzed Heck reaction as described above (Scheme 4.7-4.8 ). Combination with dialkyl alkenyl phosphonate 4-18 affords binding product 4-41 . For protection of aniline, see Advanced Organic Chemistry , by FA Carey and RJ Sundberg, Plenum, (2001), p. 503ff. And in Acc . Chem . Res ., 1979 , 12 , 146. Preferably, aniline is treated with Boc reagent such as Boc chloride or Boc anhydride in the presence of bases such as DMAP and triethylamine to obtain protected aniline.

If necessary, binding product 4-41 is reduced as described above (Scheme 4.7-4.8 ) to afford saturated phosphonate 4-42 . Protective Groups in Organic Chemistry , by TW Greene and PGM Wuts, Wiley, Third Edition (1999) remove the protecting group as described in chapter 7 to obtain aniline 4-43 and 4-44 .

Scheme 4.15

For example, a process for preparing Boc protected 3-bromo-4-fluoro aniline 4-45 (Aldrich) in the presence of bis (triphenylphosphine) palladium (II) chloride is described in J. Med . Dialkyl propenyl phosphonate 4-46 and J. Med . Described in Chem ., 1996 , 39 , 949 . Reaction as described in Chem ., 1992 , 35 , 1371 yields the binding product 4-47 . Boc protection of aniline is performed by treating aniline with Boc anhydride in the presence of DMAP. Product 4-47 was prepared by J. Org . Reduction by reaction with diimide as described in Chem ., 1965 , 30 , 3965 gives saturated product 4-48 . Treatment of 4-47 and 4-48 with TFA in THF or dioxane yields products 4-49 and 4-50 , respectively. The corresponding methods 4-43 and 4-44 are obtained using the above methods except using other pyridine 4-40 and / or other phosphonate 4-18 instead of halo pyridine compound 4-45 .

The methods described for the introduction of the phosphonate moiety (Scheme 4.5-4.15 ) are possible to cope with different chemicals using appropriate modifications known to those skilled in the art. Thus, methods handed down to the introduction of phosphonates on the pyridyl ring of 4- 2 can be applied to the introduction of phosphonates into aniline 4-9 and vice versa.

Example 5 Preparation of Exemplary Compounds of the Invention

Scheme 5.1

Scheme 5.2

Preferred phosphonate substituted analogues for conversion to prodrugs are described with the respective alkylation reagents and arabinofuranosylcytosine 5-1 (US Pat. No. 3,116,282, line 65 to column 25, line 25). Obtained according to the above). Scheme 5.1-5.2 shows how to link the phosphonate to 5-1 via a 5 ′ hydroxyl group. Triol 5-1 is dissolved in a solvent such as DMF, THF and treated with a phosphonate reagent containing leaving groups such as bromine, mesyl, tosyl or trifluoromethanesulfonyl in the presence of a suitable organic or inorganic base.

For example, 5-1 is dissolved in DMF and 8 equivalents of sodium hydride and J. Org . Chem. By treatment with 2 equivalents of (toluene-4-sulfonylmethyl) -phosphonic acid diethyl ester 5-5 prepared according to the method described in 1996 , 61 , 7697 Phosphonate 5-6 whose bond state is a methylene group is manufactured. Use another phosphonate reagent 5-2 instead of 5-5 Except for use, the corresponding products 5-3 containing other linking groups are obtained using the above methods.

Scheme 5.3

Scheme 5.4

Preferred phosphonate substituted analogs for conversion to prodrugs are first reacted with glycal 5-7 (obtained as described in J. Am. Chem . Soc . 1972 , 94 , 3213) with phenylselenyl chloride Perchloric acid is prepared by treatment with each phosphonate alcohol 5-8 in the presence of J. Org . Chem . 1991 , 56 , 2642-2647. The resulting chloride is oxidized with hydrogen peroxide and then double-hydroxylated the double bonds generated with MCPBA and water to produce anti-diol ( Synth. Commun . 1989 , 19 , 1939), which diazoles are triazoles. , By amine decomposition of uracil with 2-chlorophenyldichlorophosphate, pyridine and ammonia ( Bioorg . Med . Chem . Lett . 1997 , 7 , 2567) provides the desired product 5-3 . Alternatively, anti-diol can be obtained through selective protection and inversion using Mitsunobu conditions following osmium tetraoxide oxidation.

Scheme 5.3-5.4 illustrates the introduction of other phosphonate bonds. For example, 5-7 is dissolved in CH ₂ Cl ₂ and treated with silver perchlorate in the presence of 1 equivalent of phenyl selenyl chloride followed by diethyl (hydroxymethyl) phosphonate at -70 ° C. to give 5-12 . The phosphonate is transformed into the desired analog by primary oxidation with hydrogen peroxide followed by MCPBA oxidation and the final conversion of cytosine to uracil of the desired product 5-13 . Except for using other phosphonate reagents 5-8 instead of 5-11, the corresponding products 5-10 containing other linking groups are obtained using the above methods. In some cases, it may be necessary to use a suitable protecting group for the amino group of the diol as well as cytosine in the conversion of the desired prodrug. Other bases may also be used to prepare similar analogs of classes 5-3 and 5-10 .

Example  6: Preparation of Exemplary Compounds of the Invention

Representative compounds of the invention can be prepared as illustrated above. Desired phosphonate substituted analogs are prepared by reacting intermediate 6-5 (obtained as described in US Pat. No. 5,464,826) with each alkylating agent 6-6 . The preparation of phosphonate bonds of 2'2'-difluoronucleosides via 5'hydroxyl groups is illustrated above. As described in US Pat. No. 5,464,826, a suitably protected base is dissolved in a solvent such as DMF, THF and contains leaving groups such as bromine, mesyl, tosyl or trifluoromethanesulfonyl in the presence of a suitable organic or inorganic base. Treated with a phosphonate reagent.

For example, 6-1 (obtained as described in US Pat. No. 5,464,826) is dissolved in DMF, 2 equivalents of sodium hydride and J. Org . Chem . Treated with 1 equivalent of (toluene-4-sulfonylmethyl) -phosphonic acid diethyl ester 6-8 , prepared according to the method described in 1996 , 61 , 7697 to give phosphonate 6-9 in the bound state methylene group Get Except for the use of other phosphonate reagents 6-6 instead of 6-8, the above methods are used to obtain the corresponding product 6-2 containing other linking groups.

Example 7 Preparation of Exemplary Compounds of the Invention

Scheme 7.1

Compound 7-3 (X = -CH ₂ CH _2- ) is prepared as shown in Scheme 7.1 . Camputosa (US Pat. No. 4,604,463) is activated with p -nitrophenyl chloroformate in DMF and triethylamine and reacted with aminophosphonates to give compound 7-3 .

Scheme 7.2

Compound 7-4 is obtained according to known methods ( J. Chem . Soc . Perkin Trans. 2, 1972 , 2035). 10-4 of 7-4 is activated and subsequently reacted with amine 7-21 (as its acid chloride) to give 7-5 (US Pat. No. 4,604,463). Compound 7-6 is prepared by refluxing 7-5 and aminoethylphosphonate in DMF and DIPEA.

Scheme 7.3

A key intermediate is the month label (Dallavele, S. et al.) The literature (J. Med. Chem. 2000, 43, 3963-3969) a 7-hydroxy-10-hydroxy-camptothecin 7-made according to the 7 7-aldehyde derivative 7-10 was prepared by 7-7 metonymy in glacial acetic acid. 7-10 is further oxidized to give acid 7-11 . 7-10 is treated with triphenylphosphoanilidene acetaldehyde and t-butoxycarbonylmethylene triphenylphosphorane, respectively, to obtain 7-12 and 7-13 ( J. Med . Chem . 2000 , 43 , 3963 ).

Scheme 7.4

Compound 7-7 is reacted with 7-22 (US Pat. No. 4,604,463), followed by triflation phosphonate and NaH to give compound 7-8 .

Scheme 7.5

The synthesis of 7-19, 7-18, 7-17 and 7-16 It is illustrated in Scheme 7.5 .

Aldehyde 7-10, acid 7-11 , extended aldehyde 7-12 and ester 7-13 (compound 7-14 ) are reacted with 7-22 to give 7-15a, 7-15b, 7-15c and 7-15d . Compound 7-19 is prepared by reductive amination of 7-15 with aminoethylphosphonate, NaBH ₃ CN and AcOH. Compound 7-15b is activated with BOP reagent and then reacted with aminoethylphosphonate to give compound 7-18 which is then hydrogenated in the presence of 10% Pd / C to give the desired 7-17 .

Hydrogenation of 7-15d followed by a binder such as a BOP reagent. Treatment with aminoethylphosphonate in the presence of DIC affords the desired product product 7-16 .

Further manipulations can be made to the phosphonate moiety prior to the final deprotection reaction. Such modifications are described in more detail in the phosphonate interconversion section herein.

Example 8 Preparation of Exemplary Compounds of the Invention

Scheme 8.1

Hayikamtin derivatives at C-10 and O-20 scheme are 8.1 are easily prepared from hayikamtin (topotecan), as illustrated in 8.5 (US Patent No. 5,004,758). Hycamtin is reacted with an appropriate trilatated phosphonate to give an analog of 8-2 . Hycamtin is activated with p-nitrophenyl chloroformate and then reacted with the appropriate aminophosphonate nucleophile to give the desired analog 8-4 containing carbamate bonds.

Scheme 8.2

The OH group in C-10 is converted to a triflate derivative followed by the insertion of CO, followed by reaction with an aminophosphonate to give analog 8-7 . The trilate is converted to aldehyde by CO insertion, followed by reductive amination with aminophosphonate to obtain analogs of 8-6. The C-10 is protected with OH and activated with OH-20 and then reacted with an aminophosphonate to give the desired 8-8 analogue.

Scheme 8.3

Scheme 8.4

Analogues 8-12 are synthesized by Pd-catalyzed reduction of triflation 8-10 followed by activation of O-20 with p -nitrophenyl chloroformate and reaction with aminophosphonates. Hycamtin is methylated by treatment with NaH, CH ₃ I in DMF to give 10-OCH ₃ hicamtin. Analogue 8-14 is obtained from an OCH ₃ hycamptin derivative in the same manner as 8-12 .

Scheme 8.5

Preparation of analogs 8-17 is carried out by reacting 10-hydroxycamptothecin with paraformaldehyde, methylamine and acetic acid followed by reductive amination with aldehyde-phosphonate.

Scheme 8.6

As shown in Scheme 8.6 , hycamtin is reacted with diethylphosphonate in acetonitrile in the presence of Cs ₂ CO ₃ to give compound 8-18 . Reaction with p-nitrophenyl chloroformate in the presence of DIPEA in CH ₂ Cl ₂ activates OH-10 and then with aminofonate to give carbamate 8-2 .

Scheme 8.7

As shown in Scheme 8.7 , 10-OH of hycamptin is trilatated ( J. Am. Chem . Soc. , 1984 , 106 , 7500), and then CO is inserted to obtain an aldehyde intermediate ( J. Org . Chem . 1999 , 64 , 178). Reductive amination of the aldehyde with aminophosphonates followed by acid treatment yields amines 8-21 . Trilatation and CO incorporation of hycamptin provides a carboxylic acid ( J. Org . Chem . 1994 , 59 , 6683). The resulting carboxylic acid is activated with BOP-reagent and then reacted with aminophosphonate in the presence of DIPEA to give compound 8-22 . Protect 10-OH with TMS-Cl, activate 20-OH with p -nitrophenyl chloroformate and react with aminophosphonate to give phosphonate 8-23 .

Scheme 8.8

The synthesis of 8-24 and 8-25 (see 8-12 and 8-14 ) is described in Schemes 8.8 and 8.9 . 8-10 in DMF is dehydrated with dppp, Pd (OAc) ₂ and Et ₃ SiH to give 8-11 . Compound 8-24 is obtained by activating 8-11 with p -nitrophenyl chloroformate, then combining with aminophosphonate and finishing with acid.

Scheme 8.9

Hycamtin is treated with NaH in DMF and reacted with CH ₃ I to give 10-methoxy derivatives (Scheme 8.9 ). This 10-methoxy intermediate is activated with p -nitrophenyl chloroformate and then reacted with aminophosphonate and finished with acid to give the desired phosphonate 8-25 .

Scheme 8.10

Scheme 8.10 is a compound of Compound 8-26 Synthesis (example of analogues 8-17 ) is described. 9-methylaminomethyl-10-hydroxycampotesine 8-16 (prepared with hycamptin as described in US Pat. No. 5,004,758 using methylamine instead of dimethylamine) as a phosphonate with aldehyde functionality Reductive amination gives the desired product 8-26 . Further manipulations can be made to the phosphonate moiety before the final deprotection reaction. Modifications of this kind are described in more detail in the phosphonate interconversion section herein.

Example 9 Preparation of Exemplary Compounds of the Invention

Scheme 9.1

Exemplary compounds of the invention are illustrated above.

Scheme 9.2

Synthesis of examples of analogs 9-2 to 9-8 is illustrated in Schemes 9.2 , 9.3 and 9.4 . Ketone 9-9 ( Chem. Lett . 1980 , 51) and 1,2,4-triazole are reacted with n- BuLi in THF at -78 ° C to obtain alcohol 9-10 . Compound 9-10 is reacted with triflate phosphonate and NaH to give an example of 9-7 , 9-12 with X = -CH ₂ . Compound 9-10 was activated with p -nitrophenyl chloroformate and then reacted with aminoethylphosphonate in the presence of diisopropylethylamine (DIPEA) to give analogs of analog 9-8 wherein X = -CH ₂ CH _2- . Yes, you get the desired product 9-11 .

Scheme 9.3

For example, 9-13 is obtained by stirring with alpha-bromo-4-tolunitrile in 1,2,4-tetrazol ester derivative CH ₂ Cl ₂ (US Pat. No. 4,978,672). Compound 9-13 is first saponified with LiOH to give acid 9-14 . The acid is reacted with 4-fluorobenzonitrile according to the method described in US Pat. No. 4,978,672 to obtain core intermediate 9-15 . 9-15 , DIC, HOAt and aminoethylphosphonate are reacted to give an example of analog 9-2 with X = —CH ₂ CH ₂ —, 9-16 . 9-15 Reduction with borane in THF followed by reaction with triflation phosphonate and NaH gives an example of analog 9-4 , X = -CH ₂ CH _2- , 9-18 .

Scheme 9.4

Oxidation of 9-17 with MnO ₂ gives aldehyde derivative 9-19 . Treatment of 9-19 with aminoethylphosphonate yields an example of analog 9-5 , X-CH ₂ CH _2- , 9-22 . After the aldehyde 9-19 is reacted with hydroxyamines, triflate Chemistry phosphonate by reaction with X = - CH ₂ CH ₂ - Examples of the analogs 9-6, to obtain a 9-21. 9-19 was prepared using aminoethylphosphonate, NaBH ₃ CN and AcOH. Reductive amination results in compound 9-20 .

Further manipulations can be made to the phosphonate moiety prior to the final deprotection reaction. Modifications of this kind are described in more detail in the phosphonate interconversion section herein.

Example 10 Preparation of Exemplary Compounds of the Invention

Scheme 10.1

Exemplary compounds of the invention are illustrated above. The synthesis of novel phosphonate containing compounds having various linkers X is illustrated in Schemes 10.2, 10.3 and 10.4 . Examples are synthesized as shown in Schemes 10.2, 10.3 and 10.4 .

Scheme 10.2

Compounds 10-14 are 10-12 ( J. Heter C. yclic Chem . 1975 , 2 , 577) and 10-13 ( Bioorg . Med ) as previously known methods ( J. Med . Chem . 1991 , 34 , 725) . . Chem. Lett. prepared from 2001, 11, 1257). Compound 10-14 was reacted with benzyl bromide and Cs ₂ CO _{3 to} protect it with a benzyl group, treated with thionyl chloride and then cyclized with KO t -Bu ( J. Med . Chem . 1991 , 34 , 725). Get 10-15 Hydrogenation to remove benzyl group yields 10-16 . Compound 10-16 is stirred with trilatated phosphonate, Cs ₂ CO ₃ in CH ₃ CN to give the desired product 10-17 (example of analogue 10-8 with X = —CH ₂ —). Compound 10-16 was activated with p-nitrophenyl chloropromate in the presence of TEA and then reacted with aminoethylphosphonate to give 10-18 (example of analogue 10-7 with X = -CH ₂ CH _2- ). Get

Scheme 10.3

Compound 10-20 is prepared from 10-12 and 10-19 in the same manner as Compound 10-14 . Compounds 10-21 are synthesized by the method described above for 10-15 and then hydrogenated in the presence of 10% Pd / C to obtain core intermediate 10-22 . Reductive amination of 10-22 with aldehyde phosphonate, NaBH ₃ CN and AcOH affords the desired product 10-23 (example of analogue 10-9 with X = —CH ₂ CH ₂ —). Compound 10-22 is reacted with phosphonate chloroformate in the presence of TEA to give product 10-25 (example of analogue 10-11 with X = -CH ₂ CH _2- ).

Examples of analogs 10-10 , wherein X = -CH _2- , compounds of 10-24 are obtained by reaction of 10-22 with phosphonate carboxylic acid and DIC. n- BuLi, DMF is used to formyl the fadrozole to give intermediate aldehyde 10-26 ( J. Med . Chem . 2000 , 43 , 2165). 10-26 is further oxidized to give an acid which is then reacted with aminoethylphosphonate, DIC and HOAt to give the desired product 10-31 (example of analogue 10-5 with X = -CH ₂ CH _2- ). Reductive amination of 10-26 with aldehyde phosphonate, NaBH ₃ CN and AcOH affords the desired product 10-27 (example of analogue 10-2 with X = —CH ₂ CH ₂ —). Treatment of 10-26 with aminoethylphosphonate yields 10-30 (example of analogue 10-6 with X = -CH ₂ CH _2- ).

Scheme 10.4

Reduction of 10-26 with NaBH ₄ gives an alcohol derivative, followed by reaction with triflation phosphonate and NaH to give the product 10-29 (example of analogue 10-4 with X = -CH _2- ). Compound 10-26 and hydroxyamine are condensed in the presence of TEA to give oxime. Alkylation of the oxime with triflate phosphonate and NaH provides the desired compound 10-28 (example of analogue 10-3 with X = -CH _2- ). Further manipulations can be made to the phosphonate moiety prior to the final deprotection reaction. Modifications of this kind are described in more detail in the phosphonate interconversion section herein.

Example 11 Preparation of Exemplary Compounds of the Invention

Scheme 11.1

Exemplary compounds of the invention are illustrated above.

Scheme 11.2

Temozolomide, mitozolomide and derivatives thereof were synthesized by several different synthetic routes (Scheme 11.2 ). 5-aminoimidazole-4-carbozamide is reacted with alkyl isocyanate to obtain a 1- ( N -alkylcarbamoyl) derivative. This derivative is treated with sodium nitrite to obtain 11-10 ( J. Org . Chem . 1997 , 62 , 7288).

Optionally, 5-aminoimidazole-4-carbozamide is treated with sodium nitrite to obtain a diazonium salt and then reacted with alkyl isocyanate to give amides 11-10 (US Pat. No. 5,260,291). Hydrolysis conditions for hydrolyzing amide 11-10 to acids 11-13 can be selected ( J. Med . Chem . 1990 , 33 , 1393). Acids 11-13 were converted to aldehydes followed by reductive amination with aminophosphonates to give analogs 11-31 , and reacted with aminophosphonates to yield analogs 11-41 , with hydroxylamine and triflate phosphonates. Reaction gives 11-51 . Compound 11-13 is reacted with aminophosphonate and binder to give 11-30. Compounds 11-15, 11-17 , 11-18 and 11-19 , which are examples of 11-30, 11-51, 11-41 and 11-31 , respectively , can be prepared as illustrated below (Scheme 11.3 ).

Scheme 11.3

Temozolomide 11-10 is prepared stepwise by reacting 5-aminoimidazole-4-carbozamide with methyl isocyanate in acetonitrile, followed by nitration and cyclization with sodium nitrite in 50% acetic acid ( J. Org. Chem. 1997, 63, 7288). 11-10 is reacted with sodium nitrite in concentrated sulfuric acid to convert temozolomide to acid 11-14 . Acids 11-14 are treated with thionyl chloride and catalytic amounts of DMF to give acid chlorides ( J. Med . Chem . 1990 , 33 , 1393). The acid chloride is reacted with aminoethyl phosphonate to give 11-15 .

The acid chloride can be reacted with hydroxymethylamine and then reduced to DIBAL in THF to give aldehyde 11-16 . The aldehyde is further reacted with aminoethyl phosphonate and reductive amination with aminoethyl phosphonate, NaBH ₃ CN and AcOH to give 11-18 and 11-19 , respectively. Aldehyde 11-16 is reacted with hydroxylamine hydrogen chloride in the presence of TEA, followed by triflation phosphonate and NaH to afford 11-17 .

Scheme 11.4

Compounds 11-21 and 11-23, which are examples of analogs 11-6 and 11-7 , are synthesized as described above in Scheme 11.4 . Lithiated with n- BuLi in THF at −78 ° C., followed by reaction with DMF to obtain an aldehyde derivative 11-20 . Reductive amination of aldehyde 11-20 with aminoethylphosphonate, NaBH ₃ CN, AcOH affords the desired product 11-21 (example of analogue of 11-6 with X = -CH ₂ CH _2- ). The acid derivative 11-22 can be obtained by lithiating n- BuLi in THF and then reacting with CO ₂ . Acids 11-22 are reacted with amino ethyl phosphonate in the presence of a binder such as DIC, HOAt to give the desired product 11-23 (an example of an analog of 11-7 with X = -CH ₂ CH _2- ). Further manipulations can be made to the phosphonate moiety prior to the final deprotection reaction. Modifications of this kind are described in more detail in the phosphonate interconversion section herein.

Example 12 Preparation of Exemplary Compounds of the Invention

Scheme 12.1

Exemplary compounds of the invention are illustrated above.

Scheme 12.2

Analogs 12-2 (X = -CH _2- ), 12-3 (X = -CH ₂ CH _2- ), 12-4 (X =-CH ₂ CH _2- ), 12-5 (X = -CH, respectively) ₂ -), and _{12-6 (X = -CH 2 CH 2} -) a towing phosphonate section the synthesis of compounds 12-10, 12-14, 12-16, 12-15 and 12-13, containing the It is illustrated in Scheme 12-2 . Etoposides are obtained as described above (US Pat. No. 3,408,441). Etoposide is reacted with triflation phosphonate using Cs ₂ CO ₃ in acetonitrile to give phosphonate 12-10 . The etoposide is activated with p -nitrophenyl chloroformate and then reacted with aminoethyl phosphonate in the presence of TEA to give 12-13 . 12-9 is trilatated with PhN (Tf) ₂ and then CO-inserted in the presence of Pd (OAc) ₂ , pdpp, TEA in DMF-H ₂ O to give carboxylic acid derivative 12-12 . Compound 12-12 is reacted with aminoethyl phosphonate, DIC and HOAt to give 12-16 . Following triflation of etoposide, CO incorporation in the presence of Pd (OAc) ₂ , pdpp, TEA and triethylsilane in DMF affords aldehyde intermediate 12-11 . By the aldehydes 12-11 hydroxylamine hydrochloride and diisopropylethylamine (DIPEA) and the reaction was then triflate Chemistry phosphonate and reacted with NaH to obtain the phosphonate 12 to 15. The 12-11 Reductive amination with aminoethyl phosphonate, NaBH ₃ CN and AcOH affords the desired compound 12-14 .

Scheme 12.3

As shown in Scheme 12.3, it compounds 12 to 18 is 12-17 (Bioorg. Med. Chem to hinge properly protected β-d- glucopyranose, BF ₃ -Et ₂ O-dichloroethane from the -20 ℃. Lett. 1994 , 4 , 2567) is glycosylated ( J. Med . Chem . 1989 , 32 , 1418). Deprotection of the 3'-sugar hydroxyl group using zinc dust in 2: 1 THF-AcOH, followed by hydrogenation in the presence of 10% Pd / C and the 2'-sugar amino group of the phosphonate and Deprotection of the benzyl group affords free amine 12-19 . Amine derivatives 12-19 Reductive amination with aminoethyl phosphonate, NaBH ₃ CN and AcOH gives an example of analogue 12-8 with phosphonate 12-20, X = -CH ₂ CH _2- .

Scheme 12.4

As shown in Scheme 12.4, compounds 12-21 are Bioor. Med . Chem . Lett . 2001 , 11 , 2667 and J. Med . Chem . It is prepared by the method described in 1999 , 42 , 4640. Compound 12-22 was prepared by glycosylating 12-17 ( Bioorg . Med . Chem . Lett . 1994 , 4 , 2567) with 12-21 , BF ₃ -Et ₂ O in -20 ° C dichloroethane ( J. Med . Chem . 1989 , 32 , 1418). Deprotection of 2 'and 3'-sugar hydroxyl groups using zinc dust in 2: 1 THF-AcOH, followed by hydrogenation in the presence of 10% Pd / C Deprotection of the CBZ group of the benzyl group affords free amine 12-23 . Amine derivatives 12-23 to reductive amination with amino ethyl phosphonate, NaBH ₃ CN, and AcOH phosphonate _{12-24, X = - CH 2 CH} 2 - and n = 1 to obtain an example of the analog 12-7 . Further manipulations can be made to the phosphonate moiety before the final deprotection reaction. Modifications of this kind are described in more detail in the phosphonate interconversion section herein.

Example 13 : Preparation of Exemplary Compounds of the Invention

Scheme 13.1

Exemplary compounds of the invention are illustrated above. Analogs 13-15, 13-16 and 13-9 are prepared as shown in Scheme 13.2 .

Scheme 13.2

Scheme 13.3

Compound 13-13 is a precursor of analogs 13-15, 13-16 and 13-9 . Scheme 13.3 illustrates the synthesis of examples. Compounds 13-13 were prepared by the alkylation of triazoles with benzyl bromide 13-12 , followed by hydrogenation of the NO ₂ group in the presence of 10% Pd / C. Synthesis following the procedure described in 36,617. Reductive amination of 13-13 with aldehyde phosphonate, NaBH ₃ CN and AcOH yields 13-40 (example of 13-9 with X = —CH ₂ —). A solution of 13-13 , carboxylic phosphonate, DIC, HOAt is stirred at room temperature to give the products 13-42 (examples of 13-8 and 13-16 with X = -CH _2- ). Activation of hydroxymethylphosphonate with phosgene, followed by reaction with amine 13-13 in the presence of diisopropylethyl amine in CH ₂ Cl ₂ to 13-41 (X = -CH ₂ -13-7 and 13-15 Ex)

Scheme 13.4

Analogs 13-2 and 13-4 are prepared as shown in Scheme 13.4 . Compound 13-18 is prepared as described above (US Pat. No. 36,617). Ester 13-18 saponifies to give acids 13-19 , which are the key precursors of analogs 13-2 and 13-4 .

Scheme 13.5

As shown in Scheme 13.5 , compound 13-18 is first saponified with LiOH to give 13-19 . Compound 13-19 is reacted with aminoethyl phosphonate in the presence of binding reagent DIC, HOAt to give 13-21 (example of 13-2 with X = -CH _2- ). Acids 13-19 are reduced to alcohol using BH ₃ -THF and then reacted in THF at room temperature to give 13-20 (example of 13-4 with X = -CH _2- ).

Scheme 13.6

Ester 13-18 is reduced to give compound 13-22 . Aldehyde derivatives 13-22 are important intermediates for analogs 13-5 and 13-24 (Scheme 13.6 ).

Scheme 13.7

As shown in Scheme 13.7 , aldehyde 13-22 is reacted with aminoethylphosphonate to give the desired product 13-25 (examples of 13-3 and 13-52 with X = -CH ₂ CH _2- ). Aldehyde 13-22 is reacted with hydroxylamine and then triflate phosphonate to give 13-50 (examples of 13-6 and 13-24 with X = -CH ₂ CH _2- ). Compound 13-23 is obtained by reductive amination of 13-22 and aminoethylphosphonate, NaBH ₃ CN, AcOH.

Scheme 13.8

Bromo derivatives 13-27 are prepared by the method described above for anastrozole (US Pat. No. 36,617). And then reacting the compound 13-27 as Grignard reagents R ² MgBr or R ² and reacting to the presence of a Pd catalyst CH = CH ₂ to obtain a vinyl derivative, an aldehyde to obtain a 13-28 by ozone decomposition reaction. Aldehydes 13-28 are converted to analogs 13-36 and 13-10 using the methods described in Schemes 13.6 and 13.7 .

Scheme 13.9

As shown in Scheme 13.9, Pd (OAc) to 13-27 in a 100 ℃ DMF compound _{2, n -Bu 3 P, K} 2 was combined with the CH ₂ = CH ₂ in the presence of CO ₃ (Tetrahedron Lett. 2002 , 43 , 3401), and aldehyde 13-28 are obtained by ozone decomposition reaction. Aminoethyl phosphonate, NaBH ₃ CN, AcOH is by reductive amination of 13-28 with 13-32 to obtain a desired product (X = -CH ₂ - in the example 11, and 13-10-in analog 13).

Further manipulations can be made to the phosphonate moiety prior to the final deprotection reaction. Modifications of this kind are described in more detail in the phosphonate interconversion section herein.

Example 14 Preparation of Exemplary Compounds of the Invention

Scheme 14.1

Exemplary compounds of the invention are illustrated above.

Scheme 14.2

Scheme 14.2 illustrates the synthesis of novel compounds containing phosphonates.

Diethyl3-nitrocyclobutane-1,1-dicarboxylate ( J. Org . Chem . 1989 , 54 , 2869) is immediately converted into a 3-amino derivative in two steps. 3-aminocyclobutane-1,1-dicarboxylic acid sodium salt and PtCl ₂ (NH ₃ ) ₂ are reacted to give compound 14-12 (US Pat. No. 4,625,927). Compound 14-12 is immediately converted to analogs 14-2, 14-3 and 14-5 by reaction with the appropriate phosphonate in one or two steps.

Scheme 14.3

As shown in Scheme 14.3 , 3-amino-1,1-dicarboxylic acid is obtained in two steps by first saponifying the 3-nitro derivative with NaOH and then hydrogenating in the presence of 10% Pd / C. This dicarboxylic acid is first converted to disodium salt and then reacted with PtCl ₂ (NH ₃ ) ₂ according to the previously reported method (US Pat. No. 4,657,729) to give carboplatin analog 14-12 . 14-12 and phosphonate carboxylic acid, HOAt and DIC are reacted to give 14-13 . Reductive amination of 14-12 with aldehyde phosphonate, NaBH ₃ CN and AcOH affords the desired compound 14-14 (example of 14-3 with X = -CH ₂ CH _2- ). The hydroxymethyl phosphonate is activated with triphosgene to give a chloroformate derivative to react with compound 14-12 in the presence of TEA to give the desired product 14-15 (example of 14-5 with X = -CH _2- ). .

Scheme 14.4

Diethyl3-oxocyclobutane-1,1-dicarboxylate ( J. Med . Chem . 1990 , 33 , 2905) was saponified with sodium hydroxide and then reacted with hydroxylamine hydrogen chloride in the presence of TEA to form an oxime intermediate. 14-17 is obtained. The oxime dicarboxylic acid was treated with sodium hydroxide (disodium salt formation) and then reacted with the previously reported method (US Pat. No. 4,657,729) PtCl ₂ (NH ₃ ) ₂ to give the carboplatin derivative 14-18 . Get Compound 14-18 then immediately converted to an analogue 14-33. An example of 14-4 , phosphonate 14-19, is prepared by treating 14-12 with NaH and triflate phosphonate (Scheme 14.4 ).

Scheme 14.5

In Scheme 14.5 , diethyl3 -hydroxycyclobutane-1,1-dicarboxylate ( J. Med . Chem . 1990 , 33 , 2905) was saponified with disodium salts of sodium hydroxide and dicarboxylic acid and Reaction with PtCl ₂ (NH ₃ ) ₂ according to the method reported in US Pat. No. 4,657,729 yields 3-hydroxy carboplatin analog 14-22 . This analog is reacted with triflate phosphonate and converted immediately to 14-6 . Hydroxyl 14-22 The hydroxyl group is activated to convert to analog 14-7 , followed by reaction with aminophosphonate. 3-hydroxycyclobutane-1,1-dicarboxylic acid 14-21 can be converted to its 3-oxo derivative and further converted to 14-23 and 14-24 . Compound 14-23 is reacted with PtCl ₂ (NH ₃ ) ₂ according to the previously reported method (US Pat. No. 4,657,729), and then 14-9 is obtained by hydrogenation and reductive amination. Compounds 14-24 are converted to 14-8 in a three step process by hydrogenation, carboplatin formation and reaction with aminophosphonates.

Scheme 14.6

As shown in Scheme 14.6 , diethyl3 -hydroxycyclobutane-1,1-dicarboxylate ( J. Med . Chem . 1990 , 33 , 2905) is saponified with sodium hydroxide. This dicarboxylic acid disodium salt is reacted with PtCl ₂ (NH ₃ ) ₂ according to the previously reported method (US Pat. No. 4,657,729) to give 3-hydroxy carboplatin analog 14-22 . A similar body the NaH and triflate phosphonate Chemistry and reacted immediately 14-25 - is converted to (X = -CH ₂ examples of 14-6). 14-26 is obtained by activating the hydroxyl group with p -nitrophenyl chloroformate. It is reacted with the activated acid derivatives 14-26 in the presence of TEA-aminoethyl phosphonate desired product 14-27 - to obtain the (X = -CH ₂ CH ₂ in the Example 14-7). 3-oxocyclobutane-1,1-dicarboxylic acid 14-35 to CH ₂ Cl ₂ From Ph ₃ P = CHCHO or PH ₃ P = reaction and to obtain a CHCOOBn respectively 14-33 and 14-24. The disodium salt of compound 14-33 is reacted with PtCl ₂ (NH ₃ ) ₂ to form a carboplatin derivative, and then hydrogenated in the presence of 10% Pd / C to reduce the double bond, aminoethyl phosphonate , NaBH ₃ CN and a reducing AcOH 14-28 amino desired to age-obtain the (X = -CH ₂ CH ₂ in the example 14-9). The disodium salt of compound 14-33 was reacted with PtCl ₂ (NH ₃ ) ₂ and then reductive amination with aminoethyl phosphonate, NaBH ₃ CN and AcOH 14-29 (unsaturated analog of 14-28 ) Get After hydrogenation of 14-24 in the presence of 10% Pd / C, it is reacted with PtCl ₂ (NH ₃ ) ₂ and with aminoethyl phosphonate, DIC, AcOH to give compound 14-30 (X = -CH ₂ Example of 14-8 being CH _2- .

Further manipulations can be made to the phosphonate moiety prior to the final deprotection reaction. Modifications of this kind are described in more detail in the phosphonate interconversion section herein.

Example 15 Preparation of Exemplary Compounds of the Invention

Scheme 15.1

Scheme 15.2

Phosphonate analogs 15-2 are prepared from Scheme 15. As illustrated in the second 1-alkanoyloxy-methyl steroid 15-3 (U.S. Patent No. 4,591,585). The methylene group can be introduced at the 6 position according to the method reported in Synthesis 1982 , 34. Hydrolysis of 15-4 yields 1-hydroxymethyl steroid 15-5 . Alkylating 15-5 with a phosphonate reagent gives target compound 15-2 .

Scheme 15.3

Scheme 15.3 shows the preparation of phosphonate analog of X methoxy Stan (exemestane). 1-acetyloxymethyl steroid 15-6 is treated with formaldehyde acetal, phosphorus oxychloride and sodium acetate in chloroform to give 6-methylene compound 15-7 . 15-7 Hydrolysis with sodium hydroxide gives 1-hydroxymethyl steroid 15-5 . Alkylation of 15-5 with phosphonate triflate affords product 15-8 .

Further manipulations can be made to the phosphonate moiety prior to the final deprotection reaction. Modifications of this kind are described in more detail in the phosphonate interconversion section herein.

Example 16 Preparation of Exemplary Compounds of the Invention

Scheme 16.1

Scheme 16.2

Phosphonate analog 16-2 is prepared from 1-acetyloxymethyl steroid 16-3 as illustrated in Scheme 16.2 (US Pat. No. 4,591,585). Hydrolysis of 16-3 affords 1-hydroxymethyl steroid 16-4 . 16-4 is alkylated with a phosphonate reagent to afford the desired compound 16-2 .

Scheme 16.3

Scheme 16.3 shows an example of the preparation of phosphonate analogs of atamestane. Hydrolyze 1-acetyloxymethyl steroid 16-3 with sodium hydroxide to obtain 1-hydroxymethyl steroid 16-4 . 16-4 is alkylated with phosphonate triflate to afford the product 16-5 .

Further manipulations can be made to the phosphonate moiety prior to the final deprotection reaction. Modifications of this kind are described in more detail in the phosphonate interconversion section herein.

Example 17 Preparation of Exemplary Compounds of the Invention

Scheme 17.1

Exemplary compounds of the invention are illustrated above.

Scheme 17.2

As illustrated in Scheme 17.2, phosphonate analog of type 17-2 was prepared from 17-1 by reductive alkylation of the amine with a phosphonate aldehyde.

Scheme 17.3

For example (Scheme 17.3 ), 17-1 can be substituted using aldehyde 17-15 . Reductive alkylation ( Synth Commun . 1992 , 22 , 2219) affords the desired compound 17-5 .

Scheme 17.4

As illustrated in Scheme 17.4, the type 17-3 of phosphonate analogs appropriate phosphonate reagent protected by alkylation Chem 17-6 (J. Org. With 1997, 42, 3653 reported on Obtainable by the method).

Scheme 17.5

For example (Scheme 17.5 ), tri-protected epirubicin 17-7 is alkylated with phosphonate triflate, followed by basic (0.1N sodium hydroxide) and acidic (80% acetic acid) deprotection to give compound 17 Get -8

Scheme 17.6

As illustrated in Scheme 17.6, type 17-4 of phosphonate analogs by substitution reaction of the leaving group X with an appropriate nucleophile epirubicin intermediate 17-9 (J. Med. Chem. 1985 , 28, 1223 Obtainable by the method reported in).

Scheme 17.7

For example (Scheme 17.7 ), bromide 17-11 is reacted with phosphonate amine and then deprotected to give the desired product 17-12 .

Further manipulations can be made to the phosphonate moiety prior to the final deprotection reaction. Modifications of this kind are described in more detail in the phosphonate interconversion section herein.

Example 18 Preparation of Exemplary Compounds of the Invention

Scheme 18.1

Exemplary compounds of the invention are illustrated above.

Scheme 18.2

As illustrated in Scheme 18.2 , phosphonate analogs of type 1 8 -2 are prepared from adriamycin 18-1 by reductive alkylation of amines with phosphonate aldehydes.

Scheme 18.3

For example (Scheme 18.3 ), Adriamycin 18-1 Reductive alkylation with aldehyde 18-15 ( Synth . Commun . 1992 , 22 , 2219) affords the desired compound 18-5 .

Scheme 18.4

As illustrated in Scheme 18.4, type of phosphonate analog of 18-3 is suitable phosphonate reagents adriamycin 18-6 protected by alkylation with from (J. Org. Chem. 1997, 42, 3653) Manufacture.

Scheme 18.5

For example (Scheme 18.5), tri (tri) - the adriamycin 18-7 protected phosphonate was alkylated with a triflate, basic (0.1N sodium hydroxide) and acid (80% acetic acid) to the 18-deprotected compounds Get 8

Scheme 18.6

As illustrated in Scheme 18.6 , phosphonate analogs of type 18-4 were prepared from adriamycin intermediate 18-9 ( J. Med . Chem . 1985 , 28 , 1223) by substitution reaction of leaving group X using an appropriate nucleophile . Manufacture.

Scheme 18.7

For example (Scheme 18.7 ), bromide 18-10 is reacted with phosphonate amine and then deprotected to give the desired product 18-11 .

Further manipulations can be made to the phosphonate moiety prior to the final deprotection reaction. Modifications of this kind are described in more detail in the phosphonate interconversion section herein.

Example 19 Preparation of Exemplary Compounds of the Invention

Scheme 19.1

Exemplary compounds of the invention are illustrated above. Of type 19-2 , 19-3 and 19-4 Analogs are prepared from taxotel 19-1 .

Scheme 19.2

Analogization of 19-1 directly with phosphonate reagents yields analogs of type 19-2 as major products ( Tetrahedron 1993 , 49 , 2805). Selective protection of the taxotel position at C-2 ′ ( J. Org. Chem . 1995 , 60 , 761) yielded 19-6 , alkylated with phosphonate reagents and then deprotected to provide types 19-3 and 19-. Obtain an analog of 4

Scheme 19.3

For example (Scheme 19.3), in the Taxotere 19- 1 DMF tert - treated-butyldimethylsilyl chloride and triethylamine to give the mono-protected -TBS Taxotere 19-7. The alkylation of 19-7 with phosphonate triflate is followed by deprotection with tetrabutylammonium fluoride to give the desired products 19-9 and 19-8 . Taxotel 19-1 can be alkylated directly with phosphonate triflate to obtain analogs of type 19-2 .

Scheme 19.4

As illustrated in Scheme 19.4 , analogs of type 19-5 are β-lactam 19-10 and beca according to the methods reported in Bioorg . Med . Chem. Lett . 1994 , 4 , 479; Synlett 1992 , 761. From taxotel analogues 19-12 obtainable from baccatin III ( 19-11 ).

Scheme 19.5

Β-lactam 19-14 is prepared by the method of Synlett 1992 , 761, using, eg, 4-nitrobenzaldehyde (instead of benzaldehyde) as starting material (Scheme 19.5 ). 19-14 is reacted with becatin III 19-15 in the presence of 4-dimethylaminopyridine to give compound 19-16 . 19-16 is reduced with zinc in acetic acid to afford amino compound 19-18 . 19-18 is alkylated with phosphonate triflate reagent to afford the desired compound 19-17 .

Further manipulations can be made to the phosphonate moiety prior to the final deprotection reaction. Modifications of this kind are described in more detail in the phosphonate interconversion section herein.

Example 20 Preparation of Exemplary Compounds of the Invention

Scheme 20.1

Further manipulations can be made to the phosphonate moiety prior to the final deprotection reaction. This kind of variation is described in more detail in the next section.

As illustrated in Scheme 20.2 , phosphonate analogs of type 20-2 , 20-3 and 20-4 are prepared from taxol 20-1 . 20-1 directly alkylated with a phosphonate reagent to obtain the analog of type 20-2 as a major product (Tetrahedron, (1993), 49 , 2805). Selective protection of Taxol at the C-2 ′ position ( J. Org . Chem . (1995), 60 , 761) yielded 7, followed by alkylation with a phosphonate reagent, followed by deprotection to remove analogs of type 20-3 . Get Complete protection of Taxol at positions C-2 ′ and C-7 afforded 20-8 , then the C-10 hydroxyl of 20-8 was exposed and alkylated with a phosphonate reagent, followed by deprotection to obtain type 20-4 Get analogs For example (Scheme 20.3 ), Taxol 20-1 is treated with excess tert -butyldimethylsilyl chloride and triethylamine in DMF to give bis-TBS protected Taxol 8a. Treatment of 8a with hydrazine in ethanol affords compound 20-11 ( J. Org . Chem . (1995), 60 , 761). 20-11 is alkylated with phosphonate triflate and then deprotected with tetrabutylammonium fluoride to give the desired product 20-10 .

Scheme 20.2

Scheme 20.3

As illustrated in Scheme 20.4 , analogs of type 20-5 are β-lactams according to the methods reported in Bioorg . Med . Chem . Lett . (1994), 4 , 479; Synlett . (1992), 761). From Taxol analogue 20-14, which is available from 20-12 and becatin III ( 20-13, 20-16 ). Β-lactam 20-15 is prepared by the method of Synlett . (1992), 761, using, for example (Scheme 19.5 ), 4-nitrobenzoyl chloride (instead of benzoyl chloride) as starting material. 20-15 is reacted with becatin III in the presence of 4-dimethylaminopyridine to give compound 20-17 . 20-17 is reduced with zinc in acetic acid to afford amino compound 20-19 . 20-19 is alkylated with a phosphonate triflate reagent to afford the desired compound 20-18 .

Scheme 20.4

Scheme 20.5

As shown in Schemes 20.6 and 20.7 , analogs of type 20-6 can be prepared in the same manner as types 20-5 .

Scheme 20.6

Scheme 20.7

Example 21 Preparation of Exemplary Compounds of the Invention

Scheme 21.1

Further manipulations can be made to the phosphonate moiety prior to the final deprotection reaction. This kind of variation is described in more detail in the next section.

As illustrated in Scheme 21.2 , the strategy for synthesis of phosphonate analogs of type 21-2 was first introduced by introducing a phosphonate moiety into catharanthine 21-5 to obtain 21-7 and then vindoline. ) 21-10 and Conversion to final compound 21-2 is carried out using the same method used for the synthesis of vinorelbine (Bioorg. Med. Chem. Lett. (2002), 12, 505; Tetrahedron (1980), 36 , 3053).

Scheme 21.2

For example (Scheme 21.3), Catalan by hydrolysis with sodium hydroxide to the others 21-5 21-6 is obtained. 21-6 is combined with phosphonate amine to give 21-9 . 3-chloroperoxybenzoic acid (mCPBA), in trifluoroacetic acid anhydride (TFAA) and sodium beam successively treated with a hydride converts 21-9 to 21-10 and the blank rotate compounds 21-11. 21-11 is treated with N-bromosuccinimide (NBS) followed by silver tetrafluoroborate to give the desired compound 21-12 .

Scheme 21.3

In Scheme 21.4 As illustrated, similar strategies are used for the synthesis of phosphonate analogs of type 21-3 . First, the phosphonate moiety is introduced into bindolin 21-10 to obtain 21-14, and then linked to catalantine 21-5 and the final compound 21-3 using the same method as used for the synthesis of vinorelbine. Convert

Scheme 21.4

For example (Scheme 21.5 ), bindolin 21-10 is hydrolyzed with sodium hydroxide and the hydroxyls are then deprotected to give 21-20 . 21-20 is combined with phosphonate amine to give 21-15 . Finally, 21-15 and 21-5 are converted to the desired product 21-17 in the same manner as described above.

Scheme 21.5

In Scheme 21.6 As illustrated, phosphonate analogs of type 21-4 are prepared from vinorelbine 21-1 . Decomposing 21-1 to 21-18 obtained singer, then alkylated with a phosphonate reagent to obtain the analog of type 21-4.

For example (Scheme 21.7), was treated with 21-1 sodium methoxide in anhydrous methanol to give compounds 21-18. 21-18 is alkylated with phosphonate triflate in the presence of sodium hydride to afford the desired compound 21-19 .

Scheme 21.6

Scheme 21.7

Example 22 Preparation of Exemplary Compounds of the Invention

Scheme 22.1

These compounds are represented by Scheme 22.4-22. Scheme 22.2-22 with example shown in 6 . It can be prepared according to the general route shown in 3.

Scheme 22.2 : modification of sugar substituents

Scheme 22.3 : binding to epi-podophyllotoxin core

Scheme 22.4 : Modification of 4,6 glucose acetal moiety

Glucose-inducing starting material Chem . Lett . (1987), 799-802, according to the method described in glucose and benzyl glyoxylate ( J. Org . Chem . , (2002), 67 , 5408-5411). The glycosidation reaction is carried out with 4'chloroacetyl protected epipodophyllotoxin (as described above) under the catalysis of boron trifluoride (as described in reference above). The product of this reaction is dissolved in an organic solvent such as ethyl acetate and hydrogenated in the presence of Pd / C under hydrogen atmosphere. The resulting reaction mixture is filtered through Celite and the solvent is removed in vacuo. The resulting reaction product is dissolved in an organic solvent such as DMF or chloroform and then treated with a tertiary amine base such as diisopropylethylamine (DIEA) and isobutylchloroformate at a temperature of ˜−10 ° C. After activation is complete, 2-aminoethylphosphonic acid diethyl ester is added. After all the starting material has been consumed, the reaction mixture is washed with aqueous 0.1 M HCl and aqueous bicarbonate solution. After drying and removing the solvent, the crude binding product is obtained. Further purification is by chromatography. The material is dissolved in an organic solvent such as methanol and treated with zinc acetate at reflux temperature. At the end of the reaction, the mixture is cooled to room temperature and the solvent is removed in vacuo. The resulting reaction product is dissolved in an organic solvent such as chloroform and the solution is washed with aqueous 0.1 M HCl and aqueous bicarbonate solution. After drying and removing the solvent, the crude final product is obtained. Further purification is by chromatography.

Scheme 22.5 : modification of the glucose core

The starting materials (Chem. Lett., (1987 ), synthesized according to the 799-804) in an organic solvent such as DCM or THF J. Org. Treatment with diethylphosphonate ethyl carbaldehyde and sodium triacetoxyborohydride as described in Chem , (1996), 61, 3849-3862. The reaction is stopped with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. Further purification is by chromatography.

Scheme 22.6 : binding to the epi-podophyllotoxin core

Amine containing starting material (obtained as described in J. Med . Chem . , (1991), 34 , 3346-3350.) Was prepared from J. Org . Treatment with diethylphosphonato-ethylcarbaldehyde and sodium triacetoxyborohydride in an organic solvent such as DCM or THF as described in Chem , (1996), 61, 3849-3862. The reaction is stopped with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. Further purification is by chromatography.

The compounds were treated with phosphoryl trichloride in the presence of a tertiary organic amine base such as DIEA in an organic solvent such as MeCN, followed by Bioorg . Med . Chem . Lett . By treatment with an aqueous bicarbonate solution as described in (1994), 21 , 2567-2572 All final products are converted into the corresponding 4 'phosphate analogs. Final purification is by chromatography.

Example 23 Preparation of Exemplary Compounds of the Invention

These compounds are prepared according to the general route shown in Scheme 23.1 to 23.6 in the examples shown in Scheme 23.7 to 23.12.

Scheme 23.1 : reforming at C4

Scheme 23.2 : binds to C23

Scheme 23.3 : binding to N1

Scheme 23.4 : binding to C4 '

Scheme 23.5 : binding to C12 '

Scheme 23.6 : binding to C22 '

Scheme 23.7 : binding to C4

2-diethyl phosphonatoacetic acid was added to J. Med . Chem . , (1991), 34 , 1001-1018 and so on in an organic solvent such as benzene, tetrahydrofuran (THF) or chloroform, diisopropylethylamine (DIEA) and diphenyl phosphorazate (1.2 equivalents), and the like. It is mixed with the tertiary amine base of and stirred at room temperature. After the acyl azide is formed, 4-deacetylvinblastine (prepared from vinblastine according to J. Med . Chem. , (2002), 45 , 4706-4715) is added and the reaction mixture is added for 4 h. Heat to 80 ° C. ( BioChemistry (2002), 41 , 14010-14018). The reaction mixture is cooled to room temperature, washed with aqueous hydrochloric acid (HCl) (IN) and aqueous bicarbonate solution and dried. The solvent is removed to give crude product. Further purification is by chromatography.

The product of this step is dissolved in an organic solvent such as acetonitrile and the solution is cooled to -2 ° C. Strong inorganic acids (2 equivalents), such as perchloric acid, were added and then added to Pierce, "Medicinal Chemistry of Bisindole Alkaloids from Catharanthus", in The Alkaloids , Vol. 37, 145, Academic Press San Diego, (1990)] add ferrous perchlorate and hydrogen peroxide (excess). At the end of the reaction, aqueous ammonium hydroxide is added and the reaction mixture is extracted with an organic solvent such as dichloromethane (DCM). The solvent is removed in vacuo to afford crude product. Further purification is by chromatography.

Scheme 23.8 : bind to C23

Starting materials (synthesized from vinblastine as disclosed in J. Med . Chem . , (1978), 21, 88-96) were synthesized by J. Med . Treatment with 2-aminoethylphosphonic acid diethyl ester in an organic solvent such as DCM or THF at room temperature according to the method described in Chem , (1979), 22, 391-400. At the end of the reaction, the solution is washed with water, aqueous bicarbonate and water and dried. The solvent is evaporated to afford crude product. Further purification is by chromatography.

The product of this step is dissolved in an organic solvent such as DCM or THF. Pyridine was added followed by acetic anhydride and the reaction was carried out in J. Med . Chem . Stir at room temperature according to (1979), 22 , 391-400. At the end of the reaction, methanol is added and the solvent is removed in vacuo. The crude material is dissolved in an organic solvent such as DCM, washed with water and aqueous bicarbonate solution and dried. The solvent is removed in vacuo to afford crude product. Further purification is by chromatography.

The product of this step is dissolved in an organic solvent such as acetonitrile and the solution is cooled to -20 ° C. Pierce, "Medicinal Chemistry of Bisindole Alkaloids from Catharanthus", in The Alkaloids , Vol. 37, 145, Academic Press San Diego, (1990)], followed by the addition of strong inorganic acids such as perchloric acid (2 equivalents) followed by the addition of ferrous perchlorate and excess hydrogen peroxide. At the end of the reaction, aqueous ammonium hydroxide is added and the reaction mixture is extracted with an organic solvent such as DCM. The solvent is removed in vacuo to afford crude product. Further purification is by chromatography.

Scheme 23.9 : binding to N1

2-diethyl phosphonatoacetic acid was added to J. Med . Chem . , (1991), 34 , 1001-1018, dissolved in organic solvents such as benzene, THF or chloroform, and tertiary amine bases such as diisopropylethylamine (DIEA) and diphenyl phosphorazate (1.2 equivalents). Mix with and stir at room temperature. After the formation of acyl azide, N-1- (β-hydroxyethylthiomethyl) vinblastine (Phys Chemistry of Bisindole Alkaloids from Catharanthus, in The Alkaloids , Vol. 37, 145, Academic Press San Diego, (1990), prepared from vinblastine by methoxy substitution with CrO ₃ -mediated oxidation followed by β-hydroxy thioethanol in the presence of methanol) and the reaction mixture was added for 4 hours. Heat to 80 ° C. ( BioChemistry (2002), 41 , 14010-14018). The reaction mixture is cooled to room temperature, washed with aqueous HCl (1N) and aqueous bicarbonate solution and dried. The solvent is removed to give crude product. Further purification is by chromatography.

Scheme 23.10 : Binding to C4 '

Vinblastine and diethyl (cyanomethyl) phosphonate (commercially available) are described in Pierce, "Medicinal Chemistry of Bisindole Alkaloids from Catharanthus", in The Alkaloids , Vol. 37, 145, Academic Press San Diego, (1990) (as described for acetonitrile), and dissolved in concentrated sulfuric acid at a temperature of ~ 0 ℃. When the starting material is consumed the reaction mixture is carefully diluted with water and further neutralized. The resulting reaction mixture is extracted with an organic solvent such as DCM. The combined organic extracts are washed with aqueous bicarbonate solution and dried. The solvent is removed to give crude product. Further purification is by chromatography.

The product of this step is dissolved in an organic solvent such as acetonitrile and cooled to -20 ° C. Pierce, "Medicinal Chemistry of Bisindole Alkaloids from Catharanthus", in The Alkaloids , Vol. 37, 145, Academic Press San Diego, (1990)], followed by addition of strong inorganic acids, such as perchloric acid (2 equivalents), followed by the addition of ferrous perchlorate and excess hydrogen peroxide. At the end of the reaction, aqueous ammonium hydroxide is added and the reaction mixture is extracted with an organic solvent such as DCM. The solvent is removed in vacuo to afford crude product. Further purification is by chromatography.

Scheme 23.11 : binding to 12 '

Vinblastine perchloric acid according to C12'iodo-vinblastine ("Medicinal Chemistry of Bisindole Alkaloids from Catharanthus", in The Alkaloids , Vol. 37, 145, Academic Press San Diego, (1990)). Ferrous, tetra ( n -propyl) ammonium periodinate and prepared by iodide reaction with catalytic amount of ruthenium dioxide) are added to a mixture of copper iodide and potassium phosphate and 2-aminoethylphosphonic acid diethyl ester (commercially available) do. The reaction mixture is described by Buchwald in Org. Lett ., (2002), 4 , 581-584, are heated to ˜80 ° C. under an inert gas atmosphere.

At the end of the reaction the material is cooled to room temperature and the solvent is removed in vacuo. The resulting reaction mixture is extracted with an organic solvent such as DCM. The combined organic extracts are washed with aqueous bicarbonate solution and dried. The solvent is removed to give crude product. Further purification is by chromatography. The product of this step is dissolved in an organic solvent such as DCM or THF. J. Med. Chem . (1979), 22 , 391-400, pyridine is added followed by acetic anhydride and the reaction is stirred at room temperature. At the end of the reaction, methanol is added and the solvent is removed in vacuo. The crude material is dissolved in an organic solvent such as DCM, washed with water and aqueous bicarbonate solution and dried. The solvent is removed in vacuo to afford crude product. Further purification is by chromatography.

The product of this step is dissolved in an organic solvent such as acetonitrile and the solution is cooled to -20 ° C. Pierce, "Medicinal Chemistry of Bisindole Alkaloids from Catharanthus", in The Alkaloids , Vol. 37, 145, Academic Press San Diego, (1990)], followed by addition of strong inorganic acids such as perchloric acid (3 equivalents) followed by the addition of ferrous perchlorate and excess hydrogen peroxide. At the end of the reaction, aqueous ammonium hydroxide was added and The reaction mixture is extracted with an organic solvent such as DCM. The solvent is removed in vacuo to afford crude product. Further purification is by chromatography.

Scheme 23.12 : binding to 22 '

According to the starting material ("Medicinal Chemistry of Bisindole Alkaloids from Catharanthus", in The Alkaloids , Vol. 37, 145, Academic Press San Diego, (1990)) Vinbla in NaOH (5N) under reflux conditions Styrene, prepared by complete hydrolysis), is dissolved in an organic solvent such as dimethylformamide (DMF) at room temperature. Methyl iodide (1 equiv) is added followed by potassium carbonate. Continue stirring at room temperature. At the end of the reaction, the reaction is filtered to remove the solvent in vacuo. The desired C24 methyl ester is purified by chromatography. The product of step 1 is dissolved in an organic solvent such as DCM or DMF and the solution is cooled to -10 ° C. A tertiary amine base such as DIEA is added followed by a binding reagent such as iso - butylchloroformate . Stirring is continued at −10 ° C. until activation is complete. Aminoethylphosphonic acid diethyl ester is added and stirring is continued while slowly warming to 0 ° C. At the end of the reaction, the solution is warmed to room temperature and the solvent is removed in vacuo. The product is further purified by chromatography. The product of this step is dissolved in an organic solvent such as DCM or THF. J. Med . Chem . (1979), 22 , 391-400, pyridine is added followed by acetic anhydride and the reaction is stirred at room temperature. At the end of the reaction, methanol is added and the solvent is removed in vacuo. The crude material is dissolved in an organic solvent such as DCM, washed with water and aqueous bicarbonate solution and dried. The solvent is removed in vacuo to afford crude product. Further purification is by chromatography.

The product of this step is dissolved in an organic solvent such as acetonitrile and the solution is cooled to -20 ° C. Pierce, "Medicinal Chemistry of Bisindole Alkaloids from Catharanthus", in The Alkaloids , Vol. 37, 145, Academic Press San Diego, (1990)], followed by addition of strong inorganic acids such as perchloric acid (3 equivalents) followed by the addition of ferrous perchlorate and excess hydrogen peroxide. At the end of the reaction, aqueous ammonium hydroxide was added and The reaction mixture is extracted with an organic solvent such as DCM. The solvent is removed in vacuo to afford crude product. Further purification is by chromatography.

Example 24 Preparation of Exemplary Compounds of the Invention

The compounds of the present invention can be prepared according to the general route in Schemes 24.1 and 24.3 , with examples shown in Schemes 24.2 and 24.4 .

Scheme 24.1

Scheme 24.2

2-chloro-2'deoxyadenosine 24-1 (Ikehara, M. et al., J. Am. Chem . Soc ., (1963), 85 , 2344, also prepared according to the method of Ikehara, M. et al. ., J. Am. Chem . Soc . , (1965), 87 , 3, 606) can be treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added to give the desired phosphonate diester 24-2, 24-3 . .

Scheme 24.3

Scheme 24. 3 is To illustrate the preparation of compounds 24-7, 24-13 . Compound 24-1 (2-chloro-2'deoxyadenosine) is described in Ikehara, M. et al., J. Am. Chem . Soc ., (1963), 85 , 2344, and also prepared by Ikehara, M. et al., J. Am. Chem. Soc . , (1965), 87 , 3, 606. After oxidation of 5′-OH, a removal reaction was carried out to obtain glycal 24-4 (see the method of Zemlicka J. et al., J. Am. Chem. Soc . , (1972), 94 , 9, 3213). Get Phosphonates 24-5, 24-10 (Kim, C. et al., J. Org . Chem ., (1991), 56 , 2642) protected by chloroadenine at position 6 and protected by selenoetherification Get Oxidative removal of phenylselenide (as described in Kim, C. et al., J. Org . Chem ., (1991), 56 , 2642), followed by selective dihydroxylation to obtain a diol followed by diol Can be converted to a 3 'monoprotected sugar. The 2 'alcohol is acylated with phenyl chlorothioinoformate to obtain precursors for Robins deoxygenation. By continuous deoxidation , compounds 24-6, 24-12 (Metteucci, MD et al., Tetrahedron Lett ., (1987), 28 , 22, 2469, and also Robins, MJ et al., J. Org . Chem , (1995), 60 , 7902). Finally remove the protectors.

Scheme 24.4

In particular, 2-chloro-2'deoxyadenosine and compound 24-1 can be oxidized with PtO ₂ to obtain carboxylic acid 24-8 . The decarboxylation removal reaction is performed using dimethylformamide dinepentyl acetal in high temperature DMF. (Zemlicka J. et al., J. Am. Chem . Soc. , (1972), 94 , 9, 3213). Obtaining furanoid glycal 24-4 first protects the 6 position of 2-chloroadenosine using PivCl conditions as described in Greene, T., Protective Groups in Organic Chemistry , Wiley-Interscience, 1999 . The protected glycal was treated with silver perchlorate in the presence of diethyl (hydroxymethyl) phosphonate (Phillion, D. et al., Tetrahedron Lett., 1986, 27, 1477) phosphonate 24-5, 24-10 (Kim, C. et al., J. Org . Chem ., (1991), 56 , 2642). After oxidative removal of the selenide, dehydroxylation is carried out using osmium tetraoxide to obtain a diol capable of monoprotection at the 3 'position using a THP group. Further acylation of 2'alcohol with phenyl chlorothionoformate to give a precursor for robin deoxygenation and treatment with tributyltin hydride yields compounds 24-6, 24-12 (Metteucci, MD et al., Tetrahedron Lett , (1987), 28 , 22, 2469, see also Robins, MJ et al., J. Org . Chem ., (1995), 60 , 7902). Treatment with sodium methoxide to deprotect the pivaloyl group (Greene, T., Protective Groups in Organic Chemistry , Wiley-Interscience, (1999)) followed by final deprotection of the THF group in acetic acid.

Example 25 Preparation of Exemplary Compounds of the Invention

These compounds can be prepared according to the general route shown in, reaction formula 25.1 to 25.5 with the embodiments shown in Scheme 25.2 to 25.5. Final compounds that are stereoisomers or enantiomers can be purified by chromatographic methods.

Scheme 25.1 : General approach to all classes of compounds

Scheme 25.2 :

The starting carboxylic acid is mixed with a binder such as diethylcyanophosphonate or isobutylchloroformate and diisopropylethylamine in a solvent such as dimethylformamide (DMF) or N-methyl pyrrolidinone (NMP) at room temperature. DIEA), etc. ( J. Med . Chem ., (1982), 25 , 960-964 and J. Med . Chem ., (1984), 27 , 600-604). When activation is complete, 2-aminoethylphosphonic acid diethyl ester (commercially available) is added. After observing that the activated material has been consumed completely, the solvent is removed in vacuo and the product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Scheme 25.3 :

The starting carboxylic acid can be treated with a binder such as diethylcyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) in a solvent such as DMF or NMP at room temperature . Med . Chem ., (1982), 25 , 960-964 and J. Med . Chem ., (1984), 27 , 600-604). When the activation was complete, (2-amino-ethylsulfanylmethyl) -phosphonic acid diethyl ester (2-aminoethanethiol was prepared according to Tetrahedron Lett ., (1986), 27 , 1477 Prepared by base catalyzed coupling reaction into a plate). After observing that the activated material has been consumed completely, the solvent is removed in vacuo and the intermediate is separated by chromatography. Optionally, the intermediate may be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether. The intermediate is then dissolved in a mixture of water, DMF and acetic acid and treated with hydrogen peroxide solution (excess). After removal of the solvent the product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Scheme 25.4 :

The starting carboxylic acid can be treated with a binder such as diethylcyanophosphonate or isobutylchloroformate and a base such as DIEA in a solvent such as DMF or NMP at room temperature ( J. Med . Chem ., (1982). ), 25 , 960-964 and J. Med . Chem ., (1984), 27 , 600-604.). When activation is complete, ( L ) -2-amino-6- (diethylphosphonato) -hexanoic acid is added. After observing that the activated material has been consumed completely, the solvent is removed in vacuo and the product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Scheme 25.5 :

The starting carboxylic acid can be treated with a binder such as diethylcyanophosphonate or isobutylchloroformate and a base such as DIEA in a solvent such as DMF or NMP at room temperature ( J. Med . Chem ., (1982). ), 25 , 960-964 and J. Med . Chem ., (1984), 27 , 600-604). When the activation is complete, 4-amino-4- (diethylphosphonato) -butyric acid tert butylester ( J. Am. Chem . Soc ., (1995), 117 , 10879-10888) is added. After observing that the activated material has been consumed completely, the solvent is removed in vacuo and the intermediate is separated by chromatography. Optionally, the intermediate may be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether. The crude intermediate is then dissolved in DMF and treated with trifluoroacetic acid (TFA). After removal of the solvent the product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Example 26 Preparation of Exemplary Compounds of the Invention

Such compounds can be prepared according to the general route shown in Schemes 26.1-26.5 , with the embodiments shown in Schemes 2-4 . Final compounds that are stereoisomers or enantiomers can be purified by chromatographic methods.

Scheme 26.1 : general approach to all classes of compounds

If direct binding to aminopterin is inhibited by the presence of free secondary amines in the starting material (R = H), the material is converted to tert-butoxycarbonyl groups according to standard methods (Green Wutts: Protective groups in organic chemistry). R = Boc) or benzyloxycarbonyl (R = Cbz or Z).

Scheme 26.2 :

The starting carboxylic acid is bound to a solvent such as diethylcyanophosphonate or isobutylchloroformate and diisopropylethylamine (DIEA) in a solvent such as dimethylformamide (DMF) or N-methylpyrrolidinone (NMP) at room temperature. ( J. Med . Chem ., (1982), 25 , 960-964 and J. Med . Chem ., (1984), 27 , 600-604). When activation is complete, 2-aminoethylphosphonic acid diethyl ester (commercially available) is added. After observing that the activated material has been consumed completely, the solvent is removed in vacuo and the product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

In the case of R = Z, the compound is dissolved in an organic solvent such as DMF or NMP and a catalytic amount of Pd / C is added. The reaction mixture is stirred under hydrogen atmosphere until the starting material is consumed. Pd / C is filtered off and the solvent is evaporated in vacuo. The product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Scheme 26.3 :

The starting carboxylic acid is treated with a binder such as diethylcyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) in a solvent such as DMF or NMP at room temperature ( J. Med . Chem , (1982), 25 , 960-964 and J. Med . Chem ., (1984), 27 , 600-604). When the activation was complete, (2-amino-ethylsulfanylmethyl) -phosphonic acid diethyl ester (2-aminoethanethiol was prepared according to Tetrahedron Lett ., (1986), 27 , 1477 Prepared by base catalyzed coupling reaction into a plate). After observing that the activated material has been consumed completely, the solvent is removed in vacuo and the intermediate is separated by chromatography. Optionally, the intermediate may be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether. The intermediate is then dissolved in a mixture of water, DMF and acetic acid and treated with hydrogen peroxide solution (excess). After removal of the solvent the product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

In the case of R = Z, the compound is dissolved in an organic solvent such as DMF or NMP and a catalytic amount of Pd / C is added. The reaction mixture is stirred under hydrogen atmosphere until the starting material is consumed. Pd / C is filtered off and the solvent is evaporated in vacuo. The product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Scheme 26.4 :

The starting carboxylic acid can be treated with a binder such as diethylcyanophosphonate or isobutylchloroformate and a base such as DIEA in a solvent such as DMF or NMP at room temperature ( J. Med . Chem ., (1982) , 25 , 960-964 and J. Med . Chem ., (1984), 27 , 600-604.). When activation is complete, ( L ) -2-amino-6- (diethylphosphonato) -hexanoic acid is added. After observing that the activated material has been consumed completely, the solvent is removed in vacuo and the product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

In the case of R = Z, the compound is dissolved in an organic solvent such as DMF or NMP and a catalytic amount of Pd / C is added. The reaction mixture is stirred under hydrogen atmosphere until the starting material is consumed. Pd / C is filtered off and the solvent is evaporated in vacuo. The product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Scheme 26.5 :

The starting carboxylic acid can be treated with a binder such as diethylcyanophosphonate or isobutylchloroformate and a base such as DIEA in a solvent such as DMF or NMP at room temperature ( J. Med . Chem ., (1982) , 25 , 960-964 and J. Med . Chem ., (1984), 27 , 600-604). When the activation is complete, 4-amino-4- (diethylphosphonato) -butyric acid tert butylester ( J. Am. Chem . Soc ., (1995), 117 , 10879-10888) is added. After observing that the activated material has been consumed completely, the solvent is removed in vacuo and the intermediate is separated by chromatography. Optionally, the intermediate may be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether. The crude intermediate is then dissolved in DMF and treated with TFA (excess). After removal of the solvent the product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

In the case of R = Z, the compound is dissolved in an organic solvent such as DMF or NMP and a catalytic amount of Pd / C is added. The reaction mixture is stirred under hydrogen atmosphere until the starting material is consumed. Pd / C is removed and the solvent is evaporated in vacuo. The product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Example 27 Preparation of Exemplary Compounds of the Invention

Such compounds can be prepared according to the general routes shown in Schemes 27.1 and 27.3 , in conjunction with the embodiments of Schemes 27.2 and 27.4-27.6 .

Scheme 27.1

Bis-anisole derivatives of flavopyridol (see Bioorg . Med . Chem . Lett ., (2000), 10 , 1037) serve as ideal starting points for binding phosphonate moieties to piperidine nitrogen. do. After protecting the alcohol, the tertiary amine is methylated and derivatized with the selected reagent. The methyl ether and protecting groups of the alcohol are removed to give the desired analog.

Albosidib analogs having phosphonate moieties bound to piperidine nitrogen in this manner are illustrated in Scheme 27.2 .

Scheme 27.2

The alcohol is protected as acetate under standard conditions (see Greene, T., Protective Groups in Organic Chemistry , Wiley-Interscience, (1999)). The N-methylpiperidine is demethylated by reaction with a-chloroethyl chloroformate in the presence of a base such as diisopropylmethylamine (DIEA), followed by brief heating in acidic methanol.

The liberated secondary amine is condensed with (2-oxo-ethyl) -phosphonic acid diethyl ester under reducing conditions such as those using sodium cyanoborohydride in a solvent such as methanol or dimethylformamide ( Tet . Lett . (1990), page 31, 5595). The alcohol is deacetylated by treatment with sodium ethoxylate in ethanol. Finally, bis-demethylation is carried out by heating with pyridinium hydrogen chloride (see Bioorg . Med . Chem . Lett ., (2000), 10 , 1037).

Scheme 27.3

2-hydroxyacetophenone (see Bioorg . Med . Chem . Lett ., (2000), 10 , 1037) is treated with a suitable phosphonate containing benzoyl chloride derivatives. Cyclization forms a flavone ring system and removes methyl groups. Such a synthesis is illustrated in Scheme 27.4 .

Scheme 27.4

Condensation with [4- (2-chlorocarbonyl-phenoxy) -but-2-ethyl] -phosphonic acid diethyl ester (synthesized below) followed by successive treatment with sodium hydride, hydrochloric acid and sodium carbonate to give 5,7- Obtain dimethoxyflavones. Demethylation is performed as in Scheme 27.2 to obtain a 5,7-dihydroxyflavone final product (see Bioorg . Med . Chem . Lett ., (2000), 10 , 1037).

Scheme 27.5 . Synthesis of [4- (2-chlorocarbonyl-phenoxy) -but-2-ethyl] -phosphonic acid diethyl ester

The salicylic acid methyl ester is treated with a base such as sodium hydride in a solvent such as dimethylformamide or tetrahydrofuran. At the end of bubbling, excess E- 1,4-dibromobutene is added. The reaction is stopped with aqueous ammonium chloride and the product is extracted with an organic solvent such as ethyl acetate, and then the mono-alkylated product is separated by chromatography. The resulting monobromide was treated with triethylphosphite in a solvent such as toluene (or other Arbuzov reaction conditions: Engel, R., Synthesis of Carbon-Phophorus bonds, CRC press, 1988). Get The methyl ester is saponified with lithium hydroxide and treated with oxalyl chloride in a solvent such as dichloromethane in the presence of a catalytic amount of dimethylformamide to obtain an acid chloride.

Another suitable synthesis of acid chloride is illustrated below.

Scheme 27.6

The phenol is treated with a base such as sodium hydride in a solvent such as dimethylformamide or tetrahydrofuran. At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added to give the desired phosphonate diester.

Similarly, suitable reagents can be obtained from 4-hydroxybenzoic acid methyl ester to produce analogs having phosphonate moieties that are bonded to the 4-position of the phenyl ring at the flavone 2-position.

Example 28 Preparation of Exemplary Compounds of the Invention

Reduction of dose and / or improvement in efficacy is achieved by using prodrugs of analogs of vinblastine that generate reagents with increased intracellular half-life upon degradation in target cells. Such compounds are described below.

Scheme 28.1

These compounds can be prepared according to the general route shown in, reaction formula 28.2 to 28.7 in the examples shown in Scheme 28.8 to 28.13.

Scheme 28.2 : Modification at C4

Scheme 28.3 : binding to C23

Scheme 28.4 : Binding to N1

Scheme 28.5 : binding to C4 '

Scheme 28.6 : binding to C12 '

Scheme 28.7 : Binding to C22 '

Scheme 28.8 : binding to C4

2-diethyl phosphonatoacetic acid was added to J. Med . Chem . , (1991), 34 , 1001-1018 and so on in an organic solvent such as benzene, tetrahydrofuran (THF) or chloroform, and diisopropylethylamine (DIEA) and diphenyl phosphoradate (1.2 equivalents). Mix with tertiary amine base and stir at room temperature. After the acyl azide is formed, 4-deacetyl vinblastine (prepared from vinblastine according to J. Med . Chem. , (2002), 45 , 4706-4715) is added and the reaction mixture is added to the mixture for 4 h to 80 Heat to ° C. ( Bio Chemistry , (2002), 41 , 14010-14018). The reaction mixture is cooled to room temperature, washed with aqueous hydrochloric acid (HCl) (IN) and aqueous bicarbonate solution and dried. The solvent is removed to give crude product. Further purification is by chromatography.

Scheme 28.9 : binding to C23

Starting materials (synthesized from vinblastine as disclosed in J Med . Chem . , (1978), 21, 88-96) were synthesized by J. Med . Treated with 2-aminoethylphosphonic acid diethyl ester in an organic solvent such as dichloromethane (DCM) or THF at room temperature according to the method described in Chem , (1979), 22, 391-400. At the end of the reaction, the solution is washed with water, aqueous bicarbonate and water and dried. The solvent is evaporated to afford crude product. Further purification is by chromatography.

The product of this step is dissolved in an organic solvent such as DCM or THF. J. Med . Chem . Pyridine followed by acetic anhydride according to (1979), 22 , 391-400 and the reaction is stirred at room temperature. At the end of the reaction, methanol is added and the solvent is removed in vacuo. The crude material is dissolved in an organic solvent such as DCM, washed with water and aqueous bicarbonate solution and dried. The solvent is removed in vacuo to afford crude product. Further purification is by chromatography.

Scheme 28.10 : Binding to N1

2-diethyl phosphonatoacetic acid is dissolved in an organic solvent such as benzene, THF or chloroform and mixed with a tertiary amine base such as diisopropylethylamine (DIEA) and diphenyl phosphorazate (1.2 equiv) And J. Med . Chem . Stir at room temperature according to (1991), 34 , 1001-1018. After the formation of acyl azide, N-1- (β-hydroxyethylthiomethyl) vinblastine ("Medicinal Chemistry of Bisindole Alkaloids from Catharanthus", in The Alkaloids , Vol. 37, 145, Academic Press San Diego, (1990), prepared from vinblastine by methoxy substitution with CrO ₃ -mediated oxidation followed by β-hydroxy thioethanol in the presence of methanol) and the reaction mixture was added for 4 hours. Heat to 80 ° C. ( BioChemistry (2002), 41 , 14010-14018). The reaction mixture is cooled to room temperature, washed with aqueous HCl (IN) and aqueous bicarbonate solution and dried. The solvent is removed to give crude product. Further purification is by chromatography.

Scheme 28.11 : binding to C4 '

Vinblastine and diethylcyanomethylphosphonate (commercially available) are described in Pierce, "Medicinal Chemistry of Bisindole Alkaloids from Catharanthus", in The Alkaloids , Vol. 37, 145, Academic Press San Diego, (1990)], dissolved in concentrated sulfuric acid at a temperature of ~ 0 ℃. When the starting material is consumed, the reaction mixture is carefully diluted with water and further neutralized. The resulting reaction mixture is extracted with an organic solvent such as DCM. The combined organic extracts are washed with aqueous bicarbonate solution and dried. The solvent is removed to give crude product. Further purification is by chromatography.

Scheme 28.12 : binding to 12 '

Cyl iron perchlorate, tetra, according to C12'-iodo-vinblastine ("Medicinal Chemistry of Bisindole Alkaloids from Catharanthus", in The Alkaloids , Vol. 37, 145, Academic Press San Diego, (1990)). ( n -propyl) ammonium periodinate and catalytic amounts of ruthenium dioxide are prepared by iodizing vinblastine) in a mixture of copper iodide and potassium phosphate and 2-aminoethylphosphonic acid diethylester (commercially available) Add. The reaction mixture is described by Buchwald in Org . Lett ., (2002), 4 , 581-584] are heated to ˜80 ° C. under an inert gas atmosphere. At the end of the reaction the material is cooled to room temperature and the solvent is removed in vacuo. The resulting reaction mixture is extracted with an organic solvent such as DCM. The combined organic extracts are washed with aqueous bicarbonate solution and dried. The solvent is removed to give crude product. Further purification is by chromatography. The product of this step is dissolved in an organic solvent such as DCM or THF. J. Med . Chem . (1979), 22 , 391-400, pyridine is added followed by acetic anhydride and the reaction is stirred at room temperature. At the end of the reaction, methanol is added and the solvent is removed in vacuo. The crude material is dissolved in an organic solvent such as DCM, washed with water and aqueous bicarbonate solution and dried. The solvent is removed in vacuo to afford crude product. Further purification is by chromatography.

Scheme 28.13 : binding to 22 '

Vinbla in NaOH (5N) under reflux conditions, according to the starting material ("Medicinal Chemistry of Bisindole Alkaloids from Catharanthus", in The Alkaloids , Vol. 37, 145, Academic Press San Diego, (1990)). Stine is completely hydrolyzed) in an organic solvent such as dimethylformamide (DMF) at room temperature. Methyl iodide (1 equiv) is added followed by potassium carbonate. Continue stirring at room temperature. At the end of the reaction, the reaction is filtered to remove the solvent in vacuo. The desired C24 methyl ester is purified by chromatography. The product of step 1 is dissolved in an organic solvent such as DCM or DMF and the solution is cooled to -10 ° C. It is added a coupling reagent, such as butyl chloroformate - followed by a tertiary amine base such as DIEA isopropyl. Stirring is continued at −10 ° C. until activation is complete. Aminoethylphosphonic acid diethyl ester is added and stirring is continued while slowly warming up to 0 ° C. At the end of the reaction, the solution is warmed to room temperature and the solvent is removed in vacuo. The product is further purified by chromatography. The product of this step is dissolved in an organic solvent such as DCM or THF. J. Med. Pyridine is added according to Chem., (1979), 22, 391-400, then acetic anhydride is added and the reaction is stirred at room temperature. At the end of the reaction, methanol is added and the solvent is removed in vacuo. The crude material is dissolved in an organic solvent such as DCM, washed with water and aqueous bicarbonate solution and dried. The solvent is removed in vacuo to afford crude product. Further purification is by chromatography.

Example 29 Preparation of Exemplary Compounds of the Invention

Reduction of dose and / or improvement in efficacy is achieved by using prodrugs of analogs of tipifarnib that generate reagents with increased intracellular half-life upon degradation in target cells. Such compounds are described below.

Scheme 29.1

Such compounds can be prepared according to the general routes shown in Schemes 29.2 , 29.4 , 29.6 , 29.8 and 29.10 , with the embodiments shown in Schemes 29.3 , 29.5 , 29.7 , 29.9 and 29.11 .

Scheme 29.2

Scheme 29.3

Quinolone (see US Pat. No. 5,968,952) is treated with a base such as potassium carbonate in a solvent such as dimethylformamide (DMF) or tetrahydrofuran (THF). E- 1,4-dibromobutene is added in excess. The reaction is stopped with aqueous ammonium chloride and the product is extracted with an organic solvent such as ethyl acetate, and then the mono-alkylated product is separated by chromatography. The bromide is treated with triethylphosphite in a solvent such as toluene (or other Arbuzov reaction conditions: Engel, R., Synthesis of Carbon-Phophorus bonds, CRC press, 1988) to obtain the diethyl ester of the desired phosphonic acid. . Subsequently, the tertiary alcohol was added to Bioorg . Med . Chem. Convert to amine via chloride using the method described in Lett ., (2003), 13 , 1543. The enantiomers of interest are separated by chromatography or classical cleavage using chiral acid such as camphorsulfonic acid.

Scheme 29.4

Scheme 29.5

Lithiated imidazoles (n-butyl lithium, chlorotriethylsilane) which represent N-methylquinolone (see US Pat. No. 5,968,952, prepared by treating the starting material with methyl iodide and potassium carbonate in a solvent such as DMF in Scheme 29.3 ) Prepared from 1- (3-tetrahydropyranyloxy) propyl) imidazole by continuous treatment with n-butyl lithium, Bioorg . Med . Chem. Lett ., (2003), 13 , 1543). After hydrolysis of the ether protecting group, the free primary alcohol is treated with a base such as sodium hydride in a solvent such as dimethylformamide or tetrahydrofuran. At the end of bubbling, diethylphosphonomethylt replate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added to obtain the desired phosphonate diester. Subsequently, the tertiary alcohol was added to Bioorg . Med . Chem . The method described in Lett ., (2003), 13 , 1543 is used to convert amines via chlorides. The enantiomers of interest are separated by chromatography or classical cleavage using chiral acid such as camphorsulfonic acid.

Scheme 29.6

Scheme 29.7

The primary amine is condensed with (2-oxo-ethyl) -phosphonic acid diethyl ester under reducing conditions such as those using sodium cyanoborohydride in a solvent such as methanol or dimethylformamide ( Tet . Lett ) . .

Scheme 29.8

Scheme 29.9

The quinolone (see Bioorg . Med . Chem . Lett ., (2003), 13 , 1543) was N-methylated under standard conditions such as treatment with iodomethane and potassium carbonate in DMF and treated with boron tribromide Liberate. It is alkylated as in Scheme 29.3 above and the subsequent steps are similar.

Scheme 29.10

Scheme 29.11

Treatment of 5-chloro-1-pentane with triethylphosphite in a solvent such as toluene (or other Arbuzov reaction conditions: Engel, R., Synthesis of Carbon-Phophorus bonds, CRC press, 1988) Diethyl ester is obtained. Bromine-containing tipiparnib analogs (2-bromo-) are shown under the same conditions developed by Sonagashira, K .; Tohda, Y .; Hagihara, N. Tetrahedron Lett ., (1975), 4467. In addition to using 4-chloro-4'nitrobenzophenone as starting material Bioorg . Med. Chem . Lett ., (2003), prepared the same as in 13 , 1543).

Further manipulations can be made to the phosphonate moiety prior to the final deprotection reaction. Modifications of this kind are described in more detail in the phosphonate interconversion section herein.

Example 30 Preparation of Exemplary Compounds of the Invention

The compounds of the invention may be prepared as generally described in Scheme 30.1 to 30.3 in the examples shown in Scheme 30.4 to 30.6.

Scheme 30.1 : One amino substituent substitution

Scheme 30.2 : binding to one secondary alkylamine

Scheme 30.3 : chain extension

Scheme 30.4 : substitution of one amino substituent

The starting materials (synthesis described in J. Med . Chem . , (1999), 42 , 3494-3501) are described in J. Org . Diethylphosphonate ethyl carbaldehyde (1 equiv) and sodium triacetoxybo in a solvent such as tetrahydrofuran (THF) or dichloromethane (DCM) as described in Chem , (1996), 61, 3849-3862 Treat with low hydride. The reaction is stopped with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. Dry and remove the solvent to afford crude product. Further purification is by chromatography.

The product of this step is J. Med . Chem . (1999), 42 , 3494-3501, dissolved in trifluoroacetic acid (TFA) and stirred at room temperature. At the end of the reaction, benzene is added and the solvent is removed in vacuo. The crude material is pure enough for the next step.

The crude material is J. Med . Chem . , (1999), 42, in accordance with the method of 3494-3501 N, N, N ', N' tetramethylethylenediamine, water and N - (β- hydroxyethyl) - N - (β- aminoethyl) amine Dissolve in the mixture and heat the mixture to reflux for several hours. At the end of the reaction, chloroform is added and the reaction mixture is washed with dilute aqueous hydrochloric acid and water and dried. The solvent is removed to give crude product. Further purification is by chromatography.

Scheme 30.5 : bonding from one secondary alkyl amine

Mitoxantrone is described in J. Org . Treatment with diethylphosphonate ethyl carbaldehyde (1 equiv) and sodium triacetoxyborohydride in an organic solvent such as THF or DCM as described in Chem , (1996), 61, 3849-3862. The reaction is stopped with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. Dry and remove the solvent to afford crude product. Further purification is by chromatography.

Scheme 30.6 : chain extension

The starting materials (synthesis is described in J. Med . Chem . , (1999), 42 , 3494-3501) are described in J. Org . Treatment with chloroacetaldehyde (1 equiv) and sodium triacetoxyborohydride in an organic solvent such as THF or DCM as described in Chem , (1996), 61, 3849-3862. The reaction is stopped with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. Dry and remove the solvent to afford crude product. Further purification is by chromatography.

The product of this step is dissolved in an organic solvent such as dimethylformamide or acetonitrile. 3-aminopropyl phosphonic acid diethylester is added followed by potassium carbonate and sodium iodide. The reaction mixture is heated to a high temperature of ˜50-60 ° C. At the end of the reaction, the mixture is cooled to room temperature. Chloroform is added and the reaction mixture is dried with dilute aqueous hydrochloric acid and water. Dry and remove the solvent to afford crude product. Further purification is by chromatography.

The product of this step is described in J. Med . Chem . (1999), 42 , 3494-3501, dissolved in trifluoroacetic acid (TFA) and stirred at room temperature. At the end of the reaction, benzene is added and the solvent is removed in vacuo. The crude material is pure enough for the next step.

The crude material is J. Med . Chem . , (1999), 42, in accordance with the method of 3494-3501 N, N, N ', N' tetramethylethylenediamine, water and N - (β- hydroxyethyl) - N - (β- aminoethyl) amine Dissolve in the mixture and heat the mixture to reflux for several hours. At the end of the reaction, chloroform is added and the reaction mixture is washed with dilute aqueous hydrochloric acid and water and dried. The solvent is removed to give crude product. Further purification is by chromatography.

Further manipulations can be made to the phosphonate moiety prior to the final deprotection reaction. Modifications of this kind are described in more detail in the phosphonate interconversion section herein.

Example 31 Preparation of Exemplary Compounds of the Invention

Compounds of the present invention can generally be prepared as shown in Schemes 31.1-31.6 , with examples shown in Schemes 31.7-31.12 .

Scheme 31.1 : reforming in C4

Scheme 31.2 : binding to C23

Scheme 31.3 : binding to N1

Scheme 31.4 : binding to C4 '

Scheme 31.5 : binding to C12 '

Scheme 31.6 : binding to C22 '

Scheme 31.7 : binding to C4

2-diethyl phosphonatoacetic acid was added to J. Med . Chem . , (1991), 34 , 1001-1018 and so on in an organic solvent such as benzene, tetrahydrofuran (THF) or chloroform, diisopropylethylamine (DIEA) and diphenyl phosphorazate (1.2 equivalents), and the like. Is mixed with tertiary amine base and stirred at room temperature. After acyl azide is formed, bindecine is added and the reaction mixture is heated to ˜80 ° C. for 4 h ( Bio Chemistry (2002), 41 , 14010-14018). The reaction mixture is cooled to room temperature, washed with aqueous HCl (1N) and aqueous bicarbonate solution and dried. The solvent is removed to give crude product. Further purification is by chromatography.

Scheme 31.8 : binding to C23

The starting material (synthesized from vinblastine as disclosed in J Med . Chem . , (1978), 21, 88-96) was prepared by J. Med . Treated with 2-aminoethylphosphonic acid diethyl ester in an organic solvent such as dichloromethane (DCM) or THF at room temperature according to the method described in Chem , (1979), 22, 391-400. At the end of the reaction, the solution is washed with water, aqueous bicarbonate and water and dried. The solvent is evaporated to afford crude product. Further purification is by chromatography.

Scheme 31.9 : binding to N1

2-diethyl phosphonatoacetic acid was added to J. Med . Chem . , (1991), 34 , 1001-1018, dissolved in organic solvents such as benzene, THF or chloroform, and tertiary amine bases such as diisopropylethylamine (DIEA) and diphenyl phosphorazate (1.2 equivalents). Mix with and stir at room temperature. After the formation of acyl azide, N-1- (β-hydroxyethylthiomethyl) vinblastine (Pierce's [Medicinal Chemistry of Bisindole Alkaloids from Catharanthus], in The Alkaloids , Vol. 37, 145, Academic Press San Diego, (1990), prepared from vinblastine by methoxy substitution with CrO ₃ -mediated oxidation followed by β-hydroxy thioethanol in the presence of methanol) and the reaction mixture was added for 4 h. Heat to 80 ° C. ( BioChemistry (2002), 41 , 14010-14018). The reaction mixture is cooled to room temperature, washed with aqueous hydrochloric acid (HCl) (IN) and aqueous bicarbonate solution and dried. The solvent is removed to give crude product. Further purification is by chromatography.

The product of this step is dissolved in anhydrous organic solvent such as ethanol and dry liquid ammonia is added. The reaction mixture was prepared by J. Med . Chem . (1978), 21 , 88-96, are heated to a high temperature of ˜100 ° C. in a sealed reaction vessel. At the end of the reaction, the mixture is cooled to room temperature and the solvent is removed in vacuo. Further purification is by chromatography.

Scheme 31.10 : binding to C4 '

Bindesin and diethyl (cyanomethyl) phosphonate (commercially available) are described in Pierce, "Medicinal Chemistry of Bisindole Alkaloids from Catharanthus", in The Alkaloids , Vol. 37, 145, Academic Press San Diego, (1990) (as described for acetonitrile) and dissolved in concentrated sulfuric acid at a temperature of ~ 0 ℃. When the starting material has been consumed the reaction mixture is carefully diluted with water and further neutralized. The resulting reaction mixture is extracted with an organic solvent such as DCM. The combined organic extracts are washed with aqueous bicarbonate solution and dried. The solvent is removed to give crude product. Further purification is by chromatography.

Scheme 31.11 : binding to 12 '

Vinblastine according to C12'-iodo-vinblastine ("Medicinal Chemistry of Bisindole Alkaloids from Catharanthus", in The Alkaloids , Vol. 37, 145, Academic Press San Diego, (1990)). Prepared by iodide reaction with ferrous perchlorate, tetra ( n -propyl) ammonium periodinate and catalytic amount of ruthenium dioxide) into a mixture of copper iodide and potassium phosphate and 2-aminoethyl phosphonic acid diethyl ester (commercially available) Add. The reaction mixture is described by Buchwald in Org. Lett ., (2002), 4 , 581-584, are heated to ˜80 ° C. under an inert gas atmosphere. At the end of the reaction the material is cooled to room temperature and the solvent is removed in vacuo. The resulting reaction mixture is extracted with an organic solvent such as DCM. The combined organic extracts are washed with aqueous bicarbonate solution and dried. The solvent is removed to give crude product. Further purification is by chromatography.

The product of this step is dissolved in anhydrous organic solvent such as ethanol and dry liquid ammonia is added. The reaction mixture was prepared by J. Med . Chem . , (1978), 21 , 88-96 are heated to a high temperature of ~ 100 ℃ in a sealed reaction vessel. At the end of the reaction the mixture is cooled to room temperature and the solvent is removed in vacuo. Further purification is by chromatography.

Scheme 31.12 : binding to 22 '

Bindesin is described in Pierce, "Medicinal Chemistry of Bisindole Alkaloids from Catharanthus", in The Alkaloids , Vol. 37, 145, Academic Press San Diego, (1990) (technology for vinblastine), suspended in aqueous sodium hydroxide (5N) and heated to reflux for several hours. At the end of the reaction, water is added and the reaction mixture is extracted with an organic solvent such as DCM or chloroform. The combined organic extracts are washed with brine and dried. The solvent is dried in vacuo to afford crude acid. Further purification is by chromatography. The product of step 1 is dissolved in an organic solvent such as DCM or dimethylformamide and the solution is cooled to -10 ° C. It is added a coupling reagent, such as butyl chloroformate - followed by a tertiary amine base such as DIEA isopropyl. Stirring is continued at −10 ° C. until activation is complete. Aminoethylphosphonic acid diethyl ester is added and stirring is continued while slowly warming up to 0 ° C. At the end of the reaction, the solution is warmed to room temperature and the solvent is removed in vacuo. The product is further purified by chromatography.

Example 32 Preparation of Exemplary Compounds of the Invention

Scheme 32.1

Scheme 32.2

Treatment of 5-chloro-1-pentane with triethylphosphite in a solvent such as toluene (or other Arbuzov reaction conditions: see Engel, R., Synthesis of Carbon-Phophorus bonds, CRC press, 1988) Diethyl ester is obtained. This acetylene is combined with lonafarnib under the same conditions developed by Sonogashira (K .; Tohda, Y .; Hagihara, N. Tetrahedron Lett ., (1975), 4467).

Scheme 32.3

Scheme 32.4

J. Med . Chem ., (1982), 25 , 960-964 and J. Med . According to the same method as reported in Chem ., (1984), 27 , 600-604, the piperazine (see J. Med . Chem ., (1998), 41 , 4890) was activated diethylphosphonoacetic acid. Acylation yields the desired amide linkage compound. The activated diethylphosphonoacetic acid is obtained by treating with a binding reagent such as diethylcyanophosphonate and a base such as diisopropylethylamine in a solvent such as dimethylformamide at room temperature.

Scheme 32.5

Scheme 32.6

4-allyl-piperidine-1,4-dicar using standard reagents for the preparation of secondary amides such as dicyclohexylcarbodiimide (DCC) and hydroxybenztriazole (HOBT) in a solvent such as dimethylformamide. Acid mono-tert-butylester is combined with 2-aminoethylphosphonic acid diethyl ester (commercially available). The olefin is oxidized with ozone to produce a carboxylic acid, which is then combined with the piperidine reagent (see J. Med . Chem ., (1998), 41 , 4890). Finally, the piperidine nitrogen was added to trifluoroacetic acid and J. Med . Deprotection with primary urea prepared as described in Chem ., (1998), 41 , 4890.

Scheme 32.7

Scheme 32.8

4-carboxymethyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (commercially available) is treated with acidic methanol to monoprotect. The remaining acid is dissolved in a solvent such as dimethylformamide using standard reagents for the preparation of secondary amides such as dicyclohexylcarbodiimide (DCC) and hydroxybenztriazole (HOBT) to 2-aminoethylphosphonic acid diethyl ester ( Commercially available). The methyl ester is then saponified and combined with the piperazine (see J. Med . Chem ., (1998), 41 , 4890). Finally, the piperidine nitrogen was added to trifluoroacetic acid and J. Med . Deprotection with primary urea prepared as described in Chem ., (1998), 41 , 4890.

Example 33 Preparation of Exemplary Compounds of the Invention

These compounds can be prepared according to the general route shown in, reaction formula 33.1 to 33.4 in the examples shown in Scheme 33.5 to 33.8.

Scheme 33.1 : modification of phenolic substituents

Scheme 33.2 : modification of amine substituents

Scheme 33.3 : Introduction of additional substituents

Scheme 33.4 : reforming on acridine core

Scheme 33.5

Amsacrine can be treated with excess iodotrimethylsilane in a solvent such as dimethylformamide (DMF), acetonitrile (MeCN) or dichloromethane (DCM) as described in Synthesis , (1985), 274. have. The reaction can be stopped with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate, and then the free alcohol can be further purified by chromatography. The foreign material is then treated with tert -butoxycarbonyl anhydride in the presence of a tertiary amine base such as pyridine in an organic solvent such as DMF (Green and Wutts: Protective Groups in organic chemistry). The solvent is removed in vacuo and the product is further purified by chromatography. Thereafter, the mixture was treated with sodium hydride (NaH) (˜1 equivalent) in an organic solvent such as THF or DMF to generate an alkoxide anion, followed by diethylphosphonomethyl triplate ( Tetrahedron Lett ., (1986), 27 , 1477. According to the present invention). When the starting material is consumed, the reaction is stopped with water and the product is extracted with an organic solvent such as ethyl acetate. Finally, the purification may be performed by chromatography. The tert-butoxycarbonyl protecting group is removed with trifluoroacetic acid (TFA) in DCM by standard methods (Green and Wutts: Protective Groups in organic chemistry).

Scheme 33.6

J. Med . After treatment with NaH (~ 1 equivalent) in an organic solvent such as tetrahydrofuran (THF) according to the method reported in Chem ., (2000), 43 , 489, diethylphosphonomethyltriplate ( Tetrahedron Lett ., (1986), 27 , 1477) to deprotect the amazacrin. When the starting material is consumed, the reaction is stopped with water and the product is extracted with an organic solvent such as ethyl acetate. Finally, the purification may be performed by chromatography.

Scheme 33.7

2,5-dinitrophenol is converted to sodium salts by treatment with NaH in a suitable organic solvent such as THF. The salt is then reacted with carbon dioxide under Kolbe Schmitt conditions ( J. Chem . Soc . (1954), 3145). The carboxylic acid product is then subjected to isobutylchloroformate or the like in an organic solvent such as DMF in the presence of a tertiary amine base such as N, N-diisopropylmethylamine (DIEA) at a reduced temperature of Activate with the appropriate binding reagent. The activated intermediate is then reacted with 2-aminoethylphosphonic acid diethyl ester and the reaction mixture is warmed to 0 ° C. and then to room temperature. The solvent is removed in vacuo and the crude material is dissolved in an organic solvent such as ethyl acetate and washed with dilute hydrochloric acid. The product is purified by chromatography as necessary. The material is dissolved in an organic solvent such as THF and treated with sodium carbonate and methyl iodide or dimethylsulfate. After the reaction is complete, the solid is filtered off and the filtrate is concentrated in vacuo. The product is purified by chromatography as necessary. This material is then dissolved in a solvent such as ethyl acetate or DMF and hydrogenated with Pd / C under hydrogen atmosphere. The resulting reaction mixture is filtered through celite and the solvent is removed in vacuo. If the product purity is not sufficient, further purification can be performed by chromatography. From the following organic solvent such as DMF with the amine in the presence of a tertiary amine base such as DIEA J. Med. Chem . (1999), 42 , 4741-4748, with 9-chloroacridine. The solvent is removed in vacuo and the crude material is purified by chromatography. The product is then reacted with methanesulfonyl chloride in the presence of a tertiary amine base such as DIEA in an organic solvent such as DMF or THF. After removing the solvent, the final product is purified by chromatography.

Scheme 33.8

The starting material in Scheme 33.8 is J. Med . Chem . (1999), 42 , 4741-4748, which can be obtained via the reaction of 9-oxoarydidan-4-methyl-5-carboxylic acid chloride and 2-aminoethylphosphonic acid diethylester. This material is treated with thionyl chloride to give the corresponding 9-chloroacridine derivatives as described in the above references. The crude material is then dissolved in an organic solvent such as chloroform, DCM or THF and treated with 2-methoxy-4-nitroaniline. The crude product can be isolated by electrification and further purified by chromatography. This material is dissolved in an organic solvent such as DMF and reduced in the presence of Pd / C in a hydrogen atmosphere. The reaction mixture is filtered through celite and the solvent is removed in vacuo. The product can be further purified by chromatography. This material is then dissolved in an organic solvent such as THF or chloroform and treated with methanesulfonyl chloride in the presence of a tertiary amine base such as DIEA. After removing the solvent, the final product is purified by chromatography.

Example 34 Preparation of Exemplary Compounds of the Invention

These compounds can be prepared according to the general route shown in Scheme 34.1 to 34.3 in the examples shown in Scheme 34.4 to 34.6.

Scheme 34.1

Scheme 34.2

Scheme 34.3

Scheme 34.4

CEP-701 is treated with 2 equivalents of base such as sodium hydride in a solvent such as dimethylformamide or tetrahydrofuran. At the end of bubbling, excess benzyl bromide is added to obtain a double protected intermediate. After further treatment with a base such as magnesium tert -butoxide, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added to obtain the desired phosphonate diester. As described in Greene, T., Protective Groups in Organic Chemistry , Wiley-Interscience, (1999), by final deprotection by hydrogenation with a catalyst such as palladium on charcoal in a solvent such as methanol Get products

Scheme 34.5

CEP-701 can be treated with one equivalent of a base such as sodium hydride or cesium carbonate in a solvent such as dimethylformamide or tetrahydrofuran. Benzyl bromide is added to give the N-benzylated product. After further treatment with a base such as magnesium tert -butoxide, diethylphosphonomethyltriplate is added to obtain the desired phosphonate diester. The desired product is obtained by final deprotection by hydrogenation with a catalyst such as palladium on charcoal in a solvent such as methanol, using a method as described in Greene's literature (see above).

Scheme 34.6

4-hydroxybenzaldehyde was treated with a base such as sodium hydride and diethylphosphonomethyltriplate in a solvent such as dimethylformamide or tetrahydrofuran to give (4-formyl-phenoxymethyl) -phosphonic acid diethyl. To produce an ester. The product is condensed with CEP-701 while azeotropically removing the water formed in the presence of a catalytic amount of p -toluenesulfonic acid in a solvent such as toluene to obtain the desired acetal.

Further manipulations can be made on the phosphonate moiety prior to final deprotection.

Example 35 Preparation of Exemplary Compounds of the Invention

Such compounds can be prepared according to the general routes shown in Schemes 35.1 and 35.3 , with examples shown in Schemes 35.2 and 35.4 .

Scheme 35.1

Scheme 35.2

Winkley, MW, Robins, RK, J. Org . Properly protected 5 according to the method of Chem ., (1970), 35 , 2, 491 (see also Ben-Hattar J., Jiricny, J. J. Org . Chem ., (1986), 51 , 3211). -Aza-2'-deoxycytidine can be treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. Pivaloyl Compound 35-1 can be prepared by protecting 5-aza-2'-deoxycytidine with pivaloyl group (Greene, T., Protective Groups in Organic Chemistry , Wiley-Interscience, (1999)). . At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added to obtain the protected product. The pivaloyl group can be removed with sodium ethoxylated to obtain the desired phosphonate diesters 35-2 and 35-3 .

Scheme 35.3

Scheme 35.3 illustrates the preparation of compound 35-9 . Compound 35-15 is Winkley, MW, Robins, RK, J. Org . Chem ., (1970), 35 , 2, 491 and Ben-Hattar J., Jiricny, J., J. Org . Pivaloyl protected 5-aza-2′-deoxycytidine described in Chem ., (1986), 51 , 3211. Compound 5-4 is obtained by protecting the 5 alcohol after protecting the 5 'hydroxyl group. The 5 'protecting group is removed to give the free primary alcohol. Cory's one step oxidation method (Corey, EJ et al., J. Org . Chem . , (1984), 49 , 4735) can be utilized to convert the primary alcohol to ester 35-6 . Deoxidation followed by oxidative decarbonylation using a modified Hunsdiecker reaction (Chu, CK et al., Tetrahedron Lett ., (1991), 32 , 3791) yielded 35-7 to acetate 35-8 To. Stereochemistry of Vorbruggen glycosylation under Lewis acid conditions is controlled by protecting group participation at the 4 ′ position. Final deprotection affords the desired prodrug 35-9 .

Scheme 35.4

Specifically, compound 35-1 prepared by protecting 5-aza-2′-deoxycytidine (Winkley, MW, Robins, RK, J. Org . Chem ., (1970), 35 , 2, 491 and Ben -Hattar J., Jiricny, J. J. Org . Chem., (1986), 51, prepared using a chloride feet blood as in 3211) and the 5 'protected with tert--butyldiphenylsilyl (TBDPS) O-TBDPS analogs can be obtained. Further protection of the 3 'alcohol with benzoyl groups gives compound 35-10 (Teng, K., Cook, D. J. Org . Chem . (1994), 59 , 278). Fully protected compound 35-10 is selectively exposed to HF-pyridine reagent to deprotect the 5 'hydroxyl group, followed by Corey-Samuelsson oxidation (Corey, EJ, Samuelsson, B. J. Org . Chem ., (1984 ), 49 , 4735) to t -butyl ester. Deprotection of the oxidation product using trifluoroacetic acid (TFA) affords compound 35-12 . Strain hunseu dikeo reactions (Chu, CK et al., Tetrahedron Lett., (1991), 32, 3791) 35 which may be a mixture of a anomer (anomer) in the free acid of 5 'by the oxidative decarboxylation with Convert to -13 . Column chromatography can separate the anomer mixture, but need not. Since the stereochemical results of vorbrugen glycosylation are controlled by the stereochemistry of the 4'-benzoyl group due to anchimeric assistance, the separation of these isomers is unnecessary. Borbrogen glycosylation using hydroxymethylphosphonic acid diethyl ester is carried out to obtain a protected phosphonate. The final saponification reaction completes the synthesis of compound 35-20 to remove pivaloate and benzoate groups (Greene, T., Protective Groups in Organic Chemistry , Wiley-Interscience, (1999)).

Example 36 Preparation of Exemplary Compounds of the Invention

These compounds can be prepared according to the general route shown in, reaction formula 36.1 to 36.2 in the examples shown in Scheme 36.3 to 36.5.

Scheme 36.1 : modification of sugar substituents

Scheme 36.2 : binding to epi-podophyllotoxin core

Scheme 36.3 : Modification of the 4,6 glucose-acetal moiety

The glucose derived starting material is Chem . Lett . , (1987), 5-methylthiophene-2- using the method of glucose and 5-bromomethylthiophene-2-carbaldehyde (Organikum, 17 ^th edition, page 167, according to the method described in 799-802). From carboxaldehyde and N-bromosuccinimide). The glucose reaction is carried out with 4'-chloroacetyl-protected epipodophyllotoxin (described in the reference above) under the catalysis of boron trifluoride (as described in the reference above). The product of this reaction is dissolved in organic solvents such as methanol and acetic acid and treated with zinc at reflux temperature. At the end of the reaction, the mixture is cooled to room temperature and the solvent is removed in vacuo. The resulting reaction product is dissolved in an organic solvent such as chloroform and the solution is washed with aqueous 0.1 M HCl and aqueous bicarbonate solution. The crude product is obtained after drying and removing the solvent. Further purification is by chromatography. The resulting reaction product is dissolved in an organic solvent such as dimethylformamide (DMF) or chloroform, treated with a base such as sodium carbonate at a temperature of ˜40 ° C. and reacted with aminoethyldiethylphosphonate. After all the starting material has been consumed the reaction mixture is washed with aqueous 0.1 M HCl and aqueous bicarbonate solution. After drying and removing the solvent a crude product of the reaction is obtained. Further purification is by chromatography.

Scheme 36.4 : Modification of the glucose core

The starting material (synthesized from glucosamine and thiophene-2-carbaldehyde commercially available according to Chem . Lett . , (1987), 799-804) can be organic, such as dichloromethane (DCM) or tetrahydrofuran (THF). In solvent J. Org . Treatment with diethylphosphonateethylethylcarbaldehyde and sodium triacetoxyborohydride as described in Chem , (1996), 61, 3849-3862. The reaction is stopped with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. Further purification is by chromatography.

Scheme 36.5 : binding to epi-podophyllotoxin core

The above amine containing starting material (obtained as described in J. Med . Chem . , (1991), 34 , 3346-3350) was prepared in an organic solvent such as THF or DCM in J. Org . Treatment with diethylphosphonateethylethylcarbaldehyde and sodium triacetoxyborohydride as described in Chem , (1996), 61, 3849-3862. The reaction is stopped with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. Further purification is by chromatography.

All final products were treated with phosphoryl trichloride in an organic solvent such as acetonitrile and in the presence of a tertiary organic amine base such as N, N-diisopropylethylamine followed by treatment with an aqueous bicarbonate solution. Convert to 4'-phosphate analog. Final product purification is by chromatography.

Example 37 Preparation of Exemplary Compounds of the Invention

Such compounds can be prepared according to the general route shown in Schemes 37.1-37.5 .

Scheme 37.1

Staurosporin is acylated with benzoic acid derivatives such as benzoyl chloride in a solvent such as chloroform in the presence of a base such as N , N -diisopropylmethylamine (DIEA) ( Bioorg. Med . Chem . Lett . , (1994), 4 , 399). Examples of suitable phosphonate containing Midousuji taurine (midostaurin) benzoyl chloride for use in the synthesis of the analogs following Scheme 37.2 - 37.3 is illustrated in.

Scheme 37.2

4-hydroxybenzoic acid methyl ester is treated with magnesium tert-butoxide and diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) in a solvent such as tetrahydrofuran. The resulting 4- (diethoxyphosphorylmethoxy) benzoic acid methyl ester is saponified with lithium hydroxide in ethanol and reacted with oxalyl chloride in a solvent such as dichloromethane under dimethylformamide catalysis to produce an acid chloride from benzoic acid.

Scheme 37.3

3-hydroxybenzoic acid methyl ester is treated with a base such as sodium hydride in a solvent such as dimethylformamide or tetrahydrofuran. At the end of bubbling, excess E- 1,4-dibromobutene is added. The reaction is stopped with aqueous ammonium chloride and the product is extracted with an organic solvent such as ethyl acetate, and then the mono-alkylated product is separated by chromatography. The bromide was treated with triethylphosphite in a solvent such as toluene (or other Arbuzov reaction conditions: Engel, R., Synthesis of Carbon-Phophorus bonds, CRC press, 1988) 3- [4- (diethoxy- Phosphoryl) -but-2-ethyloxy] -benzoic acid methyl ester. The remaining steps are similar to those described in Scheme 37.2 .

Scheme 37.4

Alkylation of staurosporin to secondary amines has been carried out under various standard conditions (see Bioorg . Med . Chem . Lett ., (1994), 4 , 399). Synthesis examples of phosphonate-containing alkyl derivatives are shown in Scheme 37.5 .

Scheme 37.5

Staurosporin is alkylated with diethylphosphonomethyltriplate in the presence of a base such as DIEA.

Example 38 Preparation of Exemplary Compounds of the Invention

The compounds of the present invention can be prepared as generally described in Schemes 38.1 and 38.4 and Schemes 38.2 , 38.3 and 38.5 .

Scheme 38.1

The introduction of the phosphonate containing material at the quinazoline 7-position is most conveniently accomplished by alkylation of 4-piperazinylquinazoline, which is suitably protected prior to urea formation.

Scheme 38.2

6,7-dimethoxy-3,4-dihydroquinazolin-4-one is reacted with boron tribromide to obtain a mixture of mono-demethylated products. They may be separated by chromatography at this stage, but it may be more convenient to separate the mixture of acetates obtained by reacting pyridine or the like with an acetylation reagent such as acetyl chloride in the presence of a base. The 4-chloroquinazoline obtained by reacting the desired isomer with thionyl chloride (see Bioorg . Med . Chem . Lett ., (2001), 11 , 1911) is treated with piperazine-1-carboxylic acid benzyl ester.

The intermediate A is generated by removing the acetyl protecting group under standard conditions such as treatment with ammonia in methanol (see Greene, T., Protective Groups in Organic Chemistry , Wiley-Interscience, (1999)). When treated with a base such as magnesium tert -butoxide and diethylphosphonomethyltriplate (produced according to Tetrahedron Lett ., (1986), 27 , 1477), the phosphonate-containing portion is introduced at the quinazoline 7-position do. Subsequently, the benzyl carbamate protecting group is removed by hydrogenation using a catalyst such as charcoal palladium (see Greene, ibid ) in a solvent such as methanol. Condensation yields the target compound.

Scheme 38.3

In the presence of azodicarboxylate diesters such as diisopropyl azodicarboxylate and triphenylphosphine, as described by Mitsunobu ( Bull. Chem . Soc . Japan ., (1971), 44 , 3427). Intermediate A can be alkylated onto phenol by reaction with 4- (2-hydroxy-ethyl) -piperazine-1-carboxylic acid tert-butyl ester. After deprotection with trifluoroacetic acid, the secondary amine liberated under reducing conditions such as those using sodium cyanoborohydride in a solvent such as diethyl ester methanol or dimethylformamide (2-oxo-ethyl) Condensation with phosphonic acid (see Tet. Lett. (1990), 31, 5595). The remaining steps are similar to those described in Scheme 38.2 .

Scheme 38.4

The route is similar to that shown in Scheme 38.1-38.3 , except that selective demethylation at 6-position of 6,7-dimethoxy-3,4-dihydroquinazolin-4-one is used ( Bioorg . Med . Chem . Lett ., (2001), 11 , 1911). Specific examples of such synthesis are shown in Scheme 38.5 .

Scheme 38.5

After selective demethylation, the steps are similar to those described in the previous examples in that the phenol is alkylated. In this example, however, alkylation with E- 1,4-dibromobutene is carried out and the monobromide product is reacted with triethylphosphite in a solvent such as toluene (or other Arbuzov reaction conditions: Engel, R., Synthesis of Carbon-Phophorus bonds, CRC press, 1988) Purpose To obtain diethyl ester of phosphonic acid. Thereafter, the steps are again similar to those described in the previous embodiment.

Example 39 Preparation of Exemplary Compounds of the Invention

The compounds of the present invention can be prepared as described generally in Schemes 39.1 and 39.3 with examples of Schemes 39.2 and 39.4 .

Scheme 39.1

The combination of 2,3,4-trifluorobenzoic acid and aniline is carried out in a solvent such as tetrahydrofuran in the presence of a significant excess of a base such as lithium diisopropylamide at a temperature lower than or equal to atmospheric temperature in WO 2001-US Patent No. Perform as described in .22948. The phosphonate moiety can then be introduced using various means as described in Scheme 39.2 . Thereafter, as described in patent application WO 2000-US Patent No. 18347 20000705, benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluoro in a solvent such as tetrahydrofuran or dichloromethane. Treatment of benzoic acid with O- (tetrahydro-2H-pyran-2-yl) hydroxyamine and diisopropylethylamine in the presence of a binding reagent such as phosphate (PyBOP) followed by ethanolic hydrochloric acid Creates.

Scheme 39.2

2,3,4-trifluorobenzoic acid is combined with 2-iodo-5-nitroanisole (commercially available) and the methyl ether is removed under standard conditions treated with hydrobromic acid in acetic acid (Greene, T. , Protective Groups in Organic Chemistry , Wiley-Interscience, (1999). The benzoic acid is dissolved in acidic methanol and esterified. The phenol is then treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added to obtain the desired phosphonate diester. The benzoic acid (preparation Scheme 39.1 for the coupling reaction to form the hydroxyxamate ester) is saponified with lithium hydroxide in a solvent such as tetrahydrofuran or ethanol.

Scheme 39.3

Iodine substituents present in PD-184352 are used to introduce the phosphonate containing moieties as illustrated in Scheme 39.4 .

Scheme 39.4

Treatment of 5-chloro-1-pentane with triethylphosphite in a solvent such as toluene (or other Arbuzov reaction conditions: see Engel, R., Synthesis of Carbon-Phophorus bonds, CRC press, 1988) Diethyl ester is obtained. This acetylene is reacted with 39.5 under the same conditions developed by Sonogashira (K .; Tohda, Y .; Hagihara, N. Tetrahedron Lett ., (1975), 4467).

Example 40 Preparation of Exemplary Compounds of the Invention

The compounds can be prepared as generally described in Scheme 40.1-40.5 with the embodiment shown in Scheme 40.2-40.4 . Final compounds that are stereoisomers or enantiomers can be purified by chromatographic methods.

Scheme 40.1 : General approach to all classes of compounds

If direct binding to aminopterin is inhibited by the presence of free secondary amines in the starting material (R = H), the material is converted to tert-butoxycarbonyl groups (Green Wutts: Protective groups in organic chemistry). R = Boc) or benzyloxycarbonyl (R = Cbz or Z).

Scheme 40.2 : Embodiment for class A

The starting carboxylic acid is bound to a solvent such as diethylcyanophosphonate or isobutylchloroformate and diisopropylethylamine (DIEA) in a solvent such as dimethylformamide (DMF) or N-methylpyrrolidinone (NMP) at room temperature. ( J. Med . Chem ., (1982), 25 , 960-964 and J. Med . Chem ., (1984), 27 , 600-604). When activation is complete, 2-aminoethylphosphonic acid diethyl ester (commercially available) is added. After observing that the activated material has been consumed completely, the solvent is removed in vacuo and the product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

When R = Z, the compound is dissolved in an organic solvent such as DMF or NMP and a catalytic amount of Pd / C is added. The reaction mixture is stirred under hydrogen atmosphere until the starting material is consumed. Pd / C is removed and the solvent is evaporated in vacuo. The product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Scheme 40.3 : Second embodiment for class A

The starting carboxylic acid is treated with a binder such as diethylcyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) in a solvent such as DMF or NMP at room temperature ( J. Med . Chem , (1982), 25 , 960-964 and J. Med . Chem ., (1984), 27 , 600-604). When the activation was complete, (2-amino-ethylsulfanylmethyl) -phosphonic acid diethyl ester (2-aminoethanethiol was prepared according to Tetrahedron Lett ., (1986), 27 , 1477 Plate and base catalyzed bond reaction) are added. After observing that the activated material has been consumed completely, the solvent is removed in vacuo and the intermediate is separated by chromatography. Optionally, the intermediate may be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether. The intermediate is then dissolved in a mixture of water, DMF and acetic acid and treated with hydrogen peroxide solution (excess). After removal of the solvent the product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

When R = Z, the compound is dissolved in an organic solvent such as DMF or NMP and a catalytic amount of Pd / C is added. The reaction mixture is stirred under hydrogen atmosphere until the starting material is consumed. Pd / C is removed and the solvent is evaporated in vacuo. The product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Scheme 40.4

The starting carboxylic acid can be treated with a binder such as diethylcyanophosphonate or isobutylchloroformate and a base such as DIEA in a solvent such as DMF or NMP at room temperature ( J. Med . Chem ., (1982) , 25 , 960-964 and J. Med . Chem ., (1984), 27 , 600-604.). When activation is complete, ( L ) -2-amino-6- (diethylphosphonato) -hexanoic acid is added. After observing that the activated material has been consumed completely, the solvent is removed in vacuo and the product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

When R = Z, the compound is dissolved in an organic solvent such as DMF or NMP and a catalytic amount of Pd / C is added. The reaction mixture is stirred under hydrogen atmosphere until the starting material is consumed. Pd / C is removed and the solvent is evaporated in vacuo. The product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Scheme 40.5

The starting carboxylic acid can be treated with a binder such as diethylcyanophosphonate or isobutylchloroformate and a base such as DIEA in a solvent such as DMF or NMP at room temperature ( J. Med . Chem ., (1982) , 25 , 960-964 and J. Med . Chem ., (1984), 27 , 600-604). When the activation is complete, 4-amino-4- (diethylphosphonato) -butyric acid tert butylester ( J. Am. Chem . Soc ., (1995), 117 , 10879-10888) is added. After observing that the activated material has been consumed completely, the solvent is removed in vacuo and the intermediate is separated by chromatography. Optionally, the intermediate may be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether. The crude intermediate is then dissolved in DMF and treated with TFA (excess). After removal of the solvent the product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

When R = Z, the compound is dissolved in an organic solvent such as DMF or NMP and a catalytic amount of Pd / C is added. The reaction mixture is stirred under hydrogen atmosphere until the starting material is consumed. Pd / C is removed and the solvent is evaporated in vacuo. The product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Example 41 Preparation of Exemplary Compounds of the Invention

The compounds of the present invention can be prepared according to the general route shown in Schemes 41.1-41.5 , with the embodiment shown in Schemes 41.2 41.4 . Final compounds that are stereoisomers or enantiomers can be purified by chromatographic methods.

Scheme 41.1 : general approach to the compounds of the present invention

Scheme 41.2 :

The starting carboxylic acid is treated with a binder such as diethylcyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) in a solvent such as DMF or NMP at room temperature ( J. Med . Chem , (1982), 25 , 960-964 and J. Med . Chem ., (1984), 27 , 600-604). When activation is complete, 2-aminoethylphosphonic acid diethyl ester (commercially available) is added. After observing that the activated material has been consumed completely, the solvent is removed in vacuo and the product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Scheme 41.3 :

The starting carboxylic acid is treated with a binder such as diethylcyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) in a solvent such as DMF or NMP at room temperature ( J. Med . Chem , (1982), 25 , 960-964 and J. Med . Chem ., (1984), 27 , 600-604). When the activation was complete, (2-amino-ethylsulfanylmethyl) -phosphonic acid diethyl ester (2-aminoethanethiol was prepared according to Tetrahedron Lett ., (1986), 27 , 1477 Prepared by base catalyzed coupling reaction into a plate). After observing that the activated material has been consumed completely, the solvent is removed in vacuo and the intermediate is separated by chromatography. Optionally, the intermediate may be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether. The intermediate is then dissolved in a mixture of water, DMF and acetic acid and treated with hydrogen peroxide solution (excess). After removal of the solvent the product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Scheme 41.4 :

The starting carboxylic acid can be treated with a binder such as diethylcyanophosphonate or isobutylchloroformate and a base such as DIEA in a solvent such as DMF or NMP at room temperature ( J. Med . Chem ., (1982) , 25 , 960-964 and J. Med . Chem ., (1984), 27 , 600-604.). When activation is complete, ( L ) -2-amino-6- (diethylphosphonato) -hexanoic acid is added. After observing that the activated material has been consumed completely, the solvent is removed in vacuo and the product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Scheme 41.5 :

The starting carboxylic acid can be treated with a binder such as diethylcyanophosphonate or isobutylchloroformate and a base such as DIEA in a solvent such as DMF or NMP at room temperature ( J. Med . Chem ., (1982) , 25 , 960-964 and J. Med . Chem ., (1984), 27 , 600-604). When the activation is complete, 4-amino-4- (diethylphosphonato) -butyric acid tert butylester ( J. Am. Chem . Soc ., (1995), 117 , 10879-10888) is added. After observing that the activated material has been consumed completely, the solvent is removed in vacuo and the intermediate is separated by chromatography. Optionally, the intermediate may be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether. The crude intermediate is then dissolved in DMF and treated with TFA (excess). After removal of the solvent the product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Example 42 Preparation of Exemplary Compounds of the Invention

Compounds of the invention can be prepared as generally described in Scheme 42.1 , with examples shown in Scheme 42.2 .

Scheme 42. 1

Scheme 42. 1 shows the preparation of certain prodrugs of other Cedi shot (tacedinaline). The synthesis was designed so that the binding of the prodrug moiety was performed later in the synthesis. The synthesis is terminated by reducing the nitro group. Many methods have been reported for such reduction, hydrogenation, Raney nickel, tin chloride dihydrate, some of them (Suzuki, T. et al., J. Med . Chem ., (1999), 42 , 3001 ).

Scheme 42.2

42.2 illustrates in more detail the preparation of certain prodrug-linked tasedinlines. Compound 42-1 can be prepared according to US Pat. No. 5,137,918. Compound 42-1 is treated with a base such as sodium hydride in a solvent such as dimethylformamide or tetrahydrofuran. At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added to give the desired phosphonate diesters 42-2, 42-5 . The nitro group is reduced by hydrogenation or Raney nickel conditions to obtain the desired prodrug.

Example 43 Preparation of Exemplary Compounds of the Invention

The compounds of the present invention can be prepared as generally described in Scheme 43.1 , with examples shown in Scheme 43.2 .

Scheme 43.1

Scheme 43.2

5-nitro-isobenzofuran-1,3-dione (commercially available) was used as Bioorg . Med . Chem . Convert to 5-amino-2- (2,6-dioxo-piperidin-3-yl) -isoindole-1,3-dione according to the method reported in Lett ., (1999), 9 , 1625. . This amine intermediate is reductively aminated with diethylphosphonoacetaldehyde (obtained from ozone decomposition of diethylallylphosphonate) in the presence of a reducing agent such as sodium triacetoxyborohydride to obtain the desired amine linker analog ( J . Org. Chem., (1996 ), 61, 3849). Optionally, the amine is prepared from J. Med . Chem ., (1982), 25 , 960 and J. Med . Acylated with activated diethylphosphonoacetic acid according to the method reported in Chem ., (1984), 27 , 600 to give the desired amide linkage compound. The activated diethylphosphonoacetic acid can be obtained by treating with a binding reagent such as diethylcyanophosphonate and a base such as diisopropylethylamine in a solvent such as dimethylformamide at room temperature.

2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -pentanedioic acid (commercially available) was added to triethylamine and 1-hydroxybenzotriazole in a solvent such as acetonitrile. , 4-methoxybenzylamine and 1,3-dicyclohexylcarbodiimide. After the reaction was completed, J. Med . The solvent is removed and the residue is purified by chromatography according to the method as reported in Chem ., (2003), 46 , 3793 to produce the desired analog.

Example 44 Preparation of Exemplary Compounds of the Invention

The compounds of the present invention can be prepared as described generally in Scheme 44.1 , with examples shown in Scheme 44.2 .

Scheme 44.1

Scheme 44.2

Schemes 44.1 and 44.2 represent the synthesis of prodrugs of TLK-286. The mixture of binding products having two carboxylic acids in the prodrug moiety is separated by HPLC to give the desired product. Aminoethyl diethylphosphonate can be purchased from Fluka as an oxalate salt that can be liberated using triethylami in the reaction medium. Peptide defect reactions are generally carried out in dimethylformamide (DMF) with the addition of dichloromethane. Carbodiimide binding reagents can be used in the presence of dimethylaminopyrine to speed up the reaction. Hydroxybenztriazole (HOBt) can be used to prevent racemization.

Example 45 Preparation of Exemplary Compounds of the Invention

The compounds of the present invention can be prepared as described generally in Schemes 45.1-45.2 , with examples shown in Scheme 45.3 .

Scheme 45.1 : Modification of one aminoethyl substituent

Scheme 45.2 : Quaternization in the pyridine moiety

Scheme 45.3 : Modification at aminoethyl substituent

Pixantrone is described in J. Org . (2-oxoethyl) phosphonic acid diethylester (1 equiv) and sodium in organic solvents such as tetrahydrofuran (THF) or dichloromethane (DCM) as described in Chem , (1996), 61, 3849-3862 Treated with triacetoxyborohydride. The reaction is stopped with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. Chromatography separates the product, other regioisomers and bis-alkylated materials.

Scheme 45.4 : Modification at the pyridine moiety

Pixanthrone is dissolved in an organic solvent such as dimethylformamide (DMF), THF or chloroform according to standard literature methods (Greene, TW: Protective groups in organic chemistry, Wiley-Interscience, (1999)) and tert-butoxycarbonyl anhydride The solvent is removed in vacuo The crude material is dissolved in an organic solvent such as chloroform and the solution is washed with aqueous 0.1 N HCl and aqueous bicarbonate solution The solution is dried and the solvent is removed in vacuo. If necessary, the product is further purified by chromatography The product of step 1 is dissolved in an organic solvent such as and DMF and bromoacetic acid (1 equivalent) are added to the solution under an inert gas atmosphere such as nitrogen. Heat to a high temperature of -70 ° C. When the reaction is complete, the solvent is removed in vacuo and the product is further purified by chromatography This material is either chloroform or DMF. Dissolved in an organic solvent, and the presence of a binding reagent such as dicyclohexylcarbodiimide (DCC), an organic tertiary amine base such as diisopropylethylamine (DIEA) and a catalytic amount of N, N-dimethylaminopyridine (DMAP) Under reaction with 2-aminoethylphosphonic acid diethyl ester (commercially available) At the end of the reaction, the reaction mixture is filtered and the solvent is removed in vacuo The crude material is dissolved in DCM and standardized at room temperature (Greene, Treatment with trifluoroacetic acid according to TW: Protective groups in organic chemistry, Wiley-Interscience (1999) At the end of the reaction the solvent is removed in vacuo to give the final product which is further purified by chromatography.

Example 46 Preparation of Exemplary Compounds of the Invention

The compounds of the present invention can be prepared as described generally in Schemes 46.1 and 46.3 , with examples shown in Schemes 46.2 and 46.4 .

Scheme 46.1

Scheme 46.2

Properly protected 2′-deoxycoformycin prepared according to US Pat. No. 3,923,785 (also recorded in Chan, E. et al., J. Org . Chem ., (1982), 47 , 3457) It can be treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. Truong, TV et al. J. Org . Chem . (8R) -6- (t-butoxycarbonyl) -8-[(t-butyldimethylsilyl) oxy] -3,6,7,8-tetrahead prepared by (1993), 58 , 6090 Chan, E. et al., J. Org . Using imidazo [4,5-d]-[1,3] diazapine . Compounds 46-1 , 46-3, which are fully protected by the borbrogen glycosylation reaction as described in Chem ., (1982), 47 , 3457, are prepared. At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added to give the desired phosphonate diesters 46-1 , 46-3 .

Scheme 46.3

Scheme 46.3 illustrates the preparation of compound 46-9 . Compound 46-1 , (8- (tert-butyl-dimethyl-silanyloxy) -3- (4-hydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl) -7,8-dihydro-3H-imidazo [4,5-d] [1,3] diazepine-6-carboxylic acid tert-butyl ester) are described in Truong, TV et al. J. Org . Chem ., (1993), 58 , 6090 and Chan, E. et al., J. Org . It may be prepared as described in Chem ., (1982), 47 , 3457. By removal of the carboxylic acid after oxidation of 5′-OH, glycal 46-5 (see the method of Zemlicka J. et al., J. Am. Chem . Soc . , (1972), 94 , 9, 3213) Get Phosphonate 46-6 (Kim, C. et al., J. Org . Chem ., (1991), 56 , 2642) protected by selenoetheration is obtained. Oxidative removal of phenylselenide (as described in Kim, C. et al., J. Org . Chem ., (1991), 56 , 2642) followed by selective dehydroxylation to obtain diols, followed by mono Tetrahydropyran protected compound 46-7 can be obtained. Acylating the 2 'alcohol with phenyl chlorothioinoformate yields a precursor for robin deoxygenation. Following deoxygenation, compounds 46-8 (Metteuci, MD et al. Tetrahedron Lett ., (1987), 28 , 22, 2459, and Robins, MJ et al. J. Org . Chem ., (1995), 60 , 7902). When the first protection proceeds exclusively at the 3 '2' position, the order of formation of the protected alcohol and thiocarbonate formation can also be reversed. In this case, 2 'thiocarbonate is first formed, followed by protection of the 3' hydroxyl group and final robin deoxygenation. Trifluoroacetic acid (TFA) -mediated deprotection removes all three protecting groups to give compound 46-9 .

Scheme 46.4

Specifically, compound 46-3 (Truong, TV et al., J. Org . Chem ., (1993), 58 , 6090 and Chan, E. et al., J. Org . Chem ., (1982), 47 , 3457) is oxidized with PtO ₂ to give carboxylic acid 2.2 . The decarboxylation removal reaction is performed using dimethylformamide dinepentylacetal (Zemlicka J. et al., J. Am. Chem . Soc . , (1972), 94 , 9, 3213) in hot DMF. Once furanoid glycal 46-11 is obtained, it is treated with phenylselenyl chloride for selenoetheration, followed by diethyl (hydroxymethyl) phosphonate (Phillion, D. et al., Tetrahedron Lett ., (1986), 27 , 1477), treated with silver perchloric acid to obtain phosphonate 46-12 (Kim, C. et al., J. Org . Chem ., (1991), 56 , 2642). The selenide is subjected to an oxidative removal reaction followed by dehydroxylation with osmium tetraoxide to obtain a diol, which is converted to mono-protected tetrahydropyranyl ether compound 46-13 . Acylating the 2 'alcohol with phenyl chlorothioinoformate to obtain a precursor for robin deoxygenation followed by tributyltin hydride compound 46-14 (Metteuci, MD et al., Tetrahedron Lett ., (1987) , 28 , 22, 2459, see also Robins, MJ et al., J. Org . Chem ., (1995), 60 , 7902). Remove all protecting groups using TFA to give compound 46-9 (Greene, T., Protective Groups in Organic Chemistry , Wiley-Interscience, (1999)).

Example 47 Preparation of Exemplary Compounds of the Invention

Such compounds can be prepared according to the general routes shown in Schemes 47.1 and 47.3 , with examples shown in Schemes 47.2 and 47.4 .

Scheme 47.1

Scheme 47.2

N- (1-β-D-arabinofuranosyl-1,2-dihydro-2-oxo-4-pyrimidinyl) docosanamide (US Pat. No. 3,991,045, also see Akiyama, M. et al. , Chem . Pharm . Bull ., (1978), 26 , 3, 981) are treated with a base such as sodium hydride in a solvent such as dimethylformamide or tetrahydrofuran. At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added to give the desired phosphonate diesters 47-2, 47-3 .

Scheme 47.3

Scheme 47.3 illustrates the preparation of compound 47-9 .

Compound 47-1 is prepared according to US Pat. No. 3,991,045. 2 'and 3' alcohols are protected after protecting the 5 'hydroxyl to give compound 47-4 . The 5 'protecting group is removed to obtain the free primary alcohol which is the oxidation precursor. The primary alcohol can be transformed into ester 47-6 using the one-step oxidation method of corey (Corey, EJ et al., J. Org . Chem ., (1984), 49 , 4735). After deesterification the modified Hunsu decker reaction (Chu, CK et al., Tetrahedron Lett ., (1991), 32 , 3791) converts 47-7 to acetate 47-8 by oxidative decarbonylation used. Borbrogen glycosylation using Lewis acid conditions is controlled by protecting group participation in the 4 'position. Final deprotection affords the desired prodrug 47-9 .

Scheme 47.4

Specifically, compound 47-1 , N- (1-β-D-arabinofuranosyl-1,2-dihydro-2-oxo-4-pyrimidinyl) docosanamide (US Pat. No. 3,991,045) Is selectively protected with a tert-butyldiphenylsilyl (TBDPS) group to give a 5'-0-TBDPS analog. Further protection of the 3 'and 4' alcohols as benzoate esters yields compound 47-10 (Teng, K., Cook, D. J. Org . Chem ., (1994), 59 , 278). Fully protected compound 47-10 was selectively exposed to HF-pyridine reagent to deprotect the 5 'hydroxyl group, followed by Corey-Samuelsson oxidation (Corey, EJ, Samuelsson, B. J. Org . Chem ., (1984) , 49 , 4735) can be used to oxidize to t -butyl ester. The esterification product is deesterified with trifluoroacetic acid to give compound 47-13 . Acetate 47-14 , which may be a mixture of anomers at 5 ′ by acidic decarboxylation using a modified Hunsdicker reaction (Chu, CK et al., Tetrahedron Lett ., (1991), 32 , 3791). To. Column chromatography can separate the anomers, but need not. Since the stereochemical results of vorbrugen glycosylation are controlled by the stereochemistry of the 4'-benzoyl group due to adjacent group assist, the separation of these isomers is unnecessary. Borbrogen glycosylation with hydroxymethylphosphonic acid diethyl ester is carried out to obtain a protected phosphonate. Final deprotection using hydrolysis conditions completes the synthesis of Compound 47-15 .

Example 48 Preparation of Exemplary Compounds of the Invention

Such compounds can be prepared according to the general routes shown in Schemes 48.1 and 48.3 , with examples shown in Schemes 48.2 and 48.4 .

Scheme 48.1

Scheme 48.2

Properly protected 2-chloro-9- (2-deoxy-2-fluoro-β-D-arabinofuranosyl) -9H-purine prepared according to US Pat. No. 5,034,518 (also described in WO 03011877). -6-amine 48-1 is treated with a base such as sodium hydride in a solvent such as dimethylformamide or tetrahydrofuran. Protecting 2-chloro-9- (2-deoxy-2-fluoro-β-D-arabinofuranosyl) -9H-purin-6-amine with pivaloyl group gives pivaloyl compound 48-1 Formation (Greene, T., Protective Groups in Organic Chemistry , Wiley-Interscience, (1999)). At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added to obtain the protected products 48-2, 48-3 . The pivaloyl group is removed with sodium ethoxylate to obtain the desired phosphonate diesters 48-2, 48-3 .

Scheme 48.3

Scheme 48.3 illustrates the preparation of compound 48-8 .

Compound 48-4 , 9- (2-deoxy-aD-ribofuranosyl) -2-fluoroadenine is described in Montgomery, J. et al., J. Med . Chem . , (1969), 12 , 3, 498. Oxidation of the 5'-OH followed by elimination provides glycal 48-5 (see method of Zemlicka J. et al., J. Am. Chem . Soc . , (1972), 94 , 9, 3213). Protection of the chloroadenine at the 6 position followed by selenoetherification provides protected phosphonate 48-6 (Kim, C. et al., J. Org . Chem ., (1991), 56 , 2642). Oxidative removal of phenylselenide (as described in Kim, C. et al., J. Org . Chem ., (1991), 56 , 2642), followed by selective dihydroxylation to obtain a diol followed by diol Can be converted to 2 'protected alcohol. After protecting the 3 'alcohol, the protecting group is removed from the 2' hydroxyl group to give compound 48-7 . The compound can be exposed to dimethylaminosulfur trifluoride (DAST) and pyridine to simultaneously achieve inversion of fluorination and stereochemistry at the 2 'position (Pankiewicz, KW et al., J. Org . Chem ., (1992). ), 57 , 553, see also Pankiewicz, KW et al., J. Org . Chem ., (1992), 57 , 7315). Finally, the protecting groups are removed to give compound 48-8 .

Scheme 48.4

Specifically, 9- (2-deoxy-aD-ribofuranosyl) 2- fluoroadenine , compound 48-4 (Montgomery, J. et. Al., J. Med . Chem . , (1969), 12 , 3, 498) is oxidized with PtO ₂ to give carboxylic acid 48-9 . Decarboxylation is carried out in dimethylformamide at high temperature using dimethylformamide dineopentylacetal (Zemlicka J. et al., J. Am. Chem . Soc . , (1972), 94 , 9, 3213 ). Furanoid glycal 48-5 was obtained by first obtaining 6 of 2-chloroadenosine with pivaloyl chloride using conditions as described in Greene, T., Protective Groups in Organic Chemistry , Wiley-Interscience, (1999). -Protect the position. The protected glycal in the presence of diethyl (hydroxymethyl) phosphonate (Phillion, D. et al., Tetrahedron Lett., (1986), 27, 1477) was treated with silver perchloric acid to phosphonate 48-. 10 (Kim, C. et al., J. Org . Chem ., (1991), 56 , 2642). The selenide was subjected to an oxidative removal reaction, followed by dihydroxylation with osmium tetraoxide to obtain a diol, which was first subjected to silylation in 2'-OH, followed by protecting the 3 'alcohol with an acetate group and then removing the silyl group. Protection to convert to mono-protected acetate 48-12 . DAST converts 2 'alcohol to 2' fluoride with opposite stereochemistry (Pankiewicz, KW et al., J. Org . Chem ., (1992), 57 , 553, and also Pankiewicz, KW et al., J. Org . Chem ., (1992), 57 , 7315). Compound 48-13 is also obtained by removing 3 'acetate under conditions deprotecting pivaloyl group (Greene, T., Protective Groups in Organic Chemistry , Wiley-Interscience, (1999)).

Example 49 Preparation of Exemplary Compounds of the Invention

Representative compounds of the present invention can be prepared according to the general routes shown in Schemes 49.1 and 49.3 , with examples shown in Schemes 49.2 and 49.4 .

Scheme 49.1

Scheme 49.2

Boc-protected (1S) -1- (9-deazaguan-9-yl) -1,4-dideoxy-1,4-imino-D-ribitol, compounds 49-1, 49-3 (1S) -1- (9-deazaguan-9-yl) -1,4-dideoxy-1,4-imino-D-ribitol (WO 9,919,338 and Evans, GB et al., Tetrahedron , ( 2000), 56 , 3053 and Evans, GB et al., J. Med . Chem . (2003), 46 , 3412) described in Greene, T., Protective Groups in Organic Chemistry , Wiley-Interscience, (1999). Prepared by stirring with Boc anhydride. Then compound 49-1, 49-3 Treatment with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. At the end of bubbling, deprotection of the Boc group with trifluoroacetic acid (TFA), followed by addition of diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) Phosphonate diester 49-2 and 49-4 are obtained.

Scheme 49.3

Scheme 49.3 illustrates the preparation of compound 49-16 .

A deprotection of compound 49-5 (the hydrogen chloride salt, (1 R) -1- (9- aza having hypoxanthine-9-yl) oxy-1,4-imino-1,2,4-de - D- erythro - pentitol ) is prepared using di- t -butyl dicarbonate in dichloromethane, as described in Evans, GB et al., Tetrahedron , (2000), 56 , 3053. Glycal 49-6 is obtained by oxidation of 5′-OH followed by elimination reaction (see method of Zemlicka J. et al., J. Am. Chem . Soc . , (1972), 94 , 9, 3213). Phosphonate 49-7 protected by selenoetheration is obtained (Kim, C. et al., J. Org . Chem ., (1991), 56 , 2642). Oxidative removal of phenylselenide (as described in Kim, C. et al., J. Org . Chem ., (1991), 56 , 2642) followed by selective dehydroxylation to afford the desired diol 49-9 . Get Finally, remove the protector.

Scheme 49.4

Specifically, (1R) -1- (9-deazahyoxanthin-9-yl) -1 prepared as HCl salt as described in Evans, GB et al., Tetrahedron , (2000), 56 , 3053. The, 2,4- trideoxy -1,4-imino-D- erythro - pentitol is first protected and then oxidized with PtO ₂ to give carboxylic acid 49-11 . The removal reaction is carried out using decarboxyl dimethylformamide dineopentyl acetal in high temperature dimethylformamide (Zemlicka J. et al., J. Am. Chem . Soc . , (1972), 94 , 9, 3213 ). After selenoetherification, the protected glycal was treated with silver perchlorate in the presence of diethyl (hydroxymethyl) phosphonate (Phillion, D. et al., Tetrahedron Lett., 1986, 27, 1477) Phonates 49-13 are obtained (Kim, C. et al., J. Org . Chem ., (1991), 56 , 2642). The selenide is subjected to an oxidative removal reaction and then dehydroxylated using osmium tetraoxide to obtain diol 49-15 . Compound 49-16 is obtained by removing an amine protecting group according to the method of Greene, T., Protective Groups in Organic Chemistry , Wiley-Interscience, (1999).

Example 50 Preparation of Exemplary Compounds of the Invention

Scheme 50.1

This compound can be prepared according to the general route shown in, reaction formula 50.2 to 50.4 in the examples shown in Scheme 50.5 to 50.7.

Scheme 50.2 : Reformation at C10

Scheme 50.3 : Nitro group functionalization

Scheme 50.4 : modification at C7

Scheme 50.5 : Reformation at C10

10-hydroxycamphorthesin (prepared from commercially available campotescine according to J. Org . Chem . , (1995), 60 , 5739-5740) is dissolved in a mixture of sulfuric acid and nitric acid under ice cooling. At the end of the reaction, the resulting reaction solution is poured on ice. The precipitates are collected and washed with water, cold ethanol and diethyl ether. If necessary, the product is recrystallized for further purification ( J. Med . Chem ., (2001), 44 , 1594-602). The product of step 1 is dissolved in an organic solvent such as tetrahydrofuran (THF), acetonitrile or dimethylformamide (DMF) and treated with a base such as sodium hydride. At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added to obtain the desired phosphonate ester. The product is further purified by chromatography.

Scheme 50.6 : Reforming of nitro groups to C9

Rubetican is dissolved in an organic solvent such as DMF or ethyl acetate and hydrogenated in the presence of Pd / C under hydrogen atmosphere. At the end of the reaction, the crude suspension is filtered through celite and the solvent is removed in vacuo. If necessary, the product is further purified by chromatography. The product of step 1 was dissolved in an organic solvent such as THF, acetonitrile or DMF, and J. Org . Treatment with (2-oxoethyl) phosphonic acid diethylester (1 equiv) and sodium triacetoxyborohydride as described in Chem , (1996), 61, 3849-3862. The reaction is stopped with aqueous sodium bicarbonate and the product is collected as the resulting precipitate. The product is further purified by chromatography.

Scheme 50.7 : Reformation at C7

10-hydroxycamphorthecin is converted to the corresponding C7 aldehyde according to the literature procedure ( J. Med . Chem . , (2000), 43 , 3963-3969). The product of this step is dissolved in an organic solvent such as THF, acetonitrile or DMF, and J. Org . Treatment with aminoethylphosphonic acid diethylester (1 equiv.) And sodium triacetoxyborohydride as described in Chem , (1996), 61, 3849-3862. The reaction was stopped with aqueous sodium bicarbonate and the product was Purify by chromatography. The product of this stage is dissolved in a mixture of sulfuric acid and nitric acid under ice cooling. At the end of the reaction, the resulting reaction solution is poured on ice. The precipitates are collected and washed with water, cold ethanol and diethyl ether. If necessary, the product is recrystallized and further purified ( J. Med . Chem ., (2001), 44 , 1594-602).

The product was reduced by further conversion to C10 (according to J. Med . Chem . , (1991), 34 , 98-107).

The synthesized free C10 hydroxy compound is dissolved in an organic solvent such as DMF under an inert gas atmosphere. After addition of a tertiary organic amine base such as rutidine, N-phenyltrifluoromethanesulfonimide is added. The reaction mixture is stirred overnight at room temperature. When all the starting material has been consumed, a second tertiary organic amine base such as triethylamine is added followed by the addition of a class of palladium (II) such as Pd (OAc) ₂ and a phosphine such as triphenylphosphine and the concentrated formic acid. Add. The reaction mixture is heated to an elevated temperature of about 60 ° C. At the end of the reaction, the solvent is removed in vacuo and the product is triturated with a small amount of water and dried. The product is further purified by chromatography.

Example 51 Preparation of Exemplary Compounds of the Invention

Dose reduction and / or improvement in efficacy is achieved by using prodrugs of analogs of BAY-43-9006 that generate reagents with increased intracellular half-life upon degradation in target cells. Such compounds are described below.

Scheme 51.1

Such compounds can be prepared according to the general routes shown in Schemes 51.2, 51.4, 51.6 and 51.8 , with the embodiments illustrated in Schemes 51.3, 51.5, 51.7 and 51.9 .

Scheme 51.2

Scheme 51.3

2-aminoethylphosphonic acid diethyl ester (commercially available product) using a standard reagent for preparing secondary amides such as dicyclohexylcarbodiimide (DCC) and hydroxybenztriazole (HOBT) in a solvent such as dimethylformamide )

Scheme 51.4

Aniline containing a phosphonate moiety is treated with 4- (4-aminophenoxy) -pyridine-2-carboxylic acid methylamide (US Pat. No. 2002/0165394) in a solvent such as toluene in the presence of a reagent such as phosgene. Bind to form urea (see Bioorg . Med . Chem . Lett ., (2001), 11 , 2775).

4- (4-aminophenoxy) -pyridine-2-carboxylic acid methylamide is converted to 4-fluoronitrobenzene (4-hydroxypridine-) in a solvent such as dimethylformamide using a base such as cesium carbonate. After alkylating 2-carboxylic acid methylamide, it forms by reducing nitro group with tin chloride (II) in solvent, such as ethanol.

The synthesis of suitable phosphonate containing aniline is illustrated in Scheme 51.5 .

Scheme 51.5

2-chloro-5-nitrophenol is alkylated with an excess of E- 1,4-dibromobutene in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide. The monobromide product is treated with triethylphosphite in a solvent such as toluene (or other Arbuzov reaction conditions: Engel, R., Synthesis of Carbon-Phophorus bonds, CRC press, 1988). Finally, the nitro group is reduced with tin chloride (II) in a solvent such as ethanol.

Scheme 51.6

4-chloro-3-trifluoromethylaniline is combined with aniline containing a 4-phenoxy-substituted phosphonate moiety in a manner similar to that shown in Scheme 51.4 to form urea. The synthesis of suitable phosphonate containing aniline is illustrated in Scheme 51.7 .

Scheme 51.7

(3-benzyloxy) phenol is treated with magnesium t-butoxide and diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) in a solvent such as tetrahydrofuran. Benzyl groups are removed by hydrogenation using a catalyst such as palladium on charcoal in a solvent such as methanol, as described in Greene, T., Protective Groups in Organic Chemistry , Wiley-Interscience, (1999). The phenol is alkylated with 4-fluoronitrobenzene in a solvent such as dimethylformamide with a base such as potassium carbonate.

Finally, the nitro group is reduced as in Scheme 51.5 .

Scheme 51.8

4-Chloro-3-trifluoromethylaniline is combined with aniline containing a 4-phenoxy-substituted phosphonate moiety in a manner similar to that shown in Scheme 51.4 to form urea. The synthesis of suitable phosphonate-containing anilines is illustrated in Scheme 51.9 .

Scheme 51.9

2-Chloro-5-nitrobenzoyl chloride is reacted with 2-aminoethylphosphonic acid diethyl ester. Thereafter, the chloride is reacted with 4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide in the presence of a base such as potassium carbonate in a solvent such as tetrahydrofuran to substitute a biaryl ether motif. And reduction of the nitro group as in the previous example to obtain aniline for binding in the urea forming step.

Example 52 Preparation of Exemplary Compounds of the Invention

Reduction of dose and / or improvement of efficacy is achieved by using prodrugs of analogs of SAHA that generate reagents with increased intracellular half-life upon degradation in target cells. Such phosphonate prodrug drug compounds are described below.

Scheme 52.1

Such compounds can be prepared according to the general routes shown in Schemes 52.2 and 52.4 , with examples shown in Schemes 52.3 and 52.5 .

Scheme 52.2

Scheme 52.3

Scheme 52.2 shows the synthesis of prodrugs 52-3, 52-13 (WO 118,171 and WO 03,032,921). Differentially protected octadiodioic acid (reported in US Pat. No. 23,232) can be monodeprotected to give 52-6, 52-11 . The monovalent acid is combined with 4-aminophenol using standard peptide binding conditions to yield compounds 52-7, 52-12 . After hydrolysis of the remaining esters, protected hydroxylamides are formed to yield compound 52-9 . At the end of the synthesis, phenolic moieties are used to bind prodrug units.

Specifically, octanedioic acid tert-butyl ester methyl ester is monodeprotected using trifluoroacetic acid (TFA) to give compounds 52-6, 52-11 . Binding free acid to 4- (methylamino) phenol (Nag, A. et al ., Indian J. Chem . Sect. B. , (1989), 64 , 1 as well as US Pat. No. 2,397,911) Amide 52 -7, 52-12 . The acid 52-8 can be obtained by hydrolyzing the methyl ester with LiOH. TBDPSO-NH _2, makes the EDC and NN- dimethylamino pyridine, and the like of the carbodiimide by the peptide coupling conditions using the mid to form a protected hydroxy TBDPS- rocks ahmik acid compound 52-9. Phenol 52-9 can be treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added to obtain protected phosphonate diesters 52-3 , 52-13 . Compound 52-3 , 52-13 can be obtained by removing a TBDPS group using TFA.

Scheme 52.4

Compounds 52-4, 52-16, 52-17 can be prepared from advanced intermediate 52-14 reported in WO 0118171. After protecting the hydroxylamide, the Cbz group is removed to give compounds 52-15 and 52-19 . Aldehydes 52-18, 52-20 and then reductive amination using a (Digital Specialty Chemicals, Inc.), by removing the protective group to obtain a mid-hydroxy roksa prodrug 52-4, 52-16, 52-17.

Scheme 52.5

The Cbz protected 52-14 can be prepared as described in WO 0118171. TBDPS is used to protect the hydroxamide (Greene, T., Protective Groups in Organic Chemistry , Wiley-Interscience, (1999)) to remove the Cbz group to yield compounds 52-15 , 52-19 . 52-15, by reductive amination of the free amine with an aldehyde 52-19 52-18, 52-20 available purchased from Digital Specialty Chemicals captured (and Olson, GL et al., J. Med. Chem., (1995) , 38, 15, 2866). Prodrugs 52-4 , 52-16, 52-17 are formed.

Example 53 Preparation of Exemplary Compounds of the Invention

Reduction of dose and / or improvement in efficacy is achieved by using prodrugs of analogs of thalidomide (thalidomide) that generate reagents with increased intracellular half-life upon degradation in target cells. Such compounds are described below.

Scheme 53.1

Such compounds can be prepared according to the general route shown in Scheme 53.2 , with the embodiments illustrated in Scheme 53.3 .

Scheme 53.2

Scheme 53.3

2-Methyl-4-nitrobenzoic acid methyl ester (commercially available) was obtained from Bioorg . Med . Chem . 3- (5-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6 according to the methods reported in Lett ., (1999), 9 , 1625 -Convert to Dion. This amine intermediate is subjected to reethylation of diethylphosphonoacetaldehyde in the presence of a reducing agent such as sodium triacetoxyborohydride (obtained from ozone decomposition of diethylallylphosphonate) to obtain the desired amine linker analog ( J . Org. Chem., (1996 ), 61, 3849). Optionally, the amine is prepared from J. Med . Chem ., (1982), 25 , 960 and J. Med . Acylated with activated diethylphosphonoacetic acid according to the same method as reported in Chem ., (1984), 27 , 600 to give the desired amide linker compound. The activated diethylphosphonoacetic acid can be obtained by treating with a binding reagent such as diethylcyanophosphonate and a base such as diisopropylethylamine in a solvent such as dimethylformamide at room temperature.

2-Methyl-3-nitrobenzoic acid methyl ester (commercially available) is treated with N-bromosuccinimide under light in a solvent such as carbon tetrachloride to produce 2-bromomethyl-3-nitrobenzoic acid methyl ester. This benzylic bromide was dissolved in a solvent such as dimethylformamide in the presence of a base such as triethylamine. [2- (3-amino-2,6-dioxo-piperidin-1-yl) -ethyl] -phosphonic acid Treatment with diethyl ester (see below for the preparation of this compound). The binding product is then reduced by hydrogenation ( Bioorg . Med . Chem . Lett ., (1999), 9 , 1625) to obtain the desired analog. [2- (3-Amino-2,6-dioxo-piperidin-1-yl) -ethyl] -phosphonic acid diethylester is described in J. Med . Chem ., (2003) 46 , 3793. Thus, benzyloxycarbonyl-protected glutaric acid may be converted to triethylamine, 1-hydroxybenzotriazole, diethyl2-aminoethylphosphonate and 1,3-dicyclohexylcarbodii in a solvent such as acetonitrile. Treat with mead. After the reaction is complete, the solvent is removed and the residue is purified by chromatography to give a cyclic product which is hydrogenated in the presence of a palladium catalyst to give the desired intermediate.

Example 54 Preparation of Exemplary Compounds of the Invention

Reduction of dose and / or improvement of efficacy is achieved by using prodrugs of analogs of MS-275 that generate reagents with increased intracellular half-life upon degradation in target cells. Such phosphonate prodrug drug compounds are described below.

Scheme 54.1

Such compounds can be prepared according to the general route shown in Scheme 54.2 , with examples shown in Scheme 54.3 .

Scheme 54.2

Scheme 54.2 shows the preparation of the prodrug of MS-275.

Compound 54-4 (prepared according to CH 569714 and Chem Abstr. 78, 16049) was prepared by the formation of carbonyl imidazole intermediate followed by the activation of alcohol by addition of 4- (aminomethyl) benzoic acid to carbamate 54-5 Transform to The 54-5 carboxylic acid is then combined with 2-aminoaniline to give compound 54-6 . Following hydrolysis of the ester, the acid is combined with an amino phosphonate prodrug to complete the synthesis of prodrug 54-2 .

Scheme 54.3

Scheme 54.3 illustrates the preparation of prodrug linked MS-275 in more detail. Compound 54-7 is prepared according to the reported method (CH 569714 as well as Chem Abstr. 78, 16049). 54-7 is condensed with 4- (aminomethyl) benzoic acid (manufactured by Aldrich) using 1,1'-carbonyldiimidazole to obtain carboxylic acid 54-8 (Suzuki, T. et al., J . Med. Chem., (1999 ), 42, 3001). Acid 54-8 is treated with oxalyl chloride and then reacted with imidazole to convert to acylchloride to obtain the imidazole intermediate. It is then reacted with 2-aminoaniline in the presence of trifluoroacetic acid (TFA) to form 54-9 . After hydrolysis of the methyl ester, it is combined with diethylaminoethylphosphonate (Fluka) to give prodrug 54-10 .

Preparation of prodrug 54-3 follows a method similar to that described above.

Starting material, 5-hydroxymethylnicotinic acid methyl ester, can be prepared according to Hemel JV et al., Nucleosides Nucleosides , (1996), 15 , 1203. The subsequent step is as shown in Scheme 54.3 .

Example 55 Preparation of Exemplary Compounds of the Invention

Representative compounds of the invention can be prepared according to the general route shown in Scheme 55.1 , with examples shown in Scheme 55.2 .

Scheme 55.1

Scheme 55.1 represents the preparation of prodrug 55-7 .

Compound 55-1 , 4-formylcinnamic acid is first esterified to give aldehyde 55-2 (WO 03039599). The aldehyde is reductive aminated with 3- (2-aminoethyl) -1H-indol-5-ol (commercially available from Aldrich) to give compound 55-3 . Compound 55-4 is obtained by alkylating a secondary amine at 55-3 with protected 2-bromoethanol. Phenolic 55-4 It can be treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. At the end of bubbling, the desired phosphonate diester 55-5 is obtained by addition of a dialkyl phosphonate such as diethylphosphonomethyltriplate (produced according to Tetrahedron Lett ., (1986), 27 , 1477). . Compound 55-6 is obtained by forming N-hydroxy amide with hydroxylamine in the base. Final removal of the protecting group on the primary alcohol affords prodrug 55-7 .

Scheme 55.2

Scheme 55.2 illustrates the detailed synthesis of the prodrug of LAQ-824. 4-formylcinnamic acid is first esterified to give methyl ester 52-14 (WO 03039599). The aldehyde of 52-14 is reductive aminated with 3- (2-aminoethyl) -1H-indol-5-ol ( commercially available from Aldrich) to give amine 55-8 . The amine is alkylated with (2-bromoethoxy) -tert-butyldimethylsilane to give compound 55-9 . Phenol 55-9 is alkylated with phosphonomethyl triflate to give phosphonate 55-10 . Hydroxylamine is used in the basic reaction medium to form N-hydroxy amide. Finally remove TBDMS to obtain prodrug 55-12 .

For other syntheses, for example, 1H-indole-6-ol (commercially available from Toronto Research Chemicals) as the corresponding starting material can be used following the same route as the synthetic route described above.

Example 56 Preparation of Exemplary Compounds of the Invention

Such compounds can be prepared according to the general routes shown in Schemes 56.1 and 56.3 , with examples shown in Schemes 56.2 and 56.4 .

Scheme 56.1

Scheme 56.2

Arabinofuranosyl-2-fluoroadenine 56-1 (prepared according to the method of Montgomery, J. et al ., J. Med . Chem ., (1969), 12 , 3, 498) or dimethylformamide Treatment with a base such as sodium hydride in a solvent such as tetrahydrofuran. At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added to give the desired phosphonate diester 56.2 .

Scheme 56.3

Scheme 56.3 illustrates the preparation of compound 56-8 .

Compound 56-4 (9- (2-deoxy-aD-ribofuranosyl) 2-fluoroadenine) was found in Montgomery, J. et. al., J. Med . Chem . , (1969), 12 , 3, 498 as well as US Pat. No. 4,210,745. Glycal 56-5 is obtained by oxidation of 5′-OH followed by elimination reaction (see method of Zemlicka J. et al., J. Am. Chem. Soc . , (1972), 94 , 9, 3213). After protecting fluoroadenine at position 6, phosphonate 56-6 protected by selenoetheration is obtained (Kim, C. et al., J. Org . Chem ., (1991), 56 , 2642 ). Oxidative removal of the phenyl-selenide which by selective de-hydroxylation followed by (Kim, C. et al., J. Org. Chem., (1991), 56, as described in 2642) converted to a mono-triflate Get Dior The 3 'alcohol is protected to give compound 56-7 . The compound is exposed to LiOAc to convert stereochemistry at the 2 'position to obtain the protected desired stereoisomer of the product. Finally remove the protectors.

Scheme 56.4

Specifically, 9- (2-deoxy-aD-ribofuranosyl) 2- fluoroadenine , compound 56-4 , (Montgomery, J. et. Al., J. Med . Chem . , (1969), 12 , 3, 498 and US Pat. No. 4,210,745) are oxidized with PtO ₂ to give carboxylic acid 56-9 . Decarboxylation removal is carried out using dimethylformamide dinepentylacetal in high temperature DMF (Zemlicka J. et al., J. Am. Chem . Soc . , (1972), 94 , 9, 3213). Once furanoid glycal 56-5 is obtained, the 6-position of 2-fluoroadenosine is first determined using PivCl conditions as described in Greene, T., Protective Groups in Organic Chemistry , Wiley-Interscience, (1999). Protect. The protected glycal is treated with silver perchlorate in the presence of diethyl (hydroxylmethyl) phosphonate (Phillion, D. et al., Tetrahedron Lett., 1986, 27, 1477) to give phosphonate 56.10 ( Kim, C. et al., J. Org . Chem ., (1991), 56 , 2642). The selenide is subjected to an oxidative removal reaction and then dehydroxylated with osmium tetraoxide to obtain a diol, which is converted to mono-protected triflate 56-12 . The arrangement of the 2 'alcohols can be reversed by substitution of the triflate with an acetate group. Deprotecting pivaloyl groups (Greene, T., Protective Groups in Organic Chemistry , Wiley-Interscience, (1999)) also removes the newly bound 2 'acetate. The final deprotection of THP groups in acidic media can be achieved.

Example 57 Preparation of Exemplary Compounds of the Invention

Compounds of the invention are prepared as generally shown in Scheme 57.1 , with examples shown in Scheme 57.2 .

Scheme 57.1

Scheme 57-2

Such compounds can be prepared via reductive amination of phosphonate containing aldehydes using pyranorubicin itself. Such aldehydes are synth . Commun . (1992), 22 , 2219.

Example 58 Preparation of Exemplary Compounds of the Invention

The compounds of the present invention are prepared as generally described in the following schemes.

Scheme 58.1

Scheme 58.2

The Cbz protecting group is used to protect the amino sugar portion of daunorubicin, as described in Greene, T., Protective Groups in Organic Chemistry , Wiley-interscience publication, (1999) to produce 58-7 . The alcohol is treated with a base such as sodium hydride in a solvent such as dichloromethane, tetrahydrofuran or dimethylformamide. At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added and after purification the desired phosphonate diester 58-6 is obtained. The desired product is obtained by final deprotection by hydrogenation using a catalyst such as charcoal palladium in a solvent such as methanol using the method of Greene et al.

Alkyl derivatives of amino nitrogen per have been reported (Farquhar, D. et. Al. , J. Med. Chem., (1998), 41, 6, 965). The binding of the phosphonate prodrug moiety to this amine via alkylation is shown in Scheme 58.3 . Scheme 58.4 provides an embodiment of the 58-9 preparation.

Scheme 58.3

Scheme 58.4

Prodrug 58-9 can be prepared via reductive amination of phosphonate containing aldehydes using daunorubicin itself. Such aldehydes are synth . Commun . (1992), 22 , 2219.

Further manipulations can be made to the phosphonate moiety prior to final deprotection. Modifications of this kind are described in more detail below.

Example 59 Preparation of Exemplary Compounds of the Invention

Representative compounds of Formulas 59-4 and 59-7 can be prepared according to the general route shown in Scheme 59.1 together with the examples shown in Scheme 59.2 .

Scheme 59.1

Scheme 59.2

Cbz protecting groups are used to protect the aminosugar portion of idarubicin to produce 59-5 , as described in Greene, T., Protective Groups in Organic Chemistry , Wiley-interscience publication, (1999). The alcohol is treated with a base such as sodium hydride in a solvent such as dichloromethane, tetrahydrofuran or dimethylformamide. At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added and after purification the desired phosphonate diester 59-6 is obtained. The desired product is obtained by final deprotection by hydrogenation using a catalyst such as charcoal palladium in a solvent such as methanol using the method of Greene et al.

Alkyl derivatives of amino nitrogen per have been reported (Farquhar, D. et. Al. , J. Med. Chem., (1998), 41, 6, 965). The binding of the phosphonate prodrug moiety to this amine via alkylation is shown in Scheme 59.3 . Scheme 59.4 provides an embodiment of the 59-9 preparation.

Scheme 59.3

Scheme 59.4

Prodrug 59-9 can be prepared via reductive amination of phosphonate containing aldehydes with idarubicin itself. Such aldehydes are synth . Commun . (1992), 22 , 2219.

Example 60 Preparation of Exemplary Compounds of the Invention

Representative compounds of the invention may be prepared according to the general route shown in, reaction formula 60.1 to 60.3 in the examples shown in Scheme 60.4 to 60.6.

Scheme 60.1 : reforming at C7

Scheme 60.2 : functionalization of nitro groups

Scheme 60.3 : reforming at C10

Scheme 60.4 : reforming at C7

Exatecan is dissolved in an organic solvent such as tetrahydrofuran (THF), acetonitrile or dimethylformamide (DMF), and J. Org . Treated with (2-oxo-ethyl) -phosphonic acid diethylester (1 equiv) and sodium triacetoxyborohydride as described in Chem , ((1996)), 61, 3849-3862. The reaction is stopped with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. The product is further purified by chromatography.

Scheme 60.5 : modification of the nitro group of C9

Exatecan is dissolved in an organic solvent such as carbon tetrachloride. Add N-bromo succinimide (NBS) followed by azobisisobutyronitrile (AIBN) according to the method of Organikum, 17 ^th edition, Deutscher Verlag der Wissenschaften, (1988), 167. The reaction is heated to reflux for several hours. At the end of the reaction the mixture is cooled to room temperature. The reaction is filtered and the solvent is removed in vacuo to afford crude product. Chromatography further separates the regioisomer product.

The product of step 1 is dissolved in an organic solvent such as acetonitrile or DMF and treated with aminoethylphosphonic acid diethylester (excess), sodium iodide (1 equiv) and sodium carbonate (1 equiv). The reaction mixture is heated to an elevated temperature of ˜50-60 ° C. At the end of the reaction, the mixture is cooled to room temperature and filtered. The resulting reaction product is dissolved in an organic solvent such as dichloromethane (DCM), chloroform or benzene and the solution is washed with aqueous hydrochloric acid (HCl) (0.1 N) and dried. Filter and remove the solvent in vacuo to afford crude product. The product is further purified by chromatography.

Scheme 60.6 : reforming at C10

Exatecan is dissolved in an organic solvent such as DMF, DCM or acetonitrile. Tert. Butoxycarbonyl anhydride is added followed by catalytic amounts of 4-dimethylaminopyridine (DMAP) (Green and Wuts, Protective Groups in Organic Chemistry , Wiley and Sons, NY, (1999)). Continue stirring at room temperature. At the end of the reaction, water is added and the resulting reaction mixture is extracted with an organic solvent such as DCM or chloroform and dried. The solvent is removed to give crude product. Further purification is by chromatography.

The product of step 1 is dissolved in an organic solvent such as THF, DMF or chloroform and treated with aqueous sodium hydroxide (NaOH). Stirring is continued at room temperature until conversion to open lactone is observed. The solvent is removed in vacuo and the crude material is dissolved in an organic solvent such as methanol or DMF. Aminoethylphosphonic acid diethyl ester was added and J. Am. Chem . Soc . (1957), 79 , 385-391 is modified to heat the reaction at reflux for a prolonged period of time. At the end of the reaction, the mixture is cooled to room temperature and acidified with aqueous HCl. J. Am. Chem . Soc. Stirring is continued until the formation of lactones is observed according to (1966), 88 , 3888-3890. The solvent is removed in vacuo and the mixture is partitioned between an organic solvent such as chloroform or DCM and aqueous HCl (0.1N). The organic layer is separated and the solvent is removed in vacuo. The crude material is dissolved in an organic solvent such as DCM or chloroform and treated with trifluoroacetic acid (TFA) (Green and Wuts, Protective Groups in Organic Chemistry , Wiley and Sons, NY, (1999)). At the end of the reaction, solid sodium bicarbonate is added and the reaction is filtered. The solvent is removed in vacuo. The product is further purified by chromatography.

Example 61 Preparation of Exemplary Compounds of the Invention

Representative compounds of the invention may be prepared according to the general route shown in, reaction formula 61.1 to 61.3 in the examples shown in Scheme 61.4 to 61.6.

Scheme 61.1 : Modification at ω guanidine nitrogen

Scheme 61.2 : Modification at α guanidine nitrogen

Scheme 61.3 : binding to C2

Scheme 61.4 : Modification at ω guanidine nitrogen

Synthesis of Aromatic Starting Materials (1):

2-cyanophenylbromide (commercially available) is dissolved in an organic solvent such as N-methylpyrrolidinone (NMP) or dimethylformamide (DMF) in an inert gas atmosphere. Sodium carbonate, triphenylphosphine and methyl acrylate are added followed by palladium (II) acetate (Pd (OAc) ₂ ). The reaction mixture was converted to Chem . Rev. (2000), 100 , 3009 according to the method of heating to a high temperature of ~ 100 ~ 140 ℃. At the end of the reaction, the reaction mixture is cooled to room temperature and filtered through celite. The solvent is removed to give crude product. Further purification is by chromatography.

The crude material obtained from step 1 is dissolved in a mixture of organic solvents such as benzene and ethanol under an inert gas atmosphere. Wilkinson's catalyst [RhCl (PPh ₃ ) ₃ ] was added and the reaction mixture was added to J. Org . Chem . , (1969), 34 , 3684-3685 in a hydrogen atmosphere of ˜60-80 psi and heated to a high temperature of ˜60 ° C. At the end of the reaction, the reaction mixture is cooled to room temperature and the solvent is removed in vacuo. The crude material is triturated with diethyl ether and the catalyst is removed by filtration through celite. The solvent is removed to obtain a crude material. Further purification is by chromatography.

The crude material of step 2 was dissolved in polyphosphoric acid and Org . Lett . , (2001), 3 , and 279-281 are heated to a high temperature of ~ 90 ℃ in the atmosphere of an inert gas. At the end of the reaction, the mixture is cooled to room temperature, poured into ice and extracted with an organic solvent such as diethyl ether. The combined organic extracts are washed with brine and dried. The solvent is removed to give crude product. Further purification is by chromatography.

Synthesis of Guanidine Derivatives (2):

Di (imidazol-1-yl) methaneimine is dissolved in an organic solvent such as tetrahydrofuran (THF) and then treated with J. Org . Chem . (2002), 67 , 7553-7556 and reacts with 2-aminoethyl phosphonic acid diethyl ester at room temperature. At the end of the reaction, water is added and the product is extracted with an organic solvent such as dichloromethane (DCM). The combined organic layers are washed with saturated aqueous ammonium chloride solution, water and brine and dried. The solvent is removed to give crude material. Further purification is by chromatography.

The product of this step is dissolved in an organic solvent such as DMF and reacted with hydrazine in a closed vessel at a high temperature of ˜100 ° C. according to a method slightly modified in the above reference. At the end of the reaction, the mixture is cooled to room temperature and water is added. The product is extracted with an organic solvent such as DCM. The combined organic layers are washed with saturated aqueous ammonium chloride solution, water and brine and dried. The solvent is removed to give crude material. Further purification is by chromatography.

Final work (3):

The products of reaction steps (1) and (2) are dissolved in an organic solvent such as ethanol and treated with a catalytic amount of concentrated sulfuric acid. This mixture is described in J. Med . Chem . Heated to reflux for a minimum amount of time, as described in (1993), 36 , 46-54. The reaction mixture is cooled to room temperature and the solvent is removed in vacuo. The product is dissolved in an organic solvent such as ethyl acetate or chloroform and washed with water. The organic layer is dried and the solvent is removed in vacuo. Further purification is by chromatography.

The product of this step is dissolved in a mixture of organic solvents such as diethyl ether and ethanol. The solution is saturated with hydrochloric acid gas at 0 ° C. and maintained at this temperature for a prolonged period of time. At the end of the reaction, diethyl ether is added to cause product precipitation. The precipitates are collected and dried in vacuo. The crude material is dissolved in an organic solvent such as ethanol and ammonium saturated ethanol is added. The mixture is heated to an elevated temperature of ˜70 ° C. for several hours. At the end of the reaction, the mixture is cooled to room temperature and the solvent is removed in vacuo. The product is further purified by recrystallization or chromatography with an ethanol / diethyl ether mixture.

Scheme 61.5 : Modification on α guanidine nitrogen

Synthesis of Guanidine Derivatives (1).

Tert. Butyl carbazate (commercially available) was prepared from J. Org . Treatment with diethylphosphonateethylethylcarbaldehyde and sodium triacetoxyborohydride in an organic solvent such as DCM or THF as described in Chem , (1996), 61, 3849-3862. The reaction is stopped with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. Further purification is by chromatography.

The product of this step was dissolved in an organic solvent such as THF and J. Org . Chem . , (2002), 67 , 7553-7556, with di (imidazol-1-yl) methanimine. At the end of the reaction, water is added and the product is extracted with an organic solvent such as DCM. The combined organic layers are washed with saturated aqueous ammonium chloride solution, water, brine and dried. The solvent is removed to give crude material. Further purification is by chromatography.

The product of this step is dissolved in an organic solvent such as DMF and reacted with ammonia at an elevated temperature of ˜100 ° C. in a closed vessel according to a method slightly modified in the above reference. At the end of the reaction, the mixture is cooled to room temperature and water is added. The product is extracted with an organic solvent such as DCM. The combined organic layers are washed with saturated aqueous ammonium chloride solution, water and brine and dried. The solvent is removed to give crude material. Further purification is by chromatography.

The product of this step is dissolved in an organic solvent such as DCM and treated with trifluoroacetic acid (TFA) according to the methods of Green and Wuts, Protective Groups in Organic Chemistry . At the end of the reaction, sodium bicarbonate is added and the reaction mixture is filtered. The solvent is removed in vacuo to afford crude product. Further purification is by chromatography.

Final work (3):

The products of the reaction are dissolved in an organic solvent such as ethanol and treated with a catalytic amount of concentrated sulfuric acid. This mixture is described in J. Med . Chem . Heated to reflux for a minimum amount of time, as described in (1993), 36 , 46-54. The reaction mixture is cooled to room temperature and the solvent is removed in vacuo. The product is dissolved in an organic solvent such as ethyl acetate or chloroform and washed with water. The organic layer is dried and the solvent is removed in vacuo. Further purification is by chromatography.

The product of this step is dissolved in a mixture of organic solvents such as diethyl ether and ethanol. The solution is saturated with hydrochloric acid gas at 0 ° C. and maintained at this temperature for a prolonged period of time. At the end of the reaction, diethyl ether is added to cause product precipitation. The precipitates are collected and dried in vacuo. The crude material is dissolved in an organic solvent such as ethanol and ammonium saturated ethanol is added. The mixture is heated to an elevated temperature of ˜70 ° C. for several hours. At the end of the reaction, the mixture is cooled to room temperature and the solvent is removed in vacuo. The product is further purified by recrystallization or chromatography with an ethanol / diethyl ether mixture.

Scheme 61.6 : binding to C2

In Scheme 61.4 , the product of step (1) is dissolved in an organic solvent such as THF and the solution is cooled to -78 ° C. Lithium diisopropylamide solution is added and the reaction mixture is stirred for a few minutes. When deprotonation was complete, excess E- 1,4 dibromobutene was added and the reaction was warmed to room temperature. The reaction is stopped with an aqueous ammonium chloride solution and the product is extracted with an organic solvent such as ethyl acetate or chloroform. Dry and remove the solvent to afford crude product. Further purification is by chromatography.

The product of this step is heated with ethyl phosphite in an organic solvent such as toluene at an elevated temperature of ˜110 ° C. according to the method described in Engel, R., Synthesis of Carbon Phosphorus bonds, CRC press (1988). At the end of the reaction, the mixture is cooled to room temperature and the solvent is removed in vacuo to afford crude product. Further purification is by chromatography.

The reaction product is dissolved in an organic solvent such as aminoguanidine ethanol and treated with a catalytic amount of concentrated sulfuric acid. This mixture is described in J. Med . Chem . Heated to reflux for a minimum amount of time, as described in (1993), 36 , 46-54. The reaction mixture is cooled to room temperature and the solvent is removed in vacuo. The product is dissolved in an organic solvent such as ethyl acetate or chloroform and washed with water. The organic layer is dried and the solvent is removed in vacuo. Further purification is by chromatography.

The product of this step is dissolved in a mixture of organic solvents such as diethyl ether and ethanol. The solution is saturated with hydrochloric acid gas at 0 ° C. and kept at 0 ° C. for an extended period of time. At the end of the reaction, diethyl ether is added to cause product precipitation. The precipitates are collected and dried in vacuo. The crude material is dissolved in an organic solvent such as ethanol and ammonium saturated ethanol is added. The mixture is heated to an elevated temperature of ˜70 ° C. for several hours. At the end of the reaction, the mixture is cooled to room temperature and the solvent is removed in vacuo. The product is further purified by recrystallization or chromatography with an ethanol / diethyl ether mixture.

Further manipulations can be made to the phosphonate moiety prior to the final deprotection reaction. This kind of variation is described in more detail in the next section.

Example 62 Preparation of Exemplary Compounds of the Invention

Representative compounds of 62-4 and 62-7 are prepared according to the general route shown in Scheme 62.1 together with the examples shown in Scheme 62.2 .

Scheme 62.1

Scheme 62.2

Cbz protecting groups are used to protect the aminosugar portion of adriamycin as described in Greene, T., Protective Groups in Organic Chemistry , Wiley-interscience publication, (1999). The protection of primary alcohols making 62-5 using acetate protecting groups is described (US Pat. No. 4,303,785). The alcohol is treated with a base such as sodium hydride in a solvent such as dichloromethane, tetrahydrofuran or dimethylformamide. At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added and after purification the desired phosphonate diester 62-6 is obtained. After final deprotection by hydrogenation with a catalyst such as charcoal palladium in a solvent such as methanol using a method such as Greene et al., The compound is exposed to potassium carbonate to obtain the desired product.

Alkyl derivatives of amino sugar nitrogen have been reported (Farquhar, D. et. Al., J. Med . Chem ., (1998), 41 , 6, 965). The binding of the phosphonate prodrug moiety to this amine via alkylation is shown in Scheme 62.3 . Scheme 62.4 is to provide a specific example of the manufacturing 62-9.

Scheme 62.3

Scheme 62.4

Prodrug 62-9 was prepared through reductive amination of phosphonate-containing aldehydes using adriamycin itself. It can manufacture. Such aldehydes are synth . Commun . (1992), 22 , 2219.

Example 63 Preparation of Exemplary Compounds of the Invention

Background and Application of Skeletal Compounds

Some triaryl ethylenes are useful in the treatment of hypercholesterolemia and osteoporosis by acting as selective estrogen receptor modulators. Line 3, page 5 of WO01 / 36360 describes one such derivative, Osemifene. The present invention provides novel Osfemiphene analogue 63-1 . As shown in formula 63-2, 63-3 and 63-4, such a novel trehalose feminist pen analogs both said Genie the utility of AGI-1067, provides cellular accumulation as described below as needed

Process for preparing the new compound:

The synthesis of Osfemifen, 63-1 is described in WO01 / 36360. As shown in Schemes 63.1-63.2 , Compound 63-1 is treated with dialkylphosphonoalkyltrifluoromethylsulfonate in a solvent such as pyridine or a nonbasic solvent such as dichloromethane containing a base such as triethylamine. Obtain ether of 63-1 . Using methylsilbromide in a solvent such as DMF or acetonitrile to remove the alkoxyl group from the phosphonate moiety, the resulting compound was prepared using the desired prodrug 63-2, using the phosphonate ester and amidate preparation methods described below . Convert it to 63-3, 63-4 .

Scheme 63. 2 describes the synthesis of compound 63-9 , which is a special member of the general class of compounds represented by structures 63-2, 63-3, 63-4 . Treated with the compound 63-1 and treated with diethyl phosphono methyl trifluoroacetate in pyridine as a sulfonate, 63-5 to 63-6 to obtain the ether. Compound 63-6 is treated with trimethylsilylbromide in acetonitrile to give free phosphonic acid 63-7 . Compound 63-7 was then treated with dicyclohexylcarbodiimide and phenol in DMF to give monophenol ester 63-8 and then condensed with isopropyl ester of alanine using alditiol and triphenylphosphine in DMF. Obtain objective prodrug 63-9 .

Scheme 63.1

Scheme 63.2

Example 64 Preparation of Exemplary Compounds of the Invention

The synthesis sequence of examples of such phosphonates is described in Scheme 64.1 .

Scheme 64.1 .

Synthetic precursors of rapamycin, everolimus, are shown in Bioorg . Med . Chem . O -arylated using an appropriate aryl bismuth reagent according to the method reported in Lett , (1995), 5 , 1035. Treatment of 3- (dimethyl-t-butylsilyloxy) bromobenzene with butyllithium in magnesium or tetrahydrofuran in diethylether and reaction of the resulting organometallic reagent with bismuth trichloride to produce triarylbismucin Let's do it. After treatment with 1-1.2 equivalents of acetic acid, the bismuth (V) reagent is mixed with rapamycin and copper (II) acetate. The reaction is allowed to proceed at room temperature or at reflux if necessary for one day to afford the desired 3- (dimethyl-t-butylsilyloxy) phenyl ether. After removal of the dimethyl-t-butylsilyl protecting group, O -alkylation with diethyl (bromomethyl) phosphonate in the presence of silver oxide gives the desired everolimus analog containing diethylphosphonate. Silver ion assisted reactions have been used to mediate alkylation to immunosuppressive macrolides that are structurally similar to rapamycin (see J. Med . Chem ., (1998), 41 , 1764).

Scheme 64.2 .

Ever As shown in sirolimus-indol-phosphonate analog of the reel ethers Scheme 64.2, bis silent intermediate turn of the key tree, J. Org. Chem . (1998), 63 , 6721, in the same manner as in the previous example, except that it is obtained from 5-bromoindole.

Example 65 Preparation of Exemplary Compounds of the Invention

The synthesis sequence of examples of such phosphonates is described in Scheme 65.1 .

Scheme 65.1 .

Sirolimus is shown as Bioorg . Med . Chem . O -arylated using an appropriate aryl bismuth reagent according to the method reported in Lett , (1995), 5 , 1035. Treatment of 3- (dimethyl-t-butylsilyloxy) bromobenzene with butyllithium in magnesium or tetrahydrofuran in diethylether and reaction of the resulting organometallic reagent with bismuth trichloride to produce triarylbismucin Let's do it. After treatment with 1-1.2 equivalents of acetic acid, the bismuth (V) reagent is mixed with sirolimus and copper (II) acetate. The reaction is allowed to proceed at room temperature or at reflux if necessary for one day to afford the desired 3- (dimethyl-t-butylsilyloxy) phenyl ether. After removal of the dimethyl-t-butylsilyl protecting group, O -alkylation with diethyl (bromomethyl) phosphonate in the presence of silver oxide gives the desired sirolimus analog containing diethylphosphonate. Silver ion assisted reactions have been used to mediate alkylation to immunosuppressive macrolides that are structurally similar to sirolimus (see J. Med . Chem ., (1998), 41 , 1764).

Scheme 65.2 .

Phosphonate analogs of sirolimus indolyl ethers have the core triindolylbismucin intermediate as shown in Scheme 65.2 . J. Org . Chem . (1998), 63 , 6721, in the same manner as in the previous example, except that it is obtained from 5-bromoindole.

Example 66 Preparation of Exemplary Compounds of the Invention

Methods for the synthesis of such compounds are described in WO 09/613266 according to the general route shown in Schemes 66.1-66.3 .

Scheme 66.1

Examples of the synthesis of suitable phosphonate-containing phenylalanine derivatives are shown below.

Scheme 66.2

The protected tyrosine derivative can be treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added to give the desired phosphonate diester. The carboxylate is then selectively hydrolyzed using a hydroxide ion source such as lithium hydroxide in a solvent such as ethanol to obtain a phosphonate containing reagent in a form suitable for the synthesis of bortezomib analogs.

Scheme 66.3

The protected tyrosine derivative can be treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. At the end of bubbling, excess E- 1,4-dibromobutene is added. The reaction is stopped with aqueous ammonium chloride and the product is extracted with an organic solvent such as ethyl acetate, and then the monoalkylated product is chromatographed. Separate by graphy. It is then heated together with triethylphosphite in a solvent such as toluene (or other Arbuzov reaction conditions: Engel, R., Synthesis of Carbon-Phophorus bonds, CRC press, 1988) to obtain the diethyl ester of the phosphonic acid of interest. . The carboxylate is then selectively hydrolyzed using a hydroxide ion source such as lithium hydroxide in a solvent such as ethanol to obtain a phosphonate containing reagent in a form suitable for the synthesis of bortezomib analogs.

Example 67 Preparation of Exemplary Compounds of the Invention

Reduction of dose and / or improvement of efficacy is achieved by using prodrugs of analogs of VX-148 that result in reagents with increased intracellular half-life upon degradation in target cells. Such compounds are described below.

Scheme 67.1

Such compounds can be prepared according to the general routes shown in Schemes 67.2 , 67.4 and 67.5 , with examples shown in Schemes 67.3 and 67.6 .

Scheme 67.2 .

The 3,5-difunctionalized nitrobenzene derivative is a phosphonate moiety linked to a phenyl ring at the desired position prepared for binding in a fully elaborated VX-148 analogue using methods developed for parent compounds Provide a suitable starting point for reagents containing

Scheme 67.3

3-hydroxy-5-nitro-benzoic acid is temporarily heated in thionyl chloride to produce acid chloride. This is then condensed with O, N-dimethyl-hydroxylamine in the presence of a base such as triethylamine to give a Weinreb amide which produces an acetophenone derivative upon reaction with methyl lithium. This is then treated with a base such as potassium carbonate in a bipolar aprotic solvent such as dimethylformamide in the presence of excess E- 1,4-dibromobutene. Monobromide was isolated by chromatography and then treated with triethylphosphite in a solvent such as toluene (or other Arbuzov reaction conditions: Engel, R., Synthesis of Carbon-Phosphorus bonds, CRC press, (1988)) Phosphonate diethyl ester is produced. Subsequently, the carbonyl group of acetophenone is reduced and produced enantiomerically using an appropriate homochiral oxazaborolidin as disclosed by Cory ( J. Am. Chem . Soc ., (1987), 109 , 5551). The substituted alcohol is substituted with azide using the same method as described by Mitsunobu ( Bull. Chem . Soc . Japan ., (1971), 44 , 3427). The azide is reduced to an amine under Staudinger conditions ( Helv . Chim . Act ., (1919), 2 , 635) and protected as t-butyl carbonate. Finally, tin (II) -mediated reduction of nitrobene produces the desired aniline.

Scheme 67.4 .

Reagents suitable for the synthesis of phosphonate analogs are prepared from 2-hydroxy-5-nitro-benzoic acid by a route similar to that shown in Scheme 67.3 .

Scheme 67.5 .

As in US Pat. No. 6,054,472 and US Pat. No. 6,344,465, examples of the synthesis of reagents suitable for binding reactions are illustrated in Scheme 67.6 below.

Scheme 67.6

3-tert-butoxycarbonylamino-3- (3-nitro-phenyl) -propionic acid (commercially available) was subjected to dicyclohexylcarbodiimide (DCC) and hydroxybenztriazole (HOBT) in a solvent such as dimethylformamide. It is combined with 2-aminoethylphosphonic acid diethyl ester (commercially available) using standard reagents for the preparation of secondary amides such as these. The nitro group is then reduced in a manner similar to that described in Scheme 67.3 .

Example 68 Preparation of Exemplary Compounds of the Invention

Such compounds can be prepared according to the general routes shown in Schemes 68.1 , 68.3 and 68.4 , with examples shown in Schemes 68.2 and 68.5 .

Scheme 68.1

3,5-difunctionalized nitrobenzene derivatives are linked to a phenyl ring at the desired position prepared for binding in a fully elaborated merimepodib analogue using methods developed for parent compounds. A suitable starting point for reagents containing phonate moieties is provided.

Scheme 68.2

3-hydroxy-5-nitro-benzoic acid is temporarily heated in acidic methanol to produce the methyl ester. This is then treated with a base such as potassium carbonate in a bipolar aprotic solvent such as dimethylformamide in the presence of excess E- 1,4-dibromobutene. Monobromide was isolated by chromatography and then treated with triethylphosphite in a solvent such as toluene (or other Arbuzov reaction conditions: Engel, R., Synthesis of Carbon-Phosphorus bonds, CRC press, (1988)) Phosphonate diethyl ester is produced. The benzoate ester is then saponified to reduce and the resulting alcohol is substituted with azide using a method such as that disclosed by Mitsunobu ( Bull. Chem . Soc . Japan ., (1971), 44 , 3427). The azide is reduced to amine under Studdinger conditions ( Helv . Chim . Act ., (1919), 2 , 635) and protected as t-butyl carbonate. Finally, tin (II) -mediated reduction of nitrobene produces the desired aniline.

Scheme 68.3 .

Suitable reagents for the synthesis of type II phosphonate analogs are prepared from 2-hydroxy-5-nitro-benzoic acid by a similar route as shown in Scheme 68.2 .

Scheme 68.4 . General Route to Type III Analogs

As in US Pat. No. 6,054,472 and US Pat. No. 6,344,465, synthesis examples of reagents suitable for binding reactions are illustrated in Scheme 68.5 below.

Scheme 68.5

3-nitrobenzaldehyde is reacted with Grignard reagent to introduce a tether containing a protected alcohol and simultaneously produce benzylic alcohol as shown. The alcohol is substituted with an azide in a manner similar to that described in Scheme 68.2 . After deprotection, the free alcohol was converted to diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) using a base such as magnesium tert-butoxide in a solvent such as trahydrofuran . Alkylation. The azide and nitro groups are then modified in a similar manner as described in Scheme 68.2 .

Example 69 Preparation of Exemplary Compounds of the Invention

Methods for the synthesis of such compounds are described in Batt et al, Bioorg . Med . Chem . Based on the method described in Lett ., (1995), 5 , 1549. Representative general routes are shown in Scheme 69.1 .

Scheme 69.1

Examples of the synthesis of suitable phosphonate containing analogs are shown below.

Scheme 69.2

The initial Fitzgerer condensation reaction is classically achieved by a general reaction with potassium hydroxide, as shown, with an acidic finishing process. Optionally, initial aldol condensation can be carried out using diethylamine in ethanol and the quinoline ring can be formed in a second step mediated by an acid such as hydrochloric acid in a salt such as 1,4-dioxane. After removing the benzyl protecting group through hydrogenation, the phenol can be treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added to obtain the desired phosphonate diester. The carboxylate is deprotected by treatment with lithium hydroxide in ethanol.

Scheme 69.3

The synthesis is similar to that shown in Scheme 69.2 , except that after deprotonation of the phenol, E- 1,4-dibromobutene is added in excess. The reaction is stopped with aqueous ammonium chloride and the product is extracted with an organic solvent such as ethyl acetate, and then the mono-alkylated product is separated by chromatography. The resulting bromide is treated with triethylphosphite in a solvent such as toluene to produce diethyl ester of the desired phosphonic acid, and the carboxylic acid is deprotected as before.

Example 70 Preparation of Exemplary Compounds of the Invention

Dexamethasone (Dexamethasone) formula 70-1 (U.S. Patent No. 3007923), and phosphonate ester substituent to 70-4 R ¹ is H, alkyl, alkenyl, aryl or aralkyl which are shown in Scheme 70.1. Compound 70-4 comprises a phosphonate moiety (R ¹ O) ₂ P (O) linked to the nucleus by various linking groups represented by “links” in the linkage structure.

Scheme 70.1

Scheme 70.2-70.12 illustrates the synthesis of phosphonate compounds of the invention and intermediate compounds useful for their synthesis.

Protection of reactive substituents.

Depending on the reaction conditions used, it may be necessary to protect certain reactive substituents from unwanted reactions by protecting them prior to the reactions described by those skilled in the art and later deprotecting the substituents.

Protection and deprotection of functional groups are described, for example, in Protective Groups in Organic Chemistry , by TW Greene and PGM Wuts, Wiley, Second Edition Described in 1990. The protection and deprotection of steroidal ketones and alcohols is described in Organic Reactions in Steroid Chemistry, Vol. 1, J. Fried and JA Edwards, van Nostrand Reinhold, (1972), p. Described in 375ff. Reactive substituents that can be protected are shown in the accompanying schemes, for example, [OH], [O] and the like. For example, Scheme 70.1 represents the protection-deprotection sequence in which the steroid side chains are protected as bis-methylenedioxy (BMD) moieties. In this sequence, dexamethasone 70-1 Protective Groups in Organic Chemistry , by TW Greene and PGM Wuts, Wiley, Second Edition (1990), p. Reaction with an acid catalyst such as paraformaldehyde and hydrochloric acid as described in 223 yields BMD derivative 70-2 . The phosphonate moiety is then introduced using the method described below to obtain phosphonate ester 70-3 . The BMD portion was then replaced with Protective Groups in Organic Chemistry , by TW Greene and PGM Wuts, Wiley, Second Edition (1990), p. For example triol 70-4 is obtained by treatment with 50% aqueous acetic acid as described in 223.

Phosphonates  Preparation of esters 70-7, 70-14, 70-18, 70-20, 70-120, 70-22 and 70-27.

Schemes 70.2-70.6 show the preparation of phosphonates in which phosphonates are bound by imino or imineoxy groups and various carbon chains. In this method, the BMD-protected derivative 70-2 is substituted with alkyl, alkenyl, cycloalkyl or cycloalkenyl groups or amides, esters, oximes, sulfoxides, wherein R ² contains heteroatoms O, S or N as necessary. Or an aryl, heteroaryl or aralkyl group optionally substituted with a functional group such as sulfone or, if necessary, heteroatoms O, S or N and X may be subsequently converted to a phosphonate group or a phosphonate-containing substituent It is reacted with amine or hydroxylamine 70-5 which is a group. For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxy and the like. In an aprotic solvent such as pyridine or xylene or alcoholic solvent such as ethanol, if necessary, the reaction is carried out between the same molar amount of reactants in the presence of an acid catalyst to obtain imine or oxime. Preparation of steroidal 3-ketones is described in Anal. BiOCH., 1978, 86, 133. and J. Mass. Spectrom., (1995), 30, 497. The BMD-protected side chain compound 70-6 is then converted to triol 70-7 as described in Scheme 70.1 .

Schemes 70.2-70.6 illustrate the preparation of hydroxylamine ethers comprising phosphonate groups. In this method, Lv is reacted with a bromo or Boc- a methyl sulfonyloxy leaving group such as a phosphonate 70-8 of trifluoroacetic hydroxylamine 70-9 (Aldrich) to obtain the ether 70-10. The reaction is carried out between equal molar amounts of reactants in a polar solvent such as dimethylformamide or tetrahydrofuran in the presence of a base such as potassium hydroxide or dimethylmananopyridine. Then deprotection, for example with trifluoroacetic acid, yields hydroxylamine ether 70-11 .

Scheme 70.2. Phosphonate A2

Scheme 70.3 illustrates the preparation of phosphonate 70-14 in which phosphonates are linked by imineoxy groups. In this process, substrate 70-2 was prepared as described above from dialkyl trifluoromethylsulfonyloxymethyl phosphonate (Tet. Lett., 1986, 27, 1477) and Boc-hydroxylamine as described above. Reaction with phosphonomethyl hydroxylamine 70-12 gives oxime 70-13 and deprotection to give triol 70-14 . The oxime preparation reaction is carried out using the same molar amount of reactants at ambient temperature in ethanol-acetic acid solution.

Hydroxylamine ether instead of 70-12 except that a different oxime ether 70-5, and use of the method to obtain the corresponding product 70-7.

Scheme 70.3

Scheme 70.4 illustrates the preparation of compounds 70-18 , 70-20 and 70-180 , wherein phosphonates are linked by pyridyl methoxy groups. In this method, the dieneon 70-2 as described above. Reaction with O- (3-bromo-5-pyridylmethyl) hydroxylamine 70-15 prepared from 3-bromo-5-bromomethylpyridine (WO 95/28400) as described above, After deprotection, oxime 70-16 is obtained. Followed by a dialkyl phosphite 70-17 and the reaction product in the presence of a palladium catalyst to obtain a phosphonate 70-18. The preparation of arylphosphonates by the coupling reaction between brominated aryl and dialkyl phosphites is described in J. Med. Chem., 35, 1371, (1992). The reaction is carried out in an inert solvent such as toluene in the presence of a base such as triethylamine and a catalytic amount of tetrakis (triphenylphosphine) palladium (0). Optionally, bromo compound 70-16 is combined with dialkyl vinylphosphonate 70-19 (Aldrich) to give phosphonate 70-20 . The combination of olefins and aryl halides by the Heck reaction is described, for example, in Advanced organic chemistry, by FA Carey and RJ Sundberg, Plenum, (2001), p. 503ff and Acc. Chem. Res., 12, 146, (1979). Aryl bromide and olefins are prepared in the presence of a palladium (0) catalyst such as tetrakis (triphenylphosphine) palladium (0) or a palladium (II) catalyst such as palladium (II) acetate and, if necessary, triethylamine or potassium carbonate. And in the presence of a base such as dimethylformamide or dioxane in a polar solvent. If necessary, for example, by reaction with diimide, the styrenoid double bond present in the product 70-20 is reduced to produce a saturated analog 70-120 . Reduction of olefin bonds is described in Comprehensive Organic Transformations, by RC Larock, VCH, (1989), p. 6ff. Such modifications are achieved by, for example, catalytic hydrogenation using palladium and hydrogen or hydrogen donors on carbon catalysts or the use of diimides or diboranes.

Compound 70- was used using the above method except that other bromo-substituted aryl or heteroaryl alkoxy hydroxylamines, and / or other dialkyl alkenyl phosphonates were used instead of bromopyridyloxy reagent 70-15. 18, to obtain a product similar to the 70-20 and 70-120.

Scheme 70.4

Scheme 70.5 shows the preparation of phosphonates 70-22 wherein phosphonates are bonded by imino groups. In this method, substrate 70-2 is reacted with dialkyl 2-aminophenyl phosphonate 70-21 , (Syn., (1999), 1368) to give imine product 70-22 after deprotection. The reaction is carried out in a hydrocarbon solvent such as toluene or xylene under azeotropic conditions in the presence of a basic catalyst such as sodium methoxide or an acid catalyst such as p-toluenesulfonic acid.

2-aminophenyl phosphonate in place of other carbonate 70-21 amino-and is, except for the use of a substituted aryl or heteroaryl phosphonate using the above method to obtain a product similar to 70-22.

Scheme 70.5

Scheme 70.6 shows the preparation of phosphonates 70-27 wherein phosphonates are bonded by imino groups or amide linkages. In this method, the diene 70-2 Reaction with O- (2-carboxyethyl) hydroxylamine 70-23 (J. Med. Chem., 1990, 33, 1423) affords oxime 70-24 . The reaction of steroidal 1,4-dien-3-one with substituted hydroxylamines is described in J. Steroid BiOCH., (1976), 7, 795, which reactions are carried out in polar organic solvents such as pyridine or methanol. If necessary, the reaction is carried out using the same molar amount of reactants in the presence of acetic acid or sodium acetate. By the following reaction and the oxime-dialkyl aminomethyl phosphonate 70-25 (AsInEx) to obtain the amide oxime 70-26. The preparation of amides from carboxylic acids and derivatives is described, for example, in Organic Functional Group Preparations, by SRSandler and W. Karo, Academic Press, (1968), p. 274 and Comprehensive Organic Transformations, by RC Larock, VCH, (1989), p. 972ff. The carboxylic acid is, for example, in the presence of an activating agent such as dicyclohexylcarbodiimide or diisopropylcarbodiimide, if necessary, for example, hydroxybenztriazole, N-hydroxysuccinimide or N-hydride. The amide is obtained by reacting with an amine in an aprotic solvent such as pyridine, DMF or dichloromethane in the presence of oxypyridone.

Optionally, the carboxylic acid is first changed to active derivatives such as acid chlorides, anhydrides, mixed anhydrides, imidazolides, and the like, followed by reaction with an amine in the presence of an organic base such as pyridine to obtain an amide. Conversion of the carboxylic acid to the corresponding acid chloride is achieved by treating the carboxylic acid with a reagent such as thionyl chloride or oxalyl chloride in the presence of a catalytic amount of dimethylformamide, if necessary, in an inert organic solvent such as dichloromethane. Can be.

The amide product 70-26 is then converted to triol 70-27 , as described in Scheme 70.1 .

Hydroxylamine 70-25 instead of another carboxy-and by using the above method to obtain a similar product to 70-27 except that a substituted phosphonate-substituted hydroxylamine, and / or other amino.

Scheme 70.6

Phosphonates  Preparation of esters 70-33, 70-35, 70-40, 70-41, 70-47, 70-147 and 70-48.

Scheme 70.7-70.9 illustrates the preparation of phosphonate esters in which a phosphonate group is bonded to the 1 'or 2' position of the pyrazole ring by an aromatic or heteroaromatic group, a hetero atom and various carbon chains. In this method, the BMD-protected diene 70-2 is reduced to give 1,2-dihydro product 70-74 . Catalytic hydrogenation reactions are described, for example, in J. Med. Proceed with tris (triphenylphosphine) rhodium (I) chloride as described in Chem., (2001), 44, 602. The product was then J. Am. Chem. As described in Soc., 1964, 86, 1520, a 2-formyl product 70-28 is obtained by reacting with a base such as ethyl formate and sodium hydride in an inert solvent such as toluene or dimethylformamide. The compound is then reacted with heteroaryl hydrazine 70-29 , which is one of alkyl, aralkyl, aryl or a group wherein the substituent X is modified with a phosphonate group or subsequently with a phosphonate containing substituent. For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction yields the isomeric 2'- and 1'-aryl pyrazoles 70-30 and 70-31 . Pyrazole formation reactions are described in J. Am. Chem. As described in Soc., 1964, 86, 1520, it is carried out using the same molar amount of reactants in an acidic solvent such as acetic acid. Then pyrazoles 70-30 and 70-31 can be prepared as in Scheme 70.8-70. The method described in 9 is used to modify phosphonates 70-35 and 70-33 via BMD-protected intermediates 70-34 and 70-32 .

Scheme 70.7. Phosphonates M3 and M4

Scheme 70.8 illustrates the preparation of phosphonates in which phosphonates are bonded by phenyl rings and alkoxy or acetylene linkers. In this method, ketoaldehyde 70-28 is Reaction with 3-hydroxyphenylhydrazine 70-36 (Japanese Patent JP 03011081) yields pyrazoles 70-70 and 70-37 . The 2'-substituted isomer 70-70 is then reacted with 1 molar equivalent of trifluoromethylsulfonyl chloride and dimethylaminopyridine in a dichloromethane solution at ambient temperature to give triflate 70-39 . The product was then reacted with dialkyl propynylphosphonate 70-71 (Syn (1999), 2027), triethylamine and a catalytic amount of tetrakis (triphenylphosphine) palladium (0) in toluene solution to acetylene system Product 70-73 is obtained. The palladium-catalyzed coupling reaction of terminal acetylene with aryl triflate is described in WO 0230930. The BMD protecting group is then removed to give triol 70-41 .

Optionally, 1'-substituted pyrazole 70-37 is reacted with dialkyl 2-hydroxyethyl phosphonate 70-72 (Epsilon) in a Mitsunobu reaction to give ether 70-38 . The preparation of aromatic ethers by Mitsunobu reaction is described, for example, in Comprehensive Organic Transformations, by RC Larock, VCH, 1989, p. 448 and Advanced organic chemistry, Part B, by FA Carey and RJ Sundberg, Plenum, (2001), p. 153-4 and Org. React., (1992), 42, 335. The phenol and alcohol components are reacted in the presence of dialkyl azodicarboxylate and triarylphosphine in an aprotic solvent such as, for example, tetrahydrofuran, to obtain an ether or thioether product. The process is also described in Org. React., (1992), 42, 335-656. The following products 70 to 38 Deprotection yields triol 70-40 .

Products similar to 70-41 and 70-40 are obtained using this method except using other acetylene- or hydroxyl-substituted phosphonates. The functionalization method is interchangeable between pyrazole substrates 70-70 and 70-37 .

Scheme 70.8

Scheme 70.9 illustrates the preparation of phosphonates in which phosphonate groups are bonded by benzyl and benzyl groups or by saturated or unsaturated carbon chains. In this method, ketoaldehyde 70-28 is Reaction with 3-bromobenzyl hydrazine 70-75 (US Pat. No. 4,370,339) yields pyrazoles 70-42 and 70-43 . It was coupled with a dialkyl vinyl phosphonate 70-76 (Aldrich) the 1'-substituted isomer 70-42 in the presence of a palladium catalyst phosphonate 70-46 is obtained. The product is then deprotected to give triol 70-47 . If necessary, the styrenoid double bonds present in products 70-47 are reduced as described above to give saturated analogs 70-147 .

Optionally, the 2'-substituted pyrazole 70-43 is reacted with dialkyl phosphite in the presence of a palladium catalyst to produce and deprotect phosphonate 70-44 to give triol 70-48 . The preparation of arylphosphonates by the coupling reaction between brominated aryl and dialkyl phosphites is described in J. Med. Chem., 35, 1371, (1992). This reaction is carried out in a solvent such as toluene in the presence of a base such as triethylamine and tetrakis (triphenylphosphine) palladium (0).

Using the method except for using another bromo-substituted aralkyl, aryl or heteroaryl alkoxy hydrazine and / or other dialkyl alkenyl phosphonate instead of bromobenzyl reagent 70-75 , Compound 70-47 Similar products to 70-147 and 70-48 are obtained.

Scheme 70.9

Schemes 70.10-70.12 show the preparation of phosphonate esters in which phosphonate groups are bonded by various carbon linkages. In this method, by reacting the keto aldehyde to the obtained pyrazole derivatives of hydrazine 70-28 70-49. The reaction of hydrazine with steroidal 2-formyl-3-ketone is described in J. Am. Chem. Soc, 1964, 86, 1520. The reaction is carried out in acetic acid at ambient temperature. The pyrazole product is then reacted with bromomethyl compound 70-77 as described above for R ² and X to obtain alkylation products 70-50 and 70-51 . Alkylation of substituted pyrazoles is described, for example, in Heter ° C yclic Chemistry, by TL Gilchrist, Longman, (1992), p. 309. The reaction is carried out in the presence of a base such as dimethylaminopyridine or lithium hexamethyldisilazide in a polar solvent such as dimethylformamide or tetrahydrofuran. The X except for the case of a dialkyl phosphono, and the product to 70-50 and 70-51 using the methods described above in the present specification is converted to a phosphonate 70-52 and 70-53, and then de-protected to the triol 70 -54 and 70-55 are obtained.

Scheme 7.10. Phosphonates M3 and M4

As shown in Scheme 70.11 , pyrazole 70-49 is reacted with 1 molar equivalent of dialkyl bromoacetonyl phosphonate 70-78 (Tet., 1978, 34, 649) as described above to form alkylated pyrazoles. 70-82 and 70-83 are obtained. Deprotection then yields triols 70-84 and 70-85 .

Scheme 70.11

As shown in Scheme 70.12 , pyrazole 70-49 is reacted with 1,4-bis (bromomethyl) benzene 70-86 as described above to give pyrazole 70-87 and 70-56 . The product was subjected to arbuzoph reaction and trialkyl phosphite at 120 ° C. to convert the bromomethyl substituent to a dialkyl phosphonomethyl substituent to deprotect the side chains, followed by phosphonates 70-57 and 70-58 . Manufacture. The Arbuzoph reaction was performed in Handb. Organophophorus Chem., (1992), 115-72. In this process, the substrate is heated with 5 to 50 times the molar excess of trialkyl phosphite at 60 ° C to about 160 ° C.

Products similar to 70-57 and 70-58 are obtained using this method, except that other dibromide is used instead of dibromide 70-86 .

Scheme 70.12

Example 72 Preparation of Exemplary Compounds of the Invention

Methods for the synthesis of such compounds according to the general route shown in Westwood et al, J. Med. Chem., (1996), 39, 4608-462.

Scheme 72.1

Examples of the synthesis of suitable phosphonate-containing aniline are shown below.

Scheme 72.2

Scheme 72.3

Example 73 Preparation of Exemplary Compounds of the Invention

The compounds of the present invention are prepared according to the general route shown in Scheme 73.1 in Westwood et al, J. Med. It may be prepared as generally described by Chem ., (1996), 39 , 4608-4621.

Scheme 73.1

Examples of the synthesis of suitable phosphonate-containing aniline are shown below.

Scheme 73.2

3-nitrophenol was alkylated with E- 1,4-dibromobutene and the resulting monobromide was treated with triethylphosphite in a solvent such as toluene (or other Arbuzov reaction conditions: Engel, R., Synthesis of Carbon-Phophorus bonds, CRC press, 1988) Purpose Obtain diethyl ester of phosphonic acid. Finally, the desired aniline is produced by tin (II) -mediated reduction of nitrobenzene.

Scheme 73.3

The methyl ester of 3-nitro-4-trifluoromethylbenzoic acid is treated with tin (II) chloride to produce aniline. The 3-iodobenzoic acid is produced by diazotization reaction and potassium iodide treatment. Synthesis of teriflunomide analogues by diethylphosphonate esters bound via acetylene linkages using palladium catalysis and benzoate ester saponification followed by Curtius rearrangement of acyl azide Obtain aniline suitable for inclusion in the

Example 74 Preparation of Exemplary Compounds of the Invention

Scheme 74.1 : General approach to all classes of compounds

Scheme 74.2 : Embodiment for Formula M1

J. Am. Chem . Soc . , (1948), 70 , 1922-1926 starting carboxylic acid synthesized in a solvent such as DMF or NMP, such as diethyl cyanophosphonate or isobutylchloroformate and diisopropylethylamine (DIEA Treatment at room temperature ( J. Med . Chem ., (1982), 25 , 960-964 and J. Med . Chem ., (1984), 27 , 600-604). When activation is complete, 2-aminoethylphosphonic acid diethyl ester (commercially available) is added. After observing that the activated material has been consumed completely, the solvent is removed in vacuo and the product is separated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Scheme 74.3 :

The starting carboxylic acid is treated at room temperature with a base such as diisopropylethylamine (DIEA) and a binding reagent such as diethylcyanophosphonate or isobutylchloroformate in a solvent such as DMF or NMP. ( J. Med . Chem ., (1982), 25 , 960-964 and J. Med . Chem ., (1984), 27 , 600-604). When the activation was complete, (2-amino-ethylsulfanylmethyl) -phosphonic acid diethyl ester (2-aminoethanethiol was prepared by Tetrahedron Lett ., (1986), 27 , 1477, diethylphosphonomethyl Prepared by base catalyzed coupling reaction with triflate). After observing that the activated material has been consumed completely, the solvent is removed in vacuo and the intermediate is isolated by chromatography. Optionally, the intermediate may be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether. The intermediate is then dissolved in a mixture of water, DMF and acetic acid and treated with hydrogen peroxide solution (excess). After removal of the solvent the product is isolated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Scheme 74.4 :

The starting carboxylic acid is treated with a binding reagent such as diethylcyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature in a solvent such as DMF or NMP ( J. Med . Chem . , (1982), 25 , 960-964 and J. Med . Chem ., (1984), 27 , 600-604.). When activation is complete, ( L ) -2-amino-6- (diethylphosphonato) -hexanoic acid is added. After observing that the activated material has been consumed completely, the solvent is removed in vacuo and the product is isolated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Scheme 74.5 :

The starting carboxylic acid is treated with a binding reagent such as diethylcyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature in a solvent such as DMF or NMP ( J. Med . Chem . , (1982), 25 , 960-964 and J. Med . Chem ., (1984), 27 , 600-604). When the activation is complete, 4-amino-4- (diethylphosphonato) -butyric acid tert butylester ( J. Am. Chem . Soc ., (1995), 117 , 10879-10888) is added. After observing that the activated material has been consumed completely, the solvent is removed in vacuo and the intermediate is isolated by chromatography. Optionally, the intermediate may be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether. The crude intermediate is then dissolved in DMF and treated with TFA (excess). After removal of the solvent the product is isolated by chromatography. Optionally, the product can be separated by precipitation from the reaction solution using an organic solvent such as diethyl ether.

Example 75 Preparation of Exemplary Compounds of the Invention

Phosphorus-containing merimepodive analogue 75-2 is synthesized by alkylation from the parent compound. Merimepodive 75-1 is obtained by the method described in US Pat. No. 6,054,472 and US Pat. No. 6,344,465. Scheme 75.1-75. 2 represents the synthesis | combining method of 75-2 and 75-4 . The methoxy group of merimepodib 75-1 is demethylated with phenolic OH using appropriate reagents such as boron tribromide. The phosphonate moiety is introduced into the phenolic OH in a suitable aprotic solvent, such as DMF, and then containing a leaving group such as bromine, mesyl, tosyl or trifluoromethanesulfonyl in the presence of a suitable organic or inorganic base. Treat with phonate reagent 75-40 , 75-41 .

Scheme 75.1

For example, a 75-1 solution in dichloromethane is treated with boron tribromide to yield demethylated compound 75-3 . Compound 75-3 was then treated with cesium carbonate and 1 equivalent of (trifluoromethanesulfonyloxy) methylphosphonic acid diethyl ester 75-41 As shown in Scheme 75.2 , merimepodive-phosphonate 75-4 is obtained in which the linker is a methylene group. Using the method above except using another phosphonate reagent 75-40 The corresponding product 75-2 containing another linking group is obtained.

Scheme 75.2

Schemes 75.3-75.4 represent the synthesis of merimepodive analogs 75-2 , 75-12 and 75-13 . Imidazole containing intermediate 75-7 is Tetrahedron Lett. (1993), 34 , 595 using the Shih process to synthesize from aldehyde 75-6 . Compound 75-6 is prepared by a two step process described in US Pat. No. 5,807,876, US Pat. No. 6,054,472 and US Pat. No. 6,344,465. The imidazole is protected using a suitable reagent such as 2- (trimethylsilyl) ethoxymethyl (SEM) chloride and the compound 75-8 is synthesized in the synthesis of 75-1 in US Pat. No. 6,054,472 and US Pat. No. 6,344,465. by a process similar to the one described for step 75 is converted to 10. After removing the protecting group on the imidazole of 75-10 , a phosphonate containing moiety is introduced into the imidazole, as shown in Scheme 75.4 .

Scheme 75.3

For example, the compounds and processes the 75-10 as tetrabutylammonium fluoride in THF under reflux conditions using sodium hydride as base to 75-11 and the resulting alkylated with 75-41, 75-42 obtained two isomers following purification We separate by graphography

Scheme 75-4

Scheme 75.5-75. 6 represents the preparation of merimepodive analogs 75-17 . Tetrasubstituted benzene derivatives are described in the literature (Ichikawa and Ichibagase Yakugaku). Zasshi (1963), 83 , 103; Norio, A. et al . Tetrahedron Lett . (1992), 33 (37) , 5403). After protecting the phenolic OH with a suitable protecting group such as benzyl, compound 75-16 is synthesized using the same method as for the synthesis of 75-1 described in US Pat. No. 6,054,472 and US Pat. No. 6,344,465. After removal of the protecting group, the phosphonate containing moiety is introduced into the phenolic OH using phosphonate reagent 75-45 containing the appropriate leaving group.

For example, a solution of 75-18 obtained by the process of Norio et al. ( Tetrahedron Lett . (1992), 33 (37) , 5403) was treated with sodium hydride and 1 equivalent of benzyl bromide in DMF to yield 75-19 . Get From 75-6 then 75-1 converts the U.S. Patent No. 6,054,472 and U.S. Patent No. 75-19 compound through a series of steps reported by the No. 6,344,465 with respect to the synthesis by 75-20. After removal of the benzyl protecting group of 75-20 by catalytic hydrogenation, (methanesulfonyloxymethyl trifluoromethyl) of sodium hydride in DMF and 1 equivalent phosphorylation by alkylation of the phenol produced by using methyl phosphonic acid diethyl ester 75-42 The nate containing moieties are combined to give 75-21 .

Scheme 75.5

Scheme 75.6

Scheme 75.7-75.8 It represents the synthesis of merimedovive analogs 75-26 . Compound 75-22 , an intermediate in the synthesis of 75-1 , is treated with carbonyldiimidazole or triphosgene, followed by compound 75-23 having the means to bind the phosphonate moiety. Compounds 75-23 containing temporary substituents are commercially available or are available from Zolfigol, MA et. Al . Indian J. Chem. Sect. B (2001), 40 , 1191 and De Jongh, RO et al . Recl . Synthesis from trisubstituted phenols having cyano and nitro groups available by Trav . Chim . Pays-Bas (1968), 87 , 1327). The resulting 75-24 using the methods described in U.S. Patent No. 6,054,472 and U.S. Patent No. 6344465 No. For the synthesis of 75-1 is converted to 75-25. After deprotecting the benzyl group of 75-25 , the phosphonate moiety of 75-26 is bound.

For example, substituting the bromine substituent of compound 75-27 as a cyano group by a de species (De Jongh, RO) method such as (Recl. Trav. Chim. Pays -Bas (1968), 87, 1327) and the methoxy group Compound 75-28 is obtained by converting into a benzyloxy group as a protecting group. After the cyano group is selectively reduced by borane to the aminomethyl group, the amino group is protected by the Boc group, and then the nitro group is reduced by using tin (II) chloride to produce compound 75-29 . By the following processes a substituted aniline 75-29 in U.S. Patent No. 6,054,472 and U.S. Patent mixture of compounds 75-22 and carbonyldiimidazole, as described for the synthesis of Claim 6344465 75-1 from call urea 75 Produces -30 Compounds 75-30 are readily converted to analogues of 75-1 containing an 75-31, benzyloxy. After dehydrogenation of the benzyl group using catalytic hydrogenation, 75-32 is produced by combining the phosphonate moieties using 75-41, 75-42 in the presence of cesium carbonate.

Scheme 75.7

Scheme 75.8

Example 76 Preparation of Exemplary Compounds of the Invention

Tamoxifen and Torremifen Citrate Phosphonates Prodrug  Produce

Many tamoxifen analogs have been prepared and tested. A high degree of flexibility is observed in the aminoethyl portion of the substituted compounds (Meegan et al. Anti-Cancer Drug Design , (2001), 16 , 57).

Based on the available SAR, this position is selected as one means for binding of the prodrug moiety. Many tamoxifen analogs with advantageous profiles have been reported. See Meegan, MJ, Lloyd, DG, Current Medicinal Chemistry , (2003), 10 , 181 for a review of many tamoxifen analogs. Given that this analogue is similar to tamoxifen, one can apply the prodrug approach to the same location as tamoxifen. Many addition sites on the tamoxifen core can be utilized to bind the prodrug group. Given the well-established scale up method for tamoxifen, the binding of prodrugs via aminoethanol groups on the B ring is an option. The original synthesis of tamoxifen (Harper et al., GB1064629 and Harper et al., GB1013907) has recently been modified (Smyth, TP, Corby, BW, Organic Pr Cessess Research & Development , (1997), 1 , 264). ). This new method was developed for large scale manufacturing. In addition, the introduction of aminoethyl groups bonded to the B ring is carried out at the end of the synthesis, which favors one prodrug synthesis.

Scheme 76.1 (all compound numbers in this scheme are relevant only in this example)

The synthesis of compounds such as phosphonate 1 (of Scheme 76.1 ) is illustrated above. Using acetic anhydride, the compounds 1.1 and 1.2 (Scheme 76.1), trifluoromethyl and condensed as described in Smith (Smyth) etc. Organic Pr ℃ ess Research & Development, (1997), 1, 264. Substitution of halogen using amino-linker-phosphonate affords compound 1.4 (in Scheme 76.1 ). In order to introduce the last aromatic group, the final Grignard reaction is carried out, followed by dehydration in an acidic medium to obtain Compound 1 (Scheme 76.1 ). The order of the last two steps can be changed. First, a greenid reaction is performed to introduce a tetrasubstituted olefin, and then halogen is substituted (McCague R. , J. Chem . Res ., 1986, 0771). The final product is a mixture of cis and trans isomers separated by crystallization. Further modifications to the aromatic A ring are possible by the choice of substituents attached to the aryl bromide used in the Grignard reaction.

Scheme 76.2 (all compound numbers in this scheme are relevant only in this example)

Specifically, compound 1.3 (Scheme 76.2 ) is prepared as described in the literature. By substituting chlorine of 1.3 to perform the alkylation with aminoethyl phosphonate to produce a 1. 4 (Scheme 76.2). The Grignard reaction with bromobenzene gives compound 1.5 (Scheme 76.2 ), which is dehydrated under acidic conditions to give compound 1 (Scheme 76.2 ) as an HCl salt. Its citrate salt is another useful compound. Other salts may also be produced.

Scheme 76.3 (All compound numbers in this scheme are relevant only in this example)

The synthesis of many toremifene analogs is described in detail in US Pat. No. 4,696,949. Scheme 76.3 shows the synthesis of the prodrug of toremifene. The prodrug is introduced early in the synthesis. It is possible to initially protect 4-hydroxy benzophenone and remove its protecting group near the end of the synthetic sequence. In this case, the prodrug group is introduced near the end of the synthesis. The preparation method shown in Scheme 76.3 uses 4-hydroxy benzophenone as starting material. Two carbon linkers are combined and then activated for the synthesis of compound 2.3 (Scheme 76.3 ). In this step, aminophosphonate 2.1.1 is introduced to complete the left half of the molecule. After adding cinnamic aldehyde to lithium aluminum hydride, benzophenone 2.4 is added to obtain diol 2.5 (Scheme 76.3 ). Deionization of 2.5 and conversion of 4-OH to chlorine are obtained by addition of thionyl chloride to give compound 2.6 (Scheme 76.3 ). Final product 2 (Scheme 76.3 ) is prepared by the formation of the desired salt.

Scheme 76.4 (all compound numbers in this scheme are relevant only in this example)

Specifically, 4-hydroxy benzophenone is substituted with CH ₂ Cl ₂ In a reaction with 1-mesyl ethane diol to give 2.2 (Scheme 76.4 ). The addition of alcohol 2.2 (scheme 76.4) in 2.3 mesylate (Scheme 76.4) is carried out using mesyl chloride in CH ₂ Cl ₂ to Lai using TEA as scavenger (scavenger). Mesylate 2.3 in EtOH at 80 ° C. is alkylated with N -methyl amino ethyl phosphonate 2.1.1 (Scheme 76.4 ) to give compound 2.4 (Scheme 76.4 ). 2.4 (1 equivalent) is added to a mixture of cinnamic aldehyde (1 equiv) and lithium aluminum hydride (0.55 equiv) in THF, followed by stirring at room temperature for 30 minutes to give compound 2.5 (Scheme 76.4 ). Dehydration of 2.5 (Scheme 76.4 ) with thionyl chloride in toluene was completed after 3 hours at 80 ° C. to give compound 2.6 (Scheme 76.4 ). Various salts can be prepared sequentially. The citrate salt of toremifene is one exemplary compound. As noted above, further modification of the phosphonate prodrug to phosphonate diesters, bisamidates or monoamidates can be done.

Example 77 Preparation of Exemplary Compounds of the Invention

Preparation of Phosphonate Prodrugs of Raloxifene Hydrogen Chloride

Many raloxifene structural studies have been studied, and the SAR of the drug's heterogeneity is well established. Briefly, the hydroxyl substituent of the aryl ring of raloxifene is important for the latent activity of the compound as expected. C-6 OH is positioned to bind to the ER residual pair Arg 394 / Glu in the same manner as 3-OH of estradiol. In addition, 4'-OH, which is similar to 17β-OH of estradiol, was analyzed by His 524 as demonstrated by crystal structure studies (Anzo, et al., J. Natl . Cancer Inst ., (1996), 88 , 123). Combine with The amines of the piperidine ring are also important for binding to aspartate 351 of the estrogen receptor. This amine also plays a role in tissue specificity. On the other hand, N, N-dialkyl analogues of many raloxifenes exhibit comparable activity to the parent compound. Thus, substitution of prodrug groups at the ends of the compounds is a preferred embodiment of this action. Three kinds of substitutions are presented in this specification. Three are changes in the binding of prodrugs to tertiary amine regions (Scheme 77.1 ). Another binding position on raloxifene is the carbonyl position. Given that this carbonyl moiety can be easily substituted with a single oxygen, this position can be used as a potential means for phosphonate prodrugs (Palkowitz, et al., J. Med. Chem ., (1997). , 40 , 10, 1407).

First, the phosphonate prodrug is prepared according to the general scheme 77.2-77.3 . Properly protected diols are bound to the phenolic position of 4-hydroxyl benzoic acid methyl ester by the Williamson ether synthesis method. The protecting group is removed to yield compound 77-5 . The hydroxyl group is replaced with a suitable leaving group such as mesyl, bromide of trifluoromethylsulfonyl, followed by addition of the amino phosphonate prodrug moiety to afford compounds 77-6, 77-50 . After methyl ester liberation, acid chlorides are activated to form acid chlorides as reported in Jones, et al . J. Med . Chem ., 1984, 27 , 1057. Shifts (Kost et al, Zh Org Khim , 1970, 6, 1503...), (Jones, CD, EP 0062503) the product of compound 77-7, 77-33, 77-25 in the Friedel-Crafts Flats studded The well-developed annealing (Friedal-Crafts aroylation) to obtain the protected target compound. Finally deprotection yields compound 77-9 . Other salts can be prepared to improve the solubility of the final compound.

Specific examples of such general routes are shown in Scheme 77.3 . Compound 77-4 is alkylated with TMS protected diol 77-23 using K ₂ CO ₃ in DMF. The silyl protecting group is removed cleanly with TFA to give precursor 77-5 . CH ₂ Cl ₂ 77-5 was activated by mesylate formation with MsCl and TEA in the middle, followed by addition of amino ethyl phosphonate 77-22, 77-32 to give amines 77-6, 77-50 . After removing the methyl ester protecting group of 77-6 and 77-50, the one-pot two-step reaction of Friedel-Crafts aroylation -deprotection was well progressed using thioethanol to give the final compound 77-. 10, 77-35 HCl salt is produced.

The production of pyrerazil phosphonate prodrugs is carried out in the same manner as for compounds 77-10, 77-35 . The synthesis of 77-24, 77-40 proceeds with mono protected piperazine and 2-hydroxyethyl phosphonate. Subsequent steps in the synthesis are as described in Schemes 77.2-77.3 . Use specifically TEA as scavenger and that CH ₂ Cl ₂ from 77-5 to 77-24 by the addition of 77-40 to obtain a 77-12, 77-42. As described above, deprotection of methyl ester, activation of acid with thionyl chloride and Friedel-Crafts aroylation are carried out. Compounds 77-15 and 77-16 are produced by in situ deprotection of methyl ether with triethylsilane. The final product is converted to a bis-HCl salt to improve solubility.

The production of phosphonate prodrugs 77-18, 77-19 is achieved from commercial raloxifene hydrogen chloride. Reductive amination with aminophosphonate affords the desired product. The reaction is CH ₂ Cl ₂ It is performed using 77-15 and 77-16 equivalent sodium cyanoborohydride in the inside. The resulting two enantiomers are separated by chiral chromatography.

Scheme 77.1

Scheme 77.2

Scheme 77.3

Scheme 77.4

Scheme 77.5

Scheme 77.6

Scheme 77.7

Example 78 Preparation of Exemplary Compounds of the Invention

Mycophenolate Of mycophenolate mofetil Phosphonates Prodrug  Produce

As demonstrated by compounds 78-1 to 78-4 (Scheme 78.1 ), three regions of mycophenolate mofetil are utilized for the binding of phosphonate prodrugs onto mycophenolic acids. The carboxylic acid is also substituted with phosphonic acid which is part of its prodrug moiety as in compound 78-3 .

The morpholino ethyl moiety, which acts as a prodrug to enhance bioavailability, is replaced by a phosphonate prodrug means as shown in Scheme 78.2-78.3 . Mycophenolic acids are commercially available, such as, for example, Sigma Chemical Company, St. It is available for purchase from Louis, Mo. Activation of carboxylic acid 78-5 in the presence of free phenol is followed by addition of an alcohol containing a phosphonate group to give the desired product (US Pat. No. 4,786,637). Specifically, mycophenolic acid 78-5 is dissolved in dichloromethane. After addition of thionyl chloride, a catalytic amount of DMF is added. The reaction mixture is stirred at room temperature for 3 hours, after which the volatile components are removed in vacuo. The phosphonate-alcohol is dissolved in dichloromethane and cooled to 4 ° C. in an ice bath. The mycophenolic acid chloride 78-7 is dissolved in dichloromethane and the above cooling solution is added. After stirring at 4 ° C. for 90 minutes, the reaction mixture is washed with water and then with aqueous sodium bicarbonate. The organic solution is dried and evaporated to afford phosphonate prodrugs 78-6, 78-8 .

The C-4 phenol position provides a reactive means for further analogs (Scheme 78.4-78.5 ). Once the carboxylic acid is closed by morpholino ethyl as in compound 78-9 or by phosphonate prodrugs as in compounds 78-6, 78-8 , the phenol is alkylated under basic conditions. Bases such as pyridine, potassium carbonate or triethylamine are used. Leaving groups such as trifluoromethylsulfonate, mesylate, bromide or iodide are bound to the phosphonate prodrug subunit and reacted with compound 78-9 in the presence of a base. Compounds 78-2, 78-45 can be used directly or in the form of salts. Of the salts that can be prepared, the chloride and bisulfate salts are particularly important.

The preparation of compounds 78-10, 78-11 is shown in more detail in Scheme 78.5 . Compound 78-7 is prepared as described in Scheme 78.3 . The morpholino ethanol solution in dichloromethane is cooled to 4 ° C. The mycophenolic acid chloride 78-7 is dissolved in dichloromethane and the cooling solution is added. This solution is stirred for 90 minutes to obtain compound 78-9 . The reaction mixture is washed with water and dried over sodium sulfate. The solvent is removed to give compound 78-9 . Alkylation at the phenolic position of 78-9 is accomplished by suspending the compound in pyridine. Triflate 78-30 is added to the solution and the mixture is stirred at room temperature for 90 minutes. The reaction mixture is poured into water and the product is extracted with ethyl acetate. The organic layer is removed to give compounds 78-2 and 78-45 . Hydrogen chloride salts of 78-2 and 78-45 are also prepared. Compounds 78-2, 78-45 are dissolved in isopropanol and the solution is added to a mixture of hydrogen chloride in isopropanol. The hydrogen chloride salts 78-10 and 78-11 are collected by filtration and dried in vacuo.

The carboxylic acid of the mycophenolic acid is substituted with phosphonic acid which acts as prodrug means. In order to remove the side chain containing a carboxylic acid, the conversion of the acid chloride ester 78-7 to 78-13, 78-33. After protecting the phenol with a silyl group, it is dehydroxylated and the diol is cleaved to give aldehydes 78-15, 78-19 (Pankiewicz, et al., J. Med . Chem ., (2002), 45 , 703 ), (Patterson et al., US Pat. No. 5,444,072) (Scheme 78.6-78.7 ). A wittig reaction is performed with lide 78-50, 78-31 containing appropriately protected phosphonate to afford the desired compound 78-16, 78-20 . Final deprotection affords compound 78-17 .

Mycophenolate esters 78-13, 78-33 are prepared by stirring the acid chloride 78-7 with MeOH. The phenol position of the mycophenolate ester is then protected by a silyl group such as TBS to give compounds 78-14 and 78-18 . If the phenol position is protected, aldehydes 78-15, 78-19 are obtained by dihydroxylation with osmium tetraoxide followed by periodinate cleavage reaction. Aldehyde 78-15, 78-19 and excess lide 78-50, 78-31 are heated to reflux in benzene for 24 hours. The reaction mixture is concentrated and the residue is purified by column chromatography to give olefins 78-16, 78-20 (Pankiewics et al., J. Med . Chem ., (2002), 45 , 703). Final deprotection with HF-pyridine affords the final product 78-17 . After demethylation of mycophenolate ester 78-9 , another point of attachment of the compound is revealed (Scheme 78.8-78.9 ). To this end, 4-OH is covered with a protecting group such as a silyl group. Once 6-MeO is demethylated and alkylated, the protecting group is removed at position 4 to produce the final product. The morphonyl ethanol group is initially loaded and is accompanied by an alkylation step. Another group acting as a protector is initially mounted and later removed. In this case, the last step is the formation of the morpholinoethyl ester prodrug.

The synthesis of compound 78-4 is shown in Scheme 78.9 . Phenol 78-9 to CH ₂ Cl ₂ Protected with TBS using imidazole as the base. Demethylation with thiolate nucleophile affords compounds 78-26, 78-22 . Various methods can also be used, as described in Protective groups in Organic Chemistry by Greene and Wuts. Alkylation of 6-OH using triflate of phosphonate prodrugs proceeds well using K ₂ CO ₃ or TEA. The products 78-27, 78-24 are obtained by removing the TBS groups and final deprotection.

Further manipulations can be made to the phosphonate moiety prior to the final deprotection reaction. Modifications of this kind are described in more detail in the phosphonate interconversion section herein.

Scheme 78.1

Scheme 78.2

Scheme 78.3

Scheme 78.4

Scheme 78.5

Scheme 78.6

Scheme 78.7

Scheme 78.8

Scheme 78.9

Example 79 Preparation of Exemplary Compounds of the Invention

Analogs of type 79-2 are obtained by derivatization on C-21 hydroxy groups with alkylation of dexamethasone 79-1 with the appropriate phosphonates. Scheme 79.1

Scheme 79.1

The primary hydroxy protons are extracted with sodium hydride in 79-1 and then diethylphosphonate triflate is added to give ether 79-3 . (Scheme 79.2 )

Scheme 79.2

Phosphonate appendages linked to C-11 hydroxy groups are obtained by utilizing the protecting group of dexamethasone 79-1 (Scheme 79.3 ). After protecting the primary hydroxy group, protected intermediate 79-4 is alkylated at a more exposed C-11 hydroxy position. Final deprotection gives the desired product 79-6 .

Scheme 79.3

Dexamethasone 79-1 is protected as silyl ether using standard TBSCl and imidazole conditions ( J. Am. Chem . Soc . 1972, 94 , 6190) (Scheme 79.4 ). After alkylation with diethylphosphonate triflate , the resulting intermediate 79-8 is treated with TBAF to give diol 79-9 .

Scheme 79.4

Synthesis of C-21 phosphonate analogs of type 79-12 is shown in Scheme 79.5 . This time, dexamethasone 79-1 is protected in two less obscured positions to obtain alcohol 79-10 to alkylate the exposed hydroxy group with the appropriate phosphonate. The protecting group is removed to complete the synthesis of analog 79-12 .

Scheme 79.5

Again dexamethasone 79-1 is protected as its TBS ether, in the case of the second protection more severe health is used (Scheme 79.6 ). After alkylation with diethylphosphonate triflate , the resulting intermediate 79-14 was treated with TBAF to afford the desired phosphonate 79-15 . Get

Scheme 79.6

Example 81 Preparation of Exemplary Compounds of the Invention

Phosphonates  contain PNP  Inhibitor Prodrug  Experiment result

Dissolve in the diacid (100 mg, 0.304 mmol), amino acid (100 mg, 0.651 mmol), phenol (145 mg, 1.54 mmol) and triethylamine (510 μl, 3.66 mmol) pyridine (5 mL). The mixture is heated to 60 ° C. for 5 minutes. To this reaction mixture is added a solution of triphenylphosphine (560 mg, 2.14 mmol) and alditiol (2) (470 mg, 2.13 mmol) and dissolved in pyridine (5 mL). The reaction is then heated at 60 ° C. for 12 hours. The reaction mixture is diluted in EtOAc and washed with H ₂ O, saturated NaHCO ₃ (aq) and brine. The organic layer was dried (MgSO ₄ ), concentrated and purified by chromatography on silica gel (1% MeOH / CH ₂ Cl ₂ → 10% MeOH / CH ₂ Cl ₂ ) to give monoamidate 81-1 (5 mg, 3%). ) And bisamidate 81-2 (5 mg, 3%). For 81-1 : ¹ H NMR (300 MHz, CD ₃ OD) δ 7.78 (1H, m), 7.35 (2H, m), 7.20 (3H, m), 4.18-3.95 (5H, m), 2.24- 1.90 (2H, m), 1.87-1.62 (4H, m), 1.38-1.18 (6H, m), 1.02 (6H, m); ³¹ P NMR (121 MHz, CD ₃ OD) δ 36.3, 35.3; LC-MS (Method: 0.5 min 95% H ₂ O / 5% MeCN → 5 min 0% H ₂ O / 100% MeCN, rt = 2.18 min.C ₂₃ H ₃₄ N ₆ O ₅ P (MH ⁺ ) Calculated MS: 505.2.Measured 505.2 For 81-2 : ¹ H NMR (300 MHz, CD ₃ OD) δ 7.77 (1H, s), 4.23-3.92 (8H, m), 2.04-1.50 (6H, m), 1.42 (3H, d), 1.40 (3H, d), 1.28 (3H, t), 1.22 (3H, t), 1.02 (3H, s), 1.01 (3H, s); ³¹ P NMR (121 MHz, CD ₃ OD) δ 33.9; LC-MS (Method: 0.5 min 95% H ₂ O / 5% MeCN → 5 min 0% H ₂ O / 100% MeCN, rt = 1.79 min. C ₂₂ H ₃₉ N ₇ MS calculated for O ₆ P (MH ⁺ ): 528.3.

Dissolve in the diacid (25 mg, 0.072 mmol), amino acid (25 mg, 0.16 mmol), phenol (38 mg, 0.40 mmol) and triethylamine (127 μl, 0.911 mmol) pyridine (1.25 mL). The mixture is heated to 60 ° C. for 5 minutes. To this reaction mixture is added a solution of triphenylphosphine (140 mg, 0.534 mmol) and aldehyde (2) (119 mg, 0.540 mmol) and dissolved in pyridine (1.25 mL). The reaction is then heated at 60 ° C. for 12 hours. Another batch of diacid (12 mg, 0.035 mmol) is treated as described above. The reaction mixtures from both batches are combined and diluted in EtOAc and washed with H ₂ O, saturated NaHCO ₃ (aq) and brine. The organic layer was dried (MgSO ₄ ), concentrated and purified by chromatography on silica gel (1% MeOH / CH ₂ Cl ₂ → 10% MeOH / CH ₂ Cl ₂ ) monoamidate 81-3 (3 mg, 8% ) And bisamidate 81-4 (8 mg, 20%). For 81-3 : ¹ H NMR (300 MHz, CD ₃ OD) δ 8.38-8.08 (1H, m), 7.78-7.60 (2H, m), 7.50-7.18 (8H, m), 6.67-6.05 (1H , m), 5.60-5.30 (2H, m), 4.63 (1H, bs), 4.25-3.95 (3H, m), 1.37 (3H, m), 1.18 (3H, m); ³¹ P NMR (121 MHz, CD ₃ OD) δ 21.5, 20.2; LC-MS (Method: 0.5 min 95% H ₂ O / 5% MeCN → 5 min 0% H ₂ O / 100% MeCN, rt = 1.98 min.C ₂₅ H ₂₈ N ₆ O ₅ P (MH ⁺ ) the MS calculated: 523.2 523.2 for the measurement ^{81-4:.. 1 H NMR (} 300 MHz, CD 3 OD) δ 8.15 (1H, dd), 7.72 (1H, s), 7.67 (1H, m), 7.39 (2H, m), 7.28 (1H, m), 6.44 (1H, dd), 5.40 (2H, s), 4.23-3.90 (6H, m), 1.42 (6H, m), 1.27 (3H, t), 1.18 (3H, t); ³¹ P NMR (121 MHz, CD ₃ OD) δ 19.7; LC-MS (Method: 0.5 min 95% H ₂ O / 5% MeCN → 5 min 0% H ₂ O / 100% MeCN , rt = 1.86 min.MS calculated for C ₂₄ H ₃₃ N ₇ O ₆ P (MH ⁺ ): 546.2.

Bulb drug cleavage analysis

PBMC  Isolation of the extract:

Fresh human PBMCs are obtained from patients suffering from leukophoresis and placed within plasma and treated within 24 hours after extraction. Purification using the Ficoll-Paque method. PBMC cells are harvested by centrifugation at 1200 X g for 5 minutes and resuspended in RBC lysis buffer (155 mM NH ₄ Cl, 0.1 mM EDTA, 10 mM KHCO ₃ ) and washed three times. The washed cells are suspended in lysis buffer (0.2x10 ⁹ cells in 1 ml of 10 mM Tris, pH 7.4, 150 mM NaCl, 20 mM CaCl ₂ , 1 mM DTT and 1% NP40) and incubated for 20 minutes on ice. The PBMC crude extract is centrifuged at 1000 X g for 30 minutes to remove undissolved cells and the desorption solution is centrifuged at 100,000 X g for 1 hour. The 100,000 X g desorbent (PBMC extract: P0) is harvested, frozen rapidly in liquid nitrogen and stored at -70 ° C.

PBMC  Protocol for Degradation Measurement of Prodrugs by Extracts:

The reaction mixture contains 25 mM MesNa (pH 6.5), 100 mM NaCl, 1 mM DTT, 0.1% NP-40, 30 mM substrate and various amounts of enzyme in a final volume of 100 μl. Enzymatic reactions were performed at 37 ^° C. for 10-120 minutes and stopped at 3-4 individual time points by adding 180 μl of ice cold methanol. Samples are incubated at −20 ° C. for 30 minutes and centrifuged at 13,000 RPM for 30 minutes (at 4 ° C.). The desorbent is transferred to a 96 well plate and evaporated under vacuum using a speedvac. The precipitate is dissolved in 100 μl of 20 mM CH ₃ COONH ₄ + 5% Ac. The disappearance of prodrug was measured by HPLC monitoring at 260 nm. The intrinsic activity of PBMC extract on prodrugs is defined as v (rate of degradation) / μg protein = pmoles / min / μg.

result

compound Intrinsic activity of human PBMC extract (pmol / min / μg) 81-1 3.48 81-2 0.65 81-3 4.9 81-4 0.38

Example 82 Preparation of Exemplary Compounds of the Invention

A series of inhibitors of PNP are reasonably designed to mimic the transition state of the enzyme. This class is collectively called Immucillins. Depending on the enzyme used for rational design of the inhibitor, slightly different structures have been proposed and synthesized.

A high potency analogue that inhibits PNP enzymes from Mycobacterium tuberculosis ( MtPNP) , called DADMe-ImmG, has the following structure (Lewandowics A. et al., BiO Chemistry , (2003), 42 , 6057).

Scheme 82.1

Reduction of dose and / or improvement of efficacy is achieved by using prodrugs of DADMe-ImmG that generate reagents with increased intracellular half-life upon degradation in target cells. Such compounds are shown below (Scheme 82.2 ).

Scheme 82.2 :

Compounds such as 82-1 are prepared according to the general route shown in Scheme 82.3 , with examples shown in Scheme 82.4 .

Scheme 82.3

Scheme 82.4

The preparation of DADMe-ImmG is reported in Lewandowics A. et al., BiO Chemistry , (2003), 42 , 6057. Tertiary nitrogen of the ring may not interfere with alkylation of the secondary alcohol, in which case standard protection and deprotection protocols as described by Greene, T. Protective groups in Organic Chemistry , Wiley-Interscience, (1999) This can be used if necessary but does not need to be protected. Alcohol 82-3 is reacted with a base, followed by addition of an appropriately neutralized phosphonate to obtain the protected product. Deprotection as a whole gives the desired phosphonate 82-4 .

Compounds such as 82-2 are prepared according to the general route shown in Scheme 82.5 , with examples shown in Scheme 82.6 .

Scheme 82.5

The preparation of DADMe-ImmG is reported in Lewandowics A. et al., BiO Chemistry , (2003), 42 , 6057. Primary alcohols are blocked by the methods described in Greene, T., Protective groups in Organic Chemistry , Wiley-Interscience, (1999). After reacting the secondary alcohol in the base, the appropriately neutralized phosphonate is added to obtain the protected product. Deprotection yields the desired phosphonate.

Scheme 82.6

Specifically, the protected DADMe derivative may be treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. At the end of bubbling, diethylphosphonoethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added to give the desired phosphonate ester. The protecting group is removed to obtain the desired phosphonate ester as described in Greene, T., Protective groups in Organic Chemistry , Wiley-Interscience, (1999).

Example 83 Preparation of Exemplary Compounds of the Invention

Scheme 83.1

Parent molecule:

General target structure:

It is shown in the following synthetic schemes towards a specific target 83-8 and 83-9.

Scheme 83.2

References for this reaction: J. Med . Chem . (1996), 39 , 4608

Additional Compounds: The synthesis of targets 83-13 and 83-14 is shown below.

Scheme 83.3

Example 84 Preparation of Exemplary Compounds of the Invention

Leflunomide (along with its active metabolite, structure is shown below) (see US Pat. No. 4,284,786) is an isoxosol that inhibits various T-lymphocyte actions through the inhibition of dihydroorotate dehydrogenase. Derivatives (Copeland et al, BiO Chem., (1996), 35, 1270).

Scheme 84.1

The active metabolite of leflunomide (A771726, also known as teriflunomide, see US Pat. No. 6,288,098) has a very long half-life in humans, including skin rash, itching, diarrhea, abdominal pain, nausea. Considering the known side effects of the compound, including vomiting, weight loss, hypertension, dizziness and reversible hair loss, this is a cause of interest. Also reported more serious medical injuries include pleural involvement, vasculitis and hepatotoxicity. In addition, Stevens-Johnson syndrome and toxic epidermal necrosis have been described only in rare cases.

Reduction of dose and / or improvement of efficacy is achieved by using prodrugs of leflunomide or derivatives thereof that result in reagents with increased intracellular half-life upon degradation in target cells. The same concept can be applied to FK778 (MNA-715) (see US Pat. No. 5,308,86), a reagent with similar modes of action. Such compounds are described below.

Scheme 84.2

Methods for the synthesis of such compounds are described in Westwood et al, J. Med. Chem., (1996), 39, 4608-4621.

Scheme 84.3

Examples of the synthesis of suitable phosphonate-containing aniline are shown below.

Scheme 84.4

Scheme 84.5

Example 85 Preparation of Exemplary Compounds of the Invention

Brequinar (structure is as follows, see US Pat. No. 4,680,299 and US Pat. No. 5,032,597) is an inhibitor of dehydroorotate dehydrogenase ( BioChemical Pharmacology 1990, 40, 709-714).

Scheme 85.1

The compound was clinically investigated as an immunosuppressant or anticancer agent, but its efficacy was disappointing, probably due to the narrow therapeutic window resulting from an excessively long half-life that would make higher doses impossible.

To solve these problems, the use of prodrugs of Brequinar analogs, as well as other quinoline inhibitors of dehydroorotate dehydrogenase, which generate active substances with intracellular half-lives that persist when compared to plasma concentrations in target cells. do. The therapeutic index of such agents may be significantly improved over Brequinar itself. Such compounds are described below.

Scheme 85.2

Methods for the synthesis of such compounds are described in Batt et al, Bioorg . Med . Chem . Based on the method described in Lett ., (1995), 5 , 1549. Representative general routes are shown in Schemes 85.3-85.5 .

Scheme 85.3

Examples of the synthesis of suitable phosphonate analogs are shown below.

Scheme 85.4

Scheme 85.5

Example 86 Preparation of Exemplary Compounds of the Invention

Scheme 86.1: (2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzo Monoamino } -Methyl) -phosphonic acid Diethyl ester

Diethylcia in a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (67.0 mg, 177 mmol) in DMF (3.0 mL) Nophosphonate (34.8 μl, 230 mmol) and diisopropylethylamine (Hunig's Base, DIEA, 30.4 μl, 177 mmol) are added. The solution is stirred at ambient temperature for 4 hours and diethyl (aminomethyl) -phosphonate (45.4 mg, 177 mmol) is added. The solution was stirred for another 4 hours and the starting material was observed to be consumed completely. The solvent was removed in vacuo and the residue was purified by silica gel chromatography using MeOH-CH ₂ Cl ₂ (10-30%) to complete the reaction. The product collected from the chromatography step was pure enough for the next reaction.

A small amount of product (20 mg) was repurified by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 12.9 mg (76%) of pure product. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.19 (t, 6H, J = 7.2 Hz), 3.21 (s, 3H), 3.70 (m, 2H), 4.00 (q, 4H, J = 7.2 Hz) , 4.81 (s, 2H), 6.81 (d, 2H, J = 9 Hz), 7.71 (d, 2H, J = 9 Hz), 8.40 (br s, 1H), 8.61 (s, 1H). ^{31 P (121.4 MHz, DMSO- d} 6) δ 23.4. MS ( m / z ) 475.2 [M + H] ⁺ , 597.2 [M + Na] ⁺ .

Scheme 86.2: (2- {4-[(2,4-Diamino-phthalin-6-ylmethyl) -methyl-amino] -benzo Monoamino }- methyl ) -Phosphonic acid

Crude (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -ethyl) after silica gel column chromatography in dry DMF (0.90 mL) To a solution of phosphonic acid diethylester (60 mg, 126 mmol) trimethylsilyl bromide (bromotrimethylsilane, TMSBr, 130.6 μl, 1,010 mmol) was added at ambient temperature. The solution was then heated at 70 ° C. for 4.0 h and then the reaction mixture was cooled to room temperature. The solvent volume was reduced to ˜700 μl in vacuo and diluted with H ₂ O (100 μl).

This solution was purified by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 26.8 mg (51%) of the title compound as a yellow solid. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 3.18 (s, 3H), 3.50 (m, 2H), 4.77 (s, 2H), 6.79 (d, 2H, J = 9 Hz), 7.79 (d, 2H, J = 9 Hz), 8.07 (br s, 1 H), 8.56 (s, 1 H); MS ( m / z ) 419.2 [M + H] ⁺ .

Scheme 86.3: (2- {4-[(2,4- Diamino - Putridine -6- Methyl )- methyl -Amino]- Benzoylamino } -Ethyl) -phosphonic acid Diethyl ester

Diethylsia in a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (61.2 mg, 161 mmol) in DMF (2.8 mL) Nophosphonate (31.8 μl, 210 mmol) and DIEA (27.8 μl, 161 mmol) were added. The solution was stirred at ambient temperature for 4 hours and diethyl (aminoethyl) phosphonate (43.8 mg, 161 mmol) was added. After stirring the solution for 3 more hours, it was observed that the starting material was consumed completely. The solvent was removed in vacuo and the residue was purified by silica gel chromatography using MeOH-CH ₂ Cl ₂ (10-30%) to complete the reaction. The product collected from the chromatography step was pure enough for the next reaction. A small amount of product (32 mg) was repurified by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 19 mg (70%) of pure product. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.21 (t, 6H, J = 7 Hz), 1.95- 2.05 (m, 2H), 3.20 (s, 3H), 3.13- 3.22 (m, 2H), 3.98 (appt septet, 4H, J = 7 Hz), 4.79 (s, 2H), 6.80 (d, 2H, J = 9 Hz), 7.65 (d, 2H, J = 9 Hz), 8.20 (br s, 1H ), 8.60 (s, 1 H). ³¹ P (121.4 MHz, DMSO- d ₆ ) δ 28.9. MS ( m / z ) 489.2 [M + H] ⁺ , 511.2 [M + Na] ⁺ .

Scheme 86.4: (2- {4-[(2,4-Diamino-phthyridin-6-ylmethyl) -methyl-amino]- Benzoylamino } -Ethyl) -phosphonic acid

Crude (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -ethyl) after silica gel column chromatography in dry DMF (1.00 mL) To a solution of phosphonic acid diethylester (61 mg, 125 mmol) was added TMSBr (129.0 μl, 999.2 mmol) at ambient temperature. The solution was then heated at 70 ° C. for 5.5 h and LCMS analysis confirmed that the reaction was 90% complete. The reaction mixture was cooled to room temperature and further stirred for 12 hours. The reaction was completed by removing the solvent in vacuo and dissolving the residue in DMF / H ₂ O (800 μl, 1: 1) and 1N aqueous NaOH (15 μl). The product was purified by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 29 mg (53%) of the title compound as a yellow solid. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.67-1.85 (m, 2H), 3.19 (s, 3H), 3.25- 3.40 (m, 2H), 4.76 (s, 2H), 6.71 (br s, 2H), 5.80 (d, 2H, J = 9 Hz), 7.64 (d, 2H, J = 9 Hz), 7.73 (br s, 2H), 8.15 (br s, 1H), 8.56 (s, 1H). ³¹ P (121.4 MHz, DMSO- d ₆ ) δ 23.0. MS ( m / z ) 431.3 [M ⁻ H] ⁻ .

Scheme 86.5: (2- {4-[(2,4-Diamino-phthalin-6-ylmethyl) -methyl-amino] -benzo Monoamino } -Propyl) -phosphonic acid Diethyl ester

Diethylsia in a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (61.2 mg, 161 mmol) in DMF (2.8 mL) Nophosphonate (31.8 μl, 210 mmol) and DIEA (27.8 μl, 161 mmol) were added. The solution was stirred at ambient temperature for 3 hours and diethyl (aminopropyl) phosphonate (34.9 mg, 122.6 mmol) was added. After stirring the solution for 2 more hours it was observed that the starting material was consumed completely. The solvent was removed in vacuo and the residue was purified by silica gel chromatography using MeOH-CH ₂ Cl ₂ (10-30%) to complete the reaction. The product (65.5 mg) collected in the chromatography step was pure enough for the next reaction. A small amount (32.8 mg) was rearranged by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 23.2 mg (75%) of pure product. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.20 (t, 6H, J = 7.2 Hz), 1.64- 1.75 (m, 4H), 3.22 (s, 3H), 3.41 (m, 2H), 3.98 ( appt septet, 4H, J = 7.2 Hz), 4.85 (s, 2H), 6.79 (d, 2H, J = 9 Hz), 7.68 (d, 2H, J = 9 Hz), 8.17 (br s, 1H), 8.70 (s, 1 H); ^{31 P (121.4 MHz, DMSO- d} 6) δ 31.9; MS ( m / z ) 503.2 [M + H] ⁺ .

Scheme 86.6: (2- {4-[(2,4-Diamino-phthyridin-6-ylmethyl) -methyl-amino] -benzo Monoamino } -Propyl) -phosphonic acid

Crude (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -propyl) after silica gel column chromatography in dry DMF (0.50 mL) To a solution of phosphonic acid diethyl ester (32.2 mg, 66.2 mmol) was added TMSBr (68.0 μl, 529.6 mmol) at ambient temperature. The solution was then heated at 70 ° C. for 1.0 h and LCMS analysis confirmed the reaction was complete. The reaction mixture was cooled to room temperature and water (60 μl) and methanol (60 μl) were added. The resulting mixture was purified by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 11.2 mg (38%) of the title compound as a yellow solid. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.50 (m, 2H), 1.61 (m, 2H), 3.22 (s, 3H), 3.25- 3.40 (m, 2H), 4.84 (s, 2H), 6.80 (d, 2H, J = 9 Hz), 7.69 (d, 2H, J = 9 Hz), 8.20 (br s, 1H), 8.69 (s, 1H). ³¹ P (121.4 MHz, DMSO- d ₆ ) δ 26.3. MS ( m / z ) 447.3 [M ⁻ H] ⁻ .

Scheme 86.7: 2-[(2- {4-[(2,4-diaminopteridin-6-ylmethyl) methyl-amino] benzo Monoamino } -Ethyl) phenoxyphosphinoyloxy] propionic acid ethyl ester [diastereomer mixture in phosphorus]

Diethylcia in a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (60.0 mg, 158.3 mmol) in DMF (2.5 mL) Nophosphonate (31.2 μl, 205.7 mmol) and DIEA (81.8 μl, 474.9 mmol) were added. The solution was stirred at ambient temperature for 3.5 hours and ( S ) -2-[(2-aminoethyl) phenoxyphosphinoyloxy] -propionic acid ethyl ester mono acetate salt in DMF (200 μl) (57.1 mg, 158.3 mmol (Diastereomeric mixture in phosphorus) solution was added. The solution was further stirred for 1.5 hours before the starting material was consumed completely. The solvent was removed in vacuo and the crude material was purified by silica gel chromatography using MeOH-CH ₂ Cl ₂ (10-30%). A small amount of product (32.8 mg) was re-purified by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 15.8 mg (65%) of pure product. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.17 1.27 (m, 3H), 1.32 (d, 2H, J = 7.5 Hz), 1.42 (d, 1H, J = 7.5 Hz) 2.27 (m, 2H) , 3.19 (s, 3H), 3.53 (m, 2H), 4.08 4.14 (m, 2H), 4.77 (s, 2H), 4.98 (m, 1H), 6.72 (br s, 1H), 6.81 (d, 2H , J = 9 Hz), 7.21 (m, 3H), 7.36 (m, 2H), 7.66 (d, 2H, J = 9 Hz), 8.26 (br s, 1H), 8.56 (s, 1H); ³¹ P (121.4 MHz, DMSO- d ₆ ) δ 26.6, 27.4. MS ( m / z ) 609.2 [M + H] ⁺ .

Scheme 86.8: 2-[(2- {4-[(2,4-diaminopteridin-6-ylmethyl) methyl-amino] benzo Monoamino } -Ethyl) phenoxyphosphinoyloxy] -propionic acid [diastereomer mixture in phosphorus]

2-[(2- {4-[(2,4-diaminopteridin-6-ylmethyl) methyl-amino] benzoylamino} ethyl) phenoxy-phosphinoyloxy] propionic acid ethyl ester in DMF To the diastereomer mixture at 40.0 mg, 65.7 mmol) (0.4 mL) solution, acetonitrile (0.2 mL) and water (0.2 mL) were added aqueous sodium hydroxide (1 N, 131.4 μl). The solution was stirred at ambient temperature for 4 hours. The solvent was removed in vacuo and the crude product was purified by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 23.7 mg (71.3%) of the pure product. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.30 (d, 2H, J = 6.9 Hz), 1.79 (m, 2H), 3.21 (s, 3H), 3.37 (m, 2H), 4.61 (m, 1H), 4.81 (s, 2H), 6.79 (d, 2H, J = 8.7 Hz), 7.64 (d, 2H, J = 9.7 Hz), 8.25 (br s, 1H), 8.63 (s, 1H); ³¹ P (121.4 MHz, DMSO- d ₆ ) δ 25.1. MS ( m / z ) 505.2 [M + H] ⁺ .

Scheme 86.9: 2-[(2- {4-[(2,4-diaminopteridin-6-ylmethyl) methylamino] -benzo Monoamino } Ethyl) phenoxyphosphinoyloxy] propionic acid ethyl ester [diastereomer in phosphorus In volume  pure]

Diethylcyanophosphonate in a solution of 4-[(2,4-diaminopteridin-6-ylmethyl) -methyl-amino] benzoic acid hemihydrochloride dihydrate (101.9 mg, 268.9 mmol) in DMF (3.3 mL) (53.0 μl, 349.5 mmol) and DIEA (138.0 μl, 806.7 mmol) were added. The solution was stirred at ambient temperature for 2.5 hours and then ( S ) -2-[(2-aminoethyl) phenoxyphosphinoyloxy] -propionic acid ethyl ester monoacetic acid salt in DMF (500 μl) Stereoisomerically pure; 268.9 mmol) was added. After stirring the solution for another 30 minutes, it was observed that the starting material was consumed completely. The solvent was removed in vacuo and the crude material was purified by silica gel chromatography using MeOH-CH ₂ Cl ₂ (10-30%). A small amount of product (40.0 mg) was re-purified by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 28.7 mg (75.1%) of pure product. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.15 (t, 3H, J = 7.2 Hz), 1.44 (d, 3H, J = 6.9 Hz), 2.26 (m, 2H), 3.23 (s, 3H) , 3.51 (m, 2H), 4.09 (q, 2H, J = 7.2 Hz), 4.86 (s, 2H), 5.01 (m, 1H), 6.81 (d, 2H, J = 9.3 Hz), 7.21 (m, 3H), 7.35 (m, 2H), 7.68 (d, 2H, J = 9.3 Hz), 8.29 (br s, 1H), 8.71 (s, 1H); ^{31 P (121.4 MHz, DMSO- d} 6) δ 26.6. MS ( m / z ) 609.2 [M + H] ⁺ .

Scheme 86.10: 2-[(2- {4-[(2,4-Diaminopteridin-6-ylmethyl) methylamino] -benzoylamino} -ethyl) -phenoxyphosphinoylamino] propionic acid ethyl ester (Diastereomeric mixtures in phosphorus)

Diethylsia in a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (39.6 mg, 104.0 mmol) in DMF (1.2 mL) Nophosphonate (20.6 μl, 136.1 mmol) and DIEA (36.0 μl, 209.4 mmol) were added. The solution was stirred at ambient temperature for 3 hours and the ( S ) -2-[(2-aminoethyl) phenoxyphosphinoylamino] propionic acid ethyl ester monoacetic acid salt in DMF (200 μl) (diastereomer in phosphorus) Mixture; 104.0 mmol) was added. After stirring the solution for another 30 minutes, it was observed that the starting material was consumed completely. An equivalent portion of the reaction (66%) was purified by silica gel chromatography using MeOH-CH ₂ Cl ₂ (10-30%) to give 27.2 mg of crude product. A small amount of product (10.0 mg) was re-purified by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 4.2 mg (26%) of pure product. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.11 (t, 3H, J = 6.9 Hz), 1.18 (d, 3H, J = 7.2 Hz), 2.06- 2.17 (m, 2H), 3.20 (s, 3H), 3.51 (m, 2H), 3.88 (m, 1H), 4.02 (m, 2H), 4.79 (s, 2H), 5.61 (m, 1H), 6.80 (d, 2H, J = 9 Hz), 6.98 (br s, 1H), 7.18 (m, 3H), 7.32 (m, 2H), 7.67 (d, 2H, J = 9 Hz), 8.20 (br s, 1H), 8.59 (s, 1H) ³¹ P _{(121.4 MHz, DMSO- d 6)} δ 29.5, 30.1. MS ( m / z ) 608.2 [M + H] ⁺ .

Scheme 86.11: 2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzo Monoamino } -6- ( Diethoxy - Phosphoryl )- Hexanoic acid

Diethylcyano in a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (63.0 mg, 166.2 mmol) in DMF (2.8 mL) Phosphonate (30.8 μl, 199.4 mmol) and DIEA (85.8 μl, 498.6 mmol) were added. The solution was stirred at ambient temperature for 3.5 hours and (L) -2-amino-6-diethylphosphonatohexanoic acid (44.3 mg, 166.2 mmol) was added. The solution was further stirred for 48 hours. The solvent was removed in vacuo and the residue was purified by silica gel chromatography using MeOH-CH ₂ Cl ₂ (10-30%) to complete the reaction. The product (87 mg) collected in the chromatography step was pure enough for the next reaction. An equal portion (51.0 mg) of the product is purified by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 24.7 mg (44%) of the pure product. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.18 (t, 6H, J = 6.9 Hz), 1.42 (m, 4H), 1.65 (m, 4H), 3.20 (s, 3H), 3.92 (m, 4H), 4.29 (m, 1H), 4.78 (s, 2H), 6.72 (br s, 1H), 6.81 (d, 2H, J = 9 Hz), 7.73 (d, 2H, J = 9 Hz), 8.14 (d, 1 H, J = 7.8 Hz), 8.56 (s, 1 H); ^{31 P (121.4 MHz, DMSO- d} 6) δ 31.8; MS ( m / z ) 574.3 [M] ⁺ .

Scheme 86.12: 2- {4-[(2,4-diaminopteridin-6-ylmethyl) methylamino] -benzo Monoamino } -6- ( Phosphoryl ) Hexanoic acid

Crude (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino}) after silica gel column chromatography in dry DMF (0.60 mL) -2 To a solution of '( L )-(6'-(phosphonic acid diethylester) hexanoic acid) (20 mg, 34.6 mmol) was added TMSBr (18.0 μl, 139.2 mmol) at ambient temperature. The solution was heated at 70 ° C. for 18 hours and then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and dissolved in DMF (400 μl) and water (60 μl). This solution was purified by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 8.9 mg (49%) of the product as a yellow solid. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.45 (m, 6H), 1.75 (m, 2H), 3.20 (s, 3H), 4.25 (m, 1H), 4.77 (s, 2H), 6.62 ( br s, 1H), 6.80 (d, 2H, J = 8.7 Hz), 7.73 (d, 2H, J = 8.7 Hz), 8.14 (br s, 1H), 8.55 (s, 1H); MS ( m / z ) 519.2 [M + H] ⁺ .

Scheme 86.13: 2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzo Monoamino } -6 '-( Monophenyl - Phosphonates ) Hexanoic acid

The ethyl-TMS ester is hydrolyzed under appropriate conditions to prepare the corresponding acid of the present invention.

Intermediate 2- {4-[(2,4-Diamino-Pethridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6 '-(monophenyl-phosphonate) -hexanoic acid TMS Ethanol esters can be prepared as follows.

a. (L )-2- Cbz -Amino- Hexanoic acid -6-phosphonic acid

To a suspension of ( L ) -2-amino-6- (diethoxyphosphonyl) hexanoic acid (106 mg, 396.8 mmol) in dry DMF (2.00 mL) was added TMSBr (307.0 μl, 2,381.0 mmol) at ambient temperature. . The solution was then heated at 70 ° C. for 2 hours and then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo. The crude material was dissolved in water (0.25 mL) and NaOH (1-N, 2.50 mL). Benzyl chloroformate (79.3 μl, 555.5 mmol) was added and stirring continued at room temperature. After 2 hours, the solution was washed with ether (2 mL) and the aqueous layer was acidified to pH 1 with aqueous HC. The aqueous layer was extracted with EtOAc (3x 5 mL). The combined organic extracts were dried over sodium sulfate. The solvent was filtered off and evaporated to afford a crude product pure enough for subsequent modification. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.42 1.65 (m, 8H), 3.90 (m, 1H), 5.02 (s, 2H), 7.32 (s, 5H), 7.55 (m, 1H), 7.94 (s, 1 H); ^{31 P (121.4 MHz, DMSO- d} 6) δ 26.5; MS ( m / z ) 345.6 [M + H] ⁺ .

b. ( L ) -2--amino- Hexanoic acid  2 'TMS ethyl ester-6-phosphonic acid Monophenyl  ester

To a solution of ( L ) -2-Cbz-amino-hexanoic acid-6-phosphonic acid (137.3 mg, 397.9 mmol) in 2-TMS ethanol (2.5 mL) was added acetyl chloride (50 μl). Stirring was continued at room temperature. After 22 hours a complete conversion was observed. The solvent was removed in vacuo. The crude material was pure enough for the next step.

One half (198.9 mmol) of the crude material was dissolved in toluene (3.0 mL) at room temperature. Thionyl chloride (167.2 mg, 1,416.0 mmol) was added and the reaction mixture was heated at 70 ° C. (oil bath). After 4 hours, the reaction was cooled to room temperature and the solvent was removed in vacuo. The crude material was redissolved in methylene chloride (2.0 mL) and a solution of phenol (36.6 mg, 389.0 mmol) and DIEA (67.0 μl, 389.0 mmol) in methylene chloride (1.0 mL) was added. Stirring was continued at room temperature. After 4 hours the solvent was removed in vacuo.

The crude material was dissolved in tetrahydrofuran (THF) (3.0 mL) and aqueous sodium hydroxide solution (1N, 0.885 mL) was added. Stirring was continued at room temperature. After 14 hours the solvent was removed in vacuo to afford crude phosphonate monophenyl ester (63.8 mg). This material was dissolved in 2-TMS ethanol (1.0 mL) and acetyl chloride (20 μl) was added. Stirring was continued at room temperature. After 22 hours it was observed to be completely converted to the carboxylate ester. The solvent was removed in vacuo. The material was pure enough for the next step.

Half (75 mmol) of the crude material was dissolved in ethanol (1.5 mL). Pd / C (5%, 20 mg) was added and the reaction was placed under hydrogen gas atmosphere. After 1.5 h, celite was added and the resulting reaction mixture was filtered through celite. The solvent was removed in vacuo and the crude material was used in the next step without further purification.

c. 2- {4-[(2,4- Diamino - Putridine -6- Methyl )- methyl -Amino]- Benzoylamino  } -6 '-(Monophenyl-phosphonate) -hexanoic acid TMS ethanol ester

Diethylcyano in a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (22.7 mg, 60.0 mmol) in DMF (0.80 mL) Phosphonate (12.4 μl, 78.0 mmol) and DIEA (31.0 μl, 180.0 mmol) were added. The solution was stirred for 1 h at ambient temperature and (L) -2-amino-6-monophenoxyphosphonatohexanoic acid 2 'TMS ethyl ester (70.5 mmol) suspended in DMF (0.2 mL) was added. The solution was further stirred for 3.5 hours. The resulting reaction mixture was purified by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 2- {4-[(2,4-diamino-phthyridin-6-yl Methyl) -methyl-amino] -benzoylamino} -6 '-(monophenyl-phosphonate) -hexanoic acid TMS ethanol ester 19.4 mg (46%) were obtained. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 0.0 (s, 9H), 0.91 (t, 2H, J = 8.1 Hz), 1.42 1.53 (m, 4H), 1.67-1.76 (m, 4H), 3.24 (s, 3H), 4.10 (t, 2H, J = 8.1 Hz), 4.29 (m, 1H), 4.86 (s, 2H), 6.81 (d, 2H, J = 9 Hz), 7.12 (m, 3H) , 7. 31 (m, 2H), 7.74 (d, 2H, J = 9 Hz), 8.14 (d, 1H, J = 7.8 Hz), 8.71 (s, 1H); ^{31 P (121.4 MHz, DMSO- d} 6) δ 26.2; MS ( m / z ) 695.2 [M] ⁺ .

Scheme 86.14: 2- {4-[(2,4-Diamino-phthalidin-6-ylmethyl) methylamino] -bene Crude amino } -6 '-( Monophenyl  Mono (S) ethyl Lactate - Phosphonates ) Hexanoic acid

The ethyl-TMS ester is hydrolyzed under appropriate conditions to prepare the corresponding acid of the present invention.

Intermediate 2- {4-[(2,4-Diamino-Pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6 '-(monophenyl mono (S) ethyl lactate-force Phonate) -hexanoic acid TMS ethanol ester can be prepared as follows.

2- {4-[(2,4- Diamino - Putridine -6- Methyl )- methyl -Amino]- Benzoylamino } -6 '-(monophenyl mono (S) ethyl Lactate - Phosphonates )- Hexanoic acid TMS ethanol ester

2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6 '-(monophenyl-phosphonate) in DMF (0.70 mL) PyBOP (32.4 mg, 62.4 mmol), DIEA (21.4 mg, 166.4 mmol) and (S) ethyl lactate (19.6 mg, 166.4 mmol) in a solution of -hexanoic acid TMS ethanol ester (14.5 mg, 20.8 mmol, Example 225) Was added. The reaction mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was purified by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 13.5 mg (81%) of the pure product diastereomeric mixture (~ 4: 1) in phosphorus. ) ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.0 (s, 9H), 1.02 (t, 2H, J = 8.7 Hz), 1.23 (t, 3H, J = 9.3 Hz), 1.35 (d, 2.4H, J = 6.6 Hz), 1.42 1.53 (m, 4.6H), 1.67-1.86 (m, 4H), 3.14 (s, 3H), 4.03 4.27 (m, 4H), 4.71 (br s, 3H), 4.98 (m, 0.8H), 5.10 (m, 0.2H), 6.57 (d, 2H, J = 7.5 Hz), 7.00 (m, 1H), 7.16 (m, 3H), 7. 30 (m, 2H), 7.63 (d , 2H, J = 7.5 Hz), 8.43 (s, 1H); ^{31 P (121.4 MHz, DMSO- d} 6) δ 30.5, 29.2; MS ( m / z ) 795.2 [M] ⁺ .

Example 87 Preparation of Exemplary Compounds of the Invention

Recently, the PNP inhibitor PNP-405 (also described as PNU-405) was initiated at the ACS Conference (2000). This compound inhibits purine nucleotide phosphorylase with an IC ₅₀ of 20 nM (structure is shown below).

Scheme 87.1

Reduction of dose and / or improvement in efficacy is achieved by using prodrugs of PNP-405 that generate reagents with increased intracellular half-life upon degradation in target cells. Such compounds are shown below (Scheme 87.2 ).

Scheme 87.2

Compounds such as 87-2, 87-5 and the like are prepared according to the general route shown in Scheme 87.3 together with the examples shown in Scheme 87.4 .

Scheme 87.3

Scheme 87.4

PNP-405 was prepared according to the method of the literature [Littler, BJ et al., 7 th International Conference on Organic Pr ℃ ess Research and Development, New Orleans, LA, March 16-19, (2003)]. PNP-405 is treated with a base such as sodium hydride in a solvent such as dimethylformamide or tetrahydrofuran. At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added to give compound 87-6 as the desired product.

The compounds of Scheme 87.2 (where X═O, Z═CH ₂ OH) are described in Littler, BJ et al., 7 ^th International Conference on Organic Pr ° Cess Research and Development, New Orleans, LA, March 16-19, (2003)] (Scheme 87.5 and 87.6 ). The starting material, 2-benzyloxyphenylacetic acid (available from Av ° Cadodo), is acylated via mixed anhydride with the indicated oxazolidinone at 80-85 ° C. using triethylamine as the base. Low temperature alkylation with bromoacetonitrile results in the formation of compound 87-9 having a good diastereomeric ratio. Chiral aids are removed under reducing conditions to give compound 87-10 without racemization. The resulting alcohol is protected by a trityl group to give compound 87-11 . Subsequent pyrrole ring formation and cyclo-guanidinylation to prepare 6-membered 2-aminopyrimidinone rings can be done as illustrated in Scheme 87.6 .

Scheme 87.5 :

The compounds of Scheme 87.2 , where X = O, Z = H, can be prepared according to the general route illustrated above. The starting material, 3- (2-benzyloxy-phenyl) -propionitrile, can be prepared by Lewis acid-mediated reaction of acrylonitrile and phenol according to US Pat. No. 2,789,995, published in 1954. Intermediate 87-11 provides compounds of Schemes 87.1 and 87.1 through the same synthetic steps as described herein.

The pyrrole ring structure can be completed in three steps from 3- (2-benzyloxy-phenyl) -propionitrile. Formation of 3-hydroxy-acrylonitrile 87-13 is achieved by exposure of 87-12 to LDA and ethyl formate.

This product is condensed with 2-amino-malonic acid diethyl ester in EtOH and sodium acetate to give compound 87-14 to undergo a decarboxylating cyclization reaction in a basic medium of NaOH and EtOH to give pyrrole 87-15 . In some synthesis, the trityl protecting group of the benzyl alcohol is removed at this stage. Subsequently, compound 87-16 is obtained by guanidinylation reaction with cyanamide , treated with sodium hydroxide to cyclize to form a 2-aminopyrimidinone ring (compound 87-17 ). The phenolic protecting group is removed under hydrogenation conditions to obtain the free phenol used as the binding site for the prodrug group. Various linkers can be used to bind to the prodrug partial skeletal molecule. A particular example of the use of diethylphosphonomethyltriplate as a starting material is illustrated below. Therefore compound 87-18 is treated with a base such as sodium hydride or cesium carbonate in a solvent such as tetrahydrofuran or dimethylformamide. At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., (1986), 27 , 1477) is added to give the compound of Scheme 87.2 .

Scheme 87.6 :

Of Scheme 87.2 Compounds (where X = O, Y = H, Z = CH ₂ OH) can be prepared from 4-benzyloxyphenylacetic acid (commercially available from Aldrich). According to a reaction sequence similar to that shown in Scheme 87.7 , intermediates 87-24 can be prepared (Scheme 87.7 ). In the order shown in Schemes 87.6 , 87-24 . To the desired product in Scheme 87.2 .

Scheme 87.7 :

Example 88 Preparation of Exemplary Compounds of the Invention

Phosphorus containing thiazolidinedione derivative 88-2 is synthesized from the parent compound by alkylation. Parent compound 88-1 is obtained by the process described in US Pat. No. 4,572,912. Scheme 88.1 illustrates coupling the phosphonate linking group to the phenolic OH of 88-1 to obtain the compound of formula 88-2 . Compound 88-1 was dissolved in a suitable aprotic solvent such as DMF, and then a suitable organic or leaving group in the presence of an inorganic base, for example, bromine, mesyl, phosphonate reagents containing methanesulfonyl as tosyl or trifluoromethyl ( 88-30 ). In the scheme of this example, A ^o -LG refers to a phosphonate compound bound to a leaving group such as, for example, halogen, triflate, mesylate or toluenesulfonate, as described herein.

Scheme 88.1

For example, (methanesulfonyloxymethyl trifluoromethyl) 88-3 to a solution of DMF of cesium carbonate and one equivalent of methyl-phosphonic acid diethyl ester 88-18, 88-25 by treatment with a methylene group connected, as it is shown in Scheme 88.2 The resulting troglitazone-phosphonate 88-4 is obtained. Other 88-1 and Except for using phosphonate reagents 88-30 and 88-40 , the above process can be used to obtain the corresponding product 88-2 containing other substituents and linking groups.

Scheme 88.2

Scheme 88.3 shows the preparation of phosphorus-containing thiazolidinedione derivatives of type 88-7, 88-20 . The parent compound 88-5 is obtained by the process described in U.S. Patent No. 4,572,912. The phenolic OH and thiazolidinedione units are protected with appropriate protecting groups such as SEM groups and the carbonyl groups are reduced using suitable reducing agents such as sodium borohydride to generate hydroxyl groups at the C4 position of the chroman alcohol analog. Alcohol 88-6 is then treated with a suitable chloroformate ester such as carbonate such as phenyl chloroformate or p -nitrophenyl chloroformate or bis ( p -nitrophenyl) carbonate to produce the active carbonate. The resulting active carbonate is reacted with a phosphonate reagent 88-35 containing amino groups followed by deprotection of the protecting groups to prepare phosphonates of type 88-7, 88-20 .

Scheme 88.3

For example, a 88-8 solution in THF is treated with diisopropylethylamine and two equivalents of 2- (trimethylsilyl) ethoxymethyl chloride to protect the phenolic OH and thiazolidinedione units. The methanol solution of the protected product is then reduced using sodium borohydride to give alcohol 88-9 . Treatment of alcohol 88-9 with phenyl chloroformate to give phenyl carbonate, reaction with 2-aminoethyl-phosphonate diethyl ester 88-12 to obtain a protected phosphonate derivative, followed by tetrabutylammonium fluorine in THF Deprotection with the ride yields 88-10 . 88-5 and another phosphonate corresponding product, except that the carbonate reagent and 88-35 Using the method comprising the further substituents and opened gyeolgi 88-7, it is possible to obtain 88-20.

Scheme 88.4

Scheme 88.5 illustrates the preparation of phosphorus containing thiazolidinedione derivatives. In a suitable aprotic solvent such as DMF, thiazolidinedione 88-11 is alkylated to produce thiazolidinedione 88-13 having a phosphorus containing moiety, and then in the presence of a suitable organic or inorganic leaving group such as bromine, Treatment with phosphonate reagents 88-30, 88-40 containing mesyl, tosyl or trifluoromethanesulfonyl. Then the compound is reacted with a benzaldehyde 88-13 88-14 having a protected phenol to the para-position. The protecting group R ⁸⁸ may be a protecting group for phenolic OH, such as an alkoxyalkyl group such as methoxymethyl group, aralkyl group such as benzyl group, 2-tetrahydropyranyl group and acyl group such as acetyl or benzoyl group, preferably benzyl group. have. The reaction is carried out in an aprotic solvent such as toluene, at a suitable elevated temperature such as the reflux temperature of the solvent, preferably in the presence of a suitable catalyst such as piperidinium acetate or benzoate. The water produced during the reaction is advantageously removed from the reaction mixture, for example using a Dean and Stark apparatus. The reduction of the of 88-15 to 88-16 are preferably on the carbon-palladium catalysts, it is accomplished by suitable catalyst such as 10% palladium on charcoal catalyst (U.S. Patent No. 6,288,095). The combination of the Chroman alcohol homologues 88-17 and 88-16 Achieved by the method described in J. American Oil Chemical Society (1974), 51 , 200 or US Pat. No. 4,572,912, and appropriately protecting alcoholic functional groups as described in US Pat. No. 4,572,912 and using Mitsunobu conditions. do.

Scheme 88.5

For example, (methanesulfonyloxymethyl trifluoromethyl) methyl phosphonic acid diethyl ester 88-18, a treatment with 88-25 group connected to a methylene group as shown in Scheme 88.6 88-11 a solution in DMF with sodium hydride and one equivalent of Thiazolidinedione-phosphonate 88-19 is obtained. The thiazolidinedione-phosphonate 88-19 was then reacted with benzaldehyde 88-20 containing benzyloxy substituents with a Dean-Stark equipment under reflux conditions in the presence of catalytic piperidinium acetate in toluene to give 88-21 . Get 88-21 is obtained by catalytic 88-21 reduction by catalytic hydrogenation in dioxane in the presence of 10% palladium on charcoal. 88-22 and under diethyl azodicarboxylate and tri presence of triphenylphosphine The SEM groups are protected with TBAF after the reaction between chromman alcohol analogs 88-23 to produce 88-24 . Other chroman alcohol analogues and phosphonate reagents 88-30 and 88-40 are used above to obtain the corresponding products 88-2 with different substituents and linkages, except that

Scheme 88.6

Example 89: Preparation of Exemplary Compounds of the Invention

Scheme K2 - K4 Phosphonate Compounds of the Invention The synthesis | combination of K2 - K4 and the synthesis | combination of the intermediate compound which are necessary for the synthesis are illustrated.

Protection of reactive substituents.

Depending on the reaction conditions used, it may be necessary to protect certain reactive substituents from unwanted reactions by protecting them prior to the reaction according to the knowledge of those skilled in the art, and later deprotecting the ventilator.

Protection and deprotection of functional groups are described, for example, in Protective Groups in Organic Chemistry , by TW Greene and PGM Wuts, Wiley, Second Edition 1990]. The protection and deprotection of steroidal ketones and alcohols is described in Organic Reactions in Steroid Chemistry, Vol. 1, J. Fried and JA Edwards, van Nostrand Reinhold, (1972), p. 375ff. Reactive substituents that can be protected are shown in the accompanying schemes, such as, for example, [OH], [O] and the like.

Scheme K1

For example, Scheme K1 represents a protection-deprotection sequence in which the steroid side chain is protected as a bis-methylenedioxy (BMD) moiety. The sequence in the 6α, 9α-difluoro-methyl--16β -11β, 17α, 21- trihydroxy-1,4-diene-frame geuneu -3,21- dione K1 .1 (U.S. Pat. 4,619,921) Protective Groups in Organic Chemistry , by TW Greene and PGM Wuts, Wiley, Second Edition (1990), p. 22] by the reaction with an acid catalyst, such as para-formaldehyde and hydrochloric acid as described in 3 to obtain the BMD derivative K1 .2. The phosphonate moiety is then introduced using the method described below to obtain phosphonate ester K1 .3 . The BMD portion is then described in Protective Groups in Organic Chemistry , by TW Greene and PGM Wuts, Wiley, Second Edition (1990), p. 223, for example, by treatment with 50% aqueous acetic acid to hydrolyze to give triol K1 .4 . The latter compound was then converted to Chem. Pharm. The procedure described in Bull., 1986, 34, 1613 is used to convert to 17,21- cyclic ortho ester K1 .5 . The substrate is reacted with 2 molar equivalents of triethyl orthopropionate and a catalytic amount of p-toluenesulfonic acid in 70 ° C. dimethylformamide.

The product is then reacted with excess trimethylsilyl chloride in dimethylformamide at ambient temperature to produce 21-chloro 17-propionate product K1 .6 .

Optionally, J. Med . The substrate K1 .4 is converted to the product K1 .6 by the method described in Chem ., (1987), 30: 1581. In this method, a 21-hydroxy group is activated by reacting with mesylchloride in pyridine to convert to 21-mesylate and then replacing the mesylate group by reacting with lithium chloride in dimethylformamide to obtain a 21-chloro intermediate. The hydroxyl group was esterified to give 21-chloro-17-propionate derivative K1 . Gets 6 Selective acylation of 17 hydroxyl groups in the presence of 11 hydroxyl groups is described in J. Med . Chem ., (1987), 30: 158.

Phosphonates  ester K2 Manufacturing.

Scheme K2 . Phosphonates K2

Scheme K2 represents the preparation of phosphonate K2 wherein the phosphonate is bound by an imino or imineoxy group and various carbon chains. In this method, the BMD-protected derivative K1 . 2 is an alkyl, alkenyl, cycloalkyl or cycloalkenyl group or an amide, ester, oxime, sulfoxide or sulfone containing R ² as hetero atom O, S or N as necessary or a hetero atom as necessary An amine or hydroxylamine K2 which is an optionally substituted aryl, heteroaryl or aralkyl group comprising O, S or N and X can be subsequently converted to a phosphonate group or a phosphonate containing substituent . React with 1 For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxy and the like. In an aprotic solvent such as pyridine or xylene or alcoholic solvent such as ethanol, if necessary, the reaction is carried out between the same molar amount of reactants in the presence of an acid catalyst to obtain imine or oxime. Preparation of steroidal 3-ketones is described in Anal. BiOCH., 1978, 86, 133. and J. Mass. Spectrom., (1995), 30, 497. Then the BMD-protected side chain compound K2 . 2 is converted to the triol .3a K2 as described in the following reaction formula K2 21-propionate 17-chloro product K2. Convert to 3

Scheme K2 also illustrates the preparation of hydroxylamine ethers comprising phosphonate groups. In this method, Lv is a phosphonate K2 . Wherein Lv is a leaving group such as bromo or trifluoromethylsulfonyloxy . Boc- 4 hydroxylamine K2 .5 (Aldrich) and the reaction to obtain the ether K2 .6. The reaction is carried out between equal molar amounts of reactants in a polar solvent such as dimethylformamide or tetrahydrofuran in the presence of a base such as potassium hydroxide or dimethylmananopyridine. Then, for example, tree and deprotected by treatment with acid to obtain a K2-fluoro .7 hydroxylamine ether.

Scheme K2

Example 89-A

Scheme K2 , Example 89-A , illustrates the preparation of phosphonate K2 wherein phosphonates are linked by imineoxy groups. In this method, a substrate K1 .2 dialkyl tree methylsulfonyl oxymethyl phosphonate fluoro (Tet. Lett., 1986, 27, 1477) and a hydroxyl Boc- a dialkyl phosphine, prepared as described above from the amine Phonomethyl hydroxylamine K2 . Reaction with 8 gives oxime K2 .9 . Deprotection then affords triol K2 .10a to prepare 21-chloro 17-propionate compound K2 .10b . The oxime formation reaction is carried out using the same molar amount of reactants at ambient temperature in ethanol-acetic acid solution.

Other oxime ethers instead of hydroxylamine ether K2 .8 K2 . But using 1, using the above method to obtain a corresponding product K2 .3b.

Scheme K2

Example 89-B

Scheme K2 , Example 89-B , illustrates the preparation of compound K2 in which phosphonates are linked by thienylmethoxy oxime groups. In this method, the dieneon K1.2 is described above . O- (4-bromo-2-thienylmethoxy) hydroxylamine K2 prepared from 4-bromo-5-bromomethylthiophene (WO 9420456) . 11 and reacted as described above, after deprotection of the side chain, to obtain the oxime K2 .12. Followed by a dialkyl phosphite K2 .13 and the reaction product in the presence of a palladium catalyst to obtain a phosphonate K2 .14a. The preparation of arylphosphonates by the coupling reaction between brominated aryl and dialkyl phosphites is described in J. Med. Chem., 35, 1371, (1992). The reaction is carried out in an inert solvent such as toluene in the presence of a base such as triethylamine and a catalytic amount of tetrakis (triphenylphosphine) palladium (0).

Alternatively, by combining bromo K2 .12 parent compound with a dialkyl butenyl phosphonate K2 .15 (Aldrich) to obtain the phosphonate K2 .16a. The combination of olefins and aryl halides by the Heck reaction is described, for example, in Advanced organic chemistry, by FA Carey and RJ Sundberg, Plenum, (2001), p. 503ff and Acc. Chem. Res., 12, 146, (1979). Aryl bromide and olefins are prepared in the presence of a palladium (0) catalyst such as tetrakis (triphenylphosphine) palladium (0) or a palladium (II) catalyst such as palladium (II) acetate and, if necessary, triethylamine or potassium carbonate. And in the presence of a base such as dimethylformamide or dioxane in a polar solvent. If necessary, for example by reaction with a diimide reducing the double bond present in the product K2 .16a to produce the saturated analog of K2 .17a. Reduction of olefin bonds is described in Comprehensive Organic Transformations, by RC Larock, VCH, (1989), p. 6ff. Such modifications are achieved by, for example, catalytic hydrogenation using palladium and hydrogen or hydrogen donors on carbon catalysts or the use of diimides or diboranes. As a thereby following the conversion product .16a K2 and K2 .17a with 21-chloro-17-propionate analog .16b K2 and K2 .17b.

Bomo -dihydroxy-20 reagent in place of K2 .11 other Bromo to-use the substituted aryl or heteroaryl alkoxy hydroxylamine and / or and the other method except that the di-alkyl alkenyl use of phosphonate compound K2. 14b, a similar product is obtained in K2 K2 .16b and .17b.

Scheme K2 , Example 89-C

Scheme K2 , Example 89-C, shows the preparation of phosphonate K2 wherein the phosphonate is bound by an imino group. In this method, as the substrate K1 .2 described above, 4-amino-2-bromothiophene (Tet 43:. 3295 (1987 )) and dialkyl phosphite prepared by palladium catalyzed coupling between a dialkyl 4 amino-2-thienyl phosphonate is reacted with carbonate K2.18 obtain the imine product K2 .19a after deprotection. The imine formation reaction is carried out at reflux temperature in a hydrocarbon solvent such as toluene or xylene under azeotropic conditions in the presence of a basic catalyst such as sodium methoxide or an acid catalyst such as p-toluenesulfonic acid. The product is then converted to 21-chloro 17-propionate compound K2 .19b

To using and, the method but using the substituted aryl or heteroaryl phosphonate K2 .19b - 4- amino-thienyl phosphonate K2 .18 other amino in place of Get a similar product.

Scheme K2 , Example 89-D

Scheme K2 , Example 89-D, shows the preparation of phosphonate K2 wherein the phosphonate is bonded by an oxyimino group or an amide linkage. In this method, the diene K1.2 O- (4- amino-butyl) hydroxylamine K2 .20 (Pol J. Chem 55: .. 1163 (1981)) is reacted with the oxime obtained K2 .21. The reaction of steroidal 1,4-dien-3-one with substituted hydroxylamines is described in J. Steroid BiOCH., (1976), 7, 795, which reactions are carried out in polar organic solvents such as pyridine or methanol. If necessary, the reaction is carried out using the same molar amount of reactants in the presence of acetic acid or sodium acetate. Then the product of a dialkyl 2-hydroxyethyl phosphonate K2 .22 (Epsilon) and carbonyl di-imidazole and by reacting the obtained cover mate oxime K2 .23. Preparation of carbamate is described, for example, in AR Katritzky, Comprehensive Organic Functional Group Transformations, 6: 416ff (Pergamon, 1995) and SR Sandler and W. Karo, Organic Functional Group Preparations, 260ff (Academic Press, 1986). have. In this method, the amine is reacted with a functional equivalent such as phosgene or carbonyl diimidazole, triphosgene, pentafluorophenyl carbonate in an inert aprotic solvent such as dichloromethane or tetrahydrofuran to react the corresponding active acylamine. Get The latter compound is then reacted with alcohol to give carbamate. Then the carbamate product K2 . As described in Scheme 23, the K1 is converted into 21-chloro-17-propionate product K2 .24b.

Hydroxylamine K2 .22 place of other amino-substituted hydroxylamines and / or other hydroxy- and to the use of the above method but using the substituted phosphonate is obtained is similar to the product K2 .24b.

Phosphonates  ester K3  And K4 Manufacturing.

Scheme K3 . Example K3 And K4

Scheme K3 illustrates the preparation of phosphonate esters K3 and K4 wherein the phosphonate group is bonded to the 1 'or 2' position of the pyrazole ring by an aromatic or heteroaromatic group, a hetero atom and various carbon chains. In this method, BMD-protected diene K1 . By reduction of 2 to obtain a K3 .1 1,2- dihydro product. Catalytic hydrogenation reactions are described, for example, in J. Med. Proceed with Tris (triphenylphosphine) rhodium (I) chloride as described in Chem., 44: 602 (2001). The product was then J. Am. Chem . Soc . 86: 1520 to give (1964) the reaction with a base such as ethyl formate and sodium hydride in an inert solvent such as toluene or dimethylformamide, as described to obtain the 2-formyl product K3 .2. As a thereby following the reaction of the compound alkyl, aralkyl, aryl or a substituent group and X is a phosphonate group or a heteroaryl group, one of the hydrazine of the K3 .3 group is subsequently transformed into a phosphonate-containing substituents. For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. This reaction yields the isomeric 2'- and 1'-aryl pyrazoles K3.4 and K3 .5 . Pyrazole formation reactions are described in J. Am. Chem . Soc . 86: 1520 (1964), using the same molar amount of reactant in an acidic solvent such as acetic acid. Then pyrazol-K3 and K3 .4 .5 an example embodiment, and 89-E by using the method described in 89- F via a protected intermediate BMD- K3 and K3 .6 .7 21- chloro-17-Pro propionate phosphorylation transform into carbonate .8b K3 and K3 .9b.

Scheme K3, Example 89-E

Scheme K3, Example 89-E, shows the preparation of phosphonates K3 and K4 in which phosphonates are bonded by amide linkages. In this method, as described above, the keto-aldehyde K3 .2, 3- carboxypropyl hydrazine K3 .10 (Ind J. Exp Biol 32 :... 218 (1994)) was reacted with pyrazol-.11 K3 and K3. Get 12 Then 2'-substituted isomer K3 .11 is reacted with a dialkyl 4-aminophenyl phosphonate K3 .13 (Epsilon) and dicyclohexyl carbodiimide in 1 mol equivalent of dimethylformamide solution of ambient temperature amide K3 Get .14 Amide preparation from carboxylic acids and derivatives is described, for example, in SRSandler and W. Karo, Organic Functional Group Preparations, 274 (Academic Press, 1968) and RC Larock, Comprehensive Organic Transformations, 972ff (VCH, 1989). It is. The carboxylic acid is, for example, in the presence of an activating agent such as dicyclohexylcarbodiimide or diisopropylcarbodiimide, if necessary, for example, hydroxybenztriazole, N-hydroxysuccinimide or N-hydride. The amide is obtained by reacting with the amine in an aprotic solvent such as pyridine, DMF or dichloromethane in the presence of oxypyridone.

Optionally, the carboxylic acid is first changed to an active derivative such as acid chloride, anhydride, mixed anhydride, imidazolide, and the like, followed by reaction with the amine in the presence of an organic base such as pyridine, for example, to obtain an amide.

Conversion of the carboxylic acid to the corresponding acid chloride is achieved by treating the carboxylic acid with a reagent such as thionyl chloride or oxalyl chloride, if necessary, in the presence of a catalytic amount of dimethylformamide in an organic solvent such as dichloromethane. do.

Then removes the BMD protecting group and converting the product to a 21-chloro-17-propionate product K3 .16b.

Optionally, 1'-substituted pyrazole K3 . As it described for 12 above, with a dialkyl was coupled with amino methyl phosphonate K3 .17 (Interchim) to obtain an amide K3 .18. Followed by protecting the product K3 .18 gained triol K3 .19a converts the latter compound with 21-chloro-17-propionate K3 .19b.

Except for using other amino-substituted phosphonates and / or other carboxy-substituted hydrazines, K3 .16b and K3 .19b can be used using this method. Get similar products. The functionalization methods are interchangeable between pyrazole substrates K3 .11 and K3 .12 .

Scheme K3 , Example 89-F

Scheme K3 , Example 89-F , illustrates the preparation of phosphonates K3 and K4 in which phosphonate groups are linked by aryl rings and propenyl linkages. In this method, as described above, the keto-aldehyde K3.2, allyl hydrazine K3 .20 (Zh Org Khim, 3 :... 983 (1967)) and produced by reacting a pyrazole .22 .21 K3 and K3 Let's do it. A 1'-substituted isomers K3 .21 a dialkyl 3-bromophenyl phosphonate K3.23 phosphonate K3 was coupled with (Epsilon) .24, as described in Scheme K2 Get Followed by the product obtained by deprotection of triol K3 .25a converts to 21-chloro-17-propionate Compound K3 .25b.

Optionally, 2'-substituted pyrazole K3 . A as described above, 22, dialkyl 5-bromo-2-thienyl phosphonate K3 .26 (Syn., 455 ( 2003)) was prepared and deprotected a phosphonate .27 K3 was coupled with the product to convert to 21-chloro-17-propionate analog K3 .28b.

Propenyl hydrazine K3 .20 other alkenyl instead of hydrazine and / or different dialkyl bromo- and using the above method but using the substituted phosphonate to obtain a product similar to compound K3 .25b and K3.28b .

Scheme K4 . Phosphonates K3 and K4

Scheme K4 illustrates the preparation of phosphonate esters K3 and K4 in which phosphonate groups are linked by various carbon linking groups. In this method, it is reacted with a keto-aldehyde K3 .2 hydrazine to obtain a pyrazole derivative .1 K4. The reaction of hydrazine with steroidal 2-formyl-3-ketone is described in J. Am. Chem . Soc , 86: 1520 (1964). The reaction is carried out in acetic acid at ambient temperature. Then the sol-pyrazol the product R ² and X group by reacting methyl bromide with the parent compound K4 .2 as defined above to obtain the alkylated product K4 and K4 .3 .4. Alkylation of substituted pyrazoles is described, for example, in TL Gilchrist, Heter yclic Chemistry, 309 (Longman, 1992). The reaction is carried out using the same molar amount of substrate in the presence of a base such as dimethylaminopyridine, lithium hexamethyldisilazide in a polar solvent such as dimethylformamide or tetrahydrofuran. The X except for the case of a dialkyl phosphono, and product .3 K4 and K4. 4 phosphonates K4 .5 and K4 . It was converted to 6, and deprotection / chlorination / acylated to give the 21-chloro-17-propionate compound K4 and K4 .7b .8b.

Scheme K4

Example 89-G

In Scheme K4 , Example 89-G As shown, pyrazole K4.1 was converted to 2-bromobenzyl bromide Reaction with K4 .9 yields pyrazoles K4 .10 and K4 .11 . Then, as described above the product, it was coupled with a dialkyl phosphite, the deprotection and modification of a side chain as described above is obtained after the 21-propionate 17-chloro-K4 and K4 .12b .13b.

Scheme K4 , Example 89-H

In Scheme K4 , Example 89-H A,, in tetrahydrofuran solution in cyclohexanone 4-bromomethyl-K4 .14 (WO 9737959) to yield alkylate product K4 and K4 .14 .15, as described above pyrazole .1 K4 as shown Get Then the 1'-substituted isomer K4 . 15 is reacted with a dialkyl aminomethyl phosphonate K.19 (Interchim) and sodium cyanoborohydride by reductive amination reaction, after deprotection and side chain modification to give 21-chloro 17-propionate K4 .17b . Get

Preparation of amines by reductive amination methods is described, for example, in RC Larock, Comprehensive Organic Transformations, 421 (VCH, 1989) and FA Carey and RJ Sundberg, Advanced organic chemistry, Part B, 269 (Plenum, 2001). Described. In this method, the amine component and the aldehyde or ketone component are added to the titanium tetraisopro as necessary in the presence of a reducing agent such as borane, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminum hydride. J. Org . Chem . , React together as described in 55: 2552 (1990).

Subjecting a 2'-substituted-pyrazol sol K4 .16 set of the same reaction to give the amine phosphonate K4.18b.

Other bromomethyl-substituted aldehyde or ketone and / or other amino- using the above method but using a substituted phosphonium neyiteueul obtain a product similar to K4 and K4 .17b .18b.

Example 90 Preparation of Exemplary Compounds of the Invention

Schemes 1 and 2 are phosphonate compounds of the present invention, M1 And To illustrate the synthesis of intermediate compounds for the synthesis of M2 and their synthesis.

Protection of reactive substituents

Depending on the reaction conditions used, it may be necessary to protect certain reactive substituents from unwanted reactions by protecting them prior to the reaction according to the knowledge of those skilled in the art and later deprotecting the substituents.

Protection and deprotection of functional groups are described, for example, in TW Greene and PGM Wuts, Protective Groups in Organic Chemistry (Second Edition, Wiley, 1991). The protection and deprotection of steroidal ketones and alcohols is described in J. Chem. Fried and JA Edwards, Organic Reactions in Steroid Chemistry, Vol. 1 375ff (van Nostrand Reinhold, 1972). Reactive substituents that can be protected are shown in the accompanying schemes, such as, for example, [OH], [O] and the like.

Phosphonates  ester M1 Manufacture

Scheme 1

Scheme 1 , Example 90-A

Scheme 1 is phosphonate M1 The preparation of (Compound 1 in Scheme 1 ) is shown. Scheme 1 , Example 90-A shows an example of Scheme 1 . In Scheme 1 , Example 90-A , 5-hydroxy-1-β-D-ribofuranosyl-1 H -imidazole-4-carboxamide 1.1 (prepared according to US Pat. No. 3888843) was prepared. It can be treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., 1986 , 27 , 1477) is added to give the desired phosphonate diester 1 .

Phosphonates  ester M2 Manufacture

Scheme 2

Scheme 2 is phosphonate ester M2 It illustrates the preparation of (Compound in Scheme 2 ). Compound 2.1 , 5-hydroxy-1- (4-hydroxy-5-hydroxymethyl-tetrahydro-furan-2-ylmethyl) -1H-imidazole-4-carboxylic acid amide is 3,5-bis- It can be prepared by adding imidazole base (JP publication 76 88965) to protected 2-deoxy-D- erythro -pentofuranosylchloride (Hayashi, M. et al., Chem . Pharm . Bull ., 1975 , 23 , 1, 245; Montgomery, JA et al. , J. Med . Chem ., 1969 , 12 , 3, 498 and Iwamoto, RH et al., J. Med . Chem ., 1963 , 6 , 684). Compound 2.1 is then protected on imidazole-4-ol. Glycal 2.3 is obtained by oxidation of 5′-OH followed by elimination reaction (see method of Zemlicka J. et al., J. Am. Chem . Soc . , 1972 , 94 , 9, 3213). Phosphonate 2.4 protected by selenoetheration is obtained (Kim, C. et al., J. Org . Chem ., 1991 , 56 , 2642). Oxidative removal of phenyl selenide (as described in Kim, C. et al., J. Org . Chem ., 1991 , 56 , 2642) followed by selective dehydroxylation to diol 2.6 . Get Finally, the protecting group is removed to obtain compound 2 .

Scheme 2 , Example 90-C

Scheme 2 , Example 90-C is phosphonate M2 The preparation of (Compound 2) in this example is exemplified. Specifically, 3,5-bis-protected 2-deoxy-D- erythro -pentofuranosyl chloride (Hayashi, M. et al., Chem . Pharm . Bull ., 1975 , 23 , 1, 245; Imidazole base (JP publication 76) in Montgomery, JA et al ., J. Med . Chem ., 1969 , 12 , 3, 498 and Iwamoto, RH et al., J. Med. Chem ., 1963 , 6 , 684). 88965 and Schipper, E. et al., J. Am. Chem . Soc . , 1952 , 74 , 350), which can be prepared 2.1 , 5-hydroxy-1- (4-hydroxy-5- Hydroxymethyl-tetrahydrofuran-2-ylmethyl) -1H-imidazole-4-carboxylic acid amide is first protected using a TBS group. Then carboxylic acid 2.2 is obtained using PtO ₂ . The decarboxylation reaction is carried out using dimethylformamide dienopentylacetal in high temperature DMF (Zemlicka J. et al., J. Am. Chem . Soc . , 1972 , 94 , 9, 3213). Once furanoid glycal 2.3 is obtained, it is treated with and treated with silver perchlorate in the presence of diethyl (hydroxylmethyl) phosphonate (Phillion, D. et al., Tetrahedron Lett., 1986, 27, 1477). Phosphonate 2.4 is obtained (Kim, C. et al., J. Org . Chem ., 1991 , 56 , 2642). Furanoids provide diols with the desired stereochemistry. Deprotection of the TBS group using TBAF affords compound 2 .

Example 91: Preparation of Exemplary Compounds of the Invention

Scheme I

Example 91-A [2- (4- {4- [4-Methyl-3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -phenylcarbamoyl] -benzyl} -piperazine- 1-yl) -ethyl] -phosphonic acid diethyl ester

DMF N- [4-Methyl-3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -phenyl] -4-piperazin-1-ylmethyl-benzamide in 2.5 mL (30 mg, 0.06 mmol, Zimmermann et al., Bioorg . Med. Chem . Lett . 1996 , 6 , 1221), diethyl 2-bromoethylphosphonate (30 μl, 0.12 mmol) and K ₂ CO 3 (20 mg, 0.16 mmol) The mixture of was heated at 110 ° C. for 8 hours and then observed by LCMS analysis that most of the starting material was consumed. Solid material was removed by filtration. The filtrate was diluted with water and then extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness. The crude material was purified by silica gel chromatography using 10% MeOH / CH ₂ Cl ₂ to afford 28 mg (55%) of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.32 (t, 6H), 1.92-20.3 (m, 4H), 2.35 (s, 3H), 2.5 (bs, 6H), 2.64 (m, 2H), 3.56 ( s, 2H), 4.05-4.14 (m, 4H), 7.07 (s, 1H), 7.18 (d, 2H, J = 5 Hz), 7.30 (dd, 1H, J = 6, 8 Hz), 7.33-7.45 (m, 3H), 7.84 (d, 2H, J = 8 Hz), 8.01 (s, 1H), 8.51 (dd, 2H, J = 4, 9 Hz), 8.58 (d, 1H, J = 2 Hz) , 8.70 (dd, 1H, J = 2, 5 Hz), 9.25 (s, 1H); ³¹ P (121.4 MHz, CDCl ₃ ) δ 30.5; MS ( m / z ) 644 [M + H] ⁺ .

Example 91-B [2- (4- {4- [4-Methyl-3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -phenylcarbamoyl] -benzyl} -piperazine- 1-yl) -ethyl] -phosphonic acid

[2- (4- {4- [4-Methyl-3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -phenylcarbamoyl] -benzyl} -piperazine in DMF (1 mL) To a solution of -1-yl) -ethyl] -phosphonic acid diethyl ester (8 mg, 0.012 mmol) was added TMSBr (15 μl, 0.12 mmol) at room temperature. The reaction was carried out for 14 hours at room temperature. TMSBr (20 μl) was further added and heated at 110 ° C. for 12 hours to confirm the reaction was complete by LCMS. The reaction was cooled to room temperature and the reaction was stopped by adding MeOH. The reaction mixture was dried under reduced pressure and the residue was purified over 20 minutes by RP HPLC using a C18 column with a gradient of H ₂ O-acetonitrile (5-100%) to give 4.2 mg (50%) of the product as mono. Obtained with -TFA salt. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.80-1.84 (m, 2H), 2.08-2.02 (m, 2H), 2.23 (s, 3H), 3.07 (bs, 4H), 3.30-3.32 (2H, Overlapped with solvent), 3.89 (m, 2H), 4.01 (s, 2H), 6.87 (s, 1H), 7.23-7.3 (m, 3H), 7.52-7.60 (m, 3H), 8.01 (d, 2H , J = 8 Hz), 8.08 (dd, 1H, J = 2, 5 Hz), 8.30 (s, 1H), 8.58 (d, 1H, J = 5 Hz), 8.89 (d, 1H, J = 2 Hz ), 9.22 (dd, 1H, J = 2, 5 Hz), 9.63 (s, 1H); ³¹ P (121.4 MHz, CD ₃ OD) δ 21.9; MS ( m / z ) 588 [M + H] ⁺ .

Scheme II

Example 91-C 2-{[2- (4- {4- [4-Methyl-3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -phenylcarbamoyl] -benzyl}- Piperazin-1-yl) -ethyl] -phenoxy-phosphinoyloxy} -propionic acid ethyl ester

N- [4-methyl-3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -phenyl] -4-piperazin-1-ylmethyl in 1% acetic acid / DMF (1.5 mL) solution A solution of benzamide (20 mg, 0.04 mmol) and 2-[(2-oxo-ethyl) -phenoxy-phosphinoyloxy] -propionic acid ethyl ester (60 mg, 0.2 mmol) was stirred at room temperature for 7 hours. NaCNBH ₃ (30 mg, 0.24 mmol) was then added. The resulting mixture was stirred for a further 30 minutes, then LCMS observed the completion of the reaction. After evaporation of the solvent, the residue was taken up in CH ₂ Cl ₂ and extracted with saturated aqueous NaHCO ₃ . The organic extract was dried in vacuo and the residue was purified by silica gel chromatography using MeOH-CH ₂ Cl ₂ (7%) to give 8 mg (26%) of the product. ³¹ P NMR (121.4 MHz, CDCl ₃ ) δ 27.2, 28.6; MS ( m / z ) 764 [M + H] ⁺ .

Example 91-D 2- {hydroxy- [2- (4- {4- [4-methyl-3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -phenylcarbamoyl]- Benzyl} -piperazin-1-yl) -ethyl] -phosphinoyloxy} -propionic acid

2-{[2- (4- {4- [4-methyl-3- (4-pyridin-3-yl-pyrimidin-2-ylamino) -phenyl in 2: 1 acetonitrile / water (0.3 mL) To a solution of carbamoyl] -benzyl} -piperazin-1-yl) -ethyl] -phenoxy-phosphinoyloxy} -propionic acid ethyl ester (6 mg, 0.008 mmol) was added 1N NaOH (50 μl, 0.048 mmol). It was. After the solution was stirred at room temperature, the reaction was observed to be complete by LCMS. The reaction was acidified with 1N HCl (50 μl) solution and purified over 20 minutes by RP HPLC using a C18 column with a gradient of H ₂ O-acetonitrile (5-100%) to give 2 mg (38%) of product. ) ¹ H NMR (300 MHz, CD ₃ OD) δ 1.51 (d, 3H, J = 7 Hz), 2.04 (m, 2H), 2.33 (s, 3H), 2.96 (bs, 4H), 3.31 (m, 2H ), 3.4 (bs, 4H), 3.89 (s, 2H), 4.88 (1H, can overlap with solvent), 7.30 (m, 2H), 7.48-7.57 (m, 4H), 7.96-7.99 (m, 4H) , 8.32 (s, 1H), 8.56 (d, 1H, J = 5 Hz), 8.86 (d, 1H, J = 2 Hz), 9.10 (dd, 1H, J = 2, 5 Hz), 9.59 (s, 1H); ³¹ P (121.4 MHz, CD ₃ OD) δ 20.0; MS ( m / z ) 660 [M + H] ⁺ .

Example 92 Preparation of Exemplary Compounds of the Invention

Scheme I

Example 92-A 6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1, 3-dihydro-isobenzofuran-5-yl]- 4-Methyl-hex-4-enoic acid methyl ester

6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl- in THF (3 mL) at 0 ° C. To a solution of hex-4-enoic acid methyl ester (222 mg, 0.66 mmol), PPh ₃ (260 mg, 0.996 mmol) and diethylazodicarboxylate (173 mg, 0.996 mmol) in THF (3 mL) A solution of trimethylsilyl ethanol (142 μl, 0.996 mmol) was added. The resulting yellow solution was warmed to room temperature and stirred overnight. The solution was concentrated to dryness and the reaction was finished by adding ether and hexane. Triphenylphosphine oxide was filtered off and the filtrate was concentrated and purified by silica gel chromatography to give 248 mg of the desired product as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.03 (s, 9H), 1.18-1.30 (m, 2H), 1.81 (s, 3H), 2.18 (s, 3H), 2.25- 2.33 (m, 2H), 2.37-2.45 (m, 2H), 3.42 (d, 2H, J = 7 Hz), 3.62 (s, 3H), 3.77 (s, 3H), 4.25- 4.35 (m, 2H), 5.13 (s, 2H) , 5.12- 5.22 (m, 1 H).

Example 92-B [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -acetaldehyde

To 6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-in in MeOH (10 mL), CH ₂ Cl ₂ (10 mL) and pyridine (50 μl, 0.618 mmol) Methoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid methyl ester (618 mg, 1.42 mmol) solution was prepared by Smith, DB et al., J. Org . Cooled to −70 ° C. using a dry ice / acetone bath according to the method of Chem ., 1996 , 61 , 6, 2236. The reaction was bubbled through a gas dispersion tube until the reaction color became blue (15 minutes). The ozone line was replaced with a stream of nitrogen and bubbling for another 15 minutes and the blue color disappeared. To this solution was added some thiourea (75.7 mg, 0.994 mmol) at -70 ° C and the cooling bath was removed. The reaction was warmed to room temperature and stirred for 15 minutes. The reaction was finished by filtering off the solid thiourea S-dioxide and then partitioned between CH ₂ Cl ₂ and water. The organic layer was removed. The aqueous layer was washed once more with CH ₂ Cl ₂ and the organic extracts were collected. The organic layer was washed with aqueous 1N HCl, saturated NaHCO ₃ and brine. The organic extract was dried in vacuo and purified by silica gel chromatography to give 357 mg (75%) of the product as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ -0.01 (s, 9H), 1.05- 1.15 (m, 2H), 2.15 (s, 3H), 3.69 (s, 3H), 3.78 (d, 2H, J = 1 Hz), 4.27-4.39 (m, 2H), 5.11 (s, 2H), 9.72 (d, 1H, J = 1 Hz).

Example 92-C 4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl]- 2-methyl-but-2-enal

[6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -acetium in toluene (2 mL) Aldehyde (70 mg, 0.21 mmol) was heated overnight at 100 ° C. with 2- (triphenylphosphanilidene) -propionaldehyde (72.9 mg, 0.23 mmol). A second portion of 2- (triphenyl-phosphanilidene) -propionaldehyde (33 mg, 0.11 mmol) was added and the reaction mixture was further heated for 1 day. After concentration, the residue was purified by silica gel chromatography to give 54 mg (83%) of the desired product as pale yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.00 (s, 9H), 1.10-1.21 (m, 2H), 1.87 (s, 3H), 2.16 (s, 3H), 3.67-3.76 (m, 2H), 3.74 (s, 3H), 4.27-4.39 (m, 2H), 5.11 (s, 2H), 6.40-6.48 (m, 1H), 9.2 (s, 1H).

Example 92-D 6- (4-hydroxy-3-methyl-but-2-ethyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H- Isobenzofuran-1-one

4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] in methanol (5 mL) A solution of -2-methyl-but-2-enal (103 mg, 0.27 mmol) was cooled to 0 ° C. CeCl ₃ solution (0.68 mL, MeOH: H ₂ O, 9: 1) was added followed by LiBH ₄ (0.14 mL, 0.28 mmol 2M solution in THF). The ice bath was removed and the reaction mixture was warmed to room temperature. The reaction mixture was further stirred for 40 minutes and then TLC confirmed that the starting aldehyde was consumed completely. Aqueous 1N HCl (0.5 mL) was added to finish the reaction and the product was extracted with CH ₂ Cl ₂ . The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography to give 100 mg (97%) of the product as a clear liquid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.00 (s, 9H), 1.20 (dd, 2H, J = 7, 8 Hz), 1.81 (s, 3H), 2.13 (s, 3H), 3.38-3.50 ( m, 2H), 3.74 (s, 3H), 3.95 (s, 2H), 4.27 (dd, 2H, J = 7, 8 Hz), 5.08 (s, 2H), 5.17-5.44 (m, 1H).

Example 92-E Phosphoric Acid Mono- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran- 5-yl] -2-methyl-but-2-ethyl} ester

6- (4-hydroxy-3-methyl-but-2-ethyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H- in dioxane (2 mL) 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one (56.7 mg) in a solution of isobenzofuran-1-one (75 mg, 0.20 mmol) and DIEA (49 μl, 0.28 mmol) , 0.28 mmol) was added according to the method of Shadid, B. et al., Tetrahedron , 1989 , 45 , 12, 3889. After 10 minutes another portion of 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one (40 mg, 0.20 mmol) and DIEA (35 μl, 0.20 mmol) were added. The reaction was allowed to proceed further for 1 hour at room temperature, and then the reaction was stopped by addition of H ₂ O. The solution was stirred for another 10 minutes and concentrated in vacuo to a small volume. The product was triturated with diethyl ether and co-evaporated from acetonitrile (4 x 10 mL) to afford the product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.03 (s, 9H), 1.08-1.30 (m, 2H), 1.84 (br s, 3H), 2.17 (s, 3H), 3.46 (br s, 2H), 3.76 (s, 3H), 4.21- 4.39 (m, 4H), 5.12 (s, 2H), 5.43-5.60 (m, 1H), 7.83 (br s, 1H); ³¹ P (121.4 MHz, CDCl ₃ ) δ 7.22; MS ( m / z ) 441 [M ⁻ H] ⁻ .

Example 92-F mono- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5 -Yl] -2-methyl-but-2-ethyl} ester

Phosphoric acid mono- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzo in dioxane (1 mL) Furan-5-yl] -2-methyl-but-2-ethyl} ester (27 mg, 0.06 mmol) solution was diluted with DIEA (21 μl, 0.12 mmol) and N, O-bis (trimethylsilyl) acetamide (29 μl , 0.12 mmol) was stirred at room temperature for 3 hours. 2,2'-Dipyridyldisulfide (16 mg, 0.072 mmol) was added to the reaction solution, and the mixture was further stirred at room temperature for 2 hours. The reaction mixture was diluted by addition of H ₂ O and the solution was After stirring for 2 more hours it was concentrated. The residue was dissolved in 10% TFA / CH ₂ Cl ₂ solution and stirred at room temperature for 9 hours. The reaction mixture was dried under reduced pressure and the product was purified by reverse phase HPLC to give the desired product as a white solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.87 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J = 7 Hz), 3.79 (s, 3H), 4.28 (d, 2H , J = 6 Hz), 5.26 (s, 2H), 5.50- 5.61 (m, 1H); ³¹ P (121.4 MHz, CD ₃ OD) δ 0.50; MS ( m / z ) 357 [M ⁻ H] ⁻ .

Example 92-G 6- (2-hydroxy-ethyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one

[6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -acet in THF (5 mL) To an aldehyde (97 mg, 0.29 mmol) solution was added an equal portion (150 μl, 0.300 mmol) of 2 M LiBH ₄ in THF. The reaction mixture was stirred at room temperature for 1 hour and then TLC observed that the starting material was consumed completely. Aqueous 1N HCl solution was added to finish the reaction mixture and extracted with EtOAc. The organic layer was dried in vacuo and the residue was purified by silica gel chromatography to give the product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.00 (s, 9H), 1.20 (dd, 2H, J = 7, 9 Hz), 2.07 (br s, 1H), 2.14 (s, 3H), 2.97 (t , 2H, J = 6 Hz), 3.76 (t, 2H, J = 6 Hz), 3.77 (s, 3H), 4.32 (dd, 2H, J = 7, 8 Hz), 5.08 (s, 2H).

Example 92-H {2- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -Ethoxymethyl} -phosphonic acid diisopropyl ester

Of 6- (2-hydroxy-ethyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one (79 mg, 0.23 mmol) The mixture was heated at 70 ° C. overnight with bromomethylphosphonic acid diisopropyl ester (120 mg, 0.46 mmol) in DMF (2 mL) in the presence of lithium t -butoxide (22 mg, 0.27 mmol). The reaction mixture was purified by reverse phase HPLC to give the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.00 (s, 9H), 1.13- 1.25 (m, 2H), 1.26 (t, 12H, J = 6 Hz), 2.12 (s, 3H), 2.98 (t, 2H, J = 7 Hz), 3.60- 3.73 (m, 4H), 3.77 (s, 3H), 4.05- 4.16 (m, 2H), 4.62-4.74 (m, 2H), 5.07 (s, 2H); MS ( m / z ) 539 [M + Na] ⁺ .

Example 92-I [2- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -ethoxymethyl] -phosphonic acid

{2- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) in acetonitrile (2 mL) and 2,6-lutidine (25 μl, 0.21 mmol) Trimethylsilyl bromide (27 μl, 0.21 mmol) in a solution of −1,3-dihydro-isobenzofuran-5-yl] -ethoxymethyl} -phosphonic acid diisopropyl ester (7.5 mg, 0.014 mmol) at room temperature Added. After the reaction was run for 18 hours, LCMS confirmed that the reaction was completed. MeOH was added and concentrated to stop the reaction. The residue was purified by reverse phase HPLC using a C18 column. The collected product was dispersed in 10% TFA / CH ₂ Cl ₂ solution to completely decompose the TMSE group. The reaction mixture was lyophilized to give the desired product. ¹ H NMR (300 MHz, CD ₃ OD) δ 2.12 (s, 3H), 2.98 (t, 2H, J = 7 Hz), 3.66- 3.76 (m, 4H), 3.78 (s, 3H), 5.21 (s , 2H); MS ( m / z ) 331 [M ⁻ H] ⁻ .

A. Scheme II

Example 92-J 6- (4-Bromo-3-methyl-but-2-ethyl) -7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one

Polymer-supported triphenylphosphine (3 mmol / g, 0.5 g) was immersed in dichloromethane (10 mL) for 1 hour. 7-hydroxy-6- (4-hydroxy-3-methyl-but-2-ethyl) -5-methoxy-4-methyl-3H-isobenzofuran-1-one (100 mg, 0.36 mmol) and Carbon tetrabromide (143 mg, 0.43 mmol) was added sequentially and the mixture was stirred at rt for 1 h. Further carbon tetrabromide (143 mg, 0.43 mmol) was added and the mixture was further stirred for 1 hour. The mixture was filtered and the filtrate was concentrated. The residue was chromatographed on silica gel (0% to 60% ethyl acetate / hexanes) to give 6- (4-bromo-3-methyl-but-2-ethyl) -7-hydroxy-5-methoxy-4 -Methyl-3H-isobenzofuran-1-one was obtained as an oil (52 mg, 42%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.95 (s, 3H), 2.16 (s, 3H), 3.44 (d, J = 7.2, 2H), 3.78 (s, 3H), 3.98 (s, 2H), 5.21 (s, 2 H), 5.68 (t, J = 7.2 Hz, 1 H), 7.71 (brs, 1 H).

Example 92-K [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2 -Ethyl] -phosphonic acid dimethyl ester

6- (4-Bromo-3-methyl-but-2-ethyl) -7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran- in trimethyl phosphite (1.0 mL, 8.5 mmol) The 1-one (33 mg, 0.097 mmol) solution was heated at 100 ° C. for 1 h and LCMS confirmed the reaction was complete. The reaction was completed by removing excess trimethyl phosphite under reduced pressure and the residue was purified by silica gel chromatography using EtOAc-hexane (20-100%) to give 20 mg (60%) of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.90 (s, 3H), 2.09 (s, 3H), 2.48 (d, 2H, J = 22 Hz), 3.38 (t, 2H, J = 6 Hz), 3.64 (d, 6H, J = 11 Hz), 3.72 (s, 3H), 5.14 (s, 2H), 5.33 (q, 1H, J = 6 Hz), 7.65 (br s, 1H); MS ( m / z ) 371 [M + H] ⁺ .

[4- (4-Hydroxy-6 -methoxy- 7- methyl- 3-oxo-1,3 -dihydro - isobenzofuran -5-yl) -2-methyl-but-2-ethyl] -force Phonic acid (LC-2095-49): [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzo in acetonitrile (2 mL) at 0 ° C. In a solution of furan-5-yl) -2-methyl-but-2-ethyl] -phosphonic acid dimethyl ester (18 mg, 0.049 mmol), TMSBr (63 μl, 0.49 mmol) and 2,6-lutidine (85 μl, 0.73 mmol) was added. The reaction solution was warmed to ambient temperature. The solution was stirred at room temperature for 2 hours and then observed by LCMS to complete the reaction. The reaction was cooled to 0 ° C. and stopped by addition of MeOH. The reaction mixture was dried under reduced pressure and the residue was purified over 20 minutes by RP HPLC using a C18 column with a gradient of H ₂ O-acetonitrile (5-0%) to give 12.2 mg (73%) of product. . ¹ H NMR (300 MHz, CD ₃ OD) δ 1.95 (s, 3H), 2.15 (s, 3H), 2.48 (d, 2H, J = 22 Hz), 3.44 (t, 2H, J = 6 Hz), 3.79 (s, 3H), 5.24 (s, 2H), 5.38 (q, 1H, J = 7 Hz), 6.87 (br s, 1H); MS ( m / z ) 341 [M ⁻ H] ⁻ .

[4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-ethyloxymethyl] -Phosphonic acid diisopropyl ester: 7-hydroxy-6- (4-hydroxy-3-methyl-but-2-ethyl) -5-methoxy-4-methyl-3H-iso in DMF (3 mL) Benzofuran-1-one (50 mg, 0.18 mmol, Pankiewicz et al., J. Med . Chem . 2002, 45 , 703), diisopropyl bromomethylphosphonate (93 mg, 0.36 mmol) and lithium t The butoxide (1M in THF, 0.54 mL) mixture was heated at 70 ° C. for 5 hours. The reaction was stopped with 1N HC. The mixture was poured into 5% aqueous lithium chloride, extracted with ethyl acetate and concentrated. The residue was purified by chromatography on silica gel to give [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)- 2-Methyl-but-2-ethyloxymethyl] -phosphonic acid diisopropyl ester was obtained as an oil (25 mg, 32%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.25 (m, 12H), 1.79 (s, 3H), 2.05 (s, 3H), 3.37 (d, J = 6.6 Hz, 2H), 3.58 (d, 2H) , 3.77 (s, 3H), 3.97 (m, 2H), 4.68 (m, 2H), 5.19 (s, 2H), 5.45 (t, J = 6.6 Hz, 1H), 7.83 (s, 1H).

Example 92-L [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2 -Ethyloxymethyl] -phosphonic acid

[4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-ethyl in acetonitrile To a solution of oxymethyl] -phosphonic acid diisopropyl ester (25 mg, 0.055 mmol) and 2,6-lutidine (0.18 mL, 1.65 mmol) was added trimethylsilyl bromide (0.126 mL, 1.1 mmol) at 0 ° C. The mixture was warmed to rt and stirred for 4 h. The reaction was stopped at 0 ° C. with methanol and the resulting mixture was concentrated. The residue was purified by preparative reverse phase HPLC to remove the solvent, followed by [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5- Il) -2-methyl-but-2-ethyloxymethyl] -phosphonic acid was obtained as an oil (17 mg, 83%). ¹ H NMR (300 MHz, CD ₃ OD) δ 1.81 (s, 3H), 2.06 (s, 3H), 3.40 (d, J = 6.6 Hz, 2H), 3.50 (d, 2H), 3.77 (s, 3H ), 3.97 (s, 2H), 5.20 (s, 2H), 5.47 (t, J = 6.6 Hz, 1H); MS ( m / z ) 371 [M ⁻ H] ⁻ .

Example 92-M [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2 -Ethyloxymethyl] -phosphonic acid monophenylester and [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)- 2-Methyl-but-2-ethyloxymethyl] -phosphonic acid diphenyl ester

[4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl in DMF (0.4 mL) at 0 ° C. -But-2-ethyloxymethyl] -phosphonic acid (49 mg, 0.13 mmol) solution and phenol (62 mg, 0.65 mmol) in dicyclohexyl carbodiimide (107 mg, 0.52 mmol) in DMF (0.6 mL) and DMAP (8 mg, 0.065 mmol) was added slowly. The reaction was warmed to room temperature and heated to 140 ° C. for 10 hours. After cooling to room temperature the mixture was filtered and extracted with aqueous 1N NaOH solution. The aqueous layer was acidified with aqueous 1N HCl and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by reverse phase HPLC to give [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl 18.5 mg of -but-2-ethyloxymethyl] -phosphonic acid monophenylester (product) as a pale yellow solid was obtained [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1, 4.1 mg of 3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-ethyloxymethyl] -phosphonic acid diphenyl ester (product) were also obtained as a pale yellow solid. Main products: ¹ H NMR (300 MHz, CD ₃ OD) δ 1.82 (s, 3H), 2.16 (s, 3H), 3.46 (d, 2H, J = 7 Hz), 3.70 (d, 2H, J = 8 Hz), 3.77 (s, 3H), 3.96 (s, 2H), 5.25 (s, 2H), 5.52 (t, 1H, J = 8 Hz), 7.10- 7.21 (m, 3H), 7.30 (t, 2H , J = 8 Hz); ³¹ P (121.4 MHz, CD ₃ OD) δ 17.3; MS ( m / z ) 449.0 [M + H] ⁺ , 471.2 [M + Na] ^+. Product: ¹ H NMR (300 MHz, CD ₃ OD) δ 1.82 (s, 3H), 2.15 (s, 3H), 3.47 (d, 2H, J = 7 Hz), 3.77 (s, 3H), 3.98- 4.06 (m, 4H), 5.25 (s, 2H), 5.50- 5.61 (m, 1H), 7.10- 7.25 (m, 6H), 7.30-7.41 (m, 4H); ³¹ P (121.4 MHz, CD ₃ OD) δ 16.3; MS ( m / z ) 525.2 [M + H] ⁺ , 547.2 [M + Na] ⁺ .

Example 92-N 2-{[4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl- But-2-ethyloxymethyl] -phenoxy-phosphinoyloxy} -propionic acid ethyl ester

[4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but- in pyridine (0.5 mL) PyBOP (32 mg, 0.060 mmol) was added to a solution of 2-ethyloxymethyl] -phosphonic acid monophenylester (18.5 mg, 0.040 mmol) and ethyl (S)-(-)-lactate (47 μl, 0.400 mmol). Added. The solution was stirred at rt for 1 h and further PyBOP (21 mg, 0.040 mmol) was added. The solution was stirred for another 1 hour and concentrated. The residue was purified by HPLC to give 7.5 mg of the desired product as a clear oil. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.22 and 1.25 (t, 3H, J = 7 Hz), 1.42 and 1.50 (d, 3H, J = 7 Hz ), 1.82 and 1.83 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J = 7 Hz), 3.78 (s, 3H), 3.89 (d, 1H, J = 8 Hz), 3.93- 4.02 (m, 3H), 4.10-4.22 ( m, 2H), 4.94-5.08 (m, 1H), 5.25 (s, 2H), 5.50-5.60 (m, 1H), 7.15- 7.27 (m, 3H), 7.33-7.41 (m, 2H); ³¹ P (121.4 MHz, CD ₃ OD) δ 18.9, 20.3; MS ( m / z ) 549.2 [M + H] ⁺ , 571.3 [M + Na] ⁺ .

B. Scheme III

Example 92-O [5- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -3-methyl-pent-3 -Enyl] -phosphonic acid diethyl ester

Butyl lithium (1.6 M in hexane, 1 mL) was added to the same volume of THF at -20 ° C. Then a solution of diethylmethylphosphonate (220 mg, 1.45 mmol) in THF (1 mL) was added dropwise and the mixture was stirred for 30 minutes. After cooling to −60 ° C., the solution was transferred via cannula to a vial containing copper (I) iodide (276 mg, 1.45 mmol) and the resulting mixture was stirred at −30 ° C. for 1 hour. 6- (4-Bromo-3-methyl-but-2-ethyl) -7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one (50 mL) in THF (1 mL) mg, 0.15 mmol) solution was added and the mixture was warmed to 0 ° C. for 2 h and then saturated aqueous ammonium chloride was added. The reaction mixture was acidified with 2N HCl and extracted with ethyl acetate. The ethyl acetate extract was concentrated and the residue was chromatographed with silica gel (40% to 100% ethyl acetate / hexane) to give [5- (4-hydroxy-6-methoxy-7-methyl-3-oxo- 1,3-dihydro-isobenzofuran-5-yl) -3-methyl-pent-3-enyl] -phosphonic acid diethylester oil (27 mg, contaminated with starting diethylmethylphosphonate) Got as. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.32 (m, 6H), 1.8-1.9 (m, 5H), 2.18 (s, 3H), 2.25 (m, 2H), 3.42 (d, J = 7.2, 2H ), 3.78 (s, 3H), 4.15 (m, 4H), 5.21 (s, 2H), 5.24 (t, J = 7.2 Hz, 1H), 7.65 (s, 1H).

Example 92-P [5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -3-methyl-pent-3 -Enyl] -phosphonic acid monoethyl ester

[5- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -3-methyl-pent-3-enyl] -force A mixture of phonic acid diethylester (27 mg, 0.066 mmol), LiOH (200 mg), MeOH (3 mL) and water (1 mL) was stirred at 70 ° C. for 4 hours. After cooling, the reaction solution was acidified with 2N HCl, mixed with brine and extracted with ethyl acetate / acetonitrile. The organic extract was concentrated and the residue was purified by preparative reverse phase HPLC (acetonitrile and 0.1% aqueous CF ₃ COOH) to [5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1 , 3-dihydro-isobenzofuran-5-yl) -3-methyl-pent-3-enyl] -phosphonic acid monoethyl ester (7 mg, 28%) was obtained. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.28 (t, J = 6.9, 3H), 1.7-1.9 (m, 5H), 2.20 (s, 3H), 2.2-2.3 (m, 2H), 3.41 ( d, J = 6.6 Hz, 2H), 3.80 (s, 3H), 4.02 (m, 2H), 5.2-5.3 (m, 3H).

4. Scheme IV

Example 92-Q [5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -3-methyl-penta-1 , 3-dienyl] -phosphonic acid dimethyl ester

To a solution of tetramethylene methylene diphosphonate (102 mg, 0.44 mmol) in THF (2.5 mL) was added a solution of sodium bis (trimethylsilyl) amide in THF (1.0 M, 0.44 mL). After stirring for 30 minutes, 4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2 in THF (2.5 mL) -2 -Methyl-but-2-enal (30 mg, 0.11 mmol, Pankiewicz, et al., J. Med . Chem . 45, 703) was added and stirring was continued for 15 minutes. The reaction was stopped with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. After evaporation of the solvent, the residue was purified by silica gel chromatography eluting with ethyl acetate (50% to 100%) / hexanes to give [5- (4-hydroxy-6-methoxy-7-methyl-3- Oxo-1,3-dihydro-isobenzofuran-5-yl) -3-methyl-penta-1,3-dienyl] -phosphonic acid dimethyl ester (30 mg, 71%) was obtained as an oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.80 (s, 3H), 2.04 (s, 3H), 3.45 (d, J = 6.6 Hz, 2H), 3.76 (s, 3H), 3.88 (d, 6H) , 5.20 (s, 3H), 5.55 (m, 1H), 5.95 (m, 1H), 7.05 (m, 1H), 7.65 (s, 1H).

Example 92-R [5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -3-methyl-penta-1 , 3-dienyl] -phosphonic acid

[5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -3-methyl-penta- in acetonitrile at 0 ° C. Trimethylsilyl bromide (0.183 mL, 1.71 mmol) was added to a solution of 1,3-dienyl] -phosphonic acid dimethyl ester (22 mg, 0.057 mmol) and 2,6-lutidine (0.22 mL, 1.71 mmol). The mixture was warmed to rt and stirred for 1 h. The reaction was stopped at 0 ° C. with methanol and the resulting mixture was concentrated. The residue was purified by preparative reverse phase HPLC to remove the solvent, then [5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5- Il) -3-methyl-penta-1,3-dienyl] -phosphonic acid was obtained as a solid (13 mg, 65%). ¹ H NMR (300 MHz, CD ₃ OD) δ 1.91 (s, 3H), 2.10 (s, 3H), 3.55 (d, J = 6.6 Hz, 2H), 3.75 (s, 3H), 5.2 (s, 2H ), 5.6-5.8 (m, 2H), 6.9 (m, 1H).

III

Scheme I

Example 92-S 2- (4-Bromo-but-2-ethyl) -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzo Furan-5-yl) -4-methyl-hex-4-enoic acid methyl ester

To a cooled (-78 ° C) solution of mycophenolic acid methyl ester (138 mg, 0.41 mmol) in THF (2.5 mL) was added a THF solution (1.0 M, 0.98 mL) of sodium bis (trimethylsilyl) amide. After stirring for 30 minutes, a solution of 1,4-dibromo-2-butene (950 mg, 4.1 mmol) in THF (2.5 mL) was added and stirring continued for 10 minutes. The resulting mixture was warmed to -30 ° C and stored at this temperature for 16 hours. The reaction was stopped with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate to evaporate the solvent, and then the residue was purified by chromatography on silica gel eluting with ethyl acetate (0% to 40%) / hexanes to give 2- (4-bromo-but-2- Ethyl) -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic Acid methyl ester (150 mg, 78%) was obtained as oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.75 (s, 3H), 2.0-2.4 (m, 8H), 2.62 (m, 1H), 3.37 (d, J = 6.6 Hz, 2H), 3.58 (s, 3H), 3.76 (s, 3H), 3.88 (d, J = 4.8 Hz, 2H), 5.1-5.3 (m, 3H), 5.67 (brs, 2H), 7.67 (s, 1H).

Example 92-T 2- [4- (Dimethoxy-phosphoryl) -but-2-ethyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3 -Dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl ester

Under N ₂ atmosphere, 2- (4-bromo-but-2-ethyl) -6- (4-hydroxy-6-methoxy-7-methyl-3- in trimethyl phosphite (2.5 mL, 21.1 mmol) A solution of oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl ester (490 mg, 1.05 mmol) was heated at 120 ° C. for 1 hour. The reaction was cooled to room temperature. After removal of the solvent in vacuo, the reaction mixture was finished by chromatography with EtOAc-hexanes to give 460 mg (88%) of the product as an oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.77 (s, 3H), 2.081-2.31 (m, 4H), 2.15 (s, 3H), 2.52 (d, 1H, J = 22 Hz), 2.54 (d, 1H, J = 22 Hz), 2.55- 2.63 (m, 1H), 3.36 (d, 2H, J = 7 Hz), 3.57 (s, 3H), 3.72 (d, 6H, J = 11 Hz), 3.76 ( s, 3H), 5.20 (s, 2H), 5.20- 5.26 (m, 1H), 5.36- 5.56 (m, 2H), 7.69 (s, 1H); ³¹ P (121.4 MHz, CDCl ₃ ) δ 30.1; MS ( m / z ) 497.2 [M + H] ⁺ , 519.2 [M + Na] ⁺ .

Example 92-U 2- [4- (dimethoxy-phosphoryl) -but-2-ethyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3- Dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid

1: 2- [4- (dimethoxy-phosphoryl) -but-2-ethyl] -6- (4-hydroxy-6-meth in a solution of H ₂ O / MeOH / THF (8 mL) at 2: Toxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl ester (460 mg, 0.927 mmol) was added at ambient temperature. Stir with LiOH.H ₂ O (78 mg, 1.86 mmol) for 12 h. A second batch of LiOH.H ₂ O (40 mg, 0.952 mmol) was added. The reaction mixture was further stirred at room temperature for 16 hours, after which time the reaction was observed to proceed no further. The reaction was stopped by addition of a saturated aqueous solution of NH ₄ Cl. The organic layer was removed in vacuo and the product was extracted with EtOAc from the aqueous layer acidified by addition of 5 drops of 2N HCl. The product was further purified by chromatography to give the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.79 (s, 3H), 2.08-2.38 (m, 4H), 2.15 (s, 3H), 2.53 (d, 1H, J = 22 Hz), 2.60 (d, 1H, J = 22 Hz), 2.57-2.64 (m, 1H), 3.38 (d, 2H, J = 7 Hz), 3.72 (d, 6H, J = 11 Hz) 3.76 (s, 3H), 5.20 (s , 2H), 5.27 (t, 1H, J = 6 Hz), 5.36- 5.63 (m, 2H); ³¹ P (121.4 MHz, CDCl ₃ ) δ 30.5; MS ( m / z ) 481.2 [M ⁻ H] ⁻ .

Example 92-V 2- [4- (2- [4- (dimethoxy-phosphoryl) -but-2-ethyl] -6- (4-hydroxy-6-methoxy-7-methyl-3- Oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid

2- [4- (dimethoxy-phosphoryl) -but-2-ethyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1, in acetonitrile (2 mL), In a solution of 3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid (25 mg, 0.052 mmol) 2,6-lutidine (60 μl, 0.52 mmol) and TMSBr ( 67 μl, 0.52 mmol) was added. The reaction was allowed to proceed for 45 minutes and confirmed by LCMS. The reaction mixture was concentrated under reduced pressure and stopped with aqueous NaOH solution (1 mL). The product was purified by reverse phase HPLC on a C18 column to give 14.2 mg (60%) of the product as a solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.81 (s, 3H), 2.081-2.31 (m, 4H), 2.16 (s, 3H), 2.45 (d, 1H, J = 22 Hz), 2.47 (d , 1H, J = 22 Hz), 2.55- 2.63 (m, 1H), 3.38 (d, 2H, J = 7 Hz), 3.77 (s, 3H), 5.25 (s, 2H), 5.20- 5.36 (m, 1H), 5.36- 5.56 (m, 2H); ³¹ P (121.4 MHz, CD ₃ OD) δ 25.4; MS ( m / z ) 453 [M ⁻ H] ⁻ .

Example 92-W 2- [4- (Dimethoxy-phosphoryl) -but-2-ethyl] -6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl- Ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester

2- [4- (dimethoxy-phosphoryl) -but-2-ethyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3 in THF (8.00 mL) A solution of -dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid (160 mg, 0.332 mmol) and trimethylsilylethanol (160 mg, 1.36 mmol) was added to triphenylphosphine ( 345 mg, 1.33 mmol). Diethylazodicarboxylate (230 μl, 1.33 mmol) was added to this solution at 0 ° C. The mixture was warmed to rt and stirred for 16 h. Further triphenylphosphine (180 mg, 0.692 mmol), trimethylsilylethanol (160 mg, 1.36 mmol) and diethylazodicarboxylate (115 μl, 0.665 mmol) were added and the reaction mixture was added for 1 more day at room temperature. Stirred. The reaction was finished by removing the solvent in vacuo and purified by silica gel chromatography to give 192 mg (85%) of the product as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.03 (s, 9H), 0.05 (s, 9H), 0.93- 0.96 (m, 2H), 1.20- 1.29 (m, 2H), 1.78 (s, 3H), 2.01- 2.32 (m, 4H), 2.17 (s, 3H), 2.51 (d, 1H, J = 22 Hz), 2.58 (d, 1H, J = 22 Hz), 2.50- 2.60 (m, 1H), 3.37 (d, 2H, J = 7 Hz), 3.72 (d, 6H, J = 11 Hz), 3.76 (s, 3H), 4.08 (appt t, 2H, J = 8 Hz), 4.30 (appt t, 2H, J = 8 Hz), 5.12 (s, 2H), 5.15- 5.25 (m, 1H), 5.36- 5.63 (m, 2H); ³¹ P (121.4 MHz, CDCl ₃ ) δ 29.3; MS ( m / z ) 705.3 [M + Na] ⁺ .

Example 92-X 2- [4- (hydroxy-methoxy-phosphoryl) -but-2-ethyl] -6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethyl Silanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester

2- [4- (dimethoxy-phosphoryl) -but-2-ethyl] -6- [6-methoxy-7-methyl-3-oxo-4- in tert -butylamine (2.8 mL, 27 mmol) (2-Trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester (184 mg, 0.270 mmol) was heated at 60 ° C. for 24 h. The solution was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography using MeOH / CH ₂ Cl ₂ (0-30%) to afford 75 mg of product as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.01 (s, 9H), 0.04 (s, 9H), 0.89 (appt t, 2H, J = 9 Hz), 1.23 (appt t, 2H, J = 9 Hz) , 1.77 (s, 3H), 2.01- 2.31 (m, 4H), 2.17 (s, 3H), 2.36 (d, 1H, J = 22 Hz), 2.38 (d, 1H, J = 22 Hz), 2.52 ( septet, 1H, J = 9 Hz), 3.39 (d, 2H, J = 7 Hz), 3.51 (d, 3H, J = 11 Hz), 4.01- 4.08 (m, 2H), 4.30 (dd, 2H, J = 8, 9 Hz), 5.11 (s, 2H), 5.19 (br t, 1H, J = 6 Hz), 5.33- 5.56 (m, 2H), 8.49 (br s, 1H); ³¹ P (121.4 MHz, CDCl ₃ ) δ 22.1; MS ( m / z ) 667.4 [M + Na] ⁺ .

Example 92-Y 2- {4-[(1-Ethoxycarbonyl-ethoxy) -methoxy-phosphoryl] -but-2-ethyl} -6- [6-methoxy-7-methyl-3 -Oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester

2- [4- (hydroxy-methoxy-phosphoryl) -but-2-ethyl] -6- [6-methoxy-7-methyl-3-oxo-4- (2- in DMF (1.5 mL) Trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester (67 mg, 0.10 mmol) , PyBOP (234 mg, 0.450 mmol) solution was stirred with ethyl (S)-(-)-lactate (53 mg, 0.45 mmol) and DIEA (174 μl, 1.00 mmol) at ambient temperature for 1 hour and starting material It was observed that this was consumed completely. Saturated aqueous sodium chloride and ethyl acetate were added to finish the reaction. The organic layer was separated and washed with 5% aqueous lithium chloride solution. The organic layer was dried in vacuo and the residue was purified by silica gel chromatography using MeOH-CH ₂ Cl ₂ (0- 20%) to give 57 mg (74%) of the desired product as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.02 (s, 9H), 0.05 (s, 9H), 0.88- 0.94 (m, 2H), 1.20- 1.30 (m, 2H), 1.29 (t, 3H, J = 7 Hz), 1.45 (d, 3H, J = 7 Hz), 1.78 (s, 3H), 2.01- 2.31 (m, 4H), 2.17 (s, 3H), 2.50- 2.58 (m, 1H), 2.65 (d, 1H, J = 22 Hz), 2.67 (d, 1H, J = 22 Hz), 3.39 (d, 2H, J = 7 Hz), 3.69 and 3.77 (d, 3H, J = 11 Hz), 3.76 (s, 3H), 4.07 (appt t, 2H, J = 7 Hz), 4.20 (dq, 2H, J = 3, 7 Hz), 4.29 (appt t, 2H, J = 9 Hz), 4.85-4.99 ( m, 1H), 5.12 (s, 2H), 5.19 (brt, 1H, J = 6 Hz), 5.33- 5.61 (m, 2H); ³¹ P (121.4 MHz, CDCl ₃ ) δ 28.9, 29.9; MS ( m / z ) 791.4 [M + Na] ⁺ .

Example 92-Z 2- {4-[(1-Ethoxycarbonyl-ethoxy) -methoxy-phosphoryl] -but-2-ethyl} -6- (4-hydroxy-6-methoxy- 7-Methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid

2- {4-[(1-ethoxycarbonyl-ethoxy) -methoxy-phosphoryl] -but-2-ethyl} -6- [6-methoxy-7-methyl- in THF (1 mL) 3-Oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanyl- Ethyl ester (14 mg, 0.018 mmol) solution was stirred with 1M TBAF solution in THF (55 μl, 0.055 mmol) for 1 hour. The reaction mixture was concentrated in vacuo and the reaction was completed by extracting the product from aqueous 1N HCl solution with EtOAc. The organic layer was washed with brine and dried. The product was purified by silica gel column chromatography EtOH-EtOAc (0-10%). The product was dissolved in CH ₂ Cl ₂ and the compound was further purified through a 13 mm Acrodisc syringe filter with 0.45 mm nylon membrane to give 8 mg (77%) of product. ¹ H NMR (300 MHz, CDCl ₃ ) 0.92 (t, 3H, J = 7 Hz), 1.30 (d, 3H, J = 8 Hz), 1.79 (s, 3H), 2.10-2.39 (m, 4H), 2.15 (s, 3H), 2.53 (d, 1H, J = 8 Hz), 2.65 (d, 1H, J = 22 Hz), 2.68 (d, 1H, J = 22 Hz), 3.38 (d, 2H, J = 7 Hz), 3.70 and 3.74 (d, 3H, J = 11 Hz), 3.76 (s, 3H), 4.07 (m, 2H), 4.96 (dq, 1H, J = 7 Hz), 5.20 (s, 2H ), 5.27 (br t, 1H, J = 7 Hz), 5.33- 5.55 (m, 2H), 7.51- 7.56 (m, 1H), 7.68-7.74 (m, 1H); ³¹ P (121.4 MHz, CDCl ₃ ) δ 29.0, 30.1; MS ( m / z ) 569.2 [M + H] ⁺ , 591.3 [M + Na] ⁺ .

Example 92-AA 2- {4-[(1-carboxy-ethoxy) -hydroxy-phosphoryl] -but-2-ethyl} -6- [6-methoxy-7-methyl-3-oxo- 4- (2-Trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester

2- {4-[(1-ethoxycarbonyl-ethoxy) -methoxy-phosphoryl] -but-2-ethyl} -6- [6-meth in tert -butylamine (1 mL, 9.6 mmol) Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid The 2-trimethylsilanylethyl ester (12 mg, 0.016 mmol) solution was heated at 65 ° C. for 16 h. The solution was cooled to room temperature and concentrated to afford crude product as an oil. ¹ H NMR (300 MHz, CDCl ₃ ) 0.03 (s, 9H), 0.04 (s, 9H), 0.86- 0.98 (m, 2H), 1.22- 1.33 (m, 2H), 1.50 (d, 3H, J = 7 Hz), 1.78 (s, 3H), 2.05- 2.30 (m, 4H), 2.10 (s, 3H), 2.48-2.63 (m, 3H), 3.40 (d, 2H, J = 7 Hz), 3.76 ( s, 3H), 4.08 (appt t, 2H, J = 9 Hz), 4.25- 4.33 (m, 2H), 4.75- 4.84 (m, 1H), 5.13 (s, 2H), 5.15- 5.23 (m, 1H ), 5.33- 5.55 (m, 2H); ³¹ P (121.4 MHz, CDCl ₃ ) δ 28.9; MS ( m / z ) 725.3 [M ⁻ H] ⁻ .

Example 92-AB 2- {4-[(1-carboxy-ethoxy) -hydroxy-phosphoryl] -but-2-ethyl} -6- (4-hydroxy-6-methoxy-7-methyl -3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid

Crude 2- {4-[(1-carboxy-ethoxy) -hydroxy-phosphoryl] -but-2-ethyl} -6- [6-methoxy- in THF (1M, 54 μl, 0.054 mmol) 7-Methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2- A solution of trimethylsilanyl-ethyl ester (AC-2101-59) and tetrabutylammonium fluoride was stirred with THF (1 mL) at ambient temperature for 2 hours and tetrabutylammonium fluoride in THF (54 μL, 0.054 mmol) Extra amount was added. Stirring the reaction further for 16 hours to complete the reaction. The reaction mixture was concentrated in vacuo and the product was purified by reverse phase HPLC using Phenomenex Synergi 5 m Hydro RP 80A column (50 × 21.2 mm) with H ₂ O, 0.1% TFA-CH ₃ CN, 0.1% TFA. Purification gave the product (8.0 mg) as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) 1.51 (d, 3H, J = 7 Hz), 1.79 (s, 3H), 2.05- 2.40 (m, 4H), 2.11 (s, 3H), 2.49-2.71 (m , 3H), 3.38 (d, 2H, J = 6 Hz), 3.76 (s, 3H), 4.85 (br s, 1H), 5.20 (s, 2H), 5.21- 5.30 (m, 1H), 5.33- 5.63 (m, 2H); ³¹ P (121.4 MHz, CDCl ₃ ) δ 27.7; MS ( m / z ) 525.2 [M ⁻ H] ⁻ .

Scheme II

Example 92-AC 2- {4-[(1-ethoxycarbonyl-ethylamine) -methoxy-phosphoryl] -but-2-ethyl} -6- [6-methoxy-7-methyl-3 -Oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl Ester

2- [4- (hydroxy-methoxy-phosphoryl) -but-2-ethyl] -6- [6-methoxy-7-methyl-3-oxo-4- (2- in DMF (1.0 mL) Trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester (20 mg, 0.030 mmol) , A solution of PyBOP (62.4 mg, 0.120 mmol) with L-alanine ethyl ester hydrogen chloride (18 mg, 0.12 mmol) and DIEA (26 μl, 0.15 mmol) for 1 hour at ambient temperature and the starting material was consumed completely Observed. The reaction was finished by adding water until the reaction solution became cloudy. A minimum amount of DMF was added until the reaction became clear again. The reaction mixture was filtered through Acrodisc (13 mm syringe filter with 0.45 mm nylon membrane) and purified by reverse phase HPLC using a Phenomenex Synergi 5 m Hydro RP 80A column (50 × 21.2 mm) eluting with water and acetonitrile. The portions containing the product were collected together and dried in vacuo to remove acetonitrile. The aqueous layer was saturated with sodium chloride and extracted with EtOAc and acetonitrile to give 7.2 mg of product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.03 (s, 9H), 0.05 (s, 9H), 0.923 (appt t, 2H, J = 8 Hz), 1.18-1.31 (m, 5H), 1.41 (t , 3H, J = 7 Hz), 1.78 (s, 3H), 2.03- 2.36 (m, 4H), 2.18 (s, 3H), 2.43- 2.63 (m, 3H), 3.10-3.30 (m, 1H), 3.40 (d, 2H, J = 7 Hz), 3.62 and 3.65 (d, 3H, J = 11 Hz), 3.76 (s, 3H), 4.03-4.12 (m, 2H), 4.20 (dq, 2H, J = 2, 7 Hz), 4.29 (appt t, 2H, J = 8 Hz), 5.12 (s, 2H), 5.18-5.28 (m, 1H), 5.33- 5.67 (m, 2H); ³¹ P (121.4 MHz, CDCl ₃ ) δ 30.4, 31.2; MS ( m / z ) 790.4 [M + Na] ⁺ .

Example 92-AD 2- {4-[(1-Ethoxycarbonyl-ethylamine) -methoxy-phosphoryl] -but-2-ethyl} -6- (4-hydroxy-6-methoxy- 7-Methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid

2- {4-[(1-ethoxycarbonyl-ethylamine) -methoxy-phosphoryl] -but-2-ethyl} -6- [6-methoxy-7- in THF (1 mL) at room temperature Methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsila TBAF (40 μl, 1M solution in THF) was added to a solution of neyl-ethyl ester (7.2 mg, 9.38 mmol). The reaction mixture was stirred for 20 minutes and LCMS confirmed that the starting material was completely converted to the desired product. The reaction mixture was dried in vacuo and dissolved again in DMF. The product was purified by RP HPLC using H ₂ O-CH ₃ CN as eluent and using a Phenomenex Synergi 5 m Hydro RP 80A column (50 × 21.2 mm). The portion containing the desired product was collected and further purified with Dowex 50WX8-400 packed on a 4.5 cm × 2 cm column eluting the sodium salt in H ₂ O-MeOH (1: 1) to give 3.2 mg of the desired product. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.26 (dd, 3H, J = 4, 7 Hz), 1.37 (t, 3H, J = 8 Hz), 1.80 (s, 3H), 2.00- 2.22 (m , 4H), 2.10 (s, 3H), 2.25- 2.60 (m, 3H), 3.37 (d, 2H, J = 7 Hz), 3.60 and 3.65 (d, 3H, J = 11 Hz), 3.74 (s, 3H), 3.83-3.96 (m, 1H), 4.18 (q, 2H, J = 8 Hz), 5.15 (s, 2H), 5.25- 5.42 (m, 2H), 5.55- 5.69 (m, 1H); ³¹ P (121.4 MHz, CD ₃ OD) δ 33.8, 34.2; MS ( m / z ) 568.2 [M + H] ⁺ , 590.3 [M + Na] ⁺ .

Example 92- AE 6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2- [4- (hydroxy -Methoxy-phosphoryl) -but-2-ethyl] -4-methyl-hex-4-enoic acid

2- [4- (hydroxy-methoxy-phosphoryl) -but-2-ethyl] -6- [6-methoxy-7-methyl-3-oxo-4- (2- in THF (1 mL) In trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanylethyl ester (11 mg, 0.016 mmol) TBAF (50 μl, 1M solution in THF) was added at room temperature. The solution was stirred for 16 h and concentrated. The solution was dried under reduced pressure and resuspended in DMF (0.8 mL) and water (0.25 mL). The solution was filtered through Acrodisc (13 mm syringe filter with 0.45 mm nylon membrane) and eluted with H ₂ O, 0.1% TFA-CH ₃ CN, 0.1% TFA, and a Phenomenex Synergi 5 m Hydro RP 80A column (50 x 21.2 mm). Purified by RP HPLC using The product from the column is ion exchange chromatographed (in the sodium salt form of Dowex 50WX8-400) using a 2 x 4.5 cm column, eluting with H ₂ O-MeOH (1: 1) to give 7.5 mg of the desired product as an oil. . ¹ H NMR (300 MHz, CDCl ₃ ) 1.80 (s, 3H), 2.01- 2.29 (m, 5H), 2.11 (s, 3H), 2.35 (d, 2H, J = 22 Hz), 3.38 (d, 2H , J = 7 Hz), 3.53 (d, 3H, J = 11 Hz), 3.75 (s, 3H), 5.19 (s, 2H), 5.26 (t, 1H, J = 6 Hz), 5.43- 5.54 (m , 2H); ³¹ P (121.4 MHz, CDCl ₃ ) δ 23.5; MS ( m / z ) 469.2 [M + H] ⁺ , 491.3 [M + Na] ⁺ .

Scheme III

Example 92- AF 2- [4- (diethoxy-phosphoryl) -but-2-ethyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3- Dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl ester:

2- (4-Bromo-but-2-ethyl) -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-iso in toluene (30 mL) A solution of benzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl ester (140 mg, 0.30 mmol) and triethylphosphite (600 mg, 3.6 mmol) was refluxed for 20 hours. The mixture was concentrated and chromatographed with silica gel eluting with ethyl acetate (60% to 100%) / hexanes to give 2- [4- (diethoxy-phosphoryl) -but-2-ethyl] -6- ( 4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl ester (oil 70 mg, 43%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.27 (m, 6H), 1.79 (s, 3H), 2.0-2.7 (m, 8H), 3.37 (d, J = 6.6 Hz), 3.52 (s, 3H) , 3.75 (s, 3H), 4.08 (m, 4H), 5.20 m, 3H), 5.45 (m, 2H).

Example 92-AG 2- [4- (diethoxy-phosphoryl) -but-2-ethyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3- Dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid

2- [4- (diethoxy-phosphoryl) -but-2-ethyl] -6- (4-hydroxy-6-methoxy-7- in a mixed solvent of THF (6 mL) and water (1 mL) Of methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl ester (33 mg, 0.063 mmol) and lithium hydroxide (44 mg) The mixture was stirred at rt for 6 h. The organic solvent was removed and the residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate. The ethyl acetate extract was concentrated to 2- [4- (diethoxy-phosphoryl) -but-2-ethyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1 , 3-Dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid was obtained as an oil (30 mg, 100%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.27 (m, 6H), 1.79 (s, 3H), 2.0-2.7 (m, 8H), 3.37 (d, J = 6.6 Hz), 3.75 (s, 3H) , 4.08 (m, 4H), 5.19 (s, 2H), 5.25 (m, 1H), 5.44 (m, 1H), 5.55 (m, 1H), 5.45 (m, 2H).

Example 92-AH 2- [4- (ethoxy-hydroxy-phosphoryl) -but-2-ethyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1 , 3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid

2- [4- (diethoxy-phosphoryl) -but-2-ethyl] -6- (4-hydroxy-6-methoxy-7- in a mixed solvent of methanol (3 mL) and water (1 mL) Of methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl ester (25 mg, 0.048 mmol) and lithium hydroxide (200 mg) The mixture was stirred at 70 ° C. for 2 hours. The organic solvent was removed and then acidified with 2N HCl and extracted with ethyl acetate / acetonitrile. The organic extract was concentrated and the residue was purified by preparative reverse phase HPLC (acetonitrile and 0.1% aqueous CF ₃ COOH) to give 22- [4- (ethoxy-hydroxy-phosphoryl) -but-2-ethyl ] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid Was obtained as oil (15 mg, 89%). ¹ H NMR (300 MHz, CD ₃ OD) δ 1.25 (t, J = 6.9 Hz, 3H), 1.81 (s, 3H), 2.1-2.6 (m, 8H), 3.40 (d, J = 6.6 Hz, 2H ), 3.77 (s, 3H), 3.97 (m, 2H), 5.1-5.3 (m, 3H), 5.67 (brs, 2H).

Example 93 Preparation of Exemplary Compounds of the Invention

1

1, and like compounds may be prepared according to the general route shown in, reaction formula 1 in the examples shown in Scheme 2.

Scheme 1:

Scheme 2:

Boc-protected (1S) -1- (9-deazaguan-9-yl) -1,4-dideoxy-1,4-imino-D-ribitol, compound 1.1.1 is (1S)- 1- (9-deazaguan-9-yl) -1,4-dideoxy-1,4-imino-D-ribitol (WO 9,919,338, Evans, GB et al., Tetrahedron , 2000 , 56 , 3053 And Evans, GB et al., J. Med . Chem . 2003 , 46 , 3412) are prepared by stirring with Boc anhydride as described in Greene, T., Protective Groups in Organic Chemistry , Wiley-Interscience, 1999. . Compound 1.1.1 is then treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., 1986 , 27 , 1477) was added and the target phosphonate was deprotected using trifluoroacetic acid (TFA). Get 1

Compounds such as 2 and 3 can be prepared according to the general route shown in Scheme 3 , with examples shown in Scheme 4 .

Scheme 3:

Scheme 4:

Boc-protected (1S) -1- (9-deazaguan-9-yl) -1,4-dideoxy-1,4-imino-D-ribitol, compound 1.1 is (1S) -1- (9-deazaguan-9-yl) -1,4-dideoxy-1,4-imino-D-ribitol (WO 9,919,338, Evans, GB et al., Tetrahedron , 2000 , 56 , 3053 and GB et al., J. Med . Chem . 2003 , 46 , 3412) are prepared by stirring with Boc anhydride as described in Greene, T., Protective Groups in Organic Chemistry , Wiley-Interscience, 1999. Subsequently, deprotection of the primary alcohol using a TBS group was carried out using TBSCl and imidazole in a solvent such as CH ₂ Cl ₂ as described in Greene, T., Protective Groups in Organic Chemistry , Wiley-Interscience, 1999 Compound 1.1 is obtained. Compound 1.1 is then treated with a base such as sodium hydride in a solvent such as tetrahydrofuran or dimethylformamide. At the end of bubbling, diethylphosphonomethyltriplate (prepared according to Tetrahedron Lett ., 1986 , 27 , 1477) was added and the target phosphonate was deprotected using trifluoroacetic acid (TFA). Diesters 2 and 3 are obtained. Compounds 2 and 3 may also be prepared by more than 2 'OH-protected analog of the complex 1.1, when alkylated to then use a diethyl phosphono methyl triflate to obtain Compound (2) exclusively. Compound 3 can also be prepared by binding another protecting group at the 3'OH position, then deprotecting the 2'OH, alkylating with diethylphosphonomethyltriplate at the 2 'center and then deprotecting entirely.

Example 94 Preparation of Exemplary Compounds of the Invention

Mo molecule:

General goal structure:

Synthetic schemes for specific targets I are shown below.

Scheme 1

Recommended solution for O-alkylation: Mix phenol and Cs ₂ CO ₃ (ca. 1: 1.2) in DMF and stir at 0 ° C. for 30 minutes. Triflate (1.2 eq.) Is added. The reaction will complete in 1 hour.

Experiments on trifluoromethanesulfonyloxymethylphosphonate will be provided separately.

Additional Compounds: The next target II will be prepared after the initial biological assessment of target I.

Scheme 2

References for campotesin-7-aldehydes: Chem . Pharm . Bull. 1991 , 39 , 2574.

References to the reaction of Wittig Ilide with Campotesin aldehyde: J. Med . Chem . 2000 , 43 , 3963.

Example 95 Preparation of Exemplary Compounds of the Invention

Mo molecule:

General goal structure:

The synthetic schemes for the particular target I are shown below.

Scheme 1

Reference for reductive amination of anthracyclines: J. Med . Chem . 1998 , 41 , 965.

Experiments will be provided on aldehyde intermediates from allyl phosphonates.

Additional Compounds: The next two goals II and III will be prepared after the initial biological assessment of goal 1.

Reference for N-acylation of anthracyclines: J. Med . Chem . 1980 , 23 , 1166

Example 96 Preparation of Exemplary Compounds of the Invention

Mo molecule:

Target Class:

Synthetic schemes for specific targets I and II are shown below.

Scheme 1

References on the synthesis of target I: Org. Pro. Res. Dev. A web publication will be provided.

Additional Compounds: The following goals III and IV will be prepared after the initial biological evaluation of goals I and II.

Scheme 2

Scheme 3

Mycophenolate

Representative compounds of the present invention having the following formulas can be prepared as described in Examples 201-204 .

For example, three regions of mycophenolate mofetil can be utilized for the binding of phosphonate prodrugs as evidenced by compounds D , E and G shown above. The carboxylic acid can also be replaced with phosphonic acid as in compound F.

Example  201 Preparation of Representative Compounds of Formula 204

Representative compounds of the invention can be prepared as illustrated above. The morpholino ethyl moiety can be used as a prodrug functional group to enhance bioavailability and can be replaced with a phosphonate prodrug as indicated above. Mycophenolic acids are described, for example, in Sigma Chemical Company, St. It can be purchased from Louis, Mo. The addition of a phosphonate group containing alcohol after activation of carboxylic acid 201.1 in the presence of free phenol forms the desired product 201.3 (US 4,786,637). Certain compounds of the present invention can be prepared as follows.

Mycophenolic acid 201.1 is dissolved in dichloromethane. After adding thionyl chloride, a catalytic amount of DMF is added. The reaction mixture is stirred at room temperature for 3 hours and then the volatile components are removed in vacuo. The phosphonate-alcohol is dissolved in dichloromethane and cooled to about 4 ° C. in an ice bath. Dissolving mycophenolic acid chloride 201.2 sex in dichloromethane and is added to the cooled solution. After stirring at about 4 ° C. for 90 minutes, the reaction mixture is washed with water and then with aqueous sodium bicarbonate. The organic solution is dried and evaporated to afford phosphonate 201.3 .

Example  202 Preparation of Representative Compounds of Formula 207

Representative compounds of the invention can be prepared as illustrated above. The C-4 phenol position provides reactive means for further analogs as exemplified above. As in compound 202.2 , if the carboxylic acid of 202.1 is protected by morpholino ethyl, the phenol can be alkylated under basic conditions. Bases such as pyridine, potassium carbonate or triethylamine are used. Leaving groups such as trifluoromethylsulfonate, mesylate, bromide or iodine are bound to the phosphonate prodrug subunit and reacted with compound 202.2 in the presence of a base. Compound 202.3 can be used directly or in the form of a salt, compound 202.4 . Of the many salts that can be prepared, the chloride and bisulfate salts are one particular embodiment of the present invention. Certain compounds of the present invention can be prepared as follows.

Compound 202.5 is prepared similar to compound 201.2 (as described in Example 201). The solution of morpholino ethanol in dichloromethane is cooled to about 4 ° C. Dissolving mycophenolic acid chloride 202.5 sex in dichloromethane and is added to the cooled solution. This solution is stirred for about 90 minutes to give compound 202.2 . The reaction mixture is washed with water and dried over sodium sulfate. Removal of solvent gives compound 202.2 , isolated. Of 202.2 Alkylation at the phenolic position is accomplished by suspending the compound in pyridine. Triflate 202.6 is added to the solution and the mixture is stirred at room temperature for about 90 minutes. The reaction mixture is poured into water and the product is extracted with ethyl acetate. The organic layer is removed to give compound 202.7 . If desired, a hydrogen chloride salt of 202.7 may be prepared. Compound 202.7 is dissolved in isopropanol and the solution is added to a mixture of hydrogen chloride in isopropanone. The hydrogen chloride salt 202.8 is filtered and dried in vacuo.

Example  203 Preparation of Representative Compounds of Formula 205

Representative compounds of the invention can be prepared as illustrated above. The carboxylic acid of the mycophenolic acid can be replaced with phosphonic acid which can also serve as prodrug means. To remove the carboxylic acid containing side chain, acid chloride 202.5 (prepared in Example 202) is converted to ester 203.1 . After protecting the phenol with a silyl group, it is dehydroxylated and its diol is decomposed to produce aldehyde 203.3 (Pankiewicz, et al., J. Med . Chem ., 2002, 45 , 703), (Patterson et al. US 5,444,072) (Example 20). By a reaction with Wittig 203.4 lead containing a suitably protected phosphonate to obtain the desired compound 203.5. Final deprotection affords compound 203.6 . Certain compounds of the present invention can be prepared as follows.

Mycophenolate ester 203.8 can be prepared simply by stirring the acid chloride 203.7 with MeOH. The phenol position of the mycophenolate ester is then protected with a silyl group such as TBS to give compound 203.9 . If the phenol position is protected, aldehyde 203.10 is obtained by diiodylation with osmium tetraoxide followed by periodinate decomposition. Aldehyde 203.10 and Excess lide 203.11 is heated to reflux in benzene for about 24 hours. The reaction mixture is concentrated and the residue is purified by column chromatography to give olefin 203.12 (Pankiewics et al., J. Med . Chem ., 2002, 45 , 703). Final deprotection with HF-pyridine affords the final product 203.13 .

Example  204 Preparation of Representative Compounds of Formula 208

Representative compounds of the invention can be prepared as illustrated above. Another point of attachment of the compound may be deprotected after demethylation of mycophenolate ester 204.2 as illustrated above. To this end, 4-OH needs to be masked with a protecting group (P) such as a silyl group. By demethylating and alkylating 6-MeO, the protecting group at position 4 is removed to give the final product 204.4 . The morphonyl ethanol group is initially attached to maintain its bond during the alkylation step. Other protecting groups can be initially combined and later removed. In the latter kind of synthesis, the final step is the formation of morpholinoethyl ester prodrugs. Certain compounds of the present invention can be prepared as follows.

Phenol 204.5 is protected with TBS groups using imidazole as the base in CH ₂ Cl ₂ to give 204.6 . Demethylation with thiolate nucleophile yields compound 204.7 . As described in Protective Groups in Organic Chemistry by Greene and Wuts, various other methods described in the literature can also be used. Alkylation of 6-OH with triflate of phosphonate proceeds well using K ₂ CO ₃ or TEA, whereby 204.8 is obtained. Deprotection of the TBS group yields the product 204.9 .

Example  251: Preparation of Representative Compounds of the Invention.

Representative compounds of the invention can be prepared as illustrated above.

[4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-yl) -2-methyl-but-2-ethyloxymethyl] -phosphonic acid Diisopropyl  ester

7-hydroxy-6- (4-hydroxy-3-methyl-but-2-ethyl) -5-methoxy-4-methyl-3H-isobenzofuran-1-one 1A in DMF (3 mL) 50 mg, 0.18 mmol, Pankiewicz et al ., J. Med . Chem ., 45 , 703), diisopropyl bromomethylphosphonate (93 mg, 0.36 mmol) and lithium t -butoxide (1M in THF, 0.54 mL) was heated at 70 ° C. for 5 hours. The reaction was stopped with 1N HC. The mixture was poured into 5% aqueous lithium chloride, extracted with ethyl acetate and concentrated. The residue was purified by chromatography on silica gel to give [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)- 2-Methyl-but-2-ethyloxymethyl] -phosphonic acid diisopropyl ester 1B (25 mg, 32%) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ-1.25 (m, 12H), 1.79 (s, 3H), 2.05 (s, 3H), 3.37 (d, J = 6.6 Hz, 2H), 3.58 (d, 2H ), 3.77 (s, 3H), 3.97 (m, 2H), 4.68 (m, 2H), 5.19 (s, 2H), 5.45 (t, J = 6.6 Hz, 1H), 7.83 (s, 1H) ppm.

[4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-yl) -2-methyl-but-2-ethyloxymethyl] -phosphonic acid and [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3- Dehydro Isobenzofuran-5-yl) -2-methyl-but-2-ethyloxymethyl] -phosphonic acid Monoisopropyl  ester

[4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but- in acetonitrile at 0 ° C. Add trimethylsilyl bromide (0.126 mL, 1.1 mmol) to a solution of 2-ethyloxymethyl] -phosphonic acid diisopropyl ester 1B (25 mg, 0.055 mmol) and 2,6-lutidine (0.18 mL, 1.65 mmol) It was. The mixture was warmed to rt and stirred for 4 h. At 0 ° C. the reaction was stopped with methanol and the resulting mixture was concentrated. The residue was purified by preparative reverse phase HPLC to remove the solvent, followed by [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5- Il) -2-methyl-but-2-ethyloxymethyl] -phosphonic acid 1C was obtained as oil (17 mg, 83%), ¹ H NMR (300 MHz, CD ₃ OD) δ 1.81 (s, 3H), 2.06 (s, 3H), 3.40 (d, J = 6.6 Hz, 2H), 3.50 (d, 2H), 3.77 (s, 3H), 3.97 (s, 2H), 5.20 (s, 2H), 5.47 (t , J = 6.6 Hz, 1H), [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl -But-2-ethyloxymethyl] -phosphonic acid monoisopropyl ester 1D was obtained as oil (2 mg, 7%). ¹ H NMR (300 MHz, CD ₃ OD) δ? 1.23 (d, 6H), 1.81 (s, 3H), 2.08 (s, 3H), 3.40 (d, J = 6.6 Hz, 2H), 3.50 (d, 2H), 3.77 (s, 3H), 3.90 (s , 2H), 4.50 (m, 1H), 5.20 (s, 2H), 5.47 (t, J = 6.6 Hz, 1H) ppm.

Example  252: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

[5- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -3- methyl -Penta-1,3-dienyl] -phosphonic acid dimethyl ester

To a solution of tetramethylene methylene diphosphonate (102 mg, 0.44 mmol) in THF (2.5 mL) was added a solution of THF of sodium bis (trimethylsilyl) amide (1.0 M, 0.44 mL). After stirring for 30 minutes, 4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2 in THF (2.5 mL) -2 A solution of -methyl-but-2-enal 2A (30 mg, 0.11 mmol, Pankiewicz et al ., J. Med . Chem ., 45, 703) was added and stirring was continued for 15 minutes. The reaction was stopped with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting with ethyl acetate (50% to 100%) / hexanes to [5- (4-hydroxy-6-methoxy-7-methyl-3 -Oxo-1,3-dihydro-isobenzofuran-5-yl) -3-methyl-penta-1,3-dienyl] -phosphonic acid dimethyl ester 2B (30 mg, 71%) was obtained as an oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.80 (s, 3H), 2.04 (s, 3H), 3.45 (d, J = 6.6 Hz, 2H), 3.76 (s, 3H), 3.88 (d, 6H) , 5.20 (s, 3H), 5.55 (m, 1H), 5.95 (m, 1H), 7.05 (m, 1H), 7.65 (s, 1H) ppm.

[5- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -3- methyl Penta-1,3- Dienyl ] -Phosphonic acid

[5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -3-methyl-penta- in acetonitrile at 0 ° C. To a solution of 1,3-dienyl] -phosphonic acid dimethyl ester 2B (22 mg, 0.057 mmol) and 2,6-lutidine (0.22 mL, 1.71 mmol) was added trimethylsilyl bromide (0.183 mL, 1.71 mmol). . The mixture was warmed to rt and stirred for 1 h. At 0 ° C. the reaction was stopped with methanol and the resulting mixture was concentrated. The residue was purified by preparative reverse phase HPLC to remove the solvent, then [5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5- Il) -3-methyl-penta-1,3-dienyl] -phosphonic acid 2C was obtained as a solid (13 mg, 65%). ¹ H NMR (300 MHz, CD ₃ OD) δ 1.91 (s, 3H), 2.10 (s, 3H), 3.55 (d, J = 6.6 Hz, 2H), 3.75 (s, 3H), 5.2 (s, 2H ), 5.6-5.8 (m, 2H), 6.9 (m, 1H) ppm.

Example 253: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

6- (4- Bromo -3- methyl - Boot -2-ethyl) -7-hydroxy-5- Methoxy -4- methyl -3H- Isobenzofuran -1-on

Polymer-supported triphenylphosphine (3 mmol / g, 0.5 g) was soaked in dichloromethane (10 mL) for 1 hour. 7-hydroxy-6- (4-hydroxy-3-methyl-but-2-ethyl) -5-methoxy-4-methyl-3H-isobenzofuran-1-one1A (100 mg, 0.36 mmol) And carbon tetrabromide (143 mg, 0.43 mmol) were added sequentially and the mixture was shaken at room temperature for 1 hour. Further carbon tetrabromide (143 mg, 0.43 mmol) was added and the mixture was further stirred for 1 hour. The mixture was filtered and the filtrate was concentrated. The residue was chromatographed on silica gel (0% to 60% ethyl acetate / hexanes) to give 6- (4-bromo-3-methyl-but-2-ethyl) -7-hydroxy-5-methoxy-4 Obtained with -methyl-3H-isobenzofuran-1-one3B oil (52 mg, 42%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.95 (s, 3H), 2.16 (s, 3H), 3.44 (d, J = 7.2 Hz, 2H), 3.78 (s, 3H), 3.98 (s, 2H) , 5.21 (s, 2H), 5.68 (t, J = 7.2 Hz, 1H), 7.71 (brs, 1H) ppm.

[5- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -3- methyl -Pent-3-enyl] -phosphonic acid Diethyl ester

At -20 ° C n-butyl lithium (1.6 M in hexane, 1 mL) was added to the same volume of THF. Then a solution of diethylmethylphosphonate (220 mg, 1.45 mmol) in THF (1 mL) was added dropwise and the solution was stirred for 30 minutes. After cooling to −60 ° C., the solution was transferred via cannula to a vial containing copper (I) iodide (276 mg, 1.45 mmol) and the resulting mixture was stirred at −30 ° C. for 1 hour. 6- (4-Bromo-3-methyl-but-2-ethyl) -7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one3B in THF (1 mL) 50 mg, 0.15 mmol) solution was added and the mixture was warmed to 0 ° C. for 2 hours before saturated aqueous ammonium chloride was added. The reaction mixture was acidified with 2N HCl and extracted with ethyl acetate. The ethyl acetate extract was concentrated and the residue was chromatographed with silica gel (40% to 100% ethyl acetate / hexane) to give [5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1 , 3-dihydro-isobenzofuran-5-yl) -3-methyl-pent-3-enyl] -phosphonic acid diethylester 3C oil (27 mg, contaminated with starting dimethylmethylphosphonate) ). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.32 (m, 6H), 1.8-1.9 (m, 5H), 2.18 (s, 3H), 2.25 (m, 2H), 3.42 (d, J = 7.2 Hz, 2H), 3.78 (s, 3H), 4.15 (m, 4H), 5.21 (s, 2H), 5.24 (t, J = 7.2 Hz, 1H), 7.65 (s, 1H) ppm.

[5- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -3- methyl -Pent-3-enyl] -phosphonic acid Monoethyl  ester

[5- (4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -3-methyl-pent-3-enyl] -force A mixture of phonic acid diethylester 3C (27 mg, 0.066 mmol), LiOH (200 mg), MeOH (3 mL) and water (1 mL) was stirred at 70 ° C. for 4 hours. After cooling, the reaction solution was acidified with 2N HCl, mixed with brine and extracted with ethyl acetate / acetonitrile. The organic extract was concentrated and the residue was purified by preparative reverse phase HPLC (acetonitrile and 0.1% aqueous CF ₃ COOH) [5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1 , 3-dihydro-isobenzofuran-5-yl) -3-methyl-pent-3-enyl] -phosphonic acid monoethyl ester 3D (7 mg, 28%) was obtained. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.28 (t, J = 6.9 Hz, 3H), 1.7-1.9 (m, 5H), 2.20 (s, 3H), 2.2-2.3 (m, 2H), 3.41 (d, J = 6.6 Hz, 2H), 3.80 (s, 3H), 4.02 (m, 2H), 5.2-5.3 (m, 3H) ppm.

[5- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -3- methyl - Pent -3- Enil ] -Phosphonic acid

{5- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-iso in DMF (0.5 mL) and DCM (0.5 mL) Benzofuran-5-yl] -3-methyl-pent-3-enyl} -phosphonic acid diethylester (20 mg, 0.039 mmol) in a solution of TMSBr (50.5 μl, 0.39 mmol) followed by 2,6-lutidine ( 45.3 μl, 0.39 mmol) was added. After the reaction was run for 1 hour, LCMS confirmed that the reaction was completed. The reaction mixture was stopped with MeOH and concentrated to dryness. The residue was purified by preparative reverse phase HPLC. The portion containing the desired product was concentrated and treated with 10% TFA / DCM for 5 minutes. After concentration, the residue was purified by preparative reverse phase HPLC to give [5- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) 7 mg (50%) of 3-methyl-pent-3-enyl] -phosphonic acid were obtained as a solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.66-1.78 (m, 5H), 2.10 (s, 3H), 2.16-2.22 (m, 2H), 3.34 (d, J = 7.2 Hz, 2H), 3.72 (s, 3H), 5.16 (s, 2H), 5.20 (t, J = 7.2 Hz, 1H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 31.57 ppm; MS ( m / z ) 355 [M−H] ⁻ , 357 [M + H] ⁺ .

Example  254: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

2- (4-bromo-boot-2-ethyl) -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-iso benzofuran-5-yl Sodium bis (trimethylsilyl) in a cooled (-78 ° C) solution of mycophenolic acid methyl ester 4A (138 mg, 0.41 mmol) in 4-methyl-hex-4-enoic acid methyl ester THF (2.5 mL) THF solution of amide (1.0 M, 0.98 mL) was added. After stirring for 30 minutes, a solution of 1,4-dibromo-2-butene (950 mg, 4.1 mmol) in THF (2.5 mL) was added and stirring continued for 10 minutes. The resulting mixture was warmed to -30 ° C and stored at this temperature for 16 hours. The reaction was stopped with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate to evaporate the solvent, and the residue was purified by chromatography on silica gel eluting with ethyl acetate (0% to 40%) / hexanes to give 2- (4-bromo-but-2 -Ethyl) -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-eno Ixane methyl ester 4B (150 mg, 78%) was obtained as oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.75 (s, 3H), 2.0-2.4 (m, 8H), 2.62 (m, 1H), 3.37 (d, J = 6.6 Hz, 2H), 3.58 (s, 3H), 3.76 (s, 3H), 3.88 (d, J = 4.8 Hz, 2H), 5.1-5.3 (m, 3H), 5.67 (brs, 2H), 7.67 (s, 1H) ppm.

2- [4- ( Diethoxy - Phosphoryl )- Boot -2-ethyl] -6- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl  ester

2- (4-Bromo-but-2-ethyl) -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-iso in toluene (30 mL) A solution of benzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl ester 4B (140 mg, 0.30 mmol) and triethylphosphite (600 mg, 3.6 mmol) was stirred with reflux for 20 hours It was. The mixture was concentrated and chromatographed on silica gel eluting with ethyl acetate (60% to 100%) / hexanes to give 2- [4- (diethoxy-phosphoryl) -but-2-ethyl] -6- (4-hydride Roxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl ester 4C oil (70 mg , 43%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.27 (m, 6H), 1.79 (s, 3H), 2.0-2.7 (m, 8H), 3.37 (d, J = 6.6 Hz), 3.52 (s, 3H) , 3.75 (s, 3H), 4.08 (m, 4H), 5.20 m, 3H), 5.45 (m, 2H) ppm.

2- [4- (diethoxy-phosphoryl) -but-2-ethyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzo Furan-5-yl) -4-methyl-hex-4-enoic acid 2- [4- (diethoxy-phosphoryl) -but-2-ethyl in a mixture of THF (6 mL) and water (1 mL) ] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid A mixture of methyl ester 4C (33 mg, 0.063 mmol) and lithium hydroxide (44 mg) was stirred at rt for 6 h. The organic solvent was removed and the residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate. The ethyl acetate extract was concentrated to give 2- [4- (diethoxy-phosphoryl) -but-2-ethyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1, 3-Dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid 4D was obtained as oil (30 mg, 100%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.27 (m, 6H), 1.79 (s, 3H), 2.0-2.7 (m, 8H), 3.37 (d, J = 6.6 Hz), 3.75 (s, 3H ), 4.08 (m, 4H), 5.19 (s, 2H), 5.25 (m, 1H), 5.44 (m, 1H), 5.55 (m, 1H), 5.45 (m, 2H) ppm.

2- [4- ( Ethoxy -Hydroxy- Phosphoryl )- Boot -2-ethyl] -6- (4-hydroxy-6- Methoxy -7-Methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid

2- [4- (diethoxy-phosphoryl) -but-2-ethyl] -6- (4-hydroxy-6-methoxy-7-methyl in a mixture of methanol (3 mL) and water (1 mL) Of 3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl ester 4C (25 mg, 0.048 mmol) and lithium hydroxide (200 mg) The mixture was stirred at 70 ° C. for 2 hours. The organic solvent was evaporated, acidified with 2N HCl and extracted with ethyl acetate / acetonitrile. The organic extract was concentrated and the residue was purified by preparative reverse phase HPLC (acetonitrile and 0.1% aqueous CF ₃ COOH) 2- [4- (ethoxy-hydroxy-phosphoryl) -but-2-ethyl] -6 -(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid 4E (15 mg, 89%). ¹ H NMR (300 MHz, CD ₃ OD) δ 1.25 (t, J = 6.9 Hz, 3H), 1.81 (s, 3H), 2.1-2.6 (m, 8H), 3.40 (d, J = 6.6 Hz, 2H ), 3.77 (s, 3H), 3.97 (m, 2H), 5.1-5.3 (m, 3H), 5.67 (brs, 2H) ppm.

2- [4- ( Dimethoxy - Phosphoryl )- Boot -2-ethyl] -6- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro Isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl  ester

Under N ₂ atmosphere, 2- (4-bromo-but-2-ethyl) -6- (4-hydroxy-6-methoxy-7-methyl-3- in trimethylphosphite (2.5 mL, 21.1 mmol) A solution of oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl ester (490 mg, 1.05 mmol) was heated at 120 ° C. for 1 hour. The reaction was cooled to room temperature. The solvent was removed in vacuo and chromatographed with EtOAc-hexanes to finish the reaction mixture to give 460 mg (88%) of the product as an oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.77 (s, 3H), 2.081-2.31 (m, 4H), 2.15 (s, 3H), 2.52 (d, 1H, J = 22 Hz), 2.54 (d, 1H, J = 22 Hz), 2.55- 2.63 (m, 1H), 3.36 (d, 2H, J = 7 Hz), 3.57 (s, 3H), 3.72 (d, 6H, J = 11 Hz), 3.76 ( s, 3H), 5.20 (s, 2H), 5.20- 5.26 (m, 1H), 5.36- 5.56 (m, 2H), 7.69 (s, 1H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 30.1 ppm; MS ( m / z ) 497.2 [M + H] ⁺ , 519.2 [M + Na] ⁺ .

2- [4- ( Dimethoxy - Phosphoryl )- Boot -2-ethyl] -6- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid

1: 2- [4- (dimethoxy-phosphoryl) -but-2-ethyl] -6- (4-hydroxy-6-meth in a solution of H ₂ O, MeOH, THF (8 mL) Toxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid methyl ester (460 mg, 0.927 mmol) was added to LiOH.H. Stir with ₂ 0 (78 mg, 1.86 mmol) at ambient temperature for 12 hours. A second batch of LiOH.H ₂ O (40 mg, 0.952 mmol) was added. After the reaction mixture was stirred further for 16 hours at room temperature, it was observed that the reaction no longer proceeded. The reaction was stopped by addition of saturated aqueous NH ₄ Cl solution. The organic layer was removed in vacuo and the product was extracted with EtOAc from the acidified aqueous layer by addition of 5 drops of 2N HCl. The product was further purified by chromatography to give the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.79 (s, 3H), 2.08-2.38 (m, 4H), 2.15 (s, 3H), 2.53 (d, 1H, J = 22 Hz), 2.60 (d, 1H, J = 22 Hz), 2.57-2.64 (m, 1H), 3.38 (d, 2H, J = 7 Hz), 3.72 (d, 6H, J = 11 Hz) 3.76 (s, 3H), 5.20 (s , 2H), 5.27 (t, 1H, J = 6 Hz), 5.36- 5.63 (m, 2H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 30.5 ppm; MS ( m / z ) 481.2 [M ⁻ H] ⁻ .

2- [4- (2- [4- ( Dimethoxy - Phosphoryl )- Boot -2-ethyl] -6- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid

2- [4- (dimethoxy-phosphoryl) -but-2-ethyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1, in acetonitrile (2 mL), In a solution of 3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid (25 mg, 0.052 mmol) 2,6-lutidine (60 μl, 0.52 mmol) and TMSBr ( 67 μl, 0.52 mmol) was added. The reaction was allowed to proceed for 45 minutes and confirmed by LCMS. The reaction mixture was concentrated under reduced pressure and stopped with aqueous NaOH solution (1 mL). The product was purified by RP HPLC (H ₂ O, 0.1% TFA-acetonitrile, using a C18 column with a gradient of 0.1% TFA) to give 14.2 mg (60%) of the product as a solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.81 (s, 3H), 2.081-2.31 (m, 4H), 2.16 (s, 3H), 2.45 (d, 1H, J = 22 Hz), 2.47 (d , 1H, J = 22 Hz), 2.55- 2.63 (m, 1H), 3.38 (d, 2H, J = 7 Hz), 3.77 (s, 3H), 5.25 (s, 2H), 5.20- 5.36 (m, 1H), 5.36- 5.56 (m, 2H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 25.4 ppm; MS ( m / z ) 453 [M ⁻ H] ⁻ .

2- [4- ( Dimethoxy - Phosphoryl )- Boot -2-ethyl] -6- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl -Ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2- Trimethylsilanyl Ethyl ester

2- [4- (dimethoxy-phosphoryl) -but-2-ethyl] -6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3 in THF (8.00 mL) A solution of -dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid (160 mg, 0.332 mmol) and trimethylsilylethanol (160 mg, 1.36 mmol) was added to triphenylphosphine ( 345 mg, 1.33 mmol). Diethylazodicarboxylate (230 μl, 1.33 mmol) was added to this solution at 0 ° C. The mixture was warmed to rt and stirred for 16 h. Further triphenylphosphine (180 mg, 0.692 mmol), trimethylsilylethanol (160 mg, 1.36 mmol) and diethylazodicarboxylate (115 μl, 0.665 mmol) were added and the reaction mixture was allowed to stand at room temperature for 1 day. Further stirred. The solvent was removed in vacuo and the residue was purified by silica gel chromography to complete the reaction to give 192 mg (85%) of the product as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.03 (s, 9H), 0.05 (s, 9H), 0.93- 0.96 (m, 2H), 1.20- 1.29 (m, 2H), 1.78 (s, 3H), 2.01- 2.32 (m, 4H), 2.17 (s, 3H), 2.51 (d, 1H, J = 22 Hz), 2.58 (d, 1H, J = 22 Hz), 2.50- 2.60 (m, 1H), 3.37 (d, 2H, J = 7 Hz), 3.72 (d, 6H, J = 11 Hz), 3.76 (s, 3H), 4.08 (appt t, 2H, J = 8 Hz), 4.30 (appt t, 2H, J = 8 Hz), 5.12 (s, 2H), 5.15- 5.25 (m, 1H), 5.36- 5.63 (m, 2H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 29.3 ppm; MS ( m / z ) 705.3 [M + Na] ⁺ .

2- [4- (hydroxy- Methoxy - Phosphoryl )- Boot -2-ethyl] -6- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl -Ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2- Trimethylsilanyl Ethyl ester

2- [4- (dimethoxy-phosphoryl) -but-2-ethyl] -6- [6-methoxy-7-methyl-3-oxo-4- in tert -butylamine (2.8 mL, 27 mmol) (2-Trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester (184 mg, 0.270 mmol) was heated at 60 ° C. for 24 h. The solution was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography using MeOH / CH ₂ Cl ₂ (0- 30%) to afford 75 mg of product as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.01 (s, 9H), 0.04 (s, 9H), 0.89 (appt t, 2H, J = 9 Hz), 1.23 (appt t, 2H, J = 9 Hz) , 1.77 (s, 3H), 2.01- 2.31 (m, 4H), 2.17 (s, 3H), 2.36 (d, 1H, J = 22 Hz), 2.38 (d, 1H, J = 22 Hz), 2.52 ( septet, 1H, J = 9 Hz), 3.39 (d, 2H, J = 7 Hz), 3.51 (d, 3H, J = 11 Hz), 4.01- 4.08 (m, 2H), 4.30 (dd, 2H, J = 8, 9 Hz), 5.11 (s, 2H), 5.19 (br t, 1H, J = 6 Hz), 5.33- 5.56 (m, 2H), 8.49 (br s, 1H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 22.1 ppm; MS ( m / z ) 667.4 [M + Na] ⁺ .

2- {4-[(1- Ethoxycarbonyl - Ethoxy )- Methoxy - Phosphoryl ]- Boot -2-ethyl} -6- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro - Isobenzofuran -5-day] -4- methyl - Hex -4- Enoick  Acid 2- Trimethylsilanyl Ethyl ester

2- [4- (hydroxy-methoxy-phosphoryl) -but-2-ethyl] -6- [6-methoxy-7-methyl-3-oxo-4- (2- in DMF (1.5 mL) Trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester (67 mg, 0.10 mmol) And a solution of PyBOP (234 mg, 0.450 mmol) with ethyl (S)-(-)-lactate (53 mg, 0.45 mmol) and DIEA (174 μl, 1.00 mmol) at ambient temperature for 1 hour It was observed that starting material was consumed completely. Saturated aqueous sodium chloride and ethyl acetate were added to finish the reaction. The organic layer was separated and washed with 5% aqueous lithium chloride solution. The organic layer was dried in vacuo and the residue was purified by silica gel chromatography using MeOH-CH ₂ Cl ₂ (0-20%) to give 57 mg (74%) of the desired product as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.02 (s, 9H), 0.05 (s, 9H), 0.88- 0.94 (m, 2H), 1.20- 1.30 (m, 2H), 1.29 (t, 3H, J = 7 Hz), 1.45 (d, 3H, J = 7 Hz), 1.78 (s, 3H), 2.01- 2.31 (m, 4H), 2.17 (s, 3H), 2.50- 2.58 (m, 1H), 2.65 (d, 1H, J = 22 Hz), 2.67 (d, 1H, J = 22 Hz), 3.39 (d, 2H, J = 7 Hz), 3.69 and 3.77 (d, 3H, J = 11 Hz), 3.76 (s, 3H), 4.07 (appt t, 2H, J = 7 Hz), 4.20 (dq, 2H, J = 3, 7 Hz), 4.29 (appt t, 2H, J = 9 Hz), 4.85-4.99 ( m, 1H), 5.12 (s, 2H), 5.19 (brt, 1H, J = 6 Hz), 5.33- 5.61 (m, 2H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 28.9, 29.9 ppm; MS ( m / z ) 791.4 [M + Na] ⁺ .

2- {4-[(1- Ethoxycarbonyl - Ethoxy )- Methoxy - Phosphoryl ]- Boot -2-ethyl} -6- (4-hydrate Roxy -6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -4- methyl - Hex -4-enoic acid

2- {4-[(1-ethoxycarbonyl-ethoxy) -methoxy-phosphoryl] -but-2-ethyl} -6- [6-methoxy-7-methyl- in THF (1 mL) 3-Oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanyl- Ethyl ester (14 mg, 0.018 mmol) solution was stirred with TBAF 1M solution in THF (55 μl, 0.055 mmol) for 1 hour. The reaction mixture was concentrated, acidified with 1N HCl and extracted with EtOAc. The organic layer was washed with brine and dried. The product was purified by silica gel column chromatography EtOH-EtOAc (0-10%). The product was dissolved in CH ₂ Cl ₂ and the compound was further purified by passing through a 13 mm acrodisk syringe filter with 0.45 mm nylon membrane to give 8 mg (77%) of the product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.92 (t, 3H, J = 7 Hz), 1.30 (d, 3H, J = 8 Hz), 1.79 (s, 3H), 2.10-2.39 (m, 4H) , 2.15 (s, 3H), 2.53 (d, 1H, J = 8 Hz), 2.65 (d, 1H, J = 22 Hz), 2.68 (d, 1H, J = 22 Hz), 3.38 (d, 2H, J = 7 Hz), 3.70 and 3.74 (d, 3H, J = 11 Hz), 3.76 (s, 3H), 4.07 (m, 2H), 4.96 (dq, 1H, J = 7 Hz), 5.20 (s, 2H), 5.27 (br t, 1H, J = 7 Hz), 5.33- 5.55 (m, 2H), 7.51- 7.56 (m, 1H), 7.68-7.74 (m, 1H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 29.0, 30.1 ppm; MS ( m / z ) 569.2 [M + H] ⁺ , 591.3 [M + Na] ⁺ .

2- {4-[(1- Carboxy - Ethoxy ) -Hydroxy- Phosphoryl ]- Boot -2-ethyl} -6- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro - Isobenzofuran -5-day] -4- methyl - Hex -4- Enoick  Acid 2- Trimethylsilanyl Ethyl ester

2- {4-[(1-ethoxycarbonyl-ethoxy) -methoxy-phosphoryl] -but-2-ethyl} -6- [6-meth in tert -butylamine (1 mL, 9.6 mmol) Methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid The 2-trimethylsilanylethyl ester (12 mg, 0.016 mmol) solution was heated at 65 ° C. for 16 h. The solution was cooled to room temperature and concentrated to afford crude product as an oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.03 (s, 9H), 0.04 (s, 9H), 0.86- 0.98 (m, 2H), 1.22- 1.33 (m, 2H), 1.50 (d, 3H, J = 7 Hz), 1.78 (s, 3H), 2.05- 2.30 (m, 4H), 2.10 (s, 3H), 2.48-2.63 (m, 3H), 3.40 (d, 2H, J = 7 Hz), 3.76 (s, 3H), 4.08 (appt t, 2H, J = 9 Hz), 4.25- 4.33 (m, 2H), 4.75- 4.84 (m, 1H), 5.13 (s, 2H), 5.15- 5.23 (m, 1H), 5.33- 5.55 (m, 2H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 28.9 ppm; MS ( m / z ) 725.3 [M ⁻ H] ⁻ .

2- {4-[(1- Carboxy - Ethoxy ) -Hydroxy- Phosphoryl ]- Boot -2-ethyl} -6- (4-hydroxy-6- Methoxy -7-Methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid

Crude 2- {4-[(1-carboxy-ethoxy) -hydroxy-phosphoryl] -but-2-ethyl} -6- [6-methoxy- in THF (1M, 54 μl, 0.054 mmol) 7-Methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2- Trimethylsilanyl-ethyl ester (AC-2101-59) and tetrabutylammonium fluoride solution were stirred with THF (1 mL) for 2 hours at ambient temperature, tetrabutylammonium fluoride (54 μl, 0.054 mmol in THF) ) Was further added. The reaction was stirred for 16 hours more, and the reaction was complete. The reaction mixture was concentrated in vacuo and the product was RP HPLC using H ₂ O, 0.1% TFA-CH ₃ CN, 0.1% TFA as eluent and using a Phenomenex Synergi 5 m Hydro RP 80A column (50 × 21.2 mm). The roll was purified to give the product (8.0 mg) as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.51 (d, 3H, J = 7 Hz), 1.79 (s, 3H), 2.05- 2.40 (m, 4H), 2.11 (s, 3H), 2.49-2.71 ( m, 3H), 3.38 (d, 2H, J = 6 Hz), 3.76 (s, 3H), 4.85 (br s, 1H), 5.20 (s, 2H), 5.21- 5.30 (m, 1H), 5.33- 5.63 (m, 2 H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 27.7 ppm; MS ( m / z ) 525.2 [M ⁻ H] ⁻ .

2- {4-[(1- Ethoxycarbonyl - Ethylamine )- Methoxy - Phosphoryl ]- Boot -2-ethyl} -6- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro - Isobenzofuran -5-day] -4- methyl - Hex 4-enoic acid 2- Trimethylsilanyl Ethyl ester

2- [4- (hydroxy-methoxy-phosphoryl) -but-2-ethyl] -6- [6-methoxy-7-methyl-3-oxo-4- (2- in DMF (1.0 mL) Trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester (20 mg, 0.030 mmol) , A solution of PyBOP (62.4 mg, 0.120 mmol) with L-alanine ethyl ester hydrogen chloride (18 mg, 0.12 mmol) and DIEA (26 μl, 0.15 mmol) for 1 hour at ambient temperature, after which the starting material was Observe that it was consumed. The reaction was finished by adding water until the reaction solution became cloudy. DMF was added dropwise until the mixture became clear again. The reaction mixture was filtered through an acrodisk (13 mm syringe filter with 0.45 mm nylon membrane) and purified by RP HPLC using a Phenomenex Synergi 5 m Hydro RP 80A column (50 × 21.2 mm) eluting with water and acetonitrile. The portions containing the product were collected together and concentrated in vacuo to remove acetonitrile. The residual solution was saturated with sodium chloride and extracted with EtOAc and acetonitrile to give 7.2 mg of product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.03 (s, 9H), 0.05 (s, 9H), 0.923 (appt t, 2H, J = 8 Hz), 1.18-1.31 (m, 5H), 1.41 (t , 3H, J = 7 Hz), 1.78 (s, 3H), 2.03- 2.36 (m, 4H), 2.18 (s, 3H), 2.43- 2.63 (m, 3H), 3.10-3.30 (m, 1H), 3.40 (d, 2H, J = 7 Hz), 3.62 and 3.65 (d, 3H, J = 11 Hz), 3.76 (s, 3H), 4.03-4.12 (m, 2H), 4.20 (dq, 2H, J = 2, 7 Hz), 4.29 (appt t, 2H, J = 8 Hz), 5.12 (s, 2H), 5.18-5.28 (m, 1H), 5.33- 5.67 (m, 2H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 30.4, 31.2 ppm; MS ( m / z ) 790.4 [M + Na] ⁺ .

2- {4-[(1- Ethoxycarbonyl - Ethylamine )- Methoxy - Phosphoryl ]- Boot -2-ethyl} -6- (4-hydroxy-6- Methoxy -7-Methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl-hex-4-enoic acid

2- {4-[(1-ethoxycarbonyl-ethylamine) -methoxy-phosphoryl] -but-2-ethyl} -6- [6-methoxy-7-methyl- in THF (1 mL) 3-Oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanyl- To the solution of ethyl ester (7.2 mg, 9.38 mmol) TBAF (40 μl, 1M solution in THF) was added at room temperature. After stirring the reaction mixture for 20 minutes, LCMS confirmed that the starting material was completely converted to the desired product. The reaction mixture was dried in vacuo and dissolved again in DMF. The product was purified by RP HPLC using a Phenomenex Synergi 5 m Hydro RP 80A column (50 × 21.2 mm) eluting with H ₂ O—CH ₃ CN. The portion containing the desired product was collected and purified by Dowex 50WX8-400 packed on a 4.5 cm x 2 cm column eluting the sodium salt in H ₂ O-MeOH (1: 1) to give 3.2 mg of the desired product. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.26 (dd, 3H, J = 4, 7 Hz), 1.37 (t, 3H, J = 8 Hz), 1.80 (s, 3H), 2.00- 2.22 (m , 4H), 2.10 (s, 3H), 2.25- 2.60 (m, 3H), 3.37 (d, 2H, J = 7 Hz), 3.60 and 3.65 (d, 3H, J = 11 Hz), 3.74 (s, 3H), 3.83-3.96 (m, 1H), 4.18 (q, 2H, J = 8 Hz), 5.15 (s, 2H), 5.25- 5.42 (m, 2H), 5.55- 5.69 (m, 1H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 33.8, 34.2 ppm; MS ( m / z ) 568.2 [M + H] ⁺ , 590.3 [M + Na] ⁺ .

6- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-yl) -2- [4- (hydroxy-methoxy-phosphoryl) -but-2-ethyl] -4-methyl-hex-4-enoic acid

2- [4- (hydroxy-methoxy-phosphoryl) -but-2-ethyl] -6- [6-methoxy-7-methyl-3-oxo-4- (2- in THF (1 mL) Trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid 2-trimethylsilanylethyl ester (11 mg, 0.016 mmol) solution To this was added TBAF (50 μl, 1M solution in THF) at room temperature. The solution was stirred for 16 h and concentrated. The solution was dried under reduced pressure and resuspended in DMF (0.8 mL) and water (0.25 mL). The solution was filtered through an acrodisk (13 mm syringe filter with 0.45 mm nylon membrane) and a Phenomenex Synergi 5 m Hydro RP 80A column (50 x 21.2 mm) eluting with H ₂ O, 0.1% TFA-CH ₃ CN, 0.1% TFA. Purified by RP HPLC using The product from the column was purified by ion exchange chromatography (in the form of the sodium salt of Dowex 50WX8-400) using a 2 x 4.5 cm column, eluting with H ₂ O-MeOH (1: 1) to convert 7.5 mg of the desired product into oil. Got it. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.80 (s, 3H), 2.01- 2.29 (m, 5H), 2.11 (s, 3H), 2.35 (d, 2H, J = 22 Hz), 3.38 (d, 2H, J = 7 Hz), 3.53 (d, 3H, J = 11 Hz), 3.75 (s, 3H), 5.19 (s, 2H), 5.26 (t, 1H, J = 6 Hz), 5.43- 5.54 ( m, 2H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 23.5 ppm; MS ( m / z ) 469.2 [M + H] ⁺ , 491.3 [M + Na] ⁺ .

6- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro Isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid methyl  ester

6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -4-methyl in THF (3 mL) at 0 ° C. THF (3) in a solution of hex-4-enoic acid methyl ester (222 mg, 0.66 mmol), triphenylphosphine (260 mg, 0.996 mmol) and diethylazodicarboxylate (173 mg, 0.996 mmol) A solution of 2-trimethylsilylethanol (142 μl, 0.996 mmol) in mL) was added. The resulting yellow solution was warmed to room temperature and stirred overnight. The reaction was concentrated to dryness and ether and hexanes added. Triphenylphosphine oxide was filtered off and the filtrate was concentrated and purified by silica gel chromatography to give 248 mg of the desired product as colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.03 (s, 9H), 1.18-1.30 (m, 2H), 1.81 (s, 3H), 2.18 (s, 3H), 2.25- 2.33 (m, 2H), 2.37-2.45 (m, 2H), 3.42 (d, 2H, J = 7 Hz), 3.62 (s, 3H), 3.77 (s, 3H), 4.25- 4.35 (m, 2H), 5.13 (s, 2H) , 5.12- 5.22 (m, 1 H) ppm.

[6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro - Isobenzofuran -5-day] -acetaldehyde

To 6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-in in MeOH (10 mL), CH ₂ Cl ₂ (10 mL) and pyridine (50 μl, 0.618 mmol) Methoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid methyl ester (618 mg, 1.42 mmol) solution was prepared by Smith, DB et al ., J. Org . Cooled to −70 ° C. using a dry ice / acetone bath according to the method of Chem ., 1996 , 61 , 6, 2236. The reaction was bubbled with an ozone stream through a gas dispersion tube until the reaction became blue (15 minutes). The ozone line was replaced with a stream of nitrogen and bubbling for another 15 minutes and the blue color disappeared. To this solution was added some thiourea (75.7 mg, 0.994 mmol) at -70 ° C and the cooling bath was removed. The reaction was warmed to room temperature and stirred for 15 minutes. The reaction was finished by filtering off the solid thiourea S-dioxide and then partitioned between CH ₂ Cl ₂ and water. The organic layer was removed. The aqueous layer was washed once more with CH ₂ Cl ₂ and the organic extracts were collected. The organic layer was washed with aqueous 1N HCl, saturated NaHCO ₃ and brine. The organic extract was dried in vacuo and purified by silica gel chromatography to give 357 mg (75%) of the product as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ -0.01 (s, 9H), 1.05- 1.15 (m, 2H), 2.15 (s, 3H), 3.69 (s, 3H), 3.78 (d, 2H, J = 1 Hz), 4.27-4.39 (m, 2H), 5.11 (s, 2H), 9.72 (d, 1H, J = 1 Hz) ppm.

4- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro - Isobenzofuran -5-day] -2- methyl - Boot -2- Yen

[6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -acetium in toluene (2 mL) Aldehyde (70 mg, 0.21 mmol) was heated at 100 ° C. with 2- (triphenyl-phosphanilidene) -propionaldehyde (72.9 mg, 0.23 mmol) overnight. A second portion of 2- (triphenyl-phosphanilidene) -propionaldehyde (33 mg, 0.11 mmol) was added and the reaction mixture was heated another day. After concentration, the residue was purified by silica gel chromatography to give 54 mg (83%) of the desired product as pale yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.00 (s, 9H), 1.10-1.21 (m, 2H), 1.87 (s, 3H), 2.16 (s, 3H), 3.67-3.76 (m, 2H), 3.74 (s, 3H), 4.27-4.39 (m, 2H), 5.11 (s, 2H), 6.40-6.48 (m, 1H), 9.2 (s, 1H) ppm.

6- (4-hydroxy-3- methyl - Boot -2-ethyl) -5- Methoxy -4- methyl -7- (2- Trimethylsilanyl - Ethoxy ) -3H- Isobenzofuran -1-on

4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] in methanol (5 mL) The 2-methyl-but-2-enal (103 mg, 0.27 mmol) solution was cooled to 0 ° C. CeCl ₃ solution (0.68 mL, MeOH: H ₂ O, 9: 1) was added followed by LiBH ₄ (0.14 mL, 0.28 mmol of 2M solution in THF). The ice bath was removed and the reaction mixture was warmed to room temperature. After stirring the reaction mixture for 40 more minutes, TLC confirmed that the starting aldehyde was consumed completely. Aqueous 1N HCl (0.5 mL) was added to finish the reaction and the product was extracted with CH ₂ Cl ₂ . The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography to give 100 mg (97%) of the product as a clear liquid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.00 (s, 9H), 1.20 (dd, 2H, J = 7, 8 Hz), 1.81 (s, 3H), 2.13 (s, 3H), 3.38-3.50 ( m, 2H), 3.74 (s, 3H), 3.95 (s, 2H), 4.27 (dd, 2H, J = 7, 8 Hz), 5.08 (s, 2H), 5.17-5.44 (m, 1H) ppm.

6- (2-hydroxy-ethyl) -5- Methoxy -4- methyl -7- (2- Trimethylsilanyl - Ethoxy ) -3H- Isobenzofuran -1-on

[6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -acet in THF (5 mL) To a solution of aldehyde (97 mg, 0.29 mmol) was added 2 M LiBH ₄ (150 μl, 0.300 mmol) in THF. The reaction mixture was stirred for 1 hour at room temperature and observed by TLC that the starting material was consumed completely. Aqueous 1N HCl solution was added to finish the reaction mixture and extracted with EtOAc. The organic layer was dried in vacuo and the residue was purified by silica gel chromatography to give the product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.00 (s, 9H), 1.20 (dd, 2H, J = 7, 9 Hz), 2.07 (br s, 1H), 2.14 (s, 3H), 2.97 (t , 2H, J = 6 Hz), 3.76 (t, 2H, J = 6 Hz), 3.77 (s, 3H), 4.32 (dd, 2H, J = 7, 8 Hz), 5.08 (s, 2H) ppm.

{2- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro -Isobenzofuran-5-yl] -ethoxymethyl} -phosphonic acid Diisopropyl  ester

6- (2-hydroxy-ethyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl- in the presence of lithium t -butoxide (22 mg, 0.27 mmol) in DMF (2 mL) A mixture of ethoxy) -3H-isobenzofuran-1-one (79 mg, 0.23 mmol) was heated with bromomethylphosphonic acid diisopropyl ester (120 mg, 0.46 mmol) at 70 ° C. overnight the reaction mixture was Purification by RP HPLC (acetonitrile and 0.1% aqueous CF ₃ COOH) afforded the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.00 (s, 9H), 1.13- 1.25 (m, 2H), 1.26 (t, 12H, J = 6 Hz), 2.12 (s, 3H), 2.98 (t, 2H, J = 7 Hz), 3.60- 3.73 (m, 4H), 3.77 (s, 3H), 4.05- 4.16 (m, 2H), 4.62-4.74 (m, 2H), 5.07 (s, 2H) ppm; MS ( m / z ) 539 [M + Na] ⁺ .

Example  255: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

[2- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5 days)- Ethoxymethyl ] -Phosphonic acid

{2- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) in acetonitrile (2 mL) and 2,6-lutidine (25 μl, 0.21 mmol) Trimethylsilyl bromide (27 μl, 0.21 mmol) was added to a solution of -1,3-dihydro-isobenzofuran-5-yl] -ethoxymethyl} -phosphonic acid diisopropyl ester (7.5 mg, 0.014 mmol) at room temperature. Was added. After the reaction was run for 18 hours, LCMS confirmed that the reaction was completed. The reaction was stopped by adding MeOH and concentrated. The residue was purified by RP-HPLC using a C18 column. The combined products were dissolved in _a solution of 10% TFA / CH ₂ Cl ₂ and completely deprotected. The reaction mixture was lyophilized to give the desired product. ¹ H NMR (300 MHz, CD ₃ OD) δ 2.12 (s, 3H), 2.98 (t, 2H, J = 7 Hz), 3.66- 3.76 (m, 4H), 3.78 (s, 3H), 5.21 (s , 2H) ppm; MS ( m / z ) 331 [M ⁻ H] ⁻ .

Example  256: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

6- (4- Bromo -3- methyl - Boot -2-ethyl) -7-hydroxy-5- Methoxy -4- methyl -3H- Isobenzofuran -1-on

Polymer-supported triphenylphosphine (3 mmol / g, 0.5 g) was soaked in dichloromethane (10 mL) for 1 hour. 7-hydroxy-6- (4-hydroxy-3-methyl-but-2-ethyl) -5-methoxy-4-methyl-3H-isobenzofuran-1-one (100 mg, 0.36 mmol) and Carbon tetrabromide (143 mg, 0.43 mmol) was added sequentially and the mixture was shaken at room temperature for 1 hour. Further carbon tetrabromide (143 mg, 0.43 mmol) was added and the mixture was further stirred for 1 hour. The mixture was filtered and the filtrate was concentrated. The residue was chromatographed on silica gel (0% to 60% ethyl acetate / hexanes) to give 6- (4-bromo-3-methyl-but-2-ethyl) -7-hydroxy-5-methoxy-4 -Methyl-3H-isobenzofuran-1-one was obtained as an oil (52 mg, 42%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.95 (s, 3H), 2.16 (s, 3H), 3.44 (d, J = 7.2, 2H), 3.78 (s, 3H), 3.98 (s, 2H), 5.21 (s, 2H), 5.68 (t, J = 7.2 Hz, 1H), 7.71 (brs, 1H) ppm.

[4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -2- methyl -But-2-ethyl] -phosphonic acid dimethyl ester

6- (4-Bromo-3-methyl-but-2-ethyl) -7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran- in trimethylphosphite (1.0 mL, 8.5 mmol) The 1-one (33 mg, 0.097 mmol) solution was heated to 100 ° C. for 1 h and LCMS confirmed the reaction was complete. The reaction was completed by removing excess reagent under reduced pressure and the residue was purified by silica gel chromatography using EtOAc-hexane (20-100%) to give 20 mg (60%) of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.90 (s, 3H), 2.09 (s, 3H), 2.48 (d, 2H, J = 22 Hz), 3.38 (t, 2H, J = 6 Hz), 3.64 (d, 6H, J = 11 Hz), 3.72 (s, 3H), 5.14 (s, 2H), 5.33 (q, 1H, J = 6 Hz), 7.65 (br s, 1H) ppm; MS ( m / z ) 371 [M + H] ⁺ .

Example  257: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

[4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -2- methyl - Boot -2-ethyl] -phosphonic acid

[4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2- in acetonitrile (2 mL) at 0 ° C. To a solution of methyl-but-2-ethyl] -phosphonic acid dimethyl ester (18 mg, 0.049 mmol) was added TMSBr (63 μl, 0.49 mmol) and 2,6-lutidine (85 μl, 0.73 mmol). The reaction solution was warmed to room temperature and stirred for 2 hours, and then observed by LCMS that the reaction was complete. The reaction was cooled to 0 ° C. and stopped by addition of MeOH. The reaction mixture was concentrated under reduced pressure and the residue was purified over 20 minutes by RP HPLC using a C18 column with a gradient of H ₂ O-acetonitrile (5-0%) to afford 12.2 mg (73%) of product. . ¹ H NMR (300 MHz, CD ₃ OD) δ 1.95 (s, 3H), 2.15 (s, 3H), 2.48 (d, 2H, J = 22 Hz), 3.44 (t, 2H, J = 6 Hz), 3.79 (s, 3H), 5.24 (s, 2H), 5.38 (q, 1H, J = 7 Hz), 6.87 (br s, 1H) ppm; MS ( m / z ) 341 [M ⁻ H] ⁻ .

Example  258: Preparation of representative compounds of the present invention.

Representative compounds of the present invention can be prepared as follows.

[4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-yl) -2-methyl-but-2-ethyloxymethyl] -phosphonic acid Monophenyl ester  And [4- (4-hydroxy-6-meth Toxi -7- methyl -3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-ethyloxymethyl] -phosphonic acid Diphenyl  ester

[4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran in DMF (0.4 mL) and phenol (62 mg, 0.65 mmol) at 0 ° C. -5-yl) -2-methyl-but-2-ethyloxymethyl] -phosphonic acid (49 mg, 0.13 mmol) in dicyclohexyl carbodiimide (107 mg, 0.52 mmol) in DMF (0.6 mL) and DMAP (8 mg, 0.065 mmol) was added slowly. The reaction was warmed to room temperature and heated to 140 ° C. for 10 hours. After cooling to room temperature the mixture was filtered and extracted with aqueous 1N NaOH solution. The aqueous layer was acidified with aqueous 1N HCl and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by RP HPLC to give [4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl -But-2-ethyloxymethyl] -phosphonic acid monophenylester (main product, Example 8) 18.5 mg was obtained as a pale yellow solid [4- (4-hydroxy-6-methoxy-7-methyl-3- 4.1 mg of oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but-2-ethyloxymethyl] -phosphonic acid diphenyl ester (product) were also obtained as a pale yellow solid. Main products: ¹ H NMR (300 MHz, CD ₃ OD) δ 1.82 (s, 3H), 2.16 (s, 3H), 3.46 (d, 2H, J = 7 Hz), 3.70 (d, 2H, J = 8 Hz ), 3.77 (s, 3H), 3.96 (s, 2H), 5.25 (s, 2H), 5.52 (t, 1H, J = 8 Hz), 7.10- 7.21 (m, 3H), 7.30 (t, 2H, J = 8 Hz) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 17.3 ppm; MS ( m / z ) 449.0 [M + H] ⁺ , 471.2 [M + Na] ⁺ . Product: ¹ H NMR (300 MHz, CD ₃ OD) δ 1.82 (s, 3H), 2.15 (s, 3H), 3.47 (d, 2H, J = 7 Hz), 3.77 (s, 3H), 3.98- 4.06 (m, 4H), 5.25 (s, 2H), 5.50- 5.61 (m, 1H), 7.10- 7.25 (m, 6H), 7.30-7.41 (m, 4H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 16.3 ppm; MS ( m / z ) 525.2 [M + H] ⁺ , 547.2 [M + Na] ⁺ .

Example  259: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

2-{[4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-yl) -2-methyl-but-2-ethyloxymethyl] -phenoxy-phosphinoyloxy} -propionic acid ethyl ester

[4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but- in pyridine (0.5 mL) PyBOP (32 mg, 0.060 mmol) was added to a solution of 2-ethyloxymethyl] -phosphonic acid monophenylester (18.5 mg, 0.040 mmol) and ethyl (S)-(-)-lactate (47 μl, 0.400 mmol). Added. The solution was stirred at rt for 1 h and further PyBOP (21 mg, 0.040 mmol) was added. The solution was stirred for another 1 hour and concentrated. The residue was purified by HPLC to give 7.5 mg of the desired product as a clear oil. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.22 and 1.25 (t, 3H, J = 7 Hz), 1.42 and 1.50 (d, 3H, J = 7 Hz ), 1.82 and 1.83 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J = 7 Hz), 3.78 (s, 3H), 3.89 (d, 1H, J = 8 Hz), 3.93- 4.02 (m, 3H), 4.10-4.22 ( m, 2H), 4.94-5.08 (m, 1H), 5.25 (s, 2H), 5.50-5.60 (m, 1H), 7.15- 7.27 (m, 3H), 7.33-7.41 (m, 2H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 18.9, 20.3 ppm (diastereomer in phosphorus), MS ( m / z ) 549.2 [M + H] ⁺ , 571.3 [M + Na] ⁺ .

Example  260: Preparation of representative compounds of the present invention.

Representative compounds of the present invention can be prepared as follows.

2-{[4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-yl) -2-methyl-but-2-ethyloxymethyl] -phenoxy-phosphinoylamino} -propionic acid ethyl ester

[4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but- in pyridine (1.0 mL) PyBOP (70 mg, 0.14 mmol) was added to a solution of 2-ethyloxymethyl] -phosphonic acid monophenylester (20 mg, 0.045 mmol) and L-alanine ethyl ester hydrogen chloride (68.5 mg, 0.45 mmol). After stirring overnight, the mixture was concentrated and the residue was purified by RP HPLC using C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA to give 3.6 mg of product as a colorless gel. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.17-1.3 (m, 6H), 1.8-1.9 (m, 3H), 2.16 (s, 3H), 3.17 (m, 1H), 3.47 (d, 2H) , 3.72-3.8 (m, 5H), 3.92-4.2 (m, 4H), 5.25 (s, 2H), 5.54 (m, 1H), 7.18 (m, 3H), 7.33 (m, 2H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 24.1, 25.0 ppm (diastereomer in phosphorus), MS ( m / z ) 546.2 [MH] ⁺ .

Example  261: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

[4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -2- Me Ethyl-but-2-ethyloxymethyl] -phosphonic acid Monomethyl  ester

[4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl-but- in methanol (0.5 mL) To a solution of 2-ethyloxymethyl] -phosphonic acid diphenyl ester (53 mg, 0.1 mmol) was added 1N NaOH aqueous solution (300 μl). After stirring overnight, the mixture was concentrated and the residue was purified by RP HPLC using C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA to give 5 mg of product phosphonic acid monophenylester ( 7 mg) and phosphonic acid dimethyl ester (14.5 mg) as a colorless gel. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.84 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J = 7 Hz), 3.6 (d, 2H, J = 12 Hz), 3.75 (d, 3H, J = 11 Hz), 3.79 (s, 3H), 3.94 (s, 2H), 5.26 (s, 2H), 5.53 (t, 1H, J = 7 Hz) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 21.5 ppm; MS (m / z) 385.2 [ MH] +, 387.1 [M + H] +.

Example  262: Preparation of representative compounds of the present invention.

Representative compounds of the present invention can be prepared as follows.

(2- {4- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro Isobenzofuran-5-yl] -2-methyl-but-2-ethylamino} -ethyl) -phosphonic acid Diethyl ester

4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5- in DMF (1.5 mL) at room temperature Il] -2-methyl-but-2-enal (84 mg, 0.22 mmol), (2-amino-ethyl) -phosphonic acid diethylester oxalate (91 mg, 0.33 mmol) and sodium triacetoxyborohydride To a solution of (93 mg, 0.44 mmol) was added acetic acid (60 μl, 1.0 mmol). The solution was stirred for 2 days and then the reaction was stopped by addition of saturated aqueous sodium bicarbonate solution and EtOAc. The organic layer was separated and concentrated under reduced pressure. The residue was purified by RP HPLC using a C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA to give 115 mg (96%) of the product as an oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.04 (s, 9H), 1.16- 1.27 (m, 2H), 1.34 (t, 6H, J = 7 Hz), 1.94 (s, 3H), 2.18 (s, 3H), 2.20- 2.31 (m, 2H), 3.13- 3.31 (m, 2H), 3.48 (d, 2H, J = 7 Hz), 3.54 (s, 2H), 3.78 (s, 3H), 4.14 (pent , 4H, J = 7 Hz), 4.30- 4.37 (m, 2H), 5.13 (s, 2H), 5.65 (t, 1H, J = 7 Hz), 6.23 (br s, 2H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 27.8 ppm; MS ( m / z ) 542.3 [M + H] ⁺ , 564.2 [M + Na] ⁺ .

{2- [4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -2- methyl - Boot -2- Ethylamino ] -Ethyl} -phosphonic acid

(2- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl at ambient temperature ] -2-methyl-but-2-ethylamino} -ethyl) -phosphonic acid diethylester (30 mg, 0.055 mmol), TMSBr (72 μl, 0.55 mmol) and 2,6-lutidine (64 μl, 0.55 mmol) was stirred in CH ₂ Cl ₂ (1 mL) and DMF (0.5 mL) for 1 h. The reaction mixture was purified by RP HPLC using C18 column with a gradient of H 2 O, 0.1% TFA-acetonitrile, 0.1% TFA to give 7.8 mg of product as a white solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.96 (s, 3H), 1.95-2.07 (m, 2H), 2.16 (s, 3H), 3.10-3.24 (m, 2H), 3.51 (d, 2H, J = 7 Hz), 3.57 (s, 2H), 3.81 (s, 3H), 5.25 (s, 2H), 5.73 (t, 1H, J = 7 Hz) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 20.2 ppm; ¹⁹ F NMR (282.6 MHz, CD ₃ OD) δ −74.0 ppm; MS ( m / z ) 386.3 [M + H] ⁺ .

Example  263: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

[2-( Methanesulfonyl -{4- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but-2-ethyl} -amino) -ethyl] -phosphonic acid Diethyl ester

(2- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-iso in CH ₂ Cl ₂ (0.5 mL) Benzofuran-5-yl] -2-methyl-but-2-ethylamino} -ethyl) -phosphonic acid diethylester (45 mg, 0.092 mmol) was added to a solution of methanesulfonyl chloride (21 μl, 0.28 mmol) at ambient temperature. ) And pyridine (45 μl, 0.55 mmol) overnight. Two drops of water were added to stop the reaction. The reaction mixture was concentrated and purified by RP HPLC using C18 column with a gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA to give 36 mg of product (63%) as a clear gel. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.05 (s, 9H), 1.18-1.29 (m, 2H), 1.29 (t, 6H, J = 7 Hz), 1.85 (s, 3H), 2.00- 2.13 ( m, 2H), 2.19 (s, 3H), 2.85 (s, 3H), 3.32- 3.43 (m, 2H), 3.47 (d, 2H, J = 7 Hz), 3.69 (s, 2H), 3.79 (s , 3H), 4.05 (pent, 4H, J = 7 Hz), 4.30- 4.37 (m, 2H), 5.13 (s, 2H), 5.45 (t, 1H, J = 7 Hz) ppm; ³¹ P (121.4 MHz, CD ₃ Cl) δ 27.5 ppm; MS ( m / z ) 642.2 [M + Na] ⁺ .

(2-{[4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -2- methyl - Boot -2-ethyl]- Methanesulfonyl -Amino} -ethyl) -phosphonic acid

[2- (Methanesulfonyl- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-di in acetonitrile (0.5 mL) Hydro-isobenzofuran-5-yl] -2-methyl-but-2-ethyl} -amino) -ethyl] -phosphonic acid diethylester (18 mg, 0.029 mmol) was dissolved in TMSBr (38 μl, 0.29 mmol). And 2,6-lutidine (34 μl, 0.29 mmol) at room temperature for 2 hours. The reaction was finished by adding EtOAc and aqueous 1N HCl. The organic layer was washed with brine and the solvent was removed in vacuo. The residue was suspended in 10% TFA-CH ₂ Cl ₂ solution for 10 minutes and then dried to give 9.9 mg (73%) of the desired product as a white solid. ¹ H NMR (300 MHz, DMSO- d6 ) δ 1.76 (s, 3H), 1.76-1.88 (m, 2H), 2.10 (s, 3H), 2.87 (s, 3H), 3.24- 3.35 (m, 2H) , 3.39 (d, 2H, J = 7 Hz), 3.65 (s, 2H), 3.75 (s, 3H), 5.22 (s, 2H), 5.41-5.48 (m, 1H) ppm; ³¹ P (121.4 MHz, DMSO- d6 ) δ 21.4 ppm; MS ( m / z ) 464.1 [M + H] ⁺ .

Example  264: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

[2- (acetyl- {4- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but-2-ethyl} -amino) -ethyl] -phosphonic acid die Tilester

(2- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran- in acetic acid (0.5 mL) To a solution of 5-yl] -2-methyl-but-2-ethylamino} -ethyl) -phosphonic acid diethyl ester (32 mg, 0.059 mmol) was added acetic anhydride (0.5 mL). The solution was stirred at room temperature for 90 minutes and the reaction was stopped by adding 2 drops of water. The solution was dried in vacuo and the residue was purified by RP HPLC using a C18 column with a gradient of H 2 O, 0.1% TFA-acetonitrile, 0.1% TFA to give 28 mg of product (81%) as a clear gel. NMR data of this compound show two rotamers in a ratio of 70:30. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.05 (s, 9H), 1.17-1.27 (m, 2H), 1.30 and 1.31 (t, 6H, J = 7 Hz), 1.70-1.79 (m, 2H), 1.76 (s, 3H), 2.00 (s, 3H), 2.18 (s, 3H), 3.40- 3.52 (m, 2H), 3.46 (d, 2H, J = 7 Hz), 3.77 (s, 3H), 3.79 And 3.93 (s, 3H), 4.07 (pent, 4H, J = 7 Hz), 4.27-4.35 (m, 2H), 5.13 (s, 2H), 5.22- 5.30 (m, 1H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 27.5 and 28.9 ppm; MS ( m / z ) 584.1 [M + H] ⁺ , 606.2 [M + Na] ⁺ .

(2- {acetyl- [4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -2- methyl - Boot -2-ethyl] -amino} -ethyl) -phosphonic acid

[2- (acetyl- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro- in acetonitrile (0.5 mL) TMSBr (31 μL, 0.24 mmol) and 2 in a solution of isobenzofuran-5-yl] -2-methyl-but-2-ethyl} -ethyl] -phosphonic acid diethylester (14 mg, 0.024 mmol) , 6-rutidine (28 μl, 0.24 mmol) was added. The solution was stirred at rt for 1 h. The reaction was stopped by addition of methanol and aqueous 1N HCl. The product was extracted with EtOAc. The combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. The product was purified by RP HPLC using a C18 column with a gradient of H 2 O, 0.1% TFA-acetonitrile, 0.1% TFA to give 5.4 mg (53%) of the product as a white solid. NMR data of this compound represent two rotamers. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.67 and 1.73 (s, 3H), 1.85-2.12 (m, 5H), 2.13 (s, 3H), 3.30-3.61 (m, 4H), 3.75 (s, 3H ), 3.76 (br s, 2 H), 5.17 (s, 2 H), 5.31 (br s, 1 H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 27.5 and 28.8 ppm; MS ( m / z ) 428.2 [M + H] ⁺ , 450.2 [M + Na] ⁺ .

Example  265: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

[2- (benzyl- {4- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro Ro-isobenzofuran-5-yl] -2-methyl-but-2-ethyl} -amino) -ethyl] -phosphonic acid Diethyl ester Porn

(2- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2 -Methyl-but-2-ethylamino} -ethyl) -phosphonic acid diethylester (30 mg, 0.055 mmol), benzaldehyde (5.6 μl, 0.055 mmol) and sodium triacetoxyborohydride (23 mg, 0.11 mmol) The solution of was stirred with acetic acid (15.7 μl, 0.28 mmol) in DMF (0.5 mL) overnight at room temperature. The reaction was stopped with 10% aqueous Na ₂ CO ₃ solution and the product was extracted with EtOAc. The organic layer was dried and concentrated under reduced pressure. The product was purified by RP HPLC using a C18 column with a gradient of H 2 O, 0.1% TFA-acetonitrile, 0.1% TFA to give 15 mg (43%) of the product as a clear gel. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.02 (s, 9H), 1.18-1.25 (m, 2H), 1.24 (t, 6H, J = 7 Hz), 1.86 (s, 3H), 1.88- 2.02 ( m, 2H), 2.16 (s, 3H), 2.65- 2.74 (m, 2H), 3.93 (s, 2H), 3.46 (br d, 4H, J = 7 Hz), 3.76 (s, 3H), 4.00 ( pent, 4H, J = 7 Hz), 4.25- 4.34 (m, 2H), 5.11 (s, 2H), 5.34- 5.43 (m, 1H), 7.18-7.33 (m, 5H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 30.9 ppm; MS ( m / z ) 632.4 [M + H] ⁺ , 654.3 [M + Na] ⁺ .

(2- {benzyl- [4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -2- methyl - Boot -2-ethyl] -amino} -ethyl) -phosphonic acid

(2- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran in acetonitrile (0.5 mL) -5-yl] -2-methyl-but-2-ethylamino} -ethyl) -phosphonic acid diethylester (15 mg, 0.024 mmol) was dissolved in TMSBr (31 μl, 0.24 mmol) and 2,6-lutidine. (28 μl, 0.24 mmol). The solution was stirred at ambient temperature for 1 hour and stopped with methanol. The solvent was removed under reduced pressure and the residue was purified by RP HPLC using C18 column with a gradient of H 2 O, 0.1% TFA-acetonitrile, 0.1% TFA to give 11 mg (93%) of the product as a white solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.89 (s, 3H), 2.03- 2.15 (m, 2H), 2.14 (s, 3H), 3.30- 3.47 (m, 2H), 3.50 (br s, 2H ), 3.62 (br s, 2H), 3.79 (s, 3H), 4.28 (s, 2H), 5.23 (s, 2H), 5.76 (br s, 1H), 7.46 (br s, 5H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 20.1 ppm; MS ( m / z ) 476.3 [M + H] ⁺ , 498.3 [M + Na] ⁺ .

Example  266: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

[2-( Formyl -{4- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro - Isobenzofuran -5-yl] -2-methyl-but-2-ethyl} -amino) -ethyl] -phosphonic acid Diethyl ester

(2- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran- in formic acid (1 mL) 5-yl] -2-methyl-but-2-ethylamino} -ethyl) -phosphonic acid diethyl ester (74 mg, 0.14 mmol) was added to a solution of formic anhydride (1 mL) and the solution was allowed to stand at room temperature for 1 hour. Was stirred. The reaction mixture was concentrated and the crude product was used for the next step. NMR data of this compound show two rotamers in a ratio of 70:30. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.05 (s, 9H), 1.18-1.28 (m, 2H), 1.28 and 1.30 (t, 6H, J = 7 Hz), 1.74 (s, 3H), 1.84- 2.08 (m, 2H), 2.19 (s, 3H), 3.34- 3.45 (m, 2H), 3.47 (d, 2H, J = 7 Hz), 3.72 and 3.87 (s, 2H), 3.78 and 3.79 (s, 3H), 4.06 and 4.07 (pent, 4H, J = 7 Hz), 4.26- 4.37 (m, 2H), 5.13 (s, 2H), 5.30-5.46 (m, 1H), 8.03 and 8.19 (s, 1H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 27.5 and 28.1 ppm; MS ( m / z ) 570.1 [M + H] ⁺ , 592.2 [M + Na] ⁺ .

(2-{ Formyl -[4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -2- methyl - Boot -2-ethyl] -amino} -ethyl) -phosphonic acid

Crude [2- (formyl- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3- in acetonitrile (1 mL) TMSBr (177 μl, 1.4 mmol) in dihydro-isobenzofuran-5-yl] -2-methyl-but-2-ethyl} -amino) -ethyl] -phosphonic acid diethylester (78 mg, 0.14 mmol) solution ) And 2,6-lutidine (163 μl, 1.4 mmol) were added. The solution was stirred at room temperature for 1 hour and the reaction was stopped by addition of methanol and 1N aqueous HCl. The product was extracted with EtOAc and purified by RP HPLC using C18 column with a gradient of H 2 O, 0.1% TFA-acetonitrile, 0.1% TFA to give 29 mg of the product as a white solid. NMR data of this compound show two rotamers at a ratio of about 70:30. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.62 and 1.64 (s, 3H), 1.83-1.98 (m, 2H), 2.16 (s, 3H), 3.38-3.55 (m, 4H), 3.78 (s, 3H), 3.80 and 3.91 (s, 2H), 5.22 (s, 2H), 5.39-5.52 (m, 1H), 8.03 and 8.18 (s, 1H) ppm; MS ( m / z ) 414.2 [M + H] ⁺ , 436.2 [M + Na] ⁺ .

Example  267: Preparation of representative compounds of the present invention.

Representative compounds of the present invention can be prepared as follows.

({4- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro Isobenzofuran-5-yl] -2-methyl-but-2-ethylamino} -methyl) -phosphonic acid Diethyl ester

4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] in DMF (10 mL) -2-methyl-but-2-enal (500 mg, 1.33 mmol), (2-aminomethyl) phosphonic acid diethylester oxalate (376 mg, 1.46 mmol), sodium triacetoxyborohydride (563 mg, 2.66 mmol) was added acetic acid (380 μL, 6.65 mmol) at room temperature. The solution was stirred overnight and the reaction was stopped by addition of saturated aqueous sodium bicarbonate solution and EtOAc. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 500 mg (71%) of the product as an oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.00 (s, 9H), 1.13- 1.23 (m, 2H), 1.25 and 1.27 (t, 6H, J = 7 Hz), 1.65- 1.75 (m, 2H), 1.77 (s, 3H), 2.13 (s, 3H), 2.80 (s, 1H), 3.14 (s, 2H), 3.41 (d, 2H, J = 7 Hz), 3.73 (s, 3H), 4.08 and 4.09 (pent, 4H, J = 7 Hz), 4.20- 4.30 (m, 2H), 5.08 (s, 2H), 5.30 (t, 1H, J = 7 Hz) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 26.5 ppm; MS ( m / z ) 528.1 [M + H] ⁺ , 550.2 [M + Na] ⁺ .

{[4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -2- methyl - Boot -2- Ethylamino ]- methyl } -Phosphonic acid

({4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5- in DMF (0.5 mL) In a solution of yl] -2-methyl-but-2-ethylamino} -methyl) -phosphonic acid diethylester (20 mg, 0.038 mmol), TMSBr (49 μl, 0.38 mmol) and 2,6-lutidine (44 Μl, 0.38 mmol) was added. The solution was stirred at room temperature for 1 hour and methanol was added to stop the reaction. The product was purified by RP HPLC using a C18 column with a gradient of H 2 O, 0.1% TFA-acetonitrile, 0.1% TFA to give 5.6 mg of the product as a white solid. ¹ H NMR (300 MHz, CD ₃ OD and CDCl ₃ ) δ 1.93 (s, 3H), 2.13 (s, 3H), 2.94 (br d, 2H, J = 11 Hz), 3.42-3.53 (m, 2H) , 3.60 (s, 2H), 3.78 (s, 3H), 5.22 (s, 2H), 5.71 (br s, 1H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 8.5 ppm; MS ( m / z ) 372.2 [M + H] ⁺ , 743.2 [2M + H] ⁺ .

Example  268: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

2-({2- [4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -2- methyl -But-2-ethylamino] -ethyl} -phenoxy-phosphinoyloxy) -propionic acid ethyl ester

4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-buty 2-enal (188 mg, 0.5 mmol) solution was diluted with 2-[(2-aminoethyl) phenoxy-phosphinoyloxy] -propionic acid ethyl ester acetic acid salt in CH ₂ Cl ₂ (3 mL) (315.8 mg, 0.75 mmol) and then stirred at ambient temperature for 2 hours. Sodium triacetoxyborohydride (159 mg, 0.75 mmol) was added to the solution and the reaction proceeded for 1 hour. The reaction was stopped by addition of a saturated aqueous solution of NaHCO ₃ and the product was extracted with EtOAc. The organic layer was removed under reduced pressure and the residue was resuspended in 10% TFA / CH ₂ Cl ₂ for 1 hour. The reaction mixture was concentrated and the product was purified by RP HPLC using a C18 column with a gradient of H 2 O, 0.1% TFA-acetonitrile, 0.1% TFA to give 198 mg of the product as a white solid. NMR data of this compound show diastereomers in two phosphorus in a ratio of about 45:55. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.23 and 1.24 (t, 3H, J = 7 Hz), 1.38 and 1.52 (d, 3H, J = 7 Hz), 1.97 and 1.98 (s, 3H), 2.14 (s, 3H), 2.44- 2.66 (m, 2H), 3.31- 3.48 (m, 2H), 3.51 (d, 2H, J = 7 Hz), 3.66 (d, 2H, J = 5 Hz), 3.80 ( s, 3H), 4.10-4.27 (m, 2H), 4.90-5.10 (m, 1H), 5.20 (s, 2H), 5.73-5.82 (m, 1H), 7.15- 7.27 (m, 3H), 7.35- 7.45 (m, 2 H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 22.6, 24.3 ppm; MS ( m / z ) 561.9 [M + H] ⁺ .

Example  269: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

2- [hydroxy- (2- {4- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro - Isobenzofuran -5-day] -2- methyl - Boot -2- Ethylamino }-ethyl)- Phosphinoyloxy ] -Propionic acid ethyl ester

4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-buty A 2-enal (38 mg, 0.1 mmol) solution was added to 2-[(2-aminoethyl) -phenoxy-phosphinoyloxy] -propionic acid ethyl ester acetic acid (63 mg, 0.15 in CH ₂ Cl ₂ (1 mL). mmol) and then stirred at ambient temperature for 2 hours. Sodium triacetoxyborohydride (32 mg, 0.15 mmol) was added to the solution and the reaction proceeded for 1 hour. The reaction was stopped by addition of a saturated aqueous solution of NaHCO ₃ and the product was extracted with EtOAc. The organic layer was removed under reduced pressure and the residue was resuspended in 10% TFA / CH ₂ Cl ₂ for 1 hour. The reaction mixture was concentrated and the product was purified by RP HPLC using C18 column with a gradient of H 2 O, 0.1% TFA-acetonitrile, 0.1% TFA to give 15 mg of product (154-2). ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.04 (s, 9H), 1.15- 1.24 (m, 2H), 1.26 (t, 3H, J = 7 Hz), 1.48 (d, 3H, J = 7 Hz) , 1.93 (s, 3H), 2.10-2.25 (m, 2H), 2.18 (s, 3H), 3.10-3.31 (m, 2H), 3.48 (d, 2H, J = 7 Hz), 3.48-3.61 (m , 2H), 3.77 (s, 3H), 4.04- 4.21 (m, 2H), 4.29-4.40 (m, 2H), 4.81-4.92 (m, 1H), 5.13 (s, 2H), 5.64 (t, 1H , J = 7 Hz), 8.70-9.11 (m, 3H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 21.9 ppm; MS ( m / z ) 586.3 [M + H] ⁺ , 1171.4 [2M + H] ⁺ .

2- (hydroxy- {2- [4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -2- methyl - Boot -2- Ethylamino ]-ethyl}- Phosphinoyloxy ) -Propionic acid

2- [hydroxy- (2- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) in 10% TFA-CH ₂ Cl ₂ (1 mL) ) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but-2-ethylamino} -ethyl) -phosphinoyloxy] -propionic acid ethyl ester (15 mg, 0.026 mmol) solution Was stirred at ambient temperature for 10 minutes. The solvent was removed to complete the reaction. The residue was dissolved in THF (0.5 mL) and water (0.4 mL) and 1N aqueous NaOH solution (0.1 mL) was added. The solution was stirred at room temperature for 20 minutes and acidified with 1N aqueous HCl solution. The resulting solution was purified by RP HPLC using a C18 column with a gradient of H 2 O, 0.1% TFA-acetonitrile, 0.1% TFA to give 6.8 mg of the product as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.38 (d, 3H, J = 7 Hz), 1.91 (s, 3H), 2.13 (s, 3H), 2.12- 2.28 (m, 2H), 3.12- 3.33 ( m, 2H), 3.41 (d, 2H, J = 6 Hz), 3.56 (br s, 2H), 3.75 (s, 3H), 4.71- 4.88 (m, 1H), 5.16 (s, 2H), 5.58- 5.71 (m, 1 H), 7.88 (br s, 3 H), 8.60 (br s, 1 H), 8.78 (br s, 1 H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 22.0 ppm; MS ( m / z ) 458.3 [M + H] ⁺ , 480.3 [M + Na] ⁺ .

Example  270: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

{One- Cyano -5- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro - Isobenzofuran -5-yl] -3-methyl-pent-3-enyl} -phosphonic acid Diethyl ester

To a solution of diethylcyanomethylphosphonate (241 mg, 1.38 mmol) in THF (1 mL) was added a THF solution of sodium bis (trimethylsilyl) amide (1.0 M, 1.13 mL, 1.15 mmol). After stirring for 30 minutes, the solution was poured into 6- (4-bromo-3-methyl-but-2-ethyl) -7-hydroxy-5-methoxy-4-methyl-3H- in THF (1 mL). To the solution of isobenzofuran-1-one (100 mg, 0.23 mmol) was added dropwise. The resulting mixture was stirred at rt for 1 h, then saturated aqueous ammonium chloride was added. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to dryness. The residue was purified by silica gel column chromatography to give 110 mg (90%) of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.04 (s, 9H), 1.24 (dd, J = 7, 8 Hz, 2H), 1.36 (t, 6H), 1.86 (s, 3H), 2.17 (s, 3H), 2.43-2.57 (m, 2H), 3.04-3.17 (m, 1H), 3.47 (d, J = 7.2 Hz, 2H), 3.79 (s, 3H), 4.12-4.37 (m, 6H), 5.13 (s, 2H), 5.44 (t, J = 7.2 Hz, 1H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 18.18 ppm; MS ( m / z ) 560 [M + Na] ⁺ .

[One- Cyano -5- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-yl) -3-methyl-pent-3-enyl] -phosphonic acid Diethyl ester

{1-Cyano-5- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] 3-Methyl-pent-3-enyl} -phosphonic acid diethylester (25 mg, 0.047 mmol) was dissolved in 10% TFA / CH ₂ Cl ₂ (5 mL) solution and stirred at room temperature for 2 hours. The reaction mixture was dried under reduced pressure and the product was purified by RP-HPLC to give 16 mg (80%) of the desired product as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.38 (t, 6H), 1.86 (s, 3H), 2.15 (s, 3H), 2.40-2.58 (m, 2H), 3.01-3.14 (m, 1H), 3.45 (d, J = 7.2 Hz, 2H), 3.79 (s, 3H), 4.18-4.30 (m, 4H), 5.21 (s, 2H), 5.48 (t, J = 7.2 Hz, 1H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 18.09 ppm; MS ( m / z ) 436 [M−H] ⁻ , 438 [M + H] ⁺ .

Example  271: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

[One- Cyano -5- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -3- methyl - Pent -3- Enil ] -Phosphonic acid

{1-Cyano-5- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-iso in acetonitrile (2 mL) In a solution of benzofuran-5-yl] -3-methyl-pent-3-enyl} -phosphonic acid diethylester (35 mg, 0.065 mmol), TMSBr (180 μl, 1.38 mmol) and 2,6-lutidine (160 Μl, 1.38 mmol) was added. The reaction solution was stirred at room temperature for 1 hour and then stopped with MeOH. The reaction mixture was dried under reduced pressure and the residue was purified by RP HPLC using a C18 column with a gradient of H 2 O, 0.1% TFA-acetonitrile, 0.1% TFA to give 15 mg (60%) of the desired product. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.86 (s, 3H), 2.15 (s, 3H), 2.38-2.57 (m, 2H), 3.17-3.28 (m, 1H), 3.44 (d, J = 7.2 Hz, 2H), 3.80 (s, 3H), 5.25 (s, 2H), 5.47 (t, J = 7.2 Hz, 1H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 15.28 ppm; MS ( m / z ) 380 [M−H] ⁻ , 382 [M + H] ⁺ .

Example  272: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

{One- Cyano -5- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro Isobenzofuran-5-yl] -1,3-dimethyl-pent-3-enyl} -phosphonic acid Diethyl ester

In THF (0.5 mL) {1-Cyano-5- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] To a solution of 3-methyl-pent-3-enyl} -phosphonic acid diethyl ester (45 mg, 0.084 mmol) was added sodium bis (trimethylsilyl) amide (1.0 M, 1.13 mL, 1.15 mmol). After stirring for 20 minutes, methane iodide (52 μl, 0.84 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was stopped with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to dryness. The residue was purified by RP HPLC using a C18 column with a gradient of H 2 O, 0.1% TFA-acetonitrile, 0.1% TFA to give 6.6 mg (23%) of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.00 (s, 9H), 1.16 (dd, J = 7, 8 Hz, 2H), 1.31 (t, 6H), 1.38 (d, 3H), 1.92 (s, 3H), 2.17 (s, 3H), 2.23 (m, 1H), 2.65 (m, 1H), 3.30-3.42 (m, 2H), 3.73 (s, 3H), 4.14-4.27 (m, 6H), 5.08 (s, 2H), 5.28 (t, J = 7.2 Hz, 1H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 22.26 ppm; MS ( m / z ) 574 [M + Na] ⁺ .

[One- Cyano -5- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-yl) -1,3-dimethyl- Pent -3- Enil ] -Phosphonic acid

{1-cyano-5- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3 in DMF (0.5 mL) and DCM (0.5 mL) -Dihydro-isobenzofuran-5-yl] -1,3-dimethyl-pent-3-enyl} -phosphonic acid diethylester (18 mg, 0.04 mmol) in solution TMSBr (51 μL, 0.4 mmol) and 2 , 6-Lutidine (46 μl, 0.4 mmol) was added. The reaction solution was stirred overnight at room temperature and then stopped with MeOH. The reaction mixture was dried under reduced pressure and the residue was purified by RP HPLC using C18 column with a gradient of H 2 O, 0.1% TFA-acetonitrile, 0.1% TFA to give 4.5 mg (33%) of the desired product. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.37 (d, 3H), 1.87 (s, 3H), 2.13 (s, 3H), 2.26 (m, 1H), 2.64 (m, 1H), 3.39 (m , 2H), 3.75 (s, 3H), 5.18 (s, 2H), 5.34 (m, 1H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 21.47 ppm; MS ( m / z ) 422 [M−H] ⁻ , 424 [M + H] ⁺ .

Example  273: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

2-ethyl-4- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- D-Hydro - Isobenzofuran -5 days]- Boot -2- Yen

In toluene (14 mL) [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1, 3-dihydro-isobenzofuran-5-yl] -acetaldehyde (1.5 g, 4.46 mmol) solution was heated at 100 ° C. overnight with 2- (triphenyl-phosphanilidene) -butyraldehyde (1.68 g, 5.35 mmol). A second portion of 2- (triphenyl-phosphanilidene) -butyraldehyde (495 mg, 1.49 mmol) was added and the reaction mixture was heated another day. After concentration, the residue was purified by silica gel chromatography to give 1.3 g (83%) of the desired product as an oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.01 (s, 9H), 1.03 (t, 3H), 1.10-1.21 (m, 2H), 2.15 (s, 3H), 2.15-2.44 (m, 2H), 3.67-3.76 (m, 2H), 3.74 (s, 3H), 4.31- 4.36 (m, 2H), 5.10 (s, 2H), 6.34-6.38 (m, 1H), 9.28 (s, 1H) ppm.

6- (3- Hydroxymethyl - Pent -2- Enil ) -5- Methoxy -4- methyl -7- (2- Trimethylsilanyl - Ethoxy ) -3H- Isobenzofuran -1-on

2-ethyl-4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-di in methanol (10 mL) and THF (10 mL) Hydro-isobenzofuran-5-yl] -but-2-enal (1.3 g, 3.30 mmol) solution was cooled to 0 ° C. CeCl ₃ solution (8.25 mL, 0.4M, MeOH: H ₂ O, 9: 1) was added followed by LiBH ₄ (1.66 mL, 3.30 mmol of 2M solution in THF). The ice bath was removed and the reaction mixture was warmed to room temperature. The reaction mixture was stirred for a further 40 minutes and TLC confirmed that the starting aldehyde was consumed completely. The reaction was finished by addition of aqueous 1N HCl and the product was extracted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography to give 948 mg (73%) of the product as colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.00 (s, 9H), 1.07 (t, 3H), 1.20 (dd, 2H, J = 7, 8 Hz), 2.13 (s, 3H), 2.38-2.50 ( m, 2H), 3.77 (s, 3H), 3.99 (s, 2H), 4.27 (dd, 2H, J = 7, 8 Hz), 5.08 (s, 2H), 5.34 (t, J = 7.2 Hz, 1H ) ppm.

6- (3- Bromomethyl - Pent -2- Enil ) -5- Methoxy -4- methyl -7- (2- Trimethylsilanyl - Ethoxy ) -3H- Isobenzofuran -1-on

Polymer-supported triphenylphosphine (3 mmol / g, 0.66 g) was immersed in dichloromethane (6 mL) for 1 hour. 6- (3-hydroxymethyl-pent-2-enyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one (260 mg , 0.66 mmol) and carbon tetrabromide (657 mg, 1.98 mmol) were added sequentially and the mixture was shaken at room temperature for 1 hour. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography to give 233 mg (77%) of the product as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.00 (s, 9H), 1.08 (t, 3H), 1.20 (dd, 2H, J = 7, 8 Hz), 2.14 (s, 3H), 2.35-2.43 ( m, 2H), 3.44 (d, J = 7.2, 2H), 3.73 (s, 3H), 3.95 (s, 2H), 4.27 (dd, 2H, J = 7, 8 Hz), 5.08 (s, 2H) , 5.53 (t, J = 7.2 Hz, 1H) ppm.

[2-ethyl-4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5 days)- Boot -2-ethyl] -phosphonic acid

6- (3-bromomethyl-pent-2-enyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H in trimethylphosphite (1.5 mL, 12.75 mmol) The solution of isobenzofuran-1-one (230 mg, 0.5 mmol) was heated to 100 ° C. for 4 hours. The reaction was finished by removing excess trimethylphosphite under reduced pressure. The residue was dissolved in acetonitrile (1 mL) and TMSBr (646 μl, 5.0 mmol) and 2,6-lutidine (580 μl, 5.0 mmol) were added at 0 ° C. The reaction solution was warmed to room temperature and stirred for 4 hours. The reaction was cooled to 0 ° C. and stopped by addition of MeOH. The reaction mixture was dried under reduced pressure and the residue was purified by RP HPLC using C18 column with a gradient of H 2 O, 0.1% TFA-acetonitrile, 0.1% TFA to give 77 mg (58%) of product. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.08 (t, 3H), 2.16 (s, 3H), 2.43 (m, 2H), 2.48 (d, 2H, J = 22 Hz), 3.46 (t, 2H , J = 6 Hz), 3.79 (s, 3H), 5.25 (s, 2H), 5.38 (q, 1H, J = 7 Hz) ppm .; ³¹ P (121.4 MHz, CD ₃ OD) δ 25.65 ppm .; MS ( m / z ) 355 [M−H] ⁻ , 357 [M + H] ⁺ .

Example  274: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

{One- Cyano -3-ethyl-5- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro Isobenzofuran-5-yl] -pent-3-enyl} -phosphonic acid Diethyl ester

To a solution of diethylcyanomethylphosphonate (233 mg, 1.32 mmol) in THF (1 mL) was added a THF solution (1.0 M, 1.21 mL, 1.21 mmol) of sodium bis (trimethylsilyl) amide. After stirring for 30 minutes, the solution was added to 6- (3-bromomethyl-pent-2-enyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl- in THF (1 mL). To the solution of methoxy) -3H-isobenzofuran-1-one (100 mg, 0.22 mmol) was added dropwise. The resulting mixture was stirred at rt overnight before saturated aqueous ammonium chloride was added. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to dryness. The residue was purified by preparative reverse phase HPLC to give 51 mg (42%) of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.04 (s, 9H), 1.07 (t, 3H), 1.24 (dd, 2H, J = 7, 8 Hz), 1.36 (t, 6H), 2.12 (m, 1H), 2.18 (s, 3H), 2.35-2.47 (m, 2H), 2.67 (m, 1H), 3.00-3.14 (m, 1H), 3.44 (d, J = 7.2, 2H), 3.79 (s, 3H), 4.12-4.37 (m, 6H), 5.13 (s, 2H), 5.38 (t, J = 7.2 Hz, 1H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 18.26 ppm; MS ( m / z ) 574 [M + Na] ⁺ .

[One- Cyano -3-ethyl-5- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5 days)- Pent -3- Enil ] -Phosphonic acid

{1-Cyano-3-ethyl-5- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran- 5-yl] -pent-3-enyl} -phosphonic acid diethylester (19.5 mg, 0.035 mmol) was dissolved in 10% TFA / CH ₂ Cl ₂ (2 mL) solution and stirred at room temperature for 10 minutes. The reaction mixture was dried under reduced pressure and purified by RP-HPLC to give 9.5 mg (61%) of the desired product. This material was dissolved in DMF (0.5 mL) and DCM (0.5 mL) and TMSBr (27 μl, 0.2 mmol) and 2,6-lutidine (23 μl, 0.2 mmol) were added. The reaction solution was stirred overnight at room temperature and then stopped with MeOH. The reaction mixture was dried under reduced pressure and the residue was purified by RP HPLC using C18 column with a gradient of H 2 O, 0.1% TFA-acetonitrile, 0.1% TFA to give 5.1 mg (65%) of the desired product as a white solid. . ¹ H NMR (300 MHz, CD ₃ OD) δ 1.10 (t, 3H), 2.16 (s, 3H), 2.23-2.52 (m, 3H), 2.67 (m, 1H), 3.05-3.20 (m, 1H) , 3.48 (d, J = 7.2, 2H), 3.81 (s, 3H), 5.26 (s, 2H), 5.43 (t, J = 7.2 Hz, 1H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 14.18 ppm; MS ( m / z ) 394 [M−H] ⁻ , 396 [M + H] ⁺ .

Example  275: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

{2-ethyl-4- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro - Isobenzofuran -5-yl] -but-2-ethyloxymethyl} -phosphonic acid Diisopropyl  ester

Bromomethylphosphonate diisopropyl ester (680 mg, 2.62 mmol) and 6- (3-hydroxymethyl-pent-2-enyl) -5-methoxy-4-methyl-7- in DMF (3 mL) To a solution of (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one (688 mg, 1.75 mmol) was added lithium t-butoxide (1.0 M in THF, 2.6 mL). The reaction was heated at 70 ° C. for 2 hours. After cooling to ambient temperature, further bromomethylphosphonate diisopropyl ester (680 mg, 2.62 mmol) and lithium t-butoxide (1.0 M in THF; 2.6 mL) were added. The reaction mixture was heated at 70 ° C. for another hour, then cooled and extracted with lithium chloride (5% aqueous) and ethyl acetate solution. The organic extract was dried and the product was purified by chromatography on silica gel eluting with hexane-ethyl acetate to give 347 mg (35%) of the product as colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.04 (s, 9H), 1.09 (t, 3H, J = 7.5 Hz), 1.20- 1.26 (m, 2H), 1.31 (t, 12H, J = 6 Hz) , 2.18 (s, 3H), 2.29 (q, 2H, J = 7.5 Hz), 3.5 (m, 2H), 3.59 (d, 2H, J = 8.7 Hz), 3.78 (s, 3H), 3.98 (s, 2H), 4.28-4.35 (m, 2H), 4.6-4.8 (m, 2H), 5.13 (s, 2H), 5.4 (t, 1H, J = 7 Hz) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 20.26 ppm; MS ( m / z ) 593.3 [M + Na] ⁺ .

[2-ethyl-4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5 days)- Boot -2- Ethyloxymethyl ] -Phosphonic acid

{2-ethyl-4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran in acetonitrile (5 mL) -5-yl] -but-2-ethyloxymethyl} -phosphonic acid diisopropyl ester (347 mg, 0.61 mmol) in a solution of 2,6-lutidine (0.71 mL, 6.1 mmol) and bromotrimethylsilane (0.786 mL , 6.1 mmol) was added. The mixture was stirred at rt for 3 h, stopped with methanol (5 mL), then concentrated and partitioned between ethyl acetate and 1N HCl (aq). The organic layer was concentrated to give free phosphonic acid as colorless oil (205 mg, 70%). This material (20 mg) was dissolved in a solution of trifluoroacetic acid (0.3 mL) and dichloromethane (2.7 mL) and stirred at ambient temperature for 30 minutes. After concentration, the residue was purified by RP HPLC using a C18 column with a gradient of H 2 O, 0.1% TFA-acetonitrile, 0.1% TFA to give the product as a white solid (10 mg) after freeze drying. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.007 (t, 3H, J = 7.5 Hz), 2.13 (s, 3H), 2.32 (q, 2H, J = 7.5 Hz), 3.41 (d, 2H, J = 6.3 Hz), 3.56 (d, 2H, J = 9 Hz), 3.75 (s, 3H), 3.95 (s, 2H), 5.16 (s, 2H), 5.43 (t, 1H, J = 6.3 Hz) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 22.8 ppm; MS (m / z) 385.2 [ MH] +, 387.1 [M + H] +.

Example  276: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

6- Allyloxy -3- methyl -4- Trifluoromethanesulfonyloxy Phthalic acid dimethyl ester

6-allyloxy-4-hydroxy-3-methyl-phthalic acid dimethyl ester (8.06 g, 28.8 mmol) in dichloromethane (DCM) (20 mL) at 0 ° C. [JW Patterson, Tetrahedron, 1993 , 49 , 4789- To acetic acid according to 4798] and to a solution of pyridine (11.4 g, 144.0 mmol). The reaction was stirred at 0 ° C. for 2 hours, after which additional triacid anhydride (3 mL) was added. Stirring was continued for 1 hour at 0 ° C. The reaction mixture was poured into a mixture of DCM and HCl (1N). The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over sodium sulfate. Filtration and evaporation of the solvent in vacuo gave the crude product which was then purified by silica gel chromatography to give 8.39 g of product as oil. ¹ H NMR (300 MHz, CDCl ₃ ): = 2.32 (s, 3H), 3.89 (s, 6H), 4.60 (m, 2H), 5.33 (d, J = 9.3 Hz, 1H), 5.41 (d, J = 18.6 Hz, 1H), 5.95 (m, 1H), 6.95 (s, 1H) ppm; ¹⁹ F NMR (282 MHz, CDCl ₃ ): = -74 ppm.

6-hydroxy-3- methyl -4- Trifluoromethanesulfonyloxy Phthalic acid dimethyl ester

Tetrakistriphenylphosphine palladium (8.39 g, 20.3 mmol) in a solution of 6-allyloxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethyl ester (8.39 g, 20.3 mmol) in toluene (20 mL) at room temperature under a nitrogen atmosphere. 0.47 g, 0.40 mmol) and diethylamine (2.97 g, 40.86 mmol) were added. Stirring was continued at room temperature until all starting material was consumed. The resulting reaction mixture was partitioned between diethyl ether and HCl (0.1 N). The organic layer was washed with brine and dried over sodium sulfate. Filtration and evaporation of the solvent in vacuo gave the crude product which was then purified by silica gel chromatography to give 4.16 g (55%) of the desired product as an off-white solid. ¹ H NMR (300 MHz, CDCl ₃ ): = 2.20 (s, 3H), 3.93 (s, 3H), 3.95 (s, 3H), 7.01 (s, 1H) ppm; ¹⁹ F NMR (282 MHz, CDCl ₃ ): = -74 ppm.

6-hydroxy-3- methyl 4-vinyl-phthalic acid dimethyl ester

Lithium chloride (743 mg, 17.5 mmol) in a solution of 6-hydroxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethyl ester (2.17 g, 5.85 mmol) in N -methyl pyrrolidinone (15 mL) ) And triphenyllacin (179 mg, 0.585 mmol) were added. Tributylvinyl tin (2.04 g, 6.43 mmol) was added, followed by tris (tribenzylideneacetone) dipalladium (0) -chloroform adduct (90 mg, 0.087 mmol). The reaction was placed under nitrogen atmosphere and heated at 60 ° C. for 18 hours. The reaction was cooled to room temperature and poured into a mixture of ice (20 g), EtOAc (40 mL) and potassium fluoride (1 g). Stirring was continued for 1 hour. The aqueous layer was extracted with EtOAc and the organic extract was filtered through celite. The combined organic layers were washed with water and dried over sodium sulfate. Filtration and evaporation of the solvent in vacuo gave the crude product, which was then purified by silica gel chromatography to give 1.27 g (87%) of the product as a pure white solid. ¹ H NMR (300 MHz, CDCl ₃ ): = 2.16 (s, 3H), 3.91 (s, 3H), 3.92 (s, 3H), 5.46 (dd, J = 11.1, 1.2 Hz, 1H), 5.72 (dd , J = 17.1, 0.9 Hz, 1H), 6.86 (dd, J = 17.1, 11.1 Hz, 1H), 7.14 (s, 1H), 10.79 (s, 1H) ppm.

4-ethyl-6-hydroxy-3- methyl Phthalic acid dimethyl ester

6-hydroxy-3-methyl-4-vinyl-phthalic acid dimethyl ester (1.27 g, 5.11 mmol) was dissolved in benzene (10 mL) and EtOAc (10 mL). Tristriphenylphosphine rhodium chloride (150 mg) was added and the reaction was placed under hydrogen atmosphere. Stirring was continued at room temperature. After 14 hours, the solvent was removed in vacuo and the crude material was purified by silica gel chromatography to give 1.14 g (88%) of the desired product as a pure white solid. ¹ H NMR (300 MHz, CDCl ₃ ): = 1.19 (t, J = 7.8 Hz, 3H), 2.10 (s, 3H), 2.60 (q, J = 7.8 Hz, 2H), 3.89 (s, 6H), 6.87 (s, 1 H), 10.79 (s, 1 H) ppm.

One 6- Allyloxy -4-ethyl-3- methyl Phthalic acid dimethyl ester

4-ethyl-6-hydroxy-3-methyl-phthalic acid dimethyl ester (1.01 g, 4.02 mmol) was dissolved in DMF (5 mL). Potassium carbonate (3.33 g, 24.14 mmol) was added followed by allyl bromide (2.92 g, 24.14 mmol). The suspension was heated at 60 ° C. After 14 hours, the reaction was cooled to room temperature and filtered. The solvent was removed in vacuo and the crude material was purified by silica gel chromatography to give 0.976 g (83%) of the desired product as colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ): = 1.16 (t, J = 7.2 Hz, 3H), 2.20 (s, 3H), 2.62 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 3.84 (s, 3H), 4.57 (m, 2H), 5.26 (dd, J = 9.3, 1.5 Hz, 1H), 5.41 (dd, J = 13.5, 1.5 Hz, 1H), 5.98 (m, 1H), 6.82 (s, 1H) ppm.

4-allyl-5-ethyl-3-hydroxy-6- methyl Phthalic acid dimethyl ester

6-allyloxy-4-ethyl-3-methyl-phthalic acid dimethyl ester (1.25 g, 4.28 mmol) was heated at 210 ° C. under a nitrogen atmosphere. After 14 hours, the reaction was cooled to room temperature. The crude material was purified by silica gel chromatography to give 0.971 g (77%) of the desired product as colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ): = 1.14 (t, J = 7.8 Hz, 3H), 2.17 (s, 3H), 2.68 (q, J = 7.8 Hz, 2H), 3.49 (m, 2H), 3.86 (s, 3H), 3.89 (s, 3H), 4.89 5.01 (m, 2H), 5.93 (m, 1H), 11.22 (s, 1H) ppm.

5 6-allyl-5-ethyl-7-hydroxy-4- methyl -3H- Isobenzofuran -1-on

4-allyl-5-ethyl-3-hydroxy-6-methyl-phthalic acid dimethyl ester (0.971 g, 3.32 mmol) was dissolved in MeOH (8 mL) at room temperature. A solution of sodium hydroxide (0.798 g, 19.95 mmol) in water (10 mL) was added and the suspension was heated at 55 ° C. After 16 hours, the reaction was cooled to room temperature and washed with diethyl ether. The aqueous layer was acidified (1N HCl) and the suspension was extracted with EtOAc. The combined organic layers were dried over sodium sulfate. Filtration and evaporation of the solvent in vacuo gave the desired bis acid as a white solid (0.846 g, 98%, M ⁺ = 263).

The bis acid was dissolved in acetic acid (6 mL) and HCl (conc., 1.5 mL). The reaction was heated at 80 ° C. Zn flour (0.635 g, 9.72 mmol each) was added in portions every hour for 7 hours. Stirring was continued for 10 hours at 80 ° C. The reaction was cooled to room temperature and water was added. The resulting suspension was extracted with EtOAc. The combined organic extracts were washed with sodium bicarbonate solution and dried over sodium sulfate. Filtration and evaporation of the solvent in vacuo gave the crude product, which was then purified by silica gel chromatography to give 0.375 g (50%) of the product as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ): = 1.14 (t, J = 7.5 Hz, 3H), 2.18 (s, 3H), 2.71 (q, J = 7.5 Hz, 2H), 3.49 (m, 2H), 4.95 (d, J = 17.1 Hz, 1H), 5.02 (d, J = 10.2 Hz, 1H), 5.23 (s, 2H), 5.98 (m, 1H), 7.66 (s, 1H) ppm.

5 6-allyl-5-ethyl-4- methyl -7- (2- Trimethylsilanyl - Ethoxy ) -3H- Isobenzofuran -1-on

6-allyl-5-ethyl-7-hydroxy-4-methyl-3H-isobenzofuran-1-one (199 mg, 0.857 mmol) in THF (3 mL) at 0 ° C., PPh ₃ (337 mg, 1.286) mmol) and 2-trimethylsilylethanol were added diisopropyl azodicarboxylate (259 mg, 1.286 mmol). The resulting yellow solution was warmed to room temperature and stirred for 1 hour. The solvent was removed in vacuo and the crude material was dissolved in diethyl ether (3 mL). Hexane (1.5 mL) was added. Triphenylphosphine oxide was filtered off and the filtrate was concentrated and purified by silica gel chromatography to give the desired product (261 mg, 92%) as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ): = 0.04 (s, 9H), 1.15 (t, J = 7.8 Hz, 3H), 1.25 (m, 2H), 2.20 (s, 3H), 2.73 (q, J = 7.8 Hz, 2H), 3.54 (m, 2H), 4.28 (m, 2H), 4.95 (d, J = 17.1 Hz, 1H), 5.02 (d, J = 10.2 Hz, 1H), 5.15 (s, 2H ), 5.95 (m, 1H) ppm.

[6-ethyl-7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro - Isobenzofuran -5-day] -acetaldehyde

6-allyl-5-ethyl-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzo in MeOH (5 mL), CH ₂ Cl ₂ (5 mL) and pyridine (50 mL) Furan-1-one (261 mg, 0.788 mmol) solution was prepared using Smith, DB et al., J. Org . Cooled to −78 ° C. using a dry ice / acetone bath according to the method of Chem ., 1996 , 61 , 6, 2236. The reaction was bubbled through a gas dispersion tube until the reaction color became blue (15 minutes). The ozone line was replaced with a stream of nitrogen and bubbling for another 15 minutes and the blue color disappeared. To this solution was added some thiourea (59.9 mg, 0.788 mmol) at -78 ° C and the cooling bath was removed. The reaction was warmed to room temperature and stirred for 15 minutes. The reaction mixture was filtered and then partitioned between CH ₂ Cl ₂ and water. The organic layer was removed. The aqueous layer was washed once more with CH ₂ Cl ₂ and the organic extracts were collected. The organic layer was washed with aqueous 1N HCl, saturated NaHCO ₃ and brine and dried over sodium sulfate. Filtration and evaporation of the solvent in vacuo gave the crude product, which was then purified by silica gel chromatography to give 181 mg (69%) of the product white as a solid. ¹ H NMR (300 MHz, CDCl ₃ ): = 0.04 (s, 9H), 1.11 (t, J = 7.5 Hz, 3H), 1.19 (m, 2H), 2.21 (s, 3H), 2.66 (q, J = 7.5 Hz, 2H), 3.90 (s, 2H), 4.36 (m, 2H), 5.18 (s, 2H), 9.71 (s, 1H) ppm.

4- [6-ethyl-7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro - Isobenzofuran -5-day] -2- methyl - Boot -2- Yen

[6-ethyl-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -acetaldehyde in toluene (3 mL) (90 mg, 0.269 mmol) and 2- (triphenyl-phosphorylidene) -propionaldehyde (72.9 mg, 0.23 mmol) were heated at 100 ° C. After 15 hours, the second portion of 2- (triphenyl-phosphanilidene) -propionaldehyde (33 mg, 0.11 mmol) was added and the reaction mixture was further heated for 9 hours. Toluene was removed in vacuo and the residue was purified by silica gel chromatography to give 77.6 mg (77%) of the desired product as pale yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ): = 0.03 (s, 9H), 1.15 (t, J = 7.5 Hz, 3H), 1.21 (m, 2H), 1.93 (s, 3H), 2.21 (s, 3H ), 2.71 (q, J = 7.5 Hz, 2H), 3.82 (d, J = 6.9 Hz, 2H), 4.34 (m, 2H), 5.18 (s, 2H), 6.38 (m, 1H), 9.35 (s , 1H) ppm.

5-ethyl-6- (4-hydroxy-3- methyl - Boot -2-ethyl) -4- methyl -7- (2- Trimethylsilanyl - Ethoxy ) -3H- Isobenzofuran -1-on

4- [6-ethyl-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but- 2-ene (77.6 mg, 0.207 mmol) was dissolved in MeOH (4 mL). A solution of CeCl ₃ (51.1 mg, 0.207 mmol) in MeOH / water (9/1, 0.66 mL) was added and the solution was cooled to 0 ° C. A solution of lithium borohydride in THF (2M, 0.105 mL) was added dropwise. After 15 minutes, the reaction was stopped with 1N HCl (0.5 mL). MeOH was removed in vacuo and the crude material was partitioned between DCM and water. The aqueous layer was extracted with DCM and the combined organic layers were washed with sodium bicarbonate solution and dried over sodium sulfate. Filtration and evaporation of the solvent gave crude oil, which was then purified by silica gel chromatography to give 57.2 mg (73%) of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ): = 0.04 (s, 9H), 1.15 (t, J = 7.8 Hz, 3H), 1.26 (m, 2H), 1.86 (s, 3H), 2.19 (s, 3H ), 2.72 (q, J = 7.8 Hz, 2H), 3.52 (d, J = 6.3 Hz, 2H), 3.99 (s, 2H), 4.34 (m, 2H), 5.14 (s, 2H), 5.32 (m , 1H) ppm.

6- (4- Bromo -3- methyl - Boot -2-ethyl) -5-ethyl-4- methyl -7- (2- Trimethylsilanyl - Ethoxy ) -3H- Isobenzofuran -1-on

5-ethyl-6- (4-hydroxy-3-methyl-but-2-ethyl) -4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one ( 57.2 mg, 0.152 mmol) was dissolved in DCM (3.5 mL). Polymer-bound triphenylphosphine (3 mmol / g, 152.1 mg) was added and the mixture was mechanically stirred at room temperature. Carbon tetrabromide (151.3 mg, 0.456 mmol) was added and the solution stirred at room temperature. After 2 hours, the reaction was filtered and the solvent removed in vacuo. The crude material was purified by silica gel chromatography to give 58.0 mg (87%) of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ): = 0.04 (s, 9H), 1.15 (t, J = 7.8 Hz, 3H), 1.25 (m, 2H), 1.95 (s, 3H), 2.20 (s, 3H ), 2.70 (q, J = 7.8 Hz, 2H), 3.52 (d, J = 6.3 Hz, 2H), 3.94 (s, 2H), 4.28 (m, 2H), 5.14 (s, 2H), 5.50 (m , 1H) ppm.

{4- [6-ethyl-7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro - Isobenzofuran -5-day] -2- methyl - Boot 2-ethyl} -phosphonic acid

4- [6'-ethyl-7'-methyl-3'-oxo-4 '-(2' '-trimethylsilanyl-ethoxy) -1', 3'-dihydro in trimethylphosphite (0.8 mL) -Isobenzofuran-5'-yl] -2-methyl-but-2-ethyl bromide (58 mg, 0.132 mmol) solution was heated at 110 ° C. After 2 hours, the reaction was complete. The reaction was cooled to room temperature and excess trimethylphosphite was removed in vacuo. The crude material was used for the next step without further purification.

The crude product of the Arbuzov reaction was dissolved in MeCN (0.8 mL). Trimethylsilyl bromide (202.2 mg, 1.321 mmol) was added and the reaction stirred at room temperature. After 15 minutes, Lutidine (155.7 mg, 1.453 mmol) was added and stirring continued at room temperature. After 2 hours, further trimethylsilyl bromide (202.2 mg, 1.321 mmol) was added and stirring continued at room temperature. After 4 hours, the reaction was stopped with MeOH (2 mL). The solvent was evaporated in vacuo and the crude material was purified by RP-HPLC (eluent: water / MeCN). The product containing portions are combined and lyophilized to give 2.3 mg (5.1%) of free phosphonic acid. ¹ H NMR (300 MHz, DMSO-d6): = 1.07 (t, J = 7.5 Hz, 3H), 1.84 (s, 3H), 2.14 (s, 3H), 2.64 (q, J = 7.5 Hz, 2H) , 3.34 (m, 4H), 5.06 (m, 1H), 5.25 (s, 2H) ppm; ³¹ P NMR (121 MHz, DMSO-d 6): = 22.19 ppm; MS = 341 [M ⁺ +1].

Example  277: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

[2-ethyl-4- [6-ethyl-7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro - Isobenzofuran -5 days]- Boot -2- Yen

[6-ethyl-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -acetaldehyde in toluene (3 mL) (90 mg, 0.269 mmol) and 2- (triphenyl-phosphorylidene) -butyraldehyde (98.4 mg, 0.296 mmol) were heated at 100 ° C. After 15 hours, the second portion of 2- (triphenyl-phosphanilidene) -butyraldehyde (98.4 mg, 0.296 mmol) was added and the reaction mixture was further heated for 33 hours. After concentration, the residue was purified by silica gel chromatography to give 50.3 mg (48%) of the desired product as pale yellow oil.

5-ethyl-6- (3- Hydroxymethyl - Pent -2- Enil )-4- methyl -7- (2- Trimethylsilanyl - Ethoxy ) -3H- Isobenzofuran -1-on

2-ethyl-4- [6-ethyl-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -but- 2-ene (50.3 mg, 0.129 mmol) was dissolved in MeOH (3 mL). A solution of CeCl ₃ (31.9 mg, 0.129 mmol) in MeOH / water (9/1, 0.66 mL) was added and the solution was cooled to 0 ° C. Lithium borohydride solution (2M, 0.065 mL) in THF was added dropwise. After 10 minutes, the reaction was stopped with 1N HCl (0.5 mL). Methanol was removed in vacuo and the crude material was partitioned between DCM and water. The aqueous layer was extracted with DCM and the combined organic layers were washed with sodium bicarbonate solution and dried over sodium sulfate. Filtration and evaporation of the solvent in vacuo gave crude oil which was then purified by silica gel chromatography to give 35.4 mg (70%) of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ): = 0.04 (s, 9H), 1.10 1.19 (m, 6H), 1.26 (m, 2H), 2.19 (s, 3H), 2.32 (q, J = 7.5 Hz, 2H), 2.72 (q, J = 7.5 Hz, 2H), 3.54 (d, J = 6.6 Hz, 2H), 4.05 (s, 2H), 4.26 (m, 2H), 5.14 (s, 2H), 5.27 ( m, 1H) ppm.

6- (3- Bromomethyl - Pent -2- Enil ) -5-ethyl-4- methyl -7- (2- Trimethylsilanyl - Ethoxy ) -3H- Isobenzofuran -1-on

5-ethyl-6- (3-hydroxymethyl-pent-2-enyl) -4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one (35.4 mg, 0.090 mmol) was dissolved in DCM (3.0 mL). Polymer-bound triphenylphosphine (3 mmol / g, 90.7 mg) was added and the mixture was mechanically stirred at room temperature. Carbon tetrabromide (90.2 mg, 0.272 mmol) was added and the solution was stirred at room temperature. After 2 hours, the reaction was filtered and the solvent removed in vacuo. The crude material was purified by silica gel chromatography to give 32.0 mg (78%) of the desired product. The material was used for the next step without further analysis.

[2-ethyl-4- (6-ethyl-4-hydroxy-7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5 days)- Boot -2-ethyl] -phosphonic acid

6- (3-Bromomethyl-pent-2-enyl) -5-ethyl-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H-isobenzofuran in trimethylphosphite (0.8 mL) The -1-one (32 mg, 0.070 mmol) solution was heated at 110 ° C. After 2 hours, the reaction was complete. The reaction was cooled to room temperature and excess trimethylphosphite was removed in vacuo. The crude material was used for the next step without further purification.

The crude product of the Arbuzov reaction was dissolved in MeCN (0.8 mL). Trimethylsilyl bromide (108.0 mg, 0.706 mmol) was added and the reaction stirred at room temperature. After 2 hours, further trimethylsilyl bromide (108.0 mg, 0.706 mmol) was added and stirring continued at room temperature. After 3 hours, the reaction was stopped with MeOH (2 mL). The solvent was evaporated in vacuo and the crude material was purified by RP-HPLC (eluent: water / MeCN). The product containing portions are combined and lyophilized to give 15.7 mg (63%) of the product. ¹ H NMR (300 MHz, DMSO-d6): = 0.98-1.09 (m, 6H), 2.10 (s, 3H), 2.30 (m, 2H), 2.64 (q, J = 7.5 Hz, 2H), 3.38 ( m, 4H), 5.03 (m, 1H), 5.25 (s, 2H) ppm; ³¹ P NMR (121 MHz, DMSO-d 6): = 22.26 ppm; MS = 355 [M ⁺ +1].

Example  278: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

(2- {4- [6-ethyl-7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro Isobenzofuran-5-yl] -2-methyl-but-2-ethylamino} -ethyl) -phosphonic acid Diethyl ester

4- [6-ethyl-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl-but- 2-ene (19.7 mg, 0.052 mmol) and aminoethylphosphonic acid diethylester oxalate salt (15.6 mg, 0.057 mmol) were dissolved in DMF (0.5 mL). Acetic acid (15.7 mg, 0.263 mmol) was added followed by sodium triacetoxyborohydride (22.3 mg, 0.105 mmol). After 4 hours, the resulting reaction mixture was purified by RP-HPLC (eluent: water / MeCN) to give 27.7 mg (97%) of the desired product after freeze drying. ¹ H NMR (300 MHz, CDCl ₃ ): = 0.04 (s, 9H), 1.14 (t, J = 7.5 Hz, 3H), 1.26 (m, 2H), 1.30 (t, J = 7.2 Hz, 6H), 1.95 (s, 3H), 2.19 (s, 3H), 2.23 (m, 2H), 2.68 (q, J = 7.5 Hz, 2H), 3.18 (m, 2H), 3.53 (s, 2H), 4.13 (m , 4H), 4.28 (m, 2H), 5.15 (s, 2H), 5.51 (m, 1H) ppm; ³¹ P NMR (121 MHz, CDCl ₃ ): = 27.39 ppm; MS = 540 [M ⁺ +1].

2- [4-(-ethyl-4-hydroxy-7- methyl Oxo-1,3- Dehydro - Isobenzofuran -5-day) -2- methyl - Boot -2- Ethylamino ] -Ethyl} -phosphonic acid:

(2- {4- [6-ethyl-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2- Methyl-but-2-ethylamino} -ethyl) -phosphonic acid diethylester (27.7 mg, 0.051 mmol) was dissolved in DMF (0.5 mL) and DCM (0.5 mL). Trimethylsilyl bromide (78.3 mg, 0.512 mmol) was added and the reaction stirred at rt. After 20 hours, the reaction was stopped with MeOH (0.3 mL). The solvent was evaporated in vacuo and the crude material was purified by RP-HPLC (eluent: water / MeCN). Product-containing combined freeze drying gave 14.2 mg (57%) of free phosphonic acid [MS: 484 M ⁺ +1].

The material was dissolved in DCM (0.5 mL). TFA (0.05 mL) was added and stirring continued at room temperature. After 20 minutes, the solvent was removed in vacuo and the crude material was purified by RP-HPLC (eluent: water / MeCN * 0.1% TFA). The product containing portions were combined and lyophilized to give 7.6 mg (52%) of the product as a TFA salt. ¹ H NMR (300 MHz, DMSO-d6) δ = 1.07 (t, J = 7.5 Hz, 3H), 1.84 (s, 3H), 1.90 (m, 2H), 2.11 (s, 3H), 2.63 (q, J = 7.5 Hz, 2H), 2.99 (m, 2H), 3.43 (d, J = 6.3 Hz, 2H), 3.51 (s, 2H), 5.26 (s, 2H), 5.45 (m, 1H) ppm; ³¹ P NMR (121 MHz, DMSO-d 6) δ = 20.02 ppm; MS = 384 [M ⁺ +1].

2- {2-ethyl-4- [6-ethyl-7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dihydro Isobenzofuran-5-yl] -but-2-ethylamino} -ethyl) -phosphonic acid Diethyl ester

2-ethyl-4- [6-ethyl-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -but- 2-ene (26.6 mg, 0.068 mmol) and aminoethylphosphonic acid diethylester oxalate salt (20.4 mg, 0.075 mmol) were dissolved in DMF (0.8 mL). Acetic acid (20.5 mg, 0.342 mmol) was added followed by sodium triacetoxyborohydride (27.6 mg, 0.137 mmol). After 8 h, the resulting reaction mixture was purified by RP-HPLC (eluent: water / MeCN) to give 24.9 mg (65%) of the desired product after freeze drying. ¹ H NMR (300 MHz, CDCl ₃₎ δ = 0.05 (s, 9H), 1.10-1.24 (m, 8H), 1.35 (t, J = 7.5 Hz, 6H), 2.19 (s, 3H), 2.23 (m , 2H), 2.35 (q, J = 7.8 Hz, 2H), 2.70 (q, J = 7.2 Hz, 2H), 3.25 (m, 2H), 3.56 (m, 4H), 4.15 (m, 4H), 4.29 (m, 2H), 5.15 (s, 2H), 5.47 (m, 1H) ppm; ³¹ P NMR (121 MHz, CDCl ₃₎ δ = 27.71 ppm; MS = 554 [M ⁺ +1].

{2- [2-ethyl-4- (6-ethyl-4-hydroxy-7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5 days)- Boot -2- Ethylamino ] -Ethyl} -phosphonic acid

(2- {2-ethyl-4- [6-ethyl-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl ] -But-2-ethylamino} -ethyl) -phosphonic acid diethylester (24.9 mg, 0.045 mmol) was dissolved in DMF (0.5 mL) and DCM (0.5 mL). Trimethylsilyl bromide (68.7 mg, 0.449 mmol) was added and the reaction stirred at room temperature. After 20 hours, the reaction was stopped with MeOH (0.15 mL). The solvent was evaporated in vacuo and the crude material was purified by RP-HPLC (eluent: water / MeCN). The product containing portions were combined and lyophilized to give 8.0 mg of free phosphonic acid [MS: 498 M ⁺ +1].

This material was dissolved in DCM (0.5 mL). TFA (0.05 mL) was added and stirring continued at room temperature. After 20 minutes, the solvent was removed in vacuo and the crude material was purified by RP-HPLC (eluent: water / MeCN * 0.1% TFA). The product containing portions were combined and lyophilized to give 4.4 mg (54%) of the product as a TFA salt. ¹ H NMR (300 MHz, DMSO-d6) δ = 1.05 (m, 6H), 1.60 (m, 2H), 2.10 (s, 3H), 2.67 (q, J = 7.5 Hz, 2H), 2.63 (q, J = 6.9 Hz, 2H), 2.93 (m, 2H), 3.45 (m, 4H), 5.24 (s, 2H), 5.36 (m, 1H) ppm .; ³¹ P NMR (121 MHz, DMSO-d6) δ = 16.93 ppm; MS = 398 [M ⁺ +1].

Example  279: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

2-({4- [6-ethyl-7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro Isobenzofuran-5-yl] -2-methyl-but-2-ethyl} -phenoxy-phosphinoylamino) -ethyl propionate Ster

4- [6'-Ethyl-7'-methyl-3'-oxo-4 '-(2' '-trimethylsilanyl-ethoxy) -1', 3'-dihydro-isobenzofuran-5'- Il] -2-methyl-but-2-en-phosphonic acid (44.8 mg, 0.101 mmol), dicyclohexylcarbodiimide (52.6 mg, 0.254 mmol) and phenol (95.8 mg, 1.018 mmol) were pyridine (0.3 mL ) And heated at 70 ° C. for 4 h. The reaction mixture was cooled to room temperature and pyridine was removed in vacuo. The crude material was partitioned between DCM and HCl (0.1 N). The aqueous layer was extracted with DCM and the combined organic layers were dried over sodium sulfate. Filtration and evaporation of the solvent in vacuo yielded the crude material which was used in the next step without further purification.

The crude material was dissolved in MeCN (0.8 mL) and water (0.3 mL). Aqueous sodium hydroxide solution (2N, 0.8 mL) was added in part (0.2 mL). After all of the starting material was consumed, the organic solvent was removed in vacuo and the crude material was partitioned between chloroform and aqueous HCl (1N). The aqueous layer was extracted with chloroform. The combined organic layers were dried over sodium sulfate. Filtration and evaporation of the solvent gave the crude product as a mixture of monophenyl ester and symmetric anhydride.

The crude material and ethyl ( L ) -alanine hydrogen chloride salt (78.1 mg, 0.509 mmol) of the previous step were dissolved in DMF (0.4 mL). DMAP (1.2 mg, catalytic) was added followed by diisopropylethylamine (131.3 mg, 1.018 mmol). Stirring was continued at room temperature. After 20 minutes complete conversion of the anhydride was observed. After 2 hours, PyBOP (101 mg, 0.202 mmol) was added and stirring continued at room temperature. The reaction was filtered and purified by the resulting reaction solution RP-HPLC (eluent: water / MeCN). The product containing portions were combined and lyophilized to give the product (15.7 mg, 25% for 3 steps) as a white powder. ¹ H NMR (300 MHz, CDCl ₃₎ δ = 0.03 (s, 9H), 1.13 1.28 (m, 8H), 2.03 (s, 3H), 2.19 (s, 3H), 2.62 2.74 (m, 4H), 3.38 (m, 1H), 3.53 (t, J = 6.3 Hz, 2H), 4.03 (m, 3H), 4.30 (m, 2H), 5.14 (s, 2H), 5.31 (m, 1H), 7.11 7.17 (m , 3H), 7.25 7.30 (m, 2H) ppm; ³¹ P NMR (121 MHz, CDCl ₃₎ δ = 27.04, 27.73 ppm; MS = 615 [M ⁺⁺ 1].

2 {[4- (6-ethyl-4-hydroxy-7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-yl) -2-methyl-but-2-ethyl] -phenoxy-phosphinoylamino} -propionic acid ethyl ester

2-({4- [6-ethyl-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2- Methyl-but-2-ethyl} -phenoxy-phosphinoylamino) -propionic acid ethyl ester (7.5 mg, 0.012 mmol) was dissolved in TFA / DCM (10%, 0.3 mL) at −20 ° C. The reaction mixture was warmed to 0 ° C. and stirred at this temperature for 45 minutes. Pyridine (0.09 mL) was added and the solvent was removed in vacuo. The crude material was purified by RP-HPLC (eluent: water / MeCN). The product containing portions were combined and lyophilized to give a white powder (5.5 mg, 87%). ¹ H NMR (300 MHz, CDCl ₃₎ δ = 1.12 1.29 (m, 6H), 2.03 (s, 3H), 2.17 (s, 3H), 2.65 2.74 (m, 4H), 3.38 (m, 1H), 3.53 (t, J = 6.3 Hz, 2H), 4.03 (m, 3H), 5.22 (s, 2H), 5.36 (m, 1H), 7.11 7.16 (m, 3H), 7.24 7.30 (m, 2H), 7.72 ( m, 1H) ppm; ³¹ P NMR (121 MHz, CDCl ₃₎ δ = 27.11, 27.57 ppm; MS = 515 [M ⁺⁺ 1].

Example  280: Preparation of representative compounds of the present invention.

Representative compounds of the present invention can be prepared as follows.

6- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro - Isobenzofuran -5-yl] -4-methyl-hex-4-enoic acid

6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro- in a mixture of methanol (20 mL) and water (7 mL) A mixture of isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid methyl ester (1.5 g, 3.45 mmol) and sodium hydroxide (552 mg) was stirred at rt for 1 h. The solution was acidified with 1N HCl. The precipitate was collected by suction filtration and washed with water to give the desired product (1.2 g, 83%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.02 (s, 9H), 1.15- 1.22 (m, 2H), 1.76 (s, 3H), 2.13 (s, 3H), 2.12- 2.28 (m, 2H), 2.35- 2.41 (m, 2H), 3.37 (d, 2H, J = 7 Hz), 3.71 (s, 3H), 4.22- 4.28 (m, 2H), 5.07 (s, 2H), 5.13- 5.17 (m, 1H) ppm; MS ( m / z ) 419.3 [M ⁻ H] ⁻ , 443.2 [M + Na] ⁺ .

({6- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro Isobenzofuran-5-yl] -4-methyl-hex-4-enoylamino} -methyl) -phosphonic acid Diethyl ester

6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5 in THF (1 mL) at 0 ° C. To a -yl] -4-methyl-hex-4-enoic acid (50 mg, 0.12 mmol) solution isobutylchloroformate (17 μl, 0.13 mmol) and triethylamine (50 μl, 0.36 mmol) were added. . After stirring at 0 ° C. for 2 hours, diethyl (aminomethyl) phosphonate oxalate (62 mg, 0.26 mmol) was added and stirring continued at room temperature for 20 minutes. After removal of the solvent, the residue was purified by preparative reverse phase HPLC to give 54.8 mg (81%) of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.03 (s, 9H), 1.15- 1.22 (m, 2H), 1.31 (t, 6H), 1.81 (s, 3H), 2.18 (s, 3H), 2.30 ( m, 4H), 3.41 (d, 2H, J = 7 Hz), 3.65 (dd, 2H, J = 6, 12 Hz), 3.77 (s, 3H), 3.77-4.16 (m, 4H), 4.26-4.32 (m, 2H), 5.12 (s, 2H), 5.17-5.19 (m, 1H), 5.86 (bs, 1H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 23.01 ppm; MS ( m / z ) 568 [M ⁻ H] ⁻ , 592 [M + Na] ⁺ .

{[6- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -4- methyl - Hex -4- enoyl Amino]- methyl } -Phosphonic acid

({6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5 in acetonitrile (1 mL) To the solution of -yl] -4-methyl-hex-4-enoylamino} -methyl) -phosphonic acid diethyl ester (40 mg, 0.07 mmol) was added TMSBr (91 μl, 0.7 mmol), followed by 2,6- Lutidine (81.5 μl, 0.7 mmol) was added. The reaction was run overnight and LCMS confirmed the completion of the reaction. The reaction mixture was stopped with MeOH and concentrated to dryness. The residue was purified by preparative reverse phase HPLC to give 2.6 mg (9%) of the desired product as a white solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.67 (s, 3H), 2.17 (m, 5H), 2.30-2.46 (m, 2H), 2.80-2.86 (m, 2H), 3.55 (m, 2H) , 3.82 (s, 3H), 5.26 (s, 3H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 10.27 ppm; MS ( m / z ) 412 [M−H] ⁻ , 414 [M + H] ⁺ .

Example  281: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

(2- {6- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro Isobenzofuran-5-yl] -4-methyl-hex-4-enoylamino} -ethyl) -phosphonic acid diethyl ester Porn

6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5 in THF (1 mL) at 0 ° C. To a -yl] -4-methyl-hex-4-enoic acid (50 mg, 0.12 mmol) solution isobutylchloroformate (17 μl, 0.13 mmol) and triethylamine (50 μl, 0.36 mmol) were added. . After stirring for 2 h at 0 ° C., diethyl (aminoethyl) phosphonate oxalate (62 mg, 0.26 mmol) was added and stirring continued for 1 h at room temperature. After removal of the solvent, the residue was purified by preparative reverse phase HPLC to afford 37 mg (54%) of the desired product as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.03 (s, 9H), 1.15- 1.22 (m, 2H), 1.31 (t, 6H), 1.81 (s, 3H), 1.85-1.93 (m, 2H), 2.18 (s, 3H), 2.30 (m, 4H), 3.41 (d, 2H, J = 7 Hz), 3.48-3.54 (m, 2H), 3.77 (s, 3H), 3.77-4.16 (m, 4H) , 4.26-4.32 (m, 2H), 5.12 (s, 2H), 5.17-5.19 (m, 1H), 6.30 (bs, 1H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 29.91 ppm; MS ( m / z ) 584 [M + H] ⁺ .

{2- [6- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -4- methyl - Hex -4- Enoylamino ] -Ethyl} -phosphonic acid

(2- {6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran in acetonitrile (1 mL) -5-yl] -4-methyl-hex-4-enoylamino} -ethyl) -phosphonic acid diethylester (36.6 mg, 0.063 mmol) was added TMSBr (81 μl, 0.63 mmol) followed by 2,6- Lutidine (73 μl, 0.63 mmol) was added. The reaction was run overnight and LCMS confirmed the completion of the reaction. The reaction mixture was stopped with MeOH and concentrated to dryness. The residue was purified by preparative reverse phase HPLC to give 5.8 mg (29%) of the desired product as a white solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.80 (s, 3H), 2.14 (m, 5H), 2.25 (m, 4H), 3.35 (m, 2H), 3.38-3.38 (m, 2H), 3.75 (s, 3H), 5.23 (s, 3H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 26.03 ppm; MS ( m / z ) 426 [M−H] ⁻ , 428 [M + H] ⁺ .

Example  282: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

{4- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro Isobenzofuran-5-yl] -2-methyl-but-2-ethyl} -phosphonic acid Diphenyl  ester

[{4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3- in DMF (6 mL) and phenol (555 mg, 5.9 mmol) In a solution of dihydro-isobenzofuran-5-yl] -2-methyl-but-2-ethyl} -phosphonic acid (260 mg, 0.59 mmol) dicyclohexyl carbodiimide (1.21 g, 5.9 mmol) and DMAP ( 36 mg, 0.295 mmol) was added. The reaction mixture was heated at 140 ° C. for 30 minutes. After cooling to rt, the mixture was partitioned between EtOAc / hexanes (1: 1) and 5% aqueous LiCl solution. The organic layer was washed repeatedly with 5% aqueous LiCl solution and then dried over Na ₂ SO ₄ . After removing the solvent, the residue was purified by silica gel chromatography to give 75 mg (21%) of the desired product. MS ( m / z ) 617 [M + Na] ⁺ .

{4- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro Isobenzofuran-5-yl] -2-methyl-but-2-ethyl} -phosphonic acid Monophenyl ester

{4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl in THF (5 mL) To a solution of] -2-methyl-but-2-ethyl} -phosphonic acid diphenyl ester (75 mg, 0.126 mmol) was added 1N NaOH (0.1 mL). The mixture was stirred at rt for 16 h. EtOAc was added and the resulting mixture was washed with 1H HCl. The organic layer was concentrated to dryness and the residue was purified by RP HPLC using C18 column with a gradient of H 2 O, 0.1% TFA-acetonitrile, 0.1% TFA to give 24.8 mg (38%) of the desired product. MS ( m / z ) 517 [M ⁻ H] ⁻ , 541 [M + Na] ⁺ .

2-({4- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro - Isobenzofuran -5-yl] -2-methyl-but-2-ethyl} -phenoxy-phosphinoyloxy) -propionic acid ethyl ester

{4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl in pyridine (1 mL) ] -2-Methyl-but-2-ethyl} -phosphonic acid monophenylester (25 mg, 0.048 mmol) and PyBOP (125 mg) in ethyl (S)-(-)-lactate (34 mg, 0.288 mmol) solution , 0.24 mmol) was added. The solution was stirred at rt for 16 h and concentrated. The residue was purified by RP HPLC using a C18 column with a gradient of H 2 O, 0.1% TFA-acetonitrile, 0.1% TFA to give 24 mg (83%) of the desired product. MS ( m / z ) 641 [M + Na] ⁺ .

2-{[4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -2- methyl - Boot -2-ethyl] -phenoxy-phosphinoyloxy} -propionic acid ethyl ester

2-({4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran- in DCM (1 mL) To a 5-yl] -2-methyl-but-2-ethyl} -phenoxy-phosphinoyloxy) -propionic acid ethyl ester (24 mg, 0.039 mmol) solution was added TFA (0.5 mL) and the mixture was stirred at room temperature. Stir for 10 minutes. The reaction mixture was dried under reduced pressure and the residue was purified by RP-HPLC to give 18 mg (90%) of the desired product as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.18-1.34 (m, 3H), 1.36-1.48 (dd, 3H), 2.02 (m, 3H), 2.17 (s, 3H), 2.78-2.98 (dd, 2H ), 3.45 (m, 2H), 3.79 (s, 3H), 4.05-4.25 (m, 2H), 4.97 (m, 1H), 5.21 (s, 2H), 5.48 (t, J = 7.2 Hz, 1H) , 7.05-7.18 (m, 5H) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 24.59, 26.13 ppm; MS ( m / z ) 517 [M−H] ⁻ , 519 [M + H] ⁺ .

Example  283: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

2-{[4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -2- methyl - Boot -2-ethyl]- Phenoxy - Phosphinoyloxy } -Propionic acid

2-{[4- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl) -2-methyl in THF (3 mL) To a solution of -but-2-ethyl] -phenoxy-phosphinoyloxy} -propionic acid ethyl ester (10 mg, 0.019 mmol) was added 1N NaOH (232 μl) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was dried under reduced pressure and the residue was purified by RP-HPLC to give 6 mg (77%) of the desired product as a clear oil. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.41 (d, J = 7 Hz, 3H), 1.97 (s, 3H), 2.16 (s, 3H), 2.59 (d, J = 22 Hz, 2H), 3.45 (m, 2H), 3.79 (s, 3H), 4.83 (m, 1H), 5.26 (s, 2H), 5.43 (t, J = 7.2 Hz, 1H) ppm; ³¹ P (121.4 MHz, CD ₃ OD) δ 27.02 ppm; MS ( m / z ) 413 [M−H] ⁻ , 415 [M + H] ⁺ .

Example  284: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

2-{[4- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-yl) -2-methyl-but-2-ethyl] -phenoxy-phosphinoylamino} -propionic acid ethyl ester

{4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -2-methyl- But-2-ethyl} -phosphonic acid monophenylester (1 g, ˜1.9 mmol) was mixed with pyBOP (2 g, 4 mmol) and DMAP (120 mg, 0.96 mmol). A solution of L-alanine ethyl ester hydrogen chloride salt (2.9 g, 19 mmol) and diisopropylethylamine (6.7 mL, 38 mmol) in pyridine (5 mL) was added to the monoacid mixture and the reaction was carried out at room temperature for 12 hours. Stirred. The reaction mixture was then concentrated and purified _twice by column chromatography (1% MeOH / CH ₂ Cl ₂ 3% MeOH / CH ₂ Cl ₂ ). The resulting oil was dissolved in vigorously stirred 10% TFA / CH ₂ Cl ₂ (30 mL) solution at -40 ° C. The reaction was gradually warmed to 0 ^{° C.} After about 3 hours, the reaction was complete. Pyridine (4.5 mL) was added and the reaction mixture was concentrated. The product was purified by preparative TLC (5% MeOH / CH ₂ Cl ₂ ) and concentrated to afford 210 mg (21%) of the desired product as a light yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.83-7.70 (m, 1H), 7.30-7.20 (m, 2H), 7.18-7.03 (m, 3H), 5.60-5.35 (m, 1H), 5.21 (s , 2H), 4.17-3.95 (m, 3H), 3.79 (s, 3H), 3.60-3.40 (m, 3H), 2.80-2.60 (m, 2H), 2.17 (m, 3H), 2.01 (m, 3H ), 1.30-1.10 (m, 6H) ppm; ³¹ P NMR (121 MHz, CDCl ₃ ) δ 28.0, 27.5 ppm; MS ( m / z ) 516 [M ⁻ H] ⁻ .

Example  285: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

2-( Dimethoxy - Phosphoryl ) -6- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl - Ethoxy ) -1,3- Dehydro Isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid methyl  ester

To a solution of trimethylphosphonoacetate (63 μl, 0.39 mmol) in THF (1 mL) at ambient temperature was added NaN (TMS) ₂ (0.39 mmol, 0.39 mL). After 30 minutes, 6- (4-bromo-3-methyl-but-2-ethyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl-ethoxy) in THF (1 mL) A solution of -3H-isobenzofuran-1-one (69 mg, 0.156 mmol) was added. Stirring was observed when the reaction mixture was stirred for 2 hours. Saturated aqueous ammonium chloride solution was added and the product was extracted with EtOAc to finalize the reaction mixture. The organic extract was dried and the product was purified by silica gel chromatography using 0-100% EtOAc-hexane to give 40 mg of the desired product as colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.05 (s, 9H), 1.20- 1.26 (m, 2H), 1.79 (s, 3H), 2.17 (s, 3H), 2.42- 2.72 (m, 2H), 3.19 (ddd, 1H, J = 4, 12, 23 Hz), 3.39 (d, 2H, J = 7 Hz), 3.62 (s, 3H), 3.75 (s, 3H), 3.77-3.84 (m, 6H) , 4.27-4.34 (m, 2H), 5.12 (s, 2H), 5.24 (t, 1H, J = 7 Hz) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 25.1 ppm; MS ( m / z ) 565.2 [M + Na] ⁺ .

6- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -4- methyl -2- Phosphono Hex-4-enoic acid methyl  ester

2- (dimethoxy-phosphoryl) -6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3 in acetonitrile (2 mL) To a solution of -dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid methyl ester (30 mg, 0.055 mmol) was added trimethylsilyl bromide (0.18 mL). After 10 minutes, 2,6-lutidine (0.16 mL) was added to the reaction at ambient temperature. The reaction was carried out for 16 hours and then concentrated to dryness. The residue was resuspended in DMF: H ₂ O (8: 2, 1 mL) and purified by RP HPLC using C18 column with gradient of H ₂ O, 0.1% TFA-acetonitrile, 0.1% TFA to give 18 mg of product. Obtained as a white powder. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.81 (s, 3H), 2.16 (s, 3H), 2.40-2.49 (m, 1H), 2.63 (dt, 1H, J = 6, 17 Hz), 3.07 (ddd, 1H, J = 4, 12, 23 Hz), 3.38 (3, 2H, J = 7 Hz), 3.52 (s, 3H), 3.77 (s, 3H), 5.25 (s, 2H), 5.28 ( t, 1H, J = 7 Hz) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 19.5 ppm; MS ( m / z ) 415.2 [M + H] ⁺ , 437.2 [M + Na] ⁺ .

Example  286: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

2-( Vis -(2,2,2- Trifluoroethoxy ) Phosphoryl ) -6- [6- Methoxy -7- methyl -3-oxo-4- (2- Trimethylsilanyl -Ethoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid methyl  s Ter

To a solution of [bis- (2,2,2-trifluoro-ethoxy) -phosphoryl] -acetic acid methyl ester (186 μl, 0.88 mmol) in anhydrous THF (2 mL) in THF (0.88 mL, 0.88 mmol) 1N NaN (TMS) ₂ solution was added. The solution was stirred at rt for 30 min and 6- (4-bromo-3-methyl-but-2-ethyl) -5-methoxy-4-methyl-7- (2- in THF (1 mL) Trimethylsilanyl-ethoxy) -3H-isobenzofuran-1-one (98 mg, 0.22 mmol) solution was added. Stirring was observed when the reaction mixture was stirred overnight. Saturated aqueous ammonium chloride solution was added and the product was extracted with EtOAc to finalize the reaction mixture. The organic extract was dried and the product was purified by RP HPLC using C18 column with gradient of H 2 O, 0.1% TFA-acetonitrile, 0.1% TFA to give 72 mg (48%) of the product as colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.05 (s, 9H), 1.22 (t, 3H, J = 7 Hz), 1.81 (s, 3H), 2.18 (s, 3H), 2.5-2.7 (m, 2H), 3.3 (ddd, 1H, J = 4, 12, 23 Hz), 3.40 (d, 2H, J = 7 Hz), 3.65 (s, 3H), 3.76 (s, 3H), 4.29-5.13 (m , 6H), 5.13 (s, 2H), 5.28 (t, 1H, J = 7 Hz) ppm; MS ( m / z ) 701.2 [M + Na] ⁺ .

2-( Vis -(2,2,2- Trifluoroethoxy ) Phosphoryl ) -6- [6- Methoxy -7- methyl -3-oxo-4- (2-hydroxyoxy) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid methyl  ester

[2- (bis- (2,2,2-trifluoroethoxy) phosphoryl) -6- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy ) -1,3-dihydro-isobenzofuran-5-yl] -4-methyl-hex-4-enoic acid methyl ester (70 mg) was added to a 10% trifluoroacetic acid solution in dichloromethane (5 mL). Dissolved. After 10 minutes, the mixture was concentrated and the product was purified by RP HPLC using a C18 column with a gradient of H 2 O, 0.1% TFA-acetonitrile, 0.1% TFA to give 45 mg (75%) of the product as colorless oil. ^{1 H NMR (300 MHz, CDCl} 3) δ 1.81 (s, 3H), 2.16 (s, 3H), 2.5- 2.7 (m, 2H), 3.3 (ddd, 1H), 3.38 (d, 2H, J = 7 Hz), 3.65 (s, 3H), 3.77 (s, 3H), 4.33- 4.43 (m, 4H), 5.21 (s, 2H), 5.33 (t, 1H, J = 7 Hz) ppm; ³¹ P (121.4 MHz, CDCl ₃ ) δ 25.8 ppm; MS ( m / z ) 601.2 [M + Na] ⁺ .

Example  287: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

6- (4-hydroxy-6- Methoxy -7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-yl) -2- [hydroxy- (2,2,2-trifluoro-ethoxy) -phosphoryl] -4-methyl-hex-4-enoic acid

1N NaOH (aq., 0.06 mL) in a solution of [bis- (2,2,2-trifluoro-ethoxy) -phosphoryl] -acetic acid methyl ester (186 μl, 0.88 mmol) in dry THF (0.5 mL) and N-methylpyrrolidinone (0.2 mL) solution was added. After 6.5 hours, another quarter of 1N NaOH (0.06 mL) was added and the mixture was stirred overnight. After concentration, the residue was suspended in DMF ("1 mL), neutralized with a few drops of TFA, purified by RP HPLC using C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA and lyophilized. The product 5.6 mg (72%) was obtained as a white powder ¹ H NMR (300 MHz, CD ₃ OD) δ 1.83 (s, 3H), 2.16 (s, 3H), 2.43-2.51 (m, 1H), 2.59 2.70 (m, 1H), 3.13 (ddd, 1H), 3.40 (d, 2H), 3.76 (s, 3H), 4.36-4.47 (m, 2H), 5.25 (s, 2H), 5.34 (t, 1H, J = 7 Hz) ppm; MS ( m / z ) 505.2 [M + Na] ⁺ .

Example  288: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

Phosphoric acid  Mono- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3- Dehydro - Isobenzofuran -5-yl] -2-methyl-but-2-ethyl} ester

6- (4-hydroxy-3-methyl-but-2-ethyl) -5-methoxy-4-methyl-7- (2-trimethylsilanyl-ethoxy) -3H- in dioxane (2 mL) 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one (56.7 mg) in a solution of isobenzofuran-1-one (75 mg, 0.20 mmol) and DIEA (49 μl, 0.28 mmol) , 0.28 mmol) was added according to the method of Shadid, B. et al., Tetrahedron , 1989 , 45 , 12, 3889. After 10 minutes, further 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one (40 mg, 0.20 mmol) and DIEA (35 μl, 0.20 mmol) were added. The reaction was allowed to proceed further for 1 hour at room temperature and then stopped by the addition of H ₂ O. The solution was stirred for another 10 minutes and concentrated to a small volume in vacuo. The product was triturated with diethyl ether and co-evaporated from acetonitrile (4 x 10 mL) to afford the product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.03 (s, 9H), 1.08-1.30 (m, 2H), 1.84 (br s, 3H), 2.17 (s, 3H), 3.46 (br s, 2H), 3.76 (s, 3H), 4.21- 4.39 (m, 4H), 5.12 (s, 2H), 5.43-5.60 (m, 1H), 7.83 (br s, 1H); ³¹ P (121.4 MHz, CDCl ₃ ) δ 7.22; MS ( m / z ) 441 [M ⁻ H] ⁻ .

Example  289: Preparation of Representative Compounds of the Invention.

Representative compounds of the present invention can be prepared as follows.

Phosphoric Acid Mono- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-di Hydro - Isobenzofuran -5-yl] -2-methyl-but-2-ethyl} ester

Phosphoric acid mono- {4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzo in dioxane (1 mL) Furan-5-yl] -2-methyl-but-2-ethyl} ester (27 mg, 0.06 mmol) solution was diluted with DIEA (21 μl, 0.12 mmol) and N, O-bis (trimethylsilyl) acetamide (29 μl , 0.12 mmol) and stirred at room temperature for 3 hours. 2,2'-Dipyridyldisulfide (16 mg, 0.072 mmol) was added to the reaction solution, and the mixture was further stirred at room temperature for 2 hours. H ₂ O was added to dilute the reaction mixture and the solution was stirred for another 2 hours before it was concentrated. The residue was purified by 10% TFA / CH ₂ Cl _2. It was dissolved in the solution and stirred for 9 hours at room temperature. The reaction mixture was dried under reduced pressure and the product was purified by reverse phase HPLC to give the desired product as a white solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 1.87 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J = 7 Hz), 3.79 (s, 3H), 4.28 (d, 2H , J = 6 Hz), 5.26 (s, 2H), 5.50- 5.61 (m, 1H); ³¹ P (121.4 MHz, CD ₃ OD) δ 0.50; MS ( m / z ) 357 [M ⁻ H] ⁻ .

Example  290: Specific embodiment of the present invention

Some compounds of the present invention are shown below.

Example  291: Preparation of Representative Compounds of the Invention

Additional representative compounds of the invention and their intermediates may be prepared according to the methods provided below.

R _One , R ₂ Having a variation in Penacetaldehyde  synthesis

The parent compound (R ₁ = OMe; R ₂ = Me) can be prepared by semi-synthesis from mycophenolic acid as follows.

To a solution of mycophenolic acid (500 g, 1.56 mol) in MeOH (4 L) under nitrogen atmosphere was added dropwise sulfuric acid (10 mL) and the suspension was stirred at room temperature for 2 hours. After 2 hours, the reaction became uniform and after a while a precipitate formed. The reaction was stirred at rt for 10 h, and TLC confirmed the completion of the reaction. The reaction was cooled to 10 ° C. in an ice bath and then filtered using a Buchner funnel. The filter cake was washed with ice cold methanol (750 mL) followed by hexane (750 mL) and dried to give 497 g (95%) of the desired product as a solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ, 1.81 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H), 2.37-2.50 (m, 4H), 3.38 (d, 2H, J = 7 Hz), 3.62 (s, 3H), 3.77 (s, 3H), 5.13 (s, 2H), 5.22 (m, 1H), 7.17 (s, 1H).

In THF (20 mL) in solution (3.99 g, 11.9 mmol), PPh ₃ (4.68 g, 17.9 mmol) and diisopropyl azodicarboxylate (3.46 mL, 17.9 mmol) in THF (60 mL) at 0 ° C. 2-trimethylsilylethanol (2.05 mL, 14.3 mmol) solution was added. The resulting yellow solution was warmed to room temperature and stirred for 4 hours. The solution was concentrated to dryness and the reaction was completed by addition of ether and hexane. Triphenylphosphine oxide was filtered off and the filtrate was concentrated and purified by silica gel chromatography to give 4.8 g (100%) as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.03 (s, 9H), 1.18-1.30 (m, 2H), 1.81 (s, 3H), 2.18 (s, 3H), 2.25- 2.33 (m, 2H), 2.37-2.45 (m, 2H), 3.42 (d, 2H, J = 7 Hz), 3.62 (s, 3H), 3.77 (s, 3H), 4.25- 4.35 (m, 2H), 5.13 (s, 2H) , 5.12- 5.22 (m, 1 H).

The solution (9.6 g, 22 mmol) in MeOH (90 mL), CH ₂ Cl ₂ (90 mL) and pyridine (0.7 mL) was cooled to −70 ° C. using a dry ice / acetone bath. The reaction was bubbled through a gas dispersion tube until the reaction color became blue (1.5 hours). The ozone line was replaced with a stream of nitrogen and bubbling for another 30 minutes and the blue color disappeared. To this solution was added some thiourea (1.2 g, 15.4 mmol) at -70 ° C and the cooling bath was removed. The reaction was warmed to rt and stirred for 15 h. The reaction was finished by filtering off the solid thiourea S-dioxide and then partitioned between CH ₂ Cl ₂ and water. The organic layer was removed. The aqueous layer was washed with CH ₂ Cl ₂ and the combined organic extracts were washed with aqueous 1N HCl, saturated NaHCO ₃ and brine. The residue was purified by silica gel chromatography to give 7.3 g (99%) as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ -0.01 (s, 9H), 1.05- 1.15 (m, 2H), 2.15 (s, 3H), 3.69 (s, 3H), 3.78 (d, 2H, J = 1 Hz), 4.27-4.39 (m, 2H), 5.11 (s, 2H), 9.72 (d, 1H, J = 1 Hz).

R _One  transform

J. Med . Chem . The starting material synthesized according to, 1996 , 39 , 4181-4196 was modified to the desired aldehyde using a similar method as described above.

J. Med . Chem . The starting material synthesized according to, 1996 , 39 , 4181-4196 was modified to the desired aldehyde using a similar method as described above.

J. Med . Chem . The starting material synthesized according to, 1996 , 39 , 4181-4196 was modified to the desired aldehyde using a similar method as described above.

The aldehyde was dissolved in an organic solvent such as methanol and sodium borohydride was added. At the end of the reaction, aqueous HCl solution is added and the solvent is removed in vacuo. Further purification is by chromatography.

The resulting alcohol was dissolved in an organic solvent such as dichloromethane (DCM). Pyridine and acetic anhydride are added and stirring is continued at room temperature. At the end of the reaction DCM was further added and the solution was washed with aqueous HCl solution, aqueous sodium bicarbonate solution and dried over sodium sulfate. Filter and remove the solvent in vacuo to afford crude product. Further purification is by chromatography.

The acetate was added to J. Med . Chem . , 1996 , 39 , 4181-4196 and dissolved in DCM and bromine was added. At the end of the reaction, DCM was further added and the solution was washed with aqueous sodium thiosulfate solution and brine. The organic layer was dried over sodium sulfate. Filtration and evaporation of the solvent gave crude material. Further purification is by chromatography.

The product of the previous step, lithium chloride, triphenyllacin, tributylvinyl tin and tris (dibenzylideneacetone) dipalladium (0) -chloroform adducts were prepared by J. Med . Chem . , 1996 , 39 , 4181-4196 and at an elevated temperature of about 55 ℃ in an organic solvent such as N -methylpyrrolidinone. At the end of the reaction, the mixture was cooled to room temperature and poured into a mixture of ice, potassium fluoride, water and ethyl acetate. Stirring was continued for 1 hour. The suspension was filtered through celite and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate. The solvent is removed in vacuo and the crude material is further purified by chromatography.

J. Org . Chem . , 1984 , 48 , 4155-4156, the product of the previous step is dissolved in an organic solvent such as DCM or THF. 1,1,1-tris (acyloxy) -1,1-dihydro-1,2benziodexo-3- (1H) -one (Dess-Martin reagent) is added and the solution is stirred at room temperature . At the end of the reaction, diethyl ether is added followed by aqueous sodium hydroxide solution. The layers were separated and the organic layer was washed with aqueous sodium hydroxide solution, water and then dried over sodium sulfate. Filtration and evaporation of the solvent give crude product. Further purification is by chromatography.

The starting material is dissolved in an organic solvent such as toluene. J. Org . Chem . , 2003 , 68 , 452-459P ( isobutylNCH ₂ CH ₂ ) ₃ N, palladium (II) acetate, tert . Sodium butoxylate and benzylamine were added and the mixture was heated at 80 ° C. At the end of the reaction, the mixture is cooled to room temperature and the solvent is removed in vacuo. The crude material is purified by chromatography. Residual acetate is removed by simple treatment with methanolic sodium methoxide.

The benzyl-protected aniline is dissolved in an organic solvent such as DMF. Palladium on carbon is added and the reaction mixture is placed under hydrogen atmosphere. At the end of the reaction, the mixture is filtered through celite. The solvent is removed in vacuo. Further purification is by chromatography.

The resulting primary aniline was dissolved in an organic solvent such as THF, acetonitrile or DMF, and J. Org . Treatment with formaldehyde and sodium triacetoxyborohydride as described in Chem , 1996 , 61, 3849-3862. The reaction is stopped with aqueous sodium bicarbonate and the product is extracted with an organic solvent such as ethyl acetate. The crude material is treated with di- t -butyl dicarbonate in organic solvents such as dimethylformamide and aqueous sodium hydroxide. The resulting carbamate is purified by chromatography.

The primary alcohol product is dissolved in an organic solvent such as DCM or THF. J. Org . Chem. , 1984 , 48 , 1,1,1-tris (acyloxy) -1,1-dihydro-1,2benzioxoxo-3- (1H) -one (Dess-Martin) according to the method of 4155-4156. Reagent) is added and the solution is stirred at room temperature. At the end of the reaction, diethyl ether is added followed by aqueous sodium hydroxide solution. The layers were separated and the organic layer was washed with aqueous sodium hydroxide solution, water and dried over sodium sulfate. Filtration and evaporation of the solvent give crude product. Further purification is by chromatography.

Recl . The starting material . Trav . Chem . It is dissolved in an organic solvent such as DCM or THF according to the method of Pay-Bas, 1982 , 101 , 460 and treated with a mixed anhydride of formic acid and pivalic acid. At the end of the reaction, the solvent and all volatiles are removed in vacuo and further purified by crude product chromatography.

The product was prepared from J. Org . Chem . , 1984 , 48 , 4155-4156 and so on in an organic solvent such as DCM or THF. 1,1,1-tris (acyloxy) -1,1-dihydro-1,2-benziodoxiol-3- (1H) -one (Dess-Martin reagent) is added and the solution is stirred at room temperature do. After addition of diethyl ether at the end of the reaction, the layers are separated and the organic layer is washed with aqueous sodium hydroxide solution, water and dried over sodium sulfate. Filtration and evaporation of the solvent give crude product. Further purification is by chromatography.

R ₂  transform

J. Med . Chem . , 1996 , 39 , 4181-4196 The starting material is dissolved in an organic solvent such as DMF and reacted with N -chlorosuccinimide. After the starting material is consumed, the reaction mixture is poured into water and the product is extracted with diethyl ether. The combined organic layers are dried over sodium sulfate. Filtration and evaporation of the solvent give the crude reaction product.

The product of step 1 is dissolved in a mixture of organic solvents such as methanol, DCM and pyridine. Cool the solution to −78 ° C. and bubble ozone into the solution until the blue color persists. Excess ozone is removed by a stream of nitrogen. Warm the reaction to room temperature and add thiourea. Continue stirring at room temperature. The reaction mixture is filtered and partitioned between DCM and water. The aqueous layer is extracted with DCM and the combined organic layers are washed with HCl (IN), saturated aqueous sodium bicarbonate solution and brine. Filtration and evaporation of the solvent give crude aldehyde. Further purification is by chromatography.

The starting material is dissolved in a mixture of organic solvents such as methanol, DCM and pyridine. Cool the solution to −78 ° C. and bubble ozone into the solution until the blue color persists. Excess ozone is removed by a stream of nitrogen. Warm the reaction to room temperature and add thiourea. Continue stirring at room temperature. The reaction mixture is filtered and partitioned between DCM and water. The aqueous layer is extracted with DCM and the combined organic layers are washed with HCl (IN), saturated aqueous sodium bicarbonate solution and brine. The solution is dried over sodium sulfate. Filtration and evaporation of the solvent give crude aldehyde. Further purification is by chromatography.

The product of step 1 is dissolved in an organic solvent such as benzene. Trifluoromethanesulfonyl chloride and dichlorotris (triphenylphosphine) ruthenium are added and the gas is removed from the solution. The reaction mixture was prepared from J. Chem . Soc , Perkin Trans. 1 , 1994 , 1339-1346 according to the method of heating at 120 ℃. At the end of the reaction the mixture is cooled to room temperature and the solvent is removed in vacuo. The product is further purified by chromatography.

Olefins and To phosphonates Connection  synthesis

Penacetaldehyde (5.3 g, 15.8 mmol) in toluene (50 mL) is heated with 2- (triphenyl-phosphanilidene) -propionaldehyde (6.8 g, 20.5 mmol) at 100 ° C. overnight. After concentration, the residue is purified by silica gel chromatography to give 4.24 g (72%) of unsaturated aldehyde as a pale yellow solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.00 (s, 9H), 1.10-1.21 (m, 2H), 1.87 (s, 3H), 2.16 (s, 3H), 3.67-3.76 (m, 2H), 3.74 (s, 3H), 4.27-4.39 (m, 2H), 5.11 (s, 2H), 6.40-6.48 (m, 1H), 9.2 (s, 1H).

The hydroxy phosphonate is treated by treating trimethylsilylethyl protected aldehyde with diethylphosphite in a solvent such as acetonitrile in the presence of a base such as triethylamine according to the method as reported in Tetrahedron, 1995 , 51 , 2099. Get The hydroxy phosphonate is O -alkylated and then treated with trifluoroacetic acid or tetrabutylammonium fluoride to remove the protecting group to produce the desired methoxy phosphonate analog.

Optionally, the aldehyde is mixed with diethyl (2-aminoethyl) phosphonate and treated with a reducing agent such as sodium triacetoxyborohydride to produce amino phosphonate analogs.

4- [6-methoxy-7-methyl-3-oxo-4- (2-trimethylsilanyl-ethoxy) -1,3-dihydro-isobenzofuran-5-yl] in methanol (5 mL) The 2-methyl-but-2-enal (103 mg, 0.27 mmol) solution is cooled to 0 ° C. CeCl ₃ solution (0.68 mL, MeOH: H ₂ O, 9: 1) is added followed by LiBH ₄ (0.14 mL, 0.28 mmol of 2M solution in THF). The ice bath was removed and the reaction mixture was warmed to room temperature. The reaction mixture is stirred for 40 more minutes and TLC confirms that the starting aldehyde has been consumed completely. Aqueous 1N HCl (0.5 mL) is added to finish the reaction and the product is extracted with CH ₂ Cl ₂ . The organic layer is washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer is concentrated under reduced pressure and the residue is purified by silica gel chromatography to give 100 mg (97%) of the product as a clear liquid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.00 (s, 9H), 1.20 (dd, 2H, J = 7, 8 Hz), 1.81 (s, 3H), 2.13 (s, 3H), 3.38-3.50 ( m, 2H), 3.74 (s, 3H), 3.95 (s, 2H), 4.27 (dd, 2H, J = 7, 8 Hz), 5.08 (s, 2H), 5.17-5.44 (m, 1H).

The polymer-supported triphenylphosphine is soaked in DCM for 1 hour. Allyl alcohol and carbon tetrabromide are added sequentially. When the reaction is complete, the mixture is filtered and the filtrate is concentrated. The bromide is purified by chromatography if necessary.

The alkali metal salt of ethyl diethoxyphosphoryl acetate (ethyl diethoxyphosphoryl acetate) in sodium hexamethyldisilazide or sodium hydride in an organic solvent such as dimethylformamide according to the method described in WO 9522538 Prepared by reaction with) to obtain an ethoxycarbonylphosphonate. The carboxylic ester groups are converted to carboxylic amide groups and hydroxymethyl groups according to conventional methods used for amide formation and ester reduction. For example, carboxylic esters are saponified with aqueous lithium hydroxide. It is activated with the acid ethyl chloroformate and reduced with sodium borohydride to give the hydroxymethyl phosphonate analog after removal of the protecting group. The acid is also converted to its acylchloride and then reacted with ethylamine to give the amide analog.

The aryl acetaldehyde is combined with 2- (diethoxyphosphoryl) -but-3-enoic acid ethyl ester according to the method as reported in Synthesis , 1999 , 282 to produce 2-vinyl substituted esters. 2-vinyl group Tetrahedron Lett . Conversion to a 2-cyclopropyl group under cyclopropaneation conditions as described in 1998 , 39 , 8621. The esters can be converted to alcohols and, if necessary, reacted as described below to produce various phosphonate-containing mycophenolic acid analogs.

Treatment with bromomethylphosphonic acid diisopropyl ester in a solvent such as dimethylformamide in the presence of a base such as the allyl alcohol lithium t -butoxide. Treatment with trifluoroacetic acid then removes the phenol protecting group.

The penacetaldehyde is described in J. Org . Chem . 1987 , 52 , 849 can be optionally converted to the allyl phosphonium salt by the method reported. The phosphonium salt is then treated with commercially available bases such as 3,3,3-trifluoro-2-oxo-propionic acid ethyl ester and sodium hydride to produce 2-trifluoromethyl substituted esters. The esters can be converted to alcohols and, if desired, further reactions as described above to produce mycophenolic acid analogs having various side chains containing phosphonate groups.

R ₄  Introduction of the variant

Enon ( Tetrahedron , 1985 , 41 , 4881-4889) and the diene ( Chem . Pharm . Bull. , 1989 , 37 , 2948-2951) were described in J. Med . According to the method of Chem ., 1996 , 39 , 4181-4196, it is dissolved in an organic solvent such as toluene, stirred at room temperature for 24 hours and further heated to reflux for 5 hours. The reaction mixture is cooled to room temperature and the solvent is removed in vacuo. Further purification by the resulting reaction product chromatography.

The product of step 1 was prepared by J. Med . According to the method of Chem ., 1996 , 39 , 4181-4196, it was dissolved in an organic solvent such as DCM and m -chloroperoxide was added. At the end of the reaction, the solution was poured into an aqueous sodium hydrogen sulfite solution. The organic layer was washed with saturated aqueous sodium bicarbonate solution and dried over sodium sulfate. Filtration and evaporation of the solvent give crude product.

The crude product was taken from J. Med . According to the method of Chem ., 1996 , 39 , 4181-4196, it is dissolved in an organic solvent such as toluene and treated with treated with dichlorodicyanoquinone (DDQ). At the end of the reaction the solvent is removed in vacuo and the crude material is further purified by chromatography.

The product was J. Med . Chem . , 1996 , 39 , 46-55 and dissolved in an organic solvent such as DCM and treated with boron trichloride at reflux temperature. At the end of the reaction the solution is washed with an aqueous HCl solution. The solution is dried over sodium sulfate. The solvent is removed to give the resulting reaction product. Further purification is by chromatography.

The product of the previous step and triphenylphosphine are dissolved in an organic solvent such as tetrahydrofuran (THF). Diisopropylazodicarboxylate (DIAD) is added dropwise at 0 ° C. Continue stirring. Add 2-trimethylsilyl ethanol solution in THF and continue stirring. At the end of the reaction, the solvent is removed in vacuo. The resulting reaction solid is extracted with a mixture of organic solvents such as hexane and diethyl ether. Collect the wash solution to remove the solvent in vacuo. The desired product is further purified by chromatography to separate from unwanted regioisomers.

The starting material is described in J. Med . Chem . , 1996 , 39 , 4181-4196 and dissolved in an organic solvent such as dimethylformamide (DMF) and reacted with N -chlorosuccinimide. After the starting material is consumed, the reaction mixture is poured into water and the product is extracted with diethyl ether. The combined organic layers are dried over sodium sulfate. Filtration and evaporation of the solvent give crude product. Further purification is by chromatography.

The starting material was dissolved in an organic solvent such as benzene and J. Am. Chem . Soc . 1966 , 88 , 5855-5866 according to the method of dimethyl sulfoxide (DMSO), dicyclohexylcarbodiimide (DCC) and orthophosphoric acid. At the end of the reaction, the suspension is washed with aqueous sodium bicarbonate and dried over sodium sulfate. Filtration and evaporation of the solvent give crude material. Further purification is by chromatography.

The product of step 1 is dissolved in an organic solvent such as DCM or THF Chem . Rev. , 1962 , 62 , 347-404. When all the starting material was consumed, the reaction was filtered to remove the solvent in vacuo. Further purification is by chromatography.

The starting material is described in J. Med . Chem . , 1996 , 39 , 4181-4196 and dissolved in an organic solvent such as DCM and bromine is added. At the end of the reaction, further DCM is added and the solution is washed with aqueous sodium thiosulfate solution and brine. The organic layer is dried over sodium sulfate. Filtration and evaporation of the solvent give crude material. Further purification is by chromatography on silica gel.

The starting materials, lithium chloride, triphenyllacin, tributylvinyl tin and tris (dibenzylideneacetone) dipalladium (0) -chloroform adduct were added to J. Med . Chem . , 1996 , 39 , 4181-4196 according to the method of heating in an organic solvent such as N -methylpyrrolidinone at an elevated temperature of about 55 ℃. At the end of the reaction, the mixture is cooled to room temperature and poured into a mixture of ice, potassium fluoride, water and ethyl acetate. Stirring is continued for 1 hour. The suspension is filtered through celite and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate. The solvent is removed in vacuo and the crude material is further purified by chromatography.

The product of step 2 is dissolved in a mixture of organic solvents such as benzene and ethyl acetate. J. Med. Chem . Tris (triphenylphosphine) rhodium (I) chloride is added according to the method of, 1996 , 39 , 4181-4196 and the reaction is placed under hydrogen atmosphere. The solvent is removed in vacuo and the crude reaction is filtered through silica gel. Further purification is by chromatography.

The starting material is dissolved in an organic solvent such as DMF. J. Med . Chem . Potassium carbonate and allyl bromide are added according to the method of, 1996 , 39 , 4181-4196 and stirring continued at room temperature. After all of the starting material has been consumed, an aqueous HCl solution and diethyl ether are added, the organic layers are combined and the solvent is removed in vacuo.

The crude material is dissolved in N, N diethylaniline and the reaction mixture is heated at an elevated temperature of about 180 ° C. At the end of the reaction, the mixture is cooled to room temperature and poured into an aqueous HCl (2N) and ethyl acetate mixture. The organic layer is washed with aqueous HCl (2N) and dried over sodium sulfate. Filtration and removal of solvent give crude product. Further purification is by chromatography.

The product of step 2 is dissolved in a mixture of organic solvents such as methanol, DCM and pyridine. Cool the solution to −78 ° C. and bubble ozone into the solution until the blue color persists. Excess ozone is removed by a stream of nitrogen. Warm the reaction to room temperature and add thiourea. Continue stirring at room temperature. The reaction mixture is filtered and partitioned between DCM and water. The aqueous layer is extracted with DCM and the combined organic layers are washed with HCl (IN), saturated aqueous sodium bicarbonate solution and brine. The solution is dried over sodium sulfate. Filtration and evaporation of the solvent give crude aldehyde. Further purification is by chromatography.

Chem that aldehyde . Rev. , 1989 , 89 , 863-927 and dissolved in an organic solvent such as THF and reacted with triphenylphosphonium sec . Propyl bromide and tert . At the end of the reaction, the solvent is removed in vacuo and the crude material is purified by chromatography.

To phosphonates Connection  Introduction

The phenol can be alkylated with a reagent of choice, if desired. If desired, the phosphonate moiety will be part of such a reagent. Optionally, it will be introduced by various means in a later step, three of which are illustrated above. For example, alkyl halides can be heated with triethylphosphite in a solvent such as toluene (or other Arbuzoph reaction conditions: Engel, R., "Synthesis of Carbon-Phosphorus Bonds," CRC press, 1988). Optionally, the epoxide can react with the anion of the dialkyl phosphinate. In later examples, the phosphonate reagent may be an electrophile. for example, Diacetyl esters of the desired phosphonic acid can be obtained by condensing the acetylide anion with phosphorus oxychloride and stopping the intermediate dichlorophosphonate with ethanol.

Example  316: Additional Representation of the Invention Mycophenolate  Preparation of the compound.

Certain compounds of the present invention can be prepared as follows.

[4- (6-ethyl-4-hydroxy-7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -2- methyl - Boot -2- Ethyloxymethyl ] -Phosphonic acid

This product is prepared using, for example, methods similar to those described in Examples 251 and 276. MS (negative mode): 369.3 [M ⁺ -1].

Example  317: Additional Representation of the Invention Mycophenolate  Preparation of the compound.

Certain compounds of the present invention can be prepared as follows.

2-{[4- (6-ethyl-4-hydroxy-7- methyl- 3-oxo-1,3 -dihydro - isobenzofuran -5-yl) -2 - methyl -but -2-ethyl Oxymethyl] -phenoxy-phosphinoylamino} -propionic acid ethyl ester For example, starting from Example 316, a method similar to that described in Example 261 is made. MS (positive mode): 546.3 [M ⁺ + 1] & 568.3 [M ⁺ + Na].

Example  318: Additional Representation of the Invention Mycophenolate  Preparation of the compound.

Certain compounds of the present invention can be prepared as follows.

2-({2- [4- (6-ethyl-4-hydroxy-7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -2- methyl - Boot -2-ethylamino] -ethyl} -phenoxy-phosphinoylamino) -propionic acid ethyl ester

This product was prepared in a reductive amination step using 2-[(2-amino-ethyl) -phenoxy-phosphinoylamino] -propionic acid ethyl ester, for example using a method similar to that described in Examples 268 and 316 Manufacture.

MS (positive mode): 559.4 [M ⁺ + 1] & 581.3 [M ⁺ + Na].

Example  319: Additional Representation of the Invention Mycophenolate  Preparation of the compound.

Certain compounds of the present invention can be prepared as follows.

2-((1- Ethoxycarbonyl - Ethylamino )-{2- [4- (6-ethyl-4-hydroxy-7- methyl -3-oxo-1,3- Dehydro - Isobenzofuran -5-day) -2- methyl - Boot -2- Ethylamino ]-ethyl}- Phosphinoyl Amino) -propionic acid ethyl ester

This product was described for example in Example 318 using 2-[(2-aminoethyl)-(1-ethoxycarbonyl-ethylamino) -phosphinoylamino] -propionic acid ethyl ester in a reductive amination step. Prepared using a similar method. MS (positive mode): 582.4 [M ⁺ + 1] & 604.3 [M ⁺ + Na].

Example 330 Synthesis of Exemplary Compounds of the Invention

Representative compound 330.4 of the present invention can be prepared as described above and described below. Compound 330.3 (250 mg, 0.65 mmol) was added to 10 mL absolute ethanol (15 mL) under argon atmosphere. After addition of NaOH (29 mg, 0.72 mmol), the reaction mixture was stirred overnight at room temperature. TLC (CHCl ₃ / MeOH, 9: 1) confirmed the completion of the reaction was confirmed to complete the reaction. The reaction mixture was concentrated to a solid and dissolved in ethyl acetate (20 mL). The solution was washed with deionized water (2x10 mL) and dried over Na ₂ S0 ₄ . Concentration gave a solid, which was then purified by silica gel column chromatography to give (CHCl ₃ / MeOH, 4: 1) compound 330.4 . Obtained as a solid (188 mg, 75%). ESI-MS m / z 383 [M + H] ^{+. 1} H NMR (300 MHz, DMSO-d ₆ ): δ 7.32 (1H, s, ArH), 6.96 (2H, s, ArH), 4.31 (2H, d, J = 9.9 Hz, OCH ₂ ), 4.18-4.08 (4H, m, 2xOCH ₂ ), 2.08 (3H, s, CH ₃ ), 2.00 (3H, s, CH ₃ ), 1.26 (6H, t, J = 7.0 Hz, CH ₃ ). ³¹ P NMR (121.7 MHz, DMSO-d ₆ / external H ₃ PO ₄₎ δ ppm 20.0-20.4 (m); HPLC: 93% pure (5 μl Sphereclone, H ₂ O: MeCN, 20 min linear from 10-90% MeCN, 1.0 mL / min).

Intermediate compound 330.3 is prepared as follows.

a. Synthesis of Compound 330.1. 2-methyl-5-nitrophenol (2.00 g, 13.05 mmol) was dissolved in dry DMF (10 mL) under argon atmosphere and cooled to 0 ° C. Diethylphosphonomethyl- O -triplate (4.70 gm, 15.66 mmol) and cesium carbonate (6.38 gm, 19.58 mmol) were added sequentially. The reaction mixture was stirred at 0 ° C for 4 h. TLC (cyclohexane / EtOAc, 1: 1) confirmed the completion of the reaction. Deionized water (15 mL) was added and the mixture was extracted with EtOAc (2 × 50 mL). The organic layer was washed with 1N HCl (20 mL) followed by water (2 × 20 mL), dried over Na ₂ SO ₄ and concentrated to semisolid. Purification by silica gel column chromatography (cyclohexane / EtOAc, 1: 1) afforded pure compound 330.1 as an oil (3.86 g, 97%).

ESI-MS m / z 304 [M + H] ⁺ .

b. Synthesis of Compound 330.2. Compound 330.1 (2.8 g, 9.24 mmol) was dissolved in 15 mL of absolute ethanol (15 mL) and 6N HCl (2 mL) under argon atmosphere. After addition of SnCl ₂ 2H ₂ O (5.26 g, 27.72 mmol), the reaction mixture was stirred overnight at room temperature. TLC (CHCl ₃ / MeOH, 9: 1) confirmed the completion of the reaction. The mixture was concentrated to semisolid and dissolved in ethyl acetate (30 mL). The ethyl acetate layer was washed with deionized water (10 mL) and saturated NaHCO ₃ (10 mL) and dried over Na ₂ SO ₄ . Concentration gave a solid which was used without purification. ESI-MS m / z 274 [M + H] ^+.

c. Synthesis of Compound 330.3. Crude compound K-105-48 (900 mg, 3.38 mmol) was dissolved in 15 mL of dry THF (15 mL) under argon atmosphere. 5-Methylisoxazole-4-carboxylic acid (381 mg, 3.00 mmol) and diisopropyl carbodiimide (511 L, 3.30 mmol) were added and the reaction mixture was stirred at rt for 6 h. TLC (CHCl ₃ / MeOH, 9: 1) confirmed the completion of the reaction. The reaction mixture was filtered and the filtrate was concentrated to give a solid, which was then dissolved in ethyl acetate (25 mL). The solution was washed with deionized water (2x10 mL) and dried over Na ₂ S0 ₄ . Concentration gave a solid, which was then purified by silica gel column chromatography (CHCl ₃ / MeOH, 95: 5) to give pure compound 330.3 as a light yellow solid (680 mg, 55%). ESI-MS m / z 383 [M + H] ^{+. 1} H NMR (300 MHz, CDCl ₃ ): δ 7.11 (1H, s, ArH), 7.06 (2H, s, ArH), 4.29-4.20 (4H, m, OCH ₂ ), 4.14 (2H, d, J = 10.4 Hz, OCH ₂ ), 2.76 (3H, s, CH ₃ ), 2.14 (3H, s, CH ₃ ), 1.37 (6H, t, J = 7.0 Hz, CH ₃ ). ³¹ P NMR (121.7 MHz, DMSO-d ₆ / external H ₃ PO ₄ ) δ ppm 19.7-20.0 (m); HPLC: 98% pure (5 μl Sphereclone, H ₂ O: MeCN, 20 min linear from 10-90% MeCN, 1.0 mL / min).

Example  331 Representative of the present invention Prednisone  Synthesis of Compounds

Representative compounds of the invention can be prepared as illustrated above. Prednisone 331.1 is alkylated with an appropriate phosphonate to derivatize at C-21 hydroxy groups to give compound 331.2 of the present invention. Certain compounds of the present invention can be prepared as follows.

The primary hydroxy proton at 331.1 is extracted with sodium hydride and then diethylphosphonate triflate is added to give ether 331.4 .

Example  332 Representative of the present invention Prednisone  Synthesis of Compounds

Representative compounds 332.3 of the present invention can be prepared as illustrated above. Prednisone 332.1 is protected in the less-hidden primary position to give alcohol 332.5 , followed by alkylation of the hydroxy group exposed with the appropriate phosphonate to give 332.6 . The protecting group is removed to complete the synthesis of analog 332.3 . Specific compounds can be prepared as follows.

Prednisone 332.1 is mono-protected with its TBS ether 332.7 . After alkylation with diethylphosphonate triflate, the resulting intermediate 332. 8 is treated with TBAF to give the desired phosphonate 332.9 .

Example 500 Synthesis of Exemplary Compounds of the Invention

Preparation of (2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -methyl) -phosphonic acid diethyl ester.

Diethylcyanopo in a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (67.0 mg, 177 mmol) in DMF (3.0 mL). Sponate (34.8 μl, 230 mmol) and diisopropylethylamine (Hunig's Base, DIEA, 30.4 μl, 177 mmol) are added. The solution is stirred at ambient temperature for 4 hours and diethyl (aminomethyl) phosphonate oxalate (45.4 mg, 177 mmol) is added. The solution is further stirred for 4 hours and the starting material is consumed completely. The solvent is removed in vacuo and the residue is purified by silica gel chromatography using MeOH-CH ₂ Cl ₂ (10-30%) to complete the reaction. The product collected from the chromatography step was pure enough for the next reaction. A small amount of product (20 mg) was repurified by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 12.9 mg (76%) of pure product. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.19 (t, 6H, J = 7.2 Hz), 3.21 (s, 3H), 3.70 (m, 2H), 4.00 (q, 4H, J = 7.2 Hz) , 4.81 (s, 2H), 6.81 (d, 2H, J = 9 Hz), 7.71 (d, 2H, J = 9 Hz), 8.40 (br s, 1H), 8.61 (s, 1H). ^{31 P (121.4 MHz, DMSO- d} 6) δ 23.4. MS ( m / z ) 475.2 [M + H] ⁺ , 597.2 [M + Na] ⁺ .

Example 501 Synthesis of Exemplary Compounds of the Invention

Preparation of (2- {4-[(2,4-Diamino-phthalin-6-ylmethyl) -methyl-amino] -benzoylamino} -methyl) -phosphonic acid

Crude (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -ethyl) after silica column chromatography in dry DMF (0.90 ml) To the solution of phosphonic acid diethyl ester (60 mg, 126 mmol) is added trimethylsilyl bromide (bromotrimethylsilane, TMSBr, 130.6 μl, 1,010 mmol) at ambient temperature. The solution was then heated at 70 ° C. for 4.0 h and then the reaction mixture was cooled to room temperature. The solvent volume was reduced to ˜700 μl in vacuo and diluted with H ₂ O (100 μl). This solution was purified by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 26.8 mg (51%) of the title compound as a yellow solid. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 3.18 (s, 3H), 3.50 (m, 2H), 4.77 (s, 2H), 6.79 (d, 2H, J = 9 Hz), 7.79 (d, 2H, J = 9 Hz), 8.07 (br s, 1 H), 8.56 (s, 1 H); MS ( m / z ) 419.2 [M + H] ⁺ .

Example 502 Synthesis of Exemplary Compounds of the Invention

 Preparation of (2- {4-[(2,4-Diamino-tertidine-6-ylmethyl) -methyl-amino] -benzoylamino} -ethyl) -phosphonic acid diethyl ester

Diethylcyanopo in a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (61.2 mg, 161 mmol) in DMF (2.8 mL) Sponate (31.8 μl, 210 mmol) and DIEA (27.8 μl, 161 mmol) were added. The solution is stirred at ambient temperature for 4 hours and diethyl (aminoethyl) phosphonate oxalate (43.8 mg, 161 mmol) is added. After stirring the solution for 3 more hours, the starting material is completely consumed. The solvent is removed in vacuo and the residue is purified by silica gel chromatography using MeOH-CH ₂ Cl ₂ (10-30%) to complete the reaction. The product collected from the chromatography step was pure enough for the next reaction. A small amount of product (32 mg) was purified again by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 19 mg (70%) of pure product. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.21 (t, 6H, J = 7 Hz), 1.95- 2.05 (m, 2H), 3.20 (s, 3H), 3.13- 3.22 (m, 2H), 3.98 (appt septet, 4H, J = 7 Hz), 4.79 (s, 2H), 6.80 (d, 2H, J = 9 Hz), 7.65 (d, 2H, J = 9 Hz), 8.20 (br s, 1H ), 8.60 (s, 1 H). ³¹ P (121.4 MHz, DMSO- d ₆ ) δ 28.9. MS ( m / z ) 489.2 [M + H] ⁺ , 511.2 [M + Na] ⁺ .

Example 503 Synthesis of Exemplary Compounds of the Invention

Preparation of (2- {4-[(2,4-Diamino-phthalin-6-ylmethyl) -methyl-amino] -benzoylamino} -ethyl) -phosphonic acid

Crude (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -ethyl) after silica column chromatography in dry DMF (1.00 mL) To the solution of phosphonic acid diethyl ester (61 mg, 125 mmol) is added TMSBr (129.0 μl, 999.2 mmol) at ambient temperature. The solution was then heated at 70 ° C. for 5.5 hours and then LCMS analysis confirmed that the reaction was 90% complete. The reaction mixture is cooled to room temperature and further stirred for 12 hours. The solvent is removed in vacuo and the residue is dissolved again in DMF / H ₂ O (800 μl, 1: 1) and 1N aqueous NaOH (15 μl) to complete the reaction. The product is H ₂ O / acetonitrile ( Purification by RP HPLC on a C ₁₈ column using 2-95%) yields 29 mg (53%) of the desired compound as a yellow solid. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.67-1.85 (m, 2H), 3.19 (s, 3H), 3.25- 3.40 (m, 2H), 4.76 (s, 2H), 6.71 (br s, 2H), 5.80 (d, 2H, J = 9 Hz), 7.64 (d, 2H, J = 9 Hz), 7.73 (br s, 2H), 8.15 (br s, 1H), 8.56 (s, 1H). ³¹ P (121.4 MHz, DMSO- d ₆ ) δ 23.0. MS ( m / z ) 431.3 [M ⁻ H] ⁻ .

Example 504 Synthesis of Exemplary Compounds of the Invention

Preparation of (2- {4-[(2,4-Diamino-Pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -propyl) -phosphonic acid diethyl ester

Diethylcyanopo in a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (61.2 mg, 161 mmol) in DMF (2.8 mL) Sponate (31.8 μl, 210 mmol) and DIEA (27.8 μl, 161 mmol) are added. The solution is stirred at ambient temperature for 3 hours and diethyl (aminopropyl) phosphonate oxalate (34.9 mg, 122.6 mmol) is added. The solution is stirred for another 2 hours and the starting material is consumed completely. The solvent is removed in vacuo and the residue is purified by silica gel chromatography using MeOH-CH ₂ Cl ₂ (10-30%) to complete the reaction. The product (65.5 mg) collected in the chromatography step was pure enough for the next reaction. A small amount of product (32.8 mg) was purified again by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 23.2 mg (75%) of pure product. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.20 (t, 6H, J = 7.2 Hz), 1.64- 1.75 (m, 4H), 3.22 (s, 3H), 3.41 (m, 2H), 3.98 ( appt septet, 4H, J = 7.2 Hz), 4.85 (s, 2H), 6.79 (d, 2H, J = 9 Hz), 7.68 (d, 2H, J = 9 Hz), 8.17 (br s, 1H), 8.70 (s, 1 H); ^{31 P (121.4 MHz, DMSO- d} 6) δ 31.9; MS ( m / z ) 503.2 [M + H] ⁺ .

Example 505 Synthesis of Exemplary Compounds of the Invention

Preparation of (2- {4-[(2,4-Diamino-phthalin-6-ylmethyl) -methyl-amino] -benzoylamino} -propyl) -phosphonic acid

Crude (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -propyl) after silica column chromatography in dry DMF (0.50 mL) To the solution of phosphonic acid diethyl ester (32.2 mg, 66.2 mmol) is added TMSBr (68.0 μl, 529.6 mmol) at ambient temperature. The solution is then heated at 70 ° C. for 1.0 h and LCMS analysis confirms that the reaction is complete. The reaction mixture is cooled to room temperature and water (60 μl) and methanol (60 μl) are added. The resulting reaction mixture is purified by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 11.2 mg (38%) of the desired compound as a yellow solid. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.50 (m, 2H), 1.61 (m, 2H), 3.22 (s, 3H), 3.25- 3.40 (m, 2H), 4.84 (s, 2H), 6.80 (d, 2H, J = 9 Hz), 7.69 (d, 2H, J = 9 Hz), 8.20 (br s, 1H), 8.69 (s, 1H). ³¹ P (121.4 MHz, DMSO- d ₆ ) δ 26.3. MS ( m / z ) 447.3 [M ⁻ H] ⁻ .

Example 506 Synthesis of Exemplary Compounds of the Invention

2-[(2- {4-[(2,4-diaminopteridin-6-ylmethyl) methylamino] benzoylamino} ethyl) -phenoxyphosphinoyloxy] propionic acid ethyl ester [part in phosphorus Stereoisomer mixture]

Diethylcyanofo in a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (60.0 mg, 158.3 mmol) in DMF (2.5 mL) Sponate (31.2 μl, 205.7 mmol) and DIEA (81.8 μl, 474.9 mmol) are added. The solution was stirred at ambient temperature for 3.5 hours, and ( S ) -2-[(2-aminoethyl) phenoxyphosphinoyloxy] propionic acid ethyl ester monoacetic acid salt in DMF (200 μl) (57.1 mg, 158.3 mmol ; Diastereomeric mixture in phosphorus) solution is added. The solution is further stirred for 1.5 hours and then the starting material is consumed completely. The solvent is removed in vacuo and the crude material is purified by silica gel chromatography using MeOH-CH ₂ Cl ₂ (10-30%). A small amount of product (24.8 mg) was purified again by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 15.8 mg (65%) of pure product. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.17 1.27 (m, 3H), 1.32 (d, 2H, J = 7.5 Hz), 1.42 (d, 1H, J = 7.5 Hz) 2.27 (m, 2H) , 3.19 (s, 3H), 3.53 (m, 2H), 4.08 4.14 (m, 2H), 4.77 (s, 2H), 4.98 (m, 1H), 6.72 (br s, 1H), 6.81 (d, 2H , J = 9 Hz), 7.21 (m, 3H), 7.36 (m, 2H), 7.66 (d, 2H, J = 9 Hz), 8.26 (br s, 1H), 8.56 (s, 1H); ³¹ P (121.4 MHz, DMSO- d ₆ ) δ 26.6, 27.4. MS ( m / z ) 609.2 [M + H] ⁺ .

Example 507 Synthesis of Exemplary Compounds of the Invention

2-[(2- {4-[(2,4-diaminopteridin-6-ylmethyl) methylamino] benzoylamino} ethyl) -phenoxyphosphinoyloxy] propionic acid [diastereomer in phosphorus Mixture]

2-[(2- {4-[(2,4-diaminopteridin-6-ylmethyl) methylamino] benzoylamino in DMF (0.4 mL), acetonitrile (0.2 mL) and water (0.2 mL) To a solution of ethyl) phenoxy-phosphinoyloxy] propionic acid ethyl ester (diastereomer mixture in phosphorus; 40.0 mg, 65.7 mmol) is added aqueous sodium hydroxide (1 N, 131.4 μl). The solution is stirred at ambient temperature for 4 hours. The solvent is removed in vacuo and the crude product is purified by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 23.7 mg (71.3%) of pure product. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.30 (d, 2H, J = 6.9 Hz), 1.79 (m, 2H), 3.21 (s, 3H), 3.37 (m, 2H), 4.61 (m, 1H), 4.81 (s, 2H), 6.79 (d, 2H, J = 8.7 Hz), 7.64 (d, 2H, J = 9.7 Hz), 8.25 (br s, 1H), 8.63 (s, 1H); ³¹ P (121.4 MHz, DMSO- d ₆ ) δ 25.1. MS ( m / z ) 505.2 [M + H] ⁺ .

Example 508 Synthesis of Exemplary Compounds of the Invention

2-[(2- {4-[(2,4-diaminopteridin-6-ylmethyl) methylamino] benzoylamino} ethyl) -phenoxyphosphinoyloxy] propionic acid ethyl ester [diasteric in phosphorus Isomerically pure]

Diethylcyanophosphonate in a solution of 4-[(2,4-diaminopteridin-6-ylmethyl) -methyl-amino] benzoic acid hemihydrochloride dihydrate (101.9 mg, 268.9 mmol) in DMF (3.3 mL) (53.0 μl, 349.5 mmol) and DIEA (138.0 μl, 806.7 mmol) are added. The solution was stirred at ambient temperature for 2.5 hours and then ( S ) -2-[(2-aminoethyl) phenoxyphosphinoyloxy] propionic acid ethyl ester monoacetic acid salt in DMF (500 μl) Isomerically pure, 268.9 mmol) is added. The solution is stirred for another 30 minutes and the starting material is consumed completely. The solvent is removed in vacuo and the crude material is purified by silica gel chromatography using MeOH-CH ₂ Cl ₂ (10-30%). A small amount (40.0 mg) in the product was purified again by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 28.7 mg (75.1%) of pure product. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.15 (t, 3H, J = 7.2 Hz), 1.44 (d, 3H, J = 6.9 Hz), 2.26 (m, 2H), 3.23 (s, 3H) , 3.51 (m, 2H), 4.09 (q, 2H, J = 7.2 Hz), 4.86 (s, 2H), 5.01 (m, 1H), 6.81 (d, 2H, J = 9.3 Hz), 7.21 (m, 3H), 7.35 (m, 2H), 7.68 (d, 2H, J = 9.3 Hz), 8.29 (br s, 1H), 8.71 (s, 1H); ^{31 P (121.4 MHz, DMSO- d} 6) δ 26.6. MS ( m / z ) 609.2 [M + H] ⁺ .

Example 509 Synthesis of Exemplary Compounds of the Invention

2-[(2- {4-[(2,4-diaminopteridin-6-ylmethyl) methylamino] benzoylamino} ethyl) -phenoxyphosphinoylamino] propionic acid ethyl ester (part in phosphorus Preparation of Stereoisomeric Mixtures)

Diethylcyanofo in a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (39.6 mg, 104.0 mmol) in DMF (1.2 mL) Sponate (20.6 μl, 136.1 mmol) and DIEA (36.0 μl, 209.4 mmol) are added. The solution was stirred at ambient temperature for 3 hours and the ( S ) -2-[(2-aminoethyl) phenoxyphosphinoylamino] propionic acid ethyl ester monoacetic acid salt in DMF (200 μl) (diastereomer in phosphorus) Mixture, 104.0 mmol) is added. The solution is stirred for another 30 minutes and then the starting material is consumed completely. Part of the reaction (66%) was purified by silica gel chromatography using MeOH-CH ₂ Cl ₂ (10-30%) to give 27.2 mg of crude product. A small amount (10.0 mg) in the product was purified again by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 4.2 mg (26%) of the pure product. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.11 (t, 3H, J = 6.9 Hz), 1.18 (d, 3H, J = 7.2 Hz), 2.06- 2.17 (m, 2H), 3.20 (s, 3H), 3.51 (m, 2H), 3.88 (m, 1H), 4.02 (m, 2H), 4.79 (s, 2H), 5.61 (m, 1H), 6.80 (d, 2H, J = 9 Hz), 6.98 (br s, 1H), 7.18 (m, 3H), 7.32 (m, 2H), 7.67 (d, 2H, J = 9 Hz), 8.20 (br s, 1H), 8.59 (s, 1H) ³¹ P _{(121.4 MHz, DMSO- d 6)} δ 29.5, 30.1. MS ( m / z ) 608.2 [M + H] ⁺ .

Example 510 Synthesis of Exemplary Compounds of the Invention

Preparation of 2- {4-[(2,4-Diamino-tertidine-6-ylmethyl) -methyl-amino] -benzoylamino} -6- (diethoxy-phosphoryl) -hexanoic acid

Diethylcyano in a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (63.0 mg, 166.2 mmol) in DMF (2.8 mL) Phosphonate (30.8 μl, 199.4 mmol) and DIEA (85.8 μl, 498.6 mmol) are added. The solution is stirred at ambient temperature for 3.5 hours and (L) -2-amino-6-diethylphosphonatohexanoic acid (44.3 mg, 166.2 mmol) is added. The solution is further stirred for 48 hours. The solvent is removed in vacuo and the residue is purified by silica gel chromatography using MeOH-CH ₂ Cl ₂ (10-30%) to complete the reaction. The product (87 mg) collected in the chromatography step was pure enough for the next reaction. A portion of the product (51.0 mg) is purified by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 24.7 mg (44%) of pure product. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.18 (t, 6H, J = 6.9 Hz), 1.42 (m, 4H), 1.65 (m, 4H), 3.20 (s, 3H), 3.92 (m, 4H), 4.29 (m, 1H), 4.78 (s, 2H), 6.72 (br s, 1H), 6.81 (d, 2H, J = 9 Hz), 7.73 (d, 2H, J = 9 Hz), 8.14 (d, 1 H, J = 7.8 Hz), 8.56 (s, 1 H); ^{31 P (121.4 MHz, DMSO- d} 6) δ 31.8; MS ( m / z ) 574.3 [M] ⁺ .

Example 511 Synthesis of Exemplary Compounds of the Invention

Preparation of 2- {4-[(2,4-diaminopteridin-6-ylmethyl) methylamino] benzoylamino} -6- (phosphoryl) hexanoic acid

Crude (2- {4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino}) after silica column chromatography in dry DMF (0.60 mL) -2 To a solution of '( L )-(6'-(phosphonic acid diethyl ester) hexanoic acid) (20 mg, 34.6 mmol) is added TMSBr (18.0 μl, 139.2 mmol) at ambient temperature. The solution was then heated at 70 ° C. for 18 hours and then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and dissolved in DMF (400 μl) and water (60 μl). This solution was purified by RP HPLC on a C ₁₈ column using H ₂ O / acetonitrile (2-95%) to give 8.9 mg (49%) of the product as a yellow solid. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.45 (m, 6H), 1.75 (m, 2H), 3.20 (s, 3H), 4.25 (m, 1H), 4.77 (s, 2H), 6.62 ( br s, 1H), 6.80 (d, 2H, J = 8.7 Hz), 7.73 (d, 2H, J = 8.7 Hz), 8.14 (br s, 1H), 8.55 (s, 1H); MS ( m / z ) 519.2 [M + H] ⁺ .

Example 512 Synthesis of Exemplary Compounds of the Invention

Preparation of ( L ) -2-Cbz-amino-hexanoic acid-6-phosphonic acid

To a suspension of ( L ) -2-amino-6- (diethoxyphosphonyl) hexanoic acid (106 mg, 396.8 mmol) in dry DMF (2.00 mL) is added TMSBr (307.0 μl, 2,381.0 mmol) at ambient temperature. The solution was then heated at 70 ° C. for 2 hours and then the reaction mixture was cooled to room temperature. The solvent is removed in vacuo. The crude material was dissolved in water (0.25 mL) and NaOH (1-N, 2.50 mL). Benzyl chloroformate (79.3 μl, 555.5 mmol) is added and stirring continued at room temperature. After 2 hours, the solution was washed with ether (2 mL) and the aqueous layer was acidified to pH 1 with aqueous HCl. The aqueous layer was extracted with EtOAc (3x 5 mL). The combined organic extracts were dried over sodium sulfate. The solvent was filtered off and evaporated to afford a crude product pure enough for subsequent modification. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.42 1.65 (m, 8H), 3.90 (m, 1H), 5.02 (s, 2H), 7.32 (s, 5H), 7.55 (m, 1H), 7.94 (s, 1 H); ^{31 P (121.4 MHz, DMSO- d} 6) δ 26.5; MS ( m / z ) 345.6 [M + H] ⁺ .

Example 513 Synthesis of Exemplary Compounds of the Invention

Preparation of ( L ) -2--amino-hexanoic acid 2 'TMS ethyl ester-6-phosphonic acid monophenyl ester

To a solution of ( L ) -2-Cbz-amino-hexanoic acid-6-phosphonic acid (137.3 mg, 397.9 mmol) in 2-TMS ethanol (2.5 mL) is added acetyl chloride (50 μl). Continue stirring at room temperature. After 22 hours a complete conversion was observed. The solvent is removed in vacuo. The crude material was pure enough for the next step.

Half (198.9 mmol) of the crude material was dissolved in toluene (3.0 mL) at room temperature. Thionyl chloride (167.2 mg, 1,416.0 mmol) is added and the reaction mixture is heated at 70 ° C. (oil bath). After 4 hours, the reaction is cooled to room temperature and the solvent is removed in vacuo. The crude material is redissolved in methylene chloride (2.0 mL) and a solution of phenol (36.6 mg, 389.0 mmol) and DIEA (67.0 μl, 389.0 mmol) in methylene chloride (1.0 mL) is added. Continue stirring at room temperature. After 4 hours the solvent is removed in vacuo.

The crude material is dissolved in tetrahydrofuran (THF) (3.0 mL) and aqueous sodium hydroxide solution (1N, 0.885 mL) is added. Continue stirring at room temperature. After 14 hours the solvent was removed in vacuo to afford crude phosphonate monophenyl ester (63.8 mg). This material is dissolved in 2-TMS ethanol (1.0 mL) and acetyl chloride (20 μl) is added. Continue stirring at room temperature. After 22 hours a complete conversion to carboxylate ester was observed. The solvent is removed in vacuo. The material was pure enough for the next step.

Half (75 mmol) of the crude material was dissolved in ethanol (1.5 mL). Pd / C (5%, 20 mg) was added and the reaction was placed under hydrogen gas atmosphere. After 1.5 hours celite is added and the resulting reaction mixture is filtered through celite. The solvent is removed in vacuo and the crude material is used in the next step without further purification.

Example 514 Synthesis of Exemplary Compounds of the Invention

2- {4-[(2,4-Diamino-Pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6 '-(monophenyl-phosphonate) -hexanoic acid TMS ethanol ester Manufacture

Diethylcyano in a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoic acid hemihydrochloride dihydrate (22.7 mg, 60.0 mmol) in DMF (0.80 mL) Phosphonate (12.4 μl, 78.0 mmol) and DIEA (31.0 μl, 180.0 mmol) were added. The solution is stirred for 1 h at ambient temperature and (L) -2-amino-6-monophenoxyphosphonatohexanoic acid 2 'TMS ethyl ester (70.5 mmol) suspended in DMF (0.2 mL) is added. The solution is further stirred for 3.5 hours. The resulting reaction mixture is purified by RP HPLC on C ₁₈ column using H ₂ O / acetonitrile (5-95%) to give 19.4 mg (46%) of pure product. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 0.0 (s, 9H), 0.91 (t, 2H, J = 8.1 Hz), 1.42 1.53 (m, 4H), 1.67-1.76 (m, 4H), 3.24 (s, 3H), 4.10 (t, 2H, J = 8.1 Hz), 4.29 (m, 1H), 4.86 (s, 2H), 6.81 (d, 2H, J = 9 Hz), 7.12 (m, 3H) , 7. 31 (m, 2H), 7.74 (d, 2H, J = 9 Hz), 8.14 (d, 1H, J = 7.8 Hz), 8.71 (s, 1H); ^{31 P (121.4 MHz, DMSO- d} 6) δ 26.2; MS ( m / z ) 695.2 [M] ⁺ .

Example 515 Synthesis of Exemplary Compounds of the Invention

2- {4-[(2,4-Diamino-tertidine-6-ylmethyl) -methyl-amino] -benzoylamino} -6 '-(monophenyl mono (S) ethyl lactate-phosphonate ) -Hexanoic acid TMS ethanol ester

2- {4-[(2,4-Diamino-pteridin-6-ylmethyl) -methyl-amino] -benzoylamino} -6 '-(monophenyl-phosphonate) in DMF (0.70 mL) To the solution of -hexanoic acid TMS ethanol ester (14.5 mg, 20.8 mmol) was added PyBOP (32.4 mg, 62.4 mmol), DIEA (21.4 mg, 166.4 mmol) and (S) ethyl lactate (19.6 mg, 166.4 mmol). The reaction mixture was stirred at room temperature for 1 hour. Purification by RP HPLC on a C ₁₈ column using the resulting reaction mixture H ₂ O / acetonitrile (5-95%) gave 13.5 mg (81%) of the pure product as a diastereomeric mixture (~ 4: 1) in phosphorus. Got it. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.0 (s, 9H), 1.02 (t, 2H, J = 8.7 Hz), 1.23 (t, 3H, J = 9.3 Hz), 1.35 (d, 2.4H, J = 6.6 Hz), 1.42 1.53 (m, 4.6H), 1.67-1.86 (m, 4H), 3.14 (s, 3H), 4.03 4.27 (m, 4H), 4.71 (br s, 3H), 4.98 (m, 0.8H), 5.10 (m, 0.2H), 6.57 (d, 2H, J = 7.5 Hz), 7.00 (m, 1H), 7.16 (m, 3H), 7. 30 (m, 2H), 7.63 (d , 2H, J = 7.5 Hz), 8.43 (s, 1H); ^{31 P (121.4 MHz, DMSO- d} 6) δ 30.5, 29.2; MS ( m / z ) 795.2 [M] ⁺ .

Example 516 Synthesis of Exemplary Compounds of the Invention

The compounds of the present invention can generally be prepared as exemplified above. For example, certain compounds of the present invention can be prepared as follows.

Rofecoxib is treated with a base such as sodium hydride in a solvent such as dimethylformamide or tetrahydrofuran. At the end of bubbling, excess E- 1,4-dibromobutene is added. The reaction is stopped with aqueous ammonium chloride and the product is extracted with an organic solvent such as ethyl acetate, and then the mono-alkylated product is separated by chromatography. The bromide thus formed is treated with triethylphosphite in a solvent such as toluene (or other Arbuzoph reaction conditions: Engel, R., Synthesis of Carbon-Phophorus bonds, CRC press, 1988). Get ester.

Example 517 Synthesis of Exemplary Compounds of the Invention

The compounds of the present invention can generally be prepared as exemplified above (see Ind . J. Chem., Sect B , 1990 , 10 , 954). The specific intermediates used in the process can be prepared as follows.

Ethyl 4-hydroxyphenylacetate is treated with a base such as sodium hydride in a solvent such as dimethylformamide or tetrahydrofuran. At the end of bubbling, excess E- 1,4-dibromobutene is added. The reaction is stopped with aqueous ammonium chloride and the product is extracted with an organic solvent such as ethyl acetate, and then the mono-alkylated product is separated by chromatography. The bromide thus formed is treated with triethylphosphite in a solvent such as toluene (or other Arbuzoph reaction conditions: Engel, R., Synthesis of Carbon-Phophorus bonds, CRC press, 1988). Get ester.

Example 518 Synthesis of Exemplary Compounds of the Invention

Scheme 518-1

Suitable oxidizing agent (s) may convert the primary alcohol (5′-hydroxy) shown in 518-1.3 to a carboxylic acid or its corresponding ester. In the case of esters, further deprotection may yield carboxylic acid 518-1.4 . Various oxidation methods are documented in the literature and can be used here. These include the following methods, i.e. (i) preparing t-butyl ester with pyridinium dichromate, t-BuOH and dichloromethane in Ac ₂ O, and converting the ester into a reagent such as trifluoroacetic acid. To deprotect and convert to the corresponding carboxylic acid (Classon, et al, Acta Chem . Scand . Ser . B; 39 ; 1985; 501-504. Cristalli, et al; J. Med . Chem .; 31 ; 1988; (Ii) Process for preparing carboxylic acids with iodobenzene diacetate and 2,2,6,6-tetramethyl-1-piperidinyloxy, free radicals (TEMPO) in acetonitrile (Epp , et al;. J. Org Chem 64;. 1999; 293-295 Jung et al;.. J. Org Chem;. 66; 2001; see 2624-2635), (iii) from chloroform and sodium periodate, chloride Method for preparing carboxylic acid using ruthenium (III) (Kim, et al, J Med . Chem . 37 ; 1994; 4020-4030. Homma, et al; J. Med . Chem .; 35 ; 1992; 2881 -2890), (iv) a process for preparing carboxylic acid using chromium trioxide in acetic acid (Olsson et al; J. Med . Chem .; 29 ; 1986; 1683-1689. Gallo-Rodriguez et al; J .. Med Chem;. 37; see 636-646); 1994; (v) Process for preparing carboxylic acid with potassium permanganate in aqueous potassium hydroxide (Ha, et al; J. Med. Chem .; 29 ; 1986; 1683-1689. Franchetti, et al; J. Med . Chem .; 41 ; 1998; 1708-1715). (Vi) Methods for preparing carboxylic acids using nucleoside oxidases from S. maltophilia (see Mahmoudian, et al; Tetrahedron; 54 ; 1998; 8171-8182) But it is not limited thereto.

Synthesis of 518-1.5 from 518-1.4 using lead tetraacetate (IV) (LG = OAc) is described by Teng et al; J. Org . Chem .; 59 ; 1994; 278-280 and Schultz, et al; J. Org . Chem .; 48 ; 1983; 3408-3412. When lead tetraacetate (IV) is used with lithium chloride (see Kochi, et al; J. Am. Chem . Soc .; 87 ; 1965; 2052), the corresponding chlorides are obtained (1.5, LG = Cl). . Using lead tetraacetate (IV) with N-chlorosuccinimide gives the same product (1.5, LG = Cl) (Wang, et al; Tet . Asym .; 1 ; 1990; 527 and Wilson et al; reference 525);. Tet Asym;. 1; 1990. Alternatively, treatment with trimethylsilyl bromide can convert the acetate leaving group (LG) to another leaving group such as bromide to give 518-1.5 (Spencer, et al; J. Org . Chem .; 64 ; 1999; 3987- 3995).

Binding of various nucleophiles with 518-1.5 (LG = OAc) is described by Teng et al; Synlett ; 1996; 346-348 and US 6,087,482; 54 columns 64 to 55 columns 20 lines. Specifically, the bond between 518-1.5 and diethylhydroxymethylphosphonate in the presence of trimethylsilyl trifluoromethanesulfonate (TMS-OTf) is described. It is conceivable that other compounds having the general structure of HO-connector-POR ^P1 R ^P2 can also be used as long as the functional groups of these compounds are compatible with the binding reaction conditions. There are many examples in the publication that describe the combination of various alcohols with 518-1.5 (LG = halogen). The reaction was performed with silver (I) salts (Kim et al; J. Org . Chem .; 56 ; 1991; 2642-2647, Toikka et al; J. Chem . Soc . Perkins Trans. Mercury (II) salts (Veeneman et al; Recl . Trav . Chim . Pays-Bas; 106 ; 1987; 129-131), boron trifluoride diethyl etherate (Kunz et al; Hel . Chim Acta ; 68 ; 1985; 283-287), tin (II) chloride (O'Leary et al; J. Org . Chem .; 59 ; 1994; 6629-6636), alkoxides (Shortnacy-Fowler et al; Nucleosides Nucleotides; 20 ; 2001; 1583-1598) and iodine (Kartha et al; J. Chem . Soc . Perkins Trans. 1 ; 2001; 770-772). These methods use 518-1.5 with various leaving groups (LG) to make 518-1.6 . It may optionally be used in combination with other methods in forming.

Introduction and removal of protecting groups in compounds is a method commonly practiced in the art of organic synthesis. Information regarding such techniques are available in the literature publications, for example, [Greene and Wuts, Protecting Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, Inc., 1999]. The main purpose is to temporarily modify the functional group so that the functional group can be maintained in a series of consecutive reactions. Afterwards, the original functional group can be recovered by a previously anti-deprotection process. Thus, variations from 518 to 1.1 to 518 to 1.2, from 518 to 1.2 518-1. The transformation to 3 and the transformation from 518-1.6 to 518-A The modification can also take place in that, while protecting a functional group that is already present in the structure of the core component of the compound (518-1 from 0.6 to 518 to 1.3).

The 5'-hydroxyl group of ribavirin ( 518-2 ) may optionally be protected by appropriate protecting groups. The product, 518-3, can be treated with benzoyl chloride, an appropriate base in the presence of a catalytic amount of 4-dimethylaminopyridine to convert 2'- and 3'-hydroxyl groups to their corresponding benzoyl esters, 518-4 . . Selective deprotection of the 5'-hydroxyl group can yield 518-5 . The following process describes similar compounds in US Pat. No. 6,087,482. 2, 518-4 may be converted to 518-7 in three steps sequence. Treating 518-7 can be treated with a binder such as trimethylsilyl trifluoromethanesulfonate in the presence of an appropriate phosphonate group containing alcohol to produce 518-8 . Finally, 518-8 can be treated with aqueous sodium hydroxide to deprotect the 2'- and 3'-hydroxyl groups to yield 518-1 . It is important to note that R ^P1 and R ^P2 in 518-8 and 518-1 do not have to be identical.

Various compounds of the general structure 518-1.1 It can be prepared or commercially available using the methods described in the literature. Townsend, Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994 and Vorbruggen and Ruh-Pohlenz, Handbook of Nucleoside Synthesis , John Wiley & Sons, Inc., 2001, prepared various compounds of general structure 518-1.1 . It is a good source of information about technology. Some exemplary precursors, starting materials and their commercial sources are as follows.

Compound 518-2.1 in Scheme 518-2 is prepared using the method described in WO 01/90121 (page 115, table). The 5'-hydroxyl in 518-2.1 is protected as t-butyldimethylsilyl (TBDMS) ether. Protecting the 2'- and 3'- hydroxyl groups as benzoyl (Bz) esters to afford 518-2.2 . You can get it. 518-2.3 can then be obtained by deprotecting the 5'-hydroxyl. The primary alcohol is converted to the corresponding acid 518-2.4 by oxidation using iodobenzenediacetate and 2,2,6,6-tetramethyl-1-piperidinyloxy, free radicals (TEMPO). 518-2.5 can be prepared by further oxidation of 518-2.4 using lead tetraacetate . It was coupled to 518 to 2.5 and diethyl hydroxymethyl-phosphonate (available from Sigma-Aldrich, Cat. No. 39,262-6 ) using TMS-OTf can be obtained from 518 to 2.6. Treatment of 518-2.6 with TMS-Br converts the phosphodiester to the corresponding phosphonic acid 518-2.7 . Deprotection of 2'- and 3'- hydroxyls as an example of general structure 518-A The base is adenine, R ¹ , R ⁵ and R ⁶ are hydrogen, R ² is a methyl group, R ³ and R ⁴ are hydroxyl groups, the linker is a methylene group and both R ^P1 and R ^{P2 are} hydroxy Obtain the Lockyl group 518-2.8 .

Scheme 518-2

Phosphonic acids in 518-2.7 and 518-2.8 are used as examples for illustration. Other forms of phosphonate can be obtained by other forms such as phosphonic acid or the corresponding diesters. See the Interconversion section of phosphonates for details.

Many compounds of the general structure 518-1.1 having sugar moieties in the L-configuration are commercially available or can be prepared by the methods described in the publication. The opposite D-array enantiomers of the aforementioned L-nucleoside analogs can be prepared from precursors that are opposite enantiomers of 518-3.1 , 518-3.2, and 518-3.3 . Scheme 518-3 illustrates the preparation of the opposite enantiomers of 518-3.1 , 518-3.2 and 518-3.3 .

Scheme 518-3

Commercially available starting materials 518-4. 1 can be converted to 518-4.4, the opposite enantiomer of 518-3.1 , using the reaction sequence shown in Scheme 518-3 . Diols are introduced on the opposite side to tert-butyldimethylsilyl (TBDMS) ethers of the hydroxymethyl group by osmium tetraoxide catalyzed dihydroxylation reactions. Diols in intermediates 518-4.3 can be protected as TBDMS ethers. At low temperatures diisobutylaluminum hydride can be used to reduce the lactone to produce 518-4.6 , which can be acetylated to convert to 518-4.6 . Deprotection of 518-4.6 yields L-ribose ( 518-4.7 ). By the acylation reaction all hydroxyl groups in 518-4.7 can be converted into the corresponding benzoyl esters. Standard binding reactions with various nucleophilic bases yield 518-4.10, the opposite enantiomer of 518-3.3 .

Scheme 518-4

The synthesis of 3-cyano-1- (2,3,5-tri-O-acetyl-D-ribofuranosyl) -1,2,4-triazole ( 518-2 ) is described in US 2002 /. 0156030 A1, page 6, paragraphs 0078 to 0079. Carboxamide compounds 518-1 (Scheme 518- ) from this starting material using the chemical modification sequences shown in Schemes 518-4 and 518-5 , respectively. 4 ) or amidine compound 518-1 (Scheme 518-5 ) can be prepared.

Scheme 518-5

Suitable protection and deprotection methods (Greene and Wuts, (1999) Protective Groups in Organic Chemistry reference) to use the 5'-hydroxyl group is protected and at the same time, 2 'and 3'-hydroxyl group is unprotected 518- 3 can be prepared (Scheme 518-4 and 518-5 ). Protection, deprotection methods can then be used to introduce protecting groups such as benzoyl groups into the 2'- and 3'-hydroxyl groups as in 518-4 and leave unprotected 5'-hydroxyl groups. By oxidation reaction, the primary alcohol in 518-4 can be converted into the corresponding carboxylic acid or its ester. The ester can optionally be deprotected to afford acid 518-5 as a product . By further oxidation with an oxidizing agent such as lead tetraacetate , 518-5 can be converted to 518-6 , the leaving group of acetate. Treatment of 518-6 with an alcohol containing a phosphonate moiety in the presence of a suitable binder such as trimethylsilyl trifluorometansulfonate will yield 518-8 as a product. Finally, treating 518-8 by the method described in US 2002/0156030 A1, page 6, paragraph 0081, will yield 518-1 as a product. Of 518-7, 518-8, and 518-1 It is important to note that R ^P1 and R ^P2 need not be identical.

Scheme 518-6

A solution of tert-butyl peroxide (t-BuOOH) in benzene (68%, 3 eq) was allyl alcohol 518-1 (synthesized as described in Tet . Letters (1997) 38: 2355-58) in benzene at room temperature and A solution of VO (acac) ₂ (final concentration 0.1 M) (Scheme 518-6) was added dropwise. After stirring for 1 hour at room temperature, saturated aqueous Na ₂ S ₂ O ₃ is added to the reaction mixture. The resulting solution is extracted with EtOAc, washed with H ₂ O and dried over sodium sulfate. After removal of the solvent, crude product 518-2 is purified by silica column chromatography.

Epoxide 518-2 and p- anisylchlorodiphenylmethane (1.5 eq) are dissolved in anhydrous pyridine (0.17 M) and stirred at 25 ° C. for 2 hours. The solvent is removed under reduced pressure and the residue is dissolved in EtOAc. The organic layer is washed with water, saturated aqueous NaHCO ₃ and dried over sodium sulfate. After removal of the solvent, crude product 518-3 is purified by silica column chromatography.

N-butyllithium (2.2 eq) is added to a solution of methyltriphenylphosphonium bromide (2 eq) in dry THF at −78 ° C. The solution is warmed to room temperature and stirred for 20 minutes. After recooling to −78 ° C., the solution is added completely to protected epoxide 518-3 (final concentration 0.06 M) in THF. The reaction mixture is warmed to room temperature and stirred for 12 hours, then H ₂ O is added and extracted with diethyl ether. The combined organic layers are dried over sodium sulfate. After removal of the solvent, crude product 518-4 is purified by silica column chromatography.

Sodium hydride (1 eq) and 2-amino-4-chloro-7 H pyrrolo [2,3-d] pyrimidine (1 eq) are dissolved in anhydrous DMF (0.06 M) and stirred at 120 ° C. for 10 minutes. . Then a 518-4 solution in DMF was added and the reaction mixture was stirred at 120 ° C. for 12 hours, then the solvent was evaporated under reduced pressure. The residue _is dissolved in CH ₂ Cl _2, washed with H ₂ O and dried over sodium sulfate. After removal of the solvent, crude product 518-5 is purified by silica column chromatography.

Compound 518-5 was dissolved in dichloromethane and 1,1,1-tris (acetyloxy) -1,1-dihydro-1,2-benzioxoxo-3- ( 1H ) -one in dichloromethane Aldrich, Dess Martin periodinane, 4 eq) solution (final concentration 0.06 M). The reaction mixture was stirred at rt for 4 h, diluted with EtOAc and poured into a solution of sodium thiosulfate in saturated aqueous sodium bicarbonate solution. The organic layer is separated and dried over sodium sulfate. After removal of the solvent, crude product 518-6 is purified by silica column chromatography.

Ketone 518-6 solution in dry THF at -78 ° C is added to a solution of methylmagnesium bromide (4 eq) in dry THF (0.1 M). The reaction mixture is stirred at −60 ° C. for 12 hours and then the reaction is stopped with saturated aqueous NH ₄ Cl solution. The mixture is filtered through celite and washed with EtOAc. The combined organic layers are washed with saturated aqueous NH ₄ Cl, water and dried over sodium sulfate. After removing the solvent, the crude product is purified by silica column chromatography.

A solution of alcohol 518-7 (0.06 M) in dry THF is treated with a solution of tetrabutyl ammonium fluoride (1.5 eq) in THF at room temperature. The reaction mixture is stirred for 3 hours and then the solvent is evaporated. Crude desilylated diol 518-8 is purified by silica column chromatography.

To a solution of diol 518-8 and benzenesulfonic acid diisopropoxy-phosphorylmethyl ester (1.2 eq) (0.1 M) in anhydrous DMF is added magnesium tert-butoxide (1 eq). The reaction mixture is heated to 80 ° C. for 12 hours. After cooling to rt, 1 N citric acid was added and extracted with EtOAc. The organic layer is neutralized with saturated aqueous NaHCO ₃ , washed with saturated aqueous NaCl and dried over sodium sulfate. After removal of the solvent, crude product 518-9 is purified by silica column chromatography.

Compound 518-9 is dissolved in 80% acetic acid and stirred at room temperature for 12 hours. After removal of the solvent, crude product 518-10 is purified by silica column chromatography.

Phosphonate esters 518-10 and 2,6-lutidine (8eq) were dissolved in CH ₃ CN and treated with trimethylsilyliodide (8 eq). After stirring for 3 hours at room temperature, triethylamine (8 eq) is added followed by methanol. After removal of the solvent, crude product 518-11 is purified by silica column chromatography.

Phosphonic diacid 518-11 is dissolved in 1,4-dioxane and treated with 4N NaOH and then heated to 100 ° C. for 4 hours. After cooling to room temperature, the reaction mixture is neutralized with 4N HCl. After removing the solvent, the crude product is purified by silica column chromatography to give 518-12 .

Scheme 518-7

Compound 518-13 (Paquette et al J. Org . Chem . (1997) 62: 1730-1736) is treated with p -methoxybenzyl bromide (1.5 eq.), Sodium hydride (1.4 eq) in dry DMF at room temperature. (Scheme 518-7). Observe the reaction by TLC to confirm 518-13 disappeared. The reaction is stopped by addition of saturated aqueous ammonium chloride solution. Extraction with diethyl ether gives the crude product, which is purified by silica gel chromatography to give 518-14 .

A 518-14 solution in THF under nitrogen atmosphere is added dropwise to a BuLi (1.2 eq) solution in THF cooled to -78 ° C. The solution is stirred for 1 h at -78 ° C. Add excess HMPA (1.4 eq). After 10 minutes, THF MeI (5 eq) solution is added. After 5 hours at −78 ° C., 20% aqueous NaH ₂ PO ₄ is added and the mixture is warmed to room temperature. Followed by extraction with diethyl ether the crude product obtained, to obtain a 518-15 was purified by silica gel chromatography.

Dichlorodicyanoquinone (DDQ) is added to a mixture of compound 518-15 in dichloromethane and water. After stirring for 2 hours at room temperature, the mixture is extracted with dichloromethane to give the crude product which is then purified by silica gel chromatography to give 518-16 .

To a 518-16 solution in dioxane at room temperature is added triphenylphosphine (2 eq.), 2-amino-6-chloropurine (2 eq). Diisopropyl azodicarboxylate (2 eq, DIAD) is added dropwise via syringe. The mixture is further stirred at room temperature for 3 hours. Water is added to stop the reaction. Extraction with ethyl acetate gives the crude product which is then purified by silica gel chromatography to give 518-17 .

Alternatively, nucleophilic bases such as palladium bound to cyclopentyl acetate can be added by the method described in Crimmins, MT (1998) Tetrahedron 54: 9229-9272.

To a solution of compound 518-17 in THF is added a 1 M solution of tetrabutylammonium fluoride (1.2 eq, TBAF) at room temperature. After several hours, saturated ammonium chloride solution is added. Extraction with ethyl acetate gives the crude product which is then purified by silica gel chromatography to give 518-18 .

Compound 518-18 , diethylbromomethylphosphonate (1.5 eq) and lithium t-butoxide (1.5 eq) are added in turn to DMF. The mixture is stirred at 80 C for several hours. The mixture is cooled to room temperature and then KH ₂ PO ₄ 1 M solution is added. Extraction with ethyl acetate gives the crude product which is then purified by silica gel chromatography to give 518-19 .

To 518-19 solution in acetone, N-methylmorpholine N-oxide (2 eq) and osmium tetraoxide (0.2 eq) are added. The mixture is stirred at rt for 16 h. 1 M aqueous sodium sulfite solution is added. After 1 hour more stirring at room temperature, the mixture is evaporated to remove most acetone. The aqueous residue is frozen and lyophilized to give crude product which is then purified by reverse phase HPLC to give 518-20 .

Iodotrimethylsilane (8 eq, TMS-I) is added to a mixture of 518-20 , 2,6-lutidine (8 eq) and acetonitrile. After stirring for 2 hours at room temperature, the mixture is poured on ice. The mixture is then cooled and lyophilized to give a residue, which is then purified by reverse phase HPLC to give 518-21 .

518-21 is dissolved in 4 N aqueous NaOH and refluxed for several hours. The mixture is cooled to room temperature, neutralized with 4N HCl and purified by reverse phase HPLC to give 518-22 .

Compound 518-22 can be converted to the corresponding diphosphophosphonate 518-23 and prodrugs using known methods.

Scheme 518-8

Dissolve 3-cyclopenten-l-ol 518-24 (108 uL, 1.2 mmol, 1.2 eq) in 5 mL of dry THF (Scheme 518-8). The solution is cooled to 0 C. 1.35 M n-BuLi (0.89 mL, 1.2 mmol, 1.2 eq) solution is added by syringe. After 10 minutes, diisopropylphosphonomethyl p-toluenesulfonate (350 mg, 1.0 mmol, 1.0 eq) is added. The mixture is stirred in 45 C bath for 3.5 h. The reaction is stopped with pH 7 aqueous phosphate buffer. Extraction with diethyl ether gives the crude product which is purified by silica gel chromatography (eluted with 45% ethyl acetate in hexane) to give 518 mg (68%) of 518-25 .

To a solution of 518-25 (168 mg, 0.69 mmol, 1 eq) in 12 mL of acetone, add 273 mg of NaHCO ₃ in 8 mL of water. The mixture is then cooled to 0 C. Oxone (519 mg, 0.85 mmol, 1.3 eq) in 4 mL of water is added in part over 5 minutes. The mixture is stirred vigorously for 2.5 hours. The mixture is then evaporated in vacuo to remove most of the acetone. The aqueous residue was extracted with ethyl acetate to give the crude product, which was then purified by silica gel chromatography to give 518-26 as a clear oil.

To a solution of 518-26 (21 mg, 0.076 mmol, 1.0 eq) in 0.25 mL of DMF is added cytosine (13 mg, 1.5 eq) and cesium carbonate (6 mg, 0.25 eq) and magnesium t-butoxide. The mixture is heated to 140 C for several hours. After cooling to room temperature, the reaction mixture is purified by reverse phase HPLC to give 12.5 mg 518-27 (42%). ¹ H NMR (CDCl 3): 9.60 (br s, 1H), 8.96 (br s, 1H), 7.87 (d, 1H), 6.21 (d, 1H), 4.84 (m, 1H), 4.78 (m, 2H) , 4.43 (m, 1H), 4.08 (s, 1H), 3.72 (m, 2H), 2.82 (m, 1H), 2.33 (m, 1H), 1.83 (m, 2H), 1.38 (m, 12H) ppm .

Alternatively, the method of WO 03/105770 can be used to add nucleophilic bases with nucleophilic amines to cyclopentyl epoxides.

The conversion to 518-28 from 518-27 is described in Scheme 518-2. Corresponding diphosphophosphonates 518-29 of 518-28 and Conversion to phosphorus prodrugs such as 518-30 can be accomplished using the methods described herein.

Cyclopentyl intermediate 518-31 can be prepared by methods similar to those described in US5206244 and US5340816 (Scheme 518-4 ). Converting the diol into cyclopentenone 518-31 and treated with IBr tenon 518-32 in the presence of the appropriate phosphonate alcohol to give a 518-33. Iodide 518-33 is substituted with inversion to yield cyclopentanone intermediate 518-34 . Exocyclic methylene 518-35 is obtained by Nysted methyleneization (US 3865848; Aldrichim. Acta (1993) 26:14) and deprotected to give 518-36 .

Cyclopentanone 518-34 may be a useful intermediate for the preparation of other compounds of the invention by reducing cyclopentyl or alkenyl Wittig or Grubb olefin to screen 518-38 to 518-37.

Scheme 518-9

Scheme 518-10 518-39 is the intermediate chamber guano cyclopentenyl tenon 518 - was converted to 40 (J. Am Chem Soc (1972 ) 94:... 3213) , and then, IBr and diethyl phosphonate iodine by treatment with methanol Obtaining the cargo 518-41 ( J. Org . Chem . (1991) 56: 2642). Nucleophilic substitution with AgOAc affords acetate 518-42 . Methyleneized using the method of Nisted (US3865848, Aldrichim . Acta 1993, 26 , 14) to give 518-43 , then adding sodium methoxylate to remove the acetate groups and inverting the resulting alcohol by Mitsunobu protocol. 518-44 is obtained by second acetate deprotection. Desilylation of 518-44 with tetra-butylammonium fluoride (TBAF) affords 518-45 .

Scheme 518-10

Specific conduct state

Example 519 Synthesis of Exemplary Compounds of the Invention

Synthesis of 519-1: 8 mL of anhydrous pyridine 3'- deoxy-uridine (995 mg, 4.36 mmol) solution in t--butyldiphenylsilyl chloride (TBDPS-Cl, 1.38 g, 5.01 mmol) and 4-dimethylaminopyridine in Pyridine (DMAP, 27 mg, 0.22 mmol) is added. The mixture is stirred at 23 C for 14 hours and then cooled to 0 C in an ice-water bath. To this mixture is added benzoyl chloride (735 mg, 0.61 mL, 5.2 mmol). The mixture is warmed to 23 ° C. and stirred for 2 h more. The mixture was concentrated in vacuo to yield a pate, which was partitioned between water and ethyl acetate. The aqueous layer was extracted once with ethyl acetate. The combined ethyl acetate layers were washed sequentially with 1 M aqueous citric acid, saturated sodium bicarbonate and brine. Dry over anhydrous sodium sulfate and concentrate in vacuo to afford the crude product as a yellow oil. Purification by silica gel chromatography (15 65% ethyl acetate in hexane) gives a colorless oil. Yield 1.35 g (54%). ¹ H NMR (DMSO-d6): 11.38 (s, 1H), 8.01 (d, J = 7.9 Hz, 2H), 7.77 (d, J = 8.2 Hz, 1H), 7.70 7.40 (m, 13H), 5.99 (s, 1H), 5.58 (m, 1H), 7.34 (d, J = 8.2 Hz, 1H), 4.47 (m, 1H), 4.03 (m, 1H), 3.84 (m, 1H), 2.43 (m, 1H), 2.21 (m, 1H), 1.03 (s, 9H) ppm. MS (m / z) 571.1 (M + H ⁺ ), 593.3 (M + Na ⁺ ).

Example 520 Synthesis of Exemplary Compounds of the Invention

Synthesis of 520-2 : Benzyl chloromethyl ether (0.54 g, 3.45 mmol), N, N-diisopropylmethylamine in a solution of 519-1 (1.31 g, 2.3 mmol) in 5 mL of anhydrous N, N-dimethylformamide (446 mg, 0.60 mL, 3.45 mmol) is added. The mixture is stirred at 23 ° C. for 4 hours. Add water The mixture was extracted with ethyl acetate. The organic layer was washed sequentially with 1 M aqueous citric acid, saturated sodium bicarbonate and brine. Dry over anhydrous sodium sulfate and concentrate in vacuo to afford the crude product as a yellow oil which is used in the next step without further purification.

The crude product obtained above was dissolved in 9 mL of THF. The solution was cooled to 0 C. 1 M TBAF solution (4.6 mL, 4.6 mmol) was added by syringe. The mixture was warmed to 23 C and stirred for 2 h more. An additional 2.3 mL of 1 M TBAF is added. The mixture was further stirred at 23 C for 2 hours. Saturated aqueous ammonium chloride was added to the solution. The mixture was evaporated in vacuo to remove most of THF. The aqueous phase was extracted with ethyl acetate. The aqueous layer was washed with brine then dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude product as a yellow oil. Purification by silica gel chromatography (30 80% ethyl acetate in hexanes) gave a white solid. Yield of 520-2 : 805 mg (77% for 2 steps). ¹ H NMR (DMSO-d6): 8.04 (m, 3H), 7.67 (t, J = 7.3 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.30 (m, 5H), 5.98 (s , 1H), 5.78 (d, J = 7.9 Hz, 1H), 5.55 (m, 1H), 5.31 (s, 2H), 5.22 (m, 1H), 4.57 (s, 2H), 4.41 (m, 1H) , 3.80 (m, 1H), 3.60 (m, 1H), 2.31 (m, 1H), 2.15 (m, 1H) ppm. MS (m / z) 453.1 (M + H ⁺ ), 475.3 (M + Na ⁺ ).

Example 521 Synthesis of Exemplary Compounds of the Invention

Synthesis of 521-3 : Iodobenzenediacetate (1.25 g, 3.89 mmol) and TEMPO (55 mg, 0.35 mmol) in 520-2 (800 mg, 1.77 mmol) solution in 3.5 mL of a 1: 1 mixture of acetonitrile / water Add. The mixture was stirred at 23 C for 14 hours. The mixture was then cooled to -78 C and lyophilized to give a solid residue. This residue was purified by silica gel chromatography (0-15% methanol in dichloromethane). Product 521-3 was obtained as a white solid. Yield: 735 mg (89%). ¹ H NMR (DMSO-d6): 8.13 (d, J = 7.6 Hz, 1H), 8.03 (d, J = 7.7 Hz, 2H), 7.68 (m, 1H), 7.58 (t, J = 7.0 Hz, 2H ), 7.29 (m, 5H), 6.04 (s, 1H), 5.85 (d, J = 8.3 Hz, 1H), 5.62 (m, 1H), 5.31 (s, 2H), 4.87 (m, 1H), 4.58 (s, 2H), 2.40-2.20 (m, 2H) ppm. MS (m / z) 467.1 (M + H ⁺ ), 489.3 (M + Na ⁺ ).

Example 522 Synthesis of Exemplary Compounds of the Invention

Synthesis of 522-4 : Lead tetraacetate (3.47 g, 7.83 mmol) is added to a deoxygenated solution of 521-3 (730 mg, 1.57 mmol) and pyridine (0.51 mL, 6.26 mmol) in 7 mL of anhydrous DMF. The mixture was shielded from light and stirred at 23 C for 14 hours. The mixture was diluted with 15 mL of ethyl acetate and 10 mL of water. This mixture was separated by filtration through a pad of celite. The aqueous phase was extracted with additional 10 mL of ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over sodium sulfate and evaporated in vacuo to afford the crude product as an oil. Crude product 522-4 was purified by silica gel chromatography (10-50% ethyl acetate in hexane). The product of two diastereomers was obtained in white foam. Yield: 400 mg (53%). ¹ H NMR (DMSO-d6): 8.01 (m, 2H), 7.82 7.63 (m, 2H), 7.57 (m, 2H), 7.31 (m, 5H), 6.58 (m, 1H), 6.17 (m, 1H ), 5.83 (m, 1H), 5.65 (m, 1H), 5.31 (s, 2H), 4.59 (s, 2H), 2.76 and 2.28 (m, 1H), 2.10 (m, 1H), 2.07 (s, 3H) ppm. MS (m / z) 481.0 (M + H ⁺ ), 503.3 (M + Na ⁺ ).

Example 523 Synthesis of Exemplary Compounds of the Invention

Synthesis of 523-5a : To a solution of 522-4 (300 mg, 0.63 mmol) in 6 mL of anhydrous dichloromethane, diethylhydroxymethylphosphonate (0.37 mL, 2.5 mmol) followed by trimethylsilyl trifluoromethanesulfonate ( 0.34 mL, 1.88 mmol) is added. The mixture was stirred at 23 ° C. for 6 hours. Triethylamine (0.44 mL, 3.15 mmol) was added followed by water. The mixture was extracted with ethyl acetate. The organic layer was washed with 1 M aqueous citric acid, saturated sodium bicarbonate and brine. Then dried over anhydrous sodium sulfate and evaporated in vacuo to give a residue. This crude product was purified by silica gel chromatography (75 95% ethyl acetate in hexane) to give two products, diastereomers of each other as shown above ( 523-5a and 523-5b ). Yield of 523-5a : 53 mg (14%). 523-5b yield: 129 mg (35%).

Analytical data for 5a : ¹ H NMR (acetonitrile-d3): 8.04 (d, J = 7.0 Hz, 2H), 7.77 (d, J = 7.9 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H ), 7.53 (m, 2H), 7.33 (m, 5H), 6.38 (d, J = 4.0 Hz, 1H), 5.80 (d, J = 8.2 Hz, 1H), 5.63 (m, 1H), 5.52 (m , 1H), 5.41 (s, 2H), 4.64 (s, 2H), 4.17 (m, 4H), 4.08 (dd, J = 13.8, 10.1 Hz, 1H), 3.92 (dd, J = 13.7, 9.5 Hz, 1H), 2.66-2.42 (m, 2H), 1.35 (t, J = 7.0 Hz, 6H) ppm. MS (m / z) 589.2 (M + H ⁺ ), 611.3 (M + Na ⁺ ). The stereochemistry of 523-5a was confirmed by additional 2D NMR experiments.

Analytical Data for 523-5b : ¹ H NMR (acetonitrile-d3): 8.08 (d, J = 7.3 Hz, 2H), 7.69 (t, J = 7.5 Hz, 1H), 7.55 (m, 2H), 7.43 (d, J = 8.2 Hz, 1H), 7.36 (m, 5H), 6.11 (d, J = 2.4 Hz, 1H), 5.77 (d, J = 8.3 Hz, 1H), 5.57 (m, 2H), 5.41 (s, 2H), 4.66 (s, 2H), 4.12 (m, 5H), 3.88 (dd, J = 14.0, 5.2 Hz, 1H), 2.82 (m, 1H), 2.25 (m, 1H), 1.27 ( t, J = 7.0 Hz, 6H) ppm. MS (m / z) 589.0 (M + H ⁺ ), 611.2 (M + Na ⁺ ).

Example 524 Synthesis of Exemplary Compounds of the Invention

Synthesis of 524-6 : 2,6-lutidine (0.43 mL, 3.74 mmol) followed by iodotrimethylsilane (0.53 mL, 3.74 mmol) in a solution of 523-5a (110 mg, 0.19 mmol) in 3 mL of acetonitrile. Add. After stirring at 23 C for 30 minutes, the mixture was heated to 40 ° C and further stirred at that temperature for 4 hours. The reaction mixture was cooled to 23 ° C. Triethylamine (0.52 mL, 3.74 mmol) was added followed by water (10 mL). The aqueous mixture was extracted twice with 5 mL of diethyl ether. The resulting aqueous solution was cooled to -78 ° C and lyophilized to give a yellow solid. This crude product was purified by reverse phase HPLC to give 524-6 . Obtained as a light yellow solid. Yield 26 mg (34%). MS (m / z) 411.3 (M ⁻ H).

Example 525 Synthesis of Exemplary Compounds of the Invention

Synthesis of 525-7 : Phosphonate 524-6 (12 mg, 0.029 mmol), carbonyldiimidazole (47 mg, 0.29 mmol) and tri-n-butylamine (5.4 mg, 0.029 mmol) in anhydrous dimethylform Dissolved in 0.3 mL of amide (DMF). The mixture was stirred at 23 ° C. for 4 hours. MeOH (0.020 mL) was added and the mixture was stirred for 30 more minutes. A solution of tributylammonium pyrophosphate (159 mg, 0.29 mmol) in 0.63 mL of anhydrous DMF was added. The resulting mixture was stirred at 23 ° C. for 14 hours. The mixture was evaporated in vacuo to remove most of the DMF. The residue was dissolved in 5 mL of water and purified by ion exchange chromatography (DEAE-cellulose resin, 0-50% triethylammonium bicarbonate in water) to give a white solid which was used directly in the next reaction.

The product obtained above was dissolved in 2 mL of water. 0.3 mL of 1 M sodium hydroxide solution in water was added. The mixture was stirred at 23 ° C. for 40 minutes. Acetic acid was added to adjust the pH of the solution to 5. The solution was diluted with water and purified by an ion exchange column (DEAE-cellulose resin, 0-50% triethylammonium bicarbonate in water) to give diphosphophosphonate 525-7 as a white solid which is the triethylammonium salt of the above formula. . Yield 10 mg (45% for 2 steps). ¹ H NMR (D ₂ O): 7.79 (d, J = 7.6 Hz, 1H), 5.89 (m, 1H), 5.85 (d, J = 7.6 Hz, 1H), 5.41 (m, 1H), 4.49 (m , 1H), 4.02 3.65 (m, 2H), 3.06 (m, 18H), 2.20 (m, 2H), 1.14 (m, 27H) ppm. ³¹ P NMR (D ₂ O): 7.46 (d, 1P), -9.45 (d, 1P), -23.11 (t, 1P) ppm. MS (m / z) 467.0 (M ⁻ H).

Example 526 Synthesis of Exemplary Compounds of the Invention

Synthesis of 526-8: water was added 0.4 mL 524-6 (16 mg, 0.039 mmol) NaOH (7.8 mg, 0.19 mmol) to a solution of. The solution was stirred at 23 ° C. for 1 hour. Acetic acid (0.012 mL) was added to the solution. The mixture was then purified by reverse phase HPLC (eluted with 100% water) to give 4.6-8 4.6 mg as a white solid (38% yield). ¹ H NMR (D ₂ O): 7.83 (d, J = 8.3 Hz, 1H), 5.86 (d, J = 3.4 Hz, 1H), 5.82 (d, J = 7.9 Hz, 1H), 4.48 (m, 1H ), 3.68 (m, 1H), 3.37 (m, 1H), 2.16 (m, 2H) ppm. ³¹ P NMR (D ₂ O): 12.60 (s, 1P) ppm. MS (m / z) 615.1 ( 2M-H -).

Scheme 526-1

A solution of tert-butyl hydroperoxide (t-BuOOH) in benzene (68%, 3 eq) at room temperature was prepared as described in allylic alcohol 526-1 ( Tet . Lett . , 38: 2355 (1997) in benzene) . Synthesis) and a drop of VO (acac) ₂ (final concentration 0.1 M) dropwise (Scheme 526-1 ). After stirring for 1 hour at room temperature, saturated aqueous Na ₂ S ₂ O _{3 was} added to the reaction mixture. The resulting solution was extracted with EtOAc, washed with H ₂ O and dried over sodium sulfate. After removing the solvent, the crude product 526-2 is purified by silica column chromatography.

Epoxide 526-2 and p- anisylchlorodiphenylmethane (1.5 eq) are dissolved in anhydrous pyridine (0.17 M) and stirred at 25 ° C. for 2 days. The solvent is removed under reduced pressure and the residue is dissolved in EtOAc. The organic layer is washed with water and dried over saturated aqueous NaHCO ₃ and sodium sulfate. After removing the solvent, the crude product 526-3 is purified by silica column chromatography.

N-butyllithium (2.2 eq) is added to a solution of methyltriphenylphosphonium bromide (2 eq) in dry THF at −78 ° C. The solution is warmed to room temperature and stirred for 20 minutes. After recooling to −78 ° C., the solution is added to fully protected epoxide 526-3 (final concentration 0.06 M) in THF. The reaction mixture is warmed to room temperature and stirred for 12 hours, then H ₂ O is added and extracted with diethyl ether. The combined organic layers are dried over sodium sulfate. After removing the solvent, the crude product 526-4 purified by silica column chromatography.

Sodium hydride (1 eq) and 2-amino-4-chloro-7H pyrrolo [2,3-d] pyrimidine (1 eq) are dissolved in anhydrous DMF (0.06 M) and stirred at 120 ° C. for 10 minutes. Then a 526-4 solution in DMF was added and the reaction mixture was stirred at 120 ° C. for 12 hours, after which the solvent was evaporated under reduced pressure. The residue is dissolved in CH ₂ Cl ₂ , washed with H ₂ O and dried over sodium sulfate. After removing the solvent, the crude product 526-5 is purified by silica column chromatography.

Compound 526-5 was dissolved in dichloromethane and 1,1,1-tris (acetyloxy) -1,1-dihydro-1,2-benzioxoxo-3- ( 1H ) -one in dichloromethane Aldrich, Dess Martin periodinane, 4 eq) solution (final concentration 0.06 M). The reaction mixture is stirred for 4 days at room temperature, then diluted with EtOAc and poured into a solution of sodium thiosulfate in saturated aqueous sodium bicarbonate solution. The organic layer is separated and dried over sodium sulfate. After removal of the solvent, crude product 6 is purified by silica column chromatography.

Ketone 526-6 solution in dry THF at -78 ° C is added to a solution of methylmagnesium bromide (4 eq) in dry THF (0.1 M). The reaction mixture is stirred at −60 ° C. for 12 h and then the reaction is stopped with saturated aqueous NH ₄ Cl solution. The mixture is filtered through celite and washed with EtOAc. The combined organic layers are washed with saturated aqueous NH ₄ Cl, water and dried over sodium sulfate. After removing the solvent, the crude product 526-7 is purified by silica column chromatography.

A solution of alcohol 7 (0.06 M) in dry THF is treated with a solution of tetrabutylammonium fluoride (1.5 eq) in THF at room temperature. The reaction mixture is stirred for 3 hours and then the solvent is evaporated. Crude desilylated diol 526-8 is purified by silica column chromatography.

Magnesium tert-butoxide (1 eq) is added to a solution (0.1 M) of diol 526-8 and benzenesulfonic acid diisopropoxy-phosphorylmethyl ester (1.2 eq) in anhydrous DMF. The reaction mixture is heated to 80 ° C. for 12 hours. After cooling to room temperature, 1 N citric acid is added and extracted with EtOAc. The organic layer is neutralized with saturated aqueous NaHCO ₃ , washed with saturated aqueous NaCl and dried over sodium sulfate. After removing the solvent, the crude product 526-9 is purified by silica column chromatography.

Compound 526-9 is dissolved in 80% acetic acid and stirred at room temperature for 12 hours. After removal of the solvent, crude product 526-10 is purified by silica column chromatography.

Phosphonate esters 526-10 and 2,6-lutidine (8eq) are dissolved in CH ₃ CN and treated with trimethylsilyliodide (8 eq). After stirring for 3 hours at room temperature, triethylamine (8 eq) is added followed by methanol. After removing the solvent, the crude product 526-11 purified by silica column chromatography.

Phosphonic diacid 526-11 is dissolved in 1,4-dioxane and treated with 4N NaOH and heated to 100 ° C. for 4 hours. After cooling to room temperature, the reaction mixture is neutralized with 4N HCl. After removal of the solvent, the crude product is purified by silica column chromatography to give 526-12 .

Scheme 526-2

Compound 526-13 (Paquette et al in J. Org . Chem . (1997) 62: 1730-1736) was treated with p -methoxybenzyl bromide (1.5 eq.), Sodium hydride (1.4 eq) in dry DMF at room temperature (Scheme 526-2). Observe the reaction by TLC to confirm disappearance of 526-13 . The reaction is stopped by addition of saturated aqueous ammonium chloride solution. Extraction with diethyl ether gives the crude product, which is purified by silica gel chromatography to give 526-14 .

A 526-14 solution in THF is added dropwise to a solution of n-BuLi (1.2 eq) in THF cooled to −78 ° C. under a nitrogen atmosphere. The solution is stirred at -78 ° C for 1 hour. Add excess HMPA (1.4 eq). After 10 minutes, MeI (5 eq) in THF is added. After 5 hours at −78 ° C., 20% aqueous NaH ₂ PO ₄ is added and the mixture is warmed to room temperature. Extracted with diethyl ether to obtain the crude product, thereby obtaining the 526-15 was purified by silica gel chromatography.

To a mixture of compound 526-15 in dichloromethane and water is added dichlorodicyanoquinone (DDQ). After stirring for 2 hours at room temperature, the mixture is extracted with dichloromethane to give the crude product which is then purified by silica gel chromatography to give 526-16 .

To the 526-16 solution in dioxane at room temperature is added triphenylphosphine (2 eq.), 2-amino-6-chloropurine (2 eq). Diisopropyl azodicarboxylate (2 eq, DIAD) is added dropwise by syringe. The mixture is stirred for another 3 hours at room temperature. Water is added to stop the reaction. Extraction with ethyl acetate gives the crude product which is then purified by silica gel chromatography to give 526-17 .

To a solution of compound 526-17 in THF is added 1 M tetrabutylammonium fluoride (1.2 eq, TBAF) solution at room temperature. After a few more hours, saturated ammonium chloride solution is added. Extraction with ethyl acetate gives the crude product which is then purified by silica gel chromatography to give 526-18 .

Compound 526-18 , diethylbromomethylphosphonate (1.5 eq) and lithium t-butoxide (1.5 eq) are added in turn to DMF. The mixture is stirred at 80 C for several hours. The mixture is cooled to room temperature and then a 1 M KH ₂ PO ₄ solution is added. Extraction with ethyl acetate gives the crude product which is then purified by silica gel chromatography to give 526-19 .

To 526-19 solution in acetone, N-methylmorpholine N-oxide (2 eq) and osmium tetraoxide (0.2 eq) are added. The mixture is stirred at rt for 16 h. 1 M aqueous sodium sulfite solution is added. After several more hours of stirring at room temperature, the mixture is evaporated to remove most of the acetone. The aqueous residue is frozen and lyophilized to give crude product which is then purified by reverse phase HPLC to give 526-20 .

Iodotrimethylsilane (8 eq, TMS-I) is added to a mixture of 526-20 , 2,6-lutidine (8 eq) and acetonitrile. After stirring for 2 hours at room temperature, the mixture is poured on ice. The mixture is then cooled and lyophilized to give a residue, which is then purified by reverse phase HPLC to give 526-21 .

526-21 is dissolved in 4N aqueous NaOH and refluxed for several hours. The mixture is cooled to room temperature, neutralized with 4N HCl and purified by reverse phase HPLC to give 526-22 .

Compounds 526-22 can be converted to the corresponding diphosphophosphonates 526-23 and prodrugs using known methods.

Scheme 526-3

3-cyclopenten-l-ol 526-24 (108 uL, 1.2 mmol, 1.2 eq) is dissolved in 5 mL of dry THF. The solution is cooled to 0 C. 1.35 M n-BuLi (0.89 mL, 1.2 mmol, 1.2 eq) solution is added by syringe. After 10 minutes, diisopropylphosphonomethyl p-toluenesulfonate (350 mg, 1.0 mmol, 1.0 eq) is added. The mixture is stirred at 45 C for 3.5 hours. The reaction is stopped with pH 7 aqueous phosphate buffer. Extraction with diethyl ether gives the crude product which is purified by silica gel chromatography (eluting with 45% ethyl acetate in hexane) to give 178 mg (68%) of 526-25 .

To a solution of 526-25 (168 mg, 0.69 mmol, 1 eq) in 12 mL of acetone, add 273 mg of NaHCO ₃ in 8 mL of water. The mixture is then cooled to 0 C. Oxone (519 mg, 0.85 mmol, 1.3 eq) in 4 mL of water is added in part over 5 minutes. The mixture is stirred vigorously for 2.5 hours. The mixture is then evaporated in vacuo to remove most of the acetone. The aqueous residue is extracted with ethyl acetate to give the crude product which is then purified by silica gel chromatography to give 526-26 as a clear oil.

To a solution of 526-26 (21 mg, 0.076 mmol, 1.0 eq) in 0.25 mL of DMF is added cytosine (13 mg, 1.5 eq) and cesium carbonate (6 mg, 0.25 eq) and magnesium t-butoxide. The mixture is heated to 140 C for several hours. After cooling to room temperature, the reaction mixture is purified by reverse phase HPLC to give 12.5 mg (42%) 526-27 . ¹ H NMR (CDCl 3): 9.60 (br s, 1H), 8.96 (br s, 1H), 7.87 (d, 1H), 6.21 (d, 1H), 4.84 (m, 1H), 4.78 (m, 2H) , 4.43 (m, 1H), 4.08 (s, 1H), 3.72 (m, 2H), 2.82 (m, 1H), 2.33 (m, 1H), 1.83 (m, 2H), 1.38 (m, 12H) ppm .

Conversion to 526-28 from 526-27 described in Scheme 526-2. 526-28 corresponding di force Po sports carbonate 526-29 and phosphorus prodrugs, e. G. Conversion of 526-30 to the can be achieved by using the methods described herein.

Cyclopentyl intermediates 526-31 can be prepared by methods analogous to those described in US5206244 and US5340816 (Scheme 526-4). Diol 526-31 cyclopentenyl tenon 526 - converted to 32 and treated with IBr in the presence of the appropriate phosphonate alcohol to give a 526-33. Iodide 526-33 is substituted with inversion to yield cyclopentanone intermediate 526-34 . Exocyclic methylene 526-35 is obtained by nysted methyleneization (US 3865848; Aldrichim . Acta (1993) 26:14), followed by deprotection to give 526-36 .

Cyclopentanone is to cyclopentyl 526-34 526-37 526-38 to the reducing or alkenyl It may be a useful intermediate for forming other compounds of the invention by Wittig or Grubb olefination.

Scheme 526-4

Scheme 526-5 is intermediate the chamber 526-39 guano cyclopentenyl tenon 526 - was converted to 40 (J. Am Chem Soc (1972 ) 94:... 3213) , and then, IBr and diethyl phosphonate iodine by treatment with methanol Obtaining the cargo 526-41 ( J. Org . Chem . (1991) 56: 2642). Nucleophilic substitution with AgOAc affords acetate 526-42 . Methyleneized using the method of Nisted (US3865848, Aldrichim . Acta 1993, 26 , 14) to give 526-43 , then sodium methoxylate was added to remove the acetate group and the resulting alcohol was inverted by Mitsunobu protocol. A second acetate deprotection gives 526-44 . Desilylation of 526-44 with tetra-butylammonium fluoride (TBAF) affords 526-45 .

Scheme 526-5

Synthesis of 2'-C-Me-UP

Example 527 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 527-1: L-Xylose (36.2 g) and anhydrous CuSO ₄ are added to a 500 mL round bottom flask. Acetone (220 mL) is added. To this slurry stirred at room temperature is added 3.6 mL of 96% sulfuric acid. The mixture is further stirred for 24 hours at room temperature under a nitrogen atmosphere. The mixture is filtered to remove solid material. The solid is washed with 50 mL of acetone. To the collected filtrate is added 25.3 mL of concentrated ammonium hydroxide. Filter to remove precipitate. The filtrate is evaporated in vacuo to give an oil which is then co-evaporated twice with absolute ethanol to give a yellow oil. The crude product is stirred vigorously with 160 mL of 0.06 M aqueous HCl at room temperature for 2.5 hours. The reaction mixture became homogeneous at the end of the reaction. Some solid NaHCO ₃ (3.26 g) is added. After gas evolution stopped, the mixture was filtered. The filtrate was frozen and lyophilized overnight to give a syrup, which was dissolved in ethyl acetate and dried over anhydrous Na ₂ SO ₄ to afford the desired diol as a yellow oil. Proton NMR shows that the product is "95% pure. Yield of this crude product: 44.5 g (96%). ¹ H NMR ( DMSO - d ₆ , 300 MHz): δ 5.79 (d, J = 3.6 Hz, 1H ), 5.13 (d, J = 4.9 Hz, 1H), 4.61 (t, J = 5.6 Hz, 1H), 4.36 (d, J = 3.6 Hz, 1H), 4.10 3.91 (m, 2H), 3.60 (m, 1H), 3.51 (m, 1H), 1.37 (s, 3H), 1.22 (s, 3H) ppm

Example 528 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 528-2: 1,2-O-isopropylidene-L-xylose (5 g, 26.3 mmol, 1.0 eq.) And 2- iodobenzoyl chloride (7.01 g, 26.3 mmol) were dried over anhydrous dichloromethane (25 mL). The solution was cooled in an ice-water bath. Triethylamine (3.85 mL, 27.6 mmol, 1.05 eq.) Was added dropwise by syringe. The mixture was stirred at 0 C for 30 minutes and warmed to room temperature over 1 hour. Water was added to the reaction mixture. The mixture was washed with 1 M aqueous HC. The aqueous layer was extracted with 20 mL of dichloromethane. The combined organic extracts were washed with a mixture of 20 mL brine and 5 mL saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a brown oil. This crude product was purified by silica gel chromatography (eluting with 0 50% EtOAc in hexanes) to afford the desired mono-ester as a yellow oil. Yield: 7.6 g (69%). ¹ H NMR ( DMSO - d ₆ , 300 MHz): δ 8.02 (d, J = 7.3 Hz, 1H), 7.73 (dd, J = 7.8, 1.7 Hz, 1H), 7.52 (t, J = 7.3 Hz, 1H) , 7.29 (td, J = 7.7, 1.8 Hz, 1H), 5.88 (d, J = 3.7 Hz, 1H), 5.51 (m, 1H), 4.45 (m, 2H), 4.12 (m, 1H), 1.38 ( s, 3H), 1.24 (s, 3H) ppm. MS (m / z): calculated value 420.01 (M + H ⁺ ), 443.00 (M + Na ⁺ ), measured value 420.9 (M + H ⁺ ), 443.0 (M + Na ⁺ ).

Example 529 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 529-3: The product obtained in the previous step (7.6 g, 18.1 mmol, 1.0 eq.) Was dissolved in 35 mL of anhydrous dichloromethane. Dess-Martin periodinane (9.6 g, 22.6 mmol, 1.25 eq.) Was added. The mixture is stirred for 14 hours at room temperature. 1 M sodium sulfite (7.5 mL) solution was added. The resulting mixture was further stirred at rt for 2 h. The pH of the aqueous phase was adjusted to 6 by addition of some saturated NaHCO ₃ solution. Separated into two layers. The aqueous phase was extracted twice with 15 mL of dichloromethane. The combined organic extracts were washed with brine and dried for 4 hours with anhydrous Na ₂ SO ₄ while stirring well. Then it was filtered and dried overnight with excess anhydrous MgSO ₄ with stirring well. The mixture was filtered and concentrated in vacuo to give a clear oil as a product which was used in the next step without further purification. Yield: 6.7 g (89%). ¹ H NMR ( DMSO - d ₆ , 300 MHz): δ 8.02 (d, J = 7.9 Hz, 1H), 7.71 (dd, J = 7.8, 1.7 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H) , 7.29 (td, J = 7.6, 1.5 Hz, 1H), 6.16 (d, J = 4.6 Hz, 1H), 4.85 (m, 1H), 4.63 (d, J = 4.6 Hz, 1H), 4.54 (dd, J = 12.2, 2.7 Hz, 1H), 4.42 (dd, J = 12.2, 4.3 Hz, 1H), 1.41 (s, 3H), 1.34 (s, 3H) ppm. MS (m / z): calculated 458.99 (M + H ₂ O + Na ⁺ ), found 459.03 (M + H ₂ O + Na ⁺ ).

Example 530 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 530-4 : The product (6.15 g, 14.7 mmol, 1.0 eq.) Obtained in the previous step was dissolved in 29 mL of anhydrous THF. The solution was cooled in an ice-water bath. A 3.0 M methyl magnesium bromide solution (5.39 mL, 16.2 mmol, 1.1 eq.) In diethyl ether was added dropwise by syringe. The mixture was stirred at 0 C for 2 hours. Aqueous citric acid solution (1 M, 10 mL) was added to the reaction mixture. The resulting mixture was evaporated in vacuo to remove most of THF. The aqueous residue was extracted twice with 10 mL of EtOAc. The organic extract was washed with saturated NaHCO ₃ and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to yield a white solid as product. Yield: 6.11 g (96%). ¹ H NMR ( DMSO - d ₆ , 300 MHz): δ 8.01 (dd, J = 8.0, 1.0 Hz, 1H), 7.71 (dd, J = 7.8, 1.7 Hz, 1H), 7.52 (td, J = 7.5, 1.0 Hz, 1H), 7.29 (td, J = 7.7, 1.8 Hz, 1H), 5.72 (d, J = 3.7 Hz, 1H), 5.13 (s, 1H), 4.46 (dd, J = 11.6, 2.3 Hz, 1H ), 4.20 (dd, J = 11.7, 8.5 Hz, 1H), 4.12 (d, J = 3.6 Hz, 1H), 4.08 (dd, J = 8.5, 2.1 Hz, 1H), 1.45 (s, 3H), 1.26 (s, 3H), 1.06 (s, 3H) ppm. MS (m / z): calculated 457.01 (M + Na ⁺ ), found 457.27 (M + Na ⁺ ).

Example 531 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 531-5: In a solution of 530-4 (6.1 g, 14.1 mmol) in 20 mL of anhydrous pyridine, triethylamine (3.13 mL, 22.5 mmol), DMAP (0.343 g, 2.8 mmol) followed by benzoyl chloride ( 2.61 mL, 22.5 mmol) was added. The mixture was stirred at 70 C for 36 hours and then cooled to room temperature. The mixture was evaporated in vacuo to remove most of the pyridine. The residue was acidified with 1 M aqueous citric acid. The resulting mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to afford crude product. This crude product was purified by silica gel chromatography (0-35% ethyl acetate in hexane) to give 5 7.0 g (92%). ¹ H NMR ( DMSO-d ₆ , 300 MHz): 8.03 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.79 (d, J = 7.7 Hz, 1H), 7.64 ( t, J = 7.9 Hz, 1H), 7.5 (m, 3H), 7.30 (t, J = 7.6 Hz, 1H), 5.92 (d, J = 3.7 Hz, 1H), 4.92 (d, J = 3.5 Hz, 1H), 4.63 (m, 1H), 4.46 (m, 2H), 1.50 (s, 3H), 1.39 (s, 3H), 1.25 (s, 3H) ppm. MS (m / z) 589.2 (M + H ⁺ ), 611.3 (M + Na ⁺ ). MS (m / z): calculated 561.04 (M + Na ⁺ ), found 561.06 (M + Na ⁺ ).

Example 532 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 532-6: 26 mL Glacial Acetic Acid To a solution of 531-5 (7.0 g, 13 mmol) in water was added acetic anhydride (7.7 mL). The solution was cooled in an ice-water bath. Concentrated sulfuric acid (1.9 mL) was added dropwise by syringe over 10 minutes. The cooling bath was removed and the solution was warmed to room temperature and stirred for another 20 minutes at that temperature. The reaction mixture was poured into a mixture of 75 mL of diethyl ether and 75 g of ice. The layers were separated and the aqueous layer was extracted with 75 mL of diethyl ether. The combined ether extracts were stirred with 250 mL of water. Solid NaHCO 3 was added in portions until gas evolution ceased. The layers were separated. The aqueous layer was extracted with 75 mL ether. The combined ether extracts were washed with brine, dried over anhydrous MgSO ₄ and concentrated in vacuo to give 6 as a yellow foam. In the product mixture there are two diastereomers of the same molecular weight, possibly two anomers. Yield: 6.76 g (89%). This crude product was used without further purification. MS (m / z): calculated 605.03 (M + Na ⁺ ), found 604.93 (M + Na ⁺ ).

Example 533 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 533-7: 532-6 (6.76 g, 11.6 mmol) was dissolved in 22 mL of dichloromethane. The solution was cooled in an ice-water bath. SnCl ₄ solution (1.0 M, 29 mL, 29 mmol) in dichloromethane was added by syringe. The cooling bath was removed and the mixture was warmed to room temperature and stirred for 1 h more. The mixture was cooled to 0 C again. Triethylamine (15 mL) was added by syringe. The resulting solution was poured into 75 g of ice and 75 mL of EtOAc mixture. The mixture was filtered through a pad of celite. The solid was washed with EtOAc. The combined filtrates were washed with saturated NaHCO ₃ , brine, dried over Na ₂ SO ₄ and concentrated in vacuo to afford the crude product, which was then purified by silica gel chromatography (25 75% EtOAc in hexanes) to 7 in a light yellow foam. Got it. Yield 6.0 g (75%). ¹ H NMR ( DMSO - d ₆ , 300 MHz): 8.00 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 7.9 Hz, 1H), 7.61 ( t, J = 7.2 Hz, 1H), 7.45 (m, 3H), 7.25 (t, J = 7.3 Hz, 1H), 5.28 (s, 1H), 5.07 (s, 1H), 4.65 (m, 2H), 4.49 (m, 1H), 4.10 3.90 (m, 5H), 3.83 (dd, J = 13.9, 9.0 Hz, 1H), 1.88 (s, 3H), 1.69 (s, 3H), 1.18 (t, J = 6.9 Hz, 6H) ppm. MS (m / z): calculated 713.06 (M + Na ⁺ ), measured 713.08 (M + Na ⁺ ).

Example 534 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 534-8: 30 mL of dichloromethane To a solution of 533-7 (4.7 g, 6.8 mmol) in 27.2 mL of 1.0 M KH ₂ PO ₄ An aqueous solution was added. A 0.8 M Na ° C. solution in water was added. The mixture was stirred at rt for 1 h. Methanol (10 mL) was added. Solid K ₂ CO ₃ was added in portions until the pH of the aqueous phase reached 9 10. The mixture was stirred for another 1 hour at room temperature. Aqueous 1 M Na ₂ SO ₃ solution (10 mL) was added and the mixture was stirred for another 30 minutes at room temperature. Separated into two layers. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to give 534-8 as a yellow foam which was used in the next step without further purification. ¹ H NMR ( DMSO - d ₆ , 300 MHz): 7.94 (d, J = 7.8 Hz, 2H), 7.68 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 5.28 ( d, J = 1.0 Hz, 1H), 5.05 (d, J = 1.2 Hz, 1H), 4.98 (t, J = 5.6 Hz, 1H), 4.34 (dd, J = 6.5, 4.6 Hz, 1H), 4.11 3.95 (m, 5H), 3.86 (dd, J = 13.7, 8.8 Hz, 1H), 3.76 (m, 1H), 3.63 (m, 1H), 1.93 (s, 3H), 1.64 (s, 3H), 1.25 ( t, J = 7.0 Hz, 6H) ppm.

³¹ P NMR ( DMSO - d ₆ ): 20.63 (s, 1P) ppm. MS (m / z): calculated value 483.14 (M + Na ⁺ ), found 483.30 (M + Na ⁺ ).

Example 535 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 535-9: To a mixture of 533-8 and 6.8 mL of acetonitrile and 6.8 mL of water obtained above was added iodobenzenediacetate (4.97 g, 15 mmol) and TEMPO (0.213 g, 1.36 mmol). The mixture was stirred vigorously for 6 hours at room temperature. It was then frozen and lyophilized to give an orange solid which was then dissolved in dichloromethane and purified by silica gel chromatography (0 10% MeOH in CH 2 Cl 2) to give 534-9 as a light yellow solid. Yield: 2.8 g (87% for 2 steps). ¹ H NMR ( DMSO - d ₆ , 300 MHz): 13.39 (br s, 1 H), 7.97 (d, J = 7.8 Hz, 2H), 7.70 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.5 Hz, 2H), 5.35 (s, 1H), 5.16 (s, 1H), 4.89 (s, 1H), 4.18 (dd, J = 13.7, 8.8 Hz, 1H), 4.06 (m, 4H), 3.88 ( dd, J = 13.4, 9.7 Hz, 1H), 1.86 (s, 3H), 1.69 (s, 3H), 1.24 (dt, J = 7.0, 2.7 Hz, 6H) ppm. ³¹ P NMR ( DMSO - d ₆ ): 20.79 (s, 1P) ppm. MS (m / z): Calculated 473.12 (MH ^-), the measurement value 472.95 (MH ^-).

Example 536 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 536-10: To a solution of 535-9 (474 mg, 1.0 mmol) in 2.0 mL of anhydrous DMF was added pyridine (238 mg, 3.0 mmol) and lead tetraacetate (1.33 g, 3.0 mmol). The mixture was stirred for 7 hours at room temperature while blocking from light. Then it was poured into a mixture of 10 g ice and 10 mL diethyl ether. The mixture was filtered to remove the precipitate. The filtrate was separated into two phases. The aqueous phase was extracted twice with ether. The combined ether extracts were washed with 1 M citric acid, saturated NaHCO ₃ and brine. After drying over anhydrous MgSO 4, the ether solution was concentrated in vacuo to afford crude 536-10 as a colorless oil which was used without further purification. Yield: 255 mg (52%). MS (m / z): calculated 511.13 (M + Na ⁺ ), measured 511.11 (M + Na ⁺ ).

Example 537 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 537-11: In a solution of 536-10 (211 mg, 0.43 mmol) in 2.0 mL of anhydrous acetonitrile, O, O-bis (trimethylsilyl) uracil (443 mg, 1.73 mmol) and TMS-OTf (384) mg, 1.73 mmol) was added. The mixture was stirred at rt for 3 h. Further 443 mg of O, O-bis (trimethylsilyl) uracil were added and the mixture was further stirred at rt for 4 h. 2, 6-Lutidine (371 mg, 3.46 mmol) followed by TMS-I (259 mg, 1.3 mmol) was added dropwise by syringe. The mixture was stirred for an additional hour at room temperature and then poured onto 10 g of ice. The mixture was frozen and filtered through celite pad. The filtrate was frozen and lyophilized to give a yellow solid, then dissolved in water and purified by reverse phase HPLC to give 537-11 as a white solid. Yield: 20 mg (10%). MS (m / z): calculated 483.08 (MH ⁻ ), found 483.34 (MH ⁻ ).

Example 538 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 538-12: 0.3 mL Water To a solution of 537-11 (17 mg, 0.035 mmol) in NaOH (4.3 mg, 0.11 mmol) was added. After stirring for 2 hours at room temperature, the mixture was acidified with trifluoroacetic acid and purified by HPLC to give 538-12 as a white powder. Yield: 5 mg (42%). ¹ H NMR ( D ₂ O , 300 MHz): 7.74 (d, J = 8.2 Hz, 1H), 5.97 (s, 1H), 5.78 (d, J = 8.2 Hz, 1H), 5.10 (d, J = 4.9 Hz , 1H), 3.86 (dd, J = 12.9, 10.0 Hz, 1H), 3.78 (d, J = 4.7 Hz, 1H), 3.65 (dd, J = 12.7, 9.3 Hz, 1H), 1.10 (s, 3H) ppm. ³¹ P NMR ( D ₂ O ): 14.60 (s, 1P) ppm. MS (m / z): calculated 337.04 (MH ⁻ ), found 337.38 (MH ⁻ ).

Example 539 Synthesis of Exemplary Compounds of the Invention

Synthesis of 3'-deoxy-CP

Example 540 Synthesis of Exemplary Compounds of the Invention

Synthesis of compound 540-2: 2,4,6-triisopropylbenzenesulfonyl chloride (65 mg, 0.21 mmol), in a stirred solution of 527-1 (50 mg, 0.11 mmol) in 1 mL of acetonitrile under nitrogen DMAP (26 mg, 0.21 mmol) and triethylamine (22 mg, 0.21 mmol) were added. The mixture was stirred at rt for 4 h. Aqueous ammonia (29%, 1 mL) was added. The mixture was stirred at rt for 2 h. After extraction with EtOAc, the residue was purified by silica gel chromatography to give 540-2 as a white solid. MS (m / z): calculated 468.15 (M + H ⁺ ), found 468.0 (M + H ⁺ ).

Example 541 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 541-3 to a Solution of 540-2 in Acetonitrile 2,6-lutidine (118 mg, 1.10 mmol) and TMS-I (165 mg, 0.84 mmol) were added. The mixture was stirred at rt for 2 h. Triethylamine was added followed by water. The mixture was then frozen and lyophilized to give a solid residue. This crude product was purified by reverse phase HPLC to give 541-3 . Obtained as a white solid. Yield 44 mg (97% for two steps). MS (m / z): calculated 410.1 (MH ⁻ ), measured 410.2 (MH ⁻ ).

Example 542 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 542-4 : NaOH (20 mg, 0.5 mmol) was added to a solution of 541-3 (40 mg, 0.097 mmol) in 0.5 mL of water. The solution was stirred at room temperature for 30 minutes. Purification by reverse phase HPLC gave 542-4 as a white solid. Yield: 28 mg (94%). ¹ H NMR (D ₂ O, 300 MHz) 7.79 (d, J = 7.6 Hz, 1H), 5.95 (d, J = 7.6 Hz, 1H), 5.88 (d, J = 2.8 Hz, 1H), 5.40 (m , 1H), 4.42 (m, 1H), 3.78 (dd, J = 12.8, 9.8 Hz, 1H), 3.55 (dd, J = 13.1, 9.7 Hz, 1H), 2.20 2.05 (m, 2H) ppm. ³¹ P NMR (D ₂ O, 300 MHz) 14.66 ppm. MS (m / z): calculated 306.05 (MH ⁻ ), found 305.8 (MH ⁻ ).

Example 543 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 543-5: Phosphonic diacid 542-4 (9 mg, 0.029 mmol) in 0.25 mL of DMF followed by tributylamine (5.4 mg, 0.03 mmol) followed by carbonyldiimidazole (48 mg, 0.3 mmol) ) Was added. The reaction mixture was stirred at rt for 4 h, MeOH (0.010 mL) was added and then further stirred for 30 min. Tributyl ammonium pyrophosphate (161 mg, 0.3 mmol) in DMF (0.64 mL) was added to the reaction mixture and stirred for 14 hours. After the solvent was removed in vacuo, the crude product was purified by ion exchange HPLC (0 40% TEAB) to give 543-5 triethylammonium salt as a white solid. Yield: 3 mg. ¹ H NMR (D ₂ O, 300 MHz) 7.78 (d, J = 7.6 Hz, 1H), 6.02 (d, J = 7.6 Hz, 1H), 5.88 (d, J = 2.9 Hz, 1H), 5.42 (m , 1H), 4.41 (m, 1H), 4.05 3.62 (m, 2H), 3.05 (q, J = 7.4 Hz, triethylammonium), 2.23 1.95 (m, 2H), 1.13 (t, J = 7.4 Hz, Triethylammonium) ppm. ³¹ P NMR (D ₂ O, 300 MHz) 7.58 (d), -8.34 (d), 22.71 (t) ppm. MS (m / z): calculated 465.98 (MH ⁻ ), found 466.16 (MH ⁻ ).

Example 544 Synthesis of Exemplary Compounds of the Invention

Synthesis of 3'-deoxy-CP

Example 545 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 545-2: t-butyldiphenylsilyl chloride (48 mL, 186 mmol) in a stirred solution of 1-O-methyl-2'-deoxy-D-ribose (23.9 g, 161.41 mmol) in pyridine under nitrogen ) Was added dropwise. After the addition was complete, N, N-dimethyl-4-aminopyridine was added as a solid. The reaction was stirred at rt for 12 h and observed by TLC. After confirming completion of the reaction by TLC, pyridine was removed under vacuum. The oily residue was suspended in ethyl acetate (150 mL) and formed white solid. The mixture was filtered and the solid was washed with 50 mL ethyl acetate. Then the solid was removed. The organic filtrates were combined and washed with water (2 × 100 mL), 1N HCl (aq) (2 × 100 mL) and sodium bicarbonate (saturated) (2 × 100 mL). The organic phases were combined and dried over MgSO ₄ (anh). Evaporation and purification by column chromatography gave a mixture of the desired diastereomer 545-2 : yield 31.15 g (50 0%). ¹ H NMR (CD ₃ CN, 300 MHz): δ 1.08 m, 9H); 1.85 m 1 H; 2.27 m 2H; 3.3 s 3H; 3.7 m 2H; 3.90 m 1 H; 4.27 m 1H; 5.06 m 1 H, 7.45 m 6 H; 7.76 m 4 H. ppm.

Example 546 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 546-3: Alcohol 545-2 (5.00 g, 12.95 mmol) and triphenylphosphine (6.79 g. 25.9 mmol) were dissolved in dry THF (50 mL) at room temperature under nitrogen. To this stirred solution was added dropwise a mixture of benzoic acid (3.162 g, 25.9 mmol) and disopropylazodicarboxylate dissolved in anhydrous THF (30 mL), and after the addition was complete, the reaction was carried out at room temperature for 12 hours. Stirred. After completion of the reaction was confirmed by TLC, the solvent was removed in vacuo. The residue was suspended in diethyl ether (60 mL). Hexane (120 mL) was added and the solid formed was filtered off. The solvent was removed by rotary evaporation and the product 546-3 was purified by column chromatography (2% to 15% EtOAc in hexanes): Yield 3.074 g (48.4%). ¹ H NMR (CD ₃ CN, 300 MHz): δ 0.98 m 9H; 2.07 m 1 H; 2.42 m 2 H; 3.35 s 3 H; 3.85 m 1 H; 3.99 m 1 H; 4.4 m 1 H; 5.10 m 1 H; 5.69 m 1 H; 7.30 m 1 H; 7.47 m 5 H; 7.65 m 6 H; 7.80 m 1 H; 7.95 m 1 H; 8.22 m 1 H ppm.

Example 547 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 547-4 : Acetal 546-3 (6.88 g, 12.95 mmol) and hydroxymethylphosphonate diethylester (7.76 mL, 52.65 mmol) were dissolved in 200 mL of toluene. Toluene was removed by rotary evaporation at 70 ° C. under vacuum to reduce the reaction volume to about 25 mL. The reaction was cooled to room temperature and p-toluene sulfonic acid monohydrate (0.490 g, 2.58 mmol) was added as a solid with toluene (200 mL). Toluene was removed by rotary evaporation at 70 ° C. under vacuum to once again reduce the reaction volume to about 25 mL.

A further two portions of toluene were added and the removal by evaporation was repeated each time. The reaction was observed by TLC and after the reaction was completed, the residue was suspended in ethyl acetate (100 mL). The organic layer was washed with sodium bicarbonate (sat), brine and then dried over MgSO ₄ (anh). The desired phosphonate 547-4 was purified by column chromatography (10% to 90% EtOAc in hexanes): yield 2.89 g (33%). ¹ H NMR ( DMSO - d ₆ , 300 MHz): δ 0.92 s 9H; 1.25 t 6 H; 2.35 t 2 H; 3.84 m 4 H; 4.05 m 4H; 4.32 q 1H; 5.37 t 1 H; 5.62 q 1H; 7.26 t 2 H; 7.30-7.55 m 8H; 7.6 δ 2H; 7.65 t 1 H; 7.8 δ 2H ppm.

Example 548 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 548-5: Silyl ether 547-4 (2.86 g, 4.57 mmol) was dissolved in a minimum amount of methanol (15 mL) and stirred at room temperature under nitrogen. Ammonium fluoride (1.69 g, 45.7 mmol) was added as a solid and the reaction was stirred at rt for 12 h. After completion of the reaction by observing the reaction by TLC, methanol was removed under a nitrogen stream. 6 mL of 1N acetic acid (aq) was added and the aqueous phase extracted with ethyl acetate (2 × 125 mL). The organic extracts were combined and dried over Na ₂ SO ₄ (anh). The final product 548-5 was purified by column chromatography (50% to 100% EtOAc in hexanes): yield 1.59 g (90%). ¹ H NMR ( DMSO - d ₆ , 300 MHz): 1.21 t 6H; 2.35 t 2 H; 3.62-3.82 m 4H; 4.05 m 4H; 4.12 q 1H; 5.30 t 1 H; 5.49 q 1H; 7.47 t 2 H; 7.65 t 1 H; 7.9 δ 2H.

Example 549 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 549-6: Primary alcohol 548-5 (1.43 g, 3.69 mmol) was dissolved in a 1: 1 mixture of acetonitrile and water (10 mL) under nitrogen. Bisacetyliodobenzene (2.61 g, 8.12 mmol) was added as a solid with catalytic amount of TEMPO (0.115 g, 0.74 mmol). The reaction was stirred at rt for 12 h and observed by TLC. After the reaction was completed, it was frozen and lyophilized. Carboxylic acid 549-6 was purified by column chromatography (0% to 10% methanol in dichloromethane): yield 0.750 g (51%). ¹ H NMR (CD ₃ CN, 300 MHz): 1.30 t 6H; 2.45 t 2 H; 3.84 m 1 H; 4.00-4.20 m 5 H; 4.8 δ 1H; 5.50 t 1 H; 5.82 q 1H; 7.54 t 2 H; 7.65 t 1 H; 7.9 δ 2H.

Example 550 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 550-7 : Anhydrous pyridine (0.027 mL, 0.33 mmol) was added to acid 549-6 (88 mg, 0.22 mmol) in DMF (3.1 mL, 0.07 M) followed by lead tetraacetate (146 mg, 0.33 mmol). It was. After 14 h at rt, Et ₂ O / H ₂ O (1: 1, 3 mL) was added. The organic layer was separated, washed with 1M aqueous citric acid, saturated aqueous NaHCO ₃ , saturated aqueous NaCl and dried over sodium sulfate. After removal of the solvent, crude product 7 (50 mg, 54%) was used directly in the next reaction.

Example 551 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 551-8: in Dichloroethane (1.1 mL, 0.1 M) Can. J. Chem . 65: N-acetoxy-diphenylcarbamoyl Gaunin (43 mg, 0.11 mmol) prepared as described in 1436 (1987) was converted to N, O-bis (trimethylsilyl) acetamide (0.054 mL, 0.22 mmol) Treated with. The reaction mixture was heated to 80 ° C. for 20 minutes and then the solvent was removed in vacuo. Crude silylated protected guanine was mixed with phosphonate 550-7 (50 mg, 0.12 mmol) in dichloroethane (1.1 mL, 0.1 M) and TMSOTf (28 μl, 0.153 mmol) was added. The reaction mixture was heated to 60 ° C. for 5 hours and then the reaction was stopped with saturated aqueous NaHCO ₃ . The solution is extracted with CH ₂ Cl ₂ , washed with saturated aqueous NaHCO ₃ and dried over sodium sulfate. After removal of the solvent, the crude product was purified by silica column chromatography (2% MeOH / CH ₂ Cl ₂ ) to give phosphonate diester 551-8 (18 mg, 22%). ¹ H NMR (CDCl ₃ , 300 MHz) 8.30 (s, 1H), 8.15 (s, 1H), 8.02 (s, 1H) 8.00 (s, 1H), 7.35 7.62 (m, 12H), 6.43 (d, 1H) ), 6.02 (m, 1H), 5.65 (m, 1H), 4.18 (q, 4H), 3.78 4.01 (m, 2H), 2.86 (m, 1H), 2.63 (m, 1H), 2.53 (s, 3H ), 1.37 (t, 6H) ppm. ³¹ P NMR (CDCl ₃ , 300 MHz) 20.07 (s) ppm. MS (m / z): calculated 744.2 (M + H ⁺ ), measured 744.9 (M + H ⁺ ).

Example 552 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 552-9: Phosphonate ester 551-8 (14 mg, 0.02 mmol) was treated with NH ₃ (2 mL, 2.0 N) in MeOH for 9 hours at room temperature. After the solvent was removed in vacuo, the crude product was purified by silica column chromatography (10% MeOH / CH ₂ Cl ₂ ) to give 552-9 . ¹ H NMR (CD ₃ OD, 300 MHz) 7.89 (s, 1H), 5.96 (d, 1H), 5.45 (m, 1H), 4.10 4.21 (q, 4H), 3.84 4.02 (m, 2H), 2.92 2.47 (m, 2H), 1.33 (t, 6H) ppm. ³¹ P NMR (CD ₃ OD, 300 MHz) 21.75 ppm. MS (m / z): calculated 404.1 (M + H ⁺ ), found 404.2 (M + H ⁺ ).

Example 553 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 553-10: Phosphonate ester guanosine derivative 552-9 (5.8 mg, 0.02 mmol) in anhydrous acetonitrile (0.15 mL, 0.1 M) to 2,6-lutidine (0.014 mL, 0.12 mmol) Iodotrimethylsilane (0.016 mL, 0.12 mmol) was then added. After stirring for 15 minutes, triethylamine (0.12 mmol) and methanol (0.020 mL) were added and the solvent was removed in vacuo. The crude product was purified by C18 reversed phase column chromatography (0 10% MeOH / H ₂ O-1% AcOH) to give phosphonic diacid 553-10 . ¹ H NMR (D ₂ O, 300 MHz) 7.91 (s, 1 H), 5.86 (d, 1 H), 5.41 (m, 1 H), 3.42 3.65 (m, 2 H), 2.25 2.36 (m, 2H) ppm. ³¹ P NMR (D ₂ O, 300 MHz) 15.16 ppm. MS (m / z): calculated 346.1 (MH ⁻ ), measured 346.3 (MH ⁻ ).

Example 554 Synthesis of Exemplary Compounds of the Invention

Synthesis of Compound 554-11: Phosphonic diacid 553-10 (2.5 mg, 7.2 mmol) in DMF (144 μl, 0.05 M) followed by tributylamine (0.0086 mL, 0.036 mmol) followed by carbonyldiimidazole (12 mg, 0.072 mmol) was added. The reaction was stirred at rt for 12 h, then MeOH (0.005 mL) was added and stirred for 30 min. Tributyl ammonium pyrophosphate (0.040 mg, 72 mmol) in DMF (0.16 mL) was added. The reaction mixture was stirred for 1 h. After the solvent was removed in vacuo, the crude product was purified by ion exchange HPLC (0-60% TEAB) to give diphosphophosphonate 554-11 . ¹ H NMR (D ₂ O, 300 MHz) 7.94 (s, 1 H), 5.85 (d, 1 H), 4.47 (m, 1 H), 3.71 3.78 (m, 2 H), 2.27 2.39 (m, 2H) ppm. ³¹ P NMR (D ₂ O, 300 MHz) 8.09 (d), 7.71 (s), 22.04 (t) ppm. MS (m / z): Calculated 505.99 (MH ^-), measure 506.2 (MH ^-).

Example 555 Synthesis of Exemplary Compounds of the Invention

The following schemes 555-5 to 555-9 illustrate the general method for preparing the [3.1.0] bicyclo hexane support of formulas 555-I and 555-II compounds. Exemplary structures, intermediates, substituents, protecting groups, reagents and synthetic routes selected in this description are for the purpose of describing general methods of preparation and are not intended to be limiting or to indicate that the methods are excellent.

[3.1.0] Bicyclo hexane supports can be synthesized by intramolecular cyclopropaneation of carbenes produced by the decomposition of diazo 1,3-ketoesters (Moon etal (2000) Organic Letters 2 (24) : 3793-3796). Essential 1,3-ketoester 555-5.1 can be prepared from the addition of an acetoacetate ester anion to an aldehyde, such as acrolein (Scheme 555-5a ). For example, ethyl acetoacetate is treated with 2 equivalents of lithium diisopropylamide at -78 ° C and then with 1 equivalent of acrolein to give 1,3-ketoester 555-5.1 (Yoshimura et al (2002) Jour. Org . Chem 67:. 5938-5945). 555-5 , wherein PG is phenyldimethylsilyl (PhMe ₂ Si-) by protecting the hydroxyl group with phenyldimethylsilyl chloride . Get 2 Other trialkylsilyl protecting groups can be used. Diazolation with p-toluenesulfonyl azide affords 555-5.3 . 555-5. 3 is treated with a carbenoid insertion catalyst such as CuSO ₄ or Rh (OAc) ₂ to give 555-5.4 as diastereomers.

Scheme 555-5a

Of 555 to 5.4 ester it can be directly saponified or hydrolyzed to the hydroxymethyl-555 to 5.5 555 to 5.6 or a carboxylic acid (Scheme 555-5b). Suitable oxidizing agent is (s) primary alcohol 555-5. 5 can be converted to carboxylic acid 555-5.6 or its esters. In the case of esters, carboxylic acids, 555-5.6 can be obtained by further deprotection. Various oxidation methods exist in the literature and can be utilized here. These include the following methods, i.e. (i) preparing t-butyl ester with pyridinium dichromate, t-BuOH and dichloromethane in Ac ₂ O, and then converting the ester into a reagent such as trifluoroacetic acid. To deprotect and convert to the corresponding carboxylic acid (Classon, et al, Acta Chem . Scand . Ser . B; 39 ; 1985; 501-504. Cristalli, et al; J. Med . Chem .; 31 ; 1988; (Ii) process for preparing carboxylic acids with iodobenzene diacetate and 2,2,6,6-tetramethyl-1-piperidinyloxy, free radicals (TEMPO) in acetonitrile (see Epp, et al ; J. Org . Chem . 64 ; 1999; 293-295. Jung et al; J. Org . Chem .; 66 ; 2001; 2624-2635), (iii) sodium periodate in chloroform, Method for preparing carboxylic acid using ruthenium (III) chloride (Kim, et al, J Med . Chem . 37 ; 1994; 4020-4030. Homma, et al; J. Med . Chem .; 35 ; 1992; 2881-2890), (iv) a process for preparing carboxylic acids using chromium trioxide in acetic acid (Olsson et al; J. Med . Chem .; 29 ; 1986; 1683-1689. Gallo-Rodriguez et al; J. Med . Chem .; 37 ; 1994; 636-646); (v) Process for preparing carboxylic acid with potassium permanganate in aqueous potassium hydroxide (Ha, et al; J. Med. Chem .; 29 ; 1986; 1683-1689. Franchetti, et al; J. Med . Chem .; 41 ; 1998; 1708-1715). (Vi) Methods for preparing carboxylic acids using nucleoside oxidases from S. maltophilia (see Mahmoudian, et al; Tetrahedron; 54 ; 1998; 8171-8182) But it is not limited thereto.

Carboxylic acid 555-5.6 Silver lead tetraacetate (IV) was obtained by decarboxylation using acetate 555-5. 7 (Teng et al; (1994) J. Org . Chem .; 59: 278-280; Schultz, et al; J. Org. Chem .; 48 ; 1983; 3408-3412). When lead tetraacetate (IV) is used together with lithium chloride (see Kochi, et al; J. Am. Chem . Soc .; 87 ; 1965; 2052), the corresponding chlorides 555-5.8 are obtained. 555-5.8 can also be obtained by using lead tetraacetate (IV) with N-chlorosuccinimide (Wang, et al; Tet . Asym .; 1 ; 1990; 527 and Wilson et al; Tet . Asym .; 1 ; 1990; 525). Optionally, the acetate can also be converted to other leaving groups such as bromide by treatment with trimethylsilyl bromide (Spencer, et al; J. Org . Chem .; 64 ; 1999; 3987-3995).

Scheme 555-5b

Intermediates 555-5.7 and 555-5.8 are described in Teng et al; Synlett ; 1996; 346-348 and US 6087482; Column 54 row 64 to column 55 row 20 can be reacted with various nucleophiles as described. Specifically, 555-5.7 can be reacted with diethylhydroxymethylphosphonate in the presence of trimethylsilyl trifluoromethanesulfonate (TMS-OTf) to give 555-5.9 (Scheme 555-5c ). As long as the functional groups in these compounds are compatible with the binding reaction conditions, it is contemplated that other compounds having the general structure of HO-connector-POR ^P1 R ^P2 can also be used. There are many examples in the publication that describe the combination of various alcohols with 1 'acetyl furanosyl compounds. The reaction was performed with silver (I) salts (Kim et al; J. Org . Chem .; 56 ; 1991; 2642-2647, Toikka et al; J. Chem . Soc . Perkins Trans. Mercury (II) salts (Veeneman et al; Recl . Trav . Chim . Pays-Bas; 106 ; 1987; 129-131), boron trifluoride diethyl etherate (Kunz et al; Hel . Chim Acta ; 68 ; 1985; 283-287), tin (II) chloride (O'Leary et al; J. Org . Chem .; 59 ; 1994; 6629-6636), alkoxides (Shortnacy-Fowler et al; Nucleosides Nucleotides; 20 ; 2001; 1583-1598) and iodine (Kartha et al; J. Chem . Soc . Perkins Trans. 1 ; 2001; 770-772). These methods can optionally be used in conjunction with other methods to form intermediates from 555-5.6 having various leaving groups (LG).

Scheme 555-5c

Introduction and removal of protecting groups from compounds (represented by PG in the structural formula of the present invention) are methods commonly practiced in the technical field of organic synthesis. Information regarding such techniques may be obtained from publications e.g. Greene and Wuts, Protecting Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, Inc., 1999. The main purpose is to temporarily modify the functional group so that the functional group can be maintained in a series of consecutive reactions. Afterwards, the original functional group can be recovered by a previously anti-deprotection process. Therefore, the modification in Scheme 555- (5a-c) aims to form a [3.1.0] support with suitable latent functional groups or reactive components.

The keto group of any intermediate such as 555-5.4 is ribofuranos-type analog 555-6 wherein Z ¹ is, for example, hydroxyl or protected hydroxyl, respectively . It can be transformed into 1 (Scheme 555-6 ) . The hydroxyl was protected as benzoyl (Bz) ester to give 555-6. Get 2 Hydrolysis of the carboxylate esters at their intersections at right angles yields 555-6.3 Reduction can yield hydroxymethyl 555-6.4 . Oxidize 555-6.4 using, for example, iodobenzenediacetate and 2,2,6,6-tetramethyl-1-piperidinyloxy, free radicals (TEMPO) to convert the primary alcohol to the corresponding acid 555-6.3 . Convert Lead tetraacetate can be used to further oxidize 555-6.3 to produce acetate 555-6.5 . 555-6.5 and the bond between hydroxyalkyl dialkylphosphonate compounds such as diethylhydroxymethylphosphonate (purchased from Sigma-Aldrich, Cat. No. 39,262-6) and TMS-OTf are 555-6.6 Can be provided. Treating 555-6.6 with TMS-Br to replace the phosphodiester with the corresponding phosphonic acid 555-6. Convert to 7 Deprotection of 2'- and 3'-hydroxyls with NH ₃ in methanol, for example, affords 555-6.8 .

Scheme 555-6

In 555- (6.6-6.8) phosphonic acid is used as an example for illustration. Other forms of phosphonate can be obtained through phosphonic acid or other forms, such as the corresponding diesters. See Schemes 555-A and 555- (1-4) for interconversion of exemplary phosphonate moieties.

Compounds such as 555-6.6 can be prepared by selective deprotection of PG and introduction of nucleophilic base moieties (B). For example, when PG is trialkylsilyl such as triethylsilyl, t-butyldimethylsilyl or phenyldimethylsilyl, 555-6. 6 may be treated with a fluoride reagent such as tetrabutylammonium fluoride in THF to selectively remove PG. The resulting hydroxyl is converted to a leaving group (LG), such as chloro or acetate 555-7.1 , under a borbrine type reaction condition, or the hydroxyl 555-7.2 is nucleophilic base or protected parent under, for example, Mitsunobu conditions. 555-7.3 can be obtained by reaction with a nucleobase reagent to produce a carbon-nitrogen bond (Scheme 555-7 ). Suitable nucleophilic bases or protected nucleobase base reagents (B) include thymidine, cytosine, adenine, guanine and their silylated forms. The resulting covalent binding site may be 9-purinyl or 1-pyrimidinyl. Other positional isomers may be obtained, and conventional separation means may be used to produce pure 555-7.3 compounds. 2 'and 3' protecting groups (Bz = benzoyl) using intermediate 555-7. By removing from 3 , 555-7.4 can be obtained. The ethyl group of 555-7.4 can be removed with a dealkylation reagent such as trimethylsilyl bromide and converted to phosphonate moieties including diphosphophosphonate and phosphophosphonate compounds according to the reactions shown in Schemes 555-A and 1-4. Phosphonic acid 555-7.5 can be obtained.

Scheme 555-7

Scheme 555-8 shows an exemplary route to 2'-β-methyl, 2'-3 'hydroxyl bicyclo adenine compounds. [3.1.0] bicyclo analogs 3 'and 5' hydroxyl groups of adenosine 555-8.1 (Kim, et al (2002) J. Med. Chem. 45: 208-218) were optionally silylated to 555-8.2 Can be obtained. 2 'hydroxyl groups can be oxidized under Dess-Martin periodinan conditions to afford 555-8.3 . 2'keto of 555-8.3 was methylated with Wittig reagent and desilylated to afford 555-8.4 . 555-8.4 is epoxidized to give 555-8.5 . Hydrogen attack on the methylene carbon of the epoxide 555 to 8.5 555 to 8.6 provides for having a 2 ', 3'-dihydroxy-a-, β- methyl-2'-motif (motif). This synthetic route can be utilized in the preparation of various 2 ', 3'-a-dihydroxy, 2'-β-methyl [3.1.0] bicyclo compounds where B = protected or unprotected nucleophilic base.

Scheme 555-8

2 ', 3'-a-dihydroxy, 2'-β-methyl [3.1.0] bicyclo compound, such as 555-8.6 The 5 'hydroxymethyl group can be introduced by a selective reaction as shown in Scheme 555-9 . The 5 'carbon can be removed by oxidative decarboxylation to bond the phosphonate moiety through an oxygen atom directly bonded to the [3.1.0] support. "A hydroxyl group of 5 'of the 5 555-8.6 tert - an optionally protected with as-butyldiphenylsilyl ether (TBDPS) and then protected as the 2' and 3 'hydroxyl silreul methoxymethyl ether can be obtained from 555 to 9.1 . The 5 'TBDPSi group is removed with tetra-butyl ammonium fluoride (TBAF) and the resulting hydroxymethyl is oxidized to carboxylic acid 555-9.2 using periodinan reagent, PhI (OAc) ₂ and TEMPO. Oxidative decarboxylation of 555-9.2 with lead tetraacetate and treatment with lithium hydroxide yields 555-9.3 . The hydroxyl of 555-9.3 is alkylated with bromomethyldiethylphosphonate to give 555-9.4 . The 555-9.5 can be obtained by removing the phosphonate ethyl group and 2 ', 3' methoxymethyl (MOM) protecting group with iodotrimethylsilane . The phosphonic acid groups of 555-9.5 are activated with, for example, carbonyldiimidazole (CDI) to react with pyrophosphate anions to give diphosphophosphonate 555-9.6 . To Schemes 555-A and 555 (1-4) Other phosphonic acid conversions can be performed as described.

Scheme 555-9

Intermediates 555-8.2 are useful for the preparation of 2 'hydroxyl [3.1.0] bicyclo compounds (Scheme 555-10 ). 2 'hydroxyl is protected with para-methoxybenzyl bromide and silyl is removed with TBAF to give 555-10.1 . The 5 'hydroxyl is protected with a TBDPSi group to give 555-10.2 . The 3 'thioester of 555-10.2 is formed with phenyl chlorothioinoformate and then reduced with tributyl tin hydride with AIBN to give 555-10.3 . Desilylated with TBAF and oxidized with BAIB and TEMPO to give carboxylic acid 555-10.4 .

Scheme 555-10

555-10 with lead tetraacetate. After oxidative decarboxylation of 4 , it is treated with lithium hydroxide to obtain hydroxyl 555-11.1 (Scheme 555-11 ). Hydroxy 555-11.1 is alkylated with bromomethyl diethylphosphonate to give 555-11.2 . Iodotrimethylsilane cleaves ethyl groups from diethylphosphonates and deprotects the para-methoxy benzyl group of 555-11.2 with ceric ammonium nitrate to obtain 555-11.3 . Activation of the phosphonate with CDI and addition of pyrophosphate affords 2'-hydroxy diphosphophosphonate [3.1.0] compound 555-11.4 .

Scheme 555-11

Example 556 Synthesis of Exemplary Compounds of the Invention

The following schemes describe the general method for preparing 2 'fluoro, 2'-3' didehydro nucleoside supports of the compounds of the present invention.

Methods of introducing fluorine at the 2 'position of ribonucleoside and nucleoside analogues are described in US 5824793; US 5859233; Choo, H. et al Journal of Medicinal Chemistry (2003), 46 (3), 389-398; Moon, H. et al Journal of the Chemical Society, Perkin Transactions 1 (2002), (15), 1800-1804; Lee, Kyeong; Choi, Y. et al Journal of Medicinal Chemistry (2002), 45 (6), 1313-1320; Lee, Kyeong; Choi, Yongseok; Hong, J. et al Nucleosides & Nucleotides (1999), 18 (4 & 5), 537-540; Lee, K. et al Journal of Medicinal Chemistry (1999), 42 (7), 1320-1328; Choi, Y. et al Tetrahedron Letters (1998), 39 (25), 4437-4440 Chen, Shu-Hui etal BioOrganic & Medicinal Chemistry Letters (1998), 8 (13), 1589-1594; Siddiqui, Maqbool et al Tetrahedron Letters (1998), 39 (13), 1657-1660; Nakayama, Toshiaki et al Nucleic Acids Symposium Series (1991), 25 (Symp. Nucleic Acids Chem., 18th, 1991), 191-2; Huang, Jai Tung et al Journal of Medicinal Chemistry (1991), 34 (5), 1640-6; Sterzycki, Roman Z et al Journal of Medicinal Chemistry (1990), 33 (8), 2150-7; Martin, Joseph A et al Journal of Medicinal Chemistry (1990), 33 (8), 2137-45; Watanabe, Kyoichi et al Journal of Medicinal Chemistry (1990), 33 (8), 2145-50; Zemlicka et al Journal of the American Chemical Society (1972) 94 (9): 3213-3218.

Scheme 556 (AF) represents the synthetic route utilized to prepare the exemplary materials shown therein.

Scheme 556-A

Of adenosine 556-A.1 The (-) enantiomer was tritylated in N-6 and 5 'hydroxyls of adenine exocyclic amine with excess trityl (Tr, triphenylmethyl, Ph ₃ C-) chloride with dimethylaminopyridine in pyridine to give bis -Trityl 556-A.2 , followed by treatment with trif. Anhydride in dichloromethane and DMAP 556-A. 3 is obtained (Scheme 556-A). 556-A.4 was substituted by replacing the 2 'triflate group with fluoride using tetra-butylammonium fluoride in THF at room temperature. Get

Scheme 556-B

Scheme 556-C

Scheme 556-D

Scheme 556-E

Scheme 556-F

Example  600

By way of example and not limitation, embodiments of the invention are named in the following table form (Table 100). The general formula for this embodiment is "MBF":

Each embodiment of the MBF is shown with a substituted nucleus Sc. Sc is described in Equation 1-336 herein. Here, A ⁰ is the point where Sc covalently bonds to Lg, which is shown in Tables 1.1 to 1.5 below. In the embodiment of Table 106, Sc is a nucleus designated by number, and each substituent is designated by letter or number in turn.

Tables 1.1 to 1.5 list the nuclei forming the embodiment of Table 106. Each nucleus Sc is given a number designated by Tables 1.1 to 1.5, which designation appears in the name of each embodiment. Similarly, Tables 10.1 to 10.19 and 20.1 to 20.36 list the selected linker groups (Lg) and drug precursors (Pd ¹ and Pd ² ) substituents, which are also designated by letters or numbers, respectively. Accordingly, the compounds of MBF include compounds containing the Sc group based on Equation 1-336 herein and compounds according to Table 100 below. In all cases, the compound of formula MBF comprises the Lg, Pd ¹ and Pd ² groups listed in the table below.

Thus, each named embodiment of Table 100 represents a nucleus numbered from Tables 1.1 to 1.5, a letter designating the linker (Lg) from Tables 10.1-10.19, and two drugs designated with two numbers from Tables 20.1-20.36. It is shown by the precursor groups Pd ¹ and Pd ² . In the figure table, each implementation state in Table 100 is represented by a system name:

Sc.Lg.Pd ¹ .Pd ²

Each Sc group appears to have a dashed line (~). The dashed line is the point where Sc covalently bonds to Lg. Q ¹ and Q ² of the linking group (Lg) do not represent groups or atoms, but should be understood as only bonding positions. Q ¹ is a position covalently bonded to the nucleus Sc and Q ² is a position covalently bonded to a phosphate atom of the formula MBF. Each drug precursor group (Pd ¹ and Pd ² ) covalently binds at the dashed (~) position of the phosphoric acid atom of MBF. Some implementations of Tables 10.1-10.19 and 20.1-20.36 may be designated by letters and numbers (Tables 10.1-10.19) or combinations of numbers and letters (Tables 20.1-20.36). For example, Table 10 lists BJ1 and BJ2. In any case, the headings in Tables 10.1-10.19 always begin with a letter and the headings in Tables 20.1-20.36 always begin with a number. The nucleus Sc is enclosed in square brackets ([]) and the covalent bond extends out of the square brackets. The covalent point of Sc and Lg may be any substitutable position on the SC. Methods of selecting binding points are described herein. By way of example, and not by way of limitation, binding points were selected from those shown in the schemes and the examples.

Table 1.1

Table 1.2

Table 1.3

Table 1.4

Table 1.5

Table 10.1

Table 10.2

Table 10.3

Table 10.4

Table 10.5

Table 10.6

Table 10.7

Table 10.8

Table 10.9

Table 10.10

Table 10.11

Table 10.12

Table 10.13

Table 10.14

Table 10.15

Table 10.16

Table 10.17

Table 10.18

Table 10.19

Table 20.1

Table 20.2

Table 20.3

Table 20.4

Table 20.5

Table 20.6

Table 20.7

Table 20.8

Table 20.9

Table 20.10

Table 20.11

Table 20.12

Table 20.13

Table 20.14

Table 20.15

Table 20.16

Table 20.17

Table 20.18

Table 20.19

Table 20.20

Table 20.21

Table 20.22

Table 20.23

Table 20.24

Table 20.25

Table 20.26

Table 20.27

Table 20.28

Table 20.29

Table 20.30

Table 20.31

Table 20.32

Table 20.33

Table 20.34

Table 20.35

Table 20.36

Table 20.37

Table 100

1.B Prodrug

     1.B. 228.228; 1.B.228.229; 1.B. 228.230; 1.B.228.231; 1.B.228.236; 1.B.228.237; 1.B.228.238; 1.B.228.239; 1.B.228.154; 1.B.228.157; 1.B.228.166; 1.B.228.169; 1.B.228.172; 1.B.228.175; 1.B.228.240; 1.B.228.244; 1.B.229.228; 1.B.229.229; 1.B.229.230; 1.B.229.231; 1.B.229.236; 1.B.229.237; 1.B.229.238; 1.B.229.239; 1.B.229.154; 1.B.229.157; 1.B.229.166; 1.B.229.169; 1.B.229.172; 1.B.229.175; 1.B.229.240; 1.B.229.244; 1.B.230.228; 1.B.230.229; 1.B.230.230; 1.B.230.231; 1.B.230.236; 1.B.230.237; 1.B.230.238; 1.B.230.239; 1.B.230.154; 1.B.230.157; 1.B.230.166; 1.B.230.169; 1.B.230.172; 1.B.230.175; 1.B.230.240; 1.B.230.244; 1.B.231.228; 1.B. 231.229; 1.B.231.230; 1.B.231.231; 1.B.231.236; 1.B.231.237; 1.B.231.238; 1.B.231.239; 1.B.231.154; 1.B.231.157; 1.B.231.166; 1.B.231.169; 1.B.231.172; 1.B.231.175; 1.B.231.240; 1.B.231.244; 1.B.236.228; 1.B. 236.229; 1.B.236.230; 1.B.236.231; 1.B.236.236; 1.B.236.237; 1.B.236.238; 1.B.236.239; 1.B.236.154; 1.B.236.157; 1.B.236.166; 1.B.236.169; 1.B.236.172; 1.B.236.175; 1.B.236.240; 1.B.236.244; 1.B.237.228; 1.B.237.229; 1.B.237.230; 1.B.237.231; 1.B.237.236; 1.B.237.237; 1.B.237.238; 1.B.237.239; 1.B.237.154; 1.B.237.157; 1.B.237.166; 1.B.237.169; 1.B.237.172; 1.B.237.175; 1.B.237.240; 1.B.237.244; 1.B.238.228; 1.B.238.229; 1.B.238.230; 1.B.238.231; 1.B.238.236; 1.B.238.237; 1.B.238.238; 1.B.238.239; 1.B.238.154; 1.B.238.157; 1.B.238.166; 1.B.238.169; 1.B.238.172; 1.B.238.175; 1.B.238.240; 1.B.238.244; 1.B.239.228; 1.B.239.229; 1.B.239.230; 1.B.239.231; 1.B.239.236; 1.B.239.237; 1.B.239.238; 1.B.239.239; 1.B.239.154; 1.B.239.157; 1.B.239.166; 1.B.239.169; 1.B.239.172; 1.B.239.175; 1.B.239.240; 1.B.239.244; 1.B.154.228; 1.B.154.229; 1.B.154.230; 1.B.154.231; 1.B.154.236; 1.B.154.237; 1.B.154.238; 1.B.154.239; 1.B.154.154; 1.B.154.157; 1.B.154.166; 1.B.154.169; 1.B.154.172; 1.B.154.175; 1.B.154.240; 1.B.154.244; 1.B.157.228; 1.B. 157.229; 1.B.157.230; 1.B.157.231; 1.B.157.236; 1.B.157.237; 1.B.157.238; 1.B.157.239; 1.B.157.154; 1.B.157.157; 1.B.157.166; 1.B.157.169; 1.B.157.172; 1.B.157.175; 1.B.157.240; 1.B.157.244; 1.B.166.228; 1.B. 166.229; 1.B.166.230; 1.B.166.231; 1.B.166.236; 1.B.166.237; 1.B.166.238; 1.B.166.239; 1.B.166.154; 1.B.166.157; 1.B.166.166; 1.B.166.169; 1.B.166.172; 1.B.166.175; 1.B.166.240; 1.B.166.244; 1.B. 169.228; 1.B. 169.229; 1.B. 169.230; 1.B. 169.231; 1.B. 169.236; 1.B. 169.237; 1.B. 169.238; 1.B. 169.239; 1.B. 169.154; 1.B. 169.157; 1.B. 169.166; 1.B. 169.169; 1.B. 169.172; 1.B. 169.175; 1.B. 169.240; 1.B. 169.244; 1.B.172.228; 1.B.172.229; 1.B.172.230; 1.B.172.231; 1.B.172.236; 1.B.172.237; 1.B.172.238; 1.B.172.239; 1.B.172.154; 1.B.172.157; 1.B.172.166; 1.B.172.169; 1.B.172.172; 1.B.172.175; 1.B.172.240; 1.B.172.244; 1.B.175.228; 1.B.175.229; 1.B.175.230; 1.B.175.231; 1.B.175.236; 1.B.175.237; 1.B.175.238; 1.B.175.239; 1.B.175.154; 1.B.175.157; 1.B.175.166; 1.B.175.169; 1.B.175.172; 1.B.175.175; 1.B.175.240; 1.B.175.244; 1.B.240.228; 1.B.240.229; 1.B.240.230; 1.B.240.231; 1.B.240.236; 1.B.240.237; 1.B.240.238; 1.B.240.239; 1.B.240.154; 1.B.240.157; 1.B.240.166; 1.B.240.169; 1.B.240.172; 1.B.240.175; 1.B.240.240; 1.B.240.244; 1.B.244.228; 1.B.244.229; 1.B.244.230; 1.B.244.231; 1.B.244.236; 1.B.244.237; 1.B.244.238; 1.B.244.239; 1.B.244.154; 1.B.244.157; 1.B.244.166; 1.B.244.169; 1.B.244.172; 1.B.244.175; 1.B.244.240; 1.B.244.244;

1.D Prodrug

     1.D. 228.228; 1.D. 228.229; 1.D. 228.230; 1.D. 228.231; 1.D. 228.236; 1.D. 228.237; 1.D. 228.238; 1.D. 228.239; 1.D. 228.154; 1.D. 228.157; 1.D. 228.166; 1.D. 228.169; 1.D. 228.172; 1.D. 228.175; 1.D. 228.240; 1.D. 228.244; 1.D.229.228; 1.D.229.229; 1.D.229.230; 1.D.229.231; 1.D.229.236; 1.D.229.237; 1.D.229.238; 1.D.229.239; 1.D.229.154; 1.D.229.157; 1.D.229.166; 1.D.229.169; 1.D.229.172; 1.D.229.175; 1.D.229.240; 1.D.229.244; 1.D. 230.228; 1.D. 230.229; 1.D.230.230; 1.D.230.231; 1.D.230.236; 1.D.230.237; 1.D.230.238; 1.D.230.239; 1.D.230.154; 1.D.230.157; 1.D.230.166; 1.D.230.169; 1.D.230.172; 1.D.230.175; 1.D.230.240; 1.D.230.244; 1.D.231.228; 1.D. 231.229; 1.D.231.230; 1.D.231.231; 1.D.231.236; 1.D.231.237; 1.D.231.238; 1.D.231.239; 1.D.231.154; 1.D.231.157; 1.D.231.166; 1.D.231.169; 1.D.231.172; 1.D.231.175; 1.D.231.240; 1.D.231.244; 1.D.236.228; 1.D. 236.229; 1.D.236.230; 1.D.236.231; 1.D.236.236; 1.D.236.237; 1.D.236.238; 1.D.236.239; 1.D.236.154; 1.D.236.157; 1.D.236.166; 1.D.236.169; 1.D.236.172; 1.D.236.175; 1.D.236.240; 1.D.236.244; 1.D. 237.228; 1.D. 237.229; 1.D.237.230; 1.D.237.231; 1.D.237.236; 1.D.237.237; 1.D.237.238; 1.D.237.239; 1.D.237.154; 1.D. 237.157; 1.D.237.166; 1.D.237.169; 1.D.237.172; 1.D.237.175; 1.D.237.240; 1.D.237.244; 1.D.238.228; 1.D.238.229; 1.D.238.230; 1.D.238.231; 1.D.238.236; 1.D.238.237; 1.D.238.238; 1.D.238.239; 1.D.238.154; 1.D.238.157; 1.D.238.166; 1.D.238.169; 1.D.238.172; 1.D.238.175; 1.D.238.240; 1.D.238.244; 1.D.239.228; 1.D.239.229; 1.D.239.230; 1.D.239.231; 1.D.239.236; 1.D.239.237; 1.D.239.238; 1.D.239.239; 1.D.239.154; 1.D.239.157; 1.D.239.166; 1.D.239.169; 1.D.239.172; 1.D.239.175; 1.D.239.240; 1.D.239.244; 1.D.154.228; 1.D.154.229; 1.D.154.230; 1.D.154.231; 1.D.154.236; 1.D.154.237; 1.D.154.238; 1.D. 154.239; 1.D.154.154; 1.D.154.157; 1.D.154.166; 1.D.154.169; 1.D.154.172; 1.D.154.175; 1.D.154.240; 1.D.154.244; 1.D.157.228; 1.D. 157.229; 1.D.157.230; 1.D.157.231; 1.D.157.236; 1.D.157.237; 1.D.157.238; 1.D.157.239; 1.D.157.154; 1.D.157.157; 1.D.157.166; 1.D.157.169; 1.D.157.172; 1.D.157.175; 1.D.157.240; 1.D.157.244; 1.D.166.228; 1.D. 166.229; 1.D.166.230; 1.D.166.231; 1.D.166.236; 1.D.166.237; 1.D.166.238; 1.D.166.239; 1.D.166.154; 1.D.166.157; 1.D.166.166; 1.D.166.169; 1.D.166.172; 1.D.166.175; 1.D.166.240; 1.D.166.244; 1.D.169.228; 1.D. 169.229; 1.D. 169.230; 1.D. 169.231; 1.D. 169.236; 1.D. 169.237; 1.D. 169.238; 1.D. 169.239; 1.D. 169.154; 1.D. 169.157; 1.D. 169.166; 1.D. 169.169; 1.D. 169.172; 1.D. 169.175; 1.D. 169.240; 1.D. 169.244; 1.D. 172.228; 1.D. 172.229; 1.D.172.230; 1.D.172.231; 1.D.172.236; 1.D.172.237; 1.D.172.238; 1.D.172.239; 1.D.172.154; 1.D.172.157; 1.D.172.166; 1.D.172.169; 1.D.172.172; 1.D.172.175; 1.D.172.240; 1.D.172.244; 1.D.175.228; 1.D. 175.229; 1.D.175.230; 1.D.175.231; 1.D.175.236; 1.D.175.237; 1.D.175.238; 1.D.175.239; 1.D.175.154; 1.D.175.157; 1.D.175.166; 1.D.175.169; 1.D.175.172; 1.D.175.175; 1.D.175.240; 1.D.175.244; 1.D.240.228; 1.D.240.229; 1.D.240.230; 1.D.240.231; 1.D.240.236; 1.D.240.237; 1.D.240.238; 1.D.240.239; 1.D.240.154; 1.D.240.157; 1.D.240.166; 1.D.240.169; 1.D.240.172; 1.D.240.175; 1.D.240.240; 1.D.240.244; 1.D.244.228; 1.D.244.229; 1.D.244.230; 1.D.244.231; 1.D.244.236; 1.D.244.237; 1.D.244.238; 1.D.244.239; 1.D.244.154; 1.D.244.157; 1.D.244.166; 1.D.244.169; 1.D.244.172; 1.D.244.175; 1.D.244.240; 1.D.244.244;

1.E's Prodrug

     1.E.228.228; 1.E.228.229; 1.E.228.230; 1.E.228.231; 1.E.228.236; 1.E.228.237; 1.E.228.238; 1.E.228.239; 1.E.228.154; 1.E.228.157; 1.E.228.166; 1.E.228.169; 1.E.228.172; 1.E.228.175; 1.E.228.240; 1.E.228.244; 1.E.229.228; 1.E.229.229; 1.E.229.230; 1.E.229.231; 1.E.229.236; 1.E.229.237; 1.E.229.238; 1.E.229.239; 1.E.229.154; 1.E.229.157; 1.E.229.166; 1.E.229.169; 1.E.229.172; 1.E.229.175; 1.E.229.240; 1.E.229.244; 1.E.230.228; 1.E.230.229; 1.E.230.230; 1.E.230.231; 1.E.230.236; 1.E.230.237; 1.E.230.238; 1.E.230.239; 1.E.230.154; 1.E.230.157; 1.E.230.166; 1.E.230.169; 1.E.230.172; 1.E.230.175; 1.E.230.240; 1.E.230.244; 1.E.231.228; 1.E.231.229; 1.E.231.230; 1.E.231.231; 1.E.231.236; 1.E.231.237; 1.E.231.238; 1.E.231.239; 1.E.231.154; 1.E.231.157; 1.E.231.166; 1.E.231.169; 1.E.231.172; 1.E.231.175; 1.E.231.240; 1.E.231.244; 1.E.236.228; 1.E.236.229; 1.E.236.230; 1.E.236.231; 1.E.236.236; 1.E.236.237; 1.E.236.238; 1.E.236.239; 1.E.236.154; 1.E.236.157; 1.E.236.166; 1.E.236.169; 1.E.236.172; 1.E.236.175; 1.E.236.240; 1.E.236.244; 1.E. 237.228; 1.E.237.229; 1.E. 237.230; 1.E.237.231; 1.E.237.236; 1.E.237.237; 1.E.237.238; 1.E.237.239; 1.E.237.154; 1.E.237.157; 1.E.237.166; 1.E. 237.169; 1.E.237.172; 1.E.237.175; 1.E.237.240; 1.E.237.244; 1.E.238.228; 1.E.238.229; 1.E.238.230; 1.E.238.231; 1.E.238.236; 1.E.238.237; 1.E.238.238; 1.E.238.239; 1.E.238.154; 1.E.238.157; 1.E.238.166; 1.E.238.169; 1.E.238.172; 1.E.238.175; 1.E.238.240; 1.E.238.244; 1.E.239.228; 1.E.239.229; 1.E.239.230; 1.E.239.231; 1.E.239.236; 1.E.239.237; 1.E.239.238; 1.E.239.239; 1.E.239.154; 1.E.239.157; 1.E.239.166; 1.E.239.169; 1.E.239.172; 1.E.239.175; 1.E.239.240; 1.E.239.244; 1.E.154.228; 1.E.154.229; 1.E.154.230; 1.E.154.231; 1.E.154.236; 1.E.154.237; 1.E.154.238; 1.E.154.239; 1.E.154.154; 1.E.154.157; 1.E.154.166; 1.E.154.169; 1.E.154.172; 1.E.154.175; 1.E.154.240; 1.E.154.244; 1.E.157.228; 1.E.157.229; 1.E.157.230; 1.E.157.231; 1.E.157.236; 1.E.157.237; 1.E.157.238; 1.E.157.239; 1.E.157.154; 1.E.157.157; 1.E.157.166; 1.E.157.169; 1.E.157.172; 1.E.157.175; 1.E.157.240; 1.E.157.244; 1.E.166.228; 1.E.166.229; 1.E.166.230; 1.E.166.231; 1.E.166.236; 1.E.166.237; 1.E.166.238; 1.E.166.239; 1.E.166.154; 1.E.166.157; 1.E.166.166; 1.E.166.169; 1.E.166.172; 1.E.166.175; 1.E.166.240; 1.E.166.244; 1.E. 169.228; 1.E.169.229; 1.E. 169.230; 1.E. 169.231; 1.E. 169.236; 1.E. 169.237; 1.E. 169.238; 1.E.169.239; 1.E. 169.154; 1.E. 169.157; 1.E. 169.166; 1.E. 169.169; 1.E. 169.172; 1.E. 169.175; 1.E. 169.240; 1.E.169.244; 1.E.172.228; 1.E.172.229; 1.E.172.230; 1.E.172.231; 1.E.172.236; 1.E.172.237; 1.E.172.238; 1.E.172.239; 1.E.172.154; 1.E.172.157; 1.E.172.166; 1.E.172.169; 1.E.172.172; 1.E.172.175; 1.E.172.240; 1.E.172.244; 1.E.175.228; 1.E.175.229; 1.E.175.230; 1.E.175.231; 1.E.175.236; 1.E.175.237; 1.E.175.238; 1.E.175.239; 1.E.175.154; 1.E.175.157; 1.E.175.166; 1.E.175.169; 1.E.175.172; 1.E.175.175; 1.E.175.240; 1.E.175.244; 1.E.240.228; 1.E.240.229; 1.E.240.230; 1.E.240.231; 1.E.240.236; 1.E.240.237; 1.E.240.238; 1.E.240.239; 1.E.240.154; 1.E.240.157; 1.E.240.166; 1.E.240.169; 1.E.240.172; 1.E.240.175; 1.E.240.240; 1.E.240.244; 1.E.244.228; 1.E.244.229; 1.E.244.230; 1.E.244.231; 1.E.244.236; 1.E.244.237; 1.E.244.238; 1.E.244.239; 1.E.244.154; 1.E.244.157; 1.E.244.166; 1.E.244.169; 1.E.244.172; 1.E.244.175; 1.E.244.240; 1.E.244.244;

1.G's Prodrug

     1.G. 228.228; 1.G.228.229; 1.G.228.230; 1.G.228.231; 1.G.228.236; 1.G.228.237; 1.G.228.238; 1.G.228.239; 1.G.228.154; 1.G. 228.157; 1.G.228.166; 1.G.228.169; 1.G.228.172; 1.G.228.175; 1.G.228.240; 1.G.228.244; 1.G.229.228; 1.G.229.229; 1.G.229.230; 1.G.229.231; 1.G.229.236; 1.G.229.237; 1.G.229.238; 1.G.229.239; 1.G.229.154; 1.G.229.157; 1.G.229.166; 1.G.229.169; 1.G.229.172; 1.G.229.175; 1.G.229.240; 1.G.229.244; 1.G.230.228; 1.G.230.229; 1.G.230.230; 1.G.230.231; 1.G.230.236; 1.G.230.237; 1.G.230.238; 1.G.230.239; 1.G.230.154; 1.G.230.157; 1.G.230.166; 1.G.230.169; 1.G.230.172; 1.G.230.175; 1.G.230.240; 1.G.230.244; 1.G.231.228; 1.G.231.229; 1.G.231.230; 1.G.231.231; 1.G.231.236; 1.G.231.237; 1.G.231.238; 1.G.231.239; 1.G.231.154; 1.G.231.157; 1.G.231.166; 1.G.231.169; 1.G.231.172; 1.G.231.175; 1.G.231.240; 1.G.231.244; 1.G.236.228; 1.G. 236.229; 1.G.236.230; 1.G.236.231; 1.G.236.236; 1.G.236.237; 1.G.236.238; 1.G.236.239; 1.G.236.154; 1.G.236.157; 1.G.236.166; 1.G.236.169; 1.G.236.172; 1.G.236.175; 1.G.236.240; 1.G.236.244; 1.G.237.228; 1.G.237.229; 1.G.237.230; 1.G.237.231; 1.G.237.236; 1.G.237.237; 1.G.237.238; 1.G.237.239; 1.G.237.154; 1.G.237.157; 1.G.237.166; 1.G.237.169; 1.G.237.172; 1.G.237.175; 1.G.237.240; 1.G.237.244; 1.G.238.228; 1.G.238.229; 1.G.238.230; 1.G.238.231; 1.G.238.236; 1.G.238.237; 1.G.238.238; 1.G.238.239; 1.G.238.154; 1.G.238.157; 1.G.238.166; 1.G.238.169; 1.G.238.172; 1.G.238.175; 1.G.238.240; 1.G.238.244; 1.G.239.228; 1.G.239.229; 1.G.239.230; 1.G.239.231; 1.G.239.236; 1.G.239.237; 1.G.239.238; 1.G.239.239; 1.G.239.154; 1.G.239.157; 1.G.239.166; 1.G.239.169; 1.G.239.172; 1.G.239.175; 1.G.239.240; 1.G.239.244; 1.G.154.228; 1.G.154.229; 1.G.154.230; 1.G.154.231; 1.G.154.236; 1.G.154.237; 1.G.154.238; 1.G.154.239; 1.G.154.154; 1.G.154.157; 1.G.154.166; 1.G.154.169; 1.G.154.172; 1.G.154.175; 1.G.154.240; 1.G.154.244; 1.G.157.228; 1.G. 157.229; 1.G.157.230; 1.G.157.231; 1.G.157.236; 1.G.157.237; 1.G.157.238; 1.G.157.239; 1.G.157.154; 1.G.157.157; 1.G.157.166; 1.G.157.169; 1.G.157.172; 1.G.157.175; 1.G.157.240; 1.G.157.244; 1.G.166.228; 1.G.166.229; 1.G.166.230; 1.G.166.231; 1.G.166.236; 1.G.166.237; 1.G.166.238; 1.G.166.239; 1.G.166.154; 1.G.166.157; 1.G.166.166; 1.G.166.169; 1.G.166.172; 1.G.166.175; 1.G.166.240; 1.G.166.244; 1.G.169.228; 1.G.169.229; 1.G.169.230; 1.G.169.231; 1.G.169.236; 1.G.169.237; 1.G.169.238; 1.G.169.239; 1.G.169.154; 1.G.169.157; 1.G.169.166; 1.G.169.169; 1.G.169.172; 1.G.169.175; 1.G.169.240; 1.G.169.244; 1.G.172.228; 1.G.172.229; 1.G.172.230; 1.G.172.231; 1.G.172.236; 1.G.172.237; 1.G.172.238; 1.G.172.239; 1.G.172.154; 1.G.172.157; 1.G.172.166; 1.G.172.169; 1.G.172.172; 1.G.172.175; 1.G.172.240; 1.G.172.244; 1.G.175.228; 1.G.175.229; 1.G.175.230; 1.G.175.231; 1.G.175.236; 1.G.175.237; 1.G.175.238; 1.G.175.239; 1.G.175.154; 1.G.175.157; 1.G.175.166; 1.G.175.169; 1.G.175.172; 1.G.175.175; 1.G.175.240; 1.G.175.244; 1.G.240.228; 1.G.240.229; 1.G.240.230; 1.G.240.231; 1.G.240.236; 1.G.240.237; 1.G.240.238; 1.G.240.239; 1.G.240.154; 1.G.240.157; 1.G.240.166; 1.G.240.169; 1.G.240.172; 1.G.240.175; 1.G.240.240; 1.G.240.244; 1.G.244.228; 1.G.244.229; 1.G.244.230; 1.G.244.231; 1.G.244.236; 1.G.244.237; 1.G.244.238; 1.G.244.239; 1.G.244.154; 1.G.244.157; 1.G.244.166; 1.G.244.169; 1.G.244.172; 1.G.244.175; 1.G.244.240; 1.G.244.244;

1.I'm Prodrug

     1.I.228.228; 1.I.228.229; 1.I.228.230; 1.I.228.231; 1.I.228.236; 1.I.228.237; 1.I.228.238; 1.I.228.239; 1.I.228.154; 1.I.228.157; 1.I.228.166; 1.I.228.169; 1.I.228.172; 1.I.228.175; 1.I.228.240; 1.I.228.244; 1.I.229.228; 1.I.229.229; 1.I.229.230; 1.I.229.231; 1.I.229.236; 1.I.229.237; 1.I.229.238; 1.I.229.239; 1.I.229.154; 1.I.229.157; 1.I.229.166; 1.I.229.169; 1.I.229.172; 1.I.229.175; 1.I.229.240; 1.I.229.244; 1.I.230.228; 1.I.230.229; 1.I.230.230; 1.I.230.231; 1.I.230.236; 1.I.230.237; 1.I.230.238; 1.I.230.239; 1.I.230.154; 1.I.230.157; 1.I.230.166; 1.I.230.169; 1.I.230.172; 1.I.230.175; 1.I.230.240; 1.I.230.244; 1.I.231.228; 1.I.231.229; 1.I.231.230; 1.I.231.231; 1.I.231.236; 1.I.231.237; 1.I.231.238; 1.I.231.239; 1.I.231.154; 1.I.231.157; 1.I.231.166; 1.I.231.169; 1.I.231.172; 1.I.231.175; 1.I.231.240; 1.I.231.244; 1.I.236.228; 1.I.236.229; 1.I.236.230; 1.I.236.231; 1.I.236.236; 1.I.236.237; 1.I.236.238; 1.I.236.239; 1.I.236.154; 1.I.236.157; 1.I.236.166; 1.I.236.169; 1.I.236.172; 1.I.236.175; 1.I.236.240; 1.I.236.244; 1.I.237.228; 1.I.237.229; 1.I.237.230; 1.I.237.231; 1.I.237.236; 1.I.237.237; 1.I.237.238; 1.I.237.239; 1.I.237.154; 1.I.237.157; 1.I.237.166; 1.I.237.169; 1.I.237.172; 1.I.237.175; 1.I.237.240; 1.I.237.244; 1.I.238.228; 1.I.238.229; 1.I.238.230; 1.I.238.231; 1.I.238.236; 1.I.238.237; 1.I.238.238; 1.I.238.239; 1.I.238.154; 1.I.238.157; 1.I.238.166; 1.I.238.169; 1.I.238.172; 1.I.238.175; 1.I.238.240; 1.I.238.244; 1.I.239.228; 1.I.239.229; 1.I.239.230; 1.I.239.231; 1.I.239.236; 1.I.239.237; 1.I.239.238; 1.I.239.239; 1.I.239.154; 1.I.239.157; 1.I.239.166; 1.I.239.169; 1.I.239.172; 1.I.239.175; 1.I.239.240; 1.I.239.244; 1.I.154.228; 1.I.154.229; 1.I.154.230; 1.I.154.231; 1.I.154.236; 1.I.154.237; 1.I.154.238; 1.I.154.239; 1.I.154.154; 1.I.154.157; 1.I.154.166; 1.I.154.169; 1.I.154.172; 1.I.154.175; 1.I.154.240; 1.I.154.244; 1.I.157.228; 1.I.157.229; 1.I.157.230; 1.I.157.231; 1.I.157.236; 1.I.157.237; 1.I.157.238; 1.I.157.239; 1.I.157.154; 1.I.157.157; 1.I.157.166; 1.I.157.169; 1.I.157.172; 1.I.157.175; 1.I.157.240; 1.I.157.244; 1.I.166.228; 1.I.166.229; 1.I.166.230; 1.I.166.231; 1.I.166.236; 1.I.166.237; 1.I.166.238; 1.I.166.239; 1.I.166.154; 1.I.166.157; 1.I.166.166; 1.I.166.169; 1.I.166.172; 1.I.166.175; 1.I.166.240; 1.I.166.244; 1.I.169.228; 1.I.169.229; 1.I.169.230; 1.I.169.231; 1.I.169.236; 1.I.169.237; 1.I.169.238; 1.I.169.239; 1.I.169.154; 1.I.169.157; 1.I.169.166; 1.I.169.169; 1.I.169.172; 1.I.169.175; 1.I.169.240; 1.I.169.244; 1.I.172.228; 1.I.172.229; 1.I.172.230; 1.I.172.231; 1.I.172.236; 1.I.172.237; 1.I.172.238; 1.I.172.239; 1.I.172.154; 1.I.172.157; 1.I.172.166; 1.I.172.169; 1.I.172.172; 1.I.172.175; 1.I.172.240; 1.I.172.244; 1.I.175.228; 1.I.175.229; 1.I.175.230; 1.I.175.231; 1.I.175.236; 1.I.175.237; 1.I.175.238; 1.I.175.239; 1.I.175.154; 1.I.175.157; 1.I.175.166; 1.I.175.169; 1.I.175.172; 1.I.175.175; 1.I.175.240; 1.I.175.244; 1.I.240.228; 1.I.240.229; 1.I.240.230; 1.I.240.231; 1.I.240.236; 1.I.240.237; 1.I.240.238; 1.I.240.239; 1.I.240.154; 1.I.240.157; 1.I.240.166; 1.I.240.169; 1.I.240.172; 1.I.240.175; 1.I.240.240; 1.I.240.244; 1.I.244.228; 1.I.244.229; 1.I.244.230; 1.I.244.231; 1.I.244.236; 1.I.244.237; 1.I.244.238; 1.I.244.239; 1.I.244.154; 1.I.244.157; 1.I.244.166; 1.I.244.169; 1.I.244.172; 1.I.244.175; 1.I.244.240; 1.I.244.244;

1.J's Prodrug

     1.J.228.228; 1.J.228.229; 1.J.228.230; 1.J.228.231; 1.J.228.236; 1.J.228.237; 1.J.228.238; 1.J.228.239; 1.J.228.154; 1.J.228.157; 1.J.228.166; 1.J.228.169; 1.J.228.172; 1.J.228.175; 1.J.228.240; 1.J.228.244; 1.J.229.228; 1.J.229.229; 1.J.229.230; 1.J.229.231; 1.J.229.236; 1.J.229.237; 1.J.229.238; 1.J.229.239; 1.J.229.154; 1.J.229.157; 1.J.229.166; 1.J.229.169; 1.J.229.172; 1.J.229.175; 1.J.229.240; 1.J.229.244; 1.J.230.228; 1.J.230.229; 1.J.230.230; 1.J.230.231; 1.J.230.236; 1.J.230.237; 1.J.230.238; 1.J.230.239; 1.J.230.154; 1.J.230.157; 1.J.230.166; 1.J.230.169; 1.J.230.172; 1.J.230.175; 1.J.230.240; 1.J.230.244; 1.J.231.228; 1.J.231.229; 1.J.231.230; 1.J.231.231; 1.J.231.236; 1.J.231.237; 1.J.231.238; 1.J.231.239; 1.J.231.154; 1.J.231.157; 1.J.231.166; 1.J.231.169; 1.J.231.172; 1.J.231.175; 1.J.231.240; 1.J.231.244; 1.J.236.228; 1.J. 236.229; 1.J.236.230; 1.J.236.231; 1.J.236.236; 1.J.236.237; 1.J.236.238; 1.J.236.239; 1.J.236.154; 1.J.236.157; 1.J.236.166; 1.J.236.169; 1.J.236.172; 1.J.236.175; 1.J.236.240; 1.J.236.244; 1.J. 237.228; 1.J. 237.229; 1.J.237.230; 1.J.237.231; 1.J.237.236; 1.J. 237.237; 1.J.237.238; 1.J.237.239; 1.J.237.154; 1.J. 237.157; 1.J. 237.166; 1.J. 237.169; 1.J.237.172; 1.J.237.175; 1.J.237.240; 1.J.237.244; 1.J.238.228; 1.J.238.229; 1.J.238.230; 1.J.238.231; 1.J.238.236; 1.J.238.237; 1.J.238.238; 1.J.238.239; 1.J.238.154; 1.J.238.157; 1.J.238.166; 1.J.238.169; 1.J.238.172; 1.J.238.175; 1.J.238.240; 1.J.238.244; 1.J.239.228; 1.J.239.229; 1.J.239.230; 1.J.239.231; 1.J.239.236; 1.J.239.237; 1.J.239.238; 1.J.239.239; 1.J.239.154; 1.J.239.157; 1.J.239.166; 1.J.239.169; 1.J.239.172; 1.J.239.175; 1.J.239.240; 1.J.239.244; 1.J.154.228; 1.J.154.229; 1.J.154.230; 1.J.154.231; 1.J.154.236; 1.J.154.237; 1.J.154.238; 1.J.154.239; 1.J.154.154; 1.J.154.157; 1.J.154.166; 1.J.154.169; 1.J.154.172; 1.J.154.175; 1.J.154.240; 1.J.154.244; 1.J.157.228; 1.J. 157.229; 1.J.157.230; 1.J.157.231; 1.J.157.236; 1.J.157.237; 1.J.157.238; 1.J.157.239; 1.J.157.154; 1.J.157.157; 1.J.157.166; 1.J.157.169; 1.J.157.172; 1.J.157.175; 1.J.157.240; 1.J.157.244; 1.J.166.228; 1.J. 166.229; 1.J.166.230; 1.J.166.231; 1.J.166.236; 1.J.166.237; 1.J.166.238; 1.J.166.239; 1.J.166.154; 1.J.166.157; 1.J.166.166; 1.J.166.169; 1.J.166.172; 1.J.166.175; 1.J.166.240; 1.J.166.244; 1.J. 169.228; 1.J. 169.229; 1.J. 169.230; 1.J. 169.231; 1.J. 169.236; 1.J. 169.237; 1.J. 169.238; 1.J. 169.239; 1.J. 169.154; 1.J. 169.157; 1.J. 169.166; 1.J. 169.169; 1.J. 169.172; 1.J. 169.175; 1.J.169.240; 1.J. 169.244; 1.J.172.228; 1.J.172.229; 1.J.172.230; 1.J.172.231; 1.J.172.236; 1.J.172.237; 1.J.172.238; 1.J.172.239; 1.J.172.154; 1.J.172.157; 1.J.172.166; 1.J.172.169; 1.J.172.172; 1.J.172.175; 1.J.172.240; 1.J.172.244; 1.J.175.228; 1.J.175.229; 1.J.175.230; 1.J.175.231; 1.J.175.236; 1.J.175.237; 1.J.175.238; 1.J.175.239; 1.J.175.154; 1.J.175.157; 1.J.175.166; 1.J.175.169; 1.J.175.172; 1.J.175.175; 1.J.175.240; 1.J.175.244; 1.J.240.228; 1.J.240.229; 1.J.240.230; 1.J.240.231; 1.J.240.236; 1.J.240.237; 1.J.240.238; 1.J.240.239; 1.J.240.154; 1.J.240.157; 1.J.240.166; 1.J.240.169; 1.J.240.172; 1.J.240.175; 1.J.240.240; 1.J.240.244; 1.J.244.228; 1.J.244.229; 1.J.244.230; 1.J.244.231; 1.J.244.236; 1.J.244.237; 1.J.244.238; 1.J.244.239; 1.J.244.154; 1.J.244.157; 1.J.244.166; 1.J.244.169; 1.J.244.172; 1.J.244.175; 1.J.244.240; 1.J.244.244;

1.L Prodrug

     1.L. 228.228; 1.L. 228.229; 1.L. 228.230; 1.L. 228.231; 1.L. 228.236; 1.L. 228.237; 1.L. 228.238; 1.L. 228.239; 1.L. 228.154; 1.L. 228.157; 1.L. 228.166; 1.L. 228.169; 1.L. 228.172; 1.L. 228.175; 1.L. 228.240; 1.L. 228.244; 1.L.229.228; 1.L.229.229; 1.L.229.230; 1.L.229.231; 1.L.229.236; 1.L.229.237; 1.L.229.238; 1.L.229.239; 1.L.229.154; 1.L.229.157; 1.L.229.166; 1.L.229.169; 1.L.229.172; 1.L.229.175; 1.L.229.240; 1.L.229.244; 1.L. 230.228; 1.L. 230.229; 1.L.230.230; 1.L.230.231; 1.L.230.236; 1.L. 230.237; 1.L.230.238; 1.L.230.239; 1.L. 230.154; 1.L. 230.157; 1.L.230.166; 1.L. 230.169; 1.L.230.172; 1.L.230.175; 1.L.230.240; 1.L.230.244; 1.L.231.228; 1.L. 231.229; 1.L.231.230; 1.L.231.231; 1.L.231.236; 1.L.231.237; 1.L.231.238; 1.L.231.239; 1.L.231.154; 1.L.231.157; 1.L.231.166; 1.L.231.169; 1.L.231.172; 1.L.231.175; 1.L.231.240; 1.L.231.244; 1.L. 236.228; 1.L. 236.229; 1.L. 236.230; 1.L. 236.231; 1.L. 236.236; 1.L. 236.237; 1.L.236.238; 1.L.236.239; 1.L.236.154; 1.L.236.157; 1.L. 236.166; 1.L. 236.169; 1.L.236.172; 1.L.236.175; 1.L.236.240; 1.L. 236.244; 1.L. 237.228; 1.L. 237.229; 1.L. 237.230; 1.L. 237.231; 1.L. 237.236; 1.L. 237.237; 1.L. 237.238; 1.L. 237.239; 1.L. 237.154; 1.L. 237.157; 1.L. 237.166; 1.L. 237.169; 1.L. 237.172; 1.L.237.175; 1.L. 237.240; 1.L. 237.244; 1.L.238.228; 1.L.238.229; 1.L.238.230; 1.L.238.231; 1.L.238.236; 1.L.238.237; 1.L.238.238; 1.L.238.239; 1.L.238.154; 1.L.238.157; 1.L. 238.166; 1.L.238.169; 1.L.238.172; 1.L.238.175; 1.L.238.240; 1.L.238.244; 1.L.239.228; 1.L.239.229; 1.L.239.230; 1.L.239.231; 1.L.239.236; 1.L.239.237; 1.L.239.238; 1.L.239.239; 1.L.239.154; 1.L.239.157; 1.L.239.166; 1.L.239.169; 1.L.239.172; 1.L.239.175; 1.L.239.240; 1.L.239.244; 1.L. 154.228; 1.L.154.229; 1.L.154.230; 1.L.154.231; 1.L.154.236; 1.L. 154.237; 1.L.154.238; 1.L.154.239; 1.L.154.154; 1.L. 154.157; 1.L. 154.166; 1.L.154.169; 1.L.154.172; 1.L.154.175; 1.L.154.240; 1.L.154.244; 1.L.157.228; 1.L. 157.229; 1.L.157.230; 1.L.157.231; 1.L.157.236; 1.L.157.237; 1.L.157.238; 1.L.157.239; 1.L.157.154; 1.L.157.157; 1.L.157.166; 1.L.157.169; 1.L.157.172; 1.L.157.175; 1.L.157.240; 1.L.157.244; 1.L. 166.228; 1.L. 166.229; 1.L. 166.230; 1.L. 166.231; 1.L. 166.236; 1.L. 166.237; 1.L. 166.238; 1.L. 166.239; 1.L. 166.154; 1.L. 166.157; 1.L. 166.166; 1.L. 166.169; 1.L. 166.172; 1.L. 166.175; 1.L.166.240; 1.L. 166.244; 1.L. 169.228; 1.L.169.229; 1.L. 169.230; 1.L. 169.231; 1.L. 169.236; 1.L. 169.237; 1.L. 169.238; 1.L. 169.239; 1.L. 169.154; 1.L. 169.157; 1.L. 169.166; 1.L. 169.169; 1.L. 169.172; 1.L. 169.175; 1.L. 169.240; 1.L. 169.244; 1.L. 172.228; 1.L. 172.229; 1.L. 172.230; 1.L. 172.231; 1.L. 172.236; 1.L. 172.237; 1.L. 172.238; 1.L. 172.239; 1.L.172.154; 1.L. 172.157; 1.L.172.166; 1.L. 172.169; 1.L. 172.172; 1.L. 172.175; 1.L.172.240; 1.L. 172.244; 1.L. 175.228; 1.L. 175.229; 1.L. 175.230; 1.L. 175.231; 1.L. 175.236; 1.L. 175.237; 1.L. 175.238; 1.L. 175.239; 1.L.175.154; 1.L. 175.157; 1.L. 175.166; 1.L. 175.169; 1.L. 175.172; 1.L. 175.175; 1.L. 175.240; 1.L. 175.244; 1.L.240.228; 1.L. 240.229; 1.L.240.230; 1.L.240.231; 1.L.240.236; 1.L.240.237; 1.L.240.238; 1.L.240.239; 1.L.240.154; 1.L.240.157; 1.L.240.166; 1.L.240.169; 1.L.240.172; 1.L.240.175; 1.L.240.240; 1.L.240.244; 1.L.244.228; 1.L.244.229; 1.L.244.230; 1.L.244.231; 1.L.244.236; 1.L.244.237; 1.L.244.238; 1.L.244.239; 1.L.244.154; 1.L.244.157; 1.L.244.166; 1.L.244.169; 1.L.244.172; 1.L.244.175; 1.L.244.240; 1.L.244.244;

1.O's Prodrug

     1.O.228.228; 1.O.228.229; 1.O.228.230; 1.228.231; 1.O.228.236; 1.O.228.237; 1.O.228.238; 1.O.228.239; 1. 228.154; 1.O.228.157; 1.O.228.166; 1.O.228.169; 1.O.228.172; 1.228.175; 1.228.240; 1.O.228.244; 1.O.229.228; 1.O.229.229; 1.O.229.230; 1.O.229.231; 1.O.229.236; 1.O.229.237; 1.O.229.238; 1.O.229.239; 1.O.229.154; 1.O.229.157; 1.O.229.166; 1.O.229.169; 1.O.229.172; 1.O.229.175; 1.O.229.240; 1.O.229.244; 1.230.228; 1.O.230.229; 1.230.230; 1.230.231; 1.230.236; 1.230.237; 1.230.238; 1.230.239; 1.230.154; 1.230.157; 1.230.166; 1.230.169; 1.230.172; 1.230.175; 1.230.240; 1.230.244; 1.O.231.228; 1.23.2929; 1.O.231.230; 1.O.231.231; 1.O.231.236; 1.O.231.237; 1.O.231.238; 1.O.231.239; 1.O.231.154; 1.O.231.157; 1.O.231.166; 1.O.231.169; 1.O.231.172; 1.O.231.175; 1.O.231.240; 1.O.231.244; 1.O.236.228; 1.O.236.229; 1.O.236.230; 1.O.236.231; 1.O.236.236; 1.O.236.237; 1.O.236.238; 1.O.236.239; 1.O.236.154; 1.O.236.157; 1.O.236.166; 1.O.236.169; 1.O.236.172; 1.O.236.175; 1.O.236.240; 1.O.236.244; 1.O.237.228; 1.O.237.229; 1.O.237.230; 1.O.237.231; 1.O.237.236; 1.O.237.237; 1.O.237.238; 1.O.237.239; 1.O.237.154; 1.O.237.157; 1.O.237.166; 1.O.237.169; 1.O.237.172; 1.O.237.175; 1.O.237.240; 1.O.237.244; 1.O.238.228; 1.238.229; 1.O.238.230; 1.O.238.231; 1.O.238.236; 1.O.238.237; 1.O.238.238; 1.238.239; 1.O.238.154; 1.O.238.157; 1.O.238.166; 1.O.238.169; 1.O.238.172; 1.238.175; 1.O.238.240; 1.O.238.244; 1.O.239.228; 1.O.239.229; 1.O.239.230; 1.O.239.231; 1.O.239.236; 1.O.239.237; 1.O.239.238; 1.O.239.239; 1.O.239.154; 1.O.239.157; 1.O.239.166; 1.O.239.169; 1.O.239.172; 1.O.239.175; 1.O.239.240; 1.O.239.244; 1.154.228; 1.154.229; 1.154.230; 1.154.231; 1.154.236; 1.154.237; 1.154.238; 1.154.239; 1.154.154; 1.154.157; 1.154.166; 1.154.169; 1.154.172; 1.154.175; 1.154.240; 1.154.244; 1.157.228; 1.O.157.229; 1.157.230; 1.157.231; 1.157.236; 1.157.237; 1.157.238; 1.157.239; 1.O.157.154; 1.157.157; 1.157.166; 1.157.169; 1.157.172; 1.157.175; 1.157.240; 1.157.244; 1.O.166.228; 1.O.166.229; 1.O.166.230; 1.O.166.231; 1.O.166.236; 1.O.166.237; 1.O.166.238; 1.O.166.239; 1.O.166.154; 1.O.166.157; 1.O.166.166; 1.O.166.169; 1.O.166.172; 1.O.166.175; 1.166.240; 1.O.166.244; 1.169.228; 1.169.229; 1.169.230; 1.O.169.231; 1.O.169.236; 1.169.237; 1.O.169.238; 1.169.239; 1.169.154; 1.169.157; 1.O.169.166; 1.169.169; 1.169.172; 1.169.175; 1.169.240; 1.O.169.244; 1.172.228; 1.O.172.229; 1.172.230; 1.172.231; 1.172.236; 1.O.172.237; 1.172.238; 1.172.239; 1.172.154; 1.O.172.157; 1.172.166; 1.172.169; 1.172.172; 1.172.175; 1.172.240; 1.O.172.244; 1.O.175.228; 1.O.175.229; 1.O.175.230; 1.175.231; 1.O.175.236; 1.O.175.237; 1.O.175.238; 1.175.239; 1.O.175.154; 1.175.157; 1.O.175.166; 1.O.175.169; 1.O.175.172; 1.175.175; 1.O.175.240; 1.O.175.244; 1.240.228; 1.O.240.229; 1.240.230; 1.240.231; 1.240.236; 1.O.240.237; 1.240.238; 1.240.239; 1.240.154; 1.240.157; 1.O.240.166; 1.O.240.169; 1.240.172; 1.240.175; 1.240.240; 1.240.244; 1.O.244.228; 1.O.244.229; 1.O.244.230; 1.O.244.231; 1.O.244.236; 1.O.244.237; 1.O.244.238; 1.244.239; 1.O.244.154; 1.O.244.157; 1.O.244.166; 1.O.244.169; 1.O.244.172; 1.O.244.175; 1.O.244.240; 1.244.244;

1.P Prodrug

     1.P. 228.228; 1.P. 228.229; 1.P. 228.230; 1.P. 228.231; 1.P. 228.236; 1.P. 228.237; 1.P. 228.238; 1.P. 228.239; 1.P. 228.154; 1.P. 228.157; 1.P. 228.166; 1.P. 228.169; 1.P. 228.172; 1.P. 228.175; 1.P. 228.240; 1.P. 228.244; 1.P.229.228; 1.P.229.229; 1.P.229.230; 1.P.229.231; 1.P.229.236; 1.P.229.237; 1.P.229.238; 1.P.229.239; 1.P.229.154; 1.P.229.157; 1.P.229.166; 1.P.229.169; 1.P.229.172; 1.P.229.175; 1.P.229.240; 1.P.229.244; 1.P.230.228; 1.P.230.229; 1.P.230.230; 1.P.230.231; 1.P.230.236; 1.P.230.237; 1.P.230.238; 1.P.230.239; 1.P.230.154; 1.P.230.157; 1.P.230.166; 1.P.230.169; 1.P.230.172; 1.P.230.175; 1.P.230.240; 1.P.230.244; 1.P.231.228; 1.P.231.229; 1.P.231.230; 1.P.231.231; 1.P.231.236; 1.P.231.237; 1.P.231.238; 1.P.231.239; 1.P.231.154; 1.P.231.157; 1.P.231.166; 1.P.231.169; 1.P.231.172; 1.P.231.175; 1.P.231.240; 1.P.231.244; 1.P.236.228; 1.P.236.229; 1.P.236.230; 1.P.236.231; 1.P.236.236; 1.P.236.237; 1.P.236.238; 1.P.236.239; 1.P.236.154; 1.P.236.157; 1.P.236.166; 1.P.236.169; 1.P.236.172; 1.P.236.175; 1.P.236.240; 1.P.236.244; 1.P.237.228; 1.P.237.229; 1.P.237.230; 1.P.237.231; 1.P.237.236; 1.P.237.237; 1.P.237.238; 1.P.237.239; 1.P.237.154; 1.P.237.157; 1.P.237.166; 1.P.237.169; 1.P.237.172; 1.P.237.175; 1.P.237.240; 1.P.237.244; 1.P.238.228; 1.P.238.229; 1.P.238.230; 1.P.238.231; 1.P.238.236; 1.P.238.237; 1.P.238.238; 1.P.238.239; 1.P.238.154; 1.P.238.157; 1.P.238.166; 1.P.238.169; 1.P.238.172; 1.P.238.175; 1.P.238.240; 1.P.238.244; 1.P.239.228; 1.P.239.229; 1.P.239.230; 1.P.239.231; 1.P.239.236; 1.P.239.237; 1.P.239.238; 1.P.239.239; 1.P.239.154; 1.P.239.157; 1.P.239.166; 1.P.239.169; 1.P.239.172; 1.P.239.175; 1.P.239.240; 1.P.239.244; 1.P.154.228; 1.P.154.229; 1.P.154.230; 1.P.154.231; 1.P.154.236; 1.P.154.237; 1.P.154.238; 1.P.154.239; 1.P.154.154; 1.P.154.157; 1.P.154.166; 1.P.154.169; 1.P.154.172; 1.P.154.175; 1.P.154.240; 1.P.154.244; 1.P.157.228; 1.P. 157.229; 1.P.157.230; 1.P.157.231; 1.P.157.236; 1.P.157.237; 1.P.157.238; 1.P.157.239; 1.P.157.154; 1.P.157.157; 1.P.157.166; 1.P.157.169; 1.P.157.172; 1.P.157.175; 1.P.157.240; 1.P.157.244; 1.P.166.228; 1.P. 166.229; 1.P.166.230; 1.P.166.231; 1.P.166.236; 1.P.166.237; 1.P.166.238; 1.P.166.239; 1.P. 166.154; 1.P. 166.157; 1.P.166.166; 1.P.166.169; 1.P.166.172; 1.P.166.175; 1.P.166.240; 1.P.166.244; 1.P. 169.228; 1.P. 169.229; 1.P. 169.230; 1.P. 169.231; 1.P. 169.236; 1.P. 169.237; 1.P. 169.238; 1.P. 169.239; 1.P. 169.154; 1.P. 169.157; 1.P. 169.166; 1.P. 169.169; 1.P. 169.172; 1.P. 169.175; 1.P. 169.240; 1.P. 169.244; 1.P. 172.228; 1.P. 172.229; 1.P.172.230; 1.P.172.231; 1.P.172.236; 1.P. 172.237; 1.P.172.238; 1.P.172.239; 1.P.172.154; 1.P. 172.157; 1.P. 172.166; 1.P.172.169; 1.P.172.172; 1.P.172.175; 1.P.172.240; 1.P.172.244; 1.P.175.228; 1.P. 175.229; 1.P.175.230; 1.P.175.231; 1.P.175.236; 1.P.175.237; 1.P.175.238; 1.P.175.239; 1.P.175.154; 1.P.175.157; 1.P.175.166; 1.P.175.169; 1.P.175.172; 1.P.175.175; 1.P.175.240; 1.P.175.244; 1.P.240.228; 1.P.240.229; 1.P.240.230; 1.P.240.231; 1.P.240.236; 1.P.240.237; 1.P.240.238; 1.P.240.239; 1.P.240.154; 1.P.240.157; 1.P.240.166; 1.P.240.169; 1.P.240.172; 1.P.240.175; 1.P.240.240; 1.P.240.244; 1.P.244.228; 1.P.244.229; 1.P.244.230; 1.P.244.231; 1.P.244.236; 1.P.244.237; 1.P.244.238; 1.P.244.239; 1.P.244.154; 1.P.244.157; 1.P.244.166; 1.P.244.169; 1.P.244.172; 1.P.244.175; 1.P.244.240; 1.P.244.244;

1.U's Prodrug

     1.U.228.228; 1.U.228.229; 1.U.228.230; 1.U.228.231; 1.U.228.236; 1.U.228.237; 1.U.228.238; 1.U.228.239; 1.U.228.154; 1.U.228.157; 1.U.228.166; 1.U.228.169; 1.U.228.172; 1.U.228.175; 1.U.228.240; 1.U.228.244; 1.U.229.228; 1.U.229.229; 1.U.229.230; 1.U.229.231; 1.U.229.236; 1.U.229.237; 1.U.229.238; 1.U.229.239; 1.U.229.154; 1.U.229.157; 1.U.229.166; 1.U.229.169; 1.U.229.172; 1.U.229.175; 1.U.229.240; 1.U.229.244; 1.U.230.228; 1.U.230.229; 1.U.230.230; 1.U.230.231; 1.U.230.236; 1.U.230.237; 1.U.230.238; 1.U.230.239; 1.U.230.154; 1.U.230.157; 1.U.230.166; 1.U.230.169; 1.U.230.172; 1.U.230.175; 1.U.230.240; 1.U.230.244; 1.U.231.228; 1.U.231.229; 1.U.231.230; 1.U.231.231; 1.U.231.236; 1.U.231.237; 1.U.231.238; 1.U.231.239; 1.U.231.154; 1.U.231.157; 1.U.231.166; 1.U.231.169; 1.U.231.172; 1.U.231.175; 1.U.231.240; 1.U.231.244; 1.U.236.228; 1.U.236.229; 1.U.236.230; 1.U.236.231; 1.U.236.236; 1.U.236.237; 1.U.236.238; 1.U.236.239; 1.U.236.154; 1.U.236.157; 1.U.236.166; 1.U.236.169; 1.U.236.172; 1.U.236.175; 1.U.236.240; 1.U.236.244; 1.U.237.228; 1.U.237.229; 1.U.237.230; 1.U.237.231; 1.U.237.236; 1.U.237.237; 1.U.237.238; 1.U.237.239; 1.U.237.154; 1.U.237.157; 1.U.237.166; 1.U.237.169; 1.U.237.172; 1.U.237.175; 1.U.237.240; 1.U.237.244; 1.U.238.228; 1.U.238.229; 1.U.238.230; 1.U.238.231; 1.U.238.236; 1.U.238.237; 1.U.238.238; 1.U.238.239; 1.U.238.154; 1.U.238.157; 1.U.238.166; 1.U.238.169; 1.U.238.172; 1.U.238.175; 1.U.238.240; 1.U.238.244; 1.U.239.228; 1.U.239.229; 1.U.239.230; 1.U.239.231; 1.U.239.236; 1.U.239.237; 1.U.239.238; 1.U.239.239; 1.U.239.154; 1.U.239.157; 1.U.239.166; 1.U.239.169; 1.U.239.172; 1.U.239.175; 1.U.239.240; 1.U.239.244; 1.U.154.228; 1.U.154.229; 1.U.154.230; 1.U.154.231; 1.U.154.236; 1.U.154.237; 1.U.154.238; 1.U.154.239; 1.U.154.154; 1.U.154.157; 1.U.154.166; 1.U.154.169; 1.U.154.172; 1.U.154.175; 1.U.154.240; 1.U.154.244; 1.U.157.228; 1.U.157.229; 1.U.157.230; 1.U.157.231; 1.U.157.236; 1.U.157.237; 1.U.157.238; 1.U.157.239; 1.U.157.154; 1.U.157.157; 1.U.157.166; 1.U.157.169; 1.U.157.172; 1.U.157.175; 1.U.157.240; 1.U.157.244; 1.U.166.228; 1.U.166.229; 1.U.166.230; 1.U.166.231; 1.U.166.236; 1.U.166.237; 1.U.166.238; 1.U.166.239; 1.U.166.154; 1.U.166.157; 1.U.166.166; 1.U.166.169; 1.U.166.172; 1.U.166.175; 1.U.166.240; 1.U.166.244; 1.U.169.228; 1.U.169.229; 1.U.169.230; 1.U.169.231; 1.U.169.236; 1.U.169.237; 1.U.169.238; 1.U.169.239; 1.U.169.154; 1.U.169.157; 1.U.169.166; 1.U.169.169; 1.U.169.172; 1.U.169.175; 1.U.169.240; 1.U.169.244; 1.U.172.228; 1.U.172.229; 1.U.172.230; 1.U.172.231; 1.U.172.236; 1.U.172.237; 1.U.172.238; 1.U.172.239; 1.U.172.154; 1.U.172.157; 1.U.172.166; 1.U.172.169; 1.U.172.172; 1.U.172.175; 1.U.172.240; 1.U.172.244; 1.U.175.228; 1.U.175.229; 1.U.175.230; 1.U.175.231; 1.U.175.236; 1.U.175.237; 1.U.175.238; 1.U.175.239; 1.U.175.154; 1.U.175.157; 1.U.175.166; 1.U.175.169; 1.U.175.172; 1.U.175.175; 1.U.175.240; 1.U.175.244; 1.U.240.228; 1.U.240.229; 1.U.240.230; 1.U.240.231; 1.U.240.236; 1.U.240.237; 1.U.240.238; 1.U.240.239; 1.U.240.154; 1.U.240.157; 1.U.240.166; 1.U.240.169; 1.U.240.172; 1.U.240.175; 1.U.240.240; 1.U.240.244; 1.U.244.228; 1.U.244.229; 1.U.244.230; 1.U.244.231; 1.U.244.236; 1.U.244.237; 1.U.244.238; 1.U.244.239; 1.U.244.154; 1.U.244.157; 1.U.244.166; 1.U.244.169; 1.U.244.172; 1.U.244.175; 1.U.244.240; 1.U.244.244;

1.W Prodrug

     1.W. 228.228; 1.W.228.229; 1.W.228.230; 1.W.228.231; 1.W.228.236; 1.W.228.237; 1.W.228.238; 1.W.228.239; 1.W.228.154; 1.W.228.157; 1.W.228.166; 1.W.228.169; 1.W.228.172; 1.W.228.175; 1.W.228.240; 1.W.228.244; 1.W.229.228; 1.W.229.229; 1.W.229.230; 1.W.229.231; 1.W.229.236; 1.W.229.237; 1.W.229.238; 1.W.229.239; 1.W.229.154; 1.W.229.157; 1.W.229.166; 1.W.229.169; 1.W.229.172; 1.W.229.175; 1.W.229.240; 1.W.229.244; 1.W.230.228; 1.W.230.229; 1.W.230.230; 1.W.230.231; 1.W.230.236; 1.W.230.237; 1.W.230.238; 1.W.230.239; 1.W.230.154; 1.W.230.157; 1.W.230.166; 1.W.230.169; 1.W.230.172; 1.W.230.175; 1.W.230.240; 1.W.230.244; 1.W.231.228; 1.W.231.229; 1.W.231.230; 1.W.231.231; 1.W.231.236; 1.W.231.237; 1.W.231.238; 1.W.231.239; 1.W.231.154; 1.W.231.157; 1.W.231.166; 1.W.231.169; 1.W.231.172; 1.W.231.175; 1.W.231.240; 1.W.231.244; 1.W.236.228; 1.W.236.229; 1.W.236.230; 1.W.236.231; 1.W.236.236; 1.W.236.237; 1.W.236.238; 1.W.236.239; 1.W.236.154; 1.W.236.157; 1.W.236.166; 1.W.236.169; 1.W.236.172; 1.W.236.175; 1.W.236.240; 1.W.236.244; 1.W.237.228; 1.W.237.229; 1.W.237.230; 1.W.237.231; 1.W.237.236; 1.W.237.237; 1.W.237.238; 1.W.237.239; 1.W.237.154; 1.W.237.157; 1.W.237.166; 1.W.237.169; 1.W.237.172; 1.W.237.175; 1.W.237.240; 1.W.237.244; 1.W.238.228; 1.W.238.229; 1.W.238.230; 1.W.238.231; 1.W.238.236; 1.W.238.237; 1.W.238.238; 1.W.238.239; 1.W.238.154; 1.W.238.157; 1.W.238.166; 1.W.238.169; 1.W.238.172; 1.W.238.175; 1.W.238.240; 1.W.238.244; 1.W.239.228; 1.W.239.229; 1.W.239.230; 1.W.239.231; 1.W.239.236; 1.W.239.237; 1.W.239.238; 1.W.239.239; 1.W.239.154; 1.W.239.157; 1.W.239.166; 1.W.239.169; 1.W.239.172; 1.W.239.175; 1.W.239.240; 1.W.239.244; 1.W.154.228; 1.W.154.229; 1.W.154.230; 1.W.154.231; 1.W.154.236; 1.W.154.237; 1.W.154.238; 1.W.154.239; 1.W.154.154; 1.W.154.157; 1.W.154.166; 1.W.154.169; 1.W.154.172; 1.W.154.175; 1.W.154.240; 1.W.154.244; 1.W.157.228; 1.W.157.229; 1.W.157.230; 1.W.157.231; 1.W.157.236; 1.W.157.237; 1.W.157.238; 1.W.157.239; 1.W.157.154; 1.W.157.157; 1.W.157.166; 1.W.157.169; 1.W.157.172; 1.W.157.175; 1.W.157.240; 1.W.157.244; 1.W.166.228; 1.W.166.229; 1.W.166.230; 1.W.166.231; 1.W.166.236; 1.W.166.237; 1.W.166.238; 1.W.166.239; 1.W.166.154; 1.W.166.157; 1.W.166.166; 1.W.166.169; 1.W.166.172; 1.W.166.175; 1.W.166.240; 1.W.166.244; 1.W. 169.228; 1.W. 169.229; 1.W. 169.230; 1.W. 169.231; 1.W. 169.236; 1.W. 169.237; 1.W. 169.238; 1.W. 169.239; 1.W. 169.154; 1.W. 169.157; 1.W. 169.166; 1.W. 169.169; 1.W. 169.172; 1.W. 169.175; 1.W.169.240; 1.W. 169.244; 1.W.172.228; 1.W.172.229; 1.W.172.230; 1.W.172.231; 1.W.172.236; 1.W.172.237; 1.W.172.238; 1.W.172.239; 1.W.172.154; 1.W.172.157; 1.W.172.166; 1.W.172.169; 1.W.172.172; 1.W.172.175; 1.W.172.240; 1.W.172.244; 1.W.175.228; 1.W.175.229; 1.W.175.230; 1.W.175.231; 1.W.175.236; 1.W.175.237; 1.W.175.238; 1.W.175.239; 1.W.175.154; 1.W.175.157; 1.W.175.166; 1.W.175.169; 1.W.175.172; 1.W.175.175; 1.W.175.240; 1.W.175.244; 1.W.240.228; 1.W.240.229; 1.W.240.230; 1.W.240.231; 1.W.240.236; 1.W.240.237; 1.W.240.238; 1.W.240.239; 1.W.240.154; 1.W.240.157; 1.W.240.166; 1.W.240.169; 1.W.240.172; 1.W.240.175; 1.W.240.240; 1.W.240.244; 1.W.244.228; 1.W.244.229; 1.W.244.230; 1.W.244.231; 1.W.244.236; 1.W.244.237; 1.W.244.238; 1.W.244.239; 1.W.244.154; 1.W.244.157; 1.W.244.166; 1.W.244.169; 1.W.244.172; 1.W.244.175; 1.W.244.240; 1.W.244.244;

1.Y's Prodrug

     1.Y. 228.228; 1.Y.228.229; 1.Y. 228.230; 1.Y.228.231; 1.Y.228.236; 1.Y.228.237; 1.Y.228.238; 1.Y.228.239; 1.Y.228.154; 1.Y.228.157; 1.Y.228.166; 1.Y.228.169; 1.Y.228.172; 1.Y.228.175; 1.Y.228.240; 1.Y.228.244; 1.Y.229.228; 1.Y.229.229; 1.Y.229.230; 1.Y.229.231; 1.Y.229.236; 1.Y.229.237; 1.Y.229.238; 1.Y.229.239; 1.Y.229.154; 1.Y.229.157; 1.Y.229.166; 1.Y.229.169; 1.Y.229.172; 1.Y.229.175; 1.Y.229.240; 1.Y.229.244; 1.Y.230.228; 1.Y.230.229; 1.Y.230.230; 1.Y.230.231; 1.Y.230.236; 1.Y.230.237; 1.Y.230.238; 1.Y.230.239; 1.Y.230.154; 1.Y.230.157; 1.Y.230.166; 1.Y.230.169; 1.Y.230.172; 1.Y.230.175; 1.Y.230.240; 1.Y.230.244; 1.Y.231.228; 1.Y.231.229; 1.Y.231.230; 1.Y.231.231; 1.Y.231.236; 1.Y.231.237; 1.Y.231.238; 1.Y.231.239; 1.Y.231.154; 1.Y.231.157; 1.Y.231.166; 1.Y.231.169; 1.Y.231.172; 1.Y.231.175; 1.Y.231.240; 1.Y.231.244; 1.Y.236.228; 1.Y.236.229; 1.Y.236.230; 1.Y.236.231; 1.Y.236.236; 1.Y.236.237; 1.Y.236.238; 1.Y.236.239; 1.Y.236.154; 1.Y.236.157; 1.Y.236.166; 1.Y.236.169; 1.Y.236.172; 1.Y.236.175; 1.Y.236.240; 1.Y.236.244; 1.Y. 237.228; 1.Y.237.229; 1.Y. 237.230; 1.Y.237.231; 1.Y.237.236; 1.Y. 237.237; 1.Y.237.238; 1.Y.237.239; 1.Y.237.154; 1.Y.237.157; 1.Y. 237.166; 1.Y. 237.169; 1.Y.237.172; 1.Y.237.175; 1.Y.237.240; 1.Y.237.244; 1.Y.238.228; 1.Y.238.229; 1.Y.238.230; 1.Y.238.231; 1.Y.238.236; 1.Y.238.237; 1.Y.238.238; 1.Y.238.239; 1.Y.238.154; 1.Y.238.157; 1.Y.238.166; 1.Y.238.169; 1.Y.238.172; 1.Y.238.175; 1.Y.238.240; 1.Y.238.244; 1.Y.239.228; 1.Y.239.229; 1.Y.239.230; 1.Y.239.231; 1.Y.239.236; 1.Y.239.237; 1.Y.239.238; 1.Y.239.239; 1.Y.239.154; 1.Y.239.157; 1.Y.239.166; 1.Y.239.169; 1.Y.239.172; 1.Y.239.175; 1.Y.239.240; 1.Y.239.244; 1.Y.154.228; 1.Y.154.229; 1.Y.154.230; 1.Y.154.231; 1.Y.154.236; 1.Y.154.237; 1.Y.154.238; 1.Y.154.239; 1.Y.154.154; 1.Y.154.157; 1.Y.154.166; 1.Y.154.169; 1.Y.154.172; 1.Y.154.175; 1.Y.154.240; 1.Y.154.244; 1.Y.157.228; 1.Y.157.229; 1.Y.157.230; 1.Y.157.231; 1.Y.157.236; 1.Y.157.237; 1.Y.157.238; 1.Y.157.239; 1.Y.157.154; 1.Y.157.157; 1.Y.157.166; 1.Y.157.169; 1.Y.157.172; 1.Y.157.175; 1.Y.157.240; 1.Y.157.244; 1.Y.166.228; 1.Y.166.229; 1.Y.166.230; 1.Y.166.231; 1.Y.166.236; 1.Y.166.237; 1.Y.166.238; 1.Y.166.239; 1.Y.166.154; 1.Y.166.157; 1.Y.166.166; 1.Y.166.169; 1.Y.166.172; 1.Y.166.175; 1.Y.166.240; 1.Y.166.244; 1.Y. 169.228; 1.Y. 169.229; 1.Y. 169.230; 1.Y. 169.231; 1.Y. 169.236; 1.Y. 169.237; 1.Y. 169.238; 1.Y.169.239; 1.Y. 169.154; 1.Y. 169.157; 1.Y. 169.166; 1.Y. 169.169; 1.Y. 169.172; 1.Y. 169.175; 1.Y.169.240; 1.Y. 169.244; 1.Y.172.228; 1.Y.172.229; 1.Y.172.230; 1.Y.172.231; 1.Y.172.236; 1.Y.172.237; 1.Y.172.238; 1.Y.172.239; 1.Y.172.154; 1.Y.172.157; 1.Y.172.166; 1.Y.172.169; 1.Y.172.172; 1.Y.172.175; 1.Y.172.240; 1.Y.172.244; 1.Y.175.228; 1.Y.175.229; 1.Y.175.230; 1.Y.175.231; 1.Y.175.236; 1.Y.175.237; 1.Y.175.238; 1.Y.175.239; 1.Y.175.154; 1.Y.175.157; 1.Y.175.166; 1.Y.175.169; 1.Y.175.172; 1.Y.175.175; 1.Y.175.240; 1.Y.175.244; 1.Y.240.228; 1.Y.240.229; 1.Y.240.230; 1.Y.240.231; 1.Y.240.236; 1.Y.240.237; 1.Y.240.238; 1.Y.240.239; 1.Y.240.154; 1.Y.240.157; 1.Y.240.166; 1.Y.240.169; 1.Y.240.172; 1.Y.240.175; 1.Y.240.240; 1.Y.240.244; 1.Y.244.228; 1.Y.244.229; 1.Y.244.230; 1.Y.244.231; 1.Y.244.236; 1.Y.244.237; 1.Y.244.238; 1.Y.244.239; 1.Y.244.154; 1.Y.244.157; 1.Y.244.166; 1.Y.244.169; 1.Y.244.172; 1.Y.244.175; 1.Y.244.240; 1.Y.244.244;

2.B Prodrug

     2.B.228.228; 2.B.228.229; 2.B.228.230; 2.B.228.231; 2.B.228.236; 2.B.228.237; 2.B.228.238; 2.B.228.239; 2.B.228.154; 2.B.228.157; 2.B.228.166; 2.B.228.169; 2.B.228.172; 2.B.228.175; 2.B.228.240; 2.B.228.244; 2.B.229.228; 2.B.229.229; 2.B.229.230; 2.B.229.231; 2.B.229.236; 2.B.229.237; 2.B.229.238; 2.B.229.239; 2.B.229.154; 2.B.229.157; 2.B.229.166; 2.B.229.169; 2.B.229.172; 2.B.229.175; 2.B.229.240; 2.B.229.244; 2.B.230.228; 2.B.230.229; 2.B.230.230; 2.B.230.231; 2.B.230.236; 2.B.230.237; 2.B.230.238; 2.B.230.239; 2.B.230.154; 2.B.230.157; 2.B.230.166; 2.B.230.169; 2.B.230.172; 2.B.230.175; 2.B.230.240; 2.B.230.244; 2.B.231.228; 2.B.231.229; 2.B.231.230; 2.B.231.231; 2.B.231.236; 2.B.231.237; 2.B.231.238; 2.B.231.239; 2.B.231.154; 2.B.231.157; 2.B.231.166; 2.B.231.169; 2.B.231.172; 2.B.231.175; 2.B.231.240; 2.B.231.244; 2.B.236.228; 2.B.236.229; 2.B.236.230; 2.B.236.231; 2.B.236.236; 2.B.236.237; 2.B.236.238; 2.B.236.239; 2.B.236.154; 2.B.236.157; 2.B.236.166; 2.B.236.169; 2.B.236.172; 2.B.236.175; 2.B.236.240; 2.B.236.244; 2.B.237.228; 2.B.237.229; 2.B.237.230; 2.B.237.231; 2.B.237.236; 2.B.237.237; 2.B.237.238; 2.B.237.239; 2.B.237.154; 2.B.237.157; 2.B.237.166; 2.B.237.169; 2.B.237.172; 2.B.237.175; 2.B.237.240; 2.B.237.244; 2.B.238.228; 2.B.238.229; 2.B.238.230; 2.B.238.231; 2.B.238.236; 2.B.238.237; 2.B.238.238; 2.B.238.239; 2.B.238.154; 2.B.238.157; 2.B.238.166; 2.B.238.169; 2.B.238.172; 2.B.238.175; 2.B.238.240; 2.B.238.244; 2.B.239.228; 2.B.239.229; 2.B.239.230; 2.B.239.231; 2.B.239.236; 2.B.239.237; 2.B.239.238; 2.B.239.239; 2.B.239.154; 2.B.239.157; 2.B.239.166; 2.B.239.169; 2.B.239.172; 2.B.239.175; 2.B.239.240; 2.B.239.244; 2.B.154.228; 2.B.154.229; 2.B.154.230; 2.B.154.231; 2.B.154.236; 2.B.154.237; 2.B.154.238; 2.B.154.239; 2.B.154.154; 2.B.154.157; 2.B.154.166; 2.B.154.169; 2.B.154.172; 2.B.154.175; 2.B.154.240; 2.B.154.244; 2.B.157.228; 2.B.157.229; 2.B.157.230; 2.B.157.231; 2.B.157.236; 2.B.157.237; 2.B.157.238; 2.B.157.239; 2.B.157.154; 2.B.157.157; 2.B.157.166; 2.B.157.169; 2.B.157.172; 2.B.157.175; 2.B.157.240; 2.B.157.244; 2.B.166.228; 2.B.166.229; 2.B.166.230; 2.B.166.231; 2.B.166.236; 2.B.166.237; 2.B.166.238; 2.B.166.239; 2.B.166.154; 2.B.166.157; 2.B.166.166; 2.B.166.169; 2.B.166.172; 2.B.166.175; 2.B.166.240; 2.B.166.244; 2.B.169.228; 2.B.169.229; 2.B.169.230; 2.B.169.231; 2.B.169.236; 2.B.169.237; 2.B.169.238; 2.B.169.239; 2.B.169.154; 2.B.169.157; 2.B.169.166; 2.B.169.169; 2.B.169.172; 2.B.169.175; 2.B.169.240; 2.B.169.244; 2.B.172.228; 2.B.172.229; 2.B.172.230; 2.B.172.231; 2.B.172.236; 2.B.172.237; 2.B.172.238; 2.B.172.239; 2.B.172.154; 2.B.172.157; 2.B.172.166; 2.B.172.169; 2.B.172.172; 2.B.172.175; 2.B.172.240; 2.B.172.244; 2.B.175.228; 2.B.175.229; 2.B.175.230; 2.B.175.231; 2.B.175.236; 2.B.175.237; 2.B.175.238; 2.B.175.239; 2.B.175.154; 2.B.175.157; 2.B.175.166; 2.B.175.169; 2.B.175.172; 2.B.175.175; 2.B.175.240; 2.B.175.244; 2.B.240.228; 2.B.240.229; 2.B.240.230; 2.B.240.231; 2.B.240.236; 2.B.240.237; 2.B.240.238; 2.B.240.239; 2.B.240.154; 2.B.240.157; 2.B.240.166; 2.B.240.169; 2.B.240.172; 2.B.240.175; 2.B.240.240; 2.B.240.244; 2.B.244.228; 2.B.244.229; 2.B.244.230; 2.B.244.231; 2.B.244.236; 2.B.244.237; 2.B.244.238; 2.B.244.239; 2.B.244.154; 2.B.244.157; 2.B.244.166; 2.B.244.169; 2.B.244.172; 2.B.244.175; 2.B.244.240; 2.B.244.244;

2.D Prodrug

     2.D.228.228; 2.D.228.229; 2.D.228.230; 2.D.228.231; 2.D.228.236; 2.D.228.237; 2.D.228.238; 2.D.228.239; 2.D.228.154; 2.D.228.157; 2.D.228.166; 2.D.228.169; 2.D.228.172; 2.D.228.175; 2.D.228.240; 2.D.228.244; 2.D.229.228; 2.D.229.229; 2.D.229.230; 2.D.229.231; 2.D.229.236; 2.D.229.237; 2.D.229.238; 2.D.229.239; 2.D.229.154; 2.D.229.157; 2.D.229.166; 2.D.229.169; 2.D.229.172; 2.D.229.175; 2.D.229.240; 2.D.229.244; 2.D.230.228; 2.D.230.229; 2.D.230.230; 2.D.230.231; 2.D.230.236; 2.D.230.237; 2.D.230.238; 2.D.230.239; 2.D.230.154; 2.D.230.157; 2.D.230.166; 2.D.230.169; 2.D.230.172; 2.D.230.175; 2.D.230.240; 2.D.230.244; 2.D.231.228; 2.D.231.229; 2.D.231.230; 2.D.231.231; 2.D.231.236; 2.D.231.237; 2.D.231.238; 2.D.231.239; 2.D.231.154; 2.D.231.157; 2.D.231.166; 2.D.231.169; 2.D.231.172; 2.D.231.175; 2.D.231.240; 2.D.231.244; 2.D.236.228; 2.D.236.229; 2.D.236.230; 2.D.236.231; 2.D.236.236; 2.D.236.237; 2.D.236.238; 2.D.236.239; 2.D.236.154; 2.D.236.157; 2.D.236.166; 2.D.236.169; 2.D.236.172; 2.D.236.175; 2.D.236.240; 2.D.236.244; 2.D.237.228; 2.D.237.229; 2.D.237.230; 2.D.237.231; 2.D.237.236; 2.D.237.237; 2.D.237.238; 2.D.237.239; 2.D.237.154; 2.D.237.157; 2.D.237.166; 2.D.237.169; 2.D.237.172; 2.D.237.175; 2.D.237.240; 2.D.237.244; 2.D.238.228; 2.D.238.229; 2.D.238.230; 2.D.238.231; 2.D.238.236; 2.D.238.237; 2.D.238.238; 2.D.238.239; 2.D.238.154; 2.D.238.157; 2.D.238.166; 2.D.238.169; 2.D.238.172; 2.D.238.175; 2.D.238.240; 2.D.238.244; 2.D.239.228; 2.D.239.229; 2.D.239.230; 2.D.239.231; 2.D.239.236; 2.D.239.237; 2.D.239.238; 2.D.239.239; 2.D.239.154; 2.D.239.157; 2.D.239.166; 2.D.239.169; 2.D.239.172; 2.D.239.175; 2.D.239.240; 2.D.239.244; 2.D.154.228; 2.D.154.229; 2.D.154.230; 2.D.154.231; 2.D.154.236; 2.D.154.237; 2.D.154.238; 2.D.154.239; 2.D.154.154; 2.D.154.157; 2.D.154.166; 2.D.154.169; 2.D.154.172; 2.D.154.175; 2.D.154.240; 2.D.154.244; 2.D.157.228; 2.D.157.229; 2.D.157.230; 2.D.157.231; 2.D.157.236; 2.D.157.237; 2.D.157.238; 2.D.157.239; 2.D.157.154; 2.D.157.157; 2.D.157.166; 2.D.157.169; 2.D.157.172; 2.D.157.175; 2.D.157.240; 2.D.157.244; 2.D.166.228; 2.D.166.229; 2.D.166.230; 2.D.166.231; 2.D.166.236; 2.D.166.237; 2.D.166.238; 2.D.166.239; 2.D.166.154; 2.D.166.157; 2.D.166.166; 2.D.166.169; 2.D.166.172; 2.D.166.175; 2.D.166.240; 2.D.166.244; 2.D. 169.228; 2.D.169.229; 2.D.169.230; 2.D.169.231; 2.D.169.236; 2.D.169.237; 2.D.169.238; 2.D. 169.239; 2.D.169.154; 2.D.169.157; 2.D.169.166; 2.D.169.169; 2.D.169.172; 2.D.169.175; 2.D.169.240; 2.D.169.244; 2.D.172.228; 2.D. 172.229; 2.D.172.230; 2.D.172.231; 2.D.172.236; 2.D.172.237; 2.D.172.238; 2.D.172.239; 2.D.172.154; 2.D.172.157; 2.D.172.166; 2.D.172.169; 2.D.172.172; 2.D.172.175; 2.D.172.240; 2.D.172.244; 2.D.175.228; 2.D.175.229; 2.D.175.230; 2.D.175.231; 2.D.175.236; 2.D.175.237; 2.D.175.238; 2.D.175.239; 2.D.175.154; 2.D.175.157; 2.D.175.166; 2.D.175.169; 2.D.175.172; 2.D.175.175; 2.D.175.240; 2.D.175.244; 2.D.240.228; 2.D.240.229; 2.D.240.230; 2.D.240.231; 2.D.240.236; 2.D.240.237; 2.D.240.238; 2.D.240.239; 2.D.240.154; 2.D.240.157; 2.D.240.166; 2.D.240.169; 2.D.240.172; 2.D.240.175; 2.D.240.240; 2.D.240.244; 2.D.244.228; 2.D.244.229; 2.D.244.230; 2.D.244.231; 2.D.244.236; 2.D.244.237; 2.D.244.238; 2.D.244.239; 2.D.244.154; 2.D.244.157; 2.D.244.166; 2.D.244.169; 2.D.244.172; 2.D.244.175; 2.D.244.240; 2.D.244.244;

2.E Prodrug

     2.E.228.228; 2.E.228.229; 2.E.228.230; 2.E.228.231; 2.E.228.236; 2.E.228.237; 2.E.228.238; 2.E.228.239; 2.E.228.154; 2.E.228.157; 2.E.228.166; 2.E.228.169; 2.E.228.172; 2.E.228.175; 2.E.228.240; 2.E.228.244; 2.E.229.228; 2.E.229.229; 2.E.229.230; 2.E.229.231; 2.E.229.236; 2.E.229.237; 2.E.229.238; 2.E.229.239; 2.E.229.154; 2.E.229.157; 2.E.229.166; 2.E.229.169; 2.E.229.172; 2.E.229.175; 2.E.229.240; 2.E.229.244; 2.E.230.228; 2.E.230.229; 2.E.230.230; 2.E.230.231; 2.E.230.236; 2.E.230.237; 2.E.230.238; 2.E.230.239; 2.E.230.154; 2.E.230.157; 2.E.230.166; 2.E.230.169; 2.E.230.172; 2.E.230.175; 2.E.230.240; 2.E.230.244; 2.E.231.228; 2.E.231.229; 2.E.231.230; 2.E.231.231; 2.E.231.236; 2.E.231.237; 2.E.231.238; 2.E.231.239; 2.E.231.154; 2.E.231.157; 2.E.231.166; 2.E.231.169; 2.E.231.172; 2.E.231.175; 2.E.231.240; 2.E.231.244; 2.E.236.228; 2.E.236.229; 2.E.236.230; 2.E.236.231; 2.E.236.236; 2.E.236.237; 2.E.236.238; 2.E.236.239; 2.E.236.154; 2.E.236.157; 2.E.236.166; 2.E.236.169; 2.E.236.172; 2.E.236.175; 2.E.236.240; 2.E.236.244; 2.E.237.228; 2.E.237.229; 2.E.237.230; 2.E.237.231; 2.E.237.236; 2.E.237.237; 2.E.237.238; 2.E.237.239; 2.E.237.154; 2.E.237.157; 2.E.237.166; 2.E.237.169; 2.E.237.172; 2.E.237.175; 2.E.237.240; 2.E.237.244; 2.E.238.228; 2.E.238.229; 2.E.238.230; 2.E.238.231; 2.E.238.236; 2.E.238.237; 2.E.238.238; 2.E.238.239; 2.E.238.154; 2.E.238.157; 2.E.238.166; 2.E.238.169; 2.E.238.172; 2.E.238.175; 2.E.238.240; 2.E.238.244; 2.E.239.228; 2.E.239.229; 2.E.239.230; 2.E.239.231; 2.E.239.236; 2.E.239.237; 2.E.239.238; 2.E.239.239; 2.E.239.154; 2.E.239.157; 2.E.239.166; 2.E.239.169; 2.E.239.172; 2.E.239.175; 2.E.239.240; 2.E.239.244; 2.E.154.228; 2.E.154.229; 2.E.154.230; 2.E.154.231; 2.E.154.236; 2.E.154.237; 2.E.154.238; 2.E.154.239; 2.E.154.154; 2.E.154.157; 2.E.154.166; 2.E.154.169; 2.E.154.172; 2.E.154.175; 2.E.154.240; 2.E.154.244; 2.E.157.228; 2.E.157.229; 2.E.157.230; 2.E.157.231; 2.E.157.236; 2.E.157.237; 2.E.157.238; 2.E.157.239; 2.E.157.154; 2.E.157.157; 2.E.157.166; 2.E.157.169; 2.E.157.172; 2.E.157.175; 2.E.157.240; 2.E.157.244; 2.E.166.228; 2.E.166.229; 2.E.166.230; 2.E.166.231; 2.E.166.236; 2.E.166.237; 2.E.166.238; 2.E.166.239; 2.E.166.154; 2.E.166.157; 2.E.166.166; 2.E.166.169; 2.E.166.172; 2.E.166.175; 2.E.166.240; 2.E.166.244; 2.E.169.228; 2.E.169.229; 2.E.169.230; 2.E.169.231; 2.E.169.236; 2.E.169.237; 2.E.169.238; 2.E.169.239; 2.E.169.154; 2.E.169.157; 2.E.169.166; 2.E.169.169; 2.E.169.172; 2.E.169.175; 2.E.169.240; 2.E.169.244; 2.E.172.228; 2.E.172.229; 2.E.172.230; 2.E.172.231; 2.E.172.236; 2.E.172.237; 2.E.172.238; 2.E.172.239; 2.E.172.154; 2.E.172.157; 2.E.172.166; 2.E.172.169; 2.E.172.172; 2.E.172.175; 2.E.172.240; 2.E.172.244; 2.E.175.228; 2.E.175.229; 2.E.175.230; 2.E.175.231; 2.E.175.236; 2.E.175.237; 2.E.175.238; 2.E.175.239; 2.E.175.154; 2.E.175.157; 2.E.175.166; 2.E.175.169; 2.E.175.172; 2.E.175.175; 2.E.175.240; 2.E.175.244; 2.E.240.228; 2.E.240.229; 2.E.240.230; 2.E.240.231; 2.E.240.236; 2.E.240.237; 2.E.240.238; 2.E.240.239; 2.E.240.154; 2.E.240.157; 2.E.240.166; 2.E.240.169; 2.E.240.172; 2.E.240.175; 2.E.240.240; 2.E.240.244; 2.E.244.228; 2.E.244.229; 2.E.244.230; 2.E.244.231; 2.E.244.236; 2.E.244.237; 2.E.244.238; 2.E.244.239; 2.E.244.154; 2.E.244.157; 2.E.244.166; 2.E.244.169; 2.E.244.172; 2.E.244.175; 2.E.244.240; 2.E.244.244;

2.G Prodrug

     2.G.228.228; 2.G.228.229; 2.G.228.230; 2.G.228.231; 2.G.228.236; 2.G.228.237; 2.G.228.238; 2.G.228.239; 2.G.228.154; 2.G.228.157; 2.G.228.166; 2.G.228.169; 2.G.228.172; 2.G.228.175; 2.G.228.240; 2.G.228.244; 2.G.229.228; 2.G.229.229; 2.G.229.230; 2.G.229.231; 2.G.229.236; 2.G.229.237; 2.G.229.238; 2.G.229.239; 2.G.229.154; 2.G.229.157; 2.G.229.166; 2.G.229.169; 2.G.229.172; 2.G.229.175; 2.G.229.240; 2.G.229.244; 2.G.230.228; 2.G.230.229; 2.G.230.230; 2.G.230.231; 2.G.230.236; 2.G.230.237; 2.G.230.238; 2.G.230.239; 2.G.230.154; 2.G.230.157; 2.G.230.166; 2.G.230.169; 2.G.230.172; 2.G.230.175; 2.G.230.240; 2.G.230.244; 2.G.231.228; 2.G.231.229; 2.G.231.230; 2.G.231.231; 2.G.231.236; 2.G.231.237; 2.G.231.238; 2.G.231.239; 2.G.231.154; 2.G.231.157; 2.G.231.166; 2.G.231.169; 2.G.231.172; 2.G.231.175; 2.G.231.240; 2.G.231.244; 2.G.236.228; 2.G.236.229; 2.G.236.230; 2.G.236.231; 2.G.236.236; 2.G.236.237; 2.G.236.238; 2.G.236.239; 2.G.236.154; 2.G.236.157; 2.G.236.166; 2.G.236.169; 2.G.236.172; 2.G.236.175; 2.G.236.240; 2.G.236.244; 2.G.237.228; 2.G.237.229; 2.G.237.230; 2.G.237.231; 2.G.237.236; 2.G.237.237; 2.G.237.238; 2.G.237.239; 2.G.237.154; 2.G.237.157; 2.G.237.166; 2.G.237.169; 2.G.237.172; 2.G.237.175; 2.G.237.240; 2.G.237.244; 2.G.238.228; 2.G.238.229; 2.G.238.230; 2.G.238.231; 2.G.238.236; 2.G.238.237; 2.G.238.238; 2.G.238.239; 2.G.238.154; 2.G.238.157; 2.G.238.166; 2.G.238.169; 2.G.238.172; 2.G.238.175; 2.G.238.240; 2.G.238.244; 2.G.239.228; 2.G.239.229; 2.G.239.230; 2.G.239.231; 2.G.239.236; 2.G.239.237; 2.G.239.238; 2.G.239.239; 2.G.239.154; 2.G.239.157; 2.G.239.166; 2.G.239.169; 2.G.239.172; 2.G.239.175; 2.G.239.240; 2.G.239.244; 2.G.154.228; 2.G.154.229; 2.G.154.230; 2.G.154.231; 2.G.154.236; 2.G.154.237; 2.G.154.238; 2.G.154.239; 2.G.154.154; 2.G.154.157; 2.G.154.166; 2.G.154.169; 2.G.154.172; 2.G.154.175; 2.G.154.240; 2.G.154.244; 2.G.157.228; 2.G.157.229; 2.G.157.230; 2.G.157.231; 2.G.157.236; 2.G.157.237; 2.G.157.238; 2.G.157.239; 2.G.157.154; 2.G.157.157; 2.G.157.166; 2.G.157.169; 2.G.157.172; 2.G.157.175; 2.G.157.240; 2.G.157.244; 2.G.166.228; 2.G.166.229; 2.G.166.230; 2.G.166.231; 2.G.166.236; 2.G.166.237; 2.G.166.238; 2.G.166.239; 2.G.166.154; 2.G.166.157; 2.G.166.166; 2.G.166.169; 2.G.166.172; 2.G.166.175; 2.G.166.240; 2.G.166.244; 2.G.169.228; 2.G.169.229; 2.G.169.230; 2.G.169.231; 2.G.169.236; 2.G.169.237; 2.G.169.238; 2.G.169.239; 2.G.169.154; 2.G.169.157; 2.G.169.166; 2.G.169.169; 2.G.169.172; 2.G.169.175; 2.G.169.240; 2.G.169.244; 2.G.172.228; 2.G.172.229; 2.G.172.230; 2.G.172.231; 2.G.172.236; 2.G.172.237; 2.G.172.238; 2.G.172.239; 2.G.172.154; 2.G.172.157; 2.G.172.166; 2.G.172.169; 2.G.172.172; 2.G.172.175; 2.G.172.240; 2.G.172.244; 2.G.175.228; 2.G.175.229; 2.G.175.230; 2.G.175.231; 2.G.175.236; 2.G.175.237; 2.G.175.238; 2.G.175.239; 2.G.175.154; 2.G.175.157; 2.G.175.166; 2.G.175.169; 2.G.175.172; 2.G.175.175; 2.G.175.240; 2.G.175.244; 2.G.240.228; 2.G.240.229; 2.G.240.230; 2.G.240.231; 2.G.240.236; 2.G.240.237; 2.G.240.238; 2.G.240.239; 2.G.240.154; 2.G.240.157; 2.G.240.166; 2.G.240.169; 2.G.240.172; 2.G.240.175; 2.G.240.240; 2.G.240.244; 2.G.244.228; 2.G.244.229; 2.G.244.230; 2.G.244.231; 2.G.244.236; 2.G.244.237; 2.G.244.238; 2.G.244.239; 2.G.244.154; 2.G.244.157; 2.G.244.166; 2.G.244.169; 2.G.244.172; 2.G.244.175; 2.G.244.240; 2.G.244.244;

2.I's Prodrug

     2.I.228.228; 2.I.228.229; 2.I.228.230; 2.I.228.231; 2.I.228.236; 2.I.228.237; 2.I.228.238; 2.I.228.239; 2.I.228.154; 2.I.228.157; 2.I.228.166; 2.I.228.169; 2.I.228.172; 2.I.228.175; 2.I.228.240; 2.I.228.244; 2.I.229.228; 2.I.229.229; 2.I.229.230; 2.I.229.231; 2.I.229.236; 2.I.229.237; 2.I.229.238; 2.I.229.239; 2.I.229.154; 2.I.229.157; 2.I.229.166; 2.I.229.169; 2.I.229.172; 2.I.229.175; 2.I.229.240; 2.I.229.244; 2.I.230.228; 2.I.230.229; 2.I.230.230; 2.I.230.231; 2.I.230.236; 2.I.230.237; 2.I.230.238; 2.I.230.239; 2.I.230.154; 2.I.230.157; 2.I.230.166; 2.I.230.169; 2.I.230.172; 2.I.230.175; 2.I.230.240; 2.I.230.244; 2.I.231.228; 2.I.231.229; 2.I.231.230; 2.I.231.231; 2.I.231.236; 2.I.231.237; 2.I.231.238; 2.I.231.239; 2.I.231.154; 2.I.231.157; 2.I.231.166; 2.I.231.169; 2.I.231.172; 2.I.231.175; 2.I.231.240; 2.I.231.244; 2.I.236.228; 2.I.236.229; 2.I.236.230; 2.I.236.231; 2.I.236.236; 2.I.236.237; 2.I.236.238; 2.I.236.239; 2.I.236.154; 2.I.236.157; 2.I.236.166; 2.I.236.169; 2.I.236.172; 2.I.236.175; 2.I.236.240; 2.I.236.244; 2.I.237.228; 2.I.237.229; 2.I.237.230; 2.I.237.231; 2.I.237.236; 2.I.237.237; 2.I.237.238; 2.I.237.239; 2.I.237.154; 2.I.237.157; 2.I.237.166; 2.I.237.169; 2.I.237.172; 2.I.237.175; 2.I.237.240; 2.I.237.244; 2.I.238.228; 2.I.238.229; 2.I.238.230; 2.I.238.231; 2.I.238.236; 2.I.238.237; 2.I.238.238; 2.I.238.239; 2.I.238.154; 2.I.238.157; 2.I.238.166; 2.I.238.169; 2.I.238.172; 2.I.238.175; 2.I.238.240; 2.I.238.244; 2.I.239.228; 2.I.239.229; 2.I.239.230; 2.I.239.231; 2.I.239.236; 2.I.239.237; 2.I.239.238; 2.I.239.239; 2.I.239.154; 2.I.239.157; 2.I.239.166; 2.I.239.169; 2.I.239.172; 2.I.239.175; 2.I.239.240; 2.I.239.244; 2.I.154.228; 2.I.154.229; 2.I.154.230; 2.I.154.231; 2.I.154.236; 2.I.154.237; 2.I.154.238; 2.I.154.239; 2.I.154.154; 2.I.154.157; 2.I.154.166; 2.I.154.169; 2.I.154.172; 2.I.154.175; 2.I.154.240; 2.I.154.244; 2.I.157.228; 2.I.157.229; 2.I.157.230; 2.I.157.231; 2.I.157.236; 2.I.157.237; 2.I.157.238; 2.I.157.239; 2.I.157.154; 2.I.157.157; 2.I.157.166; 2.I.157.169; 2.I.157.172; 2.I.157.175; 2.I.157.240; 2.I.157.244; 2.I.166.228; 2.I.166.229; 2.I.166.230; 2.I.166.231; 2.I.166.236; 2.I.166.237; 2.I.166.238; 2.I.166.239; 2.I.166.154; 2.I.166.157; 2.I.166.166; 2.I.166.169; 2.I.166.172; 2.I.166.175; 2.I.166.240; 2.I.166.244; 2.I.169.228; 2.I.169.229; 2.I.169.230; 2.I.169.231; 2.I.169.236; 2.I.169.237; 2.I.169.238; 2.I.169.239; 2.I.169.154; 2.I.169.157; 2.I.169.166; 2.I.169.169; 2.I.169.172; 2.I.169.175; 2.I.169.240; 2.I.169.244; 2.I.172.228; 2.I.172.229; 2.I.172.230; 2.I.172.231; 2.I.172.236; 2.I.172.237; 2.I.172.238; 2.I.172.239; 2.I.172.154; 2.I.172.157; 2.I.172.166; 2.I.172.169; 2.I.172.172; 2.I.172.175; 2.I.172.240; 2.I.172.244; 2.I.175.228; 2.I.175.229; 2.I.175.230; 2.I.175.231; 2.I.175.236; 2.I.175.237; 2.I.175.238; 2.I.175.239; 2.I.175.154; 2.I.175.157; 2.I.175.166; 2.I.175.169; 2.I.175.172; 2.I.175.175; 2.I.175.240; 2.I.175.244; 2.I.240.228; 2.I.240.229; 2.I.240.230; 2.I.240.231; 2.I.240.236; 2.I.240.237; 2.I.240.238; 2.I.240.239; 2.I.240.154; 2.I.240.157; 2.I.240.166; 2.I.240.169; 2.I.240.172; 2.I.240.175; 2.I.240.240; 2.I.240.244; 2.I.244.228; 2.I.244.229; 2.I.244.230; 2.I.244.231; 2.I.244.236; 2.I.244.237; 2.I.244.238; 2.I.244.239; 2.I.244.154; 2.I.244.157; 2.I.244.166; 2.I.244.169; 2.I.244.172; 2.I.244.175; 2.I.244.240; 2.I.244.244;

2.J's Prodrug

     2.J. 228.228; 2.J.228.229; 2.J.228.230; 2.J.228.231; 2.J.228.236; 2.J.228.237; 2.J.228.238; 2.J.228.239; 2.J.228.154; 2.J.228.157; 2.J.228.166; 2.J. 228.169; 2.J.228.172; 2.J.228.175; 2.J.228.240; 2.J.228.244; 2.J.229.228; 2.J.229.229; 2.J.229.230; 2.J.229.231; 2.J.229.236; 2.J.229.237; 2.J.229.238; 2.J.229.239; 2.J.229.154; 2.J.229.157; 2.J.229.166; 2.J.229.169; 2.J.229.172; 2.J.229.175; 2.J.229.240; 2.J.229.244; 2.J.230.228; 2.J.230.229; 2.J.230.230; 2.J.230.231; 2.J.230.236; 2.J.230.237; 2.J.230.238; 2.J.230.239; 2.J.230.154; 2.J.230.157; 2.J.230.166; 2.J.230.169; 2.J.230.172; 2.J.230.175; 2.J.230.240; 2.J.230.244; 2.J.231.228; 2.J.231.229; 2.J.231.230; 2.J.231.231; 2.J.231.236; 2.J.231.237; 2.J.231.238; 2.J.231.239; 2.J.231.154; 2.J.231.157; 2.J.231.166; 2.J.231.169; 2.J.231.172; 2.J.231.175; 2.J.231.240; 2.J.231.244; 2.J.236.228; 2.J. 236.229; 2.J.236.230; 2.J.236.231; 2.J.236.236; 2.J.236.237; 2.J.236.238; 2.J.236.239; 2.J.236.154; 2.J.236.157; 2.J.236.166; 2.J.236.169; 2.J.236.172; 2.J.236.175; 2.J.236.240; 2.J.236.244; 2.J. 237.228; 2.J.237.229; 2.J.237.230; 2.J.237.231; 2.J.237.236; 2.J.237.237; 2.J.237.238; 2.J.237.239; 2.J.237.154; 2.J. 237.157; 2.J.237.166; 2.J. 237.169; 2.J.237.172; 2.J.237.175; 2.J.237.240; 2.J.237.244; 2.J.238.228; 2.J.238.229; 2.J.238.230; 2.J.238.231; 2.J.238.236; 2.J.238.237; 2.J.238.238; 2.J.238.239; 2.J.238.154; 2.J.238.157; 2.J.238.166; 2.J.238.169; 2.J.238.172; 2.J.238.175; 2.J.238.240; 2.J.238.244; 2.J.239.228; 2.J.239.229; 2.J.239.230; 2.J.239.231; 2.J.239.236; 2.J.239.237; 2.J.239.238; 2.J.239.239; 2.J.239.154; 2.J.239.157; 2.J.239.166; 2.J.239.169; 2.J.239.172; 2.J.239.175; 2.J.239.240; 2.J.239.244; 2.J.154.228; 2.J.154.229; 2.J.154.230; 2.J.154.231; 2.J.154.236; 2.J.154.237; 2.J.154.238; 2.J.154.239; 2.J.154.154; 2.J.154.157; 2.J.154.166; 2.J.154.169; 2.J.154.172; 2.J.154.175; 2.J.154.240; 2.J.154.244; 2.J.157.228; 2.J.157.229; 2.J.157.230; 2.J.157.231; 2.J.157.236; 2.J.157.237; 2.J.157.238; 2.J.157.239; 2.J.157.154; 2.J.157.157; 2.J.157.166; 2.J.157.169; 2.J.157.172; 2.J.157.175; 2.J.157.240; 2.J.157.244; 2.J.166.228; 2.J. 166.229; 2.J.166.230; 2.J.166.231; 2.J.166.236; 2.J.166.237; 2.J.166.238; 2.J.166.239; 2.J.166.154; 2.J.166.157; 2.J.166.166; 2.J.166.169; 2.J.166.172; 2.J.166.175; 2.J.166.240; 2.J.166.244; 2.J. 169.228; 2.J.169.229; 2.J.169.230; 2.J. 169.231; 2.J.169.236; 2.J. 169.237; 2.J. 169.238; 2.J. 169.239; 2.J. 169.154; 2.J. 169.157; 2.J. 169.166; 2.J. 169.169; 2.J. 169.172; 2.J. 169.175; 2.J.169.240; 2.J. 169.244; 2.J.172.228; 2.J.172.229; 2.J.172.230; 2.J.172.231; 2.J.172.236; 2.J.172.237; 2.J.172.238; 2.J.172.239; 2.J.172.154; 2.J.172.157; 2.J.172.166; 2.J.172.169; 2.J.172.172; 2.J.172.175; 2.J.172.240; 2.J.172.244; 2.J.175.228; 2.J.175.229; 2.J.175.230; 2.J.175.231; 2.J.175.236; 2.J.175.237; 2.J.175.238; 2.J.175.239; 2.J.175.154; 2.J.175.157; 2.J.175.166; 2.J.175.169; 2.J.175.172; 2.J.175.175; 2.J.175.240; 2.J.175.244; 2.J.240.228; 2.J.240.229; 2.J.240.230; 2.J.240.231; 2.J.240.236; 2.J.240.237; 2.J.240.238; 2.J.240.239; 2.J.240.154; 2.J.240.157; 2.J.240.166; 2.J.240.169; 2.J.240.172; 2.J.240.175; 2.J.240.240; 2.J.240.244; 2.J.244.228; 2.J.244.229; 2.J.244.230; 2.J.244.231; 2.J.244.236; 2.J.244.237; 2.J.244.238; 2.J.244.239; 2.J.244.154; 2.J.244.157; 2.J.244.166; 2.J.244.169; 2.J.244.172; 2.J.244.175; 2.J.244.240; 2.J.244.244;

2.L Prodrug

     2.L. 228.228; 2.L. 228.229; 2.L. 228.230; 2.L. 228.231; 2.L.228.236; 2.L. 228.237; 2.L. 228.238; 2.L. 228.239; 2.L. 228.154; 2.L. 228.157; 2.L. 228.166; 2.L. 228.169; 2.L. 228.172; 2.L. 228.175; 2.L. 228.240; 2.L.228.244; 2.L.229.228; 2.L.229.229; 2.L.229.230; 2.L.229.231; 2.L.229.236; 2.L.229.237; 2.L.229.238; 2.L.229.239; 2.L.229.154; 2.L.229.157; 2.L.229.166; 2.L.229.169; 2.L.229.172; 2.L.229.175; 2.L.229.240; 2.L.229.244; 2.L.230.228; 2.L.230.229; 2.L.230.230; 2.L.230.231; 2.L.230.236; 2.L.230.237; 2.L.230.238; 2.L.230.239; 2.L.230.154; 2.L.230.157; 2.L.230.166; 2.L.230.169; 2.L.230.172; 2.L.230.175; 2.L.230.240; 2.L.230.244; 2.L.231.228; 2.L. 231.229; 2.L.231.230; 2.L.231.231; 2.L.231.236; 2.L.231.237; 2.L.231.238; 2.L.231.239; 2.L.231.154; 2.L.231.157; 2.L.231.166; 2.L.231.169; 2.L.231.172; 2.L.231.175; 2.L.231.240; 2.L.231.244; 2.L.236.228; 2.L. 236.229; 2.L.236.230; 2.L.236.231; 2.L.236.236; 2.L.236.237; 2.L.236.238; 2.L.236.239; 2.L.236.154; 2.L.236.157; 2.L.236.166; 2.L.236.169; 2.L.236.172; 2.L.236.175; 2.L.236.240; 2.L.236.244; 2.L. 237.228; 2.L. 237.229; 2.L.237.230; 2.L.237.231; 2.L.237.236; 2.L.237.237; 2.L.237.238; 2.L. 237.239; 2.L.237.154; 2.L. 237.157; 2.L.237.166; 2.L. 237.169; 2.L. 237.172; 2.L.237.175; 2.L.237.240; 2.L.237.244; 2.L.238.228; 2.L.238.229; 2.L.238.230; 2.L.238.231; 2.L.238.236; 2.L.238.237; 2.L.238.238; 2.L.238.239; 2.L.238.154; 2.L.238.157; 2.L.238.166; 2.L.238.169; 2.L.238.172; 2.L.238.175; 2.L.238.240; 2.L.238.244; 2.L.239.228; 2.L.239.229; 2.L.239.230; 2.L.239.231; 2.L.239.236; 2.L.239.237; 2.L.239.238; 2.L.239.239; 2.L.239.154; 2.L.239.157; 2.L.239.166; 2.L.239.169; 2.L.239.172; 2.L.239.175; 2.L.239.240; 2.L.239.244; 2.L.154.228; 2.L.154.229; 2.L.154.230; 2.L.154.231; 2.L.154.236; 2.L.154.237; 2.L.154.238; 2.L.154.239; 2.L.154.154; 2.L.154.157; 2.L.154.166; 2.L.154.169; 2.L.154.172; 2.L.154.175; 2.L.154.240; 2.L.154.244; 2.L.157.228; 2.L. 157.229; 2.L.157.230; 2.L.157.231; 2.L.157.236; 2.L.157.237; 2.L.157.238; 2.L.157.239; 2.L.157.154; 2.L.157.157; 2.L.157.166; 2.L.157.169; 2.L.157.172; 2.L.157.175; 2.L.157.240; 2.L.157.244; 2.L. 166.228; 2.L. 166.229; 2.L.166.230; 2.L.166.231; 2.L.166.236; 2.L.166.237; 2.L.166.238; 2.L.166.239; 2.L.166.154; 2.L.166.157; 2.L.166.166; 2.L.166.169; 2.L.166.172; 2.L.166.175; 2.L.166.240; 2.L.166.244; 2.L. 169.228; 2.L.169.229; 2.L.169.230; 2.L.169.231; 2.L.169.236; 2.L.169.237; 2.L.169.238; 2.L. 169.239; 2.L.169.154; 2.L. 169.157; 2.L. 169.166; 2.L.169.169; 2.L.169.172; 2.L.169.175; 2.L.169.240; 2.L.169.244; 2.L. 172.228; 2.L. 172.229; 2.L.172.230; 2.L. 172.231; 2.L.172.236; 2.L. 172.237; 2.L.172.238; 2.L. 172.239; 2.L.172.154; 2.L. 172.157; 2.L. 172.166; 2.L.172.169; 2.L.172.172; 2.L.172.175; 2.L.172.240; 2.L.172.244; 2.L. 175.228; 2.L. 175.229; 2.L. 175.230; 2.L.175.231; 2.L.175.236; 2.L.175.237; 2.L.175.238; 2.L. 175.239; 2.L.175.154; 2.L. 175.157; 2.L. 175.166; 2.L.175.169; 2.L.175.172; 2.L.175.175; 2.L.175.240; 2.L.175.244; 2.L.240.228; 2.L.240.229; 2.L.240.230; 2.L.240.231; 2.L.240.236; 2.L.240.237; 2.L.240.238; 2.L.240.239; 2.L.240.154; 2.L.240.157; 2.L.240.166; 2.L.240.169; 2.L.240.172; 2.L.240.175; 2.L.240.240; 2.L.240.244; 2.L.244.228; 2.L.244.229; 2.L.244.230; 2.L.244.231; 2.L.244.236; 2.L.244.237; 2.L.244.238; 2.L.244.239; 2.L.244.154; 2.L.244.157; 2.L.244.166; 2.L.244.169; 2.L.244.172; 2.L.244.175; 2.L.244.240; 2.L.244.244;

2.O's Prodrug

     2.O.228.228; 2.O.228.229; 2.O.228.230; 2.O.228.231; 2.O.228.236; 2.O.228.237; 2.O.228.238; 2.O.228.239; 2.O.228.154; 2.O.228.157; 2.O.228.166; 2.O.228.169; 2.O.228.172; 2.O.228.175; 2.O.228.240; 2.O.228.244; 2.O.229.228; 2.O.229.229; 2.O.229.230; 2.O.229.231; 2.O.229.236; 2.O.229.237; 2.O.229.238; 2.O.229.239; 2.O.229.154; 2.O.229.157; 2.O.229.166; 2.O.229.169; 2.O.229.172; 2.O.229.175; 2.O.229.240; 2.O.229.244; 2.O.230.228; 2.O.230.229; 2.O.230.230; 2.230.231; 2.O.230.236; 2.O.230.237; 2.230.238; 2.230.239; 2.230.154; 2.230.157; 2.O.230.166; 2.230.169; 2.O.230.172; 2.O.230.175; 2.O.230.240; 2.O.230.244; 2.O.231.228; 2.O.231.229; 2.O.231.230; 2.O.231.231; 2.O.231.236; 2.O.231.237; 2.O.231.238; 2.O.231.239; 2.O.231.154; 2.O.231.157; 2.O.231.166; 2.O.231.169; 2.O.231.172; 2.O.231.175; 2.O.231.240; 2.O.231.244; 2.O.236.228; 2.O.236.229; 2.O.236.230; 2.O.236.231; 2.O.236.236; 2.O.236.237; 2.O.236.238; 2.O.236.239; 2.O.236.154; 2.O.236.157; 2.O.236.166; 2.O.236.169; 2.O.236.172; 2.O.236.175; 2.O.236.240; 2.O.236.244; 2.O.237.228; 2.O.237.229; 2.O.237.230; 2.O.237.231; 2.O.237.236; 2.O.237.237; 2.O.237.238; 2.O.237.239; 2.O.237.154; 2.O.237.157; 2.O.237.166; 2.O.237.169; 2.O.237.172; 2.O.237.175; 2.O.237.240; 2.O.237.244; 2.O.238.228; 2.O.238.229; 2.O.238.230; 2.O.238.231; 2.O.238.236; 2.O.238.237; 2.O.238.238; 2.O.238.239; 2.O.238.154; 2.O.238.157; 2.O.238.166; 2.O.238.169; 2.O.238.172; 2.O.238.175; 2.O.238.240; 2.O.238.244; 2.O.239.228; 2.O.239.229; 2.O.239.230; 2.O.239.231; 2.O.239.236; 2.O.239.237; 2.O.239.238; 2.O.239.239; 2.O.239.154; 2.O.239.157; 2.O.239.166; 2.O.239.169; 2.O.239.172; 2.O.239.175; 2.O.239.240; 2.O.239.244; 2.154.228; 2.154.229; 2.154.230; 2.O.154.231; 2.O.154.236; 2.154.237; 2.O.154.238; 2.154.239; 2.O.154.154; 2.154.157; 2.O.154.166; 2.154.169; 2.154.172; 2.154.175; 2.154.240; 2.154.244; 2.O.157.228; 2.O.157.229; 2.O.157.230; 2.O.157.231; 2.O.157.236; 2.O.157.237; 2.O.157.238; 2.O.157.239; 2.O.157.154; 2.O.157.157; 2.O.157.166; 2.O.157.169; 2.O.157.172; 2.O.157.175; 2.O.157.240; 2.O.157.244; 2.O.166.228; 2.O.166.229; 2.O.166.230; 2.O.166.231; 2.O.166.236; 2.O.166.237; 2.O.166.238; 2.O.166.239; 2.O.166.154; 2.O.166.157; 2.O.166.166; 2.O.166.169; 2.O.166.172; 2.O.166.175; 2.O.166.240; 2.O.166.244; 2.O.169.228; 2.O.169.229; 2.O.169.230; 2.O.169.231; 2.O.169.236; 2.O.169.237; 2.O.169.238; 2.O.169.239; 2.O.169.154; 2.O.169.157; 2.O.169.166; 2.O.169.169; 2.O.169.172; 2.O.169.175; 2.O.169.240; 2.O.169.244; 2.O.172.228; 2.O.172.229; 2.O.172.230; 2.O.172.231; 2.O.172.236; 2.O.172.237; 2.O.172.238; 2.O.172.239; 2.O.172.154; 2.O.172.157; 2.O.172.166; 2.O.172.169; 2.O.172.172; 2.O.172.175; 2.O.172.240; 2.O.172.244; 2.O.175.228; 2.O.175.229; 2.O.175.230; 2.O.175.231; 2.O.175.236; 2.O.175.237; 2.O.175.238; 2.O.175.239; 2.O.175.154; 2.O.175.157; 2.O.175.166; 2.O.175.169; 2.O.175.172; 2.O.175.175; 2.O.175.240; 2.O.175.244; 2.O.240.228; 2.O.240.229; 2.O.240.230; 2.O.240.231; 2.O.240.236; 2.O.240.237; 2.O.240.238; 2.O.240.239; 2.O.240.154; 2.O.240.157; 2.O.240.166; 2.O.240.169; 2.O.240.172; 2.O.240.175; 2.O.240.240; 2.O.240.244; 2.O.244.228; 2.O.244.229; 2.O.244.230; 2.O.244.231; 2.O.244.236; 2.O.244.237; 2.O.244.238; 2.O.244.239; 2.O.244.154; 2.O.244.157; 2.O.244.166; 2.O.244.169; 2.O.244.172; 2.O.244.175; 2.O.244.240; 2.O.244.244;

2.P Prodrug

     2.P.228.228; 2.P.228.229; 2.P.228.230; 2.P.228.231; 2.P.228.236; 2.P.228.237; 2.P.228.238; 2.P.228.239; 2.P.228.154; 2.P. 228.157; 2.P.228.166; 2.P.228.169; 2.P.228.172; 2.P.228.175; 2.P.228.240; 2.P.228.244; 2.P.229.228; 2.P.229.229; 2.P.229.230; 2.P.229.231; 2.P.229.236; 2.P.229.237; 2.P.229.238; 2.P.229.239; 2.P.229.154; 2.P.229.157; 2.P.229.166; 2.P.229.169; 2.P.229.172; 2.P.229.175; 2.P.229.240; 2.P.229.244; 2.P.230.228; 2.P.230.229; 2.P.230.230; 2.P.230.231; 2.P.230.236; 2.P.230.237; 2.P.230.238; 2.P.230.239; 2.P.230.154; 2.P.230.157; 2.P.230.166; 2.P.230.169; 2.P.230.172; 2.P.230.175; 2.P.230.240; 2.P.230.244; 2.P.231.228; 2.P.231.229; 2.P.231.230; 2.P.231.231; 2.P.231.236; 2.P.231.237; 2.P.231.238; 2.P.231.239; 2.P.231.154; 2.P.231.157; 2.P.231.166; 2.P.231.169; 2.P.231.172; 2.P.231.175; 2.P.231.240; 2.P.231.244; 2.P.236.228; 2.P.236.229; 2.P.236.230; 2.P.236.231; 2.P.236.236; 2.P.236.237; 2.P.236.238; 2.P.236.239; 2.P.236.154; 2.P.236.157; 2.P.236.166; 2.P.236.169; 2.P.236.172; 2.P.236.175; 2.P.236.240; 2.P.236.244; 2.P.237.228; 2.P.237.229; 2.P.237.230; 2.P.237.231; 2.P.237.236; 2.P.237.237; 2.P.237.238; 2.P.237.239; 2.P.237.154; 2.P.237.157; 2.P.237.166; 2.P.237.169; 2.P.237.172; 2.P.237.175; 2.P.237.240; 2.P.237.244; 2.P.238.228; 2.P.238.229; 2.P.238.230; 2.P.238.231; 2.P.238.236; 2.P.238.237; 2.P.238.238; 2.P.238.239; 2.P.238.154; 2.P.238.157; 2.P.238.166; 2.P.238.169; 2.P.238.172; 2.P.238.175; 2.P.238.240; 2.P.238.244; 2.P.239.228; 2.P.239.229; 2.P.239.230; 2.P.239.231; 2.P.239.236; 2.P.239.237; 2.P.239.238; 2.P.239.239; 2.P.239.154; 2.P.239.157; 2.P.239.166; 2.P.239.169; 2.P.239.172; 2.P.239.175; 2.P.239.240; 2.P.239.244; 2.P.154.228; 2.P.154.229; 2.P.154.230; 2.P.154.231; 2.P.154.236; 2.P.154.237; 2.P.154.238; 2.P.154.239; 2.P.154.154; 2.P.154.157; 2.P.154.166; 2.P.154.169; 2.P.154.172; 2.P.154.175; 2.P.154.240; 2.P.154.244; 2.P.157.228; 2.P. 157.229; 2.P.157.230; 2.P.157.231; 2.P.157.236; 2.P.157.237; 2.P.157.238; 2.P.157.239; 2.P.157.154; 2.P.157.157; 2.P.157.166; 2.P.157.169; 2.P.157.172; 2.P.157.175; 2.P.157.240; 2.P.157.244; 2.P.166.228; 2.P. 166.229; 2.P.166.230; 2.P.166.231; 2.P.166.236; 2.P.166.237; 2.P.166.238; 2.P.166.239; 2.P.166.154; 2.P.166.157; 2.P.166.166; 2.P.166.169; 2.P.166.172; 2.P.166.175; 2.P.166.240; 2.P.166.244; 2.P.169.228; 2.P.169.229; 2.P.169.230; 2.P.169.231; 2.P.169.236; 2.P.169.237; 2.P.169.238; 2.P.169.239; 2.P.169.154; 2.P.169.157; 2.P.169.166; 2.P.169.169; 2.P.169.172; 2.P.169.175; 2.P.169.240; 2.P.169.244; 2.P.172.228; 2.P. 172.229; 2.P.172.230; 2.P.172.231; 2.P.172.236; 2.P.172.237; 2.P.172.238; 2.P.172.239; 2.P.172.154; 2.P.172.157; 2.P.172.166; 2.P.172.169; 2.P.172.172; 2.P.172.175; 2.P.172.240; 2.P.172.244; 2.P.175.228; 2.P. 175.229; 2.P.175.230; 2.P.175.231; 2.P.175.236; 2.P.175.237; 2.P.175.238; 2.P.175.239; 2.P.175.154; 2.P.175.157; 2.P.175.166; 2.P.175.169; 2.P.175.172; 2.P.175.175; 2.P.175.240; 2.P.175.244; 2.P.240.228; 2.P.240.229; 2.P.240.230; 2.P.240.231; 2.P.240.236; 2.P.240.237; 2.P.240.238; 2.P.240.239; 2.P.240.154; 2.P.240.157; 2.P.240.166; 2.P.240.169; 2.P.240.172; 2.P.240.175; 2.P.240.240; 2.P.240.244; 2.P.244.228; 2.P.244.229; 2.P.244.230; 2.P.244.231; 2.P.244.236; 2.P.244.237; 2.P.244.238; 2.P.244.239; 2.P.244.154; 2.P.244.157; 2.P.244.166; 2.P.244.169; 2.P.244.172; 2.P.244.175; 2.P.244.240; 2.P.244.244;

2.U's Prodrug

     2.U.228.228; 2.U.228.229; 2.U.228.230; 2.U.228.231; 2.U.228.236; 2.U.228.237; 2.U.228.238; 2.U.228.239; 2.U.228.154; 2.U.228.157; 2.U.228.166; 2.U.228.169; 2.U.228.172; 2.U.228.175; 2.U.228.240; 2.U.228.244; 2.U.229.228; 2.U.229.229; 2.U.229.230; 2.U.229.231; 2.U.229.236; 2.U.229.237; 2.U.229.238; 2.U.229.239; 2.U.229.154; 2.U.229.157; 2.U.229.166; 2.U.229.169; 2.U.229.172; 2.U.229.175; 2.U.229.240; 2.U.229.244; 2.U.230.228; 2.U.230.229; 2.U.230.230; 2.U.230.231; 2.U.230.236; 2.U.230.237; 2.U.230.238; 2.U.230.239; 2.U.230.154; 2.U.230.157; 2.U.230.166; 2.U.230.169; 2.U.230.172; 2.U.230.175; 2.U.230.240; 2.U.230.244; 2.U.231.228; 2.U.231.229; 2.U.231.230; 2.U.231.231; 2.U.231.236; 2.U.231.237; 2.U.231.238; 2.U.231.239; 2.U.231.154; 2.U.231.157; 2.U.231.166; 2.U.231.169; 2.U.231.172; 2.U.231.175; 2.U.231.240; 2.U.231.244; 2.U.236.228; 2.U.236.229; 2.U.236.230; 2.U.236.231; 2.U.236.236; 2.U.236.237; 2.U.236.238; 2.U.236.239; 2.U.236.154; 2.U.236.157; 2.U.236.166; 2.U.236.169; 2.U.236.172; 2.U.236.175; 2.U.236.240; 2.U.236.244; 2.U.237.228; 2.U.237.229; 2.U.237.230; 2.U.237.231; 2.U.237.236; 2.U.237.237; 2.U.237.238; 2.U.237.239; 2.U.237.154; 2.U.237.157; 2.U.237.166; 2.U.237.169; 2.U.237.172; 2.U.237.175; 2.U.237.240; 2.U.237.244; 2.U.238.228; 2.U.238.229; 2.U.238.230; 2.U.238.231; 2.U.238.236; 2.U.238.237; 2.U.238.238; 2.U.238.239; 2.U.238.154; 2.U.238.157; 2.U.238.166; 2.U.238.169; 2.U.238.172; 2.U.238.175; 2.U.238.240; 2.U.238.244; 2.U.239.228; 2.U.239.229; 2.U.239.230; 2.U.239.231; 2.U.239.236; 2.U.239.237; 2.U.239.238; 2.U.239.239; 2.U.239.154; 2.U.239.157; 2.U.239.166; 2.U.239.169; 2.U.239.172; 2.U.239.175; 2.U.239.240; 2.U.239.244; 2.U.154.228; 2.U.154.229; 2.U.154.230; 2.U.154.231; 2.U.154.236; 2.U.154.237; 2.U.154.238; 2.U.154.239; 2.U.154.154; 2.U.154.157; 2.U.154.166; 2.U.154.169; 2.U.154.172; 2.U.154.175; 2.U.154.240; 2.U.154.244; 2.U.157.228; 2.U.157.229; 2.U.157.230; 2.U.157.231; 2.U.157.236; 2.U.157.237; 2.U.157.238; 2.U.157.239; 2.U.157.154; 2.U.157.157; 2.U.157.166; 2.U.157.169; 2.U.157.172; 2.U.157.175; 2.U.157.240; 2.U.157.244; 2.U.166.228; 2.U.166.229; 2.U.166.230; 2.U.166.231; 2.U.166.236; 2.U.166.237; 2.U.166.238; 2.U.166.239; 2.U.166.154; 2.U.166.157; 2.U.166.166; 2.U.166.169; 2.U.166.172; 2.U.166.175; 2.U.166.240; 2.U.166.244; 2.U.169.228; 2.U.169.229; 2.U.169.230; 2.U.169.231; 2.U.169.236; 2.U.169.237; 2.U.169.238; 2.U.169.239; 2.U.169.154; 2.U.169.157; 2.U.169.166; 2.U.169.169; 2.U.169.172; 2.U.169.175; 2.U.169.240; 2.U.169.244; 2.U.172.228; 2.U.172.229; 2.U.172.230; 2.U.172.231; 2.U.172.236; 2.U.172.237; 2.U.172.238; 2.U.172.239; 2.U.172.154; 2.U.172.157; 2.U.172.166; 2.U.172.169; 2.U.172.172; 2.U.172.175; 2.U.172.240; 2.U.172.244; 2.U.175.228; 2.U.175.229; 2.U.175.230; 2.U.175.231; 2.U.175.236; 2.U.175.237; 2.U.175.238; 2.U.175.239; 2.U.175.154; 2.U.175.157; 2.U.175.166; 2.U.175.169; 2.U.175.172; 2.U.175.175; 2.U.175.240; 2.U.175.244; 2.U.240.228; 2.U.240.229; 2.U.240.230; 2.U.240.231; 2.U.240.236; 2.U.240.237; 2.U.240.238; 2.U.240.239; 2.U.240.154; 2.U.240.157; 2.U.240.166; 2.U.240.169; 2.U.240.172; 2.U.240.175; 2.U.240.240; 2.U.240.244; 2.U.244.228; 2.U.244.229; 2.U.244.230; 2.U.244.231; 2.U.244.236; 2.U.244.237; 2.U.244.238; 2.U.244.239; 2.U.244.154; 2.U.244.157; 2.U.244.166; 2.U.244.169; 2.U.244.172; 2.U.244.175; 2.U.244.240; 2.U.244.244;

2.W Prodrug

     2.W.228.228; 2.W.228.229; 2.W.228.230; 2.W.228.231; 2.W.228.236; 2.W.228.237; 2.W.228.238; 2.W.228.239; 2.W.228.154; 2.W.228.157; 2.W.228.166; 2.W.228.169; 2.W.228.172; 2.W.228.175; 2.W.228.240; 2.W.228.244; 2.W.229.228; 2.W.229.229; 2.W.229.230; 2.W.229.231; 2.W.229.236; 2.W.229.237; 2.W.229.238; 2.W.229.239; 2.W.229.154; 2.W.229.157; 2.W.229.166; 2.W.229.169; 2.W.229.172; 2.W.229.175; 2.W.229.240; 2.W.229.244; 2.W.230.228; 2.W.230.229; 2.W.230.230; 2.W.230.231; 2.W.230.236; 2.W.230.237; 2.W.230.238; 2.W.230.239; 2.W.230.154; 2.W.230.157; 2.W.230.166; 2.W.230.169; 2.W.230.172; 2.W.230.175; 2.W.230.240; 2.W.230.244; 2.W.231.228; 2.W.231.229; 2.W.231.230; 2.W.231.231; 2.W.231.236; 2.W.231.237; 2.W.231.238; 2.W.231.239; 2.W.231.154; 2.W.231.157; 2.W.231.166; 2.W.231.169; 2.W.231.172; 2.W.231.175; 2.W.231.240; 2.W.231.244; 2.W.236.228; 2.W.236.229; 2.W.236.230; 2.W.236.231; 2.W.236.236; 2.W.236.237; 2.W.236.238; 2.W.236.239; 2.W.236.154; 2.W.236.157; 2.W.236.166; 2.W.236.169; 2.W.236.172; 2.W.236.175; 2.W.236.240; 2.W.236.244; 2.W.237.228; 2.W.237.229; 2.W.237.230; 2.W.237.231; 2.W.237.236; 2.W.237.237; 2.W.237.238; 2.W.237.239; 2.W.237.154; 2.W.237.157; 2.W.237.166; 2.W.237.169; 2.W.237.172; 2.W.237.175; 2.W.237.240; 2.W.237.244; 2.W.238.228; 2.W.238.229; 2.W.238.230; 2.W.238.231; 2.W.238.236; 2.W.238.237; 2.W.238.238; 2.W.238.239; 2.W.238.154; 2.W.238.157; 2.W.238.166; 2.W.238.169; 2.W.238.172; 2.W.238.175; 2.W.238.240; 2.W.238.244; 2.W.239.228; 2.W.239.229; 2.W.239.230; 2.W.239.231; 2.W.239.236; 2.W.239.237; 2.W.239.238; 2.W.239.239; 2.W.239.154; 2.W.239.157; 2.W.239.166; 2.W.239.169; 2.W.239.172; 2.W.239.175; 2.W.239.240; 2.W.239.244; 2.W.154.228; 2.W.154.229; 2.W.154.230; 2.W.154.231; 2.W.154.236; 2.W.154.237; 2.W.154.238; 2.W.154.239; 2.W.154.154; 2.W.154.157; 2.W.154.166; 2.W.154.169; 2.W.154.172; 2.W.154.175; 2.W.154.240; 2.W.154.244; 2.W.157.228; 2.W.157.229; 2.W.157.230; 2.W.157.231; 2.W.157.236; 2.W.157.237; 2.W.157.238; 2.W.157.239; 2.W.157.154; 2.W.157.157; 2.W.157.166; 2.W.157.169; 2.W.157.172; 2.W.157.175; 2.W.157.240; 2.W.157.244; 2.W.166.228; 2.W.166.229; 2.W.166.230; 2.W.166.231; 2.W.166.236; 2.W.166.237; 2.W.166.238; 2.W.166.239; 2.W.166.154; 2.W.166.157; 2.W.166.166; 2.W.166.169; 2.W.166.172; 2.W.166.175; 2.W.166.240; 2.W.166.244; 2.W.169.228; 2.W.169.229; 2.W.169.230; 2.W.169.231; 2.W.169.236; 2.W.169.237; 2.W.169.238; 2.W.169.239; 2.W.169.154; 2.W.169.157; 2.W.169.166; 2.W.169.169; 2.W.169.172; 2.W.169.175; 2.W.169.240; 2.W.169.244; 2.W.172.228; 2.W.172.229; 2.W.172.230; 2.W.172.231; 2.W.172.236; 2.W.172.237; 2.W.172.238; 2.W.172.239; 2.W.172.154; 2.W.172.157; 2.W.172.166; 2.W.172.169; 2.W.172.172; 2.W.172.175; 2.W.172.240; 2.W.172.244; 2.W.175.228; 2.W.175.229; 2.W.175.230; 2.W.175.231; 2.W.175.236; 2.W.175.237; 2.W.175.238; 2.W.175.239; 2.W.175.154; 2.W.175.157; 2.W.175.166; 2.W.175.169; 2.W.175.172; 2.W.175.175; 2.W.175.240; 2.W.175.244; 2.W.240.228; 2.W.240.229; 2.W.240.230; 2.W.240.231; 2.W.240.236; 2.W.240.237; 2.W.240.238; 2.W.240.239; 2.W.240.154; 2.W.240.157; 2.W.240.166; 2.W.240.169; 2.W.240.172; 2.W.240.175; 2.W.240.240; 2.W.240.244; 2.W.244.228; 2.W.244.229; 2.W.244.230; 2.W.244.231; 2.W.244.236; 2.W.244.237; 2.W.244.238; 2.W.244.239; 2.W.244.154; 2.W.244.157; 2.W.244.166; 2.W.244.169; 2.W.244.172; 2.W.244.175; 2.W.244.240; 2.W.244.244;

2.Y's Prodrug

     2.Y.228.228; 2.Y.228.229; 2.Y.228.230; 2.Y.228.231; 2.Y.228.236; 2.Y.228.237; 2.Y.228.238; 2.Y.228.239; 2.Y.228.154; 2.Y.228.157; 2.Y.228.166; 2.Y.228.169; 2.Y.228.172; 2.Y.228.175; 2.Y.228.240; 2.Y.228.244; 2.Y.229.228; 2.Y.229.229; 2.Y.229.230; 2.Y.229.231; 2.Y.229.236; 2.Y.229.237; 2.Y.229.238; 2.Y.229.239; 2.Y.229.154; 2.Y.229.157; 2.Y.229.166; 2.Y.229.169; 2.Y.229.172; 2.Y.229.175; 2.Y.229.240; 2.Y.229.244; 2.Y.230.228; 2.Y.230.229; 2.Y.230.230; 2.Y.230.231; 2.Y.230.236; 2.Y.230.237; 2.Y.230.238; 2.Y.230.239; 2.Y.230.154; 2.Y.230.157; 2.Y.230.166; 2.Y.230.169; 2.Y.230.172; 2.Y.230.175; 2.Y.230.240; 2.Y.230.244; 2.Y.231.228; 2.Y.231.229; 2.Y.231.230; 2.Y.231.231; 2.Y.231.236; 2.Y.231.237; 2.Y.231.238; 2.Y.231.239; 2.Y.231.154; 2.Y.231.157; 2.Y.231.166; 2.Y.231.169; 2.Y.231.172; 2.Y.231.175; 2.Y.231.240; 2.Y.231.244; 2.Y.236.228; 2.Y.236.229; 2.Y.236.230; 2.Y.236.231; 2.Y.236.236; 2.Y.236.237; 2.Y.236.238; 2.Y.236.239; 2.Y.236.154; 2.Y.236.157; 2.Y.236.166; 2.Y.236.169; 2.Y.236.172; 2.Y.236.175; 2.Y.236.240; 2.Y.236.244; 2.Y.237.228; 2.Y.237.229; 2.Y.237.230; 2.Y.237.231; 2.Y.237.236; 2.Y.237.237; 2.Y.237.238; 2.Y.237.239; 2.Y.237.154; 2.Y.237.157; 2.Y.237.166; 2.Y.237.169; 2.Y.237.172; 2.Y.237.175; 2.Y.237.240; 2.Y.237.244; 2.Y.238.228; 2.Y.238.229; 2.Y.238.230; 2.Y.238.231; 2.Y.238.236; 2.Y.238.237; 2.Y.238.238; 2.Y.238.239; 2.Y.238.154; 2.Y.238.157; 2.Y.238.166; 2.Y.238.169; 2.Y.238.172; 2.Y.238.175; 2.Y.238.240; 2.Y.238.244; 2.Y.239.228; 2.Y.239.229; 2.Y.239.230; 2.Y.239.231; 2.Y.239.236; 2.Y.239.237; 2.Y.239.238; 2.Y.239.239; 2.Y.239.154; 2.Y.239.157; 2.Y.239.166; 2.Y.239.169; 2.Y.239.172; 2.Y.239.175; 2.Y.239.240; 2.Y.239.244; 2.Y.154.228; 2.Y.154.229; 2.Y.154.230; 2.Y.154.231; 2.Y.154.236; 2.Y.154.237; 2.Y.154.238; 2.Y.154.239; 2.Y.154.154; 2.Y.154.157; 2.Y.154.166; 2.Y.154.169; 2.Y.154.172; 2.Y.154.175; 2.Y.154.240; 2.Y.154.244; 2.Y.157.228; 2.Y.157.229; 2.Y.157.230; 2.Y.157.231; 2.Y.157.236; 2.Y.157.237; 2.Y.157.238; 2.Y.157.239; 2.Y.157.154; 2.Y.157.157; 2.Y.157.166; 2.Y.157.169; 2.Y.157.172; 2.Y.157.175; 2.Y.157.240; 2.Y.157.244; 2.Y.166.228; 2.Y.166.229; 2.Y.166.230; 2.Y.166.231; 2.Y.166.236; 2.Y.166.237; 2.Y.166.238; 2.Y.166.239; 2.Y.166.154; 2.Y.166.157; 2.Y.166.166; 2.Y.166.169; 2.Y.166.172; 2.Y.166.175; 2.Y.166.240; 2.Y.166.244; 2.Y.169.228; 2.Y.169.229; 2.Y.169.230; 2.Y.169.231; 2.Y.169.236; 2.Y.169.237; 2.Y.169.238; 2.Y.169.239; 2.Y.169.154; 2.Y.169.157; 2.Y.169.166; 2.Y.169.169; 2.Y.169.172; 2.Y.169.175; 2.Y.169.240; 2.Y.169.244; 2.Y.172.228; 2.Y.172.229; 2.Y.172.230; 2.Y.172.231; 2.Y.172.236; 2.Y.172.237; 2.Y.172.238; 2.Y.172.239; 2.Y.172.154; 2.Y.172.157; 2.Y.172.166; 2.Y.172.169; 2.Y.172.172; 2.Y.172.175; 2.Y.172.240; 2.Y.172.244; 2.Y.175.228; 2.Y.175.229; 2.Y.175.230; 2.Y.175.231; 2.Y.175.236; 2.Y.175.237; 2.Y.175.238; 2.Y.175.239; 2.Y.175.154; 2.Y.175.157; 2.Y.175.166; 2.Y.175.169; 2.Y.175.172; 2.Y.175.175; 2.Y.175.240; 2.Y.175.244; 2.Y.240.228; 2.Y.240.229; 2.Y.240.230; 2.Y.240.231; 2.Y.240.236; 2.Y.240.237; 2.Y.240.238; 2.Y.240.239; 2.Y.240.154; 2.Y.240.157; 2.Y.240.166; 2.Y.240.169; 2.Y.240.172; 2.Y.240.175; 2.Y.240.240; 2.Y.240.244; 2.Y.244.228; 2.Y.244.229; 2.Y.244.230; 2.Y.244.231; 2.Y.244.236; 2.Y.244.237; 2.Y.244.238; 2.Y.244.239; 2.Y.244.154; 2.Y.244.157; 2.Y.244.166; 2.Y.244.169; 2.Y.244.172; 2.Y.244.175; 2.Y.244.240; 2.Y.244.244;

3.B Prodrug

     3.B.228.228; 3.B.228.229; 3.B.228.230; 3.B.228.231; 3.B.228.236; 3.B.228.237; 3.B.228.238; 3.B.228.239; 3.B.228.154; 3.B.228.157; 3.B.228.166; 3.B.228.169; 3.B.228.172; 3.B.228.175; 3.B.228.240; 3.B.228.244; 3.B.229.228; 3.B.229.229; 3.B.229.230; 3.B.229.231; 3.B.229.236; 3.B.229.237; 3.B.229.238; 3.B.229.239; 3.B.229.154; 3.B.229.157; 3.B.229.166; 3.B.229.169; 3.B.229.172; 3.B.229.175; 3.B.229.240; 3.B.229.244; 3.B.230.228; 3.B.230.229; 3.B.230.230; 3.B.230.231; 3.B.230.236; 3.B.230.237; 3.B.230.238; 3.B.230.239; 3.B.230.154; 3.B.230.157; 3.B.230.166; 3.B.230.169; 3.B.230.172; 3.B.230.175; 3.B.230.240; 3.B.230.244; 3.B.231.228; 3.B. 231.229; 3.B.231.230; 3.B.231.231; 3.B.231.236; 3.B.231.237; 3.B.231.238; 3.B.231.239; 3.B.231.154; 3.B.231.157; 3.B.231.166; 3.B.231.169; 3.B.231.172; 3.B.231.175; 3.B.231.240; 3.B.231.244; 3.B.236.228; 3.B.236.229; 3.B.236.230; 3.B.236.231; 3.B.236.236; 3.B.236.237; 3.B.236.238; 3.B.236.239; 3.B.236.154; 3.B.236.157; 3.B.236.166; 3.B.236.169; 3.B.236.172; 3.B.236.175; 3.B.236.240; 3.B.236.244; 3.B.237.228; 3.B.237.229; 3.B.237.230; 3.B.237.231; 3.B.237.236; 3.B.237.237; 3.B.237.238; 3.B.237.239; 3.B.237.154; 3.B.237.157; 3.B.237.166; 3.B.237.169; 3.B.237.172; 3.B.237.175; 3.B.237.240; 3.B.237.244; 3.B.238.228; 3.B.238.229; 3.B.238.230; 3.B.238.231; 3.B.238.236; 3.B.238.237; 3.B.238.238; 3.B.238.239; 3.B.238.154; 3.B.238.157; 3.B.238.166; 3.B.238.169; 3.B.238.172; 3.B.238.175; 3.B.238.240; 3.B.238.244; 3.B.239.228; 3.B.239.229; 3.B.239.230; 3.B.239.231; 3.B.239.236; 3.B.239.237; 3.B.239.238; 3.B.239.239; 3.B.239.154; 3.B.239.157; 3.B.239.166; 3.B.239.169; 3.B.239.172; 3.B.239.175; 3.B.239.240; 3.B.239.244; 3.B.154.228; 3.B.154.229; 3.B.154.230; 3.B.154.231; 3.B.154.236; 3.B.154.237; 3.B.154.238; 3.B.154.239; 3.B.154.154; 3.B.154.157; 3.B.154.166; 3.B.154.169; 3.B.154.172; 3.B.154.175; 3.B.154.240; 3.B.154.244; 3.B.157.228; 3.B. 157.229; 3.B.157.230; 3.B.157.231; 3.B.157.236; 3.B.157.237; 3.B.157.238; 3.B.157.239; 3.B.157.154; 3.B.157.157; 3.B.157.166; 3.B.157.169; 3.B.157.172; 3.B.157.175; 3.B.157.240; 3.B.157.244; 3.B.166.228; 3.B.166.229; 3.B.166.230; 3.B.166.231; 3.B.166.236; 3.B.166.237; 3.B.166.238; 3.B.166.239; 3.B.166.154; 3.B.166.157; 3.B.166.166; 3.B.166.169; 3.B.166.172; 3.B.166.175; 3.B.166.240; 3.B.166.244; 3.B. 169.228; 3.B.169.229; 3.B.169.230; 3.B.169.231; 3.B.169.236; 3.B. 169.237; 3.B.169.238; 3.B. 169.239; 3.B.169.154; 3.B. 169.157; 3.B.169.166; 3.B.169.169; 3.B.169.172; 3.B.169.175; 3.B.169.240; 3.B.169.244; 3.B.172.228; 3.B.172.229; 3.B.172.230; 3.B.172.231; 3.B.172.236; 3.B.172.237; 3.B.172.238; 3.B.172.239; 3.B.172.154; 3.B.172.157; 3.B.172.166; 3.B.172.169; 3.B.172.172; 3.B.172.175; 3.B.172.240; 3.B.172.244; 3.B.175.228; 3.B.175.229; 3.B.175.230; 3.B.175.231; 3.B.175.236; 3.B.175.237; 3.B.175.238; 3.B.175.239; 3.B.175.154; 3.B.175.157; 3.B.175.166; 3.B.175.169; 3.B.175.172; 3.B.175.175; 3.B.175.240; 3.B.175.244; 3.B.240.228; 3.B.240.229; 3.B.240.230; 3.B.240.231; 3.B.240.236; 3.B.240.237; 3.B.240.238; 3.B.240.239; 3.B.240.154; 3.B.240.157; 3.B.240.166; 3.B.240.169; 3.B.240.172; 3.B.240.175; 3.B.240.240; 3.B.240.244; 3.B.244.228; 3.B.244.229; 3.B.244.230; 3.B.244.231; 3.B.244.236; 3.B.244.237; 3.B.244.238; 3.B.244.239; 3.B.244.154; 3.B.244.157; 3.B.244.166; 3.B.244.169; 3.B.244.172; 3.B.244.175; 3.B.244.240; 3.B.244.244;

3.D Prodrug

     3.D.228.228; 3.D.228.229; 3.D.228.230; 3.D.228.231; 3.D.228.236; 3.D.228.237; 3.D.228.238; 3.D.228.239; 3.D.228.154; 3.D.228.157; 3.D.228.166; 3.D.228.169; 3.D.228.172; 3.D.228.175; 3.D.228.240; 3.D.228.244; 3.D.229.228; 3.D.229.229; 3.D.229.230; 3.D.229.231; 3.D.229.236; 3.D.229.237; 3.D.229.238; 3.D.229.239; 3.D.229.154; 3.D.229.157; 3.D.229.166; 3.D.229.169; 3.D.229.172; 3.D.229.175; 3.D.229.240; 3.D.229.244; 3.D.230.228; 3.D.230.229; 3.D.230.230; 3.D.230.231; 3.D.230.236; 3.D.230.237; 3.D.230.238; 3.D.230.239; 3.D.230.154; 3.D.230.157; 3.D.230.166; 3.D.230.169; 3.D.230.172; 3.D.230.175; 3.D.230.240; 3.D.230.244; 3.D.231.228; 3.D.231.229; 3.D.231.230; 3.D.231.231; 3.D.231.236; 3.D.231.237; 3.D.231.238; 3.D.231.239; 3.D.231.154; 3.D.231.157; 3.D.231.166; 3.D.231.169; 3.D.231.172; 3.D.231.175; 3.D.231.240; 3.D.231.244; 3.D.236.228; 3.D.236.229; 3.D.236.230; 3.D.236.231; 3.D.236.236; 3.D.236.237; 3.D.236.238; 3.D.236.239; 3.D.236.154; 3.D.236.157; 3.D.236.166; 3.D.236.169; 3.D.236.172; 3.D.236.175; 3.D.236.240; 3.D.236.244; 3.D.237.228; 3.D.237.229; 3.D.237.230; 3.D.237.231; 3.D.237.236; 3.D.237.237; 3.D.237.238; 3.D.237.239; 3.D.237.154; 3.D.237.157; 3.D.237.166; 3.D.237.169; 3.D.237.172; 3.D.237.175; 3.D.237.240; 3.D.237.244; 3.D.238.228; 3.D.238.229; 3.D.238.230; 3.D.238.231; 3.D.238.236; 3.D.238.237; 3.D.238.238; 3.D.238.239; 3.D.238.154; 3.D.238.157; 3.D.238.166; 3.D.238.169; 3.D.238.172; 3.D.238.175; 3.D.238.240; 3.D.238.244; 3.D.239.228; 3.D.239.229; 3.D.239.230; 3.D.239.231; 3.D.239.236; 3.D.239.237; 3.D.239.238; 3.D.239.239; 3.D.239.154; 3.D.239.157; 3.D.239.166; 3.D.239.169; 3.D.239.172; 3.D.239.175; 3.D.239.240; 3.D.239.244; 3.D.154.228; 3.D.154.229; 3.D.154.230; 3.D.154.231; 3.D.154.236; 3.D.154.237; 3.D.154.238; 3.D.154.239; 3.D.154.154; 3.D.154.157; 3.D.154.166; 3.D.154.169; 3.D.154.172; 3.D.154.175; 3.D.154.240; 3.D.154.244; 3.D.157.228; 3.D.157.229; 3.D.157.230; 3.D.157.231; 3.D.157.236; 3.D.157.237; 3.D.157.238; 3.D.157.239; 3.D.157.154; 3.D.157.157; 3.D.157.166; 3.D.157.169; 3.D.157.172; 3.D.157.175; 3.D.157.240; 3.D.157.244; 3.D.166.228; 3.D.166.229; 3.D.166.230; 3.D.166.231; 3.D.166.236; 3.D.166.237; 3.D.166.238; 3.D.166.239; 3.D.166.154; 3.D.166.157; 3.D.166.166; 3.D.166.169; 3.D.166.172; 3.D.166.175; 3.D.166.240; 3.D.166.244; 3.D. 169.228; 3.D. 169.229; 3.D. 169.230; 3.D. 169.231; 3.D. 169.236; 3.D. 169.237; 3.D. 169.238; 3.D. 169.239; 3.D. 169.154; 3.D. 169.157; 3.D. 169.166; 3.D.169.169; 3.D. 169.172; 3.D. 169.175; 3.D.169.240; 3.D.169.244; 3.D.172.228; 3.D. 172.229; 3.D.172.230; 3.D.172.231; 3.D.172.236; 3.D.172.237; 3.D.172.238; 3.D.172.239; 3.D.172.154; 3.D.172.157; 3.D.172.166; 3.D.172.169; 3.D.172.172; 3.D.172.175; 3.D.172.240; 3.D.172.244; 3.D.175.228; 3.D.175.229; 3.D.175.230; 3.D.175.231; 3.D.175.236; 3.D.175.237; 3.D.175.238; 3.D.175.239; 3.D.175.154; 3.D.175.157; 3.D.175.166; 3.D.175.169; 3.D.175.172; 3.D.175.175; 3.D.175.240; 3.D.175.244; 3.D.240.228; 3.D.240.229; 3.D.240.230; 3.D.240.231; 3.D.240.236; 3.D.240.237; 3.D.240.238; 3.D.240.239; 3.D.240.154; 3.D.240.157; 3.D.240.166; 3.D.240.169; 3.D.240.172; 3.D.240.175; 3.D.240.240; 3.D.240.244; 3.D.244.228; 3.D.244.229; 3.D.244.230; 3.D.244.231; 3.D.244.236; 3.D.244.237; 3.D.244.238; 3.D.244.239; 3.D.244.154; 3.D.244.157; 3.D.244.166; 3.D.244.169; 3.D.244.172; 3.D.244.175; 3.D.244.240; 3.D.244.244;

3.E's Prodrug

     3.E.228.228; 3.E.228.229; 3.E.228.230; 3.E.228.231; 3.E.228.236; 3.E.228.237; 3.E.228.238; 3.E.228.239; 3.E.228.154; 3.E.228.157; 3.E.228.166; 3.E.228.169; 3.E.228.172; 3.E.228.175; 3.E.228.240; 3.E.228.244; 3.E.229.228; 3.E.229.229; 3.E.229.230; 3.E.229.231; 3.E.229.236; 3.E.229.237; 3.E.229.238; 3.E.229.239; 3.E.229.154; 3.E.229.157; 3.E.229.166; 3.E.229.169; 3.E.229.172; 3.E.229.175; 3.E.229.240; 3.E.229.244; 3.E.230.228; 3.E.230.229; 3.E.230.230; 3.E.230.231; 3.E.230.236; 3.E.230.237; 3.E.230.238; 3.E.230.239; 3.E.230.154; 3.E.230.157; 3.E.230.166; 3.E.230.169; 3.E.230.172; 3.E.230.175; 3.E.230.240; 3.E.230.244; 3.E.231.228; 3.E.231.229; 3.E.231.230; 3.E.231.231; 3.E.231.236; 3.E.231.237; 3.E.231.238; 3.E.231.239; 3.E.231.154; 3.E.231.157; 3.E.231.166; 3.E.231.169; 3.E.231.172; 3.E.231.175; 3.E.231.240; 3.E.231.244; 3.E.236.228; 3.E.236.229; 3.E.236.230; 3.E.236.231; 3.E.236.236; 3.E.236.237; 3.E.236.238; 3.E.236.239; 3.E.236.154; 3.E.236.157; 3.E.236.166; 3.E.236.169; 3.E.236.172; 3.E.236.175; 3.E.236.240; 3.E.236.244; 3.E.237.228; 3.E.237.229; 3.E.237.230; 3.E.237.231; 3.E.237.236; 3.E.237.237; 3.E.237.238; 3.E.237.239; 3.E.237.154; 3.E.237.157; 3.E.237.166; 3.E.237.169; 3.E.237.172; 3.E.237.175; 3.E.237.240; 3.E.237.244; 3.E.238.228; 3.E.238.229; 3.E.238.230; 3.E.238.231; 3.E.238.236; 3.E.238.237; 3.E.238.238; 3.E.238.239; 3.E.238.154; 3.E.238.157; 3.E.238.166; 3.E.238.169; 3.E.238.172; 3.E.238.175; 3.E.238.240; 3.E.238.244; 3.E.239.228; 3.E.239.229; 3.E.239.230; 3.E.239.231; 3.E.239.236; 3.E.239.237; 3.E.239.238; 3.E.239.239; 3.E.239.154; 3.E.239.157; 3.E.239.166; 3.E.239.169; 3.E.239.172; 3.E.239.175; 3.E.239.240; 3.E.239.244; 3.E.154.228; 3.E.154.229; 3.E.154.230; 3.E.154.231; 3.E.154.236; 3.E.154.237; 3.E.154.238; 3.E.154.239; 3.E.154.154; 3.E.154.157; 3.E.154.166; 3.E.154.169; 3.E.154.172; 3.E.154.175; 3.E.154.240; 3.E.154.244; 3.E.157.228; 3.E.157.229; 3.E.157.230; 3.E.157.231; 3.E.157.236; 3.E.157.237; 3.E.157.238; 3.E.157.239; 3.E.157.154; 3.E.157.157; 3.E.157.166; 3.E.157.169; 3.E.157.172; 3.E.157.175; 3.E.157.240; 3.E.157.244; 3.E.166.228; 3.E.166.229; 3.E.166.230; 3.E.166.231; 3.E.166.236; 3.E.166.237; 3.E.166.238; 3.E.166.239; 3.E.166.154; 3.E.166.157; 3.E.166.166; 3.E.166.169; 3.E.166.172; 3.E.166.175; 3.E.166.240; 3.E.166.244; 3.E. 169.228; 3.E.169.229; 3.E.169.230; 3.E.169.231; 3.E.169.236; 3.E.169.237; 3.E.169.238; 3.E.169.239; 3.E.169.154; 3.E. 169.157; 3.E.169.166; 3.E.169.169; 3.E.169.172; 3.E.169.175; 3.E.169.240; 3.E.169.244; 3.E.172.228; 3.E.172.229; 3.E.172.230; 3.E.172.231; 3.E.172.236; 3.E.172.237; 3.E.172.238; 3.E.172.239; 3.E.172.154; 3.E.172.157; 3.E.172.166; 3.E.172.169; 3.E.172.172; 3.E.172.175; 3.E.172.240; 3.E.172.244; 3.E.175.228; 3.E.175.229; 3.E.175.230; 3.E.175.231; 3.E.175.236; 3.E.175.237; 3.E.175.238; 3.E.175.239; 3.E.175.154; 3.E.175.157; 3.E.175.166; 3.E.175.169; 3.E.175.172; 3.E.175.175; 3.E.175.240; 3.E.175.244; 3.E.240.228; 3.E.240.229; 3.E.240.230; 3.E.240.231; 3.E.240.236; 3.E.240.237; 3.E.240.238; 3.E.240.239; 3.E.240.154; 3.E.240.157; 3.E.240.166; 3.E.240.169; 3.E.240.172; 3.E.240.175; 3.E.240.240; 3.E.240.244; 3.E.244.228; 3.E.244.229; 3.E.244.230; 3.E.244.231; 3.E.244.236; 3.E.244.237; 3.E.244.238; 3.E.244.239; 3.E.244.154; 3.E.244.157; 3.E.244.166; 3.E.244.169; 3.E.244.172; 3.E.244.175; 3.E.244.240; 3.E.244.244;

3.G, Prodrug

     3.G.228.228; 3.G.228.229; 3.G.228.230; 3.G.228.231; 3.G.228.236; 3.G.228.237; 3.G.228.238; 3.G.228.239; 3.G.228.154; 3.G.228.157; 3.G.228.166; 3.G.228.169; 3.G.228.172; 3.G.228.175; 3.G.228.240; 3.G.228.244; 3.G.229.228; 3.G.229.229; 3.G.229.230; 3.G.229.231; 3.G.229.236; 3.G.229.237; 3.G.229.238; 3.G.229.239; 3.G.229.154; 3.G.229.157; 3.G.229.166; 3.G.229.169; 3.G.229.172; 3.G.229.175; 3.G.229.240; 3.G.229.244; 3.G.230.228; 3.G.230.229; 3.G.230.230; 3.G.230.231; 3.G.230.236; 3.G.230.237; 3.G.230.238; 3.G.230.239; 3.G.230.154; 3.G.230.157; 3.G.230.166; 3.G.230.169; 3.G.230.172; 3.G.230.175; 3.G.230.240; 3.G.230.244; 3.G.231.228; 3.G.231.229; 3.G.231.230; 3.G.231.231; 3.G.231.236; 3.G.231.237; 3.G.231.238; 3.G.231.239; 3.G.231.154; 3.G.231.157; 3.G.231.166; 3.G.231.169; 3.G.231.172; 3.G.231.175; 3.G.231.240; 3.G.231.244; 3.G.236.228; 3.G.236.229; 3.G.236.230; 3.G.236.231; 3.G.236.236; 3.G.236.237; 3.G.236.238; 3.G.236.239; 3.G.236.154; 3.G.236.157; 3.G.236.166; 3.G.236.169; 3.G.236.172; 3.G.236.175; 3.G.236.240; 3.G.236.244; 3.G.237.228; 3.G.237.229; 3.G.237.230; 3.G.237.231; 3.G.237.236; 3.G.237.237; 3.G.237.238; 3.G.237.239; 3.G.237.154; 3.G.237.157; 3.G.237.166; 3.G.237.169; 3.G.237.172; 3.G.237.175; 3.G.237.240; 3.G.237.244; 3.G.238.228; 3.G.238.229; 3.G.238.230; 3.G.238.231; 3.G.238.236; 3.G.238.237; 3.G.238.238; 3.G.238.239; 3.G.238.154; 3.G.238.157; 3.G.238.166; 3.G.238.169; 3.G.238.172; 3.G.238.175; 3.G.238.240; 3.G.238.244; 3.G.239.228; 3.G.239.229; 3.G.239.230; 3.G.239.231; 3.G.239.236; 3.G.239.237; 3.G.239.238; 3.G.239.239; 3.G.239.154; 3.G.239.157; 3.G.239.166; 3.G.239.169; 3.G.239.172; 3.G.239.175; 3.G.239.240; 3.G.239.244; 3.G.154.228; 3.G.154.229; 3.G.154.230; 3.G.154.231; 3.G.154.236; 3.G.154.237; 3.G.154.238; 3.G.154.239; 3.G.154.154; 3.G.154.157; 3.G.154.166; 3.G.154.169; 3.G.154.172; 3.G.154.175; 3.G.154.240; 3.G.154.244; 3.G.157.228; 3.G. 157.229; 3.G.157.230; 3.G.157.231; 3.G.157.236; 3.G.157.237; 3.G.157.238; 3.G.157.239; 3.G.157.154; 3.G.157.157; 3.G.157.166; 3.G.157.169; 3.G.157.172; 3.G.157.175; 3.G.157.240; 3.G.157.244; 3.G.166.228; 3.G.166.229; 3.G.166.230; 3.G.166.231; 3.G.166.236; 3.G.166.237; 3.G.166.238; 3.G.166.239; 3.G.166.154; 3.G.166.157; 3.G.166.166; 3.G.166.169; 3.G.166.172; 3.G.166.175; 3.G.166.240; 3.G.166.244; 3.G.169.228; 3.G.169.229; 3.G.169.230; 3.G.169.231; 3.G.169.236; 3.G.169.237; 3.G.169.238; 3.G.169.239; 3.G.169.154; 3.G.169.157; 3.G.169.166; 3.G.169.169; 3.G.169.172; 3.G.169.175; 3.G.169.240; 3.G.169.244; 3.G.172.228; 3.G.172.229; 3.G.172.230; 3.G.172.231; 3.G.172.236; 3.G.172.237; 3.G.172.238; 3.G.172.239; 3.G.172.154; 3.G.172.157; 3.G.172.166; 3.G.172.169; 3.G.172.172; 3.G.172.175; 3.G.172.240; 3.G.172.244; 3.G.175.228; 3.G. 175.229; 3.G.175.230; 3.G.175.231; 3.G.175.236; 3.G.175.237; 3.G.175.238; 3.G.175.239; 3.G.175.154; 3.G.175.157; 3.G.175.166; 3.G.175.169; 3.G.175.172; 3.G.175.175; 3.G.175.240; 3.G.175.244; 3.G.240.228; 3.G.240.229; 3.G.240.230; 3.G.240.231; 3.G.240.236; 3.G.240.237; 3.G.240.238; 3.G.240.239; 3.G.240.154; 3.G.240.157; 3.G.240.166; 3.G.240.169; 3.G.240.172; 3.G.240.175; 3.G.240.240; 3.G.240.244; 3.G.244.228; 3.G.244.229; 3.G.244.230; 3.G.244.231; 3.G.244.236; 3.G.244.237; 3.G.244.238; 3.G.244.239; 3.G.244.154; 3.G.244.157; 3.G.244.166; 3.G.244.169; 3.G.244.172; 3.G.244.175; 3.G.244.240; 3.G.244.244;

3.I's Prodrug

     3.I.228.228; 3.I.228.229; 3.I.228.230; 3.I.228.231; 3.I.228.236; 3.I.228.237; 3.I.228.238; 3.I.228.239; 3.I.228.154; 3.I.228.157; 3.I.228.166; 3.I.228.169; 3.I.228.172; 3.I.228.175; 3.I.228.240; 3.I.228.244; 3.I.229.228; 3.I.229.229; 3.I.229.230; 3.I.229.231; 3.I.229.236; 3.I.229.237; 3.I.229.238; 3.I.229.239; 3.I.229.154; 3.I.229.157; 3.I.229.166; 3.I.229.169; 3.I.229.172; 3.I.229.175; 3.I.229.240; 3.I.229.244; 3.I.230.228; 3.I.230.229; 3.I.230.230; 3.I.230.231; 3.I.230.236; 3.I.230.237; 3.I.230.238; 3.I.230.239; 3.I.230.154; 3.I.230.157; 3.I.230.166; 3.I.230.169; 3.I.230.172; 3.I.230.175; 3.I.230.240; 3.I.230.244; 3.I.231.228; 3.I.231.229; 3.I.231.230; 3.I.231.231; 3.I.231.236; 3.I.231.237; 3.I.231.238; 3.I.231.239; 3.I.231.154; 3.I.231.157; 3.I.231.166; 3.I.231.169; 3.I.231.172; 3.I.231.175; 3.I.231.240; 3.I.231.244; 3.I.236.228; 3.I.236.229; 3.I.236.230; 3.I.236.231; 3.I.236.236; 3.I.236.237; 3.I.236.238; 3.I.236.239; 3.I.236.154; 3.I.236.157; 3.I.236.166; 3.I.236.169; 3.I.236.172; 3.I.236.175; 3.I.236.240; 3.I.236.244; 3.I.237.228; 3.I.237.229; 3.I.237.230; 3.I.237.231; 3.I.237.236; 3.I.237.237; 3.I.237.238; 3.I.237.239; 3.I.237.154; 3.I.237.157; 3.I.237.166; 3.I.237.169; 3.I.237.172; 3.I.237.175; 3.I.237.240; 3.I.237.244; 3.I.238.228; 3.I.238.229; 3.I.238.230; 3.I.238.231; 3.I.238.236; 3.I.238.237; 3.I.238.238; 3.I.238.239; 3.I.238.154; 3.I.238.157; 3.I.238.166; 3.I.238.169; 3.I.238.172; 3.I.238.175; 3.I.238.240; 3.I.238.244; 3.I.239.228; 3.I.239.229; 3.I.239.230; 3.I.239.231; 3.I.239.236; 3.I.239.237; 3.I.239.238; 3.I.239.239; 3.I.239.154; 3.I.239.157; 3.I.239.166; 3.I.239.169; 3.I.239.172; 3.I.239.175; 3.I.239.240; 3.I.239.244; 3.I.154.228; 3.I.154.229; 3.I.154.230; 3.I.154.231; 3.I.154.236; 3.I.154.237; 3.I.154.238; 3.I.154.239; 3.I.154.154; 3.I.154.157; 3.I.154.166; 3.I.154.169; 3.I.154.172; 3.I.154.175; 3.I.154.240; 3.I.154.244; 3.I.157.228; 3.I.157.229; 3.I.157.230; 3.I.157.231; 3.I.157.236; 3.I.157.237; 3.I.157.238; 3.I.157.239; 3.I.157.154; 3.I.157.157; 3.I.157.166; 3.I.157.169; 3.I.157.172; 3.I.157.175; 3.I.157.240; 3.I.157.244; 3.I.166.228; 3.I.166.229; 3.I.166.230; 3.I.166.231; 3.I.166.236; 3.I.166.237; 3.I.166.238; 3.I.166.239; 3.I.166.154; 3.I.166.157; 3.I.166.166; 3.I.166.169; 3.I.166.172; 3.I.166.175; 3.I.166.240; 3.I.166.244; 3.I.169.228; 3.I.169.229; 3.I.169.230; 3.I.169.231; 3.I.169.236; 3.I.169.237; 3.I.169.238; 3.I.169.239; 3.I.169.154; 3.I.169.157; 3.I.169.166; 3.I.169.169; 3.I.169.172; 3.I.169.175; 3.I.169.240; 3.I.169.244; 3.I.172.228; 3.I.172.229; 3.I.172.230; 3.I.172.231; 3.I.172.236; 3.I.172.237; 3.I.172.238; 3.I.172.239; 3.I.172.154; 3.I.172.157; 3.I.172.166; 3.I.172.169; 3.I.172.172; 3.I.172.175; 3.I.172.240; 3.I.172.244; 3.I.175.228; 3.I.175.229; 3.I.175.230; 3.I.175.231; 3.I.175.236; 3.I.175.237; 3.I.175.238; 3.I.175.239; 3.I.175.154; 3.I.175.157; 3.I.175.166; 3.I.175.169; 3.I.175.172; 3.I.175.175; 3.I.175.240; 3.I.175.244; 3.I.240.228; 3.I.240.229; 3.I.240.230; 3.I.240.231; 3.I.240.236; 3.I.240.237; 3.I.240.238; 3.I.240.239; 3.I.240.154; 3.I.240.157; 3.I.240.166; 3.I.240.169; 3.I.240.172; 3.I.240.175; 3.I.240.240; 3.I.240.244; 3.I.244.228; 3.I.244.229; 3.I.244.230; 3.I.244.231; 3.I.244.236; 3.I.244.237; 3.I.244.238; 3.I.244.239; 3.I.244.154; 3.I.244.157; 3.I.244.166; 3.I.244.169; 3.I.244.172; 3.I.244.175; 3.I.244.240; 3.I.244.244;

3.J's Prodrug

     3.J. 228.228; 3.J.228.229; 3.J.228.230; 3.J.228.231; 3.J.228.236; 3.J.228.237; 3.J.228.238; 3.J.228.239; 3.J.228.154; 3.J.228.157; 3.J.228.166; 3.J.228.169; 3.J.228.172; 3.J.228.175; 3.J.228.240; 3.J.228.244; 3.J.229.228; 3.J.229.229; 3.J.229.230; 3.J.229.231; 3.J.229.236; 3.J.229.237; 3.J.229.238; 3.J.229.239; 3.J.229.154; 3.J.229.157; 3.J.229.166; 3.J.229.169; 3.J.229.172; 3.J.229.175; 3.J.229.240; 3.J.229.244; 3.J.230.228; 3.J.230.229; 3.J.230.230; 3.J.230.231; 3.J.230.236; 3.J.230.237; 3.J.230.238; 3.J.230.239; 3.J.230.154; 3.J.230.157; 3.J.230.166; 3.J.230.169; 3.J.230.172; 3.J.230.175; 3.J.230.240; 3.J.230.244; 3.J.231.228; 3.J. 231.229; 3.J.231.230; 3.J.231.231; 3.J.231.236; 3.J.231.237; 3.J.231.238; 3.J.231.239; 3.J.231.154; 3.J.231.157; 3.J.231.166; 3.J.231.169; 3.J.231.172; 3.J.231.175; 3.J.231.240; 3.J.231.244; 3.J.236.228; 3.J. 236.229; 3.J.236.230; 3.J.236.231; 3.J.236.236; 3.J.236.237; 3.J.236.238; 3.J.236.239; 3.J.236.154; 3.J.236.157; 3.J.236.166; 3.J.236.169; 3.J.236.172; 3.J.236.175; 3.J.236.240; 3.J.236.244; 3.J. 237.228; 3.J. 237.229; 3.J. 237.230; 3.J.237.231; 3.J.237.236; 3.J. 237.237; 3.J. 237.238; 3.J. 237.239; 3.J. 237.154; 3.J. 237.157; 3.J. 237.166; 3.J. 237.169; 3.J.237.172; 3.J.237.175; 3.J.237.240; 3.J.237.244; 3.J.238.228; 3.J.238.229; 3.J.238.230; 3.J.238.231; 3.J.238.236; 3.J.238.237; 3.J.238.238; 3.J.238.239; 3.J.238.154; 3.J.238.157; 3.J.238.166; 3.J.238.169; 3.J.238.172; 3.J.238.175; 3.J.238.240; 3.J.238.244; 3.J.239.228; 3.J.239.229; 3.J.239.230; 3.J.239.231; 3.J.239.236; 3.J.239.237; 3.J.239.238; 3.J.239.239; 3.J.239.154; 3.J.239.157; 3.J.239.166; 3.J.239.169; 3.J.239.172; 3.J.239.175; 3.J.239.240; 3.J.239.244; 3.J.154.228; 3.J.154.229; 3.J.154.230; 3.J.154.231; 3.J.154.236; 3.J.154.237; 3.J.154.238; 3.J.154.239; 3.J.154.154; 3.J.154.157; 3.J.154.166; 3.J.154.169; 3.J.154.172; 3.J.154.175; 3.J.154.240; 3.J.154.244; 3.J.157.228; 3.J. 157.229; 3.J.157.230; 3.J.157.231; 3.J.157.236; 3.J.157.237; 3.J.157.238; 3.J.157.239; 3.J.157.154; 3.J.157.157; 3.J.157.166; 3.J.157.169; 3.J.157.172; 3.J.157.175; 3.J.157.240; 3.J.157.244; 3.J.166.228; 3.J. 166.229; 3.J.166.230; 3.J.166.231; 3.J.166.236; 3.J.166.237; 3.J.166.238; 3.J.166.239; 3.J.166.154; 3.J.166.157; 3.J.166.166; 3.J.166.169; 3.J.166.172; 3.J.166.175; 3.J.166.240; 3.J.166.244; 3.J. 169.228; 3.J. 169.229; 3.J. 169.230; 3.J. 169.231; 3.J. 169.236; 3.J. 169.237; 3.J. 169.238; 3.J. 169.239; 3.J. 169.154; 3.J. 169.157; 3.J.169.166; 3.J. 169.169; 3.J. 169.172; 3.J. 169.175; 3.J.169.240; 3.J.169.244; 3.J.172.228; 3.J.172.229; 3.J.172.230; 3.J.172.231; 3.J.172.236; 3.J.172.237; 3.J.172.238; 3.J.172.239; 3.J.172.154; 3.J.172.157; 3.J.172.166; 3.J.172.169; 3.J.172.172; 3.J.172.175; 3.J.172.240; 3.J.172.244; 3.J.175.228; 3.J.175.229; 3.J.175.230; 3.J.175.231; 3.J.175.236; 3.J.175.237; 3.J.175.238; 3.J.175.239; 3.J.175.154; 3.J.175.157; 3.J.175.166; 3.J.175.169; 3.J.175.172; 3.J.175.175; 3.J.175.240; 3.J.175.244; 3.J.240.228; 3.J.240.229; 3.J.240.230; 3.J.240.231; 3.J.240.236; 3.J.240.237; 3.J.240.238; 3.J.240.239; 3.J.240.154; 3.J.240.157; 3.J.240.166; 3.J.240.169; 3.J.240.172; 3.J.240.175; 3.J.240.240; 3.J.240.244; 3.J.244.228; 3.J.244.229; 3.J.244.230; 3.J.244.231; 3.J.244.236; 3.J.244.237; 3.J.244.238; 3.J.244.239; 3.J.244.154; 3.J.244.157; 3.J.244.166; 3.J.244.169; 3.J.244.172; 3.J.244.175; 3.J.244.240; 3.J.244.244;

3.L Prodrug

     3.L. 228.228; 3.L. 228.229; 3.L. 228.230; 3.L. 228.231; 3.L. 228.236; 3.L. 228.237; 3.L. 228.238; 3.L. 228.239; 3.L. 228.154; 3.L. 228.157; 3.L. 228.166; 3.L. 228.169; 3.L. 228.172; 3.L. 228.175; 3.L. 228.240; 3.L. 228.244; 3.L.229.228; 3.L.229.229; 3.L.229.230; 3.L.229.231; 3.L.229.236; 3.L.229.237; 3.L.229.238; 3.L.229.239; 3.L.229.154; 3.L.229.157; 3.L.229.166; 3.L.229.169; 3.L.229.172; 3.L.229.175; 3.L.229.240; 3.L.229.244; 3.L.230.228; 3.L. 230.229; 3.L.230.230; 3.L.230.231; 3.L.230.236; 3.L.230.237; 3.L.230.238; 3.L.230.239; 3.L.230.154; 3.L.230.157; 3.L.230.166; 3.L.230.169; 3.L.230.172; 3.L.230.175; 3.L.230.240; 3.L.230.244; 3.L.231.228; 3.L. 231.229; 3.L.231.230; 3.L.231.231; 3.L.231.236; 3.L.231.237; 3.L.231.238; 3.L.231.239; 3.L.231.154; 3.L.231.157; 3.L.231.166; 3.L.231.169; 3.L.231.172; 3.L.231.175; 3.L.231.240; 3.L.231.244; 3.L. 236.228; 3.L. 236.229; 3.L.236.230; 3.L.236.231; 3.L.236.236; 3.L.236.237; 3.L.236.238; 3.L.236.239; 3.L.236.154; 3.L. 236.157; 3.L.236.166; 3.L.236.169; 3.L.236.172; 3.L.236.175; 3.L.236.240; 3.L.236.244; 3.L. 237.228; 3.L. 237.229; 3.L. 237.230; 3.L.237.231; 3.L. 237.236; 3.L. 237.237; 3.L.237.238; 3.L. 237.239; 3.L. 237.154; 3.L. 237.157; 3.L. 237.166; 3.L. 237.169; 3.L. 237.172; 3.L.237.175; 3.L.237.240; 3.L.237.244; 3.L.238.228; 3.L.238.229; 3.L.238.230; 3.L.238.231; 3.L.238.236; 3.L.238.237; 3.L.238.238; 3.L.238.239; 3.L.238.154; 3.L.238.157; 3.L.238.166; 3.L.238.169; 3.L.238.172; 3.L.238.175; 3.L.238.240; 3.L.238.244; 3.L.239.228; 3.L.239.229; 3.L.239.230; 3.L.239.231; 3.L.239.236; 3.L.239.237; 3.L.239.238; 3.L.239.239; 3.L.239.154; 3.L.239.157; 3.L.239.166; 3.L.239.169; 3.L.239.172; 3.L.239.175; 3.L.239.240; 3.L.239.244; 3.L. 154.228; 3.L.154.229; 3.L.154.230; 3.L.154.231; 3.L.154.236; 3.L.154.237; 3.L.154.238; 3.L.154.239; 3.L.154.154; 3.L.154.157; 3.L.154.166; 3.L.154.169; 3.L.154.172; 3.L.154.175; 3.L.154.240; 3.L.154.244; 3.L.157.228; 3.L. 157.229; 3.L.157.230; 3.L.157.231; 3.L.157.236; 3.L.157.237; 3.L.157.238; 3.L.157.239; 3.L.157.154; 3.L.157.157; 3.L.157.166; 3.L.157.169; 3.L.157.172; 3.L.157.175; 3.L.157.240; 3.L.157.244; 3.L. 166.228; 3.L. 166.229; 3.L. 166.230; 3.L. 166.231; 3.L. 166.236; 3.L. 166.237; 3.L. 166.238; 3.L. 166.239; 3.L. 166.154; 3.L. 166.157; 3.L. 166.166; 3.L. 166.169; 3.L. 166.172; 3.L. 166.175; 3.L.166.240; 3.L.166.244; 3.L. 169.228; 3.L. 169.229; 3.L. 169.230; 3.L. 169.231; 3.L. 169.236; 3.L. 169.237; 3.L. 169.238; 3.L. 169.239; 3.L. 169.154; 3.L. 169.157; 3.L. 169.166; 3.L. 169.169; 3.L. 169.172; 3.L. 169.175; 3.L.169.240; 3.L. 169.244; 3.L. 172.228; 3.L. 172.229; 3.L.172.230; 3.L. 172.231; 3.L.172.236; 3.L. 172.237; 3.L.172.238; 3.L. 172.239; 3.L.172.154; 3.L. 172.157; 3.L. 172.166; 3.L.172.169; 3.L.172.172; 3.L.172.175; 3.L.172.240; 3.L. 172.244; 3.L. 175.228; 3.L. 175.229; 3.L. 175.230; 3.L.175.231; 3.L. 175.236; 3.L. 175.237; 3.L. 175.238; 3.L. 175.239; 3.L. 175.154; 3.L. 175.157; 3.L. 175.166; 3.L. 175.169; 3.L. 175.172; 3.L. 175.175; 3.L.175.240; 3.L. 175.244; 3.L.240.228; 3.L.240.229; 3.L.240.230; 3.L.240.231; 3.L.240.236; 3.L.240.237; 3.L.240.238; 3.L.240.239; 3.L.240.154; 3.L.240.157; 3.L.240.166; 3.L.240.169; 3.L.240.172; 3.L.240.175; 3.L.240.240; 3.L.240.244; 3.L.244.228; 3.L.244.229; 3.L.244.230; 3.L.244.231; 3.L.244.236; 3.L.244.237; 3.L.244.238; 3.L.244.239; 3.L.244.154; 3.L.244.157; 3.L.244.166; 3.L.244.169; 3.L.244.172; 3.L.244.175; 3.L.244.240; 3.L.244.244;

3.O's Prodrug

     3.O.228.228; 3.O.228.229; 3.O.228.230; 3.O.228.231; 3.O.228.236; 3.O.228.237; 3.O.228.238; 3.O.228.239; 3.O.228.154; 3.O.228.157; 3.O.228.166; 3.O.228.169; 3.O.228.172; 3.O.228.175; 3.O.228.240; 3.O.228.244; 3.O.229.228; 3.O.229.229; 3.O.229.230; 3.O.229.231; 3.O.229.236; 3.O.229.237; 3.O.229.238; 3.O.229.239; 3.O.229.154; 3.O.229.157; 3.O.229.166; 3.O.229.169; 3.O.229.172; 3.O.229.175; 3.O.229.240; 3.O.229.244; 3.O.230.228; 3.O.230.229; 3.O.230.230; 3.O.230.231; 3.O.230.236; 3.230.237; 3.O.230.238; 3.O.230.239; 3.230.154; 3.230.157; 3.230.166; 3.230.169; 3.O.230.172; 3.230.175; 3.230.240; 3.O.230.244; 3.O.231.228; 3.O.231.229; 3.231.230; 3.O.231.231; 3.O.231.236; 3.O.231.237; 3.O.231.238; 3.O.231.239; 3.231.154; 3.O.231.157; 3.O.231.166; 3.O.231.169; 3.O.231.172; 3.O.231.175; 3.O.231.240; 3.O.231.244; 3.O.236.228; 3.O.236.229; 3.O.236.230; 3.O.236.231; 3.O.236.236; 3.O.236.237; 3.O.236.238; 3.O.236.239; 3.O.236.154; 3.O.236.157; 3.O.236.166; 3.O.236.169; 3.O.236.172; 3.O.236.175; 3.O.236.240; 3.O.236.244; 3.O.237.228; 3.O.237.229; 3.O.237.230; 3.O.237.231; 3.O.237.236; 3.O.237.237; 3.O.237.238; 3.O.237.239; 3.O.237.154; 3.O.237.157; 3.O.237.166; 3.O.237.169; 3.O.237.172; 3.O.237.175; 3.O.237.240; 3.O.237.244; 3.O.238.228; 3.O.238.229; 3.O.238.230; 3.O.238.231; 3.O.238.236; 3.O.238.237; 3.O.238.238; 3.O.238.239; 3.O.238.154; 3.O.238.157; 3.O.238.166; 3.O.238.169; 3.O.238.172; 3.O.238.175; 3.O.238.240; 3.O.238.244; 3.O.239.228; 3.O.239.229; 3.O.239.230; 3.O.239.231; 3.O.239.236; 3.O.239.237; 3.O.239.238; 3.O.239.239; 3.O.239.154; 3.O.239.157; 3.O.239.166; 3.O.239.169; 3.O.239.172; 3.O.239.175; 3.O.239.240; 3.O.239.244; 3.O.154.228; 3.O.154.229; 3.154.230; 3.O.154.231; 3.O.154.236; 3.O.154.237; 3.154.238; 3.O.154.239; 3.O.154.154; 3.O.154.157; 3.O.154.166; 3.154.169; 3.O.154.172; 3.O.154.175; 3.154.240; 3.O.154.244; 3.O.157.228; 3.O.157.229; 3.O.157.230; 3.O.157.231; 3.O.157.236; 3.O.157.237; 3.O.157.238; 3.O.157.239; 3.O.157.154; 3.O.157.157; 3.O.157.166; 3.O.157.169; 3.O.157.172; 3.O.157.175; 3.O.157.240; 3.O.157.244; 3.O.166.228; 3.O.166.229; 3.O.166.230; 3.O.166.231; 3.O.166.236; 3.O.166.237; 3.O.166.238; 3.O.166.239; 3.O.166.154; 3.O.166.157; 3.O.166.166; 3.O.166.169; 3.O.166.172; 3.O.166.175; 3.O.166.240; 3.O.166.244; 3.O.169.228; 3.O.169.229; 3.O.169.230; 3.O.169.231; 3.O.169.236; 3.O.169.237; 3.O.169.238; 3.O.169.239; 3.O.169.154; 3.O.169.157; 3.O.169.166; 3.O.169.169; 3.O.169.172; 3.O.169.175; 3.O.169.240; 3.O.169.244; 3.O.172.228; 3.O.172.229; 3.O.172.230; 3.O.172.231; 3.O.172.236; 3.O.172.237; 3.O.172.238; 3.O.172.239; 3.172.154; 3.O.172.157; 3.O.172.166; 3.O.172.169; 3.O.172.172; 3.O.172.175; 3.O.172.240; 3.O.172.244; 3.O.175.228; 3.O.175.229; 3.O.175.230; 3.O.175.231; 3.O.175.236; 3.O.175.237; 3.O.175.238; 3.O.175.239; 3.O.175.154; 3.O.175.157; 3.O.175.166; 3.O.175.169; 3.O.175.172; 3.O.175.175; 3.O.175.240; 3.O.175.244; 3.O.240.228; 3.O.240.229; 3.O.240.230; 3.O.240.231; 3.O.240.236; 3.O.240.237; 3.O.240.238; 3.O.240.239; 3.O.240.154; 3.O.240.157; 3.O.240.166; 3.O.240.169; 3.O.240.172; 3.O.240.175; 3.O.240.240; 3.O.240.244; 3.O.244.228; 3.O.244.229; 3.O.244.230; 3.O.244.231; 3.O.244.236; 3.O.244.237; 3.O.244.238; 3.O.244.239; 3.O.244.154; 3.O.244.157; 3.O.244.166; 3.O.244.169; 3.O.244.172; 3.O.244.175; 3.O.244.240; 3.O.244.244;

3.P Prodrug

     3.P.228.228; 3.P.228.229; 3.P.228.230; 3.P.228.231; 3.P.228.236; 3.P.228.237; 3.P.228.238; 3.P.228.239; 3.P.228.154; 3.P. 228.157; 3.P.228.166; 3.P.228.169; 3.P.228.172; 3.P.228.175; 3.P.228.240; 3.P.228.244; 3.P.229.228; 3.P.229.229; 3.P.229.230; 3.P.229.231; 3.P.229.236; 3.P.229.237; 3.P.229.238; 3.P.229.239; 3.P.229.154; 3.P.229.157; 3.P.229.166; 3.P.229.169; 3.P.229.172; 3.P.229.175; 3.P.229.240; 3.P.229.244; 3.P.230.228; 3.P.230.229; 3.P.230.230; 3.P.230.231; 3.P.230.236; 3.P.230.237; 3.P.230.238; 3.P.230.239; 3.P.230.154; 3.P.230.157; 3.P.230.166; 3.P.230.169; 3.P.230.172; 3.P.230.175; 3.P.230.240; 3.P.230.244; 3.P.231.228; 3.P.231.229; 3.P.231.230; 3.P.231.231; 3.P.231.236; 3.P.231.237; 3.P.231.238; 3.P.231.239; 3.P.231.154; 3.P.231.157; 3.P.231.166; 3.P.231.169; 3.P.231.172; 3.P.231.175; 3.P.231.240; 3.P.231.244; 3.P.236.228; 3.P.236.229; 3.P.236.230; 3.P.236.231; 3.P.236.236; 3.P.236.237; 3.P.236.238; 3.P.236.239; 3.P.236.154; 3.P.236.157; 3.P.236.166; 3.P.236.169; 3.P.236.172; 3.P.236.175; 3.P.236.240; 3.P.236.244; 3.P.237.228; 3.P.237.229; 3.P.237.230; 3.P.237.231; 3.P.237.236; 3.P.237.237; 3.P.237.238; 3.P.237.239; 3.P.237.154; 3.P.237.157; 3.P.237.166; 3.P.237.169; 3.P.237.172; 3.P.237.175; 3.P.237.240; 3.P.237.244; 3.P.238.228; 3.P.238.229; 3.P.238.230; 3.P.238.231; 3.P.238.236; 3.P.238.237; 3.P.238.238; 3.P.238.239; 3.P.238.154; 3.P.238.157; 3.P.238.166; 3.P.238.169; 3.P.238.172; 3.P.238.175; 3.P.238.240; 3.P.238.244; 3.P.239.228; 3.P.239.229; 3.P.239.230; 3.P.239.231; 3.P.239.236; 3.P.239.237; 3.P.239.238; 3.P.239.239; 3.P.239.154; 3.P.239.157; 3.P.239.166; 3.P.239.169; 3.P.239.172; 3.P.239.175; 3.P.239.240; 3.P.239.244; 3.P.154.228; 3.P.154.229; 3.P.154.230; 3.P.154.231; 3.P.154.236; 3.P.154.237; 3.P.154.238; 3.P.154.239; 3.P.154.154; 3.P.154.157; 3.P.154.166; 3.P.154.169; 3.P.154.172; 3.P.154.175; 3.P.154.240; 3.P.154.244; 3.P.157.228; 3.P. 157.229; 3.P.157.230; 3.P.157.231; 3.P.157.236; 3.P.157.237; 3.P.157.238; 3.P.157.239; 3.P.157.154; 3.P.157.157; 3.P.157.166; 3.P.157.169; 3.P.157.172; 3.P.157.175; 3.P.157.240; 3.P.157.244; 3.P.166.228; 3.P. 166.229; 3.P.166.230; 3.P.166.231; 3.P.166.236; 3.P.166.237; 3.P.166.238; 3.P.166.239; 3.P.166.154; 3.P.166.157; 3.P.166.166; 3.P.166.169; 3.P.166.172; 3.P.166.175; 3.P.166.240; 3.P.166.244; 3.P.169.228; 3.P. 169.229; 3.P.169.230; 3.P.169.231; 3.P.169.236; 3.P.169.237; 3.P.169.238; 3.P.169.239; 3.P.169.154; 3.P. 169.157; 3.P.169.166; 3.P.169.169; 3.P.169.172; 3.P.169.175; 3.P.169.240; 3.P.169.244; 3.P.172.228; 3.P. 172.229; 3.P.172.230; 3.P.172.231; 3.P.172.236; 3.P.172.237; 3.P.172.238; 3.P.172.239; 3.P.172.154; 3.P.172.157; 3.P.172.166; 3.P.172.169; 3.P.172.172; 3.P.172.175; 3.P.172.240; 3.P.172.244; 3.P.175.228; 3.P. 175.229; 3.P.175.230; 3.P.175.231; 3.P.175.236; 3.P.175.237; 3.P.175.238; 3.P.175.239; 3.P.175.154; 3.P.175.157; 3.P.175.166; 3.P.175.169; 3.P.175.172; 3.P.175.175; 3.P.175.240; 3.P.175.244; 3.P.240.228; 3.P.240.229; 3.P.240.230; 3.P.240.231; 3.P.240.236; 3.P.240.237; 3.P.240.238; 3.P.240.239; 3.P.240.154; 3.P.240.157; 3.P.240.166; 3.P.240.169; 3.P.240.172; 3.P.240.175; 3.P.240.240; 3.P.240.244; 3.P.244.228; 3.P.244.229; 3.P.244.230; 3.P.244.231; 3.P.244.236; 3.P.244.237; 3.P.244.238; 3.P.244.239; 3.P.244.154; 3.P.244.157; 3.P.244.166; 3.P.244.169; 3.P.244.172; 3.P.244.175; 3.P.244.240; 3.P.244.244;

3.U's Prodrug

     3.U.228.228; 3.U.228.229; 3.U.228.230; 3.U.228.231; 3.U.228.236; 3.U.228.237; 3.U.228.238; 3.U.228.239; 3.U.228.154; 3.U.228.157; 3.U.228.166; 3.U.228.169; 3.U.228.172; 3.U.228.175; 3.U.228.240; 3.U.228.244; 3.U.229.228; 3.U.229.229; 3.U.229.230; 3.U.229.231; 3.U.229.236; 3.U.229.237; 3.U.229.238; 3.U.229.239; 3.U.229.154; 3.U.229.157; 3.U.229.166; 3.U.229.169; 3.U.229.172; 3.U.229.175; 3.U.229.240; 3.U.229.244; 3.U.230.228; 3.U.230.229; 3.U.230.230; 3.U.230.231; 3.U.230.236; 3.U.230.237; 3.U.230.238; 3.U.230.239; 3.U.230.154; 3.U.230.157; 3.U.230.166; 3.U.230.169; 3.U.230.172; 3.U.230.175; 3.U.230.240; 3.U.230.244; 3.U.231.228; 3.U.231.229; 3.U.231.230; 3.U.231.231; 3.U.231.236; 3.U.231.237; 3.U.231.238; 3.U.231.239; 3.U.231.154; 3.U.231.157; 3.U.231.166; 3.U.231.169; 3.U.231.172; 3.U.231.175; 3.U.231.240; 3.U.231.244; 3.U.236.228; 3.U.236.229; 3.U.236.230; 3.U.236.231; 3.U.236.236; 3.U.236.237; 3.U.236.238; 3.U.236.239; 3.U.236.154; 3.U.236.157; 3.U.236.166; 3.U.236.169; 3.U.236.172; 3.U.236.175; 3.U.236.240; 3.U.236.244; 3.U.237.228; 3.U.237.229; 3.U.237.230; 3.U.237.231; 3.U.237.236; 3.U.237.237; 3.U.237.238; 3.U.237.239; 3.U.237.154; 3.U.237.157; 3.U.237.166; 3.U.237.169; 3.U.237.172; 3.U.237.175; 3.U.237.240; 3.U.237.244; 3.U.238.228; 3.U.238.229; 3.U.238.230; 3.U.238.231; 3.U.238.236; 3.U.238.237; 3.U.238.238; 3.U.238.239; 3.U.238.154; 3.U.238.157; 3.U.238.166; 3.U.238.169; 3.U.238.172; 3.U.238.175; 3.U.238.240; 3.U.238.244; 3.U.239.228; 3.U.239.229; 3.U.239.230; 3.U.239.231; 3.U.239.236; 3.U.239.237; 3.U.239.238; 3.U.239.239; 3.U.239.154; 3.U.239.157; 3.U.239.166; 3.U.239.169; 3.U.239.172; 3.U.239.175; 3.U.239.240; 3.U.239.244; 3.U.154.228; 3.U.154.229; 3.U.154.230; 3.U.154.231; 3.U.154.236; 3.U.154.237; 3.U.154.238; 3.U.154.239; 3.U.154.154; 3.U.154.157; 3.U.154.166; 3.U.154.169; 3.U.154.172; 3.U.154.175; 3.U.154.240; 3.U.154.244; 3.U.157.228; 3.U.157.229; 3.U.157.230; 3.U.157.231; 3.U.157.236; 3.U.157.237; 3.U.157.238; 3.U.157.239; 3.U.157.154; 3.U.157.157; 3.U.157.166; 3.U.157.169; 3.U.157.172; 3.U.157.175; 3.U.157.240; 3.U.157.244; 3.U.166.228; 3.U.166.229; 3.U.166.230; 3.U.166.231; 3.U.166.236; 3.U.166.237; 3.U.166.238; 3.U.166.239; 3.U.166.154; 3.U.166.157; 3.U.166.166; 3.U.166.169; 3.U.166.172; 3.U.166.175; 3.U.166.240; 3.U.166.244; 3.U.169.228; 3.U.169.229; 3.U.169.230; 3.U.169.231; 3.U.169.236; 3.U.169.237; 3.U.169.238; 3.U.169.239; 3.U.169.154; 3.U.169.157; 3.U.169.166; 3.U.169.169; 3.U.169.172; 3.U.169.175; 3.U.169.240; 3.U.169.244; 3.U.172.228; 3.U.172.229; 3.U.172.230; 3.U.172.231; 3.U.172.236; 3.U.172.237; 3.U.172.238; 3.U.172.239; 3.U.172.154; 3.U.172.157; 3.U.172.166; 3.U.172.169; 3.U.172.172; 3.U.172.175; 3.U.172.240; 3.U.172.244; 3.U.175.228; 3.U.175.229; 3.U.175.230; 3.U.175.231; 3.U.175.236; 3.U.175.237; 3.U.175.238; 3.U.175.239; 3.U.175.154; 3.U.175.157; 3.U.175.166; 3.U.175.169; 3.U.175.172; 3.U.175.175; 3.U.175.240; 3.U.175.244; 3.U.240.228; 3.U.240.229; 3.U.240.230; 3.U.240.231; 3.U.240.236; 3.U.240.237; 3.U.240.238; 3.U.240.239; 3.U.240.154; 3.U.240.157; 3.U.240.166; 3.U.240.169; 3.U.240.172; 3.U.240.175; 3.U.240.240; 3.U.240.244; 3.U.244.228; 3.U.244.229; 3.U.244.230; 3.U.244.231; 3.U.244.236; 3.U.244.237; 3.U.244.238; 3.U.244.239; 3.U.244.154; 3.U.244.157; 3.U.244.166; 3.U.244.169; 3.U.244.172; 3.U.244.175; 3.U.244.240; 3.U.244.244;

3.W Prodrug

     3.W. 228.228; 3.W.228.229; 3.W. 228.230; 3.W.228.231; 3.W.228.236; 3.W. 228.237; 3.W.228.238; 3.W.228.239; 3.W.228.154; 3.W. 228.157; 3.W. 228.166; 3.W.228.169; 3.W.228.172; 3.W.228.175; 3.W.228.240; 3.W.228.244; 3.W.229.228; 3.W.229.229; 3.W.229.230; 3.W.229.231; 3.W.229.236; 3.W.229.237; 3.W.229.238; 3.W.229.239; 3.W.229.154; 3.W.229.157; 3.W.229.166; 3.W.229.169; 3.W.229.172; 3.W.229.175; 3.W.229.240; 3.W.229.244; 3.W.230.228; 3.W.230.229; 3.W.230.230; 3.W.230.231; 3.W.230.236; 3.W.230.237; 3.W.230.238; 3.W.230.239; 3.W.230.154; 3.W.230.157; 3.W.230.166; 3.W.230.169; 3.W.230.172; 3.W.230.175; 3.W.230.240; 3.W.230.244; 3.W.231.228; 3.W.231.229; 3.W.231.230; 3.W.231.231; 3.W.231.236; 3.W.231.237; 3.W.231.238; 3.W.231.239; 3.W.231.154; 3.W.231.157; 3.W.231.166; 3.W.231.169; 3.W.231.172; 3.W.231.175; 3.W.231.240; 3.W.231.244; 3.W.236.228; 3.W.236.229; 3.W.236.230; 3.W.236.231; 3.W.236.236; 3.W.236.237; 3.W.236.238; 3.W.236.239; 3.W.236.154; 3.W.236.157; 3.W.236.166; 3.W.236.169; 3.W.236.172; 3.W.236.175; 3.W.236.240; 3.W.236.244; 3.W. 237.228; 3.W.237.229; 3.W.237.230; 3.W.237.231; 3.W.237.236; 3.W.237.237; 3.W.237.238; 3.W.237.239; 3.W.237.154; 3.W.237.157; 3.W.237.166; 3.W.237.169; 3.W.237.172; 3.W.237.175; 3.W.237.240; 3.W.237.244; 3.W.238.228; 3.W.238.229; 3.W.238.230; 3.W.238.231; 3.W.238.236; 3.W.238.237; 3.W.238.238; 3.W.238.239; 3.W.238.154; 3.W.238.157; 3.W.238.166; 3.W.238.169; 3.W.238.172; 3.W.238.175; 3.W.238.240; 3.W.238.244; 3.W.239.228; 3.W.239.229; 3.W.239.230; 3.W.239.231; 3.W.239.236; 3.W.239.237; 3.W.239.238; 3.W.239.239; 3.W.239.154; 3.W.239.157; 3.W.239.166; 3.W.239.169; 3.W.239.172; 3.W.239.175; 3.W.239.240; 3.W.239.244; 3.W.154.228; 3.W.154.229; 3.W.154.230; 3.W.154.231; 3.W.154.236; 3.W.154.237; 3.W.154.238; 3.W.154.239; 3.W.154.154; 3.W.154.157; 3.W.154.166; 3.W.154.169; 3.W.154.172; 3.W.154.175; 3.W.154.240; 3.W.154.244; 3.W.157.228; 3.W. 157.229; 3.W.157.230; 3.W.157.231; 3.W.157.236; 3.W.157.237; 3.W.157.238; 3.W.157.239; 3.W.157.154; 3.W.157.157; 3.W.157.166; 3.W.157.169; 3.W.157.172; 3.W.157.175; 3.W.157.240; 3.W.157.244; 3.W.166.228; 3.W.166.229; 3.W.166.230; 3.W.166.231; 3.W.166.236; 3.W.166.237; 3.W.166.238; 3.W.166.239; 3.W.166.154; 3.W.166.157; 3.W.166.166; 3.W.166.169; 3.W.166.172; 3.W.166.175; 3.W.166.240; 3.W.166.244; 3.W. 169.228; 3.W.169.229; 3.W. 169.230; 3.W. 169.231; 3.W. 169.236; 3.W. 169.237; 3.W. 169.238; 3.W. 169.239; 3.W. 169.154; 3.W. 169.157; 3.W. 169.166; 3.W.169.169; 3.W. 169.172; 3.W.169.175; 3.W.169.240; 3.W. 169.244; 3.W.172.228; 3.W.172.229; 3.W.172.230; 3.W.172.231; 3.W.172.236; 3.W.172.237; 3.W.172.238; 3.W.172.239; 3.W.172.154; 3.W.172.157; 3.W.172.166; 3.W.172.169; 3.W.172.172; 3.W.172.175; 3.W.172.240; 3.W.172.244; 3.W.175.228; 3.W.175.229; 3.W.175.230; 3.W.175.231; 3.W.175.236; 3.W.175.237; 3.W.175.238; 3.W.175.239; 3.W.175.154; 3.W.175.157; 3.W.175.166; 3.W.175.169; 3.W.175.172; 3.W.175.175; 3.W.175.240; 3.W.175.244; 3.W.240.228; 3.W.240.229; 3.W.240.230; 3.W.240.231; 3.W.240.236; 3.W.240.237; 3.W.240.238; 3.W.240.239; 3.W.240.154; 3.W.240.157; 3.W.240.166; 3.W.240.169; 3.W.240.172; 3.W.240.175; 3.W.240.240; 3.W.240.244; 3.W.244.228; 3.W.244.229; 3.W.244.230; 3.W.244.231; 3.W.244.236; 3.W.244.237; 3.W.244.238; 3.W.244.239; 3.W.244.154; 3.W.244.157; 3.W.244.166; 3.W.244.169; 3.W.244.172; 3.W.244.175; 3.W.244.240; 3.W.244.244;

3.Y's Prodrug

     3.Y. 228.228; 3.Y.228.229; 3.Y.228.230; 3.Y.228.231; 3.Y.228.236; 3.Y.228.237; 3.Y.228.238; 3.Y.228.239; 3.Y.228.154; 3.Y.228.157; 3.Y.228.166; 3.Y.228.169; 3.Y.228.172; 3.Y.228.175; 3.Y.228.240; 3.Y.228.244; 3.Y.229.228; 3.Y.229.229; 3.Y.229.230; 3.Y.229.231; 3.Y.229.236; 3.Y.229.237; 3.Y.229.238; 3.Y.229.239; 3.Y.229.154; 3.Y.229.157; 3.Y.229.166; 3.Y.229.169; 3.Y.229.172; 3.Y.229.175; 3.Y.229.240; 3.Y.229.244; 3.Y.230.228; 3.Y.230.229; 3.Y.230.230; 3.Y.230.231; 3.Y.230.236; 3.Y.230.237; 3.Y.230.238; 3.Y.230.239; 3.Y.230.154; 3.Y.230.157; 3.Y.230.166; 3.Y.230.169; 3.Y.230.172; 3.Y.230.175; 3.Y.230.240; 3.Y.230.244; 3.Y.231.228; 3.Y.231.229; 3.Y.231.230; 3.Y.231.231; 3.Y.231.236; 3.Y.231.237; 3.Y.231.238; 3.Y.231.239; 3.Y.231.154; 3.Y.231.157; 3.Y.231.166; 3.Y.231.169; 3.Y.231.172; 3.Y.231.175; 3.Y.231.240; 3.Y.231.244; 3.Y.236.228; 3.Y.236.229; 3.Y.236.230; 3.Y.236.231; 3.Y.236.236; 3.Y.236.237; 3.Y.236.238; 3.Y.236.239; 3.Y.236.154; 3.Y.236.157; 3.Y.236.166; 3.Y.236.169; 3.Y.236.172; 3.Y.236.175; 3.Y.236.240; 3.Y.236.244; 3.Y. 237.228; 3.Y.237.229; 3.Y.237.230; 3.Y.237.231; 3.Y.237.236; 3.Y.237.237; 3.Y.237.238; 3.Y.237.239; 3.Y.237.154; 3.Y. 237.157; 3.Y.237.166; 3.Y. 237.169; 3.Y.237.172; 3.Y.237.175; 3.Y.237.240; 3.Y.237.244; 3.Y.238.228; 3.Y.238.229; 3.Y.238.230; 3.Y.238.231; 3.Y.238.236; 3.Y.238.237; 3.Y.238.238; 3.Y.238.239; 3.Y.238.154; 3.Y.238.157; 3.Y.238.166; 3.Y.238.169; 3.Y.238.172; 3.Y.238.175; 3.Y.238.240; 3.Y.238.244; 3.Y.239.228; 3.Y.239.229; 3.Y.239.230; 3.Y.239.231; 3.Y.239.236; 3.Y.239.237; 3.Y.239.238; 3.Y.239.239; 3.Y.239.154; 3.Y.239.157; 3.Y.239.166; 3.Y.239.169; 3.Y.239.172; 3.Y.239.175; 3.Y.239.240; 3.Y.239.244; 3.Y.154.228; 3.Y.154.229; 3.Y.154.230; 3.Y.154.231; 3.Y.154.236; 3.Y.154.237; 3.Y.154.238; 3.Y.154.239; 3.Y.154.154; 3.Y.154.157; 3.Y.154.166; 3.Y.154.169; 3.Y.154.172; 3.Y.154.175; 3.Y.154.240; 3.Y.154.244; 3.Y.157.228; 3.Y.157.229; 3.Y.157.230; 3.Y.157.231; 3.Y.157.236; 3.Y.157.237; 3.Y.157.238; 3.Y.157.239; 3.Y.157.154; 3.Y.157.157; 3.Y.157.166; 3.Y.157.169; 3.Y.157.172; 3.Y.157.175; 3.Y.157.240; 3.Y.157.244; 3.Y.166.228; 3.Y.166.229; 3.Y.166.230; 3.Y.166.231; 3.Y.166.236; 3.Y.166.237; 3.Y.166.238; 3.Y.166.239; 3.Y.166.154; 3.Y.166.157; 3.Y.166.166; 3.Y.166.169; 3.Y.166.172; 3.Y.166.175; 3.Y.166.240; 3.Y.166.244; 3.Y. 169.228; 3.Y.169.229; 3.Y. 169.230; 3.Y.169.231; 3.Y.169.236; 3.Y. 169.237; 3.Y. 169.238; 3.Y.169.239; 3.Y.169.154; 3.Y. 169.157; 3.Y. 169.166; 3.Y.169.169; 3.Y.169.172; 3.Y.169.175; 3.Y.169.240; 3.Y.169.244; 3.Y.172.228; 3.Y.172.229; 3.Y.172.230; 3.Y.172.231; 3.Y.172.236; 3.Y.172.237; 3.Y.172.238; 3.Y.172.239; 3.Y.172.154; 3.Y.172.157; 3.Y.172.166; 3.Y.172.169; 3.Y.172.172; 3.Y.172.175; 3.Y.172.240; 3.Y.172.244; 3.Y.175.228; 3.Y.175.229; 3.Y.175.230; 3.Y.175.231; 3.Y.175.236; 3.Y.175.237; 3.Y.175.238; 3.Y.175.239; 3.Y.175.154; 3.Y.175.157; 3.Y.175.166; 3.Y.175.169; 3.Y.175.172; 3.Y.175.175; 3.Y.175.240; 3.Y.175.244; 3.Y.240.228; 3.Y.240.229; 3.Y.240.230; 3.Y.240.231; 3.Y.240.236; 3.Y.240.237; 3.Y.240.238; 3.Y.240.239; 3.Y.240.154; 3.Y.240.157; 3.Y.240.166; 3.Y.240.169; 3.Y.240.172; 3.Y.240.175; 3.Y.240.240; 3.Y.240.244; 3.Y.244.228; 3.Y.244.229; 3.Y.244.230; 3.Y.244.231; 3.Y.244.236; 3.Y.244.237; 3.Y.244.238; 3.Y.244.239; 3.Y.244.154; 3.Y.244.157; 3.Y.244.166; 3.Y.244.169; 3.Y.244.172; 3.Y.244.175; 3.Y.244.240; 3.Y.244.244;

4.B Prodrug

     4.B.228.228; 4.B.228.229; 4.B.228.230; 4.B.228.231; 4.B.228.236; 4.B.228.237; 4.B.228.238; 4.B.228.239; 4.B.228.154; 4.B.228.157; 4.B.228.166; 4.B.228.169; 4.B.228.172; 4.B.228.175; 4.B.228.240; 4.B.228.244; 4.B.229.228; 4.B.229.229; 4.B.229.230; 4.B.229.231; 4.B.229.236; 4.B.229.237; 4.B.229.238; 4.B.229.239; 4.B.229.154; 4.B.229.157; 4.B.229.166; 4.B.229.169; 4.B.229.172; 4.B.229.175; 4.B.229.240; 4.B.229.244; 4.B.230.228; 4.B.230.229; 4.B.230.230; 4.B.230.231; 4.B.230.236; 4.B.230.237; 4.B.230.238; 4.B.230.239; 4.B.230.154; 4.B.230.157; 4.B.230.166; 4.B.230.169; 4.B.230.172; 4.B.230.175; 4.B.230.240; 4.B.230.244; 4.B.231.228; 4.B.231.229; 4.B.231.230; 4.B.231.231; 4.B.231.236; 4.B.231.237; 4.B.231.238; 4.B.231.239; 4.B.231.154; 4.B.231.157; 4.B.231.166; 4.B.231.169; 4.B.231.172; 4.B.231.175; 4.B.231.240; 4.B.231.244; 4.B.236.228; 4.B.236.229; 4.B.236.230; 4.B.236.231; 4.B.236.236; 4.B.236.237; 4.B.236.238; 4.B.236.239; 4.B.236.154; 4.B.236.157; 4.B.236.166; 4.B.236.169; 4.B.236.172; 4.B.236.175; 4.B.236.240; 4.B.236.244; 4.B.237.228; 4.B.237.229; 4.B.237.230; 4.B.237.231; 4.B.237.236; 4.B.237.237; 4.B.237.238; 4.B.237.239; 4.B.237.154; 4.B.237.157; 4.B.237.166; 4.B.237.169; 4.B.237.172; 4.B.237.175; 4.B.237.240; 4.B.237.244; 4.B.238.228; 4.B.238.229; 4.B.238.230; 4.B.238.231; 4.B.238.236; 4.B.238.237; 4.B.238.238; 4.B.238.239; 4.B.238.154; 4.B.238.157; 4.B.238.166; 4.B.238.169; 4.B.238.172; 4.B.238.175; 4.B.238.240; 4.B.238.244; 4.B.239.228; 4.B.239.229; 4.B.239.230; 4.B.239.231; 4.B.239.236; 4.B.239.237; 4.B.239.238; 4.B.239.239; 4.B.239.154; 4.B.239.157; 4.B.239.166; 4.B.239.169; 4.B.239.172; 4.B.239.175; 4.B.239.240; 4.B.239.244; 4.B.154.228; 4.B.154.229; 4.B.154.230; 4.B.154.231; 4.B.154.236; 4.B.154.237; 4.B.154.238; 4.B.154.239; 4.B.154.154; 4.B.154.157; 4.B.154.166; 4.B.154.169; 4.B.154.172; 4.B.154.175; 4.B.154.240; 4.B.154.244; 4.B.157.228; 4.B.157.229; 4.B.157.230; 4.B.157.231; 4.B.157.236; 4.B.157.237; 4.B.157.238; 4.B.157.239; 4.B.157.154; 4.B.157.157; 4.B.157.166; 4.B.157.169; 4.B.157.172; 4.B.157.175; 4.B.157.240; 4.B.157.244; 4.B.166.228; 4.B.166.229; 4.B.166.230; 4.B.166.231; 4.B.166.236; 4.B.166.237; 4.B.166.238; 4.B.166.239; 4.B.166.154; 4.B.166.157; 4.B.166.166; 4.B.166.169; 4.B.166.172; 4.B.166.175; 4.B.166.240; 4.B.166.244; 4.B.169.228; 4.B.169.229; 4.B.169.230; 4.B.169.231; 4.B.169.236; 4.B.169.237; 4.B.169.238; 4.B.169.239; 4.B.169.154; 4.B.169.157; 4.B.169.166; 4.B.169.169; 4.B.169.172; 4.B.169.175; 4.B.169.240; 4.B.169.244; 4.B.172.228; 4.B.172.229; 4.B.172.230; 4.B.172.231; 4.B.172.236; 4.B.172.237; 4.B.172.238; 4.B.172.239; 4.B.172.154; 4.B.172.157; 4.B.172.166; 4.B.172.169; 4.B.172.172; 4.B.172.175; 4.B.172.240; 4.B.172.244; 4.B.175.228; 4.B.175.229; 4.B.175.230; 4.B.175.231; 4.B.175.236; 4.B.175.237; 4.B.175.238; 4.B.175.239; 4.B.175.154; 4.B.175.157; 4.B.175.166; 4.B.175.169; 4.B.175.172; 4.B.175.175; 4.B.175.240; 4.B.175.244; 4.B.240.228; 4.B.240.229; 4.B.240.230; 4.B.240.231; 4.B.240.236; 4.B.240.237; 4.B.240.238; 4.B.240.239; 4.B.240.154; 4.B.240.157; 4.B.240.166; 4.B.240.169; 4.B.240.172; 4.B.240.175; 4.B.240.240; 4.B.240.244; 4.B.244.228; 4.B.244.229; 4.B.244.230; 4.B.244.231; 4.B.244.236; 4.B.244.237; 4.B.244.238; 4.B.244.239; 4.B.244.154; 4.B.244.157; 4.B.244.166; 4.B.244.169; 4.B.244.172; 4.B.244.175; 4.B.244.240; 4.B.244.244;

4.D Prodrug

     4.D.228.228; 4.D.228.229; 4.D.228.230; 4.D.228.231; 4.D.228.236; 4.D.228.237; 4.D.228.238; 4.D.228.239; 4.D.228.154; 4.D.228.157; 4.D.228.166; 4.D.228.169; 4.D.228.172; 4.D.228.175; 4.D.228.240; 4.D.228.244; 4.D.229.228; 4.D.229.229; 4.D.229.230; 4.D.229.231; 4.D.229.236; 4.D.229.237; 4.D.229.238; 4.D.229.239; 4.D.229.154; 4.D.229.157; 4.D.229.166; 4.D.229.169; 4.D.229.172; 4.D.229.175; 4.D.229.240; 4.D.229.244; 4.D.230.228; 4.D.230.229; 4.D.230.230; 4.D.230.231; 4.D.230.236; 4.D.230.237; 4.D.230.238; 4.D.230.239; 4.D.230.154; 4.D.230.157; 4.D.230.166; 4.D.230.169; 4.D.230.172; 4.D.230.175; 4.D.230.240; 4.D.230.244; 4.D.231.228; 4.D.231.229; 4.D.231.230; 4.D.231.231; 4.D.231.236; 4.D.231.237; 4.D.231.238; 4.D.231.239; 4.D.231.154; 4.D.231.157; 4.D.231.166; 4.D.231.169; 4.D.231.172; 4.D.231.175; 4.D.231.240; 4.D.231.244; 4.D.236.228; 4.D.236.229; 4.D.236.230; 4.D.236.231; 4.D.236.236; 4.D.236.237; 4.D.236.238; 4.D.236.239; 4.D.236.154; 4.D.236.157; 4.D.236.166; 4.D.236.169; 4.D.236.172; 4.D.236.175; 4.D.236.240; 4.D.236.244; 4.D.237.228; 4.D.237.229; 4.D.237.230; 4.D.237.231; 4.D.237.236; 4.D.237.237; 4.D.237.238; 4.D.237.239; 4.D.237.154; 4.D.237.157; 4.D.237.166; 4.D.237.169; 4.D.237.172; 4.D.237.175; 4.D.237.240; 4.D.237.244; 4.D.238.228; 4.D.238.229; 4.D.238.230; 4.D.238.231; 4.D.238.236; 4.D.238.237; 4.D.238.238; 4.D.238.239; 4.D.238.154; 4.D.238.157; 4.D.238.166; 4.D.238.169; 4.D.238.172; 4.D.238.175; 4.D.238.240; 4.D.238.244; 4.D.239.228; 4.D.239.229; 4.D.239.230; 4.D.239.231; 4.D.239.236; 4.D.239.237; 4.D.239.238; 4.D.239.239; 4.D.239.154; 4.D.239.157; 4.D.239.166; 4.D.239.169; 4.D.239.172; 4.D.239.175; 4.D.239.240; 4.D.239.244; 4.D.154.228; 4.D.154.229; 4.D.154.230; 4.D.154.231; 4.D.154.236; 4.D.154.237; 4.D.154.238; 4.D.154.239; 4.D.154.154; 4.D.154.157; 4.D.154.166; 4.D.154.169; 4.D.154.172; 4.D.154.175; 4.D.154.240; 4.D.154.244; 4.D.157.228; 4.D.157.229; 4.D.157.230; 4.D.157.231; 4.D.157.236; 4.D.157.237; 4.D.157.238; 4.D.157.239; 4.D.157.154; 4.D.157.157; 4.D.157.166; 4.D.157.169; 4.D.157.172; 4.D.157.175; 4.D.157.240; 4.D.157.244; 4.D.166.228; 4.D.166.229; 4.D.166.230; 4.D.166.231; 4.D.166.236; 4.D.166.237; 4.D.166.238; 4.D.166.239; 4.D.166.154; 4.D.166.157; 4.D.166.166; 4.D.166.169; 4.D.166.172; 4.D.166.175; 4.D.166.240; 4.D.166.244; 4.D.169.228; 4.D.169.229; 4.D.169.230; 4.D.169.231; 4.D.169.236; 4.D.169.237; 4.D.169.238; 4.D.169.239; 4.D.169.154; 4.D.169.157; 4.D.169.166; 4.D.169.169; 4.D.169.172; 4.D.169.175; 4.D.169.240; 4.D.169.244; 4.D.172.228; 4.D.172.229; 4.D.172.230; 4.D.172.231; 4.D.172.236; 4.D.172.237; 4.D.172.238; 4.D.172.239; 4.D.172.154; 4.D.172.157; 4.D.172.166; 4.D.172.169; 4.D.172.172; 4.D.172.175; 4.D.172.240; 4.D.172.244; 4.D.175.228; 4.D.175.229; 4.D.175.230; 4.D.175.231; 4.D.175.236; 4.D.175.237; 4.D.175.238; 4.D.175.239; 4.D.175.154; 4.D.175.157; 4.D.175.166; 4.D.175.169; 4.D.175.172; 4.D.175.175; 4.D.175.240; 4.D.175.244; 4.D.240.228; 4.D.240.229; 4.D.240.230; 4.D.240.231; 4.D.240.236; 4.D.240.237; 4.D.240.238; 4.D.240.239; 4.D.240.154; 4.D.240.157; 4.D.240.166; 4.D.240.169; 4.D.240.172; 4.D.240.175; 4.D.240.240; 4.D.240.244; 4.D.244.228; 4.D.244.229; 4.D.244.230; 4.D.244.231; 4.D.244.236; 4.D.244.237; 4.D.244.238; 4.D.244.239; 4.D.244.154; 4.D.244.157; 4.D.244.166; 4.D.244.169; 4.D.244.172; 4.D.244.175; 4.D.244.240; 4.D.244.244;

4.E's Prodrug

     4.E.228.228; 4.E.228.229; 4.E.228.230; 4.E.228.231; 4.E.228.236; 4.E.228.237; 4.E.228.238; 4.E.228.239; 4.E.228.154; 4.E.228.157; 4.E.228.166; 4.E.228.169; 4.E.228.172; 4.E.228.175; 4.E.228.240; 4.E.228.244; 4.E.229.228; 4.E.229.229; 4.E.229.230; 4.E.229.231; 4.E.229.236; 4.E.229.237; 4.E.229.238; 4.E.229.239; 4.E.229.154; 4.E.229.157; 4.E.229.166; 4.E.229.169; 4.E.229.172; 4.E.229.175; 4.E.229.240; 4.E.229.244; 4.E.230.228; 4.E.230.229; 4.E.230.230; 4.E.230.231; 4.E.230.236; 4.E.230.237; 4.E.230.238; 4.E.230.239; 4.E.230.154; 4.E.230.157; 4.E.230.166; 4.E.230.169; 4.E.230.172; 4.E.230.175; 4.E.230.240; 4.E.230.244; 4.E.231.228; 4.E.231.229; 4.E.231.230; 4.E.231.231; 4.E.231.236; 4.E.231.237; 4.E.231.238; 4.E.231.239; 4.E.231.154; 4.E.231.157; 4.E.231.166; 4.E.231.169; 4.E.231.172; 4.E.231.175; 4.E.231.240; 4.E.231.244; 4.E.236.228; 4.E.236.229; 4.E.236.230; 4.E.236.231; 4.E.236.236; 4.E.236.237; 4.E.236.238; 4.E.236.239; 4.E.236.154; 4.E.236.157; 4.E.236.166; 4.E.236.169; 4.E.236.172; 4.E.236.175; 4.E.236.240; 4.E.236.244; 4.E.237.228; 4.E.237.229; 4.E.237.230; 4.E.237.231; 4.E.237.236; 4.E.237.237; 4.E.237.238; 4.E.237.239; 4.E.237.154; 4.E.237.157; 4.E.237.166; 4.E.237.169; 4.E.237.172; 4.E.237.175; 4.E.237.240; 4.E.237.244; 4.E.238.228; 4.E.238.229; 4.E.238.230; 4.E.238.231; 4.E.238.236; 4.E.238.237; 4.E.238.238; 4.E.238.239; 4.E.238.154; 4.E.238.157; 4.E.238.166; 4.E.238.169; 4.E.238.172; 4.E.238.175; 4.E.238.240; 4.E.238.244; 4.E.239.228; 4.E.239.229; 4.E.239.230; 4.E.239.231; 4.E.239.236; 4.E.239.237; 4.E.239.238; 4.E.239.239; 4.E.239.154; 4.E.239.157; 4.E.239.166; 4.E.239.169; 4.E.239.172; 4.E.239.175; 4.E.239.240; 4.E.239.244; 4.E.154.228; 4.E.154.229; 4.E.154.230; 4.E.154.231; 4.E.154.236; 4.E.154.237; 4.E.154.238; 4.E.154.239; 4.E.154.154; 4.E.154.157; 4.E.154.166; 4.E.154.169; 4.E.154.172; 4.E.154.175; 4.E.154.240; 4.E.154.244; 4.E.157.228; 4.E.157.229; 4.E.157.230; 4.E.157.231; 4.E.157.236; 4.E.157.237; 4.E.157.238; 4.E.157.239; 4.E.157.154; 4.E.157.157; 4.E.157.166; 4.E.157.169; 4.E.157.172; 4.E.157.175; 4.E.157.240; 4.E.157.244; 4.E.166.228; 4.E.166.229; 4.E.166.230; 4.E.166.231; 4.E.166.236; 4.E.166.237; 4.E.166.238; 4.E.166.239; 4.E.166.154; 4.E.166.157; 4.E.166.166; 4.E.166.169; 4.E.166.172; 4.E.166.175; 4.E.166.240; 4.E.166.244; 4.E.169.228; 4.E.169.229; 4.E.169.230; 4.E.169.231; 4.E.169.236; 4.E.169.237; 4.E.169.238; 4.E.169.239; 4.E.169.154; 4.E.169.157; 4.E.169.166; 4.E.169.169; 4.E.169.172; 4.E.169.175; 4.E.169.240; 4.E.169.244; 4.E.172.228; 4.E.172.229; 4.E.172.230; 4.E.172.231; 4.E.172.236; 4.E.172.237; 4.E.172.238; 4.E.172.239; 4.E.172.154; 4.E.172.157; 4.E.172.166; 4.E.172.169; 4.E.172.172; 4.E.172.175; 4.E.172.240; 4.E.172.244; 4.E.175.228; 4.E.175.229; 4.E.175.230; 4.E.175.231; 4.E.175.236; 4.E.175.237; 4.E.175.238; 4.E.175.239; 4.E.175.154; 4.E.175.157; 4.E.175.166; 4.E.175.169; 4.E.175.172; 4.E.175.175; 4.E.175.240; 4.E.175.244; 4.E.240.228; 4.E.240.229; 4.E.240.230; 4.E.240.231; 4.E.240.236; 4.E.240.237; 4.E.240.238; 4.E.240.239; 4.E.240.154; 4.E.240.157; 4.E.240.166; 4.E.240.169; 4.E.240.172; 4.E.240.175; 4.E.240.240; 4.E.240.244; 4.E.244.228; 4.E.244.229; 4.E.244.230; 4.E.244.231; 4.E.244.236; 4.E.244.237; 4.E.244.238; 4.E.244.239; 4.E.244.154; 4.E.244.157; 4.E.244.166; 4.E.244.169; 4.E.244.172; 4.E.244.175; 4.E.244.240; 4.E.244.244;

4.G's Prodrug

     4.G.228.228; 4.G.228.229; 4.G.228.230; 4.G.228.231; 4.G.228.236; 4.G.228.237; 4.G.228.238; 4.G.228.239; 4.G.228.154; 4.G.228.157; 4.G.228.166; 4.G.228.169; 4.G.228.172; 4.G.228.175; 4.G.228.240; 4.G.228.244; 4.G.229.228; 4.G.229.229; 4.G.229.230; 4.G.229.231; 4.G.229.236; 4.G.229.237; 4.G.229.238; 4.G.229.239; 4.G.229.154; 4.G.229.157; 4.G.229.166; 4.G.229.169; 4.G.229.172; 4.G.229.175; 4.G.229.240; 4.G.229.244; 4.G.230.228; 4.G.230.229; 4.G.230.230; 4.G.230.231; 4.G.230.236; 4.G.230.237; 4.G.230.238; 4.G.230.239; 4.G.230.154; 4.G.230.157; 4.G.230.166; 4.G.230.169; 4.G.230.172; 4.G.230.175; 4.G.230.240; 4.G.230.244; 4.G.231.228; 4.G.231.229; 4.G.231.230; 4.G.231.231; 4.G.231.236; 4.G.231.237; 4.G.231.238; 4.G.231.239; 4.G.231.154; 4.G.231.157; 4.G.231.166; 4.G.231.169; 4.G.231.172; 4.G.231.175; 4.G.231.240; 4.G.231.244; 4.G.236.228; 4.G.236.229; 4.G.236.230; 4.G.236.231; 4.G.236.236; 4.G.236.237; 4.G.236.238; 4.G.236.239; 4.G.236.154; 4.G.236.157; 4.G.236.166; 4.G.236.169; 4.G.236.172; 4.G.236.175; 4.G.236.240; 4.G.236.244; 4.G.237.228; 4.G.237.229; 4.G.237.230; 4.G.237.231; 4.G.237.236; 4.G.237.237; 4.G.237.238; 4.G.237.239; 4.G.237.154; 4.G.237.157; 4.G.237.166; 4.G.237.169; 4.G.237.172; 4.G.237.175; 4.G.237.240; 4.G.237.244; 4.G.238.228; 4.G.238.229; 4.G.238.230; 4.G.238.231; 4.G.238.236; 4.G.238.237; 4.G.238.238; 4.G.238.239; 4.G.238.154; 4.G.238.157; 4.G.238.166; 4.G.238.169; 4.G.238.172; 4.G.238.175; 4.G.238.240; 4.G.238.244; 4.G.239.228; 4.G.239.229; 4.G.239.230; 4.G.239.231; 4.G.239.236; 4.G.239.237; 4.G.239.238; 4.G.239.239; 4.G.239.154; 4.G.239.157; 4.G.239.166; 4.G.239.169; 4.G.239.172; 4.G.239.175; 4.G.239.240; 4.G.239.244; 4.G.154.228; 4.G.154.229; 4.G.154.230; 4.G.154.231; 4.G.154.236; 4.G.154.237; 4.G.154.238; 4.G.154.239; 4.G.154.154; 4.G.154.157; 4.G.154.166; 4.G.154.169; 4.G.154.172; 4.G.154.175; 4.G.154.240; 4.G.154.244; 4.G.157.228; 4.G.157.229; 4.G.157.230; 4.G.157.231; 4.G.157.236; 4.G.157.237; 4.G.157.238; 4.G.157.239; 4.G.157.154; 4.G.157.157; 4.G.157.166; 4.G.157.169; 4.G.157.172; 4.G.157.175; 4.G.157.240; 4.G.157.244; 4.G.166.228; 4.G.166.229; 4.G.166.230; 4.G.166.231; 4.G.166.236; 4.G.166.237; 4.G.166.238; 4.G.166.239; 4.G.166.154; 4.G.166.157; 4.G.166.166; 4.G.166.169; 4.G.166.172; 4.G.166.175; 4.G.166.240; 4.G.166.244; 4.G.169.228; 4.G.169.229; 4.G.169.230; 4.G.169.231; 4.G.169.236; 4.G.169.237; 4.G.169.238; 4.G.169.239; 4.G.169.154; 4.G.169.157; 4.G.169.166; 4.G.169.169; 4.G.169.172; 4.G.169.175; 4.G.169.240; 4.G.169.244; 4.G.172.228; 4.G.172.229; 4.G.172.230; 4.G.172.231; 4.G.172.236; 4.G.172.237; 4.G.172.238; 4.G.172.239; 4.G.172.154; 4.G.172.157; 4.G.172.166; 4.G.172.169; 4.G.172.172; 4.G.172.175; 4.G.172.240; 4.G.172.244; 4.G.175.228; 4.G.175.229; 4.G.175.230; 4.G.175.231; 4.G.175.236; 4.G.175.237; 4.G.175.238; 4.G.175.239; 4.G.175.154; 4.G.175.157; 4.G.175.166; 4.G.175.169; 4.G.175.172; 4.G.175.175; 4.G.175.240; 4.G.175.244; 4.G.240.228; 4.G.240.229; 4.G.240.230; 4.G.240.231; 4.G.240.236; 4.G.240.237; 4.G.240.238; 4.G.240.239; 4.G.240.154; 4.G.240.157; 4.G.240.166; 4.G.240.169; 4.G.240.172; 4.G.240.175; 4.G.240.240; 4.G.240.244; 4.G.244.228; 4.G.244.229; 4.G.244.230; 4.G.244.231; 4.G.244.236; 4.G.244.237; 4.G.244.238; 4.G.244.239; 4.G.244.154; 4.G.244.157; 4.G.244.166; 4.G.244.169; 4.G.244.172; 4.G.244.175; 4.G.244.240; 4.G.244.244;

4.I's Prodrug

     4.I.228.228; 4.I.228.229; 4.I.228.230; 4.I.228.231; 4.I.228.236; 4.I.228.237; 4.I.228.238; 4.I.228.239; 4.I.228.154; 4.I.228.157; 4.I.228.166; 4.I.228.169; 4.I.228.172; 4.I.228.175; 4.I.228.240; 4.I.228.244; 4.I.229.228; 4.I.229.229; 4.I.229.230; 4.I.229.231; 4.I.229.236; 4.I.229.237; 4.I.229.238; 4.I.229.239; 4.I.229.154; 4.I.229.157; 4.I.229.166; 4.I.229.169; 4.I.229.172; 4.I.229.175; 4.I.229.240; 4.I.229.244; 4.I.230.228; 4.I.230.229; 4.I.230.230; 4.I.230.231; 4.I.230.236; 4.I.230.237; 4.I.230.238; 4.I.230.239; 4.I.230.154; 4.I.230.157; 4.I.230.166; 4.I.230.169; 4.I.230.172; 4.I.230.175; 4.I.230.240; 4.I.230.244; 4.I.231.228; 4.I.231.229; 4.I.231.230; 4.I.231.231; 4.I.231.236; 4.I.231.237; 4.I.231.238; 4.I.231.239; 4.I.231.154; 4.I.231.157; 4.I.231.166; 4.I.231.169; 4.I.231.172; 4.I.231.175; 4.I.231.240; 4.I.231.244; 4.I.236.228; 4.I.236.229; 4.I.236.230; 4.I.236.231; 4.I.236.236; 4.I.236.237; 4.I.236.238; 4.I.236.239; 4.I.236.154; 4.I.236.157; 4.I.236.166; 4.I.236.169; 4.I.236.172; 4.I.236.175; 4.I.236.240; 4.I.236.244; 4.I.237.228; 4.I.237.229; 4.I.237.230; 4.I.237.231; 4.I.237.236; 4.I.237.237; 4.I.237.238; 4.I.237.239; 4.I.237.154; 4.I.237.157; 4.I.237.166; 4.I.237.169; 4.I.237.172; 4.I.237.175; 4.I.237.240; 4.I.237.244; 4.I.238.228; 4.I.238.229; 4.I.238.230; 4.I.238.231; 4.I.238.236; 4.I.238.237; 4.I.238.238; 4.I.238.239; 4.I.238.154; 4.I.238.157; 4.I.238.166; 4.I.238.169; 4.I.238.172; 4.I.238.175; 4.I.238.240; 4.I.238.244; 4.I.239.228; 4.I.239.229; 4.I.239.230; 4.I.239.231; 4.I.239.236; 4.I.239.237; 4.I.239.238; 4.I.239.239; 4.I.239.154; 4.I.239.157; 4.I.239.166; 4.I.239.169; 4.I.239.172; 4.I.239.175; 4.I.239.240; 4.I.239.244; 4.I.154.228; 4.I.154.229; 4.I.154.230; 4.I.154.231; 4.I.154.236; 4.I.154.237; 4.I.154.238; 4.I.154.239; 4.I.154.154; 4.I.154.157; 4.I.154.166; 4.I.154.169; 4.I.154.172; 4.I.154.175; 4.I.154.240; 4.I.154.244; 4.I.157.228; 4.I.157.229; 4.I.157.230; 4.I.157.231; 4.I.157.236; 4.I.157.237; 4.I.157.238; 4.I.157.239; 4.I.157.154; 4.I.157.157; 4.I.157.166; 4.I.157.169; 4.I.157.172; 4.I.157.175; 4.I.157.240; 4.I.157.244; 4.I.166.228; 4.I.166.229; 4.I.166.230; 4.I.166.231; 4.I.166.236; 4.I.166.237; 4.I.166.238; 4.I.166.239; 4.I.166.154; 4.I.166.157; 4.I.166.166; 4.I.166.169; 4.I.166.172; 4.I.166.175; 4.I.166.240; 4.I.166.244; 4.I.169.228; 4.I.169.229; 4.I.169.230; 4.I.169.231; 4.I.169.236; 4.I.169.237; 4.I.169.238; 4.I.169.239; 4.I.169.154; 4.I.169.157; 4.I.169.166; 4.I.169.169; 4.I.169.172; 4.I.169.175; 4.I.169.240; 4.I.169.244; 4.I.172.228; 4.I.172.229; 4.I.172.230; 4.I.172.231; 4.I.172.236; 4.I.172.237; 4.I.172.238; 4.I.172.239; 4.I.172.154; 4.I.172.157; 4.I.172.166; 4.I.172.169; 4.I.172.172; 4.I.172.175; 4.I.172.240; 4.I.172.244; 4.I.175.228; 4.I.175.229; 4.I.175.230; 4.I.175.231; 4.I.175.236; 4.I.175.237; 4.I.175.238; 4.I.175.239; 4.I.175.154; 4.I.175.157; 4.I.175.166; 4.I.175.169; 4.I.175.172; 4.I.175.175; 4.I.175.240; 4.I.175.244; 4.I.240.228; 4.I.240.229; 4.I.240.230; 4.I.240.231; 4.I.240.236; 4.I.240.237; 4.I.240.238; 4.I.240.239; 4.I.240.154; 4.I.240.157; 4.I.240.166; 4.I.240.169; 4.I.240.172; 4.I.240.175; 4.I.240.240; 4.I.240.244; 4.I.244.228; 4.I.244.229; 4.I.244.230; 4.I.244.231; 4.I.244.236; 4.I.244.237; 4.I.244.238; 4.I.244.239; 4.I.244.154; 4.I.244.157; 4.I.244.166; 4.I.244.169; 4.I.244.172; 4.I.244.175; 4.I.244.240; 4.I.244.244;

4.J's Prodrug

     4.J.228.228; 4.J.228.229; 4.J.228.230; 4.J.228.231; 4.J.228.236; 4.J.228.237; 4.J.228.238; 4.J.228.239; 4.J.228.154; 4.J.228.157; 4.J.228.166; 4.J.228.169; 4.J.228.172; 4.J.228.175; 4.J.228.240; 4.J.228.244; 4.J.229.228; 4.J.229.229; 4.J.229.230; 4.J.229.231; 4.J.229.236; 4.J.229.237; 4.J.229.238; 4.J.229.239; 4.J.229.154; 4.J.229.157; 4.J.229.166; 4.J.229.169; 4.J.229.172; 4.J.229.175; 4.J.229.240; 4.J.229.244; 4.J.230.228; 4.J.230.229; 4.J.230.230; 4.J.230.231; 4.J.230.236; 4.J.230.237; 4.J.230.238; 4.J.230.239; 4.J.230.154; 4.J.230.157; 4.J.230.166; 4.J.230.169; 4.J.230.172; 4.J.230.175; 4.J.230.240; 4.J.230.244; 4.J.231.228; 4.J.231.229; 4.J.231.230; 4.J.231.231; 4.J.231.236; 4.J.231.237; 4.J.231.238; 4.J.231.239; 4.J.231.154; 4.J.231.157; 4.J.231.166; 4.J.231.169; 4.J.231.172; 4.J.231.175; 4.J.231.240; 4.J.231.244; 4.J.236.228; 4.J.236.229; 4.J.236.230; 4.J.236.231; 4.J.236.236; 4.J.236.237; 4.J.236.238; 4.J.236.239; 4.J.236.154; 4.J.236.157; 4.J.236.166; 4.J.236.169; 4.J.236.172; 4.J.236.175; 4.J.236.240; 4.J.236.244; 4.J. 237.228; 4.J.237.229; 4.J. 237.230; 4.J.237.231; 4.J.237.236; 4.J.237.237; 4.J. 237.238; 4.J.237.239; 4.J.237.154; 4.J. 237.157; 4.J.237.166; 4.J. 237.169; 4.J.237.172; 4.J.237.175; 4.J.237.240; 4.J.237.244; 4.J.238.228; 4.J.238.229; 4.J.238.230; 4.J.238.231; 4.J.238.236; 4.J.238.237; 4.J.238.238; 4.J.238.239; 4.J.238.154; 4.J.238.157; 4.J.238.166; 4.J.238.169; 4.J.238.172; 4.J.238.175; 4.J.238.240; 4.J.238.244; 4.J.239.228; 4.J.239.229; 4.J.239.230; 4.J.239.231; 4.J.239.236; 4.J.239.237; 4.J.239.238; 4.J.239.239; 4.J.239.154; 4.J.239.157; 4.J.239.166; 4.J.239.169; 4.J.239.172; 4.J.239.175; 4.J.239.240; 4.J.239.244; 4.J.154.228; 4.J.154.229; 4.J.154.230; 4.J.154.231; 4.J.154.236; 4.J.154.237; 4.J.154.238; 4.J.154.239; 4.J.154.154; 4.J.154.157; 4.J.154.166; 4.J.154.169; 4.J.154.172; 4.J.154.175; 4.J.154.240; 4.J.154.244; 4.J.157.228; 4.J.157.229; 4.J.157.230; 4.J.157.231; 4.J.157.236; 4.J.157.237; 4.J.157.238; 4.J.157.239; 4.J.157.154; 4.J.157.157; 4.J.157.166; 4.J.157.169; 4.J.157.172; 4.J.157.175; 4.J.157.240; 4.J.157.244; 4.J.166.228; 4.J.166.229; 4.J.166.230; 4.J.166.231; 4.J.166.236; 4.J.166.237; 4.J.166.238; 4.J.166.239; 4.J.166.154; 4.J.166.157; 4.J.166.166; 4.J.166.169; 4.J.166.172; 4.J.166.175; 4.J.166.240; 4.J.166.244; 4.J. 169.228; 4.J.169.229; 4.J. 169.230; 4.J. 169.231; 4.J.169.236; 4.J. 169.237; 4.J. 169.238; 4.J. 169.239; 4.J.169.154; 4.J. 169.157; 4.J. 169.166; 4.J. 169.169; 4.J.169.172; 4.J.169.175; 4.J.169.240; 4.J. 169.244; 4.J.172.228; 4.J.172.229; 4.J.172.230; 4.J.172.231; 4.J.172.236; 4.J.172.237; 4.J.172.238; 4.J.172.239; 4.J.172.154; 4.J.172.157; 4.J.172.166; 4.J.172.169; 4.J.172.172; 4.J.172.175; 4.J.172.240; 4.J.172.244; 4.J.175.228; 4.J.175.229; 4.J.175.230; 4.J.175.231; 4.J.175.236; 4.J.175.237; 4.J.175.238; 4.J.175.239; 4.J.175.154; 4.J.175.157; 4.J.175.166; 4.J.175.169; 4.J.175.172; 4.J.175.175; 4.J.175.240; 4.J.175.244; 4.J.240.228; 4.J.240.229; 4.J.240.230; 4.J.240.231; 4.J.240.236; 4.J.240.237; 4.J.240.238; 4.J.240.239; 4.J.240.154; 4.J.240.157; 4.J.240.166; 4.J.240.169; 4.J.240.172; 4.J.240.175; 4.J.240.240; 4.J.240.244; 4.J.244.228; 4.J.244.229; 4.J.244.230; 4.J.244.231; 4.J.244.236; 4.J.244.237; 4.J.244.238; 4.J.244.239; 4.J.244.154; 4.J.244.157; 4.J.244.166; 4.J.244.169; 4.J.244.172; 4.J.244.175; 4.J.244.240; 4.J.244.244;

4.L Prodrug

     4.L. 228.228; 4.L. 228.229; 4.L. 228.230; 4.L. 228.231; 4.L. 228.236; 4.L. 228.237; 4.L. 228.238; 4.L. 228.239; 4.L. 228.154; 4.L. 228.157; 4.L. 228.166; 4.L. 228.169; 4.L. 228.172; 4.L. 228.175; 4.L. 228.240; 4.L. 228.244; 4.L.229.228; 4.L.229.229; 4.L.229.230; 4.L.229.231; 4.L.229.236; 4.L.229.237; 4.L.229.238; 4.L.229.239; 4.L.229.154; 4.L.229.157; 4.L.229.166; 4.L.229.169; 4.L.229.172; 4.L.229.175; 4.L.229.240; 4.L.229.244; 4.L. 230.228; 4.L. 230.229; 4.L.230.230; 4.L.230.231; 4.L.230.236; 4.L.230.237; 4.L.230.238; 4.L.230.239; 4.L.230.154; 4.L.230.157; 4.L.230.166; 4.L.230.169; 4.L.230.172; 4.L.230.175; 4.L.230.240; 4.L.230.244; 4.L.231.228; 4.L. 231.229; 4.L.231.230; 4.L.231.231; 4.L.231.236; 4.L.231.237; 4.L.231.238; 4.L.231.239; 4.L.231.154; 4.L.231.157; 4.L.231.166; 4.L.231.169; 4.L.231.172; 4.L.231.175; 4.L.231.240; 4.L.231.244; 4.L. 236.228; 4.L. 236.229; 4.L. 236.230; 4.L. 236.231; 4.L.236.236; 4.L. 236.237; 4.L.236.238; 4.L. 236.239; 4.L. 236.154; 4.L. 236.157; 4.L. 236.166; 4.L. 236.169; 4.L.236.172; 4.L. 236.175; 4.L. 236.240; 4.L.236.244; 4.L. 237.228; 4.L. 237.229; 4.L. 237.230; 4.L. 237.231; 4.L. 237.236; 4.L. 237.237; 4.L. 237.238; 4.L. 237.239; 4.L. 237.154; 4.L. 237.157; 4.L. 237.166; 4.L. 237.169; 4.L. 237.172; 4.L. 237.175; 4.L. 237.240; 4.L. 237.244; 4.L. 238.228; 4.L.238.229; 4.L.238.230; 4.L.238.231; 4.L.238.236; 4.L.238.237; 4.L.238.238; 4.L.238.239; 4.L.238.154; 4.L. 238.157; 4.L. 238.166; 4.L. 238.169; 4.L.238.172; 4.L.238.175; 4.L.238.240; 4.L.238.244; 4.L.239.228; 4.L.239.229; 4.L.239.230; 4.L.239.231; 4.L.239.236; 4.L.239.237; 4.L.239.238; 4.L.239.239; 4.L.239.154; 4.L.239.157; 4.L.239.166; 4.L.239.169; 4.L.239.172; 4.L.239.175; 4.L.239.240; 4.L.239.244; 4.L. 154.228; 4.L.154.229; 4.L.154.230; 4.L.154.231; 4.L.154.236; 4.L.154.237; 4.L.154.238; 4.L. 154.239; 4.L.154.154; 4.L. 154.157; 4.L.154.166; 4.L.154.169; 4.L.154.172; 4.L.154.175; 4.L.154.240; 4.L.154.244; 4.L.157.228; 4.L. 157.229; 4.L.157.230; 4.L.157.231; 4.L.157.236; 4.L.157.237; 4.L.157.238; 4.L.157.239; 4.L.157.154; 4.L.157.157; 4.L.157.166; 4.L.157.169; 4.L.157.172; 4.L.157.175; 4.L.157.240; 4.L.157.244; 4.L. 166.228; 4.L. 166.229; 4.L. 166.230; 4.L. 166.231; 4.L. 166.236; 4.L. 166.237; 4.L.166.238; 4.L. 166.239; 4.L. 166.154; 4.L. 166.157; 4.L. 166.166; 4.L. 166.169; 4.L. 166.172; 4.L. 166.175; 4.L. 166.240; 4.L.166.244; 4.L. 169.228; 4.L. 169.229; 4.L. 169.230; 4.L. 169.231; 4.L. 169.236; 4.L. 169.237; 4.L. 169.238; 4.L. 169.239; 4.L. 169.154; 4.L. 169.157; 4.L. 169.166; 4.L. 169.169; 4.L. 169.172; 4.L. 169.175; 4.L. 169.240; 4.L. 169.244; 4.L. 172.228; 4.L. 172.229; 4.L. 172.230; 4.L. 172.231; 4.L. 172.236; 4.L. 172.237; 4.L. 172.238; 4.L. 172.239; 4.L. 172.154; 4.L. 172.157; 4.L. 172.166; 4.L. 172.169; 4.L.172.172; 4.L. 172.175; 4.L. 172.240; 4.L. 172.244; 4.L.175.228; 4.L. 175.229; 4.L. 175.230; 4.L.175.231; 4.L. 175.236; 4.L. 175.237; 4.L. 175.238; 4.L. 175.239; 4.L.175.154; 4.L. 175.157; 4.L. 175.166; 4.L. 175.169; 4.L. 175.172; 4.L. 175.175; 4.L. 175.240; 4.L. 175.244; 4.L.240.228; 4.L.240.229; 4.L.240.230; 4.L.240.231; 4.L.240.236; 4.L.240.237; 4.L.240.238; 4.L.240.239; 4.L.240.154; 4.L.240.157; 4.L.240.166; 4.L.240.169; 4.L.240.172; 4.L.240.175; 4.L.240.240; 4.L.240.244; 4.L.244.228; 4.L.244.229; 4.L.244.230; 4.L.244.231; 4.L.244.236; 4.L.244.237; 4.L.244.238; 4.L.244.239; 4.L.244.154; 4.L.244.157; 4.L.244.166; 4.L.244.169; 4.L.244.172; 4.L.244.175; 4.L.244.240; 4.L.244.244;

4.O's Prodrug

     4.O.228.228; 4.O.228.229; 4.O.228.230; 4.O.228.231; 4.O.228.236; 4.O.228.237; 4.O.228.238; 4.O.228.239; 4.O.228.154; 4.O.228.157; 4.O.228.166; 4.O.228.169; 4.O.228.172; 4.O.228.175; 4.O.228.240; 4.O.228.244; 4.O.229.228; 4.O.229.229; 4.O.229.230; 4.O.229.231; 4.O.229.236; 4.O.229.237; 4.O.229.238; 4.O.229.239; 4.O.229.154; 4.O.229.157; 4.O.229.166; 4.O.229.169; 4.O.229.172; 4.O.229.175; 4.O.229.240; 4.O.229.244; 4.O.230.228; 4.O.230.229; 4.230.230; 4.O.230.231; 4.O.230.236; 4.O.230.237; 4.230.238; 4.O.230.239; 4.230.154; 4.230.157; 4.O.230.166; 4.O.230.169; 4.O.230.172; 4.230.175; 4.230.240; 4.O.230.244; 4.O.231.228; 4.O.231.229; 4.O.231.230; 4.O.231.231; 4.O.231.236; 4.O.231.237; 4.O.231.238; 4.O.231.239; 4.O.231.154; 4.O.231.157; 4.O.231.166; 4.O.231.169; 4.O.231.172; 4.O.231.175; 4.O.231.240; 4.O.231.244; 4.O.236.228; 4.O.236.229; 4.O.236.230; 4.O.236.231; 4.O.236.236; 4.O.236.237; 4.O.236.238; 4.O.236.239; 4.O.236.154; 4.O.236.157; 4.O.236.166; 4.O.236.169; 4.O.236.172; 4.O.236.175; 4.O.236.240; 4.O.236.244; 4.O.237.228; 4.O.237.229; 4.237.230; 4.O.237.231; 4.O.237.236; 4.O.237.237; 4.O.237.238; 4.O.237.239; 4.237.154; 4.O.237.157; 4.O.237.166; 4.O.237.169; 4.O.237.172; 4.O.237.175; 4.O.237.240; 4.O.237.244; 4.O.238.228; 4.O.238.229; 4.O.238.230; 4.O.238.231; 4.O.238.236; 4.O.238.237; 4.O.238.238; 4.O.238.239; 4.O.238.154; 4.O.238.157; 4.O.238.166; 4.O.238.169; 4.O.238.172; 4.O.238.175; 4.O.238.240; 4.O.238.244; 4.O.239.228; 4.O.239.229; 4.O.239.230; 4.O.239.231; 4.O.239.236; 4.O.239.237; 4.O.239.238; 4.O.239.239; 4.O.239.154; 4.O.239.157; 4.O.239.166; 4.O.239.169; 4.O.239.172; 4.O.239.175; 4.O.239.240; 4.O.239.244; 4.O.154.228; 4.154.229; 4.154.230; 4.O.154.231; 4.O.154.236; 4.O.154.237; 4.154.238; 4.154.239; 4.154.154; 4.154.157; 4.O.154.166; 4.154.169; 4.154.172; 4.154.175; 4.154.240; 4.O.154.244; 4.O.157.228; 4.O.157.229; 4.O.157.230; 4.O.157.231; 4.O.157.236; 4.O.157.237; 4.O.157.238; 4.O.157.239; 4.O.157.154; 4.O.157.157; 4.O.157.166; 4.O.157.169; 4.157.172; 4.157.175; 4.O.157.240; 4.O.157.244; 4.O.166.228; 4.O.166.229; 4.O.166.230; 4.O.166.231; 4.O.166.236; 4.O.166.237; 4.O.166.238; 4.O.166.239; 4.O.166.154; 4.O.166.157; 4.O.166.166; 4.O.166.169; 4.O.166.172; 4.O.166.175; 4.O.166.240; 4.O.166.244; 4.O.169.228; 4.O.169.229; 4.O.169.230; 4.O.169.231; 4.O.169.236; 4.O.169.237; 4.O.169.238; 4.O.169.239; 4.O.169.154; 4.O.169.157; 4.O.169.166; 4.O.169.169; 4.O.169.172; 4.O.169.175; 4.O.169.240; 4.O.169.244; 4.O.172.228; 4.O.172.229; 4.O.172.230; 4.O.172.231; 4.O.172.236; 4.O.172.237; 4.O.172.238; 4.O.172.239; 4.O.172.154; 4.O.172.157; 4.O.172.166; 4.O.172.169; 4.O.172.172; 4.O.172.175; 4.O.172.240; 4.O.172.244; 4.O.175.228; 4.O.175.229; 4.O.175.230; 4.O.175.231; 4.O.175.236; 4.O.175.237; 4.O.175.238; 4.O.175.239; 4.O.175.154; 4.O.175.157; 4.O.175.166; 4.O.175.169; 4.O.175.172; 4.O.175.175; 4.O.175.240; 4.O.175.244; 4.O.240.228; 4.O.240.229; 4.O.240.230; 4.O.240.231; 4.O.240.236; 4.O.240.237; 4.O.240.238; 4.O.240.239; 4.O.240.154; 4.O.240.157; 4.O.240.166; 4.O.240.169; 4.O.240.172; 4.O.240.175; 4.O.240.240; 4.O.240.244; 4.O.244.228; 4.O.244.229; 4.O.244.230; 4.O.244.231; 4.O.244.236; 4.O.244.237; 4.O.244.238; 4.O.244.239; 4.O.244.154; 4.O.244.157; 4.O.244.166; 4.O.244.169; 4.O.244.172; 4.O.244.175; 4.O.244.240; 4.O.244.244;

4.P's Prodrug

     4.P.228.228; 4.P.228.229; 4.P.228.230; 4.P.228.231; 4.P.228.236; 4.P.228.237; 4.P.228.238; 4.P.228.239; 4.P.228.154; 4.P.228.157; 4.P.228.166; 4.P.228.169; 4.P.228.172; 4.P.228.175; 4.P.228.240; 4.P.228.244; 4.P.229.228; 4.P.229.229; 4.P.229.230; 4.P.229.231; 4.P.229.236; 4.P.229.237; 4.P.229.238; 4.P.229.239; 4.P.229.154; 4.P.229.157; 4.P.229.166; 4.P.229.169; 4.P.229.172; 4.P.229.175; 4.P.229.240; 4.P.229.244; 4.P.230.228; 4.P.230.229; 4.P.230.230; 4.P.230.231; 4.P.230.236; 4.P.230.237; 4.P.230.238; 4.P.230.239; 4.P.230.154; 4.P.230.157; 4.P.230.166; 4.P.230.169; 4.P.230.172; 4.P.230.175; 4.P.230.240; 4.P.230.244; 4.P.231.228; 4.P.231.229; 4.P.231.230; 4.P.231.231; 4.P.231.236; 4.P.231.237; 4.P.231.238; 4.P.231.239; 4.P.231.154; 4.P.231.157; 4.P.231.166; 4.P.231.169; 4.P.231.172; 4.P.231.175; 4.P.231.240; 4.P.231.244; 4.P.236.228; 4.P.236.229; 4.P.236.230; 4.P.236.231; 4.P.236.236; 4.P.236.237; 4.P.236.238; 4.P.236.239; 4.P.236.154; 4.P.236.157; 4.P.236.166; 4.P.236.169; 4.P.236.172; 4.P.236.175; 4.P.236.240; 4.P.236.244; 4.P.237.228; 4.P.237.229; 4.P.237.230; 4.P.237.231; 4.P.237.236; 4.P.237.237; 4.P.237.238; 4.P.237.239; 4.P.237.154; 4.P.237.157; 4.P.237.166; 4.P.237.169; 4.P.237.172; 4.P.237.175; 4.P.237.240; 4.P.237.244; 4.P.238.228; 4.P.238.229; 4.P.238.230; 4.P.238.231; 4.P.238.236; 4.P.238.237; 4.P.238.238; 4.P.238.239; 4.P.238.154; 4.P.238.157; 4.P.238.166; 4.P.238.169; 4.P.238.172; 4.P.238.175; 4.P.238.240; 4.P.238.244; 4.P.239.228; 4.P.239.229; 4.P.239.230; 4.P.239.231; 4.P.239.236; 4.P.239.237; 4.P.239.238; 4.P.239.239; 4.P.239.154; 4.P.239.157; 4.P.239.166; 4.P.239.169; 4.P.239.172; 4.P.239.175; 4.P.239.240; 4.P.239.244; 4.P.154.228; 4.P.154.229; 4.P.154.230; 4.P.154.231; 4.P.154.236; 4.P.154.237; 4.P.154.238; 4.P.154.239; 4.P.154.154; 4.P.154.157; 4.P.154.166; 4.P.154.169; 4.P.154.172; 4.P.154.175; 4.P.154.240; 4.P.154.244; 4.P.157.228; 4.P.157.229; 4.P.157.230; 4.P.157.231; 4.P.157.236; 4.P.157.237; 4.P.157.238; 4.P.157.239; 4.P.157.154; 4.P.157.157; 4.P.157.166; 4.P.157.169; 4.P.157.172; 4.P.157.175; 4.P.157.240; 4.P.157.244; 4.P.166.228; 4.P. 166.229; 4.P.166.230; 4.P.166.231; 4.P.166.236; 4.P.166.237; 4.P.166.238; 4.P.166.239; 4.P.166.154; 4.P.166.157; 4.P.166.166; 4.P.166.169; 4.P.166.172; 4.P.166.175; 4.P.166.240; 4.P.166.244; 4.P.169.228; 4.P.169.229; 4.P.169.230; 4.P.169.231; 4.P.169.236; 4.P.169.237; 4.P.169.238; 4.P.169.239; 4.P.169.154; 4.P.169.157; 4.P.169.166; 4.P.169.169; 4.P.169.172; 4.P.169.175; 4.P.169.240; 4.P.169.244; 4.P.172.228; 4.P.172.229; 4.P.172.230; 4.P.172.231; 4.P.172.236; 4.P.172.237; 4.P.172.238; 4.P.172.239; 4.P.172.154; 4.P.172.157; 4.P.172.166; 4.P.172.169; 4.P.172.172; 4.P.172.175; 4.P.172.240; 4.P.172.244; 4.P.175.228; 4.P.175.229; 4.P.175.230; 4.P.175.231; 4.P.175.236; 4.P.175.237; 4.P.175.238; 4.P.175.239; 4.P.175.154; 4.P.175.157; 4.P.175.166; 4.P.175.169; 4.P.175.172; 4.P.175.175; 4.P.175.240; 4.P.175.244; 4.P.240.228; 4.P.240.229; 4.P.240.230; 4.P.240.231; 4.P.240.236; 4.P.240.237; 4.P.240.238; 4.P.240.239; 4.P.240.154; 4.P.240.157; 4.P.240.166; 4.P.240.169; 4.P.240.172; 4.P.240.175; 4.P.240.240; 4.P.240.244; 4.P.244.228; 4.P.244.229; 4.P.244.230; 4.P.244.231; 4.P.244.236; 4.P.244.237; 4.P.244.238; 4.P.244.239; 4.P.244.154; 4.P.244.157; 4.P.244.166; 4.P.244.169; 4.P.244.172; 4.P.244.175; 4.P.244.240; 4.P.244.244;

4.U's Prodrug

     4.U.228.228; 4.U.228.229; 4.U.228.230; 4.U.228.231; 4.U.228.236; 4.U.228.237; 4.U.228.238; 4.U.228.239; 4.U.228.154; 4.U.228.157; 4.U.228.166; 4.U.228.169; 4.U.228.172; 4.U.228.175; 4.U.228.240; 4.U.228.244; 4.U.229.228; 4.U.229.229; 4.U.229.230; 4.U.229.231; 4.U.229.236; 4.U.229.237; 4.U.229.238; 4.U.229.239; 4.U.229.154; 4.U.229.157; 4.U.229.166; 4.U.229.169; 4.U.229.172; 4.U.229.175; 4.U.229.240; 4.U.229.244; 4.U.230.228; 4.U.230.229; 4.U.230.230; 4.U.230.231; 4.U.230.236; 4.U.230.237; 4.U.230.238; 4.U.230.239; 4.U.230.154; 4.U.230.157; 4.U.230.166; 4.U.230.169; 4.U.230.172; 4.U.230.175; 4.U.230.240; 4.U.230.244; 4.U.231.228; 4.U.231.229; 4.U.231.230; 4.U.231.231; 4.U.231.236; 4.U.231.237; 4.U.231.238; 4.U.231.239; 4.U.231.154; 4.U.231.157; 4.U.231.166; 4.U.231.169; 4.U.231.172; 4.U.231.175; 4.U.231.240; 4.U.231.244; 4.U.236.228; 4.U.236.229; 4.U.236.230; 4.U.236.231; 4.U.236.236; 4.U.236.237; 4.U.236.238; 4.U.236.239; 4.U.236.154; 4.U.236.157; 4.U.236.166; 4.U.236.169; 4.U.236.172; 4.U.236.175; 4.U.236.240; 4.U.236.244; 4.U.237.228; 4.U.237.229; 4.U.237.230; 4.U.237.231; 4.U.237.236; 4.U.237.237; 4.U.237.238; 4.U.237.239; 4.U.237.154; 4.U.237.157; 4.U.237.166; 4.U.237.169; 4.U.237.172; 4.U.237.175; 4.U.237.240; 4.U.237.244; 4.U.238.228; 4.U.238.229; 4.U.238.230; 4.U.238.231; 4.U.238.236; 4.U.238.237; 4.U.238.238; 4.U.238.239; 4.U.238.154; 4.U.238.157; 4.U.238.166; 4.U.238.169; 4.U.238.172; 4.U.238.175; 4.U.238.240; 4.U.238.244; 4.U.239.228; 4.U.239.229; 4.U.239.230; 4.U.239.231; 4.U.239.236; 4.U.239.237; 4.U.239.238; 4.U.239.239; 4.U.239.154; 4.U.239.157; 4.U.239.166; 4.U.239.169; 4.U.239.172; 4.U.239.175; 4.U.239.240; 4.U.239.244; 4.U.154.228; 4.U.154.229; 4.U.154.230; 4.U.154.231; 4.U.154.236; 4.U.154.237; 4.U.154.238; 4.U.154.239; 4.U.154.154; 4.U.154.157; 4.U.154.166; 4.U.154.169; 4.U.154.172; 4.U.154.175; 4.U.154.240; 4.U.154.244; 4.U.157.228; 4.U.157.229; 4.U.157.230; 4.U.157.231; 4.U.157.236; 4.U.157.237; 4.U.157.238; 4.U.157.239; 4.U.157.154; 4.U.157.157; 4.U.157.166; 4.U.157.169; 4.U.157.172; 4.U.157.175; 4.U.157.240; 4.U.157.244; 4.U.166.228; 4.U.166.229; 4.U.166.230; 4.U.166.231; 4.U.166.236; 4.U.166.237; 4.U.166.238; 4.U.166.239; 4.U.166.154; 4.U.166.157; 4.U.166.166; 4.U.166.169; 4.U.166.172; 4.U.166.175; 4.U.166.240; 4.U.166.244; 4.U.169.228; 4.U.169.229; 4.U.169.230; 4.U.169.231; 4.U.169.236; 4.U.169.237; 4.U.169.238; 4.U.169.239; 4.U.169.154; 4.U.169.157; 4.U.169.166; 4.U.169.169; 4.U.169.172; 4.U.169.175; 4.U.169.240; 4.U.169.244; 4.U.172.228; 4.U.172.229; 4.U.172.230; 4.U.172.231; 4.U.172.236; 4.U.172.237; 4.U.172.238; 4.U.172.239; 4.U.172.154; 4.U.172.157; 4.U.172.166; 4.U.172.169; 4.U.172.172; 4.U.172.175; 4.U.172.240; 4.U.172.244; 4.U.175.228; 4.U.175.229; 4.U.175.230; 4.U.175.231; 4.U.175.236; 4.U.175.237; 4.U.175.238; 4.U.175.239; 4.U.175.154; 4.U.175.157; 4.U.175.166; 4.U.175.169; 4.U.175.172; 4.U.175.175; 4.U.175.240; 4.U.175.244; 4.U.240.228; 4.U.240.229; 4.U.240.230; 4.U.240.231; 4.U.240.236; 4.U.240.237; 4.U.240.238; 4.U.240.239; 4.U.240.154; 4.U.240.157; 4.U.240.166; 4.U.240.169; 4.U.240.172; 4.U.240.175; 4.U.240.240; 4.U.240.244; 4.U.244.228; 4.U.244.229; 4.U.244.230; 4.U.244.231; 4.U.244.236; 4.U.244.237; 4.U.244.238; 4.U.244.239; 4.U.244.154; 4.U.244.157; 4.U.244.166; 4.U.244.169; 4.U.244.172; 4.U.244.175; 4.U.244.240; 4.U.244.244;

4.W Prodrug

     4.W. 228.228; 4.W.228.229; 4.W.228.230; 4.W.228.231; 4.W.228.236; 4.W.228.237; 4.W.228.238; 4.W.228.239; 4.W.228.154; 4.W.228.157; 4.W.228.166; 4.W.228.169; 4.W.228.172; 4.W.228.175; 4.W.228.240; 4.W.228.244; 4.W.229.228; 4.W.229.229; 4.W.229.230; 4.W.229.231; 4.W.229.236; 4.W.229.237; 4.W.229.238; 4.W.229.239; 4.W.229.154; 4.W.229.157; 4.W.229.166; 4.W.229.169; 4.W.229.172; 4.W.229.175; 4.W.229.240; 4.W.229.244; 4.W.230.228; 4.W.230.229; 4.W.230.230; 4.W.230.231; 4.W.230.236; 4.W.230.237; 4.W.230.238; 4.W.230.239; 4.W.230.154; 4.W.230.157; 4.W.230.166; 4.W.230.169; 4.W.230.172; 4.W.230.175; 4.W.230.240; 4.W.230.244; 4.W.231.228; 4.W.231.229; 4.W.231.230; 4.W.231.231; 4.W.231.236; 4.W.231.237; 4.W.231.238; 4.W.231.239; 4.W.231.154; 4.W.231.157; 4.W.231.166; 4.W.231.169; 4.W.231.172; 4.W.231.175; 4.W.231.240; 4.W.231.244; 4.W.236.228; 4.W.236.229; 4.W.236.230; 4.W.236.231; 4.W.236.236; 4.W.236.237; 4.W.236.238; 4.W.236.239; 4.W.236.154; 4.W.236.157; 4.W.236.166; 4.W.236.169; 4.W.236.172; 4.W.236.175; 4.W.236.240; 4.W.236.244; 4.W.237.228; 4.W.237.229; 4.W.237.230; 4.W.237.231; 4.W.237.236; 4.W.237.237; 4.W.237.238; 4.W.237.239; 4.W.237.154; 4.W.237.157; 4.W.237.166; 4.W. 237.169; 4.W.237.172; 4.W.237.175; 4.W.237.240; 4.W.237.244; 4.W.238.228; 4.W.238.229; 4.W.238.230; 4.W.238.231; 4.W.238.236; 4.W.238.237; 4.W.238.238; 4.W.238.239; 4.W.238.154; 4.W.238.157; 4.W.238.166; 4.W.238.169; 4.W.238.172; 4.W.238.175; 4.W.238.240; 4.W.238.244; 4.W.239.228; 4.W.239.229; 4.W.239.230; 4.W.239.231; 4.W.239.236; 4.W.239.237; 4.W.239.238; 4.W.239.239; 4.W.239.154; 4.W.239.157; 4.W.239.166; 4.W.239.169; 4.W.239.172; 4.W.239.175; 4.W.239.240; 4.W.239.244; 4.W.154.228; 4.W.154.229; 4.W.154.230; 4.W.154.231; 4.W.154.236; 4.W.154.237; 4.W.154.238; 4.W.154.239; 4.W.154.154; 4.W.154.157; 4.W.154.166; 4.W.154.169; 4.W.154.172; 4.W.154.175; 4.W.154.240; 4.W.154.244; 4.W.157.228; 4.W. 157.229; 4.W.157.230; 4.W.157.231; 4.W.157.236; 4.W.157.237; 4.W.157.238; 4.W.157.239; 4.W.157.154; 4.W.157.157; 4.W.157.166; 4.W.157.169; 4.W.157.172; 4.W.157.175; 4.W.157.240; 4.W.157.244; 4.W.166.228; 4.W.166.229; 4.W.166.230; 4.W.166.231; 4.W.166.236; 4.W.166.237; 4.W.166.238; 4.W.166.239; 4.W.166.154; 4.W.166.157; 4.W.166.166; 4.W.166.169; 4.W.166.172; 4.W.166.175; 4.W.166.240; 4.W.166.244; 4.W. 169.228; 4.W. 169.229; 4.W. 169.230; 4.W. 169.231; 4.W. 169.236; 4.W. 169.237; 4.W. 169.238; 4.W. 169.239; 4.W. 169.154; 4.W. 169.157; 4.W. 169.166; 4.W. 169.169; 4.W. 169.172; 4.W. 169.175; 4.W. 169.240; 4.W. 169.244; 4.W.172.228; 4.W. 172.229; 4.W.172.230; 4.W.172.231; 4.W.172.236; 4.W.172.237; 4.W.172.238; 4.W.172.239; 4.W.172.154; 4.W.172.157; 4.W.172.166; 4.W.172.169; 4.W.172.172; 4.W.172.175; 4.W.172.240; 4.W.172.244; 4.W.175.228; 4.W.175.229; 4.W.175.230; 4.W.175.231; 4.W.175.236; 4.W.175.237; 4.W.175.238; 4.W.175.239; 4.W.175.154; 4.W.175.157; 4.W.175.166; 4.W.175.169; 4.W.175.172; 4.W.175.175; 4.W.175.240; 4.W.175.244; 4.W.240.228; 4.W.240.229; 4.W.240.230; 4.W.240.231; 4.W.240.236; 4.W.240.237; 4.W.240.238; 4.W.240.239; 4.W.240.154; 4.W.240.157; 4.W.240.166; 4.W.240.169; 4.W.240.172; 4.W.240.175; 4.W.240.240; 4.W.240.244; 4.W.244.228; 4.W.244.229; 4.W.244.230; 4.W.244.231; 4.W.244.236; 4.W.244.237; 4.W.244.238; 4.W.244.239; 4.W.244.154; 4.W.244.157; 4.W.244.166; 4.W.244.169; 4.W.244.172; 4.W.244.175; 4.W.244.240; 4.W.244.244;

4.Y's Prodrug

     4.Y.228.228; 4.Y.228.229; 4.Y.228.230; 4.Y.228.231; 4.Y.228.236; 4.Y.228.237; 4.Y.228.238; 4.Y.228.239; 4.Y.228.154; 4.Y.228.157; 4.Y.228.166; 4.Y.228.169; 4.Y.228.172; 4.Y.228.175; 4.Y.228.240; 4.Y.228.244; 4.Y.229.228; 4.Y.229.229; 4.Y.229.230; 4.Y.229.231; 4.Y.229.236; 4.Y.229.237; 4.Y.229.238; 4.Y.229.239; 4.Y.229.154; 4.Y.229.157; 4.Y.229.166; 4.Y.229.169; 4.Y.229.172; 4.Y.229.175; 4.Y.229.240; 4.Y.229.244; 4.Y.230.228; 4.Y.230.229; 4.Y.230.230; 4.Y.230.231; 4.Y.230.236; 4.Y.230.237; 4.Y.230.238; 4.Y.230.239; 4.Y.230.154; 4.Y.230.157; 4.Y.230.166; 4.Y.230.169; 4.Y.230.172; 4.Y.230.175; 4.Y.230.240; 4.Y.230.244; 4.Y.231.228; 4.Y.231.229; 4.Y.231.230; 4.Y.231.231; 4.Y.231.236; 4.Y.231.237; 4.Y.231.238; 4.Y.231.239; 4.Y.231.154; 4.Y.231.157; 4.Y.231.166; 4.Y.231.169; 4.Y.231.172; 4.Y.231.175; 4.Y.231.240; 4.Y.231.244; 4.Y.236.228; 4.Y.236.229; 4.Y.236.230; 4.Y.236.231; 4.Y.236.236; 4.Y.236.237; 4.Y.236.238; 4.Y.236.239; 4.Y.236.154; 4.Y.236.157; 4.Y.236.166; 4.Y.236.169; 4.Y.236.172; 4.Y.236.175; 4.Y.236.240; 4.Y.236.244; 4.Y.237.228; 4.Y.237.229; 4.Y.237.230; 4.Y.237.231; 4.Y.237.236; 4.Y.237.237; 4.Y.237.238; 4.Y.237.239; 4.Y.237.154; 4.Y.237.157; 4.Y.237.166; 4.Y.237.169; 4.Y.237.172; 4.Y.237.175; 4.Y.237.240; 4.Y.237.244; 4.Y.238.228; 4.Y.238.229; 4.Y.238.230; 4.Y.238.231; 4.Y.238.236; 4.Y.238.237; 4.Y.238.238; 4.Y.238.239; 4.Y.238.154; 4.Y.238.157; 4.Y.238.166; 4.Y.238.169; 4.Y.238.172; 4.Y.238.175; 4.Y.238.240; 4.Y.238.244; 4.Y.239.228; 4.Y.239.229; 4.Y.239.230; 4.Y.239.231; 4.Y.239.236; 4.Y.239.237; 4.Y.239.238; 4.Y.239.239; 4.Y.239.154; 4.Y.239.157; 4.Y.239.166; 4.Y.239.169; 4.Y.239.172; 4.Y.239.175; 4.Y.239.240; 4.Y.239.244; 4.Y.154.228; 4.Y.154.229; 4.Y.154.230; 4.Y.154.231; 4.Y.154.236; 4.Y.154.237; 4.Y.154.238; 4.Y.154.239; 4.Y.154.154; 4.Y.154.157; 4.Y.154.166; 4.Y.154.169; 4.Y.154.172; 4.Y.154.175; 4.Y.154.240; 4.Y.154.244; 4.Y.157.228; 4.Y.157.229; 4.Y.157.230; 4.Y.157.231; 4.Y.157.236; 4.Y.157.237; 4.Y.157.238; 4.Y.157.239; 4.Y.157.154; 4.Y.157.157; 4.Y.157.166; 4.Y.157.169; 4.Y.157.172; 4.Y.157.175; 4.Y.157.240; 4.Y.157.244; 4.Y.166.228; 4.Y.166.229; 4.Y.166.230; 4.Y.166.231; 4.Y.166.236; 4.Y.166.237; 4.Y.166.238; 4.Y.166.239; 4.Y.166.154; 4.Y.166.157; 4.Y.166.166; 4.Y.166.169; 4.Y.166.172; 4.Y.166.175; 4.Y.166.240; 4.Y.166.244; 4.Y.169.228; 4.Y.169.229; 4.Y. 169.230; 4.Y.169.231; 4.Y.169.236; 4.Y.169.237; 4.Y. 169.238; 4.Y.169.239; 4.Y.169.154; 4.Y.169.157; 4.Y.169.166; 4.Y.169.169; 4.Y.169.172; 4.Y.169.175; 4.Y.169.240; 4.Y.169.244; 4.Y.172.228; 4.Y.172.229; 4.Y.172.230; 4.Y.172.231; 4.Y.172.236; 4.Y.172.237; 4.Y.172.238; 4.Y.172.239; 4.Y.172.154; 4.Y.172.157; 4.Y.172.166; 4.Y.172.169; 4.Y.172.172; 4.Y.172.175; 4.Y.172.240; 4.Y.172.244; 4.Y.175.228; 4.Y.175.229; 4.Y.175.230; 4.Y.175.231; 4.Y.175.236; 4.Y.175.237; 4.Y.175.238; 4.Y.175.239; 4.Y.175.154; 4.Y.175.157; 4.Y.175.166; 4.Y.175.169; 4.Y.175.172; 4.Y.175.175; 4.Y.175.240; 4.Y.175.244; 4.Y.240.228; 4.Y.240.229; 4.Y.240.230; 4.Y.240.231; 4.Y.240.236; 4.Y.240.237; 4.Y.240.238; 4.Y.240.239; 4.Y.240.154; 4.Y.240.157; 4.Y.240.166; 4.Y.240.169; 4.Y.240.172; 4.Y.240.175; 4.Y.240.240; 4.Y.240.244; 4.Y.244.228; 4.Y.244.229; 4.Y.244.230; 4.Y.244.231; 4.Y.244.236; 4.Y.244.237; 4.Y.244.238; 4.Y.244.239; 4.Y.244.154; 4.Y.244.157; 4.Y.244.166; 4.Y.244.169; 4.Y.244.172; 4.Y.244.175; 4.Y.244.240; 4.Y.244.244;

5.B's Prodrug

    5.B.228.228; 5.B.228.229; 5.B.228.230; 5.B.228.231; 5.B.228.236; 5.B.228.237; 5.B.228.238; 5.B.228.239; 5.B.228.154; 5.B.228.157; 5.B.228.166; 5.B.228.169; 5.B.228.172; 5.B.228.175; 5.B.228.240; 5.B.228.244; 5.B.229.228; 5.B.229.229; 5.B.229.230; 5.B.229.231; 5.B.229.236; 5.B.229.237; 5.B.229.238; 5.B.229.239; 5.B.229.154; 5.B.229.157; 5.B.229.166; 5.B.229.169; 5.B.229.172; 5.B.229.175; 5.B.229.240; 5.B.229.244; 5.B.230.228; 5.B.230.229; 5.B.230.230; 5.B.230.231; 5.B.230.236; 5.B.230.237; 5.B.230.238; 5.B.230.239; 5.B.230.154; 5.B.230.157; 5.B.230.166; 5.B.230.169; 5.B.230.172; 5.B.230.175; 5.B.230.240; 5.B.230.244; 5.B.231.228; 5.B.231.229; 5.B.231.230; 5.B.231.231; 5.B.231.236; 5.B.231.237; 5.B.231.238; 5.B.231.239; 5.B.231.154; 5.B.231.157; 5.B.231.166; 5.B.231.169; 5.B.231.172; 5.B.231.175; 5.B.231.240; 5.B.231.244; 5.B.236.228; 5.B.236.229; 5.B.236.230; 5.B.236.231; 5.B.236.236; 5.B.236.237; 5.B.236.238; 5.B.236.239; 5.B.236.154; 5.B.236.157; 5.B.236.166; 5.B.236.169; 5.B.236.172; 5.B.236.175; 5.B.236.240; 5.B.236.244; 5.B.237.228; 5.B.237.229; 5.B.237.230; 5.B.237.231; 5.B.237.236; 5.B.237.237; 5.B.237.238; 5.B.237.239; 5.B.237.154; 5.B.237.157; 5.B.237.166; 5.B.237.169; 5.B.237.172; 5.B.237.175; 5.B.237.240; 5.B.237.244; 5.B.238.228; 5.B.238.229; 5.B.238.230; 5.B.238.231; 5.B.238.236; 5.B.238.237; 5.B.238.238; 5.B.238.239; 5.B.238.154; 5.B.238.157; 5.B.238.166; 5.B.238.169; 5.B.238.172; 5.B.238.175; 5.B.238.240; 5.B.238.244; 5.B.239.228; 5.B.239.229; 5.B.239.230; 5.B.239.231; 5.B.239.236; 5.B.239.237; 5.B.239.238; 5.B.239.239; 5.B.239.154; 5.B.239.157; 5.B.239.166; 5.B.239.169; 5.B.239.172; 5.B.239.175; 5.B.239.240; 5.B.239.244; 5.B.154.228; 5.B.154.229; 5.B.154.230; 5.B.154.231; 5.B.154.236; 5.B.154.237; 5.B.154.238; 5.B.154.239; 5.B.154.154; 5.B.154.157; 5.B.154.166; 5.B.154.169; 5.B.154.172; 5.B.154.175; 5.B.154.240; 5.B.154.244; 5.B.157.228; 5.B.157.229; 5.B.157.230; 5.B.157.231; 5.B.157.236; 5.B.157.237; 5.B.157.238; 5.B.157.239; 5.B.157.154; 5.B.157.157; 5.B.157.166; 5.B.157.169; 5.B.157.172; 5.B.157.175; 5.B.157.240; 5.B.157.244; 5.B.166.228; 5.B.166.229; 5.B.166.230; 5.B.166.231; 5.B.166.236; 5.B.166.237; 5.B.166.238; 5.B.166.239; 5.B.166.154; 5.B.166.157; 5.B.166.166; 5.B.166.169; 5.B.166.172; 5.B.166.175; 5.B.166.240; 5.B.166.244; 5.B.169.228; 5.B.169.229; 5.B.169.230; 5.B.169.231; 5.B.169.236; 5.B.169.237; 5.B.169.238; 5.B.169.239; 5.B.169.154; 5.B.169.157; 5.B.169.166; 5.B.169.169; 5.B.169.172; 5.B.169.175; 5.B.169.240; 5.B.169.244; 5.B.172.228; 5.B.172.229; 5.B.172.230; 5.B.172.231; 5.B.172.236; 5.B.172.237; 5.B.172.238; 5.B.172.239; 5.B.172.154; 5.B.172.157; 5.B.172.166; 5.B.172.169; 5.B.172.172; 5.B.172.175; 5.B.172.240; 5.B.172.244; 5.B.175.228; 5.B.175.229; 5.B.175.230; 5.B.175.231; 5.B.175.236; 5.B.175.237; 5.B.175.238; 5.B.175.239; 5.B.175.154; 5.B.175.157; 5.B.175.166; 5.B.175.169; 5.B.175.172; 5.B.175.175; 5.B.175.240; 5.B.175.244; 5.B.240.228; 5.B.240.229; 5.B.240.230; 5.B.240.231; 5.B.240.236; 5.B.240.237; 5.B.240.238; 5.B.240.239; 5.B.240.154; 5.B.240.157; 5.B.240.166; 5.B.240.169; 5.B.240.172; 5.B.240.175; 5.B.240.240; 5.B.240.244; 5.B.244.228; 5.B.244.229; 5.B.244.230; 5.B.244.231; 5.B.244.236; 5.B.244.237; 5.B.244.238; 5.B.244.239; 5.B.244.154; 5.B.244.157; 5.B.244.166; 5.B.244.169; 5.B.244.172; 5.B.244.175; 5.B.244.240; 5.B.244.244;

5.D Prodrug

     5.D.228.228; 5.D.228.229; 5.D.228.230; 5.D.228.231; 5.D.228.236; 5.D.228.237; 5.D.228.238; 5.D.228.239; 5.D.228.154; 5.D.228.157; 5.D.228.166; 5.D.228.169; 5.D.228.172; 5.D.228.175; 5.D.228.240; 5.D.228.244; 5.D.229.228; 5.D.229.229; 5.D.229.230; 5.D.229.231; 5.D.229.236; 5.D.229.237; 5.D.229.238; 5.D.229.239; 5.D.229.154; 5.D.229.157; 5.D.229.166; 5.D.229.169; 5.D.229.172; 5.D.229.175; 5.D.229.240; 5.D.229.244; 5.D.230.228; 5.D.230.229; 5.D.230.230; 5.D.230.231; 5.D.230.236; 5.D.230.237; 5.D.230.238; 5.D.230.239; 5.D.230.154; 5.D.230.157; 5.D.230.166; 5.D.230.169; 5.D.230.172; 5.D.230.175; 5.D.230.240; 5.D.230.244; 5.D.231.228; 5.D.231.229; 5.D.231.230; 5.D.231.231; 5.D.231.236; 5.D.231.237; 5.D.231.238; 5.D.231.239; 5.D.231.154; 5.D.231.157; 5.D.231.166; 5.D.231.169; 5.D.231.172; 5.D.231.175; 5.D.231.240; 5.D.231.244; 5.D.236.228; 5.D.236.229; 5.D.236.230; 5.D.236.231; 5.D.236.236; 5.D.236.237; 5.D.236.238; 5.D.236.239; 5.D.236.154; 5.D.236.157; 5.D.236.166; 5.D.236.169; 5.D.236.172; 5.D.236.175; 5.D.236.240; 5.D.236.244; 5.D.237.228; 5.D.237.229; 5.D.237.230; 5.D.237.231; 5.D.237.236; 5.D.237.237; 5.D.237.238; 5.D.237.239; 5.D.237.154; 5.D.237.157; 5.D.237.166; 5.D.237.169; 5.D.237.172; 5.D.237.175; 5.D.237.240; 5.D.237.244; 5.D.238.228; 5.D.238.229; 5.D.238.230; 5.D.238.231; 5.D.238.236; 5.D.238.237; 5.D.238.238; 5.D.238.239; 5.D.238.154; 5.D.238.157; 5.D.238.166; 5.D.238.169; 5.D.238.172; 5.D.238.175; 5.D.238.240; 5.D.238.244; 5.D.239.228; 5.D.239.229; 5.D.239.230; 5.D.239.231; 5.D.239.236; 5.D.239.237; 5.D.239.238; 5.D.239.239; 5.D.239.154; 5.D.239.157; 5.D.239.166; 5.D.239.169; 5.D.239.172; 5.D.239.175; 5.D.239.240; 5.D.239.244; 5.D.154.228; 5.D.154.229; 5.D.154.230; 5.D.154.231; 5.D.154.236; 5.D.154.237; 5.D.154.238; 5.D.154.239; 5.D.154.154; 5.D.154.157; 5.D.154.166; 5.D.154.169; 5.D.154.172; 5.D.154.175; 5.D.154.240; 5.D.154.244; 5.D.157.228; 5.D. 157.229; 5.D.157.230; 5.D.157.231; 5.D.157.236; 5.D.157.237; 5.D.157.238; 5.D.157.239; 5.D.157.154; 5.D.157.157; 5.D.157.166; 5.D.157.169; 5.D.157.172; 5.D.157.175; 5.D.157.240; 5.D.157.244; 5.D.166.228; 5.D.166.229; 5.D.166.230; 5.D.166.231; 5.D.166.236; 5.D.166.237; 5.D.166.238; 5.D.166.239; 5.D.166.154; 5.D.166.157; 5.D.166.166; 5.D.166.169; 5.D.166.172; 5.D.166.175; 5.D.166.240; 5.D.166.244; 5.D. 169.228; 5.D.169.229; 5.D.169.230; 5.D.169.231; 5.D.169.236; 5.D.169.237; 5.D.169.238; 5.D. 169.239; 5.D.169.154; 5.D.169.157; 5.D.169.166; 5.D.169.169; 5.D.169.172; 5.D.169.175; 5.D.169.240; 5.D.169.244; 5.D.172.228; 5.D. 172.229; 5.D.172.230; 5.D.172.231; 5.D.172.236; 5.D.172.237; 5.D.172.238; 5.D.172.239; 5.D.172.154; 5.D.172.157; 5.D.172.166; 5.D.172.169; 5.D.172.172; 5.D.172.175; 5.D.172.240; 5.D.172.244; 5.D.175.228; 5.D. 175.229; 5.D.175.230; 5.D.175.231; 5.D.175.236; 5.D.175.237; 5.D.175.238; 5.D.175.239; 5.D.175.154; 5.D.175.157; 5.D.175.166; 5.D.175.169; 5.D.175.172; 5.D.175.175; 5.D.175.240; 5.D.175.244; 5.D.240.228; 5.D.240.229; 5.D.240.230; 5.D.240.231; 5.D.240.236; 5.D.240.237; 5.D.240.238; 5.D.240.239; 5.D.240.154; 5.D.240.157; 5.D.240.166; 5.D.240.169; 5.D.240.172; 5.D.240.175; 5.D.240.240; 5.D.240.244; 5.D.244.228; 5.D.244.229; 5.D.244.230; 5.D.244.231; 5.D.244.236; 5.D.244.237; 5.D.244.238; 5.D.244.239; 5.D.244.154; 5.D.244.157; 5.D.244.166; 5.D.244.169; 5.D.244.172; 5.D.244.175; 5.D.244.240; 5.D.244.244;

5.E Prodrug

5.E.228.228; 5.E.228.229; 5.E.228.230; 5.E.228.231; 5.E.228.236; 5.E.228.237; 5.E.228.238; 5.E.228.239; 5.E.228.154; 5.E.228.157; 5.E.228.166; 5.E.228.169; 5.E.228.172; 5.E.228.175; 5.E.228.240; 5.E.228.244; 5.E.229.228; 5.E.229.229; 5.E.229.230; 5.E.229.231; 5.E.229.236; 5.E.229.237; 5.E.229.238; 5.E.229.239; 5.E.229.154; 5.E.229.157; 5.E.229.166; 5.E.229.169; 5.E.229.172; 5.E.229.175; 5.E.229.240; 5.E.229.244; 5.E.230.228; 5.E.230.229; 5.E.230.230; 5.E.230.231; 5.E.230.236; 5.E.230.237; 5.E.230.238; 5.E.230.239; 5.E.230.154; 5.E.230.157; 5.E.230.166; 5.E.230.169; 5.E.230.172; 5.E.230.175; 5.E.230.240; 5.E.230.244; 5.E.231.228; 5.E.231.229; 5.E.231.230; 5.E.231.231; 5.E.231.236; 5.E.231.237; 5.E.231.238; 5.E.231.239; 5.E.231.154; 5.E.231.157; 5.E.231.166; 5.E.231.169; 5.E.231.172; 5.E.231.175; 5.E.231.240; 5.E.231.244; 5.E.236.228; 5.E.236.229; 5.E.236.230; 5.E.236.231; 5.E.236.236; 5.E.236.237; 5.E.236.238; 5.E.236.239; 5.E.236.154; 5.E.236.157; 5.E.236.166; 5.E.236.169; 5.E.236.172; 5.E.236.175; 5.E.236.240; 5.E.236.244; 5.E.237.228; 5.E.237.229; 5.E.237.230; 5.E.237.231; 5.E.237.236; 5.E.237.237; 5.E.237.238; 5.E.237.239; 5.E.237.154; 5.E.237.157; 5.E.237.166; 5.E.237.169; 5.E.237.172; 5.E.237.175; 5.E.237.240; 5.E.237.244; 5.E.238.228; 5.E.238.229; 5.E.238.230; 5.E.238.231; 5.E.238.236; 5.E.238.237; 5.E.238.238; 5.E.238.239; 5.E.238.154; 5.E.238.157; 5.E.238.166; 5.E.238.169; 5.E.238.172; 5.E.238.175; 5.E.238.240; 5.E.238.244; 5.E.239.228; 5.E.239.229; 5.E.239.230; 5.E.239.231; 5.E.239.236; 5.E.239.237; 5.E.239.238; 5.E.239.239; 5.E.239.154; 5.E.239.157; 5.E.239.166; 5.E.239.169; 5.E.239.172; 5.E.239.175; 5.E.239.240; 5.E.239.244; 5.E.154.228; 5.E.154.229; 5.E.154.230; 5.E.154.231; 5.E.154.236; 5.E.154.237; 5.E.154.238; 5.E.154.239; 5.E.154.154; 5.E.154.157; 5.E.154.166; 5.E.154.169; 5.E.154.172; 5.E.154.175; 5.E.154.240; 5.E.154.244; 5.E.157.228; 5.E.157.229; 5.E.157.230; 5.E.157.231; 5.E.157.236; 5.E.157.237; 5.E.157.238; 5.E.157.239; 5.E.157.154; 5.E.157.157; 5.E.157.166; 5.E.157.169; 5.E.157.172; 5.E.157.175; 5.E.157.240; 5.E.157.244; 5.E.166.228; 5.E.166.229; 5.E.166.230; 5.E.166.231; 5.E.166.236; 5.E.166.237; 5.E.166.238; 5.E.166.239; 5.E.166.154; 5.E.166.157; 5.E.166.166; 5.E.166.169; 5.E.166.172; 5.E.166.175; 5.E.166.240; 5.E.166.244; 5.E.169.228; 5.E.169.229; 5.E.169.230; 5.E.169.231; 5.E.169.236; 5.E.169.237; 5.E.169.238; 5.E.169.239; 5.E.169.154; 5.E.169.157; 5.E.169.166; 5.E.169.169; 5.E.169.172; 5.E.169.175; 5.E.169.240; 5.E.169.244; 5.E.172.228; 5.E.172.229; 5.E.172.230; 5.E.172.231; 5.E.172.236; 5.E.172.237; 5.E.172.238; 5.E.172.239; 5.E.172.154; 5.E.172.157; 5.E.172.166; 5.E.172.169; 5.E.172.172; 5.E.172.175; 5.E.172.240; 5.E.172.244; 5.E.175.228; 5.E.175.229; 5.E.175.230; 5.E.175.231; 5.E.175.236; 5.E.175.237; 5.E.175.238; 5.E.175.239; 5.E.175.154; 5.E.175.157; 5.E.175.166; 5.E.175.169; 5.E.175.172; 5.E.175.175; 5.E.175.240; 5.E.175.244; 5.E.240.228; 5.E.240.229; 5.E.240.230; 5.E.240.231; 5.E.240.236; 5.E.240.237; 5.E.240.238; 5.E.240.239; 5.E.240.154; 5.E.240.157; 5.E.240.166; 5.E.240.169; 5.E.240.172; 5.E.240.175; 5.E.240.240; 5.E.240.244; 5.E.244.228; 5.E.244.229; 5.E.244.230; 5.E.244.231; 5.E.244.236; 5.E.244.237; 5.E.244.238; 5.E.244.239; 5.E.244.154; 5.E.244.157; 5.E.244.166; 5.E.244.169; 5.E.244.172; 5.E.244.175; 5.E.244.240; 5.E.244.244;

5.G's Prodrug

     5.G.228.228; 5.G.228.229; 5.G.228.230; 5.G.228.231; 5.G.228.236; 5.G.228.237; 5.G.228.238; 5.G.228.239; 5.G.228.154; 5.G.228.157; 5.G.228.166; 5.G.228.169; 5.G.228.172; 5.G.228.175; 5.G.228.240; 5.G.228.244; 5.G.229.228; 5.G.229.229; 5.G.229.230; 5.G.229.231; 5.G.229.236; 5.G.229.237; 5.G.229.238; 5.G.229.239; 5.G.229.154; 5.G.229.157; 5.G.229.166; 5.G.229.169; 5.G.229.172; 5.G.229.175; 5.G.229.240; 5.G.229.244; 5.G.230.228; 5.G.230.229; 5.G.230.230; 5.G.230.231; 5.G.230.236; 5.G.230.237; 5.G.230.238; 5.G.230.239; 5.G.230.154; 5.G.230.157; 5.G.230.166; 5.G.230.169; 5.G.230.172; 5.G.230.175; 5.G.230.240; 5.G.230.244; 5.G.231.228; 5.G.231.229; 5.G.231.230; 5.G.231.231; 5.G.231.236; 5.G.231.237; 5.G.231.238; 5.G.231.239; 5.G.231.154; 5.G.231.157; 5.G.231.166; 5.G.231.169; 5.G.231.172; 5.G.231.175; 5.G.231.240; 5.G.231.244; 5.G.236.228; 5.G.236.229; 5.G.236.230; 5.G.236.231; 5.G.236.236; 5.G.236.237; 5.G.236.238; 5.G.236.239; 5.G.236.154; 5.G.236.157; 5.G.236.166; 5.G.236.169; 5.G.236.172; 5.G.236.175; 5.G.236.240; 5.G.236.244; 5.G.237.228; 5.G.237.229; 5.G.237.230; 5.G.237.231; 5.G.237.236; 5.G.237.237; 5.G.237.238; 5.G.237.239; 5.G.237.154; 5.G.237.157; 5.G.237.166; 5.G.237.169; 5.G.237.172; 5.G.237.175; 5.G.237.240; 5.G.237.244; 5.G.238.228; 5.G.238.229; 5.G.238.230; 5.G.238.231; 5.G.238.236; 5.G.238.237; 5.G.238.238; 5.G.238.239; 5.G.238.154; 5.G.238.157; 5.G.238.166; 5.G.238.169; 5.G.238.172; 5.G.238.175; 5.G.238.240; 5.G.238.244; 5.G.239.228; 5.G.239.229; 5.G.239.230; 5.G.239.231; 5.G.239.236; 5.G.239.237; 5.G.239.238; 5.G.239.239; 5.G.239.154; 5.G.239.157; 5.G.239.166; 5.G.239.169; 5.G.239.172; 5.G.239.175; 5.G.239.240; 5.G.239.244; 5.G.154.228; 5.G.154.229; 5.G.154.230; 5.G.154.231; 5.G.154.236; 5.G.154.237; 5.G.154.238; 5.G.154.239; 5.G.154.154; 5.G.154.157; 5.G.154.166; 5.G.154.169; 5.G.154.172; 5.G.154.175; 5.G.154.240; 5.G.154.244; 5.G.157.228; 5.G.157.229; 5.G.157.230; 5.G.157.231; 5.G.157.236; 5.G.157.237; 5.G.157.238; 5.G.157.239; 5.G.157.154; 5.G.157.157; 5.G.157.166; 5.G.157.169; 5.G.157.172; 5.G.157.175; 5.G.157.240; 5.G.157.244; 5.G.166.228; 5.G.166.229; 5.G.166.230; 5.G.166.231; 5.G.166.236; 5.G.166.237; 5.G.166.238; 5.G.166.239; 5.G.166.154; 5.G.166.157; 5.G.166.166; 5.G.166.169; 5.G.166.172; 5.G.166.175; 5.G.166.240; 5.G.166.244; 5.G.169.228; 5.G.169.229; 5.G.169.230; 5.G.169.231; 5.G.169.236; 5.G.169.237; 5.G.169.238; 5.G.169.239; 5.G.169.154; 5.G.169.157; 5.G.169.166; 5.G.169.169; 5.G.169.172; 5.G.169.175; 5.G.169.240; 5.G.169.244; 5.G.172.228; 5.G.172.229; 5.G.172.230; 5.G.172.231; 5.G.172.236; 5.G.172.237; 5.G.172.238; 5.G.172.239; 5.G.172.154; 5.G.172.157; 5.G.172.166; 5.G.172.169; 5.G.172.172; 5.G.172.175; 5.G.172.240; 5.G.172.244; 5.G.175.228; 5.G.175.229; 5.G.175.230; 5.G.175.231; 5.G.175.236; 5.G.175.237; 5.G.175.238; 5.G.175.239; 5.G.175.154; 5.G.175.157; 5.G.175.166; 5.G.175.169; 5.G.175.172; 5.G.175.175; 5.G.175.240; 5.G.175.244; 5.G.240.228; 5.G.240.229; 5.G.240.230; 5.G.240.231; 5.G.240.236; 5.G.240.237; 5.G.240.238; 5.G.240.239; 5.G.240.154; 5.G.240.157; 5.G.240.166; 5.G.240.169; 5.G.240.172; 5.G.240.175; 5.G.240.240; 5.G.240.244; 5.G.244.228; 5.G.244.229; 5.G.244.230; 5.G.244.231; 5.G.244.236; 5.G.244.237; 5.G.244.238; 5.G.244.239; 5.G.244.154; 5.G.244.157; 5.G.244.166; 5.G.244.169; 5.G.244.172; 5.G.244.175; 5.G.244.240; 5.G.244.244;

5.I's Prodrug

     5.I.228.228; 5.I.228.229; 5.I.228.230; 5.I.228.231; 5.I.228.236; 5.I.228.237; 5.I.228.238; 5.I.228.239; 5.I.228.154; 5.I.228.157; 5.I.228.166; 5.I.228.169; 5.I.228.172; 5.I.228.175; 5.I.228.240; 5.I.228.244; 5.I.229.228; 5.I.229.229; 5.I.229.230; 5.I.229.231; 5.I.229.236; 5.I.229.237; 5.I.229.238; 5.I.229.239; 5.I.229.154; 5.I.229.157; 5.I.229.166; 5.I.229.169; 5.I.229.172; 5.I.229.175; 5.I.229.240; 5.I.229.244; 5.I.230.228; 5.I.230.229; 5.I.230.230; 5.I.230.231; 5.I.230.236; 5.I.230.237; 5.I.230.238; 5.I.230.239; 5.I.230.154; 5.I.230.157; 5.I.230.166; 5.I.230.169; 5.I.230.172; 5.I.230.175; 5.I.230.240; 5.I.230.244; 5.I.231.228; 5.I.231.229; 5.I.231.230; 5.I.231.231; 5.I.231.236; 5.I.231.237; 5.I.231.238; 5.I.231.239; 5.I.231.154; 5.I.231.157; 5.I.231.166; 5.I.231.169; 5.I.231.172; 5.I.231.175; 5.I.231.240; 5.I.231.244; 5.I.236.228; 5.I.236.229; 5.I.236.230; 5.I.236.231; 5.I.236.236; 5.I.236.237; 5.I.236.238; 5.I.236.239; 5.I.236.154; 5.I.236.157; 5.I.236.166; 5.I.236.169; 5.I.236.172; 5.I.236.175; 5.I.236.240; 5.I.236.244; 5.I.237.228; 5.I.237.229; 5.I.237.230; 5.I.237.231; 5.I.237.236; 5.I.237.237; 5.I.237.238; 5.I.237.239; 5.I.237.154; 5.I.237.157; 5.I.237.166; 5.I.237.169; 5.I.237.172; 5.I.237.175; 5.I.237.240; 5.I.237.244; 5.I.238.228; 5.I.238.229; 5.I.238.230; 5.I.238.231; 5.I.238.236; 5.I.238.237; 5.I.238.238; 5.I.238.239; 5.I.238.154; 5.I.238.157; 5.I.238.166; 5.I.238.169; 5.I.238.172; 5.I.238.175; 5.I.238.240; 5.I.238.244; 5.I.239.228; 5.I.239.229; 5.I.239.230; 5.I.239.231; 5.I.239.236; 5.I.239.237; 5.I.239.238; 5.I.239.239; 5.I.239.154; 5.I.239.157; 5.I.239.166; 5.I.239.169; 5.I.239.172; 5.I.239.175; 5.I.239.240; 5.I.239.244; 5.I.154.228; 5.I.154.229; 5.I.154.230; 5.I.154.231; 5.I.154.236; 5.I.154.237; 5.I.154.238; 5.I.154.239; 5.I.154.154; 5.I.154.157; 5.I.154.166; 5.I.154.169; 5.I.154.172; 5.I.154.175; 5.I.154.240; 5.I.154.244; 5.I.157.228; 5.I.157.229; 5.I.157.230; 5.I.157.231; 5.I.157.236; 5.I.157.237; 5.I.157.238; 5.I.157.239; 5.I.157.154; 5.I.157.157; 5.I.157.166; 5.I.157.169; 5.I.157.172; 5.I.157.175; 5.I.157.240; 5.I.157.244; 5.I.166.228; 5.I.166.229; 5.I.166.230; 5.I.166.231; 5.I.166.236; 5.I.166.237; 5.I.166.238; 5.I.166.239; 5.I.166.154; 5.I.166.157; 5.I.166.166; 5.I.166.169; 5.I.166.172; 5.I.166.175; 5.I.166.240; 5.I.166.244; 5.I.169.228; 5.I.169.229; 5.I.169.230; 5.I.169.231; 5.I.169.236; 5.I.169.237; 5.I.169.238; 5.I.169.239; 5.I.169.154; 5.I.169.157; 5.I.169.166; 5.I.169.169; 5.I.169.172; 5.I.169.175; 5.I.169.240; 5.I.169.244; 5.I.172.228; 5.I.172.229; 5.I.172.230; 5.I.172.231; 5.I.172.236; 5.I.172.237; 5.I.172.238; 5.I.172.239; 5.I.172.154; 5.I.172.157; 5.I.172.166; 5.I.172.169; 5.I.172.172; 5.I.172.175; 5.I.172.240; 5.I.172.244; 5.I.175.228; 5.I.175.229; 5.I.175.230; 5.I.175.231; 5.I.175.236; 5.I.175.237; 5.I.175.238; 5.I.175.239; 5.I.175.154; 5.I.175.157; 5.I.175.166; 5.I.175.169; 5.I.175.172; 5.I.175.175; 5.I.175.240; 5.I.175.244; 5.I.240.228; 5.I.240.229; 5.I.240.230; 5.I.240.231; 5.I.240.236; 5.I.240.237; 5.I.240.238; 5.I.240.239; 5.I.240.154; 5.I.240.157; 5.I.240.166; 5.I.240.169; 5.I.240.172; 5.I.240.175; 5.I.240.240; 5.I.240.244; 5.I.244.228; 5.I.244.229; 5.I.244.230; 5.I.244.231; 5.I.244.236; 5.I.244.237; 5.I.244.238; 5.I.244.239; 5.I.244.154; 5.I.244.157; 5.I.244.166; 5.I.244.169; 5.I.244.172; 5.I.244.175; 5.I.244.240; 5.I.244.244;

5.J's Prodrug

     5.J. 228.228; 5.J.228.229; 5.J.228.230; 5.J.228.231; 5.J.228.236; 5.J.228.237; 5.J.228.238; 5.J.228.239; 5.J.228.154; 5.J.228.157; 5.J.228.166; 5.J.228.169; 5.J.228.172; 5.J.228.175; 5.J.228.240; 5.J.228.244; 5.J.229.228; 5.J.229.229; 5.J.229.230; 5.J.229.231; 5.J.229.236; 5.J.229.237; 5.J.229.238; 5.J.229.239; 5.J.229.154; 5.J.229.157; 5.J.229.166; 5.J.229.169; 5.J.229.172; 5.J.229.175; 5.J.229.240; 5.J.229.244; 5.J.230.228; 5.J.230.229; 5.J.230.230; 5.J.230.231; 5.J.230.236; 5.J.230.237; 5.J.230.238; 5.J.230.239; 5.J.230.154; 5.J.230.157; 5.J.230.166; 5.J.230.169; 5.J.230.172; 5.J.230.175; 5.J.230.240; 5.J.230.244; 5.J.231.228; 5.J. 231.229; 5.J.231.230; 5.J.231.231; 5.J.231.236; 5.J.231.237; 5.J.231.238; 5.J.231.239; 5.J.231.154; 5.J.231.157; 5.J.231.166; 5.J.231.169; 5.J.231.172; 5.J.231.175; 5.J.231.240; 5.J.231.244; 5.J.236.228; 5.J. 236.229; 5.J.236.230; 5.J.236.231; 5.J.236.236; 5.J.236.237; 5.J.236.238; 5.J.236.239; 5.J.236.154; 5.J.236.157; 5.J.236.166; 5.J.236.169; 5.J.236.172; 5.J.236.175; 5.J.236.240; 5.J.236.244; 5.J. 237.228; 5.J. 237.229; 5.J. 237.230; 5.J.237.231; 5.J.237.236; 5.J. 237.237; 5.J. 237.238; 5.J. 237.239; 5.J.237.154; 5.J. 237.157; 5.J. 237.166; 5.J. 237.169; 5.J. 237.172; 5.J.237.175; 5.J. 237.240; 5.J.237.244; 5.J.238.228; 5.J.238.229; 5.J.238.230; 5.J.238.231; 5.J.238.236; 5.J.238.237; 5.J.238.238; 5.J.238.239; 5.J.238.154; 5.J.238.157; 5.J.238.166; 5.J.238.169; 5.J.238.172; 5.J.238.175; 5.J.238.240; 5.J.238.244; 5.J.239.228; 5.J.239.229; 5.J.239.230; 5.J.239.231; 5.J.239.236; 5.J.239.237; 5.J.239.238; 5.J.239.239; 5.J.239.154; 5.J.239.157; 5.J.239.166; 5.J.239.169; 5.J.239.172; 5.J.239.175; 5.J.239.240; 5.J.239.244; 5.J.154.228; 5.J.154.229; 5.J.154.230; 5.J.154.231; 5.J.154.236; 5.J.154.237; 5.J.154.238; 5.J.154.239; 5.J.154.154; 5.J.154.157; 5.J.154.166; 5.J.154.169; 5.J.154.172; 5.J.154.175; 5.J.154.240; 5.J.154.244; 5.J.157.228; 5.J.157.229; 5.J.157.230; 5.J.157.231; 5.J.157.236; 5.J.157.237; 5.J.157.238; 5.J.157.239; 5.J.157.154; 5.J.157.157; 5.J.157.166; 5.J.157.169; 5.J.157.172; 5.J.157.175; 5.J.157.240; 5.J.157.244; 5.J.166.228; 5.J. 166.229; 5.J.166.230; 5.J.166.231; 5.J.166.236; 5.J.166.237; 5.J.166.238; 5.J.166.239; 5.J.166.154; 5.J.166.157; 5.J.166.166; 5.J.166.169; 5.J.166.172; 5.J.166.175; 5.J.166.240; 5.J.166.244; 5.J. 169.228; 5.J. 169.229; 5.J. 169.230; 5.J. 169.231; 5.J. 169.236; 5.J. 169.237; 5.J. 169.238; 5.J. 169.239; 5.J. 169.154; 5.J. 169.157; 5.J. 169.166; 5.J. 169.169; 5.J. 169.172; 5.J. 169.175; 5.J. 169.240; 5.J. 169.244; 5.J.172.228; 5.J.172.229; 5.J.172.230; 5.J.172.231; 5.J.172.236; 5.J.172.237; 5.J.172.238; 5.J.172.239; 5.J.172.154; 5.J.172.157; 5.J.172.166; 5.J.172.169; 5.J.172.172; 5.J.172.175; 5.J.172.240; 5.J.172.244; 5.J.175.228; 5.J.175.229; 5.J.175.230; 5.J.175.231; 5.J.175.236; 5.J.175.237; 5.J.175.238; 5.J.175.239; 5.J.175.154; 5.J.175.157; 5.J.175.166; 5.J.175.169; 5.J.175.172; 5.J.175.175; 5.J.175.240; 5.J.175.244; 5.J.240.228; 5.J.240.229; 5.J.240.230; 5.J.240.231; 5.J.240.236; 5.J.240.237; 5.J.240.238; 5.J.240.239; 5.J.240.154; 5.J.240.157; 5.J.240.166; 5.J.240.169; 5.J.240.172; 5.J.240.175; 5.J.240.240; 5.J.240.244; 5.J.244.228; 5.J.244.229; 5.J.244.230; 5.J.244.231; 5.J.244.236; 5.J.244.237; 5.J.244.238; 5.J.244.239; 5.J.244.154; 5.J.244.157; 5.J.244.166; 5.J.244.169; 5.J.244.172; 5.J.244.175; 5.J.244.240; 5.J.244.244;

5.L Prodrug

     5.L. 228.228; 5.L. 228.229; 5.L. 228.230; 5.L. 228.231; 5.L. 228.236; 5.L. 228.237; 5.L. 228.238; 5.L. 228.239; 5.L. 228.154; 5.L. 228.157; 5.L. 228.166; 5.L. 228.169; 5.L. 228.172; 5.L. 228.175; 5.L. 228.240; 5.L. 228.244; 5.L.229.228; 5.L.229.229; 5.L.229.230; 5.L.229.231; 5.L.229.236; 5.L.229.237; 5.L.229.238; 5.L.229.239; 5.L.229.154; 5.L.229.157; 5.L.229.166; 5.L.229.169; 5.L.229.172; 5.L.229.175; 5.L.229.240; 5.L.229.244; 5.L.230.228; 5.L. 230.229; 5.L.230.230; 5.L.230.231; 5.L.230.236; 5.L.230.237; 5.L.230.238; 5.L.230.239; 5.L.230.154; 5.L.230.157; 5.L.230.166; 5.L.230.169; 5.L.230.172; 5.L.230.175; 5.L.230.240; 5.L.230.244; 5.L.231.228; 5.L. 231.229; 5.L.231.230; 5.L.231.231; 5.L.231.236; 5.L.231.237; 5.L.231.238; 5.L.231.239; 5.L.231.154; 5.L.231.157; 5.L.231.166; 5.L.231.169; 5.L.231.172; 5.L.231.175; 5.L.231.240; 5.L.231.244; 5.L. 236.228; 5.L. 236.229; 5.L.236.230; 5.L.236.231; 5.L.236.236; 5.L.236.237; 5.L.236.238; 5.L.236.239; 5.L.236.154; 5.L. 236.157; 5.L.236.166; 5.L.236.169; 5.L.236.172; 5.L.236.175; 5.L.236.240; 5.L.236.244; 5.L. 237.228; 5.L. 237.229; 5.L. 237.230; 5.L. 237.231; 5.L. 237.236; 5.L. 237.237; 5.L.237.238; 5.L. 237.239; 5.L. 237.154; 5.L. 237.157; 5.L. 237.166; 5.L. 237.169; 5.L. 237.172; 5.L. 237.175; 5.L.237.240; 5.L.237.244; 5.L.238.228; 5.L.238.229; 5.L.238.230; 5.L.238.231; 5.L.238.236; 5.L.238.237; 5.L.238.238; 5.L.238.239; 5.L.238.154; 5.L.238.157; 5.L.238.166; 5.L.238.169; 5.L.238.172; 5.L.238.175; 5.L.238.240; 5.L.238.244; 5.L.239.228; 5.L.239.229; 5.L.239.230; 5.L.239.231; 5.L.239.236; 5.L.239.237; 5.L.239.238; 5.L.239.239; 5.L.239.154; 5.L.239.157; 5.L.239.166; 5.L.239.169; 5.L.239.172; 5.L.239.175; 5.L.239.240; 5.L.239.244; 5.L.154.228; 5.L.154.229; 5.L.154.230; 5.L.154.231; 5.L.154.236; 5.L.154.237; 5.L.154.238; 5.L.154.239; 5.L.154.154; 5.L.154.157; 5.L.154.166; 5.L.154.169; 5.L.154.172; 5.L.154.175; 5.L.154.240; 5.L.154.244; 5.L.157.228; 5.L. 157.229; 5.L.157.230; 5.L.157.231; 5.L.157.236; 5.L.157.237; 5.L.157.238; 5.L.157.239; 5.L.157.154; 5.L.157.157; 5.L.157.166; 5.L.157.169; 5.L.157.172; 5.L.157.175; 5.L.157.240; 5.L.157.244; 5.L. 166.228; 5.L. 166.229; 5.L.166.230; 5.L.166.231; 5.L.166.236; 5.L.166.237; 5.L.166.238; 5.L.166.239; 5.L.166.154; 5.L.166.157; 5.L.166.166; 5.L.166.169; 5.L.166.172; 5.L.166.175; 5.L.166.240; 5.L.166.244; 5.L. 169.228; 5.L. 169.229; 5.L. 169.230; 5.L. 169.231; 5.L. 169.236; 5.L. 169.237; 5.L. 169.238; 5.L. 169.239; 5.L. 169.154; 5.L. 169.157; 5.L. 169.166; 5.L.169.169; 5.L.169.172; 5.L. 169.175; 5.L.169.240; 5.L. 169.244; 5.L. 172.228; 5.L. 172.229; 5.L. 172.230; 5.L. 172.231; 5.L. 172.236; 5.L. 172.237; 5.L.172.238; 5.L. 172.239; 5.L. 172.154; 5.L. 172.157; 5.L. 172.166; 5.L.172.169; 5.L.172.172; 5.L.172.175; 5.L.172.240; 5.L.172.244; 5.L. 175.228; 5.L. 175.229; 5.L. 175.230; 5.L. 175.231; 5.L. 175.236; 5.L. 175.237; 5.L. 175.238; 5.L. 175.239; 5.L. 175.154; 5.L. 175.157; 5.L. 175.166; 5.L. 175.169; 5.L. 175.172; 5.L. 175.175; 5.L. 175.240; 5.L. 175.244; 5.L.240.228; 5.L.240.229; 5.L.240.230; 5.L.240.231; 5.L.240.236; 5.L.240.237; 5.L.240.238; 5.L.240.239; 5.L.240.154; 5.L.240.157; 5.L.240.166; 5.L.240.169; 5.L.240.172; 5.L.240.175; 5.L.240.240; 5.L.240.244; 5.L.244.228; 5.L.244.229; 5.L.244.230; 5.L.244.231; 5.L.244.236; 5.L.244.237; 5.L.244.238; 5.L.244.239; 5.L.244.154; 5.L.244.157; 5.L.244.166; 5.L.244.169; 5.L.244.172; 5.L.244.175; 5.L.244.240; 5.L.244.244;

5.O's Prodrug

     5.O.228.228; 5.O.228.229; 5.O.228.230; 5.O.228.231; 5.O.228.236; 5.O.228.237; 5.O.228.238; 5.O.228.239; 5.O.228.154; 5.O.228.157; 5.O.228.166; 5.O.228.169; 5.O.228.172; 5.O.228.175; 5.O.228.240; 5.O.228.244; 5.O.229.228; 5.O.229.229; 5.O.229.230; 5.O.229.231; 5.O.229.236; 5.O.229.237; 5.O.229.238; 5.O.229.239; 5.O.229.154; 5.O.229.157; 5.O.229.166; 5.O.229.169; 5.O.229.172; 5.O.229.175; 5.O.229.240; 5.O.229.244; 5.O.230.228; 5.O.230.229; 5.O.230.230; 5.230.231; 5.O.230.236; 5.O.230.237; 5.O.230.238; 5.O.230.239; 5.230.154; 5.230.157; 5.O.230.166; 5.230.169; 5.O.230.172; 5.O.230.175; 5.230.240; 5.O.230.244; 5.O.231.228; 5.O.231.229; 5.O.231.230; 5.O.231.231; 5.O.231.236; 5.O.231.237; 5.O.231.238; 5.O.231.239; 5.O.231.154; 5.O.231.157; 5.O.231.166; 5.O.231.169; 5.O.231.172; 5.O.231.175; 5.O.231.240; 5.O.231.244; 5.O.236.228; 5.O.236.229; 5.O.236.230; 5.O.236.231; 5.O.236.236; 5.O.236.237; 5.O.236.238; 5.O.236.239; 5.O.236.154; 5.O.236.157; 5.O.236.166; 5.O.236.169; 5.O.236.172; 5.O.236.175; 5.O.236.240; 5.O.236.244; 5.O.237.228; 5.O.237.229; 5.O.237.230; 5.O.237.231; 5.O.237.236; 5.O.237.237; 5.O.237.238; 5.O.237.239; 5.O.237.154; 5.O.237.157; 5.O.237.166; 5.O.237.169; 5.O.237.172; 5.O.237.175; 5.O.237.240; 5.O.237.244; 5.O.238.228; 5.O.238.229; 5.O.238.230; 5.O.238.231; 5.O.238.236; 5.O.238.237; 5.O.238.238; 5.O.238.239; 5.O.238.154; 5.O.238.157; 5.O.238.166; 5.O.238.169; 5.O.238.172; 5.O.238.175; 5.O.238.240; 5.O.238.244; 5.O.239.228; 5.O.239.229; 5.O.239.230; 5.O.239.231; 5.O.239.236; 5.O.239.237; 5.O.239.238; 5.O.239.239; 5.O.239.154; 5.O.239.157; 5.O.239.166; 5.O.239.169; 5.O.239.172; 5.O.239.175; 5.O.239.240; 5.O.239.244; 5.154.228; 5.O.154.229; 5.O.154.230; 5.O.154.231; 5.O.154.236; 5.O.154.237; 5.O.154.238; 5.154.239; 5.O.154.154; 5.154.157; 5.O.154.166; 5.O.154.169; 5.O.154.172; 5.O.154.175; 5.154.240; 5.O.154.244; 5.O.157.228; 5.O.157.229; 5.O.157.230; 5.O.157.231; 5.O.157.236; 5.O.157.237; 5.O.157.238; 5.O.157.239; 5.O.157.154; 5.O.157.157; 5.O.157.166; 5.O.157.169; 5.O.157.172; 5.O.157.175; 5.O.157.240; 5.O.157.244; 5.O.166.228; 5.O.166.229; 5.O.166.230; 5.O.166.231; 5.O.166.236; 5.O.166.237; 5.O.166.238; 5.O.166.239; 5.O.166.154; 5.O.166.157; 5.O.166.166; 5.O.166.169; 5.O.166.172; 5.O.166.175; 5.O.166.240; 5.O.166.244; 5.O.169.228; 5.O.169.229; 5.O.169.230; 5.O.169.231; 5.O.169.236; 5.O.169.237; 5.O.169.238; 5.O.169.239; 5.O.169.154; 5.O.169.157; 5.O.169.166; 5.O.169.169; 5.O.169.172; 5.O.169.175; 5.O.169.240; 5.O.169.244; 5.O.172.228; 5.O.172.229; 5.O.172.230; 5.O.172.231; 5.O.172.236; 5.O.172.237; 5.O.172.238; 5.O.172.239; 5.O.172.154; 5.O.172.157; 5.O.172.166; 5.O.172.169; 5.O.172.172; 5.O.172.175; 5.O.172.240; 5.O.172.244; 5.O.175.228; 5.O.175.229; 5.O.175.230; 5.O.175.231; 5.O.175.236; 5.O.175.237; 5.O.175.238; 5.O.175.239; 5.O.175.154; 5.O.175.157; 5.O.175.166; 5.O.175.169; 5.O.175.172; 5.O.175.175; 5.O.175.240; 5.O.175.244; 5.O.240.228; 5.O.240.229; 5.O.240.230; 5.O.240.231; 5.O.240.236; 5.O.240.237; 5.O.240.238; 5.O.240.239; 5.O.240.154; 5.O.240.157; 5.O.240.166; 5.O.240.169; 5.O.240.172; 5.O.240.175; 5.O.240.240; 5.O.240.244; 5.O.244.228; 5.O.244.229; 5.O.244.230; 5.O.244.231; 5.O.244.236; 5.O.244.237; 5.O.244.238; 5.O.244.239; 5.O.244.154; 5.O.244.157; 5.O.244.166; 5.O.244.169; 5.O.244.172; 5.O.244.175; 5.O.244.240; 5.O.244.244;

5.P Prodrug

     5.P. 228.228; 5.P. 228.229; 5.P. 228.230; 5.P.228.231; 5.P.228.236; 5.P.228.237; 5.P.228.238; 5.P.228.239; 5.P. 228.154; 5.P. 228.157; 5.P. 228.166; 5.P.228.169; 5.P. 228.172; 5.P.228.175; 5.P.228.240; 5.P.228.244; 5.P.229.228; 5.P.229.229; 5.P.229.230; 5.P.229.231; 5.P.229.236; 5.P.229.237; 5.P.229.238; 5.P.229.239; 5.P.229.154; 5.P.229.157; 5.P.229.166; 5.P.229.169; 5.P.229.172; 5.P.229.175; 5.P.229.240; 5.P.229.244; 5.P.230.228; 5.P.230.229; 5.P.230.230; 5.P.230.231; 5.P.230.236; 5.P.230.237; 5.P.230.238; 5.P.230.239; 5.P.230.154; 5.P.230.157; 5.P.230.166; 5.P.230.169; 5.P.230.172; 5.P.230.175; 5.P.230.240; 5.P.230.244; 5.P.231.228; 5.P.231.229; 5.P.231.230; 5.P.231.231; 5.P.231.236; 5.P.231.237; 5.P.231.238; 5.P.231.239; 5.P.231.154; 5.P.231.157; 5.P.231.166; 5.P.231.169; 5.P.231.172; 5.P.231.175; 5.P.231.240; 5.P.231.244; 5.P.236.228; 5.P.236.229; 5.P.236.230; 5.P.236.231; 5.P.236.236; 5.P.236.237; 5.P.236.238; 5.P.236.239; 5.P.236.154; 5.P.236.157; 5.P.236.166; 5.P.236.169; 5.P.236.172; 5.P.236.175; 5.P.236.240; 5.P.236.244; 5.P.237.228; 5.P.237.229; 5.P.237.230; 5.P.237.231; 5.P.237.236; 5.P.237.237; 5.P.237.238; 5.P.237.239; 5.P.237.154; 5.P.237.157; 5.P.237.166; 5.P.237.169; 5.P.237.172; 5.P.237.175; 5.P.237.240; 5.P.237.244; 5.P.238.228; 5.P.238.229; 5.P.238.230; 5.P.238.231; 5.P.238.236; 5.P.238.237; 5.P.238.238; 5.P.238.239; 5.P.238.154; 5.P.238.157; 5.P.238.166; 5.P.238.169; 5.P.238.172; 5.P.238.175; 5.P.238.240; 5.P.238.244; 5.P.239.228; 5.P.239.229; 5.P.239.230; 5.P.239.231; 5.P.239.236; 5.P.239.237; 5.P.239.238; 5.P.239.239; 5.P.239.154; 5.P.239.157; 5.P.239.166; 5.P.239.169; 5.P.239.172; 5.P.239.175; 5.P.239.240; 5.P.239.244; 5.P.154.228; 5.P.154.229; 5.P.154.230; 5.P.154.231; 5.P.154.236; 5.P.154.237; 5.P.154.238; 5.P.154.239; 5.P.154.154; 5.P.154.157; 5.P.154.166; 5.P.154.169; 5.P.154.172; 5.P.154.175; 5.P.154.240; 5.P.154.244; 5.P.157.228; 5.P. 157.229; 5.P.157.230; 5.P.157.231; 5.P.157.236; 5.P.157.237; 5.P.157.238; 5.P.157.239; 5.P.157.154; 5.P.157.157; 5.P.157.166; 5.P.157.169; 5.P.157.172; 5.P.157.175; 5.P.157.240; 5.P.157.244; 5.P.166.228; 5.P. 166.229; 5.P.166.230; 5.P.166.231; 5.P.166.236; 5.P.166.237; 5.P.166.238; 5.P.166.239; 5.P.166.154; 5.P.166.157; 5.P.166.166; 5.P.166.169; 5.P.166.172; 5.P.166.175; 5.P.166.240; 5.P.166.244; 5.P. 169.228; 5.P.169.229; 5.P.169.230; 5.P.169.231; 5.P.169.236; 5.P.169.237; 5.P.169.238; 5.P. 169.239; 5.P.169.154; 5.P. 169.157; 5.P.169.166; 5.P.169.169; 5.P.169.172; 5.P.169.175; 5.P.169.240; 5.P.169.244; 5.P.172.228; 5.P. 172.229; 5.P.172.230; 5.P.172.231; 5.P.172.236; 5.P.172.237; 5.P.172.238; 5.P.172.239; 5.P.172.154; 5.P.172.157; 5.P.172.166; 5.P.172.169; 5.P.172.172; 5.P.172.175; 5.P.172.240; 5.P.172.244; 5.P.175.228; 5.P. 175.229; 5.P.175.230; 5.P.175.231; 5.P.175.236; 5.P.175.237; 5.P.175.238; 5.P.175.239; 5.P.175.154; 5.P.175.157; 5.P.175.166; 5.P.175.169; 5.P.175.172; 5.P.175.175; 5.P.175.240; 5.P.175.244; 5.P.240.228; 5.P.240.229; 5.P.240.230; 5.P.240.231; 5.P.240.236; 5.P.240.237; 5.P.240.238; 5.P.240.239; 5.P.240.154; 5.P.240.157; 5.P.240.166; 5.P.240.169; 5.P.240.172; 5.P.240.175; 5.P.240.240; 5.P.240.244; 5.P.244.228; 5.P.244.229; 5.P.244.230; 5.P.244.231; 5.P.244.236; 5.P.244.237; 5.P.244.238; 5.P.244.239; 5.P.244.154; 5.P.244.157; 5.P.244.166; 5.P.244.169; 5.P.244.172; 5.P.244.175; 5.P.244.240; 5.P.244.244;

5.U's Prodrug

     5.U.228.228; 5.U.228.229; 5.U.228.230; 5.U.228.231; 5.U.228.236; 5.U.228.237; 5.U.228.238; 5.U.228.239; 5.U.228.154; 5.U.228.157; 5.U.228.166; 5.U.228.169; 5.U.228.172; 5.U.228.175; 5.U.228.240; 5.U.228.244; 5.U.229.228; 5.U.229.229; 5.U.229.230; 5.U.229.231; 5.U.229.236; 5.U.229.237; 5.U.229.238; 5.U.229.239; 5.U.229.154; 5.U.229.157; 5.U.229.166; 5.U.229.169; 5.U.229.172; 5.U.229.175; 5.U.229.240; 5.U.229.244; 5.U.230.228; 5.U.230.229; 5.U.230.230; 5.U.230.231; 5.U.230.236; 5.U.230.237; 5.U.230.238; 5.U.230.239; 5.U.230.154; 5.U.230.157; 5.U.230.166; 5.U.230.169; 5.U.230.172; 5.U.230.175; 5.U.230.240; 5.U.230.244; 5.U.231.228; 5.U.231.229; 5.U.231.230; 5.U.231.231; 5.U.231.236; 5.U.231.237; 5.U.231.238; 5.U.231.239; 5.U.231.154; 5.U.231.157; 5.U.231.166; 5.U.231.169; 5.U.231.172; 5.U.231.175; 5.U.231.240; 5.U.231.244; 5.U.236.228; 5.U.236.229; 5.U.236.230; 5.U.236.231; 5.U.236.236; 5.U.236.237; 5.U.236.238; 5.U.236.239; 5.U.236.154; 5.U.236.157; 5.U.236.166; 5.U.236.169; 5.U.236.172; 5.U.236.175; 5.U.236.240; 5.U.236.244; 5.U.237.228; 5.U.237.229; 5.U.237.230; 5.U.237.231; 5.U.237.236; 5.U.237.237; 5.U.237.238; 5.U.237.239; 5.U.237.154; 5.U.237.157; 5.U.237.166; 5.U.237.169; 5.U.237.172; 5.U.237.175; 5.U.237.240; 5.U.237.244; 5.U.238.228; 5.U.238.229; 5.U.238.230; 5.U.238.231; 5.U.238.236; 5.U.238.237; 5.U.238.238; 5.U.238.239; 5.U.238.154; 5.U.238.157; 5.U.238.166; 5.U.238.169; 5.U.238.172; 5.U.238.175; 5.U.238.240; 5.U.238.244; 5.U.239.228; 5.U.239.229; 5.U.239.230; 5.U.239.231; 5.U.239.236; 5.U.239.237; 5.U.239.238; 5.U.239.239; 5.U.239.154; 5.U.239.157; 5.U.239.166; 5.U.239.169; 5.U.239.172; 5.U.239.175; 5.U.239.240; 5.U.239.244; 5.U.154.228; 5.U.154.229; 5.U.154.230; 5.U.154.231; 5.U.154.236; 5.U.154.237; 5.U.154.238; 5.U.154.239; 5.U.154.154; 5.U.154.157; 5.U.154.166; 5.U.154.169; 5.U.154.172; 5.U.154.175; 5.U.154.240; 5.U.154.244; 5.U.157.228; 5.U.157.229; 5.U.157.230; 5.U.157.231; 5.U.157.236; 5.U.157.237; 5.U.157.238; 5.U.157.239; 5.U.157.154; 5.U.157.157; 5.U.157.166; 5.U.157.169; 5.U.157.172; 5.U.157.175; 5.U.157.240; 5.U.157.244; 5.U.166.228; 5.U.166.229; 5.U.166.230; 5.U.166.231; 5.U.166.236; 5.U.166.237; 5.U.166.238; 5.U.166.239; 5.U.166.154; 5.U.166.157; 5.U.166.166; 5.U.166.169; 5.U.166.172; 5.U.166.175; 5.U.166.240; 5.U.166.244; 5.U.169.228; 5.U.169.229; 5.U.169.230; 5.U.169.231; 5.U.169.236; 5.U.169.237; 5.U.169.238; 5.U.169.239; 5.U.169.154; 5.U.169.157; 5.U.169.166; 5.U.169.169; 5.U.169.172; 5.U.169.175; 5.U.169.240; 5.U.169.244; 5.U.172.228; 5.U.172.229; 5.U.172.230; 5.U.172.231; 5.U.172.236; 5.U.172.237; 5.U.172.238; 5.U.172.239; 5.U.172.154; 5.U.172.157; 5.U.172.166; 5.U.172.169; 5.U.172.172; 5.U.172.175; 5.U.172.240; 5.U.172.244; 5.U.175.228; 5.U.175.229; 5.U.175.230; 5.U.175.231; 5.U.175.236; 5.U.175.237; 5.U.175.238; 5.U.175.239; 5.U.175.154; 5.U.175.157; 5.U.175.166; 5.U.175.169; 5.U.175.172; 5.U.175.175; 5.U.175.240; 5.U.175.244; 5.U.240.228; 5.U.240.229; 5.U.240.230; 5.U.240.231; 5.U.240.236; 5.U.240.237; 5.U.240.238; 5.U.240.239; 5.U.240.154; 5.U.240.157; 5.U.240.166; 5.U.240.169; 5.U.240.172; 5.U.240.175; 5.U.240.240; 5.U.240.244; 5.U.244.228; 5.U.244.229; 5.U.244.230; 5.U.244.231; 5.U.244.236; 5.U.244.237; 5.U.244.238; 5.U.244.239; 5.U.244.154; 5.U.244.157; 5.U.244.166; 5.U.244.169; 5.U.244.172; 5.U.244.175; 5.U.244.240; 5.U.244.244;

5.W Prodrug

     5.W.228.228; 5.W.228.229; 5.W.228.230; 5.W.228.231; 5.W.228.236; 5.W.228.237; 5.W.228.238; 5.W.228.239; 5.W.228.154; 5.W.228.157; 5.W.228.166; 5.W.228.169; 5.W.228.172; 5.W.228.175; 5.W.228.240; 5.W.228.244; 5.W.229.228; 5.W.229.229; 5.W.229.230; 5.W.229.231; 5.W.229.236; 5.W.229.237; 5.W.229.238; 5.W.229.239; 5.W.229.154; 5.W.229.157; 5.W.229.166; 5.W.229.169; 5.W.229.172; 5.W.229.175; 5.W.229.240; 5.W.229.244; 5.W.230.228; 5.W.230.229; 5.W.230.230; 5.W.230.231; 5.W.230.236; 5.W.230.237; 5.W.230.238; 5.W.230.239; 5.W.230.154; 5.W.230.157; 5.W.230.166; 5.W.230.169; 5.W.230.172; 5.W.230.175; 5.W.230.240; 5.W.230.244; 5.W.231.228; 5.W.231.229; 5.W.231.230; 5.W.231.231; 5.W.231.236; 5.W.231.237; 5.W.231.238; 5.W.231.239; 5.W.231.154; 5.W.231.157; 5.W.231.166; 5.W.231.169; 5.W.231.172; 5.W.231.175; 5.W.231.240; 5.W.231.244; 5.W.236.228; 5.W.236.229; 5.W.236.230; 5.W.236.231; 5.W.236.236; 5.W.236.237; 5.W.236.238; 5.W.236.239; 5.W.236.154; 5.W.236.157; 5.W.236.166; 5.W.236.169; 5.W.236.172; 5.W.236.175; 5.W.236.240; 5.W.236.244; 5.W.237.228; 5.W.237.229; 5.W.237.230; 5.W.237.231; 5.W.237.236; 5.W.237.237; 5.W.237.238; 5.W.237.239; 5.W.237.154; 5.W.237.157; 5.W.237.166; 5.W.237.169; 5.W.237.172; 5.W.237.175; 5.W.237.240; 5.W.237.244; 5.W.238.228; 5.W.238.229; 5.W.238.230; 5.W.238.231; 5.W.238.236; 5.W.238.237; 5.W.238.238; 5.W.238.239; 5.W.238.154; 5.W.238.157; 5.W.238.166; 5.W.238.169; 5.W.238.172; 5.W.238.175; 5.W.238.240; 5.W.238.244; 5.W.239.228; 5.W.239.229; 5.W.239.230; 5.W.239.231; 5.W.239.236; 5.W.239.237; 5.W.239.238; 5.W.239.239; 5.W.239.154; 5.W.239.157; 5.W.239.166; 5.W.239.169; 5.W.239.172; 5.W.239.175; 5.W.239.240; 5.W.239.244; 5.W.154.228; 5.W.154.229; 5.W.154.230; 5.W.154.231; 5.W.154.236; 5.W.154.237; 5.W.154.238; 5.W.154.239; 5.W.154.154; 5.W.154.157; 5.W.154.166; 5.W.154.169; 5.W.154.172; 5.W.154.175; 5.W.154.240; 5.W.154.244; 5.W.157.228; 5.W. 157.229; 5.W.157.230; 5.W.157.231; 5.W.157.236; 5.W.157.237; 5.W.157.238; 5.W.157.239; 5.W.157.154; 5.W.157.157; 5.W.157.166; 5.W.157.169; 5.W.157.172; 5.W.157.175; 5.W.157.240; 5.W.157.244; 5.W.166.228; 5.W.166.229; 5.W.166.230; 5.W.166.231; 5.W.166.236; 5.W.166.237; 5.W.166.238; 5.W.166.239; 5.W.166.154; 5.W.166.157; 5.W.166.166; 5.W.166.169; 5.W.166.172; 5.W.166.175; 5.W.166.240; 5.W.166.244; 5.W. 169.228; 5.W.169.229; 5.W. 169.230; 5.W. 169.231; 5.W.169.236; 5.W. 169.237; 5.W. 169.238; 5.W. 169.239; 5.W.169.154; 5.W. 169.157; 5.W. 169.166; 5.W.169.169; 5.W.169.172; 5.W.169.175; 5.W.169.240; 5.W.169.244; 5.W.172.228; 5.W. 172.229; 5.W.172.230; 5.W.172.231; 5.W.172.236; 5.W.172.237; 5.W.172.238; 5.W.172.239; 5.W.172.154; 5.W.172.157; 5.W.172.166; 5.W.172.169; 5.W.172.172; 5.W.172.175; 5.W.172.240; 5.W.172.244; 5.W.175.228; 5.W. 175.229; 5.W.175.230; 5.W.175.231; 5.W.175.236; 5.W.175.237; 5.W.175.238; 5.W.175.239; 5.W.175.154; 5.W.175.157; 5.W.175.166; 5.W.175.169; 5.W.175.172; 5.W.175.175; 5.W.175.240; 5.W.175.244; 5.W.240.228; 5.W.240.229; 5.W.240.230; 5.W.240.231; 5.W.240.236; 5.W.240.237; 5.W.240.238; 5.W.240.239; 5.W.240.154; 5.W.240.157; 5.W.240.166; 5.W.240.169; 5.W.240.172; 5.W.240.175; 5.W.240.240; 5.W.240.244; 5.W.244.228; 5.W.244.229; 5.W.244.230; 5.W.244.231; 5.W.244.236; 5.W.244.237; 5.W.244.238; 5.W.244.239; 5.W.244.154; 5.W.244.157; 5.W.244.166; 5.W.244.169; 5.W.244.172; 5.W.244.175; 5.W.244.240; 5.W.244.244;

5.Y's Prodrug

     5.Y.228.228; 5.Y.228.229; 5.Y.228.230; 5.Y.228.231; 5.Y.228.236; 5.Y.228.237; 5.Y.228.238; 5.Y.228.239; 5.Y.228.154; 5.Y.228.157; 5.Y.228.166; 5.Y.228.169; 5.Y.228.172; 5.Y.228.175; 5.Y.228.240; 5.Y.228.244; 5.Y.229.228; 5.Y.229.229; 5.Y.229.230; 5.Y.229.231; 5.Y.229.236; 5.Y.229.237; 5.Y.229.238; 5.Y.229.239; 5.Y.229.154; 5.Y.229.157; 5.Y.229.166; 5.Y.229.169; 5.Y.229.172; 5.Y.229.175; 5.Y.229.240; 5.Y.229.244; 5.Y.230.228; 5.Y.230.229; 5.Y.230.230; 5.Y.230.231; 5.Y.230.236; 5.Y.230.237; 5.Y.230.238; 5.Y.230.239; 5.Y.230.154; 5.Y.230.157; 5.Y.230.166; 5.Y.230.169; 5.Y.230.172; 5.Y.230.175; 5.Y.230.240; 5.Y.230.244; 5.Y.231.228; 5.Y.231.229; 5.Y.231.230; 5.Y.231.231; 5.Y.231.236; 5.Y.231.237; 5.Y.231.238; 5.Y.231.239; 5.Y.231.154; 5.Y.231.157; 5.Y.231.166; 5.Y.231.169; 5.Y.231.172; 5.Y.231.175; 5.Y.231.240; 5.Y.231.244; 5.Y.236.228; 5.Y.236.229; 5.Y.236.230; 5.Y.236.231; 5.Y.236.236; 5.Y.236.237; 5.Y.236.238; 5.Y.236.239; 5.Y.236.154; 5.Y.236.157; 5.Y.236.166; 5.Y.236.169; 5.Y.236.172; 5.Y.236.175; 5.Y.236.240; 5.Y.236.244; 5.Y.237.228; 5.Y.237.229; 5.Y.237.230; 5.Y.237.231; 5.Y.237.236; 5.Y.237.237; 5.Y.237.238; 5.Y.237.239; 5.Y.237.154; 5.Y.237.157; 5.Y.237.166; 5.Y.237.169; 5.Y.237.172; 5.Y.237.175; 5.Y.237.240; 5.Y.237.244; 5.Y.238.228; 5.Y.238.229; 5.Y.238.230; 5.Y.238.231; 5.Y.238.236; 5.Y.238.237; 5.Y.238.238; 5.Y.238.239; 5.Y.238.154; 5.Y.238.157; 5.Y.238.166; 5.Y.238.169; 5.Y.238.172; 5.Y.238.175; 5.Y.238.240; 5.Y.238.244; 5.Y.239.228; 5.Y.239.229; 5.Y.239.230; 5.Y.239.231; 5.Y.239.236; 5.Y.239.237; 5.Y.239.238; 5.Y.239.239; 5.Y.239.154; 5.Y.239.157; 5.Y.239.166; 5.Y.239.169; 5.Y.239.172; 5.Y.239.175; 5.Y.239.240; 5.Y.239.244; 5.Y.154.228; 5.Y.154.229; 5.Y.154.230; 5.Y.154.231; 5.Y.154.236; 5.Y.154.237; 5.Y.154.238; 5.Y.154.239; 5.Y.154.154; 5.Y.154.157; 5.Y.154.166; 5.Y.154.169; 5.Y.154.172; 5.Y.154.175; 5.Y.154.240; 5.Y.154.244; 5.Y.157.228; 5.Y.157.229; 5.Y.157.230; 5.Y.157.231; 5.Y.157.236; 5.Y.157.237; 5.Y.157.238; 5.Y.157.239; 5.Y.157.154; 5.Y.157.157; 5.Y.157.166; 5.Y.157.169; 5.Y.157.172; 5.Y.157.175; 5.Y.157.240; 5.Y.157.244; 5.Y.166.228; 5.Y.166.229; 5.Y.166.230; 5.Y.166.231; 5.Y.166.236; 5.Y.166.237; 5.Y.166.238; 5.Y.166.239; 5.Y.166.154; 5.Y.166.157; 5.Y.166.166; 5.Y.166.169; 5.Y.166.172; 5.Y.166.175; 5.Y.166.240; 5.Y.166.244; 5.Y.169.228; 5.Y.169.229; 5.Y.169.230; 5.Y.169.231; 5.Y.169.236; 5.Y.169.237; 5.Y.169.238; 5.Y.169.239; 5.Y.169.154; 5.Y.169.157; 5.Y.169.166; 5.Y.169.169; 5.Y.169.172; 5.Y.169.175; 5.Y.169.240; 5.Y.169.244; 5.Y.172.228; 5.Y.172.229; 5.Y.172.230; 5.Y.172.231; 5.Y.172.236; 5.Y.172.237; 5.Y.172.238; 5.Y.172.239; 5.Y.172.154; 5.Y.172.157; 5.Y.172.166; 5.Y.172.169; 5.Y.172.172; 5.Y.172.175; 5.Y.172.240; 5.Y.172.244; 5.Y.175.228; 5.Y.175.229; 5.Y.175.230; 5.Y.175.231; 5.Y.175.236; 5.Y.175.237; 5.Y.175.238; 5.Y.175.239; 5.Y.175.154; 5.Y.175.157; 5.Y.175.166; 5.Y.175.169; 5.Y.175.172; 5.Y.175.175; 5.Y.175.240; 5.Y.175.244; 5.Y.240.228; 5.Y.240.229; 5.Y.240.230; 5.Y.240.231; 5.Y.240.236; 5.Y.240.237; 5.Y.240.238; 5.Y.240.239; 5.Y.240.154; 5.Y.240.157; 5.Y.240.166; 5.Y.240.169; 5.Y.240.172; 5.Y.240.175; 5.Y.240.240; 5.Y.240.244; 5.Y.244.228; 5.Y.244.229; 5.Y.244.230; 5.Y.244.231; 5.Y.244.236; 5.Y.244.237; 5.Y.244.238; 5.Y.244.239; 5.Y.244.154; 5.Y.244.157; 5.Y.244.166; 5.Y.244.169; 5.Y.244.172; 5.Y.244.175; 5.Y.244.240; 5.Y.244.244;

6.B Prodrug

     6.B.228.228; 6.B.228.229; 6.B. 228.230; 6.B.228.231; 6.B.228.236; 6.B.228.237; 6.B.228.238; 6.B.228.239; 6.B.228.154; 6.B.228.157; 6.B.228.166; 6.B.228.169; 6.B.228.172; 6.B.228.175; 6.B.228.240; 6.B.228.244; 6.B.229.228; 6.B.229.229; 6.B.229.230; 6.B.229.231; 6.B.229.236; 6.B.229.237; 6.B.229.238; 6.B.229.239; 6.B.229.154; 6.B.229.157; 6.B.229.166; 6.B.229.169; 6.B.229.172; 6.B.229.175; 6.B.229.240; 6.B.229.244; 6.B.230.228; 6.B.230.229; 6.B.230.230; 6.B.230.231; 6.B.230.236; 6.B.230.237; 6.B.230.238; 6.B.230.239; 6.B.230.154; 6.B.230.157; 6.B.230.166; 6.B.230.169; 6.B.230.172; 6.B.230.175; 6.B.230.240; 6.B.230.244; 6.B.231.228; 6.B.231.229; 6.B.231.230; 6.B.231.231; 6.B.231.236; 6.B.231.237; 6.B.231.238; 6.B.231.239; 6.B.231.154; 6.B.231.157; 6.B.231.166; 6.B.231.169; 6.B.231.172; 6.B.231.175; 6.B.231.240; 6.B.231.244; 6.B.236.228; 6.B. 236.229; 6.B.236.230; 6.B.236.231; 6.B.236.236; 6.B.236.237; 6.B.236.238; 6.B.236.239; 6.B.236.154; 6.B.236.157; 6.B.236.166; 6.B.236.169; 6.B.236.172; 6.B.236.175; 6.B.236.240; 6.B.236.244; 6.B.237.228; 6.B.237.229; 6.B.237.230; 6.B.237.231; 6.B.237.236; 6.B.237.237; 6.B.237.238; 6.B.237.239; 6.B.237.154; 6.B.237.157; 6.B.237.166; 6.B.237.169; 6.B.237.172; 6.B.237.175; 6.B.237.240; 6.B.237.244; 6.B.238.228; 6.B.238.229; 6.B.238.230; 6.B.238.231; 6.B.238.236; 6.B.238.237; 6.B.238.238; 6.B.238.239; 6.B.238.154; 6.B.238.157; 6.B.238.166; 6.B.238.169; 6.B.238.172; 6.B.238.175; 6.B.238.240; 6.B.238.244; 6.B.239.228; 6.B.239.229; 6.B.239.230; 6.B.239.231; 6.B.239.236; 6.B.239.237; 6.B.239.238; 6.B.239.239; 6.B.239.154; 6.B.239.157; 6.B.239.166; 6.B.239.169; 6.B.239.172; 6.B.239.175; 6.B.239.240; 6.B.239.244; 6.B.154.228; 6.B.154.229; 6.B.154.230; 6.B.154.231; 6.B.154.236; 6.B.154.237; 6.B.154.238; 6.B.154.239; 6.B.154.154; 6.B.154.157; 6.B.154.166; 6.B.154.169; 6.B.154.172; 6.B.154.175; 6.B.154.240; 6.B.154.244; 6.B.157.228; 6.B. 157.229; 6.B.157.230; 6.B.157.231; 6.B.157.236; 6.B.157.237; 6.B.157.238; 6.B.157.239; 6.B.157.154; 6.B.157.157; 6.B.157.166; 6.B.157.169; 6.B.157.172; 6.B.157.175; 6.B.157.240; 6.B.157.244; 6.B.166.228; 6.B.166.229; 6.B.166.230; 6.B.166.231; 6.B.166.236; 6.B.166.237; 6.B.166.238; 6.B.166.239; 6.B.166.154; 6.B.166.157; 6.B.166.166; 6.B.166.169; 6.B.166.172; 6.B.166.175; 6.B.166.240; 6.B.166.244; 6.B. 169.228; 6.B.169.229; 6.B. 169.230; 6.B.169.231; 6.B.169.236; 6.B.169.237; 6.B.169.238; 6.B.169.239; 6.B.169.154; 6.B. 169.157; 6.B.169.166; 6.B.169.169; 6.B.169.172; 6.B.169.175; 6.B.169.240; 6.B.169.244; 6.B.172.228; 6.B.172.229; 6.B.172.230; 6.B.172.231; 6.B.172.236; 6.B.172.237; 6.B.172.238; 6.B.172.239; 6.B.172.154; 6.B.172.157; 6.B.172.166; 6.B.172.169; 6.B.172.172; 6.B.172.175; 6.B.172.240; 6.B.172.244; 6.B.175.228; 6.B.175.229; 6.B.175.230; 6.B.175.231; 6.B.175.236; 6.B.175.237; 6.B.175.238; 6.B.175.239; 6.B.175.154; 6.B.175.157; 6.B.175.166; 6.B.175.169; 6.B.175.172; 6.B.175.175; 6.B.175.240; 6.B.175.244; 6.B.240.228; 6.B.240.229; 6.B.240.230; 6.B.240.231; 6.B.240.236; 6.B.240.237; 6.B.240.238; 6.B.240.239; 6.B.240.154; 6.B.240.157; 6.B.240.166; 6.B.240.169; 6.B.240.172; 6.B.240.175; 6.B.240.240; 6.B.240.244; 6.B.244.228; 6.B.244.229; 6.B.244.230; 6.B.244.231; 6.B.244.236; 6.B.244.237; 6.B.244.238; 6.B.244.239; 6.B.244.154; 6.B.244.157; 6.B.244.166; 6.B.244.169; 6.B.244.172; 6.B.244.175; 6.B.244.240; 6.B.244.244;

6.D Prodrug

     6.D. 228.228; 6.D. 228.229; 6.D. 228.230; 6.D. 228.231; 6.D.228.236; 6.D. 228.237; 6.D.228.238; 6.D. 228.239; 6.D.228.154; 6.D. 228.157; 6.D. 228.166; 6.D.228.169; 6.D.228.172; 6.D. 228.175; 6.D.228.240; 6.D.228.244; 6.D.229.228; 6.D.229.229; 6.D.229.230; 6.D.229.231; 6.D.229.236; 6.D.229.237; 6.D.229.238; 6.D.229.239; 6.D.229.154; 6.D.229.157; 6.D.229.166; 6.D.229.169; 6.D.229.172; 6.D.229.175; 6.D.229.240; 6.D.229.244; 6.D.230.228; 6.D.230.229; 6.D.230.230; 6.D.230.231; 6.D.230.236; 6.D.230.237; 6.D.230.238; 6.D.230.239; 6.D.230.154; 6.D.230.157; 6.D.230.166; 6.D.230.169; 6.D.230.172; 6.D.230.175; 6.D.230.240; 6.D.230.244; 6.D.231.228; 6.D.231.229; 6.D.231.230; 6.D.231.231; 6.D.231.236; 6.D.231.237; 6.D.231.238; 6.D.231.239; 6.D.231.154; 6.D.231.157; 6.D.231.166; 6.D.231.169; 6.D.231.172; 6.D.231.175; 6.D.231.240; 6.D.231.244; 6.D.236.228; 6.D.236.229; 6.D.236.230; 6.D.236.231; 6.D.236.236; 6.D.236.237; 6.D.236.238; 6.D.236.239; 6.D.236.154; 6.D.236.157; 6.D.236.166; 6.D.236.169; 6.D.236.172; 6.D.236.175; 6.D.236.240; 6.D.236.244; 6.D.237.228; 6.D.237.229; 6.D.237.230; 6.D.237.231; 6.D.237.236; 6.D.237.237; 6.D.237.238; 6.D.237.239; 6.D.237.154; 6.D.237.157; 6.D.237.166; 6.D.237.169; 6.D.237.172; 6.D.237.175; 6.D.237.240; 6.D.237.244; 6.D.238.228; 6.D.238.229; 6.D.238.230; 6.D.238.231; 6.D.238.236; 6.D.238.237; 6.D.238.238; 6.D.238.239; 6.D.238.154; 6.D.238.157; 6.D.238.166; 6.D.238.169; 6.D.238.172; 6.D.238.175; 6.D.238.240; 6.D.238.244; 6.D.239.228; 6.D.239.229; 6.D.239.230; 6.D.239.231; 6.D.239.236; 6.D.239.237; 6.D.239.238; 6.D.239.239; 6.D.239.154; 6.D.239.157; 6.D.239.166; 6.D.239.169; 6.D.239.172; 6.D.239.175; 6.D.239.240; 6.D.239.244; 6.D.154.228; 6.D.154.229; 6.D.154.230; 6.D.154.231; 6.D.154.236; 6.D.154.237; 6.D.154.238; 6.D.154.239; 6.D.154.154; 6.D.154.157; 6.D.154.166; 6.D.154.169; 6.D.154.172; 6.D.154.175; 6.D.154.240; 6.D.154.244; 6.D.157.228; 6.D. 157.229; 6.D.157.230; 6.D.157.231; 6.D.157.236; 6.D.157.237; 6.D.157.238; 6.D.157.239; 6.D.157.154; 6.D.157.157; 6.D.157.166; 6.D.157.169; 6.D.157.172; 6.D.157.175; 6.D.157.240; 6.D.157.244; 6.D.166.228; 6.D.166.229; 6.D.166.230; 6.D.166.231; 6.D.166.236; 6.D.166.237; 6.D.166.238; 6.D.166.239; 6.D.166.154; 6.D.166.157; 6.D.166.166; 6.D.166.169; 6.D.166.172; 6.D.166.175; 6.D.166.240; 6.D.166.244; 6.D. 169.228; 6.D. 169.229; 6.D. 169.230; 6.D. 169.231; 6.D. 169.236; 6.D. 169.237; 6.D. 169.238; 6.D. 169.239; 6.D.169.154; 6.D. 169.157; 6.D. 169.166; 6.D. 169.169; 6.D. 169.172; 6.D.169.175; 6.D. 169.240; 6.D. 169.244; 6.D.172.228; 6.D. 172.229; 6.D.172.230; 6.D.172.231; 6.D.172.236; 6.D.172.237; 6.D.172.238; 6.D.172.239; 6.D.172.154; 6.D.172.157; 6.D.172.166; 6.D.172.169; 6.D.172.172; 6.D.172.175; 6.D.172.240; 6.D.172.244; 6.D.175.228; 6.D. 175.229; 6.D.175.230; 6.D.175.231; 6.D.175.236; 6.D.175.237; 6.D.175.238; 6.D.175.239; 6.D.175.154; 6.D.175.157; 6.D.175.166; 6.D.175.169; 6.D.175.172; 6.D.175.175; 6.D.175.240; 6.D.175.244; 6.D.240.228; 6.D.240.229; 6.D.240.230; 6.D.240.231; 6.D.240.236; 6.D.240.237; 6.D.240.238; 6.D.240.239; 6.D.240.154; 6.D.240.157; 6.D.240.166; 6.D.240.169; 6.D.240.172; 6.D.240.175; 6.D.240.240; 6.D.240.244; 6.D.244.228; 6.D.244.229; 6.D.244.230; 6.D.244.231; 6.D.244.236; 6.D.244.237; 6.D.244.238; 6.D.244.239; 6.D.244.154; 6.D.244.157; 6.D.244.166; 6.D.244.169; 6.D.244.172; 6.D.244.175; 6.D.244.240; 6.D.244.244;

6.E Prodrug

     6.E.228.228; 6.E.228.229; 6.E.228.230; 6.E.228.231; 6.E.228.236; 6.E.228.237; 6.E.228.238; 6.E.228.239; 6.E.228.154; 6.E.228.157; 6.E.228.166; 6.E.228.169; 6.E.228.172; 6.E.228.175; 6.E.228.240; 6.E.228.244; 6.E.229.228; 6.E.229.229; 6.E.229.230; 6.E.229.231; 6.E.229.236; 6.E.229.237; 6.E.229.238; 6.E.229.239; 6.E.229.154; 6.E.229.157; 6.E.229.166; 6.E.229.169; 6.E.229.172; 6.E.229.175; 6.E.229.240; 6.E.229.244; 6.E.230.228; 6.E.230.229; 6.E.230.230; 6.E.230.231; 6.E.230.236; 6.E.230.237; 6.E.230.238; 6.E.230.239; 6.E.230.154; 6.E.230.157; 6.E.230.166; 6.E.230.169; 6.E.230.172; 6.E.230.175; 6.E.230.240; 6.E.230.244; 6.E.231.228; 6.E.231.229; 6.E.231.230; 6.E.231.231; 6.E.231.236; 6.E.231.237; 6.E.231.238; 6.E.231.239; 6.E.231.154; 6.E.231.157; 6.E.231.166; 6.E.231.169; 6.E.231.172; 6.E.231.175; 6.E.231.240; 6.E.231.244; 6.E.236.228; 6.E.236.229; 6.E.236.230; 6.E.236.231; 6.E.236.236; 6.E.236.237; 6.E.236.238; 6.E.236.239; 6.E.236.154; 6.E.236.157; 6.E.236.166; 6.E.236.169; 6.E.236.172; 6.E.236.175; 6.E.236.240; 6.E.236.244; 6.E.237.228; 6.E.237.229; 6.E.237.230; 6.E.237.231; 6.E.237.236; 6.E.237.237; 6.E.237.238; 6.E.237.239; 6.E.237.154; 6.E.237.157; 6.E.237.166; 6.E.237.169; 6.E.237.172; 6.E.237.175; 6.E.237.240; 6.E.237.244; 6.E.238.228; 6.E.238.229; 6.E.238.230; 6.E.238.231; 6.E.238.236; 6.E.238.237; 6.E.238.238; 6.E.238.239; 6.E.238.154; 6.E.238.157; 6.E.238.166; 6.E.238.169; 6.E.238.172; 6.E.238.175; 6.E.238.240; 6.E.238.244; 6.E.239.228; 6.E.239.229; 6.E.239.230; 6.E.239.231; 6.E.239.236; 6.E.239.237; 6.E.239.238; 6.E.239.239; 6.E.239.154; 6.E.239.157; 6.E.239.166; 6.E.239.169; 6.E.239.172; 6.E.239.175; 6.E.239.240; 6.E.239.244; 6.E.154.228; 6.E.154.229; 6.E.154.230; 6.E.154.231; 6.E.154.236; 6.E.154.237; 6.E.154.238; 6.E.154.239; 6.E.154.154; 6.E.154.157; 6.E.154.166; 6.E.154.169; 6.E.154.172; 6.E.154.175; 6.E.154.240; 6.E.154.244; 6.E.157.228; 6.E.157.229; 6.E.157.230; 6.E.157.231; 6.E.157.236; 6.E.157.237; 6.E.157.238; 6.E.157.239; 6.E.157.154; 6.E.157.157; 6.E.157.166; 6.E.157.169; 6.E.157.172; 6.E.157.175; 6.E.157.240; 6.E.157.244; 6.E.166.228; 6.E.166.229; 6.E.166.230; 6.E.166.231; 6.E.166.236; 6.E.166.237; 6.E.166.238; 6.E.166.239; 6.E.166.154; 6.E.166.157; 6.E.166.166; 6.E.166.169; 6.E.166.172; 6.E.166.175; 6.E.166.240; 6.E.166.244; 6.E. 169.228; 6.E.169.229; 6.E.169.230; 6.E.169.231; 6.E.169.236; 6.E.169.237; 6.E.169.238; 6.E.169.239; 6.E.169.154; 6.E.169.157; 6.E.169.166; 6.E.169.169; 6.E.169.172; 6.E.169.175; 6.E.169.240; 6.E.169.244; 6.E.172.228; 6.E.172.229; 6.E.172.230; 6.E.172.231; 6.E.172.236; 6.E.172.237; 6.E.172.238; 6.E.172.239; 6.E.172.154; 6.E.172.157; 6.E.172.166; 6.E.172.169; 6.E.172.172; 6.E.172.175; 6.E.172.240; 6.E.172.244; 6.E.175.228; 6.E.175.229; 6.E.175.230; 6.E.175.231; 6.E.175.236; 6.E.175.237; 6.E.175.238; 6.E.175.239; 6.E.175.154; 6.E.175.157; 6.E.175.166; 6.E.175.169; 6.E.175.172; 6.E.175.175; 6.E.175.240; 6.E.175.244; 6.E.240.228; 6.E.240.229; 6.E.240.230; 6.E.240.231; 6.E.240.236; 6.E.240.237; 6.E.240.238; 6.E.240.239; 6.E.240.154; 6.E.240.157; 6.E.240.166; 6.E.240.169; 6.E.240.172; 6.E.240.175; 6.E.240.240; 6.E.240.244; 6.E.244.228; 6.E.244.229; 6.E.244.230; 6.E.244.231; 6.E.244.236; 6.E.244.237; 6.E.244.238; 6.E.244.239; 6.E.244.154; 6.E.244.157; 6.E.244.166; 6.E.244.169; 6.E.244.172; 6.E.244.175; 6.E.244.240; 6.E.244.244;

6.G's Prodrug

     6.G. 228.228; 6.G. 228.229; 6.G. 228.230; 6.G. 228.231; 6.G. 228.236; 6.G. 228.237; 6.G.228.238; 6.G. 228.239; 6.G. 228.154; 6.G. 228.157; 6.G. 228.166; 6.G. 228.169; 6.G.228.172; 6.G. 228.175; 6.G. 228.240; 6.G. 228.244; 6.G.229.228; 6.G.229.229; 6.G.229.230; 6.G.229.231; 6.G.229.236; 6.G.229.237; 6.G.229.238; 6.G.229.239; 6.G.229.154; 6.G.229.157; 6.G.229.166; 6.G.229.169; 6.G.229.172; 6.G.229.175; 6.G.229.240; 6.G.229.244; 6.G.230.228; 6.G.230.229; 6.G.230.230; 6.G.230.231; 6.G.230.236; 6.G.230.237; 6.G.230.238; 6.G.230.239; 6.G.230.154; 6.G.230.157; 6.G.230.166; 6.G.230.169; 6.G.230.172; 6.G.230.175; 6.G.230.240; 6.G.230.244; 6.G.231.228; 6.G.231.229; 6.G.231.230; 6.G.231.231; 6.G.231.236; 6.G.231.237; 6.G.231.238; 6.G.231.239; 6.G.231.154; 6.G.231.157; 6.G.231.166; 6.G.231.169; 6.G.231.172; 6.G.231.175; 6.G.231.240; 6.G.231.244; 6.G.236.228; 6.G. 236.229; 6.G.236.230; 6.G.236.231; 6.G.236.236; 6.G.236.237; 6.G.236.238; 6.G.236.239; 6.G.236.154; 6.G.236.157; 6.G.236.166; 6.G.236.169; 6.G.236.172; 6.G.236.175; 6.G.236.240; 6.G.236.244; 6.G. 237.228; 6.G. 237.229; 6.G. 237.230; 6.G. 237.231; 6.G.237.236; 6.G. 237.237; 6.G.237.238; 6.G.237.239; 6.G. 237.154; 6.G. 237.157; 6.G. 237.166; 6.G. 237.169; 6.G.237.172; 6.G. 237.175; 6.G.237.240; 6.G.237.244; 6.G.238.228; 6.G.238.229; 6.G.238.230; 6.G.238.231; 6.G.238.236; 6.G.238.237; 6.G.238.238; 6.G.238.239; 6.G.238.154; 6.G.238.157; 6.G.238.166; 6.G.238.169; 6.G.238.172; 6.G.238.175; 6.G.238.240; 6.G.238.244; 6.G.239.228; 6.G.239.229; 6.G.239.230; 6.G.239.231; 6.G.239.236; 6.G.239.237; 6.G.239.238; 6.G.239.239; 6.G.239.154; 6.G.239.157; 6.G.239.166; 6.G.239.169; 6.G.239.172; 6.G.239.175; 6.G.239.240; 6.G.239.244; 6.G.154.228; 6.G.154.229; 6.G.154.230; 6.G.154.231; 6.G.154.236; 6.G.154.237; 6.G.154.238; 6.G.154.239; 6.G.154.154; 6.G.154.157; 6.G.154.166; 6.G.154.169; 6.G.154.172; 6.G.154.175; 6.G.154.240; 6.G.154.244; 6.G.157.228; 6.G. 157.229; 6.G.157.230; 6.G.157.231; 6.G.157.236; 6.G.157.237; 6.G.157.238; 6.G.157.239; 6.G.157.154; 6.G.157.157; 6.G.157.166; 6.G.157.169; 6.G.157.172; 6.G.157.175; 6.G.157.240; 6.G.157.244; 6.G.166.228; 6.G. 166.229; 6.G.166.230; 6.G.166.231; 6.G.166.236; 6.G.166.237; 6.G.166.238; 6.G.166.239; 6.G.166.154; 6.G.166.157; 6.G.166.166; 6.G.166.169; 6.G.166.172; 6.G.166.175; 6.G.166.240; 6.G.166.244; 6.G. 169.228; 6.G.169.229; 6.G. 169.230; 6.G. 169.231; 6.G.169.236; 6.G. 169.237; 6.G. 169.238; 6.G.169.239; 6.G.169.154; 6.G. 169.157; 6.G. 169.166; 6.G.169.169; 6.G.169.172; 6.G.169.175; 6.G.169.240; 6.G.169.244; 6.G.172.228; 6.G.172.229; 6.G.172.230; 6.G.172.231; 6.G.172.236; 6.G.172.237; 6.G.172.238; 6.G.172.239; 6.G.172.154; 6.G.172.157; 6.G.172.166; 6.G.172.169; 6.G.172.172; 6.G.172.175; 6.G.172.240; 6.G.172.244; 6.G.175.228; 6.G. 175.229; 6.G.175.230; 6.G.175.231; 6.G.175.236; 6.G.175.237; 6.G.175.238; 6.G.175.239; 6.G.175.154; 6.G.175.157; 6.G.175.166; 6.G.175.169; 6.G.175.172; 6.G.175.175; 6.G.175.240; 6.G.175.244; 6.G.240.228; 6.G.240.229; 6.G.240.230; 6.G.240.231; 6.G.240.236; 6.G.240.237; 6.G.240.238; 6.G.240.239; 6.G.240.154; 6.G.240.157; 6.G.240.166; 6.G.240.169; 6.G.240.172; 6.G.240.175; 6.G.240.240; 6.G.240.244; 6.G.244.228; 6.G.244.229; 6.G.244.230; 6.G.244.231; 6.G.244.236; 6.G.244.237; 6.G.244.238; 6.G.244.239; 6.G.244.154; 6.G.244.157; 6.G.244.166; 6.G.244.169; 6.G.244.172; 6.G.244.175; 6.G.244.240; 6.G.244.244;

6.I'm Prodrug

     6.I.228.228; 6.I.228.229; 6.I.228.230; 6.I.228.231; 6.I.228.236; 6.I.228.237; 6.I.228.238; 6.I.228.239; 6.I.228.154; 6.I.228.157; 6.I.228.166; 6.I.228.169; 6.I.228.172; 6.I.228.175; 6.I.228.240; 6.I.228.244; 6.I.229.228; 6.I.229.229; 6.I.229.230; 6.I.229.231; 6.I.229.236; 6.I.229.237; 6.I.229.238; 6.I.229.239; 6.I.229.154; 6.I.229.157; 6.I.229.166; 6.I.229.169; 6.I.229.172; 6.I.229.175; 6.I.229.240; 6.I.229.244; 6.I.230.228; 6.I.230.229; 6.I.230.230; 6.I.230.231; 6.I.230.236; 6.I.230.237; 6.I.230.238; 6.I.230.239; 6.I.230.154; 6.I.230.157; 6.I.230.166; 6.I.230.169; 6.I.230.172; 6.I.230.175; 6.I.230.240; 6.I.230.244; 6.I.231.228; 6.I.231.229; 6.I.231.230; 6.I.231.231; 6.I.231.236; 6.I.231.237; 6.I.231.238; 6.I.231.239; 6.I.231.154; 6.I.231.157; 6.I.231.166; 6.I.231.169; 6.I.231.172; 6.I.231.175; 6.I.231.240; 6.I.231.244; 6.I.236.228; 6.I.236.229; 6.I.236.230; 6.I.236.231; 6.I.236.236; 6.I.236.237; 6.I.236.238; 6.I.236.239; 6.I.236.154; 6.I.236.157; 6.I.236.166; 6.I.236.169; 6.I.236.172; 6.I.236.175; 6.I.236.240; 6.I.236.244; 6.I.237.228; 6.I.237.229; 6.I.237.230; 6.I.237.231; 6.I.237.236; 6.I.237.237; 6.I.237.238; 6.I.237.239; 6.I.237.154; 6.I.237.157; 6.I.237.166; 6.I.237.169; 6.I.237.172; 6.I.237.175; 6.I.237.240; 6.I.237.244; 6.I.238.228; 6.I.238.229; 6.I.238.230; 6.I.238.231; 6.I.238.236; 6.I.238.237; 6.I.238.238; 6.I.238.239; 6.I.238.154; 6.I.238.157; 6.I.238.166; 6.I.238.169; 6.I.238.172; 6.I.238.175; 6.I.238.240; 6.I.238.244; 6.I.239.228; 6.I.239.229; 6.I.239.230; 6.I.239.231; 6.I.239.236; 6.I.239.237; 6.I.239.238; 6.I.239.239; 6.I.239.154; 6.I.239.157; 6.I.239.166; 6.I.239.169; 6.I.239.172; 6.I.239.175; 6.I.239.240; 6.I.239.244; 6.I.154.228; 6.I.154.229; 6.I.154.230; 6.I.154.231; 6.I.154.236; 6.I.154.237; 6.I.154.238; 6.I.154.239; 6.I.154.154; 6.I.154.157; 6.I.154.166; 6.I.154.169; 6.I.154.172; 6.I.154.175; 6.I.154.240; 6.I.154.244; 6.I.157.228; 6.I.157.229; 6.I.157.230; 6.I.157.231; 6.I.157.236; 6.I.157.237; 6.I.157.238; 6.I.157.239; 6.I.157.154; 6.I.157.157; 6.I.157.166; 6.I.157.169; 6.I.157.172; 6.I.157.175; 6.I.157.240; 6.I.157.244; 6.I.166.228; 6.I.166.229; 6.I.166.230; 6.I.166.231; 6.I.166.236; 6.I.166.237; 6.I.166.238; 6.I.166.239; 6.I.166.154; 6.I.166.157; 6.I.166.166; 6.I.166.169; 6.I.166.172; 6.I.166.175; 6.I.166.240; 6.I.166.244; 6.I.169.228; 6.I.169.229; 6.I.169.230; 6.I.169.231; 6.I.169.236; 6.I.169.237; 6.I.169.238; 6.I.169.239; 6.I.169.154; 6.I.169.157; 6.I.169.166; 6.I.169.169; 6.I.169.172; 6.I.169.175; 6.I.169.240; 6.I.169.244; 6.I.172.228; 6.I.172.229; 6.I.172.230; 6.I.172.231; 6.I.172.236; 6.I.172.237; 6.I.172.238; 6.I.172.239; 6.I.172.154; 6.I.172.157; 6.I.172.166; 6.I.172.169; 6.I.172.172; 6.I.172.175; 6.I.172.240; 6.I.172.244; 6.I.175.228; 6.I.175.229; 6.I.175.230; 6.I.175.231; 6.I.175.236; 6.I.175.237; 6.I.175.238; 6.I.175.239; 6.I.175.154; 6.I.175.157; 6.I.175.166; 6.I.175.169; 6.I.175.172; 6.I.175.175; 6.I.175.240; 6.I.175.244; 6.I.240.228; 6.I.240.229; 6.I.240.230; 6.I.240.231; 6.I.240.236; 6.I.240.237; 6.I.240.238; 6.I.240.239; 6.I.240.154; 6.I.240.157; 6.I.240.166; 6.I.240.169; 6.I.240.172; 6.I.240.175; 6.I.240.240; 6.I.240.244; 6.I.244.228; 6.I.244.229; 6.I.244.230; 6.I.244.231; 6.I.244.236; 6.I.244.237; 6.I.244.238; 6.I.244.239; 6.I.244.154; 6.I.244.157; 6.I.244.166; 6.I.244.169; 6.I.244.172; 6.I.244.175; 6.I.244.240; 6.I.244.244;

6.J's Prodrug

     6.J. 228.228; 6.J. 228.229; 6.J. 228.230; 6.J. 228.231; 6.J. 228.236; 6.J. 228.237; 6.J. 228.238; 6.J. 228.239; 6.J. 228.154; 6.J.228.157; 6.J. 228.166; 6.J. 228.169; 6.J.228.172; 6.J. 228.175; 6.J.228.240; 6.J. 228.244; 6.J.229.228; 6.J.229.229; 6.J.229.230; 6.J.229.231; 6.J.229.236; 6.J.229.237; 6.J.229.238; 6.J.229.239; 6.J.229.154; 6.J.229.157; 6.J.229.166; 6.J.229.169; 6.J.229.172; 6.J.229.175; 6.J.229.240; 6.J.229.244; 6.J. 230.228; 6.J. 230.229; 6.J.230.230; 6.J.230.231; 6.J.230.236; 6.J.230.237; 6.J.230.238; 6.J.230.239; 6.J.230.154; 6.J. 230.157; 6.J. 230.166; 6.J. 230.169; 6.J.230.172; 6.J.230.175; 6.J.230.240; 6.J.230.244; 6.J.231.228; 6.J. 231.229; 6.J.231.230; 6.J.231.231; 6.J.231.236; 6.J.231.237; 6.J.231.238; 6.J.231.239; 6.J.231.154; 6.J.231.157; 6.J.231.166; 6.J.231.169; 6.J.231.172; 6.J.231.175; 6.J.231.240; 6.J.231.244; 6.J.236.228; 6.J. 236.229; 6.J.236.230; 6.J.236.231; 6.J.236.236; 6.J.236.237; 6.J.236.238; 6.J.236.239; 6.J.236.154; 6.J.236.157; 6.J.236.166; 6.J.236.169; 6.J.236.172; 6.J.236.175; 6.J.236.240; 6.J.236.244; 6.J. 237.228; 6.J. 237.229; 6.J. 237.230; 6.J. 237.231; 6.J. 237.236; 6.J. 237.237; 6.J. 237.238; 6.J. 237.239; 6.J. 237.154; 6.J. 237.157; 6.J. 237.166; 6.J. 237.169; 6.J. 237.172; 6.J. 237.175; 6.J. 237.240; 6.J. 237.244; 6.J. 238.228; 6.J.238.229; 6.J.238.230; 6.J.238.231; 6.J.238.236; 6.J.238.237; 6.J.238.238; 6.J.238.239; 6.J.238.154; 6.J.238.157; 6.J. 238.166; 6.J.238.169; 6.J.238.172; 6.J.238.175; 6.J. 238.240; 6.J.238.244; 6.J.239.228; 6.J.239.229; 6.J.239.230; 6.J.239.231; 6.J.239.236; 6.J.239.237; 6.J.239.238; 6.J.239.239; 6.J.239.154; 6.J.239.157; 6.J.239.166; 6.J.239.169; 6.J.239.172; 6.J.239.175; 6.J.239.240; 6.J.239.244; 6.J.154.228; 6.J.154.229; 6.J.154.230; 6.J.154.231; 6.J.154.236; 6.J.154.237; 6.J.154.238; 6.J.154.239; 6.J.154.154; 6.J.154.157; 6.J.154.166; 6.J.154.169; 6.J.154.172; 6.J.154.175; 6.J.154.240; 6.J.154.244; 6.J.157.228; 6.J. 157.229; 6.J.157.230; 6.J.157.231; 6.J.157.236; 6.J.157.237; 6.J.157.238; 6.J.157.239; 6.J.157.154; 6.J.157.157; 6.J.157.166; 6.J.157.169; 6.J.157.172; 6.J.157.175; 6.J.157.240; 6.J.157.244; 6.J.166.228; 6.J. 166.229; 6.J.166.230; 6.J.166.231; 6.J.166.236; 6.J.166.237; 6.J.166.238; 6.J.166.239; 6.J.166.154; 6.J.166.157; 6.J.166.166; 6.J.166.169; 6.J.166.172; 6.J.166.175; 6.J.166.240; 6.J.166.244; 6.J. 169.228; 6.J. 169.229; 6.J. 169.230; 6.J. 169.231; 6.J. 169.236; 6.J. 169.237; 6.J. 169.238; 6.J. 169.239; 6.J. 169.154; 6.J. 169.157; 6.J. 169.166; 6.J. 169.169; 6.J. 169.172; 6.J. 169.175; 6.J. 169.240; 6.J. 169.244; 6.J.172.228; 6.J. 172.229; 6.J.172.230; 6.J.172.231; 6.J.172.236; 6.J.172.237; 6.J.172.238; 6.J.172.239; 6.J.172.154; 6.J.172.157; 6.J.172.166; 6.J.172.169; 6.J.172.172; 6.J.172.175; 6.J.172.240; 6.J.172.244; 6.J.175.228; 6.J.175.229; 6.J.175.230; 6.J.175.231; 6.J.175.236; 6.J.175.237; 6.J.175.238; 6.J.175.239; 6.J.175.154; 6.J.175.157; 6.J.175.166; 6.J.175.169; 6.J.175.172; 6.J.175.175; 6.J.175.240; 6.J.175.244; 6.J.240.228; 6.J.240.229; 6.J.240.230; 6.J.240.231; 6.J.240.236; 6.J.240.237; 6.J.240.238; 6.J.240.239; 6.J.240.154; 6.J.240.157; 6.J.240.166; 6.J.240.169; 6.J.240.172; 6.J.240.175; 6.J.240.240; 6.J.240.244; 6.J.244.228; 6.J.244.229; 6.J.244.230; 6.J.244.231; 6.J.244.236; 6.J.244.237; 6.J.244.238; 6.J.244.239; 6.J.244.154; 6.J.244.157; 6.J.244.166; 6.J.244.169; 6.J.244.172; 6.J.244.175; 6.J.244.240; 6.J.244.244;

6.L Prodrug

     6.L. 228.228; 6.L. 228.229; 6.L. 228.230; 6.L. 228.231; 6.L. 228.236; 6.L. 228.237; 6.L. 228.238; 6.L. 228.239; 6.L. 228.154; 6.L. 228.157; 6.L. 228.166; 6.L. 228.169; 6.L. 228.172; 6.L. 228.175; 6.L. 228.240; 6.L. 228.244; 6.L.229.228; 6.L.229.229; 6.L.229.230; 6.L.229.231; 6.L.229.236; 6.L.229.237; 6.L.229.238; 6.L.229.239; 6.L.229.154; 6.L.229.157; 6.L.229.166; 6.L.229.169; 6.L.229.172; 6.L.229.175; 6.L.229.240; 6.L.229.244; 6.L. 230.228; 6.L. 230.229; 6.L. 230.230; 6.L. 230.231; 6.L. 230.236; 6.L. 230.237; 6.L.230.238; 6.L. 230.239; 6.L. 230.154; 6.L. 230.157; 6.L. 230.166; 6.L.230.169; 6.L.230.172; 6.L. 230.175; 6.L.230.240; 6.L.230.244; 6.L. 231.228; 6.L. 231.229; 6.L.231.230; 6.L.231.231; 6.L.231.236; 6.L. 231.237; 6.L.231.238; 6.L.231.239; 6.L.231.154; 6.L.231.157; 6.L.231.166; 6.L.231.169; 6.L.231.172; 6.L.231.175; 6.L.231.240; 6.L.231.244; 6.L. 236.228; 6.L. 236.229; 6.L. 236.230; 6.L. 236.231; 6.L. 236.236; 6.L. 236.237; 6.L. 236.238; 6.L. 236.239; 6.L. 236.154; 6.L. 236.157; 6.L. 236.166; 6.L. 236.169; 6.L. 236.172; 6.L. 236.175; 6.L. 236.240; 6.L. 236.244; 6.L. 237.228; 6.L. 237.229; 6.L. 237.230; 6.L. 237.231; 6.L. 237.236; 6.L. 237.237; 6.L. 237.238; 6.L. 237.239; 6.L. 237.154; 6.L.237.157; 6.L. 237.166; 6.L. 237.169; 6.L. 237.172; 6.L. 237.175; 6.L. 237.240; 6.L. 237.244; 6.L. 238.228; 6.L.238.229; 6.L. 238.230; 6.L. 238.231; 6.L. 238.236; 6.L. 238.237; 6.L.238.238; 6.L. 238.239; 6.L. 238.154; 6.L. 238.157; 6.L.238.166; 6.L. 238.169; 6.L. 238.172; 6.L. 238.175; 6.L.238.240; 6.L.238.244; 6.L.239.228; 6.L.239.229; 6.L.239.230; 6.L.239.231; 6.L.239.236; 6.L.239.237; 6.L.239.238; 6.L.239.239; 6.L.239.154; 6.L.239.157; 6.L.239.166; 6.L.239.169; 6.L.239.172; 6.L.239.175; 6.L.239.240; 6.L.239.244; 6.L. 154.228; 6.L.154.229; 6.L.154.230; 6.L. 154.231; 6.L.154.236; 6.L. 154.237; 6.L.154.238; 6.L. 154.239; 6.L. 154.154; 6.L. 154.157; 6.L. 154.166; 6.L. 154.169; 6.L.154.172; 6.L.154.175; 6.L.154.240; 6.L.154.244; 6.L. 157.228; 6.L. 157.229; 6.L.157.230; 6.L.157.231; 6.L.157.236; 6.L. 157.237; 6.L.157.238; 6.L.157.239; 6.L.157.154; 6.L.157.157; 6.L. 157.166; 6.L.157.169; 6.L.157.172; 6.L.157.175; 6.L.157.240; 6.L.157.244; 6.L. 166.228; 6.L. 166.229; 6.L. 166.230; 6.L. 166.231; 6.L. 166.236; 6.L. 166.237; 6.L. 166.238; 6.L.166.239; 6.L. 166.154; 6.L. 166.157; 6.L. 166.166; 6.L. 166.169; 6.L. 166.172; 6.L. 166.175; 6.L. 166.240; 6.L. 166.244; 6.L.169.228; 6.L. 169.229; 6.L. 169.230; 6.L. 169.231; 6.L. 169.236; 6.L. 169.237; 6.L. 169.238; 6.L. 169.239; 6.L. 169.154; 6.L. 169.157; 6.L. 169.166; 6.L. 169.169; 6.L. 169.172; 6.L. 169.175; 6.L. 169.240; 6.L. 169.244; 6.L. 172.228; 6.L. 172.229; 6.L. 172.230; 6.L. 172.231; 6.L. 172.236; 6.L. 172.237; 6.L. 172.238; 6.L. 172.239; 6.L. 172.154; 6.L. 172.157; 6.L. 172.166; 6.L. 172.169; 6.L. 172.172; 6.L. 172.175; 6.L. 172.240; 6.L. 172.244; 6.L. 175.228; 6.L. 175.229; 6.L. 175.230; 6.L. 175.231; 6.L. 175.236; 6.L. 175.237; 6.L. 175.238; 6.L. 175.239; 6.L.175.154; 6.L. 175.157; 6.L. 175.166; 6.L. 175.169; 6.L. 175.172; 6.L. 175.175; 6.L. 175.240; 6.L. 175.244; 6.L.240.228; 6.L. 240.229; 6.L.240.230; 6.L.240.231; 6.L.240.236; 6.L.240.237; 6.L.240.238; 6.L.240.239; 6.L.240.154; 6.L.240.157; 6.L.240.166; 6.L.240.169; 6.L.240.172; 6.L.240.175; 6.L.240.240; 6.L.240.244; 6.L.244.228; 6.L.244.229; 6.L.244.230; 6.L.244.231; 6.L.244.236; 6.L.244.237; 6.L.244.238; 6.L.244.239; 6.L.244.154; 6.L.244.157; 6.L.244.166; 6.L.244.169; 6.L.244.172; 6.L.244.175; 6.L.244.240; 6.L.244.244;

6.O's Prodrug

     6.O.228.228; 6.O.228.229; 6.O.228.230; 6.O.228.231; 6.O.228.236; 6.O.228.237; 6.O.228.238; 6.O.228.239; 6.O.228.154; 6.O.228.157; 6.O.228.166; 6.O.228.169; 6.O.228.172; 6.O.228.175; 6.O.228.240; 6.O.228.244; 6.O.229.228; 6.O.229.229; 6.O.229.230; 6.O.229.231; 6.O.229.236; 6.O.229.237; 6.O.229.238; 6.O.229.239; 6.O.229.154; 6.O.229.157; 6.O.229.166; 6.O.229.169; 6.O.229.172; 6.O.229.175; 6.O.229.240; 6.O.229.244; 6.O.230.228; 6.O.230.229; 6.O.230.230; 6.O.230.231; 6.O.230.236; 6.O.230.237; 6.O.230.238; 6.O.230.239; 6.O.230.154; 6.O.230.157; 6.O.230.166; 6.O.230.169; 6.O.230.172; 6.O.230.175; 6.O.230.240; 6.O.230.244; 6.O.231.228; 6.23.2929; 6.O.231.230; 6.O.231.231; 6.O.231.236; 6.O.231.237; 6.O.231.238; 6.O.231.239; 6.O.231.154; 6.O.231.157; 6.O.231.166; 6.O.231.169; 6.O.231.172; 6.O.231.175; 6.O.231.240; 6.O.231.244; 6.O.236.228; 6.O.236.229; 6.O.236.230; 6.O.236.231; 6.O.236.236; 6.O.236.237; 6.O.236.238; 6.O.236.239; 6.O.236.154; 6.O.236.157; 6.O.236.166; 6.O.236.169; 6.O.236.172; 6.O.236.175; 6.O.236.240; 6.O.236.244; 6.O.237.228; 6.O.237.229; 6.O.237.230; 6.O.237.231; 6.O.237.236; 6.O.237.237; 6.O.237.238; 6.O.237.239; 6.O.237.154; 6.O.237.157; 6.O.237.166; 6.O.237.169; 6.O.237.172; 6.O.237.175; 6.O.237.240; 6.O.237.244; 6.O.238.228; 6.O.238.229; 6.O.238.230; 6.O.238.231; 6.O.238.236; 6.O.238.237; 6.O.238.238; 6.O.238.239; 6.O.238.154; 6.O.238.157; 6.O.238.166; 6.O.238.169; 6.O.238.172; 6.O.238.175; 6.O.238.240; 6.O.238.244; 6.O.239.228; 6.O.239.229; 6.O.239.230; 6.O.239.231; 6.O.239.236; 6.O.239.237; 6.O.239.238; 6.O.239.239; 6.O.239.154; 6.O.239.157; 6.O.239.166; 6.O.239.169; 6.O.239.172; 6.O.239.175; 6.O.239.240; 6.O.239.244; 6.O.154.228; 6.O.154.229; 6.O.154.230; 6.O.154.231; 6.O.154.236; 6.O.154.237; 6.O.154.238; 6.O.154.239; 6.O.154.154; 6.O.154.157; 6.O.154.166; 6.O.154.169; 6.O.154.172; 6.O.154.175; 6.O.154.240; 6.O.154.244; 6.O.157.228; 6.O.157.229; 6.O.157.230; 6.O.157.231; 6.O.157.236; 6.O.157.237; 6.O.157.238; 6.O.157.239; 6.O.157.154; 6.O.157.157; 6.O.157.166; 6.O.157.169; 6.O.157.172; 6.O.157.175; 6.O.157.240; 6.O.157.244; 6.O.166.228; 6.O.166.229; 6.O.166.230; 6.O.166.231; 6.O.166.236; 6.O.166.237; 6.O.166.238; 6.O.166.239; 6.O.166.154; 6.O.166.157; 6.O.166.166; 6.O.166.169; 6.O.166.172; 6.O.166.175; 6.O.166.240; 6.O.166.244; 6.O.169.228; 6.O.169.229; 6.O.169.230; 6.O.169.231; 6.O.169.236; 6.O.169.237; 6.O.169.238; 6.O.169.239; 6.O.169.154; 6.O.169.157; 6.O.169.166; 6.O.169.169; 6.O.169.172; 6.O.169.175; 6.O.169.240; 6.O.169.244; 6.O.172.228; 6.O.172.229; 6.O.172.230; 6.O.172.231; 6.O.172.236; 6.O.172.237; 6.O.172.238; 6.O.172.239; 6.O.172.154; 6.O.172.157; 6.O.172.166; 6.O.172.169; 6.O.172.172; 6.O.172.175; 6.O.172.240; 6.O.172.244; 6.O.175.228; 6.O.175.229; 6.O.175.230; 6.O.175.231; 6.O.175.236; 6.O.175.237; 6.O.175.238; 6.O.175.239; 6.O.175.154; 6.O.175.157; 6.O.175.166; 6.O.175.169; 6.O.175.172; 6.O.175.175; 6.O.175.240; 6.O.175.244; 6.O.240.228; 6.O.240.229; 6.O.240.230; 6.O.240.231; 6.O.240.236; 6.O.240.237; 6.O.240.238; 6.O.240.239; 6.O.240.154; 6.O.240.157; 6.O.240.166; 6.O.240.169; 6.O.240.172; 6.O.240.175; 6.O.240.240; 6.O.240.244; 6.O.244.228; 6.O.244.229; 6.O.244.230; 6.O.244.231; 6.O.244.236; 6.O.244.237; 6.O.244.238; 6.O.244.239; 6.O.244.154; 6.O.244.157; 6.O.244.166; 6.O.244.169; 6.O.244.172; 6.O.244.175; 6.O.244.240; 6.O.244.244;

6.P Prodrug

     6.P. 228.228; 6.P. 228.229; 6.P. 228.230; 6.P. 228.231; 6.P. 228.236; 6.P. 228.237; 6.P. 228.238; 6.P.228.239; 6.P. 228.154; 6.P. 228.157; 6.P. 228.166; 6.P. 228.169; 6.P. 228.172; 6.P. 228.175; 6.P. 228.240; 6.P. 228.244; 6.P.229.228; 6.P.229.229; 6.P.229.230; 6.P.229.231; 6.P.229.236; 6.P.229.237; 6.P.229.238; 6.P.229.239; 6.P.229.154; 6.P.229.157; 6.P.229.166; 6.P.229.169; 6.P.229.172; 6.P.229.175; 6.P.229.240; 6.P.229.244; 6.P.230.228; 6.P.230.229; 6.P.230.230; 6.P.230.231; 6.P.230.236; 6.P.230.237; 6.P.230.238; 6.P.230.239; 6.P.230.154; 6.P.230.157; 6.P.230.166; 6.P.230.169; 6.P.230.172; 6.P.230.175; 6.P.230.240; 6.P.230.244; 6.P.231.228; 6.P.231.229; 6.P.231.230; 6.P.231.231; 6.P.231.236; 6.P.231.237; 6.P.231.238; 6.P.231.239; 6.P.231.154; 6.P.231.157; 6.P.231.166; 6.P.231.169; 6.P.231.172; 6.P.231.175; 6.P.231.240; 6.P.231.244; 6.P.236.228; 6.P.236.229; 6.P.236.230; 6.P.236.231; 6.P.236.236; 6.P.236.237; 6.P.236.238; 6.P.236.239; 6.P.236.154; 6.P.236.157; 6.P.236.166; 6.P.236.169; 6.P.236.172; 6.P.236.175; 6.P.236.240; 6.P.236.244; 6.P. 237.228; 6.P.237.229; 6.P. 237.230; 6.P.237.231; 6.P.237.236; 6.P.237.237; 6.P.237.238; 6.P.237.239; 6.P.237.154; 6.P.237.157; 6.P.237.166; 6.P.237.169; 6.P.237.172; 6.P.237.175; 6.P.237.240; 6.P.237.244; 6.P.238.228; 6.P.238.229; 6.P.238.230; 6.P.238.231; 6.P.238.236; 6.P.238.237; 6.P.238.238; 6.P.238.239; 6.P.238.154; 6.P.238.157; 6.P.238.166; 6.P.238.169; 6.P.238.172; 6.P.238.175; 6.P.238.240; 6.P.238.244; 6.P.239.228; 6.P.239.229; 6.P.239.230; 6.P.239.231; 6.P.239.236; 6.P.239.237; 6.P.239.238; 6.P.239.239; 6.P.239.154; 6.P.239.157; 6.P.239.166; 6.P.239.169; 6.P.239.172; 6.P.239.175; 6.P.239.240; 6.P.239.244; 6.P.154.228; 6.P.154.229; 6.P.154.230; 6.P.154.231; 6.P.154.236; 6.P.154.237; 6.P.154.238; 6.P.154.239; 6.P.154.154; 6.P.154.157; 6.P.154.166; 6.P.154.169; 6.P.154.172; 6.P.154.175; 6.P.154.240; 6.P.154.244; 6.P.157.228; 6.P. 157.229; 6.P.157.230; 6.P.157.231; 6.P.157.236; 6.P.157.237; 6.P.157.238; 6.P.157.239; 6.P.157.154; 6.P.157.157; 6.P.157.166; 6.P.157.169; 6.P.157.172; 6.P.157.175; 6.P.157.240; 6.P.157.244; 6.P.166.228; 6.P. 166.229; 6.P.166.230; 6.P.166.231; 6.P.166.236; 6.P.166.237; 6.P.166.238; 6.P.166.239; 6.P.166.154; 6.P.166.157; 6.P.166.166; 6.P.166.169; 6.P.166.172; 6.P.166.175; 6.P.166.240; 6.P.166.244; 6.P. 169.228; 6.P. 169.229; 6.P. 169.230; 6.P. 169.231; 6.P. 169.236; 6.P. 169.237; 6.P. 169.238; 6.P. 169.239; 6.P. 169.154; 6.P. 169.157; 6.P. 169.166; 6.P. 169.169; 6.P. 169.172; 6.P. 169.175; 6.P. 169.240; 6.P. 169.244; 6.P.172.228; 6.P. 172.229; 6.P.172.230; 6.P.172.231; 6.P.172.236; 6.P.172.237; 6.P.172.238; 6.P.172.239; 6.P.172.154; 6.P.172.157; 6.P.172.166; 6.P.172.169; 6.P.172.172; 6.P.172.175; 6.P.172.240; 6.P.172.244; 6.P.175.228; 6.P. 175.229; 6.P.175.230; 6.P.175.231; 6.P.175.236; 6.P.175.237; 6.P.175.238; 6.P.175.239; 6.P.175.154; 6.P.175.157; 6.P.175.166; 6.P.175.169; 6.P.175.172; 6.P.175.175; 6.P.175.240; 6.P.175.244; 6.P.240.228; 6.P.240.229; 6.P.240.230; 6.P.240.231; 6.P.240.236; 6.P.240.237; 6.P.240.238; 6.P.240.239; 6.P.240.154; 6.P.240.157; 6.P.240.166; 6.P.240.169; 6.P.240.172; 6.P.240.175; 6.P.240.240; 6.P.240.244; 6.P.244.228; 6.P.244.229; 6.P.244.230; 6.P.244.231; 6.P.244.236; 6.P.244.237; 6.P.244.238; 6.P.244.239; 6.P.244.154; 6.P.244.157; 6.P.244.166; 6.P.244.169; 6.P.244.172; 6.P.244.175; 6.P.244.240; 6.P.244.244;

6.U's Prodrug

     6.U. 228.228; 6.U.228.229; 6.U.228.230; 6.U.228.231; 6.U.228.236; 6.U.228.237; 6.U.228.238; 6.U.228.239; 6.U.228.154; 6.U.228.157; 6.U.228.166; 6.U.228.169; 6.U.228.172; 6.U.228.175; 6.U.228.240; 6.U.228.244; 6.U.229.228; 6.U.229.229; 6.U.229.230; 6.U.229.231; 6.U.229.236; 6.U.229.237; 6.U.229.238; 6.U.229.239; 6.U.229.154; 6.U.229.157; 6.U.229.166; 6.U.229.169; 6.U.229.172; 6.U.229.175; 6.U.229.240; 6.U.229.244; 6.U.230.228; 6.U.230.229; 6.U.230.230; 6.U.230.231; 6.U.230.236; 6.U.230.237; 6.U.230.238; 6.U.230.239; 6.U.230.154; 6.U.230.157; 6.U.230.166; 6.U.230.169; 6.U.230.172; 6.U.230.175; 6.U.230.240; 6.U.230.244; 6.U.231.228; 6.U.231.229; 6.U.231.230; 6.U.231.231; 6.U.231.236; 6.U.231.237; 6.U.231.238; 6.U.231.239; 6.U.231.154; 6.U.231.157; 6.U.231.166; 6.U.231.169; 6.U.231.172; 6.U.231.175; 6.U.231.240; 6.U.231.244; 6.U.236.228; 6.U.236.229; 6.U.236.230; 6.U.236.231; 6.U.236.236; 6.U.236.237; 6.U.236.238; 6.U.236.239; 6.U.236.154; 6.U.236.157; 6.U.236.166; 6.U.236.169; 6.U.236.172; 6.U.236.175; 6.U.236.240; 6.U.236.244; 6.U.237.228; 6.U.237.229; 6.U.237.230; 6.U.237.231; 6.U.237.236; 6.U.237.237; 6.U.237.238; 6.U.237.239; 6.U.237.154; 6.U.237.157; 6.U.237.166; 6.U.237.169; 6.U.237.172; 6.U.237.175; 6.U.237.240; 6.U.237.244; 6.U.238.228; 6.U.238.229; 6.U.238.230; 6.U.238.231; 6.U.238.236; 6.U.238.237; 6.U.238.238; 6.U.238.239; 6.U.238.154; 6.U.238.157; 6.U.238.166; 6.U.238.169; 6.U.238.172; 6.U.238.175; 6.U.238.240; 6.U.238.244; 6.U.239.228; 6.U.239.229; 6.U.239.230; 6.U.239.231; 6.U.239.236; 6.U.239.237; 6.U.239.238; 6.U.239.239; 6.U.239.154; 6.U.239.157; 6.U.239.166; 6.U.239.169; 6.U.239.172; 6.U.239.175; 6.U.239.240; 6.U.239.244; 6.U.154.228; 6.U.154.229; 6.U.154.230; 6.U.154.231; 6.U.154.236; 6.U.154.237; 6.U.154.238; 6.U.154.239; 6.U.154.154; 6.U.154.157; 6.U.154.166; 6.U.154.169; 6.U.154.172; 6.U.154.175; 6.U.154.240; 6.U.154.244; 6.U.157.228; 6.U.157.229; 6.U.157.230; 6.U.157.231; 6.U.157.236; 6.U.157.237; 6.U.157.238; 6.U.157.239; 6.U.157.154; 6.U.157.157; 6.U.157.166; 6.U.157.169; 6.U.157.172; 6.U.157.175; 6.U.157.240; 6.U.157.244; 6.U.166.228; 6.U.166.229; 6.U.166.230; 6.U.166.231; 6.U.166.236; 6.U.166.237; 6.U.166.238; 6.U.166.239; 6.U.166.154; 6.U.166.157; 6.U.166.166; 6.U.166.169; 6.U.166.172; 6.U.166.175; 6.U.166.240; 6.U.166.244; 6.U.169.228; 6.U.169.229; 6.U.169.230; 6.U.169.231; 6.U.169.236; 6.U.169.237; 6.U.169.238; 6.U.169.239; 6.U.169.154; 6.U.169.157; 6.U.169.166; 6.U.169.169; 6.U.169.172; 6.U.169.175; 6.U.169.240; 6.U.169.244; 6.U.172.228; 6.U.172.229; 6.U.172.230; 6.U.172.231; 6.U.172.236; 6.U.172.237; 6.U.172.238; 6.U.172.239; 6.U.172.154; 6.U.172.157; 6.U.172.166; 6.U.172.169; 6.U.172.172; 6.U.172.175; 6.U.172.240; 6.U.172.244; 6.U.175.228; 6.U.175.229; 6.U.175.230; 6.U.175.231; 6.U.175.236; 6.U.175.237; 6.U.175.238; 6.U.175.239; 6.U.175.154; 6.U.175.157; 6.U.175.166; 6.U.175.169; 6.U.175.172; 6.U.175.175; 6.U.175.240; 6.U.175.244; 6.U.240.228; 6.U.240.229; 6.U.240.230; 6.U.240.231; 6.U.240.236; 6.U.240.237; 6.U.240.238; 6.U.240.239; 6.U.240.154; 6.U.240.157; 6.U.240.166; 6.U.240.169; 6.U.240.172; 6.U.240.175; 6.U.240.240; 6.U.240.244; 6.U.244.228; 6.U.244.229; 6.U.244.230; 6.U.244.231; 6.U.244.236; 6.U.244.237; 6.U.244.238; 6.U.244.239; 6.U.244.154; 6.U.244.157; 6.U.244.166; 6.U.244.169; 6.U.244.172; 6.U.244.175; 6.U.244.240; 6.U.244.244;

6.W Prodrug

     6.W. 228.228; 6.W. 228.229; 6.W. 228.230; 6.W. 228.231; 6.W. 228.236; 6.W. 228.237; 6.W. 228.238; 6.W. 228.239; 6.W. 228.154; 6.W. 228.157; 6.W. 228.166; 6.W. 228.169; 6.W. 228.172; 6.W. 228.175; 6.W. 228.240; 6.W. 228.244; 6.W.229.228; 6.W.229.229; 6.W.229.230; 6.W.229.231; 6.W.229.236; 6.W.229.237; 6.W.229.238; 6.W.229.239; 6.W.229.154; 6.W.229.157; 6.W.229.166; 6.W.229.169; 6.W.229.172; 6.W.229.175; 6.W.229.240; 6.W.229.244; 6.W.230.228; 6.W.230.229; 6.W.230.230; 6.W.230.231; 6.W.230.236; 6.W.230.237; 6.W.230.238; 6.W.230.239; 6.W.230.154; 6.W.230.157; 6.W.230.166; 6.W.230.169; 6.W.230.172; 6.W.230.175; 6.W.230.240; 6.W.230.244; 6.W.231.228; 6.W.231.229; 6.W.231.230; 6.W.231.231; 6.W.231.236; 6.W.231.237; 6.W.231.238; 6.W.231.239; 6.W.231.154; 6.W.231.157; 6.W.231.166; 6.W.231.169; 6.W.231.172; 6.W.231.175; 6.W.231.240; 6.W.231.244; 6.W.236.228; 6.W.236.229; 6.W.236.230; 6.W.236.231; 6.W.236.236; 6.W.236.237; 6.W.236.238; 6.W.236.239; 6.W.236.154; 6.W.236.157; 6.W.236.166; 6.W.236.169; 6.W.236.172; 6.W.236.175; 6.W.236.240; 6.W.236.244; 6.W. 237.228; 6.W.237.229; 6.W. 237.230; 6.W. 237.231; 6.W. 237.236; 6.W. 237.237; 6.W. 237.238; 6.W. 237.239; 6.W. 237.154; 6.W. 237.157; 6.W. 237.166; 6.W. 237.169; 6.W. 237.172; 6.W. 237.175; 6.W.237.240; 6.W.237.244; 6.W.238.228; 6.W.238.229; 6.W.238.230; 6.W.238.231; 6.W.238.236; 6.W.238.237; 6.W.238.238; 6.W.238.239; 6.W.238.154; 6.W.238.157; 6.W.238.166; 6.W.238.169; 6.W.238.172; 6.W.238.175; 6.W.238.240; 6.W.238.244; 6.W.239.228; 6.W.239.229; 6.W.239.230; 6.W.239.231; 6.W.239.236; 6.W.239.237; 6.W.239.238; 6.W.239.239; 6.W.239.154; 6.W.239.157; 6.W.239.166; 6.W.239.169; 6.W.239.172; 6.W.239.175; 6.W.239.240; 6.W.239.244; 6.W.154.228; 6.W.154.229; 6.W.154.230; 6.W.154.231; 6.W.154.236; 6.W.154.237; 6.W.154.238; 6.W.154.239; 6.W.154.154; 6.W.154.157; 6.W.154.166; 6.W.154.169; 6.W.154.172; 6.W.154.175; 6.W.154.240; 6.W.154.244; 6.W.157.228; 6.W. 157.229; 6.W.157.230; 6.W.157.231; 6.W.157.236; 6.W.157.237; 6.W.157.238; 6.W.157.239; 6.W.157.154; 6.W.157.157; 6.W.157.166; 6.W.157.169; 6.W.157.172; 6.W.157.175; 6.W.157.240; 6.W.157.244; 6.W.166.228; 6.W.166.229; 6.W.166.230; 6.W.166.231; 6.W.166.236; 6.W.166.237; 6.W.166.238; 6.W.166.239; 6.W.166.154; 6.W.166.157; 6.W.166.166; 6.W.166.169; 6.W.166.172; 6.W.166.175; 6.W.166.240; 6.W.166.244; 6.W. 169.228; 6.W. 169.229; 6.W. 169.230; 6.W. 169.231; 6.W. 169.236; 6.W. 169.237; 6.W. 169.238; 6.W. 169.239; 6.W. 169.154; 6.W. 169.157; 6.W. 169.166; 6.W. 169.169; 6.W. 169.172; 6.W. 169.175; 6.W. 169.240; 6.W. 169.244; 6.W.172.228; 6.W.172.229; 6.W.172.230; 6.W.172.231; 6.W.172.236; 6.W.172.237; 6.W.172.238; 6.W.172.239; 6.W.172.154; 6.W.172.157; 6.W.172.166; 6.W.172.169; 6.W.172.172; 6.W.172.175; 6.W.172.240; 6.W.172.244; 6.W.175.228; 6.W.175.229; 6.W.175.230; 6.W.175.231; 6.W.175.236; 6.W.175.237; 6.W.175.238; 6.W.175.239; 6.W.175.154; 6.W.175.157; 6.W.175.166; 6.W.175.169; 6.W.175.172; 6.W.175.175; 6.W.175.240; 6.W.175.244; 6.W.240.228; 6.W.240.229; 6.W.240.230; 6.W.240.231; 6.W.240.236; 6.W.240.237; 6.W.240.238; 6.W.240.239; 6.W.240.154; 6.W.240.157; 6.W.240.166; 6.W.240.169; 6.W.240.172; 6.W.240.175; 6.W.240.240; 6.W.240.244; 6.W.244.228; 6.W.244.229; 6.W.244.230; 6.W.244.231; 6.W.244.236; 6.W.244.237; 6.W.244.238; 6.W.244.239; 6.W.244.154; 6.W.244.157; 6.W.244.166; 6.W.244.169; 6.W.244.172; 6.W.244.175; 6.W.244.240; 6.W.244.244;

6.Y's Prodrug

     6.Y. 228.228; 6.Y.228.229; 6.Y. 228.230; 6.Y.228.231; 6.Y.228.236; 6.Y. 228.237; 6.Y.228.238; 6.Y. 228.239; 6.Y.228.154; 6.Y.228.157; 6.Y.228.166; 6.Y. 228.169; 6.Y.228.172; 6.Y. 228.175; 6.Y. 228.240; 6.Y.228.244; 6.Y.229.228; 6.Y.229.229; 6.Y.229.230; 6.Y.229.231; 6.Y.229.236; 6.Y.229.237; 6.Y.229.238; 6.Y.229.239; 6.Y.229.154; 6.Y.229.157; 6.Y.229.166; 6.Y.229.169; 6.Y.229.172; 6.Y.229.175; 6.Y.229.240; 6.Y.229.244; 6.Y.230.228; 6.Y.230.229; 6.Y.230.230; 6.Y.230.231; 6.Y.230.236; 6.Y.230.237; 6.Y.230.238; 6.Y.230.239; 6.Y.230.154; 6.Y.230.157; 6.Y.230.166; 6.Y.230.169; 6.Y.230.172; 6.Y.230.175; 6.Y.230.240; 6.Y.230.244; 6.Y.231.228; 6.Y.231.229; 6.Y.231.230; 6.Y.231.231; 6.Y.231.236; 6.Y.231.237; 6.Y.231.238; 6.Y.231.239; 6.Y.231.154; 6.Y.231.157; 6.Y.231.166; 6.Y.231.169; 6.Y.231.172; 6.Y.231.175; 6.Y.231.240; 6.Y.231.244; 6.Y.236.228; 6.Y.236.229; 6.Y.236.230; 6.Y.236.231; 6.Y.236.236; 6.Y.236.237; 6.Y.236.238; 6.Y.236.239; 6.Y.236.154; 6.Y.236.157; 6.Y.236.166; 6.Y.236.169; 6.Y.236.172; 6.Y.236.175; 6.Y.236.240; 6.Y.236.244; 6.Y. 237.228; 6.Y.237.229; 6.Y. 237.230; 6.Y. 237.231; 6.Y. 237.236; 6.Y. 237.237; 6.Y. 237.238; 6.Y. 237.239; 6.Y. 237.154; 6.Y. 237.157; 6.Y. 237.166; 6.Y. 237.169; 6.Y. 237.172; 6.Y. 237.175; 6.Y. 237.240; 6.Y. 237.244; 6.Y.238.228; 6.Y.238.229; 6.Y.238.230; 6.Y.238.231; 6.Y.238.236; 6.Y.238.237; 6.Y.238.238; 6.Y.238.239; 6.Y.238.154; 6.Y.238.157; 6.Y.238.166; 6.Y.238.169; 6.Y.238.172; 6.Y.238.175; 6.Y.238.240; 6.Y.238.244; 6.Y.239.228; 6.Y.239.229; 6.Y.239.230; 6.Y.239.231; 6.Y.239.236; 6.Y.239.237; 6.Y.239.238; 6.Y.239.239; 6.Y.239.154; 6.Y.239.157; 6.Y.239.166; 6.Y.239.169; 6.Y.239.172; 6.Y.239.175; 6.Y.239.240; 6.Y.239.244; 6.Y.154.228; 6.Y.154.229; 6.Y.154.230; 6.Y.154.231; 6.Y.154.236; 6.Y.154.237; 6.Y.154.238; 6.Y.154.239; 6.Y.154.154; 6.Y.154.157; 6.Y.154.166; 6.Y.154.169; 6.Y.154.172; 6.Y.154.175; 6.Y.154.240; 6.Y.154.244; 6.Y.157.228; 6.Y.157.229; 6.Y.157.230; 6.Y.157.231; 6.Y.157.236; 6.Y.157.237; 6.Y.157.238; 6.Y.157.239; 6.Y.157.154; 6.Y.157.157; 6.Y.157.166; 6.Y.157.169; 6.Y.157.172; 6.Y.157.175; 6.Y.157.240; 6.Y.157.244; 6.Y.166.228; 6.Y.166.229; 6.Y.166.230; 6.Y.166.231; 6.Y.166.236; 6.Y.166.237; 6.Y.166.238; 6.Y.166.239; 6.Y.166.154; 6.Y.166.157; 6.Y.166.166; 6.Y.166.169; 6.Y.166.172; 6.Y.166.175; 6.Y.166.240; 6.Y.166.244; 6.Y. 169.228; 6.Y.169.229; 6.Y.169.230; 6.Y. 169.231; 6.Y. 169.236; 6.Y. 169.237; 6.Y. 169.238; 6.Y. 169.239; 6.Y. 169.154; 6.Y. 169.157; 6.Y. 169.166; 6.Y. 169.169; 6.Y. 169.172; 6.Y. 169.175; 6.Y. 169.240; 6.Y. 169.244; 6.Y.172.228; 6.Y.172.229; 6.Y.172.230; 6.Y.172.231; 6.Y.172.236; 6.Y.172.237; 6.Y.172.238; 6.Y.172.239; 6.Y.172.154; 6.Y.172.157; 6.Y.172.166; 6.Y.172.169; 6.Y.172.172; 6.Y.172.175; 6.Y.172.240; 6.Y.172.244; 6.Y.175.228; 6.Y.175.229; 6.Y. 175.230; 6.Y.175.231; 6.Y.175.236; 6.Y.175.237; 6.Y.175.238; 6.Y.175.239; 6.Y.175.154; 6.Y.175.157; 6.Y.175.166; 6.Y.175.169; 6.Y.175.172; 6.Y.175.175; 6.Y.175.240; 6.Y.175.244; 6.Y.240.228; 6.Y.240.229; 6.Y.240.230; 6.Y.240.231; 6.Y.240.236; 6.Y.240.237; 6.Y.240.238; 6.Y.240.239; 6.Y.240.154; 6.Y.240.157; 6.Y.240.166; 6.Y.240.169; 6.Y.240.172; 6.Y.240.175; 6.Y.240.240; 6.Y.240.244; 6.Y.244.228; 6.Y.244.229; 6.Y.244.230; 6.Y.244.231; 6.Y.244.236; 6.Y.244.237; 6.Y.244.238; 6.Y.244.239; 6.Y.244.154; 6.Y.244.157; 6.Y.244.166; 6.Y.244.169; 6.Y.244.172; 6.Y.244.175; 6.Y.244.240; 6.Y.244.244;

7.AH Prodrug

     7.AH.4.157; 7.AH.4.158; 7.AH.4.196; 7.AH. 4.223; 7.AH. 4.240; 7.AH. 4.244; 7.AH.4.243; 7.AH. 4.247; 7.AH.5.157; 7.AH.5.158; 7.AH.5.196; 7.AH.5.223; 7.AH.5.240; 7.AH.5.244; 7.AH.5.243; 7.AH.5.247; 7.AH. 7.157; 7.AH. 7.158; 7.AH. 7.196; 7.AH.7.223; 7.AH.7.240; 7.AH.7.244; 7.AH. 7.243; 7.AH.7.247; 7.AH. 15.157; 7.AH. 15.158; 7.AH. 15.196; 7.AH. 15.223; 7.AH. 15.240; 7.AH. 15.244; 7.AH.15.243; 7.AH. 15.247; 7.AH. 16.157; 7.AH. 16.158; 7.AH. 16.196; 7.AH. 16.223; 7.AH. 16.240; 7.AH. 16.244; 7.AH. 16.243; 7.AH. 16.247; 7.AH. 18.157; 7.AH. 18.158; 7.AH. 18.196; 7.AH. 18.223; 7.AH. 18.240; 7.AH. 18.244; 7.AH. 18.243; 7.AH. 18.247; 7.AH. 26.157; 7.AH. 26.158; 7.AH. 26.196; 7.AH. 26.223; 7.AH. 26.240; 7.AH. 26.244; 7.AH. 26.243; 7.AH. 26.247; 7.AH. 27.157; 7.AH. 27.158; 7.AH. 27.196; 7.AH. 27.223; 7.AH. 27.240; 7.AH. 27.244; 7.AH. 27.243; 7.AH. 27.247; 7.AH. 29.157; 7.AH.29.158; 7.AH.29.196; 7.AH.29.223; 7.AH.29.240; 7.AH.29.244; 7.AH.29.243; 7.AH.29.247; 7.AH. 54.157; 7.AH. 54.158; 7.AH. 54.196; 7.AH. 54.223; 7.AH. 54.240; 7.AH. 54.244; 7.AH. 54.243; 7.AH. 54.247; 7.AH. 55.157; 7.AH. 55.158; 7.AH.55.196; 7.AH.55.223; 7.AH.55.240; 7.AH.55.244; 7.AH.55.243; 7.AH.55.247; 7.AH. 56.157; 7.AH. 56.158; 7.AH. 56.196; 7.AH. 56.223; 7.AH. 56.240; 7.AH. 56.244; 7.AH. 56.243; 7.AH. 56.247; 7.AH.157.157; 7.AH.157.158; 7.AH.157.196; 7.AH.157.223; 7.AH.157.240; 7.AH.157.244; 7.AH. 157.243; 7.AH.157.247; 7.AH. 196.157; 7.AH. 196.158; 7.AH. 196.196; 7.AH. 196.223; 7.AH.196.240; 7.AH.196.244; 7.AH.196.243; 7.AH.196.247; 7.AH.223.157; 7.AH.223.158; 7.AH.223.196; 7.AH.223.223; 7.AH.223.240; 7.AH.223.244; 7.AH.223.243; 7.AH.223.247; 7.AH. 240.157; 7.AH. 240.158; 7.AH. 240.196; 7.AH. 240.223; 7.AH. 240.240; 7.AH. 240.244; 7.AH.240.243; 7.AH. 240.247; 7.AH.244.157; 7.AH.244.158; 7.AH.244.196; 7.AH.244.223; 7.AH.244.240; 7.AH.244.244; 7.AH.244.243; 7.AH.244.247; 7.AH. 247.157; 7.AH. 247.158; 7.AH. 247.196; 7.AH.247.223; 7.AH.247.240; 7.AH.247.244; 7.AH.247.243; 7.AH. 247.247;

7. AJ of Prodrug

     7.AJ.4.157; 7.AJ.4.158; 7.AJ.4.196; 7.AJ.4.223; 7.AJ.4.240; 7.AJ.4.244; 7.AJ.4.243; 7.AJ.4.247; 7.AJ.5.157; 7.AJ.5.158; 7.AJ.5.196; 7.AJ.5.223; 7.AJ.5.240; 7.AJ.5.244; 7.AJ.5.243; 7.AJ.5.247; 7.AJ.7.157; 7.AJ.7.158; 7.AJ.7.196; 7.AJ.7.223; 7.AJ.7.240; 7.AJ.7.244; 7.AJ.7.243; 7.AJ.7.247; 7.AJ. 15.157; 7.AJ.15.158; 7.AJ. 15.196; 7.AJ.15.223; 7.AJ. 15.240; 7.AJ. 15.244; 7.AJ.15.243; 7.AJ.15.247; 7.AJ. 16.157; 7.AJ. 16.158; 7.AJ. 16.196; 7.AJ.16.223; 7.AJ. 16.240; 7.AJ.16.244; 7.AJ.16.243; 7.AJ.16.247; 7.AJ. 18.157; 7.AJ. 18.158; 7.AJ. 18.196; 7.AJ. 18.223; 7.AJ. 18.240; 7.AJ. 18.244; 7.AJ. 18.243; 7.AJ. 18.247; 7.AJ. 26.157; 7.AJ. 26.158; 7.AJ. 26.196; 7.AJ. 26.223; 7.AJ. 26.240; 7.AJ. 26.244; 7.AJ.26.243; 7.AJ. 26.247; 7.AJ. 27.157; 7.AJ.27.158; 7.AJ. 27.196; 7.AJ.27.223; 7.AJ.27.240; 7.AJ.27.244; 7.AJ.27.243; 7.AJ.27.247; 7.AJ.29.157; 7.AJ.29.158; 7.AJ.29.196; 7.AJ.29.223; 7.AJ.29.240; 7.AJ.29.244; 7.AJ.29.243; 7.AJ.29.247; 7.AJ. 54.157; 7.AJ. 54.158; 7.AJ. 54.196; 7.AJ. 54.223; 7.AJ. 54.240; 7.AJ. 54.244; 7.AJ. 54.243; 7.AJ. 54.247; 7.AJ. 55.157; 7.AJ. 55.158; 7.AJ. 55.196; 7.AJ.55.223; 7.AJ.55.240; 7.AJ.55.244; 7.AJ.55.243; 7.AJ. 55.247; 7.AJ. 56.157; 7.AJ. 56.158; 7.AJ. 56.196; 7.AJ. 56.223; 7.AJ. 56.240; 7.AJ. 56.244; 7.AJ. 56.243; 7.AJ. 56.247; 7.AJ.157.157; 7.AJ.157.158; 7.AJ.157.196; 7.AJ.157.223; 7.AJ.157.240; 7.AJ.157.244; 7.AJ. 157.243; 7.AJ.157.247; 7.AJ. 196.157; 7.AJ.196.158; 7.AJ. 196.196; 7.AJ. 196.223; 7.AJ.196.240; 7.AJ.196.244; 7.AJ. 196.243; 7.AJ.196.247; 7.AJ.223.157; 7.AJ.223.158; 7.AJ.223.196; 7.AJ.223.223; 7.AJ.223.240; 7.AJ.223.244; 7.AJ.223.243; 7.AJ.223.247; 7.AJ. 240.157; 7.AJ.240.158; 7.AJ. 240.196; 7.AJ. 240.223; 7.AJ.240.240; 7.AJ.240.244; 7.AJ.240.243; 7.AJ.240.247; 7.AJ.244.157; 7.AJ.244.158; 7.AJ.244.196; 7.AJ.244.223; 7.AJ.244.240; 7.AJ.244.244; 7.AJ.244.243; 7.AJ.244.247; 7.AJ.247.157; 7.AJ.247.158; 7.AJ.247.196; 7.AJ.247.223; 7.AJ.247.240; 7.AJ.247.244; 7.AJ.247.243; 7.AJ.247.247;

7.AN's Prodrug

     7.AN.4.157; 7.AN.4.158; 7.AN.4.196; 7.AN.4.223; 7.AN.4.240; 7.AN.4.244; 7.AN.4.243; 7.AN.4.247; 7.AN.5.157; 7.AN.5.158; 7.AN.5.196; 7.AN.5.223; 7.AN.5.240; 7.AN.5.244; 7.AN.5.243; 7.AN.5.247; 7.AN.7.157; 7.AN.7.158; 7.AN.7.196; 7.AN.7.223; 7.AN.7.240; 7.AN.7.244; 7.AN.7.243; 7.AN.7.247; 7.AN.15.157; 7.AN.15.158; 7.AN.15.196; 7.AN.15.223; 7.AN.15.240; 7.AN.15.244; 7.AN.15.243; 7.AN.15.247; 7.AN.16.157; 7.AN.16.158; 7.AN.16.196; 7.AN.16.223; 7.AN.16.240; 7.AN.16.244; 7.AN.16.243; 7.AN.16.247; 7.AN.18.157; 7.AN.18.158; 7.AN.18.196; 7.AN.18.223; 7.AN.18.240; 7.AN.18.244; 7.AN.18.243; 7.AN.18.247; 7.AN.26.157; 7.AN.26.158; 7.AN.26.196; 7.AN.26.223; 7.AN.26.240; 7.AN.26.244; 7.AN.26.243; 7.AN.26.247; 7.AN.27.157; 7.AN.27.158; 7.AN.27.196; 7.AN.27.223; 7.AN.27.240; 7.AN.27.244; 7.AN.27.243; 7.AN.27.247; 7.AN.29.157; 7.AN.29.158; 7.AN.29.196; 7.AN.29.223; 7.AN.29.240; 7.AN.29.244; 7.AN.29.243; 7.AN.29.247; 7.AN.54.157; 7.AN.54.158; 7.AN.54.196; 7.AN.54.223; 7.AN.54.240; 7.AN.54.244; 7.AN.54.243; 7.AN.54.247; 7.AN.55.157; 7.AN.55.158; 7.AN.55.196; 7.AN.55.223; 7.AN.55.240; 7.AN.55.244; 7.AN.55.243; 7.AN.55.247; 7.AN.56.157; 7.AN.56.158; 7.AN.56.196; 7.AN.56.223; 7.AN.56.240; 7.AN.56.244; 7.AN.56.243; 7.AN.56.247; 7.AN.157.157; 7.AN.157.158; 7.AN.157.196; 7.AN.157.223; 7.AN.157.240; 7.AN.157.244; 7.AN.157.243; 7.AN.157.247; 7.AN.196.157; 7.AN.196.158; 7.AN.196.196; 7.AN.196.223; 7.AN.196.240; 7.AN.196.244; 7.AN.196.243; 7.AN.196.247; 7.AN.223.157; 7.AN.223.158; 7.AN.223.196; 7.AN.223.223; 7.AN.223.240; 7.AN.223.244; 7.AN.223.243; 7.AN.223.247; 7.AN.240.157; 7.AN.240.158; 7.AN.240.196; 7.AN.240.223; 7.AN.240.240; 7.AN.240.244; 7.AN.240.243; 7.AN.240.247; 7.AN.244.157; 7.AN.244.158; 7.AN.244.196; 7.AN.244.223; 7.AN.244.240; 7.AN.244.244; 7.AN.244.243; 7.AN.244.247; 7.AN.247.157; 7.AN.247.158; 7.AN.247.196; 7.AN.247.223; 7.AN.247.240; 7.AN.247.244; 7.AN.247.243; 7.AN.247.247;

7.AP Prodrug

     7.AP.4.157; 7.AP.4.158; 7.AP.4.196; 7.AP.4.223; 7.AP.4.240; 7.AP.4.244; 7.AP.4.243; 7.AP.4.247; 7.AP.5.157; 7.AP.5.158; 7.AP.5.196; 7.AP.5.223; 7.AP.5.240; 7.AP.5.244; 7.AP.5.243; 7.AP.5.247; 7.AP.7.157; 7.AP.7.158; 7.AP.7.196; 7.AP.7.223; 7.AP.7.240; 7.AP.7.244; 7.AP.7.243; 7.AP.7.247; 7.AP.15.157; 7.AP.15.158; 7.AP.15.196; 7.AP.15.223; 7.AP.15.240; 7.AP.15.244; 7.AP.15.243; 7.AP.15.247; 7.AP.16.157; 7.AP.16.158; 7.AP.16.196; 7.AP.16.223; 7.AP.16.240; 7.AP.16.244; 7.AP.16.243; 7.AP.16.247; 7.AP.18.157; 7.AP.18.158; 7.AP.18.196; 7.AP.18.223; 7.AP.18.240; 7.AP.18.244; 7.AP.18.243; 7.AP.18.247; 7.AP.26.157; 7.AP.26.158; 7.AP.26.196; 7.AP.26.223; 7.AP.26.240; 7.AP.26.244; 7.AP.26.243; 7.AP.26.247; 7.AP.27.157; 7.AP.27.158; 7.AP.27.196; 7.AP.27.223; 7.AP.27.240; 7.AP.27.244; 7.AP.27.243; 7.AP.27.247; 7.AP.29.157; 7.AP.29.158; 7.AP.29.196; 7.AP.29.223; 7.AP.29.240; 7.AP.29.244; 7.AP.29.243; 7.AP.29.247; 7.AP.54.157; 7.AP.54.158; 7.AP.54.196; 7.AP.54.223; 7.AP.54.240; 7.AP.54.244; 7.AP.54.243; 7.AP.54.247; 7.AP.55.157; 7.AP.55.158; 7.AP.55.196; 7.AP.55.223; 7.AP.55.240; 7.AP.55.244; 7.AP.55.243; 7.AP.55.247; 7.AP.56.157; 7.AP.56.158; 7.AP.56.196; 7.AP.56.223; 7.AP.56.240; 7.AP.56.244; 7.AP.56.243; 7.AP.56.247; 7.AP.157.157; 7.AP.157.158; 7.AP.157.196; 7.AP.157.223; 7.AP.157.240; 7.AP.157.244; 7.AP.157.243; 7.AP.157.247; 7.AP.196.157; 7.AP.196.158; 7.AP.196.196; 7.AP.196.223; 7.AP.196.240; 7.AP.196.244; 7.AP.196.243; 7.AP.196.247; 7.AP.223.157; 7.AP.223.158; 7.AP.223.196; 7.AP.223.223; 7.AP.223.240; 7.AP.223.244; 7.AP.223.243; 7.AP.223.247; 7.AP.240.157; 7.AP.240.158; 7.AP.240.196; 7.AP.240.223; 7.AP.240.240; 7.AP.240.244; 7.AP.240.243; 7.AP.240.247; 7.AP.244.157; 7.AP.244.158; 7.AP.244.196; 7.AP.244.223; 7.AP.244.240; 7.AP.244.244; 7.AP.244.243; 7.AP.244.247; 7.AP.247.157; 7.AP.247.158; 7.AP.247.196; 7.AP.247.223; 7.AP.247.240; 7.AP.247.244; 7.AP.247.243; 7.AP.247.247;

7.AZ Prodrug

     7.AZ.4.157; 7.AZ.4.158; 7.AZ.4.196; 7.AZ.4.223; 7.AZ.4.240; 7.AZ.4.244; 7.AZ.4.243; 7.AZ.4.247; 7.AZ.5.157; 7.AZ.5.158; 7.AZ.5.196; 7.AZ.5.223; 7.AZ.5.240; 7.AZ.5.244; 7.AZ.5.243; 7.AZ.5.247; 7.AZ.7.157; 7.AZ.7.158; 7.AZ.7.196; 7.AZ.7.223; 7.AZ.7.240; 7.AZ.7.244; 7.AZ.7.243; 7.AZ.7.247; 7.AZ. 15.157; 7.AZ. 15.158; 7.AZ. 15.196; 7.AZ. 15.223; 7.AZ. 15.240; 7.AZ. 15.244; 7.AZ. 15.243; 7.AZ. 15.247; 7.AZ. 16.157; 7.AZ. 16.158; 7.AZ. 16.196; 7.AZ. 16.223; 7.AZ. 16.240; 7.AZ. 16.244; 7.AZ. 16.243; 7.AZ. 16.247; 7.AZ. 18.157; 7.AZ. 18.158; 7.AZ. 18.196; 7.AZ. 18.223; 7.AZ. 18.240; 7.AZ. 18.244; 7.AZ. 18.243; 7.AZ. 18.247; 7.AZ. 26.157; 7.AZ. 26.158; 7.AZ. 26.196; 7.AZ. 26.223; 7.AZ. 26.240; 7.AZ. 26.244; 7.AZ. 26.243; 7.AZ. 26.247; 7.AZ. 27.157; 7.AZ. 27.158; 7.AZ. 27.196; 7.AZ. 27.223; 7.AZ. 27.240; 7.AZ. 27.244; 7.AZ. 27.243; 7.AZ. 27.247; 7.AZ. 29.157; 7.AZ. 29.158; 7.AZ. 29.196; 7.AZ.29.223; 7.AZ.29.240; 7.AZ.29.244; 7.AZ.29.243; 7.AZ.29.247; 7.AZ. 54.157; 7.AZ. 54.158; 7.AZ. 54.196; 7.AZ. 54.223; 7.AZ. 54.240; 7.AZ. 54.244; 7.AZ. 54.243; 7.AZ. 54.247; 7.AZ. 55.157; 7.AZ. 55.158; 7.AZ. 55.196; 7.AZ. 55.223; 7.AZ.55.240; 7.AZ.55.244; 7.AZ.55.243; 7.AZ.55.247; 7.AZ. 56.157; 7.AZ. 56.158; 7.AZ. 56.196; 7.AZ. 56.223; 7.AZ. 56.240; 7.AZ. 56.244; 7.AZ. 56.243; 7.AZ. 56.247; 7.AZ.157.157; 7.AZ.157.158; 7.AZ.157.196; 7.AZ.157.223; 7.AZ.157.240; 7.AZ.157.244; 7.AZ. 157.243; 7.AZ.157.247; 7.AZ. 196.157; 7.AZ. 196.158; 7.AZ. 196.196; 7.AZ. 196.223; 7.AZ. 196.240; 7.AZ. 196.244; 7.AZ. 196.243; 7.AZ.196.247; 7.AZ.223.157; 7.AZ.223.158; 7.AZ.223.196; 7.AZ.223.223; 7.AZ.223.240; 7.AZ.223.244; 7.AZ.223.243; 7.AZ.223.247; 7.AZ. 240.157; 7.AZ. 240.158; 7.AZ.240.196; 7.AZ. 240.223; 7.AZ.240.240; 7.AZ.240.244; 7.AZ. 240.243; 7.AZ.240.247; 7.AZ.244.157; 7.AZ.244.158; 7.AZ.244.196; 7.AZ.244.223; 7.AZ.244.240; 7.AZ.244.244; 7.AZ.244.243; 7.AZ.244.247; 7.AZ.247.157; 7.AZ.247.158; 7.AZ.247.196; 7.AZ.247.223; 7.AZ.247.240; 7.AZ.247.244; 7.AZ. 247.243; 7.AZ.247.247;

7. BF of Prodrug

     7.BF.4.157; 7.BF.4.158; 7.BF.4.196; 7.BF.4.223; 7.BF.4.240; 7.BF.4.244; 7.BF.4.243; 7.BF.4.247; 7.BF.5.157; 7.BF.5.158; 7.BF.5.196; 7.BF.5.223; 7.BF.5.240; 7.BF.5.244; 7.BF.5.243; 7.BF.5.247; 7.BF.7.157; 7.BF.7.158; 7.BF.7.196; 7.BF.7.223; 7.BF.7.240; 7.BF.7.244; 7.BF.7.243; 7.BF.7.247; 7.BF. 15.157; 7.BF. 15.158; 7.BF. 15.196; 7.BF. 15.223; 7.BF. 15.240; 7.BF. 15.244; 7.BF.15.243; 7.BF. 15.247; 7.BF. 16.157; 7.BF. 16.158; 7.BF. 16.196; 7.BF. 16.223; 7.BF. 16.240; 7.BF. 16.244; 7.BF. 16.243; 7.BF. 16.247; 7.BF. 18.157; 7.BF. 18.158; 7.BF. 18.196; 7.BF. 18.223; 7.BF. 18.240; 7.BF. 18.244; 7.BF. 18.243; 7.BF. 18.247; 7.BF. 26.157; 7.BF. 26.158; 7.BF. 26.196; 7.BF. 26.223; 7.BF. 26.240; 7.BF. 26.244; 7.BF. 26.243; 7.BF. 26.247; 7.BF. 27.157; 7.BF. 27.158; 7.BF. 27.196; 7.BF. 27.223; 7.BF. 27.240; 7.BF. 27.244; 7.BF. 27.243; 7.BF. 27.247; 7.BF. 29.157; 7.BF. 29.158; 7.BF. 29.196; 7.BF.29.223; 7.BF. 29.240; 7.BF.29.244; 7.BF. 29.243; 7.BF.29.247; 7.BF. 54.157; 7.BF. 54.158; 7.BF. 54.196; 7.BF. 54.223; 7.BF. 54.240; 7.BF. 54.244; 7.BF. 54.243; 7.BF. 54.247; 7.BF. 55.157; 7.BF. 55.158; 7.BF. 55.196; 7.BF. 55.223; 7.BF. 55.240; 7.BF. 55.244; 7.BF. 55.243; 7.BF. 55.247; 7.BF. 56.157; 7.BF. 56.158; 7.BF. 56.196; 7.BF. 56.223; 7.BF. 56.240; 7.BF. 56.244; 7.BF. 56.243; 7.BF. 56.247; 7.BF.157.157; 7.BF.157.158; 7.BF.157.196; 7.BF.157.223; 7.BF.157.240; 7.BF.157.244; 7.BF. 157.243; 7.BF.157.247; 7.BF.196.157; 7.BF.196.158; 7.BF.196.196; 7.BF.196.223; 7.BF.196.240; 7.BF.196.244; 7.BF. 196.243; 7.BF.196.247; 7.BF.223.157; 7.BF.223.158; 7.BF.223.196; 7.BF.223.223; 7.BF.223.240; 7.BF.223.244; 7.BF.223.243; 7.BF.223.247; 7.BF.240.157; 7.BF.240.158; 7.BF.240.196; 7.BF.240.223; 7.BF.240.240; 7.BF.240.244; 7.BF.240.243; 7.BF.240.247; 7.BF.244.157; 7.BF.244.158; 7.BF.244.196; 7.BF.244.223; 7.BF.244.240; 7.BF.244.244; 7.BF.244.243; 7.BF.244.247; 7.BF.247.157; 7.BF.247.158; 7.BF.247.196; 7.BF.247.223; 7.BF.247.240; 7.BF.247.244; 7.BF.247.243; 7.BF.247.247;

7.CI Prodrug

     7.CI.4.157; 7.CI.4.158; 7.CI.4.196; 7.CI.4.223; 7.CI.4.240; 7.CI.4.244; 7.CI.4.243; 7.CI.4.247; 7.CI.5.157; 7.CI.5.158; 7.CI.5.196; 7.CI.5.223; 7.CI.5.240; 7.CI.5.244; 7.CI.5.243; 7.CI.5.247; 7.CI.7.157; 7.CI.7.158; 7.CI.7.196; 7.CI.7.223; 7.CI.7.240; 7.CI.7.244; 7.CI.7.243; 7.CI.7.247; 7.CI.15.157; 7.CI.15.158; 7.CI.15.196; 7.CI.15.223; 7.CI.15.240; 7.CI.15.244; 7.CI.15.243; 7.CI.15.247; 7.CI.16.157; 7.CI.16.158; 7.CI.16.196; 7.CI.16.223; 7.CI.16.240; 7.CI.16.244; 7.CI.16.243; 7.CI.16.247; 7.CI.18.157; 7.CI.18.158; 7.CI.18.196; 7.CI.18.223; 7.CI.18.240; 7.CI.18.244; 7.CI.18.243; 7.CI.18.247; 7.CI.26.157; 7.CI.26.158; 7.CI.26.196; 7.CI.26.223; 7.CI.26.240; 7.CI.26.244; 7.CI.26.243; 7.CI.26.247; 7.CI.27.157; 7.CI.27.158; 7.CI.27.196; 7.CI.27.223; 7.CI.27.240; 7.CI.27.244; 7.CI.27.243; 7.CI.27.247; 7.CI.29.157; 7.CI.29.158; 7.CI.29.196; 7.CI.29.223; 7.CI.29.240; 7.CI.29.244; 7.CI.29.243; 7.CI.29.247; 7.CI.54.157; 7.CI.54.158; 7.CI.54.196; 7.CI.54.223; 7.CI.54.240; 7.CI.54.244; 7.CI.54.243; 7.CI.54.247; 7.CI.55.157; 7.CI.55.158; 7.CI.55.196; 7.CI.55.223; 7.CI.55.240; 7.CI.55.244; 7.CI.55.243; 7.CI.55.247; 7.CI.56.157; 7.CI.56.158; 7.CI.56.196; 7.CI.56.223; 7.CI.56.240; 7.CI.56.244; 7.CI.56.243; 7.CI.56.247; 7.CI.157.157; 7.CI.157.158; 7.CI.157.196; 7.CI.157.223; 7.CI.157.240; 7.CI.157.244; 7.CI.157.243; 7.CI.157.247; 7.CI.196.157; 7.CI.196.158; 7.CI.196.196; 7.CI.196.223; 7.CI.196.240; 7.CI.196.244; 7.CI.196.243; 7.CI.196.247; 7.CI.223.157; 7.CI.223.158; 7.CI.223.196; 7.CI.223.223; 7.CI.223.240; 7.CI.223.244; 7.CI.223.243; 7.CI.223.247; 7.CI.240.157; 7.CI.240.158; 7.CI.240.196; 7.CI.240.223; 7.CI.240.240; 7.CI.240.244; 7.CI.240.243; 7.CI.240.247; 7.CI.244.157; 7.CI.244.158; 7.CI.244.196; 7.CI.244.223; 7.CI.244.240; 7.CI.244.244; 7.CI.244.243; 7.CI.244.247; 7.CI.247.157; 7.CI.247.158; 7.CI.247.196; 7.CI.247.223; 7.CI.247.240; 7.CI.247.244; 7.CI.247.243; 7.CI.247.247;

7.CO's Prodrug

     7.CO.4.157; 7.CO.4.158; 7.CO.4.196; 7.CO.4.223; 7.CO.4.240; 7.CO.4.244; 7.CO.4.243; 7.CO.4.247; 7.CO.5.157; 7.CO.5.158; 7.CO.5.196; 7.CO.5.223; 7.CO.5.240; 7.CO.5.244; 7.CO.5.243; 7.CO.5.247; 7.CO.7.157; 7.CO.7.158; 7.CO.7.196; 7.CO.7.223; 7.CO.7.240; 7.CO.7.244; 7.CO.7.243; 7.CO.7.247; 7.CO.15.157; 7.CO.15.158; 7.CO.15.196; 7.CO.15.223; 7.CO.15.240; 7.CO.15.244; 7.CO.15.243; 7.CO.15.247; 7.CO.16.157; 7.CO.16.158; 7.CO.16.196; 7.CO.16.223; 7.CO.16.240; 7.CO.16.244; 7.CO.16.243; 7.CO.16.247; 7.CO.18.157; 7.CO.18.158; 7.CO.18.196; 7.CO.18.223; 7.CO.18.240; 7.CO.18.244; 7.CO.18.243; 7.CO.18.247; 7.CO.26.157; 7.CO.26.158; 7.CO.26.196; 7.CO.26.223; 7.CO.26.240; 7.CO.26.244; 7.CO.26.243; 7.CO.26.247; 7.CO.27.157; 7.CO.27.158; 7.CO.27.196; 7.CO.27.223; 7.CO.27.240; 7.CO.27.244; 7.CO.27.243; 7.CO.27.247; 7.CO.29.157; 7.CO.29.158; 7.CO.29.196; 7.CO.29.223; 7.CO.29.240; 7.CO.29.244; 7.CO.29.243; 7.CO.29.247; 7.CO.54.157; 7.CO.54.158; 7.CO.54.196; 7.CO.54.223; 7.CO.54.240; 7.CO.54.244; 7.CO.54.243; 7.CO.54.247; 7.CO.55.157; 7.CO.55.158; 7.CO.55.196; 7.CO.55.223; 7.CO.55.240; 7.CO.55.244; 7.CO.55.243; 7.CO.55.247; 7.CO.56.157; 7.CO.56.158; 7.CO.56.196; 7.CO.56.223; 7.CO.56.240; 7.CO.56.244; 7.CO.56.243; 7.CO.56.247; 7.CO.157.157; 7.CO.157.158; 7.CO.157.196; 7.CO.157.223; 7.CO.157.240; 7.CO.157.244; 7.CO.157.243; 7.CO.157.247; 7.CO.196.157; 7.CO.196.158; 7.CO.196.196; 7.CO.196.223; 7.CO.196.240; 7.CO.196.244; 7.CO.196.243; 7.CO.196.247; 7.CO.223.157; 7.CO.223.158; 7.CO.223.196; 7.CO.223.223; 7.CO.223.240; 7.CO.223.244; 7.CO.223.243; 7.CO.223.247; 7.CO.240.157; 7.CO.240.158; 7.CO.240.196; 7.CO.240.223; 7.CO.240.240; 7.CO.240.244; 7.CO.240.243; 7.CO.240.247; 7.CO.244.157; 7.CO.244.158; 7.CO.244.196; 7.CO.244.223; 7.CO.244.240; 7.CO.244.244; 7.CO.244.243; 7.CO.244.247; 7.CO.4.157; 7.CO.4.158; 7.CO.4.196; 7.CO.4.223; 7.CO.4.240; 7.CO.4.244; 7.CO.4.243; 7.CO.4.247;

8.AH Prodrug

     8.AH.4.157; 8.AH.4.158; 8.AH.4.196; 8.AH.4.223; 8.AH. 4.240; 8.AH.4.244; 8.AH.4.243; 8.AH.4.247; 8.AH.5.157; 8.AH.5.158; 8.AH.5.196; 8.AH.5.223; 8.AH.5.240; 8.AH.5.244; 8.AH.5.243; 8.AH.5.247; 8.AH. 7.157; 8.AH. 7.158; 8.AH.7.196; 8.AH.7.223; 8.AH.7.240; 8.AH.7.244; 8.AH.7.243; 8.AH.7.247; 8.AH. 15.157; 8.AH. 15.158; 8.AH. 15.196; 8.AH. 15.223; 8.AH. 15.240; 8.AH. 15.244; 8.AH.15.243; 8.AH. 15.247; 8.AH. 16.157; 8.AH. 16.158; 8.AH. 16.196; 8.AH. 16.223; 8.AH. 16.240; 8.AH. 16.244; 8.AH.16.243; 8.AH. 16.247; 8.AH. 18.157; 8.AH. 18.158; 8.AH. 18.196; 8.AH. 18.223; 8.AH. 18.240; 8.AH. 18.244; 8.AH. 18.243; 8.AH. 18.247; 8.AH. 26.157; 8.AH. 26.158; 8.AH. 26.196; 8.AH. 26.223; 8.AH. 26.240; 8.AH. 26.244; 8.AH.26.243; 8.AH. 26.247; 8.AH. 27.157; 8.AH. 27.158; 8.AH. 27.196; 8.AH. 27.223; 8.AH. 27.240; 8.AH.27.244; 8.AH.27.243; 8.AH. 27.247; 8.AH.29.157; 8.AH.29.158; 8.AH.29.196; 8.AH.29.223; 8.AH.29.240; 8.AH.29.244; 8.AH.29.243; 8.AH.29.247; 8.AH. 54.157; 8.AH. 54.158; 8.AH. 54.196; 8.AH. 54.223; 8.AH. 54.240; 8.AH. 54.244; 8.AH. 54.243; 8.AH. 54.247; 8.AH.55.157; 8.AH.55.158; 8.AH.55.196; 8.AH.55.223; 8.AH.55.240; 8.AH.55.244; 8.AH.55.243; 8.AH.55.247; 8.AH. 56.157; 8.AH. 56.158; 8.AH. 56.196; 8.AH. 56.223; 8.AH. 56.240; 8.AH. 56.244; 8.AH. 56.243; 8.AH. 56.247; 8.AH.157.157; 8.AH.157.158; 8.AH.157.196; 8.AH.157.223; 8.AH.157.240; 8.AH.157.244; 8.AH. 157.243; 8.AH.157.247; 8.AH. 196.157; 8.AH.196.158; 8.AH.196.196; 8.AH.196.223; 8.AH.196.240; 8.AH.196.244; 8.AH.196.243; 8.AH.196.247; 8.AH.223.157; 8.AH.223.158; 8.AH.223.196; 8.AH.223.223; 8.AH.223.240; 8.AH.223.244; 8.AH.223.243; 8.AH.223.247; 8.AH. 240.157; 8.AH. 240.158; 8.AH. 240.196; 8.AH.240.223; 8.AH.240.240; 8.AH.240.244; 8.AH.240.243; 8.AH.240.247; 8.AH.244.157; 8.AH.244.158; 8.AH.244.196; 8.AH.244.223; 8.AH.244.240; 8.AH.244.244; 8.AH.244.243; 8.AH.244.247; 8.AH.247.157; 8.AH.247.158; 8.AH.247.196; 8.AH.247.223; 8.AH.247.240; 8.AH.247.244; 8.AH.247.243; 8.AH.247.247;

8. AJ of Prodrug

     8.AJ.4.157; 8.AJ.4.158; 8.AJ.4.196; 8.AJ.4.223; 8.AJ.4.240; 8.AJ.4.244; 8.AJ.4.243; 8.AJ.4.247; 8.AJ.5.157; 8.AJ.5.158; 8.AJ.5.196; 8.AJ.5.223; 8.AJ.5.240; 8.AJ.5.244; 8.AJ.5.243; 8.AJ.5.247; 8.AJ.7.157; 8.AJ.7.158; 8.AJ.7.196; 8.AJ.7.223; 8.AJ.7.240; 8.AJ.7.244; 8.AJ.7.243; 8.AJ.7.247; 8.AJ.15.157; 8.AJ. 15.158; 8.AJ. 15.196; 8.AJ. 15.223; 8.AJ. 15.240; 8.AJ.15.244; 8.AJ.15.243; 8.AJ.15.247; 8.AJ.16.157; 8.AJ. 16.158; 8.AJ. 16.196; 8.AJ.16.223; 8.AJ. 16.240; 8.AJ.16.244; 8.AJ.16.243; 8.AJ.16.247; 8.AJ. 18.157; 8.AJ. 18.158; 8.AJ. 18.196; 8.AJ. 18.223; 8.AJ. 18.240; 8.AJ. 18.244; 8.AJ. 18.243; 8.AJ.18.247; 8.AJ. 26.157; 8.AJ. 26.158; 8.AJ. 26.196; 8.AJ. 26.223; 8.AJ. 26.240; 8.AJ. 26.244; 8.AJ.26.243; 8.AJ. 26.247; 8.AJ.27.157; 8.AJ.27.158; 8.AJ.27.196; 8.AJ.27.223; 8.AJ.27.240; 8.AJ.27.244; 8.AJ.27.243; 8.AJ.27.247; 8.AJ.29.157; 8.AJ.29.158; 8.AJ.29.196; 8.AJ.29.223; 8.AJ.29.240; 8.AJ.29.244; 8.AJ.29.243; 8.AJ.29.247; 8.AJ. 54.157; 8.AJ. 54.158; 8.AJ. 54.196; 8.AJ. 54.223; 8.AJ. 54.240; 8.AJ. 54.244; 8.AJ. 54.243; 8.AJ. 54.247; 8.AJ.55.157; 8.AJ. 55.158; 8.AJ. 55.196; 8.AJ.55.223; 8.AJ.55.240; 8.AJ.55.244; 8.AJ.55.243; 8.AJ.55.247; 8.AJ. 56.157; 8.AJ. 56.158; 8.AJ. 56.196; 8.AJ. 56.223; 8.AJ. 56.240; 8.AJ. 56.244; 8.AJ. 56.243; 8.AJ. 56.247; 8.AJ.157.157; 8.AJ.157.158; 8.AJ.157.196; 8.AJ.157.223; 8.AJ.157.240; 8.AJ.157.244; 8.AJ. 157.243; 8.AJ.157.247; 8.AJ. 196.157; 8.AJ.196.158; 8.AJ.196.196; 8.AJ.196.223; 8.AJ.196.240; 8.AJ.196.244; 8.AJ. 196.243; 8.AJ.196.247; 8.AJ.223.157; 8.AJ.223.158; 8.AJ.223.196; 8.AJ.223.223; 8.AJ.223.240; 8.AJ.223.244; 8.AJ.223.243; 8.AJ.223.247; 8.AJ.240.157; 8.AJ.240.158; 8.AJ. 240.196; 8.AJ.240.223; 8.AJ.240.240; 8.AJ.240.244; 8.AJ.240.243; 8.AJ.240.247; 8.AJ.244.157; 8.AJ.244.158; 8.AJ.244.196; 8.AJ.244.223; 8.AJ.244.240; 8.AJ.244.244; 8.AJ.244.243; 8.AJ.244.247; 8.AJ.247.157; 8.AJ.247.158; 8.AJ.247.196; 8.AJ.247.223; 8.AJ.247.240; 8.AJ.247.244; 8.AJ.247.243; 8.AJ.247.247;

8.AN's Prodrug

     8.AN.4.157; 8.AN.4.158; 8.AN.4.196; 8.AN.4.223; 8.AN.4.240; 8.AN.4.244; 8.AN.4.243; 8.AN.4.247; 8.AN.5.157; 8.AN.5.158; 8.AN.5.196; 8.AN.5.223; 8.AN.5.240; 8.AN.5.244; 8.AN.5.243; 8.AN.5.247; 8.AN.7.157; 8.AN.7.158; 8.AN.7.196; 8.AN.7.223; 8.AN.7.240; 8.AN.7.244; 8.AN.7.243; 8.AN.7.247; 8.AN.15.157; 8.AN.15.158; 8.AN.15.196; 8.AN.15.223; 8.AN.15.240; 8.AN.15.244; 8.AN.15.243; 8.AN.15.247; 8.AN.16.157; 8.AN.16.158; 8.AN.16.196; 8.AN.16.223; 8.AN.16.240; 8.AN.16.244; 8.AN.16.243; 8.AN.16.247; 8.AN.18.157; 8.AN.18.158; 8.AN.18.196; 8.AN.18.223; 8.AN.18.240; 8.AN.18.244; 8.AN.18.243; 8.AN.18.247; 8.AN.26.157; 8.AN.26.158; 8.AN.26.196; 8.AN.26.223; 8.AN.26.240; 8.AN.26.244; 8.AN.26.243; 8.AN.26.247; 8.AN.27.157; 8.AN.27.158; 8.AN.27.196; 8.AN.27.223; 8.AN.27.240; 8.AN.27.244; 8.AN.27.243; 8.AN.27.247; 8.AN.29.157; 8.AN.29.158; 8.AN.29.196; 8.AN.29.223; 8.AN.29.240; 8.AN.29.244; 8.AN.29.243; 8.AN.29.247; 8.AN.54.157; 8.AN.54.158; 8.AN.54.196; 8.AN.54.223; 8.AN.54.240; 8.AN.54.244; 8.AN.54.243; 8.AN.54.247; 8.AN.55.157; 8.AN.55.158; 8.AN.55.196; 8.AN.55.223; 8.AN.55.240; 8.AN.55.244; 8.AN.55.243; 8.AN.55.247; 8.AN.56.157; 8.AN.56.158; 8.AN.56.196; 8.AN.56.223; 8.AN.56.240; 8.AN.56.244; 8.AN.56.243; 8.AN.56.247; 8.AN.157.157; 8.AN.157.158; 8.AN.157.196; 8.AN.157.223; 8.AN.157.240; 8.AN.157.244; 8.AN.157.243; 8.AN.157.247; 8.AN.196.157; 8.AN.196.158; 8.AN.196.196; 8.AN.196.223; 8.AN.196.240; 8.AN.196.244; 8.AN.196.243; 8.AN.196.247; 8.AN.223.157; 8.AN.223.158; 8.AN.223.196; 8.AN.223.223; 8.AN.223.240; 8.AN.223.244; 8.AN.223.243; 8.AN.223.247; 8.AN.240.157; 8.AN.240.158; 8.AN.240.196; 8.AN.240.223; 8.AN.240.240; 8.AN.240.244; 8.AN.240.243; 8.AN.240.247; 8.AN.244.157; 8.AN.244.158; 8.AN.244.196; 8.AN.244.223; 8.AN.244.240; 8.AN.244.244; 8.AN.244.243; 8.AN.244.247; 8.AN.247.157; 8.AN.247.158; 8.AN.247.196; 8.AN.247.223; 8.AN.247.240; 8.AN.247.244; 8.AN.247.243; 8.AN.247.247;

8.AP Prodrug

     8.AP.4.157; 8.AP.4.158; 8.AP.4.196; 8.AP.4.223; 8.AP.4.240; 8.AP.4.244; 8.AP.4.243; 8.AP.4.247; 8.AP.5.157; 8.AP.5.158; 8.AP.5.196; 8.AP.5.223; 8.AP.5.240; 8.AP.5.244; 8.AP.5.243; 8.AP.5.247; 8.AP.7.157; 8.AP.7.158; 8.AP.7.196; 8.AP.7.223; 8.AP.7.240; 8.AP.7.244; 8.AP.7.243; 8.AP.7.247; 8.AP.15.157; 8.AP.15.158; 8.AP.15.196; 8.AP.15.223; 8.AP.15.240; 8.AP.15.244; 8.AP.15.243; 8.AP.15.247; 8.AP.16.157; 8.AP.16.158; 8.AP.16.196; 8.AP.16.223; 8.AP.16.240; 8.AP.16.244; 8.AP.16.243; 8.AP.16.247; 8.AP.18.157; 8.AP.18.158; 8.AP.18.196; 8.AP.18.223; 8.AP.18.240; 8.AP.18.244; 8.AP.18.243; 8.AP.18.247; 8.AP.26.157; 8.AP.26.158; 8.AP.26.196; 8.AP.26.223; 8.AP.26.240; 8.AP.26.244; 8.AP.26.243; 8.AP.26.247; 8.AP.27.157; 8.AP.27.158; 8.AP.27.196; 8.AP.27.223; 8.AP.27.240; 8.AP.27.244; 8.AP.27.243; 8.AP.27.247; 8.AP.29.157; 8.AP.29.158; 8.AP.29.196; 8.AP.29.223; 8.AP.29.240; 8.AP.29.244; 8.AP.29.243; 8.AP.29.247; 8.AP.54.157; 8.AP.54.158; 8.AP.54.196; 8.AP.54.223; 8.AP.54.240; 8.AP.54.244; 8.AP.54.243; 8.AP.54.247; 8.AP.55.157; 8.AP.55.158; 8.AP.55.196; 8.AP.55.223; 8.AP.55.240; 8.AP.55.244; 8.AP.55.243; 8.AP.55.247; 8.AP.56.157; 8.AP.56.158; 8.AP.56.196; 8.AP.56.223; 8.AP.56.240; 8.AP.56.244; 8.AP.56.243; 8.AP.56.247; 8.AP.157.157; 8.AP.157.158; 8.AP.157.196; 8.AP.157.223; 8.AP.157.240; 8.AP.157.244; 8.AP.157.243; 8.AP.157.247; 8.AP.196.157; 8.AP.196.158; 8.AP.196.196; 8.AP.196.223; 8.AP.196.240; 8.AP.196.244; 8.AP.196.243; 8.AP.196.247; 8.AP.223.157; 8.AP.223.158; 8.AP.223.196; 8.AP.223.223; 8.AP.223.240; 8.AP.223.244; 8.AP.223.243; 8.AP.223.247; 8.AP.240.157; 8.AP.240.158; 8.AP.240.196; 8.AP.240.223; 8.AP.240.240; 8.AP.240.244; 8.AP.240.243; 8.AP.240.247; 8.AP.244.157; 8.AP.244.158; 8.AP.244.196; 8.AP.244.223; 8.AP.244.240; 8.AP.244.244; 8.AP.244.243; 8.AP.244.247; 8.AP.247.157; 8.AP.247.158; 8.AP.247.196; 8.AP.247.223; 8.AP.247.240; 8.AP.247.244; 8.AP.247.243; 8.AP.247.247;

8.AZ Prodrug

     8.AZ.4.157; 8.AZ.4.158; 8.AZ.4.196; 8.AZ.4.223; 8.AZ.4.240; 8.AZ.4.244; 8.AZ.4.243; 8.AZ.4.247; 8.AZ.5.157; 8.AZ.5.158; 8.AZ.5.196; 8.AZ.5.223; 8.AZ.5.240; 8.AZ.5.244; 8.AZ.5.243; 8.AZ.5.247; 8.AZ.7.157; 8.AZ.7.158; 8.AZ.7.196; 8.AZ.7.223; 8.AZ.7.240; 8.AZ.7.244; 8.AZ.7.243; 8.AZ.7.247; 8.AZ. 15.157; 8.AZ. 15.158; 8.AZ. 15.196; 8.AZ. 15.223; 8.AZ. 15.240; 8.AZ. 15.244; 8.AZ.15.243; 8.AZ. 15.247; 8.AZ. 16.157; 8.AZ. 16.158; 8.AZ. 16.196; 8.AZ. 16.223; 8.AZ. 16.240; 8.AZ. 16.244; 8.AZ. 16.243; 8.AZ. 16.247; 8.AZ. 18.157; 8.AZ. 18.158; 8.AZ. 18.196; 8.AZ. 18.223; 8.AZ. 18.240; 8.AZ. 18.244; 8.AZ. 18.243; 8.AZ. 18.247; 8.AZ. 26.157; 8.AZ. 26.158; 8.AZ. 26.196; 8.AZ. 26.223; 8.AZ. 26.240; 8.AZ. 26.244; 8.AZ.26.243; 8.AZ. 26.247; 8.AZ. 27.157; 8.AZ. 27.158; 8.AZ. 27.196; 8.AZ.27.223; 8.AZ.27.240; 8.AZ.27.244; 8.AZ.27.243; 8.AZ.27.247; 8.AZ. 29.157; 8.AZ. 29.158; 8.AZ. 29.196; 8.AZ.29.223; 8.AZ.29.240; 8.AZ.29.244; 8.AZ.29.243; 8.AZ.29.247; 8.AZ. 54.157; 8.AZ. 54.158; 8.AZ. 54.196; 8.AZ. 54.223; 8.AZ. 54.240; 8.AZ. 54.244; 8.AZ. 54.243; 8.AZ. 54.247; 8.AZ. 55.157; 8.AZ. 55.158; 8.AZ. 55.196; 8.AZ.55.223; 8.AZ.55.240; 8.AZ.55.244; 8.AZ.55.243; 8.AZ.55.247; 8.AZ. 56.157; 8.AZ. 56.158; 8.AZ. 56.196; 8.AZ. 56.223; 8.AZ. 56.240; 8.AZ. 56.244; 8.AZ. 56.243; 8.AZ. 56.247; 8.AZ.157.157; 8.AZ.157.158; 8.AZ.157.196; 8.AZ.157.223; 8.AZ.157.240; 8.AZ.157.244; 8.AZ. 157.243; 8.AZ.157.247; 8.AZ. 196.157; 8.AZ. 196.158; 8.AZ. 196.196; 8.AZ. 196.223; 8.AZ. 196.240; 8.AZ. 196.244; 8.AZ. 196.243; 8.AZ. 196.247; 8.AZ.223.157; 8.AZ.223.158; 8.AZ.223.196; 8.AZ.223.223; 8.AZ.223.240; 8.AZ.223.244; 8.AZ.223.243; 8.AZ.223.247; 8.AZ. 240.157; 8.AZ.240.158; 8.AZ. 240.196; 8.AZ.240.223; 8.AZ.240.240; 8.AZ.240.244; 8.AZ. 240.243; 8.AZ.240.247; 8.AZ.244.157; 8.AZ.244.158; 8.AZ.244.196; 8.AZ.244.223; 8.AZ.244.240; 8.AZ.244.244; 8.AZ.244.243; 8.AZ.244.247; 8.AZ.247.157; 8.AZ.247.158; 8.AZ.247.196; 8.AZ.247.223; 8.AZ.247.240; 8.AZ.247.244; 8.AZ.247.243; 8.AZ.247.247;

8. BF of Prodrug

     8.BF.4.157; 8.BF.4.158; 8.BF.4.196; 8. BF.4.223; 8.BF.4.240; 8.BF.4.244; 8.BF.4.243; 8.BF.4.247; 8.BF.5.157; 8.BF.5.158; 8.BF.5.196; 8.BF.5.223; 8.BF.5.240; 8.BF.5.244; 8.BF.5.243; 8.BF.5.247; 8.BF.7.157; 8.BF.7.158; 8.BF.7.196; 8.BF.7.223; 8.BF.7.240; 8.BF.7.244; 8.BF.7.243; 8.BF.7.247; 8.BF. 15.157; 8.BF. 15.158; 8.BF. 15.196; 8.BF. 15.223; 8.BF. 15.240; 8.BF. 15.244; 8. BF.15.243; 8.BF. 15.247; 8.BF. 16.157; 8.BF. 16.158; 8.BF. 16.196; 8.BF. 16.223; 8.BF.16.240; 8.BF. 16.244; 8. BF.16.243; 8.BF. 16.247; 8.BF. 18.157; 8.BF. 18.158; 8.BF. 18.196; 8.BF. 18.223; 8.BF. 18.240; 8.BF. 18.244; 8.BF. 18.243; 8.BF. 18.247; 8.BF. 26.157; 8.BF. 26.158; 8. BF. 26.196; 8.BF. 26.223; 8.BF. 26.240; 8.BF. 26.244; 8.BF. 26.243; 8.BF. 26.247; 8.BF. 27.157; 8.BF. 27.158; 8.BF. 27.196; 8.BF. 27.223; 8.BF. 27.240; 8.BF.27.244; 8.BF.27.243; 8.BF. 27.247; 8.BF. 29.157; 8.BF. 29.158; 8.BF. 29.196; 8. BF.29.223; 8.BF. 29.240; 8.BF.29.244; 8.BF. 29.243; 8.BF.29.247; 8.BF. 54.157; 8.BF. 54.158; 8.BF. 54.196; 8.BF. 54.223; 8.BF. 54.240; 8.BF. 54.244; 8.BF. 54.243; 8.BF. 54.247; 8.BF. 55.157; 8.BF. 55.158; 8.BF. 55.196; 8.BF. 55.223; 8.BF. 55.240; 8.BF.55.244; 8.BF.55.243; 8.BF. 55.247; 8.BF. 56.157; 8.BF. 56.158; 8. BF. 56.196; 8.BF. 56.223; 8.BF. 56.240; 8.BF. 56.244; 8.BF. 56.243; 8.BF. 56.247; 8.BF.157.157; 8.BF.157.158; 8.BF.157.196; 8.BF.157.223; 8.BF.157.240; 8.BF.157.244; 8.BF. 157.243; 8.BF.157.247; 8.BF.196.157; 8.BF.196.158; 8.BF.196.196; 8.BF.196.223; 8.BF.196.240; 8.BF.196.244; 8.BF. 196.243; 8.BF.196.247; 8.BF.223.157; 8.BF.223.158; 8.BF.223.196; 8.BF.223.223; 8.BF.223.240; 8.BF.223.244; 8.BF.223.243; 8.BF.223.247; 8.BF.240.157; 8.BF.240.158; 8.BF.240.196; 8.BF.240.223; 8.BF.240.240; 8.BF.240.244; 8.BF.240.243; 8.BF.240.247; 8.BF.244.157; 8.BF.244.158; 8.BF.244.196; 8.BF.244.223; 8.BF.244.240; 8.BF.244.244; 8.BF.244.243; 8.BF.244.247; 8.BF.247.157; 8.BF.247.158; 8.BF.247.196; 8.BF.247.223; 8.BF.247.240; 8.BF.247.244; 8.BF.247.243; 8.BF.247.247;

8.CI Prodrug

     8.CI.4.157; 8.CI.4.158; 8.CI.4.196; 8.CI.4.223; 8.CI.4.240; 8.CI.4.244; 8.CI.4.243; 8.CI.4.247; 8.CI.5.157; 8.CI.5.158; 8.CI.5.196; 8.CI.5.223; 8.CI.5.240; 8.CI.5.244; 8.CI.5.243; 8.CI.5.247; 8.CI.7.157; 8.CI.7.158; 8.CI.7.196; 8.CI.7.223; 8.CI.7.240; 8.CI.7.244; 8.CI.7.243; 8.CI.7.247; 8.CI.15.157; 8.CI.15.158; 8.CI.15.196; 8.CI.15.223; 8.CI.15.240; 8.CI.15.244; 8.CI.15.243; 8.CI.15.247; 8.CI.16.157; 8.CI.16.158; 8.CI.16.196; 8.CI.16.223; 8.CI.16.240; 8.CI.16.244; 8.CI.16.243; 8.CI.16.247; 8.CI.18.157; 8.CI.18.158; 8.CI.18.196; 8.CI.18.223; 8.CI.18.240; 8.CI.18.244; 8.CI.18.243; 8.CI.18.247; 8.CI.26.157; 8.CI.26.158; 8.CI.26.196; 8.CI.26.223; 8.CI.26.240; 8.CI.26.244; 8.CI.26.243; 8.CI.26.247; 8.CI.27.157; 8.CI.27.158; 8.CI.27.196; 8.CI.27.223; 8.CI.27.240; 8.CI.27.244; 8.CI.27.243; 8.CI.27.247; 8.CI.29.157; 8.CI.29.158; 8.CI.29.196; 8.CI.29.223; 8.CI.29.240; 8.CI.29.244; 8.CI.29.243; 8.CI.29.247; 8.CI.54.157; 8.CI.54.158; 8.CI.54.196; 8.CI.54.223; 8.CI.54.240; 8.CI.54.244; 8.CI.54.243; 8.CI.54.247; 8.CI.55.157; 8.CI.55.158; 8.CI.55.196; 8.CI.55.223; 8.CI.55.240; 8.CI.55.244; 8.CI.55.243; 8.CI.55.247; 8.CI.56.157; 8.CI.56.158; 8.CI.56.196; 8.CI.56.223; 8.CI.56.240; 8.CI.56.244; 8.CI.56.243; 8.CI.56.247; 8.CI.157.157; 8.CI.157.158; 8.CI.157.196; 8.CI.157.223; 8.CI.157.240; 8.CI.157.244; 8.CI.157.243; 8.CI.157.247; 8.CI.196.157; 8.CI.196.158; 8.CI.196.196; 8.CI.196.223; 8.CI.196.240; 8.CI.196.244; 8.CI.196.243; 8.CI.196.247; 8.CI.223.157; 8.CI.223.158; 8.CI.223.196; 8.CI.223.223; 8.CI.223.240; 8.CI.223.244; 8.CI.223.243; 8.CI.223.247; 8.CI.240.157; 8.CI.240.158; 8.CI.240.196; 8.CI.240.223; 8.CI.240.240; 8.CI.240.244; 8.CI.240.243; 8.CI.240.247; 8.CI.244.157; 8.CI.244.158; 8.CI.244.196; 8.CI.244.223; 8.CI.244.240; 8.CI.244.244; 8.CI.244.243; 8.CI.244.247; 8.CI.247.157; 8.CI.247.158; 8.CI.247.196; 8.CI.247.223; 8.CI.247.240; 8.CI.247.244; 8.CI.247.243; 8.CI.247.247;

8.CO's Prodrug

     8.CO.4.157; 8.CO.4.158; 8.CO.4.196; 8.CO.4.223; 8.CO.4.240; 8.CO.4.244; 8.CO.4.243; 8.CO.4.247; 8.CO.5.157; 8.CO.5.158; 8.CO.5.196; 8.CO.5.223; 8.CO.5.240; 8.CO.5.244; 8.CO.5.243; 8.CO.5.247; 8.CO.7.157; 8.CO.7.158; 8.CO.7.196; 8.CO.7.223; 8.CO.7.240; 8.CO.7.244; 8.CO.7.243; 8.CO.7.247; 8.CO.15.157; 8.CO.15.158; 8.CO.15.196; 8.CO.15.223; 8.CO.15.240; 8.CO.15.244; 8.CO.15.243; 8.CO.15.247; 8.CO.16.157; 8.CO.16.158; 8.CO.16.196; 8.CO.16.223; 8.CO.16.240; 8.CO.16.244; 8.CO.16.243; 8.CO.16.247; 8.CO.18.157; 8.CO.18.158; 8.CO.18.196; 8.CO.18.223; 8.CO.18.240; 8.CO.18.244; 8.CO.18.243; 8.CO.18.247; 8.CO.26.157; 8.CO.26.158; 8.CO.26.196; 8.CO.26.223; 8.CO.26.240; 8.CO.26.244; 8.CO.26.243; 8.CO.26.247; 8.CO.27.157; 8.CO.27.158; 8.CO.27.196; 8.CO.27.223; 8.CO.27.240; 8.CO.27.244; 8.CO.27.243; 8.CO.27.247; 8.CO.29.157; 8.CO.29.158; 8.CO.29.196; 8.CO.29.223; 8.CO.29.240; 8.CO.29.244; 8.CO.29.243; 8.CO.29.247; 8.CO.54.157; 8.CO.54.158; 8.CO.54.196; 8.CO.54.223; 8.CO.54.240; 8.CO.54.244; 8.CO.54.243; 8.CO.54.247; 8.CO.55.157; 8.CO.55.158; 8.CO.55.196; 8.CO.55.223; 8.CO.55.240; 8.CO.55.244; 8.CO.55.243; 8.CO.55.247; 8.CO.56.157; 8.CO.56.158; 8.CO.56.196; 8.CO.56.223; 8.CO.56.240; 8.CO.56.244; 8.CO.56.243; 8.CO.56.247; 8.CO.157.157; 8.CO.157.158; 8.CO.157.196; 8.CO.157.223; 8.CO.157.240; 8.CO.157.244; 8.CO.157.243; 8.CO.157.247; 8.CO.196.157; 8.CO.196.158; 8.CO.196.196; 8.CO.196.223; 8.CO.196.240; 8.CO.196.244; 8.CO.196.243; 8.CO.196.247; 8.CO.223.157; 8.CO.223.158; 8.CO.223.196; 8.CO.223.223; 8.CO.223.240; 8.CO.223.244; 8.CO.223.243; 8.CO.223.247; 8.CO.240.157; 8.CO.240.158; 8.CO.240.196; 8.CO.240.223; 8.CO.240.240; 8.CO.240.244; 8.CO.240.243; 8.CO.240.247; 8.CO.244.157; 8.CO.244.158; 8.CO.244.196; 8.CO.244.223; 8.CO.244.240; 8.CO.244.244; 8.CO.244.243; 8.CO.244.247; 8.CO.247.157; 8.CO.247.158; 8.CO.247.196; 8.CO.247.223; 8.CO.247.240; 8.CO.247.244; 8.CO.247.243; 8.CO.247.247;

9.AH Prodrug

     9.AH.4.157; 9.AH.4.158; 9.AH.4.196; 9.AH.4.223; 9.AH. 4.240; 9.AH.4.244; 9.AH.4.243; 9.AH.4.247; 9.AH.5.157; 9.AH.5.158; 9.AH.5.196; 9.AH.5.223; 9.AH.5.240; 9.AH.5.244; 9.AH.5.243; 9.AH.5.247; 9.AH. 7.157; 9.AH. 7.158; 9.AH.7.196; 9.AH.7.223; 9.AH.7.240; 9.AH.7.244; 9.AH.7.243; 9.AH.7.247; 9.AH. 15.157; 9.AH. 15.158; 9.AH. 15.196; 9.AH. 15.223; 9.AH. 15.240; 9.AH. 15.244; 9.AH.15.243; 9.AH. 15.247; 9.AH. 16.157; 9.AH. 16.158; 9.AH. 16.196; 9.AH. 16.223; 9.AH. 16.240; 9.AH. 16.244; 9.AH. 16.243; 9.AH. 16.247; 9.AH. 18.157; 9.AH. 18.158; 9.AH. 18.196; 9.AH. 18.223; 9.AH. 18.240; 9.AH. 18.244; 9.AH. 18.243; 9.AH. 18.247; 9.AH. 26.157; 9.AH. 26.158; 9.AH. 26.196; 9.AH. 26.223; 9.AH. 26.240; 9.AH. 26.244; 9.AH.26.243; 9.AH. 26.247; 9.AH. 27.157; 9.AH. 27.158; 9.AH. 27.196; 9.AH. 27.223; 9.AH. 27.240; 9.AH. 27.244; 9.AH.27.243; 9.AH. 27.247; 9.AH. 29.157; 9.AH.29.158; 9.AH.29.196; 9.AH.29.223; 9.AH.29.240; 9.AH.29.244; 9.AH.29.243; 9.AH.29.247; 9.AH. 54.157; 9.AH. 54.158; 9.AH.54.196; 9.AH. 54.223; 9.AH. 54.240; 9.AH. 54.244; 9.AH. 54.243; 9.AH. 54.247; 9.AH.55.157; 9.AH.55.158; 9.AH.55.196; 9.AH.55.223; 9.AH.55.240; 9.AH.55.244; 9.AH.55.243; 9.AH.55.247; 9.AH. 56.157; 9.AH. 56.158; 9.AH. 56.196; 9.AH. 56.223; 9.AH. 56.240; 9.AH. 56.244; 9.AH. 56.243; 9.AH. 56.247; 9.AH.157.157; 9.AH.157.158; 9.AH.157.196; 9.AH.157.223; 9.AH.157.240; 9.AH.157.244; 9.AH. 157.243; 9.AH.157.247; 9.AH. 196.157; 9.AH.196.158; 9.AH.196.196; 9.AH.196.223; 9.AH.196.240; 9.AH.196.244; 9.AH.196.243; 9.AH.196.247; 9.AH.223.157; 9.AH.223.158; 9.AH.223.196; 9.AH.223.223; 9.AH.223.240; 9.AH.223.244; 9.AH.223.243; 9.AH.223.247; 9.AH. 240.157; 9.AH.240.158; 9.AH. 240.196; 9.AH. 240.223; 9.AH. 240.240; 9.AH. 240.244; 9.AH.240.243; 9.AH. 240.247; 9.AH.244.157; 9.AH.244.158; 9.AH.244.196; 9.AH.244.223; 9.AH.244.240; 9.AH.244.244; 9.AH.244.243; 9.AH.244.247; 9.AH. 247.157; 9.AH.247.158; 9.AH. 247.196; 9.AH.247.223; 9.AH.247.240; 9.AH.247.244; 9.AH.247.243; 9.AH.247.247;

9. AJ of Prodrug

     9.AJ.4.157; 9.AJ.4.158; 9.AJ.4.196; 9.AJ.4.223; 9.AJ.4.240; 9.AJ.4.244; 9.AJ.4.243; 9.AJ.4.247; 9.AJ.5.157; 9.AJ.5.158; 9.AJ.5.196; 9.AJ.5.223; 9.AJ.5.240; 9.AJ.5.244; 9.AJ.5.243; 9.AJ.5.247; 9.AJ.7.157; 9.AJ.7.158; 9.AJ.7.196; 9.AJ.7.223; 9.AJ.7.240; 9.AJ.7.244; 9.AJ.7.243; 9.AJ.7.247; 9.AJ. 15.157; 9.AJ. 15.158; 9.AJ. 15.196; 9.AJ.15.223; 9.AJ. 15.240; 9.AJ. 15.244; 9.AJ.15.243; 9.AJ.15.247; 9.AJ. 16.157; 9.AJ. 16.158; 9.AJ. 16.196; 9.AJ. 16.223; 9.AJ. 16.240; 9.AJ. 16.244; 9.AJ.16.243; 9.AJ. 16.247; 9.AJ. 18.157; 9.AJ. 18.158; 9.AJ. 18.196; 9.AJ. 18.223; 9.AJ. 18.240; 9.AJ. 18.244; 9.AJ. 18.243; 9.AJ.18.247; 9.AJ. 26.157; 9.AJ. 26.158; 9.AJ. 26.196; 9.AJ. 26.223; 9.AJ. 26.240; 9.AJ. 26.244; 9.AJ.26.243; 9.AJ. 26.247; 9.AJ. 27.157; 9.AJ.27.158; 9.AJ. 27.196; 9.AJ.27.223; 9.AJ. 27.240; 9.AJ.27.244; 9.AJ.27.243; 9.AJ.27.247; 9.AJ.29.157; 9.AJ.29.158; 9.AJ.29.196; 9.AJ.29.223; 9.AJ.29.240; 9.AJ.29.244; 9.AJ.29.243; 9.AJ.29.247; 9.AJ. 54.157; 9.AJ. 54.158; 9.AJ. 54.196; 9.AJ. 54.223; 9.AJ. 54.240; 9.AJ. 54.244; 9.AJ. 54.243; 9.AJ. 54.247; 9.AJ.55.157; 9.AJ. 55.158; 9.AJ.55.196; 9.AJ.55.223; 9.AJ.55.240; 9.AJ.55.244; 9.AJ.55.243; 9.AJ.55.247; 9.AJ. 56.157; 9.AJ. 56.158; 9.AJ. 56.196; 9.AJ. 56.223; 9.AJ. 56.240; 9.AJ. 56.244; 9.AJ. 56.243; 9.AJ. 56.247; 9.AJ.157.157; 9.AJ.157.158; 9.AJ.157.196; 9.AJ.157.223; 9.AJ.157.240; 9.AJ.157.244; 9.AJ. 157.243; 9.AJ.157.247; 9.AJ. 196.157; 9.AJ.196.158; 9.AJ. 196.196; 9.AJ. 196.223; 9.AJ.196.240; 9.AJ.196.244; 9.AJ. 196.243; 9.AJ.196.247; 9.AJ.223.157; 9.AJ.223.158; 9.AJ.223.196; 9.AJ.223.223; 9.AJ.223.240; 9.AJ.223.244; 9.AJ.223.243; 9.AJ.223.247; 9.AJ. 240.157; 9.AJ. 240.158; 9.AJ. 240.196; 9.AJ. 240.223; 9.AJ.240.240; 9.AJ.240.244; 9.AJ. 240.243; 9.AJ.240.247; 9.AJ.244.157; 9.AJ.244.158; 9.AJ.244.196; 9.AJ.244.223; 9.AJ.244.240; 9.AJ.244.244; 9.AJ.244.243; 9.AJ.244.247; 9.AJ.247.157; 9.AJ.247.158; 9.AJ. 247.196; 9.AJ.247.223; 9.AJ.247.240; 9.AJ.247.244; 9.AJ.247.243; 9.AJ.247.247;

9.AN's Prodrug

     9.AN.4.157; 9.AN.4.158; 9.AN.4.196; 9.AN.4.223; 9.AN.4.240; 9.AN.4.244; 9.AN.4.243; 9.AN.4.247; 9.AN.5.157; 9.AN.5.158; 9.AN.5.196; 9.AN.5.223; 9.AN.5.240; 9.AN.5.244; 9.AN.5.243; 9.AN.5.247; 9.AN.7.157; 9.AN.7.158; 9.AN.7.196; 9.AN.7.223; 9.AN.7.240; 9.AN.7.244; 9.AN.7.243; 9.AN.7.247; 9.AN.15.157; 9.AN.15.158; 9.AN.15.196; 9.AN.15.223; 9.AN.15.240; 9.AN.15.244; 9.AN.15.243; 9.AN.15.247; 9.AN.16.157; 9.AN.16.158; 9.AN.16.196; 9.AN.16.223; 9.AN.16.240; 9.AN.16.244; 9.AN.16.243; 9.AN.16.247; 9.AN.18.157; 9.AN.18.158; 9.AN.18.196; 9.AN.18.223; 9.AN.18.240; 9.AN.18.244; 9.AN.18.243; 9.AN.18.247; 9.AN.26.157; 9.AN.26.158; 9.AN.26.196; 9.AN.26.223; 9.AN.26.240; 9.AN.26.244; 9.AN.26.243; 9.AN.26.247; 9.AN.27.157; 9.AN.27.158; 9.AN.27.196; 9.AN.27.223; 9.AN.27.240; 9.AN.27.244; 9.AN.27.243; 9.AN.27.247; 9.AN.29.157; 9.AN.29.158; 9.AN.29.196; 9.AN.29.223; 9.AN.29.240; 9.AN.29.244; 9.AN.29.243; 9.AN.29.247; 9.AN.54.157; 9.AN.54.158; 9.AN.54.196; 9.AN.54.223; 9.AN.54.240; 9.AN.54.244; 9.AN.54.243; 9.AN.54.247; 9.AN.55.157; 9.AN.55.158; 9.AN.55.196; 9.AN.55.223; 9.AN.55.240; 9.AN.55.244; 9.AN.55.243; 9.AN.55.247; 9.AN.56.157; 9.AN.56.158; 9.AN.56.196; 9.AN.56.223; 9.AN.56.240; 9.AN.56.244; 9.AN.56.243; 9.AN.56.247; 9.AN.157.157; 9.AN.157.158; 9.AN.157.196; 9.AN.157.223; 9.AN.157.240; 9.AN.157.244; 9.AN.157.243; 9.AN.157.247; 9.AN.196.157; 9.AN.196.158; 9.AN.196.196; 9.AN.196.223; 9.AN.196.240; 9.AN.196.244; 9.AN.196.243; 9.AN.196.247; 9.AN.223.157; 9.AN.223.158; 9.AN.223.196; 9.AN.223.223; 9.AN.223.240; 9.AN.223.244; 9.AN.223.243; 9.AN.223.247; 9.AN.240.157; 9.AN.240.158; 9.AN.240.196; 9.AN.240.223; 9.AN.240.240; 9.AN.240.244; 9.AN.240.243; 9.AN.240.247; 9.AN.244.157; 9.AN.244.158; 9.AN.244.196; 9.AN.244.223; 9.AN.244.240; 9.AN.244.244; 9.AN.244.243; 9.AN.244.247; 9.AN.247.157; 9.AN.247.158; 9.AN.247.196; 9.AN.247.223; 9.AN.247.240; 9.AN.247.244; 9.AN.247.243; 9.AN.247.247;

9.AP Prodrug

     9.AP.4.157; 9.AP.4.158; 9.AP.4.196; 9.AP.4.223; 9.AP.4.240; 9.AP.4.244; 9.AP.4.243; 9.AP.4.247; 9.AP.5.157; 9.AP.5.158; 9.AP.5.196; 9.AP.5.223; 9.AP.5.240; 9.AP.5.244; 9.AP.5.243; 9.AP.5.247; 9.AP.7.157; 9.AP.7.158; 9.AP.7.196; 9.AP.7.223; 9.AP.7.240; 9.AP.7.244; 9.AP.7.243; 9.AP.7.247; 9.AP.15.157; 9.AP.15.158; 9.AP.15.196; 9.AP.15.223; 9.AP.15.240; 9.AP.15.244; 9.AP.15.243; 9.AP.15.247; 9.AP.16.157; 9.AP.16.158; 9.AP 16.196; 9.AP.16.223; 9.AP.16.240; 9.AP.16.244; 9.AP.16.243; 9.AP.16.247; 9.AP.18.157; 9.AP.18.158; 9.AP.18.196; 9.AP.18.223; 9.AP.18.240; 9.AP.18.244; 9.AP.18.243; 9.AP.18.247; 9.AP.26.157; 9.AP.26.158; 9.AP.26.196; 9.AP.26.223; 9.AP.26.240; 9.AP.26.244; 9.AP.26.243; 9.AP.26.247; 9.AP.27.157; 9.AP.27.158; 9.AP.27.196; 9.AP.27.223; 9.AP.27.240; 9.AP.27.244; 9.AP.27.243; 9.AP.27.247; 9.AP.29.157; 9.AP.29.158; 9.AP.29.196; 9.AP.29.223; 9.AP.29.240; 9.AP.29.244; 9.AP.29.243; 9.AP.29.247; 9.AP.54.157; 9.AP.54.158; 9.AP.54.196; 9.AP.54.223; 9.AP.54.240; 9.AP.54.244; 9.AP.54.243; 9.AP.54.247; 9.AP.55.157; 9.AP.55.158; 9.AP 55.196; 9.AP.55.223; 9.AP.55.240; 9.AP.55.244; 9.AP.55.243; 9.AP.55.247; 9.AP.56.157; 9.AP.56.158; 9.AP.56.196; 9.AP.56.223; 9.AP.56.240; 9.AP.56.244; 9.AP.56.243; 9.AP.56.247; 9.AP.157.157; 9.AP.157.158; 9.AP.157.196; 9.AP.157.223; 9.AP.157.240; 9.AP.157.244; 9.AP.157.243; 9.AP.157.247; 9.AP.196.157; 9.AP.196.158; 9.AP.196.196; 9.AP.196.223; 9.AP.196.240; 9.AP.196.244; 9.AP.196.243; 9.AP.196.247; 9.AP.223.157; 9.AP.223.158; 9.AP.223.196; 9.AP.223.223; 9.AP.223.240; 9.AP.223.244; 9.AP.223.243; 9.AP.223.247; 9.AP.240.157; 9.AP.240.158; 9.AP.240.196; 9.AP.240.223; 9.AP.240.240; 9.AP.240.244; 9.AP.240.243; 9.AP.240.247; 9.AP.244.157; 9.AP.244.158; 9.AP.244.196; 9.AP.244.223; 9.AP.244.240; 9.AP.244.244; 9.AP.244.243; 9.AP.244.247; 9.AP.247.157; 9.AP.247.158; 9.AP.247.196; 9.AP.247.223; 9.AP.247.240; 9.AP.247.244; 9.AP.247.243; 9.AP.247.247;

9.az Prodrug

     9.AZ.4.157; 9.AZ.4.158; 9.AZ.4.196; 9.AZ.4.223; 9.AZ. 4.240; 9.AZ.4.244; 9.AZ.4.243; 9.AZ.4.247; 9.AZ.5.157; 9.AZ.5.158; 9.AZ.5.196; 9.AZ.5.223; 9.AZ.5.240; 9.AZ.5.244; 9.AZ.5.243; 9.AZ.5.247; 9.AZ.7.157; 9.AZ.7.158; 9.AZ.7.196; 9.AZ.7.223; 9.AZ.7.240; 9.AZ.7.244; 9.AZ.7.243; 9.AZ.7.247; 9.AZ. 15.157; 9.AZ. 15.158; 9.AZ. 15.196; 9.AZ. 15.223; 9.AZ. 15.240; 9.AZ. 15.244; 9.AZ. 15.243; 9.AZ. 15.247; 9.AZ. 16.157; 9.AZ. 16.158; 9.AZ. 16.196; 9.AZ. 16.223; 9.AZ. 16.240; 9.AZ. 16.244; 9.AZ. 16.243; 9.AZ. 16.247; 9.AZ. 18.157; 9.AZ. 18.158; 9.AZ. 18.196; 9.AZ. 18.223; 9.AZ. 18.240; 9.AZ. 18.244; 9.AZ. 18.243; 9.AZ. 18.247; 9.AZ. 26.157; 9.AZ. 26.158; 9.AZ. 26.196; 9.AZ. 26.223; 9.AZ. 26.240; 9.AZ. 26.244; 9.AZ. 26.243; 9.AZ. 26.247; 9.AZ. 27.157; 9.AZ. 27.158; 9.AZ. 27.196; 9.AZ. 27.223; 9.AZ. 27.240; 9.AZ. 27.244; 9.AZ. 27.243; 9.AZ. 27.247; 9.AZ. 29.157; 9.AZ. 29.158; 9.AZ. 29.196; 9.AZ. 29.223; 9.AZ. 29.240; 9.AZ. 29.244; 9.AZ. 29.243; 9.AZ.29.247; 9.AZ. 54.157; 9.AZ. 54.158; 9.AZ. 54.196; 9.AZ. 54.223; 9.AZ. 54.240; 9.AZ. 54.244; 9.AZ. 54.243; 9.AZ. 54.247; 9.AZ. 55.157; 9.AZ. 55.158; 9.AZ. 55.196; 9.AZ. 55.223; 9.AZ. 55.240; 9.AZ.55.244; 9.AZ.55.243; 9.AZ.55.247; 9.AZ. 56.157; 9.AZ. 56.158; 9.AZ. 56.196; 9.AZ. 56.223; 9.AZ. 56.240; 9.AZ. 56.244; 9.AZ. 56.243; 9.AZ. 56.247; 9.AZ.157.157; 9.AZ.157.158; 9.AZ.157.196; 9.AZ.157.223; 9.AZ.157.240; 9.AZ.157.244; 9.AZ. 157.243; 9.AZ.157.247; 9.AZ. 196.157; 9.AZ. 196.158; 9.AZ. 196.196; 9.AZ. 196.223; 9.AZ. 196.240; 9.AZ. 196.244; 9.AZ. 196.243; 9.AZ. 196.247; 9.AZ.223.157; 9.AZ.223.158; 9.AZ.223.196; 9.AZ.223.223; 9.AZ.223.240; 9.AZ.223.244; 9.AZ.223.243; 9.AZ.223.247; 9.AZ. 240.157; 9.AZ. 240.158; 9.AZ. 240.196; 9.AZ. 240.223; 9.AZ.240.240; 9.AZ. 240.244; 9.AZ. 240.243; 9.AZ.240.247; 9.AZ.244.157; 9.AZ.244.158; 9.AZ.244.196; 9.AZ.244.223; 9.AZ.244.240; 9.AZ.244.244; 9.AZ.244.243; 9.AZ.244.247; 9.AZ.247.157; 9.AZ.247.158; 9.AZ.247.196; 9.AZ.247.223; 9.AZ.247.240; 9.AZ.247.244; 9.AZ. 247.243; 9.AZ.247.247;

9. BF of Prodrug

     9.BF.4.157; 9.BF.4.158; 9.BF.4.196; 9.BF.4.223; 9.BF.4.240; 9.BF.4.244; 9.BF.4.243; 9.BF.4.247; 9.BF.5.157; 9.BF.5.158; 9.BF.5.196; 9.BF.5.223; 9.BF.5.240; 9.BF.5.244; 9.BF.5.243; 9.BF.5.247; 9.BF.7.157; 9.BF.7.158; 9.BF.7.196; 9.BF.7.223; 9.BF.7.240; 9.BF.7.244; 9.BF.7.243; 9.BF.7.247; 9.BF. 15.157; 9.BF. 15.158; 9.BF. 15.196; 9.BF. 15.223; 9.BF. 15.240; 9.BF. 15.244; 9.BF. 15.243; 9.BF. 15.247; 9.BF. 16.157; 9.BF. 16.158; 9.BF. 16.196; 9.BF. 16.223; 9.BF. 16.240; 9.BF. 16.244; 9.BF. 16.243; 9.BF. 16.247; 9.BF. 18.157; 9.BF. 18.158; 9.BF. 18.196; 9.BF. 18.223; 9.BF. 18.240; 9.BF. 18.244; 9.BF. 18.243; 9.BF. 18.247; 9.BF. 26.157; 9.BF. 26.158; 9.BF. 26.196; 9.BF. 26.223; 9.BF. 26.240; 9.BF. 26.244; 9.BF. 26.243; 9.BF. 26.247; 9.BF. 27.157; 9.BF. 27.158; 9.BF. 27.196; 9.BF. 27.223; 9.BF. 27.240; 9.BF.27.244; 9.BF.27.243; 9.BF.27.247; 9.BF. 29.157; 9.BF. 29.158; 9.BF. 29.196; 9.BF.29.223; 9.BF. 29.240; 9.BF.29.244; 9.BF. 29.243; 9.BF.29.247; 9.BF. 54.157; 9.BF. 54.158; 9.BF. 54.196; 9.BF. 54.223; 9.BF. 54.240; 9.BF. 54.244; 9.BF. 54.243; 9.BF. 54.247; 9.BF. 55.157; 9.BF. 55.158; 9.BF. 55.196; 9.BF. 55.223; 9.BF. 55.240; 9.BF. 55.244; 9.BF.55.243; 9.BF. 55.247; 9.BF. 56.157; 9.BF. 56.158; 9.BF. 56.196; 9.BF. 56.223; 9.BF. 56.240; 9.BF. 56.244; 9.BF. 56.243; 9.BF. 56.247; 9.BF.157.157; 9.BF.157.158; 9.BF.157.196; 9.BF.157.223; 9.BF.157.240; 9.BF.157.244; 9.BF. 157.243; 9.BF.157.247; 9.BF.196.157; 9.BF.196.158; 9.BF.196.196; 9.BF.196.223; 9.BF.196.240; 9.BF.196.244; 9.BF. 196.243; 9.BF.196.247; 9.BF.223.157; 9.BF.223.158; 9.BF.223.196; 9.BF.223.223; 9.BF.223.240; 9.BF.223.244; 9.BF.223.243; 9.BF.223.247; 9.BF.240.157; 9.BF.240.158; 9.BF.240.196; 9.BF.240.223; 9.BF.240.240; 9.BF.240.244; 9.BF.240.243; 9.BF.240.247; 9.BF.244.157; 9.BF.244.158; 9.BF.244.196; 9.BF.244.223; 9.BF.244.240; 9.BF.244.244; 9.BF.244.243; 9.BF.244.247; 9.BF.247.157; 9.BF.247.158; 9.BF.247.196; 9.BF.247.223; 9.BF.247.240; 9.BF.247.244; 9.BF.247.243; 9.BF.247.247;

9.CI Prodrug

     9.CI.4.157; 9.CI.4.158; 9.CI.4.196; 9.CI.4.223; 9.CI.4.240; 9.CI.4.244; 9.CI.4.243; 9.CI.4.247; 9.CI.5.157; 9.CI.5.158; 9.CI.5.196; 9.CI.5.223; 9.CI.5.240; 9.CI.5.244; 9.CI.5.243; 9.CI.5.247; 9.CI.7.157; 9.CI.7.158; 9.CI.7.196; 9.CI.7.223; 9.CI.7.240; 9.CI.7.244; 9.CI.7.243; 9.CI.7.247; 9.CI.15.157; 9.CI.15.158; 9.CI.15.196; 9.CI.15.223; 9.CI.15.240; 9.CI.15.244; 9.CI.15.243; 9.CI.15.247; 9.CI.16.157; 9.CI.16.158; 9.CI.16.196; 9.CI.16.223; 9.CI.16.240; 9.CI.16.244; 9.CI.16.243; 9.CI.16.247; 9.CI.18.157; 9.CI.18.158; 9.CI.18.196; 9.CI.18.223; 9.CI.18.240; 9.CI.18.244; 9.CI.18.243; 9.CI.18.247; 9.CI.26.157; 9.CI.26.158; 9.CI.26.196; 9.CI.26.223; 9.CI.26.240; 9.CI.26.244; 9.CI.26.243; 9.CI.26.247; 9.CI.27.157; 9.CI.27.158; 9.CI.27.196; 9.CI.27.223; 9.CI.27.240; 9.CI.27.244; 9.CI.27.243; 9.CI.27.247; 9.CI.29.157; 9.CI.29.158; 9.CI.29.196; 9.CI.29.223; 9.CI.29.240; 9.CI.29.244; 9.CI.29.243; 9.CI.29.247; 9.CI.54.157; 9.CI.54.158; 9.CI.54.196; 9.CI.54.223; 9.CI.54.240; 9.CI.54.244; 9.CI.54.243; 9.CI.54.247; 9.CI.55.157; 9.CI.55.158; 9.CI.55.196; 9.CI.55.223; 9.CI.55.240; 9.CI.55.244; 9.CI.55.243; 9.CI.55.247; 9.CI.56.157; 9.CI.56.158; 9.CI.56.196; 9.CI.56.223; 9.CI.56.240; 9.CI.56.244; 9.CI.56.243; 9.CI.56.247; 9.CI.157.157; 9.CI.157.158; 9.CI.157.196; 9.CI.157.223; 9.CI.157.240; 9.CI.157.244; 9.CI.157.243; 9.CI.157.247; 9.CI.196.157; 9.CI.196.158; 9.CI.196.196; 9.CI.196.223; 9.CI.196.240; 9.CI.196.244; 9.CI.196.243; 9.CI.196.247; 9.CI.223.157; 9.CI.223.158; 9.CI.223.196; 9.CI.223.223; 9.CI.223.240; 9.CI.223.244; 9.CI.223.243; 9.CI.223.247; 9.CI.240.157; 9.CI.240.158; 9.CI.240.196; 9.CI.240.223; 9.CI.240.240; 9.CI.240.244; 9.CI.240.243; 9.CI.240.247; 9.CI.244.157; 9.CI.244.158; 9.CI.244.196; 9.CI.244.223; 9.CI.244.240; 9.CI.244.244; 9.CI.244.243; 9.CI.244.247; 9.CI.247.157; 9.CI.247.158; 9.CI.247.196; 9.CI.247.223; 9.CI.247.240; 9.CI.247.244; 9.CI.247.243; 9.CI.247.247;

9.CO's Prodrug

     9.CO.4.157; 9.CO.4.158; 9.CO.4.196; 9.CO.4.223; 9.CO.4.240; 9.CO.4.244; 9.CO.4.243; 9.CO.4.247; 9.CO.5.157; 9.CO.5.158; 9.CO.5.196; 9.CO.5.223; 9.CO.5.240; 9.CO.5.244; 9.CO.5.243; 9.CO.5.247; 9.CO.7.157; 9.CO.7.158; 9.CO.7.196; 9.CO.7.223; 9.CO.7.240; 9.CO.7.244; 9.CO.7.243; 9.CO.7.247; 9.CO.15.157; 9.CO.15.158; 9.CO.15.196; 9.CO.15.223; 9.CO.15.240; 9.CO.15.244; 9.CO.15.243; 9.CO.15.247; 9.CO.16.157; 9.CO.16.158; 9.CO.16.196; 9.CO.16.223; 9.CO.16.240; 9.CO.16.244; 9.CO.16.243; 9.CO.16.247; 9.CO.18.157; 9.CO.18.158; 9.CO.18.196; 9.CO.18.223; 9.CO.18.240; 9.CO.18.244; 9.CO.18.243; 9.CO.18.247; 9.CO.26.157; 9.CO.26.158; 9.CO.26.196; 9.CO.26.223; 9.CO.26.240; 9.CO.26.244; 9.CO.26.243; 9.CO.26.247; 9.CO.27.157; 9.CO.27.158; 9.CO.27.196; 9.CO.27.223; 9.CO.27.240; 9.CO.27.244; 9.CO.27.243; 9.CO.27.247; 9.CO.29.157; 9.CO.29.158; 9.CO.29.196; 9.CO.29.223; 9.CO.29.240; 9.CO.29.244; 9.CO.29.243; 9.CO.29.247; 9.CO.54.157; 9.CO.54.158; 9.CO.54.196; 9.CO.54.223; 9.CO.54.240; 9.CO.54.244; 9.CO.54.243; 9.CO.54.247; 9.CO.55.157; 9.CO.55.158; 9.CO.55.196; 9.CO.55.223; 9.CO.55.240; 9.CO.55.244; 9.CO.55.243; 9.CO.55.247; 9.CO.56.157; 9.CO.56.158; 9.CO.56.196; 9.CO.56.223; 9.CO.56.240; 9.CO.56.244; 9.CO.56.243; 9.CO.56.247; 9.CO.157.157; 9.CO.157.158; 9.CO.157.196; 9.CO.157.223; 9.CO.157.240; 9.CO.157.244; 9.CO.157.243; 9.CO.157.247; 9.CO.196.157; 9.CO.196.158; 9.CO.196.196; 9.CO.196.223; 9.CO.196.240; 9.CO.196.244; 9.CO.196.243; 9.CO.196.247; 9.CO.223.157; 9.CO.223.158; 9.CO.223.196; 9.CO.223.223; 9.CO.223.240; 9.CO.223.244; 9.CO.223.243; 9.CO.223.247; 9.CO.240.157; 9.CO.240.158; 9.CO.240.196; 9.CO.240.223; 9.CO.240.240; 9.CO.240.244; 9.CO.240.243; 9.CO.240.247; 9.CO.244.157; 9.CO.244.158; 9.CO.244.196; 9.CO.244.223; 9.CO.244.240; 9.CO.244.244; 9.CO.244.243; 9.CO.244.247; 9.CO.247.157; 9.CO.247.158; 9.CO.247.196; 9.CO.247.223; 9.CO.247.240; 9.CO.247.244; 9.CO.247.243; 9.CO.247.247;

10.AH Prodrug

     10.AH.4.157; 10.AH.4.158; 10.AH.4.196; 10.AH. 4.223; 10.AH. 4.240; 10.AH. 4.244; 10.AH.4.243; 10.AH. 4.247; 10.AH.5.157; 10.AH.5.158; 10.AH.5.196; 10.AH.5.223; 10.AH.5.240; 10.AH.5.244; 10.AH.5.243; 10.AH.5.247; 10.AH.7.157; 10.AH. 7.158; 10.AH.7.196; 10.AH.7.223; 10.AH.7.240; 10.AH.7.244; 10.AH. 7.243; 10.AH.7.247; 10.AH. 15.157; 10.AH. 15.158; 10.AH. 15.196; 10.AH. 15.223; 10.AH. 15.240; 10.AH. 15.244; 10.AH.15.243; 10.AH. 15.247; 10.AH. 16.157; 10.AH. 16.158; 10.AH. 16.196; 10.AH. 16.223; 10.AH. 16.240; 10.AH. 16.244; 10. AH. 16.243; 10.AH. 16.247; 10.AH. 18.157; 10.AH. 18.158; 10.AH. 18.196; 10.AH. 18.223; 10.AH. 18.240; 10.AH. 18.244; 10.AH. 18.243; 10.AH. 18.247; 10.AH. 26.157; 10.AH. 26.158; 10.AH. 26.196; 10.AH. 26.223; 10.AH. 26.240; 10.AH. 26.244; 10. AH.26.243; 10.AH. 26.247; 10.AH. 27.157; 10.AH. 27.158; 10.AH. 27.196; 10.AH. 27.223; 10.AH. 27.240; 10.AH. 27.244; 10.AH. 27.243; 10.AH. 27.247; 10. AH. 29.157; 10.AH. 29.158; 10.AH. 29.196; 10.AH. 29.223; 10.AH. 29.240; 10.AH. 29.244; 10.AH. 29.243; 10.AH. 29.247; 10.AH. 54.157; 10.AH. 54.158; 10.AH. 54.196; 10. AH. 54.223; 10.AH. 54.240; 10.AH. 54.244; 10.AH. 54.243; 10.AH. 54.247; 10.AH.55.157; 10.AH. 55.158; 10.AH. 55.196; 10.AH. 55.223; 10.AH. 55.240; 10.AH. 55.244; 10.AH.55.243; 10.AH. 55.247; 10.AH. 56.157; 10.AH. 56.158; 10. AH. 56.196; 10.AH. 56.223; 10.AH. 56.240; 10.AH. 56.244; 10.AH. 56.243; 10.AH. 56.247; 10.AH.157.157; 10.AH.157.158; 10.AH. 157.196; 10.AH.157.223; 10.AH.157.240; 10.AH.157.244; 10. AH. 157.243; 10.AH.157.247; 10.AH. 196.157; 10.AH. 196.158; 10.AH. 196.196; 10.AH. 196.223; 10.AH. 196.240; 10.AH. 196.244; 10. AH. 196.243; 10.AH. 196.247; 10.AH.223.157; 10.AH.223.158; 10.AH.223.196; 10.AH.223.223; 10.AH.223.240; 10.AH.223.244; 10.AH.223.243; 10.AH.223.247; 10. AH. 240.157; 10.AH. 240.158; 10. AH. 240.196; 10. AH. 240.223; 10.AH. 240.240; 10. AH. 240.244; 10. AH. 240.243; 10. AH. 240.247; 10.AH.244.157; 10.AH.244.158; 10.AH.244.196; 10.AH.244.223; 10.AH.244.240; 10.AH.244.244; 10.AH.244.243; 10.AH.244.247; 10.AH. 247.157; 10.AH. 247.158; 10.AH. 247.196; 10.AH. 247.223; 10.AH. 247.240; 10.AH. 247.244; 10. AH. 247.243; 10.AH. 247.247;

10. AJ of Prodrug

     10.AJ.4.157; 10.AJ.4.158; 10.AJ.4.196; 10.AJ.4.223; 10.AJ.4.240; 10.AJ.4.244; 10.AJ.4.243; 10.AJ.4.247; 10.AJ.5.157; 10.AJ.5.158; 10.AJ.5.196; 10.AJ.5.223; 10.AJ.5.240; 10.AJ.5.244; 10. AJ.5.243; 10. AJ.5.247; 10.AJ.7.157; 10.AJ.7.158; 10.AJ.7.196; 10.AJ.7.223; 10.AJ.7.240; 10.AJ.7.244; 10.AJ.7.243; 10.AJ.7.247; 10.AJ. 15.157; 10.AJ. 15.158; 10. AJ. 15.196; 10.AJ. 15.223; 10.AJ. 15.240; 10.AJ. 15.244; 10. AJ.15.243; 10.AJ.15.247; 10. AJ. 16.157; 10.AJ. 16.158; 10. AJ. 16.196; 10. AJ.16.223; 10.AJ. 16.240; 10.AJ.16.244; 10. AJ.16.243; 10.AJ.16.247; 10. AJ. 18.157; 10. AJ. 18.158; 10. AJ. 18.196; 10. AJ.18.223; 10.AJ. 18.240; 10.AJ.18.244; 10. AJ. 18.243; 10.AJ.18.247; 10. AJ. 26.157; 10. AJ. 26.158; 10. AJ. 26.196; 10. AJ. 26.223; 10. AJ. 26.240; 10. AJ. 26.244; 10. AJ.26.243; 10. AJ. 26.247; 10.AJ.27.157; 10.AJ.27.158; 10.AJ.27.196; 10.AJ.27.223; 10.AJ.27.240; 10.AJ.27.244; 10.AJ.27.243; 10.AJ.27.247; 10. AJ.29.157; 10. AJ.29.158; 10. AJ.29.196; 10. AJ.29.223; 10. AJ.29.240; 10. AJ.29.244; 10. AJ.29.243; 10. AJ.29.247; 10. AJ. 54.157; 10. AJ. 54.158; 10. AJ. 54.196; 10. AJ. 54.223; 10. AJ. 54.240; 10. AJ. 54.244; 10. AJ. 54.243; 10. AJ. 54.247; 10. AJ.55.157; 10.AJ.55.158; 10. AJ. 55.196; 10. AJ.55.223; 10.AJ.55.240; 10.AJ.55.244; 10. AJ.55.243; 10.AJ.55.247; 10. AJ. 56.157; 10. AJ. 56.158; 10. AJ. 56.196; 10. AJ. 56.223; 10. AJ. 56.240; 10. AJ. 56.244; 10. AJ. 56.243; 10. AJ. 56.247; 10. AJ.157.157; 10.AJ.157.158; 10. AJ.157.196; 10. AJ.157.223; 10.AJ.157.240; 10.AJ.157.244; 10. AJ. 157.243; 10.AJ.157.247; 10. AJ.196.157; 10. AJ.196.158; 10. AJ.196.196; 10. AJ.196.223; 10. AJ. 196.240; 10. AJ.196.244; 10. AJ. 196.243; 10. AJ.196.247; 10. AJ.223.157; 10.AJ.223.158; 10. AJ.223.196; 10. AJ.223.223; 10.AJ.223.240; 10. AJ.223.244; 10. AJ.223.243; 10.AJ.223.247; 10. AJ.240.157; 10.AJ.240.158; 10. AJ. 240.196; 10. AJ.240.223; 10.AJ.240.240; 10.AJ.240.244; 10. AJ. 240.243; 10.AJ.240.247; 10.AJ.244.157; 10.AJ.244.158; 10.AJ.244.196; 10.AJ.244.223; 10.AJ.244.240; 10.AJ.244.244; 10.AJ.244.243; 10.AJ.244.247; 10.AJ.247.157; 10.AJ.247.158; 10.AJ.247.196; 10.AJ.247.223; 10.AJ.247.240; 10.AJ.247.244; 10. AJ.247.243; 10.AJ.247.247;

10.AN's Prodrug

     10.AN.4.157; 10.AN.4.158; 10.AN.4.196; 10.AN.4.223; 10.AN.4.240; 10.AN.4.244; 10.AN.4.243; 10.AN.4.247; 10.AN.5.157; 10.AN.5.158; 10.AN.5.196; 10.AN.5.223; 10.AN.5.240; 10.AN.5.244; 10.AN.5.243; 10.AN.5.247; 10.AN.7.157; 10.AN.7.158; 10.AN.7.196; 10.AN.7.223; 10.AN.7.240; 10.AN.7.244; 10.AN.7.243; 10.AN.7.247; 10.AN.15.157; 10.AN.15.158; 10.AN.15.196; 10.AN.15.223; 10.AN.15.240; 10.AN.15.244; 10.AN.15.243; 10.AN.15.247; 10.AN.16.157; 10.AN.16.158; 10.AN.16.196; 10.AN.16.223; 10.AN.16.240; 10.AN.16.244; 10.AN.16.243; 10.AN.16.247; 10.AN.18.157; 10.AN.18.158; 10.AN.18.196; 10.AN.18.223; 10.AN.18.240; 10.AN.18.244; 10.AN.18.243; 10.AN.18.247; 10.AN.26.157; 10.AN.26.158; 10.AN.26.196; 10.AN.26.223; 10.AN.26.240; 10.AN.26.244; 10.AN.26.243; 10.AN.26.247; 10.AN.27.157; 10.AN.27.158; 10.AN.27.196; 10.AN.27.223; 10.AN.27.240; 10.AN.27.244; 10.AN.27.243; 10.AN.27.247; 10.AN.29.157; 10.AN.29.158; 10.AN.29.196; 10.AN.29.223; 10.AN.29.240; 10.AN.29.244; 10.AN.29.243; 10.AN.29.247; 10.AN.54.157; 10.AN.54.158; 10.AN.54.196; 10.AN.54.223; 10.AN.54.240; 10.AN.54.244; 10.AN.54.243; 10.AN.54.247; 10.AN.55.157; 10.AN.55.158; 10.AN.55.196; 10.AN.55.223; 10.AN.55.240; 10.AN.55.244; 10.AN.55.243; 10.AN.55.247; 10.AN.56.157; 10.AN.56.158; 10.AN.56.196; 10.AN.56.223; 10.AN.56.240; 10.AN.56.244; 10.AN.56.243; 10.AN.56.247; 10.AN.157.157; 10.AN.157.158; 10.AN.157.196; 10.AN.157.223; 10.AN.157.240; 10.AN.157.244; 10.AN.157.243; 10.AN.157.247; 10.AN.196.157; 10.AN.196.158; 10.AN.196.196; 10.AN.196.223; 10.AN.196.240; 10.AN.196.244; 10.AN.196.243; 10.AN.196.247; 10.AN.223.157; 10.AN.223.158; 10.AN.223.196; 10.AN.223.223; 10.AN.223.240; 10.AN.223.244; 10.AN.223.243; 10.AN.223.247; 10.AN.240.157; 10.AN.240.158; 10.AN.240.196; 10.AN.240.223; 10.AN.240.240; 10.AN.240.244; 10.AN.240.243; 10.AN.240.247; 10.AN.244.157; 10.AN.244.158; 10.AN.244.196; 10.AN.244.223; 10.AN.244.240; 10.AN.244.244; 10.AN.244.243; 10.AN.244.247; 10.AN.247.157; 10.AN.247.158; 10.AN.247.196; 10.AN.247.223; 10.AN.247.240; 10.AN.247.244; 10.AN.247.243; 10.AN.247.247;

10.AP Prodrug

     10.AP.4.157; 10.AP.4.158; 10.AP.4.196; 10.AP.4.223; 10.AP.4.240; 10.AP.4.244; 10.AP.4.243; 10.AP.4.247; 10.AP.5.157; 10.AP.5.158; 10.AP.5.196; 10.AP.5.223; 10.AP.5.240; 10.AP.5.244; 10.AP.5.243; 10.AP.5.247; 10.AP.7.157; 10.AP.7.158; 10.AP.7.196; 10.AP.7.223; 10.AP.7.240; 10.AP.7.244; 10.AP.7.243; 10.AP.7.247; 10.AP.15.157; 10.AP.15.158; 10.AP.15.196; 10.AP.15.223; 10.AP.15.240; 10.AP.15.244; 10.AP.15.243; 10.AP.15.247; 10.AP.16.157; 10.AP.16.158; 10.AP.16.196; 10.AP.16.223; 10.AP.16.240; 10.AP.16.244; 10.AP.16.243; 10.AP.16.247; 10.AP.18.157; 10.AP.18.158; 10.AP.18.196; 10.AP.18.223; 10.AP.18.240; 10.AP.18.244; 10.AP.18.243; 10.AP.18.247; 10.AP.26.157; 10.AP.26.158; 10.AP.26.196; 10.AP.26.223; 10.AP.26.240; 10.AP.26.244; 10.AP.26.243; 10.AP.26.247; 10.AP.27.157; 10.AP.27.158; 10.AP.27.196; 10.AP.27.223; 10.AP.27.240; 10.AP.27.244; 10.AP.27.243; 10.AP.27.247; 10.AP.29.157; 10.AP.29.158; 10.AP.29.196; 10.AP.29.223; 10.AP.29.240; 10.AP.29.244; 10.AP.29.243; 10.AP.29.247; 10.AP.54.157; 10.AP.54.158; 10.AP.54.196; 10.AP.54.223; 10.AP.54.240; 10.AP.54.244; 10.AP.54.243; 10.AP.54.247; 10.AP.55.157; 10.AP.55.158; 10.AP.55.196; 10.AP.55.223; 10.AP.55.240; 10.AP.55.244; 10.AP.55.243; 10.AP.55.247; 10.AP.56.157; 10.AP.56.158; 10.AP.56.196; 10.AP.56.223; 10.AP.56.240; 10.AP.56.244; 10.AP.56.243; 10.AP.56.247; 10.AP.157.157; 10.AP.157.158; 10.AP.157.196; 10.AP.157.223; 10.AP.157.240; 10.AP.157.244; 10.AP.157.243; 10.AP.157.247; 10.AP.196.157; 10.AP.196.158; 10.AP.196.196; 10.AP.196.223; 10.AP.196.240; 10.AP.196.244; 10.AP.196.243; 10.AP.196.247; 10.AP.223.157; 10.AP.223.158; 10.AP.223.196; 10.AP.223.223; 10.AP.223.240; 10.AP.223.244; 10.AP.223.243; 10.AP.223.247; 10.AP.240.157; 10.AP.240.158; 10.AP.240.196; 10.AP.240.223; 10.AP.240.240; 10.AP.240.244; 10.AP.240.243; 10.AP.240.247; 10.AP.244.157; 10.AP.244.158; 10.AP.244.196; 10.AP.244.223; 10.AP.244.240; 10.AP.244.244; 10.AP.244.243; 10.AP.244.247; 10.AP.247.157; 10.AP.247.158; 10.AP.247.196; 10.AP.247.223; 10.AP.247.240; 10.AP.247.244; 10.AP.247.243; 10.AP.247.247;

10.AZ Prodrug

     10.AZ.4.157; 10.AZ.4.158; 10.AZ.4.196; 10.AZ.4.223; 10.AZ.4.240; 10.AZ.4.244; 10.AZ.4.243; 10.AZ.4.247; 10.AZ.5.157; 10.AZ.5.158; 10.AZ.5.196; 10.AZ.5.223; 10.AZ.5.240; 10.AZ.5.244; 10.AZ.5.243; 10.AZ.5.247; 10.AZ.7.157; 10.AZ.7.158; 10.AZ.7.196; 10.AZ.7.223; 10.AZ.7.240; 10.AZ.7.244; 10.AZ.7.243; 10.AZ.7.247; 10.AZ. 15.157; 10.AZ. 15.158; 10.AZ. 15.196; 10.AZ. 15.223; 10.AZ. 15.240; 10.AZ.15.244; 10. AZ. 15.243; 10.AZ.15.247; 10.AZ. 16.157; 10.AZ. 16.158; 10.AZ. 16.196; 10.AZ. 16.223; 10.AZ. 16.240; 10.AZ.16.244; 10. AZ. 16.243; 10.AZ.16.247; 10.AZ. 18.157; 10.AZ.18.158; 10.AZ.18.196; 10.AZ.18.223; 10.AZ. 18.240; 10.AZ.18.244; 10.AZ. 18.243; 10.AZ.18.247; 10.AZ. 26.157; 10.AZ. 26.158; 10.AZ. 26.196; 10.AZ.26.223; 10.AZ. 26.240; 10.AZ.26.244; 10.AZ.26.243; 10.AZ.26.247; 10.AZ.27.157; 10.AZ.27.158; 10.AZ.27.196; 10.AZ.27.223; 10.AZ.27.240; 10.AZ.27.244; 10.AZ.27.243; 10.AZ.27.247; 10.AZ. 29.157; 10.AZ.29.158; 10.AZ. 29.196; 10.AZ.29.223; 10.AZ.29.240; 10.AZ.29.244; 10.AZ.29.243; 10.AZ.29.247; 10.AZ. 54.157; 10.AZ. 54.158; 10. AZ. 54.196; 10.AZ.54.223; 10.AZ. 54.240; 10.AZ.54.244; 10.AZ. 54.243; 10.AZ.54.247; 10.AZ.55.157; 10.AZ.55.158; 10.AZ.55.196; 10.AZ.55.223; 10.AZ.55.240; 10.AZ.55.244; 10.AZ.55.243; 10.AZ.55.247; 10.AZ. 56.157; 10.AZ. 56.158; 10.AZ. 56.196; 10.AZ. 56.223; 10.AZ. 56.240; 10.AZ. 56.244; 10.AZ. 56.243; 10.AZ.56.247; 10.AZ.157.157; 10.AZ.157.158; 10.AZ.157.196; 10.AZ.157.223; 10.AZ.157.240; 10.AZ.157.244; 10.AZ. 157.243; 10.AZ.157.247; 10.AZ. 196.157; 10.AZ. 196.158; 10.AZ. 196.196; 10.AZ. 196.223; 10.AZ. 196.240; 10.AZ.196.244; 10. AZ. 196.243; 10.AZ.196.247; 10.AZ.223.157; 10.AZ.223.158; 10.AZ.223.196; 10.AZ.223.223; 10.AZ.223.240; 10.AZ.223.244; 10.AZ.223.243; 10.AZ.223.247; 10.AZ.240.157; 10.AZ.240.158; 10. AZ. 240.196; 10.AZ.240.223; 10.AZ.240.240; 10.AZ.240.244; 10.AZ.240.243; 10.AZ.240.247; 10.AZ.244.157; 10.AZ.244.158; 10.AZ.244.196; 10.AZ.244.223; 10.AZ.244.240; 10.AZ.244.244; 10.AZ.244.243; 10.AZ.244.247; 10.AZ.247.157; 10.AZ.247.158; 10.AZ.247.196; 10.AZ.247.223; 10.AZ.247.240; 10.AZ.247.244; 10.AZ.247.243; 10.AZ.247.247;

10. BF of Prodrug

     10. BF.4.157; 10. BF.4.158; 10. BF.4.196; 10. BF.4.223; 10. BF.4.240; 10. BF.4.244; 10. BF.4.243; 10. BF.4.247; 10. BF.5.157; 10. BF.5.158; 10. BF.5.196; 10. BF.5.223; 10. BF.5.240; 10. BF.5.244; 10. BF.5.243; 10. BF.5.247; 10. BF.7.157; 10. BF.7.158; 10. BF.7.196; 10. BF.7.223; 10. BF.7.240; 10. BF.7.244; 10. BF.7.243; 10. BF.7.247; 10. BF. 15.157; 10. BF. 15.158; 10. BF. 15.196; 10. BF.15.223; 10. BF. 15.240; 10. BF.15.244; 10. BF.15.243; 10. BF. 15.247; 10. BF.16.157; 10. BF.16.158; 10. BF.16.196; 10. BF.16.223; 10. BF.16.240; 10. BF.16.244; 10. BF.16.243; 10. BF.16.247; 10. BF. 18.157; 10. BF. 18.158; 10. BF. 18.196; 10. BF. 18.223; 10. BF. 18.240; 10. BF. 18.244; 10. BF. 18.243; 10. BF.18.247; 10. BF. 26.157; 10. BF. 26.158; 10. BF. 26.196; 10. BF. 26.223; 10. BF. 26.240; 10. BF. 26.244; 10. BF.26.243; 10. BF. 26.247; 10. BF. 27.157; 10. BF.27.158; 10. BF. 27.196; 10. BF.27.223; 10. BF. 27.240; 10. BF.27.244; 10. BF.27.243; 10. BF.27.247; 10. BF.29.157; 10. BF.29.158; 10. BF.29.196; 10. BF.29.223; 10. BF.29.240; 10. BF.29.244; 10. BF.29.243; 10. BF.29.247; 10. BF. 54.157; 10. BF. 54.158; 10. BF. 54.196; 10. BF. 54.223; 10. BF. 54.240; 10. BF. 54.244; 10. BF. 54.243; 10. BF. 54.247; 10. BF.55.157; 10. BF.55.158; 10. BF. 55.196; 10. BF.55.223; 10. BF.55.240; 10. BF.55.244; 10. BF.55.243; 10. BF.55.247; 10. BF. 56.157; 10. BF. 56.158; 10. BF. 56.196; 10. BF. 56.223; 10. BF. 56.240; 10. BF. 56.244; 10. BF. 56.243; 10. BF. 56.247; 10. BF.157.157; 10. BF.157.158; 10. BF.157.196; 10. BF.157.223; 10. BF.157.240; 10. BF.157.244; 10. BF. 157.243; 10. BF.157.247; 10. BF.196.157; 10. BF.196.158; 10. BF.196.196; 10. BF.196.223; 10. BF.196.240; 10. BF.196.244; 10. BF.196.243; 10. BF.196.247; 10. BF.223.157; 10. BF.223.158; 10. BF.223.196; 10. BF.223.223; 10. BF.223.240; 10. BF.223.244; 10. BF.223.243; 10. BF.223.247; 10. BF.240.157; 10. BF.240.158; 10. BF.240.196; 10. BF.240.223; 10. BF.240.240; 10. BF.240.244; 10. BF.240.243; 10. BF.240.247; 10. BF.244.157; 10. BF.244.158; 10. BF.244.196; 10. BF.244.223; 10. BF.244.240; 10. BF.244.244; 10. BF.244.243; 10. BF.244.247; 10. BF.247.157; 10. BF.247.158; 10. BF.247.196; 10. BF.247.223; 10. BF.247.240; 10. BF.247.244; 10. BF.247.243; 10. BF.247.247;

10. of CI Prodrug

     10.CI.4.157; 10.CI.4.158; 10.CI.4.196; 10.CI.4.223; 10.CI.4.240; 10.CI.4.244; 10.CI.4.243; 10.CI.4.247; 10.CI.5.157; 10.CI.5.158; 10.CI.5.196; 10.CI.5.223; 10.CI.5.240; 10.CI.5.244; 10.CI.5.243; 10.CI.5.247; 10.CI.7.157; 10.CI.7.158; 10.CI.7.196; 10.CI.7.223; 10.CI.7.240; 10.CI.7.244; 10.CI.7.243; 10.CI.7.247; 10.CI.15.157; 10.CI.15.158; 10.CI.15.196; 10.CI.15.223; 10.CI.15.240; 10.CI.15.244; 10.CI.15.243; 10.CI.15.247; 10.CI.16.157; 10.CI.16.158; 10.CI.16.196; 10.CI.16.223; 10.CI.16.240; 10.CI.16.244; 10.CI.16.243; 10.CI.16.247; 10.CI.18.157; 10.CI.18.158; 10.CI.18.196; 10.CI.18.223; 10.CI.18.240; 10.CI.18.244; 10.CI.18.243; 10.CI.18.247; 10.CI.26.157; 10.CI.26.158; 10.CI.26.196; 10.CI.26.223; 10.CI.26.240; 10.CI.26.244; 10.CI.26.243; 10.CI.26.247; 10.CI.27.157; 10.CI.27.158; 10.CI.27.196; 10.CI.27.223; 10.CI.27.240; 10.CI.27.244; 10.CI.27.243; 10.CI.27.247; 10.CI.29.157; 10.CI.29.158; 10.CI.29.196; 10.CI.29.223; 10.CI.29.240; 10.CI.29.244; 10.CI.29.243; 10.CI.29.247; 10.CI.54.157; 10.CI.54.158; 10.CI.54.196; 10.CI.54.223; 10.CI.54.240; 10.CI.54.244; 10.CI.54.243; 10.CI.54.247; 10.CI.55.157; 10.CI.55.158; 10.CI.55.196; 10.CI.55.223; 10.CI.55.240; 10.CI.55.244; 10.CI.55.243; 10.CI.55.247; 10.CI.56.157; 10.CI.56.158; 10.CI.56.196; 10.CI.56.223; 10.CI.56.240; 10.CI.56.244; 10.CI.56.243; 10.CI.56.247; 10.CI.157.157; 10.CI.157.158; 10.CI.157.196; 10.CI.157.223; 10.CI.157.240; 10.CI.157.244; 10.CI.157.243; 10.CI.157.247; 10.CI.196.157; 10.CI.196.158; 10.CI.196.196; 10.CI.196.223; 10.CI.196.240; 10.CI.196.244; 10.CI.196.243; 10.CI.196.247; 10.CI.223.157; 10.CI.223.158; 10.CI.223.196; 10.CI.223.223; 10.CI.223.240; 10.CI.223.244; 10.CI.223.243; 10.CI.223.247; 10.CI.240.157; 10.CI.240.158; 10.CI.240.196; 10.CI.240.223; 10.CI.240.240; 10.CI.240.244; 10.CI.240.243; 10.CI.240.247; 10.CI.244.157; 10.CI.244.158; 10.CI.244.196; 10.CI.244.223; 10.CI.244.240; 10.CI.244.244; 10.CI.244.243; 10.CI.244.247; 10.CI.247.157; 10.CI.247.158; 10.CI.247.196; 10.CI.247.223; 10.CI.247.240; 10.CI.247.244; 10.CI.247.243; 10.CI.247.247;

10. of CO Prodrug

     10.CO.4.157; 10.CO.4.158; 10.CO.4.196; 10.CO.4.223; 10.CO.4.240; 10.CO.4.244; 10.CO.4.243; 10.CO.4.247; 10.CO.5.157; 10.CO.5.158; 10.CO.5.196; 10.CO.5.223; 10.CO.5.240; 10.CO.5.244; 10.CO.5.243; 10.CO.5.247; 10.CO.7.157; 10.CO.7.158; 10.CO.7.196; 10.CO.7.223; 10.CO.7.240; 10.CO.7.244; 10.CO.7.243; 10.CO.7.247; 10.CO.15.157; 10.CO.15.158; 10.CO.15.196; 10.CO.15.223; 10.CO.15.240; 10.CO.15.244; 10.CO.15.243; 10.CO.15.247; 10.CO.16.157; 10.CO.16.158; 10.CO.16.196; 10.CO.16.223; 10.CO.16.240; 10.CO.16.244; 10.CO.16.243; 10.CO.16.247; 10.CO.18.157; 10.CO.18.158; 10.CO.18.196; 10.CO.18.223; 10.CO.18.240; 10.CO.18.244; 10.CO.18.243; 10.CO.18.247; 10.CO.26.157; 10.CO.26.158; 10.CO.26.196; 10.CO.26.223; 10.CO.26.240; 10.CO.26.244; 10.CO.26.243; 10.CO.26.247; 10.CO.27.157; 10.CO.27.158; 10.CO.27.196; 10.CO.27.223; 10.CO.27.240; 10.CO.27.244; 10.CO.27.243; 10.CO.27.247; 10.CO.29.157; 10.CO.29.158; 10.CO.29.196; 10.CO.29.223; 10.CO.29.240; 10.CO.29.244; 10.CO.29.243; 10.CO.29.247; 10.CO.54.157; 10.CO.54.158; 10.CO.54.196; 10.CO.54.223; 10.CO.54.240; 10.CO.54.244; 10.CO.54.243; 10.CO.54.247; 10.CO.55.157; 10.CO.55.158; 10.CO.55.196; 10.CO.55.223; 10.CO.55.240; 10.CO.55.244; 10.CO.55.243; 10.CO.55.247; 10. CO. 56.157; 10.CO.56.158; 10. CO. 56.196; 10.CO.56.223; 10.CO.56.240; 10.CO.56.244; 10.CO.56.243; 10.CO.56.247; 10.CO.157.157; 10.CO.157.158; 10.CO.157.196; 10.CO.157.223; 10.CO.157.240; 10.CO.157.244; 10.CO.157.243; 10.CO.157.247; 10.CO.196.157; 10.CO.196.158; 10.CO.196.196; 10.CO.196.223; 10.CO.196.240; 10.CO.196.244; 10.CO.196.243; 10.CO.196.247; 10.CO.223.157; 10.CO.223.158; 10.CO.223.196; 10.CO.223.223; 10.CO.223.240; 10.CO.223.244; 10.CO.223.243; 10.CO.223.247; 10.CO.240.157; 10.CO.240.158; 10.CO.240.196; 10.CO.240.223; 10.CO.240.240; 10.CO.240.244; 10.CO.240.243; 10.CO.240.247; 10.CO.244.157; 10.CO.244.158; 10.CO.244.196; 10.CO.244.223; 10.CO.244.240; 10.CO.244.244; 10.CO.244.243; 10.CO.244.247; 10.CO.247.157; 10.CO.247.158; 10.CO.247.196; 10.CO.247.223; 10.CO.247.240; 10.CO.247.244; 10.CO.247.243; 10.CO.247.247;

11.AH Prodrug

     11.AH.4.157; 11.AH.4.158; 11.AH.4.196; 11.AH.4.223; 11.AH. 4.240; 11.AH.4.244; 11.AH.4.243; 11.AH.4.247; 11.AH.5.157; 11.AH.5.158; 11.AH.5.196; 11.AH.5.223; 11.AH.5.240; 11.AH.5.244; 11.AH.5.243; 11.AH.5.247; 11.AH.7.157; 11.AH.7.158; 11.AH.7.196; 11.AH.7.223; 11.AH.7.240; 11.AH.7.244; 11.AH.7.243; 11.AH.7.247; 11.AH. 15.157; 11.AH. 15.158; 11.AH. 15.196; 11.AH. 15.223; 11.AH. 15.240; 11.AH. 15.244; 11.AH.15.243; 11.AH. 15.247; 11.AH. 16.157; 11.AH. 16.158; 11.AH. 16.196; 11.AH. 16.223; 11.AH. 16.240; 11.AH. 16.244; 11.AH.16.243; 11.AH. 16.247; 11.AH. 18.157; 11.AH. 18.158; 11.AH. 18.196; 11.AH. 18.223; 11.AH. 18.240; 11.AH. 18.244; 11.AH. 18.243; 11.AH. 18.247; 11.AH. 26.157; 11.AH. 26.158; 11.AH. 26.196; 11.AH. 26.223; 11.AH. 26.240; 11.AH. 26.244; 11.AH.26.243; 11.AH. 26.247; 11.AH. 27.157; 11.AH. 27.158; 11.AH. 27.196; 11.AH.27.223; 11.AH. 27.240; 11.AH.27.244; 11.AH.27.243; 11.AH.27.247; 11.AH.29.157; 11.AH.29.158; 11.AH.29.196; 11.AH.29.223; 11.AH.29.240; 11.AH.29.244; 11.AH.29.243; 11.AH.29.247; 11.AH. 54.157; 11.AH. 54.158; 11.AH. 54.196; 11.AH. 54.223; 11.AH. 54.240; 11.AH. 54.244; 11.AH. 54.243; 11.AH. 54.247; 11.AH.55.157; 11.AH.55.158; 11.AH.55.196; 11.AH.55.223; 11.AH.55.240; 11.AH.55.244; 11.AH.55.243; 11.AH.55.247; 11.AH. 56.157; 11.AH. 56.158; 11.AH. 56.196; 11.AH. 56.223; 11.AH. 56.240; 11.AH. 56.244; 11.AH. 56.243; 11.AH. 56.247; 11.AH.157.157; 11.AH.157.158; 11.AH.157.196; 11.AH.157.223; 11.AH.157.240; 11.AH.157.244; 11.AH. 157.243; 11.AH.157.247; 11.AH.196.157; 11.AH.196.158; 11.AH.196.196; 11.AH.196.223; 11.AH.196.240; 11.AH.196.244; 11.AH.196.243; 11.AH.196.247; 11.AH.223.157; 11.AH.223.158; 11.AH.223.196; 11.AH.223.223; 11.AH.223.240; 11.AH.223.244; 11.AH.223.243; 11.AH.223.247; 11.AH.240.157; 11.AH. 240.158; 11.AH. 240.196; 11.AH. 240.223; 11.AH.240.240; 11.AH.240.244; 11.AH.240.243; 11.AH.240.247; 11.AH.244.157; 11.AH.244.158; 11.AH.244.196; 11.AH.244.223; 11.AH.244.240; 11.AH.244.244; 11.AH.244.243; 11.AH.244.247; 11.AH. 247.157; 11.AH.247.158; 11.AH. 247.196; 11.AH.247.223; 11.AH. 247.240; 11.AH.247.244; 11.AH.247.243; 11.AH.247.247;

11. AJ of Prodrug

     11.AJ.4.157; 11.AJ.4.158; 11.AJ.4.196; 11.AJ.4.223; 11.AJ.4.240; 11.AJ.4.244; 11.AJ.4.243; 11.AJ.4.247; 11.AJ.5.157; 11.AJ.5.158; 11.AJ.5.196; 11.AJ.5.223; 11.AJ.5.240; 11.AJ.5.244; 11.AJ.5.243; 11.AJ.5.247; 11.AJ.7.157; 11.AJ.7.158; 11.AJ.7.196; 11.AJ.7.223; 11.AJ.7.240; 11.AJ.7.244; 11.AJ.7.243; 11.AJ.7.247; 11.AJ. 15.157; 11.AJ.15.158; 11.AJ. 15.196; 11.AJ.15.223; 11.AJ. 15.240; 11.AJ. 15.244; 11.AJ.15.243; 11.AJ.15.247; 11.AJ. 16.157; 11.AJ. 16.158; 11.AJ. 16.196; 11.AJ. 16.223; 11.AJ. 16.240; 11.AJ.16.244; 11.AJ.16.243; 11.AJ.16.247; 11.AJ. 18.157; 11.AJ. 18.158; 11.AJ. 18.196; 11.AJ. 18.223; 11.AJ. 18.240; 11.AJ. 18.244; 11.AJ. 18.243; 11.AJ. 18.247; 11.AJ. 26.157; 11.AJ. 26.158; 11.AJ. 26.196; 11.AJ. 26.223; 11.AJ. 26.240; 11.AJ. 26.244; 11.AJ.26.243; 11.AJ. 26.247; 11.AJ. 27.157; 11.AJ.27.158; 11.AJ.27.196; 11.AJ.27.223; 11.AJ.27.240; 11.AJ.27.244; 11.AJ.27.243; 11.AJ.27.247; 11.AJ.29.157; 11.AJ.29.158; 11.AJ.29.196; 11.AJ.29.223; 11.AJ.29.240; 11.AJ.29.244; 11.AJ.29.243; 11.AJ.29.247; 11.AJ. 54.157; 11.AJ. 54.158; 11.AJ. 54.196; 11.AJ. 54.223; 11.AJ. 54.240; 11.AJ. 54.244; 11.AJ. 54.243; 11.AJ. 54.247; 11.AJ.55.157; 11.AJ.55.158; 11.AJ. 55.196; 11.AJ.55.223; 11.AJ.55.240; 11.AJ. 55.244; 11.AJ.55.243; 11.AJ.55.247; 11.AJ. 56.157; 11.AJ. 56.158; 11.AJ. 56.196; 11.AJ. 56.223; 11.AJ. 56.240; 11.AJ. 56.244; 11.AJ. 56.243; 11.AJ. 56.247; 11.AJ.157.157; 11.AJ.157.158; 11.AJ.157.196; 11.AJ.157.223; 11.AJ.157.240; 11.AJ.157.244; 11.AJ. 157.243; 11.AJ.157.247; 11.AJ. 196.157; 11.AJ.196.158; 11.AJ. 196.196; 11.AJ. 196.223; 11.AJ. 196.240; 11.AJ.196.244; 11.AJ. 196.243; 11.AJ.196.247; 11.AJ.223.157; 11.AJ.223.158; 11.AJ.223.196; 11.AJ.223.223; 11.AJ.223.240; 11.AJ.223.244; 11.AJ.223.243; 11.AJ.223.247; 11.AJ.240.157; 11.AJ.240.158; 11.AJ. 240.196; 11.AJ.240.223; 11.AJ.240.240; 11.AJ.240.244; 11.AJ. 240.243; 11.AJ.240.247; 11.AJ.244.157; 11.AJ.244.158; 11.AJ.244.196; 11.AJ.244.223; 11.AJ.244.240; 11.AJ.244.244; 11.AJ.244.243; 11.AJ.244.247; 11.AJ.247.157; 11.AJ.247.158; 11.AJ.247.196; 11.AJ.247.223; 11.AJ.247.240; 11.AJ.247.244; 11.AJ.247.243; 11.AJ.247.247;

11.AN's Prodrug

     11.AN.4.157; 11.AN.4.158; 11.AN.4.196; 11.AN.4.223; 11.AN.4.240; 11.AN.4.244; 11.AN.4.243; 11.AN.4.247; 11.AN.5.157; 11.AN.5.158; 11.AN.5.196; 11.AN.5.223; 11.AN.5.240; 11.AN.5.244; 11.AN.5.243; 11.AN.5.247; 11.AN.7.157; 11.AN.7.158; 11.AN.7.196; 11.AN.7.223; 11.AN.7.240; 11.AN.7.244; 11.AN.7.243; 11.AN.7.247; 11.AN.15.157; 11.AN.15.158; 11.AN.15.196; 11.AN.15.223; 11.AN.15.240; 11.AN.15.244; 11.AN.15.243; 11.AN.15.247; 11.AN.16.157; 11.AN.16.158; 11.AN.16.196; 11.AN.16.223; 11.AN.16.240; 11.AN.16.244; 11.AN.16.243; 11.AN.16.247; 11.AN.18.157; 11.AN.18.158; 11.AN.18.196; 11.AN.18.223; 11.AN.18.240; 11.AN.18.244; 11.AN.18.243; 11.AN.18.247; 11.AN.26.157; 11.AN.26.158; 11.AN.26.196; 11.AN.26.223; 11.AN.26.240; 11.AN.26.244; 11.AN.26.243; 11.AN.26.247; 11.AN.27.157; 11.AN.27.158; 11.AN.27.196; 11.AN.27.223; 11.AN.27.240; 11.AN.27.244; 11.AN.27.243; 11.AN.27.247; 11.AN.29.157; 11.AN.29.158; 11.AN.29.196; 11.AN.29.223; 11.AN.29.240; 11.AN.29.244; 11.AN.29.243; 11.AN.29.247; 11.AN.54.157; 11.AN.54.158; 11.AN.54.196; 11.AN.54.223; 11.AN.54.240; 11.AN.54.244; 11.AN.54.243; 11.AN.54.247; 11.AN 55.157; 11.AN.55.158; 11.AN 55.196; 11.AN 55.223; 11.AN.55.240; 11.AN.55.244; 11.AN.55.243; 11.AN.55.247; 11.AN 56.157; 11.AN.56.158; 11.AN.56.196; 11.AN.56.223; 11.AN.56.240; 11.AN.56.244; 11.AN.56.243; 11.AN.56.247; 11.AN.157.157; 11.AN.157.158; 11.AN.157.196; 11.AN.157.223; 11.AN.157.240; 11.AN.157.244; 11.AN.157.243; 11.AN.157.247; 11.AN.196.157; 11.AN.196.158; 11.AN.196.196; 11.AN.196.223; 11.AN.196.240; 11.AN.196.244; 11.AN.196.243; 11.AN.196.247; 11.AN.223.157; 11.AN.223.158; 11.AN.223.196; 11.AN.223.223; 11.AN.223.240; 11.AN.223.244; 11.AN.223.243; 11.AN.223.247; 11.AN.240.157; 11.AN.240.158; 11.AN.240.196; 11.AN.240.223; 11.AN.240.240; 11.AN.240.244; 11.AN.240.243; 11.AN.240.247; 11.AN.244.157; 11.AN.244.158; 11.AN.244.196; 11.AN.244.223; 11.AN.244.240; 11.AN.244.244; 11.AN.244.243; 11.AN.244.247; 11.AN.247.157; 11.AN.247.158; 11.AN.247.196; 11.AN.247.223; 11.AN.247.240; 11.AN.247.244; 11.AN.247.243; 11.AN.247.247;

11.AP Prodrug

     11.AP.4.157; 11.AP.4.158; 11.AP.4.196; 11.AP.4.223; 11.AP.4.240; 11.AP.4.244; 11.AP.4.243; 11.AP.4.247; 11.AP.5.157; 11.AP.5.158; 11.AP.5.196; 11.AP.5.223; 11.AP.5.240; 11.AP.5.244; 11.AP.5.243; 11.AP.5.247; 11.AP.7.157; 11.AP.7.158; 11.AP.7.196; 11.AP.7.223; 11.AP.7.240; 11.AP.7.244; 11.AP.7.243; 11.AP.7.247; 11.AP.15.157; 11.AP.15.158; 11.AP.15.196; 11.AP.15.223; 11.AP.15.240; 11.AP.15.244; 11.AP.15.243; 11.AP.15.247; 11.AP.16.157; 11.AP.16.158; 11.AP 16.196; 11.AP.16.223; 11.AP.16.240; 11.AP.16.244; 11.AP.16.243; 11.AP.16.247; 11.AP.18.157; 11.AP.18.158; 11.AP.18.196; 11.AP.18.223; 11.AP.18.240; 11.AP.18.244; 11.AP.18.243; 11.AP.18.247; 11.AP.26.157; 11.AP.26.158; 11.AP.26.196; 11.AP.26.223; 11.AP.26.240; 11.AP.26.244; 11.AP.26.243; 11.AP.26.247; 11.AP.27.157; 11.AP.27.158; 11.AP.27.196; 11.AP.27.223; 11.AP.27.240; 11.AP.27.244; 11.AP.27.243; 11.AP.27.247; 11.AP.29.157; 11.AP.29.158; 11.AP.29.196; 11.AP.29.223; 11.AP.29.240; 11.AP.29.244; 11.AP.29.243; 11.AP.29.247; 11.AP.54.157; 11.AP.54.158; 11.AP.54.196; 11.AP.54.223; 11.AP.54.240; 11.AP.54.244; 11.AP.54.243; 11.AP.54.247; 11.AP.55.157; 11.AP.55.158; 11.AP.55.196; 11.AP.55.223; 11.AP.55.240; 11.AP.55.244; 11.AP.55.243; 11.AP.55.247; 11.AP.56.157; 11.AP.56.158; 11.AP.56.196; 11.AP.56.223; 11.AP.56.240; 11.AP.56.244; 11.AP.56.243; 11.AP.56.247; 11.AP.157.157; 11.AP.157.158; 11.AP.157.196; 11.AP.157.223; 11.AP.157.240; 11.AP.157.244; 11.AP. 157.243; 11.AP.157.247; 11.AP.196.157; 11.AP.196.158; 11.AP.196.196; 11.AP.196.223; 11.AP.196.240; 11.AP.196.244; 11.AP.196.243; 11.AP.196.247; 11.AP.223.157; 11.AP.223.158; 11.AP.223.196; 11.AP.223.223; 11.AP.223.240; 11.AP.223.244; 11.AP.223.243; 11.AP.223.247; 11.AP.240.157; 11.AP.240.158; 11.AP.240.196; 11.AP.240.223; 11.AP.240.240; 11.AP.240.244; 11.AP.240.243; 11.AP.240.247; 11.AP.244.157; 11.AP.244.158; 11.AP.244.196; 11.AP.244.223; 11.AP.244.240; 11.AP.244.244; 11.AP.244.243; 11.AP.244.247; 11.AP.247.157; 11.AP.247.158; 11.AP.247.196; 11.AP.247.223; 11.AP.247.240; 11.AP.247.244; 11.AP.247.243; 11.AP.247.247;

11.AZ Prodrug

     11.AZ.4.157; 11.AZ.4.158; 11.AZ.4.196; 11.AZ.4.223; 11.AZ.4.240; 11.AZ.4.244; 11.AZ.4.243; 11.AZ.4.247; 11.AZ.5.157; 11.AZ.5.158; 11.AZ.5.196; 11.AZ.5.223; 11.AZ.5.240; 11.AZ.5.244; 11.AZ.5.243; 11.AZ.5.247; 11.AZ.7.157; 11.AZ.7.158; 11.AZ.7.196; 11.AZ.7.223; 11.AZ.7.240; 11.AZ.7.244; 11.AZ.7.243; 11.AZ.7.247; 11.AZ. 15.157; 11.AZ. 15.158; 11.AZ. 15.196; 11.AZ. 15.223; 11.AZ. 15.240; 11.AZ. 15.244; 11.AZ.15.243; 11.AZ. 15.247; 11.AZ. 16.157; 11.AZ. 16.158; 11.AZ. 16.196; 11.AZ. 16.223; 11.AZ. 16.240; 11.AZ. 16.244; 11.AZ.16.243; 11.AZ. 16.247; 11.AZ. 18.157; 11.AZ. 18.158; 11.AZ. 18.196; 11.AZ. 18.223; 11.AZ. 18.240; 11.AZ. 18.244; 11.AZ. 18.243; 11.AZ. 18.247; 11.AZ. 26.157; 11.AZ. 26.158; 11.AZ. 26.196; 11.AZ. 26.223; 11.AZ. 26.240; 11.AZ. 26.244; 11.AZ.26.243; 11.AZ. 26.247; 11.AZ. 27.157; 11.AZ. 27.158; 11.AZ. 27.196; 11.AZ. 27.223; 11.AZ. 27.240; 11.AZ. 27.244; 11.AZ. 27.243; 11.AZ. 27.247; 11.AZ. 29.157; 11.AZ. 29.158; 11.AZ. 29.196; 11.AZ. 29.223; 11.AZ. 29.240; 11.AZ. 29.244; 11.AZ. 29.243; 11.AZ. 29.247; 11.AZ. 54.157; 11.AZ. 54.158; 11.AZ. 54.196; 11.AZ. 54.223; 11.AZ. 54.240; 11.AZ. 54.244; 11.AZ. 54.243; 11.AZ. 54.247; 11.AZ. 55.157; 11.AZ. 55.158; 11.AZ. 55.196; 11.AZ. 55.223; 11.AZ. 55.240; 11.AZ. 55.244; 11.AZ.55.243; 11.AZ. 55.247; 11.AZ. 56.157; 11.AZ. 56.158; 11.AZ. 56.196; 11.AZ. 56.223; 11.AZ. 56.240; 11.AZ. 56.244; 11.AZ. 56.243; 11.AZ. 56.247; 11.AZ.157.157; 11.AZ.157.158; 11.AZ.157.196; 11.AZ.157.223; 11.AZ.157.240; 11.AZ.157.244; 11.AZ. 157.243; 11.AZ.157.247; 11.AZ. 196.157; 11.AZ. 196.158; 11.AZ. 196.196; 11.AZ. 196.223; 11.AZ. 196.240; 11.AZ. 196.244; 11.AZ. 196.243; 11.AZ. 196.247; 11.AZ.223.157; 11.AZ.223.158; 11.AZ.223.196; 11.AZ.223.223; 11.AZ.223.240; 11.AZ.223.244; 11.AZ.223.243; 11.AZ.223.247; 11.AZ. 240.157; 11.AZ. 240.158; 11.AZ. 240.196; 11.AZ.240.223; 11.AZ.240.240; 11.AZ.240.244; 11.AZ. 240.243; 11.AZ.240.247; 11.AZ.244.157; 11.AZ.244.158; 11.AZ.244.196; 11.AZ.244.223; 11.AZ.244.240; 11.AZ.244.244; 11.AZ.244.243; 11.AZ.244.247; 11.AZ.247.157; 11.AZ.247.158; 11.AZ.247.196; 11.AZ.247.223; 11.AZ.247.240; 11.AZ.247.244; 11.AZ. 247.243; 11.AZ.247.247;

11. BF of Prodrug

     11.BF.4.157; 11.BF.4.158; 11.BF.4.196; 11.BF.4.223; 11.BF.4.240; 11.BF.4.244; 11.BF.4.243; 11.BF.4.247; 11.BF.5.157; 11.BF.5.158; 11.BF.5.196; 11.BF.5.223; 11.BF.5.240; 11.BF.5.244; 11.BF.5.243; 11.BF.5.247; 11.BF.7.157; 11.BF.7.158; 11.BF.7.196; 11.BF.7.223; 11.BF.7.240; 11.BF.7.244; 11.BF.7.243; 11.BF.7.247; 11.BF. 15.157; 11.BF. 15.158; 11.BF. 15.196; 11.BF. 15.223; 11.BF. 15.240; 11.BF. 15.244; 11.BF.15.243; 11.BF. 15.247; 11.BF. 16.157; 11.BF. 16.158; 11.BF. 16.196; 11.BF. 16.223; 11.BF. 16.240; 11.BF. 16.244; 11.BF.16.243; 11.BF.16.247; 11.BF. 18.157; 11.BF. 18.158; 11.BF. 18.196; 11.BF. 18.223; 11.BF. 18.240; 11.BF. 18.244; 11.BF. 18.243; 11.BF. 18.247; 11.BF. 26.157; 11.BF. 26.158; 11.BF. 26.196; 11.BF. 26.223; 11.BF. 26.240; 11.BF. 26.244; 11.BF. 26.243; 11.BF. 26.247; 11.BF. 27.157; 11.BF. 27.158; 11.BF. 27.196; 11.BF.27.223; 11.BF. 27.240; 11.BF.27.244; 11.BF.27.243; 11.BF.27.247; 11.BF. 29.157; 11.BF. 29.158; 11.BF. 29.196; 11.BF.29.223; 11.BF.29.240; 11.BF.29.244; 11.BF.29.243; 11.BF.29.247; 11.BF. 54.157; 11.BF. 54.158; 11.BF. 54.196; 11.BF. 54.223; 11.BF. 54.240; 11.BF. 54.244; 11.BF. 54.243; 11.BF. 54.247; 11.BF. 55.157; 11.BF. 55.158; 11.BF. 55.196; 11.BF. 55.223; 11.BF. 55.240; 11.BF. 55.244; 11.BF.55.243; 11.BF. 55.247; 11.BF. 56.157; 11.BF. 56.158; 11.BF. 56.196; 11.BF. 56.223; 11.BF. 56.240; 11.BF. 56.244; 11.BF. 56.243; 11.BF. 56.247; 11.BF.157.157; 11.BF.157.158; 11.BF.157.196; 11.BF.157.223; 11.BF.157.240; 11.BF.157.244; 11.BF. 157.243; 11.BF.157.247; 11.BF.196.157; 11.BF.196.158; 11.BF.196.196; 11.BF.196.223; 11.BF.196.240; 11.BF.196.244; 11.BF. 196.243; 11.BF.196.247; 11.BF.223.157; 11.BF.223.158; 11.BF.223.196; 11.BF.223.223; 11.BF.223.240; 11.BF.223.244; 11.BF.223.243; 11.BF.223.247; 11.BF.240.157; 11.BF.240.158; 11.BF.240.196; 11.BF.240.223; 11.BF.240.240; 11.BF.240.244; 11.BF.240.243; 11.BF.240.247; 11.BF.244.157; 11.BF.244.158; 11.BF.244.196; 11.BF.244.223; 11.BF.244.240; 11.BF.244.244; 11.BF.244.243; 11.BF.244.247; 11.BF.247.157; 11.BF.247.158; 11.BF.247.196; 11.BF.247.223; 11.BF.247.240; 11.BF.247.244; 11.BF.247.243; 11.BF.247.247;

11.CI Prodrug

     11.CI.4.157; 11.CI.4.158; 11.CI.4.196; 11.CI.4.223; 11.CI.4.240; 11.CI.4.244; 11.CI.4.243; 11.CI.4.247; 11.CI.5.157; 11.CI.5.158; 11.CI.5.196; 11.CI.5.223; 11.CI.5.240; 11.CI.5.244; 11.CI.5.243; 11.CI.5.247; 11.CI.7.157; 11.CI.7.158; 11.CI.7.196; 11.CI.7.223; 11.CI.7.240; 11.CI.7.244; 11.CI.7.243; 11.CI.7.247; 11.CI.15.157; 11.CI.15.158; 11.CI.15.196; 11.CI.15.223; 11.CI.15.240; 11.CI.15.244; 11.CI.15.243; 11.CI.15.247; 11.CI.16.157; 11.CI.16.158; 11.CI.16.196; 11.CI.16.223; 11.CI.16.240; 11.CI.16.244; 11.CI.16.243; 11.CI.16.247; 11.CI.18.157; 11.CI.18.158; 11.CI.18.196; 11.CI.18.223; 11.CI.18.240; 11.CI.18.244; 11.CI.18.243; 11.CI.18.247; 11.CI.26.157; 11.CI.26.158; 11.CI.26.196; 11.CI.26.223; 11.CI.26.240; 11.CI.26.244; 11.CI.26.243; 11.CI.26.247; 11.CI.27.157; 11.CI.27.158; 11.CI.27.196; 11.CI.27.223; 11.CI.27.240; 11.CI.27.244; 11.CI.27.243; 11.CI.27.247; 11.CI.29.157; 11.CI.29.158; 11.CI.29.196; 11.CI.29.223; 11.CI.29.240; 11.CI.29.244; 11.CI.29.243; 11.CI.29.247; 11.CI.54.157; 11.CI.54.158; 11.CI.54.196; 11.CI.54.223; 11.CI.54.240; 11.CI.54.244; 11.CI.54.243; 11.CI.54.247; 11.CI.55.157; 11.CI.55.158; 11.CI.55.196; 11.CI.55.223; 11.CI.55.240; 11.CI.55.244; 11.CI.55.243; 11.CI.55.247; 11.CI.56.157; 11.CI.56.158; 11.CI.56.196; 11.CI.56.223; 11.CI.56.240; 11.CI.56.244; 11.CI.56.243; 11.CI.56.247; 11.CI.157.157; 11.CI.157.158; 11.CI.157.196; 11.CI.157.223; 11.CI.157.240; 11.CI.157.244; 11.CI.157.243; 11.CI.157.247; 11.CI.196.157; 11.CI.196.158; 11.CI.196.196; 11.CI.196.223; 11.CI.196.240; 11.CI.196.244; 11.CI.196.243; 11.CI.196.247; 11.CI.223.157; 11.CI.223.158; 11.CI.223.196; 11.CI.223.223; 11.CI.223.240; 11.CI.223.244; 11.CI.223.243; 11.CI.223.247; 11.CI.240.157; 11.CI.240.158; 11.CI.240.196; 11.CI.240.223; 11.CI.240.240; 11.CI.240.244; 11.CI.240.243; 11.CI.240.247; 11.CI.244.157; 11.CI.244.158; 11.CI.244.196; 11.CI.244.223; 11.CI.244.240; 11.CI.244.244; 11.CI.244.243; 11.CI.244.247; 11.CI.247.157; 11.CI.247.158; 11.CI.247.196; 11.CI.247.223; 11.CI.247.240; 11.CI.247.244; 11.CI.247.243; 11.CI.247.247;

11.CO's Prodrug

     11.CO.4.157; 11.CO.4.158; 11.CO.4.196; 11.CO.4.223; 11.CO.4.240; 11.CO.4.244; 11.CO.4.243; 11.CO.4.247; 11.CO.5.157; 11.CO.5.158; 11.CO.5.196; 11.CO.5.223; 11.CO.5.240; 11.CO.5.244; 11.CO.5.243; 11.CO.5.247; 11.CO.7.157; 11.CO.7.158; 11.CO.7.196; 11.CO.7.223; 11.CO.7.240; 11.CO.7.244; 11.CO.7.243; 11.CO.7.247; 11.CO.15.157; 11.CO.15.158; 11.CO.15.196; 11.CO.15.223; 11.CO.15.240; 11.CO.15.244; 11.CO.15.243; 11.CO.15.247; 11.CO.16.157; 11.CO.16.158; 11.CO.16.196; 11.CO.16.223; 11.CO.16.240; 11.CO.16.244; 11.CO.16.243; 11.CO.16.247; 11.CO.18.157; 11.CO.18.158; 11.CO. 18.196; 11.CO.18.223; 11.CO.18.240; 11.CO.18.244; 11.CO. 18.243; 11.CO.18.247; 11.CO.26.157; 11.CO.26.158; 11.CO.26.196; 11.CO.26.223; 11.CO.26.240; 11.CO.26.244; 11.CO.26.243; 11.CO.26.247; 11.CO.27.157; 11.CO.27.158; 11.CO.27.196; 11.CO.27.223; 11.CO.27.240; 11.CO.27.244; 11.CO.27.243; 11.CO.27.247; 11.CO.29.157; 11.CO.29.158; 11.CO.29.196; 11.CO.29.223; 11.CO.29.240; 11.CO.29.244; 11.CO.29.243; 11.CO.29.247; 11.CO.54.157; 11.CO.54.158; 11.CO.54.196; 11.CO.54.223; 11.CO.54.240; 11.CO.54.244; 11.CO.54.243; 11.CO.54.247; 11.CO.55.157; 11.CO.55.158; 11.CO.55.196; 11.CO.55.223; 11.CO.55.240; 11.CO.55.244; 11.CO.55.243; 11.CO.55.247; 11.CO.56.157; 11.CO.56.158; 11.CO.56.196; 11.CO.56.223; 11.CO.56.240; 11.CO.56.244; 11.CO.56.243; 11.CO.56.247; 11.CO.157.157; 11.CO.157.158; 11.CO.157.196; 11.CO.157.223; 11.CO.157.240; 11.CO.157.244; 11.CO.157.243; 11.CO.157.247; 11.CO.196.157; 11.CO.196.158; 11.CO.196.196; 11.CO.196.223; 11.CO.196.240; 11.CO.196.244; 11.CO.196.243; 11.CO.196.247; 11.CO.223.157; 11.CO.223.158; 11.CO.223.196; 11.CO.223.223; 11.CO.223.240; 11.CO.223.244; 11.CO.223.243; 11.CO.223.247; 11.CO.240.157; 11.CO.240.158; 11.CO.240.196; 11.CO.240.223; 11.CO.240.240; 11.CO.240.244; 11.CO.240.243; 11.CO.240.247; 11.CO.244.157; 11.CO.244.158; 11.CO.244.196; 11.CO.244.223; 11.CO.244.240; 11.CO.244.244; 11.CO.244.243; 11.CO.244.247; 11.CO.247.157; 11.CO.247.158; 11.CO.247.196; 11.CO.247.223; 11.CO.247.240; 11.CO.247.244; 11.CO.247.243; 11.CO.247.247;

12.AH Prodrug

     12.AH.4.157; 12.AH.4.158; 12.AH.4.196; 12.AH. 4.223; 12.AH. 4.240; 12.AH. 4.244; 12.AH.4.243; 12. AH. 4.247; 12.AH.5.157; 12.AH.5.158; 12.AH.5.196; 12.AH.5.223; 12.AH.5.240; 12.AH.5.244; 12.AH.5.243; 12.AH.5.247; 12. AH. 7.157; 12. AH. 7.158; 12. AH. 7.196; 12.AH. 7.223; 12.AH.7.240; 12.AH. 7.244; 12.AH. 7.243; 12.AH. 7.247; 12. AH. 15.157; 12.AH. 15.158; 12.AH. 15.196; 12.AH. 15.223; 12.AH. 15.240; 12.AH. 15.244; 12. AH. 15.243; 12.AH. 15.247; 12. AH. 16.157; 12.AH. 16.158; 12.AH. 16.196; 12. AH. 16.223; 12.AH. 16.240; 12.AH. 16.244; 12. AH. 16.243; 12.AH. 16.247; 12. AH. 18.157; 12.AH. 18.158; 12.AH. 18.196; 12. AH. 18.223; 12.AH. 18.240; 12.AH. 18.244; 12.AH. 18.243; 12. AH. 18.247; 12. AH. 26.157; 12.AH. 26.158; 12.AH. 26.196; 12.AH. 26.223; 12.AH. 26.240; 12.AH. 26.244; 12. AH. 26.243; 12. AH. 26.247; 12. AH. 27.157; 12.AH. 27.158; 12.AH. 27.196; 12.AH. 27.223; 12.AH. 27.240; 12. AH. 27.244; 12.AH. 27.243; 12. AH. 27.247; 12. AH. 29.157; 12.AH. 29.158; 12. AH. 29.196; 12.AH. 29.223; 12.AH. 29.240; 12. AH. 29.244; 12.AH.29.243; 12. AH. 29.247; 12.AH. 54.157; 12. AH. 54.158; 12. AH. 54.196; 12.AH. 54.223; 12.AH. 54.240; 12. AH. 54.244; 12. AH. 54.243; 12. AH. 54.247; 12. AH 55.157; 12.AH. 55.158; 12. AH 55.196; 12.AH.55.223; 12.AH. 55.240; 12.AH. 55.244; 12.AH.55.243; 12. AH. 55.247; 12. AH. 56.157; 12.AH. 56.158; 12. AH. 56.196; 12. AH. 56.223; 12.AH. 56.240; 12. AH. 56.244; 12.AH. 56.243; 12. AH. 56.247; 12. AH.157.157; 12. AH.157.158; 12. AH.157.196; 12. AH.157.223; 12. AH.157.240; 12. AH.157.244; 12. AH. 157.243; 12. AH.157.247; 12. AH. 196.157; 12.AH. 196.158; 12. AH. 196.196; 12. AH. 196.223; 12.AH. 196.240; 12.AH. 196.244; 12. AH. 196.243; 12. AH. 196.247; 12. AH. 223.157; 12.AH.223.158; 12.AH.223.196; 12.AH.223.223; 12.AH.223.240; 12.AH.223.244; 12.AH.223.243; 12.AH.223.247; 12. AH. 240.157; 12. AH. 240.158; 12. AH. 240.196; 12. AH. 240.223; 12. AH. 240.240; 12. AH. 240.244; 12. AH. 240.243; 12. AH. 240.247; 12.AH.244.157; 12.AH.244.158; 12.AH.244.196; 12.AH.244.223; 12.AH.244.240; 12.AH.244.244; 12.AH.244.243; 12.AH.244.247; 12.AH. 247.157; 12.AH. 247.158; 12.AH. 247.196; 12.AH. 247.223; 12.AH. 247.240; 12.AH. 247.244; 12. AH. 247.243; 12.AH. 247.247;

12. AJ of Prodrug

     12.AJ.4.157; 12.AJ.4.158; 12.AJ.4.196; 12.AJ.4.223; 12.AJ.4.240; 12.AJ.4.244; 12.AJ.4.243; 12.AJ.4.247; 12.AJ.5.157; 12.AJ.5.158; 12.AJ.5.196; 12.AJ.5.223; 12.AJ.5.240; 12.AJ.5.244; 12.AJ.5.243; 12.AJ.5.247; 12.AJ.7.157; 12.AJ.7.158; 12.AJ.7.196; 12.AJ.7.223; 12.AJ.7.240; 12.AJ.7.244; 12.AJ.7.243; 12.AJ.7.247; 12.AJ. 15.157; 12.AJ. 15.158; 12.AJ. 15.196; 12.AJ. 15.223; 12.AJ. 15.240; 12.AJ. 15.244; 12.AJ.15.243; 12.AJ. 15.247; 12.AJ. 16.157; 12.AJ. 16.158; 12.AJ. 16.196; 12.AJ. 16.223; 12.AJ. 16.240; 12.AJ. 16.244; 12.AJ.16.243; 12.AJ. 16.247; 12.AJ. 18.157; 12.AJ. 18.158; 12. AJ. 18.196; 12.AJ. 18.223; 12.AJ. 18.240; 12.AJ. 18.244; 12.AJ. 18.243; 12.AJ.18.247; 12.AJ. 26.157; 12.AJ. 26.158; 12.AJ. 26.196; 12.AJ. 26.223; 12.AJ. 26.240; 12.AJ. 26.244; 12.AJ.26.243; 12.AJ. 26.247; 12.AJ.27.157; 12.AJ.27.158; 12.AJ.27.196; 12.AJ.27.223; 12.AJ.27.240; 12.AJ.27.244; 12.AJ.27.243; 12.AJ.27.247; 12.AJ.29.157; 12.AJ.29.158; 12.AJ.29.196; 12.AJ.29.223; 12.AJ.29.240; 12.AJ.29.244; 12.AJ.29.243; 12.AJ.29.247; 12.AJ. 54.157; 12.AJ. 54.158; 12. AJ. 54.196; 12.AJ. 54.223; 12.AJ. 54.240; 12.AJ. 54.244; 12.AJ. 54.243; 12.AJ. 54.247; 12.AJ.55.157; 12.AJ. 55.158; 12. AJ. 55.196; 12.AJ.55.223; 12.AJ. 55.240; 12.AJ.55.244; 12.AJ.55.243; 12.AJ.55.247; 12.AJ. 56.157; 12.AJ. 56.158; 12. AJ. 56.196; 12.AJ. 56.223; 12.AJ. 56.240; 12.AJ. 56.244; 12.AJ. 56.243; 12.AJ. 56.247; 12.AJ.157.157; 12.AJ.157.158; 12.AJ.157.196; 12.AJ.157.223; 12.AJ.157.240; 12.AJ.157.244; 12. AJ. 157.243; 12.AJ.157.247; 12. AJ. 196.157; 12. AJ. 196.158; 12. AJ. 196.196; 12. AJ. 196.223; 12. AJ. 196.240; 12. AJ. 196.244; 12. AJ. 196.243; 12. AJ. 196.247; 12.AJ.223.157; 12.AJ.223.158; 12.AJ.223.196; 12.AJ.223.223; 12.AJ.223.240; 12.AJ.223.244; 12.AJ.223.243; 12.AJ.223.247; 12. AJ. 240.157; 12.AJ. 240.158; 12. AJ. 240.196; 12.AJ.240.223; 12.AJ.240.240; 12.AJ.240.244; 12.AJ.240.243; 12.AJ.240.247; 12.AJ.244.157; 12.AJ.244.158; 12.AJ.244.196; 12.AJ.244.223; 12.AJ.244.240; 12.AJ.244.244; 12.AJ.244.243; 12.AJ.244.247; 12.AJ.247.157; 12.AJ.247.158; 12.AJ.247.196; 12.AJ.247.223; 12.AJ.247.240; 12.AJ.247.244; 12.AJ.247.243; 12.AJ.247.247;

12.AN's Prodrug

     12.AN.4.157; 12.AN.4.158; 12.AN.4.196; 12.AN.4.223; 12.AN.4.240; 12.AN.4.244; 12.AN.4.243; 12.AN.4.247; 12.AN.5.157; 12.AN.5.158; 12.AN.5.196; 12.AN.5.223; 12.AN.5.240; 12.AN.5.244; 12.AN.5.243; 12.AN.5.247; 12.AN.7.157; 12.AN.7.158; 12.AN.7.196; 12.AN.7.223; 12.AN.7.240; 12.AN.7.244; 12.AN.7.243; 12.AN.7.247; 12.AN.15.157; 12.AN.15.158; 12.AN.15.196; 12.AN.15.223; 12.AN.15.240; 12.AN.15.244; 12.AN.15.243; 12.AN.15.247; 12.AN.16.157; 12.AN.16.158; 12.AN.16.196; 12.AN.16.223; 12.AN.16.240; 12.AN.16.244; 12.AN.16.243; 12.AN.16.247; 12.AN.18.157; 12.AN.18.158; 12.AN.18.196; 12.AN.18.223; 12.AN.18.240; 12.AN.18.244; 12.AN.18.243; 12.AN.18.247; 12.AN.26.157; 12.AN.26.158; 12.AN.26.196; 12.AN.26.223; 12.AN.26.240; 12.AN.26.244; 12.AN.26.243; 12.AN.26.247; 12.AN.27.157; 12.AN.27.158; 12.AN.27.196; 12.AN.27.223; 12.AN.27.240; 12.AN.27.244; 12.AN.27.243; 12.AN.27.247; 12.AN.29.157; 12.AN.29.158; 12.AN.29.196; 12.AN.29.223; 12.AN.29.240; 12.AN.29.244; 12.AN.29.243; 12.AN.29.247; 12.AN.54.157; 12.AN.54.158; 12.AN.54.196; 12.AN.54.223; 12.AN.54.240; 12.AN.54.244; 12.AN.54.243; 12.AN.54.247; 12.AN.55.157; 12.AN.55.158; 12.AN.55.196; 12.AN.55.223; 12.AN.55.240; 12.AN.55.244; 12.AN.55.243; 12.AN.55.247; 12.AN.56.157; 12.AN.56.158; 12.AN.56.196; 12.AN.56.223; 12.AN.56.240; 12.AN.56.244; 12.AN.56.243; 12.AN.56.247; 12.AN.157.157; 12.AN.157.158; 12.AN.157.196; 12.AN.157.223; 12.AN.157.240; 12.AN.157.244; 12.AN.157.243; 12.AN.157.247; 12.AN.196.157; 12.AN.196.158; 12.AN.196.196; 12.AN.196.223; 12.AN.196.240; 12.AN.196.244; 12.AN.196.243; 12.AN.196.247; 12.AN.223.157; 12.AN.223.158; 12.AN.223.196; 12.AN.223.223; 12.AN.223.240; 12.AN.223.244; 12.AN.223.243; 12.AN.223.247; 12.AN.240.157; 12.AN.240.158; 12.AN.240.196; 12.AN.240.223; 12.AN.240.240; 12.AN.240.244; 12.AN.240.243; 12.AN.240.247; 12.AN.244.157; 12.AN.244.158; 12.AN.244.196; 12.AN.244.223; 12.AN.244.240; 12.AN.244.244; 12.AN.244.243; 12.AN.244.247; 12.AN.247.157; 12.AN.247.158; 12.AN.247.196; 12.AN.247.223; 12.AN.247.240; 12.AN.247.244; 12.AN.247.243; 12.AN.247.247;

12.AP Prodrug

     12.AP.4.157; 12.AP.4.158; 12.AP.4.196; 12.AP.4.223; 12.AP.4.240; 12.AP.4.244; 12.AP.4.243; 12.AP.4.247; 12.AP.5.157; 12.AP.5.158; 12.AP.5.196; 12.AP.5.223; 12.AP.5.240; 12.AP.5.244; 12.AP.5.243; 12.AP.5.247; 12.AP.7.157; 12.AP.7.158; 12.AP.7.196; 12.AP.7.223; 12.AP.7.240; 12.AP.7.244; 12.AP.7.243; 12.AP.7.247; 12.AP.15.157; 12.AP.15.158; 12.AP.15.196; 12.AP.15.223; 12.AP.15.240; 12.AP.15.244; 12.AP.15.243; 12.AP.15.247; 12.AP.16.157; 12.AP.16.158; 12.AP.16.196; 12.AP.16.223; 12.AP.16.240; 12.AP.16.244; 12.AP.16.243; 12.AP.16.247; 12.AP.18.157; 12.AP.18.158; 12.AP.18.196; 12.AP.18.223; 12.AP.18.240; 12.AP.18.244; 12.AP.18.243; 12.AP.18.247; 12.AP.26.157; 12.AP.26.158; 12.AP.26.196; 12.AP.26.223; 12.AP.26.240; 12.AP.26.244; 12.AP.26.243; 12.AP.26.247; 12.AP.27.157; 12.AP.27.158; 12.AP.27.196; 12.AP.27.223; 12.AP.27.240; 12.AP.27.244; 12.AP.27.243; 12.AP.27.247; 12.AP.29.157; 12.AP.29.158; 12.AP.29.196; 12.AP.29.223; 12.AP.29.240; 12.AP.29.244; 12.AP.29.243; 12.AP.29.247; 12.AP.54.157; 12.AP.54.158; 12.AP.54.196; 12.AP.54.223; 12.AP.54.240; 12.AP.54.244; 12.AP.54.243; 12.AP.54.247; 12.AP.55.157; 12.AP.55.158; 12.AP.55.196; 12.AP.55.223; 12.AP.55.240; 12.AP.55.244; 12.AP.55.243; 12.AP.55.247; 12.AP.56.157; 12.AP.56.158; 12.AP.56.196; 12.AP.56.223; 12.AP.56.240; 12.AP.56.244; 12.AP.56.243; 12.AP.56.247; 12.AP.157.157; 12.AP.157.158; 12.AP.157.196; 12.AP.157.223; 12.AP.157.240; 12.AP.157.244; 12.AP.157.243; 12.AP.157.247; 12.AP.196.157; 12.AP.196.158; 12.AP.196.196; 12.AP.196.223; 12.AP.196.240; 12.AP.196.244; 12.AP.196.243; 12.AP.196.247; 12.AP.223.157; 12.AP.223.158; 12.AP.223.196; 12.AP.223.223; 12.AP.223.240; 12.AP.223.244; 12.AP.223.243; 12.AP.223.247; 12.AP.240.157; 12.AP.240.158; 12.AP.240.196; 12.AP.240.223; 12.AP.240.240; 12.AP.240.244; 12.AP.240.243; 12.AP.240.247; 12.AP.244.157; 12.AP.244.158; 12.AP.244.196; 12.AP.244.223; 12.AP.244.240; 12.AP.244.244; 12.AP.244.243; 12.AP.244.247; 12.AP.247.157; 12.AP.247.158; 12.AP.247.196; 12.AP.247.223; 12.AP.247.240; 12.AP.247.244; 12.AP.247.243; 12.AP.247.247;

12.AZ Prodrug

     12.AZ.4.157; 12.AZ.4.158; 12.AZ.4.196; 12.AZ.4.223; 12.AZ.4.240; 12.AZ.4.244; 12.AZ.4.243; 12.AZ.4.247; 12.AZ.5.157; 12.AZ.5.158; 12.AZ.5.196; 12.AZ.5.223; 12.AZ.5.240; 12.AZ.5.244; 12.AZ.5.243; 12.AZ.5.247; 12.AZ.7.157; 12.AZ.7.158; 12.AZ.7.196; 12.AZ.7.223; 12.AZ.7.240; 12.AZ.7.244; 12.AZ.7.243; 12.AZ.7.247; 12.AZ. 15.157; 12.AZ. 15.158; 12.AZ. 15.196; 12.AZ. 15.223; 12.AZ. 15.240; 12.AZ. 15.244; 12. AZ. 15.243; 12.AZ. 15.247; 12.AZ. 16.157; 12.AZ. 16.158; 12.AZ. 16.196; 12.AZ. 16.223; 12.AZ. 16.240; 12.AZ. 16.244; 12. AZ. 16.243; 12.AZ. 16.247; 12.AZ. 18.157; 12.AZ. 18.158; 12.AZ. 18.196; 12.AZ. 18.223; 12.AZ. 18.240; 12.AZ. 18.244; 12.AZ. 18.243; 12.AZ.18.247; 12.AZ. 26.157; 12.AZ. 26.158; 12.AZ. 26.196; 12.AZ. 26.223; 12.AZ. 26.240; 12.AZ. 26.244; 12. AZ. 26.243; 12.AZ. 26.247; 12.AZ. 27.157; 12.AZ.27.158; 12.AZ. 27.196; 12.AZ.27.223; 12.AZ.27.240; 12.AZ.27.244; 12.AZ.27.243; 12.AZ.27.247; 12.AZ. 29.157; 12.AZ.29.158; 12.AZ. 29.196; 12.AZ.29.223; 12.AZ.29.240; 12.AZ.29.244; 12.AZ.29.243; 12.AZ.29.247; 12.AZ. 54.157; 12.AZ. 54.158; 12.AZ. 54.196; 12.AZ. 54.223; 12.AZ. 54.240; 12.AZ. 54.244; 12.AZ. 54.243; 12.AZ. 54.247; 12.AZ.55.157; 12.AZ.55.158; 12.AZ.55.196; 12.AZ.55.223; 12.AZ.55.240; 12.AZ.55.244; 12.AZ.55.243; 12.AZ.55.247; 12.AZ. 56.157; 12.AZ. 56.158; 12.AZ. 56.196; 12.AZ. 56.223; 12.AZ. 56.240; 12.AZ. 56.244; 12.AZ. 56.243; 12.AZ. 56.247; 12.AZ.157.157; 12.AZ.157.158; 12.AZ.157.196; 12.AZ.157.223; 12.AZ.157.240; 12.AZ.157.244; 12.AZ. 157.243; 12.AZ.157.247; 12.AZ. 196.157; 12.AZ. 196.158; 12.AZ. 196.196; 12.AZ. 196.223; 12.AZ. 196.240; 12.AZ. 196.244; 12. AZ. 196.243; 12.AZ. 196.247; 12.AZ.223.157; 12.AZ.223.158; 12.AZ.223.196; 12.AZ.223.223; 12.AZ.223.240; 12.AZ.223.244; 12.AZ.223.243; 12.AZ.223.247; 12.AZ. 240.157; 12.AZ.240.158; 12.AZ. 240.196; 12.AZ.240.223; 12.AZ.240.240; 12.AZ.240.244; 12.AZ. 240.243; 12.AZ.240.247; 12.AZ.244.157; 12.AZ.244.158; 12.AZ.244.196; 12.AZ.244.223; 12.AZ.244.240; 12.AZ.244.244; 12.AZ.244.243; 12.AZ.244.247; 12.AZ.247.157; 12.AZ.247.158; 12.AZ.247.196; 12.AZ.247.223; 12.AZ.247.240; 12.AZ.247.244; 12. AZ. 247.243; 12.AZ.247.247;

12. BF of Prodrug

     12. BF.4.157; 12. BF.4.158; 12. BF.4.196; 12. BF.4.223; 12.BF.4.240; 12. BF.4.244; 12.BF.4.243; 12.BF.4.247; 12. BF.5.157; 12. BF.5.158; 12. BF.5.196; 12. BF.5.223; 12. BF.5.240; 12. BF.5.244; 12. BF.5.243; 12. BF.5.247; 12. BF.7.157; 12. BF.7.158; 12. BF.7.196; 12. BF.7.223; 12. BF.7.240; 12. BF.7.244; 12. BF.7.243; 12. BF.7.247; 12. BF. 15.157; 12.BF. 15.158; 12. BF. 15.196; 12. BF. 15.223; 12.BF. 15.240; 12.BF. 15.244; 12. BF.15.243; 12.BF. 15.247; 12. BF. 16.157; 12.BF. 16.158; 12. BF. 16.196; 12. BF.16.223; 12.BF. 16.240; 12. BF.16.244; 12. BF.16.243; 12. BF.16.247; 12. BF. 18.157; 12. BF. 18.158; 12. BF. 18.196; 12. BF. 18.223; 12.BF. 18.240; 12. BF. 18.244; 12. BF. 18.243; 12. BF. 18.247; 12. BF. 26.157; 12.BF. 26.158; 12. BF. 26.196; 12. BF. 26.223; 12. BF. 26.240; 12. BF. 26.244; 12. BF.26.243; 12. BF. 26.247; 12. BF. 27.157; 12.BF.27.158; 12. BF. 27.196; 12.BF.27.223; 12.BF.27.240; 12.BF.27.244; 12.BF.27.243; 12.BF.27.247; 12. BF.29.157; 12.BF.29.158; 12. BF.29.196; 12. BF.29.223; 12.BF.29.240; 12. BF.29.244; 12. BF.29.243; 12. BF.29.247; 12. BF. 54.157; 12. BF. 54.158; 12. BF. 54.196; 12. BF. 54.223; 12. BF. 54.240; 12. BF. 54.244; 12. BF. 54.243; 12. BF. 54.247; 12. BF. 55.157; 12. BF. 55.158; 12. BF. 55.196; 12. BF. 55.223; 12.BF. 55.240; 12. BF.55.244; 12.BF.55.243; 12. BF.55.247; 12. BF. 56.157; 12. BF. 56.158; 12. BF. 56.196; 12. BF. 56.223; 12. BF. 56.240; 12. BF. 56.244; 12. BF. 56.243; 12. BF. 56.247; 12. BF.157.157; 12. BF.157.158; 12. BF.157.196; 12. BF.157.223; 12. BF.157.240; 12. BF.157.244; 12. BF. 157.243; 12. BF.157.247; 12. BF.196.157; 12. BF.196.158; 12. BF.196.196; 12. BF.196.223; 12. BF.196.240; 12. BF.196.244; 12. BF.196.243; 12. BF.196.247; 12. BF.223.157; 12.BF.223.158; 12. BF.223.196; 12. BF.223.223; 12.BF.223.240; 12. BF.223.244; 12. BF.223.243; 12. BF.223.247; 12. BF.240.157; 12.BF.240.158; 12. BF.240.196; 12. BF.240.223; 12.BF.240.240; 12. BF.240.244; 12. BF.240.243; 12.BF.240.247; 12. BF.244.157; 12.BF.244.158; 12. BF.244.196; 12. BF.244.223; 12.BF.244.240; 12.BF.244.244; 12.BF.244.243; 12.BF.244.247; 12.BF.247.157; 12.BF.247.158; 12. BF.247.196; 12.BF.247.223; 12.BF.247.240; 12.BF.247.244; 12. BF.247.243; 12.BF.247.247;

12. of CI Prodrug

     12.CI.4.157; 12.CI.4.158; 12.CI.4.196; 12.CI.4.223; 12.CI.4.240; 12.CI.4.244; 12.CI.4.243; 12.CI.4.247; 12.CI.5.157; 12.CI.5.158; 12.CI.5.196; 12.CI.5.223; 12.CI.5.240; 12.CI.5.244; 12.CI.5.243; 12.CI.5.247; 12.CI.7.157; 12.CI.7.158; 12.CI.7.196; 12.CI.7.223; 12.CI.7.240; 12.CI.7.244; 12.CI.7.243; 12.CI.7.247; 12.CI.15.157; 12.CI.15.158; 12.CI.15.196; 12.CI.15.223; 12.CI.15.240; 12.CI.15.244; 12.CI.15.243; 12.CI.15.247; 12.CI.16.157; 12.CI.16.158; 12.CI.16.196; 12.CI.16.223; 12.CI.16.240; 12.CI.16.244; 12.CI.16.243; 12.CI.16.247; 12.CI.18.157; 12.CI.18.158; 12.CI.18.196; 12.CI.18.223; 12.CI.18.240; 12.CI.18.244; 12.CI.18.243; 12.CI.18.247; 12.CI.26.157; 12.CI.26.158; 12.CI.26.196; 12.CI.26.223; 12.CI.26.240; 12.CI.26.244; 12.CI.26.243; 12.CI.26.247; 12.CI.27.157; 12.CI.27.158; 12.CI.27.196; 12.CI.27.223; 12.CI.27.240; 12.CI.27.244; 12.CI.27.243; 12.CI.27.247; 12.CI.29.157; 12.CI.29.158; 12.CI.29.196; 12.CI.29.223; 12.CI.29.240; 12.CI.29.244; 12.CI.29.243; 12.CI.29.247; 12.CI.54.157; 12.CI.54.158; 12.CI.54.196; 12.CI.54.223; 12.CI.54.240; 12.CI.54.244; 12.CI.54.243; 12.CI.54.247; 12.CI.55.157; 12.CI.55.158; 12.CI.55.196; 12.CI.55.223; 12.CI.55.240; 12.CI.55.244; 12.CI.55.243; 12.CI.55.247; 12.CI.56.157; 12.CI.56.158; 12.CI.56.196; 12.CI.56.223; 12.CI.56.240; 12.CI.56.244; 12.CI.56.243; 12.CI.56.247; 12.CI.157.157; 12.CI.157.158; 12.CI.157.196; 12.CI.157.223; 12.CI.157.240; 12.CI.157.244; 12.CI.157.243; 12.CI.157.247; 12.CI.196.157; 12.CI.196.158; 12.CI.196.196; 12.CI.196.223; 12.CI.196.240; 12.CI.196.244; 12.CI.196.243; 12.CI.196.247; 12.CI.223.157; 12.CI.223.158; 12.CI.223.196; 12.CI.223.223; 12.CI.223.240; 12.CI.223.244; 12.CI.223.243; 12.CI.223.247; 12.CI.240.157; 12.CI.240.158; 12.CI.240.196; 12.CI.240.223; 12.CI.240.240; 12.CI.240.244; 12.CI.240.243; 12.CI.240.247; 12.CI.244.157; 12.CI.244.158; 12.CI.244.196; 12.CI.244.223; 12.CI.244.240; 12.CI.244.244; 12.CI.244.243; 12.CI.244.247; 12.CI.247.157; 12.CI.247.158; 12.CI.247.196; 12.CI.247.223; 12.CI.247.240; 12.CI.247.244; 12.CI.247.243; 12.CI.247.247;

12. of CO Prodrug

     12.CO.4.157; 12.CO.4.158; 12.CO.4.196; 12.CO.4.223; 12.CO.4.240; 12.CO.4.244; 12.CO.4.243; 12.CO.4.247; 12.CO.5.157; 12.CO.5.158; 12.CO.5.196; 12.CO.5.223; 12.CO.5.240; 12.CO.5.244; 12.CO.5.243; 12.CO.5.247; 12.CO.7.157; 12.CO.7.158; 12.CO.7.196; 12.CO.7.223; 12.CO.7.240; 12.CO.7.244; 12.CO.7.243; 12.CO.7.247; 12.CO.15.157; 12.CO.15.158; 12.CO.15.196; 12.CO.15.223; 12.CO.15.240; 12.CO.15.244; 12.CO.15.243; 12.CO.15.247; 12.CO.16.157; 12.CO.16.158; 12.CO.16.196; 12.CO.16.223; 12.CO.16.240; 12.CO.16.244; 12.CO.16.243; 12.CO.16.247; 12.CO.18.157; 12.CO.18.158; 12.CO.18.196; 12.CO.18.223; 12.CO.18.240; 12.CO.18.244; 12.CO.18.243; 12.CO.18.247; 12.CO.26.157; 12.CO.26.158; 12.CO.26.196; 12.CO.26.223; 12.CO.26.240; 12.CO.26.244; 12.CO.26.243; 12.CO.26.247; 12.CO.27.157; 12.CO.27.158; 12.CO.27.196; 12.CO.27.223; 12.CO.27.240; 12.CO.27.244; 12.CO.27.243; 12.CO.27.247; 12.CO.29.157; 12.CO.29.158; 12.CO.29.196; 12.CO.29.223; 12.CO.29.240; 12.CO.29.244; 12.CO.29.243; 12.CO.29.247; 12.CO.54.157; 12.CO.54.158; 12.CO.54.196; 12.CO.54.223; 12.CO.54.240; 12.CO.54.244; 12.CO.54.243; 12.CO.54.247; 12.CO.55.157; 12.CO.55.158; 12.CO.55.196; 12.CO.55.223; 12.CO.55.240; 12.CO.55.244; 12.CO.55.243; 12.CO.55.247; 12.CO.56.157; 12.CO.56.158; 12.CO.56.196; 12.CO.56.223; 12.CO.56.240; 12.CO.56.244; 12.CO.56.243; 12.CO.56.247; 12.CO.157.157; 12.CO.157.158; 12.CO.157.196; 12.CO.157.223; 12.CO.157.240; 12.CO.157.244; 12.CO.157.243; 12.CO.157.247; 12.CO.196.157; 12.CO.196.158; 12.CO.196.196; 12.CO.196.223; 12.CO.196.240; 12.CO.196.244; 12.CO.196.243; 12.CO.196.247; 12.CO.223.157; 12.CO.223.158; 12.CO.223.196; 12.CO.223.223; 12.CO.223.240; 12.CO.223.244; 12.CO.223.243; 12.CO.223.247; 12.CO.240.157; 12.CO.240.158; 12.CO.240.196; 12.CO.240.223; 12.CO.240.240; 12.CO.240.244; 12.CO.240.243; 12.CO.240.247; 12.CO.244.157; 12.CO.244.158; 12.CO.244.196; 12.CO.244.223; 12.CO.244.240; 12.CO.244.244; 12.CO.244.243; 12.CO.244.247; 12.CO.247.157; 12.CO.247.158; 12.CO.247.196; 12.CO.247.223; 12.CO.247.240; 12.CO.247.244; 12.CO.247.243; 12.CO.247.247.

13.B Prodrug

     13.B.228.228; 13.B.228.229; 13.B.228.230; 13.B.228.231; 13.B.228.236; 13.B.228.237; 13.B.228.238; 13.B.228.239; 13.B.228.154; 13.B.228.157; 13.B.228.166; 13.B.228.169; 13.B.228.172; 13.B.228.175; 13.B.228.240; 13.B.228.244; 13.B.229.228; 13.B.229.229; 13.B.229.230; 13.B.229.231; 13.B.229.236; 13.B.229.237; 13.B.229.238; 13.B.229.239; 13.B.229.154; 13.B.229.157; 13.B.229.166; 13.B.229.169; 13.B.229.172; 13.B.229.175; 13.B.229.240; 13.B.229.244; 13.B.230.228; 13.B.230.229; 13.B.230.230; 13.B.230.231; 13.B.230.236; 13.B.230.237; 13.B.230.238; 13.B.230.239; 13.B.230.154; 13.B.230.157; 13.B.230.166; 13.B.230.169; 13.B.230.172; 13.B.230.175; 13.B.230.240; 13.B.230.244; 13.B.231.228; 13.B.231.229; 13.B.231.230; 13.B.231.231; 13.B.231.236; 13.B.231.237; 13.B.231.238; 13.B.231.239; 13.B.231.154; 13.B.231.157; 13.B.231.166; 13.B.231.169; 13.B.231.172; 13.B.231.175; 13.B.231.240; 13.B.231.244; 13.B.236.228; 13.B.236.229; 13.B.236.230; 13.B.236.231; 13.B.236.236; 13.B.236.237; 13.B.236.238; 13.B.236.239; 13.B.236.154; 13.B.236.157; 13.B.236.166; 13.B.236.169; 13.B.236.172; 13.B.236.175; 13.B.236.240; 13.B.236.244; 13.B.237.228; 13.B.237.229; 13.B.237.230; 13.B.237.231; 13.B.237.236; 13.B.237.237; 13.B.237.238; 13.B.237.239; 13.B.237.154; 13.B.237.157; 13.B.237.166; 13.B.237.169; 13.B.237.172; 13.B.237.175; 13.B.237.240; 13.B.237.244; 13.B.238.228; 13.B.238.229; 13.B.238.230; 13.B.238.231; 13.B.238.236; 13.B.238.237; 13.B.238.238; 13.B.238.239; 13.B.238.154; 13.B.238.157; 13.B.238.166; 13.B.238.169; 13.B.238.172; 13.B.238.175; 13.B.238.240; 13.B.238.244; 13.B.239.228; 13.B.239.229; 13.B.239.230; 13.B.239.231; 13.B.239.236; 13.B.239.237; 13.B.239.238; 13.B.239.239; 13.B.239.154; 13.B.239.157; 13.B.239.166; 13.B.239.169; 13.B.239.172; 13.B.239.175; 13.B.239.240; 13.B.239.244; 13.B.154.228; 13.B.154.229; 13.B.154.230; 13.B.154.231; 13.B.154.236; 13.B.154.237; 13.B.154.238; 13.B.154.239; 13.B.154.154; 13.B.154.157; 13.B.154.166; 13.B.154.169; 13.B.154.172; 13.B.154.175; 13.B.154.240; 13.B.154.244; 13.B.157.228; 13.B. 157.229; 13.B.157.230; 13.B.157.231; 13.B.157.236; 13.B.157.237; 13.B.157.238; 13.B.157.239; 13.B.157.154; 13.B.157.157; 13.B.157.166; 13.B.157.169; 13.B.157.172; 13.B.157.175; 13.B.157.240; 13.B.157.244; 13.B.166.228; 13.B.166.229; 13.B.166.230; 13.B.166.231; 13.B.166.236; 13.B.166.237; 13.B.166.238; 13.B.166.239; 13.B.166.154; 13.B.166.157; 13.B.166.166; 13.B.166.169; 13.B.166.172; 13.B.166.175; 13.B.166.240; 13.B.166.244; 13.B.169.228; 13.B.169.229; 13.B.169.230; 13.B.169.231; 13.B.169.236; 13.B.169.237; 13.B.169.238; 13.B.169.239; 13.B.169.154; 13.B. 169.157; 13.B.169.166; 13.B.169.169; 13.B.169.172; 13.B.169.175; 13.B.169.240; 13.B.169.244; 13.B.172.228; 13.B.172.229; 13.B.172.230; 13.B.172.231; 13.B.172.236; 13.B.172.237; 13.B.172.238; 13.B.172.239; 13.B.172.154; 13.B.172.157; 13.B.172.166; 13.B.172.169; 13.B.172.172; 13.B.172.175; 13.B.172.240; 13.B.172.244; 13.B.175.228; 13.B.175.229; 13.B.175.230; 13.B.175.231; 13.B.175.236; 13.B.175.237; 13.B.175.238; 13.B.175.239; 13.B.175.154; 13.B.175.157; 13.B.175.166; 13.B.175.169; 13.B.175.172; 13.B.175.175; 13.B.175.240; 13.B.175.244; 13.B.240.228; 13.B.240.229; 13.B.240.230; 13.B.240.231; 13.B.240.236; 13.B.240.237; 13.B.240.238; 13.B.240.239; 13.B.240.154; 13.B.240.157; 13.B.240.166; 13.B.240.169; 13.B.240.172; 13.B.240.175; 13.B.240.240; 13.B.240.244; 13.B.244.228; 13.B.244.229; 13.B.244.230; 13.B.244.231; 13.B.244.236; 13.B.244.237; 13.B.244.238; 13.B.244.239; 13.B.244.154; 13.B.244.157; 13.B.244.166; 13.B.244.169; 13.B.244.172; 13.B.244.175; 13.B.244.240; 13.B.244.244;

13.D Prodrug

     13.D.228.228; 13.D.228.229; 13.D.228.230; 13.D.228.231; 13.D.228.236; 13.D.228.237; 13.D.228.238; 13.D.228.239; 13.D.228.154; 13.D.228.157; 13.D.228.166; 13.D.228.169; 13.D.228.172; 13.D.228.175; 13.D.228.240; 13.D.228.244; 13.D.229.228; 13.D.229.229; 13.D.229.230; 13.D.229.231; 13.D.229.236; 13.D.229.237; 13.D.229.238; 13.D.229.239; 13.D.229.154; 13.D.229.157; 13.D.229.166; 13.D.229.169; 13.D.229.172; 13.D.229.175; 13.D.229.240; 13.D.229.244; 13.D.230.228; 13.D.230.229; 13.D.230.230; 13.D.230.231; 13.D.230.236; 13.D.230.237; 13.D.230.238; 13.D.230.239; 13.D.230.154; 13.D.230.157; 13.D.230.166; 13.D.230.169; 13.D.230.172; 13.D.230.175; 13.D.230.240; 13.D.230.244; 13.D.231.228; 13.D.231.229; 13.D.231.230; 13.D.231.231; 13.D.231.236; 13.D.231.237; 13.D.231.238; 13.D.231.239; 13.D.231.154; 13.D.231.157; 13.D.231.166; 13.D.231.169; 13.D.231.172; 13.D.231.175; 13.D.231.240; 13.D.231.244; 13.D.236.228; 13.D.236.229; 13.D.236.230; 13.D.236.231; 13.D.236.236; 13.D.236.237; 13.D.236.238; 13.D.236.239; 13.D.236.154; 13.D.236.157; 13.D.236.166; 13.D.236.169; 13.D.236.172; 13.D.236.175; 13.D.236.240; 13.D.236.244; 13.D.237.228; 13.D.237.229; 13.D.237.230; 13.D.237.231; 13.D.237.236; 13.D.237.237; 13.D.237.238; 13.D.237.239; 13.D.237.154; 13.D.237.157; 13.D.237.166; 13.D.237.169; 13.D.237.172; 13.D.237.175; 13.D.237.240; 13.D.237.244; 13.D.238.228; 13.D.238.229; 13.D.238.230; 13.D.238.231; 13.D.238.236; 13.D.238.237; 13.D.238.238; 13.D.238.239; 13.D.238.154; 13.D.238.157; 13.D.238.166; 13.D.238.169; 13.D.238.172; 13.D.238.175; 13.D.238.240; 13.D.238.244; 13.D.239.228; 13.D.239.229; 13.D.239.230; 13.D.239.231; 13.D.239.236; 13.D.239.237; 13.D.239.238; 13.D.239.239; 13.D.239.154; 13.D.239.157; 13.D.239.166; 13.D.239.169; 13.D.239.172; 13.D.239.175; 13.D.239.240; 13.D.239.244; 13.D.154.228; 13.D.154.229; 13.D.154.230; 13.D.154.231; 13.D.154.236; 13.D.154.237; 13.D.154.238; 13.D.154.239; 13.D.154.154; 13.D.154.157; 13.D.154.166; 13.D.154.169; 13.D.154.172; 13.D.154.175; 13.D.154.240; 13.D.154.244; 13.D.157.228; 13.D.157.229; 13.D.157.230; 13.D.157.231; 13.D.157.236; 13.D.157.237; 13.D.157.238; 13.D.157.239; 13.D.157.154; 13.D.157.157; 13.D.157.166; 13.D.157.169; 13.D.157.172; 13.D.157.175; 13.D.157.240; 13.D.157.244; 13.D.166.228; 13.D.166.229; 13.D.166.230; 13.D.166.231; 13.D.166.236; 13.D.166.237; 13.D.166.238; 13.D.166.239; 13.D.166.154; 13.D.166.157; 13.D.166.166; 13.D.166.169; 13.D.166.172; 13.D.166.175; 13.D.166.240; 13.D.166.244; 13.D. 169.228; 13.D. 169.229; 13.D. 169.230; 13.D. 169.231; 13.D. 169.236; 13.D. 169.237; 13.D. 169.238; 13.D. 169.239; 13.D. 169.154; 13.D. 169.157; 13.D. 169.166; 13.D. 169.169; 13.D. 169.172; 13.D. 169.175; 13.D. 169.240; 13.D. 169.244; 13.D.172.228; 13.D. 172.229; 13.D.172.230; 13.D.172.231; 13.D.172.236; 13.D.172.237; 13.D.172.238; 13.D.172.239; 13.D.172.154; 13.D.172.157; 13.D.172.166; 13.D.172.169; 13.D.172.172; 13.D.172.175; 13.D.172.240; 13.D.172.244; 13.D.175.228; 13.D.175.229; 13.D.175.230; 13.D.175.231; 13.D.175.236; 13.D.175.237; 13.D.175.238; 13.D.175.239; 13.D.175.154; 13.D.175.157; 13.D.175.166; 13.D.175.169; 13.D.175.172; 13.D.175.175; 13.D.175.240; 13.D.175.244; 13.D.240.228; 13.D.240.229; 13.D.240.230; 13.D.240.231; 13.D.240.236; 13.D.240.237; 13.D.240.238; 13.D.240.239; 13.D.240.154; 13.D.240.157; 13.D.240.166; 13.D.240.169; 13.D.240.172; 13.D.240.175; 13.D.240.240; 13.D.240.244; 13.D.244.228; 13.D.244.229; 13.D.244.230; 13.D.244.231; 13.D.244.236; 13.D.244.237; 13.D.244.238; 13.D.244.239; 13.D.244.154; 13.D.244.157; 13.D.244.166; 13.D.244.169; 13.D.244.172; 13.D.244.175; 13.D.244.240; 13.D.244.244;

13.E's Prodrug

     13.E.228.228; 13.E.228.229; 13.E.228.230; 13.E.228.231; 13.E.228.236; 13.E.228.237; 13.E.228.238; 13.E.228.239; 13.E.228.154; 13.E.228.157; 13.E.228.166; 13.E.228.169; 13.E.228.172; 13.E.228.175; 13.E.228.240; 13.E.228.244; 13.E.229.228; 13.E.229.229; 13.E.229.230; 13.E.229.231; 13.E.229.236; 13.E.229.237; 13.E.229.238; 13.E.229.239; 13.E.229.154; 13.E.229.157; 13.E.229.166; 13.E.229.169; 13.E.229.172; 13.E.229.175; 13.E.229.240; 13.E.229.244; 13.E.230.228; 13.E.230.229; 13.E.230.230; 13.E.230.231; 13.E.230.236; 13.E.230.237; 13.E.230.238; 13.E.230.239; 13.E.230.154; 13.E.230.157; 13.E.230.166; 13.E.230.169; 13.E.230.172; 13.E.230.175; 13.E.230.240; 13.E.230.244; 13.E.231.228; 13.E.231.229; 13.E.231.230; 13.E.231.231; 13.E.231.236; 13.E.231.237; 13.E.231.238; 13.E.231.239; 13.E.231.154; 13.E.231.157; 13.E.231.166; 13.E.231.169; 13.E.231.172; 13.E.231.175; 13.E.231.240; 13.E.231.244; 13.E.236.228; 13.E.236.229; 13.E.236.230; 13.E.236.231; 13.E.236.236; 13.E.236.237; 13.E.236.238; 13.E.236.239; 13.E.236.154; 13.E.236.157; 13.E.236.166; 13.E.236.169; 13.E.236.172; 13.E.236.175; 13.E.236.240; 13.E.236.244; 13.E.237.228; 13.E.237.229; 13.E.237.230; 13.E.237.231; 13.E.237.236; 13.E.237.237; 13.E.237.238; 13.E.237.239; 13.E.237.154; 13.E.237.157; 13.E.237.166; 13.E.237.169; 13.E.237.172; 13.E.237.175; 13.E.237.240; 13.E.237.244; 13.E.238.228; 13.E.238.229; 13.E.238.230; 13.E.238.231; 13.E.238.236; 13.E.238.237; 13.E.238.238; 13.E.238.239; 13.E.238.154; 13.E.238.157; 13.E.238.166; 13.E.238.169; 13.E.238.172; 13.E.238.175; 13.E.238.240; 13.E.238.244; 13.E.239.228; 13.E.239.229; 13.E.239.230; 13.E.239.231; 13.E.239.236; 13.E.239.237; 13.E.239.238; 13.E.239.239; 13.E.239.154; 13.E.239.157; 13.E.239.166; 13.E.239.169; 13.E.239.172; 13.E.239.175; 13.E.239.240; 13.E.239.244; 13.E.154.228; 13.E.154.229; 13.E.154.230; 13.E.154.231; 13.E.154.236; 13.E.154.237; 13.E.154.238; 13.E.154.239; 13.E.154.154; 13.E.154.157; 13.E.154.166; 13.E.154.169; 13.E.154.172; 13.E.154.175; 13.E.154.240; 13.E.154.244; 13.E.157.228; 13.E.157.229; 13.E.157.230; 13.E.157.231; 13.E.157.236; 13.E.157.237; 13.E.157.238; 13.E.157.239; 13.E.157.154; 13.E.157.157; 13.E.157.166; 13.E.157.169; 13.E.157.172; 13.E.157.175; 13.E.157.240; 13.E.157.244; 13.E.166.228; 13.E.166.229; 13.E.166.230; 13.E.166.231; 13.E.166.236; 13.E.166.237; 13.E.166.238; 13.E.166.239; 13.E.166.154; 13.E.166.157; 13.E.166.166; 13.E.166.169; 13.E.166.172; 13.E.166.175; 13.E.166.240; 13.E.166.244; 13.E.169.228; 13.E.169.229; 13.E.169.230; 13.E.169.231; 13.E.169.236; 13.E.169.237; 13.E.169.238; 13.E.169.239; 13.E.169.154; 13.E.169.157; 13.E.169.166; 13.E.169.169; 13.E.169.172; 13.E.169.175; 13.E.169.240; 13.E.169.244; 13.E.172.228; 13.E.172.229; 13.E.172.230; 13.E.172.231; 13.E.172.236; 13.E.172.237; 13.E.172.238; 13.E.172.239; 13.E.172.154; 13.E.172.157; 13.E.172.166; 13.E.172.169; 13.E.172.172; 13.E.172.175; 13.E.172.240; 13.E.172.244; 13.E.175.228; 13.E.175.229; 13.E.175.230; 13.E.175.231; 13.E.175.236; 13.E.175.237; 13.E.175.238; 13.E.175.239; 13.E.175.154; 13.E.175.157; 13.E.175.166; 13.E.175.169; 13.E.175.172; 13.E.175.175; 13.E.175.240; 13.E.175.244; 13.E.240.228; 13.E.240.229; 13.E.240.230; 13.E.240.231; 13.E.240.236; 13.E.240.237; 13.E.240.238; 13.E.240.239; 13.E.240.154; 13.E.240.157; 13.E.240.166; 13.E.240.169; 13.E.240.172; 13.E.240.175; 13.E.240.240; 13.E.240.244; 13.E.244.228; 13.E.244.229; 13.E.244.230; 13.E.244.231; 13.E.244.236; 13.E.244.237; 13.E.244.238; 13.E.244.239; 13.E.244.154; 13.E.244.157; 13.E.244.166; 13.E.244.169; 13.E.244.172; 13.E.244.175; 13.E.244.240; 13.E.244.244;

13.G Prodrug

     13.G.228.228; 13.G.228.229; 13.G.228.230; 13.G.228.231; 13.G.228.236; 13.G.228.237; 13.G.228.238; 13.G.228.239; 13.G.228.154; 13.G. 228.157; 13.G.228.166; 13.G. 228.169; 13.G.228.172; 13.G.228.175; 13.G.228.240; 13.G.228.244; 13.G.229.228; 13.G.229.229; 13.G.229.230; 13.G.229.231; 13.G.229.236; 13.G.229.237; 13.G.229.238; 13.G.229.239; 13.G.229.154; 13.G.229.157; 13.G.229.166; 13.G.229.169; 13.G.229.172; 13.G.229.175; 13.G.229.240; 13.G.229.244; 13.G.230.228; 13.G.230.229; 13.G.230.230; 13.G.230.231; 13.G.230.236; 13.G.230.237; 13.G.230.238; 13.G.230.239; 13.G.230.154; 13.G.230.157; 13.G.230.166; 13.G.230.169; 13.G.230.172; 13.G.230.175; 13.G.230.240; 13.G.230.244; 13.G.231.228; 13.G.231.229; 13.G.231.230; 13.G.231.231; 13.G.231.236; 13.G.231.237; 13.G.231.238; 13.G.231.239; 13.G.231.154; 13.G.231.157; 13.G.231.166; 13.G.231.169; 13.G.231.172; 13.G.231.175; 13.G.231.240; 13.G.231.244; 13.G.236.228; 13.G. 236.229; 13.G.236.230; 13.G.236.231; 13.G.236.236; 13.G.236.237; 13.G.236.238; 13.G.236.239; 13.G.236.154; 13.G.236.157; 13.G.236.166; 13.G.236.169; 13.G.236.172; 13.G.236.175; 13.G.236.240; 13.G.236.244; 13.G.237.228; 13.G. 237.229; 13.G.237.230; 13.G.237.231; 13.G.237.236; 13.G.237.237; 13.G.237.238; 13.G.237.239; 13.G.237.154; 13.G.237.157; 13.G.237.166; 13.G. 237.169; 13.G.237.172; 13.G.237.175; 13.G.237.240; 13.G.237.244; 13.G.238.228; 13.G.238.229; 13.G.238.230; 13.G.238.231; 13.G.238.236; 13.G.238.237; 13.G.238.238; 13.G.238.239; 13.G.238.154; 13.G.238.157; 13.G.238.166; 13.G.238.169; 13.G.238.172; 13.G.238.175; 13.G.238.240; 13.G.238.244; 13.G.239.228; 13.G.239.229; 13.G.239.230; 13.G.239.231; 13.G.239.236; 13.G.239.237; 13.G.239.238; 13.G.239.239; 13.G.239.154; 13.G.239.157; 13.G.239.166; 13.G.239.169; 13.G.239.172; 13.G.239.175; 13.G.239.240; 13.G.239.244; 13.G.154.228; 13.G.154.229; 13.G.154.230; 13.G.154.231; 13.G.154.236; 13.G.154.237; 13.G.154.238; 13.G.154.239; 13.G.154.154; 13.G.154.157; 13.G.154.166; 13.G.154.169; 13.G.154.172; 13.G.154.175; 13.G.154.240; 13.G.154.244; 13.G.157.228; 13.G. 157.229; 13.G.157.230; 13.G.157.231; 13.G.157.236; 13.G.157.237; 13.G.157.238; 13.G.157.239; 13.G.157.154; 13.G.157.157; 13.G.157.166; 13.G.157.169; 13.G.157.172; 13.G.157.175; 13.G.157.240; 13.G.157.244; 13.G.166.228; 13.G.166.229; 13.G.166.230; 13.G.166.231; 13.G.166.236; 13.G.166.237; 13.G.166.238; 13.G.166.239; 13.G.166.154; 13.G.166.157; 13.G.166.166; 13.G.166.169; 13.G.166.172; 13.G.166.175; 13.G.166.240; 13.G.166.244; 13.G. 169.228; 13.G.169.229; 13.G. 169.230; 13.G. 169.231; 13.G.169.236; 13.G. 169.237; 13.G.169.238; 13.G. 169.239; 13.G.169.154; 13.G. 169.157; 13.G. 169.166; 13.G.169.169; 13.G.169.172; 13.G.169.175; 13.G.169.240; 13.G.169.244; 13.G.172.228; 13.G. 172.229; 13.G.172.230; 13.G.172.231; 13.G.172.236; 13.G.172.237; 13.G.172.238; 13.G.172.239; 13.G.172.154; 13.G.172.157; 13.G.172.166; 13.G.172.169; 13.G.172.172; 13.G.172.175; 13.G.172.240; 13.G.172.244; 13.G.175.228; 13.G. 175.229; 13.G.175.230; 13.G.175.231; 13.G.175.236; 13.G.175.237; 13.G.175.238; 13.G.175.239; 13.G.175.154; 13.G.175.157; 13.G.175.166; 13.G.175.169; 13.G.175.172; 13.G.175.175; 13.G.175.240; 13.G.175.244; 13.G.240.228; 13.G.240.229; 13.G.240.230; 13.G.240.231; 13.G.240.236; 13.G.240.237; 13.G.240.238; 13.G.240.239; 13.G.240.154; 13.G.240.157; 13.G.240.166; 13.G.240.169; 13.G.240.172; 13.G.240.175; 13.G.240.240; 13.G.240.244; 13.G.244.228; 13.G.244.229; 13.G.244.230; 13.G.244.231; 13.G.244.236; 13.G.244.237; 13.G.244.238; 13.G.244.239; 13.G.244.154; 13.G.244.157; 13.G.244.166; 13.G.244.169; 13.G.244.172; 13.G.244.175; 13.G.244.240; 13.G.244.244;

13.I's Prodrug

13.I.228.228; 13.I.228.229; 13.I.228.230; 13.I.228.231; 13.I.228.236; 13.I.228.237; 13.I.228.238; 13.I.228.239; 13.I.228.154; 13.I.228.157; 13.I.228.166; 13.I.228.169; 13.I.228.172; 13.I.228.175; 13.I.228.240; 13.I.228.244; 13.I.229.228; 13.I.229.229; 13.I.229.230; 13.I.229.231; 13.I.229.236; 13.I.229.237; 13.I.229.238; 13.I.229.239; 13.I.229.154; 13.I.229.157; 13.I.229.166; 13.I.229.169; 13.I.229.172; 13.I.229.175; 13.I.229.240; 13.I.229.244; 13.I.230.228; 13.I.230.229; 13.I.230.230; 13.I.230.231; 13.I.230.236; 13.I.230.237; 13.I.230.238; 13.I.230.239; 13.I.230.154; 13.I.230.157; 13.I.230.166; 13.I.230.169; 13.I.230.172; 13.I.230.175; 13.I.230.240; 13.I.230.244; 13.I.231.228; 13.I.231.229; 13.I.231.230; 13.I.231.231; 13.I.231.236; 13.I.231.237; 13.I.231.238; 13.I.231.239; 13.I.231.154; 13.I.231.157; 13.I.231.166; 13.I.231.169; 13.I.231.172; 13.I.231.175; 13.I.231.240; 13.I.231.244; 13.I.236.228; 13.I.236.229; 13.I.236.230; 13.I.236.231; 13.I.236.236; 13.I.236.237; 13.I.236.238; 13.I.236.239; 13.I.236.154; 13.I.236.157; 13.I.236.166; 13.I.236.169; 13.I.236.172; 13.I.236.175; 13.I.236.240; 13.I.236.244; 13.I.237.228; 13.I.237.229; 13.I.237.230; 13.I.237.231; 13.I.237.236; 13.I.237.237; 13.I.237.238; 13.I.237.239; 13.I.237.154; 13.I.237.157; 13.I.237.166; 13.I.237.169; 13.I.237.172; 13.I.237.175; 13.I.237.240; 13.I.237.244; 13.I.238.228; 13.I.238.229; 13.I.238.230; 13.I.238.231; 13.I.238.236; 13.I.238.237; 13.I.238.238; 13.I.238.239; 13.I.238.154; 13.I.238.157; 13.I.238.166; 13.I.238.169; 13.I.238.172; 13.I.238.175; 13.I.238.240; 13.I.238.244; 13.I.239.228; 13.I.239.229; 13.I.239.230; 13.I.239.231; 13.I.239.236; 13.I.239.237; 13.I.239.238; 13.I.239.239; 13.I.239.154; 13.I.239.157; 13.I.239.166; 13.I.239.169; 13.I.239.172; 13.I.239.175; 13.I.239.240; 13.I.239.244; 13.I.154.228; 13.I.154.229; 13.I.154.230; 13.I.154.231; 13.I.154.236; 13.I.154.237; 13.I.154.238; 13.I.154.239; 13.I.154.154; 13.I.154.157; 13.I.154.166; 13.I.154.169; 13.I.154.172; 13.I.154.175; 13.I.154.240; 13.I.154.244; 13.I.157.228; 13.I.157.229; 13.I.157.230; 13.I.157.231; 13.I.157.236; 13.I.157.237; 13.I.157.238; 13.I.157.239; 13.I.157.154; 13.I.157.157; 13.I.157.166; 13.I.157.169; 13.I.157.172; 13.I.157.175; 13.I.157.240; 13.I.157.244; 13.I.166.228; 13.I.166.229; 13.I.166.230; 13.I.166.231; 13.I.166.236; 13.I.166.237; 13.I.166.238; 13.I.166.239; 13.I.166.154; 13.I.166.157; 13.I.166.166; 13.I.166.169; 13.I.166.172; 13.I.166.175; 13.I.166.240; 13.I.166.244; 13.I.169.228; 13.I.169.229; 13.I.169.230; 13.I.169.231; 13.I.169.236; 13.I.169.237; 13.I.169.238; 13.I.169.239; 13.I.169.154; 13.I.169.157; 13.I.169.166; 13.I.169.169; 13.I.169.172; 13.I.169.175; 13.I.169.240; 13.I.169.244; 13.I.172.228; 13.I.172.229; 13.I.172.230; 13.I.172.231; 13.I.172.236; 13.I.172.237; 13.I.172.238; 13.I.172.239; 13.I.172.154; 13.I.172.157; 13.I.172.166; 13.I.172.169; 13.I.172.172; 13.I.172.175; 13.I.172.240; 13.I.172.244; 13.I.175.228; 13.I.175.229; 13.I.175.230; 13.I.175.231; 13.I.175.236; 13.I.175.237; 13.I.175.238; 13.I.175.239; 13.I.175.154; 13.I.175.157; 13.I.175.166; 13.I.175.169; 13.I.175.172; 13.I.175.175; 13.I.175.240; 13.I.175.244; 13.I.240.228; 13.I.240.229; 13.I.240.230; 13.I.240.231; 13.I.240.236; 13.I.240.237; 13.I.240.238; 13.I.240.239; 13.I.240.154; 13.I.240.157; 13.I.240.166; 13.I.240.169; 13.I.240.172; 13.I.240.175; 13.I.240.240; 13.I.240.244; 13.I.244.228; 13.I.244.229; 13.I.244.230; 13.I.244.231; 13.I.244.236; 13.I.244.237; 13.I.244.238; 13.I.244.239; 13.I.244.154; 13.I.244.157; 13.I.244.166; 13.I.244.169; 13.I.244.172; 13.I.244.175; 13.I.244.240; 13.I.244.244;

13.J's Prodrug

     13.J.228.228; 13.J.228.229; 13.J.228.230; 13.J.228.231; 13.J.228.236; 13.J.228.237; 13.J.228.238; 13.J.228.239; 13.J.228.154; 13.J.228.157; 13.J.228.166; 13.J.228.169; 13.J.228.172; 13.J.228.175; 13.J.228.240; 13.J.228.244; 13.J.229.228; 13.J.229.229; 13.J.229.230; 13.J.229.231; 13.J.229.236; 13.J.229.237; 13.J.229.238; 13.J.229.239; 13.J.229.154; 13.J.229.157; 13.J.229.166; 13.J.229.169; 13.J.229.172; 13.J.229.175; 13.J.229.240; 13.J.229.244; 13.J.230.228; 13.J.230.229; 13.J.230.230; 13.J.230.231; 13.J.230.236; 13.J.230.237; 13.J.230.238; 13.J.230.239; 13.J.230.154; 13.J.230.157; 13.J.230.166; 13.J.230.169; 13.J.230.172; 13.J.230.175; 13.J.230.240; 13.J.230.244; 13.J.231.228; 13.J.231.229; 13.J.231.230; 13.J.231.231; 13.J.231.236; 13.J.231.237; 13.J.231.238; 13.J.231.239; 13.J.231.154; 13.J.231.157; 13.J.231.166; 13.J.231.169; 13.J.231.172; 13.J.231.175; 13.J.231.240; 13.J.231.244; 13.J.236.228; 13.J.236.229; 13.J.236.230; 13.J.236.231; 13.J.236.236; 13.J.236.237; 13.J.236.238; 13.J.236.239; 13.J.236.154; 13.J.236.157; 13.J.236.166; 13.J.236.169; 13.J.236.172; 13.J.236.175; 13.J.236.240; 13.J.236.244; 13.J.237.228; 13.J.237.229; 13.J.237.230; 13.J.237.231; 13.J.237.236; 13.J.237.237; 13.J.237.238; 13.J.237.239; 13.J.237.154; 13.J.237.157; 13.J.237.166; 13.J.237.169; 13.J.237.172; 13.J.237.175; 13.J.237.240; 13.J.237.244; 13.J.238.228; 13.J.238.229; 13.J.238.230; 13.J.238.231; 13.J.238.236; 13.J.238.237; 13.J.238.238; 13.J.238.239; 13.J.238.154; 13.J.238.157; 13.J.238.166; 13.J.238.169; 13.J.238.172; 13.J.238.175; 13.J.238.240; 13.J.238.244; 13.J.239.228; 13.J.239.229; 13.J.239.230; 13.J.239.231; 13.J.239.236; 13.J.239.237; 13.J.239.238; 13.J.239.239; 13.J.239.154; 13.J.239.157; 13.J.239.166; 13.J.239.169; 13.J.239.172; 13.J.239.175; 13.J.239.240; 13.J.239.244; 13.J.154.228; 13.J.154.229; 13.J.154.230; 13.J.154.231; 13.J.154.236; 13.J.154.237; 13.J.154.238; 13.J.154.239; 13.J.154.154; 13.J.154.157; 13.J.154.166; 13.J.154.169; 13.J.154.172; 13.J.154.175; 13.J.154.240; 13.J.154.244; 13.J.157.228; 13.J.157.229; 13.J.157.230; 13.J.157.231; 13.J.157.236; 13.J.157.237; 13.J.157.238; 13.J.157.239; 13.J.157.154; 13.J.157.157; 13.J.157.166; 13.J.157.169; 13.J.157.172; 13.J.157.175; 13.J.157.240; 13.J.157.244; 13.J.166.228; 13.J.166.229; 13.J.166.230; 13.J.166.231; 13.J.166.236; 13.J.166.237; 13.J.166.238; 13.J.166.239; 13.J.166.154; 13.J.166.157; 13.J.166.166; 13.J.166.169; 13.J.166.172; 13.J.166.175; 13.J.166.240; 13.J.166.244; 13.J. 169.228; 13.J.169.229; 13.J. 169.230; 13.J. 169.231; 13.J. 169.236; 13.J. 169.237; 13.J. 169.238; 13.J. 169.239; 13.J. 169.154; 13.J. 169.157; 13.J. 169.166; 13.J. 169.169; 13.J. 169.172; 13.J. 169.175; 13.J. 169.240; 13.J. 169.244; 13.J.172.228; 13.J.172.229; 13.J.172.230; 13.J.172.231; 13.J.172.236; 13.J.172.237; 13.J.172.238; 13.J.172.239; 13.J.172.154; 13.J.172.157; 13.J.172.166; 13.J.172.169; 13.J.172.172; 13.J.172.175; 13.J.172.240; 13.J.172.244; 13.J.175.228; 13.J.175.229; 13.J.175.230; 13.J.175.231; 13.J.175.236; 13.J.175.237; 13.J.175.238; 13.J.175.239; 13.J.175.154; 13.J.175.157; 13.J.175.166; 13.J.175.169; 13.J.175.172; 13.J.175.175; 13.J.175.240; 13.J.175.244; 13.J.240.228; 13.J.240.229; 13.J.240.230; 13.J.240.231; 13.J.240.236; 13.J.240.237; 13.J.240.238; 13.J.240.239; 13.J.240.154; 13.J.240.157; 13.J.240.166; 13.J.240.169; 13.J.240.172; 13.J.240.175; 13.J.240.240; 13.J.240.244; 13.J.244.228; 13.J.244.229; 13.J.244.230; 13.J.244.231; 13.J.244.236; 13.J.244.237; 13.J.244.238; 13.J.244.239; 13.J.244.154; 13.J.244.157; 13.J.244.166; 13.J.244.169; 13.J.244.172; 13.J.244.175; 13.J.244.240; 13.J.244.244;

13.L Prodrug

     13.L. 228.228; 13.L. 228.229; 13.L. 228.230; 13.L. 228.231; 13.L. 228.236; 13.L. 228.237; 13.L. 228.238; 13.L. 228.239; 13.L. 228.154; 13.L. 228.157; 13.L. 228.166; 13.L. 228.169; 13.L. 228.172; 13.L. 228.175; 13.L. 228.240; 13.L. 228.244; 13.L.229.228; 13.L.229.229; 13.L.229.230; 13.L.229.231; 13.L.229.236; 13.L.229.237; 13.L.229.238; 13.L.229.239; 13.L.229.154; 13.L.229.157; 13.L.229.166; 13.L.229.169; 13.L.229.172; 13.L.229.175; 13.L.229.240; 13.L.229.244; 13.L.230.228; 13.L. 230.229; 13.L.230.230; 13.L.230.231; 13.L.230.236; 13.L.230.237; 13.L.230.238; 13.L.230.239; 13.L.230.154; 13.L.230.157; 13.L.230.166; 13.L.230.169; 13.L.230.172; 13.L.230.175; 13.L.230.240; 13.L.230.244; 13.L.231.228; 13.L. 231.229; 13.L.231.230; 13.L.231.231; 13.L.231.236; 13.L.231.237; 13.L.231.238; 13.L.231.239; 13.L.231.154; 13.L.231.157; 13.L.231.166; 13.L.231.169; 13.L.231.172; 13.L.231.175; 13.L.231.240; 13.L.231.244; 13.L. 236.228; 13.L. 236.229; 13.L. 236.230; 13.L.236.231; 13.L.236.236; 13.L. 236.237; 13.L.236.238; 13.L.236.239; 13.L.236.154; 13.L. 236.157; 13.L. 236.166; 13.L. 236.169; 13.L.236.172; 13.L.236.175; 13.L.236.240; 13.L.236.244; 13.L. 237.228; 13.L. 237.229; 13.L. 237.230; 13.L. 237.231; 13.L. 237.236; 13.L. 237.237; 13.L. 237.238; 13.L. 237.239; 13.L. 237.154; 13.L. 237.157; 13.L. 237.166; 13.L. 237.169; 13.L. 237.172; 13.L. 237.175; 13.L. 237.240; 13.L. 237.244; 13.L. 238.228; 13.L.238.229; 13.L.238.230; 13.L.238.231; 13.L.238.236; 13.L.238.237; 13.L.238.238; 13.L.238.239; 13.L.238.154; 13.L.238.157; 13.L. 238.166; 13.L.238.169; 13.L.238.172; 13.L.238.175; 13.L.238.240; 13.L.238.244; 13.L.239.228; 13.L.239.229; 13.L.239.230; 13.L.239.231; 13.L.239.236; 13.L.239.237; 13.L.239.238; 13.L.239.239; 13.L.239.154; 13.L.239.157; 13.L.239.166; 13.L.239.169; 13.L.239.172; 13.L.239.175; 13.L.239.240; 13.L.239.244; 13.L. 154.228; 13.L. 154.229; 13.L. 154.230; 13.L. 154.231; 13.L. 154.236; 13.L. 154.237; 13.L. 154.238; 13.L. 154.239; 13.L. 154.154; 13.L. 154.157; 13.L. 154.166; 13.L. 154.169; 13.L. 154.172; 13.L. 154.175; 13.L.154.240; 13.L. 154.244; 13.L. 157.228; 13.L. 157.229; 13.L.157.230; 13.L.157.231; 13.L.157.236; 13.L. 157.237; 13.L.157.238; 13.L.157.239; 13.L.157.154; 13.L. 157.157; 13.L. 157.166; 13.L. 157.169; 13.L.157.172; 13.L.157.175; 13.L.157.240; 13.L.157.244; 13.L. 166.228; 13.L. 166.229; 13.L. 166.230; 13.L. 166.231; 13.L. 166.236; 13.L. 166.237; 13.L. 166.238; 13.L. 166.239; 13.L. 166.154; 13.L. 166.157; 13.L. 166.166; 13.L. 166.169; 13.L. 166.172; 13.L. 166.175; 13.L. 166.240; 13.L. 166.244; 13.L. 169.228; 13.L. 169.229; 13.L. 169.230; 13.L. 169.231; 13.L. 169.236; 13.L. 169.237; 13.L. 169.238; 13.L. 169.239; 13.L. 169.154; 13.L. 169.157; 13.L. 169.166; 13.L. 169.169; 13.L. 169.172; 13.L. 169.175; 13.L. 169.240; 13.L. 169.244; 13.L. 172.228; 13.L. 172.229; 13.L. 172.230; 13.L. 172.231; 13.L. 172.236; 13.L. 172.237; 13.L. 172.238; 13.L. 172.239; 13.L. 172.154; 13.L. 172.157; 13.L. 172.166; 13.L. 172.169; 13.L. 172.172; 13.L. 172.175; 13.L. 172.240; 13.L. 172.244; 13.L. 175.228; 13.L. 175.229; 13.L. 175.230; 13.L. 175.231; 13.L. 175.236; 13.L. 175.237; 13.L. 175.238; 13.L. 175.239; 13.L. 175.154; 13.L. 175.157; 13.L. 175.166; 13.L. 175.169; 13.L. 175.172; 13.L. 175.175; 13.L. 175.240; 13.L. 175.244; 13.L.240.228; 13.L.240.229; 13.L.240.230; 13.L.240.231; 13.L.240.236; 13.L.240.237; 13.L.240.238; 13.L.240.239; 13.L.240.154; 13.L.240.157; 13.L.240.166; 13.L.240.169; 13.L.240.172; 13.L.240.175; 13.L.240.240; 13.L.240.244; 13.L.244.228; 13.L.244.229; 13.L.244.230; 13.L.244.231; 13.L.244.236; 13.L.244.237; 13.L.244.238; 13.L.244.239; 13.L.244.154; 13.L.244.157; 13.L.244.166; 13.L.244.169; 13.L.244.172; 13.L.244.175; 13.L.244.240; 13.L.244.244;

13.O's Prodrug

     13.O.228.228; 13.O.228.229; 13.O.228.230; 13.O.228.231; 13.O.228.236; 13.O.228.237; 13.O.228.238; 13.O.228.239; 13.O.228.154; 13.O.228.157; 13.O.228.166; 13.O.228.169; 13.O.228.172; 13.O.228.175; 13.O.228.240; 13.O.228.244; 13.O.229.228; 13.O.229.229; 13.O.229.230; 13.O.229.231; 13.O.229.236; 13.O.229.237; 13.O.229.238; 13.O.229.239; 13.O.229.154; 13.O.229.157; 13.O.229.166; 13.O.229.169; 13.O.229.172; 13.O.229.175; 13.O.229.240; 13.O.229.244; 13.O.230.228; 13.O.230.229; 13.O.230.230; 13.O.230.231; 13.O.230.236; 13.O.230.237; 13.O.230.238; 13.O.230.239; 13.O.230.154; 13.O.230.157; 13.O.230.166; 13.O.230.169; 13.O.230.172; 13.O.230.175; 13.O.230.240; 13.O.230.244; 13.O.231.228; 13.O.231.229; 13.O.231.230; 13.O.231.231; 13.O.231.236; 13.O.231.237; 13.O.231.238; 13.O.231.239; 13.O.231.154; 13.O.231.157; 13.O.231.166; 13.O.231.169; 13.O.231.172; 13.O.231.175; 13.O.231.240; 13.O.231.244; 13.O.236.228; 13.O.236.229; 13.O.236.230; 13.O.236.231; 13.O.236.236; 13.O.236.237; 13.O.236.238; 13.O.236.239; 13.O.236.154; 13.O.236.157; 13.O.236.166; 13.O.236.169; 13.O.236.172; 13.O.236.175; 13.O.236.240; 13.O.236.244; 13.O.237.228; 13.O.237.229; 13.O.237.230; 13.O.237.231; 13.O.237.236; 13.O.237.237; 13.O.237.238; 13.O.237.239; 13.O.237.154; 13.O.237.157; 13.O.237.166; 13.O.237.169; 13.O.237.172; 13.O.237.175; 13.O.237.240; 13.O.237.244; 13.O.238.228; 13.O.238.229; 13.O.238.230; 13.O.238.231; 13.O.238.236; 13.O.238.237; 13.O.238.238; 13.O.238.239; 13.O.238.154; 13.O.238.157; 13.O.238.166; 13.O.238.169; 13.O.238.172; 13.O.238.175; 13.O.238.240; 13.O.238.244; 13.O.239.228; 13.O.239.229; 13.O.239.230; 13.O.239.231; 13.O.239.236; 13.O.239.237; 13.O.239.238; 13.O.239.239; 13.O.239.154; 13.O.239.157; 13.O.239.166; 13.O.239.169; 13.O.239.172; 13.O.239.175; 13.O.239.240; 13.O.239.244; 13.O.154.228; 13.O.154.229; 13.O.154.230; 13.O.154.231; 13.O.154.236; 13.O.154.237; 13.O.154.238; 13.O.154.239; 13.O.154.154; 13.O.154.157; 13.O.154.166; 13.O.154.169; 13.O.154.172; 13.O.154.175; 13.O.154.240; 13.O.154.244; 13.O.157.228; 13.O.157.229; 13.O.157.230; 13.O.157.231; 13.O.157.236; 13.O.157.237; 13.O.157.238; 13.O.157.239; 13.O.157.154; 13.O.157.157; 13.O.157.166; 13.O.157.169; 13.O.157.172; 13.O.157.175; 13.O.157.240; 13.O.157.244; 13.O.166.228; 13.O.166.229; 13.O.166.230; 13.O.166.231; 13.O.166.236; 13.O.166.237; 13.O.166.238; 13.O.166.239; 13.O.166.154; 13.O.166.157; 13.O.166.166; 13.O.166.169; 13.O.166.172; 13.O.166.175; 13.O.166.240; 13.O.166.244; 13.O.169.228; 13.O.169.229; 13.O.169.230; 13.O.169.231; 13.O.169.236; 13.O.169.237; 13.O.169.238; 13.O.169.239; 13.O.169.154; 13.O.169.157; 13.O.169.166; 13.O.169.169; 13.O.169.172; 13.O.169.175; 13.O.169.240; 13.O.169.244; 13.O.172.228; 13.O.172.229; 13.O.172.230; 13.O.172.231; 13.O.172.236; 13.O.172.237; 13.O.172.238; 13.O.172.239; 13.O.172.154; 13.O.172.157; 13.O.172.166; 13.O.172.169; 13.O.172.172; 13.O.172.175; 13.O.172.240; 13.O.172.244; 13.O.175.228; 13.O.175.229; 13.O.175.230; 13.O.175.231; 13.O.175.236; 13.O.175.237; 13.O.175.238; 13.O.175.239; 13.O.175.154; 13.O.175.157; 13.O.175.166; 13.O.175.169; 13.O.175.172; 13.O.175.175; 13.O.175.240; 13.O.175.244; 13.O.240.228; 13.O.240.229; 13.O.240.230; 13.O.240.231; 13.O.240.236; 13.O.240.237; 13.O.240.238; 13.O.240.239; 13.O.240.154; 13.O.240.157; 13.O.240.166; 13.O.240.169; 13.O.240.172; 13.O.240.175; 13.O.240.240; 13.O.240.244; 13.O.244.228; 13.O.244.229; 13.O.244.230; 13.O.244.231; 13.O.244.236; 13.O.244.237; 13.O.244.238; 13.O.244.239; 13.O.244.154; 13.O.244.157; 13.O.244.166; 13.O.244.169; 13.O.244.172; 13.O.244.175; 13.O.244.240; 13.O.244.244;

13.P Prodrug

     13.P. 228.228; 13.P. 228.229; 13.P. 228.230; 13.P. 228.231; 13.P. 228.236; 13.P. 228.237; 13.P. 228.238; 13.P. 228.239; 13.P. 228.154; 13.P. 228.157; 13.P. 228.166; 13.P. 228.169; 13.P. 228.172; 13.P. 228.175; 13.P. 228.240; 13.P. 228.244; 13.P.229.228; 13.P.229.229; 13.P.229.230; 13.P.229.231; 13.P.229.236; 13.P.229.237; 13.P.229.238; 13.P.229.239; 13.P.229.154; 13.P.229.157; 13.P.229.166; 13.P.229.169; 13.P.229.172; 13.P.229.175; 13.P.229.240; 13.P.229.244; 13.P.230.228; 13.P.230.229; 13.P.230.230; 13.P.230.231; 13.P.230.236; 13.P.230.237; 13.P.230.238; 13.P.230.239; 13.P.230.154; 13.P.230.157; 13.P.230.166; 13.P.230.169; 13.P.230.172; 13.P.230.175; 13.P.230.240; 13.P.230.244; 13.P.231.228; 13.P.231.229; 13.P.231.230; 13.P.231.231; 13.P.231.236; 13.P.231.237; 13.P.231.238; 13.P.231.239; 13.P.231.154; 13.P.231.157; 13.P.231.166; 13.P.231.169; 13.P.231.172; 13.P.231.175; 13.P.231.240; 13.P.231.244; 13.P.236.228; 13.P.236.229; 13.P.236.230; 13.P.236.231; 13.P.236.236; 13.P.236.237; 13.P.236.238; 13.P.236.239; 13.P.236.154; 13.P.236.157; 13.P.236.166; 13.P.236.169; 13.P.236.172; 13.P.236.175; 13.P.236.240; 13.P.236.244; 13.P.237.228; 13.P.237.229; 13.P.237.230; 13.P.237.231; 13.P.237.236; 13.P.237.237; 13.P.237.238; 13.P.237.239; 13.P. 237.154; 13.P. 237.157; 13.P.237.166; 13.P.237.169; 13.P.237.172; 13.P.237.175; 13.P.237.240; 13.P.237.244; 13.P.238.228; 13.P.238.229; 13.P.238.230; 13.P.238.231; 13.P.238.236; 13.P.238.237; 13.P.238.238; 13.P.238.239; 13.P.238.154; 13.P.238.157; 13.P.238.166; 13.P.238.169; 13.P.238.172; 13.P.238.175; 13.P.238.240; 13.P.238.244; 13.P.239.228; 13.P.239.229; 13.P.239.230; 13.P.239.231; 13.P.239.236; 13.P.239.237; 13.P.239.238; 13.P.239.239; 13.P.239.154; 13.P.239.157; 13.P.239.166; 13.P.239.169; 13.P.239.172; 13.P.239.175; 13.P.239.240; 13.P.239.244; 13.P.154.228; 13.P.154.229; 13.P.154.230; 13.P.154.231; 13.P.154.236; 13.P.154.237; 13.P.154.238; 13.P.154.239; 13.P.154.154; 13.P.154.157; 13.P.154.166; 13.P.154.169; 13.P.154.172; 13.P.154.175; 13.P.154.240; 13.P.154.244; 13.P.157.228; 13.P. 157.229; 13.P.157.230; 13.P.157.231; 13.P.157.236; 13.P.157.237; 13.P.157.238; 13.P.157.239; 13.P.157.154; 13.P.157.157; 13.P.157.166; 13.P.157.169; 13.P.157.172; 13.P.157.175; 13.P.157.240; 13.P.157.244; 13.P.166.228; 13.P. 166.229; 13.P.166.230; 13.P.166.231; 13.P.166.236; 13.P.166.237; 13.P.166.238; 13.P.166.239; 13.P.166.154; 13.P.166.157; 13.P.166.166; 13.P.166.169; 13.P.166.172; 13.P.166.175; 13.P.166.240; 13.P.166.244; 13.P. 169.228; 13.P. 169.229; 13.P. 169.230; 13.P. 169.231; 13.P. 169.236; 13.P. 169.237; 13.P. 169.238; 13.P. 169.239; 13.P. 169.154; 13.P. 169.157; 13.P. 169.166; 13.P. 169.169; 13.P. 169.172; 13.P. 169.175; 13.P. 169.240; 13.P. 169.244; 13.P. 172.228; 13.P. 172.229; 13.P. 172.230; 13.P.172.231; 13.P.172.236; 13.P. 172.237; 13.P.172.238; 13.P.172.239; 13.P.172.154; 13.P. 172.157; 13.P. 172.166; 13.P.172.169; 13.P.172.172; 13.P.172.175; 13.P.172.240; 13.P. 172.244; 13.P.175.228; 13.P. 175.229; 13.P.175.230; 13.P.175.231; 13.P.175.236; 13.P.175.237; 13.P.175.238; 13.P.175.239; 13.P.175.154; 13.P.175.157; 13.P.175.166; 13.P.175.169; 13.P.175.172; 13.P.175.175; 13.P.175.240; 13.P.175.244; 13.P.240.228; 13.P.240.229; 13.P.240.230; 13.P.240.231; 13.P.240.236; 13.P.240.237; 13.P.240.238; 13.P.240.239; 13.P.240.154; 13.P.240.157; 13.P.240.166; 13.P.240.169; 13.P.240.172; 13.P.240.175; 13.P.240.240; 13.P.240.244; 13.P.244.228; 13.P.244.229; 13.P.244.230; 13.P.244.231; 13.P.244.236; 13.P.244.237; 13.P.244.238; 13.P.244.239; 13.P.244.154; 13.P.244.157; 13.P.244.166; 13.P.244.169; 13.P.244.172; 13.P.244.175; 13.P.244.240; 13.P.244.244;

13.U's Prodrug

     13.U.228.228; 13.U.228.229; 13.U.228.230; 13.U.228.231; 13.U.228.236; 13.U.228.237; 13.U.228.238; 13.U.228.239; 13.U.228.154; 13.U.228.157; 13.U.228.166; 13.U.228.169; 13.U.228.172; 13.U.228.175; 13.U.228.240; 13.U.228.244; 13.U.229.228; 13.U.229.229; 13.U.229.230; 13.U.229.231; 13.U.229.236; 13.U.229.237; 13.U.229.238; 13.U.229.239; 13.U.229.154; 13.U.229.157; 13.U.229.166; 13.U.229.169; 13.U.229.172; 13.U.229.175; 13.U.229.240; 13.U.229.244; 13.U.230.228; 13.U.230.229; 13.U.230.230; 13.U.230.231; 13.U.230.236; 13.U.230.237; 13.U.230.238; 13.U.230.239; 13.U.230.154; 13.U.230.157; 13.U.230.166; 13.U.230.169; 13.U.230.172; 13.U.230.175; 13.U.230.240; 13.U.230.244; 13.U.231.228; 13.U.231.229; 13.U.231.230; 13.U.231.231; 13.U.231.236; 13.U.231.237; 13.U.231.238; 13.U.231.239; 13.U.231.154; 13.U.231.157; 13.U.231.166; 13.U.231.169; 13.U.231.172; 13.U.231.175; 13.U.231.240; 13.U.231.244; 13.U.236.228; 13.U.236.229; 13.U.236.230; 13.U.236.231; 13.U.236.236; 13.U.236.237; 13.U.236.238; 13.U.236.239; 13.U.236.154; 13.U.236.157; 13.U.236.166; 13.U.236.169; 13.U.236.172; 13.U.236.175; 13.U.236.240; 13.U.236.244; 13.U.237.228; 13.U.237.229; 13.U.237.230; 13.U.237.231; 13.U.237.236; 13.U.237.237; 13.U.237.238; 13.U.237.239; 13.U.237.154; 13.U.237.157; 13.U.237.166; 13.U.237.169; 13.U.237.172; 13.U.237.175; 13.U.237.240; 13.U.237.244; 13.U.238.228; 13.U.238.229; 13.U.238.230; 13.U.238.231; 13.U.238.236; 13.U.238.237; 13.U.238.238; 13.U.238.239; 13.U.238.154; 13.U.238.157; 13.U.238.166; 13.U.238.169; 13.U.238.172; 13.U.238.175; 13.U.238.240; 13.U.238.244; 13.U.239.228; 13.U.239.229; 13.U.239.230; 13.U.239.231; 13.U.239.236; 13.U.239.237; 13.U.239.238; 13.U.239.239; 13.U.239.154; 13.U.239.157; 13.U.239.166; 13.U.239.169; 13.U.239.172; 13.U.239.175; 13.U.239.240; 13.U.239.244; 13.U.154.228; 13.U.154.229; 13.U.154.230; 13.U.154.231; 13.U.154.236; 13.U.154.237; 13.U.154.238; 13.U.154.239; 13.U.154.154; 13.U.154.157; 13.U.154.166; 13.U.154.169; 13.U.154.172; 13.U.154.175; 13.U.154.240; 13.U.154.244; 13.U.157.228; 13.U.157.229; 13.U.157.230; 13.U.157.231; 13.U.157.236; 13.U.157.237; 13.U.157.238; 13.U.157.239; 13.U.157.154; 13.U.157.157; 13.U.157.166; 13.U.157.169; 13.U.157.172; 13.U.157.175; 13.U.157.240; 13.U.157.244; 13.U.166.228; 13.U.166.229; 13.U.166.230; 13.U.166.231; 13.U.166.236; 13.U.166.237; 13.U.166.238; 13.U.166.239; 13.U.166.154; 13.U.166.157; 13.U.166.166; 13.U.166.169; 13.U.166.172; 13.U.166.175; 13.U.166.240; 13.U.166.244; 13.U.169.228; 13.U.169.229; 13.U.169.230; 13.U.169.231; 13.U.169.236; 13.U.169.237; 13.U.169.238; 13.U.169.239; 13.U.169.154; 13.U.169.157; 13.U.169.166; 13.U.169.169; 13.U.169.172; 13.U.169.175; 13.U.169.240; 13.U.169.244; 13.U.172.228; 13.U.172.229; 13.U.172.230; 13.U.172.231; 13.U.172.236; 13.U.172.237; 13.U.172.238; 13.U.172.239; 13.U.172.154; 13.U.172.157; 13.U.172.166; 13.U.172.169; 13.U.172.172; 13.U.172.175; 13.U.172.240; 13.U.172.244; 13.U.175.228; 13.U.175.229; 13.U.175.230; 13.U.175.231; 13.U.175.236; 13.U.175.237; 13.U.175.238; 13.U.175.239; 13.U.175.154; 13.U.175.157; 13.U.175.166; 13.U.175.169; 13.U.175.172; 13.U.175.175; 13.U.175.240; 13.U.175.244; 13.U.240.228; 13.U.240.229; 13.U.240.230; 13.U.240.231; 13.U.240.236; 13.U.240.237; 13.U.240.238; 13.U.240.239; 13.U.240.154; 13.U.240.157; 13.U.240.166; 13.U.240.169; 13.U.240.172; 13.U.240.175; 13.U.240.240; 13.U.240.244; 13.U.244.228; 13.U.244.229; 13.U.244.230; 13.U.244.231; 13.U.244.236; 13.U.244.237; 13.U.244.238; 13.U.244.239; 13.U.244.154; 13.U.244.157; 13.U.244.166; 13.U.244.169; 13.U.244.172; 13.U.244.175; 13.U.244.240; 13.U.244.244;

13.W Prodrug

     13.W.228.228; 13.W.228.229; 13.W.228.230; 13.W.228.231; 13.W.228.236; 13.W.228.237; 13.W.228.238; 13.W.228.239; 13.W.228.154; 13.W.228.157; 13.W.228.166; 13.W.228.169; 13.W.228.172; 13.W.228.175; 13.W.228.240; 13.W.228.244; 13.W.229.228; 13.W.229.229; 13.W.229.230; 13.W.229.231; 13.W.229.236; 13.W.229.237; 13.W.229.238; 13.W.229.239; 13.W.229.154; 13.W.229.157; 13.W.229.166; 13.W.229.169; 13.W.229.172; 13.W.229.175; 13.W.229.240; 13.W.229.244; 13.W.230.228; 13.W.230.229; 13.W.230.230; 13.W.230.231; 13.W.230.236; 13.W.230.237; 13.W.230.238; 13.W.230.239; 13.W.230.154; 13.W.230.157; 13.W.230.166; 13.W.230.169; 13.W.230.172; 13.W.230.175; 13.W.230.240; 13.W.230.244; 13.W.231.228; 13.W.231.229; 13.W.231.230; 13.W.231.231; 13.W.231.236; 13.W.231.237; 13.W.231.238; 13.W.231.239; 13.W.231.154; 13.W.231.157; 13.W.231.166; 13.W.231.169; 13.W.231.172; 13.W.231.175; 13.W.231.240; 13.W.231.244; 13.W.236.228; 13.W.236.229; 13.W.236.230; 13.W.236.231; 13.W.236.236; 13.W.236.237; 13.W.236.238; 13.W.236.239; 13.W.236.154; 13.W.236.157; 13.W.236.166; 13.W.236.169; 13.W.236.172; 13.W.236.175; 13.W.236.240; 13.W.236.244; 13.W.237.228; 13.W.237.229; 13.W.237.230; 13.W.237.231; 13.W.237.236; 13.W.237.237; 13.W.237.238; 13.W.237.239; 13.W.237.154; 13.W.237.157; 13.W.237.166; 13.W.237.169; 13.W.237.172; 13.W.237.175; 13.W.237.240; 13.W.237.244; 13.W.238.228; 13.W.238.229; 13.W.238.230; 13.W.238.231; 13.W.238.236; 13.W.238.237; 13.W.238.238; 13.W.238.239; 13.W.238.154; 13.W.238.157; 13.W.238.166; 13.W.238.169; 13.W.238.172; 13.W.238.175; 13.W.238.240; 13.W.238.244; 13.W.239.228; 13.W.239.229; 13.W.239.230; 13.W.239.231; 13.W.239.236; 13.W.239.237; 13.W.239.238; 13.W.239.239; 13.W.239.154; 13.W.239.157; 13.W.239.166; 13.W.239.169; 13.W.239.172; 13.W.239.175; 13.W.239.240; 13.W.239.244; 13.W.154.228; 13.W.154.229; 13.W.154.230; 13.W.154.231; 13.W.154.236; 13.W.154.237; 13.W.154.238; 13.W.154.239; 13.W.154.154; 13.W.154.157; 13.W.154.166; 13.W.154.169; 13.W.154.172; 13.W.154.175; 13.W.154.240; 13.W.154.244; 13.W.157.228; 13.W. 157.229; 13.W.157.230; 13.W.157.231; 13.W.157.236; 13.W.157.237; 13.W.157.238; 13.W.157.239; 13.W.157.154; 13.W.157.157; 13.W.157.166; 13.W.157.169; 13.W.157.172; 13.W.157.175; 13.W.157.240; 13.W.157.244; 13.W.166.228; 13.W.166.229; 13.W.166.230; 13.W.166.231; 13.W.166.236; 13.W.166.237; 13.W.166.238; 13.W.166.239; 13.W.166.154; 13.W.166.157; 13.W.166.166; 13.W.166.169; 13.W.166.172; 13.W.166.175; 13.W.166.240; 13.W.166.244; 13.W. 169.228; 13.W.169.229; 13.W. 169.230; 13.W. 169.231; 13.W.169.236; 13.W. 169.237; 13.W. 169.238; 13.W. 169.239; 13.W. 169.154; 13.W. 169.157; 13.W. 169.166; 13.W. 169.169; 13.W. 169.172; 13.W. 169.175; 13.W.169.240; 13.W.169.244; 13.W.172.228; 13.W.172.229; 13.W.172.230; 13.W.172.231; 13.W.172.236; 13.W.172.237; 13.W.172.238; 13.W.172.239; 13.W.172.154; 13.W.172.157; 13.W.172.166; 13.W.172.169; 13.W.172.172; 13.W.172.175; 13.W.172.240; 13.W.172.244; 13.W.175.228; 13.W.175.229; 13.W.175.230; 13.W.175.231; 13.W.175.236; 13.W.175.237; 13.W.175.238; 13.W.175.239; 13.W.175.154; 13.W.175.157; 13.W.175.166; 13.W.175.169; 13.W.175.172; 13.W.175.175; 13.W.175.240; 13.W.175.244; 13.W.240.228; 13.W.240.229; 13.W.240.230; 13.W.240.231; 13.W.240.236; 13.W.240.237; 13.W.240.238; 13.W.240.239; 13.W.240.154; 13.W.240.157; 13.W.240.166; 13.W.240.169; 13.W.240.172; 13.W.240.175; 13.W.240.240; 13.W.240.244; 13.W.244.228; 13.W.244.229; 13.W.244.230; 13.W.244.231; 13.W.244.236; 13.W.244.237; 13.W.244.238; 13.W.244.239; 13.W.244.154; 13.W.244.157; 13.W.244.166; 13.W.244.169; 13.W.244.172; 13.W.244.175; 13.W.244.240; 13.W.244.244;

13.Y's Prodrug

     13.Y.228.228; 13.Y.228.229; 13.Y.228.230; 13.Y.228.231; 13.Y.228.236; 13.Y.228.237; 13.Y.228.238; 13.Y.228.239; 13.Y.228.154; 13.Y.228.157; 13.Y.228.166; 13.Y.228.169; 13.Y.228.172; 13.Y.228.175; 13.Y.228.240; 13.Y.228.244; 13.Y.229.228; 13.Y.229.229; 13.Y.229.230; 13.Y.229.231; 13.Y.229.236; 13.Y.229.237; 13.Y.229.238; 13.Y.229.239; 13.Y.229.154; 13.Y.229.157; 13.Y.229.166; 13.Y.229.169; 13.Y.229.172; 13.Y.229.175; 13.Y.229.240; 13.Y.229.244; 13.Y.230.228; 13.Y.230.229; 13.Y.230.230; 13.Y.230.231; 13.Y.230.236; 13.Y.230.237; 13.Y.230.238; 13.Y.230.239; 13.Y.230.154; 13.Y.230.157; 13.Y.230.166; 13.Y.230.169; 13.Y.230.172; 13.Y.230.175; 13.Y.230.240; 13.Y.230.244; 13.Y.231.228; 13.Y.231.229; 13.Y.231.230; 13.Y.231.231; 13.Y.231.236; 13.Y.231.237; 13.Y.231.238; 13.Y.231.239; 13.Y.231.154; 13.Y.231.157; 13.Y.231.166; 13.Y.231.169; 13.Y.231.172; 13.Y.231.175; 13.Y.231.240; 13.Y.231.244; 13.Y.236.228; 13.Y.236.229; 13.Y.236.230; 13.Y.236.231; 13.Y.236.236; 13.Y.236.237; 13.Y.236.238; 13.Y.236.239; 13.Y.236.154; 13.Y.236.157; 13.Y.236.166; 13.Y.236.169; 13.Y.236.172; 13.Y.236.175; 13.Y.236.240; 13.Y.236.244; 13.Y.237.228; 13.Y.237.229; 13.Y.237.230; 13.Y.237.231; 13.Y.237.236; 13.Y.237.237; 13.Y.237.238; 13.Y.237.239; 13.Y.237.154; 13.Y.237.157; 13.Y.237.166; 13.Y.237.169; 13.Y.237.172; 13.Y.237.175; 13.Y.237.240; 13.Y.237.244; 13.Y.238.228; 13.Y.238.229; 13.Y.238.230; 13.Y.238.231; 13.Y.238.236; 13.Y.238.237; 13.Y.238.238; 13.Y.238.239; 13.Y.238.154; 13.Y.238.157; 13.Y.238.166; 13.Y.238.169; 13.Y.238.172; 13.Y.238.175; 13.Y.238.240; 13.Y.238.244; 13.Y.239.228; 13.Y.239.229; 13.Y.239.230; 13.Y.239.231; 13.Y.239.236; 13.Y.239.237; 13.Y.239.238; 13.Y.239.239; 13.Y.239.154; 13.Y.239.157; 13.Y.239.166; 13.Y.239.169; 13.Y.239.172; 13.Y.239.175; 13.Y.239.240; 13.Y.239.244; 13.Y.154.228; 13.Y.154.229; 13.Y.154.230; 13.Y.154.231; 13.Y.154.236; 13.Y.154.237; 13.Y.154.238; 13.Y.154.239; 13.Y.154.154; 13.Y.154.157; 13.Y.154.166; 13.Y.154.169; 13.Y.154.172; 13.Y.154.175; 13.Y.154.240; 13.Y.154.244; 13.Y.157.228; 13.Y.157.229; 13.Y.157.230; 13.Y.157.231; 13.Y.157.236; 13.Y.157.237; 13.Y.157.238; 13.Y.157.239; 13.Y.157.154; 13.Y.157.157; 13.Y.157.166; 13.Y.157.169; 13.Y.157.172; 13.Y.157.175; 13.Y.157.240; 13.Y.157.244; 13.Y.166.228; 13.Y.166.229; 13.Y.166.230; 13.Y.166.231; 13.Y.166.236; 13.Y.166.237; 13.Y.166.238; 13.Y.166.239; 13.Y.166.154; 13.Y.166.157; 13.Y.166.166; 13.Y.166.169; 13.Y.166.172; 13.Y.166.175; 13.Y.166.240; 13.Y.166.244; 13.Y. 169.228; 13.Y.169.229; 13.Y. 169.230; 13.Y. 169.231; 13.Y.169.236; 13.Y. 169.237; 13.Y. 169.238; 13.Y.169.239; 13.Y.169.154; 13.Y. 169.157; 13.Y.169.166; 13.Y.169.169; 13.Y.169.172; 13.Y. 169.175; 13.Y. 169.240; 13.Y.169.244; 13.Y.172.228; 13.Y.172.229; 13.Y.172.230; 13.Y.172.231; 13.Y.172.236; 13.Y.172.237; 13.Y.172.238; 13.Y.172.239; 13.Y.172.154; 13.Y.172.157; 13.Y.172.166; 13.Y.172.169; 13.Y.172.172; 13.Y.172.175; 13.Y.172.240; 13.Y.172.244; 13.Y.175.228; 13.Y.175.229; 13.Y.175.230; 13.Y.175.231; 13.Y.175.236; 13.Y.175.237; 13.Y.175.238; 13.Y.175.239; 13.Y.175.154; 13.Y.175.157; 13.Y.175.166; 13.Y.175.169; 13.Y.175.172; 13.Y.175.175; 13.Y.175.240; 13.Y.175.244; 13.Y.240.228; 13.Y.240.229; 13.Y.240.230; 13.Y.240.231; 13.Y.240.236; 13.Y.240.237; 13.Y.240.238; 13.Y.240.239; 13.Y.240.154; 13.Y.240.157; 13.Y.240.166; 13.Y.240.169; 13.Y.240.172; 13.Y.240.175; 13.Y.240.240; 13.Y.240.244; 13.Y.244.228; 13.Y.244.229; 13.Y.244.230; 13.Y.244.231; 13.Y.244.236; 13.Y.244.237; 13.Y.244.238; 13.Y.244.239; 13.Y.244.154; 13.Y.244.157; 13.Y.244.166; 13.Y.244.169; 13.Y.244.172; 13.Y.244.175; 13.Y.244.240; 13.Y.244.244;

14.AH Prodrug

     14.AH.4.157; 14.AH.4.158; 14.AH.4.196; 14.AH.4.223; 14.AH. 4.240; 14.AH.4.244; 14.AH.4.243; 14.AH.4.247; 14.AH.5.157; 14.AH.5.158; 14.AH.5.196; 14.AH.5.223; 14.AH.5.240; 14.AH.5.244; 14.AH.5.243; 14.AH.5.247; 14.AH. 7.157; 14.AH. 7.158; 14.AH.7.196; 14.AH.7.223; 14.AH.7.240; 14.AH.7.244; 14.AH.7.243; 14.AH.7.247; 14.AH. 15.157; 14.AH. 15.158; 14.AH. 15.196; 14.AH. 15.223; 14.AH. 15.240; 14.AH. 15.244; 14.AH.15.243; 14.AH. 15.247; 14.AH. 16.157; 14.AH. 16.158; 14.AH. 16.196; 14.AH. 16.223; 14.AH. 16.240; 14.AH. 16.244; 14.AH.16.243; 14.AH. 16.247; 14.AH. 18.157; 14.AH. 18.158; 14.AH. 18.196; 14.AH. 18.223; 14.AH. 18.240; 14.AH. 18.244; 14.AH. 18.243; 14.AH. 18.247; 14.AH. 26.157; 14.AH. 26.158; 14.AH. 26.196; 14.AH. 26.223; 14.AH. 26.240; 14.AH. 26.244; 14.AH.26.243; 14.AH. 26.247; 14.AH. 27.157; 14.AH. 27.158; 14.AH. 27.196; 14.AH.27.223; 14.AH. 27.240; 14.AH.27.244; 14.AH.27.243; 14.AH. 27.247; 14.AH.29.157; 14.AH.29.158; 14.AH.29.196; 14.AH.29.223; 14.AH.29.240; 14.AH.29.244; 14.AH.29.243; 14.AH.29.247; 14.AH. 54.157; 14.AH. 54.158; 14.AH. 54.196; 14.AH. 54.223; 14.AH. 54.240; 14.AH. 54.244; 14.AH. 54.243; 14.AH. 54.247; 14.AH.55.157; 14.AH.55.158; 14.AH.55.196; 14.AH.55.223; 14.AH.55.240; 14.AH.55.244; 14.AH.55.243; 14.AH.55.247; 14.AH. 56.157; 14.AH. 56.158; 14.AH. 56.196; 14.AH. 56.223; 14.AH. 56.240; 14.AH. 56.244; 14.AH. 56.243; 14.AH. 56.247; 14.AH.157.157; 14.AH.157.158; 14.AH.157.196; 14.AH.157.223; 14.AH.157.240; 14.AH.157.244; 14.AH. 157.243; 14.AH.157.247; 14.AH.196.157; 14.AH.196.158; 14.AH.196.196; 14.AH.196.223; 14.AH.196.240; 14.AH.196.244; 14.AH.196.243; 14.AH.196.247; 14.AH.223.157; 14.AH.223.158; 14.AH.223.196; 14.AH.223.223; 14.AH.223.240; 14.AH.223.244; 14.AH.223.243; 14.AH.223.247; 14.AH. 240.157; 14.AH. 240.158; 14.AH. 240.196; 14.AH.240.223; 14.AH.240.240; 14.AH.240.244; 14.AH.240.243; 14.AH.240.247; 14.AH.244.157; 14.AH.244.158; 14.AH.244.196; 14.AH.244.223; 14.AH.244.240; 14.AH.244.244; 14.AH.244.243; 14.AH.244.247; 14.AH. 247.157; 14.AH. 247.158; 14.AH. 247.196; 14.AH.247.223; 14.AH. 247.240; 14.AH.247.244; 14.AH.247.243; 14.AH. 247.247;

14. AJ of Prodrug

     14.AJ.4.157; 14.AJ.4.158; 14.AJ.4.196; 14.AJ.4.223; 14.AJ.4.240; 14.AJ.4.244; 14.AJ.4.243; 14.AJ.4.247; 14.AJ.5.157; 14.AJ.5.158; 14.AJ.5.196; 14.AJ.5.223; 14.AJ.5.240; 14.AJ.5.244; 14.AJ.5.243; 14.AJ.5.247; 14.AJ.7.157; 14.AJ.7.158; 14.AJ.7.196; 14.AJ.7.223; 14.AJ.7.240; 14.AJ.7.244; 14.AJ.7.243; 14.AJ.7.247; 14.AJ. 15.157; 14.AJ. 15.158; 14.AJ. 15.196; 14.AJ. 15.223; 14.AJ. 15.240; 14.AJ. 15.244; 14.AJ.15.243; 14.AJ. 15.247; 14.AJ. 16.157; 14.AJ. 16.158; 14.AJ. 16.196; 14.AJ. 16.223; 14.AJ. 16.240; 14.AJ. 16.244; 14.AJ.16.243; 14.AJ. 16.247; 14.AJ. 18.157; 14.AJ. 18.158; 14.AJ. 18.196; 14.AJ. 18.223; 14.AJ. 18.240; 14.AJ. 18.244; 14.AJ. 18.243; 14.AJ. 18.247; 14.AJ. 26.157; 14.AJ. 26.158; 14.AJ. 26.196; 14.AJ. 26.223; 14.AJ. 26.240; 14.AJ. 26.244; 14.AJ.26.243; 14.AJ. 26.247; 14.AJ. 27.157; 14.AJ. 27.158; 14.AJ. 27.196; 14.AJ.27.223; 14.AJ. 27.240; 14.AJ. 27.244; 14.AJ.27.243; 14.AJ.27.247; 14.AJ.29.157; 14.AJ.29.158; 14.AJ.29.196; 14.AJ.29.223; 14.AJ.29.240; 14.AJ.29.244; 14.AJ.29.243; 14.AJ.29.247; 14.AJ. 54.157; 14.AJ. 54.158; 14.AJ. 54.196; 14.AJ. 54.223; 14.AJ. 54.240; 14.AJ. 54.244; 14.AJ. 54.243; 14.AJ. 54.247; 14.AJ. 55.157; 14.AJ. 55.158; 14.AJ. 55.196; 14.AJ.55.223; 14.AJ. 55.240; 14.AJ. 55.244; 14.AJ.55.243; 14.AJ. 55.247; 14.AJ. 56.157; 14.AJ. 56.158; 14.AJ. 56.196; 14.AJ. 56.223; 14.AJ. 56.240; 14.AJ. 56.244; 14.AJ. 56.243; 14.AJ. 56.247; 14.AJ.157.157; 14.AJ.157.158; 14.AJ.157.196; 14.AJ.157.223; 14.AJ.157.240; 14.AJ.157.244; 14.AJ. 157.243; 14.AJ.157.247; 14.AJ. 196.157; 14.AJ. 196.158; 14.AJ. 196.196; 14.AJ. 196.223; 14.AJ. 196.240; 14.AJ. 196.244; 14.AJ. 196.243; 14.AJ.196.247; 14.AJ.223.157; 14.AJ.223.158; 14.AJ.223.196; 14.AJ.223.223; 14.AJ.223.240; 14.AJ.223.244; 14.AJ.223.243; 14.AJ.223.247; 14.AJ. 240.157; 14.AJ. 240.158; 14.AJ. 240.196; 14.AJ. 240.223; 14.AJ.240.240; 14.AJ. 240.244; 14.AJ. 240.243; 14.AJ. 240.247; 14.AJ.244.157; 14.AJ.244.158; 14.AJ.244.196; 14.AJ.244.223; 14.AJ.244.240; 14.AJ.244.244; 14.AJ.244.243; 14.AJ.244.247; 14.AJ.247.157; 14.AJ.247.158; 14.AJ.247.196; 14.AJ.247.223; 14.AJ.247.240; 14.AJ.247.244; 14.AJ.247.243; 14.AJ.247.247;

14.AN's Prodrug

     14.AN.4.157; 14.AN.4.158; 14.AN.4.196; 14.AN.4.223; 14.AN.4.240; 14.AN.4.244; 14.AN.4.243; 14.AN.4.247; 14.AN.5.157; 14.AN.5.158; 14.AN.5.196; 14.AN.5.223; 14.AN.5.240; 14.AN.5.244; 14.AN.5.243; 14.AN.5.247; 14.AN.7.157; 14.AN.7.158; 14.AN.7.196; 14.AN.7.223; 14.AN.7.240; 14.AN.7.244; 14.AN.7.243; 14.AN.7.247; 14.AN.15.157; 14.AN.15.158; 14.AN.15.196; 14.AN.15.223; 14.AN.15.240; 14.AN.15.244; 14.AN.15.243; 14.AN.15.247; 14.AN.16.157; 14.AN.16.158; 14.AN.16.196; 14.AN.16.223; 14.AN.16.240; 14.AN.16.244; 14.AN.16.243; 14.AN.16.247; 14.AN.18.157; 14.AN.18.158; 14.AN.18.196; 14.AN.18.223; 14.AN.18.240; 14.AN.18.244; 14.AN.18.243; 14.AN.18.247; 14.AN.26.157; 14.AN.26.158; 14.AN.26.196; 14.AN.26.223; 14.AN.26.240; 14.AN.26.244; 14.AN.26.243; 14.AN.26.247; 14.AN.27.157; 14.AN.27.158; 14.AN.27.196; 14.AN.27.223; 14.AN.27.240; 14.AN.27.244; 14.AN.27.243; 14.AN.27.247; 14.AN.29.157; 14.AN.29.158; 14.AN.29.196; 14.AN.29.223; 14.AN.29.240; 14.AN.29.244; 14.AN.29.243; 14.AN.29.247; 14.AN.54.157; 14.AN.54.158; 14.AN.54.196; 14.AN.54.223; 14.AN.54.240; 14.AN.54.244; 14.AN.54.243; 14.AN.54.247; 14.AN.55.157; 14.AN.55.158; 14.AN.55.196; 14.AN.55.223; 14.AN.55.240; 14.AN.55.244; 14.AN.55.243; 14.AN.55.247; 14.AN.56.157; 14.AN.56.158; 14.AN.56.196; 14.AN.56.223; 14.AN.56.240; 14.AN.56.244; 14.AN.56.243; 14.AN.56.247; 14.AN.157.157; 14.AN.157.158; 14.AN.157.196; 14.AN.157.223; 14.AN.157.240; 14.AN.157.244; 14.AN.157.243; 14.AN.157.247; 14.AN.196.157; 14.AN.196.158; 14.AN.196.196; 14.AN.196.223; 14.AN.196.240; 14.AN.196.244; 14.AN.196.243; 14.AN.196.247; 14.AN.223.157; 14.AN.223.158; 14.AN.223.196; 14.AN.223.223; 14.AN.223.240; 14.AN.223.244; 14.AN.223.243; 14.AN.223.247; 14.AN.240.157; 14.AN.240.158; 14.AN.240.196; 14.AN.240.223; 14.AN.240.240; 14.AN.240.244; 14.AN.240.243; 14.AN.240.247; 14.AN.244.157; 14.AN.244.158; 14.AN.244.196; 14.AN.244.223; 14.AN.244.240; 14.AN.244.244; 14.AN.244.243; 14.AN.244.247; 14.AN.247.157; 14.AN.247.158; 14.AN.247.196; 14.AN.247.223; 14.AN.247.240; 14.AN.247.244; 14.AN.247.243; 14.AN.247.247;

14.AP Prodrug

     14.AP.4.157; 14.AP.4.158; 14.AP.4.196; 14.AP.4.223; 14.AP.4.240; 14.AP.4.244; 14.AP.4.243; 14.AP.4.247; 14.AP.5.157; 14.AP.5.158; 14.AP.5.196; 14.AP.5.223; 14.AP.5.240; 14.AP.5.244; 14.AP.5.243; 14.AP.5.247; 14.AP.7.157; 14.AP.7.158; 14.AP.7.196; 14.AP.7.223; 14.AP.7.240; 14.AP.7.244; 14.AP.7.243; 14.AP.7.247; 14.AP.15.157; 14.AP.15.158; 14.AP.15.196; 14.AP.15.223; 14.AP.15.240; 14.AP.15.244; 14.AP.15.243; 14.AP.15.247; 14.AP.16.157; 14.AP.16.158; 14.AP.16.196; 14.AP.16.223; 14.AP.16.240; 14.AP.16.244; 14.AP.16.243; 14.AP.16.247; 14.AP.18.157; 14.AP.18.158; 14.AP.18.196; 14.AP.18.223; 14.AP.18.240; 14.AP.18.244; 14.AP.18.243; 14.AP.18.247; 14.AP.26.157; 14.AP.26.158; 14.AP.26.196; 14.AP.26.223; 14.AP.26.240; 14.AP.26.244; 14.AP.26.243; 14.AP.26.247; 14.AP.27.157; 14.AP.27.158; 14.AP.27.196; 14.AP.27.223; 14.AP.27.240; 14.AP.27.244; 14.AP.27.243; 14.AP.27.247; 14.AP.29.157; 14.AP.29.158; 14.AP.29.196; 14.AP.29.223; 14.AP.29.240; 14.AP.29.244; 14.AP.29.243; 14.AP.29.247; 14.AP.54.157; 14.AP.54.158; 14.AP.54.196; 14.AP.54.223; 14.AP.54.240; 14.AP.54.244; 14.AP.54.243; 14.AP.54.247; 14.AP.55.157; 14.AP.55.158; 14.AP.55.196; 14.AP.55.223; 14.AP.55.240; 14.AP.55.244; 14.AP.55.243; 14.AP.55.247; 14.AP.56.157; 14.AP.56.158; 14.AP.56.196; 14.AP.56.223; 14.AP.56.240; 14.AP.56.244; 14.AP.56.243; 14.AP.56.247; 14.AP.157.157; 14.AP.157.158; 14.AP.157.196; 14.AP.157.223; 14.AP.157.240; 14.AP.157.244; 14.AP.157.243; 14.AP.157.247; 14.AP.196.157; 14.AP.196.158; 14.AP.196.196; 14.AP.196.223; 14.AP.196.240; 14.AP.196.244; 14.AP.196.243; 14.AP.196.247; 14.AP.223.157; 14.AP.223.158; 14.AP.223.196; 14.AP.223.223; 14.AP.223.240; 14.AP.223.244; 14.AP.223.243; 14.AP.223.247; 14.AP.240.157; 14.AP.240.158; 14.AP.240.196; 14.AP.240.223; 14.AP.240.240; 14.AP.240.244; 14.AP.240.243; 14.AP.240.247; 14.AP.244.157; 14.AP.244.158; 14.AP.244.196; 14.AP.244.223; 14.AP.244.240; 14.AP.244.244; 14.AP.244.243; 14.AP.244.247; 14.AP.247.157; 14.AP.247.158; 14.AP.247.196; 14.AP.247.223; 14.AP.247.240; 14.AP.247.244; 14.AP.247.243; 14.AP.247.247;

14.AZ Prodrug

     14.AZ.4.157; 14.AZ.4.158; 14.AZ.4.196; 14.AZ.4.223; 14.AZ.4.240; 14.AZ.4.244; 14.AZ.4.243; 14.AZ.4.247; 14.AZ.5.157; 14.AZ.5.158; 14.AZ.5.196; 14.AZ.5.223; 14.AZ.5.240; 14.AZ.5.244; 14.AZ.5.243; 14.AZ.5.247; 14.AZ.7.157; 14.AZ.7.158; 14.AZ.7.196; 14.AZ.7.223; 14.AZ.7.240; 14.AZ.7.244; 14.AZ.7.243; 14.AZ.7.247; 14.AZ. 15.157; 14.AZ. 15.158; 14.AZ. 15.196; 14.AZ. 15.223; 14.AZ. 15.240; 14.AZ. 15.244; 14.AZ.15.243; 14.AZ. 15.247; 14.AZ. 16.157; 14.AZ. 16.158; 14.AZ. 16.196; 14.AZ. 16.223; 14.AZ. 16.240; 14.AZ. 16.244; 14.AZ.16.243; 14.AZ. 16.247; 14.AZ. 18.157; 14.AZ. 18.158; 14.AZ. 18.196; 14.AZ. 18.223; 14.AZ. 18.240; 14.AZ. 18.244; 14.AZ. 18.243; 14.AZ. 18.247; 14.AZ. 26.157; 14.AZ. 26.158; 14.AZ. 26.196; 14.AZ.26.223; 14.AZ.26.240; 14.AZ.26.244; 14.AZ.26.243; 14.AZ.26.247; 14.AZ. 27.157; 14.AZ.27.158; 14.AZ. 27.196; 14.AZ.27.223; 14.AZ.27.240; 14.AZ.27.244; 14.AZ.27.243; 14.AZ.27.247; 14.AZ.29.157; 14.AZ.29.158; 14.AZ. 29.196; 14.AZ.29.223; 14.AZ.29.240; 14.AZ.29.244; 14.AZ.29.243; 14.AZ.29.247; 14.AZ. 54.157; 14.AZ. 54.158; 14.AZ. 54.196; 14.AZ. 54.223; 14.AZ. 54.240; 14.AZ. 54.244; 14.AZ. 54.243; 14.AZ.54.247; 14.AZ.55.157; 14.AZ.55.158; 14.AZ.55.196; 14.AZ.55.223; 14.AZ.55.240; 14.AZ.55.244; 14.AZ.55.243; 14.AZ.55.247; 14.AZ. 56.157; 14.AZ. 56.158; 14.AZ. 56.196; 14.AZ. 56.223; 14.AZ. 56.240; 14.AZ. 56.244; 14.AZ. 56.243; 14.AZ. 56.247; 14.AZ.157.157; 14.AZ.157.158; 14.AZ.157.196; 14.AZ.157.223; 14.AZ.157.240; 14.AZ.157.244; 14.AZ. 157.243; 14.AZ.157.247; 14.AZ. 196.157; 14.AZ. 196.158; 14.AZ. 196.196; 14.AZ. 196.223; 14.AZ. 196.240; 14.AZ. 196.244; 14.AZ. 196.243; 14.AZ. 196.247; 14.AZ.223.157; 14.AZ.223.158; 14.AZ.223.196; 14.AZ.223.223; 14.AZ.223.240; 14.AZ.223.244; 14.AZ.223.243; 14.AZ.223.247; 14.AZ. 240.157; 14.AZ.240.158; 14.AZ. 240.196; 14.AZ.240.223; 14.AZ.240.240; 14.AZ.240.244; 14.AZ. 240.243; 14.AZ.240.247; 14.AZ.244.157; 14.AZ.244.158; 14.AZ.244.196; 14.AZ.244.223; 14.AZ.244.240; 14.AZ.244.244; 14.AZ.244.243; 14.AZ.244.247; 14.AZ.247.157; 14.AZ.247.158; 14.AZ.247.196; 14.AZ.247.223; 14.AZ.247.240; 14.AZ.247.244; 14.AZ. 247.243; 14.AZ.247.247;

14. BF of Prodrug

     14.BF.4.157; 14.BF.4.158; 14.BF.4.196; 14.BF.4.223; 14.BF.4.240; 14.BF.4.244; 14.BF.4.243; 14.BF.4.247; 14.BF.5.157; 14.BF.5.158; 14.BF.5.196; 14.BF.5.223; 14.BF.5.240; 14.BF.5.244; 14.BF.5.243; 14.BF.5.247; 14.BF.7.157; 14.BF.7.158; 14.BF.7.196; 14.BF.7.223; 14.BF.7.240; 14.BF.7.244; 14.BF.7.243; 14.BF.7.247; 14.BF. 15.157; 14.BF. 15.158; 14.BF. 15.196; 14.BF. 15.223; 14.BF. 15.240; 14.BF. 15.244; 14.BF.15.243; 14.BF. 15.247; 14.BF. 16.157; 14.BF. 16.158; 14.BF. 16.196; 14.BF. 16.223; 14.BF. 16.240; 14.BF. 16.244; 14.BF.16.243; 14.BF.16.247; 14.BF. 18.157; 14.BF. 18.158; 14.BF. 18.196; 14.BF. 18.223; 14.BF. 18.240; 14.BF. 18.244; 14.BF. 18.243; 14.BF. 18.247; 14.BF. 26.157; 14.BF. 26.158; 14.BF. 26.196; 14.BF. 26.223; 14.BF. 26.240; 14.BF. 26.244; 14.BF.26.243; 14.BF. 26.247; 14.BF. 27.157; 14.BF. 27.158; 14.BF. 27.196; 14.BF. 27.223; 14.BF. 27.240; 14.BF.27.244; 14.BF.27.243; 14.BF.27.247; 14.BF. 29.157; 14.BF. 29.158; 14.BF. 29.196; 14.BF.29.223; 14.BF. 29.240; 14.BF.29.244; 14.BF.29.243; 14.BF.29.247; 14.BF. 54.157; 14.BF. 54.158; 14.BF. 54.196; 14.BF. 54.223; 14.BF. 54.240; 14.BF. 54.244; 14.BF. 54.243; 14.BF. 54.247; 14.BF. 55.157; 14.BF. 55.158; 14.BF. 55.196; 14.BF. 55.223; 14.BF. 55.240; 14.BF. 55.244; 14.BF. 55.243; 14.BF. 55.247; 14.BF. 56.157; 14.BF. 56.158; 14.BF. 56.196; 14.BF. 56.223; 14.BF. 56.240; 14.BF. 56.244; 14.BF. 56.243; 14.BF. 56.247; 14.BF.157.157; 14.BF.157.158; 14.BF.157.196; 14.BF.157.223; 14.BF.157.240; 14.BF.157.244; 14.BF. 157.243; 14.BF.157.247; 14.BF.196.157; 14.BF.196.158; 14.BF.196.196; 14.BF.196.223; 14.BF.196.240; 14.BF.196.244; 14.BF. 196.243; 14.BF.196.247; 14.BF.223.157; 14.BF.223.158; 14.BF.223.196; 14.BF.223.223; 14.BF.223.240; 14.BF.223.244; 14.BF.223.243; 14.BF.223.247; 14.BF.240.157; 14.BF.240.158; 14.BF. 240.196; 14.BF.240.223; 14.BF.240.240; 14.BF.240.244; 14.BF.240.243; 14.BF.240.247; 14.BF.244.157; 14.BF.244.158; 14.BF.244.196; 14.BF.244.223; 14.BF.244.240; 14.BF.244.244; 14.BF.244.243; 14.BF.244.247; 14.BF.247.157; 14.BF.247.158; 14.BF.247.196; 14.BF.247.223; 14.BF.247.240; 14.BF.247.244; 14.BF.247.243; 14.BF.247.247;

14.CI Prodrug

     14.CI.4.157; 14.CI.4.158; 14.CI.4.196; 14.CI.4.223; 14.CI.4.240; 14.CI.4.244; 14.CI.4.243; 14.CI.4.247; 14.CI.5.157; 14.CI.5.158; 14.CI.5.196; 14.CI.5.223; 14.CI.5.240; 14.CI.5.244; 14.CI.5.243; 14.CI.5.247; 14.CI.7.157; 14.CI.7.158; 14.CI.7.196; 14.CI.7.223; 14.CI.7.240; 14.CI.7.244; 14.CI.7.243; 14.CI.7.247; 14.CI.15.157; 14.CI.15.158; 14.CI.15.196; 14.CI.15.223; 14.CI.15.240; 14.CI.15.244; 14.CI.15.243; 14.CI.15.247; 14.CI.16.157; 14.CI.16.158; 14.CI.16.196; 14.CI.16.223; 14.CI.16.240; 14.CI.16.244; 14.CI.16.243; 14.CI.16.247; 14.CI.18.157; 14.CI.18.158; 14.CI.18.196; 14.CI.18.223; 14.CI.18.240; 14.CI.18.244; 14.CI.18.243; 14.CI.18.247; 14.CI.26.157; 14.CI.26.158; 14.CI.26.196; 14.CI.26.223; 14.CI.26.240; 14.CI.26.244; 14.CI.26.243; 14.CI.26.247; 14.CI.27.157; 14.CI.27.158; 14.CI.27.196; 14.CI.27.223; 14.CI.27.240; 14.CI.27.244; 14.CI.27.243; 14.CI.27.247; 14.CI.29.157; 14.CI.29.158; 14.CI.29.196; 14.CI.29.223; 14.CI.29.240; 14.CI.29.244; 14.CI.29.243; 14.CI.29.247; 14.CI.54.157; 14.CI.54.158; 14.CI.54.196; 14.CI.54.223; 14.CI.54.240; 14.CI.54.244; 14.CI.54.243; 14.CI.54.247; 14.CI.55.157; 14.CI.55.158; 14.CI.55.196; 14.CI.55.223; 14.CI.55.240; 14.CI.55.244; 14.CI.55.243; 14.CI.55.247; 14.CI.56.157; 14.CI.56.158; 14.CI.56.196; 14.CI.56.223; 14.CI.56.240; 14.CI.56.244; 14.CI.56.243; 14.CI.56.247; 14.CI.157.157; 14.CI.157.158; 14.CI.157.196; 14.CI.157.223; 14.CI.157.240; 14.CI.157.244; 14.CI.157.243; 14.CI.157.247; 14.CI.196.157; 14.CI.196.158; 14.CI.196.196; 14.CI.196.223; 14.CI.196.240; 14.CI.196.244; 14.CI.196.243; 14.CI.196.247; 14.CI.223.157; 14.CI.223.158; 14.CI.223.196; 14.CI.223.223; 14.CI.223.240; 14.CI.223.244; 14.CI.223.243; 14.CI.223.247; 14.CI.240.157; 14.CI.240.158; 14.CI.240.196; 14.CI.240.223; 14.CI.240.240; 14.CI.240.244; 14.CI.240.243; 14.CI.240.247; 14.CI.244.157; 14.CI.244.158; 14.CI.244.196; 14.CI.244.223; 14.CI.244.240; 14.CI.244.244; 14.CI.244.243; 14.CI.244.247; 14.CI.247.157; 14.CI.247.158; 14.CI.247.196; 14.CI.247.223; 14.CI.247.240; 14.CI.247.244; 14.CI.247.243; 14.CI.247.247;

14.CO's Prodrug

     14.CO.4.157; 14.CO.4.158; 14.CO.4.196; 14.CO.4.223; 14.CO.4.240; 14.CO.4.244; 14.CO.4.243; 14.CO.4.247; 14.CO.5.157; 14.CO.5.158; 14.CO.5.196; 14.CO.5.223; 14.CO.5.240; 14.CO.5.244; 14.CO.5.243; 14.CO.5.247; 14.CO.7.157; 14.CO.7.158; 14.CO.7.196; 14.CO.7.223; 14.CO.7.240; 14.CO.7.244; 14.CO.7.243; 14.CO.7.247; 14.CO.15.157; 14.CO.15.158; 14.CO.15.196; 14.CO.15.223; 14.CO.15.240; 14.CO.15.244; 14.CO.15.243; 14.CO.15.247; 14.CO.16.157; 14.CO.16.158; 14.CO.16.196; 14.CO.16.223; 14.CO.16.240; 14.CO.16.244; 14.CO.16.243; 14.CO.16.247; 14.CO.18.157; 14.CO.18.158; 14.CO.18.196; 14.CO.18.223; 14.CO.18.240; 14.CO.18.244; 14.CO.18.243; 14.CO.18.247; 14.CO.26.157; 14.CO.26.158; 14.CO.26.196; 14.CO.26.223; 14.CO.26.240; 14.CO.26.244; 14.CO.26.243; 14.CO.26.247; 14.CO.27.157; 14.CO.27.158; 14.CO.27.196; 14.CO.27.223; 14.CO.27.240; 14.CO.27.244; 14.CO.27.243; 14.CO.27.247; 14.CO.29.157; 14.CO.29.158; 14.CO.29.196; 14.CO.29.223; 14.CO.29.240; 14.CO.29.244; 14.CO.29.243; 14.CO.29.247; 14.CO.54.157; 14.CO.54.158; 14.CO.54.196; 14.CO.54.223; 14.CO.54.240; 14.CO.54.244; 14.CO.54.243; 14.CO.54.247; 14.CO.55.157; 14.CO.55.158; 14.CO.55.196; 14.CO.55.223; 14.CO.55.240; 14.CO.55.244; 14.CO.55.243; 14.CO.55.247; 14.CO.56.157; 14.CO.56.158; 14.CO.56.196; 14.CO.56.223; 14.CO.56.240; 14.CO.56.244; 14.CO.56.243; 14.CO.56.247; 14.CO.157.157; 14.CO.157.158; 14.CO.157.196; 14.CO.157.223; 14.CO.157.240; 14.CO.157.244; 14.CO.157.243; 14.CO.157.247; 14.CO.196.157; 14.CO.196.158; 14.CO.196.196; 14.CO.196.223; 14.CO.196.240; 14.CO.196.244; 14.CO.196.243; 14.CO.196.247; 14.CO.223.157; 14.CO.223.158; 14.CO.223.196; 14.CO.223.223; 14.CO.223.240; 14.CO.223.244; 14.CO.223.243; 14.CO.223.247; 14.CO.240.157; 14.CO.240.158; 14.CO.240.196; 14.CO.240.223; 14.CO.240.240; 14.CO.240.244; 14.CO.240.243; 14.CO.240.247; 14.CO.244.157; 14.CO.244.158; 14.CO.244.196; 14.CO.244.223; 14.CO.244.240; 14.CO.244.244; 14.CO.244.243; 14.CO.244.247; 14.CO.4.157; 14.CO.4.158; 14.CO.4.196; 14.CO.4.223; 14.CO.4.240; 14.CO.4.244; 14.CO.4.243; 14.CO.4.247.

All documents and patents cited above are incorporated by reference in their place. Specifically, the cited portions or pages of the cited documents mentioned above are specifically incorporated by reference. The present invention has been described in sufficient detail to enable those skilled in the art to make and use the subject matter of the following claims. It is apparent that the compositions and methods of the following claims may be modified within the spirit and scope of the invention.

In the claims of this specification, the superscript and subscript of a given variable are different. For example, R ₁ is R ¹ It is different from.

Claims (249)

A complex comprising an anticancer compound bound to at least one phosphonate group, or a pharmaceutically acceptable salt or solvate thereof. The complex of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is one of Formula 500-601 substituted with one or more A ⁰ groups. Among the above formulas, A ⁰ is A ¹ , A ² or W ^{3, provided} that the complex contains at least one A ¹ , A ¹ is

A ² is

A ³ is

Is, Y ¹ is independently O, S, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), or N (N (R ^x ) (R ^x ))ego, Y ² is independently one bond, O, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), N (N (R ^x ) (R ^x )), -S (O) _M2- , or -S (O) _M2 -S (O) _M2 -and when Y ² is bonded to two phosphorus atoms, Y ² is also C (R ² ) ( R ² ); R ^x is independently H, R ¹ , R ² , W ³ , a protecting group, or

Is here, R ^y is independently H, W ³ , R ² or a protecting group R ¹ is independently H or alkyl having 1 to 18 carbon atoms, R ² is independently H, R ¹ , R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups, or taken together at a carbon atom, two R ² groups are carbon 3 to Forms an eight carbon ring, which ring may be substituted with 0 to 3 R ³ groups), R ³ is R ^3a, inde R ^3b, R ^3c or R ^3d, but if R ³ is bonded to a hetero atom, R ³ is R ^3c or R ^3d and, R ^3a is F, Cl, Br, I, -CN, N ₃ or -NO ₂ , R ^3b is Y ¹ , R ^3c is -R ^x , -N (R ^x ) (R ^x ), -SR ^x , -S (O) R ^x , -S (O) ₂ R ^x , -S (O) (OR ^x ),- S (O) ₂ (OR ^x ), -OC (Y ¹ ) R ^x , -OC (Y ¹ ) OR ^x , -OC (Y ¹ ) (N (R ^x ) (R ^x )), -SC (Y ¹ ) R ^x , -SC (Y ¹ ) OR ^x , -SC (Y ¹ ) (N (R ^x ) (R ^x )), -N (R ^x ) C (Y ¹ ) R ^x , -N (R ^x ) C (Y ¹ ) OR ^x , or -N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x )) R ^3d is -C (Y ¹ ) R ^x , -C (Y ¹ ) OR ^x or -C (Y ¹ ) (N (R ^x ) (R ^x )), R ⁴ is alkyl having 1 to 18 carbon atoms, alkenyl having 2 to 18 carbon atoms, or alkynyl having 2 to 18 carbon atoms, R ⁵ is R ⁴ , wherein each R ⁴ is substituted with 0-3 R ³ groups, W ³ is W ⁴ or W ⁵ , W ⁴ is R ⁵ , -C (Y ¹ ) R ⁵ , -C (Y ¹ ) W ⁵ , -SO _M2 R ⁵ , or -SO _M2 W ⁵ , W _⁵ is carbocycle or heterocycle, wherein W ⁵ is independently substituted with 0 to 3 R _² groups, W ⁶ is W ³ independently substituted with 1, 2, or 3 A ³ groups, M2 is 0, 1 or 2, M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, M1a, M1c, and M1d are independently 0 or 1, M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. The complex or a pharmaceutically acceptable salt or solvate thereof according to claim 2, wherein the complex or a pharmaceutically acceptable salt or solvate thereof is represented by the following formula. [DRUG]-(A ⁰ ) _nn In the above formula, DRUG is a compound of any one of formulas 500-601 , and nn is 1, 2, or 3. According to claim 2, wherein the complex conjugate will, one of the formulas 1-336. Wherein one A ⁰ is A ¹ , X ⁵⁰ is H, F or Cl, and X ⁵¹ Is H or Cl. The complex according to any one of claims 2 to 4, wherein each A ¹ is represented by the following formula.

The complex according to any one of claims 2 to 4, wherein each A ¹ is represented by the following formula.

The complex according to any one of claims 2 to 4, wherein each A ¹ is represented by the following formula.

The complex according to any one of claims 2 to 4, wherein each A ¹ is represented by the following formula.

The complex according to any one of claims 2 to 4, wherein each A ¹ is represented by the following formula.

Wherein W ^5a is a carbocycle or heterocycle, wherein W ^5a is independently substituted with 0 or 1 R ² groups. The complex of any one of claims 2-4 wherein M 12a is 1. 5. The complex according to any one of claims 2 to 4, wherein each A ¹ is represented by the following formula.

The complex according to any one of claims 2 to 4, wherein each A ¹ is represented by the following formula.

The complex according to any one of claims 2 to 4, wherein each A ¹ is represented by the following formula.

In the above formula, W ^5a is independently a carbocycle substituted with 0 or 1 R ² groups. The complex according to any one of claims 2 to 4, wherein each A ¹ is represented by the following formula.

In the above formula, Y ^2b is O or N (R ² ) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8. The complex according to any one of claims 2 to 4, wherein each A ¹ is represented by the following formula.

In the above formula, W ^5a is independently a carbocycle substituted with 0 or 1 R ² groups. The complex according to any one of claims 2 to 4, wherein each A ¹ is represented by the following formula.

Wherein W ^5a is a carbocycle or heterocycle, wherein W ^5a is independently substituted with 0 or 1 R ² groups. The complex according to any one of claims 2 to 4, wherein each A ¹ is represented by the following formula.

In the above formula, Y ^2b is O or N (R ² ) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8. The complex according to any one of claims 2 to 17, wherein each A ² is represented by the following formula.

The complex according to any one of claims 2 to 17, wherein each A ² is represented by the following formula.

18. The complex of any one of claims 2 to 17, wherein each M12b is one. The compound of claim 20, wherein M 12b is 0, Y ² is a bond, and W ⁵ is a carbocycle or heterocycle, wherein W ⁵ is optionally and independently substituted with 1, 2 or 3 R ² groups It is complex). The complex according to any one of claims 2 to 17, wherein each A ² is represented by the following formula.

Wherein W ^5a is a carbocycle or heterocycle, wherein W ^5a is optionally and independently substituted with 1, 2, or 3 R ² groups. The complex of claim 22, wherein M12a is 1. 18. The complex of claim ² , wherein each A ² is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl and substituted pyridyl. The complex according to any one of claims 2 to 17, wherein each A ² is represented by the following formula.

The complex according to any one of claims 2 to 17, wherein each A ² is represented by the following formula.

27. The complex of claim 26, wherein said M12b is 1. The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

In the above formula, Y ^1a is O or S, and Y ^2a is O, N (R ^x ) or S. The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

In the above formula, Y ^2b is O or N (R ^x ). The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

In the above formula, Y ^2b is O or N (R ^x ) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8. The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

In the above formula, Y ^2b is O or N (R ^x ) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8. 34. The complex of claim 33, wherein M12d is 1. The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

The complex of claim 36, wherein W ⁵ is carbocycle. The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

The complex of claim 38 wherein W ⁵ is phenyl. 40. The complex of claim 39, wherein M12b is 1. The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

In the above formula, Y ^1a is O or S, and Y ^2a is O, N (R ^x ) or S. The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

In the above formula, Y ^2b is O or N (R ^x ). The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

In the above formula, Y ^2b is O or N (R ^x ) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8. 44. The complex of claim 43, wherein R ¹ is H. 45. The complex of claim 44, wherein M12d is one. The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

Wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R ² groups. The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

Wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R ² groups. The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

28. The complex of any one of claims 2 to 27, wherein each A ³ is represented by the formula: In the above formula, Y ^1a is O or S, and Y ^2a is O, N (R ² ) or S.

The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

In the above formula, Y ^1a is O or S, Y ^2b is O or N (R ² ), and Y ^2c is O, N (R ^y ) or S. The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

Wherein Y ^1a is O or S, Y ^2b is O or N (R ² ), Y ^2d is O or N (R ^y ), and M12d is 1, 2, 3, 4, 5, 6, 7 or 8. The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

In the above formula, Y ^2b is O or N (R ² ) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8. The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

In the above formula, Y ^2b is O or N (R ² ). The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

In the above formula, Y ^1a is O or S, and Y ^2a is O, N (R ² ) or S. The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

In the above formula, Y ^1a is O or S, Y ^2b is O or N (R ² ), and Y ^2c is O, N (R ^y ) or S. 28. The complex of any one of claims 2 to 27, wherein each A ³ is represented by the formula:

Wherein Y ^1a is O or S, Y ^2b is O or N (R ² ), Y ^2d is O or N (R ^y ), and M12d is 1, 2, 3, 4, 5, 6, 7 or 8. 28. The complex of any one of claims 2 to 27, wherein each A ³ is represented by the formula:

In the above formula, Y ^2b is O or N (R ² ) and M 12d is 1, 2, 3, 4, 5, 6, 7 or 8. The complex according to any one of claims 2 to 27, wherein each A ³ is represented by the formula:

In the above formula, Y ^2b is O or N (R ² ). The complex according to claim 3, wherein A ⁰ is represented by the following formula.

Wherein each R is independently alkyl. The complex according to any one of claims 1, 2, 3 or 4, wherein the complex is represented by the following formula, or a pharmaceutically acceptable salt or solvate thereof.

In the above formula, DRUG is an anticancer compound, Y ¹ is independently O, S, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), or N (N (R ^x ) (R ^x )), Y ² is independently one bond, O, N (R ^x ), N (O) (R ^x ), N (OR ^x ), N (O) (OR ^x ), N (N (R ^x ) (R ^x )), -S (O) _M2- , or -S (O) _M2 -S (O) _M2- , R ^x is independently H, R ² , W ³ , a protecting group, or

Is, R ^y is independently H, W ³ , R ² or a protecting group, R ² is independently H, R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups, R ³ is R ^3a , R ^3b , R ^3c or R ^3d (but R ³ When is bonded to a hetero atom, R ³ is R ^3c or R ^3d ), R ^3a is F, Cl, Br, I, -CN, N ₃ or -NO ₂ , R ^3b is Y ¹ , R ^3c is -R ^x , -N (R ^x ) (R ^x ), -SR ^x , -S (O) R ^x , -S (O) ₂ R ^x , -S (O) (OR ^x ),- S (O) ₂ (OR ^x ), -OC (Y ¹ ) R ^x , -OC (Y ¹ ) OR ^x , -OC (Y ¹ ) (N (R ^x ) (R ^x )), -SC (Y ¹ ) R ^x , -SC (Y ¹ ) OR ^x , -SC (Y ¹ ) (N (R ^x ) (R ^x )), -N (R ^x ) C (Y ¹ ) R ^x , -N (R ^x ) C (Y ¹ ) OR ^x , or -N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x )) R ^3d is -C (Y ¹ ) R ^x , -C (Y ¹ ) OR ^x or -C (Y ¹ ) (N (R ^x ) (R ^x )), R ⁴ is alkyl having 1 to 18 carbon atoms, alkenyl having 2 to 18 carbon atoms, or alkynyl having 2 to 18 carbon atoms, R ⁵ is R ⁴ , wherein each R ⁴ is substituted with 0 to 3 R ³ groups, W ³ is W ⁴ or W ⁵ , W ⁴ is R ⁵ , -C (Y ¹ ) R ⁵ , -C (Y ¹ ) W ⁵ , -SO ₂ R ⁵ , or -SO ₂ W ⁵ , W ⁵ is carbocycle or heterocycle, wherein W ⁵ is independently substituted with 0 to 3 R ² groups, M2 is 1, 2, or 3, M1a, M1c and M1d are independently 0 or 1, M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, nn is 1, 2, or 3, L is one direct bond or a bonding group. 65. The complex of claim 64, wherein each R ^x is represented by the formula:

In the above formula, Y ^1a is O or S, and Y ^2c is O, N (R ^y ) or S. 65. The complex of claim 64, wherein each R ^x is represented by the formula:

In the above formula, Y ^1a is O or S, and Y ^2d is O or N (R ^y ). 65. The complex of claim 64, wherein each R ^x is represented by the formula:

The complex of any of claims 65-67 wherein each R ^y is independently H or alkyl having 1 to 10 carbon atoms. 65. The complex of claim 64, wherein each R ^x is represented by the formula:

65. The complex of claim 64, wherein each R ^x is represented by the formula:

65. The complex of claim 64, wherein each R ^x is represented by the formula:

65. The complex of claim 64, wherein each Y ¹ is O or S. 65. The complex of claim 64, wherein each Y ² is O, N (R ^y ) or S. 74. The complex of any one of claims 64 to 73, wherein nn is 1. 74. The complex of any one of claims 64-73, wherein nn is 2. 74. The complex of any one of claims 64 to 73, wherein nn is 3. 65. The complex of claim 64, wherein said anticancer compound is a compound of Formula 500-601 . 78. The complex of claim 77, wherein each L has a molecular weight of about 200 Daltons to about 400 Daltons. 78. The composite of claim 77, wherein each L is from about 5 angstroms to about 300 angstroms in length. The method of claim 77 wherein each L is a formula of the complex to which either one of compounds 500-601 with phosphonate groups of the separation to about 5 Angstroms to about 200 Angstroms in the. 78. The compound of claim 77, wherein each L is a divalent branched or straight chain, saturated or unsaturated hydrocarbon chain having 2 to 25 carbon atoms, wherein at least one carbon atom is substituted by (-O-) as needed, The hydrocarbon chain may be (C ₁ -C ₆ ) alkoxy, (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₆ ) alkanoyloxy, ( C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkylthio, azido, cyano, nitro, halo, hydroxy, oxo (═O), carboxy, aryl, aryloxy, heteroaryl and hetero Substituted with one or more substituents selected from aryloxy. 78. The compound of claim 77, wherein each L is a formula WA wherein A is (C ₁ -C ₂₄ ) alkylene, (C ₂ -C ₂₄ ) alkenylene, (C ₂ -C ₂₄ ) alkynylene, (C ₃ -C ₈ ) cycloalkylene, (C ₆ -C ₁₀ ) aryl, or a combination thereof, each W is -N (R) C (= 0)-, -C (= 0) N (R)-, -OC (= O)-, -C (= O) O-, -O-, -S-, -S (O)-, -S (O) _2- , -N (R)-, -C ( = O), -N (R) C = N (R) -N (R)-, -C (R) = N (R)-, -S (O) _M2 -N (R)-, -N (R) -S (O) _M2- , or one direct bond, wherein each R is independently H or alkyl having from 1 to 10 carbons. Phosphorus complex. 83. The complex of claim 82, wherein each A has 1-10 carbon atoms in the alkylene. 78. The complex of claim 77, wherein each L is a divalent radical formed from a peptide. 78. The complex of claim 77, wherein each L is a divalent radical formed from amino acid. 78. The composition of claim 77, wherein each L is poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine, poly- And a divalent radical formed from L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine, poly-L-lysine or poly-L-lysine-L-tyrosine. 78. The compound of claim 77, wherein each L is a formula W- (CH ₂ ) _n where n is from about 1 to about 10 and W is -N (R) C (= 0)-, -C (= 0) N (R)-, -OC (= O)-, -C (= O) O-, -O-, -S-, -S (O)-, -S (O) _2- , -C (= O)-, -N (R)-, -N (R) C = N (R) -N (R)-, -C (R) = N (R)-, -S (O) _{M 2} —N (R) —, —N (R) —S (O) _{M 2} —, or one direct bond, wherein each R is independently H or (C ₁ -C ₆ ) alkyl] Complex. 78. The complex of claim 77, wherein each L is methylene, ethylene or propylene. 78. The complex of claim 77, wherein each L is bonded to P at L carbon atoms. 89. The complex of any one of claims 1 to 89, wherein the complex is isolated and purified. 91. The complex of any one of claims 1-90, which is not a compound with anti-inflammatory action. 101. The complex of any one of claims 1-99, which is not an anti-infective compound. 92. The complex of any one of claims 1-92, which is not a compound that is active against immune mediated diseases. 94. The complex of any one of claims 1-93, which is not a compound having activity against metabolic diseases. 95. The complex of any one of the preceding claims, wherein the complex is not an antiviral agent. 97. The complex of any one of the preceding claims, wherein the complex is not nucleosides. 97. The complex of any one of the preceding claims, wherein the complex is not an IMPDH inhibitor. 98. The complex of any one of the preceding claims, wherein the complex is not an antimetabolic agent. 99. The complex of any one of the preceding claims, wherein the complex is not a PNP inhibitor. The compound of any one of claims 1-100, wherein the anticancer compound is of the formulas 501 , 519 , 597 , 541 , 518 , 558 , 591 , 593 , 592 , 503 , 504 , 505 , 506 , 542 , 544 , 545 Complex which is not a compound of any one of 546 , 516 or 512 Anticancer complexes described herein. Compound of formula MBF. 102. The compound of claim 102 selected from Table 100. 108. A pharmaceutical preparation comprising a pharmaceutically acceptable excipient and a complex as described in any one of claims 1 to 89 and 91 to 106 or a compound as described in claims 102 or 103. Composition. 108. A unit dose containing a pharmaceutically acceptable excipient and a complex as described in any one of claims 1 to 89 and 91 to 106 or a compound as described in claims 102 or 103. Formulation. 108. Samples requiring treatment are ex vivo or in vivo with the complexes described in any one of claims 1-89 and 91-106 or with the compounds of claims 102-103. A method of inhibiting tumor growth comprising contacting. 107. The method of claim 106, wherein said contact occurs in vivo. 107. The tumor according to any one of claims 106 to 107, wherein the tumor is the chest, lungs, thyroid, lymph nodes, genitourinary system, kidney, ureter, bladder, ovary, tetis, prostate, musculoskeletal system, bone, skeletal muscle of a mammal. , Bone marrow, gastrointestinal tract, stomach, esophagus, small intestine, colon, rectum, pancreas, liver, smooth muscle, central or peripheral nervous system, brain, spinal cord, nerves, head, neck, ears, eyes, nasopharynx, mouth pharynx, salivary glands, heart The vasculature, oral cavity, tongue, larynx, hypopharyngeal, soft tissue, skin, cervix, anus, retina, and / or heart. 108. Cancer of an animal comprising administering to a mammal the compound of any one of claims 1-89 and 91-106 or the compound of claim 102 or 103 Symptoms and effects How to treat. 108. A treatment comprising administering to a mammal a compound as described in any one of claims 1 to 89 and 91 to 106 or a compound as described in claims 102 or 103. A method for inhibiting tumorous disease in stray animals. 117. The method of claim 110, wherein the tumor is acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, cutaneous T-cell lymphoma, hairy cell leukemia, or non-Hodgkin's lymphoma. 111. The method of claim 106-111, wherein the compound is formulated with a pharmaceutically acceptable carrier. 118. The method of claim 112, wherein the formulation further comprises a second active ingredient. 103. A complex as described in any one of claims 1 to 89 and 91 to 106 or a compound as described in claims 102 or 103 for use in medical therapy. Use of the complex of any one of claims 1-89 and 91-106 or the compound of claim 102 or 103 for the manufacture of a drug for inhibiting tumor growth in an animal . 116. The method of claim 115, wherein the tumor is a mammalian chest, lungs, thyroid gland, lymph nodes, urogenital system, kidneys, ureters, bladder, ovary, tetis, prostate, musculoskeletal system, bone, skeletal muscle, bone marrow, gastrointestinal tract, stomach, esophagus, Small intestine, colon, rectum, pancreas, liver, smooth muscle, central or peripheral nervous system, brain, spinal cord, nerves, head, neck, ears, eyes, nasopharynx, mouth pharynx, salivary glands, cardiovascular system, oral cavity, tongue, larynx, hypopharyngeal , Soft tissue, skin, cervix, anus, retina, and / or heart. 106. A complex as described in any one of claims 1 to 89 and 91 to 106 or a compound as described in claims 102 or 103 for the preparation of a drug for inhibiting a tumorous disease in a mammal. Use of 118. The use of claim 117, wherein the tumor is acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, cutaneous T-cell lymphoma, hairy cell leukemia or non-Hodgkin's lymphoma. The complex according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, represented by the following formula.

Where B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebulaline , Nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, high foxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propy Nylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothylmine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthylmine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazoles and pyrazolo [3,4-D] pyrimidines, X is selected from O, C (R ^y ) ₂ , C = C (R ^y ) ₂ , NR and S, Z ¹ is independently selected from H, OH, OR, NR ₂ , CN, NO ₂ , SH, SR, F, Cl, Br and I; Z ² is H, C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl and C ₁ -C ₈ Selected from substituted alkynyl, Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR) or N-NR ₂ , Y ² is independently bonded, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, SS, S (O) Or S (O) ₂ , M2 is 0, 1 or 2, R ^y is independently H, F, Cl, Br, I, OH, R, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR ), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR, -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR or -N (R) C (= Y ¹ ) N (R) ₂ , amino (-NH ₂ ), ammonium (-NH ₃ ⁺ ), alkylamino, dialkylamino, trialkylammonium, C ₁ -C ₈ alkyl, C ₁ -C ₈ halo Alkyl, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered cyclic sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium , C ₁ -C ₈ alkylhydroxyl, C ₁ -C ₈ alkylthiol, alkylsulfone (-SO ₂ R), arylsulfone (-SO ₂ Ar), arylsulfoxide (-SOAr), arylthio (-SAr) , Sulfonamide (-SO ₂ NR ₂ ), alkylsulfoxide (-SOR), ester (-C (= O) OR), amido (-C (= O) NR ₂ ), 5-7 member Cyclic lactams, 5-7 membered cyclic lactones, nitrile (- CN), azido (-N ₃ ), nitro (-NO ₂ ), C ₁ -C ₈ alkoxy (-OR), C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ al Kenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle , C ₂ -C ₂₀ substituted heterocycle, polyethyleneoxy, protecting group (PG) or W ³ , or when bonded together, R ^y forms a carbocycle ring of 3 to 7 carbon atoms, R ^x is independently R ^y , a protecting group or

here, M1a, M1c and M1d are independently 0 or 1, M 12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, and R is C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl , C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle or protecting group, W ³ is W ⁴ or W ⁵ , W ⁴ is R, -C (Y ¹ ) R ^y , -C (Y ¹ ) W ⁵ , -SO ₂ R ^y or -SO ₂ W ⁵ , W ⁵ is independent Carbocycle or heterocycle substituted with 0 to 3 R ^y groups. 119. The compound of claim 119, wherein C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ substituted aryl and C ₂ -C ₂₀ substituted heterocycle are F , Cl, Br, I, OH, -NH ₂ , -NH ₃ ⁺ , -NHR, -NR ₂ , -NR ₃ ⁺ , C ₁ -C ₈ haloalkyl, carboxylate, sulfate, sulfamate, sulfonate , 5-7 cyclic sultam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium, C ₁ -C ₈ alkylhydroxyl, C _1- C ₈ alkylthiol, -SO ₂ R, -SO ₂ Ar, -SOAr, -SAr, -SO ₂ NR ₂ , -SOR, -CO ₂ R, -C (= O) NR ₂ , 5-7 member ) Cyclic lactams, 5-7 membered cyclic lactones, -CN, -N ₃ , -NO ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ trifluoroalkyl, C ₁ -C ₈ alkyl , C ₃ -C ₁₂ carbocycle, C ₆ -C ₂₀ aryl, C ₂ -C ₂₀ heterocycle, independently substituted with one or more substituents selected from polyethyleneoxy, phosphonate, phosphate and prodrug moieties . 119. The complex of claim 119, wherein the protecting group is selected from a carboxyl ester, carboxamide, aryl ether, alkyl ether, trialkylsilyl ether, sulfonic acid ester, carbonate and carbamate. 119. The complex of claim 119, wherein W ⁵ is selected from the following structures.

119. The complex of claim 119, wherein X is O and R ^y is H .. 119. The complex of claim 119, wherein X is C = CH ₂ and R ^y is H. 119. The complex of claim 119, wherein Z ¹ is OH. 119. The complex of claim 119, wherein Z ² is C ₁ -C ₈ alkyl or substituted C ₁ -C ₈ alkyl. 126. The complex of claim 126, wherein Z ² is CH ₃ . 119. The complex of claim 119, wherein

119. The complex of claim 119, wherein

119. The complex of claim 119, wherein

119. The complex of claim 119, wherein

119. The complex of claim 119, wherein

119. The complex of claim 119, wherein

119. The complex of claim 119, wherein

119. The complex of claim 119, wherein

119. The complex of claim 119, wherein

136. The complex of claim 136, wherein Z ¹ is OH. 136. The complex of claim 136, wherein Z ² is C ₁ -C ₈ alkyl or C ₁ -C ₈ substituted alkyl. 138. The complex of claim 138, wherein Z ² is CH ₃ . 119. The complex of claim 119, wherein

119. The complex of claim 119, wherein

119. The complex of claim 119, wherein

119. The complex of claim 119, wherein

119. The complex of claim 119, wherein

119. The complex of claim 119, wherein

119. The complex of claim 119, wherein

119. The complex of claim 119, wherein

147. The complex of claim 147, wherein

Wherein R ² is H or C ₁ -C ₈ alkyl. 148. The complex of claim 148, wherein

148. The complex of claim 148, wherein

Where Y ^2c is O, N (R ^y ) or S. 151. The complex of claim 150, wherein

151. The complex of claim 151, wherein Y ^2c is O. 151. The complex of claim 151, wherein Y ^2c is N (CH ₃ ). 151. The complex of claim 151, wherein R ^y is H or C ₁ -C ₈ alkyl. 119. The complex of claim 119, wherein the substituted triazole is represented by the following structure.

A composition represented by the following formula or a pharmaceutically acceptable salt or solvate thereof.

Where B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebulaline , Nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propy Nilecytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothylmine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthylmine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazoles and pyrazolo [3,4-D] pyrimidines, Z ¹ is independently selected from H, OH, OR, NR ₂ , CN, NO ₂ , SH, SR, F, Cl, Br and I, Z ² is H, C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl and C ₁ -C ₈ Selected from substituted alkynyl, R ^y is independently H, F, Cl, Br, I, OH, R, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR ), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR, -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR or -N (R) C (= Y ¹ ) N (R) ₂ , amino (-NH ₂ ), ammonium (-NH ₃ ⁺ ), alkylamino, dialkylamino, trialkylammonium, C ₁ -C ₈ alkyl, C ₁ -C ₈ halo Alkyl, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered cyclic sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium , C ₁ -C ₈ alkylhydroxyl, C ₁ -C ₈ alkylthiol, alkylsulfone (-SO ₂ R), arylsulfone (-SO ₂ Ar), arylsulfoxide (-SOAr), arylthio (-SAr) , Sulfonamide (-SO ₂ NR ₂ ), alkylsulfoxide (-SOR), ester (-C (= O) OR), amido (-C (= O) NR ₂ ), 5-7 member Cyclic lactams, 5-7 membered cyclic lactones, nitrile (- CN), azido (-N ₃ ), nitro (-NO ₂ ), C ₁ -C ₈ alkoxy (-OR), C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ al Kenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle , C ₂ -C ₂₀ substituted heterocycle, polyethyleneoxy, protecting group (PG) or W ³ , or when bonded together, R ^y forms a carbocycle ring of 3 to 7 carbon atoms, R is C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl , C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle or a protecting group, W ³ is W ⁴ or W ⁵ , W ⁴ is R, -C (Y ¹ ) R ^y , -C (Y ¹ ) W ⁵ , -SO ₂ R ^y or -SO ₂ W ⁵ , W ⁵ is independent Carbocycle or heterocycle substituted with 0 to 3 R ^y groups. 162. The composition of claim 156, wherein

Wherein PG is selected from ether formers, thioether formers, ester formers, thioester formers, silyl-ether formers, amide formers, acetal formers, ketal formers, carbonate formers, carbamate formers, urea formers, amino acid complexes and polypeptide complexes. It is a protector. 119. The complex of claim 119, which may accumulate in human PBMCs. 158. The complex of claim 158, wherein the bioavailability of the complex or the intracellular metabolites of the complex in human PBMCs is improved compared to analogs of the complexes that do not contain prodrug moieties (phosphonate group (s)). 158. The complex of claim 158, wherein the intracellular half-life of the complex or the intracellular metabolite of the complex in human PBMCs is improved when compared to an analog of the complex that does not contain a prodrug moiety. 161. The complex of claim 160, wherein the half life is improved by at least about 50%. 161. The complex of claim 160, wherein the half life is improved by at least about 100%. 158. The complex of claim 158, wherein the intracellular half-life of the metabolite of the complex in human PBMCs or the intracellular metabolite of the complex is improved compared to an analog of its metabolite that does not contain a prodrug moiety. 158. The complex of claim 158, wherein the half life is improved by at least about 50%. 158. The complex of claim 158, wherein the half life is improved by at least about 100%. 158. The complex of claim 158, wherein the half life is improved by at least 100%. 119. A composition comprising a pharmaceutically acceptable salt and a complex of claim 119 or a pharmaceutically acceptable salt or solvate thereof in a therapeutically effective amount. The complex according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, represented by the following formula.

Where B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebulaline , Nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propy Nylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothylmine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthylmine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazoles and pyrazolo [3,4-D] pyrimidines, X is selected from O, C (R ^y ) ₂ , OC (R ^y ) ₂ , NR and S, Z ¹ is independently selected from H, OH, OR, NR ₂ , CN, NO ₂ , SH, SR, F, Cl, Br and I, Z ² is H, C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl and C ₁ -C ₈ Selected from substituted alkynyl, Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR) or N-NR ₂ , Y ² is independently bonded, O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, SS, S (O) Or S (O) ₂ , M2 is 0, 1 or 2, R ^y is independently H, F, Cl, Br, I, OH, R, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR ), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR, -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR or -N (R) C (= Y ¹ ) N (R) ₂ , amino (-NH ₂ ), ammonium (-NH ₃ ⁺ ), alkylamino, dialkylamino, trialkylammonium, C ₁ -C ₈ alkyl, C ₁ -C ₈ halo Alkyl, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered cyclic sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium , C ₁ -C ₈ alkylhydroxyl, C ₁ -C ₈ alkylthiol, alkylsulfone (-SO ₂ R), arylsulfone (-SO ₂ Ar), arylsulfoxide (-SOAr), arylthio (-SAr) , Sulfonamide (-SO ₂ NR ₂ ), alkylsulfoxide (-SOR), ester (-C (= O) OR), amido (-C (= O) NR ₂ ), 5-7 member Cyclic lactams, 5-7 membered cyclic lactones, nitrile (- CN), azido (-N ₃ ), nitro (-NO ₂ ), C ₁ -C ₈ alkoxy (-OR), C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ al Kenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle , C ₂ -C ₂₀ substituted heterocycle, polyethyleneoxy, protecting group or W ³ , or when bonded together, R ^y forms a carbocycle ring of 3 to 7 carbon atoms, R ^x is independently represented by R ^y , a protecting group or the following formula,

here, M1a, M1c and M1d are independently 0 or 1, M 12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, and R is C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl , C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle or protecting group, W ³ is W ⁴ or W ⁵ , W ⁴ is R, -C (Y ¹ ) R ^y , -C (Y ¹ ) W ⁵ , -SO ₂ R ^y or -SO ₂ W ⁵ , W ⁵ is independent Carbocycle or heterocycle substituted with 0 to 3 R ^y groups. 168. The compound of claim 168, wherein C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ substituted aryl and C ₂ -C ₂₀ substituted heterocycle are F , Cl, Br, I, OH, -NH ₂ , -NH ₃ ⁺ , -NHR, -NR ₂ , -NR ₃ ⁺ , C ₁ -C ₈ haloalkyl, carboxylate, sulfate, sulfamate, sulfonate, 5-7 cyclic sultam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium, C ₁ -C ₈ alkylhydroxyl, C ₁ -C ₈ alkylthiol, -SO ₂ R, -SO ₂ Ar, -SOAr, -SAr, -SO ₂ NR ₂ , -SOR, -CO ₂ R, -C (= O) NR ₂ , 5-7 member Cyclic lactams, 5-7 membered cyclic lactones, -CN, -N ₃ , -NO ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ trifluoroalkyl, C ₁ -C ₈ alkyl, And is independently substituted with one or more substituents selected from C ₃ -C ₁₂ carbocycles, C ₆ -C ₂₀ aryl, C ₂ -C ₂₀ heterocycles, polyethyleneoxy, phosphonates, phosphates and prodrug moieties. 168. The complex of claim 168, wherein said protecting group is selected from carboxyl esters, carboxamides, aryl ethers, alkyl ethers, trialkylsilyl ethers, sulfonic acid esters, carbonates and carbamates. 168. The complex of claim 168, wherein W ⁵ is selected from the following structure.

168. The complex of claim 168, wherein X is O and R ^y is H. 175. The complex of claim 168, wherein the complex is represented by the formula:

168. The complex of claim 168, wherein the complex is represented by the formula:

174. The complex of claim 174, wherein Z ¹ is OH. 174. The complex of claim 174, wherein Z ² is CH ₃ . 174. The complex of claim 173, wherein the complex is represented by the formula:

181. The complex of claim 177, wherein Z ² is C ₁ -C ₈ alkyl or C ₁ -C ₈ substituted alkyl. 177. The complex of claim 177, wherein the complex is represented by the formula:

177. The complex of claim 177, wherein the complex is represented by the formula:

174. The complex of claim 173, wherein the complex is represented by the formula:

181. The complex of claim 181, which is represented by the following structural formula.

182. The complex of claim 182, which is represented by the following structural formula.

185. The complex of claim 183, represented by the following structural formula.

185. The complex of claim 184, which is represented by the following structural formula.

Wherein R ² is H or C ₁ -C ₈ alkyl. 185. The complex of claim 185, wherein the complex is represented by the formula:

186. The complex of claim 186, which is represented by the following structural formula.

Where Y ^2c is O, N (R ^y ) or S. 187. The complex of claim 187, which is represented by the following structural formula.

185. The complex of claim 188, wherein Y ^2c is O. 185. The complex of claim 188, wherein Y ^2c is N (CH ₃ ). 168. The complex of claim 168, wherein the substituted triazole has the structure:

The complex according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, represented by the following formula.

Where B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebulaline , Nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propy Nylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothylmine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthylmine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazoles and pyrazolo [3,4-D] pyrimidines, X ^a is selected from O, NR and S, Z ¹ is independently selected from H, OH, OR, NR ₂ , CN, NO ₂ , SH, SR, F, Cl, Br and I, Z ² is H, C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl and C ₁ -C ₈ Selected from substituted alkynyl, R ^y is independently H, F, Cl, Br, I, OH, R, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR ), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR, -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR or -N (R) C (= Y ¹ ) N (R) ₂ , amino (-NH ₂ ), ammonium (-NH ₃ ⁺ ), alkylamino, dialkylamino, trialkylammonium, C ₁ -C ₈ alkyl, C ₁ -C ₈ halo Alkyl, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered cyclic sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium , C ₁ -C ₈ alkylhydroxyl, C ₁ -C ₈ alkylthiol, alkylsulfone (-SO ₂ R), arylsulfone (-SO ₂ Ar), arylsulfoxide (-SOAr), arylthio (-SAr) , Sulfonamide (-SO ₂ NR ₂ ), alkylsulfoxide (-SOR), ester (-C (= O) OR), amido (-C (= O) NR ₂ ), 5-7 member Cyclic lactams, 5-7 membered cyclic lactones, nitrile (- CN), azido (-N ₃ ), nitro (-NO ₂ ), C ₁ -C ₈ alkoxy (-OR), C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ al Kenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle , C ₂ -C ₂₀ substituted heterocycle, polyethyleneoxy, protecting group or W ³ , or when bonded together, R ^y forms a carbocycle ring of 3 to 7 carbon atoms, R is C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl , C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle or protecting group, W ³ is W ⁴ or W ⁵ , W ⁴ is R, -C (Y ¹ ) R ^y , -C (Y ¹ ) W ⁵ , -SO ₂ R ^y or -SO ₂ W ⁵ , W ⁵ is independent Carbocycle or heterocycle substituted with 0 to 3 R ^y groups. 192. The complex of claim 192, which is represented by Formula IIa.

Wherein PG is selected from ether formers, thioether formers, ester formers, thioester formers, silyl-ether formers, amide formers, acetal formers, ketal formers, carbonate formers, carbamate formers, urea formers, amino acid complexes and polypeptide complexes It is a protector. 168. The complex or pharmaceutically acceptable salt or solvate of claim 168, which may accumulate in human PBMCs. 194. The complex of claim 194, wherein the bioavailability of the complex or the intracellular metabolite of the complex in human PBMCs is improved compared to an analog of the complex that does not contain a prodrug moiety (phosphonate group (s)). 158. The complex of claim 158, wherein the intracellular half-life of the complex or the intracellular metabolite of the complex in human PBMCs is improved when compared to an analog of the complex that does not contain a prodrug moiety. 196. The complex of claim 196, wherein the half life is improved by at least about 50%. 196. The complex of claim 196, wherein the half life is improved by at least about 100%. 194. The complex of claim 194, wherein the intracellular half-life of the metabolite of the complex or the intracellular metabolite of the complex in human PBMC is improved when compared to an analog of its metabolite that does not contain a prodrug moiety. 199. The complex of claim 199, wherein the half life is improved by at least about 50%. 199. The complex of claim 199, wherein the half life is improved by at least about 100%. 199. The complex of claim 199, wherein the half life is improved by at least 100%. A composition comprising a pharmaceutically acceptable salt and a complex of claim 168 or a pharmaceutically acceptable salt or solvate thereof in a therapeutically effective amount. The complex according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, represented by the following formula.

Where B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguin, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebula Lean, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5- Propynylcytosine, isocytocin, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothylmine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine , O ⁴ -methyltilmin, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazoles and pyrazolo [3,4-D] pyrimidines, X is selected from O, C (R ^y ) ₂ , OC (R ^y ) ₂ , NR and S, Z is independently selected from H, OH, OR, NR ₂ , CN, NO ₂ , SH, SR, F, Cl, Br and I, Y ¹ is independently O, S, NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR) or N-NR ₂ , Y ² is independently O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, SS, S (O) or S (O) is ₂ , M2 is 0, 1 or 2, R ^y is independently H, F, Cl, Br, I, OH, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR , -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR or -N (R) C (= Y ¹ ) N (R) ₂ , amino (-NH ₂ ), ammonium (-NH ₃ ⁺ ), alkylamino, dialkylamino, trialkylammonium, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, Carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered cyclic sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium, C ₁ -C ₈ alkylhydroxyl, C ₁ -C ₈ alkylthiol, alkylsulfone (-SO ₂ R), arylsulfone (-SO ₂ Ar), arylsulfoxide (-SOAr), arylthio (-SAr), sulfone Amide (-SO ₂ NR ₂ ), alkylsulfoxide (-SOR), ester (-C (= O) OR), amido (-C (= O) NR ₂ ), 5-7 member cyclic Lactams, 5-7 membered cyclic lactones, nitrile (-CN) , Azido (-N ₃ ), nitro (-NO ₂ ), C ₁ -C ₈ alkoxy (-OR), C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle, polyethyleneoxy or W ³ , or when bonded together, R ^y forms a carbocycle ring of 3 to 7 carbon atoms, R ^x is independently R ^y , a protecting group or

here, M1a, M1c and M1d are independently 0 or 1, M 12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, and R is C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl , C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle or protecting group, W ³ is W ⁴ or W ⁵ , W ⁴ is R, -C (Y ¹ ) R ^y , -C (Y ¹ ) W ⁵ , -SO ₂ R ^y or -SO ₂ W ⁵ , W ⁵ is independent Carbocycle or heterocycle substituted with 0 to 3 R ^y groups. 205. The compound of claim 204, wherein C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ substituted aryl and C ₂ -C ₂₀ substituted heterocycle are F , Cl, Br, I, OH, -NH ₂ , -NH ₃ ⁺ , -NHR, -NR ₂ , -NR ₃ ⁺ , C ₁ -C ₈ haloalkyl, carboxylate, sulfate, sulfamate, sulfonate, 5-7 cyclic sultam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium, C ₁ -C ₈ alkylhydroxyl, C ₁ -C ₈ alkylthiol, -SO ₂ R, -SO ₂ Ar, -SOAr, -SAr, -SO ₂ NR ₂ , -SOR, -CO ₂ R, -C (= O) NR ₂ , 5-7 member Cyclic lactams, 5-7 membered cyclic lactones, -CN, -N ₃ , -NO ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ trifluoroalkyl, C ₁ -C ₈ alkyl, And is independently substituted with one or more substituents selected from C ₃ -C ₁₂ carbocycles, C ₆ -C ₂₀ aryl, C ₂ -C ₂₀ heterocycles, polyethyleneoxy, phosphonates, phosphates and prodrug moieties. 204. The complex of claim 204, wherein said protecting group is selected from carboxyl esters, carboxamides, aryl ethers, alkyl ethers, trialkylsilyl ethers, sulfonic acid esters, carbonates and carbamates. 204. The complex of claim 204, wherein W ⁵ is selected from the following structures.

204. The complex of claim 204, wherein X is O and each R ^y is H. 204. The complex of claim 204, wherein the complex is a divided enantiomer having the structure:

204. The complex of claim 204, wherein the complex is a divided enantiomer having the structure:

209. The complex of claim 209, wherein the complex is represented by the formula:

209. The complex of claim 209, wherein the complex is represented by the formula:

218. The complex of claim 212, represented by the following structural formula.

213. The complex of claim 213, which is represented by the following structural formula.

214. The complex of claim 214, wherein the complex is represented by the formula:

221. The complex of claim 215, wherein the complex is represented by the formula:

Wherein R ² is H or C ₁ -C ₈ alkyl. 216. The complex of claim 216, wherein the complex is represented by the formula:

221. The complex of claim 217, wherein the complex is represented by the formula:

218. The complex of claim 217, wherein Z is H. 218. The complex of claim 217, wherein B is adenine. 221. The complex of claim 217, wherein the complex is represented by the formula:

Where Y ^2c is O, N (R ^y ) or S. 221. The complex of claim 221, wherein the complex is represented by the formula:

222. The complex of claim 222, wherein Y ^2c is O. 222. The complex of claim 222, wherein Y ^2c is N (CH ₃ ). 204. The complex of claim 204, wherein the substituted triazole has the structure:

The complex according to claim 1, which is represented by the following formula:

Where B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebulaline , Nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propy Nylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothylmine, 4-thiouracil, O ⁶ -methylguanine, N ⁶ -methyladenine, O ⁴ -methylthylmine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazoles and pyrazolo [3,4-D] pyrimidines, X is selected from O, C (R ^y ) ₂ , OC (R ^y ) ₂ , NR and S, Z is independently selected from H, OH, OR, NR ₂ , CN, NO ₂ , SH, SR, F, Cl, Br and I, Y ² is independently O, CR ₂ , NR, ⁺ N (O) (R), N (OR), ⁺ N (O) (OR), N-NR ₂ , S, SS, S (O) or S (O) is ₂ , R ^y is independently H, F, Cl, Br, I, OH, -C (= Y ¹ ) R, -C (= Y ¹ ) OR, -C (= Y ¹ ) N (R) ₂ , -N (R) ₂ ,- ⁺ N (R) ₃ , -SR, -S (O) R, -S (O) ₂ R, -S (O) (OR), -S (O) ₂ (OR), -OC (= Y ¹ ) R, -OC (= Y ¹ ) OR, -OC (= Y ¹ ) (N (R) ₂ ), -SC (= Y ¹ ) R, -SC (= Y ¹ ) OR , -SC (= Y ¹ ) (N (R) ₂ ), -N (R) C (= Y ¹ ) R, -N (R) C (= Y ¹ ) OR or -N (R) C (= Y ¹ ) N (R) ₂ , amino (-NH ₂ ), ammonium (-NH ₃ ⁺ ), alkylamino, dialkylamino, trialkylammonium, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, Carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered cyclic sulfam, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium, C ₁ -C ₈ alkylhydroxyl, C ₁ -C ₈ alkylthiol, alkylsulfone (-SO ₂ R), arylsulfone (-SO ₂ Ar), arylsulfoxide (-SOAr), arylthio (-SAr), sulfone Amide (-SO ₂ NR ₂ ), alkylsulfoxide (-SOR), ester (-C (= O) OR), amido (-C (= O) NR ₂ ), 5-7 member cyclic Lactams, 5-7 membered cyclic lactones, nitrile (-CN) , Azido (-N ₃ ), nitro (-NO ₂ ), C ₁ -C ₈ alkoxy (-OR), C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle, polyethyleneoxy or W ³ , or when bonded together, R ^y forms a carbocycle ring of 3 to 7 carbon atoms, R is C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ substituted alkenyl, C ₁ -C ₈ alkynyl, C ₁ -C ₈ substituted alkynyl , C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₂ -C ₂₀ heterocycle, C ₂ -C ₂₀ substituted heterocycle or protecting group, PG is a protecting group selected from ether formers, ester formers, silyl-ether formers, amide formers, acetal formers, ketal formers, carbonate formers, carbamate formers, amino acids and polypeptides. 204. The complex or pharmaceutically acceptable salt or solvate of claim 204, which may accumulate in human PBMCs. 227. The complex of claim 227, wherein the bioavailability of the complex or the intracellular metabolite of the complex in human PBMCs is improved compared to an analog of the complex that does not contain a prodrug moiety. 227. The complex of claim 227, wherein the intracellular half-life of the complex or the intracellular metabolite of the complex in human PBMCs is improved when compared to an analog of the complex that does not contain a prodrug moiety. 229. The complex of claim 229, wherein the half life is improved by at least about 50%. 229. The complex of claim 229, wherein the half life is improved by at least about 100%. 228. The complex of claim 229, wherein the intracellular half-life of the metabolite of the complex or the intracellular metabolite of the complex in human PBMCs is improved when compared to an analog of its metabolite that does not contain a prodrug moiety. 238. The complex of claim 232, wherein the half life is improved by at least about 50%. 238. The complex of claim 232, wherein the half life is improved by at least about 100%. 235. The complex of claim 235, wherein the half life is improved by at least 100%. A composition comprising a pharmaceutically acceptable salt and a complex of claim 232 or a pharmaceutically acceptable salt or solvate thereof in a therapeutically effective amount. A method for inhibiting tumor growth, comprising contacting a sample requiring treatment with the complex described in any one of claims 119-235 in vitro or in vivo. 237. The method of claim 237, wherein said contact occurs in vivo. 237. The method of claim 237, wherein the tumor is a mammalian chest, lungs, thyroid gland, lymph node, urogenital system, kidney, ureter, bladder, ovary, tetis, prostate, musculoskeletal system, bone, skeletal muscle, bone marrow, gastrointestinal tract, stomach, esophagus, Small intestine, colon, rectum, pancreas, liver, smooth muscle, central or peripheral nervous system, brain, spinal cord, nerves, head, neck, ears, eyes, nasopharynx, mouth pharynx, salivary glands, cardiovascular system, oral cavity, tongue, larynx, hypopharyngeal , Soft tissue, skin, cervix, anus, retina, and / or heart. 235. A method of treating cancer symptoms and effects in an animal comprising administering to the mammal a complex as described in any one of claims 119 to 235. 235. A method for inhibiting a neoplastic disease in a stray animal in need of treatment comprising administering to a mammal the complex described in any one of claims 119-235. 241. The method of claim 241, wherein the tumor is acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, cutaneous T-cell lymphoma, hairy cell leukemia or non-Hodgkin's lymphoma. 242. The method of claim 242, wherein the compound is formulated with a pharmaceutically acceptable carrier. 245. The method of claim 243, wherein the formulation further comprises a second active ingredient. 235. The complex of any one of claims 119-235 for use in medical therapy. Use of a complex as described in any one of claims 119 to 235 for the manufacture of a drug for inhibiting tumor growth in an animal. 246. The method of claim 246, wherein the tumor is the chest, lungs, thyroid, lymph nodes, genitourinary system, kidney, ureter, bladder, ovary, tethys, prostate, musculoskeletal system, bone, skeletal muscle, bone marrow, gastrointestinal tract, stomach, esophagus, Small intestine, colon, rectum, pancreas, liver, smooth muscle, central or peripheral nervous system, brain, spinal cord, nerves, head, neck, ears, eyes, nasopharynx, mouth pharynx, salivary glands, cardiovascular system, oral cavity, tongue, larynx, hypopharyngeal , Soft tissue, skin, cervix, anus, retina, and / or heart. Use of a complex as described in any one of claims 119 to 235 for the manufacture of a medicament for inhibiting a tumorous disease in a mammal. 248. The use of claim 248, wherein the tumor is acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, cutaneous T-cell lymphoma, hairy cell leukemia or non-Hodgkin's lymphoma.